Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases 3030677265, 9783030677268

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Nenad Blau · Carlo Dionisi Vici  Carlos R. Ferreira · Christine Vianey-Saban  Clara D. M. van Karnebeek   Editors

Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases Second Edition

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Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

Nenad Blau  •  Carlo Dionisi Vici Carlos R. Ferreira  •  Christine Vianey-Saban Clara D. M. van Karnebeek Editors

Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases Second Edition

Editors Nenad Blau Division of Metabolism University Children’s Hospital Zürich Switzerland Carlos R. Ferreira Division of Genetics and Metabolism Children’s National Health System Washington, DC USA Clara D. M. van Karnebeek Departments of Pediatrics and Human Genetics Emma Children’s Hospital, Amsterdam University Medical Centers Amsterdam The Netherlands

Carlo Dionisi Vici Division of Metabolic Disease, Department of Pediatric Subspecialties Bambino Gesù Children’s Hospital-IRCCS Rome Italy Christine Vianey-Saban Department of Inborn Errors of Metabolism and Newborn Screening CHU Lyon, Centre de Biologie et de Pathologie Est Bron Cedex France

ISBN 978-3-030-67726-8    ISBN 978-3-030-67727-5 (eBook) https://doi.org/10.1007/978-3-030-67727-5 © Springer Nature Switzerland AG 2022, corrected publication 2022 Open Access  Chapter 73 is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). For further details see licence information in the chapter. This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Stephen Irwin Goodman (1938–2020) The Editors take this opportunity to acknowledge Stephen Irwin Goodman, MD—one of the pioneers in the field of diagnosis and treatment of inborn errors of metabolism, who passed away while this book was in press, on October 30, 2020—for his longstanding efforts and contributions to our series Physician’s Guide in Inherited Metabolic Disease. A founding member of both the Society for Inherited Metabolic Disorders and the American College of Medical Genetics (and Genomics), Steve spent his entire professional career at the University of Colorado in Denver with his wife, Patricia, their daughters Michelle and Karen, and their families. Steve is remembered for his role in establishing the diagnostic methods for organic acidemias, for writing a seminal text on use of GC-MS for analysis of organic acids (with Sanford Markey), defining and characterizing glutaric acidurias type I and II, and contributing knowledge to the diagnosis and management of many other inborn errors of metabolism. In recognition of his constant guidance and valuable contributions (see Chap. 71), we wish to dedicate this edition of the Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases to his memory. Nenad Blau Carlo Dionisi Vici Carlos R. Ferreira Christine Vianey-Saban Clara D.M. van Karnebeek

Foreword

A new edition for an old subject The study of inborn errors of metabolism arguably began with Garrod’s seminal 1902 paper on alkaptonuria (Garrod 1902). At the time, the diagnosis of this disorder was achieved using state-of-the-art technology: visual inspection of recently voided urine. Garrod’s genius was to use this method to identify and collect a large number of individuals with this rare disorder and to recognize, with input from Bateson, that the familial clustering and distribution of affected individuals (19 affected of 48 individuals in 9 sibships) was consistent with observations made by Gregor Mendel in pea plants some 37 years earlier. An additional feature of alkaptonuria, crucial for Garrod’s study, is that, at the phenotypic level, it is a relatively mild disorder with minimal, if any, effect on life span. To quote Garrod, “an alternative course of metabolism, harmless and usually congenital and lifelong.” Thus, it was possible for Garrod to collect affected individuals, many of whom were adults at the time of diagnosis. From this modest beginning, Garrod not only demonstrated that Mendelism held true in humans, but also suggested that alkaptonuria and a handful of similar disorders (cystinuria, pentosuria, and albinism) were “merely extreme examples of variations in chemical behavior which are probably everywhere present in minor degree” so that “just as no two individuals of a species are absolutely identical in bodily structure neither are their chemical processes carried out on exactly the same lines.” First stated in 1902, these ideas lead to Garrod’s definition in 1931 (Garrod 1931) of “chemical individuality” as genetically determined biochemical characteristics and capabilities which confer “predisposition to and immunities from the various mishaps which are spoken of as diseases.” We are only now beginning to put meat on the bones of these prescient predictions. From Garrod’s time to the present, progress in identifying specific inborn errors of metabolism has been dependent on technological advances. Thus, in the early 1950s following the development of the first amino acid analyzer, a host of “new” (really “newly recognized”) disorders were described on the basis of abnormal patterns of amino acids in plasma and/or urine. Similarly, the development of GC/MS technology leads to the recognition of many organic acidemias, and the development of tissue culture and somatic cell genetic techniques leads to a burst of newly recognized lysosomal storage diseases. Currently, we are experiencing at least two technologic revolutions: genomic sequencing methods that began with the seminal 2009 paper of Ng et al. (2009) showing that the cause of rare Mendelian disorders could be identified by applying genomic methods to well-­phenotyped patients and, more recently, the development of unstructured metabolomic methods that measure thousands of metabolites not previously examined by classical biochemical methods. Application of genomic methods has already had a profound effect on our identification and diagnosis of patients with inborn errors (Posey et al. 2019; Bamshad et al. 2019). Advances and widespread application of metabolomics seems likely to have a similar effect (Burrage et al. 2019; Miller et al. 2015). Moreover, the two technologies are synergistic in their power to identify newly recognized monogenic disorders and to expose their pathophysiology.

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While exciting and gratifying, this rapid expansion of the number of recognizable inborn errors is a daunting challenge to the beleaguered clinicians who take care of these patients; one can never know what the next patient who comes to clinic will have: a defect in purine ­metabolism; a problem in lysosomal function; a peroxisome biogenesis disorder; or some tRNA charging abnormality impairing translation. The possibilities are as broad as all biology and hence justify newly revised editions of this text and associated online resources. A salient challenge derived from the rapid expansion of our field and any such effort to describe it, is how to modernize the definition of inborn errors of metabolism, a term, after all, that has been in use since 1908 when Garrod coined it in his Croonian lectures (Garrod 1908). Recent efforts to update the definition have included inclusion of phenotypic features, diagnostic technologies, and limitations to specific biological systems (Morava et al. 2015; Ferreira et al. 2019). While useful, phenotypic features for any disorder are always variable and typically overlap with those of other disorders. Diagnostic technology changes over time and will continue to do so. A focus on biologic systems is useful for understanding pathophysiology, but the margins of any particular system often overlap with those of others and, currently, we do not have a well-defined list of all biological systems. Based on these considerations, I argue that we consider all monogenic disorders as Garrodian inborn errors of metabolism. This gene-based definition is enriched by a foundation built on genetic principles and emphasizes the discrete monogenic cause of these disorders. It also benefits from the fact that it is easier to enumerate and designate all the genes in the genome than all the phenotypes that bring patients to our clinics. For example, at the time I write this (25 November 2020), OMIM lists 4355 genes with variants that cause monogenic disease (OMIM® n.d.). This number is increasing steadily with no asymptote in sight (Posey et al. 2019; Bamshad et al. 2019). Moreover, all monogenic disorders have an associated biochemical phenotype increasingly recognized by standard or newly developed technologies such as metabolomics or proteomics. Identification of the biochemical abnormalities associated with each monogenic disease is sometimes challenging but feasible and leads to improved understanding of the pathophysiology of each disorder, a necessary step on the path to rational development of treatment. One possible concern of a gene-based definition of IEM is that for some genes, allelic heterogeneity produces phenotypic variation which in some instances is so extreme that we do not a priori expect variants in the same gene to underlie the apparently discrete phenotypes. For example, variants in FBN1 can cause either Marfan syndrome (OMIM 154700) with tall stature, arachnodactyly, loose joints, ectopia lentis and aortic root aneurysms or stiff skin syndrome (OMIM 184900) with short stature, no arachnodactyly, limited range of joint mobility, and no ocular nor aortic symptoms. In fact, about a third of disease genes listed in OMIM are responsible for two or more clinically discrete phenotypes (OMIM® n.d.). A gene-based definition of IEM would, however, anticipate this biologic complexity and incorporate it so that each gene would be linked to a specific phenotype or set of phenotypes, with the benefit that we would expect these genotype–phenotype relationships as a part of disease biology and use them to inform our understanding of the disorders and the function of the protein(s) encoded by each gene. Using this definition, the ultimate number of IEMs depends on how many genes are found to house variants of major effect, sufficient to produce a phenotype. The fact that evolution seems to care about (conserve) the vast majority of protein-coding genes in the genome suggests that certain variants in nearly all protein-coding genes will ultimately be found to be capable of producing a monogenic phenotype (and thus, by this definition, be considered an inborn error of metabolism or, perhaps better, simply an inborn error). This logic suggests that long non-coding RNA genes, which are less well conserved, may play a much smaller role in monogenic disease. How this will end up in the future is an uncertain but exciting prospect.

Foreword

Foreword

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One thing for sure is that new resources for clinicians and investigators such as this new edition of a Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases will be much needed and appreciated. David Valle McKusick-Nathans Department of Genetic Medicine The Johns Hopkins University School of Medicine Baltimore, MD, USA

References Bamshad MJ, et  al. Mendelian gene discovery: fast and furious with no end in sight. Am J Hum Genet. 2019;105:448–55. Burrage LC, et al. Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders. Genet Med. 2019;21:1977–86. Ferreira CR, et al. A proposed nosology of inborn errors of metabolism. Genet Med. 2019;21:102–6. Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. The Lancet. 1902;2:1616–20. Garrod AE.  The Croonian Lectures on inborn errors of metabolism. The Lancet. 1908;2:1–7, 73–9, 142–8, 214–20. Garrod AE. Inborn factors in disease. Oxford University Press; 1931. Miller MJ, et al. Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism. J Inherit Metab Dis. 2015;38:1029–39. Morava E, et al. Quo vadis: the re-definition of inborn metabolic diseases. J Inherit Metab Dis. 2015;38:1003–6. Ng SB, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461:272–6. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 24 November 2020. https://omim.org/ Posey JE, et al., Insights into genetics, human biology, and disease gleaned from family based genomic studies. Genet Med. 2019;21:798–812.

Preface

Our expert faculty of more than 170 recognized authorities has broadened the scope and content of this book, the fourth edition of the Physician’s Guide series. We overhauled the structure of the book to accommodate 18 new chapters: 73 chapters now address almost 1200 inherited metabolic disorders. The original edition, published in 1996, focused on diagnosis only and was translated into Chinese in 2001. Today, along with a comprehensive update to this vital aspect of care, the current edition presents the state of the art on the treatment and follow-up, providing insight into the full clinical course of these rare diseases. Based upon their experience, our expert faculty have created flowcharts and diagnostic algorithms for each disorder. Initially, recommendations on confirmatory tests and initial treatment regimens are provided for practitioners who lack extensive experience in the management of inborn errors of metabolism. The second part of each chapter describes the treatment of groups of disorders in more detail. The book presents the signs and symptoms of most of the recognized inborn errors of metabolism in relation to age, with a chronological sequence of signs and symptoms from infancy through childhood, adolescence, and adulthood. In addition, reference and pathological values are provided for each of the disorders to simplify and facilitate the interpretation of the results of laboratory tests. The guide will also be available in an eBook format that will allow the user to locate a disorder rapidly, using standard searches with keywords. Additionally, the entire content of this edition is stored in a single database, IEMbase (http://www.iembase.org). This comprehensive online resource provides the foundation for the current and future knowledge base of inborn errors of metabolism. While the major goals of this edition remain comparable to those of earlier editions, we, the Editors, feel that this new edition takes clinical practice in rare metabolic disorders to the next level. We hope that our readers will find this edition helpful, both now and in the future, for the treatment and care of patients with inborn errors of metabolism. Finally, we acknowledge the former Editors, Dr. Marinus Duran and Dr. K. Michael Gibson in supporting this book project. Zürich, Switzerland Rome, Italy  Washington, DC, USA  Lyon, France  Amsterdam, The Netherlands 

Nenad Blau Carlo Dionisi Vici Carlos R. Ferreira Christine Vianey-Saban Clara D. M. van Karnebeek

The original version of this book has been updated: fifth Editor Dr. Clara D. M. van Karnebeek’s affiliation has been updated. A Correction to this book is available at https://doi.org/10.1007/978-3-030-67727-5_74

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How to Use This Book

This book is meant to supply clinicians and clinical biochemists with data that should facilitate the diagnosis of an inherited metabolic disorder. No information about detailed laboratory methods is given; rather, the relationship between laboratory data and clinical signs and symptoms is highlighted. Furthermore the current knowledge on the immediate emergency intervention, standard treatment, and experimental options is given. Entry to the book is achieved by scanning either of the indices, i.e., the signs and symptoms index, the tests index, or the disorders index. Due to the great clinical variability of inherited metabolic diseases, one should not restrict oneself to one disorder when observing a given symptom or sign. Most chapters have a uniform layout as given below. In a few chapters, however, this was not possible, and information is given for the entire related group of disorders in the chapter.

Introduction The introduction gives a brief overview of the clinical conditions described in the chapter and relates them to the biochemical abnormalities. Key references for further reading are provided.

Nomenclature Disorders in each chapter are numbered in accordance with the corresponding OMIM number, gene symbols and gene products, and chromosomal localization if known.

Metabolic Pathway Disorders are identified by corresponding reference numbers at the step where the defect is localized. Pathological metabolites (“markers”) are given in most chapters.

Signs and Symptoms The tables describe most, if not all, of the signs and symptoms for each disorder, including its reference number, and the most important laboratory tests, in relation to age. In all instances, the signs and symptoms are found in the untreated patients. The signs written in bold represent characteristic features of the particular disease. ± indicates that a sign or symptom may occur but is not inevitably present. + indicates that a sign or symptom is always or nearly always present. If there are significant clinical signs and symptoms which exceed the usual, or if changes occur, this is indicated with + to + + +, etc.

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How to Use This Book

n (normal) is used only when it is significant and may be useful in distinguishing one condition from another. Relative increases or decreases of substances, compounds, metabolites, etc., are indicated with the use of arrows; for example, metabolite X ↑ to ↓↓↓. Where metabolite X may change, it would be indicated by n-↑ for a possible increase or ↓-n for a possible decrease, whichever the case. In all tables, the test substance, material, compound, metabolite, etc., are listed and the source—(U), (B), (CSF), (P), (RBC), etc.—is given in parentheses, with an arrow or arrows indicating increase/decrease or relative increase/decrease. Body fluids, cells, tissues, etc., are defined as: P

Plasma

CV

Chorionic villi

S

Serum

AF

Amniotic fluid

B

Blood

AFC

Amniocytes

U

Urine

CCV

Cultured chorionic villi

CSF

Cerebrospinal fluid

PLT

Platelets

RBC

Red blood cells

WBC

White blood cells

LYM

Lymphocytes

Hb

Hemoglobin

FB

Fibroblasts

creat

Creatinine

BM

Bone marrow

Age groups are defined as: Neonatal

Birth to 1 month

Infancy

1–18 months

Childhood

1.5–11 years

Adolescence

11–16 years

Adulthood

>16 years

Reference Values/Pathological Values/Differential Diagnosis Reference and pathological values are listed for all parameters relevant to the diagnosis according to the specimen (e.g., P, U, CSF) and age. For some parameters, reference values depend on methodology and may differ from chapter to chapter. Methods are specified where necessary. Pathological values are listed either as absolute values or with symbols (e.g., ↑, ↓) according to the disorder. Values are limited to the analyses which can be performed in a laboratory experienced in selective screening. Data on enzyme studies are not given in most cases, but can be found in the pertinent literature.

Loading Tests There is a brief description of the tests, with a table or figure to illustrate the interpretation.

How to Use This Book

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Diagnostic Flow Chart The flow charts use simple yes/no algorithms to demonstrate the sequence for differential diagnosis, starting with clinical symptoms or general tests and proceeding to specific tests and a final diagnosis.

Specimen Collection This table lists preconditions, material, handling, and pitfalls for each parameter used in the diagnosis.

Prenatal Diagnosis This table lists the tissue or specimen, timing, and pitfalls for each disorder.

DNA Analysis This table lists the tissue or specimen and methodology for each disorder.

Treatment and Follow-Up This section outlines urgent treatment to consider before a definitive diagnosis is established for each (or each group of) disorder(s). Long-term treatment and alternative therapeutic options are highlighted in this book.

Indices Three indices are included: (1) disorders, (2) signs and symptoms, and (3) tests and medications. Each entry is linked to the corresponding disorder or page.

Contents

Part I General Subjects and Profiles 1 Newborn Screening for Inborn Errors of Metabolism �����������������������������������������    3 Ralph Fingerhut, Janice Fletcher, and Enzo Ranieri 2 Simple Tests and Routine Chemistry ���������������������������������������������������������������������   17 Carlos R. Ferreira and Nenad Blau 3 Amino Acids���������������������������������������������������������������������������������������������������������������   41 Marzia Pasquali and Nicola Longo 4 Organic Acids �����������������������������������������������������������������������������������������������������������   51 Isabel Tavares de Almeida and Antonia Ribes 5 Acylcarnitines�����������������������������������������������������������������������������������������������������������   65 Dietrich Matern 6 Lysosomals�����������������������������������������������������������������������������������������������������������������   75 Silvia Funghini, Sabrina Malvagia, Giulia Polo, and Giancarlo la Marca 7 Untargeted Metabolomics: Next-­Generation Metabolic Screening���������������������   85 Karlien L. M. Coene, Judith J. M. Jans, Udo F. H. Engelke, and Ron A. Wevers 8 MRI and In Vivo Spectroscopy of the Brain ���������������������������������������������������������   95 Matthew T. Whitehead and Andrea Gropman 9 Genomic Approaches for the Diagnosis of Inborn Errors of Metabolism�����������  147 Sarah L. Stenton, Johannes A. Mayr, Saskia B. Wortmann, and Holger Prokisch 10 Other -omics Approaches and Their Integration for the Diagnosis and Treatment of Inborn Errors of Metabolism ���������������������������������������������������  163 Clara D. M. van Karnebeek and Nanda Verhoeven-Duif 11 Emergency Diagnostic Procedures and Emergency Treatment���������������������������  171 Stephanie Grünewald, James Davison, Diego Martinelli, and Carlo Dionisi Vici 12 Nosology of Inborn Errors of Metabolism�������������������������������������������������������������  183 Carlos R. Ferreira Part II Disorders of Nitrogen-Containing Compounds 13 Purine and Pyrimidine Disorders���������������������������������������������������������������������������  191 Jörgen Bierau and Ivan Šebesta 14 Disorders of Nucleotide Metabolism�����������������������������������������������������������������������  213 Min Ae Lee-Kirsch, Victoria Tüngler, Simona Orcesi, and Davide Tonduti

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15 Disorders of Creatine Metabolism��������������������������������������������������������������������������  235 Sylvia Stöckler-Ipsiroglu, Olivier Braissant, and Andreas Schulze 16 Disorder of Glutathione Metabolism ���������������������������������������������������������������������  251 Verena Peters and Johannes Zschocke 17 Disorders of Ammonia Detoxification���������������������������������������������������������������������  263 Johannes Häberle and Vicente Rubio 18 Amino Acid Transport Defects���������������������������������������������������������������������������������  291 Manuel Palacín, Stefan Bröer, and Gaia Novarino 19 Disorders of Monoamine Metabolism���������������������������������������������������������������������  313 Thomas Opladen and Georg F. Hoffmann 20 Disorders of Phenylalanine and Tetrahydrobiopterin Metabolism���������������������  331 Alberto Burlina, Francjan J. van Spronsen, and Nenad Blau 21 Tyrosine Metabolism �����������������������������������������������������������������������������������������������  353 Francjan J. van Spronsen, Alberto Burlina, and Carlo Dionisi Vici 22 Disorders of Sulfur Amino Acid and Hydrogen Sulfide Metabolism�������������������  365 Ivo Barić, Viktor Kožich, and Brian Fowler 23 Disorders of Branched-Chain Amino Acid Metabolism���������������������������������������  391 Manuel Schiff, Jean-François Benoist, Anaïs Brassier, and Jerry Vockley 24 Disorders of Beta and Gamma Amino Acids���������������������������������������������������������  433 Phillip L. Pearl and Lance Rodan 25 Amino Acid Synthesis Deficiencies �������������������������������������������������������������������������  453 Tom J. de Koning and Gajja Salomons 26 Disorders of Glycine Metabolism ���������������������������������������������������������������������������  469 Johan L. K. Van Hove, Curtis R. Coughlin II, and Michael A. Swanson 27 Disorders of Lipoic Acid and Iron-Sulfur Protein Metabolism���������������������������  479 Antonia Ribes and Frederic Tort Part III Disorders of Vitamins, Cofactors, Metals and Minerals 28 Disorders of Cobalamin Metabolism ���������������������������������������������������������������������  497 Matthias R. Baumgartner and D. Sean Froese 29 Disorders of Folate Metabolism and Transport�����������������������������������������������������  515 Robert Steinfeld and Nenad Blau 30 Disorders of Biotin Metabolism�������������������������������������������������������������������������������  529 Bruce A. Barshop 31 Thiamine Disorders �������������������������������������������������������������������������������������������������  537 Majid Alfadhel and Marwan Nashabat 32 Disorders of Riboflavin Metabolism�����������������������������������������������������������������������  547 Christine Vianey-Saban, Cécile Acquaviva, and Annet M. Bosch 33 Disorders of Niacin, NAD, and Pantothenate Metabolism�����������������������������������  563 Anna Ardissone, Daria Diodato, Ivano Di Meo, and Valeria Tiranti 34 Vitamin B6-Dependent and Vitamin B6-Responsive Disorders�����������������������������  577 Barbara Plecko and Eduard A. Struys

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35 Molybdenum Cofactor Disorders���������������������������������������������������������������������������  593 Guenter Schwarz and Bernd C. Schwahn 36 Disorders of Copper, Zinc, and Selenium Metabolism�����������������������������������������  607 Diego Martinelli 37 Disorders of Iron Metabolism���������������������������������������������������������������������������������  625 Maria Domenica Cappellini 38 Disorders of Manganese Metabolism ���������������������������������������������������������������������  637 Karin Tuschl, Philippa B. Mills, and Peter T. Clayton Part IV Disorders of Carbohydrates 39 Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism ���������������������������������������������������������������������������������������������������������������  649 Terry G. J. Derks, Charlotte M. A. Lubout, Mathias Woidy, and René Santer 40 Disorders of the Pentose Phosphate Pathway and Polyol Metabolism ���������������  701 Mirjam M. C. Wamelink and Monique Williams 41 Congenital Hyperinsulinism �����������������������������������������������������������������������������������  713 Jean-Baptiste Arnoux, Arianna Maiorana, Marlène Rio, and Pascale de Lonlay Part V Mitochondrial Disorders of Energy Metabolism 42 Disorders of the Pyruvate Metabolism and the Krebs Cycle�������������������������������  739 Eva Morava, Linda de Meirleir, and Rosalba Carrozzo 43 Disorders of Mitochondrial Carriers ���������������������������������������������������������������������  765 Tom J. J. Schirris, Jan A. M. Smeitink, and Frans G. M. Russel 44 Isolated Mitochondrial Complex Deficiencies�������������������������������������������������������  793 Mirian C. H. Janssen, Maaike C. de Vries, Lonneke de Boer, and Richard J. Rodenburg 45 Disorders of Replication, Transcription and Translation of Mitochondrial DNA ���������������������������������������������������������������������������������������������  843 Ian J. Holt, Antonella Spinazzola, Mirian C. H. Janssen, and Johannes N. Spelbrink 46 Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control�������������������������������������������������������������������������������������������������  889 Lonneke de Boer, Maaike C. de Vries, Jan A. M. Smeitink, and Werner J. H. Koopman 47 Primary Coenzyme Q10 Deficiencies�����������������������������������������������������������������������  915 Leonardo Salviati and Rafael Artuch Part VI Disorders of Lipids 48 Mitochondrial Fatty Acid Oxidation Disorders�����������������������������������������������������  929 Ute Spiekerkoetter and Jerry Vockley 49 Disorders of Glycerol Metabolism���������������������������������������������������������������������������  959 Katrina M. Dipple 50 Disorders of Ketone Body Metabolism and Transport�����������������������������������������  967 Jörn Oliver Sass and Sarah C. Grünert

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51 Disorders of Complex Lipids�����������������������������������������������������������������������������������  981 Frédéric M. Vaz, Saskia B. Wortmann, and Fanny Mochel 52 Disorders of Eicosanoid Metabolism����������������������������������������������������������������������� 1027 Ertan Mayatepek 53 Disorders of Lipoprotein Metabolism��������������������������������������������������������������������� 1035 Amanda J. Hooper, Robert A. Hegele, and John R. Burnett 54 Disorders of Cholesterol Biosynthesis��������������������������������������������������������������������� 1057 Lisa E. Kratz and Richard I. Kelley 55 Disorders of Adrenals and Gonads������������������������������������������������������������������������� 1077 Anna Biason-Lauber 56 Disorders of Bile Acid Synthesis ����������������������������������������������������������������������������� 1095 Frédéric M. Vaz, David Cassiman, and Sacha Ferdinandusse Part VII Disorders of Tetrapyrroles 57 Disorders of Heme Metabolism������������������������������������������������������������������������������� 1115 Ulrich Stölzel, Ilja Kubisch, Thomas Stauch, and Detlef Schuppan 58 Inherited Disorders of Bilirubin Metabolism��������������������������������������������������������� 1129 Namita Roy-Chowdhury, Chandan Guha, and Jayanta Roy-Chowdhury Part VIII Storage Disorders 59 Disorders of Autophagy ������������������������������������������������������������������������������������������� 1151 Carlo Dionisi Vici, Heinz Jungbluth, Rita Carsetti, and Clara D. M. van Karnebeek 60 Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C��������������������������������������������������������������������������������������� 1177 Carla Hollak 61 The Neuronal Ceroid Lipofuscinoses ��������������������������������������������������������������������� 1207 Maurizio Scarpa, Cinzia Maria Bellettato, and Annalisa Sechi 62 Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency��������������������������������������������������������������������������������������������������� 1235 Hidde H. Huidekoper and Esmee Oussoren 63 Oligosaccharidoses and Sialic Acid Disorders������������������������������������������������������� 1249 Michael Beck and Zoltan Lukacs 64 The Mucopolysaccharidoses ����������������������������������������������������������������������������������� 1267 Giancarlo Parenti and Roberto Giugliani 65 Cystinosis������������������������������������������������������������������������������������������������������������������� 1287 Elena Levtchenko and Francesco Emma Part IX Disorders of Peroxisomes and Oxalate 66 Peroxisomal Disorders��������������������������������������������������������������������������������������������� 1297 Ronald J. A. Wanders, Femke C. C. Klouwer, Marc Engelen, and Hans R. Waterham 67 Disorders of Oxalate Metabolism ��������������������������������������������������������������������������� 1319 Bernd Hoppe, Bodo B. Beck, and Cristina Martin-Higueras

Contents

Contents

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Part X Congenital Disorders of Glycosylation 68 Congenital Disorders of Glycosylation������������������������������������������������������������������� 1335 Jaak Jaeken and Lambert van den Heuvel Part XI Various 69 Cerebral Organic Acidurias������������������������������������������������������������������������������������� 1399 Stefan Kölker 70 3-Methylglutaconic Acidurias ��������������������������������������������������������������������������������� 1417 Saskia B. Wortmann and Johannes A. Mayr 71 Biochemical Phenotypes of Questionable Clinical Significance��������������������������� 1431 Stephen I. Goodman 72 Knowledge Base of Inborn Errors of Metabolism (IEMbase): A Practical Approach����������������������������������������������������������������������������������������������� 1449 Tamar V. Av-Shalom, Jessica J. Y. Lee, Carlos R. Ferreira, Nenad Blau, Clara D. M. van Karnebeek, and Wyeth W. Wasserman 73 WikiPathways: Integrating Pathway Knowledge with Clinical Data ����������������� 1457 Denise N. Slenter, Martina Kutmon, and Egon L. Willighagen  Correction to: Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases���������������������������������������������������������C1 Disorder Index����������������������������������������������������������������������������������������������������������� 1467 Test and Medication Index: Strange Association��������������������������������������������������� 1493 Sign and Symptoms Index��������������������������������������������������������������������������������������� 1513

Contributors

Cécile Acquaviva  CHU de Lyon, Department of Biochemistry & Molecular Biology, Division of Inborn Errors of Metabolism, Lyon University Hospital Centre, Bron, France Majid  Alfadhel King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia Anna  Ardissone Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Jean-Baptiste Arnoux  French Metabolic Network G2M, Necker-Enfants Malades Hospital, APHP, Paris, France Rafael Artuch  CIBERER, Instituto de Salud Carlos III, Madrid, Spain Clinical Chemistry Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain Pathology Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain Tamar V. Av-Shalom  Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada Ivo Barić  Division for Genetics and Metabolic Diseases, Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia Bruce A. Barshop  Department of Pediatrics, University of California San Diego, La Jolla, CA, USA Matthias  R.  Baumgartner Division of Metabolism and Children’s Research Center, University Children’s Hospital Zürich, University of Zürich, Zürich, Switzerland Bodo  B.  Beck Department of Human Genetics, University Hospital Cologne, Cologne, Germany Michael Beck  SphinCS GmbH–Clinical Science for LSD, Hochheim, Germany Cinzia Maria Bellettato  Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy Jean-François Benoist  APHP, Reference Center for Inborn Error of Metabolism and Filiere G2M, Pediatrics Department, Necker Univ Hospital, Paris, France Anna Biason-Lauber  Division of Medicine, University of Fribourg, Fribourg, Switzerland Jörgen Bierau  Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands Nenad Blau  Division of Metabolism, University Children’s Hospital, Zürich, Switzerland Annet M. Bosch  Department of Pediatrics, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands

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Olivier  Braissant Service of Clinical Chemistry, Department of Laboratories, University Hospital and University of Lausanne, Lausanne, Switzerland Anaïs Brassier  APHP, Reference Center for Inborn Error of Metabolism and Filiere G2M, Pediatrics Department, Necker Univ Hospital, Paris, France Stefan  Bröer Research School of Biology, The Australian National University, Canberra, ACT, Australia Alberto  Burlina Division of Inherited Metabolic Diseases, Reference Centre Expanded Newborn Screening, Department of Woman’s and Child’s Health, University Hospital, Padova, Italy John  R.  Burnett Department of Clinical Biochemistry, Royal Perth Hospital and Fiona Stanley Hospital, PathWest Laboratory Medicine WA, Perth, WA, Australia School of Medicine, University of Western Australia, Perth, WA, Australia Maria  Domenica  Cappellini Fondazione Ca Granda Policlinico IRCCS, Università di Milano, Milan, Spain Rosalba Carrozzo  Molecular Genetic, Bambino Gesù Children’s Hospital, Rome, Italy Rita  Carsetti Diagnostic Immunology Clinical Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy David Cassiman  Center for Metabolic Diseases, University of Leuven, Leuven, Belgium Peter T. Clayton  UCL GOS Institute of Child Health, University College, London, UK Karlien L. M. Coene  Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Curtis R. Coughlin II  Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA James Davison  Metabolic Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK Lonneke  de Boer  Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands Tom J. de Koning  Department of Clinical Sciences, Lund University, Lund, Sweden Pascale  de Lonlay French Metabolic Network G2M, Necker-Enfants Malades Hospital, APHP, Paris, France Linda de Meirleir  Department of Pediatric Neurology, UZ-Brussel, Brussels, Belgium Terry  G.  J.  Derks  Section of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands Maaike C. de Vries  Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands Ivano  Di Meo Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Daria  Diodato Neuromuscular and Neurodegenerative Disease Unit, Children Hospital Bambino Gesù, Rome, Italy Carlo  Dionisi Vici Division of Metabolism, Department of Pediatric Medicine, Bambino Gesù Children’s Research Hospital, IRCCS, Rome, Italy Katrina M. Dipple  Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, USA

Contributors

Contributors

xxv

Francesco  Emma Department of Pediatric Subspecialties, Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy Marc Engelen  Departments of Pediatric Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands Udo  F.  H.  Engelke  Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Sacha  Ferdinandusse Laboratory Genetic Metabolic Diseases, Amsterdam UMC, Amsterdam, The Netherlands Carlos R. Ferreira  Division of Genetics and Metabolism, Children’s National Health System, Washington, DC, USA Ralph Fingerhut  SYNLAB MVZ Weiden, Weiden, Germany Janice Fletcher  SA Pathology (at Women’s and Children’s Hospital), Adelaide, SA, Australia Brian  Fowler Division for Metabolic Diseases, University Children’s Hospital, Zürich, Switzerland D. Sean Froese  Division of Metabolism and Children’s Research Center, University Children’s Hospital Zürich, University of Zürich, Zürich, Switzerland Silvia  Funghini Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children’s University Hospital, Florence, Italy Roberto Giugliani  Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil Stephen  I.  Goodman  University of Colorado Denver School of Medicine, Aurora, CO, USA Andrea Gropman  Department of Neurology, Children’s National Health System, Washington, DC, USA Sarah C. Grünert  Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Freiburg, Freiburg, Germany Stephanie  Grünewald  Metabolic Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust and Institute for Child Health, London, UK Chandan Guha  Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA Departments of Radiation Oncology and Pathology, Albert Einstein College of Medicine, Bronx, NY, USA Johannes  Häberle Division of Metabolism and Children’s Research Center, University Children’s Hospital, Zürich, Switzerland Robert A. Hegele  Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada Georg F. Hoffmann  University Children’s Hospital, Heidelberg, Germany Carla Hollak  Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Ian J. Holt  Biodonostia Health Research Institute, San Sebastián, Spain IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

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CIBERNED (Center for Networked Biomedical Research on Neurodegenerative Diseases, Ministry of Economy and Competitiveness Institute Carlos III), Madrid, Spain Amanda J. Hooper  Department of Clinical Biochemistry, Royal Perth Hospital and Fiona Stanley Hospital, PathWest Laboratory Medicine WA, Perth, WA, Australia School of Medicine, University of Western Australia, Perth, WA, Australia Bernd Hoppe  Hyperoxaluria Center, German Hyperoxaluria Center, Bonn, Germany Hidde  H.  Huidekoper Center for Lysosomal and Metabolic diseases, Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands Jaak  Jaeken Center for Metabolic Disease, University Hospital Gasthuisberg, Leuven, Belgium Judith  J.  M.  Jans Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Mirian C. H. Janssen  Department of Internal Medicine, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands Heinz  Jungbluth  Department of Paediatric Neurology, Evelina Children’s Hospital, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK Richard I. Kelley  Central Pennsylvania Clinic, Belleville, PA, USA Femke C. C. Klouwer  Departments of Neurology and Pediatric Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands Stefan Kölker  Division of Pediatric Neurology and Metabolic Medicine, Clinic I, Center for Pediatric and Adolescent Medicine, Heidelberg, Germany Werner J. H. Koopman  Department of Biochemistry, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands Viktor  Kožich Department of Pediatrics and Inherited Metabolic Diseases, Charles University-First Faculty of Medicine and General University Hospital in Prague, Praha, Czech Republic Lisa  E.  Kratz Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA Ilja Kubisch  Center of Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, Metabolic Disorders, Oncology, Saxony Porphyria Center, Klinikum Chemnitz gGmbH, Chemnitz, Germany Martina Kutmon  Department of Bioinformatics—BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands Maastricht Centre for Systems Biology—MaCSBio, Maastricht University, Maastricht, The Netherlands Giancarlo la Marca  Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children’s University Hospital, Florence, Italy Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy Jessica  J.  Y.  Lee Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada Min  Ae  Lee-Kirsch Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Contributors

Contributors

xxvii

Elena  Levtchenko Department of Pediatric Nephrology, University Hospitals Leuven, Catholic University of Leuven, Leuven, Belgium Nicola Longo  University of Utah and ARUP Laboratories, Salt Lake City, UT, USA Charlotte  M.  A.  Lubout Section of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands Zoltan  Lukacs  Newborn Screening and Metabolic Diagnostics Unit, Hamburg University Medical Center, Hamburg, Germany Arianna  Maiorana Division of Metabolism, Department of Pediatric Subspecialties, Bambino Gesù Children’s Hospital, Rome, Italy Sabrina Malvagia  Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children’s University Hospital, Florence, Italy Diego Martinelli  Division of Metabolism, Department of Pediatric Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy Division of Metabolic Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy Cristina  Martin-Higueras Department of Pediatrics, Division of Pediatric Nephrology, University Hospital Bonn, Bonn, Germany Department of Basic Medical Science, Faculty of Medicine, University of La Laguna, La Laguna, Spain Dietrich Matern  Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Ertan Mayatepek  Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany Johannes A. Mayr  University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria Philippa B. Mills  UCL GOS Institute of Child Health, University College, London, UK Fanny  Mochel Reference Center for Adult Neurometabolic diseases, La Pitié-Salpêtrière University Hospital, Paris, France Eva Morava  Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA Marwan Nashabat  King Abdulaziz Medical City, Riyadh, Saudi Arabia Gaia Novarino  Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria Thomas  Opladen Division of Neuropediatrics and Metabolic Medicine, Department of Pediatrics, University Children’s Hospital, Heidelberg, Germany Simona Orcesi  Unit of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy Esmee  Oussoren  Center for Lysosomal and Metabolic diseases, Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands Manuel Palacín  Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain

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Giancarlo  Parenti  Department of Translational Medical Sciences, Federico II University, Naples, Italy Telethon Institute of Genetics and Medicine, Pozzuoli, Italy Marzia Pasquali  University of Utah and ARUP Laboratories, Salt Lake City, UT, USA Phillip  L.  Pearl Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Verena  Peters Centre for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany Barbara  Plecko Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria Giulia Polo  Division of Inherited Metabolic Diseases, Department of Women and Children’s Health, Regional Center for Expanded Neonatal Screening, University Hospital of Padova, Padova, Italy Holger  Prokisch  Institute of Human Genetics, Technische Universität München, Munich, Germany Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany Enzo Ranieri  SA Pathology (at Women’s and Children’s Hospital), Adelaide, SA, Australia Antonia  Ribes  Section of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain Marlène Rio  Genetic Department, Necker-Enfants Malades Hospital, APHP, Paris, France Lance  Rodan Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Richard  J.  Rodenburg Department of Paediatrics, Translational Metabolic Laboratory, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands Jayanta Roy-Chowdhury  Depatments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA Namita Roy-Chowdhury  Depatments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA Vicente Rubio  Structural Enzymopathology Unit, Department of Genomics and Proteomics, Instituto de Biomedicina de Valencia of the Spanish National Research Council (CSIC) and Centre for Biomedical Network Research on Rare Diseases (CIBERER-ISCIII), Valencia, Spain Frans  G.  M.  Russel Department of Pharmacology and Toxicology, Radboud Center for Mitochondrial Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Gajja Salomons  Department of Genetic Metabolic Diseases, Amsterdam University Medical Centers, Amsterdam, The Netherlands Leonardo  Salviati Clinical Genetics Unit, Department of Women and Children’s Health, University of Padova and IRP Città della Speranza, Padova, Italy René  Santer  Department of Paediatrics, University Medical Center Eppendorf, Hamburg, Germany

Contributors

Contributors

xxix

Jörn  Oliver  Sass Research Group Inborn Errors of Metabolism, Department of Natural Sciences & Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany Maurizio  Scarpa Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy Manuel Schiff APHP, Reference Center for Inborn Error of Metabolism and Filière G2M, Pediatrics Department, Necker Univ Hospital, Paris, France Tom  J.  J.  Schirris Department of Pharmacology and Toxicology, Radboud Center for Mitochondrial Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Andreas  Schulze Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada Departments of Pediatrics and Biochemistry, University of Toronto, Toronto, ON, Canada Detlef  Schuppan  Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Bernd  C.  Schwahn Willink Metabolic Unit, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Saint Mary’s Hospital, Manchester, UK Guenter  Schwarz Department of Chemistry, Center for Molecular Medicine, Institute of Biochemistry, University of Cologne, Koeln, Germany Ivan  Šebesta Institute of Medical Biochemistry and Laboratory Medicine, Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague 2, Czech Republic Annalisa Sechi  Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy Denise N. Slenter  Department of Bioinformatics—BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands Jan A. M. Smeitink  Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Johannes  N.  Spelbrink Department of Paediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands Ute Spiekerkoetter  Department of Pediatrics and Adolescent Medicine, University Children’s Hospital, Albert Ludwigs University, Freiburg, Germany Antonella  Spinazzola MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK Thomas  Stauch Department of Clinical Chemistry and Toxicology, German Competence Center for Porphyria Diagnosis and Consultation, MVZ Labor PD Dr. Volkmann und Kollegen GbR, Karlsruhe, Germany Robert  Steinfeld Division of Pediatric Neurology, University Children’s Hospital Zürich, Zürich, Switzerland

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Sarah L. Stenton  Institute of Human Genetics, Technische Universität München, Munich, Germany Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany Sylvia  Stöckler-Ipsiroglu Division of Biochemical Genetics, BC Children’s Hospital, Vancouver, BC, Canada Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada Ulrich Stölzel  Center of Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, Metabolic Disorders, Oncology, Saxony Porphyria Center, Klinikum Chemnitz gGmbH, Chemnitz, Germany Eduard A. Struys  Metabolic Unit, Clinical Chemistry, VUmc Medical Center, Amsterdam, The Netherlands Michael A. Swanson  Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA Isabel Tavares de Almeida  Metabolism and Genetics, iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal Valeria  Tiranti  Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Davide  Tonduti Child Neurology Unit, COALA (Center for Diagnosis and Treatment of Leukodystrophy)—V. Buzzi Children’s Hospital, Milano, Italy Frederic Tort  Section of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clínic de Barcelona, CIBERER, Barcelona, Spain Victoria  Tüngler Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Karin Tuschl  Department of Developmental Neurobiology, Kings College, London, UK Department of Cell and Developmental Biology, University College, London, UK UCL GOS Institute of Child Health, University College, London, UK Lambert van den Heuvel  Institute for Genetic and Metabolic Disease, Nijmegen Medical Centre, Radboud University, Nijmegen, The Netherlands Johan  L.  K.  Van Hove Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA Clara  D.  M.  van Karnebeek Departments of Pediatrics and Human Genetics, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands Francjan  J.  van Spronsen Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Groningen, The Netherlands Frédéric  M.  Vaz  Laboratory Genetic Metabolic Diseases, Amsterdam UMC, Amsterdam, The Netherlands Nanda Verhoeven-Duif  Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands Christine Vianey-Saban  CHU de Lyon, Department of Biochemistry & Molecular Biology, Division of Inborn Errors of Metabolism, Lyon University Hospital Centre, Bron, France Jerry  Vockley  Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA

Contributors

Contributors

xxxi

Mirjam  M.  C.  Wamelink  Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Ronald J. A. Wanders  Departments of Pediatrics, Emma Children’s Hospital, and Laboratory Medicine, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands Wyeth W. Wasserman  Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada Hans R. Waterham  Departments of Pediatrics, Emma Children’s Hospital, and Laboratory Medicine, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, The Netherlands Ron  A.  Wevers Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Matthew  T.  Whitehead Department of Radiology, Children’s National Health System, Washington, DC, USA Monique  Williams  Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Egon  L.  Willighagen Department of Bioinformatics—BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands Mathias Woidy  Department of Paediatrics, University Medical Center Eppendorf, Hamburg, Germany Saskia  B.  Wortmann Institute of Human Genetics, Academic Medical Center, Munich, Germany Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria Radboud Centre for Mitochondrial Medicine, Amalia Children’s Hospital, Radboudumc, Nijmegen, The Netherlands Johannes Zschocke  Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

Part I General Subjects and Profiles

1

Newborn Screening for Inborn Errors of Metabolism Ralph Fingerhut, Janice Fletcher, and Enzo Ranieri

Contents Introduction

 3

History of Newborn Screening

 4

Newborn Screening: A Public Health Program

 5

Principles and Practice in the NBS Laboratory

 6

Perspective

 15

Conclusion

 15

References

 15

Abstract

Newborn screening (NBS) is a public health measure for the early detection of inborn errors of metabolism (IEM), endocrinopathies, and a variety of other disorders, where early presymptomatic detection and treatment can prevent mental retardation, disabilities, or death, or at least can improve the quality of life and extend the life span of affected patients. Newborn screening started in the early 1960s, however there are still countries around the world, that do not have a newborn screening program. Newborn screening has evolved over the years and has become a program, that goes far beyond the laboratory test alone. However, long-term follow-up is still very often neglected by stakeholders, health insurance companies, and governmental authorities. Although this chapter focuses on the laboratory tests, which R. Fingerhut (*) SYNLAB MVZ Weiden, Weiden, Germany e-mail: [email protected] J. Fletcher · E. Ranieri SA Pathology (at Women’s and Children’s Hospital), Adelaide, SA, Australia e-mail: [email protected]

use whole blood, taken by heel prick, dried on special blood collection devices, the so-called dried blood samples (DBS), it also touches additional topics.

Introduction Newborn screening (NBS) is a public health measure for the early detection inborn errors of metabolism (IEM), endocrinopathies, and a variety of other disorders, where early presymptomtic detection and treatment can prevent mental retardation, disabilities, or death, or at least can improve the quality of life and extend the life span of affected patients. This chapter focuses on the laboratory tests, which use whole blood, taken by heel prick, dried on a special blood collection device, the so-called dried blood samples (DBS). During the last 20 years, other genetic conditions, like hemoglobinopathies, cystic fibrosis, infectious disease like HIV and CMV, immunodeficiencies like SCID, or muscular dystrophies like Duchenne muscular dystrophy (DMD), or spinal muscular atrophy (SMA), were added to the NBS panel. In

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_1

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addition, there are also conditions that use point-of-care testing, which are not lab-based tests, like newborn hearing screening, using otoacoustic testing, or screening for critical congenital heart defects (CCHD) using pulse oximetry. This chapter also provides an overview of the history of NBS, principles, goals, and some pitfalls.

History of Newborn Screening Newborn screening as a laboratory test started with the invention of the bacterial inhibition assay for the detection of phenylketonuria (PKU) in 1963 by Robert Guthrie (Guthrie and Susi 1963; Guthrie 1996). However, sometimes forgotten, at least three mothers of mentally retarded children should be mentioned, who pushed scientists on, because they would not just accept the disability of their children as fate, but wanted a diagnosis or treatment. The first is Pearl S. Buck. Although she was not successful, she wrote down the story of her child in a touching book: The Child Who Never Grew. The second are Harry and Borgny Egeland from Oslo who got in touch with Dr. Ivar Asbjørn Følling, who finally could isolate phenylpyruvic acid from the urine of their two disabled children, which also gave the name, phenylketonuria, to the disorder (Fölling 1934). Then in 1951 again there was a mother, Mrs. Jones, who had a diagnosis for her daughter Sheila (PKU), who now insisted that the pediatrician, Dr. Horst Bickel, should look for a possible treatment. Maybe the persistency of Mrs. Jones, lead Horst Bickel to introduce a phenylalaninefree diet (Bickel et al. 1953), which has been proposed a few years before by Woolf et al. (Woolf and Vulliamy 1951; Woolf et al. 1955). The initiation of treatment and the proof of effectiveness have been very well documented also on Super 8 films and can be found at https://www.youtube.com/ watch?v=OqZ7QHO5_hs. Sheila Jones’ diagnosis was made at the age 2 years with the ferric chloride test, or the FøllingTest as it is called in some countries. But although the treatment with the phenylalanine-­ free diet could improve the clinical situation of the patient, it could not reverse mental retardation. However, with the introduction of a treatment option for PKU and a simple urine test, all newborn siblings of PKU patients could be tested and treated early, from birth on. The next step was the introduction of the so-called diaper test by Dr. Centerwall et al. (1960). They adopted the ferric chloride test for newborns by just pouring ferric chloride solution onto the wet diapers of newborns to detect excreted phenylpyruvic acid. The test worked in principle, only the sensitivity was poor. With the diaper test only the very severe cases of PKU could be detected, who already had a very high concentration of phenylpyruvate in urine. And again, it was a father of a child with PKU who approached Robert Guthrie at a meeting of families with disabled children, whether he could not try to develop a more sensitive test, so that all children with PKU could be treated early enough to prevent mental retardation. This was the start of NBS for PKU in the USA

R. Fingerhut et al. Table 1.1  Wilson and Jungner classic screening criteria 1. 2.

The condition sought should be an important health problem There should be an accepted treatment for patients with recognized disease 3. Facilities for diagnosis and treatment should be available 4. There should be a recognizable latent or early symptomatic stage 5. There should be a suitable test or examination 6. The test should be acceptable to the population 7. The natural history of the condition, including development from latent to declared disease, should be adequately understood 8. There should be an agreed policy on whom to treat as patients 9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole 10. Case finding should be a continuing process and not a “once and for all” project

in 1963, and many countries followed in the following years. And still today, the NBS test, using whole blood taken by heel prick and dried on a special blood collection device, is often called the “Guthrie Test.” Then step by step new tests for other disorders were developed and included into NBS in several countries, like galactosemia (Paigen et  al. 1982), biotinidase deficiency (Heard et  al. 1984), maple syrup urine disease, MSUD (Naylor and Guthrie 1978), homocystinuria (Whiteman et  al. 1979), congenital hypothyroidism (Larsen and Broskin 1975; Dussault et  al. 1976), and congenital adrenal hyperplasia (Cacciari et al. 1982). In 1968, the World Health Organization (WHO) had initiated a study to define criteria for the introduction of population screening, which had been accomplished by Wilson and Jungner (Wilson and Jungner 1968; Jungner et al. 2017). The introduction of tandem mass spectrometry (TMS) has somehow revolutionized NBS. It changed the paradigm from one disorder—one test, to one technology—multiple disorders. This changed the interpretation of criteria no. 9 from the Wilson and Jungner criteria totally. Once TMS was introduced, the cost of adding another disorder, which could be detected in the profile of amino acids or acylcarnitines was more or less zero. Therefore, it was necessary to revise the Wilson and Jungner criteria the new situation (Andermann et al. 2008) (Table 1.1). Three points of these criteria should be especially discussed. First, criteria no. 7, “The natural history of the condition, including development from latent to declared disease, should be adequately understood.” This works easily, while screening an adult population for a certain disease. Medical history of the patients (or probands) are normally available, repeat testing can be easily done, and normally there are well-defined criteria, who should be declared as a patient (criteria no. 8). For conditions that are included in NBS, the knowledge of the natural history is not always well understood, due to several reasons. First of all, it has to be beared in mind that scientific and medical knowledge expands over time. For example, before NBS for PKU was started, variant hyperphenylalaninemias were more or less unknown, and also disorders of the cofactor metabolism of the phenylala-

1  Newborn Screening for Inborn Errors of Metabolism

nine hydroxylase, tetrahydrobiopterine, were unknown or not well understood (see Chap. xx). The introduction of NBS for PKU also developed a new “condition”: Maternal PKU, which could not be anticipated beforehand. Another example is NBS for galactosemia. It started with the measurement of total galactose in DBS (Paigen et  al. 1982), which was accomplished by the so-called Beutler test (Beutler et  al. 1964), which was a qualitative or semiquantitative test to measure the activity of the galactose-1-phosphate uridyltransferase, the enzyme deficient in classical galactosemia. The introduction of the Beutler test led to the detection of a variant form of galactosemia, the so-called Duarte-2 galactosemia. At the beginning, the patients with the Duarte-2 variant were treated the same way as patients with classical galactosemia, and it was only in the 1990s, when increasing knowledge about the natural history of galactosemia showed that these Duarte-2 variant patients normally do not need any treatment at all. And just recently, a fourth disorder in the galactose metabolism has been described, galactose mutarotase (GALM) deficiency (Iwasawa et al. 2019). Other examples are histidinemia, which was introduced in several countries, probably after a single case report (Garvey and Gordon 1969) and a method paper, which afterwards proved that elevated histidine in blood is a condition without clinical significance (Brosco et al. 2010). There are also other conditions, where the clinical relevance or the clinical penetrance of the disorder is unclear or very low, like SCADD, and 3-MCC deficiency. A last example are pilot urine newborn screening programs for neuroblastoma in Quebec, Austria, Germany, the UK, and Japan. But, although early treatment with a combination of surgery and chemotherapy seemed to work well, the death rate from neuroblastoma tumors did not change. Therefore, it was suspected that NBS for neuroblastoma had detected previously unrecognized mild tumors that would have spontaneously regressed, also without any therapy (Riley et  al. 2003; Maris and Woods 2008). Secondly, criteria no. 3, “Facilities for diagnosis and treatment should be available” in connection with criteria no. 8 again. A “facility for the diagnosis,” together with an “agreed policy on whom to treat,” should be interpreted as: After a positive NBS test, there should be a definite diagnostic test available to decide directly after the diagnostic test, whether a child has a condition, and needs immediate treatment, or whether the child is not affected, and can be released as healthy. There are some disorders that do not fulfill this criteria, for example, VLCADD, where acylcarnitine profiles can be totally normal when the patients are in an anabolic status (Spiekerkoetter et  al. 2010), or several of the lysosomal storage disorders, where the residual enzyme activity alone, cannot predict 100% whether the disease will progress, and also genetic analysis is not 100% helpful, and often there is no other metabolic marker available to determine the progression, or normalization. And the third point directly emerges from this problem, it is criteria no. 6, “The test should be acceptable to the population.” Different stakehold-

5

ers of NBS programs can have totally different opinions about it. Pediatricians and patient organizations for a certain disorder can be extremely in favor for NBS, even if there is a long time of uncertainty, whether treatment is necessary or not. At the other end, there may be a big number of parents who rather not want to have this particular disorder included because of this uncertainty. However, informed consent, although it is nowadays included in most countries is not an easy task, and the burden of false-positive NBS results have been described by several groups (Morrison and Clayton 2011; Schmidt et al. 2012; Johnson et al. 2019). Decision-making for NBS programs is not an easy task. In many countries, it is formalized like in the USA (DHHS 2013), Germany, Switzerland, the UK, for example, but although many countries have celebrated their 50th anniversary of NBS during the last years, there are still a lot of countries around the world that have not started any newborn screening, or just had some pilot programs (Pandey et  al. 2019), and sometimes NBS is only available for a small part of the population, who can afford to pay for NBS by themselves.

 ewborn Screening: A Public Health N Program Newborn screening is not just a laboratory test; it should be recognized as a whole program. It includes midwives, nurses, gynecologists, neonatologists, the laboratory, special diagnostic centers, and specialized treatment centers. NBS programs should include information material about the extent of the program for parents and midwives, nurses, gynecologists, and neonatologists, for the latter especially also information how a positive NBS result will be communicated. Ideally, there should also be designated specialized centers for the final diagnostic test, and specialized centers for the treatment. And there must be a feedback about the outcome of the diagnostic test, back to the newborn screening laboratory, in order to generate reliable statistical data: Number of newborns screened, and for each disorder, recall rate, positive predictive value (ppv), negative predictive value (npv), and incidence. The structure of NBS programs is quite diverse worldwide and also the way how new disorders are integrated into existing NBS programs is diverse. A helpful guideline for countries that have no legitimate guideline, the Recommended Uniform Screening Panel (RUSP) of the US Advisory Committee on Heritable Disorders in Newborns and Children could be a helpful guide for decision-making. The latest update can always be found at https://www.hrsa.gov/ advisory-­committees/heritable-­disorders/rusp/index.html. In addition, the Clinical and Laboratory Standards Institute (CLSI) has published several guidelines (https://clsi.org/standards/products/newborn-­screening/) for the implementation of NBS. One problem that NBS programs are faced with is often the lack of financial support for those parts of the NBS pro-

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R. Fingerhut et al.

gram that are not directly related to the laboratory test, and often there is no connection between the DBS-NBS, and newborn hearing screening, and screening for CCHD. One example is the state of Bavaria in Germany, where a public health screening center coordinates tracking of all NBS tests statewide. This includes checking of completeness, follow-­up of positive NBS results, and diagnostic tests, and also whether the patients with a definite diagnosis have been admitted to a specialized center (https://www.lgl.bayern.de/gesundheit/ praevention/kindergesundheit/neugeborenenscreening/index. htm). Another issue is often the enormous costs of new therapies, for so far untreatable disorders, like enzyme replacement therapy for LSDs, or the treament for SMA.

(a) Newborn screening is not a diagnostic test, (b) it needs further investigations to confirm a positive screening test, (c) among the screened population there can be individuals that have a low risk of having a certain condition, according to the screening result, but still can have or develop the disease. Improvements in instrumentation and methodology have continuously improved the detection limits of analytes, and the sensitivity and specificity of laboratory tests. Still every newborn screening laboratory has to define cut-offs for their primary screening test, which will effect sensitivity, specificity, ppv, and npv.

Sensitivity and Specificity

 rinciples and Practice in the NBS P Laboratory It should be kept in mind that every NBS test, whether immunoassay, enzymatic assay, metabolite determination by tandem mass spectrometry, determination of profiles by HPLC, IEF, or determination of copy numbers by rtPCR, is ONLY a SCREENING TEST, and not a diagnostic test. A definition of screening (not only NBS) has been published by Wald (1994): “Screening is the systematic application of a test or enquiry to identify individuals at sufficient risk of a specific disorder to benefit from further investigations or treatment, among persons who have not sought medical attention on account of symptoms of that disorder.” This definition implements three things: a

ideal situation normal population

b

Ideally, the distribution of metabolite concentrations or enzyme activities shows a normal distribution. Ideally, the affected and unaffected individuals are completely seperated from each other (Fig. 1.1a). However, normally there is always on overlap between these two groups (Fig. 1.1b). The cut-off is normally choosen in a way that there are no fn results. However, this would for some disorders (like CF) result in an enormous number of fp results. In these cases, a second-­ tier test can improve the situation (Fig. 1.2). But sometimes it has to be accepted that a screening test is not able to pick up all cases. However, sometimes the combination of marker metabolites can result in 100% sensitivity and 100% ­specificity, like in CPT-I deficiency (Fingerhut et al. 2001) (Fig. 1.3).

affected population

normal situation normal population

Fig. 1.1  Frequency distributions between normal and affected population

affected population

1  Newborn Screening for Inborn Errors of Metabolism Fig. 1.2  Distribution of IRT values from normal newborns and newborns with CF

7

12'000 Percentiles 95.0

10'000

99.0 99.2

frequency

8'000

99.5 99.9

6'000 CF pos. (n=27)

4'000

Equivocal CF (n=3) CF pos. with meconium ileus and normal IRT

2'000

0

0

20

40

60

100

80

120

>140

IRT (ng/mL) blood

cut off

14000 12000 10000

Frequency

Fig. 1.3  Distribution of the ratio of C0/(C16 + C18) from normal newborns (red bars), newborns on carnitine supplementation (blue circle) and newborns with CPT-I deficiency (orange crosses)

8000 6000 4000 2000

P1 b

P1 P3 a a

P2 a

P3 b

P2 b

0 1

2,5

5

10

25

50

C0/(C16+C18)

Sensitivity is the percentage of affected individuals that are detected with the respective test. Specificity is the percentage of unaffected individuals that are correctly detected as unaffected. Sensitivity  rp / rp  fn, Specificity  rn / fp  rn (rp = right positive; rn = right negative; fp = false positive; fn = false negative)

What Is a “False-Positive” Result? Different NBS programs often use different terminology. In this chapter, we will use “abnormal” result and “normal” result, which are ultimately defined by the choosen cut-off for each laboratory test. If the first measurement from a specific NBS card is “abnormal,” the test should always be repeated from the same NBS card in duplicate. This will

125

250

630

1260

(Logarithmic scale!)

eliminate a laboratory error. If two results are not plausible, the laboratory should search for an explanation. Since every test has also a certain uncertainty of measurement, this needs to be included into the cut-off consideration. If the repeat testing is again “abnormal,” this will result in a “Positive Screening Result” for a specific disorder. If then, either a second DBS is taken, or a specific diagnostic test is made, and this second test results in a “normal” test result, or the diagnostic test excludes the condition, for which the initial screening test was “positive,” then the initial screening will be called a “False-Positive” result. False-positive results (fp) are expected in NBS because the major goal is not to miss a patient that has the respective condition. There are several reasons for a false-positive screening result. (a) Screening tests with a high uncertainty of measurement also tend to have a higher fp rate. (b) Higher biological variation of the disease marker will also lead to a higher fp rate. (c) If the marker metabolite is not specific for

8

a certain disorder. (d) The metabolite level is influenced by nutrition and diet. (e) The metabolite levels are influence by the mother, for example, free carnitine levels in CUD, or Vitamin B12 levels in disorders of cobalamin metabolism. Fp result can be effectively reduced, when it is possible to use not only one primary disease markers, but several markers or additional ratios. Even more effective are second-tier tests which are more specific than the primary test, but too expensive or labor intensive to apply them directly to all DBS. For example, second-tier genetic testing in CF screening, or the determination of allo-isoleucine by HPLC or UPLC in MSUD screening (Fig.  1.4). Major causes of fp results are summarized in Table 1.2 (Table 46.2 from the previous edition of this book). When comparing fp rates between different NBS programs and published data, it is important that a clear definition has been given for fp results. For example, a DBS of a newborn with a complete glucose-6-phosphate dehydrogenase deficiency will give an abnormal screening result for classical galactosemia, if only the Beutler test is used. This could be counted as a fp result for galactosemia screening, however Fig. 1.4  Separation of leucine, isoleucine, and allo-isoleucine by UPLC-MS/MS

R. Fingerhut et al.

from the design of the Beutler test, which uses four different enzymes that are present in the DBS, galactose-­1-­phosphate uridyltransferase (GALT), phosphoglucomutase (PGM), glucose-6-phosphate dehydrogenase (G6PD), and 6-­phosphogluconate dehydrogenase, it is an expected finding, and therefore it could be as well defined as a true positive result.

What Is a “False-Negative” Result? False-negative results (fn) in screening are unwanted, but it is important to keep in mind that a screening test can never be 100% sensitive. There are several examples, where biological variability will result in fn results. One example is homocystinuria. The primary marker is methionine because the determination of total homocysteine is not feasible as a primary test. However, with methionine as a marker only patients with classical homocystinuria (cystathionine ­synthase deficiency) can be detected. In addition, earlier sampling due to improved sensitivity, earlier discharge from

1  Newborn Screening for Inborn Errors of Metabolism

9

Table 1.2 Commonlya used methods in bloodspot NBS (historic or currently used) Principle Bacterial Measures analyte by effect inhibition assay of analyte level on growth of bacteria selected for dependence on analyte Fluorescent or other colorimetric

Measures analyte by the amount of fluorescence or color compared with standard Immune assay Measures the presence of protein based on interaction with an antibody against the protein; various markers for levels, e.g., radioactivity for radioimmunoassay (RIA) Electrophoresis Measures the presence or absence of protein with specific mass and charge Enzyme assay Measures the ability of enzyme in sample to transform substrate to product; semiquantitative or quantitative determination

False positives Physiologic variations of analyte levels, effect of other medical conditions, effect of intake (feeding, hyperalimentation) Physiologic variations and effect of other medical conditions, effect of intake (feeding, hyperalimentation) Physiologic variation

Transfusion

False negative Physiologic variations of analyte levels, effects of antibiotics

Physiologic variations of analyte levels, effects of dietary intake of analytes Physiologic variation; for CF it is notable that immunoreactive trypsinogen (IRT), the marker for CF, is not elevated in babies with meconium ileus Transfusion

Heat inactivation of enzyme in transport; deficiency of other pathway required for generation of marker for product (Beutler assay for galactosemia depends on integrity of the enzyme G6PD); pseudodeficiency

Transfusion

Uses and comments The original method of screening for PKU and other IEM as designed by R. Guthrie and used until replaced by fluorescence and/or MS/MS PKU, maple syrup urine disease, homocystinuria, galactosemia

Thyroid and thyroid-stimulating hormone (for hypothyroidism); immunoreactive trypsinogen (IRT) for cystic fibrosis; steroid hormone analytes for congenital adrenal hyperplasia Hemoglobinopathies; method in use for decades also identifies carrier status Galactosemia (by assay called “Beutler”), biotinidase deficiency, some lysosomal enzymes. Can identify carriers, identifies healthy individuals with pseudodeficient states, and (especially for lysosomal disorders) identifies affected individuals who may have adult-onset phenotype PKU and other amino acidopathies, methylmalonic acidemia, and other organic acidemias, MCADD, and other disorders of fatty acid oxidation and carnitine metabolism, some urea cycle disorders. The accuracy of levels and the ability to examine ratios dramatically improve sensitivity and specificity compared with bacterial inhibition and fluorescence Occasionally used as primary screen but more often used as second-tier test for cystic fibrosis, medium-chain acyl-CoA dehydrogenase deficiency and galactosemia Will identify carriers To screen for spinal muscular atrophy, DNA testing must be used as primary method

MS/MS

Tandem mass spectrometry, inferring levels of metabolites based on amounts of (and ratios of) molecular fragments compared against isotopically labeled standards

Physiologic variations and effect of other medical conditions, effect of intake (feeding, hyperalimentation), effect of some medications

Physiologic variations of analyte levels, effects of dietary intake of analytes

DNA mutation analyses

Analyzes the presence or absence of specific sequence changes or specific known deletions or duplications

Unless method identifies all mutations (see false-negative column), it may be necessary to perform diagnostic testing on those identified by screening as having one mutation Two mutations may be present in cis in an individual who is carrier but not affected

DNA repeat size DNA—TREC

Analyzes the length of Hypothetically none triplet repeat segments Quantifies fragments of Physiologic DNA (cell receptor excision circles) generated in T-cell function maturation

For virtually all conditions, there will be false negatives if DNA is the primary screen or required to be positive as a second-tier test in screening. The number of cases missed depends on the number of mutations for which the sample is screened and the frequency with which individuals in the screened population have disease caused by mutation(s) not on the panel Mosaicism for repeat size Fragile X; should also identify carriers Some cases of adenosine Severe combined immune deaminase (ADA) deficiency, including several deficiency conditions which can present with immune deficiency, such as T-cell deficiency due to deletion of 22q

Includes methods used for IEM and for other (including nongenetic as well as non-metabolic) conditions. Less commonly used methodologies, e.g., HPLC, are not included here a

10

R. Fingerhut et al.

hospital, and inclusion of more severe disorders with earlier onset, like MSUD, will lead to more fn results because methionine rises rather slowly, even in classical homocystinuria. A second example is tyrosinemia type I.  Again using tyrosine as the primary marker will lead to fn results because in case of tyrosinemia type I it is not the enzyme block that will lead to the elevation of tyrosine, it is the liver damage that produces the elevation of tyrosine, together with elevated phenylalanine, methionine, and the branched chain amino acids. The third example is glutaric aciduria type I (GA-I). In GA-I, it is well known that the so-called non-­ excretors, patients with clinically and genetically proven GA-I that do not excrete 3-hydroxyglutaric or glutaric acid in the urine, are missed by NBS (Gallagher et al. 2005). Also for CF it is well known that the sensitivity is only around 95–96%, meaning that 4–5% of cases are missed by NBS (Heidendael et al. 2014).

trometry (FI-MS/MS). For the determination of amino acids and acylcarnitines by FI-MS/MS, there are two different methods in use. Extraction into an organic phase either (a) after derivatization to the respective butyl esters, or (b) without derivatization. The method with butylation results in higher signal intensities than the method without derivatization; however, the modern tandem MS instruments tend to be so sensitive that this has no effect on the sensitivity of the test results. It only has to be kept in mind that same isobaric compounds are not isobaric anymore after butylation, e.g., C4DC and C5OH.  Dicarboxylic acid will add two butyl ester groups, while the hydroxyacids will only have one butyl group. Table 1.3 provides an update from Fingerhut (2009) of target diseases for NBS, which can be compared with the RUSP. Table 1.4 provides a list of the primary marker metabolites that can be detected by FI-MS/MS, and possible secondary markers.

Positive and Negative Predictive Values The positive predictive value (ppv) and the negative predictive value (npv) are necessary measures, when communicating a NBS result.

npv  rn / rn  fn, ppv  rp / rp  fp

The npv and ppv describe, how reliable a test result is, related to the disease state of the respective newborn. If the npv is 100%, it means the risk for a newborn with a normal test result to have this respective disorder is zero. On the other hand, a ppv of 100% means that the chance for newborn with a positive test result, not to have the respective disorder is also zero. In reality, neither npv nor ppv reach 100%. However, the npv is normally >99.9%, but it still means that there is still a chance that a newborn with a normal test result can have the respective disease. The ppv is quite variable, and as already discussed above, dependent on the choosen cut-off. However, very often the ppv can also be dependent on the test value. For example, a TSH value of >100 mU/L has probably a ppv of 100%, while a TSH value of 21 mU/L has probably a ppv of only 1–5%. Or when we look at CF screening with second-tier genetic testing: if second-tier testing finds two disease causing mutations, the ppv is 100%, irrespective of the initial IRT value. However, if no mutation is found, then the ppv is most likely again dependent on the IRT level.

The Newborn Screening Process The primary responsibility for the whole NBS process is very often in the hands of the newborn screening laboratory, unless it is embedded in a clearly defined NBS program. The integration of non-laboratory screenings, like newborn hearing screening and screening for CCHD, is even more complex and will not be discussed in detail here. Blood Sampling

The standard specimen for NBS is capillary whole blood dried on a special blood collection device, the so-called dried blood spots (DBS). The test cards should be distributed by the screening laboratory to their customers, midwives, hospitals, pediatricians, and general physicians, and they should include all necessary information that are needed for the correct interpretation of test results. The blood collection device must have a special quality and should (ideally) by approved by FDA, or a comparable national institution (Hall 2017). Since the number of people involved in blood sampling is normally quite high, it is necessary to provide regular information and education to the customers (Evans et al. 2019). Laboratory Test

The number of tests, and the methodology used for NBS varies between different countries  (Loeber et  al. 2021). A summary is given in Table 1.3.

Methodology Confirmatory Testing

Since this book deals with inborn errors of metabolism, the description of methodology focuses on detection of amino acids and acylcarnitines by flow injection tandem mass spec-

Confirmatory testing is often not performed in the screening laboratory, but it is a crucial part of the NBS program. It is already mentioned by Wilson and Jungner (criteria no. 8):

++

+ +

----

++ ++ + + +

--

TMS TMS TMS TMS TMS TMS TMS TMS TMS TLC TLC TMS TMS TMS TMS TMS TMS

TMS

Maple syrup urine disease Homocystinuria

Tyrosinemia type I Citrullinemia

Argininosuccinic acidemia Arginase deficiency Hyperornithinemia (OAT deficiency and HHH syndrome) Nonketotic hyperglycinemia Histidinemia Hydroxyprolinemia Serin Organic acidemias Glutaric aciduria type I Isovaleric acidemia Propionic acidemia Methylmalonic acidemia (mutase) Methylmalonic acidemia (disorders of cobalamin metabolism A-D,F) Cobalamin E/G defect

Malonyl-CoA decarboxylase TMS + deficiency 3-MCC deficiency TMS − 3-Hydroxymethylglutaryl-CoA TMS lyase deficiency Holocarboxylase synthase TMS deficiency ß-Ketothiolase deficiency TMS + Disorders of glutathione TMS metabolism ß-Oxidation defects/disorders of carnitine metabolism SCAD deficiency TMS --

++ +

++ +

Relevance ranking

Methods

Disease Aminoacidopathies Phenylketonuria

Table 1.3  Target diseases for newborn screening

y y y y y

y

m m m m m

a

y y y y y

n ---

y y n

y y

y n

y

m

m m m m m

m d d

m m m

m m

m m

a

Screening Testa programs available

y

y

y

y y

y

y y y y y

n --y

y

y y

y

Therapy available

y

y

y

y

y

y

y y

n n n

y

y y

y

Benefit from early detection

(continued)

Causality between enzyme defect and clinical outcome is not proven

Very rare, but easily treatable with biotin; Reliable discrimination from 3-MCC deficiency not possible Sensitivity and specificity presumably low No prospective data

Low clinical expressivity and penetrance Reliable discrimination from 3-MCC deficiency not possible

Low methionine level is the only marker; sensitivity and specificity unknown, but presumably low; determination of homocysteine would improve NBS Very rare; no prospective data

The so-called non-excretors can be missed by NBS NBS also detects unaffected patients with mild variants Acylcarnitine profile in PA and MMA are indistinguishable Acylcarnitine profile in PA and MMA are indistinguishable Sensitivity unclear; propionylcarnitine level is soften only slightly elevated

No therapy available Benign, does not require treatment Benign, does not require treatment No prospective data available

Positive effect on outcome is not yet certain; patients with a mild biochemical phenotype might never develop symptoms Positive effect on outcome is not yet certain Very rare; first results of NBS and early treatment seem promising Normal ornithine levels during the first weeks of life

Alternative therapies for mild phenylketonuria have been introduced, and further new therapies are under investigation Early blood collection is necessary Sensitivity and specificity low with methionine as primary marker; determination of homocysteine would improve NBS

Remarks

1  Newborn Screening for Inborn Errors of Metabolism 11

++ ++

TMS TMS TMS

TMS ELISA ELISA

Carnitine transporter deficiency

CPT-I deficiency

CPT-II deficiency

Translocase deficiency Endocrinopathies Congenital hypothyroidism Congenital adrenal hyperplasia

Cystic fibrosis Diabetes mellitus type I Other diseases

Lysosomal storage disorders

Glucose-6-phosphate dehydrogenase deficiency Phosphoglucomutase deficiency Disorders of creatine metabolism

Hemoglobinopathies Sickle cell anemia Hemoglobin S/ß-thalassemia Hemoglobin SC disease Hemoglobin H Other inborn errors of metabolism Biotinidase deficiency Galactosemia

+

TMS

LCHAD/TFP deficiency

++

p

Enzyme assay TMS Enzyme assay (TMS/ fluorimetric) IRT/DNA DNA

e

++ ++

Enzyme assay Substrate and/ or enzyme assay Enzyme assay

m p

p

a a

++ ++ ++ ++

e e e e

a a

m

m

m

m

m

m m

y

y

y y

y

y y

y y y y

y y

y

y

y

y

y y

Screening Testa programs available m y

IEF/HPLC IEF/HPLC IEF/HPLC IEF/HPLC

+

++

+

+

+

TMS TMS

MCHAD deficiency VLCAD deficiency

Relevance ranking ++

Methods TMS

Disease MCAD deficiency

Table 1.3 (continued)

y y

y

y y

y

y y

y y y y

y y

y

y

y

y

y

y y

Therapy available y

y y

y

y

y y

y y y y

y y

y

y

y

y

y

y

Benefit from early detection y

“Genetic risk” screening

Very rare, no prospective data available Feasibility has been demonstrated, results on long-term outcome not yet available Long delay/uncertainty between the positive NBS result and a clear confirmation of the disease; age of onset extremely variable and not predictable

High genetic variability

Long-term outcome not as favorable as initially thought in the 1970s

Sensitivity for the salt-wasting form is good, for simple virilizing congenital adrenal hyperplasia approximately 50%

Remarks Positive effect unquestioned; however patients that might never become symptomatic are also detected Very rare; no prospective data Mild variants might be missed when the samples are taken under anabolic conditions Information on long-term outcome are rare; prognosis for TFP is rather bad Sensitivity unclear; free carnitine level can be normal postpartum, depending on maternal supply and renal loss Ratio of free carnitine to the sum of palmitoylcarnitine and stearylcarnitine is sensitive and highly specific Neonatal onset form with bad prognosis despite early diagnosis; in the late-onset form mainly skeletal muscle is involved, seems to have normal levels of acylcarnitines in the neonatal period Bad prognosis despite early diagnosis

12 R. Fingerhut et al.

TREC/KREC copy numbers ELISA ELISA HBsAg

Otoacoustic CMV viral load Toxoplasmosis viral load Nontreponemal antibodies HPLC Creatine kinase activity DNA ++

+ y ----

epd epd epd

y

y y

--

y y --

m

p

d p

mat/epd

----

m p mat

++ + --

----

y

y

y n

--

y y --

----

y

n n

--

y y --

Not recommended Not recommended, (prenatal care) Not recommended, (prenatal care)

First outcome studies are promising; however, the observation time is only 4–5 years so far

Not recommended New therapies in development

Not recommended, (prenatal care)

Not recommended, (prenatal care)

POCT

CPT-I carnitine palmitoyl transferase I, CPT-II carnitine palmitoyl transferase II, HBsAg hepatitis B surface antigen, HHH hyperornithinemia–hyperammonemia–homocitrullinuria, HPLC high performance liquid chromatography, IEF isoelectric focusing, IRT immunoreactive trypsin, LCHAD long-chain hydroxyacyl-CoA dehydrogenase, MCAD medium-chain acyl-CoA dehydrogenase, MCHAD medium-chain hydroxyacyl-CoA dehydrogenase, 3-MCC 3-methylcrotonyl-CoA carboxylase, NBS newborn screening, OAT ornithine aminotransferase, SCAD short-chain acyl-CoA dehydrogenase, SCID severe combined immunodeficiency, TFP trifunctional protein, TLC thin-layer chromatography, TMS tandem mass spectrometry, VLCAD very long-chain acyl-CoA dehydrogenase, a all, d discontinued, e ethnic, epd epidemiologic, m most, mat recommended as a prenatal screening test, n no, pilot, y yes, + + unquestioned, + favorable, - unfavorable, - - not recommended a With sufficient sensitivity and specificity, economically justifiable b Specimen for screening is urine dried on filter paper

Severe combined immunodeficiency HIV Hepatitis C Hepatitis B

Spinal muscular atrophy

Neuroblastoma screeningb Duchenne muscular dystrophy

Hearing screening Congenital CMV infection Congenital toxoplasmosis infection Congenital syphilis infection

1  Newborn Screening for Inborn Errors of Metabolism 13

14

R. Fingerhut et al.

Table 1.4  Primary markers, and secondary markers and/or ratios for FI-MS/MS Metabolite (primary) Free carnitine (C0) Free carnitine (C0) Free carnitine (C0) Acetyl carnitine (C2) Propionylcarnitine (C3)

↑ ↑

Disorder Carnitine transporter deficiency All OAs, FAO disorders CPT-I deficiency Unspecific PA, MMA Disorders of cobalamin metabolism

Malonylcarnitine (C3DC)* Butyrylcarnitine (C4) Methylmalonylcarnitine/Succinylcarnitine (C4DC)* Isovalerylcarnitine (C5) Glutarylcarnitine (C5DC)*

↑ ↑ ↑

Malonyl-CoA decarboxylase deficiency MADD MMA (mut 0)

↑

IVA

Hydroxyisovalerylcarnitine (C5-OH)*

↑

Pentenoylcarnitine (C5:1) Methylglutarylcarnitine (C6DC)* Hexanoylcarnitine (C6) Octanoylcarnitine (C8) Decanoylcarnitine (C10) Decenoylcarnitine (C10:1) Hydroxyhexanoylcarnitine (C6OH)* Dodecanoylcarnitine (C12) Tetradecanoylcarnitine (C14)

↑ ↑ ↑ ↑ ↑ ↑ N, ↑ ↑ ↑

Tetradecenoylcarnitine (C14:1)

↑

Tetradecadienoylcarnitine (C14:2)

↑

Hydoxytetradecanoylcarnitine (C14-OH) Hydroxypalmitoylcarnitine (C16-OH) Hydroxyhexadecenoylcarnitine (C16:1-OH) Hydroxyoctadecenoylcarnitine (C18:1-OH) Palmitoylcarnitine (C16) Palmitoylcarnitine (C16) Stearylcarnitine (C18) Stearylcarnitine (C18) Phenylalanine (Phe) Tyrosine (Tyr) Tyrosine (Tyr) Methionine (Met) Methionine (Met) Leucine (Leu)*

↑ ↑ ↑

3-MCC def./3-HMG-CoA lyase def./ß-Ketothiolase ß-Ketothiolase HMG-CoA lyase def. MCADD MCADD MCADD MCADD MCADD VLCADD, LCHADD, MADD VLCADD, LCHADD, MADD, CPT-II, Translocase VLCADD, LCHADD, MADD, CPT-II, Translocase VLCADD, LCHADD, MADD, CPT-II, Translocase LCHADD, CPT-II, Translocase LCHADD, CPT-II, Translocase LCHADD, CPT-II, Translocase

Valine (Val) Citrulline (Cit) Citrulline (Cit) Arginine (Arg) Arginine (Arg) Ornithine (Orn) Alanine (Ala) Alanine (Ala) Gly (Gly) 5-Oxoproline/Pyroglutamate (PyrGlu)

↑ ↑ ↓ ↓ ↑ ↑ ↑ ↓ ↑ ↑

N, ↓ N, ↓ N, ↑

↑ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↓ ↑

LCHADD, CPT-II, Translocase CPT-II, Translocase CPT-I deficiency CPT-II, Translocase CPT-I deficiency PKU, liver disease PKU Tyrosinemia Type I, II, and III Homocystinuria, MAT Disorders of cobalamin metabolism MSUD, liver disease, hydroxyprolinemia MSUD, liver disease Citrullinemia UCDs UCDs Arginase def. Hyperornithinemia Lactic acidosis MSUD NKH 5-Oxoprolinemia, Glutathionsynthase def.

Secondary markers/ratios Total carnitine ↓ C0/(C16 + C18) ↑ C3/C2, C3/C4, C3/C16 C3/C2, C3/C4, C3/C16 ↑ Met N, ↓ C3DC/C5DC C5DC, C5, C12, C14, C14:1

C5/C4, C5/C8 C5DC/C4, C5DC/C12, C5DC/C8, C5DC/ C3DC C5-OH/C3, C5:1, C6DC C5-OH; C5-OH/C3 C5-OH; C5-OH/C3 C8/C12, C8/C6, C8/C10, (C6OH)

C14:1/C4

C0/(C16 + C18) ↑ C0/(C16 + C18) ↑ Phe/Tyr Phe/Tyr Tyr/Ser Met/Leu, Met/Phe C3, C3/C2, C3/C4, C3/C16 ↑ Leu/Phe, Leu/Ala, FQ Val/Phe, Val/Ala, FQ Cit/Phe, Cit/Tyr

Arg/Phe Orn/Phe, Orn/Ser

Gly/Ala PyrGlu/Phe

Metabolites marked with an asterix (*) have isobaric compounds, that cannot be destinguished from each other with the screening method.

1  Newborn Screening for Inborn Errors of Metabolism

“There should be an agreed policy on whom to treat as patients.” That means there must be a well-defined testing for the confirmation of the so far “suspicion” that an abnormal NBS result represents. Without a definite positive confirmatory test, no screening program should count an abnormal NBS result as a detected case. Unfortunately, this is often neglected, which can be seen from a lot of publications on screening for CH during the last years that can be summarized under the title: “Increasing incidence for CH by lowering the cut-off for TSH.”

15

References

Andermann A, Blancquaert I, Beauchamp S, Dery V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008;86(4):317–9. Badawi D, Bisordi K, Timmel MJ, Sorongon S, Strovel E.  Newborn screening long term follow-up in the medical home. Int J Neonatal Screen. 2019;5(3):25. Beutler E, Baluda M, Donnell GN. A new method for the detection of galactoxemia and its carrier state. J Lab Clin Med. 1964;64:694–705. Bickel H, Gerrard J, Hickmans EM. Influence of phenylalanine intake on phenylketonuria. Lancet. 1953;265(6790):812–3. Brosco JP, Sanders LM, Dharia R, Guez G, Feudtner C.  The lure of treatment: expanded newborn screening and the curious case of hisTreatment and Follow-up tidinemia. Pediatrics. 2010;125(3):417–9. The last part of the NBS process is the referral of newborns Cacciari E, Balsamo A, Piazzi S, Salardi S, Pirazili P, Capelli M, Cassio with a positive screening test to a specialized center, initiaA, Bernardi F, Cicognani A, Zappulla F, Paolini M. Neonatal screening for congenital adrenal hyperplasia. Lancet. 1982;1(8280):1069. tion of treatment, and follow-up. While the quality of the Centerwall WR, Chinnock RF, Pusavat A. Phenylketonuria: screening NBS tests can be measured by the number of correctly programs and testing methods. Am J Public Health Nations Health. detected cases (e.g., ppv, fp rate, fn), the quality and success 1960;50:1667–77. of the NBS program will be measured by the outcome of Dussault JH, Parlow A, Letarte J, Guyda H, Laberge C. TSH measurements from blood spots on filter paper: a confirmatory screening test detected cases. Therefore, long-term outcome studies are for neonatal hypothyroidism. J Pediatr. 1976;89:550–2. extremely important for the evaluation of NBS programs Evans A, LeBlanc K, Bonhomme N, Shone SM, Gaviglio A, (Badawi et al. 2019). Unfortunately, the costs for this quality Freedenberg D, Penn J, Johnson C, Vogel B, Dolan AM, Goldenberg assessment are mostly neither covered by the health insurAJ.  A newborn screening education best practices framework: development and adoption. Int J Neonatal Screen. 2019;5(2):22. ance, within the reimbursement for NBS, nor by the health Fingerhut R, Röschinger W, Muntau AC, Dame T, Kreischer J, Arnecke authorities. This is absolutely incomprehensible in these R, Superti-Furga A, Troxler H, Liebl B, Olgemöller B, Roscher times of quality control, where nearly everything is certified, AA.  Hepatic carnitine palmitoyltransferase I deficiency: acylor accredited by any “ISO-XXXX.” carnitine profiles in blood spots are highly specific. Clin Chem. 2001;47(10):1763–8. Fingerhut R,  Olgemöller B.  Newborn screening for inborn errors of metabolism and endocrinopathies: an update. Anal Bioanal Chem. Perspective 2009;393(5):1481–97. Fölling A. Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Zt Newborn screening will steadily improve and the number of Physiol Chem. 1934;227:169–76. disorders will increase. This will be driven either by improved Gallagher RC, Cowan TM, Goodman SI, Enns GM.  Glutaryl-CoA methods and technology, which makes screening possible, dehydrogenase deficiency and newborn screening: retrospective when marker metabolites get measurable, or by new treatanalysis of a low excretor provides further evidence that some cases may be missed. Mol Genet Metab. 2005;86(3):417–20. ment option, when sofar untreatable disorders get treatable Garvey AM, Gordon N.  Histidinaemia and speech disorders. Br J by the invention of new therapeutics, like SMA. Disord Commun. 1969;4:146–50. And last but not least, the decrease in cost for next-­ Guthrie R. The introduction of newborn screening for phenylketonuria. generation sequencing (NGS), whole exome sequencing, or A personal history. Eur J Pediatr. 1996;155(Suppl 1):4–5. whole genome sequencing, have started the debate, whether Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. this will be the future of NBS (Yang et al. 2019; Phornphutkul 1963;32:338–43. and Padbury 2019). Hall K. Suitable specimen types for newborn biochemical screening: a summary. Int J Neonatal Screen. 2017;3(3):17. Heard GS, Secor McVoy JR, Wolf B. A screening method for biotinidase deficiency in newborns. Clin Chem. 1984;30(1):125–7. Conclusion Heidendael JF, Tabbers MM, De Vreede I.  False negative newborn screen and neonatal cholestasis in a premature child with cystic Newborn screening is surely one of the most effective prefibrosis. Eur J Pediatr. 2014;173(12):1581–3. ventive health care programs in the world. It has a history of Iwasawa S, Kikuchi A, Wada Y, Arai-Ichinoi N, Sakamoto O, Tamiya G, Kure S. The prevalence of GALM mutations that cause galacmore than 50  years (in some regions), not to forget those tosemia: a database of functionally evaluated variants. Mol Genet countries, where they just start to think about introducing Metab. 2019;126(4):362–7. NBS. During the last 50 years, NBS has evolved from a labo- Johnson F, Southern KW, Ulph F. Psychological impact on parents of an inconclusive diagnosis following newborn bloodspot screenratory test, to a public health care program, still there is work ing for cystic fibrosis: a qualitative study. Int J Neonatal Screen. to do to improve. In addition, new technologies will continu2019;5(2):23.

ously challenge the newborn screening laboratories.

16 Jungner L, Jungner I, Engvall M, von Döbeln U. Gunnar Jungner and the principles and practice of screening for disease. Int J Neonatal Screen. 2017;3(3):23. Larsen PR, Broskin K.  Thyroxine (T4) immunoassay using a filter paper blood samples for screening of neonates for hypothyroidism. Pediatr Res. 1975;9:604–9. Loeber JG,  Platis D, Zetterström RH,  et  al. Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010. Int J Neonatal Screen. 2021;7:15 Maris JM, Woods WG.  Screening for neuroblastoma: a resurrected idea? Lancet. 2008;371(9619):1142–3. Morrison DR, Clayton EW.  False positive newborn screening results are not always benign. Public Health Genomics. 2011;14:173–7. Naylor EW, Guthrie R. Newborn screening for maple syrup urine disease (branched-chain ketoaciduria). Pediatrics. 1978;61(2):262–6. Paigen K, Pacholec F, Levy HL.  A new method of screening for inherited disorders of galactose metabolism. J Lab Clin Med. 1982;99(6):895–907. Pandey AS, Joshi S, Rajbhandari R, Kansakar P, Dhakal S, Fingerhut R. Newborn screening for selected disorders in Nepal: a pilot study. Int J Neonatal Screen. 2019;5(2):18. Phornphutkul C, Padbury J. Large scale next generation sequencing and newborn screening: are we ready? J Pediatr. 2019;209:9–10. Riley RD, Burchill SA, Abrams KR, et  al. A systematic review and evaluation of the use of tumour markers in paediatric oncology:

R. Fingerhut et al. Ewing’s sarcoma and neuroblastoma. Health Technol Assess. 2003;7(5):1–162. Schmidt JL, Castellanos-Brown K, Childress S, Bonhomme N, Oktay JS, Terry SF, Kyler P, Davidoff A, Greene C. The impact of false-­ positive newborn screening results on families: a qualitative study. Genet Med. 2012;14(1):76–80. Spiekerkoetter U, Haussmann U, Mueller M, et  al. Tandem mass spectroscopy screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr. 2010;157(4):668–73. Wald NJ. Editorial J Med Screen. 1994;1:1–2. Whiteman PD, Clayton BE, Ersser RS, Lilly P, Seakins JWT. Changing incidence of neonatal hypermethioninaemia: implications for the detection of homocystinuria. Arch Dis Child. 1979;54:593–8. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: World Health Organisation. 1968. Woolf LI, Vulliamy DG.  Phenylketonuria with a study of the effect upon it of glutamic acid. Arch Dis Child. 1951;26(130):487–94. Woolf LI, Griffiths R, Moncrieff A. Treatment of phenylketonuria with a diet low in phenylalanine. Br Med J. 1955;1(4905):57–64. Yang Y, Wang L, Wang B, Liu S, Yu B, Wang T. Application of next-­ generation sequencing following tandem mass spectrometry to expand newborn screening for inborn errors of metabolism: a multicenter study. Front Genet. 2019;10:86.

2

Simple Tests and Routine Chemistry Carlos R. Ferreira and Nenad Blau

Content References 

Abstract

A variety of routine chemistry tests are useful in both specialist and non-specialist laboratories to assist in the differential diagnosis of inherited metabolic disorders. We provide a list of metabolic diseases associated with abnormalities in urine tests (color, odor, ferric chloride, reducing substances, DNPH, Acetest, nitroprusside test) and routine blood chemistry (hypoglycemia, hyperglycemia, hyperammonemia, hyperlactatemia, low and high creatinine, acidosis, alkalosis, hypocholesterolemia, hypercholesterolemia, hypertriglyceridemia, increased liver transaminases, increased creatine kinase, increased lactate dehydrogenase, hyperphosphatasemia, hypophosphatasemia, decreased and increased urea nitrogen, hyperuricemia and hypouricemia, hyperferritinemia and hypoferritinemia, myoglobinuria, anemia, thrombocytopenia, neutropenia, and reticulocytosis). Although some of these tests are considered obsolete in modern metabolic laboratories, we decided to include them in this chapter from the historic point of view and to maintain the information for laboratories in developing countries.

This chapter draws substantially from previous chapter by Duran M and Gibson KM (Duran and Gibson 2014), which the authors gratefully acknowledge. C. R. Ferreira Division of Genetics and Metabolism, Children’s National Health System, Washington, DC, USA e-mail: [email protected] N. Blau (*) Division of Metabolism, University Children’s Hospital, Zürich, Switzerland e-mail: [email protected]

 39

A variety of rapid qualitative tests (colorimetric, dipstick, precipitate, color and smell, etc.) are useful in both specialist and non-specialist laboratories to assist in the differential diagnosis of inherited metabolic disorders. Most are limited by some level of interference; yet these tests still have important utility, especially in emergency situations. The color and odor of a patient’s urine may be a valuable analysis for initial testing (Tables 2.1 and 2.2). Odor can only be reliably interpreted when the urine is preserved in an adequate way (pH 5–7, no signs of bacterial contamination as evidenced by a negative nitrite dipstick). Alkaptonuria patients show a rapid blackening of the urine upon standing; this process can be accelerated by adding a few drops of an ammonia solution to the urine test tube. Although most of the following simple tests are considered to be obsolete in modern metabolic laboratories, we decided to include them in this book from the historic point of view and to maintain the information for laboratories in third world counties. The ferric chloride test (Table  2.3) is employed to look for the presence of oxo-acids (formed by transamination or oxidation-­reduction reactions). This test has been routinely used in the identification of classical phenylketonuria, but several other species (in addition to the intermediates of phenylalanine metabolism) react with ferric chloride to form a number of colored complexes. An alternative for the ferric chloride test is the Phenistix dipstick. Reducing substances in urine (see Table  2.4; also commonly referred to as Benedict test or Clinitest®, Bayer Corporation) reacts with a broad spectrum of reducing sugars in urine with the formation of colored complexes (green to orange). It is commonly used for the detection of urine galactose on the suspicion of galactosemia in neonates with severe liver disease and renal Fanconi syndrome. One should

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_2

17

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Table 2.1  Color (urine) Color Black Black

Compound Homogentisic acid Melanin

Disorder—source Alkaptonuria Metastatic melanoma; levodopa or alpha-­methyldopa in alkaline urine Black Ferrous sulfide Iron sorbitol citrate Black Cresol Intoxication (household disinfectant) Purple Indirubin + indigo Purple urine bag syndrome Blue Indican Hartnup disorder; Drummond syndrome; severe intestinal malabsorption Green Pyocyanin Pseudomonas infection Green Biliverdin Hyperbiliverdinemia Green Amitriptyline, indomethacin, metoclopramide, promethazine, Drugs cimetidine, methocarbamol, propofol, triamterene, carbolic acid (phenol), methylene blue, mitoxantrone, zaleplon Green Thymol Listerine mouthwash Chlorophyll Clorets mints Green Imazosulfuron, mefenacet Herbicide intoxication Brown Methemoglobin Methemoglobinemia Brown Myoglobin Myoglobinuria Brown Metronidazole, nitrofurantoin, chloroquine, primaquine Drugs Red-­brown Hb/methemoglobin Hemoglobinuria Red Erythrocytes/lysate Hematuria Red Porphyrins Porphyria Red Pyrazolones, phenothiazines (chlorpromazine, thioridazine), Drugs deferoxamine, hydroxycobalamin (Cyanokit, ≥5 g IV) Red Doxorubicin, senna, cascara Anthraquinone Red Phenolphthalein, phenolsulfonphthalein Chemicals Light red/pink Urates Hyperuricosuria Red Beets, rhubarb, blackberries Nutritional Orange Carotene Nutritional (carrots) Orange Rifampin, phenazopyridine, warfarin Drugs Orange-­yellow Sulfasalazine Drugs Orange-­yellow Fluorescein Retinal angiography Yellow Riboflavin Vitamins Yellow Bilirubin Hyperbilirubinemia (jaundice) Chyle Chyluria; filariasis; schistosomiasis Whitea Caseous material Urinary tuberculosis Whitea White blood cells Pyluria Whitea Calcium Hypercalciuria Whitea Oxalate Hyperoxaluria Whitea Phosphate Phosphaturia Whitea Fat Lipiduria Whitea

Sediment

a

be aware that the Fanconi syndrome includes renal glucosuria; hence the presence of galactose cannot be deduced from the positive Clinitest. Dinitrophenylhydrazine (DNPH, Brady’s reagent) reacts with α-ketoacids to produce insoluble hydrazones, forming precipitates in urine samples (Table  2.5); it is seldom used nowadays, partly due to its explosive hazard. Conversely, Acetest analysis in urine (Bayer Corporation) complexes with urinary ketones (Table 2.5). Parallel use of DNPH and Acetest provides slightly more diagnostic capacity. A positive result of either test will always be followed up by an immediate analysis of urine organic acids. Acetest is also frequently used for the home monitoring of patients with MSUD and propionic and methylmalonic acidurias; it will give a good indication for the catabolic state of the patient, necessitating dietary intervention.

This test will be of use in establishing hypoketotic hypoglycemia although the degree of ketonuria in several fatty acid oxidation disorders may be marked, especially MCAD. The cyanide nitroprusside test (or Brand reaction) identifies sulfur-containing amino acids, with the formation of brightly colored complexes (Table  2.6). It will find its primary use in the detection of homocystinuria (both homocysteine and the cysteine-homocysteine disulfide react positively) and cystinuria. Arginine—and at a slower rate argininosuccinic acid—will react by forming a differently colored product (blue/green). A concern with the Brand test is the use of toxic cyanide. Additional colorimetric tests can be employed for more selective identification. The Ehrlich’s test employs 4-­dimethylaminobenzaldehyde to assess the presence of uri-

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Table 2.2  Odor (urine) Odor Musty, mousey Maple syrup or burnt sugar Sweaty feet

Compound Phenylacetic acid Sotolone (4,5-dimethyl-3-hydroxy-2[5H]-furanone) Isovaleric acid

Methanethiol 2-Oxo-4-methylthiolbutyric acid 2-Oxo-4-methylthiolbutyric acid Sulfur Trimethylamine Dimethylglycine Alpha-hydroxybutyric acid

Isovaleric acidemia 3-Hydroxy-3-methylglutaric aciduria MADD (Glutaric aciduria type 2) 3-Methylcrotonylglycinuria Multiple carboxylase deficiency Methionine adenosyltransferase deficiency (Mudd disease); methanethiol oxidase deficiency; DMSO cryoprotectant (HSCT) Methanethiol oxidase deficiency Tyrosinemia type 1 Tyrosinemia type 1 Cystinuria, cysteamine administration Trimethylaminuria; carnitine supplementation Dimethylglycinuria Oasthouse syndrome (methionine malabsorption)

4-Hydroxyphenylpyruvic acid (?)

Hawkinsinuria

Idem + butyric + isobutyric acid 3-Hydroxyisovaleric acid/3-­methylcrotonic acid Dimethylsulfide

Cat urine Cabbage-like

Rancid butter Rotten eggs Fish Dried malt or hops, celery or yeast Swimming pool, chlorine

Disorder—source Classical PKU; treatment of urea cycle disorders with phenylacetate MSUD; fenugreek; lovage

HSCT hematopoietic stem cell transplantation Table 2.4  Reducing substances (urine)

Table 2.3  Ferric chloride test (urine) Color Blue-green

Compound Phenylpyruvic acid Imidazolepyruvic acid Catecholamines Xanthurenic acid

Transient Homogentisic acid blue-green Greenish-­gray Branched chain oxoacids Green 4-Hydroxyphenylpyruvic acid Yellow Lactic acid Gray-black Melanin Deep green Bilirubins Cherry red

Acetoacetic acid

Purple red-brown Purple

2-Oxobutyric acid

Purple or green

Ketones Salicylates Phenothiazines

Disorder—source Classical PKU Histidinemia Pheochromocytoma; neuroblastoma Xanthurenic aciduria (B6 def.) Alkaptonuria MSUD Tyrosinemia types 1 and 2 Lactic acidosis Melanoma Conjugated hyperbilirubinuria Diabetic ketoacidosis; 3-oxothiolase def. + other organic acids Methionine malabsorption 3-Oxothiolase deficiency Drug treatment Drug treatment

nary porphobilinogen and urobilinogen, markers for the heritable porphyrias, but it will also react with substances such as hydroxyproline, tryptophan, citrulline, and homocitrulline. The nitrosonaphthol test represents a colorimetric analysis of 4-hydroxylated phenol acids and metabolites of tyrosine metabolism (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate). Artefactual results with nitrosonaphthol are common in patients with liver disease and severe intestinal malabsorption and those receiving parenteral nutrition. The sulfite dipstick qualitatively assesses urine

Compound Galactose

Disorder—source Galactosemia Galactokinase deficiency Fanconi-Bickel syndrome Citrin deficiency Fructose Hereditary fructose intolerance Essential fructosuria 4-Hydroxyphenylpyruvic acid Tyrosinemia types 1 and 2 Homogentisic acid Alkaptonuria Xylose Pentosuria Glucose Diabetes mellitus Renal Fanconi syndrome; cystinosis; etc. Oxalic acid Hyperoxaluria Salicylates, levodopa, cephalosporins, Drug treatment tetracyclines, isoniazid, probenecid, nalidixic acid, nicotinic acid Uric acid Hyperuricosuria Hippuric acid Treatment with sodium benzoate; severe malabsorption Ascorbic acid Excessive vitamin use Contrast agents Radiographic evaluation

sulfite, indicative of sulfite oxidase and molybdenum cofactor deficiencies. It is reputedly performed in fresh urine samples, and only few false-­positive test results have been reported, a well-known one being the use of 2-mercaptoethanesulfonate (Mesna), which can also cause false-positive results to the nitroprusside reaction. Every faint positive sulfite test result should be verified by S-sulfocysteine measurement. Routine blood chemistry provides a plethora of diagnostic insights (e.g., glucose, ammonia, blood gases, creatinine, urea, uric acid, liver enzymes, etc.) (Table  2.7). Table  2.7

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Table 2.5  Dinitrophenylhydrazine (DNPH) and Acetest (urine) DNPH + + +

Acetest − − −

(+) +

− +

− − +

+ + +

+

−

+

−

+

+

Positive compound Phenylpyruvic acid 2-Oxoisocaproic acid 2-Oxo-3-methylvaleric acid Imidazolepyruvic acid Acetone

Disorder—source Classical PKU MSUD MSUD

Histidinemia 3-Oxothiolase def.; ketosis; Succinyl-CoA:3ketoacid-CoA-transferase deficiency 2-Methylacetoacetate 3-Oxothiolase deficiency 2-Butanone 3-Oxothiolase deficiency Acetoacetate Succinyl-CoA:3-ketoacidCoA-transferase deficiency; ketosis 4-Hydroxyphenylpyru- Liver disease; Tyrosinemia vic acid types 1 and 2 2-Oxobutyric acid Methionine malabsorption Pyruvate Lactic acidosis

Table 2.6  Nitroprusside test (urine) Positive compound Cystine Cystine Cystine 3-Mercaptolactatecysteine-­ disulfide Homocystine, cysteine-­ homocysteine mixed disulfide

Glutathione Ketones + high creatinine

Disorder—source Cystinuria Generalized aminoaciduria Fanconi syndrome 3-Mercaptolactatecysteine-­ disulfiduria Homocystinuria B 12 def. and cobalamin C, D, E, G Methylene tetrahydrofolate reductase def. Cystathioninuria (bacterial formation of Hcy) Glutathionuria Dehydration

Table 2.7  Routine chemistry in blood (plasma or serum) Glucose ↓ (hypoglycemia) Name Disorders of nitrogen-containing compounds Carbonic anhydrase VA deficiency Dopamine beta-hydroxylase deficiency Adenosine kinase deficiency Maple syrup urine disease Isovaleryl-CoA dehydrogenase deficiency 2-Methylbutyryl-CoA dehydrogenase deficiency 3-Methylcrotonyl-CoA carboxylase 1 and 2 deficiency 3-Methylglutaconyl-CoA hydratase deficiency HSD10 disease 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency Propionyl-CoA-carboxylase deficiency Methylmalonyl-CoA mutase deficiency Combined MMA and MA Malonyl-CoA decarboxylase deficiency Alpha-amino adipic semialdehyde (AASA) dehydrogenase deficiency 2-Ketoadipic aciduria Disorders of vitamins, cofactors, metals, and minerals NFS1 deficiency Multiple acyl-CoA dehydrogenase deficiency Nicotinamide nucleotide transhydrogenase deficiency Pyridox(am)ine 5′-phosphate oxidase deficiency Disorders of carbohydrates Fanconi-Bickel syndromea Fructose-1-phosphate aldolase deficiency Transaldolase deficiency ATP-sensitive potassium channel regulatory subunit deficiency ATP-sensitive potassium channel pore-forming subunit deficiency Glutamate dehydrogenase superactivity HNF4-alpha deficiency HNF1-alpha deficiency Uncoupling protein 2 deficiency Hyperinsulinemic hypoglycemia 5

Gene CA5A DBH ADK BCKDHA, BCKDHB, DBT IVD ACADSB MCCC1 AUH HSD17B10 HMGCL PCCA, PCCB MMUT ACSF3 MLYCD ALDH7A1 DHTKD1 NFS1 ETFDH, ETFA, ETFB NNT PNPO SLC2A2 ALDOB TALDO1 ABCC8 KCNJ11 GLUD1 HNF4A HNF1A UCP2 INSR

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Table 2.7 (continued) Name AKT2 superactivity Glucose-6-phosphate translocase deficiency Glycogen storage disease type III Liver glycogen phosphorylase deficiency Liver glycogen synthase deficiencya Hepatic phosphorylase kinase α2 subunit deficiency Phosphorylase kinase β subunit deficiency Hepatic phosphorylase kinase γ2 subunit deficiency Constitutional AMP-activated protein kinase activation Glycogen storage disease type I a Fructose-1,6-bisphosphatase deficiency Pyruvate carboxylase deficiency Mitochondrial phosphoenolpyruvate carboxykinase deficiency Glucokinase superactivity Mitochondrial disorders of energy metabolism 2-Oxoglutarate dehydrogenase deficiency Acyl-CoA Dehydrogenase 9 deficiency Mitochondrial complex III subunit deficiency (UQCRB) Mitochondrial complex III assembly deficiency (UQCRC2) Mitochondrial complex III assembly deficiency (TTC19) Mitochondrial complex III assembly deficiency (UQCC3) Mitochondrial ATP synthase F1 subunit δ deficiency Mitochondrial cytochrome beta deficiency Mitochondrial deoxyguanosine kinase deficiency MPV17 deficiency tRNA 5-carboxymethylaminomethyl transferase deficiency Mitochondrial transcription factor A deficiency Mitochondrial ribosomal small subunit 2, 7,23 and 28 deficiency Mitochondrial tryptophanyl-tRNA synthetase deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit B deficiency MEGDEL Syndrome Barth syndrome MICOS complex subunit MIC13 deficiency Disorders of lipids Organic cation carnitine transporter 2 deficiency Carnitine palmitoyltransferase 1 deficiency Carnitine palmitoyltransferase 2 deficiency Carnitine acylcarnitine translocase deficiency Short-chain acyl-CoA dehydrogenase deficiency Medium-chain acyl-CoA dehydrogenase deficiency Very long-chain acyl-CoA dehydrogenase deficiency Short-chain l-3-hydroxyacyl-CoA dehydrogenase deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Trifunctional protein deficiency TANGO2 deficiency 3-Hydroxy-3-methylglutaryl-CoA synthase deficiency Succinyl-CoA:3-oxoacid CoA transferase deficiency Monocarboxylate transporter gain-of-function Methylacetoacetyl-CoA thiolase deficiency Glycerol kinase deficiency, isolated Catalytic phosphatidylinositol 3-kinase α subunit superactivity Congenital disorders of glycosylation Phosphomannomutase 2 deficiency PMM2-CDG Phosphomannose isomerase deficiency MPI-CDG Mannosyltransferase 6 deficiency ALG3-CDG

Gene AKT2 SLC37A4 AGL PYGL GYS2 PHKA2 PHKB PHKG2 PRKAG2 G6PC FBP1 PC PCK2 GCK OGDH ACAD9 UQCRB UQCRC2 TTC19 UQCC3 ATP5F1D MTCYB DGUOK MPV17 MTO1 TFAM MRPS2 WARS2 GATB SERAC1 TAZ MICOS13 SLC22A5 CPT1A CPT2 SLC25A20 ACADS ACADM ACADVL HADH HADHA HADHB TANGO2 HMGCS2 OXCT1 SLC16A1 ACAT1 GK PIK3CA PMM2 MPI ALG3 (continued)

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Table 2.7 (continued) Name Mannosyltransferase 8 deficiency ALG12-CDG Phosphoglucomutase 1 deficiency PGM1-CDG Glucose ↑ Disorders of nitrogen-containing compounds Pterin carbinolamine-4a-­dehydratase deficiency Disorders of vitamins, cofactors, metals, and minerals Thiamine-responsive megaloblastic anemia syndrome (SLC19A2) Hereditary hemochromatosis (type 1) Hereditary hemochromatosis (type 2a) Hereditary hemochromatosis (type 2b) Hereditary hemochromatosis (type 3) Disorders of carbohydrates Fanconi-Bickel syndromea Galactose-1-phosphate uridyltransferase deficiencyb Uridine diphosphate galactose-4-­epimerase deficiencyb ATP-sensitive potassium channel regulatory subunit superactivity ATP-sensitive potassium channel pore-forming subunit superactivity Glucokinase deficiency Liver glycogen synthase deficiencya Mitochondrial disorders of energy metabolism Mitochondrial tRNA(Ser) 2 deficiency Disorders of lipids 3-Oxothiolase deficiency Estrogen resistance Storage disorders Nephropathic cystinosis Ammonia ↑ (Hyperammonemia) Disorders of nitrogen-containing compounds N-Acetylglutamate synthase deficiency Carbamoyl phosphate synthetase I deficiency Ornithine transcarbamylase deficiency Argininosuccinate synthetase deficiency Argininosuccinate lyase deficiency Arginase 1 deficiency Mitochondrial ornithine transporter deficiency Citrin deficiency Carbonic anhydrase VA deficiency Lysinuric protein intolerance Isovaleryl-CoA dehydrogenase deficiency 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency Propionyl-CoA-carboxylase deficiency Methylmalonyl-CoA mutase deficiency Pyrroline-5-carboxylate synthetase deficiency Ornithine aminotransferase deficiency Glutamate dehydrogenase superactivity Glutamine synthetase deficiency Disorders of vitamins, cofactors, metals, and minerals Adenosylcobalamin synthesis defect—cblD-MMA Adenosylcobalamin synthesis defect—cbl A/B Mitochondrial coenzyme A transporter deficiency Disorders of carbohydrates Pyruvate carboxylase deficiency Mitochondrial disorders of energy metabolism Acyl-CoA Dehydrogenase 9 deficiency Mitochondrial complex III assembly deficiency (UQCRC2) Mitochondrial ATP synthase F1 subunit δ deficiency Transmembrane protein 70 deficiency

Gene ALG12 PGM1

PCBD1 SLC19A2 HFE HFE2 HAMP TFR2 SLC2A2 GALT GALE ABCC8 KCNJ11 GCK GYS2 MTTS2 ACAT1 ESR1 CTNS

NAGS CPS1 OTC ASS1 ASL ARG1 SLC25A15 SLC25A13 CA5A SLC7A7 IVD HMGCL PCCA, PCCB MMUT ALDH18A1 OAT GLUD1 GLUL MMADHC MMAA/B SLC25A42 PC ACAD9 UQCRC2 ATP5F1D TMEM70

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Table 2.7 (continued) Name Mitochondrial cytochrome c1 deficiency FBXL4 deficiency Combined Oxidative Phosphorylation Defect 5 Disorders of lipids Carnitine-acylcarnitine translocase deficiency Carnitine palmitoyltransferase 2 deficiency, severe Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Trifunctional protein deficiency TANGO2 deficiency Alpha-methylacetoacetic aciduria Lactate ↑ Disorders of nitrogen-containing compounds Glutathione synthetase deficiency, severe Carbonic anhydrase VA deficiency Mitochondrial sulfur dioxygenase deficiency Isovaleric acidemia Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency HSD10 disease 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency Methylmalonate semialdehyde dehydrogenase deficiency Propionyl-CoA-carboxylase deficiency Methylmalonyl-CoA mutase deficiency Combined MMA and MA Malonyl-CoA decarboxylase deficiency 3-Hydroxyisobutyrate dehydrogenase deficiency Disorders of vitamins, cofactors, metals, and minerals Lipoyltransferase 2 deficiency Lipoic acid synthase deficiency Lipoyltransferase 1 deficiency NFU1 deficiency BOLA3 deficiency Glutaredoxin 5 deficiency IBA57 deficiency ISCA1 deficiency ISCA2 deficiency ISCU deficiency NFS1 deficiency ISD11 deficiency Ferredoxin 2 deficiency Biotinidase deficiency Holocarboxylase synthetase deficiency Biotin and thiamine basal ganglia disease Thiamine metabolism dysfunction syndrome 5 Mitochondrial NAD kinase 2 deficiency Phosphopantothenoylcysteine synthetase deficiency Mitochondrial coenzyme A transporter deficiency PROSC-deficient B6-dependent epilepsy Disorders of carbohydrates Glucose-6-phosphatase deficiency Glucose-6-phosphate translocase deficiency Fructose-1,6-bisphosphatase deficiency Pyruvate carboxylase deficiency d-lactate dehydrogenase deficiency Mitochondrial disorders of energy metabolism Pyruvate dehydrogenase complex deficiency E1a

Gene CYC1 FBXL4 MRPS22 SLC25A20 CPT2 HADHA HADHB TANGO2 ACAT1

GSS CA5A ETHE1 IVD ECHS1 HSD17B10 HMGCL ALDH6A1 PCCA, PCCB MMUT ACSF3 MLYCD HIBADH LIPT2 LIAS LIPT1 NFU1 BOLA3 GLRX5 IBA57 ISCA1 ISCA2 ISCU NFS1 LYRM4 FDX2 BTD HLCS SLC19A3 TPK1 NADK2 PPCS SLC25A42 PLPBP G6PC SLC37A4 FBP1 PC LDHD PDHA1 (continued)

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Table 2.7 (continued) Name Pyruvate dehydrogenase complex deficiency E1b Dihydrolipoyl transacetylase deficiency Pyruvate dehydrogenase complex deficiency E3 X Pyruvate dehydrogenase complex deficiency PDHP ATP-specific succinyl-CoA ligase β subunit deficiency GTP-specific succinyl-CoA ligase α subunit deficiency Fumarase deficiency Mitochondrial malate dehydrogenase deficiency 2-Oxoglutarate dehydrogenase deficiency l-2-hydroxyglutarate dehydrogenase deficiency Adenine nucleotide translocator deficiency AR Mitochondrial phosphate carrier deficiency Aspartate-glutamate carrier 1 deficiency Mitochondrial complex I subunit deficiency (NDUFV1) Mitochondrial complex I subunit deficiency (NDUFV2) Mitochondrial complex I subunit deficiency (NDUFS1) Mitochondrial complex I subunit deficiency (NDUFS2) Mitochondrial complex I subunit deficiency (NDUFS3) Mitochondrial complex I subunit deficiency (NDUFS7) Mitochondrial complex I subunit deficiency (NDUFS4) Mitochondrial complex I subunit deficiency (NDUFS6) Mitochondrial complex I subunit deficiency (NDUFA1) Mitochondrial complex I subunit deficiency (NDUFA2) Mitochondrial complex I subunit deficiency (NDUFA9) Mitochondrial complex I subunit deficiency (NDUFA10) Mitochondrial complex I subunit deficiency (NDUFB3) NADH dehydrogenase β subcomplex subunit 8 deficiency Mitochondrial complex I subunit deficiency (NDUFB11) Mitochondrial complex I subunit deficiency (MTND2) Mitochondrial complex I subunit deficiency (MTND3) Mitochondrial complex I subunit deficiency (MTND4) Mitochondrial complex I subunit deficiency (MTND5) Mitochondrial complex I subunit deficiency (MTND6) NADH dehydrogenase α subcomplex subunit 6 deficiency Mitochondrial complex I subunit deficiency (NDUFB9) Mitochondrial complex I subunit deficiency (NDUFA13) Mitochondrial complex I subunit deficiency (NDUFA11) NADH dehydrogenase β subcomplex subunit 10 deficiency Mitochondrial complex I assembly deficiency (NDUFAF1) Mitochondrial complex I assembly deficiency (NDUFAF2) Mitochondrial complex I assembly deficiency (NDUFAF2) Mitochondrial complex I assembly deficiency (NDUFAF3) Mitochondrial complex I assembly deficiency (NDUFAF4) Mitochondrial complex I assembly deficiency (NDUFAF5) Mitochondrial complex I assembly deficiency (NDUFAF6) Mitochondrial complex I assembly deficiency (FOXRED1) NUBPL deficiency Acyl-CoA Dehydrogenase 9 deficiency TIMMDC1 deficiency Mitochondrial complex III subunit deficiency (UQCRB) Mitochondrial complex III assembly deficiency (UQCRC2) Mitochondrial complex III subunit deficiency (UQCRQ) GRACILE syndrome Mitochondrial complex III assembly deficiency (TTC19) Mitochondrial complex III assembly deficiency (LYRM7) UQCC2 deficiency Mitochondrial complex III assembly deficiency (UQCC3)

Gene PDHB DLAT PDHX PDP1 SUCLA2 SUCLG1 FH MDH2 OGDH L2HGDH SLC25A4 SLC25A3 SLC25A12 NDUFV1 NDUFV2 NDUFS1 NDUFS2 NDUFS3 NDUFS7 NDUFS4 NDUFS6 NDUFA1 NDUFA2 NDUFA9 NDUFA10 NDUFB3 NDUFB8 NDUFB11 MTND2 MTND3 MTND4 MTND5 MTND6 NDUFA6 NDUFB9 NDUFA13 NDUFA11 NDUFB10 NDUFAF1 NDUFAF2 NDUFAF2 NDUFAF3 NDUFAF4 NDUFAF5 NDUFAF6 FOXRED1 NUBPL ACAD9 TIMMDC1 UQCRB UQCRC2 UQCRQ BCS1L TTC19 LYRM7 UQCC2 UQCC3

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Table 2.7 (continued) Name Mitochondrial complex IV subunit deficiency (MTCO1) Mitochondrial complex IV subunit deficiency (MTCO2) Mitochondrial complex IV subunit deficiency (MTCO3) Mitochondrial complex IV subunit deficiency (COX6B1) Mitochondrial complex IV subunit deficiency (COX7B) Cytochrome c oxidase subunit 5A deficiency Mitochondrial complex IV assembly deficiency (COA6) Mitochondrial complex IV assembly deficiency (COX10) Mitochondrial complex IV assembly deficiency (COX15) Mitochondrial complex IV assembly deficiency (COX20) Mitochondrial complex IV assembly deficiency (SCO1) Mitochondrial complex IV assembly deficiency (SCO2) Mitochondrial complex IV assembly deficiency (SURF1) Leigh Syndrome with French-­Canadian Ethnicity TACO1 deficiency PET100 deficiency FASTKD2 deficiency CEP89 deficiency Mitochondrial complex IV assembly deficiency (COX14) Mitochondrial complex I subunit deficiency (NDUFA4) Mitochondrial ATP synthase F1 subunit a deficiency Mitochondrial ATP synthase F1 subunit δ deficiency Mitochondrial ATP synthase F1 subunit e deficiency Mitochondrial complex V subunit deficiency (MTATP6) DAPIT deficiency Transmembrane protein 70 deficiency Mitochondrial complex V assembly deficiency (ATPAF2) Mitochondrial cytochrome b deficiency Mitochondrial cytochrome c1 deficiency Mitochondrial Depletion Syndrome 4A Mitochondrial DNA polymerase g accessory subunit deficiency Mitochondrial deoxyguanosine kinase deficiency MPV17 deficiency Mitochondrial thymidine kinase 2 deficiency Mitochondrial ribonucelotide reductase subunit 2 deficiency Thymidine phosphorylase deficiency Mitochondrial ribonuclease H1 deficiency FBXL4 deficiency Mitochondrial RNA import protein deficiency Ribonuclease P 5′ tRNA processing enzyme deficiency Ribonuclease Z 3′ tRNA processing enzyme deficiency Mitochondrial methionyl-tRNA formyltransferase deficiency tRNA 5-taurinomethyluridine modifier deficiency tRNA 5-carboxymethylaminomethyl transferase deficiency Pseudouridine synthase 1 deficiency tRNA methyltransferase 5 deficiency Mitochondrial poly(A) exoribonuclease deficiency Mitochondrial ribosomal large subunit 3 deficiency Mitochondrial ribosomal small subunit 2 deficiency Combined Oxidative Phosphorylation Defect 2 Combined Oxidative Phosphorylation Defect 5 Mitochondrial ribosomal small subunit 14 deficiency Mitochondrial ribosomal small subunit 7 deficiency Mitochondrial ribosomal large subunit 12 deficiency Mitochondrial ribosomal small subunit 28 deficiency

Gene MTCO1 MTCO2 MTCO3 COX6B1 COX7B COX5A COA6 COX10 COX15 COX20 SCO1 SCO2 SURF1 LRPPRC TACO1 PET100 FASTKD2 CEP89 COX14 NDUFA4 ATP5F1A ATP5F1D ATP5F1E MTATP6 ATP5MD TMEM70 ATPAF2 MTCYB CYC1 POLG POLG2 DGUOK MPV17 TK2 RRM2B TYMP RNASEH1 FBXL4 PNPT1 TRMT10C ELAC2 MTFMT GTPBP3 MTO1 PUS1 TRMT5 PDE12 MRPL3 MRPS2 MRPS16 MRPS22 MRPS14 MRPS7 MRPL12 MRPS28 (continued)

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Table 2.7 (continued) Name RMND1 deficiency Combined Oxidative Phosphorylation Defect 1 Combined Oxidative Phosphorylation Defect 3 Combined Oxidative Phosphorylation Defect 4 Combined Oxidative Phosphorylation Defect 7 Mitochondrial tRNA(Arg) deficiency Mitochondrial tRNA(Asn) deficiency Mitochondrial tRNA(Cys) deficiency Mitochondrial tRNA(Glu) deficiency Mitochondrial tRNA(Gly) deficiency Mitochondrial tRNA(Ile) deficiency Mitochondrial tRNA(Leu) 1 deficiency Mitochondrial tRNA(Lys) deficiency Mitochondrial tRNA(Met) deficiency Mitochondrial tRNA(Phe) deficiency Mitochondrial tRNA(Thr) deficiency Mitochondrial tRNA(Trp) deficiency Mitochondrial arginine-tRNA synthetase deficiency Mitochondrial asparaginyl-tRNA synthetase deficiency Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation Mitochondrial cysteinyl-tRNA synthetase deficiency Mitochondrial glutamyl-tRNA synthetase deficiency Mitochondrial leucyl-tRNA synthetase deficiency Mitochondrial phenylalanyl-tRNA synthetase deficiency Mitochondrial seryl-tRNA synthetase deficiency Mitochondrial tyrosyl-tRNA synthetase deficiency Mitochondrial tryptophanyl-tRNA synthetase deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit A deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit C deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit B deficiency Mitochondrial threonyl-tRNA synthetase deficiency Peroxisomal and mitochondrial fission defect Mitochondrial fission factor deficiency STAT2 deficiency Optic Atrophy 1 and Deafness Acylglycerol kinase deficiency MEGDEL Syndrome Tafazzin deficiency TIMM50 deficiency GFER deficiency Mitochondrial processing peptidase β deficiency Mitochondrial intermediate peptidase deficiency CLPB deficiency HSP60 deficiency HTRA2 deficiency Pitrilysin metallopeptidase 1 deficiency YME1L1 deficiency Mitochondrial inorganic pyrophosphatase 2 deficiency Sideroflexin 4 deficiency Combined Oxidative Phosphorylation Defect 6 C1q binding protein deficiency MICOS complex subunit MIC13 deficiency Mitochondrial thioredoxin 2 deficiency CoQ2 deficiency CABC1/ADCK3 deficiency CoQ9 deficiency

Gene RMND1 GFM1 TSFM TUFM C12ORF65 MTTR MTTN MTTC MTTE MTTG MTTI MTTL1 MTTK MTTM MTTF MTTT MTTW RARS2 NARS2 DARS2 CARS2 EARS2 LARS2 FARS2 SARS2 YARS2 WARS2 QRSL1 GATC GATB TARS2 DNM1L MFF STAT2 OPA1 AGK SERAC1 TAZ TIMM50 GFER PMPCB MIPEP CLPB HSPD1 HTRA2 PITRM1 YMEL1 PPA2 SFXN4 AIFM1 C1QBP MICOS13 TXN2 COQ2 COQ8A COQ9

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Table 2.7 (continued) Name Disorders of lipids Carnitine acylcarnitine translocase deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Trifunctional protein deficiency TANGO2 deficiency Cytosolic acetoacetyl-CoA thiolase deficiency Mitochondrial acetyl-CoA carboxylase 2 deficiency Congenital disorders of glycosylation Heparan sulfate 6-O-sulfotransferase 2 deficiency COG6-CDG Creatinine ↓ Disorders of nitrogen-containing compounds Arginine:glycine amidinotransferase deficiency Guanidinoacetate methyltransferase deficiency Ornithine aminotransferase deficiency Creatinine ↑ Disorders of nitrogen-containing compounds Lysinuric protein intolerance Prolidase deficiency Sarcosine oxidase deficiencyc Disorders of vitamins, cofactors, metals, and minerals Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Methylmalonic aciduria, cblB type Methylmalonic aciduria and homocystinuria, cblC type Disorders of carbohydrates Transaldolase deficiency Disorders of lipids Lecithin cholesterol acyl transferase deficiency Lipoprotein glomerulopathy Storage disorders Fabry disease Galactosialidosis Nephropathic cystinosis Disorders of peroxisomes and oxalate Alanine-glyoxylate aminotransferase deficiency Glyoxylate reductase/hydroxypyruvate reductase deficiency 4-hydroxy-2-oxoglutarate aldolase deficiency Acidosis (inc. ketoacidosis and lactic acidosis) Disorders of nitrogen-containing compounds Glutathione synthetase deficiency, severe 5-Oxoprolinase deficiency Mitochondrial sulfur dioxygenase deficiency Maple syrup urine disease Isovaleryl-CoA dehydrogenase deficiency 3-Methylcrotonyl-CoA carboxylase 1 and 2 deficiency 3-Methylglutaconyl-CoA hydratase deficiency 3-Hydroxyisobutyryl-CoA deacylase deficiency HSD10 disease 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency Propionyl-CoA-carboxylase deficiency Methylmalonyl-CoA mutase deficiency Combined MMA and MA Malonyl-CoA decarboxylase deficiency 3-Hydroxyisobutyrate dehydrogenase deficiency 2-Aminoadipic 2-oxoadipic aciduria

Gene SLC25A20 HADHA HADHB TANGO2 ACAT2 ACACB HS6ST2 COG6

GATM GAMT OAT

SLC7A7 PEPD SDH MMUT MMAB MMACHC TALDO LCAT APOE GLA CTSA CTNS AGXT GRHPR HOGA1

GSS OPLAH ETHE1 BCKDHA, BCKDHB, DBT IVD MCCC1/2 AUH HIBCH HSD17B10 HMGCL PCCA, PCCB MMUT ACSF3 MLYCD HIBADH DHTKD1 (continued)

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Table 2.7 (continued) Name Disorders of vitamins, cofactors, metals, and minerals Adenosylcobalamin synthesis defect—cblD-MMA Adenosylcobalamin synthesis defect—cbl A/B Multiple acyl-CoA dehydrogenase deficiency DH 2,4-dienoyl-CoA reductase deficiency with hyperlysinemia Mitochondrial coenzyme A transporter deficiency Mitochondrial disorders of energy metabolism Pyruvate dehydrogenase complex deficiency E1a Pyruvate dehydrogenase complex deficiency E1b Pyruvate dehydrogenase complex deficiency E2 Pyruvate dehydrogenase complex deficiency E3 X Pyruvate dehydrogenase complex deficiency PDHP ATP-specific succinyl-CoA ligase β subunit deficiency GTP-specific succinyl-CoA ligase α subunit deficiency Fumarase deficiency 2-Oxoglutarate dehydrogenase deficiency SAM transporter deficiency Mitochondrial complex I subunit deficiency (NDUFV2) Mitochondrial complex I subunit deficiency (NDUFS1) Mitochondrial complex I subunit deficiency (NDUFS4) Mitochondrial complex I subunit deficiency (NDUFS6) Mitochondrial complex I subunit deficiency (NDUFA1) Mitochondrial complex I subunit deficiency (NDUFA9) Mitochondrial complex I subunit deficiency (NDUFB3) NADH dehydrogenase β subcomplex subunit 8 deficiency Mitochondrial complex I subunit deficiency (NDUFB11) Mitochondrial complex I subunit deficiency (MTND6) NADH dehydrogenase α subcomplex subunit 6 deficiency Mitochondrial complex I subunit deficiency (NDUFB9) Mitochondrial complex I subunit deficiency (NDUFA11) Mitochondrial complex I assembly deficiency (NDUFAF1) Mitochondrial complex I assembly deficiency (NDUFAF4) Mitochondrial complex I assembly deficiency (NDUFAF5) Mitochondrial complex I assembly deficiency (NDUFAF6) Mitochondrial complex I assembly deficiency (FOXRED1) Mitochondrial complex III subunit deficiency (UQCRB) Mitochondrial complex III assembly deficiency (UQCRC2) GRACILE syndrome Mitochondrial complex III assembly deficiency (UQCC3) Mitochondrial ATP synthase F1 subunit δ and e deficiency Transmembrane protein 70 deficiency Mitochondrial cytochrome c1 deficiency FBXL4 deficiency tRNA 5-carboxymethylaminomethyl transferase deficiency tRNA methyltransferase 5 deficiency Mitochondrial poly(A) exoribonuclease deficiency Mitochondrial ribosomal small subunit 28 deficiency RMND1 deficiency Mitochondrial tRNA(Cys) deficiency Mitochondrial tRNA(Met) deficiency Mitochondrial leucyl-tRNA synthetase deficiency Mitochondrial phenylalanyl-tRNA synthetase deficiency Mitochondrial tryptophanyl-tRNA synthetase deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit C deficiency UGO-1 like protein deficiency Tafazzin deficiency Mitochondrial intermediate peptidase deficiency

Gene MMADHC MMAA/B ETFA, ETFB, ETFDH NADK2 SLC25A42 PDHA1 PDHB DLAT PDHX PDP1 SUCLA2 SUCLG1 FH OGDH SLC25A26 NDUFV2 NDUFS1 NDUFS4 NDUFS6 NDUFA1 NDUFA9 NDUFB3 NDUFB8 NDUFB11 MTND6 NDUFA6 NDUFB9 NDUFA11 NDUFAF1 NDUFAF4 NDUFAF5 NDUFAF6 FOXRED1 UQCRB UQCRC2 BCS1L UQCC3 ATP5F1D/E TMEM70 CYC1 FBXL4 MTO1 TRMT5 PDE12 MRPS28 RMND1 MTTC MTTM LARS2 FARS2 WARS2 GATC SLC25A46 TAZ MIPEP

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Table 2.7 (continued) Name Mitochondrial inorganic pyrophosphatase 2 deficiency Sideroflexin 4 deficiency CoQ9 deficiency Disorders of lipids Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Trifunctional protein deficiency Succinyl-CoA:3-oxoacid CoA transferase deficiency Beta-Ketothiolase deficiency Monocarboxylate transporter-1 deficiency Mitochondrial acetyl-CoA carboxylase 2 deficiency Alkalosis Disorders of nitrogen-containing compounds Urea cycle disorders Mitochondrial disorders of energy metabolism Mitochondrial seryl-tRNA synthetase deficiency Disorders of lipids Glucocorticoid receptor deficiency Congenital adrenal hyperplasia, 17-alpha-hydroxylase def. Congenital adrenal hyperplasia, 11-β-hydroxylase deficiency 11-β-hydroxysteroid dehydrogenase type 2 deficiency Total cholesterol ↓ Disorders of nitrogen-containing compounds Malonyl-CoA decarboxylase deficiency Mitochondrial disorders of energy metabolism Tafazzin deficiency Disorders of lipids Microsomal triglyceride transfer protein deficiency Chylomicron retention disease Familial hypobetalipoproteinemia type 1 Familial hypobetalipoproteinemia type 2 Mevalonate kinase deficiency Squalene synthase deficiencyl Smith-Lemli-Opitz syndrome 3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency Peroxisomal branched-chain acyl-CoA oxidase deficiency Storage disorders Gaucher disease Congenital disorders of glycosylation PMM2-CDG MPI-CDG ALG9-CDG ALG12-CDG ALG6-CDG B4GALT1-CDG Total cholesterol ↑ Disorders of carbohydrates Glucose-6-phosphatase deficiency Glucose-6-phosphate transporter deficiency Liver glycogen phosphorylase deficiency Hepatic phosphorylase kinase α2 subunit deficiency Disorders of lipids LDL receptor deficiency LDL receptor adaptor protein 1 deficiency Hypercholesterolemia due to ligand-defective apoB PCSK9 superactivity STAP1 deficiency

Gene PPA2 SFXN4 COQ9 HADHA HADHB OXCT1 ACAT1 SLC16A1 ACACB

Several SARS2 NR3C1 CYP17A1 CYP11B1 HSD11B2

MLYCD TAZ MTTP SAR1B APOB ANGPTL3 MVK FDFT1 DHCR7 HSD3B7 ACOX2 GBA PMM2 MPI ALG9 ALG12 ALG6 B4GALT1

G6PC SLC37A4 PYGL PHKA2 LDLR LDLRAP1 APOB PCSK9 STAP1 (continued)

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Table 2.7 (continued) Name Sitosterolemia due to ABCG5 deficiency Sitosterolemia due to ABCG8 deficiency Apolipoprotein E deficiency Hepatic lipase deficiency Cholesterol 7 alpha-hydroxylase deficiency Storage disorders Acid sphingomyelinase deficiency Lysosomal acid lipase deficiency Congenital disorders of glycosylation TMEM199-CDG CCDC115-CDG ATP6AP1-CDG Triglycerides ↑ Disorders of carbohydrates Fanconi-Bickel syndrome Fructose-1-phosphate aldolase deficiency Glucose-6-phosphate translocase deficiency Glycogen storage disease type III Liver glycogen phosphorylase deficiency Hepatic phosphorylase kinase α2 subunit deficiency Phosphorylase kinase β subunit deficiency Hepatic phosphorylase kinase γ2 subunit deficiency Glucose-6-phosphatase deficiency Fructose-1,6-bisphosphatase deficiency Disorders of lipids Angiopoietin-like 3 deficiency Chylomicron retention disease Apolipoprotein E deficiency Apolipoprotein E superactivity Lipoprotein glomerulopathy Lipoprotein lipase deficiency Apolipoprotein C2 deficiency GPIHBP1 deficiency Hepatic lipase deficiency Lipase maturation factor 1 deficiency Apolipoprotein A5 deficiency Familial LCAT deficiency (complete) Tangier disease Storage disorders Lysosomal acid lipase deficiency Congenital disorders of glycosylation PIGA-CDG ASAT and ALAT (transaminases) ↑ Disorders of nitrogen-containing compounds Carbamoylphosphate synthetase 1 deficiency Ornithine transcarbamylase deficiency Argininosuccinate synthetase deficiency Argininosuccinate lyase deficiency Arginase 1 deficiency Mitochondrial ornithine transporter deficiency Citrin deficiency Lysinuric protein intolerance Tyrosinemia type 1 Glycine N-methyltransferase deficiency S-adenosylhomocysteine hydrolase deficiency Adenosine kinase deficiency 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency

Gene ABCG5 ABCG8 APOE LIPC CYP7A1 SMPD1 LIPA TMEM199 CCDC115 ATP6AP1

SLC2A2 ALDOB SLC37A4 AGL PYGL PHKA2 PHKB PHKG2 G6PC FBP1 ANGPTL3 SAR1B APOE APOE APOE LPL APOC2 GPIHBP1 LIPC LMF1 APOA5 LCAT ABCA1 LIPA PIGA

CPS1 OTC ASS1 ASL ARG1 SLC25A15 SLC25A13 SLC7A7 FAH GNMT AHCY ADK HMGCL

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31

Table 2.7 (continued) Name Disorders of vitamins, cofactors, metals, and minerals ISD11 deficiency Multiple acyl-CoA dehydrogenase deficiency Wilson disease MEDNIK syndrome Hereditary hemochromatosis (type 1) Hypermanganesemia with dystonia type 1 Disorders of carbohydrates Fanconi-Bickel syndrome Galactose-1-phosphate uridyltransferase deficiency Uridine diphosphate galactose-4-­epimerase deficiency Fructose-1-phosphate aldolase deficiency Transaldolase deficiency Amylo-1,6-glucosidase (debrancher) deficiency Glycogen branching enzyme deficiency Liver glycogen phosphorylase deficiency Hepatic phosphorylase kinase α2 subunit deficiency Phosphorylase kinase β subunit deficiency Hepatic phosphorylase kinase γ2 subunit deficiency Glycogen storage disease type II b Glucose-6-phosphatase deficiency Mitochondrial disorders of energy metabolism GTP-specific succinyl-CoA ligase α subunit deficiency Mitochondrial complex III assembly deficiency (UQCRC2) Mitochondrial deoxyguanosine kinase deficiency Mitochondrial transcription factor A deficiency Mitochondrial ribosomal small subunit 2 deficiency Mitochondrial ribosomal small subunit 16 deficiency Mitochondrial ribosomal small subunit 28 deficiency Mitochondrial ribosomal large subunit 3 deficiency Mitochondrial valyl-tRNA synthetase deficiency Disorders of lipids Trifunctional protein β subunit deficiency 3-Hydroxy-3-methylglutaryl-CoA synthase deficiency Chanarin-Dorfman syndrome 3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency Δ4-3-Oxosteroid-5β-reductase deficiency Oxysterol 7α-hydroxylase deficiency Congenital bile acid synthesis defect Disorders of peroxisomes and oxalate Zellweger spectrum disorders Congenital disorders of glycosylation PMM2-CDG MPI-CDG ALG3-CDG Dolichol-P-mannose synthase-2 deficiency DPM2-CDG Phosphoglucomutase 1 deficiency PGM1-CDG COG4-CDG ATP6AP1-CDG TMEM199-CDG CCDC115-CDG Congenital disorder of glycosylation TMEM165-CDG N-glycanase 1 deficiency

Gene LYRM4 ETFDH, ETFA, ETFB ATP7B AP1S1 HFE SLC30A10 SLC2A2 GALT GALE ALDOB TALDO1 AGL GBE1 PYGL PHKA2 PHKB PHKG2 LAMP2 G6PC SUCLG1 UQCRC2 DGUOK TFAM MRPS2 MRPS16 MRPS28 MRPL3 VARS HADHB HMGCS2 ABHD5 HSD3B7 AKR1D1 CYP7B1 ABCD3 PEX1 and other PEX genes PMM2 MPI ALG3 DPM2 PGM1 COG4 ATP6AP1 TMEM199 CCDC115 TMEM165 NGLY1 (continued)

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Table 2.7 (continued) Name Creatine kinase (CK) ↑ Disorders of nitrogen-containing compounds Adenosine monophosphate deaminase deficiency S-adenosylhomocysteine hydrolase deficiency Adenosine kinase deficiency 3-Methylglutaconyl-CoA hydratase deficiency Disorders of vitamins, cofactors, metals, and minerals ISCA1 deficiency ISCU deficiency NFS1 deficiency Ferredoxin 2 deficiency Multiple acyl-CoA dehydrogenase deficiency Mitochondrial coenzyme A transporter deficiency Disorders of carbohydrates Lysosomal alpha-1,4-glucosidase deficiency Amylo-1,6-glucosidase (debrancher) deficiency Muscle phosphorylase deficiency Muscle phosphorylase kinase deficiency Constitutional AMP-activated protein kinase activation LAMP2 deficiency Muscle phosphofructokinase deficiency Aldolase A deficiency Muscle phosphoglycerate kinase deficiency Muscle phosphoglycerate mutase deficiency Beta-enolase deficiency Lactate dehydrogenase A deficiency Mitochondrial disorders of energy metabolism Mitochondrial complex I subunit deficiency (NDUFS6) Acyl-CoA Dehydrogenase 9 deficiency Transmembrane protein 70 deficiency Mitochondrial cytochrome b deficiency Mitochondrial DNA polymerase gamma accessory subunit deficiency Mitochondrial thymidine kinase 2 deficiency DNA2 helicase deficiency Mitochondrial ribonuclease H1 deficiency Mitochondrial elongation factor Ts deficiency Mitochondrial tRNA(Ala) deficiency Mitochondrial tRNA(Asp) deficiency Mitochondrial tRNA(Glu) deficiency Mitochondrial tRNA(Gly) deficiency Mitochondrial tRNA(Leu) 1 deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit A deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit C deficiency MSTO1 deficiency Tafazzin deficiency Valosin-containing protein superactivity Pitrilysin metallopeptidase 1 deficiency C1q binding protein deficiency Mitochondrial calcium uniporter deficiency CHCHD10 deficiency CoQ2 deficiency Disorders of lipids Primary carnitine deficiency Carnitine palmitoyltransferase 2 deficiency Carnitine acylcarnitine translocase deficiency Very long-chain acyl CoA dehydrogenase deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Gene

AMPD1 AHCY ADK AUH ISCA1 ISCU NFS1 FDX2 ETFDH, ETFA, ETFB SLC25A42 GAA AGL PYGM PHKA1 PRKAG2 LAMP2 PFKM ALDOA PGK1 PGAM2 ENO3 LDHA NDUFS6 ACAD9 TMEM70 MTCYB POLG2 TK2 DNA2 RNASEH1 TSFM MTTA MTTD MTTE MTTG MTTL1 QRSL1 GATC MSTO1 TAZ VCP PITRM1 C1QBP MICU1 CHCHD10 COQ2 SLC22A5 CPT2 SLC25A20 ACADVL HADHA

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Table 2.7 (continued) Name Trifunctional protein deficiency TANGO2 deficiency Lipin 1 deficiency Chanarin-Dorfman syndrome Adipose triglyceride lipase deficiency Chylomicron retention disease Mevalonate kinase deficiency X-linked spinal and bulbar muscular atrophy, Kennedy disease Congenital disorders of glycosylation DPAGT1-CDG ALG14-CDG ALG2-CDG RFT1-CDG B4GALT1-CDG POMT1-CDG POMT2-CDG POMGNT1-CDG B3GALNT2-CDG POMK-CDG ISPD-CDG FKRP-CDG FKTN-CDG RXYLT1-CDG B4GAT1-CDG LARGE1-CDG DPM1-CDG DPM2-CDG DPM3-CDG MPDU1-CDG GNE myopathy GFPT1-CDG PGM1-CDG GMPPB-CDG COG6-CDG COG7-CDG COG8-CDG TRAPPC11-CDG TMEM165-CDG Lactate dehydrogenase (LDH) ↑ Disorders of nitrogen-containing compounds Lysinuric protein intolerance Disorders of vitamins, cofactors, metals, and minerals Dihydrofolate reductase deficiency Disorders of carbohydrates Glucose-6-phosphate dehydrogenase deficiency Mitochondrial disorders of energy metabolism Pitrilysin metallopeptidase 1 deficiency Alkaline phosphatase (ALP) ↑ Disorders of nitrogen-containing compounds Sodium-dependent multivitamin transporter deficiency Disorders of carbohydrates Transaldolase deficiency Mitochondrial disorders of energy metabolism Valosin-containing protein superactivity

Gene HADHB TANGO2 LPIN1 ABHD5 PNPLA2 SAR1B MVK AR DPAGT1 ALG14 ALG2 RFT1 B4GALT1 POMT1 POMT2 POMGNT1 B3GALNT2 POMK ISPD FKRP FKTN RXYLT1 B4GAT1 LARGE1 DPM1 DPM2 DPM3 MPDU1 GNE GFPT1 PGM1 GMPPB COG6 COG7 COG8 TRAPPC11 TMEM165

SLC7A7 DHFR G6PD PITRM1

SLC5A6 TALDO1 VCP (continued)

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Table 2.7 (continued) Name Disorders of lipids 3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency Δ4-3-Oxosteroid-5β-reductase deficiency Oxysterol 7α-hydroxylase deficiency Peroxisomal branched-chain acyl-CoA oxidase deficiency Bile acid-CoA:aminoacid N-acyl transferase deficiency Congenital disorders of glycosylation PIGA-CDG PIGH-CDG PIGW-CDG PIGN-CDG PIGO-CDG PIGT-CDG GPAA1-CDG PGAP1-CDG PGAP3-CDG PGAP2-CDG PIGB-CDG PIGY-CDG Component of COG complex 4 deficiency COG4-CDG ATP6AP1-CDG TMEM199-CDG CCDC115-CDG Alkaline phosphatase (ALP) ↓ Disorders of vitamins, cofactors, metals, and minerals Congenital hypophosphatasia Acrodermatitis enteropathica Urea ↓ Disorders of nitrogen-containing compounds Ornithine transcarbamylase deficiency Argininosuccinate synthetase deficiency Argininosuccinate lyase deficiency Arginase 1 deficiency Mitochondrial ornithine transporter deficiency Urea ↑ Disorders of vitamins, cofactors, metals, and minerals Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Methylmalonic aciduria, cblB type Methylmalonic aciduria and homocystinuria, cblC type Disorders of carbohydrates Transaldolase deficiency Disorders of lipids Lecithin cholesterol acyl transferase deficiency Disorders of peroxisomes and oxalate Peroxisomal alanine-glyoxylate aminotransferase deficiency Glyoxylate reductase/hydroxypyruvate reductase deficiency Mitochondrial 4-hydroxy-2-­oxoglutarate aldolase deficiency Uric acid ↑ Disorders of nitrogen-containing compounds Phosphoribosyl pyrophosphate synthetase 1 superactivity Hypoxanthine guanine phosphoribosyltransferase deficiency Methylmalonyl-CoA mutase deficiency Disorders of carbohydrates Fanconi-Bickel syndrome Fructose-1-phosphate aldolase deficiency Glucose-6-phosphate translocase deficiency

Gene HSD3B7 AKR1D1 CYP7B1 ACOX2 BAAT PIGA PIGH PIGW PIGN PIGO PIGT GPAA1 PGAP1 PGAP3 PGAP2 PIGB PIGY COG4 ATP6AP1 TMEM199 CCDC115

ALPL SLC39A4

OTC ASS1 ASL ARG1 SLC25A15

MMUT MMAB MMACHC TALDO LCAT AGXT GRHPR HOGA1

PRPS1 HPRT1 MMUT SLC2A2 ALDOB SLC37A4

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Table 2.7 (continued) Name Amylo-1,6-glucosidase (debrancher) deficiency Muscle phosphorylase deficiency Liver glycogen phosphorylase deficiency Muscle phosphorylase kinase deficiency Glucose-6-phosphatase deficiency Fructose-1,6-bisphosphatase deficiency Muscle phosphofructokinase deficiency Muscle phosphoglycerate mutase deficiency Lactate dehydrogenase A deficiency Mitochondrial disorders of energy metabolism Mitochondrial seryl-tRNA synthetase deficiency Uric acid ↓ Disorders of nitrogen-containing compounds

Gene AGL PYGM PYGL PHKA1 G6PC FBP1 PFKM PGAM2 LDHA

Pyrimidine 5′-nucleotidase superactivity Purine nucleoside phosphorylase deficiency Xanthine oxidase deficiency Urate transporter 1 deficiency Urate voltage-driven efflux transporter 1 deficiency Disorders of vitamins, cofactors, metals, and minerals Molybdenum cofactor deficiency A Molybdenum cofactor deficiency B Molybdenum cofactor deficiency C Molybdenum cofactor sulfurase deficiency Storage disorders Nephropathic cystinosis Ferritin ↑ Disorders of nitrogen-containing compounds Lysinuric protein intolerance Mitochondrial glycine transporter deficiency Disorders of vitamins, cofactors, metals, and minerals Glutaredoxin 5 deficiency Hereditary hemochromatosis Aceruloplasminemia Hyperferritinemia-cataract syndrome Mitochondrial disorders of energy metabolism GRACILE syndrome Mitochondrial deoxyguanosine kinase deficiency Storage disorders Gaucher disease Disorders of tetrapyrroles Erythroid 5-aminolevulinate synthase deficiency Ferritin ↓ Disorders of vitamins, cofactors, metals, and minerals Hypermanganesemia with dystonia type 1 Disorders of tetrapyrroles Ferrochelatase deficiency Erythroid 5-aminolevulinate synthase superactivity Myoglobin (urine) ↑ Disorders of vitamins, cofactors, metals, and minerals ISCU deficiency Ferredoxin 2 deficiency Disorders of carbohydrates Muscle phosphorylase deficiency Muscle phosphorylase kinase deficiency Muscle phosphofructokinase deficiency

NT5C3A

SARS2

PNP XDH SLC22A12 SLC2A9 MOCS1 MOCS2 GPHN MOCOS CTNS

SLC7A7 SLC25A38 GLRX5 HFE, HFE2, HAMP, TFR2 CP FTL BCS1L DGUOK GBA ALAS2

SLC30A10 FECH ALAS2

ISCU FDX2 PYGM PHKA1 PFKM (continued)

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Table 2.7 (continued) Name Muscle phosphoglycerate kinase deficiency Muscle phosphoglycerate mutase deficiency Beta-enolase deficiency Lactate dehydrogenase A deficiency Mitochondrial disorders of energy metabolism Mitochondrial cytochrome B deficiency Disorders of lipids Carnitine palmitoyltransferase 2 deficiency Carnitine acylcarnitine translocase deficiency Very long-chain acyl CoA dehydrogenase deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Trifunctional protein deficiency TANGO2 deficiency Lipin 1 deficiency Congenital disorders of glycosylation PGM1-CDG GMPPB-CDG Hemoglobin ↓ (anemia) Disorders of nitrogen-containing compounds CAD trifunctional protein deficiency 50 CAD-CDG Orotate phosphoribosyltransferase deficiency Pyrimidine-5′-nucleotidase I deficiency Adenylate kinase 1 deficiency Gamma-glutamylcysteine synthetase deficiency Glutathione synthetase deficiency Lysinuric protein intolerance Isobutyryl-CoA dehydrogenase deficiency Propionyl-CoA-carboxylase deficiency PCCA Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Prolidase deficiency Mitochondrial glycine transporter deficiency Disorders of vitamins, cofactors, metals, and minerals Glutaredoxin 5 deficiency ABCB7 deficiency Ferredoxin 2 deficiency Intrinsic factor deficiency Cubilin deficiency Amnionless deficiency Transcobalamin II deficiency Methylmalonic aciduria and homocystinuria, cblF type Methylmalonic aciduria and homocystinuria, cblJ type Methylmalonic aciduria and homocystinuria, cblC type Epi-cblC cblD disease Methionine synthase reductase deficiency Methionine synthase deficiency Proton-coupled folate transporter (PCFT) deficiency 5,10-Methylene-tetrahydrofolate dehydrogenase deficiency Dihydrofolate reductase deficiency Thiamine-responsive megaloblastic anemia syndrome Wilson disease Atransferrinemia Disorders of carbohydrates Glucose transporter 1 deficiency Galactose-1-phosphate uridyltransferase deficiency Glucose-6-phosphate dehydrogenase deficiency Transaldolase deficiency

Gene PGK1 PGAM2 ENO3 LDHA MT-CYB CPT2 SLC25A20 ACADVL HADHA HADHB TANGO2 LPIN1 PGM1 GMPPB

CAD UMPS NT5C3A AK1 GCLC GSS SLC7A7 ACAD8 PCCA, PPCB MMUT PEPD SLC25A38 GLRX5 ABCB7 FDX2 CBLIF CUBN AMN TCN2 LMBRD1 ABCD4 MMACHC MMACHC + PRDX1 MMADHC MTRR MTR SLC46A1 MTHFD1 DHFR SLC19A2 ATP7B TF SLC2A1 GALT G6PD TALDO1

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Table 2.7 (continued) Name HOIL1 interacting protein deficiency Muscle phosphofructokinase deficiency Aldolase A deficiency Triosephosphate isomerase deficiency Muscle phosphoglycerate kinase deficiency Pyruvate kinase deficiency Mitochondrial disorders of energy metabolism Mitochondrial dicarboxylate transporter deficiency NADH dehydrogenase beta subcomplex subunit 11 deficiency TMEM126B deficiency COX10 deficiency Mitochondrial ATP synthase F0 subunit 6 deficiency CCA-adding tRNA-­nucleotidyltransferase deficiency Pseudouridine synthase 1 deficiency Mitochondrial oxodicarboxylate carrier deficiency Mitochondrial leucyl-tRNA synthetase deficiency Mitochondrial phenylalanyl-tRNA synthetase deficiency Mitochondrial seryl-tRNA synthetase deficiency Mitochondrial tyrosyl-tRNA synthetase deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit A deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit C deficiency Mitochondrial glutamyl-­tRNA(Gln) amidotransferase subunit B deficiency DNAJC19 deficiency HSPA9 deficiency Sideroflexin 4 deficiency Disorders of lipids Thromboxane synthase deficiency Prostaglandin transporter deficiency Cytosolic phospholipase A2α deficiency Mevalonate kinase deficiency PMP70 deficiency Disorders of tetrapyrroles Erythroid 5-aminolevulinate synthase deficiency Uroporphyrinogen cosynthase deficiency Ferrochelatase deficiency GATA1 deficiency Heme oxygenase 1 deficiency Erythropoietic protoporphyria type 2 Storage disorders Gaucher disease Saposin C deficiency Lysosomal acid lipase deficiency, severe Mucopolysaccharidosis-plus Congenital disorders of glycosylation ALG8-CDG Glucose-6-phosphatase catalytic subunit 3 deficiency SEC23B-CDG Thrombocytopenia Disorders of nitrogen-containing compounds Lysinuric protein intolerance Isovaleryl-CoA dehydrogenase deficiency Propionyl-CoA-carboxylase deficiency Methylmalonyl-CoA mutase deficiency Prolidase deficiency Disorders of vitamins, cofactors, metals, and minerals 5,10-Methylene-tetrahydrofolate dehydrogenase deficiency

Gene RNF31 PFKM ALDOA TPI1 PGK1 PKLR SLC25A10 NDUFB11 TMEM126B COX10 MTATP6 TRNT1 PUS1 SLC25A21 LARS2 FARS2 SARS2 YARS2 QRSL1 GATC GATB DNAJC19 HSPA9 SFXN4 TBXAS1 SLCO2A1 PLA2G4A MVK ABCD3 ALAS2 UROS FECH GATA1 HMOX1 CLPX GBA PSAP LIPA VPS33A ALG8 G6PC3 SEC23B

SLC7A7 IVD PCCA, PCCB MMUT PEPD MTHFD1 (continued)

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Table 2.7 (continued) Name Thiamine-responsive megaloblastic anemia syndrome Wilson disease Disorders of carbohydrates Transaldolase deficiency Mitochondrial disorders of energy metabolism Mitochondrial cytochrome c deficiency Mitochondrial leucyl-tRNA synthetase deficiency Mitochondrial seryl-tRNA synthetase deficiency Disorders of lipids 3-Oxothiolase deficiency Thromboxane synthase deficiency Apolipoprotein E superactivity Mevalonate kinase deficiency Disorders of tetrapyrroles GATA1 deficiency Storage disorders Gaucher disease Saposin C deficiency Acid sphingomyelinase deficiency Congenital disorders of glycosylation ALG8-CDG STT3B-CDG Glucose-6-phosphatase catalytic subunit 3 deficiency SLC35A1-CDG Neutropenia Disorders of nitrogen-containing compounds Lysinuric protein intolerance Isovaleryl-CoA dehydrogenase deficiency Propionyl-CoA-carboxylase deficiency Methylmalonyl-CoA mutase deficiency Disorders of carbohydrates Glucose-6-phosphate translocase deficiency Mitochondrial disorders of energy metabolism Fumarase deficiency FBXL4 deficiency Tafazzin deficiency CLPB deficiency HTRA2 deficiency Disorders of lipids 3-Oxothiolase deficiency Disorders of tetrapyrroles GATA1 deficiency Congenital disorders of glycosylation PGM3-CDG Glucose-6-phosphatase catalytic subunit 3 deficiency Jagunal 1 deficiency Cohen syndrome Reticulocytosis Disorders of nitrogen-containing compounds Gamma-glutamylcysteine synthetase deficiency Glutathione synthetase deficiency Disorders of carbohydrates Glucose-6-phosphate dehydrogenase deficiency Muscle phosphofructokinase deficiency

Gene SLC19A2 ATP7B TALDO1 CYCS LARS2 SARS2 ACAT1 TBXAS1 APOE MVK GATA1 GBA PSAP SMPD1 ALG8 STT3B G6PC3 SLC35A1

SLC7A7 IVD PCCA, PCCB MMUT SLC37A4 FH FBXL4 TAZ CLPB HTRA2 ACAT1 GATA1 PGM3 G6PC3 JAGN1 VPS13B

GCLC GSS G6PD PFKM

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Table 2.7 (continued) Name Aldolase A deficiency Triosephosphate isomerase deficiency Muscle phosphoglycerate kinase deficiency Pyruvate kinase deficiency Disorders of vitamins, cofactors, metals, and minerals Wilson disease Disorders of tetrapyrroles GATA1 deficiency

Gene ALDOA TPI1 PGK1 PKLR ATP7B GATA1

Causes fasting hypoglycemia with postprandial hyperglycemia b Causes pseudohyperglycemia, as some point-of-care glucometers will falsely read galactose as glucose (discrepancy between capillary bedside glucose and venous glucose) c False elevation with the enzymatic method but not with Jaffé method a

is structured according to the proposed nosology of IEMs (Ferreira et al. 2019), and information on diseases and corresponding laboratory tests was obtained from the knowledgebase of IEMs (Lee et al. 2018). The same information can be found in most chapters of this book. Care should be taken to not only interpret one clinical chemistry test result but also always review the other test results which may guide the diagnostic algorithm in a logical direction. As an example, low blood glucose together with low plasma free fatty acids and the absence of ketones will most likely be the result of endocrine anomalies (hyperinsulinism), whereas sharply increased levels of the free fatty acids generally indicate defects of the mitochondrial fatty acid beta-oxidation.

References Duran M, Gibson KM.  Simple tests. In: Blau N, Duran M, Gibson KM, Dionisi-Vici C, editors. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Berlin-­ Heidelberg: Springer; 2014. p. 743–7. Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med. 2019;21:102–6. Lee JJY, Wasserman WW, Hoffmann GF, van Karnebeek CDM, Blau N. Knowledge base and mini-expert platform for the diagnosis of inborn errors of metabolism. Genet Med. 2018;20:151–8.

3

Amino Acids Marzia Pasquali and Nicola Longo

Contents Introduction

 41

Preanalytical Conditions

 42

Analysis

 45

Interpretation of Amino Acids Results and Reference Values

 47

References

 50

Summary

The measurement of amino acids in the blood, plasma, urine, and cerebrospinal fluid is essential for the diagnosis and monitoring of patients with different inherited metabolic diseases, including disorders of amino acid metabolism and transport, organic acidemias, and urea cycle defects. Measurement of amino acids in whole blood spotted on filter paper screens for many amino acidopathies and urea cycle defects in newborns. Plasma amino acids can identify patients with a suspected disorder of amino acid metabolism and/or aid in monitoring treatment. Urinary amino acids screen for disorders of amino acid transport (cystinuria, lysinuric protein intolerance, or Hartnup disease) or for generalized renal tubular dysfunction. The analysis of cerebrospinal fluid, usually in addition to plasma amino acids, is necessary in the evaluation of patients with neurometabolic disorders, such as glycine encephalopathy or disorders of serine metabolism. Traditionally, amino acids in biological fluids have been quantified by ion exchange chromatography using postM. Pasquali · N. Longo (*) University of Utah and ARUP Laboratories, Salt Lake City, UT, USA e-mail: [email protected]; [email protected]

column derivatization with ninhydrin and spectrophotometric detection. Newer methodologies are based on liquid chromatographic separation with detection by mass spectrometry or spectrophotometry. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of amino acids is becoming the method of choice by more and more laboratories because of its speed, sensitivity, and increased specificity. The interpretation of the results of plasma amino acid analysis requires the knowledge of metabolic disorders, availability of age-specific reference ranges, and consideration of physiological factors or medications affecting levels of individual or multiple amino acids.

Introduction Amino acids are the building block of all proteins and are therefore of vital importance for the integrity of the organism. In addition, some amino acids play an additional important role as neurotransmitters (or their precursors), modulators of neurotransmitter action, precursors of hormones, cofactors, purine, and pyrimidines. Amino

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_3

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acids, with a few exceptions, are water soluble due to the presence of both an amino and a carboxylic group that in water become ionized. Amino acids are filtered by the kidney and could be easily lost in urine in the absence of an efficient renal tubular reabsorption mechanism. There are several amino acid transporters whose deficiency can result in urinary loss of one or a group of amino acids and specific clinical manifestations. Excess amino acids are degraded by specific sets of enzymes, thereby generating energy and urea from the nitrogen group during catabolism. Defects in these enzymes cause inborn errors of amino acid metabolism, almost all of which are transmitted as autosomal recessive traits. This leads to either the buildup of the parent amino acid or its byproducts or of the catabolic products (organic acids) depending on the location of the enzyme block. The nitrogen group of the amino acid upon degradation will result in the formation of ammonia which is then removed by the urea cycle in the liver. The lack of an enzyme or transporter in this cycle will result in hyperammonemia. Accurate measurement of amino acids is essential to diagnose disorders of amino acid metabolism and to follow treatment in patients affected by aminoacidopathies, urea cycle disorders, organic acidemias, or disorders of amino acid transport. This chapter will discuss how amino acids are analyzed in biological fluids and the main alterations encountered in common disorders.

Preanalytical Conditions

M. Pasquali and N. Longo Table 3.1  Amino acid concentrations in plasma (μmol/L). The values represent the central 95% range of normal results by LC-MS/ MS.  Number of observations for each age group is indicated in parenthesis Amino acid Alanine α-Aminoadipate α-Aminobutyrate Arginine Asparagine Aspartic acid Citrulline Cystine Glutamic acid Glutamine Glycine Histidine Hydroxyproline Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Sarcosine Serine Taurine Threonine Tryptophan Tyrosine Valine

1 year (n = 4000) 160–530 ≤4 ≤40 35–125 20–80 ≤15 10–45 10–65 15–130 380–680 140–420 50–130 5–40 30–120 60–180 85–230 15–40 25–110 30–82 90–350 ≤5 60–170 30–130 60–190 25–80 35–110 120–320

Specimens Amino acids can be measured in different sample types (whole blood, plasma, cerebrospinal fluid, urine) depending upon the reason for the amino acids analysis. Whole blood spotted on filter paper is used almost universally for neonatal screening of inherited disorders of metabolism. Analysis of amino acids in plasma represents the first approach to the study of a patient with a suspected disorder of amino acid metabolism (Table  3.1) (Held et  al. 2011; Gregory et  al. 1986; Applegarth et al. 1979; Armstrong et al. 2007). This will identify elevated phenylalanine in phenylketonuria, elevated branched-chain amino acids, and the presence of alloisoleucine in maple syrup urine disease, abnormalities of citrulline, and glutamine in different urea cycle defects. The study of urinary amino acids is performed to screen for disorders of amino acids transport, such as cystinuria, lysinuric protein intolerance, or Hartnup disease (Table 3.2) (Parvy et al. 1988). In addition, it is a useful test for renal tubular capacity that becomes abnormal in most cases of renal Fanconi syndrome. The analysis of cerebrospinal fluid (CSF), usually in addition to plasma amino acids, is necessary in the evaluation of patients with neurometabolic disor-

ders, such as glycine encephalopathy or disorders of serine metabolism (Table 3.3) (Applegarth et al. 1979). Amino acids can be measured also in other biological specimens, such as vitreous fluid (Table  3.4) (Honkanen et al. 2003; Bertram et al. 2008), especially in post-mortem samples, when urine is often not available and blood is unsuitable. However, this type of analysis should be limited to laboratories with experience in these studies, since post-­mortem changes rapidly occur even in vitreous fluid. Amniotic fluid has limited value in prenatal diagnosis for aminoacidopathies. Unlike the organic acid disorders, in most amino acid disorders the metabolites do not accumulate before birth. Abnormal amino acid patterns in amniotic fluid have only been found in two of the urea cycle disorders, namely, argininosuccinate lyase deficiency (argininosuccinic acidemia) and argininosuccinate synthetase deficiency (citrullinemia type 1). Tables 3.1, 3.2, 3.3, and 3.4 (Held et al. 2011; Gregory et al. 1986; Applegarth et al. 1979; Armstrong et al. 2007; Parvy et al. 1988; Honkanen et al. 2003; Bertram et  al. 2008) list amino acid reference ranges in the blood, urine, CSF, and vitreous fluid and are included as examples. However, it should be noted that, even when using the same

3  Amino Acids

43

Table 3.2  Amino acid concentrations in urine expressed in μmol/g creatinine. The values represent the central 95% range of normal results by LC-MS/MS. Number of observations for each age group is indicated in parenthesis Amino acid Alanine a-Aminoadipate a-Aminobutyrate β-Aminoisobutyrate Arginine Asparagine Aspartic acid Citrulline Cystine Glutamic acid Glutamine Glycine Histidine Homocitrulline Hydroxyproline Isoleucine Leucine Lysine Methionine 3-Methylhistidine Ornithine Phenylalanine Phosphoethanolamine Proline Sarcosine Serine Taurine Threonine Thryptophan Tyrosine Valine

0–3 months (n = 133) 475–3330 ≤700 ≤120 ≤6680 ≤470 55–1445 ≤370 ≤145 ≤870 ≤560 380–3860 1620–19,725 325–4940 ≤675 ≤6100 ≤360 20–420 120–2270 ≤100 160–665 ≤475 45–360 ≤370 130–2340 ≤300 70–4125 95–9800 125–2890 25–395 50–870 40–425

3–12 months (n = 85) 270–3020 ≤520 ≤80 ≤6000 ≤340 45–910 ≤160 ≤75 ≤300 ≤360 310–3240 915–10,220 290–4850 ≤220 ≤1270 ≤140 20–195 55–1260 ≤60 155–390 ≤150 65–370 ≤485 ≤1190 ≤75 275–2730 ≤7400 50–1300 45–390 70–700 30–250

method and instrumentation, reference values may vary from laboratory to laboratory. Each laboratory should establish its own reference ranges.

Patient Status/Patient Information Clinical information is a necessary element for the accurate interpretation of amino acid profiles and to correctly diagnose patients with disorders of amino acid metabolism. Several common clinical features should prompt an investigation for a metabolic disorder. These include symptoms related to the CNS (lethargy, seizures, coma); GI tract (vomiting, poor feeding, failure to thrive); liver (hepatomegaly); cardiovascular, respiratory, and renal (kidney stones) systems; eye (lens dislocation, retinitis pigmentosa, optic atrophy); skeletal system; and skin. A positive family history (consanguineous parents, affected sibling or family member) and/or a positive newborn screen result should also initiate a

1–3 years (n = 82) 170–1750 ≤470 ≤70 ≤5500 ≤390 80–675 ≤65 ≤40 ≤150 ≤190 340–2225 775–6600 340–4420 ≤150 ≤100 ≤100 20–190 45–930 ≤50 150–555 ≤70 50–350 ≤440 ≤170 ≤25 390–1890 ≤9000 85–910 45–325 65–560 40–280

3–6 years (n = 67) 100–1000 ≤200 ≤60 ≤3490 ≤270 50–345 ≤25 ≤15 ≤125 ≤80 300–1525 600–4600 315–2460 ≤100 ≤35 ≤70 20–110 40–475 ≤30 130–540 ≤30 35–170 ≤235 ≤60 ≤25 260–990 ≤4400 50–380 35–150 40–300 30–160

6–12 years (n = 81) 80–930 ≤125 ≤50 ≤1720 ≤160 40–390 ≤25 ≤15 ≤100 ≤70 165–1530 310–5700 160–2380 ≤70 ≤20 ≤60 20–100 25–440 ≤30 120–440 ≤30 30–140 ≤150 ≤40 ≤25 130–1100 ≤3800 40–470 20–180 40–280 20–120

≥12 years (n = 445) 60–500 ≤100 ≤25 ≤1200 ≤100 25–180 ≤25 ≤15 ≤150 ≤52 100–665 230–3510 80–1130 ≤40 ≤30 ≤45 ≤45 ≤355 ≤20 100–340 ≤30 1 ≤60 ≤35 ≤25 90–470 ≤3200 25–250 15–95 15–150 ≤55

diagnostic metabolic work-up. One should keep in mind that the same disease may present with different symptoms at different ages and that inherited disorders of metabolism are not limited to infants and children, with late-onset diseases presenting in adulthood as well. In other words, a metabolic disorder should not be dismissed because of age. Routine chemistry laboratory tests, such as blood gases, pH, electrolytes, anion gap, glucose, and ammonia, provide clues to the kind of metabolic disorder and guide the testing. These laboratory data, along with a brief clinical history, should be made available to the metabolic laboratory for better interpretation of the results. The physiological status of the patient is also important, since significant variations can be seen in post-prandial specimen, after prolonged fasting, and during catabolism. A list of medications taken at the time of specimen collection should also be provided, since some may interfere with the analysis or may cause alterations in the concentration of some amino acids, such as increased glycine levels secondary to valproate therapy.

44

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Table 3.3  Normal range of amino acid concentrations in CSF, expressed in μmol/L, obtained by LC-MS/MS. The values represent the central 95% range of normal results by LC-MS/MS. Number of observations is indicated in parenthesis Amino acid Alanine Arginine Asparagine Aspartate Citrulline Cystine Glutamine Glutamic acid Glycine Histidine Hydroxyproline Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Taurine Threonine Tryptophan Tyrosine Valine

μmol/L (n = 921) 16–46 8–31 4–13 ≤5 ≤5 ≤5 330–630 ≤5 5–20 7–24 ≤4 ≤12 5–22 10–36 2–7 ≤10 6–20 ≤5 18–66 ≤13 14–59 ≤5 5–23 8–30

Table 3.4  Concentrations of amino acids in vitreous fluid (average ± SD, μmol/L). Modified from Honkanen et al. (2003); Bertram et al. (2008) Amino acid Alanine Arginine Asparagine Aspartate GABA Glutamate Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Serine Threonine Tyrosine Valine

μmol/L (n = 17) 159.5 ± 54.9 39.4 ± 16.3 35.8 ± 11.6 1.4 ± 1.0 0.6 ± 0.2 5.2 ± 2.3 1192.9 ± 404.4 8.5 ± 2.5 38.4 ± 10.0 37.9 ± 11.6 89.7 ± 28.4 115.4 ± 33.7 22.3 ± 8.1 44.4 ± 14.2 103.9 ± 24.4 85.5 ± 28.4 58.2 ± 18.8 112.0 ± 4.4

Specimen Collection The timing of the specimen collection is important in the detection of metabolic disorders. In acutely ill patients, the blood and urine specimens on admission are likely to be most revealing and most appropriate for metabolic screening. It is good practice to save these specimens from all patients in whom the diagnosis is unclear. For the detection of aminoacidopathies, this is not as critical as it is for other metabolic disorders. For amino acid analysis, the volume of specimen required depends on the methodology used, typically 100– 500 μL of plasma or CSF are required. The volume of urine required varies depending on creatinine concentration; each laboratory should list the minimum volumes acceptable for each analysis. For the diagnosis of most amino acid disorders, blood specimens collected after an overnight fast are preferred or, alternatively, at least 3 h after a meal. Samples from young infants should be collected immediately before the next scheduled feeding (at least 2–3 h after the last feeding). For hyperammonemia screening, postprandial samples are more suited since elevation of blood ammonia may be intermittent and present only in the fed state. It is not uncommon for a laboratory to receive a sample for amino acid analysis collected while the patient is receiving intravenous hyperalimentation. These samples are often uninterpretable as they show elevations in all the amino acids present in the IV solution. If it is possible, intravenous hyperalimentation should be discontinued for at least 2–3 h prior to specimen collection. If intravenous hyperalimentation cannot be discontinued, appropriate care should be taken in drawing the sample away from the site of entry of the solution. The concentration of the majority of the physiological amino acids is the same in red blood cells and in plasma, with exception of taurine, glutamate, aspartate, and argininosuccinate. Thus, hemolyzed samples may show an increased concentration of these amino acids. The enzyme arginase converts arginine into ornithine and urea and is expressed in red blood cells. Hemolysis will release arginase in the plasma causing hydrolysis of arginine. Therefore, a decrease in arginine with an increase in ornithine is often seen in hemolyzed samples. Whole blood collected for amino acids analysis should be spun down as soon as possible; the plasma should be kept frozen during transport and until analysis is performed. Refrigerated conditions may be acceptable for a short period of time. Improper handling of specimens can result in artifactual changes in the amino acid contents. Table 3.5 lists possible artifacts due to collection, handling, and storage of samples.

3  Amino Acids

45 Table 3.6  Nutritional status and amino acid values

Table 3.5  Collection, handling, and storage artifacts Factor/condition Contamination, bacterial Contamination, bacterial Contamination, fecal Contamination, protein Contamination, RBC Contamination, unwashed skin Contamination, WBC Contamination, WBC Hemolysis Hemolysis Serum vs. plasma Storage Storage Storage Storage Tube artifact, thrombin Tube artifact, EDTA Tube artifact, metasulfite Unspun blood left at rm. temp. Unspun blood left at rm. temp.

Source Amino acid(s) affected U Ala, Gly, Pro

Value ↑ H

U

↓ L

U

Trp, aromatic amino acids, Ser Pro, Glu, Leu, Ile, Val, OH-pro-line Cys

↓ L

U B

Orn Most amino acids

↑ H ↑ H

U B B B B U U

↑ H ↑ H ↑ H ↓ L

B B B

Tau Asp, Glu, Tau Asp, Glu, Gly, Orn Arg, Gln Serum Tau > plasma Tau Glu, Asp, GABA Gln, Asn, phosphoethanolamine Gln, Cys, homocystine Glu Gly

B B

Ninhydrin positive artifact S-sulfocysteine

↑ H

B

Orn, total homocysteine

↑ H

B

Arg, Cys, homocystine

↓ L

U

↑ H

↑ H ↓ L ↓ L ↑ H ↑ H

The conversion of arginine into ornithine by arginase can be observed even in unspun samples left at room temperature, even without obvious hemolysis. Free cystine and homocystine bind to protein and will be lost in samples that are not spun immediately and/or are stored for a prolonged period of time. The loss of cystine and homocystine is evident even when samples are stored at −20 °C, while storage at −70 °C prevents this effect. Glutamine is unstable and breaks down with prolonged storage resulting in increased glutamate. If serum is used for amino acids analysis, depending on how it has been obtained, all the artifacts listed above could be present. Low serine in urine may be due to bacterial contamination, and the presence of hydroxyproline can be due to fecal contamination. Urine is not the fluid of choice in the diagnostic investigation of an aminoacidopathy (phenylketonuria, maple syrup urine disease, homocystinuria, etc.) as plasma is a better sample type. Urine amino acids analysis is, instead, the diagnostic test when disorders of amino acid transport are investigated (cystinuria, lysinuric protein intol-

Factor/condition Diet, canned formula or milk Diet, gelatin Diet, high protein (infants) Diet, shellfish Diet, white meat from fowl Folate deficiency Kwashiorkor Kwashiorkor

Source Amino acid(s) affected U Homocitrulline

Value ↑ H

U B

Gly Met, Tyr

↑ H ↑ H

U U

↑ H ↑ H

Obesity

B

Obesity Starvation, 1–2 days (with or without vomiting) Starvation, 1–2 days (with or without vomiting) Vitamin B12 deficiency Vitamin B6 deficiency

B B

Taurine Anserine, 1-methylhistidine, carnosine Total Homocyst(e)ine Pro, Ser, Gly, Phe Leu, Ile, Val, Trp, Met, Thr, Arg Branched chain amino acids, Phe,Tyr Gly Branched chain amino acids, Gly

B

Alanine

↓ L

B

Total homocyst(e)ine

↑ H

U

Cystathionine

↑ H

B B B

↑ H ↑ H ↓ L ↑ H ↓ L ↑ H

B blood, U urine, H increased, L decreased

erance, Hartnup) or in prolidase deficiency. Although a random specimen is usually sufficient for diagnostic purposes, a timed urine collection may be required for reabsorption studies in conjunction with a plasma sample collected at mid-point. Results of urine amino acids analysis are usually reported in reference to creatinine; however for samples very diluted or very concentrated, this correction may not be very accurate. The interpretation of urine amino acids relies on patterns of amino acids more than on absolute values; therefore, a careful examination of the profile should lead to a correct diagnosis. Tables 3.5, 3.6, 3.7, and 3.8 list artifacts due to specimen collection as well as the effect of nutritional status, illnesses, and medications on amino acids values.

Analysis Amino acids studies are performed for (1) diagnostic purposes and (2) monitoring of therapy in patients with a known metabolic disorder. Methods for amino acids analysis should be sensitive (to identify even very low concentration of

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Table 3.7  Effects of illness/disease on amino acid values

Table 3.8  Effect of medications on amino acid values

Factor/condition Burn >20% of surface area (0–7 days after injury) Burn >20% of surface area (0–7 days after injury) Diabetes Hepatic disease

Source Amino acid(s) affected B Phe

Value ↑ H

U

Ala, Gly, Thr, Ser, Glu, Gln, Orn, Pro

↓ L ↑ H ↑ H

Hepatic disease

B

Hepatoblastoma Hyperinsulinism Hypoparathyroidism, primary Infection Infection Infection Ketosis Ketotic hypoglycemia Leukemia, acute

U B U

Leu, Ile, Val Tyr, Phe, Met, Orn, GABA Branched chain amino acids Cystathionine Leu, Ile, Val All amino acids

↓ L ↑ H ↑ H ↑ H ↓ L ↑ H

Leukemia, acute

U

Neuroblastoma Renal failure Renal failure Renal failure

U U U B

Renal failure Respiratory distress on oxygen Rickets

B B

All amino acids Phe/Tyr ratio All amino acids Leu, Ile, Val Ala Advanced disease: all amino acids On therapy: gly, asp, thr, ser Cystathionine Phe, Val His Phe, Cit, Cys, Gln, homocyst(e)ine Leu, Val, Ile, Glu, Ser Cystine

U

Gly

↑ H

B B

B B U B B U

↓ L ↑ H ↓ L ↑ H

↑ H ↑ H ↓ L ↑ H ↑ H ↓ L ↓ L

B blood, U urine, H increased, L decreased

amino acids), specific (to separate isomeric species), and accurate (to enable monitoring of dietary therapy). Paper chromatography, thin-layer chromatography, and two-dimensional chromatography by high-voltage electrophoresis for amino acids screening have been used in the past, but are now obsolete and should not be used for amino acids screening. Quantitative analysis of amino acids in physiological fluids can be performed by ion-exchange chromatography (IEC), reverse-phase high-performance liquid chromatography (HPLC), gas-chromatography (GC), and liquid chromatography/tandem mass spectrometry (LC-MS/MS). IEC has been the most widely used method in clinical laboratories, and it is still considered the gold standard for amino acid analysis. With this technique, amino acids are separated using a cation-exchange column and a lithium buffer system. The detection is performed by colorimetry after postcolumn derivatization with ninhydrin. The adduct between ninhydrin and primary amines has a maximum absorbance at wavelength λmax = 570 nm, while the adduct between nin-

Factor/condition Arginine infusion Arginine infusion Bile acid sequestrants (colestipol, niacin) Cyclosporin A 2-Deoxycoformycin Lysine aspirin Methotrexate therapy Methotrexate therapy Nitrous oxide anesthesia Oral contraceptives d-Phenylalanine Tamoxifen Tetracycline, renal toxicity Valproate Vigabatrin/ vinyl-GABA Vigabatrin/ vinyl-GABA Vigabatrin/ vinyl-GABA

Source B U B

Amino acid(s) affected Arg Arg, Lys, Orn, Cys Homocyst(e)ine

Value ↑ H ↑ H ↑ H

B B U B B B

Total homocysteine Homocyst(e)ine Lys Homocyst(e)ine Phe/Tyr ratio Homocyst(e)ine

↑ H ↓ L ↑ H ↑ H ↑ H ↑ H

B U B U

Pro, Gly, Ala, Val, Leu, Tyr Phe Homocyst(e)ine All amino acids

↓ L ↑ H ↓ L ↑ H

B,U U CSF

Gly ↑ H β-alanine, ↑ H β-aminoisobutyrate, GABA GABA, β-alanine ↑ H

B,U

2-Aminoadipic acid

↑ H

B blood, U urine, H increased, L decreased

hydrin and secondary amines (hydroxyproline, proline) has a λmax = 440 nm. The samples are monitored at both wavelengths to allow quantification of all physiological amino acids. This method is highly reproducible, with a wide dynamic range and excellent linearity range (5–3000 μmol/L). The disadvantage of the method is the long analysis time (90–150 min) and the lack of specificity. In fact several metabolites other than amino acids, including medications and dietary supplements, react with ninhydrin and coelute with amino acids. This is particularly challenging when evaluating urine samples. Depending on the methodology used, special processing of the sample is required to identify and quantify certain amino acids. A classic example is argininosuccinic acid. With IEC the free acid elutes in the region of neutral amino acids, often coeluting with tyrosine or leucine, depending on the buffer system and column used. Conversion of the free acid into anhydrides by boiling the deproteinized sample increases sensitivity and allows more accurate results. HPLC-based methods usually require a pre-column derivatization step with chemicals that react with the primary or secondary amino group of amino acids to form derivatives detectable with fluorescent, UV, or electrochemical detectors. The analysis time of these methods is shorter than ion-­ exchange chromatography, but sample preparation is more laborious and the derivatives may be instable. In addition, the sensitivity for some critical amino acids, such as alloisoleucine (the diagnostic amino acid for maple syrup urine disease), argininosuccinic acid (the diagnostic amino acid

3  Amino Acids

for argininosuccinic acid lyase deficiency), and homocystine may not be sufficient to identify mild elevations of these amino acids and some patients can be missed. Tandem mass spectrometry analysis of amino acids by flow injection is routinely used for neonatal screening using whole blood spotted on filter paper. Amino acids are extracted from the blood spot using an organic solvent (methanol) containing stable-isotope-labeled amino acids. The limitation of this method is that isomers and isobars cannot be separated; however, the speed of the analysis makes it a superb screening method. For diagnostic and/or monitoring purposes, similar methods can be used, and to increase the specificity, a liquid chromatographic separation is performed prior to MS/MS detection. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of amino acids in physiological fluids is now the method of choice by more and more laboratories, because of its speed, sensitivity, and increased specificity. Accurate quantitation by MS/MS requires the use of stable-isotope-labeled internal standards; ideally each amino acid quantified should have its internal standard. The detection of amino acids by MS/MS is usually done using selective reaction monitoring (SRM); therefore, the analysis is targeted. This method will not detect unusual amino acids, such as cystinylglycine (characteristic of gamma glutamyltranspeptidase deficiency), unless they are included in the method. As a consequence, amino acids analysis methods available for clinical diagnostic application are not suitable for new discovery. With the use of MS/MS for neonatal screening, milder variants of metabolic disorders are now identified, and the biochemical phenotype may be more subtle. Good communication between the testing laboratory and the physicians helps in clarifying these cases. The method used for quantifying amino acids in physiological fluids should also have a wide dynamic range, high sensitivity, sufficient to measure concentrations as low as a few micromoles/liter, and high upper limit of linearity, to accurately quantify high concentrations of amino acids for diet/therapy monitoring. Citrulline, alloisoleucine, argininosuccinic acid, and free homocystine are examples of amino acids requiring high sensitivity, with citrulline and argininosuccinic acid requiring also high upper limit of linearity. It is important to be able to detect even trace amounts of these amino acids to reach a correct diagnosis. LC-MS/MS-based methods are usually highly sensitive and specific; however, their dynamic range may not be as good as IEC.

I nterpretation of Amino Acids Results and Reference Values Clinical information, age of the patient, diet, and medications are critical to provide an accurate interpretation for metabolic testing in general, including amino acids analy-

47

sis. The interpretation of amino acid profiles relies on pattern recognition; therefore, laboratories should be familiar with metabolic disorders and the changes observed in presence of a metabolic block. In the past when most laboratories used similar methods, amino acids were reported in the order of chromatographic separation. With the advent of different methodologies, many laboratories report amino acids in alphabetical order to facilitate their reading and personal interpretation by referring physicians. All of our tables now report them in alphabetical order. Age. The normal concentration range of most amino acids changes with age, and appropriate reference ranges are essential for accurate interpretation. Renal tubular function is not mature in many infants who can have generalized aminoaciduria until several months of age. Homocitrulline in the urine of infants is usually derived from diet and is only rarely due to a metabolic disorder. Taurine is normally excreted in large amounts in the first week of life and decreases thereafter. However, the urine from infants less than 1  year of age often contains taurine from breast milk and/or taurinesupplemented formula, and the amount can fluctuate widely depending on the time of urine collection in relation to the time of feeding. Taurine is not detected in urine from infants fed unsupplemented formulas. Taurine is a constituent of several energy drinks and can increase in adolescents and young adults consuming these products. Administration of parenteral amino acid solutions can also cause altered blood amino acid patterns. The urinary excretion of glycine is quite variable. It can be of dietary origin (e.g., gelatin) as well as secondary to medication (e.g., valproate). Persistent isolated hyperglycinuria with normal plasma glycine levels suggests familial iminoglycinuria that is usually a benign variant. Urine histidine is increased during pregnancy. The concentration of plasma amino acids is low compared to normal controls during pregnancy, especially in the last trimester, due to hemodilution. In young infants, particularly in preterm infants, the quantity and quality of protein feeding has a direct effect on the plasma amino acid concentrations. The postprandial rise of total amino acids is more pronounced in infants on higher protein feeding. Transient hypertyrosinemia and hypermethioninemia can result from excessive protein load such as with the use of non-infant milk. The same pattern of elevation can be seen in premature infants or infants with immature hepatocellular function. Table 3.6 lists the most common effects of diet and nutritional status on amino acid values. Circadian rhythm is a physiological basis for higher amino acid concentrations, up to 10–15%, in the blood in the afternoon. A mild generalized increase in urine amino acids is a relatively common finding in hospitalized children. Branched-chain amino acids are elevated in blood of patients with maple syrup urine disease; however, in these patients the presence of alloisoleucine allows the correct

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M. Pasquali and N. Longo

interpretation of the results. Vomiting and poor oral intake for 1–2  days may cause mild elevations (two- to threefold) of the plasma branched-chain amino acids, and this should not be mistaken as a disease pattern. In a patient with MSUD and metabolic decompensation, the pattern of branched-chain amino acids will show a disproportionately high leucine compared to isoleucine and valine and a markedly reduced alanine in addition to the presence of alloisoleucine. With ion-exchange chromatography, alloisoleucine coelutes with cystathionine, and laboratories using this method should develop protocols to distinguish the two amino acids, such as the evaluation of the ratio of the absorbance at 570 nm and 440 nm, which is much lower for cystathionine as compared to alloisoleucine. Secondary amino acid changes can be a clue to other types of metabolic disorders such as galactosemia, organic acidemias, and disorders of pyruvate metabolism. Gross elevations of many amino acids, particularly glutamine and alanine in blood, have been reported in moribund children; however, elevations of the branched-­chain amino acids, citrulline, and arginine can be secondary to hypoxia and liver failure. Post-mortem blood shows similar but more pronounced amino acid changes (Table 3.7). Citrulline is the amino acid critical in identifying disorders of the urea cycle. It is absent or markedly reduced

in proximal blocks of the urea cycle (NAGS, CPS1, OTC deficiencies); it is markedly elevated in citrullinemia type I (argininosuccinate synthase deficiency) and, to a lower extent, in argininosuccinic aciduria (argininosuccinate lyase deficiency); and it is moderately but variably elevated in citrullinemia type II (citrin deficiency). Citrulline can also be used to assess functional enterocyte mass in patients with necrotizing enterocolitis, short bowel syndrome, and intestinal transplant. Very low levels of citrulline can be seen in these patients, usually with a completely normal concentration of all other amino acids, including glutamine. Several medications can affect the levels or interfere with quantitation of amino acids in blood and urine (Table 3.8). The use of disulfide agents, such as penicillamine, can result in the formation of unusual amino acids whose quantitation can help in determining compliance with therapy. Table 3.9 lists the amino acids and the disorders in which the amino acid level is abnormal. An abnormal concentration of an amino acid may be suggestive of several different inborn errors. Conversely, some disorders are characterized by abnormalities in several different amino acids, and analysis of the pattern of variation is more important than analysis of a single amino acid level in establishing a diagnosis. This table serves as a quick guide to more detailed information found in other chapters in this book.

Table 3.9  Pathologic conditions associated with abnormal amino acids concentrations Amino acid All amino acids All amino acids All amino acids Neutral amino acids Alanine

Source U U U U P

Alanine β-Alanine β-Alanine β-Alanine Allo-isoleucine

P P/U CSF U P/U/ CSF U U U U P P

α-Aminoadipic β-Aminoisobutyric acid δ-Aminolevulinic acid Arginine Arginine Arginine Argininosuccinate Asparagine Aspartic acid Aspartic acid Aspartylglucosamine Carnosine Citrulline

P/U/ CSF P/CSF U U P/U U P

Disorder(s) Classic galactosemia, Renal Fanconi syndrome, Lowe syndrome Tyrosinemia type 1, hereditary fructose intolerance Vitamin D-dependent rickets, mitochondrial disorders Hartnup disorder Lactic acidosis, disorders of pyruvate metabolism, mitochondrial disorders, hyperammonemic syndromes, glucagon receptor defect Maple syrup urine disease β-Alaninemia GABA-transaminase deficiency Pyrimidine disorders, methylmalonate semialdehyde dehydrogenase deficiency Maple syrup urine disease, E3 deficiency α-Aminoadipic/α-Ketoadipic aciduria β-Alaninemia, β-Aminoisobutyric acid aminotransferase deficiency (benign) Tyrosinemia type I, porphyria Cystinuria, dibasic aminoaciduria, lysinuric protein intolerance Arginase deficiency, glucagon receptor defect HHH syndrome, ornithine aminotransferase deficiency, urea cycle defects (except arginase deficiency) Argininosuccinate lyase deficiency Asparagine synthase deficiency Dicarboxylic aminoaciduria Pyruvate carboxylase deficiency type B Aspartylglucosamidase deficiency Carnosinemia Citrullinemia type I (argininosuccinate synthase deficiency), Citrullinemia type II (citrin deficiency), argininosuccinate lyase deficiency, pyruvate carboxylase deficiency type B

Value ↑ H ↑ H ↑ H ↑ H ↑ H ↓ L ↑  Η ↑ H ↑ H ↑ H ↑  Η ↑  Η ↑ H ↑ H ↑ H ↓ L ↑ H ↓ L ↑ H ↓ L ↑ H ↑ H ↑ H

3  Amino Acids

49

Table 3.9 (continued) Amino acid Citrulline

Source P

Cystathionine Cystine Cystine Formiminoglutamic acid (FIGLU) GABA GABA

P/U U P U

Glutamic acid Glutamic acid Glutamine Glutamine Glutamine

P/U P/U/ CSF U P P/U/ CSF P P

Disorder(s) Δ-pyrroline-5-carboxylate synthase deficiency, lysinuric protein intolerance, NAGS, CPS, OTC deficiencies, mitochondrial disorders Cystathionase deficiency Cystinuria, hyperlysinemia, hyperornithinemia Molybdenum cofactor deficiency, sulfite oxidase deficiency Formiminoglutamic aciduria

↑ H ↑ H ↓ L ↑ H

β-Alaninemia GABA transaminase deficiency

↑  Η ↑ H

Dicarboxylic aminoaciduria Glutamic acidemia, glutamine synthase deficiency Urea cycle defects

↑ H ↑ H ↑ H ↑ H ↓ L

↑ H ↓ L ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H ↓ L ↑ H ↓ L ↑ H ↑ H ↑ H ↑ H ↓ L ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H ↓ L

Glycine Glycine Glycylproline Hawkinsin Histidine Homoarginine Homocarnosine Homocitrulline Homocyst(e)ine

P/U/ CSF U P/CSF U U P/U P/U CSF P/U P/U

Homocyst(e)ine

P

Homocysteine-cysteine disulfide Total Homocysteine Hydroxylysine Hydroxyproline Hydroxyproline Imidodipeptides Isoleucine Leucine Lysine Lysine Lysine Lysine Methionine Methionine Methionine sulfoxide Ornithine Ornithine Ornithine Phenylalanine Phenylalanine Phosphoethanolamine Pipecolic acid Pipecolic acid Pipecolic acid Proline

P

Glutaminase deficiency (normal ammonia) Glutamine synthase deficiency, propionic acidemia, methylmalonic acidemia, maple syrup urine disease, pyruvate carboxylase deficiency Glycine encephalopathy, glycine transporter deficiency, propionic acidemia, methylmalonic acidemia, d-Glyceric aciduria Familial renal iminoglycinuria, hyperprolinemia type I and II Serine deficiency disorders Prolidase deficiency Hawkinsinuria Histidinemia Hyperlysinemia Homocarnosinosis HHH syndrome, saccharopinuria Cystathionine-β-synthase deficiency, cobalamin disorders, folate disorders, methionine synthase (MS) and MS reductase deficiency Methionine adenosyltransferase deficiency, S-Adenosylhomocysteine hydrolase deficiency, glycine-N-methyltransferase deficiency, adenosine kinase deficiency Cystathionine-β-synthase deficiency

P U U P/U U P/U P/U U P/U P P P/CSF P/U P U P P P/U P U P U P/U P

Molybdenum cofactor deficiency, sulfite oxidase deficiency Hydroxylysinuria Familial renal iminoglycinuria, hyperprolinemia type I and II Hydroxyprolinemia Prolidase deficiency Maple syrup urine disease, E3 deficiency Maple syrup urine disease, E3 deficiency Cystinuria, lysinuric protein intolerance, dibasic aminoaciduria Hyperlysinemia, saccharopinuria HHH syndrome, ornithine aminotransferase deficiency, lysinuric protein intolerance Urea cycle defects, pyruvate carboxylase deficiency type B Homocysteine remethylation disorders Cystathionine-β-synthase deficiency, hypermethioninemias Cystathionine-β-synthase deficiency, hypermethioninemias Cystinuria, dibasic aminoaciduria, hyperlysinemia, lysinuric protein intolerance HHH syndrome, ornithine aminotransferase deficiency Δ-pyrroline-5-carboxylate synthase deficiency Phenylketonuria, hyperphenylalaninemias, pterin disorders Tyrosinemia type I Hypophosphatasia Hyperlysinemia, antiquitin deficiency (pyridoxine responsive seizures) Hyperprolinemia type II Peroxisomal disorders Δ-pyrroline-5-carboxylate synthase deficiency

Glycine

Value ↓ L

↑ H ↑ H ↓ L ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H ↑ H

(continued)

50

M. Pasquali and N. Longo

Table 3.9 (continued) Amino acid Proline Proline Saccharopine Sarcosine Serine S-Sulfocysteine Taurine Threonine Tryptophan Tyrosine Tyrosine Valine

Source U P/U P/U P/U P/CSF P/U U P/CSF U P/U P P/U

Disorder(s) Familial renal iminoglycinuria Hyperprolinemia type I and II, lactic acidosis, multiple acyl-CoA dehydrogenase deficiency Saccharopinuria Sarcosinemia, mitochondrial disorders, glutaric acidemia type II, Betaine therapy Serine deficiency disorders Molybdenum cofactor deficiency, sulfite oxidase deficiency Molybdenum cofactor deficiency, sulfite oxidase deficiency, β-Alaninemia Pyridoxal phosphate-dependent seizures, citrullinemia type II (citrin deficiency) Tryptophanuria Tyrosinemia type I, II, III, transient tyrosinemia of the newborn Phenylketonuria, pterin disorders Maple syrup urine disease, E3 deficiency, branched chain amino transferase 2 deficiency

Value ↑ H ↑ H ↑ H ↑ H ↓ L ↑ H ↑ H ↑ H ↑ H ↑ H ↓ L ↑ H

P plasma, U urine, CSF cerebrospinal fluid, H high, L low

References Applegarth DA, Edelstein AD, Wong LT, Morrison BJ. Observed range of assay values for plasma and cerebrospinal fluid amino acid levels in infants and children aged 3 months to 10 years. Clin Biochem. 1979;12:173–8. Armstrong M, Jonscher K, Reisdorph NA. Analysis of 25 underivatized amino acids in human plasma using ion-pairing reversed-phase liquid chromatography/time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 2007;21:2717–26. Bertram KM, Bula DV, Pulido JS, Shippy SA, Gautam S, Lu MJ, Hatfield RM, Kim JH, Quirk MT, Arroyo JG.  Amino-acid levels in subretinal and vitreous fluid of patients with retinal detachment. Eye. 2008;22:582–9.

Gregory DM, Sovetts D, Clow CL, Scriver CR.  Plasma free amino acid values in normal children and adolescents. Metab Clin Exp. 1986;35:967–9. Held PK, White L, Pasquali M. Quantitative urine amino acid analysis using liquid chromatography tandem mass spectrometry and aTRAQ reagents. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879:2695–703. Honkanen RA, Baruah S, Zimmerman MB, Khanna CL, Weaver YK, Narkiewicz J, Waziri R, Gehrs KM, Weingeist TA, Boldt HC, Folk JC, Russell SR, Kwon YH. Vitreous amino acid concentrations in patients with glaucoma undergoing vitrectomy. Arch Ophthalmol. 2003;121:183–8. Parvy PR, Bardet JI, Rabier DM, Kamoun PP.  Age-related reference values for free amino acids in first morning urine specimens. Clin Chem. 1988;34:2092–5.

4

Organic Acids Isabel Tavares de Almeida and Antonia Ribes

Contents Introduction

 51

Preanalytical Conditions

 52

Analysis/Methods

 52

Interpretation/Reference Values

 60

Differential Diagnosis

 62

References

 63

Abstract

Organic acid disorders (OAD) are a relevant group of inborn errors of metabolism (IEM), not only in severely ill children but in adults as well, namely, with neurological symptoms. OAD are due to defect in intermediary metabolic pathways of carbohydrate, amino acids, lipids, Krebs cycle, vitamins, and nucleic acids, leading to the accumulation in the body fluids of the so-called organic acids, the metabolic pathways’ intermediates. Analysis of organic acids profiles is a powerful tool for the IEM differential diagnosis. Herein, an updated reference guide in OAD is presented, incorporating the affected protein, the altered gene, and the organic acids with diagnostic value. Valuable clues for the correct interpretation of an organic acids profile are discussed with focus on some puzzling organic acids and on the artefacts arising from diet, gut bacterial action, drugs, and sample bacterial contamination. I. Tavares de Almeida (*) Metabolism and Genetics, iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Avenida Prof. Gama Pinto, Lisboa, Portugal e-mail: [email protected] A. Ribes Section of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain e-mail: [email protected]

Introduction Organic acid disorders (OAD) are a relevant group of inborn errors of metabolism (IEM), not only in severely-ill children but as well in adults, namely, with neurological symptoms. OAD are due to defects in intermediary metabolism of various cellular components, such as amino acids, lipids, carbohydrates, Krebs cycle, vitamins, nucleic acids, and steroids. It gives rise to the accumulation, in tissues and body fluids, of diverse metabolic pathways’ intermediates: the organic acids. More than 65 organic acidurias have been described; the incidence varies, individually, from 1 out of 10,000 to >1 out of 1,000,000 live births. Collectively, their incidence approximates 1 out of 3000 live births (Villani et al. 2017). Organic acids are low-molecular weight (mass   4, i.e., values observed in plasma or urine. Consequently, accumulation of organic acids in the blood (“acidemia”) will lead to a shift in blood pH to lower values with the emerging of the so-called metabolic acidosis, which is accompanied by a negative base excess as well as an increased anion gap. The organic acids are strongly hydrophilic compounds enabling their rapid excretion into the urine (“aciduria”), the preferably biological fluid for the analysis of organic acids. Fatty

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_4

51

52

acids with chain length > C8 such as lauric, palmitic, and oleic acids are non-polar organic acids, which are bound to plasma proteins and are not excreted into the urine. Physiologically, organic acids are often present as their coenzyme A esters; good examples are propionyl-CoA and isovaleryl-CoA.  To facilitate its excretion, the metabolites are conjugated with carnitine or glycine, a process similar to the one leading to the production of acylglucuronides. Formation of acylcarnitines and acylglycines can be regarded as a process aimed at restoring the coenzyme A homeostasis, being at the same time a process of detoxification of the harmful organic acids. From a biochemical point of view, OAD are characterized by the accumulated organic acids, in body fluids, which may display a panel of organic acids, more or less specific, incorporating primary and unusual secondary metabolites, the by-­ products of alternative metabolic pathways, as well as specific acylcarnitines and/or acylglycines, often crucial in the unequivocal characterization of the OAD and a single pathognomonic metabolite (cf. N-acetylaspartic acid in Canavan disease) or the “normal” physiological metabolites in enhanced concentration (cf. methylmalonic acid in VitB12 deficiency). Organic acid analysis is a key diagnostic hint for the achievement of the differential diagnosis in systemic intoxication, in unexplained metabolic crisis, or in the presence of inexplicable routine biochemical findings such as metabolic acidosis, altered anion gap, and hypoglycemia among others. Amino acids and lipid intermediary metabolic defects, namely, branched chain amino acids and fatty acids catabolic pathways, are the leading causes of organic acidurias. Nevertheless, several hundreds of other organic acids or similar structural compounds with diagnostic value can be identified in a single run; typical examples are orotic acid, thymine, and uracil and their respectively di-hydro derivatives, glycerol, and several others derived from medication or diet. Key metabolites reference guide that may allow the biochemical diagnosis or raise the suspicion of an organic aciduria is shown in Table 4.1, which is organized, whenever possible, according the IEM-adopted classification in this book. Organic acid analysis by gas chromatography-mass spectrometry (GC/MS) is a powerful methodology providing the identification of normal and abnormal acids, which have allowed for the discovery of new disorders and the biochemical characterization of a great set of diseases. The complementation with acylcarnitine analysis becomes the basis of the expanded newborn screening by tandem mass spectrometry (MS/MS) (McHugh et al. 2011).

Preanalytical Conditions Organic acids are, in general, highly water-soluble compounds and, thus, efficiently excreted by the kidney leading to their accumulation in urine. Therefore, urine is the biological fluid of choice for the evaluation of organic acid pro-

I. Tavares de Almeida and A. Ribes

files. Other biological fluids such as plasma, CSF, or vitreous humor may be used when urine is not available. A random urine sample is usually used for the organic acid analysis. The timing of the urine collection is not really important. If the sample collection is planned, the first morning specimen is requested. The chance to detect metabolites with low concentration will be higher as well as the probability to detect key metabolites in patients with fasting intolerance. Whenever an organic acid profile is unclear and does not allow a solid diagnosis, the use of in vivo loading tests is advocated because these tests have proven to substantially enhance the organic acid excretion (Garcia-Villoria et  al. 2009). A 24-h urine collection may be requested in special occasions in the follow-up of patients, e.g., in the process of treatment monitoring. For post-mortem screening of organic aciduria, urine should be obtained via bladder puncture. In order avoid as much as possible artefactual alterations, the samples should be kept at −20 °C and shipped frozen. The more unstable organic acids (cf. ketoacids) may be degraded, and several organic acids, namely, the tricarboxylic acids, may be decreased and/ or enhanced by bacterial contamination activity. Diet and drugs are the main disturbing factors of the organic acid profile and may cause serious interpretative difficulties. The best known dietary disturbances are those caused by the use of medium-chain triglyceride containing diets giving rise to the excretion of C6-C10 dicarboxylic acids as well as (ω-1)hydroxy acids. Also partially hydrolyzed protein sources in infant formula may pose problems due to the interfering components/additives, e.g., dioctyl phthalate, which appears in the organic acid chromatogram. Various dietary carbohydrates do not survive the food processing steps and may give rise to artefacts such as furane-2,5-­dicarboxylic acid, 2,4-dihydroxybutyric acid, or glucosan (Table 4.2). For the correct evaluation of the organic acid profiles, it is mandatory to have precise information concerning the type of diet; the drugs, including vitamers; and the natural supplements under which the patients are submitted or have been, at least 48 h before sample collection.

Analysis/Methods The gold standard method for the analysis of organic acids in a biological matrix is gas-chromatography coupled with a mass spectrometry detector (GC-MS). Accordingly, the compounds of interest must be isolated from the sample’s matrix and further transformed in derivatives suitable for GC-MS analysis. The extraction of the organic acids is accomplished by solid-phase or liquid-liquid extraction, the latter one being the most widely used. For standardization of the method and internal quality control, one or two internal standards (non-­ physiological organic acid), such as 2-phenylbutyric acid or pentadecanoic acid, are added to the sample prior the extraction procedure.

Isovaleryl-CoA dehydrogenase

3-Methylcrotonyl-CoA carboxylase 3-Methylglutaconyl-CoA hydratase

3-Hydroxy-3-methyl-glutaryl-CoA lyase

Isovaleric acidemia

3-Methylcrotonylglycinuria

3-Methylglutaconic aciduria Type 1

3-Hydroxy-3-methylglutaric aciduria

HMGCL

MCCC1 MCCC2 AUH

IVD

BCKDHA BCKDHB DBT DLD

2-Ketoisocaproic acid 2-Ketoisovaleric acid 2-Keto-3-methylvaleric acid 2-Hydroxyisocaproic acid 2-Hydroxyisovaleric acid 2-Hydroxy-3-methylvaleric acid (lactic and ketoglutaric acids) Isovalerylglycine 3-Hydroxyisovaleric acid Isovalerylglutamic acid 3-Methylcrotonylglycine 3-Hydroxyisovaleric acid 3-Methylglutaconic acid 3-Methylglutaric acid 3-Hydroxyisovaleric acid 3-Hydroxy-3-methylglutaric acid 3-Methylglutaconic acid 3-Methylglutaric acid 3-Hydroxyisovaleric acid Glutaric acid 3-Methylcrotonylglycine C6-C10 Dicarboxylic acids

TAT HPD

Tyrosine aminotransferase 4-Hydroxyphenylpyruvate dioxygenase

Tyrosinemia Type II Tyrosinemia Type III

HPD HGD

FAH

Fumarylacetoacetase

Tyrosinemia Type I

Hawkinsinuria 4-hydroxyphenylpyruvate dioxygenase Alkaptonuria Homogentisic acid oxidase Organic acid disorders in branched-chain amino acid metabolism Branched-chain 2-ketoacid dehydrogenase complex Maple Syrup Urine Disease (MSUD): (BCKDC): MSUD Type 1a E1α subunit deficiency/BC ketoacid dehydrogenase MSUD Type 1b E1β subunit deficiency/BC ketoacid dehydrogenase MSUD Type 2 E2 subunit deficiency/Dihydrolipoyl transacylase BCKDC (PDHC/α-KDHC) deficiency E3 subunit deficiency/Dihydrolipoyl dehydrogenase

20

2-Hydroxyphenylacetic acid Phenyllactic acid Phenylacetic acid Phenylpyruvic acid Mandelic acid 4,6-Diketoheptanoic acid (=succinylacetone) N-Acetyl-tyrosine 4-Hydroxyphenyllactic acid 4-Hydroxyphenylpyruvic acid 4-Hydroxyphenylacetic acid 4-Hydroxyphenyllactic acid 4-Hydroxyphenylpyruvic acid 4-Hydroxyphenylacetic acid N-Acetyl-tyrosine 4-Hydroxycyclohexylacetic acid Homogentisic acid

PAH

(continued)

23

23

23

23

23

21 21

21

21

Ch. #

Key metabolites/profiles

Altered gene

Disorder Affected protein Organic acid disorders in aromatic amino acid metabolism Phenylketonuria (PKU) Phenylalanine hydroxylase

Table 4.1  Key metabolite reference guide in organic acids analysis. Symbol (#) shows the corresponding chapter number where the disorder is presented according the classification used throughout this book

4  Organic Acids 53

HIBADH HIBCH

3-Hydroxyisobutyryl-CoA deacylase 3-Hydroxyisobutyrate dehydrogenase

DHTKD1

GCDH

Malonic aciduria Combined methylmalonic and malonic aciduria Ethylmalonic aciduria (SCAD deficiency Ethylmalonyl-CoA decarboxylase and ETHE1 encephalopathy) Organic acid disorders in lysine and hydroxylysine metabolism 2-Amioadipic and 2-ketoadipic aciduria 2-Ketoadipic acid dehydrogenase (?)

Glutaryl-CoA dehydrogenase

Succinyl-CoA:glutarate-CoA transferase

Glutaric aciduria Type I

Glutaric aciduria Type III

SUGCT (C7orf10)

ECHDC1

MLYCD ACSF3

MCEE MUT MMAA MMAB MMADHC

Methylmalonyl-CoA epimerase Methylmalonyl-CoA mutase Mitochondrial Cbl transporter, CblA type Cobalamin adenosyltranferase, CblB type Cobalamin D-MMA type SUCLA2; SUCLG1 (vd.Krebs cycle) Malonyl-CoA decarboxylase Acetyl-CoA synthase (family member 3)

Isolated methylmalonic aciduria

PCCA PCCB

Propionyl-CoA carboxylase α-subunit Propionyl-CoA carboxylase β-subunit

Propionic aciduria

ALDH6A1

ACAD8 ECHS1

ACAT1

3-Oxothiolase (mitochondrial)

Isobutyryl-CoA dehydrogenase Mitochondrial short-chain enoyl-CoA hydratase (Crotonase)

Altered gene ACADSB HSD17B10

Affected protein 2-Methylbutyryl-CoA dehydrogenase 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase

Methylmalonic semialdehyde dehydrogenase Methylmalonic semialdehyde dehydrogenase deficiency

Isobutyrylglycinuria Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency Methacrylic aciduria 3-Hydroxyisobutyric aciduria

Disorder 2-Methylbutyrylglycinuria 2-Methyl-3-hidroxybutyric acidúria/HSD10 disease 2-Methylacetoacetic aciduria/β-Ketothiolase deficiency

Table 4.1 (continued)

2-Ketoadipic acid 2-Hydroxyadipic acid Dicarboxylic acids Glutaric acid 3-Hydroxyglutaric acid Glutaconic acid Glutaric acid

Malonic acid Methylmalonic acid Malonic acid Ethylmalonic acid

Key metabolites/profiles 2-Methylbutyrylglycine 2-Methyl-3-hydroxybutyric acid Tiglylglycine Ethylhydracrylic acid 2-Methyl-3-ketobutyric acid 2-Methyl-3-hydroxybutyric acid Tiglylglycine 2-Ethylhydracrylic acid Isobutrylglycine 2-Methyl-2-3-dihydroxy-butyrate 3-Methylglutaconic acid NONE, cf. 3-hydroxyisobutyryl-carnitine 3-Hydroxyisobutyric acid 3-Hydroxypropionic acid 2-Ethyl-3-hydroxypropionic acid Isobutyrylglycine Methylmalonic acid 3-Hydroxyisobutyric acid 3-Hydroxypropionic acid 3-Hydroxypropionic acid Methylcitric acid 2-Methyl-3-hydroxybutyric acid 3-Hydroxyvaleric acid Propionylglycine Methylmalonic acid 3-Hydroxypropionic acid Methylcitric acid 2-Methyl-3-hydroxybutyric acid 3-Hydroxy-valeric acid

–

69

–

–

23 23

23

23

23

23 23

23 23

23

Ch. # 23 23

54 I. Tavares de Almeida and A. Ribes

FH MDH2

AGXT

GRHPR

Organic acid disorders in oxalate metabolism Primary hyperoxaluria type I Alanine-glyoxylate amino-transferase

Glyoxylate reductase 4-Hydroxy-2-oxoglutarato aldolase, mitochondrial

Primary hyperoxaluria type II

Primary hyperoxaluria type III

HOGA1

Oxalic acid Glycolic acid Glyoxylic acid Oxalic acid l-Glyceric acid Oxalic acid Glycolic acid

Fumaric acid Citric acid Fumaric acid Malic acid Succinic acid

(continued)

67

67

67

42 42

42

42 2-Ketoglutaric acid Lactic acid Plus branched chain keto acids/2-hydroxy-keto acids Methylmalonic acid Succinic acid

OGDH DLST DLD SUCLA2 SUCLG1

50 3-Hidroxybutyric acid 2-Hydroxybutyric acid Acetoacetic acid

SCOT MCT1

32

48

L-3-Hydroxybutyric acid 3-Hydroxyglutaric acid

HADHSC –

48

48

48

48

3-Hydroxyadipic acid + lactone 3-Hydroxydicarboxylic acids Dicarboxylic acids (sat/unsat)

Ethylmalonic acid Methylsuccinic acid Dicarboxylic acids (sat/unsat.) Hexanoylglycine Suberylglycine 5-Hydroxyhexanoic acid 3-Hydroxysebacic acid Phenylpropionylglycine Dicarboxylic acids (sat/unsat)

HADHA HADHB

ACADVL

ACADM

ACADS

Very long-chain acyl-CoA dehydrogenase Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) Long-chain 3-hydroxyacyl-CoA Mitochondrial trifunctional protein (MTP) dehydrogenase deficiency Mitochondrial trifunctional protein deficiency Short-chain 3-hydroxyacyl-CoA Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) dehydrogenase deficiency (vd. riboflavin metabolism) Multiple acyl-CoA dehydrogenase deficiency Organic acid disorders in ketones bodies metabolism Succinyl-CoA:3-ketoacid transferase (SCOT) Succinyl-CoA:3-ketoacid-CoA transferase Monocarboxylate transporter1 (MCT1) deficiency Monocarboxylate transporter1 deficiency Organic acid disorders in Krebs cycle 2-Ketoglutarate dehydrogenase (KGDHC-E1 subunit) 2-Ketoglutarate dehydrogenase complex Dihydrolipoyl succinyltransferase (KGDHC-E2 subunit) (KGDHC): Dihydrolipoyl dehydrogenase (KGDHC-E3 subunit) 2-Ketoglutarate dehydrogenase deficiency KGDHC (plus BCKDC/PDHC) ATP-specific succinyl-CoA ligase β subunit Succinyl-CoA ligase β subunit (SUCLA2) Succinyl-CoA ligase α subunit (SUCLG1) deficiency GTP-specific succinyl-CoA ligase α subunit deficiency Fumaric aciduria Fumarase Malate dehydrogenase deficiency Malate dehydrogenase

Organic acid disorders in (mitochondrial) fatty acid oxidation metabolism Short-chain acyl-CoA dehydrogenase (SCAD) Short-chain acyl-CoA dehydrogenase deficiency (Ethylmalonic aciduria) Medium-chain acyl-CoA dehydrogenase Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

4  Organic Acids 55

ASPA ETHE1

Aspartoacylase Mitochondrial sulfur dioxygenase (ETHE1 protein) Glycerate kinase Glycerol kinase Succinic-semialdehyde dehydrogenase

l-2-Hydroxyglutaric acid dehydrogenase d-2-Hydroxyglutaric acid dehydrogenase Isocitrate dehydrogenase 2 Mitochondrial dysfunction

Mevalonate kinase Protein lipoilation defects

d-Glyceric aciduria Glycerol kinase deficiency 4-Hydroxybutyric aciduria

l-2-Hydroxyglutaric aciduria d-2-Hydroxyglutaric aciduria type I d-2-Hydroxyglutaric aciduria type II Methylglutaconic acidurias (MGA)–secondary: Barth syndrome Costeff syndrome MEGDEL syndrome Others

Mevalonic aciduria/Hyper-IgD syndrome Disorders of protein lipoilation

L2HGDH D2HGD IDH2 TAZ OPA3 SERAC1 DNAJ19;CLPB; HTRA2;TIMM50; TMEM70;ATPAF2; QIL1;AGK;ATP5FID MVK NFU1;ISCU;LIPT1; LIPT2; BOLA3;LIAS; IBA57;ISCA2; GLRX5;FSDX2; LYRM4;NFS1

GLYCTK GK ALDH5A1

AADC

Aromatic l-amino acid descarboxylase (AADC)

d-Lactic aciduriaa Diverse organic acid disorders Aromatic l-amino acid descarboxylase deficiency Canavan disease Ethylmalonic encephalopathy (ETHE)

Mevalonic acid + lactone 2-Hydroxyadipic acid 2-Ketoadipic acid Glutaric acid 2-Ketoglutaric acid Isobutyryl/Isovaleryl/2-methyl-butyryl-glycine

3-Methoxy-4-hydroxyphenyl-lactic acid (Vanillactic acid) N-acetylaspartic acid Ethylmalonic acid Isobutyryl/Isovaleryl-glycine d-Glyceric acid Glycerol 4-Hydroxybutyric acid + lactone Erythro-/threo- 4,5-dihydroxy-octanoic acids 2,4-dihydroxybutyric acid l-2-Hydroxyglutaric acid + lactone d-2-Hydroxyglutaric acid + Lactone 3-Methylglutaconic acid 3-Methylglutaric acid

d-Lactic acid

54 27

70/51

69 69

49 49/46 24

69 –

19

–

42

42

Lactic acid; Pyruvic acid 3-Hydroxybutyric acid; acetoacetic acid 2-ketoglutaric acid; Succinic acid Malic acid; Fumaric acid Lactic acid Pyruvic acid Plus branched chain keto acids/2-hydroxy-keto acids

PC

PDHA PDHB DLAT PDHX DLD LDHD

Ch. #

Key metabolites/profiles

Altered gene

Pyruvate dehydrogenase (E1α–subunit) Pyruvate dehydrogenase (E1β–subunit) Dihydrolipoyl acetyltransferase (E2-subunit) PDH- componente X Dihydrolipoamide dehydrogenase (PDHC-E3 subunit) d-Lactate Dehydrogenase

Pyruvate dehydrogenase complex (PDHC): Pyruvate dehydrogenase deficiency PDHC (plus BCKDC / KDHC) deficiency

Disorder Affected protein Organic acid disorders in pyruvate metabolism Pyruvate carboxylase deficiency Pyruvate carboxylase (PC)

Table 4.1 (continued)

56 I. Tavares de Almeida and A. Ribes

Riboflavin transporter 1 deficiency Brownn-Vialetto-Van Laere Syndrome Type I/Type II; Fazio-Londe Syndrome Flavin adenine dinucleotide synthetase deficiency

Folate metabolism Formiminoglutamic aciduria (FIGLURIA) Pyridoxine metabolism Pyridox(am)ine-5-phosphate oxidase deficiency Vit 6 dependent epilepsy Riboflavin metabolism Multiple acyl-CoA dehydrogenase (MADD) deficiency/Glutaric aciduria Type II (ETF-Type 2A /2B) Riboflavin-responsive MADD (ETF) MADD (ETF-DH)

Cobalamin metabolism GIF, CUBN/AMN, HC, TCbl, TCblR, CblF, CblJ, CblC, CblD, CblD-MMAtype, CblA, CblB and CblX deficiencies

Organic acidurias in vitamin metabolism Biotin metabolism Multiple carboxylase deficiency

Reversible leukoencephalopathy

Pyroglutamic aciduria

FTCD PNPO PROSC

ETFA ETFB ETFDH ETFDH

SLC52A1 SLC52A2 SLC52A3 FLAD1

Pyridox(am)ine-5-phosphate oxidase (PNPO) Pyridoxal phosphate binding protein

Electron transfer flavoprotein (ETF: α or β subunit) Electron transfer flavoprotein (ETF) Electron transfer flavoprotein dehydrogenase (ETF-DH)

Riboflavin transporter 1-RFVT1 Riboflavin transporter 2-RFVT2 Riboflavin transporter 3-RFVT3 Flavin adenine dinucleotide synthetase (FADS)

GIF/TCNIII;CUBN; AMN;TCNI;TCNII; CD320;LMBRD1; ABCD4;MMACHC; MMADCH;MMAA; MMAB; HCFC1

BTD HLCS

GSS OPLAH SLC13A3

Glutamateformimino-transferase

Uptake, intracellular transport, Cbl metabolism deficiencies

Biotinidase Holocarboxylase synthetase

Glutathione synthase 5-oxoprolinase Plasma membrane Na+/dicarboxylate cotransporter 3

Short-chain acylglycines (C4–C8) C5–C10 Dicarboxylic acids 3-Hydroxy-sebacic acid Ethylmalonic acid d-2-Hydroxyglutaric acid Glutaric acid Ethylmalonic acid Glutaric acid C5–C10 Dicarboxylic acids Short- and medium-chain acyl-Glycines (C4– C8) (can be normal)

3-Methoxy-4-hydroxyphenyl-lactic acid (vanillactic acid)

Hidantoin-5-propionic acid

Methylmalonic acid (and homocystinuria)

3-Methylcrotonylglycine 3-Hydroxyisovaleric acid 3-Hydroxypropionic acid 2-Methylcitric acid Lactic and Pyruvic acids

2-Ketoglutaric and succinic acid Fumaric acid N-acetylaspartic acid

Pyroglutamic acid

(continued)

32

32

34

29

28

30

43

16

4  Organic Acids 57

Peroxisomal biogenesis

Zellweger disease PEX1

DPYD

3-Methyl-adipic acid 2,6-dimethylsuberic acid Thymine Uracil 2-Hydroxysebacic acid Epoxydicarboxylic acids

66

24

66

24

a

Monroe et al. (2019) Abbreviations: CUBN cubilin, AMN amnionless, CblA, CblB, CblC, CblD CblF, CblJ, CblX cobalamin A,B,C,D, F,J,X; CblD-MMAtype cobalamin D-Methylmalonic type, GIF gastric intrinsic factor, HC haptocorrin, TCbl transcobalamin, TCblR transcobalamin receptor, HHH syndrome hyperornithinemia-hyperammonemia-homocitrulinuria syndrome, MEDGEL syndrome 3-methylglutaconic aciduria with deafness-encephalopathy-Leigh-like syndrome

Dihydropyrimidine dehydrogenase

PHYH

UMPS

Bifunctional enzyme: orotate phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC) Phytanoyl-CoA hydroxylase

24

Dihydrothymine Dihydrouracil Thymine Uracil ∆1-Pyrroline-5-carboxyl-glycine Thymine Uracil Orotic acid

DPYS

25 24

17

Orotic acid; (occasionally plus Uracil) 4,5-dihydroformamida-2-pyrrole carboxylic acid (cyclic derivative of citrulline)

OTC ASS ASL ARG1 SLC25A1 SLC7A7

ALDH4A1 TYMP

Ch. #

Key metabolites/profiles

Altered gene

∆-pyrroline-carboxylate dehydrogenase Thymidine phosphorylase

Thymine-uraciluria

Refsum disease

Hyperprolinaemia Type II Mitochondrial Neurogastrointestinal encephalomyopathy (MNGIE) Orotic aciduria

Disorder Affected protein Other alterations detectable through the organic acid profile Ornithine transcarbamylase (OTC) Ammonia detoxification disorders: Argininosuccinate synthase (ASS) Ornithine transcarbamylase deficiency Argininosuccinate lyase (ASL) Citrullinemia Arginase Argininosuccinic acidúria Mitochondrial Ornithine transporter Arginemia Amino acid transport system γ+L HHH syndrome Lysinuric protein intolerance Dihydropyrimidinuria Dihydropyrimidinase

Table 4.1 (continued)

58 I. Tavares de Almeida and A. Ribes

4  Organic Acids Table 4.2  Dietary, drug, non-IEM disorders and bacterial artefacts in organic acid analysis Compound N-Acetyltyrosine Aromatic acids (4-hydroxyphenyl)

Condition Parenteral feeding Gut bacterial action Liver diseases Benzoic acid Benzoate sodium therapy Bacterial contamination Cyclohexanediol Medication MCT-diet C10 > C8 > C6 dicarboxylic acids Dicarboxylic acids Valproate therapy Ethosuximide metabolites Antiepileptic therapy Di-(2-ethylhexyl)phthalate Nutramigen feeding Pregestimil feeding Ethylmalonic acid ACADS polymorphisms Furane-2,5-dicarboxylic acid Heated sugars Furoylglycine Heated sugars Glucosan Heated sugar Glutaric acid Gut bacterial action, 2-ketoadipic decarboxylation Glycerol Balm contamination Glycolic acid Ethylene glycol poisoning Hippuric acid Benzoate sodium therapy Homovanillic acid Neuroblastoma 4-Hydroxybutyric acid Gamma-hydroxyanesthesia Illegal use of 4-hydroxybutyrate 2,4-Di-hydroxybutyric acid Heated sugar 4-Hydroxycyclohexanecarboxylic acid Food processing 3-Hydroxydicarboxylic acids Coeliac disease Long fasting MCT supplementation 2-Hydroxyglutaric acid 2-ketoadipate decomposition (bacterial contamination) 5-Hydroxyhexanoic MCT-diet 2-Hydroxyhippuric acid Salicylate ingestion 5-Hydroxyindoleacetic acid Carcinoid syndrome d-2-Hydroxyisocaproic acid Short-bowel syndrome 3-Hydroxyisovaleric acid Valproate medication 7-Hydroxyoctanoic acid MCT-diet 3-Hydroxypropionic acid Gut bacterial action Colon rectal cancer Keppra metabolites Antiepileptic therapy d-Lactic acid Short-bowel syndrome Mandelic acid Albumin infusion Methylmalonic acid Vitamin B12-deficiency (vegans, vegetarian diet) d-Phenyllactic acid Short-bowel syndrome Phenytoin metabolites Antiepileptic therapy Pyroglutamic acid Glutamine decomposition Flucloxacillin toxicity Severe denutrition Renal disease Suberylglycine (trace amounts) MCT-diet Succinic acid 2-Ketoglutarate decomposition Valproate metabolites Depakine therapy Vanillactic acid Dopa therapy Vanilmandelic acid Neuroblastoma, pheochromocytoma

59

In native urine (pH  5–7), the acids are present as salts (Na+, K+). Therefore, the urine should be acidified (pH 1–2) to promote the protonation of the acids, which turns them suitable to be extracted by an organic solvent of intermediate polarity. Ethyl acetate or di-ethyl ether is the most widely used. Extraction recoveries depend on the polarity of the acid: the more hydroxyl-groups, the less recovery. For an accurate analysis, some precautions are necessary to be taken prior the extraction procedure. Keto acids deserve special attention due to the fact of being unstable compounds, thus the keto group must be protected by formation of an oxime derivative through reaction with hydroxylamine or methoxyamine; an example is succinylacetone (4,6-diketo-­ heptanoic acid), the key tyrosinemia type 1 metabolite. The analysis by GC-MS obliges volatile analytes. Organic acids do not fulfil this requirement and must be transformed in volatile derivatives. Derivatization of the acid (COOH), the hydroxy (C-OH), and the keto (C=O) groups increases their volatility. The most widely used derivatization procedure is the formation of a trimethylsilylated (TMS) derivative. This transforms the molecule into a more balloon-like structure which can easily be volatilized upon the injection and move faster along the column. The larger the molecule, the later it elutes having higher retention times that may vary slightly depending on the column and on the instrument. The derivatives are separated in the GC-capillary column, and the detection is accomplished by MS which allows the unequivocal identification of the detected metabolites. All separated compounds enter the ion source. They are ionized (obtain a positive electric charge) and fragmented and then deflected in an electromagnetic field. Variation of the electromagnetic field will cause the passage of ions with increasing mass to pass the ion exit slit and hit the ion collector (detector). The fragments of any given compound are like a fingerprint and give the unique identification of the compound. Every modern GC-MS instrument has library search facilities. This gives for each peak the most likely structure. Nevertheless, the interpretation of the library data should be done with care and the predicted structure should be cross examined with the determined retention times, i.e., the position in the total ion chromatogram. Unknown compounds with different chromatographic properties may have great similarity with fragmentation spectrum of known compounds. There are even sophisticated methods for the simultaneous deconvolution, identification, and quantitation of organic acids using a dedicated library of mass spectra and a list of retention indices (Halket et al. 1999). Several experienced laboratories have developed search routines in which the mass spectrometer automatically checks for the presence of all diagnostic organic acids listed in Table 4.1. An organic acid chromatogram may display hundreds of tiny small peaks, and a full quantitative analysis can be really

60

I. Tavares de Almeida and A. Ribes

time-consuming. Therefore, urinary organic acids analysis, in general, is run in a qualitative or semi-quantitative mode. In order achieve a visual comparison of the organic acid total ion chromatograms, the starting volume of urine used in the assay should correspond to a fixed amount of creatinine present in the sample. Precise quantification of specific metabolites, in particular cases, for differential diagnosis purposes or for the monitoring of treatment may be required. Therefore, accuracy of the organic acid analysis in the lower concentration range can be improved by using a stable isotope dilution assay. This is based on the addition of a stable isotope-labeled (13C or 2H) internal standard which behaves identically in all steps of the analysis, i.e., extraction, derivatization, and chromatographic separation. A range of applications has been developed, for example, succinylacetone for the follow-up of tyrosinemia type 1 patients (Sander et al. 2006), mevalonic acid for hyper IgD patients (Houten et al. 1999), and methylmalonic acid for vitamin B12-related disorders (Blom et al. 2007), among others. The recent availability of electrospray tandem mass spectrometers (MS/MS) together with a high range of isotope-­ labeled internal standards has resulted in the introduction of quantitative organic acid analysis in many labs by means of selective mass spectrometric detection and quantification via multiple reaction monitoring (MRM). This targeted analysis is of great value for some applications, particularly for the follow-up of some organic acidurias. However, the untar-

geted added value of GC-MS for the analysis of organic acids is still difficult to overcome. Recently, quantitative organic acid analysis by LC-QTOF/MS has been revealed as a technique that should be taken into account in the near future, particularly when urine is analyzed as a front-line specimen including also amino acids, acylcarnitines, purine and pyrimidines, and other metabolites in a unique run (Körver-Keularts et al. 2018).

Interpretation/Reference Values Interpretation of organic acid profiles is a demanding and complex issue. Besides the organic acids with diagnostic value, hundreds of substances are excreted into the urine of healthy and diseased subjects and are also detected in the organic acid chromatogram. It is therefore essential to gain experience in pattern recognition, in order to provide a reliable descriptive interpretation of the organic acid profile. This is one of the major tasks of the Biochemical Genetics Laboratory. The recognition of a normal excretion profile is the starting point. It is necessary to be aware that the excretion profile depends on the age of the individual, the diet, the use of dietary supplements or vitamers, the intake of drugs, and the physical condition (fasting, exercise, etc.). A set of organic acids will always be detectable essentially in all urine samples of healthy individuals (Table 4.3). Due to differences in

Table 4.3  Organic acids detectable essentially in all urines. Reference values of control individuals on a normal diet, without any medication and without signs of intestinal disease Compound Glycolic acid Lactic acid Oxalic acid 3-Hydroxypropionic acid 3-Hydroxy(iso)butyric acid 3-Hydroxyisovaleric acid Methylmalonic acid Ethylmalonic acid Succinic acid Phosphoric acid Glutaric acid Adipic acid 2-Hydroxyglutaric acid 3-Hydroxy-3-methylglutaric acid 2-Ketoglutaric acid 4-Hydroxyphenylacetic acid Homovanillic acid N-Acetylaspartic acid Suberic acid cis-Aconitic acid Citric acid Hippuric acid

Reference values (mmol/mol creat) 0–4 months 4 months–2 years 13–129 32–162 – 16 years)

± + +

± + +

± +

+ + + + + ↓-↓↓↓

+ + + +

+ +

↓-↓↓↓

↓-↓↓↓

Table 13.11  Adenylosuccinate lyase deficiency System CNS

Laboratory findings

Symptoms and biomarkers Autism Cerebellar hypoplasia Epilepsy Hypotonia Retardation, psychomotor Adenylosuccinate lyase (red blood cells) SAICA riboside (cerebrospinal fluid) SAICA riboside (plasma) SAICA riboside (urine) Succinyladenosine (cerebrospinal fluid) Succinyladenosine (plasma) Succinyladenosine (urine)

Neonatal (birth–1 month) ± ± ± ± +

Infancy (1–18 months) ± ± ± ± +

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years) ± ± ±

Adulthood (>16 years) ± ± ±

+

+

+

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↑↑

↑↑

↑↑

↑↑

↑↑

↑

↑

↑

↑

↑

↑↑ ↑↑

↑↑ ↑↑

↑↑ ↑↑

↑↑ ↑↑

↑↑ ↑↑

↑↑

↑↑

↑↑

↑↑

↑↑

↑↑

↑↑

↑↑

↑↑

↑↑

J. Bierau and I. Šebesta

202 Table 13.12  AICAR transformylase/IMP cyclohydrolase deficiency System CNS Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Intellectual disability Blindness Dysmorphic features AICA riboside (urine) AICAR transformylase/ IMP cyclohydrolase (fibroblasts)

Neonatal (birth–1 month) +++

Infancy (1–18 months) +++

Childhood (1.5–11 years) +++

Adolescence (11–16 years)

Adulthood (>16 years)

+++ ++

++ ++

+++ ++

↑↑↑

↑↑↑

↑↑↑

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

± +

↓

↓

↓

↑

↑

↑

↓

↓

↓

Childhood (1.5–11 years) +

Adolescence (11–16 years)

Adulthood (>16 years) +

±

Infancy (1–18 months) + ±

+ +

+ +

+ +

+ +

+ +

+

+

+

+

+

Adolescence (11–16 years) +

Adulthood (>16 years) +

Table 13.13  Adenosine monophosphate deaminase deficiency System Musculoskeletal

Other

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Exercise Intolerance Muscle cramps Acquired, associated with neuromuscular rheumatological disorders Adenosine monophosphate deaminase (muscle biopsy) Creatine kinase (plasma) Ischaemic muscle exercise tolerance test (plasma NH3)

Infancy (1–18 months)

Table 13.14  Adenosine monophosphate deaminase 2 deficiency System CNS

Musculoskeletal

Symptoms and biomarkers Retardation, motor Retardation, psychomotor Seizures Dysmorphic features Microcephaly

Neonatal (birth–1 month)

Table 13.15  Erythrocyte adenosine monophosphate deaminase 3 deficiency (reported as nondisease) System

Symptoms and biomarkers No clinical significance

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

13  Purine and Pyrimidine Disorders

203

Table 13.16  Adenosine deaminase deficiency System Digestive Haematological

Other Laboratory findings

Symptoms and biomarkers Splenomegaly Lymphopaenia Severe combined immunodeficiency (SCID) Failure to thrive Recurrent infections Adenosine deaminase (red blood cells) Deoxyadenosine (urine) Deoxyadenosine triphosphate, dATP (red blood cells) Immunoglobulins

Neonatal (birth–1 month) + +++ +++

Infancy (1–18 months) + ++ ++

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

+ +

+ +

± +++ ↓↓↓

± +++ ↓↓↓

+++ ↓↓↓

+++ ↓↓↓

+++ ↓↓↓

↑↑

↑↑

↑↑

↑↑

↑

↑↑↑

↑↑

↑↑

↑↑

↑

↓↓↓

↓↓

↓

↓

↓

Table 13.17  Adenosine deaminase 2 deficiency System Other

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Polyarteritis + nodosa Sneddon syndrome (Deoxy)adenosine deaminase (plasma)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) + + ↓↓↓

Table 13.18  Purine nucleoside phosphorylase deficiency System CNS

Haematological

Other Laboratory findings

Symptoms and biomarkers Developmental delay Spastic diplegia Tetraparesis CD4+ cells Immunodeficiency, T-cell Recurrent infections Deoxyguanosine, dGuo (plasma) Deoxyguanosine, dGuo (urine) Deoxyinosine, dIno (plasma) Deoxyinosine, dIno (urine) Purine nucleoside phosphorylase (red blood cells) Uric acid (plasma) Uric acid (urine)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years)

Adulthood (>16 yeears)

++ ++ ↓-n +

++ ++ ↓-n +

++ ++ ↓-n +

+

+

++

++

++

↑

↑

↑

↑

↑

↑↑

↑↑

↑↑

↑

↑

↑

↑

↑

↑

↑

↑↑

↑↑

↑↑

↑

↑

↓↓↓

↓↓

↓↓↓

↓↓↓

↓↓↓

↓-↓↓ ↓-↓↓

↓-↓↓ ↓-↓↓

↓-↓↓ ↓-↓↓

↓ ↓

↓ ↓

J. Bierau and I. Šebesta

204 Table 13.19  Xanthine dehydrogenase deficiency System Musculoskeletal Renal

Other

Laboratory findings

Symptoms and biomarkers Myopathy Renal failure, acute Urolithiasis Urolithiasis, xanthine stones Allopurinol to oxypurinol conversion Hypoxanthine (plasma) Hypoxanthine (urine) Uric acid (plasma) Uric acid (urine) Xanthine (plasma) Xanthine (urine)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ±

Adolescence (11–16 years) + ±

Adulthood (>16 years) + ±

±

±

± ±

± ±

± ±

± ±

± ±

+

+

+

+

+

↑

↑

↑

↑

↑

↑↑

↑↑

↑↑

↑↑

↑↑

↓-↓↓ ↓-↓↓ ↑ ↑↑

↓-↓↓ ↓-↓↓ ↑ ↑↑

↓-↓↓ ↓-↓↓ ↑ ↑↑

↓-↓↓ ↓-↓↓ ↑ ↑↑

↓-↓↓ ↓-↓↓ ↑ ↑↑

Table 13.20  Hypoxanthine guanine phosphoribosyltransferase deficiency System CNS

Metabolic Renal

Other Laboratory findings

Symptoms and biomarkers Cerebral palsy Choreoathetosis Intellectual disability Pyramidal signs Self-mutilation Spasticity Hematuria Renal failure, acute Renal stones Urinary Infections Urolithiasis Gouty arthritis AICA riboside (urine) Hypoxanthine (plasma) Hypoxanthine (urine) Hypoxanthine guanine phosphoribosyltransferase (red blood cells) Uric acid (plasma) Uric acid (urine) Xanthine (urine)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

+

Childhood (1.5–11 years) + + ± + + + + ± ± + +

Adolescence (11–16 years) + + ± + + + + ± ± + +

↑ ↑↑ ↓↓↓

↑ ↑ ↑↑ ↓↓↓

↑ ↑ ↑↑ ↓↓↓

↑ ↑ ↑↑ ↓↓↓

Adulthood (>16 years) + + ± + + + + ± ± + + ± ↑ ↑ ↑↑ ↓↓↓

+ + +

± + + +

±

±

+

↑↑ ↑↑↑ ↑

↑↑ ↑↑↑ ↑

↑↑ ↑↑↑ ↑

↑↑ ↑↑ ↑

↑↑ ↑↑ ↑

13  Purine and Pyrimidine Disorders

205

Table 13.21  Adenine phosphoribosyl transferase deficiency System Metabolic Renal

Laboratory findings

Symptoms and biomarkers Hematuria Renal colic Renal failure, acute Renal failure, chronic Urolithiasis 2,8-Dihydroxyadenine (urine) Adenine (urine) Adenine phosphoribosyl transferase (red blood cells)

Neonatal (birth–1 month) + + ± ± ↑↑

Infancy (1–18 months) + + ± + ± ↑↑

Childhood (1.5–11 years) + + ± + ± ↑↑

Adolescence (11–16 years) + + ± + ± ↑↑

Adulthood (>16 years) + + ± + ± ↑↑

↑ ↓↓

↑ ↓↓

↑ ↓↓

↑ ↓↓

↑ ↓↓

Table 13.22  Adenylate kinase 1 deficiency System CNS Haematological

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Retardation, ± psychomotor + Anaemia, nonspherocytic, haemolytic with basophilic stippling Adenylate kinase ↓↓↓ activity (erythrocytes)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

+

+

+

+

↓↓↓

↓↓↓

↓↓↓

↓↓↓

Table 13.23  Adenylate kinase 2 deficiency System Haematological

Other

Symptoms and biomarkers Congenital agranulocytosis Leukopenia Lymphopaenia Death in the first few weeks of life

Neonatal (birth–1 month) +

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + +

Table 13.24  Inosine monophosphate dehydrogenase deficiency System Eye

Symptoms and biomarkers Constricted visual fields Leber amaurosis-like Night blindness Nystagmus Pigmentary retinopathy Retinal ‘bone corpuscle; pigmentation’ Retinal dysfunction Retinal dystrophy Retinitis pigmentosa Vision loss

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

+

+

Adolescence (11–16 years) + +

Adulthood (>16 years) + + +

+

+

+

+

+ +

+

+ + + +

J. Bierau and I. Šebesta

206 Table 13.25  Inosine triphosphatase deficiency System Cardiovascular

CNS

Digestive Eye Haematological Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Electrocardiogram abnormalities Cerebral atrophy (MRI) Delayed myelination Encephalopathy Hypotonia, severe Retardation, psychomotor Seizures Feeding difficulties Cataract Erythrocyte ITP accumulation Microcephaly Childhood death Enzyme activity (FB)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

+

+

+

+

+ + +

+ + +

+ + +

+ +

+ +

+ +

± ↑↑↑

± ↑↑↑

± ↑↑↑

↑↑↑

↑↑↑

+ ± ↓↓

+ ± ↓↓

+ ± ↓↓

↓↓

↓↓

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

n-↑↑↑

n-↑↑↑

n-↑↑↑

n-↑↑↑

n-↑↑↑

±

±

±

n-↓↓

n-↓↓

n-↓↓

n-↓↓

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

Table 13.26  Inosine triphosphatase deficiency (erythrocyte) System Haematological

Other

Laboratory findings

Symptoms and biomarkers Anaemia, protection against ribavirin-induced Erythrocyte ITP accumulation Thiopurines, decreased tolerance Enzyme activity (RBC)

n-↓↓

Table 13.27 Thiopurine S-methyltransferase deficiency System Other

Symptoms and biomarkers Thiopurines, decreased tolerance

Neonatal (birth–1 month)

13  Purine and Pyrimidine Disorders

207

Table 13.28  Hyperuricaemic nephropathy, familial juvenile 1 System Musculoskeletal Renal

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Gout Chronic interstitial nephritis Nephropathy Renal failure Small medullary cysts Tubular atrophy Fractional ↓ excretion of uric acid Uric acid (plasma)

Infancy (1–18 months)

↓

Childhood (1.5–11 years)

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

+ + +

+ + +

↓

+ ↓

+ ↓

↑↑

↑↑

↑↑

Childhood (1.5–11 years)

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ↓-n n-↑

± ↓-n n-↑

± ↓-n n-↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ±

↓

↓

↓

Table 13.29  Urate transporter 1 deficiency System Renal

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Exercise-induced acute renal failure with acute tubular necrosis Urolithiasis Uric acid (plasma) Uric acid (urine)

Infancy (1–18 months)

Table 13.30  Urate voltage-driven efflux transporter 1 deficiency System Renal Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Exercise-induced acute renal failure Uric acid (plasma)

Infancy (1–18 months)

Reference and Pathological Values

18–55 years

mmol/mol creatinine Urate 2,8-di-OH-­ Adenine 569– 2605 419– 1963 295– 1508 214– 895 132– 619 99–578

>55

73–668

0–1 month 1 month–2 years 2–4 years 4–10 years 10–18 years

Ade

Ado

AICAr dAdo dGuo

0.0– 2.0 0.0– 1.0 0.0– 1.0 0.0

0.0– 3.3 0.0– 3.0 0.0– 2.0 0.0– 2.0 0.0– 2.0 0.0– 1.0 0.0– 2.0

0.0 0.0 0.0– 1.0

dIno

Guo

Hyp

Ino

Sado

SAICAr Xan

0.0– 2.0 0.0– 1.0 0.0– 1.0 0.0

2.0– 33.4 4.0– 61.0 4.0– 63.0 3.0– 33.0 1.0– 20.7 1.0– 12.8 0.0– 18.0

0.0– 4.0 0.0– 4.0 0.0– 2.0 0.0– 1.0 0.0– 1.0 0.0– 1.0 0.0– 1.0

0.0– 19.0 0.0– 18.8 0.0– 13.0 0.0– 8.0 0.0– 5.0 0.0– 4.0 0.0– 4.0

2.0– 37.0 4.0– 50.8 6.0– 40.0 4.0– 23.0 1.0– 19.4 0.0– 10.0 0.0– 24.5

0.0 0.0 0.0– 1.0

J. Bierau and I. Šebesta

208

All age groups combined (n ≥ 2600) ADA PNP

mmol/mol creatinine 135– 0.0–3.0 1666

0.0– 4.0

0.0– 2.0

0.0– 2.0

0.0

0.0

0.0– 1.0

0.0– 1.0

1.0– 45.8

0.0– 3.0

100– 400

100– 650

286– 405

0–53a

500–1900

XDH 1370– 6298

APRT ADSL

20– 660 90– 270

2–21 23–32

1.0– 39.0

134– 2900 25– 109

8–41 69– 2603

PRPP superactivity

0.0–1.0

10– 266 21–160

HPRT

0.0– 13.0

9–802

1910– 8300

ATIC (n = 1)

280

May be within reference range to spontaneous degradation of nucleosides

a

mmol/mol creatinine Oro NC-Aspartate DHO (OA) 0–1 month 0.0– 5.0 1 month–2 years 0.0– 6.0 2–4 years 0.0– 4.0 4–10 years 0.0– 3.1 10–18 years 0.0– 2.7 18–55 years 0.0– 2.0 >55 0.0– 3.8 0.0– 0.0– All age groups 4.0 4.0 combined (n ≥ 2600) DHODH 149 (n = 1) 39– 1.0– 87 78 UMPS (OPRT) 180– 9600 7–53 UMPS, partial deficiency (OPRT) TP DPD DHP UP

Ord 0.0– 18.4 0.0– 9.0 0.0– 6.0 0.0– 4.0 0.0– 3.0 0.0– 2.0 0.0– 12.0 0.0– 8.0

Ura 0.0– 10.5 0.0– 47.5 0.0– 33.0 0.0– 20.1 0.0– 15.0 0.0– 15.0 0.0– 18.6 0.0– 29.0

Thy

0.0– 3.0

DHU 0.0– 15.0 0.0– 20.0 0.0– 7.0 0.0– 6.0 0.0– 5.5 0.0– 7.0 0.0– 8.5 0.0– 10.8

DHT 0.0– 9.0 0.0– 7.0 0.0– 4.0 0.0– 3.0 0.0– 3.0 0.0– 3.0 0.0– 2.3 0.0– 5.0

5-OH-­ Me NC-BAIB NC-BALA dUrd dThd Ps-Urd Urd Ura 0.0–23.7 0.0–57.2 58.8– 0.0– 280 6.0 0.0–11.0 0.0–31.2 34.0– 0.0– 218 4.0 0.0–7.0 0.0–15.0 35.0– 0.0– 146 3.0 0.0–3.1 0.0–13.1 19.8– 0.0– 93.9 2.1 0.0–2.0 0.0–8.5 13.0– 0.0– 74.4 2.0 0.0–2.0 0.0–7.0 11.0– 0.0– 60.4 2.0 0.0–4.3 0.0–8.5 10.5– 0.0– 79.0 3.0 0.0–9.0 0.0–21.0 0.0– 0.0– 16.0– 0.0– 0.0– 1.0 1.0 182 3.0 4.0

0.0– 38 40– 465

50–77 23–48 60– 9–476 680 9–144 12– 150– 230 804 13– 94

51– 150

29– 125 24– 140

10– 490 47– 201

187–801

236–1116

13  Purine and Pyrimidine Disorders

209

Diagnostic Flowchart Signs and symptoms

Suspious case history

Laboratory tests

Automutilation

Hyperuricaemia

Gout

Hypouricaemia

(especially in the young and

Combined B- and T-cell

women)

deficiency

Severe combined

T-cell deficiency

immunodeficiency (SCID)

Non-spherocytic anaemia

Unexplained psychomotor

with basophilic stippling

retardation, seizures or hyptonia

Urate in serum and urine Purine and pyrimidine metabolites in urine

Enzyme activity assays (Erythrocytes, white blood cells, fibroblasts)

Molecular genetic analysis

Fig. 13.3  The justification for detailed purine and pyrimidine investigations includes three aspects: (a) clinical signs and symptoms (some are very characteristic such as self-mutilation or gout in young people and women or SCID (severe combined immunodeficiency) syndrome; others are shown in the information of the specific diseases), (b) a case history suspicious of an inborn error of metabolism and (c) characteristic laboratory tests. If a patient meets these criteria, the first steps are measurement of uric acid in body fluid and purine and pyrimidine

Specimen Collection This section is taken from the ERNDIM advisory document for the analysis of purines and pyrimidines (see Online Databases and Resources section for reference).

Urine Many laboratories use urine portions for diagnostic purposes, and the traditionally 24-h urine collection or overnight collection has more or less become obsolete. No preservatives are added to the urine sample; freezing the sample as soon as possible is often enough.

metabolites in urine. It is highly recommended to estimate both plasma and urine concentrations at once to be able to assess the excretion and confirm or exclude overproduction/hypoexcretion of uric acid. The exclusion of secondary causes of hyperuricaemia/hypouricaemia (such as nephropathy, tissue breakdown, Fanconi syndrome and uricosuric drugs) is very important. Confirmation of diagnosis consists of enzyme assay and finally molecular genetic analysis

If a 24-h urine collection is desired, proceed as follows: during the collection period, the urine aliquots are kept refrigerated (4  °C), and after completion, the urine is sent to the laboratory in a well-isolated package and stored in the refrigerator for max. 1 week at 4 °C until analysis or stored frozen at −20 °C when analysis is carried out after more than 1 week but within 2 months. For longer periods, storage at −80 °C is recommended. Dipstick tests for nitrite and pH should be carried out directly after receipt of the urine in order to check for bacterial contamination. In addition, qualitative tests for glucose, reducing substances, sulphite and ketone bodies should be performed. Analysis should not be performed in severely bacterially contaminated samples (pH > 7 and/or nitrite is positive).

J. Bierau and I. Šebesta

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Plasma The analysis of purines and pyrimidine can be performed in plasma obtained from blood anticoagulated with heparin as well as EDTA.  This can be adjusted according to local protocols. In the case of capillary blood, clean and disinfect the skin thoroughly before taking the blood sample to avoid contamination from the skin surface. An absolute prerequisite is that the sample is absolutely fresh, and there should preferably be no or as little delay as possible between drawing of the blood and freezing the plasma sample. Plasma samples should be stored at −20 °C or at −80 °C if stored for a prolonged period. Plasma samples should be deproteinised before most types of analysis.

CSF Please refer to your own hospital protocol for the lumbar puncture procedure. CSF samples should be deproteinised before analysis. CSF samples should be stored at −80 °C.

Prenatal Diagnosis and DNA Analysis Providing a table listing all disorders and materials in which molecular analysis can be performed is obsolete because of the modern sequencing techniques. All genes and their chromosomal localisations are listed above. In essence, any material from which DNA can be extracted is suitable for molecular analysis. There are good and reliable databases to be found on the Internet.

Treatment Summary  he Management of Purine and Pyrimidine T Disorders In the treatment of purine and pyrimidine disorders, patients and physicians need to be aware of several precautions: the dosage of allopurinol in overproduction hyperuricaemia (HPRT, PRPS) is higher than in primary gout and therefore should be reduced in the cases of renal insufficiency (risk of xanthine nephropathy!) (van Gennip et al. 2006). There is a risk of myopathy and neurotoxicity with colchicine prophylaxis in gouty patients with renal impairment and in patients receiving statins, so renal function should be assessed before prescribing colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs) (Nuki et  al. 2017).

Administration of fluorinated pyrimidine analogues in dihydropyrimidine dehydrogenase deficiency can be catastrophic; in thiopurine methyltransferase deficiency, there may be enhanced toxicity of mercaptopurines. Specific treatment is available for a small number of other purine and pyrimidine disorders at present. The reason is that, in many cases, our understanding of pathogenesis how a particular point defect in a gene produces these relatively new disorders is still incomplete and requires further studies.

The Management of Hyperuricaemia Genetic defects with hyperuricaemia and gout represent the most frequent disorders of purine metabolism (Becker 2001). The incidence of hyperuricaemia and gout is increasing. Population-based studies have estimated an incidence of up to 21% for hyperuricaemia and 1–4% for gout (Kuo et al. 2015). The Importance of Controlling Hyperuricaemia

Hyperuricaemia is the main underlying cause of gout. In addition, several studies suggest that chronic hyperuricaemia is related to the pathogenesis of multifactorial disorders such as hypertension, metabolic syndrome, chronic heart failure and chronic kidney disease (Mazzali et al. 2010; Teng et al. 2012). A recent study revealed that hyperuricaemia was a strong independent risk factor for major cardiovascular events and should be included in cardiovascular prevention strategies. Whether hypouricaemic drugs can reduce cardiovascular disease risk warrants further studies (Capuano et al. 2017). Therefore, it is important to emphasise rapid diagnosis and treatment of asymptomatic hyperuricaemia, considered as a multifactorial pathological condition very closely related to cardiovascular and renal complications. Control of hyperuricaemia should be more important to paediatricians than formerly thought. It is important to raise awareness among general practitioners to test uric acid concentrations in blood and urine more often, especially in patients with one or more risk factors for cardiovascular and renal impairment (Bove et al. 2017). The Management of Gout

Recent updated recommendations of European League Against Rheumatism (EULAR) emphasise three main principles for the efficient management of gout: Firstly, every patient with gout should be fully informed about the pathophysiology of the disease, effective treatments and associated comorbidities. Secondly, every patient with gout should receive advice regarding lifestyle changes. Alcohol, especially beer, spirits and sugar-sweetened drinks, should

13  Purine and Pyrimidine Disorders

be excluded. Avoidance of excessive intake of meat, legumes, seafood and fructose-containing foods should be recommended. Low-fat dairy products and diets high in dietary fibre should be encouraged. Weight reduction and regular exercise should be advised. Thirdly, every patient with gout should be systematically examined for associated comorbidities including hyperlipidaemia, hypertension, obesity, ­coronary heart disease, peripheral artery disease and renal impairment. Detection of chronic kidney disease is notably required. The measurement of the estimated glomerular filtration rate (eGFR) at the time of diagnosis of gout is recommended. The subsequent monitoring of eGFR should follow in parallel with measurements of uric acid concentrations in blood and urine (Richette et  al. 2017; Nuki et al. 2017). The main principle of the management of gout with pharmacotherapy is the need to reduce serum uric acid concentrations to below a target of 0.30 or 0.36 mmol/L depending on whether it is tophaceous or non-tophaceous, respectively (Robinson PC 2018). Urate-lowering therapy (ULT) should be discussed from the first presentation of the disease. Allopurinol is recommended as the first choice of ULT. Its dosage should be adjusted according to renal function. If it is not possible to achieve uric acid target concentration in blood, then febuxostat, uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be recommended (Richette et  al. 2017; Nuki et al. 2017). Febuxostat has an excellent safety and tolerability profile also in patients with moderate renal impairment, because of its hepatic metabolism. It was also shown that its serum uric acid-lowering e­ fficacy is greater than of allopurinol in patients with hyperuricaemia with or without chronic kidney disease (Bove et  al. 2017). The use of xanthine oxidase inhibitors is recommended for the overproduction-type hyperuricaemia, while uricosuric agents are recommended for the underexcretion type. However, when uricosuric drugs are used, urinary output must be sustained, and, in addition, alkalinisation of the urine to prevent urolithiasis must be considered (Becker 2001). It is important to note that all uric acid-lowering therapies should be started at low dose and titrated upwards until the target value is achieved. The recommendations for the treatment of flare are colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination. In patients with flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. For patients with refractory gout, pegloticase is recommended (Richette et al. 2017; Nuki et al. 2017). Recent study suggests that febuxostat may positively affect cardiovascular mortality in comparison with allopurinol in elderly patients with mild-to-moderate heart failure. This finding deserves further evaluation in the future (Cicero et al. 2019).

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Online Resources ERNDIM offers a range of advisory documents on laboratory analyses including purines and pyrimidines (website: www.erndim.org under the header Training and Education). The Purine and Pyrimidine Society. Scientific forum for biomedical scientists and physicians interested in purines and pyrimidines around the world (website: www.ppsociety.org).

References Assmann B, Gohlich G, Baethmann M, Wevers RA, Van Gennip AH, Van Kuilenburg AB, et  al. Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency. Neuropediatrics. 2006;37(1):20–5. Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of purine metabolism: clinical update and therapies. J Inherit Metab Dis. 2014a;37(5):669–86. Balasubramaniam S, Duley JA, Christodoulou J.  Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis. 2014b;37(5):687–98. Becker MA. Hyperuricemia and gout. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease, vol. 2. New York: McGraw-Hill; 2001. Bierau J, Sebesta I. Purine and pyrimidine disorders. In: Blau N, Duran M, Blaskovics ME, Gibson KM, Dionisi-Vici C, editors. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Berlin Heidelberg: Springer; 2014. p. 641–60. Bjursell MK, Blom HJ, Cayuela JA, Engvall ML, Lesko N, Balasubramaniam S, et al. Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am J Hum Genet. 2011;89(4):507–15. Bove M, Cicero AF, Veronesi M, Borghi C. An evidence-based review on urate-lowering treatments: implications for optimal treatment of chronic hyperuricemia. Vasc Health Risk Manag. 2017;13:23–8. Capuano V, Marchese F, Capuano R, et al. Hyperuricemia as an independent risk factor for major cardiovascular events: a 10-year cohort study from Southern Italy. J Cardiovasc Med (Hagerstown). 2017;18:159–64. Cicero AFG, Cosentino ER, Kuwabara M, Degli Esposti D, Borghi C.  Effects of allopurinol and febuxostat on cardiovascular mortality in elderly heart failure patients. Intern Emerg Med. 2019;14(6):949–56. Hirano M, Nishino I, Nishigaki Y, Marti R. Thymidine phosphorylase gene mutations cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Intern Med. 2006;45(19):1103. Kevelam SH, Bierau J, Salvarinova R, Agrawal S, Honzik T, Visser D, et al. Recessive ITPA mutations cause an early infantile encephalopathy. Ann Neurol. 2015;78(4):649–58. Koch J, Mayr JA, Alhaddad B, Rauscher C, Bierau J, Kovacs-Nagy R, et al. CAD mutations and uridine-responsive epileptic encephalopathy. Brain. 2017;140(2):279–86. Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis. 2015;74(4):661–7. Mazzali M, Kanbay M, Segal MS, Shafiu M, Jalal D, Feig DI, et  al. Uric acid and hypertension: cause or effect? Curr Rheumatol Rep. 2010;12(2):108–17. Micheli V, Camici M, Tozzi MG, Ipata PL, Sestini S, Bertelli M, et al. Neurological disorders of purine and pyrimidine metabolism. Curr Top Med Chem. 2011;11(8):923–47.

212 Monostori P, Klinke G, Hauke J, Richter S, Bierau J, Garbade SF, et al. Extended diagnosis of purine and pyrimidine disorders from urine: LC MS/MS assay development and clinical validation. PLoS One. 2019;14(2):e0212458. Nuki G, Doherty M, Richette P. Current management of gout: practical messages from 2016 EULAR guidelines. Pol Arch Intern Med. 2017;127(4):267–77. Rainger J, Bengani H, Campbell L, Anderson E, Sokhi K, Lam W, et al. Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH.  Hum Mol Genet. 2012;21(18):3969–83. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda-­ Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29–42. Robinson PC. Gout-An update of aetiology, genetics, co-morbidities and management. Maturitas. 2018;118:67–73. Sebesta I. Genetic disorders resulting in hyper- or hypouricemia. Adv Chronic Kidney Dis. 2012;19(6):398–403. Sebesta I, Stiburkova B, Krijt J. Hereditary xanthinuria is not so rare disorder of purine metabolism. Nucleosides Nucleotides Nucleic Acids. 2018;37(6):324–8.

J. Bierau and I. Šebesta Simmonds HA, Van Gennip AH.  Purine and pyrimidine disorders. In: Blau ND, Duran M, Blaskovics ME, Gibson KM, editors. Physician’s guide to the laboratory diagnosis of metabolic diseases. 2nd ed. Berlin: Springer; 2003. Teng GG, Ang LW, Saag KG, Yu MC, Yuan JM, Koh WP. Mortality due to coronary heart disease and kidney disease among middle-aged and elderly men and women with gout in the Singapore Chinese Health Study. Ann Rheum Dis. 2012;71(6):924–8. van Gennip AH, Bierau J, Nyhan WL.  Inborn errors of purine and pyrimidine metabolism. In: Blau N, Hoffmann GF, Leonard J, Clarke JTR, editors. Physician’s guide to the treatment and follow­up of metabolic diseases. Berlin: Springer; 2006. van Kuilenburg AB.  Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer. 2004;40(7):939–50. Weinshilboum RM, Otterness DM, Szumlanski CL.  Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol. 1999;39:19–52.

Disorders of Nucleotide Metabolism

14

Min Ae Lee-Kirsch, Victoria Tüngler, Simona Orcesi, and Davide Tonduti

Contents Introduction

 214

Nomenclature

 217

Metabolic Pathways

 219

Signs and Symptoms

 222

Diagnosis

 231

Treatment

 232

References

 232

Summary

Nucleotides are the building blocks of nucleic acids including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within virtually all forms of life. While DNA carries the genetic information required for building and maintaining an organism, RNA serves as an intermediary template for protein translation. Nucleic acids derived from pathogens, such as viruses, also represent important molecular patterns that can be sensed by pattern recognition M. A. Lee-Kirsch (*) · V. Tüngler Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany e-mail: [email protected] S. Orcesi Unit of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy e-mail: [email protected] D. Tonduti Child Neurology Unit, COALA (Center for Diagnosis and Treatment of Leukodystrophy) - V. Buzzi Children’s Hospital, Milano, Italy e-mail: [email protected]

receptors of the innate immune system as danger signals. Engagement of these nucleic acid-sensing receptors initiates activation of signaling cascades in the host immune cells leading to production and secretion of type I interferon (IFN) and other cytokines. The aim of the ensuing antiviral immune response is to eliminate infected cells and to restrict viral spread. As nucleic acid sensors have only limited capacity to differentiate between nonself- and self-DNA or RNA, a type I IFN response can also be initiated by endogenous nucleic acids. Such inappropriate activation of type I IFN can be detrimental to the host by promoting autoinflammation and a loss of immune tolerance leading to autoimmunity. Type I IFN activation induced by immune recognition of self-nucleic acids represents a central pathogenetic mechanism underlying disorders of nucleic acid metabolism and nucleic acid-sensing also referred to as type I interferonopathies. Nucleotides play fundamental roles in cell metabolism. They provide energy in the form of nucleoside triphosphates, function as second messenger in cell signaling, and act as cofactors of enzymatic reactions. Perturbations in

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_14

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adenosine homeostasis leading to downregulation of pyrophosphate (PPi), a key inhibitor of hydroxyapatite growth, underlie disorders of early arterial calcification. The lysosomal equilibrative nucleoside transporter 3 (ENT3) regulates intracellular nucleoside pools and thereby influences the availability of ATP and GTP, synthesis of DNA and RNA, and other metabolic pathways. Its general role in cell homeostasis likely accounts for the pleiotropy of ENT3 deficiency. Activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) mediate somatic hypermutation and class-switch recombination at the immunoglobulin gene loci, which represent key events during formation of protective antibodies by B cells. Malfunction of these pathways impedes antibody formation resulting in profound susceptibility to bacterial infections.

M. A. Lee-Kirsch et al.

predominantly autosomal recessive resulting in a loss of function of the underlying gene, although rare cases of heterozygous de novo mutations with presumably dominant negative effect have been described for TREX1 and ADAR. In contrast, AGS7 is caused by heterozygous gain-of-function mutations in IFIH1 that either occur de novo or are inherited as autosomal dominant trait with reduced penetrance (Crow et al. 2015). AGS usually begins during the first year of life with a peak between the third and sixth month. Following a period of normal psychomotor development, infants commonly present with a subacute encephalitic-like phase characterized by irritability, unexplained fevers, dystonic movements, truncal hypotonia, as well as sleeping and feeding difficulties. After a few weeks to months, the clinical picture enters a plateau phase characterized by progressive microcephaly, spasticdystonic tetraplegia with exaggerated startle r­eactions, and severe developmental delay. Children frequently present abnormal eye movements or poor visual performance, and Introduction some patients experience epilepsy. Both a neonatal and a late onset of symptoms beyond the first year of life have been Disorders of nucleotide metabolisms can be broadly divided described. Likewise, intrafamilial phenotypic variability can into disorders of nucleic acid metabolism and nucleic acid-­ be high with one sibling presenting with severe neurological sensing, disorders relating to nucleotide transport and metab- impairment and the other with only mild spasticity and norolism, and disorders of immunoglobulin hypermutation and mal intellect (Vogt et al. 2013; Tüngler et al. 2014). The major class-switching. Given the extraordinary functional diversity neuroradiological findings include leukoencephalopathy, of pathways regulating nucleotide metabolism, the pheno- basal ganglia calcification, and cerebral atrophy. Thus, the types of the associated disorders comprise a broad and clinical phenotype of AGS resembles congenital viral infecdiverse spectrum of clinical presentations. tion. In addition, some patients develop signs that are also observed in patients with the autoimmune disorder systemic lupus erythematosus including arthritis, hepatic disease, Disorders of Nucleic Acid Metabolism and Nucleic thrombocytopenia, lymphopenia, antinuclear antibodies, as Acid-Sensing well as cold-induced erythematous skin lesions, also referred to as chilblain lesions (Ramantani et al. 2010, 2011; Cuadrado Aicardi-Goutières Syndrome et al. 2015). Elevated liver function tests and thrombocytopeAicardi-Goutières syndrome (AGS) is a systemic inflamma- nia occur more commonly in cases with neonatal onset. tory disorder primarily affecting the brain and skin. It is Cerebrospinal fluid (CSF) lymphocytosis and increased characterized by inappropriate activation of the antiviral type levels of IFN-α in CSF are observed during the encephalitic I IFN axis and represents the prototypic type I interferonopa- phase but tend to gradually decrease over time (Goutieres thy (Lee-Kirsch 2017). Type I interferonopathies comprise a et  al. 1998). In the absence of lymphocytosis or IFN-α in heterogenous group of disorders caused by perturbations of CSF, elevated CSF pterins may be a less specific sign of CNS the innate immune system associated with an abnormal acti- inflammation (Blau et al. 2003). In contrast, chronic upreguvation of type I IFN. lation of interferon-stimulated genes in peripheral blood AGS is caused by mutations in seven distinct genes cells, the so-called interferon signature, can be measured in encoding 3′ repair exonuclease (TREX1, AGS1), the three sub- most patients persistently throughout the course of the disunits of ribonuclease H2 (RNASEH2B, AGS2; RNASEH2C, ease and reflects the underlying intrinsic systemic inflammaAGS3; RNASEH2A, AGS4), sterile alpha motif (SAM) and tion (Rice et  al. 2013). The interferon signature therefore HD-domain containing protein (SAMHD1, AGS5); RNA- represents a more robust diagnostic tool. specific adenosine deaminase (ADAR, AGS6), and interferoninduced helicase C domain-containing protein 1 (IFIH1, AGS7). Other AGS-Related Phenotypes All AGS-causing genes function in pathways affecting the In general, the different AGS subtypes cannot be distinmetabolism or the immune recognition of intracellular nucleic guished based on clinical grounds alone. However, certain acids including DNA and RNA (Lee-Kirsch 2017; Schlee and clinical signs appear to be more specific for distinct AGS Hartmann 2016) (Fig. 14.1). Inheritance of AGS1 to AGS6 is subtypes. Cerebral vasculopathy with early-onset strokes has

14  Disorders of Nucleotide Metabolism

been described in patients with AGS1 (TREX1) and AGS5 (SAMHD1); the latter may also present with a moyamoya-­ like phenotype (Xin et  al. 2011; Yamashiro et  al. 2013). Bilateral striatal degeneration has been observed in patients with AGS6 (ADAR) (Livingston et al. 2014). Magnetic resonance imaging (MRI) shows symmetrical signal changes with swelling followed by shrinkage of the corpus striatum. Patients present with subacute onset of dystonia, commonly triggered by infections. Dyschromatosis symmetrica hereditaria is a rare manifestation of autosomal dominant ADAR mutations found in the Japanese population. It is characterized by childhood onset of hypopigmented and hyperpigmented lesions, particularly on the extremities and not associated with AGS (Hayashi and Suzuki 2013). Isolated spastic paraparesis has been observed in patients with AGS2 (RNASEH2B), AGS6 (ADAR1), and AGS7 (IFIH1) who present with slowly progressive lower limb spasticity, normal cognitive function, and normal head growth. Usually, brain MRI is unremarkable (Crow et al. 2014). Overall, there is emerging evidence for a phenotypic continuum between AGS and other AGS-related phenotypes and other type I interferonopathies. Familial Chilblain Lupus

Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus with onset in early childhood. It is characterized by cold-induced bluish-red skin lesions in acral locations such as fingers, toes, nose, cheeks, and ears (Lee-­Kirsch et al. 2006). Patients exhibit an interferon signature in blood indicating constitutive type I IFN activation. Some patients develop arthralgia, antinuclear antibodies, immune complexes, or lymphopenia. Histological findings include perivascular inflammatory infiltrates with increased mucin, deposits of immunoglobulins or complement, and increased expression of type I IFN-induced myxovirus resistance protein 1 (Mx1) (Gunther et  al. 2013). Familial chilblain lupus is caused by heterozygous TREX mutations (CHBL1) (Rice et al. 2007; Lee-Kirsch et al. 2007). In addition, two families with familial chilblain lupus each segregating a heterozygous mutation in SAMHD1 (CHBL2) or in STING have been reported (Ravenscroft et al. 2011; König et al. 2017).

215

Singleton-Merten Syndrome Type 1 and Type 2

Singleton-Merten syndrome (SGMRT) is characterized by progressive calcifications of large vessels, dental anomalies with periodontal disease and alveolar bone loss, as well as skeletal abnormalities. Patients may also suffer from psoriasis, glaucoma, and recurrent infections. Singleton-Merten syndrome is caused by heterozygous gain-of-function mutations in interferon-induced helicase C domain-containing protein 1 (IFIH1, SGMRT1) or dead box polypeptide 58 (DDX58, SGMRT2) which encode the cytosolic dsRNA sensors, melanoma differentiation-associated gene 5 (MDA5), and retinoic acidinducible gene I (RIGI), respectively (Rutsch et al. 2015; Jang et al. 2015). STING-Associated Vasculopathy with Onset in Infancy

STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory vasculopathy characterized by ulcerating acral skin lesions, recurrent fever, and interstitial lung disease (Liu et al. 2014). Similar to patients with AGS or chilblain lupus, skin lesions in SAVI patients are aggravated by cold. Some patients demonstrate variable or transient autoantibody titers. SAVI is caused by heterozygous de novo mutations in transmembrane protein 173 (TMEM173), encoding stimulator of interferon genes (STING), the key adaptor signaling molecule of the cyclic GMP-AMP synthase (cGAS)-dependent DNA-sensing pathway (Fig. 14.1). Mutations result in a gain of function leading to constitutive activation of type I IFN. In addition, a family with SAVI and lupus-like features segregating a dominant STING mutation was reported (Jeremiah et  al. 2014). RNASET2 Deficiency

Cystic leukoencephalopathy without megalencephaly is caused by biallelic mutations in ribonuclease T2 (RNASET2), which has been implicated in the degradation of ribosomal self RNA, thereby modulating host immune responses (Henneke et al. 2009; Haud et al. 2011). It is characterized by bilateral anterior temporal cysts and white matter disease, a phenotype overlapping with congenital cytomegalovirus infection and AGS.

Retinal Vasculopathy with Leukodystrophy

OAS1 Deficiency

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal dominant disorder with onset in adolescence or early adulthood. Patients present with progressive loss of vision, cerebrovascular disease, and dementia. Some patients also develop migraine, glomerulopathy, or Raynaud’s disease. RVCL is caused by heterozygous TREX1 mutations that lead to C-terminal truncations of TREX1 with preservation of the N-terminal DNase domain (Richards et al. 2007).

Deficiency in 2′,5′-oligoadenylate synthetase 1 (OAS1) causes infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia, which is characterized by ­progressive respiratory failure with consolidations on lung imaging and recurrent respiratory viral infection. On bronchoalveolar lavage, small and non-foamy alveolar macrophages are seen. OAS1 is a member of the 2–5A synthetase family essential for innate immune responses to viral infection. Reported heterozygous OAS1 mutations occurred de

216

novo or were transmitted to offspring by a mother who carried the mutation as mosaic (Cho et al. 2018).

M. A. Lee-Kirsch et al.

Disorders of Nucleotide Transport and Metabolism

in ENPP1, which affect cysteine residues in the somatomedin B-like 2 domain, has been described in three families (Eytan et al. 2013). In addition, a recessive and more severe form of Cole disease due to homozygosity of the p.Cys120Arg allele has been reported in three families (Chourabi et al. 2018).

Pseudoxanthoma Elasticum

NT5E Deficiency

Pseudoxanthoma elasticum (PXE) is a connective tissue disorder characterized by progressive calcification of elastic fibers involving the skin, the eye, and the cardiovascular system. Typical skin lesions are yellowish papules on flexural surfaces. Retinal changes include peau d’orange and angioid streaks caused by calcification and dehiscence of Bruch’s membrane, resulting in neovascularization with subsequent visual impairment. Adult patients may develop cardiovascular disease due to premature atherosclerosis. PXE is caused by autosomal recessive mutations in ABCC6 (ATP-binding cassette, subfamily C, member 6) which belongs to the multidrug resistance-associated protein subfamily of ATP-­binding cassette transmembrane transporters (Bergen et al. 2000; Struk et  al. 2000). In rare cases, autosomal dominant inheritance has been described.

Deficiency of ecto-5′-nucleotidase (NT5E) has been described in three families (St Hilaire et al. 2011). This autosomal recessive disorder is characterized by arterial and periarticular calcifications with onset in early adulthood.

 eneralized Arterial Calcification of Infancy Type 1 G and Type 2

General arterial calcification of infancy (GACI) is characterized by calcification of the internal elastic lamina and fibrotic myointimal proliferation of muscular arteries resulting in arterial stenosis (Nitschke et al. 2012). It is often fatal within the first 6  months of life because of myocardial ischemia leading to heart failure. Radiographic findings include diffuse vascular and periarticular soft tissue calcification. Some patients also develop hypophosphatemic rickets due to reduced renal tubular phosphate reabsorption (Rutsch et al. 2008). The majority of cases is caused by autosomal recessive mutations in ENPP1 (ectonucleotide pyrophosphatase/ phosphodiesterase 1, GACI type 1), which converts ATP to AMP and pyrophosphate, an essential physiologic inhibitor of calcification (Fig. 14.2). GACI type 2 is due to biallelic mutations in ABCC6. It is usually not associated with pseudoxanthoma due to early death caused by cardiovascular disease. However, GACI patients with ENPP1 mutations who survive early childhood may develop signs of pseudoxanthoma. It is thought that ABCC6 interferes with ENPP1-­ associated metabolic pathways, possibly by modulating extracellular ATP concentrations. Cole Disease

Cole disease is characterized by congenital or early-onset punctate palmoplantar keratoderma with hypopigmented macules over the arms and legs. Some patients develop calcific tendinopathy. An autosomal dominant form due to mutations

SLC29A1 Deficiency

Lack of the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) results in the Augustine-null blood type and ectopic mineralization (Daniels et al. 2015). It represents an ill-­ defined clinical entity. SLC29A3 Deficiency

Autosomal recessive deficiency of the equilibrative nucleoside transporter 3 (ENT3, SLC29A3) underlies histiocytosis-­ lymphadenopathy plus syndrome, which encompasses a spectrum of disorders previously thought to be distinct: Faisalabad histiocytosis, sinus histiocytosis with massive lymphadenopathy, Rosai-Dorfman disease, H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (Molho-Pessach et al. 2014). In addition to histiocytosis and lymphadenopathy, recurrent fever, hepatosplenomegaly, skin manifestations, hormone deficiencies, joint contractures, or deafness can occur. Lysosomal ENT3 regulates cell homeostasis by controlling nucleoside availability and is required for T-cell survival upon activation (Wei et al. 2018).

Disorders of Immunoglobulin Class-­Switching and Hypermutation Hyper-IgM Syndrome Type 2 and Type 5

Deficiencies in the nucleic acid-modifying enzymes, activation-induced cytidine deaminase (AID), and uracil-­DNA glycosylase (UNG) cause the primary immunodeficiency disorders hyper-IgM syndrome type 2 and type 5 (Revy et al. 2000; Imai et al. 2003). Both enzymes play a central role in B cells, which function in the humoral arm of the adaptive immune system by secreting antibodies or immunoglobulin (Ig). Production of protective antibodies by activated B cells is accomplished by two processes of ­diversification, somatic hypermutation (SHM) and classswitch recombination (CSR) (Lee et  al. 2004; Stavnezer et  al. 2008). SHM introduces mutations into the variable region of Ig genes, which encodes the antigen-binding site of the Ig receptor. Repeated rounds of mutation and selec-

14  Disorders of Nucleotide Metabolism

217

tion generate high-affinity antibodies. CSR, on the other hand, involves the constant region of the Ig locus and replaces the constant region of the primary IgM antibody with the constant region of other isotypes including IgA, IgG, or IgE via deletional DNA recombination. Recombination occurs between DNA double-strand breaks introduced at defined regions (switch region) upstream of the sequences encoding the constant regions of IgA, IgG, and IgE, respectively. This process improves the ability of an Ig to remove a pathogen by augmenting its effector functions without changing its antigen specificity. SHM and CSR are initiated by AID, which converts cytosines within Ig variable regions or switch regions to uracil by deamination

(Fig.  14.3). Subsequent removal of uracil by UNG and nicking by apurinic endonuclease (APE) result in DNA single-strand breaks. These DNA lesions are either processed by error-prone DNA repair, to yield mutations during SHR, or converted to DNA d­ ouble-strand breaks, to initiate CSR (Lee et al. 2004; Stavnezer et al. 2008; Fear 2013). Deficiencies in AID or UNG abrogate SHM and CSR, leading to recurrent bacterial infections due to the inability to mount efficient antibody responses (Revy et  al. 2000; Imai et al. 2003). Patients typically exhibit normal to increased IgM; absent IgG, IgA, and IgE; as well as lymphoid hyperplasia caused by the presence of giant germinal centers.

Nomenclature

14.1 14.2 14.3

14.4

14.4

14.4

14.5

Disease name 3′ Repair exonuclease 1 deficiency 3′ Repair exonuclease 1 deficiency 3′ Repair exonuclease 1 deficiency Ribonuclease H2 subunit B deficiency Ribonuclease H2 subunit C deficiency Ribonuclease H2 subunit A deficiency SAMHD1 deficiency

Alternative disease name Aicardi-Goutières syndrome type 1 Familial chilblain lupus type 1 Retinal vasculopathy with cerebral leukodystrophy Aicardi-Goutières syndrome type 2

Disease abbreviation AGS1

Gene symbol TREX1

Chromosomal localization 3p21.31

Mode of inheritance Affected protein ARa 3-prime repair exonuclease 1 AD 3-prime repair exonuclease 1 AD 3-prime repair exonuclease 1

Disease OMIM# 225750

CHBL1

TREX1

3p21.31

RVCL

TREX1

3p21.31

AGS2

RNASEH2B 13q14.3

AR

Ribonuclease H2, subunit B

610181

Aicardi-Goutières syndrome type 3

AGS3

RNASEH2C 11q13.1

AR

Ribonuclease H2, subunit C

610329

Aicardi-Goutières syndrome type 4

AGS4

RNASEH2A 19p13.13

AR

Ribonuclease H2, subunit A

610333

Aicardi-Goutières syndrome type 5

AGS5

SAMHD1

20q11.23

AR

SAM domain- and 612952 HD domain-­ containing protein 1 SAM domain- and 614415 HD domain-­ containing protein 1 Adenosine deami- 615010 nase, RNA-specific

610448 192315

14.6

SAMHD1 deficiency

Familial chilblain lupus type 2

CHBL2

SAMHD1

20q11.23

AD

14.7

RNA-specific adenosine deaminase deficiency RNA-specific adenosine deaminase deficiency MDA5 superactivity

Aicardi-Goutières syndrome type 6

AGS6

ADAR

1q21.3

ARb

Dyschromatosis symmetrica hereditaria Aicardi-Goutières syndrome type 7

DSH1

ADAR

1q21.3

AD

Adenosine deaminase, RNA-specific

127400

AGS7

IFIH1

2q24.2

de novoc

615846

SGMRT1

IFIH1

2q24.2

AD

Interferon-induced helicase C domaincontaining protein 1, melanoma differentiation-­ associated gene 5 Interferon-induced helicase C domaincontaining protein 1. melanoma differentiation-­ associated gene 5

14.8

14.9

14.10 MDA5 superactiv- Singleton-Merten ity syndrome type 1

182250

(continued)

218

Disease name 14.11 DDX58 superactivity 14.12 STING superactivity

14.13 Ribonuclease T2 deficiency 14.14 2′,5′-oligoadenylate synthetase 1 deficiency

14.15 ABCC6 deficiency

14.16 ABCC6 deficiency 14.17 Ectonucleotide pyrophosphatase/ phosphodiesterase 1 deficiency

14.18 Ectonucleotide pyrophosphatase/ phosphodiesterase 1 dimerization deficiency 14.19 Ecto-5′nucleotidase deficiency 14.20 Equilibrative nucleoside transporter 1 deficiency 14.21 Equilibrative nucleoside transporter 3 deficiency

M. A. Lee-Kirsch et al. Alternative disease name Singleton-Merten syndrome type 2 STING-associated vasculopathy with onset in infancy (SAVI, de novo) familial chilblain lupus type (dominant) Cystic leukoencephalopathy without megalencephaly Infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia Generalized arterial calcification of infancy type 2 (severe) Pseudoxanthoma elasticum (milder)

Disease abbreviation SGMRT2

Gene symbol DDX58

Chromosomal localization 9p21.1

SAVI, CHBL3

TMEM173

5q31.2

RNASET2

6q27

AR

Ribonuclease T2

PAPHG

OAS1

12q24.13

De novo, ADe

2′,5′-oligoadenylate 618042 synthetase 1

GACI2

ABCC6

16p13.11

ARf

ATP-binding cassette, subfamily C, member 6

614473

PXE

ABCC6

16p13.11

ARf

264800

Generalized arterial GACI1, ARHR2 calcification of infancy type 1, autosomal recessive hypophosphatemic rickets type 2 Cole disease COLED

ENPP1

6q23.2

AR

ATP-binding cassette, subfamily C, member 6 Ectonucleotide pyrophosphatase/ phosphodiesterase

ENPP1

6q23.2

AD, AR

Ectonucleotide pyrophosphatase/ phosphodiesterase

615522

ACDC Arterial calcification due to deficiency of CD73 Augustine-null blood type and ectopic mineralizationg Histiocytosislymphadenopathy plus syndrome, H syndrome, familial Rosai-Dorfman disease, Faisalabad histiocytosis Hyper-IgM synHIGM2 drome type 2

NT5E

6q14.3

AR

Ecto-5-prime nucle- 211800 otidase

SLC29A1

6p21.1

AR

Equilibrative nucleoside transporter 1

SLC29A3

10q22.1

AR

Equilibrative nucle- 602782 oside transporter 3

AICDA

12p13.31

AR

Activation-induced cytidine deaminase

605258

UNG

12q24.11

AR

Uracil-DNA glycosylase

608106

14.22 Activationinduced cytidine deaminase deficiency 14.23 Uracil-DNA glyco- Hyper-IgM synsylase deficiency drome type 5

HIGM5

Heterozygous de novo mutations described in very few patients with AGS1 Heterozygous de novo mutations described in few patients with AGS6 c Autosomal dominant mutations with reduced penetrance described in patients with AGS7 d Autosomal dominant mutation in family with lupus-like disease and SAVI described e Autosomal-dominant inheritance due to maternal mosaic described in one family with PAPHG f Heterozygous carriers may express mild pseudoxanthoma elasticum g Ill-defined clinical entity a

b

Mode of inheritance Affected protein AD Retinoic acidinducible gene I De novod, Transmembrane AD protein 173; Stimulator of interferon genes

Disease OMIM# 616298 615934

612951

208000, 613312

14  Disorders of Nucleotide Metabolism

219

Metabolic Pathways

Fig. 14.1  Pathways of nucleic acid metabolism and innate immune sensing. TREX1 is a cytosolic deoxyribonuclease anchored in the outer nuclear membrane that degrades ssDNA derived from DNA repair or reverse transcription of endogenous retroelements. A lack of TREX1 causes DNA accumulation, within both the nucleus and the cytosol. Within the cytosol, ssDNA metabolites with stem loops or dsDNA are sensed by the DNA sensor cGAS which signals via STING (encoded by TMEM173) to induce type I IFN production. Activating mutations in STING cause constitutive type I IFN signaling in the absence of cGAS activation. The heterotrimeric RNase H2 maintains genome integrity by removing ribonucleotides misincorporated during DNA replication. The presence of ribonucleotides in genomic DNA enhances photodimerization of adjacent pyrimidines, which are repaired by nucleotide excision repair. A lack of RNase H2 promotes DNA damage, leading to enhanced formation of DNA repair metabolites. SAMHD1 degrades deoxynucleoside triphosphates (dNTP), thereby controlling the dNTP pool required for DNA synthesis. Loss of SAMHD1 function induces cell cycle arrest and DNA damage. DNA byproducts derived from DNA

repair cause cGAS-mediated type I IFN activation. SAMHD1 has also ribonuclease activity, suggesting that a loss of SAMHD1 may lead to RNA accumulation. ADAR modifies dsRNA through deamination of adenosine to inosine, thereby preventing recognition of dsRNA by the RNA sensor MDA5 (encoded by IFIH1). Upon binding to dsRNA, OAS1 synthesizes 2′–5′-linked oligoadenylates using ATP as substrate, which in turn activate RNase L.  This leads to RNA degradation and formation of short RNA fragments that act as ligand for RIG-I (encoded by DDX58), another cytosolic RNA sensor. Both RNA sensors, MDA5 and RIG-I, signal via mitochondrial antiviral signaling (MAVS) to activate type I IFN. Activation of either the DNA-sensing pathway led by cGAS or the RNA-sensing pathways led by MDA5 and RIG-I result in phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3) which induces expression of the IFNB gene and numerous interferon-stimulated genes (ISG). Activating mutations in RIG-I and MDA5 increases receptor affinity resulting in constitutive type I IFN signaling. RNase T2 degrades ribosomal RNA in lysosomes. A lack of RNase T2 causes RNA accumulation which may activate RNA sensors

220

Fig. 14.2  Disorders of nucleotide transport and metabolism associated with ectopic mineralization or immune homeostasis. Pyrophosphate (PPi)-regulating enzymes in concert with the nucleotides ATP and AMP along with the nucleoside adenosine regulate ectopic mineralization by inhibition of PPi-dependent hydroxyapatite crystal formation. ABCC6 mediates the release of ATP from the liver into the extracellular space. In the periphery, ATP is converted into the mineralization inhibitor pyrophosphate (PPi) and AMP by ENPP1. Loss of function of either ABCC6 or ENPP1 results in reduced PPi formation, leading to unabated ectopic mineralization. AMP is converted to adenosine and inorganic phosphate (Pi) by NT5E. Adenosine maintains adequate PPi levels by

M. A. Lee-Kirsch et al.

inhibiting tissue-nonspecific alkaline phosphatase (TNAP) which hydrolyzes PPi, through adenosine receptor-mediated signaling. A lack of NT5E causes ectopic mineralization due to decreased adenosine, which in turn decreases PPi by enhancing TNAP activity. The nucleoside transporter ENT1 has been implicated in this pathway by interfering with extracellular adenosine availability. In contrast, ENT3 regulates cell homeostasis by coordinating lysosomal function with intracellular nucleoside availability, particularly in T cells. The clinical presentation of ENT3 deficiency is highly variable and involves multiple organ systems with signs of immune dysregulation

14  Disorders of Nucleotide Metabolism

Fig. 14.3  Somatic hypermutation and class-switch recombination of immunoglobulin genes. AID initiates SHR (left) by deamination of cytosine (C) to uracil (U) within the variable region of the Ig genes which determines antigen specificity and affinity of the Ig receptor. Different DNA repair pathways are then utilized in the resolution of AID-mediated DNA lesions. If DNA replication occurs before resolution of the C/U mismatch, uracil is used as template resulting in a C to T transition in one daughter cell, or the mismatch is repaired. Alternatively, uracil is recognized by UNG which creates an abasic site that is subsequently converted into a nick by apurinic endonuclease (APE) as the first step of base excision repair (BER). Following replication by error-prone translesion synthesis polymerases (Rev1 or Pol θ),

221

transitions or transversions can occur. Resolution of the uracil mismatch may also occur via the mismatch repair pathway. Bases surrounding the initial U lesion are removed and replaced in an error-prone manner through the action of Pol ƞ and Pol ζ, leading to the spreading of mutations away from the initial site of AID action. CSR (right) also begins with AID creating a uracil at specific G-rich tandem repeated DNA sequences, the so-called switch regions, which direct deletional DNA recombination within the Ig constant regions. Following UNG-­ mediated uracil removal and nicking by APE, DNA double-strand breaks occur through factors of the BER pathway. Directed recombination is completed by nonhomologous end joining

222

M. A. Lee-Kirsch et al.

Signs and Symptoms Table 14.1 3′ Repair exonuclease 1 deficiency: Aicardi-Goutières syndrome type 1 System CNS

Digestive Immune system Cardiovascular Eye Respiratory Dermatological Laboratory findings

Symptoms and biomarkers Cerebral atrophy Cerebrovascular disease Cognitive impairment Dystonia Epileptic seizures Exaggerated startle reaction Feeding difficulties Intracerebral calcifications Irritability Leukodystrophy Microcephaly Sleep disturbances Spasticity Sterile pyrexia Hepatosplenomegaly Autoantibodies Autoimmunity Hypertrophic cardiomyopathy Glaucoma Pulmonary hypertension Chilblain lesions ASAT, ALAT (serum) C26:0 fatty acid (dried blot spot) Interferon-stimulated genes or interferon signature (PBMC) Interferon-α (CSF) Lymphocytes (CSF) Neopterin (CSF) Platelets (EDTA blood)

Neonatal (birth–1 month) ± ±

n-↑ n-↑ n-↑

Infancy (1–18 months) +++ ± ++ ++ ± +++ ++ +++ +++ +++ +++ ++ +++ ++ ++ ± ± ± ± ± + n-↑

Childhood (1.5–11 years) +++ ± ++ ++ ± +++ ++ +++ +++ +++ +++ ++ +++ ++ ± ± ± ± ± ± + n-↑

Adolescence (11–16 years) +++ ± ++ ++ ± ++ + +++ ± +++ +++ ± +++ ++ ± ± ± ± ± ± + n-↑

± ± ± ± ± ± + n-↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

n-↑ n-↑ n-↑ ↓-n

↑↑ ↑ ↑ ↓-n

n-↑ ↑ n-↑ n

n-↑ n-↑ n-↑ n

n-↑ n-↑ n-↑ n

± ± ± ± ± ± ± ± ± ± ±

Adulthood (>16 years) +++ ± ++ ++ ± + +++ +++ +++ +++

Table 14.2 3′ Repair exonuclease 1 deficiency: familial chilblain lupus type 1 System Dermatological

Musculoskeletal Immune system Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Acral violaceous plaques and nodules Chilblain lesions Nail dystrophy or loss Photosensitivity Ulcerative lesions with infarcts with gangrene Arthralgia Autoimmunity Antinuclear antibodies (serum) Interferonstimulated genes or interferon signature (PBMC)

Infancy (1–18 months) ++

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

Adulthood (>16 years) +++

++ ±

+++ ±

+++ ±

+++ ±

± ±

± ±

± ±

± ±

± ± ±

± ± ±

± ± ±

± ± ±

↑

↑↑

↑↑

↑↑

14  Disorders of Nucleotide Metabolism

223

Table 14.3 3′ Repair exonuclease 1 deficiency: retinal vasculopathy with cerebral leukodystrophy System Autonomic system Cardiovascular CNS

Digestive Eye Psychiatric Renal Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Hypertension Raynaud phenomenon Cerebral calcifications Cognitive decline Epileptic seizures Migraine Stroke Gastrointestinal bleeding Vascular retinopathy Psychiatric disturbances Nephropathy ASAT/ALAT (serum)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± ± ++ ++ ± + ++ ± + ++ ± n-↑

Table 14.4  Ribonuclease H2 subunit B, C, and A deficiency System CNS

Gastrointestinal Immune system Cardiovascular Eye Respiratory Dermatological Laboratory findings

Symptoms and biomarkers Cerebral atrophy Cerebrovascular disease Cognitive impairment Dystonia Epileptic seizures Exaggerated startle reaction Feeding difficulties Intracerebral calcifications Irritability Leukodystrophy Microcephaly Sleep disturbances Spasticity Sterile pyrexia Hepatosplenomegaly Autoantibodies Autoimmunity Hypertrophic cardiomyopathy Glaucoma Pulmonary hypertension Chilblain lesions ASAT, ALAT (serum) C26:0 fatty acid (dried blood spot) Interferon-stimulated genes or interferon signature (PBMC) Interferon-α (CSF) Lymphocytes (CSF) Neopterin (CSF) Platelets (EDTA blood)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) +++ ± ++ ++ ± +++

Childhood (1.5–11 years) +++ ± ++ ++ ± +++

Adolescence (11–16 years) +++ ± ++ ++ ± ++

Adulthood (>16 years) +++ ± ++ ++ ±

++ +++ +++ +++ +++ ++ +++ ++ ++ ± ± ±

++ +++ +++ +++ +++ ++ +++ ++ ± ± ± ±

+ +++ ± +++ +++ ± +++ ++ ± ± ± ±

+ +++

± ± ± ±

± ± + n-↑

± ± + n-↑

± ± + n-↑

± ± + n-↑

n-↑

↑↑

↑↑

↑↑

↑↑

n-↑ n-↑ n-↑ ↓-n

↑↑ ↑ ↑ ↓-n

n-↑ ↑ n-↑ n

n-↑ n-↑ n-↑ n

n-↑ n-↑ n-↑ n

± ± ± ± ± ± ± ± ± ± ±

n-↑ n-↑

+++ +++ +++

224

M. A. Lee-Kirsch et al.

Table 14.5  SAMHD1 deficiency: Aicardi-Goutières syndrome type 5 System CNS

Gastrointestinal Immune system Cardiovascular Eye Respiratory Dermatological Laboratory findings

Symptoms and biomarkers Cerebral atrophy Cerebrovascular disease (stenosis, aneurysm, moyamoya-like, stroke) Cognitive impairment Dystonia Epileptic seizures Exaggerated startle reaction Feeding difficulties Intracerebral calcifications Irritability Leukodystrophy Microcephaly Sleep disturbances Spasticity Sterile pyrexia Hepatosplenomegaly Autoantibodies Autoimmunity Hypertrophic cardiomyopathy Glaucoma Pulmonary hypertension Chilblain lesions ASAT, ALAT (serum) C26:0 fatty acid (dried blood spot) Interferon-stimulated genes or interferon signature (PBMC) Interferon-α (CSF) Lymphocytes (CSF) Neopterin (CSF) Platelets (EDTA blood)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) +++ ±

Childhood (1.5–11 years) +++ ±

Adolescence (11–16 years) +++ ±

Adulthood (>16 years) +++ ±

± ± ±

++ ++ ± +++

++ ++ ± +++

++ ++ ± ++

++ ++ ±

± ±

++ +++

++ +++

+ +++

+ +++

± ± ±

+++ +++ +++ ++ +++ ++ ++ ± ± ±

+++ +++ +++ ++ +++ ++ ± ± ± ±

± +++ +++ ± +++ ++ ± ± ± ±

± ± + n-↑

± ± + n-↑

± ± + n-↑

± ± + n-↑

n-↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

n-↑ n-↑ n-↑ ↓-n

↑↑ ↑ ↑ ↓-n

n-↑ ↑ n-↑ n

n-↑ n-↑ n-↑ n

n-↑ n-↑ n-↑ n

± ± ±

n-↑ n-↑

+++ +++ +++ ± ± ± ±

Table 14.6  SAMHD1 deficiency: familial chilblain lupus type 2 (dominant)a System Skin

Symptoms and biomarkers Chilblain lesions Photosensitivity

One patient described

a

Neonatal (birth–1 month)

Infancy (1–18 months) +++ ±

Childhood (1.5-11 years) +++ ±

Adolescence (11–16 years) +++ ±

Adulthood (>16 years) +++ ±

14  Disorders of Nucleotide Metabolism

225

Table 14.7  RNA-specific adenosine deaminase deficiency: Aicardi-Goutières syndrome type 6 Symptoms and biomarkers Bilateral striatal degeneration Cerebral atrophy Cognitive impairment Dystonia Epileptic seizures Exaggerated startle reaction Feeding difficulties Intracerebral calcifications Irritability Leukodystrophy Microcephaly Sleep disturbances Spasticity Sterile pyrexia Gastrointestinal Hepatosplenomegaly Immune system Autoantibodies Autoimmunity Cardiovascular Hypertrophic cardiomyopathy Eye Glaucoma Respiratory Pulmonary hypertension Dermatological Chilblain lesions Routine laboratory ASAT, ALAT (serum) Lymphocytes (CSF) Platelets (EDTA blood) Special laboratory Interferon-stimulated genes or interferon signature (PBMC) Interferon-α (CSF) Neopterin (CSF)

System CNS

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ±

+++ ++ ++ ± +++

+++ ++ ++ ± +++

+++ ++ ++ ± ++

+++ ++ ++ ±

± ±

++ +++

++ +++

+ +++

+ +++

± ± ±

+++ +++ +++ ++ +++ ++ ++ ± ± ±

+++ +++ +++ ++ +++ ++ ± ± ± ±

± +++ +++ ± +++ ++ ± ± ± ±

± ±

± ±

± ±

± ±

n-↑ n-↑ ↓-n n-↑

+ n-↑ ↑ ↓-n ↑↑↑

+ n-↑ ↑ n ↑↑↑

+ n-↑ n-↑ n ↑↑↑

+ n-↑ n-↑ n ↑↑↑

n-↑ n-↑

↑↑ ↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

± ± ±

+++ +++ +++ ± ± ± ±

Table 14.8  RNA-specific adenosine deaminase deficiency: dyschromatosis symmetrica hereditaria (dominant) System Dermatological

Symptoms and biomarkers Hyperpigmented and hypopigmented macules (face, dorsum hands, and feet)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years)

226

M. A. Lee-Kirsch et al.

Table 14.9  MDA5 superactivity: Aicardi-Goutières syndrome type 7 System CNS

Gastrointestinal Immune system Cardiovascular Eye Respiratory Dermatological Laboratory findings

Symptoms and biomarkers Cerebral atrophy Cognitive impairment Dystonia Epileptic seizures Exaggerated startle reaction Feeding difficulties Intracerebral calcifications Irritability Isolated spastic paraparesis Leukodystrophy Microcephaly Sleep disturbances Spasticity Sterile pyrexia Hepatosplenomegaly Autoantibodies Autoimmunity Hypertrophic cardiomyopathy Glaucoma Pulmonary hypertension Chilblain lesions ASAT, ALAT (serum) C26:0 fatty acid (dried blot spot) Interferon-stimulated genes or interferon signature (PBMC) Interferon-α (CSF) Lymphocytes (CSF) Neopterin (CSF) Platelets (EDTA blood)

Neonatal (birth–1 month) ±

Infancy (1–18 months) +++ ++ ++ ± +++ ++ +++ +++ ± +++ +++ ++ +++ ++ ++ ± ± ± ± ± + n-↑

Childhood (1.5–11 years) +++ ++ ++ ± +++ ++ +++ +++ ± +++ +++ ++ +++ ++ ± ± ± ± ± ± + n-↑

Adolescence (11–16 years) +++ ++ ++ ± ++ + +++ ± ± +++ +++ ± +++ ++ ± ± ± ± ± ± + n-↑

Adulthood (>16 years) +++ ++ ++ ±

n-↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

n-↑ n-↑ n-↑ ↓-n

↑↑ ↑ ↑ ↓-n

n-↑ ↑ n-↑ n

n-↑ n-↑ n-↑ n

n-↑ n-↑ n-↑ n

± ± ± ± ± ± ± ± ± ± ± ±

n-↑ n-↑

+ +++ ± +++ +++ +++ ± ± ± ± ± ± + n-↑

Table 14.10  MDA5 superactivity: Singleton-Merten syndrome type 1 System Cardiovascular

Teeth

Musculoskeletal

Immune system Eye Dermatological Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Aortic and mitral valve calcification Cardiac failure Abnormal dentition Alveolar bone loss Mineralization abnormalities Periodontal disease Acro-osteolysis Osteopenia, osteoporosis Short stature Recurrent infections Glaucoma Psoriasis-like Interferonstimulated genes or interferon signature (PBMC)

Infancy (1–18 months) ++

Childhood (1.5–11 years) ++

Adolescence (11–16 years) ++

Adulthood (>16 years) ++

± + +

± + + +

± + + +

± + + +

+ +

+ + +

+ + +

+ + +

± ± ± ++ ↑↑

± ± ± ++ ↑↑

± ± ± ++ ↑↑

± ± ± ++ ↑↑

14  Disorders of Nucleotide Metabolism

227

Table 14.11  DDX58 superactivity: Singleton-Merten syndrome type 2 System Cardiovascular

Musculoskeletal

Teeth Eye Dermatological Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Aortic and mitral valve calcification Cardiac failure Acro-osteolysis Phalangeal osteoarthropathy, contractures Short stature Dental anomalies Glaucoma Psoriasis-like Interferonstimulated genes or interferon signature (PBMC)

Infancy (1–18 months) ++

Childhood (1.5–11 years) ++

Adolescence (11–16 years) +

Adulthood (>16 years) +

± + +

± + +

± + +

± + +

± ± ± ++ ↑↑

± ± ± ++ ↑↑

± ± ± ++ ↑↑

± ± ± ++ ↑↑

Table 14.12  STING superactivity System Dermatological

Respiratory Musculoskeletal Immunology

Cardiovascular Laboratory findings

Symptoms and biomarkers Acral violaceous plaques and nodules Chilblain lesions Malar rash Nail dystrophy or loss Nasal septum perforation Ulcerative lesions with infarcts with gangrene Interstitial lung disease Arthralgia Fever Recurrent infections Lymphadenopathy Arterial hypertension Pulmonary hypertension Autoantibodies (pANCA, cANCA, anticardiolipin antibodies) (serum) C-reactive protein, CRP (plasma) Erythrocyte sedimentation rate (blood) Gamma globulin (serum) Interferon-stimulated genes or interferon signature (PBMC) Lymphopenia (blood)

Neonatal (birth–1 month) +++

Infancy (1–18 months) +++

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

Adulthood (>16 years) ++

++ ± ++ ±

++ ± ++ ±

++ ± ++ ±

++ ± ++ ±

++ ± ± ±

+++

+++

+++

+++

±

++ + +++ +++ ++ ± ± ↑

++ + +++ +++ ++ ± ± ↑

++ + +++ +++ ++ ± ± ↑

++ + +++ +++ ++ ± ± ↑

± + ± ± + ± ± ↑

↑↑↑

↑↑↑

↑↑

↑↑

↑

↑↑↑

↑↑↑

↑↑

↑↑

↑

↑↑ ↑↑↑

↑↑ ↑↑↑

↑↑ ↑↑↑

↑↑ ↑↑↑

↑ ↑↑

↑↑

↑↑

↑↑

↑↑

↑

228

M. A. Lee-Kirsch et al.

Table 14.13  Ribonuclease T2 deficiency System CNS

Ear Laboratory findings

Symptoms and biomarkers Athetosis Cerebral atrophy Cystic leukoencephalopathy without megalencephaly Dystonia Epileptic seizures Intracerebral calcifications Microcephaly Nystagmus Psychomotor retardation Spasticity Deafness, sensorineural Interferon-stimulated genes or interferon signature (PBMC) Lymphocytes (CSF)

Neonatal (birth–1 month) ± +++ +++

Infancy (1–18 months) ± +++ +++

Childhood (1.5–11 years) ± +++ +++

± ± + + ± ++ +++ ± n-↑

± ± + + ± ++ +++ ± n-↑

± ± + + ± ++ +++ ± n-↑

n-↑

n-↑

n-↑

Adolescence (11–16 years)

Adulthood (>16 years)

Table 14.14 2′,5′-Oligoadenylate synthetase 1 deficiency System Respiratory

Digestive Other

Laboratory findings

Symptoms and biomarkers Pulmonary alveolar proteinosis Recurrent respiratory infection Respiratory failure Splenomegaly Early death Failure to thrive Increased susceptibility to viral infection Gamma globulin (serum) Immunoglobulins (serum) Leukocytes (blood) Leukocytosis without abnormal distribution Small and non-foamy alveolar macrophages at bronchoalveolar lavage

Neonatal (birth–1 month) + + + + + + +

Infancy (1–18 months) +++ +++ +++ +++ ++ + ++

Childhood (1.5–11 years) +++ +++ +++ ++ ++ + ++

↓ ↓↓ ↓↓ +

↓↓↓ ↓↓ ↓↓ +++

↓↓↓ ↓↓ ↓↓ +++

+

+++

+++

Adolescence (11–16 years)

Adulthood (>16 years)

Table 14.15  ABCC6 deficiency: generalized arterial calcification of infancy type 2 System Cardiovascular

Musculoskeletal Renal Other

Symptoms and biomarkers Calcification of arteries Calcification of cardiac valves Cardiac failure Coronary artery disease Hypertension Myocardial infarction Joint calcifications Nephrocalcinosis Renal artery calcification Early death

Neonatal (birth–1 month)

Infancy (1–18 months) +++ ++

Childhood (1.5–11 years) +++ ++

Adolescence (11–16 years) ++ ++

+++ +++ +++ +++

+ + + + + ± + +

± ± ± ± + ± +

+ ++

Adulthood (>16 years)

14  Disorders of Nucleotide Metabolism

229

Table 14.16  ABCC6 deficiency: pseudoxanthoma elasticum System Eye

Dermatological

Cardiovascular

Other

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 mth) Angioid streaks of the retina Macular degeneration Peau d’orange retinal changes Retinal hemorrhage Visual impairment Redundant skin folds Yellowish, flat papules and plaques (lateral neck, flexural areas) Premature atherosclerosis, coronary artery disease, stroke Gastrointestinal hemorrhage Intermittent claudication Hematoxylin-eosin stainsa Skin biopsy (elastic fiber fragmentation, calcification)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ±

Adulthood (>16 years) +++

± ±

± +++

± ± ± ±

± ++ + +++

++

± ±

+++

Verhoeff-Gieson (for elastin) and von Kossa (for calcium deposits)

a

Table 14.17  Ectonucleotide pyrophosphatase/phosphodiesterase 1 deficiency System Cardiovascular

Musculoskeletal Renal Dermatological Eye Teeth Other

Laboratory findings

Symptoms and biomarkers Calcification of arteries Calcification of cardiac valves Cardiac failure Coronary artery disease Hypertension Myocardial infarction Joint calcifications Hypophosphatemic ricketsa Renal artery calcification Pseudoxanthomatous skin lesions Angioid streaks, mild retinopathy Infraocclusion, ankylosis, hypercementosis Early death Hyperphosphaturia Hypophosphatemia Prenatal signs (fetal distress, polyhydramnios, pericardial effusion) Phosphate (plasma) Phosphate (urine)

Neonatal (birth–1 month) +++ ++

Infancy (1–18 months) +++ ++

Childhood (1.5–11 years) +++ ++

Adolescence (11–16 years) ++ ++

+++ +++ +++ +++

+++ +++ +++ +++

+ + + + + ± + ±

± ± ± ± + ± + ±

±

±

±

±

+ + +

+ +

n-↓ n-↑

↓↓ ↑↑

+

++

++

±

Patients with ARHR2 show only hypophosphatemic rickets with short stature

a

Adulthood (>16 years)

230

M. A. Lee-Kirsch et al.

Table 14.18  Ectonucleotide pyrophosphatase/phosphodiesterase 1 dimerization deficiency System Dermatological

Musculoskeletal

Symptoms and biomarkers Calcinosis cutis Hyperkeratotic papules Hypopigmented macules Punctate palmoplantar keratoderma Calcific tendinopathy

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ±

± ±

+ +

++ ++

++ ++

±

±

±

±

Table 14.19 Ecto-5′-nucleotidase deficiency System Cardiovascular

Musculoskeletal

Symptoms and Neonatal biomarkers (birth–1 month) Calcification of arteries (iliac, femoral, tibial) Calcification of cardiac valve rings, aorta Intermittent claudication Calcifications of tendons Periarticular calcifications

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) +++ ± ++ ++ ++

Table 14.20  Equilibrative nucleoside transporter 1 deficiency System Musculoskeletal Hematological

Symptoms and biomarkers Periarticular calcification Pseudogout Augustine-null blood type

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + +

Table 14.21  Equilibrative nucleoside transporter 3 deficiency System Immune system

Symptoms and biomarkers Antinuclear antibodies Hepatosplenomegaly Histiocytosis (salivary glands, orbit, eyelid, spleen. testes) Hypergammaglobulinemia Leukocytosis Lymphadenopathy Recurrent fever Musculoskeletal Bone deformities Intrauterine fractures Joint contractures Dermatological Hyperpigmentation Hypertrichosis Panniculitis Ears Sensorineural deafness Endocrine system Growth hormone deficiency Hypergonadotropic hypogonadism Insulin-dependent diabetes mellitus Laboratory findings Antinuclear antibodies (serum) Erythrocyte sedimentation rate Gamma globulin (serum) Leukocytes (blood)

Neonatal Infancy (birth–1 month) (1–18 months)

± ±

±

Childhood (1.5–11 years) ± ± ++

Adolescence (11–16 years) ± ± ++

Adulthood (>16 years) ± ± ++

+ ± ++ + ±

+ ± ++ + ±

+ ± ++ + ±

± ± ± ± ± ±

± ± ± ± ± ± ± ± n-↑ ↑ ↑ n-↑

± ± ± ± ± ± ± ± n-↑ ↑ ↑ n-↑

n-↑ ↑ ↑ n-↑

14  Disorders of Nucleotide Metabolism

231

Table 14.22  Activation-induced cytidine deaminase deficiency Symptoms and Neonatal System biomarkers (birth–1 month) Immune system Lymphoid hyperplasia Recurrent bacterial infections Laboratory Defective generation of findings somatic hypermutations Giant germinal centers in lymph nodes IgG, IgA, IgE (serum) IgM (serum) Impaired Ig class-switch recombination Normal B-cell (CD19+) count

Infancy (1–18 months) +++ +++

Childhood (1.5–11 years) +++ +++

Adolescence (11–16 years) +++ +++

++

++

++

++

++

++

↓↓ ↑-n ++

↓↓ ↑-n ++

↓↓ ↑-n ++

++

++

++

Adulthood (>16 years)

Table 14.23  Uracil-DNA glycosylase deficiency System Immune system Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Lymphoid hyperplasia Recurrent bacterial infections Defective generation of somatic hypermutations Giant germinal centers in lymph nodes IgG, IgA, IgE (serum) IgM (serum) Impaired Ig class switch recombination Normal B-cell (CD19+) count

Diagnosis Genetic Testing Genetic testing by symptom-driven sequencing of a larger group of genes (panel sequencing) or by whole-exome sequencing based on next-generation sequencing has facilitated the diagnosis of rare genetic disorders. This approach is particularly useful in patients presenting with leukodys-

Infancy (1–18 months)

Childhood (1.5–11 years) +++ +++ ++

Adolescence (11–16 years) +++ +++ ++

Adulthood (>16 years) +++ +++ ++

++

++

++

↓↓ ↑-n ++

↓↓ ↑-n ++

↓↓ ↑-n ++

++

++

++

trophy, autoinflammation, or immunodeficiency, all of which comprise a broad range of differential diagnoses. While both routine and special laboratory testing (Table 14.24) may aid in the differential diagnosis, generally for all diseases discussed in this chapter, the definite diagnosis is made by providing evidence for causative mutations in a specific gene by molecular genetic analysis. Confirmation of a specific diagnosis by genetic testing will also allow prenatal diagnosis.

Specific Laboratory Investigations Table 14.24  Specific laboratory tests, which are helpful in the diagnostic workup of a patient suspected of a given disorder Disorder AGS, CHBL, SAVI AGS AGS OAS1 deficiency PXE PXE

Test Interferon signature, upregulation of IFN-stimulated genes IFN-α in CSF Pterins in CSF Alveolar macrophage morphology Elastin fibers in skin with Verhoeff-van Gieson staining Calcium deposits in skin with von Kossa staining

Material Blood drawn into heparin tubes or PAX tubes CSF CSF Bronchoalveolar lavage Skin biopsy

Preconditions, handling If heparin blood is used, samples should be processed within 24 h CSF must be shipped on dry ice to special laboratory CSF must be shipped on dry ice to special laboratory Formalin-fixed, paraffin-embedded sections

Skin biopsy

Formalin-fixed, paraffin-embedded sections

232

Treatment  amilial Chilblain Lupus, STING-­Associated F Vasculopathy, and Aicardi-­Goutières Syndrome Emerging evidence indicates that an immunomodulatory intervention targeting the type I IFN axis using Janus kinase (JAK) inhibitors might be of therapeutic value (Bienias et al. 2018). JAK inhibitors such as ruxolitinib, baricitinib, and tofacitinib block signaling at the IFN receptor. Clinical improvement and suppression of the interferon signature have been demonstrated in patients with TREX1- and STING-associated familial chilblain lupus (König et  al. 2017; Zimmermann et al. 2019). Improvement of skin lesion has also been observed in children with SAVI treated with ruxolitinib, tofacitinib, or baricitinib (Seo et  al. 2017; Frémond et al. 2016; Sanchez et al. 2018). However, pulmonary symptoms did not consistently respond to treatment. While patients with AGS treated with ruxolitinib or baricitinib also respond with suppression of type I IFN activation and some clinical amelioration (Tüngler et  al. 2016; Vanderver et al. 2020), improvement of neurological function depends on preexisting neurological damage. Given the progressive nature of AGS, a timely diagnosis is important as early therapeutic intervention can possibly ameliorate or prevent further brain damage. Although JAK inhibition represents an effective therapeutic strategy in patients with type I interferonopathies, future controlled clinical trials are required to fully assess the therapeutic effects as well as the side effects of JAK inhibitors in these patients.

M. A. Lee-Kirsch et al.

Sometimes prophylactic antibiotic therapy will be recommended for individuals who develop complications of chronic infection such as bronchiectasis.

References

Bergen AA, Plomp AS, Schuurman EJ, et  al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25:228–31. Bienias M, Brück N, Griep C, Wolf C, Kretschmer S, Kind B, Tüngler V, Berner R, Lee-Kirsch MA.  Therapeutic approaches to type I interferonopathies. Curr Rheumatol Rep. 2018;20:32. Blau N, Bonafé L, Krägeloh-Mann I, Thöny B, Kierat L, Häusler M, Ramaekers V.  Cerebrospinal fluid pterins and folates in Aicardi-­ Goutières syndrome: a new phenotype. Neurology. 2003;61: 642–7. Cho K, Yamada M, Agematsu K, et  al. Heterozygous mutations in OAS1 cause infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia. Am J Hum Genet. 2018;102:480–6. Chourabi M, Liew MS, Lim S, et  al. ENPP1 mutation causes recessive Cole disease by altering melanogenesis. J Invest Dermatol. 2018;138:291–300. Crow YJ, Zaki MS, Abdel-Hamid MS, et  al. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics. 2014;45:386–93. Crow YJ, Chase DS, Lowenstein Schmidt J, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A:296–312. Cuadrado E, Vanderver A, Brown KJ, et  al. Aicardi–Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies. Ann Rheum Dis. 2015;74(10):1931–9. Daniels G, Ballif BA, Helias V, et al. Lack of the nucleoside transporter ENT1 results in the Augustine-null blood type and ectopic mineralization. Blood. 2015;125:3651–4. Eytan O, Morice-Picard F, Sarig O, et  al. Cole disease results from mutations in ENPP1. Am J Hum Genet. 2013;93:752–7. Fear DJ.  Mechanisms regulating the targeting and activity of activation induced cytidine deaminase. Curr Opin Immunol. 2013;25: OAS1 Deficiency 619–28. Frémond M-L, Rodero MP, Jeremiah N, et  al. Efficacy of the Janus Immunoglobulin replacement therapy can improve pulmokinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy nary function. Hematopoietic stem cell transplantation is associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016;138:1752–5. considered curative treatment (Cho et al. 2018). Goutieres F, Aicardi J, Barth PG, Lebon P.  Aicardi-Goutieres syndrome: an update and results of interferon-alpha studies. Ann Neurol. 1998;44:900–7. Generalized Arterial Calcification of Infancy Type 1 Gunther C, Hillebrand M, Brunk J, Lee-Kirsch MA. Systemic involvement in TREX1-associated familial chilblain lupus. J Am Acad and Type 2 Dermatol. 2013;69:e179–81. Haud N, Kara F, Diekmann S, et  al. rnaset2 mutant zebrafish model In addition to symptomatic treatment with angiotensin-­ familial cystic leukoencephalopathy and reveal a role for RNase converting enzyme inhibitors and hydralazine, treatment T2 in degrading ribosomal RNA. PNAS. 2011;108:1099–103. with bisphosphonates can improve survival (Rutsch et  al. Hayashi M, Suzuki T.  Dyschromatosis symmetrica hereditaria. J Dermatol. 2013;40:336–43. 2008). Henneke M, Diekmann S, Ohlenbusch A, et  al. RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection. Nat Genet. 2009;41:773–5. Imai K, Slupphaug G, Lee W-I, et al. Human uracil-DNA glycosylase Hyper-IgM Syndrome Type 2 and Type 5 deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003;4:1023–8. Regular treatment with immunoglobulin replacement ther- Jang MA, Kim EK, Now H, et al. Mutations in DDX58, which encodes apy markedly reduces the frequency of bacterial infections RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015;96:266–74. and the likelihood of developing lymphoid hyperplasia.

14  Disorders of Nucleotide Metabolism Jeremiah N, Neven B, Gentili M, et  al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-­ like manifestations. J Clin Invest. 2014;124:5516–20. König N, Fiehn C, Wolf C, et al. Familial chilblain lupus due to a gain-­of-­ function mutation in STING. Ann Rheum Dis. 2017;76(2):468–72. Lee GS, Brandt VL, Roth DB. B cell development leads off with a base hit: dU:dG mismatches in class switching and hypermutation. Mol Cell. 2004;16:505–8. Lee-Kirsch MA.  The type I interferonopathies. Annu Rev Med. 2017;68:297–315. Lee-Kirsch MA, Gong M, Schulz H, Ruschendorf F, Stein A, Pfeiffer C, Ballarini A, Gahr M, Hubner N, Linne M.  Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet. 2006;79:731–7. Lee-Kirsch MA, Chowdhury D, Harvey S, et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med. 2007;85:531–7. Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18. Livingston JH, Lin J-P, Dale RC, et  al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet. 2014;51:76–82. Molho-Pessach V, Ramot Y, Camille F, Doviner V, Babay S, Luis SJ, Broshtilova V, Zlotogorski A. H syndrome: the first 79 patients. J Am Acad Dermatol. 2014;70:80–8. Nitschke Y, Baujat G, Botschen U, et  al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90:25–39. Ramantani G, Kohlhase J, Hertzberg C, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum. 2010;62:1469–77. Ramantani G, Hausler M, Niggemann P, Wessling B, Guttmann H, Mull M, Tenbrock K, Lee-Kirsch MA. Aicardi-Goutieres syndrome and systemic lupus erythematosus (SLE) in a 12-year-old boy with SAMHD1 mutations. J Child Neurol. 2011;26:1425–8. Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A. 2011;155A:235–7. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-­ IgM syndrome (HIGM2). Cell. 2000;102:565–75. Rice G, Newman WG, Dean J, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80:811–5. Rice GI, Forte GM, Szynkiewicz M, et  al. Assessment of interferon-­ related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. 2013;12:1159–69. Richards A, van den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3’-5’ DNA exonuclease TREX1 cause autosomal

233 dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39:1068–70. Rutsch F, Böyer P, Nitschke Y, et  al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008;1:133–40. Rutsch F, MacDougall M, Lu C, et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96:275–82. Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041–52. Schlee M, Hartmann G.  Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol. 2016;16:566–80. Seo J, Kang J-A, Suh DI, et al. Tofacitinib relieves symptoms of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173. J Allergy Clin Immunol. 2017;139:1396–1399.e12. St Hilaire C, Ziegler SG, Markello TC, et al. NT5E mutations and arterial calcifications. N Engl J Med. 2011;364:432–42. Stavnezer J, Guikema JEJ, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008;26:261–92. Struk B, Cai L, Zäch S, et al. Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum. J Mol Med. 2000;78:282–6. Tüngler V, Schmidt F, Hieronimus S, Reyes-Velasco C, Lee-Kirsch M. Phenotypic variability in a family with Aicardi-Goutières syndrome due to the common A177T RNASEH2B mutation. Case Rep Clin Med. 2014;3:153–6. Tüngler V, König N, Günther C, Engel K, Fiehn C, Smitka M, von der Hagen M, Berner R, Lee-Kirsch MA. Response to: “JAK inhibition in STING-associated interferonopathy” by Crow et al. Ann Rheum Dis. 2016;75:e76. Vanderver A, Adang L, Gavazzi F, et al. Janus kinase inhibition in the Aicardi-Goutières syndrome. N Engl J Med. 2020;383:986–9. Vogt J, Agrawal S, Ibrahim Z, Southwood TR, Philip S, Macpherson L, Bhole MV, Crow YJ, Oley C. Striking intrafamilial phenotypic variability in Aicardi-Goutieres syndrome associated with the recurrent Asian founder mutation in RNASEH2C. Am J Med Genet A. 2013;161A:338–42. Wei C-W, Lee C-Y, Lee D-J, et al. Equilibrative nucleoside transporter 3 regulates T cell homeostasis by coordinating lysosomal function with nucleoside availability. Cell Rep. 2018;23:2330–41. Xin B, Jones S, Puffenberger EG, et  al. Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proc Natl Acad Sci U S A. 2011;108:5372–7. Yamashiro K, Tanaka R, Li Y, Mikasa M, Hattori N. A TREX1 mutation causing cerebral vasculopathy in a patient with familial chilblain lupus. J Neurol. 2013;260:2653–5. Zimmermann N, Wolf C, Schwenke R, Lüth A, Schmidt F, Engel K, Lee-Kirsch MA, Günther C.  Assessment of clinical response to Janus kinase inhibition in patients with familial chilblain lupus and TREX1 mutation. JAMA Dermatol. 2019;155(3):342–6.

Disorders of Creatine Metabolism

15

Sylvia Stöckler-Ipsiroglu, Olivier Braissant, and Andreas Schulze

Contents Introduction

 236

Nomenclature

 236

Primary Creatine Deficiencies/AGAT, GAMT, and CrT Deficiencies

 237

Arginine: Glycine Amidinotransferase Aggregation Syndrome

 238

OAT Deficiency

 238

Diagnosis

 240

Treatments

 242

Prenatal Diagnosis

 243

DNA Testing

 244

Specimen Collection

 244

Reference Values

 245

Pathological Values

 246

Standard Treatment

 247

Dietary Treatment

 247

Alternative Therapies/Experimental Trials

 248

References

 248

S. Stöckler-Ipsiroglu (*) Division of Biochemical Genetics, BC Children’s Hospital, Vancouver, BC, Canada

A. Schulze Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada e-mail: [email protected]

Departments of Pediatrics and Biochemistry, University of Toronto, Toronto, ON, Canada e-mail: [email protected]

O. Braissant Service of Clinical Chemistry, Department of Laboratories, University Hospital and University of Lausanne, Lausanne, Switzerland e-mail: [email protected] © Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_15

235

236

S. Stöckler-Ipsiroglu et al.

Summary

Introduction

Reduced creatine levels in the brain and in body fluids/ tissues are the common denominator of primary creatine disorders (cerebral creatine deficiency syndromes types 1–3: X-linked creatine transporter (CrT/SLC6A8) deficiency, GAMT/GAMT deficiency, AGAT/GATM deficiency). Characteristic clinical features include developmental delay/intellectual disability; speech impairment and behavioral problems, combined with epilepsy; and movement disorders. Arginine:glycine amidinotransferase aggregation syndrome is a newly described genetic cause of renal Fanconi syndrome and kidney failure caused by aggregation of certain fully penetrant heterozygous GATM missense variants. OAT/OAT deficiency is a secondary creatine deficiency syndrome leading to chorioretinal degeneration. Diagnostic markers, besides brain creatine deficiency, include high or low levels of guanidinoacetate for GAMT and AGAT deficiency, a high urinary creatine excretion for CrT deficiency, and high plasma ornithine levels for OAT deficiency. Treatments comprise substitution of creatine (AGAT deficiency) combined with l-ornithine (GAMT deficiency) and arginine restricted diet (GAMT and OAT deficiency). Creatine and substrates for intracerebral creatine synthesis (l-­ arginine and l-glycine) have limited therapeutic effects in CrT deficiency. Improved outcomes after early recognition have prompted the implementation of GAMT newborn screening in various juridictions.

Creatine is synthesized by two enzymatic reactions: (1) the formation of guanidinoacetate (GAA) from arginine and glycine by l-arginine:glycine amidinotransferase (AGAT/GATM) and (2) the methylation of GAA by S-adenosyl-l-methionine:N-guanidinoacetate methyltransferase (GAMT/GAMT). The liver, pancreas, and kidney are the main sites of creatine synthesis. Creatine is transported into cells via an X-linked Na+/Cl−-dependent creatine transporter, CrT/SLC6A8. While blood-brain barrier expresses CrT allowing the brain to take up creatine, this transport from periphery has a low efficacy, and CNS must supply parts of its needs in creatine through endogenous synthesis, by expression of AGAT and GAMT (Hanna-El-Daher and Braissant 2016). Creatine plays a major role in storage and transmission of high-energy phosphates (ATP), via reversible conversion into phosphocreatine, catalyzed by creatine kinases. Creatine may also play a role in neurotransmission. Intracellular creatine and phosphocreatine are nonenzymatically converted into creatinine, which is excreted in urine. The daily creatinine excretion is directly proportional to total body creatine content. Creatine synthesis is regulated via AGAT activity. Because AGAT is inhibited by high concentrations of l-ornithine, the hyperornithinemia in ornithine aminotransferase (OAT) deficiency is associated with secondary creatine deficiency.

Nomenclature No. Disorder name 15.1 Arginine:glycine amidinotransferase deficiency 15.2 Guanidinoacetate methyltransferase deficiency 15.3 Creatine transporter deficiency

15.4 Arginine:glycine amidinotransferase aggregation syndrome 15.5 Ornithine aminotransferase deficiency

Alternative disorder names Glycine amidinotransferase deficiency – X-linked creatine deficiency syndrome, CrT, or SLC6A8 deficiency AD GATM renal Fanconi syndrome Gyrate atrophy of the choroid and retina

Disorder abbreviation AGAT

Gene symbol GATM

Chromosomal localization 15q15.3

GAMT

GAMT

19p13.3

CrT, SLC6A8, CTD

SLC6A8

Xp28

AGAT AS

GATM

15q15.3

Arginine:glycine amidinotransferase

OAT, GACR

OAT

10q26.13

Ornithine aminotransferase

Affected protein Arginine:glycine amidinotransferase Guanidinoacetate methyltransferase SLC6A8 transporter (CrT, creatine transporter)

OMIM # 612718

612736 300352

258870

15  Disorders of Creatine Metabolism

237

or various degrees of epilepsy ranging from occasional to pharmaco-resistant seizures. Additional manifestations include failure to thrive, low muscular mass, muscular hypoPrimary creatine deficiencies comprise two autosomal tonia, and movement disorders (mainly extrapyramidal). recessive inborn errors of creatine synthesis, AGAT (15.1) Myopathy and proximal muscle weakness are an additional and GAMT (15.2) deficiencies, and one X-linked defect feature in AGAT deficiency. Pathological signal intensities of creatine transport, CrT (15.3) deficiency (Mercimek-­ of the basal ganglia have mainly been described in patients Mahmutoglu and Salomons 2009). The main affected tissue with GAMT deficiency. Approximately 120 patients are in primary creatine deficiencies is the brain, which pres- known with GAMT deficiency, and less than 20 patients are ents as a strongly decreased or absent peak of creatine as known with AGAT deficiency. CrT deficiency may represent measured by proton magnetic resonance spectroscopy (1H-­ a major cause of X-linked intellectual disability accounting MRS). Developmental delay and intellectual disability are for 1–2% in males with intellectual disabilities (Rosenberg their common clinical presentation. Speech impairment is et al. 2004). Detailed clinical features are described in series most prominent even in patients with mild/moderate intel- of cases with AGAT, GAMT, and CrT (Stöckler-Ipsiroglu lectual disability. Many patients have autistic behavior and/ et al. 2014, 2015; van de Kamp et al. 2013).

 rimary Creatine Deficiencies/AGAT, GAMT, P and CrT Deficiencies

Table 15.1  Arginine:glycine amidinotransferase deficiency System CNS

Other Laboratory findings

Symptoms and biomarkers Autism Cerebral creatine deficiency Developmental delay Epilepsy Myopathy Speech delay Failure to thrive Creatine (MRS) Creatine/creatinine ratio (urine) Creatinine (plasma) Creatinine (urine) Guanidinoacetate (cerebrospinal fluid) Guanidinoacetate (plasma) Guanidinoacetate (urine)

Neonatal (birth–1 month) +++

Infancy (1–18 months) + +++

Childhood (1.5–11 years) + +++

Adolescence (11–16 years) + +++

Adulthood (>16 years) + +++

↓↓↓ ↓-n

+++ + + +++ + ↓↓↓ ↓-n

+++ + + +++ + ↓↓↓ ↓-n

+++ + + +++ + ↓↓↓ ↓-n

+++ + + +++ + ↓↓↓ ↓-n

↓-n ↓-n ↓↓↓

↓-n ↓-n ↓↓↓

↓-n ↓-n ↓↓↓

↓-n ↓-n ↓↓↓

↓-n ↓-n ↓↓↓

↓↓↓ ↓↓↓

↓↓↓ ↓↓↓

↓↓↓ ↓↓↓

↓↓↓ ↓↓↓

↓↓↓ ↓↓↓

Table 15.2  Guanidinoacetate methyltransferase deficiency System CNS

Musculoskeletal

Symptoms and biomarkers Autism Basal ganglia abnormalities (MRI) Cerebral creatine deficiency Developmental delay Epilepsy Movement disorder Speech delay Osteoporosis

Neonatal (birth–1 month)

Infancy (1–18 months) +++ +

Childhood (1.5–11 years) +++ +

Adolescence (11–16 years) +++ +

Adulthood (>16 years) +++ +

+++

+++

+++

+++

+++

+++ ++ + +++

+++ ++ + +++

+++ ++ + +++ ±

+++ ++ + +++ (continued)

238

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Table 15.2 (continued) System Laboratory findings

Symptoms and biomarkers Creatine (cerebrospinal fluid) Creatine (plasma) Creatine (urine) Creatinine (plasma) Creatinine (urine) Guanidinoacetate (cerebrospinal fluid) Guanidinoacetate (plasma) Guanidinoacetate (urine)

Neonatal (birth–1 month) ↓-n

Infancy (1–18 months) ↓↓

Childhood (1.5–11 years) ↓↓

Adolescence (11–16 years) ↓↓

Adulthood (>16 years) ↓↓

↓-n ↓-n ↓-n ↓-n ↑↑↑

↓↓ ↓↓ ↓ ↓ ↑↑↑

↓↓ ↓↓ ↓ ↓ ↑↑↑

↓↓ ↓↓ ↓ ↓ ↑↑↑

↓↓ ↓↓ ↓ ↓ ↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

Table 15.3  Creatine transporter deficiency System CNS

Digestive Musculoskeletal Laboratory findings

Symptoms and biomarkers Autism Cerebral creatine deficiency Developmental delay Epilepsy Speech delay Constipation Muscle mass, low Creatine/creatinine ratio (urine)

Neonatal (birth–1 month)

Infancy (1–18 months) +++ +++

Childhood (1.5–11 years) +++ +++

Adolescence (11–16 years) +++ +++

Adulthood (>16 years) +++ +++

+++ + +++ ± ± ↑↑

+++ + +++ ± + ↑↑

+++ + +++ ± + ↑↑

+++ + +++ ± + ↑↑

 rginine: Glycine Amidinotransferase A Aggregation Syndrome AGAT aggregation syndrome is a newly described genetic cause of renal Fanconi syndrome and kidney failure caused by mitochondrial aggregation of fully penetrant heterozygous GATM missense variants (Fanconi renotubular syndrome type 1). Four previously unreported heterozygous missense variants of evolutionary conserved amino acid residues in GATM (p.P320S, p.T336A, p.T336I, p.P341L) have been identified in these patients. Patients with this autosomal dominant disorders develop renal Fanconi syndrome with glucosuria, hyperphosphaturia, generalized hyperaminoaciduria, low molecular weight proteinuria, and metabolic acidosis. Debilitating rickets or bone deformities have not been described in these patients (Reichold et al. 2018).

OAT Deficiency OAT deficiency is a secondary creatine deficiency. Hyperornithinemia-associated gyrate atrophy of the choroid and retina is an inherited metabolic eye disease, caused by auto-

somal recessive deficiency of the l-ornithine:2-oxoacid aminotransferase (OAT) (15.5) (Valle and Simell 1995). Clinical features include progressive chorioretinal degeneration with myopia, night blindness, and loss of peripheral vision starting late in the first decade, proceeding to tunnel vision and eventually leading to blindness in the third and fourth decade. In addition to the ocular findings, some patients present systemic abnormalities. Most patients have normal intelligence. MRI findings include degenerative lesions in the white matter and premature atrophic changes. Tubular aggregates and selected atrophy of the type II fibers of skeletal muscle do not cause muscle weakness, although muscle performance of affected patients may be impaired when speed or acute strength is required. OAT is a mitochondrial matrix enzyme that requires pyridoxal phosphate (vitamin B6) for the reversible conversion of ornithine and 2-oxoglutarate to Δ1-pyrroline5-carboxylate and glutamate. In its deficiency, the accumulation of ornithine causes secondary creatine deficiency through inhibition of AGAT activity, the rate-limiting step in endogenous creatine synthesis (Näntö-Salonen et al. 1999). The pathways of creatine synthesis and transport are shown in Fig. 15.1.

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Table 15.4  Arginine:glycine amidinotransferase aggregation syndrome System Musculoskeletal

Renal

Laboratory findings

Symptoms and biomarkers Hypophosphatemic rickets Muscle weakness, progressive Osteomalacia Aminoaciduria Renal failure Renal tubular acidosis Amino acids (urine) Amino acids (urine), all Creatinine (serum) Cystine (urine) Glucose (urine) Phosphate (plasma) Phosphate (urine) Potassium (plasma) Proteins, low molecular weight (urine)

Neonatal (birth–1 month)

Infancy (1–18 months) ↑

+

+

+ ↑

+ ↑

↑

↑

↑

↑

↑

↑

Childhood (1.5–11 years) ↑

Adolescence (11–16 years) ↑

Adulthood (>16 years) ↑

+

+

+

+ +

+ +

+

+

+ + + +

+ ↑

+ ↑

+ ↑

n ↑ ↓ ↑ ↓ ↑

n ↑ ↓ ↑ ↓ ↑

↑ n ↑ ↓ ↑ ↓ ↑

Table 15.5  Ornithine aminotransferase deficiency System CNS

Digestive Eye

Metabolic Musculoskeletal

Symptoms and biomarkers Cortical atrophy (MRI) Intellectual disability Neuropathy, sensory Seizures White matter abnormalities (MRI) EM, abnormal mitochondria (liver) Atrophy, gyrate of the choroid and retina Blindness Cataract, posterior subcapsular Chorioretinal degeneration Myopia Night blindness Retinal detachment Vision, tunnel Hyperammonemia (symptomatic) EM, abnormal mitochondria (muscle) EM, type 2 fiber atrophy (muscle) EM, type 2 fiber tubular aggregates (muscle) Muscle weakness (mild proximal)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ± ± ± ++

Adulthood (>16 years) ± ± ± ± ± ± +++

+ + ++ ±

± ++ ++ 0 ± +

+++a +++ +++ +++ +++ ± +++

± ± +

± ± +

± ± ++

±

±

±

± ±

+

± ±

±

(continued)

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Table 15.5 (continued) System Laboratory findings

Symptoms and biomarkers 3-Amino-2-piperidone (urine) Ammonia (blood and plasma) Arginine (urine) Creatine (cerebrospinal fluid) Creatine (plasma) Creatine (urine) Creatine/phosphocreatine ratio (brain) (MRS) Creatine/phosphocreatine ratio (muscle) (MRS) Creatinine (plasma) Guanidinoacetate (cerebrospinal fluid) Guanidinoacetate (plasma) Guanidinoacetate (urine) Histology and EM, type 2 fiber atrophy (muscle) Lysine (urine) Ornithine (plasma) Ornithine (urine) Proline/citrulline ratio

Neonatal (birth–1 month) n n-↑↑ n n n n n

Infancy (1–18 months) ↑ n ↑ ↓↓ ↓↓ ↓↓ ↓-n

Childhood (1.5–11 years) ↑ n ↑ ↓↓ ↓↓ ↓↓ ↓

Adolescence (11–16 years) ↑ n ↑ ↓↓↓ ↓↓↓ ↓↓↓ ↓

Adulthood (>16 years) ↑ n ↑ ↓↓↓ ↓↓↓ ↓↓↓ ↓

n

↓-n

↓

↓

↓

n n n n

↓-n ↓↓ ↓↓ ↓↓

↓-n ↓↓ ↓↓ ↓↓ +

↓-n ↓↓↓ ↓↓↓ ↓↓↓ +

↓-n ↓↓↓ ↓↓↓ ↓↓↓ ++-+++

n n n ↑

↑ ↑↑↑ ↑↑↑ n

↑ ↑↑↑ ↑↑↑ n

↑ ↑↑↑ ↑↑↑ n

↑ ↑↑↑ ↑↑↑ n

>30 years

a

1: Creatine synthesis kidney, liver, pancreas brain

Arginine

Glycine

(15.01;15.04) AGAT

2-Oxoglutarate

ADP ATP CK PhosphoGuanidinoacetate guanidinoacetate

Ornithine

(15.05) OAT

S-adenosylmethionine

Glutamate

(15.02) GAMT S-adenosylhomocysteine

Glutamate 5-semialdehyde

Creatine

2: Creatine uptake

mainly brain, muscle

SLC6A8 (15.03) ATP

3: Creatine / Creatine phosphocreatine / CK system mainly brain, muscle

neurotransmission ?

4: Urinary creatinine excretion

ADP CK

Phosphocreatine

Non-enzymatic conversion

Creatinine

Creatinine

Fig. 15.1  Pathways of creatine synthesis and transport

Diagnosis AGAT, GAMT, CrT Deficiencies Primary creatine disorders may account for a high proportion of undiagnosed and potentially treatable genetic intellectual disability syndromes in children and adults (Stöckler-Ipsiroglu

and van Karnebeek 2014). Therefore, selective screening for these disorders should be included in the investigation of this population. Cerebral creatine deficiency as detected by 1HMRS is the common biochemical hallmark of AGAT, GAMT, and CrT deficiencies. Biochemical indicators include the following metabolites in urine, blood, and CSF. Increased levels of GAA in body fluids are pathognomonic for GAMT deficiency, whereas GAA levels are reduced in AGAT deficiency. Increased urinary creatine and decreased creatinine excretion, resulting in an increased urinary creatine-to-creatinine ratio, are associated with CrT deficiency (Sharer et al. 2017). Heterozygous females may also be affected clinically, but it appears that urinary creatine/creatinine ratio and cerebral creatine levels are not reliable diagnostic markers in females (van de Kamp et  al. 2011). Diagnosis of AGAT deficiency is particularly challenging as determination of urinary GAA excretion is lacking sensitivity. Determination of GAA in blood seems to be more sensitive (Stöckler-Ipsiroglu et  al. 2015). In an increasing number of cases, next-generation sequencing has provided the primary diagnosis, while determination of characteristic metabolites and enzyme activities is used for disease confirmation. Assays have been developed for the determination of AGAT, GAMT, and CrT activities in fibroblasts and white blood cells (Verhoeven et al. 2003; Berends et al. 2017; Joncquel-Chevalier Curt et al. 2018). Based on most favorable outcomes in early-diagnosed patients, newborn screening for GAMT deficiency has been implemented in several legislations (Sinclair et  al. 2016; Pasquali et  al. 2014). A second-tier LC-MS/MS assay for guanidinoacetate quantification from bloodspots removes the interference seen in the first-tier standard flow injection assay, thus greatly improving the performance of the assay.

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Functional and in silico analyses of GAMT variants reported in public databases revealed GAMT carrier estimates of 1 in 372 and 1 in 812, respectively, and a calculated disease frequency of 1 in 550,000 and 1 in 2,640,000 (Desroches et al. 2015). The rarity of the condition may explain why, after screening of over one million newborns world-wide, the 1st case has only been identified this beginning of 2021.

 rginine: Glycine Amidinotransferase Aggregation A Syndrome Extrarenal metabolic abnormalities such as creatine and GAA deficiency are not expected to occur in this condition. The diagnosis is confined to GATM DNA testing. Electron microscopy and immunofluorescence staining showing intramitochondrial filaments formed by AGAT aggregates may give a first hint (Reichold et al. 2018).

OAT Deficiency The biochemical hallmark of OAT deficiency is marked hyperornithinemia. The most important laboratory test

in this disease is therefore the amino acid analysis in plasma. In patients, plasma ornithine ranges from 400 to 1400 μmol/L (normal less than 80 to 90 μmol/L). The combination of elevated plasma ornithine and characteristic ocular findings is highly specific for the disease. Ornithine is also increased in the CSF and urine. Pathologic urinary excretion of ornithine and other dibasic amino acids (arginine, lysine, cystine) typically occurs at plasma ornithine concentrations greater than 600  μmol/L.  In plasma, lysine and creatine may be decreased. In urine, creatine, creatinine, and GAA are usually decreased. Investigation by in  vivo 1H-MRS reveals a decreased concentration of creatine and phosphocreatine in the brain and muscle. DNA testing can be performed to confirm the diagnosis. Enzyme analysis is feasible in stimulated lymphocytes but provides only sparse additional information and is not offered for routine analysis by clinical laboratories. Prenatal diagnosis is potentially possible by ornithine aminotransferase activity measurement in amniotic fluid cells or chorionic villi or by DNA testing if the genetic variant is known in the index case. The differential diagnosis of disorders of creatine meta­ bolism is shown in Fig. 15.2.

Patient

Renal symptoms

MRS of brain creatine

Neurological symptoms

Cr: normal

Other defects

Cr: decreased ↓

Measure of GAA, creatine, creatinine and/or ornithine

GAA: increased ↑ U,P,CSF

GATM sequencing, renal tubulopathy gene panel

15.04 AGAT AS

GAMT sequencing, enzyme activity

15.02 GAMT deficiency

GAA: decreased ↓ U,P

GAA,Cr: normal U,P,CSF and Cr/Crn ratio: increased ↑ U

GAA,Cr: decreased ↓ U,P and Orn: increased ↑ U,P,CSF

GATM sequencing, enzyme activity

SLC6A8 sequencing, enzyme activity

OAT sequencing, enzyme activity

15.01 AGAT deficiency

15.03 SLC6A8 deficiency

15.05 OAT deficiency

Fig. 15.2  Differential diagnosis of disorders of creatine metabolism

242

Treatments GAMT, AGAT, CrT Deficiencies In GAMT and AGAT deficiencies, correction of cerebral creatine deficiency is achieved via long-term supplementation of high dosages of creatine (given as creatine monohydrate). Clinically in AGAT deficiency, this is associated with significant improvement of myopathy, limited improvement of cognitive function in older patients, and normal development in patients treated at an early age (Stöckler-Ipsiroglu et al. 2015). In GAMT deficiency, creatine supplementation is combined with pharmacological doses of l-ornithine and/or dietary arginine restriction with the aim to reduce guanidinoacetate accumulation (Schulze et al. 2001). Treatment results in improvement of seizures and movement disorders but has limited effects on cognition and behaviors in late-treated patients, while presymptomatic/early treatment appears to completely prevent all these manifestations (Stöckler-­ Ipsiroglu et  al. 2014; Khaikin et  al. 2018). Sodium benzoate has been proposed as an additional approach to reduce the production of GAA via conjugation with glycine to form hippuric acid; however, its clinical efficacy is inconclusive (Viau et al. 2013; Mercimek-Mahmutoglu et al. 2014). In CrT deficiency, while females may benefit from creatine supplementation, treatment of male patients even with high dosages of creatine is not effective due to the absence of functional CrT.  Various combinations of l-arginine, l-­ glycine, and S-adenosyl-methionine (serving as precursors for intracerebral creatine synthesis) have also been employed. While some neurological and behavioral improvements associated with these treatments were observed in a few cases, in many others, the clinical benefit was inconclusive (Bruun

S. Stöckler-Ipsiroglu et al.

et al. 2018; Dunbar et al. 2014; Valayannopoulos et al. 2012; van de Kamp et  al. 2012). Creatine analogues and small molecule chaperone therapies are currently under preclinical investigation as treatment options.

 rginine: Glycine Amidinotransferase Aggregation A Syndrome It has been proposed that reduction of renal GATM mRNA expression via creatine supplementation may retard the formation of deleterious mitochondrial deposits (Reichold et al. 2018).

OAT Deficiency Permanent reduction of plasma ornithine below 200 μmol/L slows or stops the chorioretinal degeneration. A small proportion of patients respond to pharmacological doses of vitamin B6. Mainstay of treatment is substrate deprivation with a diet that consists of arginine restriction and argininefree amino acid supplements. Additional experimental approaches include augmentation of renal ornithine excretion by administration of pharmacological doses of l-lysine (Elpeleg and Korman 2001) or the non-metabolizable amino acid α-aminoisobutyric acid and proline supplementation. Since no form of therapy is unequivocally effective, combined treatment approaches seem necessary. Creatine administration improves the histologic abnormalities in muscle, but does not halt the progress of chorioretinal degeneration. An algorithm for the assessment of Vitamin B6 responsiveness is shown in Fig. 15.3.

15  Disorders of Creatine Metabolism

243

Vitamin B6 < 6 y 200 mg/day > 6 y 500 mg/day for 1-2 months

plasma Orn < 200 µM

YES

Significant reduction of plasma Orn

YES

Dietary Arg restriction

B6 treatment + dietary Arg restriction

plasma Orn < 200-400 µM

plasma Orn < 200 µM

NO

YES

Continue B6 treatment + dietary Arg restriction

NO

dietary Arg restriction + experimental trial with L-lysine or α-aminoisobutyric acid

Keep plasma Orn < 200-400 µM

Continue B6 treatment

NO

NO

Continue dietary Arg restriction

YES

Continue B6 treatment + dietary Arg restriction

Keep plasma Orn as low as possible

Keep plasma Orn < 200 µM

Fig. 15.3  Algorithm for the assessment of vitamin B6 responsiveness in OAT deficiency

Prenatal Diagnosis Disorder 15.1 15.2

15.3 15.4 15.5

Method/analytes AGAT/GATM activity DNA testing GAMT activity DNA testing CrT/SLC6A8 activity DNA testing AGAT/GATM DNA testing OAT activity DNA testing

Material Cultured amniotic cells Chorionic villi, cultured amniotic cells Cultured amniotic cells Chorionic villi, cultured amniotic cells Amniotic fluid Cultured amniotic cells Chorionic villi, cultured amniotic cells Cultured amniotic cells Chorionic villi, cultured amniotic cells Cultured amniotic cells Chorionic villi, cultured amniotic cells

So far, prenatal diagnosis has been documented for disorders 15.1, 15.2, and 15.5, but not for 15.3 and 15.4

Timing semester II I, II II I, II II II I, II II I,II II I, II

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DNA Testing Disorder 15.1 15.2 15.3 15.4 15.5

Tissue Genomic DNA (blood, FB, LYM, EBV-transformed lymphoblasts) Genomic DNA (blood, FB, LYM, EBV-transformed lymphoblasts) Genomic DNA (blood, FB, LYM, EBV-transformed lymphoblasts) Genomic DNA (blood, FB, LYM, EBV-transformed lymphoblasts) Genomic DNA (blood, FB, LYM, EBV-transformed lymphoblasts)

Methodology Direct sequencing, High-throughput sequencing Direct sequencing, High-throughput sequencing Direct sequencing, High-throughput sequencing Direct sequencing, High-throughput sequencing Direct sequencing, High-throughput sequencing

Mutations http://www.LOVD.nl/GATM http://www.LOVD.nl/GAMT http://www.LOVD.nl/SLC6A8

http://www.LOVD.nl/OAT

FB cultured fibroblasts, LYM lymphocytes

Specimen Collection Test Creatine

Creatinine

Preconditions Before creatine supplementation

Before creatine supplementation

Material Handling U 24-h urine or spot, store at −20 °C CSF Store at −20 °C P EDTA or heparinate, store at −20 °C U 24-h urine or spot, store at −20 °C CSF Store at −20 °C P

Creatine/creatinine ratio to test CrT/SLC6A8 deficiency

U

Guanidinoacetate

U CSF P

Ornithine

DBS U CSF P

GAMT, AGAT, CrT/SLC6A8, OAT activities

DBS dry blood spot, FB cultured fibroblasts, LYM lymphoblasts

Liver FB LYM

Pitfalls U: false positives in high-protein diet

P: probably not diagnostic in neonates U: low in patients with reduced muscle mass U: false positives in high-protein diet EDTA or heparinate, store at P: probably not diagnostic in −20 °C neonates Not sensitive in heterozygous females Can be normal in symptomatic patients 24-h urine or spot, store at −20 °C Store at −20 °C EDTA or heparinate, store at −20 °C Room temperature 24-h urine or spot, store at −20 °C Store at −20 °C EDTA or heparinate, store at −20 °C Store at −80 °C Cultured skin cells EBV-transformed lymphoblasts

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Reference Values

Guanidinoacetatea

Guanidinoacetateb

Guanidinoacetatec

Guanidinoacetated Guanidinoacetatee Creatinea

Creatineb

Creatinec

Creatined Creatinee Ornithinef

Age range 1 week–2 years 1 month–2 years 2 years–puberty Men Women No age range established 15 years 15 years Female >15 years 0–15 years >15 years No age range established No age range established

Urine [mmol/mol creatinine] 28–180 11–40 11–40

Plasma [μmol/L] 0.20–1.46 0.56–1.88 1.58–3.64 0.87–3.15

20–208 15–152 5–78 9–128

0.6–2.4 0.9–3.0 1.2–3.6

4–220 3–78

0.35–1.8 1.0–3.5

b

Amniotic fluid [μmol/L]

0.02–0.56

0.036–0.22 1.6–4.4

1 week–2 years 1 month–2 years 2 years–puberty Men Women No age range established 15 years 15 years Female >15 years 0–4 years 4–12 years >12 years 0–10 years >10 years No age range established 0–10 years >10 years

28–1700 3.4–191 3.4–360

50–124 24–109 5.5–54.7 12.8–96.8

29–1551 19–1046 7–492 12–682

34–124 28–104 12–99

6–1208 17,721 11–244

17–109 6–50

0–1 month 1–6 months 6–12 months 1–2 years 2–4 years 4–7 years 7–13 years >13 years 3×b

No data available/ presumably normal No data available/ presumably normal

No data available/may be elevated No data available/ presumably normal

No data available/ presumably normal No data available/ presumably normal

No data available/ presumably normal CSF [μmol/L]

No data available/ presumably not detectable Brain 1 H-MRS

No data available/ presumably normal Amniotic fluid [μmol/L]

Absent/very low Absent/very low

No data available/ presumably normal Normalb

1

Urine [mmol/mol creatinine] Low

Low

Low

1400a) No data available/ presumably normal Low

Normal

May be normal

Very low

No data available/ presumably normal

No data available/ presumably normal

Normal (data from 1 patient)

Low

No data available/ presumably low

Low

Plasma [μmol/L] 600–1400d

AGAT AS AGAT aggregation syndrome a Method: GC-MS. Reference: Struys et al. (2008) b Method: LC-MS/MS. Reference: Cheillan et al. (2006) c Method: HPLC, fluorescence. Reference: Schulze A. Own observation in three patients d Please note: Plasma ornithine may not be elevated in neonates and in the first months of life

No data available/ presumably normal No data available/ presumably normal No data available/ presumably normal

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247

Standard Treatment

No./symbol 15.1 AGAT 15.2 GAMT

Age All ages All ages All ages Children Adults All ages

15.5 OAT Vitamin B6 responsive formd

14 years

15.5 OAT Vitamin B6 nonresponsive formd

All ages

Dosage [mg/kg per day] 200–400a 400

Medication/diet Creatine monohydrate Creatine monohydrate l-Ornithine aspartate Low dose High dose Sodium benzoate l-Arginine intake Essential amino acid mixture (arginine free) Pyridoxine hydrochloride Diet (see below) Pyridoxine hydrochloride Diet (see below) Arginine-restricted diet (see below)

Doses per day 3–6 3–6 3–6

100b 800b 400b 100 15–25c 0.2–0.7 g essential amino acids/kg 40–200e 40–500e

3 3–5 daily meals 3–5 daily meals 2 2

Lower dosages of creatine monohydrate might be sufficient for restoration of the cerebral creatine pool in AGAT deficiency due to the absence of GAA accumulation and no subsequent competitive inhibition of creatine uptake b Aim of low-dose substitution is to provide sufficient amounts of ornithine to the urea cycle (target plasma ornithine concentration 100–200 μmol/L) in case of an arginine-restricted diet. Aim of high-dose substitution is the competitive AGAT inhibition with high intracellular ornithine concentrations (Km = 300 μmol/L) c Corresponds to 0.4–0.7 g/kg natural protein. Essential amino acid mixture supplement is necessary in order to meet age-dependent physiological amino acid/protein requirements d Target plasma ornithine concentration 1000  mg/ day).

Dietary Treatment

Protein requirement [g/kg/day] Age Infants 1.1–2.7 Children 1.0–1.7 Adults 0.8

Natural protein [g/kg/day]a 0.4 0.3–0.5 0.25

Arginine-free essential AAM Protein equivalentc [g/ Typeb day] 1 2–5 2 10–25 2 30–75

According to Dewey et al. (1996) Type 1, infantile formula; type 2, childhood formula c Spread as evenly as possible through the 24 h a

b

Beware/Pitfalls

Overtreatment through protein restriction.

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Alternative Therapies/Experimental Trials No./ symbol Age 15.3 All CrT ages All ages All ages All ages All ages 15.5 OAT

Medication/ diet Creatine monohydrate l-Arginine

Dosage mg/kg per day 100–400 400

l-Glycine

150

S-Adenosyl methionine

100

Betaine

50–250

Dosages per day Literature 3–6 Valayannopoulos et al. (2012); van de Kamp et al. 3 (2012); Mercimek-­ 3 Mahmutoglu et al. (2010); 2 Jaggumantri et al. (2015); 3 Schjelderup et al. (2021) 2–3 Heinänen et al. (1999)

Adults Creatine 1.5–2 g monohydrate per day (1–1.5 g/ m2/day) Adults l-Lysine 10–15 g 5a per day (5 g/m2/ day) Adults α-Aminoiso 0.1 5a butyric acid l-Proline 65–488 3 All ages

Peltola et al. (2000); Elpeleg and Korman (2001) Valle et al. (1981) Hayasaka et al. (1985)

Spread within the diet as evenly as possible through the 24 h

a

Beware/Pitfalls

In CrT deficiency, creatine administration might be efficient in females but less in males. In OAT deficiency, creatine administration corrects skeletal muscle abnormalities but not progress of ophthalmologic abnormalities. Studies of the long-term efficacy of these approaches have not been reported or the results are inconclusive.

References Almeida LS, Verhoeven NM, Roos B, et al. Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport. Mol Genet Metab. 2004;82:214–9. Berends LM, Struys EA, Roos B, et al. Guanidinoacetate methyltransferase activity in lymphocytes, for a fast diagnosis. JIMD Rep. 2017;37:13–7. Bruun TUJ, Sidky S, Bandeira AO, et al. Treatment outcome of creatine transporter deficiency: international retrospective cohort study. Metab Brain Dis. 2018;33(3):875–84. Cheillan D, Salomons GS, Acquaviva C, et  al. Prenatal diagnosis of guanidinoacetate methyltransferase deficiency: increased guanidinoacetate concentrations in amniotic fluid. Clin Chem. 2006;52: 775–7. Desroches CL, Patel J, Wang P, et al. Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene. Mol Genet Genomics. 2015;290(6):2163–71.

Dewey KG, Beaton G, Fjeld C, Lönnerdal B, Reeds P. Protein requirements of infants and children. Eur J Clin Nut. 1996;50(Suppl 1):S119–47. Dunbar M, Jaggumantri S, Sargent M, Stöckler-Ipsiroglu S, van Karnebeek CD.  Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab. 2014;112:259–74. Elpeleg N, Korman SH.  Sustained oral lysine supplementation in ornithine delta-aminotransferase deficiency. J Inherit Metab Dis. 2001;24:423–4. Hanna-El-Daher L, Braissant O.  Creatine synthesis and exchanges between brain cells: what can be learned from human creatine deficiencies and various experimental models? Amino Acids. 2016;48:1877–95. Hayasaka S, Saito T, Nakajima H, et al. Clinical trials of vitamin B6 and proline supplementation for gyrate atrophy of the choroid and retina. Br J Ophthalmol. 1985;69:283–90. Heinänen K, Näntö-Salonen K, Komu M, et al. Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia. Eur J Clin Invest. 1999;29:1060–5. Jaggumantri S, Dunbar M, Edgar V, et al. Treatment of creatine transporter (SLC6A8) deficiency with oral s-adenosyl methionine as adjunct to l-arginine, glycine, and creatine supplements. Pediatr Neurol. 2015;53(4):360–3e2. Joncquel M, Briand G, Valayannopoulos V, et  al. Determination of new reference values for GAA and creatine from a large cohort of controls subjects and description of the French patients affected of creatine deficiency disorders (CDS). J Inherit Metab Dis. 2011;34(Suppl 3):S128. Joncquel-Chevalier Curt M, Bout MA, Fontaine M, et  al. Functional assessment of creatine transporter in control and X-linked SLC6A8-­ deficient fibroblasts. Mol Genet Metab. 2018;123(4):463–71. Khaikin Y, Sidky S, Abdenur J, et  al. Treatment outcome of twenty-­ two patients with guanidinoacetate methyltransferase deficiency: an international retrospective cohort study. Eur J Paediatr Neurol. 2018;22(3):369–79. Mercimek-Mahmutoglu S, Salomons GS.  Creatine deficiency syndromes. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993-2019; 2009. [Updated 2015 Dec 10]. Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ, et al. Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab. 2010;101:409–12. Mercimek-Mahmutoglu S, Salomons GS, Chan A. Case Study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate. Pediatr Neurol. 2014;51:133–7. Näntö-Salonen K, Komu M, Lundbom N, et al. Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology. 1999;53:303–7. Pasquali M, Schwarz E, Jensen M, et al. Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis. 2014;37(2):231–6. Peltola K, Heinonen OJ, Näntö-Salonen K, Pulkki K, Simell O. Oral lysine feeding in gyrate atrophy with hyperornithinaemia—a pilot study. J Inherit Metab Dis. 2000;23:305–57. Reichold M, Klootwijk ED, Reinders J, et al. Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure. J Am Soc Nephrol. 2018;29(7):1849–58. Rosenberg EH, Almeida LS, Kleefstra T, et  al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 2004;75:97–105. Schjelderup J, Hope S, Vatshelle C, van Karnebeek CDM. Treatment experience in two adults with creatinfe transporter deficiency. Mol Genet Metab Rep. 2021;27:100731.

15  Disorders of Creatine Metabolism Schulze A, Ebinger F, Rating D, Mayatepek E.  Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab. 2001;74:413–9. Sharer JD, Bodamer O, Longo N, et  al. Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):256–63. Shih VE. Amino acid analysis. In: Blau N, Duran M, Blaskovics ME, Gibson KM, editors. Physician’s guide to the laboratory diagnosis of metabolic diseases. Berlin, Heidelberg, New  York: Springer; 2003. p. 11–26. Sinclair GB, van Karnebeek CD, Ester M, et al. A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening. Mol Genet Metab. 2016;118(3):173–7. Stöckler-Ipsiroglu S, van Karnebeek CD.  Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders. Semin Neurol. 2014;35(3):350–6. Stöckler-Ipsiroglu S, van Karnebeek C, Longo N, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2014;111:16–25. Stöckler-Ipsiroglu S, Apatean D, Battini R, et  al. Arginine:Glycine Amidinotransferase (AGAT) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab. 2015;116(4):252–9. Struys EA, Verhoeven-Duif N, Jakobs C. Creatine and its metabolites. In: Blau N, Duran M, Gibson MK, editors. Laboratory guide to the methods in biochemical genetics. Berlin, Heidelberg: Springer; 2008. p. 739–49. Valayannopoulos V, Boddaert N, Chabli A, et  al. Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients

249 with creatine transporter defect. J Inherit Metab Dis. 2012; 35:151–7. Valle D, Simell O.  The hyperornithinemias. In: Scriver CR, Beaudet A, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw Hill; 1995. p. 1147–85. Valle D, Walser M, Brusilow S, Kaiser-Kupfer MI, Takki K.  Gyrate atrophy of the choroid and retina: biochemical considerations and experience with an arginine-restricted diet. Ophthalmology. 1981;88:325–30. van de Kamp JM, Mancini GM, Pouwels PJ, et  al. Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet. 2011;79:264–72. van de Kamp JM, Pouwels PJ, Aarsen FK, et al. Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. J Inherit Metab Dis. 2012;35(1):141–9. van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, et  al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 2013;50:463–72. Verhoeven NM, Schor DS, Roos B, et al. Diagnostic enzyme assay that uses stable-isotope-labeled substrates to detect L-arginine:glycine amidinotransferase deficiency. Clin Chem. 2003;49(5):803–5. Viau KS, Ernst SL, Pasquali M, et  al. Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2013;110(3):255–62. Weleber RG, Kennaway NG.  Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology. 1981; 88:316–24. Young S, Struys E, Wood T (2007) Quantification of creatine and guanidinoacetate using GC-MS and LC-MS/MS for the detection of cerebral creatine deficiency syndromes. Curr Protoc Hum Genet 17.3.1–17.3.18

Disorder of Glutathione Metabolism

16

Verena Peters and Johannes Zschocke

Contents Introduction

 252

Nomenclature

 254

Metabolic Pathway

 255

Signs and Symptoms

 255

Reference Values

 259

Pathological Values

 259

Diagnostic Flowchart

 259

Specimen Collection

 260

Treatment Summary

 260

Standard Treatment

 260

Experimental Treatment

 261

Follow-Up and Monitoring

 261

References

 261

Summary

Glutathione (GSH), a tripeptide composed of glutamate, cysteine, and glycine, prevents damage caused by reactive oxygen species and is metabolized via the γ-glutamyl cycle. The reduction of glutathione disulfide (GSSG) to the sulfhydryl from glutathione (GSH) is catalyzed by glutathione reductase. Several enzymes involved in the glutathione pathway, such as γ-glutamylcysteine syntheV. Peters (*) Centre for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany e-mail: [email protected] J. Zschocke Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria e-mail: [email protected]

tase (GCLC), glutathione synthetase (GSS), glutathione peroxidase 4 (GPX4), and glutathione reductase (GSR), are regulated, at least in part, by Nrf2 through its activation of the Nrf2-antioxidant response element. GPX4 catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides at the expense of GSH. Defects have been described in all those enzymes, except for the γ-glutamyl cyclotransferase (GGCT). The disorders are inherited in autosomal recessive, Nrf2 superactivity in an autosomal dominant manner. The most frequent disorder in human is the glutathione synthetase (GSS) deficiency, which is often associated with hemolytic anemia, a clinical feature also present in γ-glutamylcysteine (GCLC) deficiency. The severe form of glutathione synthetase (GSS) deficiency is associated with 5-oxoprolinuria, metabolic acidosis, central nervous system damage, and recurrent bacterial infections. 5-Oxoprolinuria can also be

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_16

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caused by mutations in 5-oxoprolinase (OPLAH), a quite rare disease presenting with a high clinical variability. γ-Glutamyl transpeptidase (GCLC) deficiency has been found in patients with CNS involvement and glutathionuria. Dipeptidase (DPEP) deficiency has been described only in one patient with mental retardation, mild motor impairment, and partial deafness. The main clinical features of glutathione reductase (GSR) deficiency are favism and cataract. Diseases associated with glutathione peroxidase 4 (GPX4) are often associated with Sedaghatian-type spondylometaphyseal dysplasia, and Nrf2 superactivity is a multisystem disorder characterized by hypohomocysteinemia, failure to thrive, immunodeficiency, and neurodevelopmental abnormalities. Diagnosis is made by measuring the concentration of different metabolites in the γ-glutamyl cycle and homocysteine, enzyme activity, and/or mutation analysis. Treatment aims are mainly to prevent hemolytic crises and correction of acidosis.

Introduction The tripeptide glutathione (γ-glutamyl-cysteinylglycine, GSH) is the major nonprotein thiol and is present in millimolar concentrations in most mammalian cells. GSH is involved in several fundamental biological functions, including detoxification, scavenging of free radicals, redox reactions, biosynthesis of DNA, proteins, and leukotrienes, neurotransmission, as well as regulation in the cell cycle (Forman et al. 2009). The ratio of reduced (GSH) and oxidized glutathione (GSSG) is used as a measure of cellular oxidative stress. Disorders of glutathione metabolism are associated with a wide range of clinical features reflecting different pathophysiological functions: • Deficiencies of enzyme involved in the biosynthesis and regeneration of GSH (γ-glutamylcysteine synthetase, glutathione synthetase, and glutathione reductase) are associated with hemolytic anemia due to reduced redox potential in red blood cells, as well as neurological and other symptoms. • Deficiencies of enzymes involved in the breakdown of GSH (γ-glutamyl transpeptidase, γ-glutamyl cyclotransferase, and 5-oxoprolinase) may show biochemical abnormalities but are associated with no or inconsistent clinical abnormalities or have not been identified as such. • Other disorders affecting GSH metabolism include superactivity of the Nrf2-antioxidant response element which activates transcription of a range of antioxidant enzymes

V. Peters and J. Zschocke

involved in GSH biosynthesis and glutathione peroxidase 4 deficiency which causes Sedaghatian-type spondylometaphyseal dysplasia presumably due to impaired regeneration of lipid hydroperoxides. γ-Glutamylcysteine synthetase (GCLC) deficiency has been described in very few patients. It is associated with hemolytic anemia and can have a mild non-neurological phenotype or a more severe phenotype with neurological manifestations which is similar to GSS deficiency (Almusafri et al. 2017; Ferguson and Bridge 2016). Glutathione synthetase (GSS) deficiency is the most frequently diagnosed disorder of human glutathione metabolism with more than 70 patients described worldwide (Shi et  al. 1996; Signolet et  al. 2016; Soylu Ustkoyuncu et  al. 2018). Mildly affected patients show hemolytic anemia as their only clinical symptom. Moderately affected patients show additionally metabolic acidosis (without ketosis or hypoglycemia), and severely affected patients also develop progressive neurological symptoms, such as intellectual disability, seizures, or spasticity, and may develop recurrent bacterial infections caused by defective granulocyte function. Several patients died in early life due to acidosis and electrolyte imbalances (Ristoff and Larsson 2007). About 30 different mutations have been described so far. The type of mutation involved can, to some extent, predict a mild versus a more severe phenotype (Njalsson 2005). The diagnosis of GCLC and GSS deficiencies is mainly based on low glutathione levels and low activities of the enzymes in red blood cells or fibroblasts or the presence of mutations in the genes. Glutathione regeneration is catalyzed by glutathione reductase by reducing GSSG to GSH. Hereditary glutathione reductase (GSR) deficiency was first described in 1976 (van Zwieten et al. 2014). GSR is a flavoprotein, and dietary riboflavin deficiency causes a secondary GSR deficiency. In contrast to disorders in the synthesis of glutathione, the clinical outcome of glutathione reductase deficiency seems to be less severe, mainly presenting with hemolytic anemia, favism, and cataract and one patient with severe neonatal jaundice (Kamerbeek et al. 2007). The initial degradative step of GSH is catalyzed by γ-glutamyl transpeptidase (GGT). There are two known active GGT isoenzymes encoded by different genes, GGT1 and GGT5, which have different expression patterns (Heisterkamp et al. 2008). Both are membrane-bound extracellular enzymes that hydrolyze the γ-glutamyl bond and transfer the γ-glutamyl group to an acceptor, e.g., an amino acid. GSH is resistant to intracellular breakdown as both GGT isoforms are extracellular, and no other enzyme can degrade GSH.  Standard GGT biochemical assays measure

16  Disorder of Glutathione Metabolism

the GGT1 transpeptidation reaction with an artificial substrate. Only eight patients with γ-glutamyl transpeptidase (GGT1) deficiency have been reported in the literature (Darin et al. 2018). The diagnosis is based on the finding of increased levels of GSH in urine and plasma and lowered enzyme activity levels. The exact genetic alteration has only been described for two siblings with glutathionuria (Darin et al. 2018). Most of the described patients have had central nervous system involvement, but causality has not been proven. Abnormalities of leukotriene metabolism have been reported in patients with GGT deficiency (see chapter on leukotriene metabolism). Two genetic defects in the γ-glutamyl cycle have been described as causes of persistent 5-oxoprolinuria: either GSS deficiency or by 5-oxoprolinase (OPLAH) deficiency. At least 20 mutations in OPLAH have been reported to date (Calpena et  al. 2015; Sass et  al. 2016). 5-Oxoprolinuria appears not to cause clinical symptoms and has also been observed in patients with defects in other inborn errors of metabolism, homocystinuria, type 2 diabetes, or drug metabolism as well as in other contexts (Ristoff and Larsson 2007). Further, it is considered as a worsening factor of hyperammonemic encephalopathy (Rousseau et al. 2017). Cysteinylglycine is cleaved into cysteine and glycine by one of possibly several dipeptidases. A tentative deficiency of cysteinylglycine dipeptidase has been described in one patient so far, based on increased urinary cysteinylglycine and decreased activity of plasma dipeptidase. The dipeptidase also converts leukotriene D4 to leukotriene E4. Clinically, the patient presented mental retardation, mild motor impairment, and partial deafness (Mayatepek et al. 2004, 2005) (see chapter on leukotriene metabolism).

253

Cysteine is extremely unstable and rapidly auto-oxidizes to cystine extracellularly, which can generate potentially toxic oxygen free radicals. Glutathione peroxidase 4 (GPX4) catalyzes the reduction of hydrogen peroxide and organic and lipid hydroperoxides and therefore protects cells against oxidative damage. GPX4 is a selenoprotein (Sneddon et al. 2003), and loss of the gene (Gpx4) causes massive lipid peroxidation. Diseases associated with GPX4 include Sedaghatian-type spondylometaphyseal dysplasia (Smith et al. 2014) and neurodegeneration (Cardoso et  al. 2017). Sedaghatian-type spondylometaphyseal dysplasia is characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. The regulation of GSH synthesis is under tight control involving key enzymes including γ-glutamylcysteine synthetase, glutathione synthetase, and glutathione reductase. More importantly, these enzymes are all regulated, at least in part, by Nrf2 through its activation of the Nrf2-antioxidant response element (ARE; Abdul-Aziz et  al. 2015). Nrf2 superactivity has been described in four patients presenting failure to thrive, immunodeficiency, and neurological symptoms (Huppke et  al. 2017). Missense mutations were identified in the NFE2L2 gene, leading to an altered cytosolic redox balance. All four patients described so far display a similar phenotype with several prominent features including developmental delay, failure to thrive, immunodeficiency, leukoencephalopathy, and hypohomocysteinemia. Hypohomocysteinemia together with elevated activity of glucose-6-phosphate dehydrogenase allows early diagnosis (Harvey et al. 2009).

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Nomenclature

16.1

16.2 16.3 16.4 16.5 16.6

16.7

16.8

16.9

Disorders of glutathione metabolism Alternative name γ-Glutamyl transpepti- Glutathionuria; γ-glutamyl transdase deficiency ferase deficiency 5-Oxoprolinase deficiency Glutamate-cysteine γ-Glutamylcysteine synthetase deficiency ligase deficiency Glutathione synthetase deficiency, mild Glutathione synthetase deficiency, severe Dipeptidase deficiency Membrane-bound dipeptidase deficiency Glutathione reductase Hemolytic anemia deficiency due to glutathione reductase deficiency SpondylometaphyGlutathione peroxidase 4 deficiency seal dysplasia, Sedaghatian type Nrf2 superactivity Immunodeficiency, developmental delay, and hypohomocysteinemia (IEMDHH)

Abbreviation GGT1

Gene GGT1

Chromosomal Mode of localization inheritance 22q11.1-q11.2 AR

OPLAHD

OPLAH

8q24.3

GGCS

GCLC

GSSD GSSD

Affected protein Gamma-glutamyl transpeptidase

Omim 612346

AR, AD

5-Oxoprolinase

614243

6p12

AR

GSS

20q11.2

AR

GSS

20q11.2

AR

γ-Glutamylcysteine 606857 synthetase Glutathione 601002 synthetase Glutathione 601002 synthetase Dipeptidase

AR

DPEP1

GSR

8p12

AR

Glutathione reductase

138300

GPX4

19p13.3

AR

Glutathione peroxidase

138322

AD

NFE2-related transcription factor 2 (Nrf2)

600492

NFE2L2 2q31.2

16  Disorder of Glutathione Metabolism

255

Metabolic Pathway D-Glucono-1,5Lacton-6-P

Glutathione disulfide (GSSG)

NADPH GSR

G6PD

Glucose-6-P

Lipid-OH/H2O

NADP

GPX4

Glutathione (GSH)

Lipid-OOH/H2O2 ADP+Pi

GGT1/5 GSS ATP g-Glutamylcysteine

Glycine g-Glutamylamino acid

Cysteinylglycine

Dipeptidase

ADP+Pi Cysteine

GCLC

GGCT Homocysteine ATP 5-Oxoproline

Glutamate Nrf2 regulated gene

OPLAH

Fig. 16.1 The γ-glutamyl cycle for the biosynthesis and degradation of glutathione including known metabolic defects: γ-glutamylcysteine synthetase (GCLC), glutathione synthetase (GSS), γ-glutamyl transpeptidase deficiency (GGT1), 5-oxoprolinase (OPLAH), and dipeptidase. The reduction of glutathione disulfide (GSSG) to glutathione (GSH) is catalyzed by glutathione reductase (GSR), and peroxidase 4 (GPX4) catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides at the expense of GSH. γ-Glutamylcysteine synthetase

(GCLC), glutathione synthetase (GSS), peroxidase 4 (GPX4), and glutathione reductase (GSR) are regulated, at least in part, by Nrf2 through its activation of the Nrf2-antioxidant response element. No defects have been described or the γ-glutamyl cyclotransferase (GGCT). Glucose-6-phosphate dehydrogenase (G6PD) converts glucose-6-­ phosphate into 6-phosphoglucono-δ-lactone. Blood glutathione and homocysteine and urinary 5-oxoproline concentrations are important diagnostic markers

Signs and Symptoms Table 16.1 Glutathionuria System CNS Psychiatric Laboratory findings

Symptoms and biomarkers Intellectual disability Tremor Psychosis Gamma-glutamyltranspeptidase (fibroblasts) Gamma-glutamyltranspeptidase (white blood cells) Glutathione (plasma) Glutathione (red blood cells) Glutathione (urine) Leukotriene LTB4 (plasma) Leukotriene LTB4 (urine) Leukotriene LTC4 (plasma) Leukotriene LTC4 (urine) Leukotriene LTD4 (plasma) Leukotriene LTD4 (urine) Leukotriene LTE4 (plasma) Leukotriene LTE4 (urine) LTD4-synthesis in nucleated cells (white blood cells)

Neonatal (birth–1 month)

Infancy (1–18 months)

↓

Childhood (1.5–11 years) ± ± ± ↓

Adolescence (11–16 years) ± ± ± ↓

Adulthood (>16 years) ± ± ± ↓

↓ ↓

↓

↓

↓

↓

↑ n ↑ n n ↑ ↑ ↓ ↓ ↓ ↓ ↓

↑ n ↑ n n ↑ ↑ ↓ ↓ ↓ ↓ ↓

↑ n ↑ n n ↑ ↑ ↓ ↓ ↓ ↓ ↓

↑ n ↑ n n ↑ ↑ ↓ ↓ ↓ ↓ ↓

↑ n ↑ n n ↑ ↑ ↓ ↓ ↓ ↓ ↓

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Table 16.2 Oxoprolinuria System CNS

Digestive Metabolic Renal Laboratory findings

Symptoms and biomarkers Microcephaly Retardation, psychomotor Colitis Diarrhea Acidosis Urolithiasis Renal colic 5-Oxoprolinase (fibroblasts) 5-Oxoprolinase (white blood cells) 5-Oxoproline (urine)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

± ± n ± ± ↓

± ± n ± ± ↓

n

n

↓

↓

n ± ± ↓

↓

↓

↓

↓

↓

↑

↑

↑

↑

↑

Neonatal (birth–1 month) ± ± ± + ± ± n-↑ ↓↓↓

Infancy (1–18 months) ± ± ± + ± ± n-↑ ↓↓↓

Childhood (1.5–11 years) ± ± ± + ± ± n-↑ ↓↓↓

Adolescence (11–16 years) ± ± ± + ± ± n-↑ ↓↓↓

Adulthood (>16 years) ± ± ± + ± ± n-↑ ↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓ ↓ ↑

↓↓↓ ↓ ↑

↓↓↓ ↓ ↑

↓↓↓ ↓ ↑

↓↓↓ ↓ ↑

Table 16.3  Gamma-glutamylcysteine synthetase deficiency System CNS Digestive Hematological Musculoskeletal Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Neuropathy Jaundice Anemia, hemolytic Myopathy Psychosis Amino acids, all Gamma-glutamylcysteine synthetase (fibroblasts) Gamma-glutamylcysteine synthetase (red blood cells) Glutathione (red blood cells) Hemoglobin (blood) Reticulocytes (blood)

Table 16.4  Glutathione synthetase deficiency, mild System Digestive Hematological Laboratory findings

Symptoms and biomarkers Jaundice Anemia, hemolytic 5-Oxoproline (urine) Gamma-glutathione synthetase (fibroblasts) Gamma-glutathione synthetase (red blood cells) Glutathione (red blood cells) Hemoglobin (blood) Reticulocytes (blood)

Neonatal (birth–1 month) ± + n-↑ ↓↓↓

Infancy (1–18 months) ± + n-↑ ↓↓↓

Childhood (1.5–11 years) ± + n-↑ ↓↓↓

Adolescence (11–16 years) ± + n-↑ ↓↓↓

Adulthood (>16 years) ± + n-↑ ↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓ ↓ ↑

↓↓ ↓ ↑

↓↓ ↓ ↑

↓↓ ↓ ↑

↓↓ ↓ ↑

16  Disorder of Glutathione Metabolism

257

Table 16.5  Glutathione synthetase deficiency, severe System CNS

Digestive Eye

Hematological Metabolic Musculoskeletal Other

Laboratory findings

Symptoms and biomarkers Ataxia Hypertonia Hypotonia Neurological symptoms Retardation, psychomotor Seizures Jaundice Adaptation, dark impaired Corneal clouding Pigmentary retinopathy Anemia, hemolytic Acidosis Lactic acidosis Myopathy Recurrent bacterial infections Recurrent bacterial infections 5-Oxoproline (urine) Gamma-glutathione synthetase (fibroblasts) Gamma-glutathione synthetase (red blood cells) Glutathione (red blood cells) Hemoglobin (blood) Lactate (plasma) Reticulocytes (blood)

Neonatal (birth–1 month) ± ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ± ± ±

+ + + ± ±

+ + + ± ±

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± ± ± + + + ± ±

Adolescence (11–16 years) ± ± ± ± ± ± ± ± ± ± + + + ± ±

Adulthood (>16 years) ± ± ± ± ± ± ± ± ± ± + + + ± ±

± ↑↑↑ ↓↓↓

± ↑↑↑ ↓↓↓

± ↑↑↑ ↓↓↓

± ↑↑↑ ↓↓↓

± ↑↑↑ ↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓ ↓ ↑ ↑

↓↓ ↓ ↑ ↑

↓↓ ↓ ↑ ↑

↓↓ ↓ ↑ ↑

↓↓ ↓ ↑ ↑

Table 16.6  Membrane-bound dipeptidase deficiencya System CNS

Ear Musculoskeletal Laboratory findings

Symptoms and biomarkers EEG, abnormal Motor impairment Neuropathy Retardation, psychomotor Deafness, partial EMG, abnormal Foot deformity Cysteine, bound (urine) Cystine (urine) Cysteinylglycine (plasma) Cysteinylglycine (urine) Glutathione (red blood cells) Leukotriene LTD4 (urine) Leukotriene LTE4 (urine)

Neonatal (birth–1 month)

Please check chapter on leukotriene metabolism

a

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) + + + + + + + ↑ ↑ ↑ ↑ n ↑ ↓

Adulthood (>16 years)

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Table 16.7  Glutathione reductase deficiency System CNS

Symptoms and biomarkers Jaundice, severe neonatal Migraine Endocrine Hypothyroidism Eye Cataract, bilateral Hematological Anemia, hemolytic Favism Laboratory find- Bilirubin (plasma) ings Glutathione (plasma) Glutathione reductase activity (red blood cells)

Neonatal (birth–1 month) ±

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± ± ± ± ±

↑↑ ↓↓ ↓↓↓

↓↓ ↓↓↓

Table 16.8  Glutathione peroxidase 4 deficiency System Cardiovascular CNS

Symptoms and biomarkers Cardiorespiratory problems Hypotonia, severe Central nervous system abnormalities Musculoskeletal Metaphyseal chondrodysplasia Platyspondyly Rhizomelic shortening of the upper limbs, mild

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

±

±

±

± ±

± ±

± ±

Adolescence (11–16 years)

Adulthood (>16 years)

Table 16.9  Nrf2 superactivity System Cardiovascular CNS

Symptoms and biomarkers Heart failure Absence seizures Developmental delay Other Immunodeficiency Laboratory find- Creatinine (plasma) ings Cysteine (plasma) Glucose-6-phosphate dehydrogenase activity (erythrocytes) Glutathione reductase activity (erythrocytes) Homocysteine (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

↓ ↓-n n-↑

Childhood (1.5–11 years) ± ± + + ↓ ↓-n n-↑

↓-n

↓-n

↓-n

↓-n

Adolescence (11–16 years) ± ± + +

Adulthood (>16 years)

16  Disorder of Glutathione Metabolism

259

Reference Values Metabolite/activity 5-Oxoproline (U) Glutathione (RBC) G6PD activity (RBC) Homocysteine (B)

16 years) ± ± + ±-+ ++ ± ±-+ ± ± ± ↑ ↑↑ n-↑ n-↑ ↑ n-↑ ↓-n

17  Disorders of Ammonia Detoxification

271

Table 17.7  Mitochondrial ornithine transporter deficiency Symptoms and System biomarkers Autonomic system Temperature instability CNS Asterixis Ataxia Coma Confusion, episodic Developmental delay Encephalopathy Pyramidal signs Seizures Spastic paresis Stroke-like episodes Digestive Feeding, protein aversion Liver dysfunction Liver failure, acute Vomiting Eye Vision, impaired Other Failure to thrive Psychiatric Behavior, abnormal 14 C-ornithine incorporaLaboratory tion (fibroblasts) findings Ammonia (blood and plasma) Arginine (plasma) ASAT/ALAT (plasma) Citrulline (plasma) Creatine (plasma) Factor VII Factor X Glutamine (plasma) Homocitrulline (urine) Ornithine (plasma) Orotic acid (urine) Urea (plasma)

Neonatal (birth–1 month) ±

±

Infancy (1–18 months)

±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

± ± ± + ± ± ± ± ± ± ± ± ±

± ± ± + ± ± ± ± ± ± ± ± ± ± ± ± ↓

± ± ± ± + ± ± ± ± ± ± ± ± ± ± ± ± ↓

±

+ ± n-± ± n ± ± ± ± ±

n

±

↓

↓

± ± ↓

↑↑

↑↑

↑↑

↑↑

↑↑

n n-↑ n n ↓-n ↓-n n-↑ ↑↑ ↑-↑↑ n-↑ ↓-n

n n-↑ n ↓-n ↓-n ↓-n n-↑ ↑↑ ↑↑ n-↑ ↓-n

n n-↑ n ↓-n ↓-n ↓-n n-↑ ↑↑ ↑↑ n-↑ ↓-n

n n-↑ n ↓-n ↓-n ↓-n n-↑ ↑↑ ↑↑ n-↑ ↓-n

n n-↑ n ↓-n ↓-n ↓-n n-↑ ↑↑ ↑↑ n-↑ ↓-n

± n ± n ± ± ±

272

J. Häberle and V. Rubio

Table 17.8  Citrin deficiency System CNS

Digestive

Hematological Musculoskeletal Other Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Coma Confusion, episodic Consciousness disturbance Developmental delay Encephalopathy Fatigue Cholestasis, intrahepatic Hepatomegaly Jaundice Liver dysfunction Liver steatosis Low carbohydrate, high protein and high fat intake Pancreatitis, recurrent Anemia Impaired coagulation Growth retardation Failure to thrive Neuropsychiatric manifestations, sudden onset Albumin (plasma) Alpha-fetoprotein (serum) Ammonia (blood and plasma) Arginine (plasma) ASAT/ALAT (plasma) Bilirubin, total/direct (plasma) Citrulline (plasma) Erythrocyte count (blood) Galactose (plasma) Galactose (urine) Gamma-glutamyltransferase (GGT) (plasma) Glucose (plasma) Glutamine (plasma) HDL cholesterol (plasma) LDL cholesterol (plasma) Methionine (plasma) Phenylalanine (plasma) Prothrombin time Succinylacetone (plasma) Threonine (plasma) Total protein (plasma) Tyrosine (plasma)

Neonatal (birth–1 month)

Infancy Childhood (1–18 months) (1.5–11 years)

++ + ++ ++ ±

+ + + + ±

Adolescence (11–16 years) ± + ± ± ± +

Adulthood (>16 years) ± + ± ± ± +

± +

± +

±

+ ± ++ + ± ++

+ + ± +

±

± ± ±

±

↓↓ ↑↑ n-↑ n-↑ n-↑ ↑↑

↓ ↑ n-↑ n-↑ n-↑ ↑

n n n n n n

n n n-↑↑ n n n

n n ↑↑ n-↑ n n

↑-↑↑ ↓↓ ↑ ↑↑ ↑↑

↑-↑↑ ↓ ↑ ↑ ↑-n

n-↑ n n n n

n-↑ n n n n

↑↑ n n n n

n-↓ n-↑ n n ↑ ↑ n-↑ n ↑ ↓↓ ↑

n-↓ n-↑ n n ↑ ↑ n-↑ n ↑ ↓ ↑

n n n-↑ n-↑ n n n n n n n

n n n n n n n n n n n

n n-↑ n n ↑ ↑ n n ↑ n ↑

Two forms, neonatal and later form, are distinguished. The neonatal form is dominated by intrahepatic cholestasis and jaundice, generally waning out with carbohydrate-devoid formula. The adult form is dominated by the symptoms and signs of hyperammonemia. Both forms are caused by mutations in the same gene

17  Disorders of Ammonia Detoxification

273

Table 17.9  Carbonic anhydrase VA deficiency System Autonomic system CNS Digestive Metabolic Laboratory findings

Symptoms and biomarkers Temperature instability Coma Encephalopathy Feeding difficulties Vomiting Hypoglycemia 2-Oxoglutaric acid (urine) 3-Hydroxybutyric acid (urine, plasma) 3-Hydroxyisovaleric acid (urine) 3-Hydroxypropionic acid (urine) 3-Methylcrotonylglycine (urine) Acetoacetate (urine, plasma) Adipic acid (urine) Ammonia (blood and plasma) Arginine (plasma) Citrulline (plasma) Fumaric acid (urine) Glucose (plasma) Glutamine (plasma) Lactate (plasma) Orotic acid (urine) Propionylglycine (urine) Sebacic acid (urine) Suberic acid (urine)

Neonatal (birth–1 month) +

Infancy (1–18 months) ±

+ + + + + n-↑

± ± ± ± ± n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ ↑↑

n-↑ ↑

↓-n ↓-n n-↑ ↓ n-↑↑↑ n-↑↑ n n-↑

↓-n ↓-n n-↑ ↓ n-↑ n-↑ n n-↑

n-↑ n-↑

n-↑ n-↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

The following combination is unusual and can be seen as typical for this condition: hyperammonemia, decreased plasma citrulline and absence of urinary orotic acid, hypoglycemia, metabolic acidosis, high plasma lactate and urinary ketone bodies, and a urinary profile of organic acids containing carboxylase-related metabolites

274

J. Häberle and V. Rubio

Table 17.10  Lysinuric protein intolerance System Autonomic system CNS

Dermatological Digestive

Hematological Musculoskeletal Renal

Respiratory

Other Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Hypertension Coma, hyperammonemic Intellectual disability Sparse hair Diarrhea Hepatosplenomegaly ± Protein intolerance Vomiting Hemophagocytic lymphohistiocytosis, macrophage activation syndrome Bone growth n Osteoporosis Glomerulonephritis Renal failure, end stage Chest radiographs, interstitial changes Pulmonary alveolar proteinosis Respiratory insufficiency Combined hyperlipidemia Alanine (plasma) Ammonia (blood) ↑ Arginine (plasma) n Arginine (urine) Citrulline (plasma) Ferritin (serum) n Glutamine (plasma) Glycine (plasma) Lactate dehydrogen nase, LDH (plasma) Lysine (plasma) n Lysine (urine) Ornithine (plasma) n Ornithine (urine) Orotic acid (urine) Proline (plasma)

Infancy (1–18 months) ±

± ± ±

n

↑ n

↑

n-↑ n n ↑

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ±

± ± ± ± ± ± ±

± ± ± ± ± ± ±

± ± ± ± ± ± ±

↓-n ± ± –

↓-n ± ± ±

↓-n ± ± ±

±

±

±

±

±

±

±

±

±

±

±

±

↑ ↑ ↓-n ↑ ↑ ↑ ↑ ↑ n-↑

↑ ↑ ↓-n ↑ ↑ ↑ ↑ ↑ n-↑

↑ ↑ ↓-n ↑ ↑ ↑ ↑ ↑ n-↑

↓-n ↑↑ ↓-n ↑ ↑ ↑

↓-n ↑↑ ↓-n ↑ ↑ ↑

↓-n ↑↑ ↓-n ↑ ↑ ↑

17  Disorders of Ammonia Detoxification

275

Table 17.11  Pyrroline-5-carboxylate synthetase deficiency, cutis laxa phenotype 3 System CNS

Dermatological Digestive

Eye Musculoskeletal

Other

Laboratory findings

Symptoms and biomarkers Brisk reflexes Global developmental delay Hypoplasia or agenesia of corpus callosum Hypotonia, truncal Intellectual disability Microcephaly Paucity of white matter Pyramidal signs Seizures Speech delayed or absent Tortuous blood vessels Cutis laxa Wrinkled skin Feeding difficulties Frequent vomiting Gastroesophageal reflux Cataract Corneal clouding Facial dysmorphism Hernias Hip dislocation Joint contractures Joint laxity Osteopenia Osteoporosis Pes planus Progeroid appearance Short stature Failure to thrive Intrauterine growth retardation Postnatal growth restriction Ammonia (blood) Arginine (plasma) Citrulline (plasma) Creatine (brain MRS) Ornithine (plasma) Proline (plasma)

Neonatal (birth–1 month)

+

Childhood (1.5–11 years) ± +

Adolescence (11–16 years) ± +

Adulthood (>16 years) ± +

±

±

±

±

±

+

+ + + ±

+ + +

± + +

± + ±

± ±

± ±

±

± ± ± ++ ++ − to ++ − to ++ − to ++

± ± ± − to ++ − to ++ − to ++

± ± + + +

++ ± + ± ±

++ ± + ± ±

± + ± ±

±-++ − to ++ − to ++ ± + + ±

±-+ − to ++ − to ++ ± + + +

− to ++ − to ++ ± + +

± + +

+

+

+

+

n-↑ ↓-n ↓-n ↓-n ↓-n ↓-n

n-↑ ↓-n ↓-n ↓-n ↓-n ↓-n

n-↑ ↓-n ↓-n – ↓-n ↓-n

n-↑ ↓-n ↓-n – ↓-n ↓-n

+

±

++ ++ − to ++ − to ++ − to ++ + ± ++ ± ± + ±-++

++ + ±-++

n-↑ ↓-n ↓-n ↓-n ↓-n ↓-n

Infancy (1–18 months)

+

This disorder can have recessive inheritance (ARCL3B) or it can be sporadic (ADCL3), associated to monoallelic dominant variants in the ALDH18A1 gene

276

J. Häberle and V. Rubio

Table 17.12  Pyrroline-5-carboxylate synthetase deficiency, spastic paraplegia type 9B System CNS

Dermatological Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Gait disturbance Global developmental delay Intellectual disability Hypoplasia of the corpus callosum Microcephaly Pyramidal signs Seizures Spastic paraparesis/ paraplegia/tetraplegia Speech: abnormal, delayed or absent Cutis laxa Wrinkled skin Cataract Facial dysmorphism Growth retardation Joint laxity Short stature Arginine (plasma) Citrulline (plasma) Ornithine (plasma) Proline (plasma)

Neonatal (birth–1 month)

Infancy Childhood (1–18 months) (1.5–11 years) ±-++ + +

Adolescence (11–16 years) ++ +

Adulthood (>16 years) ++ +

+ ±

+ ±

+ ±

+ ±

± ± ± ±

± ± ± +

± ± ± ++

± ± ± +++

±

±

±

n n ±

n n ±

± n ± n-↓ n-↓ n-↓ n-↓

± n ± n-↓ n-↓ n-↓ n-↓

n n ± ± ± n ± n-↓ n-↓ n-↓ n-↓

n n ± ± ± n ± n-↓ n-↓ n-↓ n-↓

±

n n ± ± ± n ± n-↓ n-↓ n-↓ n-↓

This disorder has recessive inheritance

Table 17.13  Pyrroline-5-carboxylate synthetase deficiency, spastic paraplegia type 9A System CNS

Dermatological Digestive Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Dysarthria Global developmental delay Intellectual disability Increased muscular tone Pyramidal signs Spastic paraparesis/ paraplegia Spinal cord atrophy Cutis laxa Wrinkled skin Gastroesophageal reflux Vomiting Cataract Abnormal gait Growth retardation Short stature Joint laxity Muscle weakness Muscle wasting Pes cavus Arginine (plasma) Citrulline (plasma) Ornithine (plasma) Proline (plasma)

Neonatal (birth–1 month)

n n ± ±

± ±

n-↓ n-↓ n-↓ n-↓

Infancy (1–18 months) − to ±

Childhood (1.5–11 years) − to ± − to ±

Adolescence (11–16 years) − to ± − to ±

Adulthood (>16 years) − to ± − to ±

− to ± +

− to ± +

− to ± +

− to ± +

± ±

+ ±-+

+ ++

+ ++

± n n ± ± ±

± n n ± ± ± ±-+ + + n + ± ± n-↓ n-↓ n-↓ n-↓

± n n ± ± + + + + n + ± ± n-↓ n-↓ n-↓ n-↓

± n n ± ±

+ + n + ± n-↓ n-↓ n-↓ n-↓

+ + + n + ± + n-↓ n-↓ n-↓ n-↓

This disorder is dominantly inherited or has sporadic presentation, in both cases being due to monoallelic mutations in the ALDH18A1 gene

17  Disorders of Ammonia Detoxification

277

Table 17.14  Ornithine aminotransferase deficiency System CNS

Digestive Eye

Metabolic Musculoskeletal

Laboratory findings

>30 years

a

Symptoms and biomarkers Cortical atrophy (MRI) Intellectual disability Neuropathy, sensory Seizures White matter abnormalities (MRI) EM, abnormal mitochondria (liver) Atrophy, gyrate of choroid and retina Blindness Cataract, posterior subcapsular Chorioretinal degeneration Myopia Night blindness Retinal detachment Vision, tunnel Hyperammonemia (symptomatic) EM, abnormal mitochondria (muscle) EM, type 2 fiber atrophy (muscle) EM, type 2 fiber tubular aggregates (muscle) Muscle weakness (mild proximal) 3-amino-2-piperidone (urine) Ammonia (blood and plasma) Arginine (urine) Creatine (cerebrospinal fluid) Creatine (plasma) Creatine (urine) Creatine/phosphocreatine ratio (brain) (MRS) Creatine/phosphocreatine ratio (muscle) (MRS) Creatinine (plasma) Guanidinoacetate (cerebrospinal fluid) Guanidinoacetate (plasma) Guanidinoacetate (urine) Histology and EM, type 2 fiber atrophy (muscle) Lysine (urine) Ornithine (plasma) Ornithine (urine) Proline/citrulline ratio

Neonatal Infancy (birth–1 month) (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ± ± ± ++

Adulthood (>16 years) ± ± ± ± ± ± +++

+ + ++ ±

± ++ ++ 0 ± +

+++a +++ +++ +++ +++ ± +++

±

±

±

± +

± +

± ++

± ±

+

± ±

±

n n-↑↑ n n n n n

↑ n ↑ ↓↓ ↓↓ ↓↓ ↓-n

± ↑ n ↑ ↓↓ ↓↓ ↓↓ ↓

± ↑ n ↑ ↓↓↓ ↓↓↓ ↓↓↓ ↓

± ↑ n ↑ ↓↓↓ ↓↓↓ ↓↓↓ ↓

n

↓-n

↓

↓

↓

n n

↓-n ↓↓

↓-n ↓↓

↓-n ↓↓↓

↓-n ↓↓↓

n n

↓↓ ↓↓

↓↓ ↓↓ +

↓↓↓ ↓↓↓ +

↓↓↓ ↓↓↓ ++-+++

n n n ↑

↑ ↑↑↑ ↑↑↑ n

↑ ↑↑↑ ↑↑↑ n

↑ ↑↑↑ ↑↑↑ n

↑ ↑↑↑ ↑↑↑ n

278

J. Häberle and V. Rubio

Table 17.15  Glutamate dehydrogenase superactivity System CNS

Endocrine Metabolic

Laboratory findings

Symptoms and biomarkers Convulsions EEG, abnormal Epilepsy, generalized Intellectual disability Seizures Hyperinsulinism Hypoglycemia Hypoglycemia, hypoketotic Leucine sensitivity causing hypoglycemia Alpha-ketoglutarate (urine) Ammonia, fasting (blood and plasma) Free fatty acids (serum) Glucose (plasma) Insulin (plasma) Ketones (plasma) Ketones (urine)

Neonatal (birth–1 month) ± + + ± + ++ ++

Infancy (1–18 months) ± + ++ ± ± ++ ++ ++

Childhood (1.5–11 years) ± + ++ ± ± ++ + +

Adolescence (11–16 years) ± ± ± ± ± ± + +

Adulthood (>16 years) ± ± ± ± ± ± + +

++

++

++

++

++

n-↑

n-↑

n-↑

n-↑

n-↑

↑

↑

↑

↑

↑

↓

↓

↓

↓

↓

↓ ↑ ↓ ↓

↓ ↑ ↓ ↓

↓ ↑ ↓ ↓

↓ ↑ ↓ ↓

↓ ↑ ↓ ↓

Table 17.16  Glutamine synthetase deficiency System CNS

Dermatological Laboratory findings

Symptoms and biomarkers Absent head control Cerebellar hypoplasia Developmental delay EEG, abnormal Encephalopathy, epileptic Epilepsy, intractable Myelination, delayed Erythema, necrotizing Ammonia (blood and plasma) Glutamic acid (cerebrospinal fluid) Glutamic acid (plasma) Glutamine (cerebrospinal fluid) Glutamine (plasma) Glutamine (urine)

Neonatal (birth–1 month) + ± + + ++

Infancy (1–18 months) ++ ± +++ ++ ++

Childhood (1.5–11 years) ++ ± +++ ++ ++

++ ± ± ↑

++ ± ± ↑

++ ± ± ↑

n

n

n

n ↓↓

n ↓↓

n ↓↓

↓-↓↓ ↓

↓↓↓ ↓

↓↓↓ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

17  Disorders of Ammonia Detoxification

279

Table 17.17  Pyruvate carboxylase deficiency System CNS

Digestive Metabolic Other Laboratory findings

Symptoms and biomarkers Developmental delay Hypokinesia Hypotonia Parkinsonism, hypokinetic features Pyramidal signs Seizures Vomiting Hypoglycemia Failure to thrive 3-OH-butyrate/ acetoacetate ratio (plasma) Alanine (plasma) Ammonia (blood) Citrulline (plasma) Glucose (plasma) Ketones (plasma) Ketones (urine) Lactate (plasma) Lactate/pyruvate ratio Pyruvate (plasma)

Neonatal (birth–1 month) +++ ++ +++ ++

Infancy (1–18 months) +++ + +++ n

Childhood (1.5–11 years) +++ + +++ n

++ +++ +++ ± +++ ↓

++ +++ +++ ± +++

++ +++ ++ ± +++

↑ n-↑ ↑ ↓-n ↑ ↑ ↑↑ ↑↑ ↑↑

↑ n-↑ ↑ ↓-n ↑ ↑ ↑ n ↑

↑ n-↑ ↑ ↓-n ↑ ↑ ↑ n ↑

Adolescence (11–16 years)

±

↓-n

Adulthood (>16 years)

280

J. Häberle and V. Rubio

Table 17.18  Transmembrane protein 70 deficiency System Cardiovascular

CNS

Digestive

Eye Genitourinary Metabolic

Musculoskeletal Renal Respiratory

Other

Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Wolff-Parkinson-White syndrome Apnea Basal ganglia lesions (MRI) Cerebellar hypoplasia, mild Cortical atrophy (MRI) Encephalopathy Hypotonia, muscular-axial Microcephaly Retardation, psychomotor Subcortical atrophy (MRI) Gastrointestinal dysmotility Hepatomegaly Liver dysfunction Cataract Cryptorchidism Hypospadias Hyperammonemia, during crisis Hyperuricemia, during crisis Ketonuria, pronounced during crisis Lactic acidosis Metabolic acidosis Contractures Facial dysmorphism Renal tubulopathy Persistent pulmonary hypertension of the newborn Respiratory insufficiency Failure to thrive Growth retardation, postnatal Low birth weight 3-Methylglutaconic acid (urine) Alanine (plasma) Ammonia (blood and plasma) Anion gap Citrulline (plasma) Complex V activity (skeletal muscle) Creatine kinase (plasma) Glutamine (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Orotic acid (urine) Uric acid

Neonatal Infancy (birth–1 month) (1–18 months) + +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

±

±

±

±

±

± ± ± ± + + ± ± ± ± + ± ± ± ± +

± ± ± ± + + ± + ± ± + ± ± ± ± +

± ± ± ± + + ± + ± ± ± ± ± ± ± +

± ± ± ± + + ± + ± ± ± ± ± ± ± +

± ± ± ± + + ± + ± ± ± ± ± ± ± ±

+ +

+ +

+ +

+ +

± +

+ + ± ± ± ±

+ + ± ± ±

± + ± ± ±

± + ± ± ±

± ± ± ± ±

± + ± ± ↑-↑↑

± + ±

± + ±

± + ±

± + ±

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑ n-↑↑ ↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑ ↓

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ n-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ n-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ n-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ n-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ n-↑↑

17  Disorders of Ammonia Detoxification

281

Reference Values

Age Ammonia, fasting (enzymatic)a Arginineb Argininosuccinate Citrulline Ornithineb Lysine Glutaminec Alanine Proline

Age Arginine Argininosuccinate Citrulline Ornithine Lysine Glutaminec Alanine Proline Orotic acid Orotidine Uracil

Plasma (μmol/L) 1 month– 16 years)

Fifteen patients from ten Ashkenazi and one Ashkenazi-Iraqi Jews families were reported by Damseh et al. (2015), Heimer et al. (2015), and Srour et al. (2015)

302

M. Palacín et al.

Table 18.16  GLYT2 transporter deficiency System CNS

Musculoskeletal Other

Symptoms and biomarkers Head-retraction reflex Intellectual disability, mild Periodic limb movements during sleep Startle reflex Stiffness Hernias Hip dislocation Sudden infant death

Neonatal (birth–1 Infancy (1–18 month) months) ↑ ↑ ± ± ±

Childhood (1.5–11 years) ↑ ± ±

Adolescence (11–16 years) ↑ ± ±

Adulthood (>16 years) ↑ ± ±

+ +

+ + ± ±

+ + ± ±

+ ± ± ±

± ±

Metabolic Pathways (See Figs. 18.1 and 18.2) Metabolites Important for Diagnosis Hartnup disorder  Metabolites important for diagnosis: neutral amino acids in the urine (glycine is usually normal). Iminoglycinuria  Metabolites important for diagnosis: glycine, proline, hydroxyproline in urine. Hyperglycinuria  Metabolites important for diagnosis: glycine in urine (proline and hydroxyproline are normal). Cystinuria A and Cystinuria B  Due to mutations in SLC3A1 (rBAT) or SLC7A9 (b0,+AT), respectively. Metabolites important for diagnosis: cystine, lysine, arginine, and ornithine in urine. Lysinuric protein intolerance  Metabolites important for diagnosis: dibasic amino acids in the plasma (decreased) and urine (increased) and orotic acid in urine (increased). Dicarboxylic aminoaciduria  Metabolites important for diagnosis: glutamate and aspartate in the urine.

+ + ± ± ±

Methionine malabsorption syndrome  Metabolites important for diagnosis: α-hydroxybutyrate (oasthouse smell), Met, BCAA, and Ser in urine and feces. Cationic amino acid transporter 2 deficiency  Metabolites important for diagnosis: Arg, Lys, ornithine, and guanidinoacetic acid. Large neutral amino acid transporter LAT1 deficiency  Metabolites important for diagnosis: not identified, but branched chain amino acid levels are expected to be below reference values in patients. Neuronal system ciency  Metabolites identified.

A SNAT8 transporter defiimportant for diagnosis: not

Episodic ataxia due to EAAT1 defect  Metabolites important for diagnosis: not identified. ASCT1 transporter deficiency  Metabolites important for diagnosis: not identified. Hyperekplexia due to GLYT2 deficiency  Metabolites important for diagnosis: not identified.

Lysine malabsorption syndrome  Metabolites important for diagnosis: Lys, Arg, Orn in urine and plasma.

Reference Values

Dibasic aminoaciduria type I  Metabolites important for diagnosis: lysine, arginine, and ornithine in urine.

Urine amino acid levels (mmol/mol creatinine) (5–95 percentile limits) measured by amino acid analyzer.

18  Amino Acid Transport Defects Amino acid Alanine Arginine Asparagine Aspartate Citrulline Cystine Glutamate Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tyrosine Valine

Neonatal Fasting 75–244 16 years)

26  Disorders of Glycine Metabolism

475

Diagnostic Flowchart CSF and plasma amino acids

Clinical suspicion

Normal plasma glycine Contractures, apnea Consider GLYT1 sequencing

Elevated CSF glycine

Brain MRI with DWI

diffusion restriction pattern not typical of NKH

diffusion restriction pattern typical of NKH

Valproate? Other AA elevated elevated protein

Consider HIE Transient NKH Bleeding

Elevated threonine Elevated lactate, alanine Seizures Cystic lesions Low CSF PLP Optic atrophy Cardiomyopathy Pulmonary hypertension Consider PLP disorder

Consider lipoate disorder

Genetic testing AMT, GLDC, GCSH Sequencing and del/dup

Diagnosis of NKH Assess severity for prognosis and treatment guidance

Fig. 26.3  Diagnostic flowchart for children 16 years)

+++ +++

+

± ± +++ +++ +++ +++ +++ ± ± ± ↑↑↑

Childhood (1.5–11 years)

+ ± ±

± ↑↑ ↓↓

↑↑ ↓-n

n-↑ ↑↑

↑↑

n

↑↑ ↑↑ ↑↑ ↑↑ n

n n ↑↑ ↑↑↑ ↑↑ ↓↓↓

n n ↑↑ ↑↑↑ ↑↑ ↓↓↓

n

↓↓

↓↓

↓↓

↑↑

n-↑

↑↑ ↑↑ n-↑ ↓↓↓

Table 27.4  NFU1 deficiency System CNS

Digestive Musculoskeletal Pulmonary

Neonatal Symptoms and biomarkers (birth–1 month) Cerebral atrophy (MRI) Cystic leukoencephalopathy Dystonia Epileptic seizures Hypotonia Intellectual disability Lethargy + ++ Leukodystrophy Neurological regression Spastic paraparesis Spasticity Subacute demyelinating mixed motor sensory neuropathy Feeding difficulties + ++ Scoliosis Weakness + ++ Pulmonary hypertension

Infancy (1–18 months) ++ ++ ± ± ± ++

Childhood Adolescence (1.5–11 years) (11–16 years)

Adulthood (>16 years)a

++ +++ +

+ + +

+ ++

n

27  Disorders of Lipoic Acid and Iron-Sulfur Protein Metabolism

485

Table 27.4 (continued) System Other

Laboratory findings

Neonatal Infancy (birth–1 month) (1–18 months) ++

Symptoms and biomarkers Failure to thrive Stress-induced deterioration followed by partial recovery Unable to walk 2-Hydroxyadipate (urine) 2-Hydroxyglutarate (urine) 2-Ketoadipate (urine) 2-Ketoglutarate (urine) 2-Ketoglutarate dehydrogenase (fibroblasts) Complexes I–II (muscle, fibroblasts) Glutamic acid (plasma) Glycine (cerebrospinal fluid) Glycine (plasma) Glycine (urine) Lactate (cerebrospinal fluid) Lactate (plasma) Lactate (urine) Protein-bound lipoic acid (fibroblasts) Pyruvate dehydrogenase (fibroblasts)

Childhood Adolescence (1.5–11 years) (11–16 years)

Adulthood (>16 years)a + +

↓↓↓

n-↑ n-↑ ↑ ↑↑ ↓↓

↓↓↓

↓↓

↓↓

↓-n

↑↑ ↑↑ ↓↓↓

↑ ↑↑↑ ↑↑↑ ↑↑↑ ↑ ↑ n-↑ ↓↓↓

↓↓↓

↓↓

↑↑↑

↑↑ ↑↑ ↑↑ n-↑

↓↓↓

Only one adulthood patient

a

Table 27.5  BOLA3 deficiency System Cardiovascular CNS

Digestive Eye Respiratory Others Laboratory findings

Symptoms and biomarkers Cardiomyopathy Developmental delay Dystonia Hypotonia Irritability Lethargy Leukodystrophy Leukoencephalopathy Neurological regression Seizures, myoclonic Spasticity Feeding difficulties Hepatomegaly Optic atrophy Respiratory distress Failure to thrive 2-ketoglutarate dehydrogenase (fibroblasts) Complexes I–III (muscle, fibroblasts) Glycine (cerebrospinal fluid) Glycine (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Lactate (urine) Protein-bound lipoic acid (fibroblasts) Pyruvate dehydrogenase (fibroblasts)

Neonatal Infancy (birth–1 month) (1–18 months) +++ +++ ++ + ++ ± ± +++ ++ +++ ++ +++ ± +++ ± ± ++ ± ++ + ↓ ↓ ↑ ↑↑↑ ↑↑↑ ↑↑↑ ↓

↓ ↑↑↑ ↑↑ ↑↑↑ ↑↑↑ ↓-n ↓↓

Childhood Adolescence (1.5–11 years) (11–16 years)

Adulthood (>16 years)

486

A. Ribes and F. Tort

Table 27.6  Glutaredoxin 5 deficiency System CNS

Eye Hematological Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Cervical spinal cord lesions Spasticity Nystagmus Optic atrophy Anemia, sideroblastic Complexes I–III (muscle, fibroblasts) Ferritin (serum) Glycine (cerebrospinal fluid) Glycine (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Protein-bound lipoic acid (fibroblasts) Pyruvate dehydrogenase (fibroblasts) Transferrin (serum)

Infancy (1–18 months)

Childhood (1.5–11 years) +

Adolescence (11–16 years)

Adulthood (>16 years)

+ ++ ± ± + ++ ↓-n ↑

↑ ↑ n-↑ n-↑ ↓ ↓

↑

Table 27.7  IBA57 deficiency System CNS

Digestive Eye Respiratory Others

Laboratory findings

Symptoms and biomarkers Cerebral atrophy (MRI) Epileptic seizures Hypotonia Intellectual disability Leukodystrophy Neuropathy, peripheral Spastic paraplegia Spastic tetraparesis Feeding difficulties Optic atrophy Respiratory insufficiency Intrauterine growth retardation Perinatal death Polyhydramnios 2-Ketoglutarate dehydrogenase (fibroblasts) Branched-chain ketoacid dehydrogenase (fibroblasts) Complexes I–IV (muscle, fibroblasts) Glycine (cerebrospinal fluid) Glycine (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Lactate (urine) Protein-bound lipoic acid (fibroblasts) Pyruvate dehydrogenase (fibroblasts)

Two members of a single family Ten members of a single family

a

b

Neonatal (birth–1 month)a + ++ + ++

Infancy (1–18 months) ++ ± ++ ++ +++

Childhood Adolescence (1.5–11 years)b (11–16 years)

+ ++ + ++ + + ++ + ++ + ++ + ++ + ++ + ++ ↓↓ ↓↓ ↓↓

↓↓

↑↑↑ ↑↑↑ ↑↑ ↑↑ ↑↑ ↓↓↓

n-↑↑ n-↑↑ ↑↑ ↑ ↓↓↓ ↓↓↓

Adulthood (>16 years)

27  Disorders of Lipoic Acid and Iron-Sulfur Protein Metabolism

487

Table 27.8  ISCA1 deficiency System CNS

Digestive Eye Laboratory findings

Symptoms and biomarkers Deep tendon reflexes Developmental delay Leukodystrophy Neurologic deterioration Poor head control Seizures Spasticity Ventriculomegaly Feeding difficulties Nystagmus Strabismus Complexes I–IV (muscle) Creatine kinase (plasma) Glycine (plasma) Glycine (urine) Lactate (plasma) Lactate (urine) Protein-bound lipoic acid (fibroblasts) Pyruvate dehydrogenase (fibroblasts)

Neonatal (birth–1 month)

Infancy (1–18 months) ++ ++ +++ ++ + ++ ++ ++ +++ ± ± ↓↓ n-↑ n n ↑ n ↓↓↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

↓↓

Table 27.9  ISCA2 deficiency System CNS

Digestive Eye Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Axial hypotonia Cerebellar white matter abnormalities (MRI) Diffuse bilateral cerebral white matter abnormalities (MRI) Neurodevelopmental regression Seizures Spasticity, limbs Spinal cord abnormalities (MRI) Gastroesophageal reflux Nystagmus Optic atrophy 2-Ketoglutarate dehydrogenase (fibroblasts) Complexes I–IV (fibroblasts) Glycine (cerebrospinal fluid) Glycine (plasma) Glycine (urine) Lactate (cerebrospinal fluid) Lactate (plasma) mtDNA content (fibroblasts) Protein-bound lipoic acid (fibroblasts) Pyruvate dehydrogenase (fibroblasts)

Infancy (1–18 months) +++ +++ +++ +++ ± +++ + ± +++ +++ ↓↓ ↓-n ↑ n-↑ n-↑ ↑ n-↑ ↓-n ↓↓ ↓↓

Childhood Adolescence (1.5–11 years) (11–16 years)

Adulthood (>16 years)

488

A. Ribes and F. Tort

Table 27.10  ISCU deficiency Symptoms and biomarkers Cardiomyopathy Exercise intolerance Muscle weakness Myoglobinuria Myopathy Rhabdomyolysis Laboratory findings Aconitase (muscle) Complexes I–III (muscle) Creatine kinase (plasma) Lactate (plasma) Myoglobin (urine) SDH histochemistry (muscle) System Cardiovascular Musculoskeletal

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ± + + ± +++ ± ↓ ↓

Adolescence (11–16 years) ± +++ +++ ± +++ ± ↓ ↓

Adulthood (>16 years) ± +++ +++ +++ +++ +++ ↓ ↓

n-↑

n-↑

↑

↑↑ n-↑ ↓

↑↑ n-↑ ↓

↑↑ ↑↑↑ ↓

Table 27.11  ABCB7 deficiency System CNS

Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cerebellar ataxia, nonprogressive Dysarthria Ringed sideroblasts on bone marrow Protoporphyrin (red blood cells)

Infancy (1–18 months)

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

Adulthood (>16 years) +++

+++ +++

+++ +++

+++ +++

↑

↑

↑

Table 27.12  Ferredoxin 2 deficiency System CNS

Eye Hematological Musculoskeletal

Laboratory findings

Neonatal Infancy Symptoms and biomarkers (birth–1 month) (1–18 months) Axonal sensorimotor ± neuropathy Delayed motor development ++ Learning disability ± Reversible ++ leukoencephalopathy Nystagmus +++ Optic atrophy +++ Anemia, microcytic ++ Neutropenia ++ Exercise intolerance Muscle cramps Muscle weakness Myoglobinuria 3-Methylglutaconic acid (urine) Complexes I–IV (muscle, fibroblasts)) Creatine kinase (plasma) Lactate (plasma) Lactate (urine) Myoglobin (urine) Pyruvate dehydrogenase (fibroblasts)

Childhood Adolescence (1.5–11 years) (11–16 years) ++

++ +++ +++

++ ++

++ ++ ++

+++ +++ +++ +++ ↑ ↓ ↑↑↑ ↑↑ ↑↑ ↑↑↑ ↓

Adulthood (>16 years)

27  Disorders of Lipoic Acid and Iron-Sulfur Protein Metabolism

489

Table 27.13  Ferredoxin reductase deficiency System CNS

Dermatological Digestive Ear Eye

Musculoskeletal Other Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Ataxia Cerebral atrophy (MRI) Developmental delay Dysarthria Encephalopathy, progressive Hypotonia Irritability Microcephaly Motor developmental delay Neuropathy, sensory axonal Seizures Sleep disturbances Spasticity Swallowing difficulties Café au lait spot Feeding difficulties Hearing loss, sensorineural Nystagmus Optic atrophy Retinitis pigmentosa Strabismus Unable to track visually Visual impairment Muscle weakness Failure to thrive Wheelchair bound Complexes I–IV (muscle)

Infancy (1–18 months) + +++ ± ++ ± +

± ±

Childhood (1.5–11 years) ++ + ++ +++ ±

Adolescence (11–16 years) ++

Adulthood (>16 years)

+++

+++

++ ± + ++

±

+

++

+

±

+

++ +

± + +

+ +

+++

+ +++ ++

++ ±

+ ± + ++ +++ ++ ↓-n

+++

++

±

+++ + + ++ ↓-n

++

+++ ± +++

++

Table 27.14  ISD11 deficiency System CNS

Digestive

Respiratory Others Laboratory findings

Symptoms and biomarkers Epilepsy Hypotonia Lethargy Feeding difficulties Gastroesophageal reflux Hepatomegaly Respiratory distress Stridor, inspiratory Low weight gain ASAT/ALAT (plasma) Complexes I–IV (muscle, fibroblasts, leucocytes) Gamma-glutamyl transpeptidase, GGT (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Lactate (urine)

Infancy Neonatal (birth–1 month)a (1–18 months) ± + ± + + ± ++ ++ + ↑ n-↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

↑ ↑↑ ↑↑ ↑↑

Two patients of the same family: one patient died during infancy and the other was alive and asymptomatic at 20 years of age

a

Adulthood (>16 years)

490

A. Ribes and F. Tort

Table 27.15  NFS1 deficiency System Cardiovascular CNS

Digestive

Metabolic Renal Respiratory Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cardiac failure Cerebral infarction Developmental and gross motor delay Hypotonia Lethargy Seizures Anorexia Hemorrhagic pancreatitis Vomiting Hypoglycemia Renal failure Respiratory failure ASAT/ALAT (plasma) Complexes I–IV (muscle) Creatine kinase (plasma) Disseminated intravascular coagulation Glucose (plasma) Lactate (plasma)

Infancy (1–18 months)a ++ ± ±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+++ +++ ++ +++ ± ± ++ ++ ++ ↑ ↓↓ ↑ + ↓ ↑↑

Only one family with three siblings

a

Table 27.16  Frataxin deficiency System Cardiovascular CNS

Endocrine

Eye Musculoskeletal

Symptoms and biomarkers Cardiomyopathy Absent lower limb reflexes Ataxia Dysarthria Hearing, impaired Sphincter control problems Spinal cord atrophy Swallowing difficulties Abnormal glucose tolerance Diabetes Vision, decreased Pes cavus Scoliosis

Neonatal (birth–1 month)

Infancy (1–18 months)

Four well-defined clinical entities, Friedreich ataxia (FXN) (Table  27.16), myopathy with lactic acidosis and exercise intolerance (ISCU) (Table  27.10), X-linked sideroblastic anemia with ataxia (ABCB7) (Table 27.11), and sideroblastic anemia associated with particular mutations in GLRX5 (Table 27.6), were the first-described diseases related to Fe-S cluster biosynthesis or transport defects. In addition, patients with mutations in HSPA9 also presenting two well-defined phenotypes consisting in sideroblastic anemia (Schmitz-­Abe et al. 2015) or EVEN-plus syndrome (Royer-Bertrand et al.

Childhood (1.5–11 years)

Adolescence (11–16 years) ++ +++

Adulthood (>16 years) ++ +++

+++ +++ ± ±

+++ +++ ± ±

++ ±

++ ±

±

±

± ± ++ ++

± ± ++ ++

2015) (Table 27.17) were described later on. In these cases diagnosis goes directly from the clinical suspicion to molecular studies. The progress in the knowledge of these diseases started in 2011 when two parallel and independent studies identified mutations in the genes encoding for the Fe-S cluster proteins NFU1 and BOLA3 (Tables 27.4 and 27.5) in patients with a fatal mitochondrial encephalopathy with lactic acidosis, hyperglycinemia, and deficient activities of LA-dependent enzymes (Navarro-Sastre et al. 2011; Cameron et al. 2011).

27  Disorders of Lipoic Acid and Iron-Sulfur Protein Metabolism

491

Table 27.17  HSPA9 deficiency System Cardiovascular CNS

Hematological Musculoskeletal

Renal Others Laboratory findings

Symptoms and biomarkers Heart abnormalities Abnormal gait Agenesis of the corpus callosum Agenesis of the septum pellucidum Developmental delay Hypotonia Anemia, sideroblastic Anal atresia Aplasia cutis congenita on skull vertex Hypoplastic nose Microtia Short stature Shortened limbs Skeletal abnormalities Synophrys Hypoplastic kidney Vesicouretral reflux Low weight Teeth abnormalities Microcytic or macrocytic red blood cells Ringed sideroblasts in bone marrow

Neonatal (birth–1 month)

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) + ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

± ±

± ± +++

+ ++ + + +++ ++ + +

±

+++ +++ +++

+

+++ +++ ± ± +++ ±

+++

Later on, six new diseases, LIPT2, LIAS (Tables 27.1 and 27.2), GLRX5, IBA57, ISCA1, and ISCA2 (Tables 27.6, 27.7, 27.8, and 27.9), with very close clinical and biochemical phenotype to NFU1 and BOLA3 were described. It is important to remark that patients with mutations in GLRX5 can present two different phenotypes: the abovementioned sideroblastic anemia into adulthood or progressive spasticity and MRI abnormalities consistent with leukodystrophy in childhood (Table 27.6). These two phenotypes are mutation dependent. In fact, it has been demonstrated that GLRX5 protein is multifunctional and defects of the different amino acids of the protein will lead to distinct effects downstream Fe-S biosynthesis (Baker et al. 2014; Lui et al. 2016). Neonatal encephalopathy with lactic acidosis and normal glycine was observed in a patient with mutation in LIPT1 (Table 27.3) (Tort et al. 2014). This could be explained by the fact that LIPT1 is required for lipoylation, and subsequent activation, of the 2-oxoacid dehydrogenases but is not involved in the regulation of the GCS.  On the other hand, other diseases, ISCU (Table  27.10) FDX2 (Table  27.12), ISD11, and NFS1 (Tables 27.14 and 27.15), presenting also with lactic acidosis but normal glycine completed the spectrum of mitochondrial encephalopathies associated with LA and Fe-S cluster disorders. It is interesting that patients carrying mutations in ISCU and FDX2 had a similar clinical phenotype showing late-­

+++ +++

onset presentation, even into adulthood, with myopathy, rhabdomyolysis, and myoglobinuria. In addition, the recent report of patients with normal lactate, hearing loss, and visual impairment in childhood, associated with FDXR mutations (Table 27.13) highlight the wide clinical and biochemical heterogeneity of mitochondrial disorders related to Fe-S metabolism (Peng et al., 2017; Paul et al. 2017; Slone et al. 2018). To summarize, the clinical suspicion is always the first step for the diagnosis. As mentioned above, in the well-­ defined clinical syndromes, the diagnosis goes from the clinical suspicion to molecular studies, but for other diseases the analysis of both LA- and Fe-S cluster-dependent pathways is very useful to direct the defect. With few exceptions, high lactate is a common finding of these diseases (Figs. 27.2 and 27.3). Glycine elevation, due to the defective lipoylation of the H-protein of GCS, is observed in all patients with defects in LA synthesis (LIAS, LIPT2, NFU1, BOLA3, IBA57, GLRX5, and ISCA2). In contrast, glycine levels remained unaltered in individuals with mutations in LIPT1, FDX1L, LYRM4 (ISD11 protein), FDXR, and NFS1. On the other hand, analysis of LA levels is also a useful parameter. This analysis is performed using a specific antibody that recognizes the lipoylated forms of the E2 subunits of 2-oxoacid dehydrogenase complexes as well as the lipoylated H-protein of the GCS.  This approach is

492

mainly used as a research resource. Nevertheless, the fact that this antibody does not react against non-lipoylated proteins provides an efficient and cost-effective tool to identify lipoylation defects. Another useful parameter is the measurement of the respiratory chain activities, which are frequently altered in the patients with defects in biosynthesis, maturation, and delivery of Fe-S clusters but are unaltered in other defects (Figs. 27.2 and 27.3) (Tort et  al. 2016; Mayr et al. 2014). The inheritance of these diseases is autosomal recessive, except for ABCB7 that is X-linked and ISCU that can be autosomal recessive or dominant (Olsson et al. 2008; Mochel et al. 2008; Legati et al. 2017). Concerning frequency, apart from the high number of reported patients with Friedreich ataxia, the first-described Fe-S cluster disorder (Campuzano et al. 1996), the most frequently described disease is NFU1, with more than 70 reported patients. It is remarkable that 27 patients with the recently described FDXR deficiency have already been reported (Peng et al., 2017; Paul et al. 2017; Slone et al. 2018).

Diagnostic Flowchart

Fig. 27.2  Diagnostic flowchart

A. Ribes and F. Tort

Reference Values Metabolites Plasma (μmol/L) Lactate 0.5–2 Glycine 81–436 Enzyme activitiesa MRC Muscle Complex I 25–54 Complexes 18–37 I + III Complex II 37–82 Complexes 27–48 II + III Complex III 103–207 Complex IV 78–186 Citrate 127–222 synthase PDH PDH (total) 0.8–3.4

CSF (μmol/L) 0.8–2.8 3.7–8

Urine (mmol/ mol creatinine)

CSF/ plasma

110–356

16 years)b

± ± ± ± ± ± ± ± ± ↓

n-↑

Neonatal presentation extremely rare Solid data on adult patients not available c Following oral vitamin B12 load (Bor et al. 2005) d Mild Cbl-resistant proteinuria may be present in IGS (not obligatory) and help to distinguish from IFD a

b

Table 28.4  Haptocorrin deficiency System Others Laboratory findings

Symptoms and biomarkers No consistent clinical picture Holotranscobalamin (plasma) Homocysteine, total (plasma) Vitamin B12 (serum)

Neonatal (birth–1 month)

Intracellular Disorders Although disorders of intracellular Cbl metabolism share many clinical features with the forms of Cbl deficiency due to abnormal absorption and transport, some clinical manifestations are unique. Symptoms are generally more severe, and in most cases there is only a partial or no response to parenteral hydroxo-Cbl treatment (Watkins et al. 2016).

Infancy (1–18 months)

Childhood (1.5–11 years) + n n ↓

Adolescence (11–16 years) + n n ↓

Adulthood (>16 years)

Patients with combined deficiency of MeCbl and AdoCbl synthesis (cblC, cblD, cblF, cblJ) usually present within the first year of life with poor feeding, failure to thrive, developmental delay, megaloblastic anaemia and (pan)cytopenia (Tables 28.7, 28.8, 28.9, 28.10 and 28.11). In cblF and cblJ, low birth weight, minor facial abnormalities and congenital heart defects have been reported as well, while most cblJ patients have been reported to have skin hyperpigmentation and grey hair. In cblC patients, at least two distinct pheno-

28  Disorders of Cobalamin Metabolism

503

Table 28.5  Transcobalamin deficiency System CNS

Digestive Haematological

Others Laboratory findings

a

Symptoms and biomarkers Apathy Deep tendon reflexes Developmental delay Hypotonia Neurologic dysfunction Diarrhoea, chronic (pan)cytopenia Anaemia, megaloblastic Neutrophils, hypersegmented Pancytopenia Failure to thrive Holotranscobalamin (plasma) Homocysteine (urine) Homocysteine, total (plasma) Methylmalonic acid (plasma) Methylmalonic acid (urine) Vitamin B12 (serum)

Neonatal Infancy (birth–1 month) (1–18 months) ± + ↓-n ± ± ± ± ++ ± + ± ++ ± ± ± + ± ++ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↓-n

Childhood (1.5–11 years) + ↓-n ± ± ± + + + ± + + ↓ ↑ ↑ ↑ ↑ ↓-n

Adolescence (11–16 years)

Adulthooda (>16 years)

± ± ±

+ ±

±

↓

↓-n

Solid data on adult patients not available

Table 28.6  Transcobalamin receptor defect System Others Laboratory findings

Symptoms and biomarkers No consistent clinical picture Homocysteine, total (plasma) Methylmalonic acid (urine)

Neonatal (birth–1 month) + (↑) ↑

Infancy (1–18 months) + (↑) ↑

Childhooda (1.5–11 years)

Adolescencea (11–16 years)

Adulthooda (>16 years)

Few patients described, none beyond infancy

a

types differentiated by age of onset have been delineated and are related to specific mutations in MMACHC (Lerner-Ellis et al. 2009). Early-onset patients present in the first year of life with feeding problems, failure to thrive, neurological symptoms including muscular hypotonia, developmental delay and seizures (Fischer et al. 2014; Huemer et al. 2018) and more rarely with atypical haemolytic uremic syndrome and pulmonary hypertension (Beck et  al. 2017). These patients may develop multisystem pathology, which mainly presents as persistent failure to thrive, cognitive dysfunction and eye disease, which is resistant to therapy (Fischer et al. 2014; Huemer et al. 2018). In contrast, a few cblC patients have come to clinical attention after the first year of life and have presented as late as in the fourth decade (Thauvin-­ Robinet et al. 2008). Clinical findings in this group are mainly neurologic and include gait abnormalities, confusion, disori-

entation, psychosis and dementia (Fischer et al. 2014; Huemer et al. 2018). Macrocytic anaemia is found in less than half of these patients. Only three patients with epimutation of MMACHC due to genetic mutation of PRDX1 have so far been described, and these were consistent with early onset cblC disease (Gueant et al. 2018). Alternatively, 19 patients with mutation of HCFC1 (Yu et al. 2013; Gerard et al. 2015; Koufaris et al. 2016) and one patient each with mutation of ZNF143 (Pupavac et al. 2016) and THAP11 (Quintana et al. 2017) have presented in the first months of life with a somewhat similar clinical presentation to early-­onset cblC patients (Tables 28.12, 28.13 and 28.14). However, in these patients the metabolic abnormalities were milder, while the neurological presentation more severe and often included intractable seizures and severe intellectual disability.

504

M. R. Baumgartner and D. S. Froese

Tables 28.7–28.11  Adenosylcobalamin and methylcobalamin synthesis defect—cblF (28.7), cblJ (28.8), cblC (28.9), epi-cblC (28.10) and cblDMMA-HC (28.11) System Cardiovascular

CNS

Digestive Eye

Haematological Musculoskeletal Renal Others

Laboratory findings

Symptoms and biomarkers Cardiac, anomalies, malformations Cardiomyopathy Cerebral atrophy (MRI) Dementia Developmental delay Extrapyramidal signs Hypotonia Myelopathy Neurologic dysfunction Psychiatric symptoms Seizures White mater changes (MRI) Feeding difficulties Liver dysfunction Maculopathy Nystagmus Retinopathy Vision, impaired Anaemia, megaloblastic Neutrophils, hypersegmented Dysmorphic features Haemolytic uraemic syndrome Failure to thrive Life-threatening illness Low birth weight 3-Hydroxypropionic acid (urine) C3 propionylcarnitine (blood) C3 propionylcarnitine (plasma) Homocysteine (urine) Homocysteine, total (plasma) Methionine (plasma) Methylcitric acid (urine) Methylmalonic acid (plasma) Methylmalonic acid (urine) S-Adenosylmethionine (cerebrospinal fluid) S-Adenosylmethionine (plasma)

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years) ± ± ±

+ n + ± +

± ± ± ± + ± ↑ ↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑

± ±

±

± ± ++ n ++

± ± + ± ++

± ± + ± ± ± ± ± + ± ± ± ++ +

± ± + ± ± ± ± ± + ± ± + ±

± ±

±

↑ ↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↓

↑ ↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↓

↑ ↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↓

↑ ↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↓

↓

↓

↓

↓

Combined deficiencies in adulthood only reported in cblC deficiency to date

a

Adolescence Adulthood (11–16 years) (>16 years)a

± ± ± ± + ± ++ ± ± ± ± ± ± ± ± ± + ±

± ± ± + ± ++ ± ± ± ± ± ± ± ± ± ± ±

28  Disorders of Cobalamin Metabolism

505

Tables 28.12–28.14  cblC-like adensoylcobalamin and methylcobalamin defect—HCFC1(28.12), ZNF143 (28.13) and THAP11 (28.14) System CNS

Eye Haematological Musculoskeletal Others Laboratory findings

Symptoms and biomarkers Choreoathetosis Cortical malformations Developmental delay Hypotonia Infantile spasms with hypsarrhythmia Movement disorder Neurologic dysfunction Seizures, intractable Vision, impaired Macrocytosis Dysmorphic features Microcephaly Failure to thrive Life-threatening illness C3 propionylcarnitine (blood) Glycine (cerebrospinal fluid) Glycine (plasma) Homocysteine, total (plasma) Methylmalonic acid (plasma) Methylmalonic acid (urine)

Neonatal (birth–1 month) + ± ± + +

Infancy Childhood (1–18 months) (1.5–11 years) + ± +++ + +

± ++ +

± ++ +++ ± ± ± + ++ + n-↑ ↑ n-↑ n-↑ ↑ ↑

± ± + ± + n-↑ ↑ n-↑ n-↑ ↑ ↑

The clinical features of the isolated homocystinuria defects (cblE, cblG, cblD-HC) include poor feeding and vomiting with failure to thrive, megaloblastic anaemia, and neurological disease including developmental delay, cerebral atrophy, hypotonia or hypertonia, ataxia, neonatal seizures, nystagmus and visual disturbances (Huemer et  al. 2015; Huemer et al. 2017) (Tables 28.15, 28.16 and 28.17). Most patients are symptomatic in the first year of life, but isolated cases with later onset and minimal findings have also been reported (Vilaseca et al. 2003). The majority of patients with isolated MMAuria (cblA, cblB, cblD-MMA and mut) present during the newborn

Adolescence Adulthood (11–16 years) (>16 years)

n-↑ ↑ n-↑ ↑ ↑

period or infancy with metabolic crises, often precipitated by catabolic stress, e.g. induced by febrile illness. Symptoms include vomiting, dehydration, tachypnea, lethargy, failure to thrive, developmental delay, hypotonia and encephalopathy (Tables 28.18, 28.19 and 28.20). Long-term complications include chronic renal failure, developmental delay, metabolic stroke, extrapyramidal movement disorder and optic neuropathy (Baumgartner et  al. 2014; Kolker et  al. 2015). Patients with mut0 and cblB defects tend to have earlier onset of symptoms and a higher frequency of complications and deaths than those with mut− and cblA defects (Horster et al. 2007).

506

M. R. Baumgartner and D. S. Froese

Tables 28.15–28.17  Methylcobalamin synthesis defect—cblD-HC (28.15), cblE (28.16) and cblG (28.17) System CNS

Digestive Eye Haematological Others Laboratory findings

Symptoms and biomarkers Ataxia Cerebral atrophy (MRI) Developmental delay Hypertonia Hypotonia Lethargy Myelopathy Neurological symptoms Psychiatric symptoms Seizures Vomiting Nystagmus Vision, impaired Anaemia, megaloblastic Failure to thrive Homocysteine (urine) Homocysteine, total (plasma) Methionine (plasma) Methylmalonic acid (plasma)a Methylmalonic acid (urine)a S-Adenosylmethionine (cerebrospinal fluid) S-Adenosylmethionine (plasma)

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± + ± ± ± ± ± ± n n ± ++ n n ± ± ± ± ± ± ± ++ ± + ↑ ↑ ↑ ↑↑ ↓-n ↓-n n n n n ↓ ↓

Childhood (1.5–11 years) ± ± + ± ± ± n + n ± ± ± ± + + ↑ ↑↑ ↓-n n n ↓

Adolescence (11–16 years) ± ± ± ± ± ± ± + ± ± ± ± ± + ± ↑ ↑↑ ↓-n n n ↓

Adulthood (>16 years) ± ±

↑ ↑↑ ↓-n n n ↓

↓

↓

↓

± ± ± ± + ± ± ± ± ± ±

Elevated MMA in isolated cases with cblE

a

Tables 28.18–28.20  Adenosylcobalamin synthesis defect—cblD-MMA (28.18), cblA (28.19) and cblB (28.20) System Cardiovascular CNS

Digestive Eye Haematological Metabolic

Renal Others

Symptoms and biomarkers Cardiomyopathy Basal ganglia lesions (MRI) Encephalopathic crisis, acute Extrapyramidal movement disorder Hypotonia Intellectual disability Metabolic stroke Seizures Pancreatitis Vomiting Optic neuropathy (pan)cytopenia Pancytopenia Acidosis Ketosis Metabolic acidosis Renal failure, chronic Dehydration Failure to thrive Life-threatening illness

Neonatal (birth–1 month)

Infancy (1–18 months)

±

± ± ± ++ ± ± ++ ++ +++ ++ ++

± ± ±

Childhood (1.5–11 years) ± ± ± ±

Adolescence (11–16 years) ? ± ± ±

Adulthood (>16 years) ? ± ± ±

± ± ± ± ± +

± ± ± ± ± ±

± ± + + ++ ± + ± +

± ± + + ± ± ± ± +

± ± ± ± ± ± + ± ± ± ± ± + ± ± ±

± ± ± ± ± ± + ± ± ± ± ± ++ ± ±

28  Disorders of Cobalamin Metabolism

507

Tables 28.18–28.20 (continued) System Laboratory findings

Symptoms and biomarkers 3-Hydroxypropionic acid (urine) Ammonia (blood) Anion gap C3 propionylcarnitine (blood) C3 propionylcarnitine (plasma) C3/C0 acylcarnitines ratio C3/C2 acylcarnitines ratio C3/C4DC Acylcarnitines ratio Carnitine, free (dried blood spot) Carnitine, free (plasma) Homocysteine, total (plasma) Lactate (plasma) Methylcitric acid (urine) Methylmalonic acid (plasma) Methylmalonic acid (urine)

Neonatal (birth–1 month) ↑ ↑↑ + ↑↑ ↑↑ ↑ ↑ ↑ ↓↓ ↓↓ n n-↑ ↑↑ ↑↑↑ ↑↑↑

Diagnosis Haematologic investigations and measurement of serum Cbl can be helpful. Cbl levels below 125 pmol/L are almost always indicative of Cbl deficiency. However, symptomatic patients with low-normal Cbl that are responsive to Cbl treatment have been reported. Accumulating evidence indicates that plasma measurements of the biologically active Cbl holotranscobalamin may be superior to serum Cbl, and these are being introduced increasingly into the clinical setting (Nexo and Hoffmann-Lucke 2011). However, both markers may be nor-

Infancy (1–18 months) ↑ n-↑ + ↑↑ ↑↑ ↑ ↑ ↑ ↓↓ ↓↓ n n-↑ ↑↑ ↑↑↑ ↑↑↑

Childhood (1.5–11 years) ↑ n-↑ + ↑↑ ↑↑ ↑ ↑ ↑ ↓↓ ↓↓ n n-↑ ↑↑ ↑↑↑ ↑↑↑

Adolescence (11–16 years) ↑ n-↑ ± ↑↑ ↑↑ ↑ ↑ ↑ ↓↓ ↓↓ n n-↑ ↑↑ ↑↑↑ ↑↑↑

Adulthood (>16 years) ↑ n-↑ ± ↑↑ ↑↑ ↑ ↑ ↑ ↓↓ ↓↓ n n-↑ ↑↑ ↑↑↑ ↑↑↑

mal in patients with TC deficiency and inborn errors of intracellular Cbl metabolism. In these disorders, measurement of the two metabolic markers MMA and tHcy, which are sensitive indicators of Cbl deficiency, is indicated. Limitations are the specificity of tHcy which is also increased in folate deficiency and the complexity and cost of the assay for MMA. Further studies are usually required to determine the cause of Cbl deficiency, e.g. mutation analysis and/or tests for investigating Cbl absorption or enzymatic and genetic complementation studies in defects of Cbl metabolism. These tests should be performed in laboratories with specific expertise.

508

M. R. Baumgartner and D. S. Froese

Reference Values Analyte

Infant 50 16 years) ± n ± n ± ++ n

− ↑ n-↑ ↑ n-↑

− ↑ n-↑ ↑ n-↑

− ↑ n-↑ ↑ n-↑

↓-n n-↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↑ ↑ ↓

↓-n n-↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↑ ↑ ↓

↓-n n-↑↑ ↑ ↑ ↑

↓-n n-↑↑ ↑ ↑ ↑

n-↑ n-↑ ↑ ↑ ↑

n-↑ n-↑ ↑ ↑ ↑

+ ↑ n-↑

+ ↑ n-↑

↓-n n-↑↑ ↑ ↑ ↑ ↓-n ↑ ↑ ↑ ↑ ↑ ↓-n ++ ± ↑ n-↑

++ ± ↑ n-↑

++ ± ↑ n-↑

Table 32.8  Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD)—Electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO) deficiency (ETFDH gene) System CNS Digestive Musculoskeletal Others

Symptoms and biomarkers Encephalopathy, episodic Liver dysfunction Vomiting Exercise intolerance, muscle pain Muscle weakness Riboflavin responsiveness

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years) ± ± ± ± + ++ ± + ++ + +

Adolescence (11–16 years) ± ± ± +++ +++ +

Adulthood (>16 years) ± ± ± +++ +++ +

32  Disorders of Riboflavin Metabolism

557

Table 32.8 (continued) System Laboratory findings

Symptoms and biomarkers 2-Methylbutyrylglycine (U) C4-C18 acylcarnitine (P, DBS) C6-C10 dicarboxylic acids: adipic, suberic, sebacic acids (U) Carnitine, free (P, DBS) Creatine kinase (P) D-2-Hydroxyglutaric acid (U) Dimethylglycine (P, U) Ethylmalonic acid (U) Glutaric acid (U) Glutarylcarnitine—C5DC (P, DBS) Hexanoylglycine (U) Isobutyrylglycine (U) Isovalerylglycine (U) Lipid storage myopathy Sarcosine (P, U)

Neonatal Infancy (birth–1 month) (1–18 months) n-↑ n-↑ n-↑ n-↑

Childhood (1.5–11 years) n-↑ n-↑ n-↑

Adolescence (11–16 years) n-↑ n-↑ n-↑

Adulthood (>16 years) n-↑ n-↑ n-↑

↓-n n-↑

↓-n n-↑ ↑ n-↑ ↑ n-↑ n n-↑ n-↑ n-↑ ++ n-↑

↓-n n-↑ ↑ n-↑ ↑ n-↑ n n-↑ n-↑ n-↑ ++ n-↑

↓-n n-↑ ↑ n-↑ ↑ n-↑ n n-↑ n-↑ n-↑ ++ n-↑

n

No signs and symptoms table has been issued for RFVT1 deficiency since the two described affected heterozygous mothers were asymptomatic and biochemical investigation was normal away from delivery.

Reference Values Reference values for free carnitine and acylcarnitine species in plasma and dried blood spots are given in Chap. 5. Reference values for urinary organic acids are given in Chap. 4 Compound Riboflavin FAD FMN CK

Plasma 5–38 nmol/L 57–170 nmol/L 4–14 nmol/L ♂ 46–171 U/L ♀ 34–145 U/L

Whole blood 174–471 nmol/L

Pathological Values Patients with MADD, FAD synthase, and MFT deficiency usually present with an abnormal plasma/DBS acylcarnitine profile, exhibiting an increase of all chain-length acylcarni-

↓-n n-↑ ↑ n-↑ ↑ n-↑ n n-↑ n-↑ n-↑ n-↑

tines (C4, C5, C6, C8, C10:1, C10, C12:1, C12, C14:1, C14, C16:1, C16, C18:1, C18) and, in the severe form of these diseases, glutarylcarnitine (C5DC), associated with a decrease in free carnitine levels. The concentrations of these acylcarnitines are highly variable and depend of the patient’s status and of the severity of the disease. Their urinary organic acid profile is characterised by an increase of ethylmalonic acid, 2-hydroxyglutaric acid, and, most of the time but non constantly, glutaric acid, dicarboxylic acids, and acylglycine conjugates (isovalerylglycine, 2-methylbutyrylglycine, isobutyrylglycine, hexanoylglycine, suberylglycine). Plasma/ DBS acylcarnitine and urinary organic acid profiles usually normalise after riboflavin supplementation, except for the severe form of MADD and FAD synthase. An increase of CK is often reported in acute episodes, as well as an increase of transaminases. In RTD, the acylcarnitine profile and the urinary organic acid profile can be “MADD-like” or normal, and flavin levels can be decreased or normal. That is why the diagnosis relies on genetic studies.

558

C. Vianey-Saban et al.

Diagnostic Flowchart Clinical suspicion of MADD or a disorder of riboflavin metabolism: • Early onset (first months of age) of severe generalized hypotonia +/– hypoglycaemia, +/– cardiomyopathy +/– bulbar symptoms +/– respiratory insufficiency due to diaphragm paralysis • Late onset (childhood, adolescence) of: – Exercise intolerance and muscle weakness, with nausea or vomiting during exercise – Cranial neuropathy, sensorimotor axial neuropathy, hearing loss, optic atrophy

On suspicion of riboflavin transporter deficiency (RTD), start oral riboflavin (B2) 20 mg/kg/day in 3 doses immediately after blood sampling and continue until diagnosis is excluded or confirmed by mutation analysis

Plasma/blood acylcarnitine profile Urinary organic acid profile

Increase of short-, medium-and long-chain acylcarnitines: «classical» MADD profile Increase of ethylmalonic, glutaric, 2-hydroxyglutaric, acylglycines+/– dicarboxylic acids: «classical» MADD profile

Increase of not all chain length acylcarnitines: « MADD-like » profile +/– increase of ethylmalonic, 2-hydroxyglutaric acids, acylglycines: «MADD-like » profile

Normal acylcarnitine profile Normal organic acid profile High clinical suspicion of RTD

Panel of genes: ETFDH, ETFA, ETFB, SLC52A1, SLC52A2, SCLC52A3, FLAD1, SCL25A32

ETFA or ETFB (MADD)

Stop B2 suppl.

ETFDH (MADD) or FLAD1 (late onset FADS)

SLC52A1, SLC52A2, SCLC52A3 (RTD) or FLAD1 (early onset FADS)

SLC25A32 (MFT)

No mutation

B2: 100-150 mg/day, according to identified mutation(s) and/or clinical and biochemical efficacy

B2: 20-70 mg/kg/day in 3 doses

B2: 3 mg/kg/day or 100 mg/day

mtDNA sequencing

No mutation

Stop B2 WES/WGS

MT-CYB or MT-CO2

Stop B2

32  Disorders of Riboflavin Metabolism

559

This diagnosis flowchart shows how to reach a diagnosis. However, if the clinical picture is highly suggestive of MADD or of an inborn error of riboflavin metabolism, an immediate treatment with riboflavin has to be tried, directly after taking the first biological samples: minimum dose is 20  mg/kg/day in three doses in patients with neurological symptoms, while it can be lower (3 mg/kg/day) in patients with only muscular symptoms.

B2 Riboflavin, FADS FAD synthase, MADD Multiple acyl-CoA dehydrogenase deficiency, MFT Mitochondrial FAD transporter, mtDNA Mitochondrial DNA, RTD Riboflavin transporter defects, WES Whole exome sequencing, WGS Whole genome sequencing.

Specimen Collection Test Acylcarnitines

Precondition During an acute episode (if any) Fasting state Before B2 supplementation

Material Plasma Dried blood spot (DBS)

Handling Frozen (−20 °C): Plasma Room temperature: DBS

Carnitine

Plasma Dried blood spot (DBS)

Frozen (−20 °C): Plasma Room temperature: DBS

Spot urine (no addition of preservatives)

Frozen (−20 °C)

Flavins (riboflavin, FAD, FMN)

During an acute episode (if any) Fasting state Before B2 supplementation During an acute episode (if any) First morning urine sample, preferably Before B2 supplementation Before B2 supplementation

Functional tests in lymphocytes

Before B2 supplementation

EDTA blood

Functional tests in cultured fibroblasts

–

Skin biopsy

Molecular analysis

–

EDTA blood

Organic acids

EDTA plasma Frozen (−20 °C) and EDTA whole blood protected from light: Plasma and whole blood

Prenatal Diagnosis Prenatal diagnosis is available for MADD and disorders of riboflavin metabolism. Mutation analysis in DNA extracted from chorionic villi or from amniocytes is the more reliable technique, provided that the index case’s genotype has been determined. RTD deficiency can be diagnosed by mutation analysis only. Quantification of acylcarnitines and acylglycines in the supernatant of amniotic fluid can

Pitfalls False negative: Possible normal profile in RTD, lack of diagnostic acylcarnitines when severe secondary carnitine deficiency False positive: Anoxia can induce a “MADD-like” profile False negative: Frequently normal in RTD

False negative: Possible normal profile in RTD. Late-onset MADD and FAD synthase deficiency: Increase of only ethylmalonic and 2-hydroxyglutaric acids False negative: Can be normal in all disorders False positive: Decrease due to light degradation False negative: Can be normal in all disorders

Don’t centrifuge Room temperature Has to reach the lab within 48 h Room temperature in culture Cell culture medium depleted in medium riboflavin is necessary for RR-MADD and IEM of riboflavin metabolism Room temperature Identification of only one heterozygous mutation does not rule out a diagnosis

be used when an abnormal plasma acylcarnitine profile and an abnormal urinary organic acid profile have been observed in the index case, but only abnormal levels of short- and medium-chain acylcarnitines can be detected, since long-chain acylcarnitines are not excreted in urine and therefore are absent from amniotic fluid. Functional tests, such acylcarnitine profiling or fatty acid flux in cultured chorionic villi cells or amniocytes, can only be used in severe form of MADD.

560

C. Vianey-Saban et al. Prenatal diagnosis suggested −

Reliability of mutation analysis +

+ + +

+ + +

Reliability of acylcarnitines/acylglycines Reliability of quantification in AF functional tests Remarks No patients with two mutations of − − SLC52A1 gene have been identified. Heterozygous patients are asymptomatic − − − − ± Severe outcome −

−

+

−

−

−

+

±

−

+ MADD (ETF or ETF-QO) early-onset form ± MADD (ETF or ETF-QO) late onset form RR-MADD −

+

+

+

+

±

±

Depend of the severity of the clinical phenotype

+

−

−

Favourable outcome with riboflavin supplementation

Disorder RFVT1

RFVT2 RFVT3 FADS early-onset form FADS late-onset form MFT

Favourable outcome with riboflavin supplementation Favourable outcome with riboflavin supplementation Severe outcome

DNA Testing

Emergency Treatment

Multiple acyl-CoA dehydrogenase deficiency and all disorders in the transport or metabolism of riboflavin are inherited in an autosomal recessive pattern. Molecular genetic testing of all genes involved in these disorders can be performed in genomic DNA (from blood or any tissue) by Sanger methods or by MPS (massive parallel sequencing). No prevalent mutations have been identified, except three common riboflavin-­responsive mutations in the ETFDH gene mainly found in the Chinese and Taiwanese population: c.250G>A; c.770G>A; and c.1227A>C (Xi et al. 2014).

Emergency treatment for early-onset forms of MADD is high-dose glucose infusion, in association with insulin when high doses of glucose are required, and carnitine supplementation in case of carnitine depletion. Late-onset MADD may demonstrate clinical improvement with riboflavin supplementation (Grünert 2014). Immediate start of oral riboflavin supplementation on suspicion of RTD is life-saving, and supplementation needs to be continued until the diagnosis is confirmed or excluded by genetic analysis (O’Callaghan et al. 2019). In FAD synthase deficiency, especially late onset, patients demonstrate riboflavin responsivity; however riboflavin ­supplementation should initially be started in all patients (Olsen et al. 2016). In mitochondrial FAD transporter deficiency, riboflavin supplementation was highly effective in the two described patients (Schiff et al. 2016; Hellebrekers et al. 2017).

Treatment Summary Early-onset forms of MADD are treated with an emergency regime, avoidance of fasting, and a diet restricted in fat. Late-onset forms of MADD may respond to riboflavin supplementation (3  mg/kg/day or 100–150  mg/day) (Grünert 2014). On suspicion of RTD, supplementation of high-dose oral riboflavin (20–70 mg/kg/day in three doses) must be started immediately without awaiting a final diagnosis. Clinical improvement is observed in the majority of RTD patients, but sometimes it is not observed for months following the beginning of riboflavin supplementation. Supplementation with oral riboflavin has to be considered in all other disorders of riboflavin metabolism.

Standard Treatment Early-onset forms of MADD are treated with an emergency regime, avoidance of fasting, and a diet restricted in fat. Due to the accumulation of carnitine conjugates, MADD patients are prone to carnitine deficiency, which may require oral carnitine supplementation (Grünert 2014). Recommended doses of riboflavin supplementation depend of the disease. There is no literature report on effective dosing of riboflavin in MADD. Morris and Spiekekotter (2011) propose 100 mg/day, while Zschocke and Hoffmann

32  Disorders of Riboflavin Metabolism

(2011) recommend 150  mg/day in the Vademecum Metabolicum. RTD patients have demonstrated strong clinical improvements on doses of 10–70  mg/kg/day in three doses (Jaeger and Bosch 2016). There is no evidence for riboflavin dosing in FAD synthase deficiency, but a high dose seems advisable. In two patients with mitochondrial FAD transporter deficiency, a striking effect of riboflavin supplementation has been reported with doses of 30  mg/day and 3 mg/kg/day, respectively.

Experimental Treatment Long-term treatment of severe MADD patients with 3-hydroxybutyrate has been proposed, with clinical improvement in 70% of patients (reviewed by van Rijt et al. 2020). Prescribed doses ranged between 100 and 2600 mg/kg/day, divided in one to six daily doses. Cornelius et  al. (2014) reported that CoQ10 treatment can decrease ROS production in fibroblasts from RR-MADD patients and may relieve oxidative stress. This suggests that late-onset MADD patients could benefit from a combined treatment of riboflavin and CoQ10. For RTD esterified derivatives of riboflavin may increase bioavailability (Manole et al. 2017). The effects of CoQ10 in RTD are presently unclear.

Follow-Up and Monitoring The biological monitoring of patients with MADD, FAD synthase, and MFT deficiency usually associates CK, transaminases, plasma/blood acylcarnitine profile including free and total carnitine levels, and eventually urinary organic acids. Normalisation of these parameters after riboflavin supplementation is an indication of the efficacy of this treatment. General indices of nutrition in patients on a restricted diet (severe MADD), echocardiogram, liver ultrasound, and eventually nerve conduction studies should also be monitored. In adults, the monitoring is usually on an annual basis, whereas it has to be more frequent in younger patients. In RTD patients with abnormal plasma/blood acylcarnitine profiles, or urinary organic acid profiles, or abnormal flavins, a rapid normalisation is seen after supplementation of riboflavin, and these parameters may be used for monitoring. Clinical follow-up by a neurologist, ophthalmologist, and ENT specialist is warranted. In case of hearing loss, cochlear implantates are reported to be effective (Anderson et al. 2019).

561

References Anderson P, Schaefer S, Henderson L, Bruce IA. Cochlear implantation in children with auditory neuropathy: Lessons from Brown-Vialetto-­ Van Laere syndrome. Cochlear Implants Int. 2019;20(1):31–8. Auranen M, Paetau A, Piirilä P, Pohju A, Salmi T, Lamminen A, Löfberg M, Mosegaard S, Olsen RK, Tyni T. Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy. Neuromuscul Disord. 2017;27(6):581–4. Béhin A, Acquaviva-Bourdain C, Souvannanorath S, Streichenberger N, Attarian S, Bassez G, Brivet M, Fouilhoux A, Labarre-Villa A, Laquerrière A, Pérard L, Kaminsky P, Pouget J, Rigal O, Vanhulle C, Eymard B, Vianey-Saban C, Laforêt P. Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease. Rev Neurol (Paris). 2016;172:231–41. Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, Wanders RJ, Visser G, Wijburg FA, Duran M, Waterham HR. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis. 2011;34:159–64. Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ.  The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis. 2012;7:83. Cornelius N, Corydon TJ, Gregersen N, Olsen RK.  Cellular consequences of oxidative stress in riboflavin responsive multiple acyl-­ CoA dehydrogenation deficiency patient fibroblasts. Hum Mol Genet. 2014;23(16):4285–301. Frerman FE, Goodman SI.  Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts. Proc Natl Acad Sci U S A. 1985;82(13):4517–20. García-Villoria J, De Azua B, Tort F, Mosegaard S, Ugarteburu O, Texidó L, Morales-Romero B, Olsen RKJ, Ribes A. FLAD1, encoding FAD synthase, is mutated in a patient with myopathy, scoliosis and cataracts. Clin Genet. 2018;94(6):592–3. Gianscapero TA, Galluccio M, Miccolis A, Leone P, Eberini I, Iametti S, Indiveri C, Barile M.  Human FAD synthase is a bi-functional enzyme with a FAD hydrolase activity in the molybdopterin binding domain. Biochem Biophys Res Commun. 2015;465(3):443–9. Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, Raymond FL, Childs AM, Sheridan E, Edwards S, Josifova DJ. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am J Hum Genet. 2010;86:485–9. Grünert SC. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet J Rare Dis. 2014;9:117–25. Hellebrekers DMEI, Sallevelt SCEH, Theunissen TEJ, Hendrickx ATM, Gottschalk RW, Hoeijmakers JGJ, Habets DD, Bierau J, Schoonderwoerd KG, Smeets HJM. Novel SLC25A32 mutation in a patient with a severe neuromuscular phenotype. Eur J Hum Genet. 2017;25(7):886–8. Ho G, Yonezawa A, Masuda S, Inui K, Sim KG, Carpenter K, Olsen RK, Mitchell JJ, Rhead WJ, Peters G, Christodoulou J. Maternal riboflavin deficiency, resulting in transient neonatalonset glutaric aciduria type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B. Hum Mutat. 2011;32(1):E1976–84. Jaeger B, Bosch AM. Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience. J Inherit Metab Dis. 2016;39(4):559–64.

562 Jin C, Yao Y, Yonezawa A, Imai S, Yoshimatsu H, Otani Y, Omura T, Nakagawa S, Nakagawa T, Matsubara K.  Riboflavin transporters RFVT/SLC52A mediate translocation of riboflavin, rather than FMN or FAD, across plasma membrane. Biol Pharm Bull. 2017;40(11):1990–5. Manole A, Jaunmuktane Z, Hargreaves I, Ludtmann MHR, Salpietro V, Bello OD, Pope S, Pandraud A, Horga A, Scalco RS, Li A, Ashokkumar B, Lourenço CM, Heales S, Horvath R, Chinnery PF, Toro C, Singleton AB, Jacques TS, Abramov AY, Muntoni F, Hanna MG, Reilly MM, Revesz T, Kullmann DM, Jepson JEC, Houlden H.  Clinical, pathological and functional characterization of riboflavin-­ responsive neuropathy. Brain. 2017;140(11):2820–37. Morris A, Spiekekotter U.  Disorders of mitochondrial fatty acid oxidation and riboflavin metabolism. In: Saudubray JM, Baumgartner MR, Walter J, editors. Inborn metabolic diseases, diagnosis and treatment. Berlin Heidelberg New  York: Springer Verlag; 2011. p. 201–14. Mosegaard S, Bruun GH, Flyvbjerg KF, Bliksrud YT, Gregersen N, Dembic M, Annexstad E, Tangeraas T, Olsen RKJ, Andresen BS. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin responsive multiple acyl CoA dehydrogenase deficiency. Mol Genet Metab. 2017;122:182–8. Muru K, Reinson K, Künnapas K, Lilleväli H, Nochi Z, Mosegaard S, Pajusalu S, Olsen RKJ, Õunap K. FLAD1-associated multiple acylCoA dehydrogenase deficiency identified by newborn screening. Mol Genet Genomic Med. 2019;7(9):e915. O’Callaghan B, Bosch AM, Houlden H. An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency. J Inherit Metab Dis. 2019;42(4):598–607. Olsen RKJ, Koňaříková E, Giancaspero TA, Mosegaard S, Boczonadi V, Mataković L, Veauville-Merllié A, Terrile C, Schwarzmayr T, Haack TB, Auranen M, Leone P, Galluccio M, Imbard A, Gutierrez-­ Rios P, Palmfeldt J, Graf E, Vianey-Saban C, Oppenheim M, Schiff M, Pichard S, Rigal O, Pyle A, Chinnery PF, Konstantopoulou V, Möslinger D, Feichtinger RG, Talim B, Topaloglu H, Coskun T, Gucer S, Botta A, Pegoraro E, Malena A, Vergani L, Mazzà D, Zollino M, Ghezzi D, Acquaviva C, Tyni T, Boneh A, Meitinger T, Strom TM, Gregersen N, Mayr JA, Horvath R, Barile M, Prokisch

C. Vianey-Saban et al. H.  Riboflavin-responsive and -non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency. Am J Hum Genet. 2016;98(6):1130–45. Schiff M, Veauville-Merllié A, Su CH, Tzagoloff A, Rak M, Ogier de Baulny H, Boutron A, Smedts-Walters H, Romero NB, Rigal O, Rustin P, Vianey-Saban C, Acquaviva-Bourdain C. SLC25A32 mutations and riboflavin-responsive exercise intolerance. N Engl J Med. 2016;374:795–7. Spaan AN, Ijlst L, van Roermund CW, Wijburg FA, Wijburg FA, Wanders RJ, Waterham HR. Identification of the human mitochondrial FAD transporter and its potential role in multiple acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2005;86(4):441–7. van Rijt WJ, Jager EA, Allersma DP, Aktuğlu Zeybek AÇ, Bhattacharya K, Debray FG, Ellaway CJ, Gautschi M, Geraghty MT, Gil-Ortega D, Larson AA, Moore F, Morava E, Morris AA, Oishi K, Schiff M, Scholl-Bürgi S, Tchan MC, Vockley J, Witters P, Wortmann SB, van Spronsen F, Van Hove JLK, Derks TGJ. Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency. Genet Med. 2020;22(5):908–16. Xi J, Wen B, Lin J, Zhu W, Luo S, Zhao C, Li D, Lin P, Lu J, Yan C. Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2014;37(3):399–404. Yamamoto S, Inoue K, Ohta KY, Fukatsu R, Maeda JY, Yoshida Y, Yuasa H. Identification and functional characterization of rat riboflavin transporter 2. J Biochem. 2009;145(4):437–43. Yao Y, Yonezawa A, Yoshimatsu H, Masuda S, Katsura T, Inui K.  Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain. J Nutr. 2010;140(7):1220–6. Yıldız Y, Jentoft Olsen RK, Serap Sivri A, Sivri HS, Akçören Z, Nygaard HH, Tokatlı A.  Post-mortem detection of FLAD1 mutations in 2 Turkish siblings with hypotonia in early infancy. Neuromuscul Disord. 2018;28(9):787–90. Yonezawa A, Masuda S, Katsura T, Inui K. Identification and functional characterization of a novel human and rat riboflavin transporter, RFT1. Am J Physiol Cell Physiol. 2008;295(3):C632–41. Zschocke J, Hoffmann G.  Vademecum metabolicum. Friedrichsdorf, Germany: Milupa Metabolics GmbH; 2011.

Disorders of Niacin, NAD, and Pantothenate Metabolism

33

Anna Ardissone, Daria Diodato, Ivano Di Meo, and Valeria Tiranti

Contents Introduction

 564

Nomenclature

 566

Metabolic Pathway

 567

Signs and Symptoms

 568

Diagnostic Flowcharts

 572

Prenatal Diagnosis

 574

DNA Testing

 574

Treatment

 574

References

 575

Summary

Niacin or vitamin B3 and pantothenate or vitamin B5 are water-soluble vitamins acting as precursors of nicotinamide adenine dinucleotide (NAD) and Coenzyme A (CoA), respectively, two fundamental elements for every cell. The niacin-derived coenzymes NAD and NADP carry out similar oxidation and reduction reactions:

A. Ardissone Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy e-mail: [email protected] D. Diodato Neuromuscular and Neurodegenerative Disease Unit, Children Hospital Bambino Gesù, Rome, Italy e-mail: [email protected] I. Di Meo · V. Tiranti (*) Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy e-mail: [email protected]; valeria.tiranti@istituto-­besta.it

NADP is mainly involved in biosynthetic pathways, while NAD, in its reduced form NADH, supplies the mitochondrial electron transport chain with reducing equivalent and, in doing so, propels the oxidative phosphorylation. Pantothenate-derived CoA is a crucial molecule for hundred of metabolic reactions, including, among others, the Krebs cycle and the oxidation and synthesis of fatty acids. Both coenzymes play crucial roles not only in metabolism and in maintaining mitochondrial functionality but also in complex mechanisms of signalling. Moreover, by modulating deacetylation (NAD) and acetylation (CoA) of histones and transcription factors, these coenzymes also regulate gene expression. NAD biosynthetic pathways originate from four major molecules: (i) the amino acid tryptophan (Trp), (ii) nicotinic acid (NA), (iii) nicotinamide (NAM), and (iv) nicotinamide riboside (NR). Nicotinamide mononucleotide (NMN) generated from NAM and NR can also be a source of NAD. CoA is instead synthesized through the sequential activity of five enzymatic reactions belonging to the same

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_33

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Handler NAD biosynthetic pathway, catalysing the condensation of nicotinic acid mononucleotide (NaMN) with AMP (Zhang et  al., 2003), leads to Leber congenital amaurosis (LCA), an early-onset neurodegenerative condition of the human retina causing congenital blindness (Koenekoop et al., 2012). The mitochondrial kinase coded by the NADK2 gene synthesizes NADP+ (Ohashi et  al., 2012). Exome sequence investigation revealed the presence of a nonsense mutation in this gene in one subject with deficiency of 2,4-dienoyl-CoA reductase (DECR; OMIM#616034) (Houten et  al., 2014) and early-onset encephalopathy, developmental delay, movement disorder, lactic acidosis, and premature death. Mitochondria derived from patient fibroblasts displayed reduction of NADP(H) level, and real-time measurement of oxygen consumption demonstrated a reduction of the respiIntroduction ratory rate with a parallel increase in extracellular acidification. In addition to decreased activity of DECR, laboratory Disorders of Niacin and NAD Metabolism tests also showed hyperlysinaemia due to impaired activity Niacin is the term that defines both NAM and NA and is of alpha-aminoadipic semialdehyde synthase coded by the necessary to synthesize the two coenzymes NAD and NADP. AASS gene (OMIM#605113). The very severe phenotype observed in this patient could Tryptophan, NA, NAM, and NR are used to generate be ascribed not only to the combined deficiency of DECR NAD through different metabolic pathways (Fig.  33.1): NAD synthesized from NA is known as Preiss-Handler path- and AASS, two NADP-dependent mitochondrial enzymes, way; tryptophan is the starting amino acid in the de novo but also to a global deficiency of additional NADP-dependent synthesis (kynurenine pathway); the salvage pathway con- processes inside the mitochondria. Recently and thanks to exome sequencing in subjects verts NR and NAM through two enzymatic steps into nicowith complex clinical neurological presentations, new genes tinamide mononucleotide (NMN). The best-known disorder due to niacin deficiency is pel- coding for proteins responsible for elimination of damaged lagra that was endemic a century ago in rural areas and metabolites have been identified. Two genes belonging to the metabolite repair system nowadays is present, in developed countries, as secondary effect to other disorders such as tuberculosis, malabsorp- denominated NAXE (Kremer et  al., 2016) and NAXD (van tion, and alcoholism. Distinctive features of pellagra Bergen et  al., 2019) were found mutated in a childhood-­ include diarrhoea, peculiar pigmented skin rash, and onset lethal metabolic disorder with neurological involvedementia, which can be reversed by NAM and NA ment and in an early-onset encephalopathy with brain oedema and leucoencephalopathy, respectively. administration. The NAXE gene encodes an epimerase involved in the Disorders of niacin and NAD metabolism are also due to repair of NADHX and NADPHX, toxic compounds inhibitgenetic causes affecting different genes coding for enzymes ing several dehydrogenase activities. The epimerase catalydesigned to synthesize NAD, synthesize and modify NADP, ses the conversion of R-NAD(P)HX to S-NAD(P)HX so that remove toxic metabolites, and transport tryptophan. These disorders mainly impair brain functions and, in S-NAD(P)HX can be reconverted to S-NAD(P)H by the some instances, give rise to pellagra-like clinical dehydratase NAXD. In patient-derived fibroblasts, elevated concentrations of toxic compounds S-NADHX, R-NADHX, manifestations. Deficiency of nicotinamide mononucleotide adenylyl and cyclic NADHX were identified (Kremer et al., 2016; van transferase 1 (NMNAT1), a central enzyme in the Preiss-­ Bergen et al., 2019). metabolic pathway, in which pantothenate is the starting molecule. Considering the vital roles of NAD and CoA, their deficiency either due to shortage of vitamins in the diet or to genetic causes impinging on the biochemical pathways responsible for their production and proper maintenance could give rise to human diseases. We will discuss disorders of niacin and NAD separately from disorders of pantothenate for the sake of clarity even if it is clear that NAD and CoA play convergent roles in energetic metabolism and regulate common pathways.

33  Disorders of Niacin, NAD, and Pantothenate Metabolism

Homozygous or compound heterozygous mutations in the gene NNT, coding for a pyridine nucleotide transhydrogenase protein located in the inner mitochondrial membrane, cause glucocorticoid deficiency type 4 with or without mineralocorticoid deficiency (Meimaridou et  al., 2012; Yamaguchi et al., 2013; Hershkovitz et al., 2015; Weinberg-­ Shukron et al., 2015; Roucher-Boulez et al., 2016). This protein transfers a hydride ion between NAD, NAD(H), and NADP(H) (Zieger and Ware, 1997), and it contributes to functioning of the mitochondrial respiratory chain system playing a role in removing excess of reactive oxygen species in adrenal glands (Meimaridou et al., 2012). Hartnup disorder is an autosomal recessive disorder due to defective transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa causing increased level of amino acids in urine. It is characterized by symptoms like pellagra, cerebellar ataxia, and neurological manifestation. The genetic cause of this disorder was identified in 2004 (Kleta et  al. 2004) as due to mutation in the SLC6A19 gene coding for a neutral amino acid transporter. One particular amino acid transported includes tryptophan, which is required to generate NAD, and this would be the reason for the clinical manifestations resembling pellagra. Kynureninase and 3-hydroxyanthranilate 3,4-­dioxygenase deficiencies are caused by mutations in the KYNU and HAAO genes, respectively, which code for enzymes involved in the kynurenine pathway leading to NAD cofactor production from tryptophan. A first missense mutation in KYNU gene was identified in 2007 (Christensen et al. 2007) in two brothers with no pathological phenotype except for increased level of xanthurenic acid, kynurenine, and 3-­hydroxykynurenine in urine. In 2017 additional patients with a complicated multisystem syndrome were proved to carry out truncating mutations in KYNU and HAAO (Shi et al., 2017). In one affected patient analysis of plasma revealed the presence of high level of 3-hydroxykynurenine and low level of NAD, which was hypothesized to be responsible for the complicated clinical presentation characterized by vertebral, cardiac, renal, and limb defects (VCRL) observed in these patients.

565

Disorders of Pantothenate Metabolism Coenzyme A is synthesized from pantothenate in a pathway composed of five enzymatic reactions (Fig. 33.1). CoA has a relevant role not only in bioenergetic metabolism but contributes to the synthesis of cholesterol, amino acids, phospholipids, fatty acids, and neurotransmitters. This multiplicity of activities impacts massively, even if not exclusively, on the structure and function of the brain. While there are almost no reports describing deficiency of pantothenic acid due to nutritional deficits, mutations in genes coding for the first (PANK2) and last (COASY) enzymes of the CoA biosynthetic pathway are associated with neurodegenerative disorders hallmarked by iron accumulation in specific regions of the brain (NBIA). The pathogenic mechanisms linking iron accumulation to impaired CoA biosynthesis is still under investigation, but defective mitochondrial functionality seems to be one of the triggering causes of the disease as demonstrated in cellular and animal models (Orellana et  al., 2016; Brunetti et  al., 2012; Berti et  al., 2015). Recently, mutations in PPCS gene coding for the second enzyme in the CoA synthetic pathway have been identified in a completely different clinical phenotype characterized by dilated cardiomyopathy and altered acylcarnitine profile (Iuso et al., 2018). It remains to be clarified why malfunctioning of enzymes belonging to the same metabolic pathway results in great clinical heterogeneity. Mutations in SLC25A42 coding for a mitochondrial CoA transporter were found in a patient with mitochondrial myopathy and delayed motor development (Shamseldin et al. 2016) and in additional cases presenting with encephalopathy and metabolic crisis (Almannai et al., 2018; Iuso et  al., 2019). Instrumental investigations demonstrated increased serum lactate and basal ganglia lesions on MRI, in one case associated with iron deposition; muscle biopsy was performed in few cases and showed ragged-red-like fibers.

Disease name Leber congenital amaurosis 9

Alternative disease name Nicotinamide mononucleotide adenylyl transferase 1 deficiency 33.2 Mitochondrial NAD kinase 2 2,4-dienoyl-CoA reductase deficiency deficiency with hyperlysinemia 33.3 NAD(P)HX epimerase deficiency Apolipoprotein A-I binding protein deficiency 33.4 NAD(P)HX dehydratase CARKD deficiency deficiency 33.5 Nicotinamide nucleotide Glucocorticoid deficiency type 4 transhydrogenase deficiency 33.6 Hartnup disorder 33.7 Kynureninase deficiency Xanthurenic aciduria; vertebral, cardiac, renal, and limb defects syndrome type 2 33.8 3-hydroxyanthranilic acid Vertebral, cardiac, renal, and limb 3,4-dioxygenase deficiency defects syndrome type 1 33.9 Pantothenate kinase 2 deficiency Pantothenate kinase-associated neurodegeneration (PKAN); neurodegeneration with brain iron accumulation type 1 33.10 Phosphopantothenoylcysteine Autosomal recessive dilated synthetase deficiency cardiomyopathy 33.11 Coenzyme A synthase deficiency CoA synthase protein-associated neurodegeneration (CoPAN); neurodegeneration with brain iron accumulation type 6 33.12 Mitochondrial coenzyme A transporter deficiency

No. 33.1

Nomenclature

AR

AR

17q21.2

19p13.11

NAXE NAXD NNT SLC6A19 KYNU

HAAO PANK2

PPCS COASY

SLC25A42

PEBEL2 GCCD4 HND VCRL2

VCRL1 PKAN

CMD2C COPAN

1p34.2

20p13

2p21

5p15.33 2q22.2

5p12

13q34

1q22

AR

AR

AR

AR AR

AR

AR

AR

AR

PEBEL

5p13.2

NADK2

Mode of inheritance AR

DECRD

Chromosomal localization 1p36.22

Gene Symbol NMNAT1

Disease Abbreviation LCA9

616034

Disease OMIM 608553

Mitochondrial coenzyme A transporter

Phosphopantothenoylcysteine synthetase Phosphopantetheine adenylytransferase/ dephosphocoenzyme A

3-Hydroxyanthranilate 3,4-dioxygenase Pantothenate kinase type

Carbohydrate kinase domain-­ containing protein Nicotinamide nucleotide transhydrogenase B(0)AT1 L-kynurenine hydrolase

610823

615643

618189

2234200

617660

234500 617661

614736

618321

Apolipoprotein A-I binding protein 617186

Affected protein Nicotinamide nucleotide adenylyltransferase 1 2,4-dienoyl-CoA reductase

566 A. Ardissone et al.

33  Disorders of Niacin, NAD, and Pantothenate Metabolism

567

Metabolic Pathway

Kynurenine pathway (De novo) DIET

SLC6A19

Preiss-Handler pathway Niacin

Tryptophan TDO/IDO

DIET

NAD salvage pathway

NAPRT

Formylkynurenine

DIET

Nicotinic acid mononucleotide (NAMN)

KYN-F Kynurenine

Nicotinamide riboside (NR)

Nicotinamide (NAM)

NMNAT1 NAD consuming enzymes

Nicotinic acid adenine dinucleotide (NAAD)

KYNU

Pantothenate

NRK

KMO 3-Hydroxykynurenine

CoA biosynthetic pathway

NAMPT

NADS

Nicotinamide mononucleotide (NMN)

4’-Phosphopantothenate PPCS

NMNAT1

3-Hydroxyanthranilic acid HAAO

4’-Phosphopantothenoylcysteine

2-amino-3-carboxymuconate semiadehyde (ACMS)

NADPH

non enzymatic cyclization Quinolinic acid

DIET

PANK2

REDOX

NADP

NADK2

PPCDC

NAD

4’-Phosphopantetheine COASY

NNT

QPRT

Dephospho-CoA R-NADHX

NADH

NAXE

COASY

TCA cycle

CoA SLC25A42

Acetyl-CoA

Cyclic NADHX S-NADHX

NADH

NAD

Aminoacids Monosaccharides Fatty acids

NADH repair pathway

Fig. 33.1  Schematic representation of niacin, NAD, and pantothenate pathways and their interconnections For simplicity, different pathways are grouped by different colors. Proteins mutated in human diseases are in red. NAD is synthesized through two main ways: it is produced either in a de novo pathway from amino acids or in salvage pathways by recycling preformed components such as nicotinamide (NAM) back to NAD. In the kynurenine (de novo) pathway (blue), a series of enzymatic and non-enzymatic reactions converts the amino acid tryptophan to nicotinic acid mononucleotide (NAMN), which is also produced in the Preiss-Handler pathway (grey) starting from niacin. NAMN is then converted to NAD by two further enzymatic reactions. NAD and its phosphorylated derivative NADP are reduced to NADH and NADPH by catabolic and anabolic redox reactions. In the NAD salvage pathway (green), NAM molecule, which is produced by NAD consuming enzymes such as sirtuins, Poly (ADP-ribose) polymerases (PARPs), CD38, and CD157, is recycled into nicotinamide mononucleotide (NMN), which in turn is re-converted to NAD. Hydrated forms of NADH and NADPH, called NADHX and NADPHX, respectively, can be formed spontaneously under acidic conditions or enzymatically by glyceraldehyde-­3-phosphate dehydrogenase (GAPDH). NADHX and NADPHX, which are inhibitors of several dehydrogenases, are both converted back to NADH and NADPH by a series of enzymatic reactions in the repair pathway (purple)

In the CoA biosynthetic pathway (yellow), pantothenate is sequentially converted to CoA by a series of five enzymatic reactions. CoA is then used as an acyl group carrier and carbonyl-­activating group in a multitude of biochemical transformations, including tricarboxylic acid (TCA) cycle and fatty acid metabolism. Enzymes: TDO tryptophan 2,3-dioxygenase, IDO indoleamine 2,3-dioxygenase, KYN-F kynurenine formamidase, KMO kynurenine 3-­ monoxygenase, KYNU kynunerinase, HAAO 3-hydroxyanthranilate 3,4-dioxygenase, QPRT nicotinate-nucleotide pyrophosphorylase, NAPRT nicotinate phosphoribosyltransferase, NMNAT1 nicotinamide mononucleotide adenyltransferase 1, NADS glutamine-dependent NAD(+) synthetase, NAMPT nicotinamide phosphoribosyltransferase, NRK nicotinamide riboside kinase, NADK2 NAD kinase 2, NNT nicotinamide nucleotide transhydrogenase, GAPDH glyceraldehyde-3-phosphate dehydrogenase, NAXE NAD(P)HX epimerase, NAXD NAD(P)HX dehydratase, PANK2 pantothenate kinase 2, PPCS phosphopantothenoylcysteine synthetase, PPCDC phosphopantothenoylcysteine decarboxylase, COASY coenzyme A synthetase. Transporters: SLC6A19 sodiumdependent neutral amino acid transporter B(0)AT1, SLC25A42 mitochondrial coenzyme A transporter

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Signs and Symptoms Table 33.1  Nicotinamide mononucleotide adenylyl transferase 1 deficiency System Eye

Symptoms and biomarkers Attenuated retinal vessels/pigmentary retinal changes Blindness Hyperopia Macular atrophy/ coloboma Nystagmus Oculo-digital sign Slow or near-absent pupillary reactions

Neonatal (birth–1 month) ++

Infancy (1–18 months) +++

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

Adulthood (>16 years) +++

++ ++ ++

+++ +++ +++

+++ +++ +++

+++ +++ +++

+++ +++ +++

++ ++ ++

+++ ++ +++

+++ ++ +++

+++ ++ +++

+++ ++ +++

Table 33.2  Mitochondrial NAD kinase 2 deficiency System CNS

Eye Metabolic Laboratory findings

Symptoms and biomarkers Ataxia Chorea Dystonia Epilepsy Neuropathy, peripheral Optic atrophy Lactic acidosis C10:2 acylcarnitine (plasma) Lysine (plasma) Proline (plasma)

Neonatal (birth–1 month) ± ± ± +

Infancy (1–18 months) ± ± ± +

+ ↑

+ ↑

Childhood (1.5–11 years) + ± ± + + + + ↑

↑↑↑

↑↑↑

↑↑↑

Adolescence (11–16 years) +

↑↑↑ ↑↑↑

Adulthood (>16 years)

+ + n-↑

Table 33.3  NAD(P)HX epimerase deficiency System CNS Dermatological Respiratory Laboratory findings

Symptoms and biomarkers Ataxia Hypotonia Skin lesions Respiratory failure Lactate (cerebrospinal fluid)

Neonatal (birth–1 month)

Infancy (1–18 months) +++ +++ +++ +++ ↑↑

Childhood (1.5–11 years) +++ +++ +++ +++ ↑↑

Adolescence (11–16 years)

Adulthood (>16 years)

Table 33.4  NAD(P)HX dehydratase deficiency System CNS

Skin Blood Heart

Symptoms and biomarkers Ataxia Dystonia Psychiatric disturbances Psychomotor regression Lesions Pancytopenia Cardiomyopathy

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ++ ++ ±

Adolescence (11–16 years) ++ ++ ±

+++

+++

+++ ± ±

+++ ± ±

Adulthood (>16 years)

33  Disorders of Niacin, NAD, and Pantothenate Metabolism

569

Table 33.5  Nicotinamide nucleotide transhydrogenase deficiency System CNS Dermatological Endocrine Genitourinary

Metabolic Laboratory findings

Symptoms and biomarkers Addison crisis Hyperpigmentation Precocious puberty Azoospermia Cryptorchidism Testicular nodules Testicular tumour Hypoglycaemia ACTH (plasma) Aldosterone (plasma) Cortisol (plasma) Glucose (plasma Renin (plasma) Testosterone (plasma)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ± +++ ±

Childhood (1.5–11 years) ± +++ ± ± ± ± ± +++ ↑↑↑ ↓↓↓ ↓↓↓ ↓↓↓ ↑↑↑

Adolescence (11–16 years) ± +++ ±

Adulthood (>16 years) ± +++ ±

± ± +++ ↑↑↑ ↓↓↓ ↓↓↓ ↓↓↓ ↑↑↑ ↓-n

± ± +++ ↑↑↑ ↓↓↓ ↓↓↓ ↓↓↓ ↑↑↑ ↓-n

Adolescence (11–16 years) ±

Adulthood (>16 years)

n-↑

± ± n-↑

Childhood (1.5–11 years) ± ± ± ± n-↑

± ± n-↑

n-↑

↑

↑

↑

↑

↑

± ± +++ ↑↑↑ ↓↓↓ ↓↓↓ ↓↓↓ ↑↑↑

↑↑↑ ↓↓↓ ↓↓↓ ↑↑↑

Table 33.6  Hartnup disorder System CNS Dermatological Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Seizures Photosensitivity Psychosis Glutamic acid (urine) Neutral amino acids (urine)

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Table 33.7  3-Hydroxykynureninase deficiency Symptoms and System biomarkers Autonomic system Talipes Cardiovascular Hypoplastic left heart Patent ductus arteriosus CNS Speech delay Digestive Anteriorly placed anus Musculoskeletal Rhizomelia Short stature Syndactyly Renal Renal hypoplasia Laboratory 3-Hydroxykynurenine findings (urine) 3-Hydroxykynurenine; 3HK (plasma) Kynurenine (urine) NAD+ (plasma) Xanthurenic acid (urine)

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ± ± ±

± ± ± + ± +

± ± + ± + ↑

↑

↑

↓

↑ ↓ ↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

↑

↑

↑

↑

↑

↑

Adulthood (>16 yreas)

570

A. Ardissone et al.

Table 33.8  3-Hydroxyanthranilate 3,4-dioxygenase deficiency Symptoms and System biomarkers Autonomic system Talipes Cardiovascular Atrial septal defect Hypoplastic left heart CNS Intellectual disability Ear Hearing loss, sensorineural Musculoskeletal Short stature Renal Renal hypoplasia Laboratory 3-Hydroxyanthranilic findings acid; 3HAA (plasma) NAD+ (plasma)

Neonatal (birth–1 month) ± ± ± +

Infancy (1–18 months) ± ± ± ± +

Childhood (1.5–11 years) ± ± ± ± ±

+ + ↑

+ + ↑

± ± ↓

↓

↓

↓

Adolescence (11–16 years)

Adulthood (>16 years)

Table 33.9  Neurodegeneration with brain iron accumulation 1 System CNS

Eye

Musculoskeletal Psychiatric Laboratory findings

Symptoms and biomarkers Dystonia Extrapyramidal signs Intellectual disability Parkinsonism Rigidity Seizures Spasticity Abnormal eye movement Optic atrophy Retinopathy Eye-of-the-tiger-sign Depression, other psychiatric symptoms Iron (brain)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ± ± ± ± ±

±

± ±

Childhood (1.5–11 years) ++ ++ + + ++ ± ++ + + ++ +++ ±

Adolescence (11–16 years) +++ ++ + + ++ ± ++ + + ++ +++ ±

Adulthood (>16 years) +++ ++ + + ++ ± ++ + + ++ ++ +

↑

↑

↑

Table 33.10  Phosphopantothenoylcysteine synthetase deficiency System Cardiovascular CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Hypotonia, muscular Dysmorphic features Lactate (plasma)

Neonatal (birth–1 month) +

Infancy (1–18 months) +++

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

±

±

±

±

±

±

±

±

n-↑

n-↑

n-↑

n-↑

Adulthood (>16 yreas)

33  Disorders of Niacin, NAD, and Pantothenate Metabolism

571

Table 33.11  Neurodegeneration with brain iron accumulation 6 System CNS

Psychiatric Laboratory findings

Symptoms and biomarkers Areflexia Ataxia

Neonatal (birth–1 month)

Axonal neuropathy Basal ganglia abnormalities (MRI) Bradykinesia Development delay Dystonia Gait disturbance Intellectual disability Parkinsonism Spastic paraplegia Thin corpus callosum Behavioural abnormalities C0/C16 + C18 acylcarnitines ratio (dried blood spot) C16:0 acylcarnitine (dried blood spot) C18:0 acylcarnitine (dried blood spot) Carnitine, free Iron (brain)

Infancy (1–18 months)

±

+ ± + ±

Childhood (1.5–11 years) + Infancy (1–18 months) ++ ++

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

++ ++

++ ++

+ + + + + + ± +

+ ++ ++ + ++ + ++ ± ++

+ ++ ++ + ++ + ++ ± ++

↑

↓

↓

↓

↓

↓

↓

↓

↓

↑

↑

↑ ↑

↑

Table 33.12  Mitochondrial coenzyme A transporter deficiency System Cardiovascular CNS

Metabolic Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy Basal ganglia abnormalities (MRI)a Developmental delay Intellectual disability Movement disorder Seizures Metabolic crisis Myopathy Acylcarnitines (medium and long chain) Ammonia (plasma) Carnitine, free Creatine kinase (plasma) Lactate (plasma)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± +

Adulthood (>16 years) ± +

+

+

+

±

±

+

+

+

±

±

±

±

±

±

±

± + + n-↑

± + + n-↑

± + + n-↑

± ± + n-↑

± ± +

n-↑

n-↑

n-↑

n-↑

↓-n n-↑

↓-n n-↑

↓-n n-↑

↓-n n-↑

↑

↑

↑

↑

signal alteration or iron deposition or atrophy

a

572

A. Ardissone et al.

Diagnostic Flowcharts childhood onset dystonia, rigidity, spasticity +- cognitive involvement, psychiatric symptoms

Axonal neuropathy

Retinopathy + - seizures, optic atrophy

Developmental delay/regression Myopathy

Brain MRI

Eye-of-the-tiger sign

Cardiopathy Metabolic crises

Basal ganglia involvement at MRI (including iron accumulation) +-other aspecific alterations

↑ free carnitine ↓acylcarnitines (C16, C18)

COASY

PANK2

Cardiopathy

↑ serum lactate ↑ -n CK ↓ -n free carnitine ↑ -n acylcarnitines

SLC25A42

Congenital blindness

Fundus oculi, ERG

Reduced full filled ERG Severe retinal changes Macular atrophy Nystagmus

Absent/markedly reduced cone responses with normal rod ERG responses

Achromatopsia Absence of other relevant neurological signs

Leber congenital amaurosis/early-onset retinal dystrophy (LCA/EORSD)

NMNAT1 or other genes

Other relevant neurological signs: Epilepsy/developmental delay Hearing loss Renal features MRI abnormalities Metabolic abnormalities

CLN Joubert syndrome Cbl C defect Peroxisomal disorders Alstrom syndrome

↑ -n serum lactate

PPCS

33  Disorders of Niacin, NAD, and Pantothenate Metabolism

573 Skin lesions ± blood or cardiac abnormalities

Ataxia Psychomotor regression Hypotonia Respiratory failure Worsening during infections

Ataxia/Psychiatric disturbances ∂ ± Photodermatitis

Aminoaciduria ∂ aa) (neutral

Skin lesions ± blood or∂ cardiac abnormalities

NAD(P)HX dehydratase ∂ deficiency NAXD

Hartnup disorder ∂ (SLC6A19)

NAD(P)HX epimerase ∂ deficiency NAXE

Congenital defects: Vertebral Cardiac Renal Limbs (talipes)

Increased 3HK and 3HAA

3-Hydroxykynureninase deficiency KYNU

3-Hydroxyanthranilate 3,4dioxygenase deficiency HAAO

CNS involvement: Movement disorder (ataxia, dystonia) Epilepsy Optic atrophy

Increased plasma lysine levels ± DECR

± Increased serum, urinary and CSF saccharopine

Hyperlysinemia type I Mitochondrial NAD kinase 2 deficiency NADK2

574

A. Ardissone et al.

Prenatal Diagnosis Disorder Nicotinamide mononucleotide adenylyl transferase 1 deficiency Mitochondrial NAD kinase 2 deficiency NAD(P)HX epimerase deficiency NAD(P)HX dehydratase deficiency Nicotinamide nucleotide transhydrogenase deficiency Hartnup disorder

Tests recommended Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC Mutation analysis on DNA from CVS or AFC

In SLC25A42-related disorders, affected individuals are prone to metabolic decompensations with relatively mild intercurrent illnesses and therefore should be managed to promote anabolism; in acute metabolic crisis management with intravenous fluids and bicarbonate infusion will prevent permanent neurological sequela (Almannai et al., 2018).

Experimental Treatment

Clinical and experimental studies are currently underway in disorders of pantothenate metabolism, and treatments will mainly target pathogenic mechanisms. The potential for iron Kynureninase deficiency chelation using deferiprone (an iron chelator that is able to cross the blood–brain barrier) to modify disease and improve 3-Hydroxyanthranilic acid clinical symptoms is highly topical at present. To date, good 3,4-dioxygenase deficiency Pantothenate kinase 2 deficiency tolerability of deferiprone, with reduction of radiologically discernible brain iron, and clinical improvement in some Phosphopantothenoylcysteine synthetase PKAN patients was reported (Abbruzzese et  al., 2011). deficiency Another pilot phase II trial showed that deferiprone was well Coenzyme A synthase deficiency tolerated in the nine PKAN patients who completed the study, with statistically significant reduction of iron in the Mitochondrial coenzyme A transporter deficiency pallida by MRI evaluation but disappointingly without cliniCVS Chorionic villous sampling, AFC Amniotic fluid cells cal improvement of symptoms (Zorzi et al., 2011). An international randomized, double-blind, placebo-controlled trial of deferiprone was recently completed (Klopstock et  al., 2019). In PKAN patients who have residual PANK2 activity, DNA Testing the possibility of using high-dose pantothenate therapy has Genetic investigation is performed for all the diseases been considered. Pantothenate is well tolerated with no described in this chapter, on DNA extracted from peripheral known toxicity. The effect of pantothenate supplementation blood mononuclear cells (PBMC). PCR amplification and in PKAN is currently unknown although patients with atypidirect sequencing are carried out for mutation detection. In cal PKAN have anecdotally reported improvement in motor some laboratories, usage of genes panel followed by next-­ symptoms, speech, cognition, and general wellbeing while on treatment (Kurian and Hayflick 2013). generation sequencing (NGS) is available. Oral pantethine supplementation as targeted treatmente aimed to bypass the deficient enzyme in the CoA synthesis pathway was proposed in two PPCS mutated patients and Treatment showed mild clinical and instrumental improvement in one of them (Iuso et al., 2018). Summary In NADK2 deficiency, low-lysine diet has been tried In disorders of pantothenate metabolism, pharmacologic and (Houten et al., 2014; Tort et al., 2016) with reported benefisurgical interventions have focused on palliation of symp- cial effect in one case in association with other cofactors toms according to consensus clinical management guideline (ubidecarenone, idebenone, vitamin E, creatine) (Tort et al., available for PKAN (Hogarth et  al., 2017). Symptomatic 2016). NADPH supplementation has been tried in a recently treatment is aimed primarily at the dystonia, which can be reported case with a milder phenotype with initial beneficial profoundly debilitating to the affected individual and care- effect (Pomerantz et al., 2018). Treatment with nicotinic acid givers. Different treatments have been commonly used has been speculated for individuals with NAXE defect including oral baclofen, trihexyphenidyl, and clonazepam, (Kremer et  al., 2016). Oral nicotinamide treatment (50– intrathecal and intraventricular baclofen, and deep brain 100  mg/day) may prevent or resolve photodermatitis in Hartnup disorder. stimulation.

33  Disorders of Niacin, NAD, and Pantothenate Metabolism

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Vitamin B6-Dependent and Vitamin B6-Responsive Disorders

34

Barbara Plecko and Eduard A. Struys

Contents Introduction 

 578

Nomenclature 

 581

Metabolic Pathways 

 582

Signs and Symptoms 

 584

Reference and Pathologic Values 

 586

Diagnostic Flowchart 

 587

Specimen Collection 

 587

Prenatal Diagnosis 

 587

DNA Testing 

 587

Treatment 

 588

References 

 589

Summary

The importance of vitamin B6 is evident by its role as the most abundant cofactor in human metabolism. A total of six different B6 vitamers follow a complex pathway of absorption and transformation into the final active cofactor, pyridoxal 5′-phosphate (PLP), which catalyses over 100 reactions, mainly in amino acid and neurotransmitter metabolism. Over recent years, a number of genetic defects have been identified as the underlying cause of

B. Plecko (*) Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria e-mail: [email protected] E. A. Struys Metabolic Unit, Clinical Chemistry, VUmc Medical Center, Amsterdam, The Netherlands e-mail: [email protected]

vitamin B6-dependent epilepsies that need to be considered particularly in therapy-resistant seizures of unclear aetiology in the neonatal period, but also later in life. With diagnostic delay, these disorders can be fatal or may lead to irreversible brain damage. A standardised vitamin B6 trial should be part of a protocol for neonatal seizures in every institution caring for the critically ill newborn. The underlying mechanisms of vitamin B6-dependent epilepsies can be assigned to either reduced synthesis and recycling of PLP (pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency), reduced cellular uptake (congenital hypophosphatasia, HPP), inactivation of PLP by accumulating compounds (antiquitin deficiency and hyperprolinaemia type II) or disturbed intracellular PLP homeostasis (PLP-binding protein (formerly PROSC) deficiency). The disorders can be distinguished by specific biomarkers in urine, plasma or CSF and confirmed by molecular testing. Affected patients need a lifelong oral treatment with pyridoxine or pyridoxal 5′-phosphate,

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_34

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and withdrawal will inevitably lead to seizure recurrence. Pyridoxine has less severe potential side effects compared to PLP and should be the preferred vitamer wherever possible. Add-on of folinic acid may be considered in case of partial response to pyridoxine or PLP.  Lysine-restricted diet and high-dose arginine supplementation are being evaluated as add-on therapy in patients with ATQ deficiency. Due to autosomal recessive inheritance, recurrence risk for all disorders discussed here is 25% and intrauterine treatment with vitamin B6 from early pregnancy may be considered in forthcoming pregnancies. Prenatal testing is available by molecular analysis.

B. Plecko and E. A. Struys

ciency as well as in genetic disorders. Nutritional vitamin B6 deficiency is rare nowadays, eventually seen in children with severe chronic disease or on high dosages of the tuberculostatic isoniazid and cured by adequate vitamin supply. In contrast, genetically determined vitamin B6-dependent epilepsies are caused by inborn errors of metabolism that lead to reduced PLP availability (Wilson et al. 2019, Clayton 2006). To date, five different disorders are known that can be assigned to four different mechanisms:

• Reduced synthesis and recycling of PLP (pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency), MIM#610090 • Reduced cellular uptake of PLP (congenital hypophosphatasia, HPP, MIM#241500) • Inactivation of PLP by accumulating compounds (antiqIntroduction uitin deficiency, MIM#266100 and hyperprolinaemia type II, MIM#239500) Vitamin B6 is a water-soluble vitamin derived from various • Disturbed intracellular PLP homeostasis (PLP-binding animal and plant food sources as well as intestinal bacterial protein (PLPBP, formerly PROSC) deficiency, flora in six different vitamers: pyridoxal, pyridoxine-­ MIM#617290) glucoside, pyridoxamine and their 5′-phosphorylated esters. Pyridoxal 5′-phosphate is the only active cofactor and catalySeizures with resistance to common anticonvulsants ses over 140 enzymatic reactions, mainly in amino acid occur as a consequence of imbalance in PLP-dependent neumetabolism (e.g. the glycine cleavage system, serine dehy- rotransmitter—as well as in cerebral amino acid metabolism. dratase, threonine dehydratase) as well as in neurotransmit- Prematurity, poor adaptation, abdominal distension, lactic ter metabolism (e.g. GABA formation by glutamate acidosis and hypoglycaemia have been described as condecarboxylase; aromatic acid decarboxylase/AADC). The founding factors in severe manifestations of PNPO, ATQ as demand of vitamin B6 is 0.1–0.3 mg/day during infancy and well as PLPBP deficiency (Wilson et  al. 2019). A stanaround 1.2–1.4 mg/day in adulthood. As cellular uptake and dardised vitamin B6 trial with the administration of 100 mg transport across the blood-brain barrier is only possible for of pyridoxine i.v. followed by a 3-day trial with pyridoxine, free bases of vitamin B6, phosphorylated vitamers undergo 30  mg/kg/day in two single dosages is recommended for hydrolysation by intestinal phosphatases and tissue non-­ every neonate with therapy-resistant seizures of unclear aetispecific alkaline phosphatase (TNSALP), respectively ology. Specific biomarkers serve in the differentiation of (Fig. 34.1). The latter is attached to the cellular membrane by these disorders and complement the diagnostic value of a a PIGV anchor system. Within cells pyridoxine, pyridox- vitamin B6 trial. A variety of secondary biochemical findings amine and pyridoxal undergo rephosphorylation by pyri- has been described in patients with vitamin B6-dependent doxal kinase with consecutive oxidation of pyridoxine epilepsies. These include lactic acidosis, elevated threonine 5′-phosphate and pyridoxamine 5′-phosphate into pyridoxal and glycine in plasma or CSF and abnormal metabolites of 5′-phosphate (PLP) by flavin mononucleotide-dependent biogenic amines in CSF, as low homovanillic acid, low pyridox(am)ine 5′-phosphate oxidase (PNPO), which can hydroxyindoleacetic acid, increased 3-methoxytyrosine and also recycle pyridoxamine monophosphate back to PLP (sal- high vanillactate in urine. These secondary findings are all vage pathway). Though the liver seems to play an important explained by impaired function of PLP-dependent enzymes role in the formation of PLP, expression of PNPO has also in amino acid or neurotransmitter metabolism. They are nevbeen shown in human intestinal and muscle cells, as well as ertheless inconsistent and non-specific and may be found in in neurons. Enzymes involved in PLP synthesis are regulated all circumstances of (cerebral) PLP depletion. While adminby a feedback mechanism to avoid toxic PLP concentrations. istration of PLP would serve all five disorders, pyridoxine is Recently the PLP-binding protein (PLPBP, formerly named ineffective in most cases of classical PNPO deficiency as PROSC) has been shown to be crucial for intracellular PLP well as in severe PLPBP deficiency. In case of a positive homeostasis (Fig. 34.1). treatment effect, pyridoxine or PLP therapy should be conThe role of vitamin B6 in epileptogenesis has been well tinued until results of biochemical and molecular testing are recognised by the occurrence of seizures in nutritional defi- available.

34  Vitamin B6-Dependent and Vitamin B6-Responsive Disorders

Due to recent reports on attenuated phenotypes, administration of vitamin B6 should also be considered in older patients with therapy-resistant epilepsy.

579

2014) and mice (Pena et al. 2017a, b) that PA is built via the saccharopine pathway by conversion of P6C. Diagnosis is confirmed by molecular analysis of the ALDH7A1 gene also known as antiquitin, and to date a total of 165 different mutations have been described (Coughlin II et al. 2019). Antiquitin (ATQ) Deficiency In 2009, folinic acid-responsive seizures were found to be allelic to antiquitin deficiency (Gallagher et  al. 2009). The ATQ deficiency is the most prevalent form of pyridoxine-­ effect may rely on overlapping cofactor functions of folinic dependent epilepsy (PDE) and has an estimated incidence of acid and PLP. Add-on of folinic acid, 3–5 mg/kg/day, may be 1:64.000 (Coughlin II et al. 2019). Patients with ATQ defi- considered, if the initial response to pyridoxine is limited. ciency usually present with seizures soon after birth (Gospe Inheritance of ATQ deficiency is autosomal recessive with a 2017, Stockler et al. 2011). Seizures are myoclonic, tonic or 25% recurrence risk in forthcoming pregnancies. Patients, clonic with variable EEG patterns (Schmitt et al. 2010). Cra- who never received pyridoxine experience high mortality, as nial imaging may be normal or may show some grey and shown by a considerable rate of deceased siblings diagnosed white matter atrophy, hydrocephalus, thin corpus callosum retrospectively as well as some patients who had been on mega cisterna magna and also cortical dysplasia (Toldo et al. folinic acid monotherapy. Outcome of patients with ATQ 2018). Seizures are typically refractory to common anticon- deficiency treated with pyridoxine is variable, and about vulsants with a high tendency towards status epilepticus 70% have some degree of cognitive impairment (Plecko (SE). Partial response to phenobarbitone is possible. About et al. 2007; Mills et al. 2010; Bok et al. 2012). Normal IQ has 30% of PDE patients suffer from birth asphyxia or may have been described in single patients despite prolonged status signs of encephalopathy. Abdominal distension with bile-­ epilepticus (Kluger et al. 2008). stained vomiting, elevated lactate or hypoglycaemia may be confusing confounders. Atypical presentations with onset of seizures beyond infancy, initial response to common anticon- Hyperprolinaemia Type II (HP II) vulsants or response to extremely low dose of pyridoxine have been observed (van Karnebeek et  al. 2016, Sriniva- This inborn error has first been described in Irish travellers, saraghavan et al. 2018). with primary generalised seizures in late infancy or childThe antiquitin gene is located on 5q31 and encodes alpha-­ hood in 50% of affected individuals. Mental retardation may aminoadipic semialdehyde dehydrogenase, an enzyme in- be present, but several individuals were reported with normal volved in the L-lysine degradation pathway (Figs. 34.2, 34.3, school performance (Flynn et  al. 1989). A recent series 34.4 and 34.5). The accumulating compound alpha-aminoad- reported on additional anxiety problems and hallucinations ipic semialdehyde (AASA) is in equilibrium with L-Δ1- (van de Ven et al. 2014). In many patients, seizures are trigpiperideine-6-carboxylate (P6C). The latter inactivates gered by fever, are relatively benign and can be controlled by pyridoxal 5′-phosphate by a so-called Knoevenagel condensa- common anticonvulsants. Thus, several patients with this tion, leading to profound cerebral PLP deficiency (Mills et al. autosomal recessive disorder may remain undiagnosed. 2006, Footitt et al. 2011). Elevated AASA in urine serves as a HP II is caused by defective Δ1-pyrroline 5-carboxylate specific biomarker for ATQ deficiency (Table 34.1), though it dehydrogenase, leading to increased utilisation of PLP.  In may also be elevated in molybdenum cofactor—or sulfite oxi- analogy to the pathophysiologic mechanism in ATQ defidase deficiency due to secondary inhibition of antiquitin by ac- ciency, L-D1-pyrroline-5-carboxylate (P5C) inactivates PLP cumulating sulfite (Struys et al. 2012a, b). Pipecolic acid (PA) by a Knoevenagel condensation (Farrant et al. 2001). Patients is an unspecific biomarker for ATQ deficiency and is found el- show high proline on plasma amino acid analysis as well as evated in urine, plasma and CSF prior to pyridoxine treatment elevated P5C in urine, plasma and CSF (Fig. 34.6). (Plecko et  al. 2000, 2007), while urinary levels always normalise, and also plasma levels may normalise on pyridoxine therapy. 6-Oxo-pipecolate (6-oxo-PIP) was described as a po- Pyridoxal 5′- Phosphate (PLP)-Dependent Epilepsy tential novel biomarker in plasma, urine and CSF of four pa- (PNPO) Deficiency tients with ATQ deficiency, with stability at room temperature and measured by LC-MS/MS, but warrants confirmation in Pyridoxal 5′-phosphate-dependent seizures were first larger cohorts (Wempe et  al. 2019). Recent labelled isotope described in 2002 (Kuo and Wang 2002). The clinical prestudies in cultured human brain cells (Crowther et  al. 2019) sentation is indistinguishable from ATQ deficiency except support data from studies in human fibroblast (Struys et  al. for a higher rate of prematurity seen in about 60% of cases

580

(Mills et al. 2005; Levtova et al. 2015). Again, about a third of patients have perinatal distress with low APGAR scores, requiring primary intubation in some. Patients typically present with neonatal myoclonic seizures up to 2 weeks of age, sometimes accompanied by roving eye movements and most often severely abnormal EEG (Mills et al. 2005; Hoffmann et  al. 2007). One patient has been reported with infantile spasms, presenting at age 5  months (Mills et  al. 2014). Recently, a patient with PNPO deficiency was reported with seizures that could initially be controlled by common anticonvulsants over a period of 3 years (Xue et al. 2017). Cranial imaging may be normal or show marked white matter changes. Patients with PNPO deficiency may suffer from anaemia, coagulopathy, renal dysfunction as well as failure to thrive. This broader range of symptoms and very high mortality rate in untreated patients is explained by systemic PLP deficiency. Many patients have deceased siblings with a history of neonatal epileptic encephalopathy and burst suppression EEG, falsely assigned to Ohtahara syndrome. Prognosis of patients with PNPO deficiency relies on early initiation of specific treatment and may result in normal outcome (Porri et  al. 2014; Hatch et  al. 2016). Seizures and EEG changes respond to pyridoxal 5′-phosphate (PLP) within hours or days. While first patients identified with classical PNPO deficiency had seizures that were resistant to pyridoxine, it became apparent that a subgroup of patients with PNPO mutations allowing residual enzyme activity may respond to pyridoxine and paradoxically have worsening of seizures upon PLP administration (Plecko et al. 2014; Mills et al. 2014). Pyridoxal 5′-phosphate-dependent epilepsy is caused by autosomal recessive mutations in the PNPO gene (Mills et  al. 2005). PNPO encodes pyridox(am)ine 5′-phosphate oxidase, an enzyme needed for the oxidation of pyridoxine and pyridoxamine into the only active vitamin B6 cofactor, which is pyridoxal 5′-phosphate (PLP). This enzyme is expressed in all human cell types and, aside from PLP synthesis, is involved in the recycling of pyridoxamine monophosphate back to PLP (salvage pathway) as well as PLP trafficking within the cell. Elevated pyridoxamine (Footitt et  al. 2013; Ware et  al. 2014) and, even more specific, an elevated pyridoxamine to pyridoxic acid ratio in plasma (and CSF) serve as reliable biomarkers for PNPO deficiency and can be determined while on treatment (Mathis et al. 2016). Elevated plasma glycine, threonine, elevated urinary vanillactate as well as abnormal biogenic amines are inconsistent secondary findings. Glycine elevation can be marked and may mislead clinicians to consider non-ketotic hypoglycaemia instead of going for a vitamin B6 trial. Recently an LC-MS/MS-based

B. Plecko and E. A. Struys

assay for the measurement of PNPO activity in dried blood spots has been developed (Wilson et al. 2019). Diagnosis has to be confirmed by molecular analysis of the PNPO gene; prenatal diagnosis is possible. Twenty seven different mutations have been identified to date (Wilson et al. 2019).

Congenital Hypophosphatasia The main impact of congenital hypophosphatasia is poor bone mineralisation and early death due to respiratory insufficiency. Only patients with the severe, congenital, autosomal recessive form of this disease may present with therapy-resistant seizures from birth, even before skeletal signs become more prominent (Balasubramaniam et  al. 2010, Baumgartner-Sigl et al. 2007). EEG is usually severely abnormal and may show a burst suppression pattern. While seizures are resistant to common anticonvulsants, a favourable response to oral or i.v. administration of pyridoxine has been reported in single cases (Nunes et al. 2002, Baumgartner-­ Sigl et  al. 2007) while in other seizures were resistant to pyridoxine and the encephalopathy was fatal (de Roo et al. 2014). The recently licensed enzyme replacement therapy (ERT) is considered unlikely to alter CNS involvement, as ERT does not cross the blood-brain barrier. The diagnostic hallmark of congenital hypophosphatasia is a markedly decreased concentration of alkaline phosphatase in plasma, while decreased phosphate and elevated calcium concentrations can be inconsistent. Tissue non-specific alkaline phosphatase (TNSALP) is a multifunctional enzyme that processes three substrates, namely, inorganic pyrophosphate, phosphoethanolamine and PLP for cellular uptake. With respect to seizure aetiology, impaired TNSALP function leads to reduced intracellular availability of PLP, while plasma levels of PLP are (extremely) high. To date it is not well understood why patients do not show signs of systemic PLP deficiency, if there is toxicity of high extracellular PLP concentrations or if other mechanisms as morphologic changes in neurons as observed in a knock-out mouse model (Sebastián-Serrano et al. 2016) may contribute to human disease. Diagnosis is confirmed by molecular analysis of the ALPL gene.

 yridoxal-Binding Protein (PLPBP) Formerly PROSC P Deficiency With the application of a standardised vitamin trial and new techniques in genetic testing, another genetic defect causing

34  Vitamin B6-Dependent and Vitamin B6-Responsive Disorders

581

vitamin B6-dependent epilepsy has been unravelled by Darin et al. in 2016 in seven patients of four families. To date a total of 15 patients with PLPBP deficiency have been described (Darin et al. 2016, Plecko et al. 2017, Shiraku et al. 2018), all presenting with seizures from birth to 3 months of age. There is overlap with ATQ and PNPO deficiency according to seizure type as well as accompanying signs of prematurity or foetal distress, but within the cohort of PLPBP deficiency, four patients had microcephaly at birth and another four developed acquired microcephaly during the course of disease. Seven patients had a burst suppression pattern on EEG, while the remainder had diffuse slowing or (multi)focal discharges. Cranial MRI was normal in eight cases and in all other cases showed broad gyri, shallow sulcy, abnormal white matter and eventually also periventricular cysts. Ten patients were treated with pyridoxine, while five were receiving PLP at dosages ranging from a total of 100 mg to 450 mg/ day. Nine were seizure-free aside from febrile breakthrough seizures, but only five patients were on vitamin B6 mono-

therapy. Thirteen patients have intellectual impairment of variable degree, some of them with considerable delay of first vitamin B6 administration. In contrast to the aforementioned entities, PLPBP deficiency does not have a specific biomarker. Low PLP concentrations were found in CSF as unspecific clues to vitamin B6-dependent epilepsies, but alterations of amino acids and biogenic amines were inconsistent. PLPBP encodes for a protein with non-enzymatic function. It is most likely a key regulator of intracellular PLP homeostasis and important in protecting PLP from intracellular inactivation by phosphatases. Diagnosis of PLPBP deficiency relies on genetic testing, either by gene panels for epileptic encephalopathies or by next-generation sequencing. A positive vitamin B6 response to either pyridoxine or PLP but normal biomarkers for ATQ-­ PNPO as well as TNSALP deficiency may suggest PLPBP deficiency. So far a total of 14 pathogenic variants in PLPBP have been identified.

Nomenclature

No. Disorder 34.1 Pyridoxine-dependent epilepsy (PDE)

Alternative name Alpha-amino adipic semialdehyde (AASA) dehydrogenase deficiency 34.2 Pyridox(am)ine Pyridoxal 5′-phos5′-phosphate oxidase phate (PLP)-dependeficiency dent seizures 34.3 Hyperprolinaemia Pyrroline-5-carboxyltype II ate dehydrogenase deficiency 34.4 Congenital hypoPhosphoethanolaminphosphatasia uria 34.5 PLP-binding protein (Formerly PROSC deficiency deficiency)

Gene Abbreviation symbol AASADHD ALDH7A1

PNPOD

PNPO

P5CDH

ALDH4A1

HOPS

ALPL

PLPBP

PLPBP

Chromosomal Mode of localisation inheritance Affected protein 5q31 AR Alpha-amino adipic semialdehyde dehydrogenase 17q21.32 AR Pyridox(am)ine 5′-phosphate oxidase 1p36.13 AR Pyrroline-5-carboxylate dehydrogenase 1p36.12 AR Alkaline phosphatase 8p11.23 AR PLPBP

OMIM no. 266100

610090

239510

241500 604430

582

B. Plecko and E. A. Struys

Metabolic Pathways

Diet

Pyridoxal-P

Absorption

Pyridoxal

Pyridoxamine-P

IP

Pyridoxine-glucoside

IP Pyridoxamine

PK

PK Pyridoxamine-P

Pyridoxine PK Pyridoxine-P

PNPO Blood

Pyridoxal-P

Cell membrane

TNSALP

PIGV anchor Pyridoxamine

Pyridoxal Cell

PK

PK

Pyridoxamine-P

Pyridoxal-P

Pyridoxine PK Pyridoxine-P

PNPO

Fig. 34.1  Vitamin B6 is absorbed in different vitamers that are dephosphorylated by intestinal alkaline phosphatases (IP). In the liver they are then rephosphorylated to their 5′-phosphate esters by phosphate kinase (PK), and pyridox(am)ine is consequently converted into pyridoxal 5′-phosphate (PLP) by pyridoxamine 5′-phosphate oxidase (PNPO) and partly released into circulation. For cellular uptake or transport across the blood-brain barrier, phosphorylated vitamers (mainly PLP) are

hydrolysed by tissue non-specific alkaline phosphatase (TNSALP). Within the (brain) cell, rephosphorylation of PL as the major source and oxidation of pyridox(am)ine by PNPO provides PLP as the only active cofactor for intracellular enzyme reactions. Pyridoxal 5′-phosphate exhibits feedback inhibition upon PNPO activity. PLP-binding protein (PLPBP) has a non-enzymatic function and is considered a key regulator of intracellular PLP homeostasis

34  Vitamin B6-Dependent and Vitamin B6-Responsive Disorders

583 L-lysine H2N

COOH NH2

H2N

COOH

2-keto 6-amino caproic acid

O

HOOC piperideine-2-carboxylate

N

COOH

COOH

N H

NH2 saccharopine

HOOC

pipecolic acid

N

COOH

N

COOH

O

COOH NH2

piperideine-6-carboxylate

alpha aminoadipic semialdehyde

COOH

HOOC NH2

alpha aminoadipic acid

Fig. 34.2  Lysine degradation pathway. Antiquitin deficiency leads to accumulation of alpha-aminoadipic semialdehyde and piperideine-6-carboxylate and is accompanied by elevated pipecolic acid. It is now assumed

that pipecolic acid is formed via the saccharopine pathway by conversion of piperideine-6-carboxylate. Piperideine-6-carboxylate inactivates PLP by a Knoevenagel condensation, leading to cerebral PLP deficiency

Fig. 34.3  Catabolism of L-proline. In hyperprolinaemia type II, deficiency of Δ1-pyrroline-5-carboxylate (P5C) dehydrogenase leads to accumulation of glutamic acid γ semialdehyde and P5C. P5C inactivates PLP by a Knoevenagel condensation

l-proline

N

COOH

glutamic semialdehyde P5C

NH2

spontaneous O N

COOH

COOH

P5C dehydrogenase

NH2 HOOC

glutamic acid COOH

584

B. Plecko and E. A. Struys

Fig. 34.4  Scheme illustrating all five inborn errors leading to vitamin B6-dependent epilepsy. Two inborn errors within vitamin B6 metabolism leading to reduced synthesis of pyridoxal 5′-phosphate (PLP): pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency and tissue non-specific alkaline phosphatase (TNSALP) deficiency in congenital hypophosphatasia, two inborn errors leading to inactivation of PLP by a Knoevenagel condensation, hyperprolinaemia type II (P5C dehydrogenase deficiency) and antiquitin (alpha-AASA dehydrogenase) deficiency and one inborn error with impaired intracellular PLP homeostasis, PLPBP deficiency

Diet Pyridoxal (5′-P)

Pyridoxamine (5′-P)

Liver

PNPO

Pyridoxine Glucoside

PNPO

PLP L-Proline

L-Lysine

PIGV TNSAP 2

PL P5C

P6C

PLP

P5C-Dehydrogenase

AASA Dehydrogenase

PLPBP

Signs and Symptoms Table 34.1  Antiquitin deficiency System CNS

Digestive Others

Laboratory findings

Symptoms and biomarkers Agenesis/hypogenesis, corpus callosum Developmental delay Hypotonia Mega cisterna magna Seizures, pharmacoresistant Intestinal pseudo obstruction Vomiting Alpha-aminosemialdehyde pretreatment (U, P, CSF) Alpha-aminosemialdehyde under B6 treatment (U, P, CSF) Low APGAR scores Glucose (P) Lactate (P) PA pretreatment (U, P, CSF) PA under B6 treatment (CSF) PA under B6 treatment (P) PA under B6 treatment (U) PLP (CSF)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ++

± ± ± ++

± ± ±

± ± ±

± ↑↑↑

↑↑↑

↑↑

↑(↑↑)

↑

↑

↑

± ↓-n n-↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑↑ ↓↓↓

n n ↑↑↑ ↑↑ ↑ n-↑ ↓↓↓

n n ↑↑↑ ↑ ↑ n

n n

n n

↑ n-↑ n

n-↑ n

± ± +++ ± ± ↑↑↑

34  Vitamin B6-Dependent and Vitamin B6-Responsive Disorders

585

Table 34.2  Pyridox(am)ine 5′-phosphate oxidase deficiency System CNS

Digestive Others Laboratory findings

Symptoms and biomarkers Developmental delay Hypotonia Seizures, pharmacoresistant Vomiting Low APGAR scores Prematurity 3-Methoxytyrosine (CSF) 5-Hydroxyindoleacetic acid, 5-HIAA (CSF) Glucose (P) Glycine (P) Homovanillic acid, HVA (CSF) Lactate (P) PLP (CSF) Pyridoxamine /pyridoxic acid ratio Threonine (CSF) Threonine (P) Vanillactic acid (U)

Neonatal (birth–1 month) ++ ++ +++ ± ± +++ ↑↑ ↓ ↓-n n-↑ ↓-n n-↑ n-↓↓ ↑↑ n-↑ n-↑ n-↑

Infancy (1–18 months) +-+++ ++ ++ ±

↑↑ ↓ n n-↑ ↓-n n n-↓↓ ↑↑ n-↑ n-↑ n-↑

Childhood Adolescence (1.5–11 years) (11–16 years) +-+++ ± ++

Adulthood (>16 years)

n

n

n

n

n

n

↑↑

Table 34.3  Hyperprolinaemia type II System CNS

Laboratory findings

Symptoms and biomarkers Mental retardation Seizures, febrile Seizures, pharmacoresistant Hydroxyproline (P) Hydroxyproline (U) P5C (U) Proline (P) Proline (U)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± n n-↑↑↑ ↑ ↑-↑↑↑ ↑↑↑

Childhood (1.5–11 years) ± ± ± n n-↑↑↑ ↑ ↑-↑↑↑ ↑↑↑

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± n n-↑↑↑ ↑ ↑-↑↑↑ ↑↑↑

± n n-↑↑↑ ↑ ↑-↑↑↑ ↑↑↑

Neonatal (birth–1 month) n-+++ ++ +++

Infancy (1–18 months) n-+++ ++ +++

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ ++

++

++

↓↓↓

↓↓↓

↓↓

↓↓

↓↓

n-↑↑ n-↓↓ ↑↑↑

n-↑↑ n-↓↓ ↑↑↑

↑↑ ↓ ↑↑

↑-↑↑ ↓ ↑↑

↑-↑↑ ↓ ↑↑

n n-↑↑↑ ↑ ↑-↑↑↑ ↑↑↑

Table 34.4  Congenital hypophosphatasia Symptoms and biomarkers Seizures Respiratory failure Skeletal hypomineralisation Laboratory find- Alkaline phosphatase ings (P) Ca++ (P) Phosphate (P) PLP (P)

System CNS Respiratory Others

Table 34.5  PLP-binding protein (PLPBP) – formerly PROSC deficiency System CNS Skeletal Laboratory findings

Symptoms and biomarkers Seizures Microcephaly Alanine (CSF) Glycine (CSF) Proline (CSF) Threonine (CSF) Valine (CSF)

Neonatal (birth–1 month) +++ n-+++ ↑↑ ↑↑ n-↑↑ n-↑↑ n-↑↑

Infancy (1–18 months) n-+++ n-+++

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

n-+++

n-+++

n-+++

586

B. Plecko and E. A. Struys

Reference and Pathologic Values Pyridoxine-dependent epilepsy reference values Age 0.5 1 year

Alpha-­AASA (U) mmol/mol creatinine 1 year

P5C-glycine conjugate (U) Not detectable

Trace-90 (P) (μM) Trace-400 (U) Trace-50 (U) Trace-­10 (U)

Plasma values in μM; urinary values in mmol/mol creatinine Pathological values Proline All ages

500–3700 (P) 2100–40,125 (U)

Hydroxyproline All ages

P5C-glycine conjugate (U) Present

1–46 (P) 84–3769 (U)

Plasma values in μM; urinary values in mmol/mol creatinine Pyridoxal 5′-phosphate (PLP)-dependent epilepsy reference values PLP (CSF) nM 49–89

HVA (CSF) nM 300–1100

5-HIAA (CSF) nM 200–600

3-Methoxytyrosine (3-OMD) nM 16 years)

↑

↑

↑

n

n

n

n

↓↓ ↓↓ ↑

↓↓↓ ↓↓ ↑

↓↓↓ ↓↓ ↑

↓↓↓ ↓↓

↓↓↓ ↓↓

↓

↓

↓

↓

↓

↓

↓

↓

↑↑↑ ↑↑↑ ↑↑↑ ↑ ↑ ↓↓ ↓↓↓ ↑↑↑ ↑↑↑

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓↓ ↓↓↓ ↑↑↑ ↑↑↑

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓↓ ↓↓↓ ↑↑↑ ↑↑↑

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓↓ ↓↓↓ ↑↑↑ ↑↑↑

↑↑ ↑↑ ↓↓↓

Table 35.2  Molybdenum cofactor deficiency B System CNS

Digestive Eye Musculoskeletal

Renal Respiratory Laboratory findings

Symptoms and biomarkers Dystonic cerebral palsy Exaggerated startle response Hypertonia, limbs Myoclonus Orobulbar dysfunction Profound global developmental delay Reduced consciousness Seizures, tonic clonic Feeding difficulties Cerebral visual impairment Lens dislocation Dysmorphic features Hypotonia, muscular-axial Microcephaly Nephrolithiasis Apnea Alpha-aminosemialdehyde (cerebrospinal fluid) Alpha-aminosemialdehyde (urine) Cyclic pyranopterin monophosphate, cPMP (urine) Cystine (plasma) Homocysteine (plasma) Pipecolic acid (cerebrospinal fluid) Pyridoxal phosphate, PLP (cerebrospinal fluid) Pyridoxal phosphate, PLP (plasma) Sulfite (urine) Sulfocysteine (plasma) Sulfocysteine (urine) Taurine (plasma) Taurine (urine) Trimethylamine (urine) Uric acid (plasma) Urothione (urine) Xanthine (urine)

Neonatal (birth–1 Infancy month) (1–18 months) + +++ +++ + ++ ++ ++ ++ +++ ++

Childhood (1.5–11 years) ++ ++ ++ ++ +++ +++

Adolescence (11–16 years) +++

Adulthood (>16 years) +++

++ ++ +++ +++

++ ++ +++ +++

+++ +++ ++ ± + ++ ++ ±

+++ +++ ++ ± + ± ++ ±

++ +++ ++ ±

++ +++ ++ ±

++ ±

++ ±

± ↑

↑

↑

↑ ↑↑

↑ ↑↑

↑ ↑↑

↓↓ ↓↓ ↑ ↓

↓↓↓ ↓↓ ↑ ↓

↓↓↓ ↓↓ ↑ ↓

↓↓↓ ↓↓

↓↓↓ ↓↓

↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↑↑↑ ↓↓ ↓↓ ↑↑↑

↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↑↑↑ ↓↓↓ ↓↓ ↑↑↑

↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↑↑↑ ↓↓↓ ↓↓↓ ↑↑↑

↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↑↑↑ ↓↓↓ ↓↓↓ ↑↑↑

↓

++ +++ +++ + ++ +++

↑↑

↑↑ ↑↑

↓↓↓

600

G. Schwarz and B. C. Schwahn

Table 35.3  Molybdenum cofactor deficiency C System CNS

Symptoms and biomarkers Dystonic cerebral palsy Exaggerated startle response Hypertonia, limbs Myoclonus Orobulbar dysfunction Profound global developmental delay Reduced consciousness Seizures, tonic clonic Digestive Feeding difficulties Eye Cerebral visual impairment Lens dislocation Musculoskeletal Dysmorphic features Hypotonia, muscular-axial Microcephaly Renal Nephrolithiasis Respiratory Apnea Laboratory findings Alpha-aminosemialdehyde (cerebrospinal fluid) Alpha-aminosemialdehyde (urine) Cyclic pyranopterin monophosphate, cPMP (urine) Cystine (plasma) Homocysteine (plasma) Pipecolic acid (cerebrospinal fluid) Pyridoxal phosphate, PLP (cerebrospinal fluid) Pyridoxal phosphate, PLP (plasma) Sulfite (urine) Sulfocysteine (plasma) Sulfocysteine (urine) Taurine (plasma) Taurine (urine) Uric acid (plasma) Urothione (urine) Xanthine (plasma) Xanthine (urine)

Neonatal (birth–1 month) ++ + ++ +++

++ +++ +++

Infancy (1–18 months) + + ++ ++ +++ ++

Childhood (1.5–11 years) ++

Adolescence (11–16 years) +++

+++ + +++ +++

+++

Adulthood (>16 years)

+++ +++

± ↑

+ +++ +++ + + + + ++ ± ± ↑

↑

↑

n–↑

n–↑

n–↑

n–↑

↓↓ ↓-↑ ↑

↓↓↓ ↓↓ ↑

↓↓↓ ↓↓

↓↓↓ ↓↓

↓↓↓ ↓↓

↓

↓

↓

↓

↓

↓

↓

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓ n–↑ ↑↑↑ ↑↑↑

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓↓ n–↑ ↑↑↑ ↑↑↑

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓↓ n–↑ ↑↑↑ ↑↑↑

↑↑↑ ↑↑↑ ↑↑↑ ↑↑ ↑↑ ↓↓↓ n–↑ ↑↑↑ ↑↑↑

Neonatal Infancy (birth–1 month) (1–18 months) ↓ ↓

Childhood (1.5–11 years) ↓

Adolescence (11–16 years) ↓

Adulthood (>16 years) ↓

± ± ± ↑ ↑↑ ↓↓ ↓↓ ↑ ↑↑

± ± ± ↑ ↑↑ ↓↓ ↓↓ ↑ ↑↑

± ± ± ± ↑ ↑↑ ↓↓↓ ↓↓↓ ↑ ↑↑

± ± ± ± ↑ ↑↑ ↓↓ ↓↓ ↑ ↑↑

± +++ ±

+++ +++ + + + + ++ ±

++ + + ++ + ++ ±

+

↑↑ ↑↑ n–↑

Table 35.4  Molybdenum cofactor sulfurase deficiency System Metabolic

Symptoms and biomarkers Allopurinol to oxipurinol conversion Musculoskeletal Myopathy Renal Renal failure, acute Urolithiasis Urolithiasis, xanthine stones Laboratory findings Hypoxanthine (plasma) Hypoxanthine (urine) Uric acid (plasma) Uric acid (urine) Xanthine (plasma) Xanthine (urine)

± ± ± ↑ ↑↑ ↓↓ ↓↓ ↑ ↑↑

35  Molybdenum Cofactor Disorders

601

Reference and Pathological Values Purines in urine and plasma (HPLC-UV and LC-MS/MS)

Compound rangea Uric acidc Hypoxanthine Xanthine

Urine 0–1 year (n = 16) 820–1026 1–71.9 0–63.4

1–5 years (n = 47) 527–790 1–88.1 0–54.7

5–16 years (n = 27) 326–436 1–14.1 0–21.7

> 16 years (n = 26) 222–287 1–14.0 0.3–10.7

Pathological valuesb < 100 >100 > 70

>16 years (n = 26) 50 A (p.Glu116Lys), have been recently associated with a non-syndromic form of congenital diarrhea in three patients who died within the first 3 months of life due to intractable diarrhea, without showing other symptoms of MEDNIK syndrome, such as sensorineural deafness and ichthyosis (Klee et al. 2020). It is not known, however, if these missense mutations may represent hypomorphs allowing for residual AP-1 complex function in the inner ear or skin, or if the patients have died before manifesting the characteristic features of MEDNIK disease. MEDNIK-like syndrome is a recently described disease associated with two homozygous null variants in AP1B1, encoding the large β subunit of the AP-1 complex (Alsaif et al. 2019). Affected individuals showed the same neurocutaneous phenotype as MEDNIK patients, and abnormal copper metabolism highlighted by low plasma copper and ceruloplasmin, but lacked evidence of copper overload in the liver. Plasma VLCFA were also increased. Acetyl-CoA transporter deficiency (Huppke-Brendel syndrome) is a rare disorder caused by mutations in the SLC33A1 gene, encoding for a transporter (AT-1) that translocates acetyl-­CoA into the ER lumen (Huppke et al. 2012a). Disease phenotypes include developmental delay, congenital cataracts, nystagmus, hearing loss, white matter hypomyelination, cerebral and cerebellar atrophy, early death, and low serum copper and ceruloplasmin levels, with normal urine copper. The pathogenesis has not been completely elucidated so far, but an abnormal acetylation of ceruloplasmin could lead to decreased secretion, with secondarily reduced serum copper (Table 36.6). Acrodermatitis enteropathica is an autosomal recessive disorder of zinc transport caused by mutations in the SLC39A4 gene encoding ZIP4, a zinc transporter expressed at the apical membrane of the enterocytes (Wang et al. 2002), affecting zinc absorption from the gut. Clinical symptoms develop after breastfeeding is stopped, whereas babies fed with infant formula develop the disorder as early as the first 2–4 weeks of life. Patients usually show severe erythematous dermatitis, initially localized at the acral and peri-orificial sites (Neldner and Hambidge 1975). Later on, these lesions become more pustular and hyperkeratotic. Mucosal lesions include gingivitis, stomatitis, and glossitis. Total alopecia is frequent, as well as nail deformities and ophthalmologic problems (blepharitis, conjunctivitis, photophobia, and impaired dark adaption). In addition, some patients present with watery diarrhea and failure to thrive. Behavioral disturbances such as irritability, apathy, and depression are common (Table 36.7). Patients are prone to frequent infections, as zinc deficiency affects cellular and humoral immunity. If untreated, the disease worsens and can even be fatal.

D. Martinelli

When the diagnosis is suspected on a clinical basis, serum zinc levels should be measured, as they are often severely reduced. Up to 15% of patients, however, show normal values because of zinc release from catabolized tissues (Van Wouwe 1989). Measurement of zinc in other tissues, such as hair or blood cells, does not improve diagnostic accuracy. In addition, several conditions, such as chronic diarrhea or infections, can be associated with secondary reduced serum zinc levels. Low urinary zinc excretion or low alkaline phosphatase (a zincdependent enzyme) activity can support the diagnosis. The recent improvement in genetic testing owing to NGS methodologies has made other approaches, such as intestinal zinc transport studies with radiolabeled zinc, archaic. While waiting for the molecular results, zinc therapy should be started, and a positive response should be obtained within a week. The relapse of skin abnormalities after zinc withdrawal is conclusive. Additional biochemical abnormalities that can be observed are increased blood ammonia (due to the defect of ornithine transcarbamylase deficiency), hypobetalipoproteinemia, and an altered fatty acid pattern. Biochemical ­evidence of depressed humoral and cell-mediated immunity may coexist.  ransient Neonatal Zinc Deficiency T Transient neonatal zinc deficiency is due to maternal heterozygous mutations in SLC30A2, which encodes ZnT2, a zinc transporter in mammary epithelial cells. This disorder causes low maternal milk zinc concentrations. Therefore, during breastfeeding, infants show signs of zinc deficiency, resembling acrodermatitis enteropathica, but they resolve after weaning (Chowanadisai et al. 2006) (Table 36.8). Spondylocheirodysplastic Ehlers-Danlos Syndrome (SCD-EDS) The zinc transporter protein ZIP13, encoded by SLC39A13, plays a crucial role in bone, tooth, and connective tissue development. Biallelic mutations in this gene cause the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS). Affected patients exhibit both the common features of EDS, like articular hypermobility and skin hyperelasticity, and distinct physical signs such as short stature, tapering fingers, wrinkled palms, and downslanted palpebral fissures with a lack of periorbital tissue. Skeletal radiographs show platyspondyly, osteopenia, irregular endplates of the vertebral bodies, metaphyseal ­widening, and epiphyseal flattening (Giunta et al. 2008). A useful biomarker of the disease is a fivefold increase of urinary deoxypyridinoline-to-pyridinoline ratio compared to normal (Table 36.9). Serum zinc levels are normal, but the intracellular distribution of zinc is abnormal, affecting proper nuclear translocation of transcription factor SMADs, which respond to BMP and TGF-β, and are critical for connective

36  Disorders of Copper, Zinc, and Selenium Metabolism

611

tissue development. Electron microscopy studies on skin tion of the metabolism of calprotectin (Holzinger et  al. biopsies documented normal elastic fibers and collagen 2015). This protein has zinc-binding capacity, as well as fibrils (Giunta et al. 2008). antimicrobial and proinflammatory activity. Laboratory tests Birk-Landau-Perez Syndrome is an autosomal recessive show extremely high serum levels of zinc and mostly calprodisorder caused by mutations in SLC30A9, encoding ZnT9 tectin (500–12,000 times the normal levels) (Table 36.12). (Ferreira and Gahl 2017). The ZnT9 defect causes a cerebro-­ SBP2 Deficiency is due to biallelic mutations in SECISBP2, renal syndrome with early-onset intellectual disability and encoding SBP2. In all reported patients, the deficiency of tubulointerstitial nephropathy. After a normal psychomotor deiodinases causes abnormal thyroid metabolism, with eledevelopment, patients show progressive neurodegeneration, vated T4 and rT3, high/normal TSH, and low T3 levels. starting at 1–2  years of life. Brain MRI is normal (Table Additional clinical symptoms, variably present, include 36.10). ZnT9 is located in the endoplasmic reticulum, and its psychomotor or speech delay, sensorineural hearing loss, olideficiency affects zinc homeostasis, leading to decreased gospermia, and progressive congenital myopathy (Ferreira cytosolic zinc concentrations (Ferreira and Gahl 2017). and Gahl 2017). Serum selenium concentration is low, indiAsymptomatic Familial Hyperzincemia occurs as a conse- cating a global selenoprotein synthesis deficiency (Table quence of a variant form of albumin (the major transport pro- 36.13). Organic or inorganic selenium supplementation is tein in blood for zinc) with higher affinity to this metal. not able to revert thyroid function abnormalities (Ferreira Therefore, serum zinc excess is caused by increased binding and Gahl 2017). to albumin (Table 36.11). The condition has no clinical Progressive Cerebellocerebral Atrophy is caused by bialeffects, and it is also called Familial Dysalbuminemic lelic mutations in the SEPSECS (Sep (O-phosphoserine) Hyperzincemia. tRNA:Sec (selenocysteine tRNA synthetase) gene, responHyperzincemia and Hypercalprotectinemia is an autoin- sible for a severe neurodegenerative disease with intellectual flammatory disorder characterized by pustular and ulcerative disability, postnatal microcephaly and spasticity, progressive inflammatory cutaneous lesions, recurrent arthritis, hepato- atrophy of the cerebrum and cerebellum, and variable myosplenomegaly, pancytopenia, and growth failure caused by a clonic or generalized tonic-clonic seizures (Agamy et  al. mutation in the proline-serine-threonine phosphatase-­ 2010). Serum selenium is normal, and thyroid function has interacting protein 1 (PSTPIP1) gene, leading to dysregula- not been investigated in detail (Table 36.14).

Nomenclature No. 36.1

Disorder Wilson disease

36.2

Menkes disease

36.3 36.4

Occipital horn syndrome X-linked distal spinal muscular atrophy MEDNIK syndrome

36.5 36.6

Acetyl-CoA transporter deficiency

36.7

Acrodermatitis enteropathica

36.8

Zinc transporter 2 deficiency

36.9

Spondylocheirodysplastic Ehlers-Danlos syndrome 36.10 Birk-Landau-Perez syndrome

Alternative name Hepatolenticular degeneration Kinky (steely) hair disease X-linked cutis laxa

Abbreviation WND (WD)

Gene symbol ATP7B

Chromosomal localization 13q14.3

Affected protein ATP7B

OMIM No. 277900

MNK (MK)

ATP7A

Xq21.1

ATP7A

309400

OHS SMAX3

ATP7A ATP7A

Xq21.1 Xq21.1

ATP7A ATP7A

304150 300489

Martinelli syndrome

AP1S1

AP1S1

7q22.1

609313

Congenital cataracts, hearing loss, and low serum copper and ceruloplasmin Zinc-deficiency type (AEZ) Transient neonatal zinc deficiency SCD-EDS

CCHLND

SLC33A1

3q25.31

Adaptor-related complex protein 1 SLC33A1

AEZ (AE)

SLC39A4

8q24.3

ZIP4

201100

TNZD

SLC30A2

1p36.11

ZnT2

608118

EDSSPD3

SLC39A13

11p11.2

ZIP13

612350

BILAPES

SLC30A9

4p13

ZnT9

617595

614482

(continued)

612

No. Disorder 36.11 Asymptomatic familial hyperzincemia 36.12 Hyperzincemia and hypercalprotectinemia

36.13 Selenocysteine insertion sequence-binding protein 2 deficiency 36.14 O-phosphoseryl-tRNA(sec) selenium transferase deficiency

D. Martinelli

Alternative name

Abbreviation

PCH2D SelenocysteinyltRNA(sec) synthase deficiency, progressive cerebellocerebral atrophy; Pontocerebellar hypoplasia type 2D

Metabolic Pathways Metabolic Pathway for Copper (see Fig. 36.1) Metabolic Pathway for Zinc Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Zinc is a cofactor for several enzymes, including ornithine transcarbamylase, alkaline phosphatase, carbonic anhydrase, superoxide dismutase, DNA and RNA polymerases, lactate dehydrogenase, and alcohol dehydrogenase. Two groups of proteins involved in zinc transport are involved in cellular zinc homeostasis: the Zip family that mediates zinc transport from outside the cell into the cytoplasm and the ZnT family that mediates export of zinc, either into the extracellular space or into intracellular organelles. The exact role of each of these zinc transport proteins in the various cell types has not been completely elucidated. In humans, there are nine known ZnT transporters and 15 Zip transporters. The ZIP4 defect has been associated with a zinc absorption defect in the enterocytes, leading to Acrodermatitis Enteropathica. ZIP13 is relevant for bone and connective tissue development, and its loss of function is causative for the spondylocheirodysplastic

Gene symbol

Chromosomal localization

PSTPIP1

15q24.3

SECISBP2

9q22.2

SEPSECS

4p15.2

Affected protein

Proline-serinethreonine phosphataseinteracting protein 1 SECIS-binding protein 2;SBP2 O-phosphoseryltRNA(sec) selenium transferase

OMIM No.

609698

613811

form of Ehlers-Danlos syndrome. For the zinc export proteins identified in humans, the ZnT2 defect has been associated with low breast milk concentration, whereas the ZnT9 defect causes a cerebro-renal disease, Birk-Landau-Perez syndrome.

Metabolic Pathway for Selenium Selenium salts are toxic in large amounts, but trace amounts are crucial for cellular function in humans. Selenium is mainly found in foods in its organic form—selenomethionine in plant sources, selenocysteine in animal sources— while the inorganic forms of selenium—selenate and selenite—are mainly found in dietary supplements. More than 80% of the ingested selenium is absorbed through the small intestines. Most biological effects of Se are mediated by selenoproteins, proteins containing the 21st proteinogenic amino acid, selenocysteine (Sec), a cysteine analogue with a selenium-­containing selenol group in place of the sulfurcontaining thiol group. There are 25 human selenoproteins, including five forms of glutathione peroxidase, three forms of thioredoxin reductase, and three deiodinases, those three participating in thyroid hormone metabolism

36  Disorders of Copper, Zinc, and Selenium Metabolism

613

Fig. 36.1  Schematic representation of the key elements of copper homeostasis (adapted from Agamy et al. (2010)). Left panel: Copper is required for numerous processes, including mitochondrial respiration, antioxidant defense, neurotransmitter synthesis, connective tissue formation, and skin pigmentation. Dietary copper from the intestine is taken up by the enterocytes through CTR1 and transported intracellularly to ATP7A, localized in the trans-Golgi network (TGN). This protein will export copper to the portal circulation. When ATP7A is

defective, as in Menkes disease, no copper can leave the enterocyte, resulting in a systemic shortage of copper. Right panel: copper from the portal circulation is taken up through CTR1, transported to ATP7B in the trans-Golgi network (TGN). This protein will export copper to the bile canaliculus. When this pathway is defective, as in Wilson disease, the hepatocytes will gradually accumulate copper, which above a threshold level will induce cellular damage

(Ferreira and Gahl 2017). There is no specific codon for Sec; instead, the UGA codon, usually a stop codon, is made to encode selenocysteine by the presence of a selenocysteine insertion sequence (SECIS), a stem–loop structure present in the 3′-untranslated region of mRNA.  Selenocysteine synthesis occurs on a specialized tRNA, called tRNA[Ser]Sec, but there are no tRNA synthetases specific for Sec, so serine is charged onto

tRNA[Ser]Sec by Seryl-tRNA synthetase first. Ser-­ tRNA[Ser]Sec is then converted into Sec-tRNA[Ser]Sec by selenocysteine synthase (SEPSECS). A specific elongation factor, EF-Sec, directs Sec-tRNA[Ser]Sec to the ribosome, which translates UGA as selenocysteine (Sec) instead of termination. SECIS-binding protein 2 (SECISBP2) is crucial for the interaction with the SECIS element (Agamy et al. 2010).

614

D. Martinelli

Signs and Symptoms Table 36.1  Wilson disease System CNS

Digestive

Eye Hematological

Renal Laboratory findings

Symptoms and biomarkers Ataxia Basal ganglia lesions (MRI) Clumsiness Dysarthria Dystonia Handwriting Irritability Movement, abnormal Neurological symptoms Psychiatric symptoms Speech disturbances Tremor Abdominal pain Ascites Drooling Hepatosplenomegaly Jaundice Liver dysfunction Liver failure, acute Cataract Kayser-Fleischer ring Anemia, hemolytic Coagulopathy Hemolysis Leukopenia Thrombocytopenia Renal tubular acidosis Albumin (serum) ASAT/ALAT (plasma) Bilirubin (plasma) Ceruloplasmin (serum) Copper (liver) Copper (serum) Copper (urine) Prothrombin ratio

Neonatal (birth–1 month)

n n n ↓−n n ↓−n n n

Infancy (1–18 months)

n n n ↓−n n-↑ ↓−n n–↑ n

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) + +

Adulthood (>16 years) ++ ++

± n ± ± ± ± ± n n ± ± ++ ± ++ ++ ++ ++ ± + + + + + + + ↓−n ↑ n–↑ ↓−n ↑ ↓−n n–↑ n–↑

+ + + + + + + ± + + ± ++ + ++ ++ ++ ++ ± + ++ ++ ++ ++ ++ + ↓−n ↑ n–↑ ↓−n ↑ ↓−n ↑ ↑

+ ++ ++ + + ++ ++ ± ++ + ± + + ++ + ++ + ± + + ++ + ++ ++ + ↓−n ↑ n–↑ ↓−n ↑ ↓−n ↑↑ ↑

36  Disorders of Copper, Zinc, and Selenium Metabolism

615

Table 36.2  Menkes disease Symptoms and System biomarkers Autonomic system Hypothermia Cardiovascular Arterial ruptures Tortuous arteries CNS Convulsions Encephalopathy, progressive Intellectual disability Retardation, psychomotor Spasticity Dermatological Cutis laxa Digestive Feeding difficulties Genitourinary Bladder diverticula Hair Hair abnormality Kinky hair Hematological Anemia Neutropenia Musculoskeletal Connective tissue abnormalities Hernias Peculiar facies Ceruloplasmin (serum) Laboratory findings Copper (cerebrospinal fluid) Copper (duodenal) Copper (liver) Copper (serum)

Neonatal (birth–1 month) +

Infancy (1–18 months) + ± ± + ±

Childhood (1.5–11 years) + ± ± + +

±

+ +

+ +

± ± ± ± ± ± ± ±

± + + ± + + ± ± +

+ + + ± + ++ ± ± +

+ ↓ ↓

± + ↓ ↓

± + ↓ ↓

↑ ↓ ↓

↑ ↓ ↓

↑ ↓ ↓

Neonatal (birth–1 month)

Infancy (1–18 months)

± ±

± ± ± ± ± ↓−n ↓−n

±

Adolescence (11–16 years)

Adulthood (>16 years)

Table 36.3  Occipital horn syndrome System Cardiovascular Dermatological Digestive Genitourinary Musculoskeletal Renal Laboratory findings

Symptoms and biomarkers Hypotension, orthostatic Cutis laxa Diarrhea Bladder diverticula Exostosis, occipital horn Urinary infections Ceruloplasmin (serum) Copper (serum)

± n ↓−n ↓−n

Childhood (1.5–11 years) + + + + + + ↓−n ↓−n

Adolescence (11–16 years) + + + + + + ↓−n ↓−n

Adulthood (>16 years) + + + + + + ↓−n ↓−n

Table 36.4  X-linked distal spinal muscular atrophy System Musculoskeletal

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Absent tendon reflexes Muscle weakness, distal Weak tendon reflexes Copper (serum) n

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

n

n

n

Adulthood (>16 years) ± + ± n

616

D. Martinelli

Table 36.5  MEDNIK syndrome System CNS

Dermatological

Digestive

Ear Laboratory findings

Symptoms and biomarkers Cerebral atrophy (MRI) Neuropathy, peripheral Retardation, psychomotor Erythroderma Hyperkeratosis Ichthyosis Intestinal pseudo obstruction Liver dysfunction Deafness ASAT/ALAT (plasma) Bile acids (enzyme assay) (plasma) Ceruloplasmin (serum) Copper (serum) Very-long-chain fatty acids (plasma)

Neonatal (birth–1 month)

±

Infancy (1–18 months) + +

Childhood (1.5–11 years) + + +

Adolescence (11–16 years) + + +

Adulthood (>16 years) + + +

+ +

+ + + +

+ + + +

+ + + +

+ + ↑ ↑

+ + ↑ ↑

+ + ↑ ↑

↓ ↓ ↑

↓ ↓ ↑

↓ ↓ ↑

+ ↑

↑ ↓ ↓ ↑

Table 36.6  Acetyl-CoA transporter deficiency System CNS

Ear Eye Musculoskeletal Laboratory findings

Neonatal (birth–1 month) + + + + + + ↓ ↓

Symptoms and biomarkers Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Hypomyelination (MRI) Hearing loss Cataract Hypotonia, muscular-axial Ceruloplasmin (serum) Copper (serum)

Infancy (1–18 months) ++ ++ ++ ++ + ++ ↓ ↓

Childhood (1.5–11 years) ++ ++ ++ ++ + ++ ↓ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Table 36.7  Acrodermatitis enteropathica System CNS Dermatological Digestive Other Psychiatric Laboratory findings

Symptoms and biomarkers Irritability Alopecia Dermatitis Anorexia Diarrhea Failure to thrive Frequent infections Apathy Depression Alkaline phosphatase (plasma) Zinc (serum) Zinc uptake (duodenal)

Neonatal (birth–1 month) ±

±

Infancy (1–18 months) ++ + ++ ++ ++ + + +

↓–n

↓

Childhood (1.5–11 years) ++ ++ +++ ++ ++ ++ + + ± ↓

↓−n ↓

↓−n ↓

↓−n ↓

± ±

Adolescence (11–16 years) + ++ ++ + + ++ ± ± ± ↓

Adulthood (>16 years) + ++ ++ + + ++ ± ± ± ↓

↓−n ↓

↓−n ↓

36  Disorders of Copper, Zinc, and Selenium Metabolism

617

Table 36.8  Zinc transporter 2 deficiency System Dermatological

Laboratory findings

Symptoms and biomarkers Acrodermatitis enteropathica Alopecia Dermatitis Zinc (serum)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

+ ↓

+ + n

+ + n

Adolescence (11–16 years)

Adulthood (>16 years)

Table 36.9  Spondylocheirodysplastic Ehlers-Danlos syndrome System Cardiovascular Dermatological

Digestive Eye

Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Skin veins, prominent Hyperelastic, loose skin Thin skin Velvety, smooth skin Bifid uvula Blue sclerae Downslanting palpebral fissures Protuberant eyes Delayed tooth eruption Flexion contractures of fingers Growth retardation High palate Hypodontia Joint laxity Malocclusion Muscle atrophy Osteopenia Pes planus Platyspondyly Short metacarpals Short phalanges Short stature Short, wide femoral neck Slender, tapered fingers Small ilia with snail-like appearance Widened metaphyses (elbows and knees) Low birth weight Lysyl hydroxylase activity Lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP) ratio (urine) Prolyl 4-hydroxylase activity

Neonatal (birth–1 month) + + + + + + +

Infancy (1–18 months) + + + + + + +

Childhood (1.5–11 years) + + + + + + +

Adolescence (11–16 years) + + + + + + +

+

+ + + + + + + + + + + + + + + + + +

+

+

+ + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + +

+

+

+

+

n ↑

n ↑

n ↑

n

n

n

+ + + +

+ + + + + +

+

Adulthood (>16 years)

+

618

D. Martinelli

Table 36.10  Birk-Landau-Perez syndrome System Autonomic system CNS

Eye Renal Laboratory findings

Symptoms and biomarkers Hypertension

Neonatal (birth–1 month)

Infancy (1–18 months)

Ataxia Choreoathetosis Dystonia Intellectual disability Loss of speech Ptosis of eyelid Strabismus Tubulointerstitial nephritis Potassium (plasma)

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

+ + + + + + + +

+ + + + + + + +

↑

↑

Adulthood (>16 years)

Table 36.11  Asymptomatic familial hyperzincemia System Other Laboratory findings

Symptoms and biomarkers No clinical symptoms Albumin (serum) Zinc (serum)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

n ↑

n ↑

n ↑

Table 36.12  Hyperzincemia with hypercalprotectinemia System Digestive Hematological Other Laboratory findings

Symptoms and biomarkers Hepatosplenomegaly Anemia Autoinflammation Failure to thrive Frequent infections Calprotectin (serum) Zinc (serum)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

±

±

Adolescence (11–16 years) + + +

Adulthood (>16 years) + + +

+ ↑ ↑

+ ↑ ↑

Table 36.13  Selenocysteine insertion sequence-binding protein 2 deficiency System Musculoskeletal

Laboratory findings

Symptoms and biomarkers Fatty infiltration of muscles Short stature Selenium (serum) Thyrotropin Thyroxine T4 (serum) Triiodothyronin T3 (serum) Triiodothyronine, reverse rT3 (serum)

Neonatal (birth–1 month)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

+ ↓ ↑ ↑ ↓

+ ↓ ↑ ↑ ↓

+ ↓ ↑ ↑ ↓

↑

↑

↑

Adulthood (>16 years)

36  Disorders of Copper, Zinc, and Selenium Metabolism

619

Table 36.14  O-phosphoseryl-tRNA(Sec) selenium transferase deficiency System CNS

Symptoms and biomarkers Ataxia Intellectual disability Microcephaly Seizures

Neonatal (birth–1 month)

Infancy (1–18 months) + + +

Childhood (1.5–11 years) + + + +

Serum zinc

11.9–19.4 μmol/La

Urinary zinc

4.6 ± 2.6 μmol/24 ha

Adolescence (11–16 years) + + +

Adulthood (>16 years)

Reference Values Copper, ceruloplasmin, zinc, and selenium Serum copper 11–22 μmol/La Serum ceruloplasmin 1.5–3.7 μmol/L Urinary copper 1.6

16 years) + + ± + + + ↑ n–↑ ↑ ↑

Table 37.3  Hereditary hemochromatosis (typ 2b) System Cardiovascular Endocrine Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Cardiomyopathy Hypogonadism Ferritin (serum) Glucose (plasma) Iron (liver) Transferrin saturation

Table 37.4  Hereditary hemochromatosis (type 3) System Cardiovascular Dermatological Digestive Endocrine Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy Hyperpigmentation Abdominal pain Liver fibrosis Hypogonadism Arthralgia Ferritin (serum) Glucose (plasma) Iron (liver) Transferrin saturation

Neonatal (birth–1 month)

n n n n

↑ n ↑

± ↑ n ↑ ↑

Table 37.5  Ferroportin 1 deficiency System Cardiovascular Digestive Endocrine Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiopathy Liver fibrosis/ cirrhosis Diabetes Hypogonadism Arthrophaty Ferritin (serum) Transferrin saturation

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

± n n

n n

n n

n n

Adulthood (>16 years) ± + ± ± ± ↑ n–↑

37  Disorders of Iron Metabolism

631

Table 37.6  Ferritin heavy chain dysregulation System Other Laboratory findings

Symptoms and biomarkers Frequently asymptomatic. No clear link with liver damage. Ferritin (serum)

Neonatal Infancy (birth–1 month) (1–18 months) ± ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

n−↑

n−↑

n−↑

n−↑

n−↑

Table 37.7  Ferritin light chain dysregulation System Eye Laboratory findings

Symptoms and biomarkers Cataract Ferritin (serum)

Neonatal (birth–1 month)

Infancy (1–18 months)

n

n

Childhood (1.5–11 years) ± n−↑

Adolescence (11–16 years) + ↑

Adulthood (>16 years) + ↑

Table 37.8  Hereditary ceruloplasmin deficiency System Endocrine Eye Hematological Psychiatric Laboratory findings

Symptoms and biomarkers Diabetes Retinal degeneration Anemia, microcytic Neuropsychiatric symptoms Ceruloplasmin (serum) Ferritin (serum) Transferrin saturation

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ±

Adulthood (>16 years) + + + ±

↓

↓

↓

↓

↓

n−↑ ↓−n

n−↑ ↓−n

n−↑ ↓−n

↑ ↓−n

↑ ↓−n

Table 37.9  Matriptrase 2 deficiency System Hematological Laboratory findings

Symptoms and biomarkers Anemia, microcytic Ferritin (serum) Hepcidin (plasma) Transferrin saturation

Neonatal (birth–1 month) ± ↓ ↑ ↓

Infancy (1–18 months) + ↓ ↑ ↓

Childhood (1.5–11 years) + ↓ ↑ ↓

Adolescence (11–16 years) + ↓ ↑ ↓

Adulthood (>16 years) + ↓ ↑ ↓

Table 37.10 Atransferrinemia System Digestive Hematological Musculoskeletal Other Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Hemosiderosis Anemia, hypochromic Growth retardation Recurrent infections Iron (liver) Transferrin (serum)

Infancy (1–18 months)

Childhood (1.5–11 years) + +

Adolescence (11–16 years) + +

+ +

+ +

↓

↑ ↓

Adulthood (>16 years)

632

M. D. Cappellini

Table 37.11  Transferrin receptor 1 deficiency System Cardiovascular Digestive Endocrine Laboratory findings

Symptoms and biomarkers Cardiomyopathy Liver cirrhosis Diabetes Hypogonadism ASAT/ALAT (plasma) Ferritin (serum)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ±

n-↑

n-↑

↑ ↑

± ↑ ↑

Adulthood (>16 years) ± + + + ↑ ↑

Table 37.12  Divalent metal transporter 1 deficiency System Hematological Musculoskeletal Laboratory findings

Symptoms and biomarkers Anemia, microcytic Growth retardation Ferritin (serum) Iron (liver) Iron (serum) Transferrin saturation

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

± n–↑ ↑ ↑ ↑

+ n–↑ ↑ ↑ ↑

+ n–↑ ↑ ↑ ↑

+ n–↑ ↑ ↑ ↑

± n–↑ ↑ ↑ ↑

Reference and Pathological Values Serum Newborn 3–6 months 6–12 months 2–6 years 6–12 years 12–18 years (w) 12–18 years (m) >18 years (w) >18 years (m) CSF HFE

Hb (g/L) ± 2SD 185 ± 30 115 ± 20 120 ± 15 125 ± 10 135 ± 20 140 ± 20 145 ± 15 140 ± 20 155 ± 20 –

Iron (μmol/L) 6.4–33.0 6.4–33.0 6.4–33.0 6.4–33.0 6.4–33.0 6.4–33.0 6.4–33.0 6.6–26.0 10.6–28.0 0.4 (0.2–0.6) >30

Ferritin (μg/L) 110–503 4–405 4–405 4–405 4–405 9–79 9–59 6–81 30–233 – >300 (up to 5000)

Transferrin (g/L; range) 1.8 (1.42.29) 2.03 (1.58–2.57) – 2.39 (1.86–3.03) 2.17 (1.97–3.19) 2.17 (1.97–3.19) 2.17 (1.97–3.19) 2.0–3.4 – 14.4 mg/L >70

37  Disorders of Iron Metabolism

633

Diagnostic Flowchart Symtoms suggesting haemochromatosis Assessment of transferrin saturation and ferritin levels

Normal or reduced transferrin saturation and ferritin

Increased transferrin saturation and ferritin

Increased transferrin saturation and normal ferritin

White individuals

Non-white individuals

White individuals

Non-white individuals

Genetic testing for C282Y

Yearly assessment of ferritin levels

Genetic testing for C282Y

Iron MRI

Increased Individuals 30 years of age

C282Y homozygosity not detected

Assessment of plasma CP levels

Genetic testing for SLC40A1 mutations

Genetic testing for HJV, HAMP, TF and TFR2 mutations

Type 1

Iron MRI

Strong signal in liver: weak signal in spleen Steady

C282Y homozygosity detected

Normal or decreased transferrin saturation and increased ferritin

Genetic testing for TRF2 or SLC40A1 mutations

Genetic testing for CP mutations

HJV mutations detected

HAMP mutations detected

TF mutations detected

TFR2 mutations detected

SLC40A1 mutations detected

SLC40A1 mutations detected

CP mutations detected

Type 2A

Type 2B

CA

Type 3

Type 4

Ferroportin disease

HA

Nature Reviews | Disease Primers

Brissot, P. et al. (2018) Haemochromatosis (Brissot et al. 2018) Nat. Rev. Dis. Primers. doi: https://doi.org/10.1038/nrdp.2018.16

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In genetic conditions characterized by iron overload, transferrin saturation and ferritin levels are the key parameters to be assessed. However, increased ferritin levels (>300 mcg/L for men and >200 mcg/L for women) need rigorous interpretation before they are assigned to iron overload. Several conditions can be associated with increased ferritin levels independent of substantial iron overload such as metabolic syndrome (which is the most frequent cause), alcoholism, inflammation, and marked cytolysis. Despite these limitations, increased ferritin levels are critical for the diagnosis of hemochromatosis. Any acquired iron overload situation must be excluded (i.e., blood transfusions, dyserythropoiesis, or parenteral iron supplementation) by clinical history; family history could be helpful in some cases. Ethnicity is important considering the fact that HFE-associated hemochromatosis is observed almost exclusively in Caucasians and more frequently in men because the phenotypic expression of hemochromatosis is usually less pronounced in women. Age of onset is also important as HFE-associated (type 1) and TFR2-associated (type 3) hemochromatosis are generally observed in individuals >30  years of age, whereas clinical expression in younger individuals is typical of HJV-related (type 2A) or HAMP-related (type 2B) hemochromatosis. The non-HFE hemochromatosis diseases are very rare, in contrast to HFE-associated hemochromatosis.

Treatment Phlebotomy (weekly) remains the key of treatment for hemochromatosis. The goal of phlebotomy is to reach iron depletion to prevent tissue damage. After achieving such iron balance, maintenance phlebotomy (1–4 yearly) is advisable lifelong. In the most severe cases with decompensated cirrhosis or heart failure (for example, individuals with severe juvenile hemochromatosis) that badly tolerate phlebotomy, adjunctive oral chelation can be used. Phlebotomies are also efficient for treatment of patients with loss-of-function ferroportin disease but should be carried out on a less intensive schedule given the risk of anemia (Kowdley et al. 2019). Although randomized clinical trials are missing, a sufficient body of data has suggested that phlebotomy therapy can improve chronic fatigue and cardiac function, stabilize liver disease, reverse hepatic fibrosis, and reduce skin pigmentation in patients with hemochromatosis (Adams and Barton 2010). The effectiveness of phlebotomy is much better if it starts before the development of severe organ damage such as cirrhosis. An alternative to phlebotomy could be erythrocytapheresis; this procedure could be useful in patients suffering from hypoproteinemia or thrombocytopenia (Rombout-Sestrienkova et al. 2016). A phase I/II clinical trial with Deferasirox in non-cirrhotic HFE hemochromato-

M. D. Cappellini

sis patients has been conducted, showing a dose-dependent ferritin reduction. IRIDA, differently than classical iron deficiency anemia where hepcidin levels are low or even undetectable, has normal or high hepcidin levels, and is resistant to oral iron and only partially responsive to intravenous iron, which still remains the advisable treatment.

Future Treatments Although phlebotomy is inexpensive, safe, and effective in reversing many complications of iron overload, it is not well tolerated by a minority of patients. Moreover, phlebotomy is not feasible in iron-loading anemias because the patients become even more anemic. For these reasons, there is a consensus that novel therapeutic approaches are needed for all iron overload diseases. As hepcidin represents the iron homeostasis controller, the use of hepcidin agonists or antagonists could be beneficial, depending on the specific disorder (Katsarou and Pantopoulos 2018). (a) Hepcidin agonists include compounds that mimic the activity of hepcidin and agents that increase the production of hepcidin by targeting hepcidin-regulatory molecules. The potential of these future drugs includes the improvement in erythropoiesis as shown in thalassemia mouse models and in phase I/II clinical trial. (b) Hepcidin antagonists may be beneficial in IRIDA or in anemias associated with a variety of inflammatory disorders and malignancies, and in chronic renal disease with or without inflammatory etiology.

References Adams PC, Barton JC.  How I treat hemochromatosis. Blood. 2010;116:317–25. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, et al. Iron-overload-­ related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358(3):221–30. Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr. 2017;106:1559S–66S. Andrews NC. Forging a field: the golden age of iron biology. Blood. 2008;112:219–30. Arezes J, Foy N, McHugh K, et al. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 2018;132:1473–7. Beaumont-Epinette MP, Delobel JB, Ropert M, et al. Hereditary hypotransferrinemia can lead to elevated transferrin saturation and when associated to HFE or HAMP mutations to iron overload. Blood Cells Mol Dis. 2015;54:151–4. Brissot P, Pietrangelo A, Adams PC. Hemochromatosis. Nat Rev Dis Primers. 2018; article 18016. Brissot P, Troadec MB, Loréal O, Brissot E. Pathophysiology and classification of iron overload diseases; update 2018. Transfus Clin Biol. 2019;26:80–8. Camaschella C. Iron deficiency. Blood. 2019;133:30–9.

37  Disorders of Iron Metabolism Coffey R, Ganz T. Iron Homestasis: an anthropocentric perspective. J Biol Chem. 2017;292(31):12727–34. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93:1721–41. Ganz T, Nemeth E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol. 2015;15:500–10. Iolascon A, Camaschella C, Pospisilova D, et al. Natural history of recessive inheritance of DMT1 mutations. J Pediatr. 2008;152:136–9. Katsarou A, Pantopoulos K.  Hepcidin therapeutics. Pharmaceuticals. 2018;11:E127. Kawabata H. Transferrin and transferrin receptors update. Free Radic Biol Med. 2019;133:46–54. Kong X, Xie L, Zhu H, et  al. Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review. Orphanet J Rare Dis. 2019;14:171. Kono S.  Aceruloplasminemia: an update. Int Rev Neurobiol. 2013;110:125–51. Kowdley KV, Brown KE, Ahn J, Sundaram V.  ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114:1202–18. Kuwata T, Okada Y, Yamamoto T, et  al. Structure, function, folding and aggregation of a Neuroferritinopathy-related ferritin variant. Biochemistry. 2019;58:2318–25.

635 Muckenthaler MU, Galy B, Hentze MW.  Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197–213. Nemeth E, Tuttle MS, Powelson J, et  al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–3. Papanikolaou G, Pantopoulos K. Systemic iron homeostasis and erythropoiesis. IUBMB Life. 2017;69:399–413. Pietrangelo A. Ferroportin disease: pathogenesis, diagnosis and treatment. Haematologica. 2017;102(12):1972–84. Piperno A, Alessio M.  Aceruloplasminemia: waiting for an efficient therapy. Front Neurosci. 2018;12:903. Rombout-Sestrienkova E, van Kraij MG, Koek GH.  How we manage patients with hereditary hemochromatosis. Br J Haematol. 2016;175:759–70. Silvestri L, Pagani A, Nai A, et al. The serine pro- tease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502–11. Tsantoula F, Kioumi A, Germenis AE, Speletas M. Hereditary hyperferritinemia cataract syndrome as a cause of childhood hyperferritinemia. J Pediatr Hematol Oncol. 2014;36:304.

Disorders of Manganese Metabolism

38

Karin Tuschl, Philippa B. Mills, and Peter T. Clayton

Contents Introduction

 638

Nomenclature

 640

Metabolic Pathways

 641

Signs and Symptoms

 642

Reference Values

 643

Pathological Values

 643

Diagnostic Flowchart

 643

Specimen Collection

 643

Prenatal Diagnosis

 644

DNA Testing

 644

Treatment Summary

 644

Standard Treatment

 644

References

 645

Summary

K. Tuschl (*) Department of Developmental Neurobiology, Kings College, London, UK Department of Cell and Developmental Biology, University College, London, UK UCL GOS Institute of Child Health, University College, London, UK e-mail: [email protected] P. B. Mills · P. T. Clayton UCL GOS Institute of Child Health, University College, London, UK e-mail: [email protected]; [email protected]

Manganese is an essential trace metal that is a constituent of metalloenzymes and is required as an enzyme activator. Blood manganese levels are under tight homeostatic control by the liver as both manganese overload and deficiency impair neuronal function and integrity. To date, three inherited manganese transporter defects have been identified that lead to abnormal blood manganese levels: mutations in SLC30A10 (hypermanganesaemia with dystonia 1, HMNDYT1) and SLC39A14 (hypermanganesaemia with dystonia 2, HMNDYT2) cause manganese overload, while mutations in SLC39A8 (Congenital Disorder of Glycosylation, Type IIn; CDG2N) cause manganese deficiency. SLC39A14 and SLC30A10 are required for hepatic uptake and adequate biliary excretion of manganese, respec-

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_38

637

638

tively. Both these transporter defects are characterised by childhood-onset, progressive Parkinsonism-dystonia due to the accumulation of manganese in the basal ganglia, particularly the globus pallidus, with pathognomonic MRI brain appearances of hyperintensity on T1-weighted images. Whole blood manganese levels are highly raised. In addition to the movement disorder, SLC30A10 loss-of-function causes liver disease, polycythaemia and depletion of iron stores. Intravenous chelation with disodium calcium edetate and iron supplementation effectively lowers the manganese load and can lead to significant improvement in neurological symptoms and halt the progress of liver disease. SLC39A8 is required for manganese uptake into the organism. Loss-of-function leads to a manganese deficiency syndrome characterised by neurodevelopmental delay, seizures, dystonia and short stature. Biochemically, SLC39A8 deficiency causes hypomanganesaemia and a characteristic dysglycosylation pattern corresponding to a type II congenital disorder of glycosylation because manganese acts as a cofactor for the β-1,4-galactosyltransferase. In addition, manganese deficiency leads to respiratory chain abnormalities and Leigh-like mitochondrial disease. Manganese supplementation can improve clinical symptoms and normalise biochemical findings. Manganese dyshomeostasis has also been observed in a juvenile type of Parkinson’s disease associated with supranuclear gaze palsy, spasticity and dementia due to mutations in ATP13A2 (PARK9), also known as Kufor-­ Rakeb Syndrome. ATP13A2 has been shown to transport manganese from the cytosol to the lysosome. In addition, the phenotype can vary from neuronal ceroid lipofuscinosis type 12 (CLN12) to complicated hereditary spastic paraplegia (HSP).

Introduction Manganese is one of the six transition metals essential for human metabolism. It is required as a cofactor for numerous enzymatic reactions including glycosylation and phosphorylation, and is involved in amino acid, lipid and carbohydrate metabolism, immune function, bone and connective tissue growth and blood clotting. As a constituent of metalloenzymes such as the manganese superoxide dismutase, it acts as a scavenger of reactive oxygen species (Chen et al. 2015). Manganese levels are under precise homeostatic control because both excess and deficiency of manganese are deleterious for neuronal function and integrity. Excess manganese accumulates in the basal ganglia and causes a clinical syndrome known as manganism—an extrapyramidal movement

K. Tuschl et al.

disorder characterised by dystonia, bradykinesia and rigidity, accompanied by psychiatric and cognitive defects (Chen et al. 2015). Manganese overload can occur in inherited manganese transporter defects (HMNDYT1 and HMNDYT2 caused by mutations in SLC30A10 and SLC39A14, respectively) or as a result of environmental overexposure, excess manganese in parenteral nutrition or impaired hepatic excretion in patients with liver cirrhosis (Tuschl et al. 2012, 2016; Quadri et  al. 2012). Manganese deficiency, on the other hand, leads to dysglycosylation and impaired mitochondrial function. Due to its ubiquitous presence in the diet, acquired manganese deficiency rarely occurs and, hence, deficiency of manganese is only observed in an inherited manganese transporter defect caused by SLC39A8 mutations (congenital disorder of glycosylation type IIn) (Park et al. 2015a; Boycott et al. 2015; Riley et al. 2017). Tight homeostatic control of intestinal absorption and biliary excretion of manganese maintains stable tissue concentrations of the metal. This requires a group of solute carrier (SLC) transporters localised at the cell membrane. SLC39A8 and SLC39A14 facilitate uptake of manganese into the cell, while SLC30A10 mediates manganese efflux (Leyva-Illades et  al. 2014; Clayton 2017). SLC39A14 appears to be the main transporter allowing for the uptake of manganese into the liver, the primary regulator of manganese homeostasis. Manganese transport also occurs at iron transporters including DMT1, transferrin/transferrin receptor complex and ferroportin, as well as the dopamine (DAT) and citrate transporters (Peres et  al. 2016). Because iron competes with manganese for transport, iron supplementation can reduce manganese levels in disorders associated with excess manganese (Clayton 2017). Within the cell, manganese is transported via a number of transporters including ATP13A1 at the endoplasmic reticulum, SPCA1 at the Golgi, ATP13A2 at the lysosome and Mfrn-1 and DMT1 at the mitochondria (Chen et  al. 2015; Sorensen et  al. 2018; Christenson et al. 2018). Hypermanganesaemia with dystonia 1 (HMNDYT1) caused by biallelic mutations in SLC30A10 was the first inherited manganese transporter defect described. Impaired biliary excretion leads to accumulation of manganese in the liver and brain, resulting in liver disease and generalised dystonia. Manganese deposition in the brain causes characteristic neurodegenerative features including severe neuronal loss in the globus pallidus and a vacuolated myelinopathy. MRI brain appearances are pathognomonic with hyperintensity on T1-weighted images of the globus pallidus and striatum, and the white matter of the cerebrum and cerebellum, midbrain, dorsal pons and medulla, while the ventral pons is typically spared (Fig.  38.1a, b). T2-weighted images show c­orresponding hypointensity of the globus pallidus and striatum (Fig.  38.1c). Activation of erythropoietin

38  Disorders of Manganese Metabolism

a

639

b

c

Fig. 38.1  Characteristic MRI brain appearances due to manganese overload in SLC30A10 (HMNDYT1) and SLC39A14 (HMNDYT2) transporter defects (Tuschl et al. 2016). (a, b) T1-weighted MR imaging shows hyperintensity of the globus pallidus and striatum (blue

arrow), and the white matter in the cerebrum, cerebellum, midbrain, dorsal pons (white arrows) with a pathognomonic sparing of the ventral pons (red star). (c) T2-weighted MR imaging shows corresponding hypointensity of the globus pallidus and striatum (blue arrow)

gene expression due to excess manganese leads to polycythaemia, which often precedes clinical symptoms. Whole blood manganese levels are significantly raised and usually exceed 1000 nmol/L. Another characteristic is a depletion of iron stores with increased total iron-binding capacity and low ferritin values. Some patients develop hypothyroidism, which is consistent with findings in SLC30A10 knockout mice (Hutchens et  al. 2017). Disease onset is usually within the first few years of life with progressive, generalised dystonia; however, cases of adultonset atypical Parkinson’s disease have been described. Some patients have also presented with primary hypotonia or spastic paraplegia (Gospe Jr. et al. 2000; Gulab et al. 2018; Zaki et al. 2018). Manganese chelation with intravenous disodium calcium edetate, in combination with iron supplementation to reduce the uptake of manganese, reduces manganese blood and tissue levels, improves neurological symptoms and halts liver disease progression (Tuschl et al. 2012, 1993; Quadri et al. 2012, 2015). Biallelic mutations in SLC39A14 cause hypermanganesaemia with dystonia 2 (HMNDYT2) due to impaired uptake of manganese into the liver for subsequent biliary excretion. Manganese accumulates in extrahepatic tissues, causing an isolated neurological phenotype of rapidly progressive Parkinsonism-dystonia with onset in infancy or childhood. Whole blood manganese levels are highly raised and MRI brain appearances are identical to that of HMNDYT1 (Fig.  38.1). Hypointensity of the globus pallidus and striatum on T2-weighted images is often pronounced and may be mistaken as the eye of the tiger sign observed in neurodegeneration with brain iron accumulation (NBIA) disorder. Chelation therapy with disodium calcium edetate has been

used with some success; however, clinical response is poor in most patients, most likely due to advanced disease progression and significant degree of neurodegeneration (Tuschl et al. 2016, 1993; Zeglam et al. 2018). Inherited manganese deficiency with low blood manganese levels is caused by biallelic mutations in SLC39A8 and leads to a type II congenital disorder of glycosylation (Type IIn; CDG2N). Dysglycosylation occurs because manganese is a cofactor for the β-1,4-galactosyltransferase, essential for galactosylation of glycan chains. Affected individuals present as early as infancy with neurodevelopmental delay, hypotonia, seizures, dystonia, ataxia, vision and hearing impairment, dysmorphism and short stature/dwarfism (Park et al. 2015a; Boycott et  al. 2015). This disorder may also manifest with Leigh-like mitochondrial disease including features such as raised CSF lactate, respiratory chain abnormalities, bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebellar atrophy (Riley et  al. 2017). Treatment has been attempted with oral manganese sulphate with remarkable clinical and biochemical improvement. Upon manganese supplementation, the glycosylation pattern and blood manganese levels normalised. Clinically, this was associated with cessation of seizures and improvement in hearing, vision and motor abilities (Park et al. 2017). There is evidence that manganese dyshomeostasis also plays a role in individuals with mutations in ATP13A2. ATP13A2 facilitates manganese transport into the lysosome and thereby protects cells from manganese toxicity. Biallelic mutations in ATP13A2 have been reported in three neurodegenerative disorders with parkinsonism as a shared clinical

640

K. Tuschl et al.

feature: (1) Juvenile-onset Parkinson’s disease (PARK9), also known as Kufor-Rakeb-Syndrome, which is ­accompanied by supranuclear gaze palsy, dementia and generalised brain atrophy (Racette et al. 2012). (2) Neuronal ceroid lipofuscinosis (CLN12) with typical accumulation of autofluorescent lipopigment, which presents with learning difficulties, parkinsonism, spinocerebellar ataxia, bulbar syndrome and pyramidal involvement (Bras et al. 2012). (3) Complex hereditary spastic paraplegia (SPG78), which is accompanied by ataxia and neuropathy, parkinsonism and cognitive decline (Estrada-

Cuzcano et  al. 2017). The parkinsonian features tend to respond well to treatment with levodopa; however, dyskinesias develop early. In addition, heterozygous mutations in ATP13A2 pose a genetic risk factor for early-­onset Parkinson’s disease (Park et al. 2015b). Despite the fact that ATP13A2 is involved in manganese transport, blood manganese levels are normal in affected individuals. T2-weighted MR images show iron accumulation in the basal ganglia, and, hence, ATP13A2 mutations are also classified as an NBIA disorder (Schneider et al. 2010) (Fig. 38.2).

Nomenclature

No. Disorder 38.1 Hypermanganesemia with Dystonia 1

Alternative name SLC30A10 deficiency; Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia SLC39A14 deficiency

38.2 Hypermanganesemia with Dystonia 2 SLC39A8 deficiency 38.3 Congenital Disorder of Glycosylation, Type IIn 38.4 Parkinson disease 9 Kufor-Rakeb Syndrome; Neuronal ceroid lipofuscinosis 12; Complex hereditary spastic paraplegia 78

Chromosomal Abbreviation Gene symbol location HMNDYT1 SLC30A10 1q41

Mode of Inheritance AR

Affected protein SLC30A10 (ZNT10)

HMNDYT2

SLC39A14

8p21.3

AR

CDG2N

SLC39A8

4q24

AR

SLC39A14 (ZIP14) SLC39A8 (ZIP8)

PARK9, NCL12, SPG78

ATP13A2

1p36

AR

ATP13A2

OMIM 613280

617013 616721

606693

38  Disorders of Manganese Metabolism

641

Metabolic Pathways a

b

Normal Systemic circulation

HMNDYT1 (SLC30A10) → Hypermanganesaemia

Systemic circulation

IVC SLC39A14

Aorta

→ Mn neurotoxicity

Mn

IVC SLC39A14

→ Liver disease

Aorta

→ Polycythaemia

→ Cirrhosis Liver

Liver

SLC30A10

SLC30A10

Mn

Biliary excretion

SLC39A14

Stomach

Stomach Enterohepatic circulation

Enterohepatic circulation

Small intestine

Portal vein

Small intestine

Portal vein

SLC39A8

SLC39A8

c

d

HMNDYT2 (SLC39A14)

Systemic circulation

Mn IVC

SLC39A14

Mn

Biliary excretion

SLC39A14

→ Hypermanganesaemia

CDG2N (SLC39A8) Systemic circulation

Mn

→ Mn neurotoxicity

→ Hypomanganesaemia → Mn deficiency

IVC SLC39A14

Aorta

Aorta

Liver

Liver

SLC30A10

SLC30A10

Biliary excretion

SLC39A14

Mn

Stomach

Stomach Enterohepatic circulation Portal vein

Small intestine SLC39A8

Fig. 38.2  Our current understanding of how manganese homeostasis (a) is maintained under physiological conditions and (b–d) is impaired in manganese transporter defects (Tuschl et  al. 2016). (a) In healthy individuals, manganese from the diet is taken up in the small intestine via SLC39A8 and enters the liver via SLC39A14. The liver regulates blood manganese levels via biliary excretion through SLC30A10. (b) In SLC30A10 deficiency (HMNDYT1), biliary excretion of manganese is

Mn

Biliary excretion

SLC39A14

Enterohepatic circulation Portal vein

Small intestine SLC39A8

impaired leading to accumulation of manganese in the liver (causing liver cirrhosis and polycythaemia), the blood (hypermanganesaemia) and the brain where it causes neurotoxicity within the globus pallidus resulting in dystonia. (c) In SLC39A14 deficiency (HMNDYT2), manganese uptake into the liver is reduced and manganese accumulates in extrahepatic tissues. (d) In SLC39A8 deficiency (CDG2N), uptake of manganese is impaired resulting in systemic manganese deficiency

642

K. Tuschl et al.

Signs and Symptoms Table 38.1  Hypermanganesemia with dystonia type 1 System CNS

Digestive

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Dysarthria Dystonia Hypotonia Parkinsonism Spasticity T1 hyperintensity brain (MRI) Hepatomegaly Jaundice Liver cirrhosis Ferritin (serum) Hemoglobin (blood) Manganese (blood) Total iron binding capacity (TIBC)

Infancy (1–18 months) ± ± ± ± ± ±

Childhood (1.5–11 years) + + ± + ± +

Adolescence (11–16 years) + + ± + ± +

Adulthood (>16 years) + + ± + ± +

± ± ± ↓ ↑ ↑ ↑

± ± ± ↓ ↑ ↑ ↑

± ± ± ↓ ↑ ↑ ↑

± ± ± ↓ ↑ ↑ ↑

Table 38.2  Hypermanganesemia with dystonia type 2 System CNS

Laboratory findings

Symptoms and biomarkers Dysarthria Dystonia Parkinsonism T1 hyperintensity brain (MRI) Manganese (blood)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± ±

Childhood (1.5–11 years) + + + +

Adolescence (11–16 years) + + + +

Adulthood (>16 years) + + + +

↑

↑

↑

↑

Table 38.3  Congenital disorder of glycosylation type IIn System CNS

Eye Musculoskeletal

Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Hyperreflexia Hypotonia + Intellectual disability Seizures Strabismus Osteopenia Scoliosis Short stature Recurrent infections Manganese (blood) Manganese (urine) Sialotransferrins, type 2 + pattern (serum) Zinc (serum) Zinc (urine)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

± ± + ++ ± + ± ± ± ± ↓↓ n−↑ +

±

↓↓ n−↑ +

± ± + ++ ± + ± ± ± ± ↓↓ n−↑ +

↓ n

↓ n

↓ n

+ ++ ± + ± ±

+ ++ ± + ± ± ±

38  Disorders of Manganese Metabolism

643

Table 38.4  Parkinson disease type 9 System CNS

Metabolic Musculoskeletal Psychiatric

Symptoms and biomarkers Akinesia Cognitive dysfunction Dysarthria Extrapyramidal movement disorder Gait disturbance Movement disorder Myoclonus Neurodegenerative disease EM, storage material Rigidity Behavioral abnormalities

Neonatal (birth–1 month) n n n n

Infancy (1–18 months) n n n n

Childhood (1.5–11 years) n + n n

Adolescence (11–16 years) ++ ++ + +

Adulthood (>16 years) +++ +++ ++ ++

n n n n

n n n n

n n n n

n n

n n

n n

++ + + + +++ ++ +

+++ ++ +++ ++ +++ +++ ++

Reference Values Mn (B) Zn (S) Hb (B)

Diagnostic Flowchart Reference value 73–325 nmol/L 8–20 μmol/L

Prepubertal 0–6 days 7 days 8 days–3 months 3 months–4 years 5–12 years Postpubertal Female Male

HMNDYT1 and HMNDYT2 Childhood-onset, progressive Parkinsonism-dystonia

145–220 g/L 140–186 g/L 95–125 g/L 110–140 g/L 115–140 g/L

• •

131–175 g/L 130–175 g/L 50–90 μmol/L 7–150 μg/L

TIBC (S) Ferritin (S)

• • •

Whole blood Mn ↑ Brain MRI: T1 hyperintensity globus pallidus

Liver function tests ↑ Haemoglobin ↑ Ferritin ↓, TIBC ↑

SLC30A10 mutation analysis (HMNDYT1)

• • •

Liver function tests normal Haemoglobin normal Ferritin, TIBC normal

SLC39A14 mutation analysis (HMNDYT2)

Pathological Values

HMNDYT1 (SLC30A10 deficiency) HMNDYT2 (SLC39A14 deficiency) CDG2N (SLC39A8 deficiency)

Mn (B) ↑

Zn (S) N

Hb (B) ↑

TIBC (S) ↑

Ferritin (S) ↓

↑

N

N

N

N

↓

↓/N

N

N

N

N = normal, ↑ = increased relative to reference range, ↓ = decreased relative to reference range

In any individuals with childhood-onset, progressive Parkinsonism-dystonia, whole blood manganese levels should be determined as well as brain MR imaging obtained. If features of manganese accumulation are identified, the above diagnostic algorithm should be followed.

Specimen Collection Test Precondition Material Handling Pitfalls Mn (B) – Blood Ambient False elevation due to contamination. Secondary causes of hypermanganesaemia due to liver disease, environmental manganese exposure, parenteral nutrition.

644

K. Tuschl et al.

Ideally, blood for metal determination should be collected in trace-metal-free EDTA blood containers. Alternatively, if such containers are unavailable, common EDTA blood containers can be used and an empty blood container analysed in parallel to rule out background contamination of the container.

Prenatal Diagnosis Prenatal diagnosis can be performed by molecular analysis of all four disorders of manganese transport provided the mutation of each biological parent is known. DNA can be isolated from cells directly or by culture after amniocentesis, from chorionic villous samples, from maternal blood, or at the preimplantation stage.

DNA Testing Genetic diagnosis can be made by standard molecular diagnostic procedures including gene sequencing of SLC30A10, SLC39A14, SLC39A8 and ATP13A2, whole exome sequencing, and deletion/duplication analysis using genomic DNA of any source.

cium edetate in combination with iron supplementation to maintain iron parameters (TIBC, ferritin) within the high normal range. Individuals with HMNDYT1 deficiency seem to respond well with improvement of Parkinsonism-dystonia and liver disease, normalization of haemoglobin, reduction in blood manganese levels and manganese accumulation on brain MRI.  However, individuals with HMNDYT2 have a less favourable response, probably due to advanced disease progression and different disease pathogenesis. Chelation treatment can lead to a deficiency of calcium, zinc, copper and selenium, which need frequent monitoring and supplementation as required (Tuschl et al. 2016, 1993).

CDG2N High-dose manganese supplementation in individuals with CDG2N can improve neurological symptoms and normalise glycosylation and blood manganese levels. Therapy requires close monitoring of glycosylation assays and blood manganese to prevent manganese toxicity (Park et  al. 2017). In addition, galactose and uridine supplementation can normalise glycosylation patterns (Park et al. 2015a; Riley et al. 2017).

PARK9

Treatment Summary HMNDYT1 and HMNDYT2 The recommended treatment for disorders of manganese overload including HMNDYT1 and HMNDYT2 is the regular chelation of manganese with intravenous disodium cal-

Initially, the parkinsonian features in individuals with ATP13A2 mutations tend to respond well to the standard treatment of Parkinson’s disease with levodopa. However, early development of dyskinesias and visual hallucinations complicates treatment (Schneider et al. 2010; Di Fonzo et al. 2007).

Standard Treatment Therapy HMNDYT1 Disodium calcium edetate Ferrous sulphate/fumarate HMNDYT2 Disodium calcium edetate Ferrous sulphate/fumarate CDG2N

Manganese sulphate

PARK9

Carbidopa/levodopa (and standard Parkinson’s disease treatment)

iv = intravenous, po = peroral

Application Dose iv 20 mg/kg/dose (max 1 g) twice daily for 5–8 days every 4 weeks po To keep iron parameters within the normal range (TIBC low normal, ferritin high normal) iv 20 mg/kg/dose (max 1 g) twice daily for 5–8 days every 4 weeks po To keep iron parameters within the normal range (TIBC low normal, ferritin high normal) po 15–20 mg/kg to keep blood manganese within the normal range po 150–1000 mg daily in 3–4 divided doses

Duration Lifelong Lifelong Lifelong Lifelong Lifelong Lifelong

38  Disorders of Manganese Metabolism

References

645

Peres TV, Schettinger MR, Chen P, Carvalho F, Avila DS, Bowman AB, et al. Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies. BMC Pharmacol Boycott KM, Beaulieu CL, Kernohan KD, Gebril OH, Mhanni A, Toxicol. 2016;17(1):57. Chudley AE, et  al. Autosomal-recessive intellectual disability Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, with cerebellar atrophy syndrome caused by mutation of the manet  al. Mutations in SLC30A10 cause parkinsonism and dystonia ganese and zinc transporter gene SLC39A8. Am J Hum Genet. with hypermanganesemia, polycythemia, and chronic liver disease. 2015;97(6):886–93. Am J Hum Genet. 2012;90(3):467–77. Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro RJ.  Mutation Quadri M, Kamate M, Sharma S, Olgiati S, Graafland J, Breedveld GJ, of the parkinsonism gene ATP13A2 causes neuronal ceroid-­ et  al. Manganese transport disorder: Novel SLC30A10 mutations lipofuscinosis. Hum Mol Genet. 2012;21(12):2646–50. and early phenotypes. Mov Disord. 2015;30(7):996–1001. Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello MM, Racette BA, Aschner M, Guilarte TR, Dydak U, Criswell SR, Zheng Bowman AB, et al. Manganese homeostasis in the nervous system. W.  Pathophysiology of manganese-associated neurotoxicity. J Neurochem. 2015;134(4):601–10. Neurotoxicology. 2012;33(4):881–6. Christenson ET, Gallegos AS, Banerjee A. In vitro reconstitution, funcRiley LG, Cowley MJ, Gayevskiy V, Roscioli T, Thorburn DR, Prelog tional dissection, and mutational analysis of metal ion transport by K, et  al. A SLC39A8 variant causes manganese deficiency, and mitoferrin-1. J Biol Chem. 2018;293(10):3819–28. glycosylation and mitochondrial disorders. J Inherit Metab Dis. Clayton PT.  Inherited disorders of transition metal metabolism: an 2017;40(2):261–9. update. J Inherit Metab Dis. 2017;40(4):519–29. Schneider SA, Paisan-Ruiz C, Quinn NP, Lees AJ, Houlden H, Hardy J, Di Fonzo A, Chien HF, Socal M, Giraudo S, Tassorelli C, Iliceto G, et al. ATP13A2 mutations (PARK9) cause neurodegeneration with et  al. ATP13A2 missense mutations in juvenile parkinsonism and brain iron accumulation. Mov Disord. 2010;25(8):979–84. young onset Parkinson disease. Neurology. 2007;68(19):1557–62. Sorensen DM, Holemans T, van Veen S, Martin S, Arslan T, Haagendahl Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, IW, et al. Parkinson disease related ATP13A2 evolved early in aniHolemans T, et  al. Loss-of-function mutations in the ATP13A2/ mal evolution. uPLoS One. 2018;13(3):e0193228. PARK9 gene cause complicated hereditary spastic paraplegia Tuschl K, Clayton PT, Gospe SM, Mills PB.  Dystonia/parkinsonism, (SPG78). Brain. 2017;140(2):287–305. hypermanganesemia, polycythemia, and chronic liver disease. In: Gospe SM Jr, Caruso RD, Clegg MS, Keen CL, Pimstone NR, Ducore Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens JM, et al. Paraparesis, hypermanganesaemia, and polycythaemia: a K, Amemiya A, editors. SourceGeneReviews®. Seattle, WA: novel presentation of cirrhosis. Arch Dis Child. 2000;83(5):439–42. University of Washington, Seattle; 1993–2019. Gulab S, Kayyali HR, Al-Said Y.  Atypical neurologic phenotype and Tuschl K, Gregory A, Meyer E, Clayton PT, Hayflick SJ, Mills PB, novel SLC30A10 mutation in two brothers with hereditary hyperet  al. SLC39A14 deficiency. In: Adam MP, Ardinger HH, Pagon manganesemia. Neuropediatrics. 2018;49(1):72–5. RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. Hutchens S, Liu C, Jursa T, Shawlot W, Chaffee BK, Yin W, et  al. SourceGeneReviews®. Seattle, WA: University of Washington, Deficiency in the manganese efflux transporter SLC30A10 induces Seattle; 1993–2019. severe hypothyroidism in mice. J Biol Chem. 2017;292(23): Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, et al. 9760–73. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hyperLeyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, manganesemia caused by mutations in SLC30A10, a manganese Swaim CD, et  al. SLC30A10 is a cell surface-localized mantransporter in man. Am J Hum Genet. 2012;90(3):457–66. ganese efflux transporter, and Parkinsonism-causing mutations Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada block its intracellular trafficking and efflux activity. J Neurosci. A, et al. Mutations in SLC39A14 disrupt manganese homeostasis 2014;34(42):14079–95. and cause childhood-onset parkinsonism-dystonia. Nat Commun. Park JH, Hogrebe M, Gruneberg M, DuChesne I, von der Heiden AL, 2016;7:11601. Reunert J, et al. SLC39A8 deficiency: a disorder of manganese transZaki MS, Issa MY, Elbendary HM, El-Karaksy H, Hosny H, Ghobrial port and glycosylation. Am J Hum Genet. 2015a;97(6):894–903. C, et al. Hypermanganesemia with dystonia, polycythemia and cirPark JS, Blair NF, Sue CM. The role of ATP13A2 in Parkinson’s disrhosis in 10 patients: Six novel SLC30A10 mutations and further ease: Clinical phenotypes and molecular mechanisms. Mov Disord. phenotype delineation. Clin Genet. 2018;93(4):905–12. 2015b;30(6):770–9. Zeglam A, Abugrara A, Kabuka M. Autosomal-recessive iron deficiency Park JH, Hogrebe M, Fobker M, Brackmann R, Fiedler B, Reunert anemia, dystonia and hypermanganesemia caused by new variJ, et  al. SLC39A8 deficiency: biochemical correction and ant mutation of the manganese transporter gene SLC39A14. Acta major clinical improvement by manganese therapy. Genet Med. Neurol Belg. 2018; https://doi.org/10.1007/s13760-­018-­1024-­7. 2017;20(2):259–68.

Part IV Disorders of Carbohydrates

Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

39

Terry G. J. Derks, Charlotte M. A. Lubout, Mathias Woidy, and René Santer

Contents Introduction

 650

Nomenclature

 653

Metabolic Pathways

 657

Signs and Symptoms

 660

Diagnosis

 681

Treatment Summary

 687

Novel Treatments

 696

Online Resources

 698

References

 699

Summary

Carbohydrates are an important source of energy in the human organism. Within the body, glucose is the most abundant monosaccharide that can be stored as glycogen, a branched polymer with a protein core (glycogenin), mainly in liver and muscle. Inborn errors of metabolism may affect the uptake, distribution and reabsorption of

T. G. J. Derks · C. M. A. Lubout Section of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands e-mail: [email protected]; [email protected] M. Woidy · R. Santer (*) Department of Paediatrics, University Medical Center Eppendorf, Hamburg, Germany e-mail: [email protected]; [email protected]

monosaccharides in different organs, a process that is meticulously regulated by a system of transporter proteins. Congenital disorders may impair the intestinal digestion of disaccharides and the conversion of monosaccharides (fructose, galactose) into glucose. They can further affect glycogen synthesis, glycogen breakdown (glycogenolysis), glucose metabolism to acetyl-CoA (glycolysis) and de novo synthesis of glucose (gluconeogenesis). Glucose absorption and transport disorders present with a very variable clinical picture depending on which of the organ- and substrate-specific transporters is affected. Likewise, disorders of galactose and fructose metabolism affect different organs due to the accumulation of toxic intermediates. After the introduction of these monosaccharides with the diet, impaired liver function is frequently among the first signs.

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_39

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650

Glycogen storage diseases can be divided into those mainly presenting with hepatic manifestations (hepatomegaly, fasting intolerance, hypoglycaemia) and those with muscular presentations (exertion intolerance, rhabdomyolysis). Some show a combination of these symptoms, cardiomyopathy may be an additional feature and further accompanying signs, for example, haemolytic anaemia, may be observed depending on tissue distribution of the affected protein. Management of most carbohydrate disorders requires symptomatic measures, supportive care and a multidisciplinary approach. In some conditions, dietetic treatment is possible which may have its basis in an exclusion of certain di- or monosaccharides. Outcome, however, is highly variable and mainly depends on the underlying type of disorder. Causal treatment is not available for most diseases and for some patients, organ transplantation (liver, kidney, heart) is an option. Experimental treatments may include enzyme replacement therapy (available, e.g., for lysosomal α-glucosidase deficiency, GSD-IIa) and gene therapy.

Introduction The disorders in this chapter can be divided into disorders of carbohydrate absorption and transmembrane transport, galactose and fructose metabolism, glycolysis, glycogen synthesis, glycogenolysis and gluconeogenesis (Nomenclature Table). Most are inherited according to an autosomal recessive trait. The clinical presentations can be acute or chronic, mild or severe, in some even life threatening. The clinical features are highly variable and can be understood when considering age- and organ-specific pathophysiology. Other groups of metabolic disorders of carbohydrate metabolism are mentioned in Chaps. 40 (pentose phosphate pathway and polyol metabolism), 41 (insulin secretion and signalling) and 61 (oligosaccharidoses and sialic acid disorders).

 isorders of Carbohydrate Absorption D and Transmembrane Transport Dietary carbohydrates (disaccharides, oligo- and polysaccharides, starch) have to be digested to monosaccharides before entering the human organism. Congenital defects at this step include congenital lactase, sucrose-isomaltase and trehalase deficiencies. The cellular uptake and release of glucose and other monosaccharides is a protein-mediated process. Such pro-

T. G. J. Derks et al.

teins are embedded into the cell membrane and can be regarded as hydrophilic pores within the hydrophobic lipid bilayer. Monosaccharide transporters are substrate- and stereospecific. Their action is saturable and, like for an enzymatic reaction, kinetic characteristics can be described by affinity constants. The number of transporter protein molecules determines maximal transport velocity (vmax). Three classes of monosaccharide transporters have been associated with human diseases. The SGLT (sodium-­ dependent glucose transporter) family is characterised by the fact that glucose transport is coupled with sodium transport. Since the driving force for this type of transport is the electrochemical gradient for sodium (produced by the cellular Na+/K+-ATPase system), glucose can be (actively) transported against its own gradient. A second family, the GLUT (glucose transporter) proteins, mediates so-called facilitative diffusion along an existing glucose gradient and, in the past, members of this family have been regarded to function as ‘passive’ transporters. However, GLUT proteins are hormonally and substrate regulated; thus, they play a pivotal role in the regulation of carbohydrate metabolism. As an example, one of the key functions of insulin is the translocation of GLUT4-bearing vesicles to the cell membrane of muscle cells and adipocytes, allowing glucose influx. The genes of the growing number of members of both the SGLT and GLUT families have been identified during recent years. This was a key step in the study of the function of these proteins, of their tissue-specific expression and in the identification of genetic defects. Knowledge of the tissue-­ specific expression of monosaccharide transporter proteins helps define the clinical picture of the different disease entities. Many tissues carry more than one type of transporter and many members of the monosaccharide transporter families are expressed in more than one tissue. Therefore, congenital disorders of different isoforms of monosaccharide transporters may present with a complex clinical picture and may involve different organ systems. Well-characterised disease entities are congenital intestinal glucose-galactose malabsorption (GGM, SGLT1 defect), the glucose transporter-1 deficiency syndrome (GLUT1-D) and the Fanconi-Bickel syndrome (FBS, GLUT2 defect). In contrast, due to the high solubility of glucose, renal glucosuria due to SGLT2 deficiency (SGLT2-D) or due to the rare defect of an SGLT2-­ associated protein in the renal tubular cell membrane (MAP17), is rarely accompanied by specific clinical symptoms and, like some of the amino acid transporter defects, it can be classified as a ‘non-disease’. The diagnosis has, however, a clinical significance as it prevents repeated investigation for diabetes mellitus in these patients. Only recently, an inborn error affecting a member of a third monosaccharide transporter family, the glucose/proton cotransporters (encoded by the SLC45 gene family), has been described. In this condition, glucose supply to neuronal

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

cells is impaired with symptoms of developmental delay, psychiatric features, and epilepsy (Srour et al. 2017).

Disorders of Galactose and Fructose Metabolism There are four known disorders of galactose metabolism affecting the enzymes of the Leloir pathway: galactose mutarotase deficiency (GALM-D), galactokinase deficiency (GALK-D), galactose-1-phosphate uridyltransferase deficiency (galactosaemia, GALT-D), and uridine diphosphate galactose-4-epimerase deficiency (GALE-D). Among these disorders, galactosaemia is the most common and can be the most severe. Several partial defects of transferase deficiency have been reported, of which the best known is the Duarte-2 variant (Berry et al. 2016). Unlike most disorders in this chapter that highly depend on clinical ascertainment/clinical and biochemical pattern recognition, all four disorders of galactose metabolism can be identified by newborn screening programs. These programs are based on enzymatic investigations and detection of increased amounts of galactose and galactose-1-phosphate in dried blood spots. The clinical manifestations of classic galactosaemia occur after galactose is introduced with the diet and the accumulation of metabolic intermediates is responsible for organ damage. Galactitol causes cataract formation, while galactose-1-phosphate (together with phosphate depletion) is a key factor for hepatic, renal tubular and central nervous manifestations. Four disorders affecting fructose metabolism are known: fructokinase deficiency (FK-D), fructose-1-phosphate aldolase deficiency (hereditary fructose intolerance, HFI), fructose-­1,6-bisphosphatase deficiency (FBP-D) and glycerate kinase deficiency (GLYCTK-D). While FK-D is a ­non-­disease, severe symptoms in HFI occur after the ingestion of fructose and are the consequence of accumulation of fructose-­1-phosphate, with secondary effects mainly on liver cell metabolism, phosphate depletion and protein glycosylation. FBP-D is a disorder of gluconeogenesis; symptoms may occur in the fasted state and without fructose ingestion, although fructose may enhance these effects. For GLYCTK-D, which is related to fructose metabolism but also impairs several other metabolic pathways, see Chap. 71.

Disorders of Glycolysis Defects in the glycolysis pathway may present as muscle glycogen storage disorders, while others result in haemolysis as they affect erythrocyte metabolism (Bianchi et al. 2019, Tarnopolsky 2018). Some present with both muscle symptoms and haemolysis or give rise to mostly neurological symptoms (Fermo et al. 2019). Genetic variants in HK1, the

651

gene coding for hexokinase 1, can present as four distinct clinical pictures: haemolytic anaemia due to loss of hexokinase enzymatic activity on one side, and hereditary motor and sensory neuropathy (Russe type, HMSNR), retinitis pigmentosa type 79 (RP79), and a recently described neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) on the other  (Jamwal  et  al. 2019, Okur et  al. 2019).

 isorders of Glycogen Synthesis D and Glycogenolysis Glycogen storage disorders (GSDs) result from enzymatic blocks or impaired transporter function in the pathway of glycogen degradation (glycogenolysis) but defects of glycogen synthesis in liver and muscle have also been termed ‘glycogenoses’ (GSD-0, GSD-IV). Simply speaking, glycogen storage disorders with cytosolic glycogen accumulation may present as a disease of liver only (GSD-I, GSD-III, GSD-VI and GSD-IX), of liver and kidney (FBS, GSD-I), with liver involvement and (cardio)myopathy (GSD-III, GSD-IX) and myopathy without liver involvement (GSD-V, GSD-VII, rare muscular types (Tarnopolsky 2018)). Lysosomal storage of glycogen results in a multisystem disorder generally presenting with cardiac and/or muscular problems (GSD-II). GSD-I, GSD-III, GSD-VI and GSD-IX are similar in physical appearance and are usually detected during infancy or childhood because of fasting intolerance, failure to thrive and marked hepatomegaly (and, generally, without splenomegaly or cholestasis) (Fig. 39.1). Hypoglycaemia is another leading sign in hepatic GSDs, which is most severe in GSD-I where both glycogenolysis and gluconeogenesis are affected. Muscle is unable to produce glucose for systemic use, because glucose-6-phosphatase activity is absent. Classical muscle GSDs involve skeletal muscle and present with muscle weakness, exertion intolerance and/or myoglobinuria, but are usually not diagnosed before late childhood and adolescence. Rare muscle GSDs with defects in the glycolysis pathway of muscle may, however, present with a more complex clinical picture. Disorders in which detection of polyglucosan bodies is a hallmark are related to GSDs. Examples are muscle glycogenin-­1 deficiency, Laforin deficiency and Malin deficiency. Polyglucosan bodies can be found in many tissues but are typically found in muscle or brain. The presence of such insoluble aggregates of abnormally branched glycogen with increased phosphorylation and (in brain) ubiquitination is associated with impaired autophagy. Since such cases with unstable glycogen are rare, the clinical and biochemical phenotypes of the disorders are incompletely defined (Sullivan et al. 2017). Finally, glycogenolysis is impaired in a congenital disorder of glycosylation, phosphoglucomutase-1 deficiency,

652

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which is discussed in more detail elsewhere in this book (see Chaps. 58 and 66).

Disorders of Gluconeogenesis Glucose can be formed from non-hexose precursors such as lactate, pyruvate, glycerol and amino acids, a metabolic pathway called gluconeogenesis. Three non-reversible reactions of glycolysis characterise the disorders of gluconeogenesis, which are featured by fasting intolerance with associated recurrent hypoglycaemia and lactic acidosis, with or without ketosis. The mitochondrial matrix enzyme pyruvate carboxylase converts pyruvate to oxaloacetate, a central metabolite involved in gluconeogenesis, the urea cycle, the citric acid cycle, the glyoxylate cycle, amino acid

synthesis and fatty acid synthesis. Hence, central nervous system signs and symptoms are part of the clinical phenotype and hyperammonaemia and severe metabolic acidosis may occur. In phosphoenolpyruvate carboxykinase deficiency, an extremely rare condition which may result from deficiency of a mitochondrial or a cytosolic enzyme, the conversion of oxaloacetate into phosphoenolpyruvate is deficient. Fructose-­1,6-bisphosphatase deficiency causes relatively mild fasting intolerance, severe lactic acidosis and moderate hepatomegaly during metabolic crises. The disorders involved in the conversion of glucose-6-phosphate into glucose affect both glycogenolysis and gluconeogenesis. Defects of the hepatic proteins result in severe fasting intolerance; in patients with glucose-6-phosphatase catalytic subunit-3 deficiency, the neutrophil enzyme, severe congenital neutropenia is found.

Isolated Hepatomegaly (age 4 –18 months)

–

+ Further symptoms and laboratory findings

Disorder of glycogenolysis and gluconeogenesis

Disorder of glycogenolysis

Disorder of glycogenolysis and severe tubulopathy

Disorder of glycogen synthesis (with abnormal glycogen)

(symptomatic) hypoglycaemia with poor fasting tolerance (2– 4 hrs) absence of ketosis hyperventilation due to lactic acidosis (fasted) stable hyperlipidaemia kidneys enlarged on ultrasound

moderate propensity to hypoglycaemia and only after longer fasting periods preprandial hyperlipidaemia fasting ketosis (foetor acetonaemicus, ketostix +–+++)

moderate propensity to hypoglycaemia and only after longer fasting periods fasting ketosis kidneys enlarged on ultrasound plus: glucosuria, aminoaciduria, phosphaturia, proteinuria, polyuria

absence of hypoglycaemia, progressive liver dysfunction cirrhosis

signs of myopathy ?? (CK elevation ??) + –

GSD type I

GSD type III

GSD type VI, IX

Fig. 39.1  Flowchart for clinical differentiation of hepatic glycogen storage disorders

FBS

GSD type IV

39.14

39.13

39.12

39.11

39.10

39.9

Brain glucose Intellectual transporter developmental SLC45A1 disorder with deficiency neuropsychiatric features Glucose transporter 2 Fanconi-Bickel deficiency syndrome Disorders of galactose and fructose metabolism Galactose mutarotase Galactosaemia type 4 deficiency Galactokinase Galactosaemia type 2 deficiency Galactose-1-phosphate Galactosaemia type 1 uridyltransferase deficiency Galactose epimerase Galactosaemia type 3 deficiency Essential fructosuria Fructokinase Ketohexokinase deficiency deficiency

39.8

Neuronal glucose transporter deficiency

Blood-brain barrier glucose transporter 1 deficiency

Glucose transporter-1 deficiency

FK-D

KHK

GALE

GALT

GALT-D

GALE-D

GALK1

GALM

GALK-D

GALM-D

SLC2A2

SLC45A1

IDDNPF

FBS

SLC2A1

PDZK1IP1

SLC5A2

TREH SLC5A1

SI

LCT

Gene Symbol

GLUT1-D

Alternative Disease Alternative Disease Disease Name Name 1 Disease Name 2 Abbreviation Disorders of carbohydrate absorption and transmembrane transport Congenital lactase Congenital alactasia CL-D deficiency Congenital sucraseCSI-D isomaltase deficiency Trehalase deficiency Trehalose intolerance TREH-D Glucose-galactose SGLT1 GGM Intestinal sodiumdeficiency glucose cotransporter malabsorption 1 deficiency SGLT2 SGLT2-D Renal sodium-glucose Familial renal glucosuria type 1 deficiency cotransporter 2 deficiency MAP17 deficiency Familial renal MAP17-D glucosuria type 2

39.7

39.6

39.5

39.3 39.4

39.2

39.1

No

Nomenclature

2p23.3

1p36.11

9p13.3

17q25.1

2p22.1

3q26.2

1p36.23

1p34.2

AR

AR

AR

AR

AR

AR

AR

AD, AR

AR

AD, AR

16p11.2

1p33

AR AR

AR

AR

Mode of Inheritance

11q23.3 22q12.3

3q26.1

2q21.3

Chromosomal Localisation

233100

612119 606824

222900

223000

Disease OMIM

Fructokinase

Galactose-1phosphate uridyltransferase Galactose epimerase

Galactokinase

(continued)

229800

230350

230400

230200

Galactose mutarotase 618881

Glucose transporter-2 227810

607178 Membraneassociated protein (MAP17) Glucose transporter 1 601042; 606777; 612126; 614847; 608885 Solute carrier family 617532 45, member 1

Sodium-glucose cotransporter-2

Trehalase Sodium-glucose cotransporter-1

Sucrase-isomaltase

Lactase

Affected Protein

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism 653

39.31

39.30

39.29

39.28

39.27

39.26

39.25

39.24

39.23

39.22

39.21

39.20

39.19

39.18

39.17

39.16

No 39.15

Lactate dehydrogenase B deficiency

Alternative Disease Alternative Disease Name Name 1 Disease Name 2 Hereditary fructose Fructose-1-phosphate Aldolase B intolerance aldolase deficiency deficiency Disorders of glycolysis Haemolytic anaemia due to hexokinase deficiency Neurodevelopmental disorder with visual defects and brain anomalies Hereditary motor and Charcot-Marie-Tooth disease type 4G sensory neuropathy, Russe type Retinitis pigmentosa type 79 Glucokinase Permanent neonatal deficiency diabetes mellitus; MODY type 2 Familial Glucokinase superactivity hyperinsulinaemic hypoglycaemia type 3 Glucose-6-phosphate Haemolytic anaemia, isomerase deficiency nonspheric, due to GPI deficency Glycogen storage Tarui disease Muscle disease type VII phosphofructokinase deficiency Aldolase A deficiency Glycogen storage disease type XII Triose phosphate Haemolytic anaemia due to isomerase deficiency triosephosphate isomerase deficiency Phosphoglycerate kinase deficiency Glycogen storage DiMauro disease Muscle disease type X phosphoglycerate mutase deficiency Glycogen storage Enolase β deficiency disease type XIII Pyruvate kinase deficiency Lactate dehydrogenase Glycogen storage A deficiency disease type XI GCK

GPI

PFKM

HHF3

G6PI-D

GSD-VII

LDHB-D

LDHA-D

PK-D

LDHB

LDHA

PKLR

ENO3

PGAM2

GSD-X

GSD-XIII

PGK1

TPI1

PGK-D

TPI-D

ALDOA

GCK

MODY2

ALDOA-D

HK1

HK1

HMSNR

RP79

HK1

HK1

HK1-D

NEDVIBA

Gene Symbol ALDOB

Disease Abbreviation HFI

12p12.1

11p15.1

1q22

17p13.2

7p13

Xq21.1

12p13.31

16p11.2

12q13.11

19q13.11

7p13

7p13

10q22.1

10q22.1

10q22.1

10q22.1

Chromosomal Localisation 9q31.1

AD, AR

AR

AR

AR

AR

XLR

AR

AR

AR

AR

AD

AD

AD

AR

AD

AR

Mode of Inheritance AR

613470

602485

606176; 125851

617460

605285

618547

235700

Lactate dehydrogenase subunit M Lactate dehydrogenase subunit H

Pyruvate kinase

Triosephosphate isomerase Phosphoglycerate kinase Muscle phosphoglycerate mutase Enolase β

Aldolase A

614128

612933

266200

612932

261670

300653

615512

611881

Muscle 232800 phosphofructokinase

Glucose phosphate isomerase

Glucokinase

Glucokinase

Hexokinase 1

Hexokinase 1

Hexokinase 1

Hexokinase 1

Affected Protein Disease OMIM Fructose-1-phosphate 229600 aldolase

654 T. G. J. Derks et al.

39.46

39.45

39.44

39.43

39.42

39.41

GSD-0a

Glycogen storage disease type III Glycogen storage disease type Ia Neutropenia, severe, congenital, type 4 von Gierke disease Dursun syndrome

Cori disease

Hers disease

Glycogen storage disease type VI

G6PC G6PC3

G6PC3-D

AGL

PYGL

PYGM

GSD-Ia

GSD-III

GSD-VI

McArdle disease GSD-V

PRKAG2

AMPK-A

PHKB

GSD-IXb

PHKG2

PHKA2

GSD-IXa

GSD-IXc

PHKA1

GSD-IXd

GBE1

GYS2

GYS1

GYG1

GSD-XV

GSD-0b

Gene Symbol LDHD

Disease Abbreviation D-LDH-D

Andersen disease GSD-IV

Polyglucosan body myopathy type 2

Alternative Disease Name 2

Glycogen storage disease type V

Glycogen storage disease type IXc

Hepatic phosphorylase kinase γ2 subunit deficiency Constitutional AMP-activated protein kinase activation Muscle glycogen phosphorylase deficiency Hepatic glycogen phosphorylase deficiency Glycogen debranching enzyme deficiency Glucose-6phosphatase deficiency Glucose-6phosphatase catalytic subunit 3 deficiency

39.40

39.39

39.38

39.37

39.36

39.35

Muscle glycogen Glycogen storage synthase deficiency disease type 0b Hepatic glycogen Glycogen storage synthase deficiency disease type 0a Glycogen branching Glycogen storage enzyme deficiency disease type IV Disorders of glycogenolysis Muscle phosphorylase Glycogen storage disease type IXd kinase α1 subunit deficiency Hepatic phosphorylase Glycogen storage disease type IXa kinase α2 subunit deficiency Phosphorylase kinase Glycogen storage β subunit deficiency disease type IXb

Alternative Disease Disease Name Name 1 Hereditary D-lactic D-Lactate aciduria dehydrogenase deficiency Disorders of glycogen synthesis Muscle glycogenin 1 Glycogen storage deficiency disease type XV

39.34

39.33

No 39.32

17q21.31

17q21.31

1p21.2

14q22.1

11q13.1

7q36.1

16p11.2

16q12.1

Xp22.13

Xq13.1

3p12.2

12p12.1

19q13.33

3q24

Chromosomal Localisation 16q23.1

AR

AR

AR

AR

AR

AD

AR

AR

XLR

XLR

AR

AR

AR

AR

Mode of Inheritance AR

613507; 616199

Disease OMIM 245450

232700

232600

261740; 600858; 194200

613027

261750

306000

300559

232500; 263570

(continued)

Amylo-1,6232400 glucosidase Glucose-6232200 phosphatase 612541 Glucose-6phosphatase catalytic subunit 3

Liver glycogen phosphorylase

Muscle phosphorylase kinase α1 subunit Hepatic phosphorylase kinase α2 subunit Hepatic and muscle phosphorylase kinase β subunit Hepatic phosphorylase kinase γ2 subunit AMP-activated protein kinase γ2 subunit Muscle glycogen phosphorylase

Glycogen branching enzyme

Glycogen synthase 2 240600

Glycogen synthase 1 611556

Glycogenin 1

Affected Protein D-lactate dehydrogenase

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism 655

HOIL1 interacting protein deficiency Laforin deficiency

39.49

39.57

39.56

39.55

39.54

39.53

39.52

39.51

Polyglucosan body myopathy type 1

Alternative Disease Name 1 Glycogen storage disease type Ib

Progressive myoclonic epilepsy type 2A Malin deficiency Progressive myoclonic epilepsy type 2B Glycogen storage Lysosomal α-1,4glucosidase deficiency disease type IIa Lysosome-associated Glycogen storage disease type IIb membrane protein 2 deficiency Disorders of gluconeogenesis Pyruvate carboxylase deficiency PEPCK deficiency, Mitochondrial phosphoenolpyruvate mitochondrial carboxykinase deficiency PEPCK deficiency, Cytosolic phosphoenolpyruvate cytosolic carboxykinase deficiency Fructose-1,6bisphosphatase deficiency

HOIL1 deficiency

39.48

39.50

Disease Name Glucose-6-phosphate translocase deficiency

No 39.47

PC PCK2

PCK1

FBP1

mtPCK-D

cPCK-D

FBP-D

LAMP2

PC-D

GSD-IIb

Danon disease

GAA

NHLRC1

EPM2B-D

GSD-IIa

EPM2A

EPM2A-D

Pompe disease

RNF31

RBCK1

Gene Symbol SLC37A4

HOIL1-IP-D

Alternative Disease Disease Name 2 Abbreviation Glycogen storage GSD-Ib disease type I non-a HOIL1-D

9q22.32

20q13.31

14q11-q12

11q13.2

Xq24

17q25.3

6p22.3

6q24.3

14q12

20p13

Chromosomal Localisation 11q23.3

AR

AR

AR

AR

XLD

AR

AR

AR

AR

AR

Mode of Inheritance AR

254780

254780

612487

615895

Fructose-1,6bisphosphatase

229700

261680 Cytosolic phosphoenolpyruvate carboxykinase

261650 Mitochondrial phosphoenolpyruvate carboxykinase

Pyruvate carboxylase 266150

Alpha-1,4232300 glucosidase Lysosome-associated 300257 membrane protein 2

Malin

Linear ubiquitin chain assembly complex Ring finger protein 31 Laforin glucan phosphatase

Affected Protein Disease OMIM Glucose-6-phosphate 232220 translocase

656 T. G. J. Derks et al.

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

Metabolic Pathways

657

Accordingly, disorders of organ-specific glucose transport are systematically depicted in Fig. 39.2, galactose and fructose metabolism are presented in Figs.  39.3 and 39.4, respectively. The major steps in disorders affecting glycogen synthesis and breakdown and defects of glycolysis and gluconeogenesis are presented in Fig. 39.5. The steps of glycogenolysis impaired in the different types of glycogen storage diseases are shown in detail in Fig. 39.6.

Metabolic pathways of carbohydrate metabolism discussed in this chapter are divided into (i) carbohydrate absorption and transmembrane transport in different organs, (ii) the intracellular pathways linking the metabolism of other monosaccharides to glucose metabolism, (iii) glycolysis, glycogen synthesis and glycogenolysis and (iv) gluconeogenesis.

Glia cells Neurons

Glc

GLYCOGEN

Glc

CSF 39.08

Glc

GLYCOGEN

Hepatocytes

Glucose from food

GLUT3

39.07

Glc

Endothelial cells (“Blood Brain Barrier“)

39.09

Muscle cells Adipocytes

GLUT4

Glc 39.05 + 39.06

Glc Enterocytes

BLOOD

39.09

GLYCOGEN

39.04

Glc Glc

39.09

Renal tubulus cells

39.04

b cells

Insulin secretion “active“ transport: SGLT1 SLC5A1 39.04

SGLT2 SLC5A2 39.05

URINE H+-dependent transport:

“passive“ transport: GLUT1 SLC2A1 39.07

39.09

GLUT2 SLC2A2 39.09

GLUT3 SLC2A3

Fig. 39.2  Cellular uptake and release of glucose and transcellular transport mediated by specific transporter proteins. Transport across cell membranes is indicated by arrows. Transporter proteins are depicted by different symbols. Round symbols represent sodium-­ dependent ‘active’ transporters (encoded by genes of the SLC5 family), rectangular symbols stand for facilitative, so-called ‘passive’ transport-

GLUT4 SLC2A4

vesicular transport:

PAST-A SLC45A1 39.08

ers (encoded by genes of the SLC2 family), and the star-shaped symbol represents a member of the novel glucose/proton cotransporters (encoded by genes of the SLC45 family). Known defects are shown by pink bars and the respective number. GLUT3 Glucose transporter-3, GLUT4 Glucose transporter-4, CSF Cerebrospinal fluid

658

T. G. J. Derks et al.

( Lactose )

Lactose

Glycogen

complex carbohydrates

complex carbohydrates 39.01

39.13 UDP-Glc

UDP-Gal 39.04

39.10

39.09

b-D-Gal

39.11 a-D-Gal

b-D-Gal

Gal-1-P 39.12

39.04

Galactitol Galactonate

39.09

Glc

Glc-1-P

Glc Glc-6-P

Enterocytes

Glc

Glc

(Liver) Cell

Fig. 39.3  Metabolic pathway of galactose metabolism

39.04

39.09 Glc

Glc

Glc-1-P

Glc-6-P

Glc

Glc

Frc-6-P ?

?

Frc

Frc-1-P -39.15 Sorbitol * Dehydrogenase Sorbitol

Sorbitol 39.03

39.14 Frc

Glyceraldehyde

39.02

Dihydroxyacetone-P

D-Glycerate ** 3-P-Glycerate

Sucrose Trehalose Isomaltose Dextrin / Starch Enterocytes

39.57 Frc-1,6-P2

Glyceraldehyde-3-P

Pyr

(Liver) Cell

Fig. 39.4  Metabolic pathway of fructose metabolism (* Note added in proof: Biallelic variants in the gene of sorbitol dehydrogenase (asterisk) have only recently been reported as a cause of a

common and potentially treatable hereditary neuropathy; see Cortese et  al. 2020), ** for glycerate kinase deficiency (d-glyceric acidemia, GLYCTK-D) see Chap. 71

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism Fig. 39.5  Principal steps in glycogen synthesis and degradation. Note that the scheme is a summary of pathways in different tissues. Tissue-specific isoforms of enzymes (e.g., in liver and muscle) may result in different disease entities with tissue-related signs and symptoms. eR endoplasmic reticulum, * see Chaps. 58 and 66

39.48 39.49 39.50 39.51

Stabilisation

39.36 39.35 39.34 39.33

Glycogen 39.37 39.38 39.39 39.40 39.42 39.43

UDP-Glc

659

Lysosome

39.53 39.52

Limit Dextrin 39.44 Glc

Glc-1-P Phosphoglucomutase * Glc-6-P

Glc 39.04 39.05 39.07 39.08 39.09

?

39.47

39.22

Glc-6-P 39.45 39.46

Frc-6-P

Glc Glc

Glc

Glc eR

39.23

39.57

Frc-1,6-DiP 39.24 Glyceraldehyde-3-P

1,3-DiP-Glycerate 39.26 Cytosol

3-P-Glycerate 39.27 2-P-Glycerate 39.28 Phosphoenolpyruvate 39.29

39.56

39.30 39.31 L-Lac D-Lac

Pyr 39.55

39.54

39.32 Krebs Cycle

660

T. G. J. Derks et al. subunit a 39.37 (M) 39.38 subunit b 39.39 (L,M) subunit g 39.40 (L) subunit d

(L) Glycogen

Phosphorylase-b-Kinase

Phosphorylase b

Phosphorylase a

39.42 (M) 39.43 (L) Limit dextrin

4-alpha-Glucanotransferase, Amylo-1,6-Glucosidase 39.44 (L,M)

Phosphoglucomutase *

Glucose-6-phosphatase system 39.47 (L, PMNs) 39.45 (L) 39.46 (PMNs)

Glucose

Fig. 39.6  Metabolic pathway of glycogen degradation. Note that the scheme is a summary of pathways in different tissues. Impairment of tissue-­specific isoforms of enzymes (L, liver; M, muscle,

PMNs, polymorph nuclear cells) results in different disease entities with tissue-related signs and symptoms. *see Chaps. 58 and 66

Signs and Symptoms Table 39.1  Congenital lactase deficiency (see also Wanes et al. 2019) System Digestive Other

Renal Laboratory findings

Symptoms and biomarkers Diarrhea, profuse, osmotica Dehydrationa Failure to thrivea Hypovolaemic shocka Urolithiasisa Isomaltase activity (intestinal mucosa) Lactase activity in intestinal biopsy Maltase activity (intestinal mucosa) pHa Reducing sugars (stool)a Sodium (plasma)a Sucrase activity (intestinal mucosa)

Neonatal (birth–1 month) +++

Infancy (1–18 months) +++

Childhood (1.5–11 years) ++

Adolescence (11–16 years) ++

Adulthood (>16 years) ++

+++ ± ± ± n

+++ ± ± ± n

++ ± ± ± n

++ ± ± ±

++ ± ± ±

↓ - ↓↓↓

↓ - ↓↓↓

↓ - ↓↓↓

↓ - ↓↓↓

↓ - ↓↓↓

n

n

n

n - ↓↓↓ ↑

n - ↓↓↓ ↑

n-↓ ↑

n-↓ ↑

n-↓ ↑

n - ↑↑↑ n

n - ↑↑↑ n

n - ↑↑↑ n

n - ↑↑↑

n - ↑↑↑

Disease features occur on a lactose-containing diet

a

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

661

Table 39.2  Congenital sucrase-isomaltase deficiency System Digestive

Other Renal Laboratory findings

Symptoms and biomarkers Dehydrationa Diarrhea, profuse, osmotica Diarrheaa,b Failure to thrivea,b Malabsorptiona,b Urolithiasisa pHa,b Reducing sugars (stool) Sodium (plasma)a,b Sucrase-Isomaltase activity in intestinal biopsy

Neonatal (birth–1 month) n n n n n n n n n ↓ - ↓↓↓

Infancy (1–18 months) ± ± ± ± ± ± n-↓ n n-↓ ↓ - ↓↓↓

Childhood (1.5–11 years) ± ± ± ± ± ± n-↓ n n-↓ ↓ - ↓↓↓

Adolescence (11–16 years) ± ± ± ± ± ± n-↓ n n-↓ ↓ - ↓↓↓

Adulthood (>16 years) ± ± ± ± ± ± n-↓ n n-↓ ↓ - ↓↓↓

Disease features occur on a sucrose-containing diet Disease features occur on a oligosaccharide/starch-containing diet

a

b

Table 39.3  Trehalase deficiency System Digestive

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Abdominal paina Diarrheaa Rectal flatulencea Reducing sugars (stool)a Treahalase activity in ↓ - ↓↓↓ intestinal biopsy

Infancy (1–18 months)

Childhood (1.5–11 years)

↓ - ↓↓↓

↓ - ↓↓↓

Adolescence (11–16 years) + + + n ↓ - ↓↓↓

Adulthood (>16 years) + + + n ↓ - ↓↓↓

Disease features occur on a trehalose-containing diet

a

Table 39.4  Intestinal glucose-galactose malabsorption System Digestive Other

Renal Laboratory findings

a

Symptoms and biomarkers Diarrhea, profuse, osmotica Dehydrationa Failure to thrivea Hypovolaemic shocka Urolithiasisa Fructose loading test, p.o. Galactose loading test, p.o. Galactose uptake by enterocytes Glucose (urine) Glucose loading test, p.o. Glucose uptake by enterocytes pHa Reducing sugars (stool)a Sodium (plasma)a

Neonatal (birth–1 month) +++ +++ n ± n n + ↓

Infancy (1–18 months) +++ +++ ± ± ± n + ↓

Childhood (1.5–11 years) ++ ++ ± ± ± n + ↓

Adolescence (11–16 years) ++ ++ ± ± ± n + ↓

Adulthood (>16 years) ++ ++ ± ± ± n + ↓

n-↑ + ↓

n-↑ + ↓

n-↑ + ↓

n-↑ + ↓

n-↑ + ↓

n-↓↓↓ ↑ n-↑↑↑

n-↓↓↓ ↑ n-↑↑↑

n-↓ ↑ n-↑↑↑

n-↓ ↑ n-↑↑↑

n-↓ ↑ n-↑↑↑

Disease features occur on a glucose- nd/or galactose-containing diet

Table 39.5  Renal glucosuria (see also Santer and Calado 2010; Ghezzi et al. 2018) System Laboratory findings

Symptoms and biomarkers Amino acids (urine) Glucose (plasma) Glucose (urine)

Neonatal (birth–1 month) n-↑

Infancy (1–18 months) n-↑

Childhood (1.5–11 years) n-↑

Adolescence (11–16 years) n-↑

Adulthood (>16 years) n-↑

n ↑-↑↑↑

n ↑-↑↑↑

n ↑-↑↑↑

n ↑-↑↑↑

n ↑-↑↑↑

662

T. G. J. Derks et al.

Table 39.6  MAP17 deficiency (see also Coady et al. 2016) System Laboratory findings

Symptoms and biomarkers Glucose (plasma) Glucose (urine)

Neonatal (birth–1 month) n

Infancy (1–18 months) n

Childhood (1.5–11 years) n ↑-↑↑

Adolescence (11–16 years) n

Adulthood (>16 years) n

Table 39.7  Glucose transporter-1 deficiency System CNS

Haematological Laboratory findings

Symptoms and biomarkers Aquired microcephaly Ataxia Developmental delay Dystonia Hypotonia, muscular-axial Intellectual disability Movement disorder, complex, paroxysmal Seizuresa Anaemia, haemolytic, induced by cold exposure Glucose (cerebrospinal fluid) / Glucose (plasma) ratioc Glucose (cerebrospinal fluid)b Glucose uptake (red blood cells) GLUT1 in RBC (Western blot) Lactate (cerebrospinal fluid)

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ± ± ±

Adulthood (>16 years) ± ± ± ± ± ± ±

± ±

± ±

± ±

± ±

↓

↓

↓

↓

↓

↓ ↓

↓ ↓

↓ ↓

↓ ↓

↓ ↓

↓ ↓-n

↓ ↓-n

↓ ↓-n

↓ ↓-n

↓ ↓-n

In classical GLUT1-D seizures often start before age 2 years Do not misinterpret the results of random postictal lumbar punctures that can give false-high blood glucose concentrations and an abnormal ratio c In case of a clinical suspicion perform determination of CSF/plasma glucose ratio in samples drawn after at least 4 h of fasting with sample for blood glucose drawn first. The ratio is less reliable than the absolute glucose in CSF a

b

Table 39.8  Neuronal glucose transporter deficiency (SLC45A1 deficiency) System CNS

Musculoskeletal Psychiatric

Laboratory findings

Symptoms and biomarkers Intellectual disability Seizures Stereotyped hand movements Dysmorphic features Anxiety Autism Behavioral abnormalities Glucose (cerebrospinal fluid) Glucose (plasma)

Neonatal Infancy (birth–1 month) (1–18 months)

Childhood (1.5–11 years) + ±

Adolescence (11–16 years) + +

+ + n n

Adulthood (>16 years) + + ± + + ± + n n

Table 39.9  Glucose transporter 2 deficiency (Fanconi-Bickel syndrome) System Digestive

Eye Musculoskeletal Renal

Symptoms and biomarkers Hepatomegaly Loose stools Malabsorption Cataract Rickets Short stature Hyperfiltration Nephromegaly Renal failure Renal tubulopathy, generalised

Neonatal (birth–1 month) n ± ±

Childhood Adolescence (1.5–11 years) (11–16 years) n - ↑↑↑ n - ↑↑

n

Infancy (1–18 months) n - ↑↑↑ ± ± ± ± ++

n

±

±

±

±

±

± +++

± +++ ± ± ± ±

Adulthood (>16 years) n - ↑↑

+++ ± ± ± ±

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

663

Table 39.9 (continued) System Laboratory findings

Symptoms and biomarkers Alkaline Phosphatase (plasma) Amino acids (urine) ASAT/ALAT (plasma) Calcium (urine) Cholesterol (serum) Enzymes of galactose metabolism Galactitol (urine)a Galactose (blood spot) Galactose (plasma)a Galactose (urine)a Glucose (urine) Glucose, fasted (plasma) Glucose, fed (plasma) Glycogen (liver) Glycogenolytic enzymes (all tissues) Phosphate (plasma) Phosphate (urine) Rrenal tubular acidosis Triglycerides (serum) Uric acid (plasma)

Neonatal (birth–1 month) n-↑ n-↑ n-↑ n-↑ n-↑ n n-↑ ± ± n-↑ ↑-↑↑↑ ↓-n n-↑ n-↑ n n -↓ n-↑ ± n-↑ ↑

Infancy (1–18 months) n-↑ n-↑ n-↑ n-↑ n-↑ n n-↑

Childhood (1.5–11 years) n-↑ n-↑ n-↑ n-↑ n-↑ n n-↑

Adolescence (11–16 years) n-↑ n-↑ n-↑ n-↑ n-↑ n n-↑

Adulthood (>16 years) n-↑ n-↑ n-↑ n-↑ n n-↑

± n-↑ ↑-↑↑↑ ↓-n n - ↑↑ ↑-↑↑↑ n n -↓ n-↑ ± n-↑ ↑

± n-↑ ↑-↑↑↑ ↓-n n - ↑↑ ↑-↑↑↑ n n -↓ n-↑ ± n-↑ ↑

± n-↑ ↑-↑↑↑ ↓-n n - ↑↑ ↑-↑↑ n n -↓ n-↑ ± n-↑ ↑

± n-↑ ↑-↑↑↑ ↓-n n - ↑↑ ↑-↑↑ n n -↓ n-↑ ± n-↑ ↑

On a galactose-containing diet

a

Table 39.10  Galactose mutarotase deficiency (see also Wada et al. 2019) System Eye Laboratory findings

Symptoms and biomarkers Cataracta Galactose (plasma)a Galactose (urine)a Galactose mutarotase activity (lymphocytes) Galactose-1-phosphate (red blood cells)a

Neonatal (birth–1 month) + ↑ ↑ ↓

Infancy (1–18 months) + ↑ ↑ ↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

↑

n-↑

Neonatal (birth–1 month) + + ↑ ↓

Infancy (1–18 months) + + ↑ ↓

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

↑ ↓

↑ ↓

↑ ↓

↓

↓

↓

↓

↓

↑ ↑ n

↑ ↑ n

↑ ↑ n

↑ ↑ n

↑ ↑ n

n

n

n

n

n

+

+

+

+

+

On a galactose-containing diet

a

Table 39.11  Galactokinase deficiency System Eye Other Laboratory findings

Symptoms and biomarkers Cataracta Pseudotumor cerebria Galactitol (urine)a Galactokinase (fibroblasts) Galactokinase (red blood cells)a Galactose (plasma)a Galactose (urine)a Galactose-1-phosphate (red blood cells)a Galactose-1-phosphate uridyltransferase (red blood cells) Reducing substances (urine)a

On a galactose-containing diet

a

664

T. G. J. Derks et al.

Table 39.12  Galactose-1-phosphate uridyltransferase (deficiency Galactosaemia) System CNS Digestive

Endocrine Eye Genitourinary Haematological Other Laboratory findings

Symptoms and biomarkers Brain edema (MRI)a Intellectual disability Anorexiaa Hepatomegalya Liver cirrhosisa Liver failurea Vomitinga Hypergonadotropic hypogonadism, female Cataracta Ovarian failure Anaemia, hemolytica E. coli sepsisa Early deatha Amino acids (urine)a ASAT/ALAT (plasma)a Bilirubin (plasma)a Calcium (urine)a Coagulation factors (plasma) a Galactitol (urine)a Galactose (blood spot) Galactose (plasma)a Galactose (urine)a Galactose-1-phosphate (red blood cells) Galactose-1-phosphate uridyltransferase (red blood cells) Glucose (urine)a Phosphate (urine)a Proteins, total (urine)a Reducing substances (urine)a Sialotransferrins, type 1 pattern (serum)a

Neonatal Infancy Childhood Adolescence (birth–1 month) (1–18 months) (1.5–11 years) (11–16 years) + ± ± + + + + + + + + + + + + + ± ± + + + + + + ↑ ↑ n-↑ n-↑ ↑ ↑ n-↑ n-↑ ↑ ↑ n-↑ n-↑ ↑ ↑ n-↑ n-↑ ↓ ↓ ↓-n ↓-n ↑ ↑ ↑ ↑

Adulthood (>16 years)

+ ± +

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓

↑ ↑ ↑ +

↑ ↑ ↑ + n-↑

n-↑ n-↑ n-↑ + n-↑

n-↑ n-↑ n-↑ + n-↑

n-↑ n-↑ n-↑ + n-↑

±

n-↑ n-↑ n-↑ n-↑ ↓-n ↑

On a galactose-containing diet

a

Table 39.13  Uridine diphosphate galactose-4-epimerase deficiency System Digestive

Eye Other Laboratory findings

Symptoms and biomarkers Anorexiaa Hepatomegalya Liver cirrhosisa Liver failurea Vomitinga Cataracta Early deatha Amino acids (urine)a ASAT/ALAT (plasma)a Bilirubin (plasma)a Calcium (urine)a Coagulation factors (plasma)a Galactose (plasma)a Galactose (urine)a Galactose-1-phosphate (red blood cells)a Glucose (urine)a Phosphate (urine)a Proteins, total (urine)a Reducing substances (urine)a UPD-Gal epimerase (liver) UPD-Gal epimerase (red blood cells)

On a galactose-containing diet

a

Neonatal (birth–1 month) ± ± ± ± ± ± n-↑ n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n-↑ n-↑ n-↑ ± n-↓ ↓

Infancy (1–18 months) ± ± ± ± ± ± ± n-↑ n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n-↑ n-↑ n-↑ ± n-↓ ↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

n-↑ n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n-↑ n-↑ n-↑ ± n-↓ ↓

n-↑ n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n-↑ n-↑ n-↑ ± n-↓ ↓

±

n-↑ n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n-↑ n-↑ n-↑ ± n-↓ ↓

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

665

Table 39.14  Essential fructosuria System Other Laboratory findings

Symptoms and biomarkers No clinical significance Glucose (urine) Ketohexokinase (liver) Reducing substances (urine)a

Neonatal (birth–1 month) + n ↓ +

Infancy (1–18 months) + n ↓ +

Childhood (1.5–11 years) + n ↓ +

Adolescence (11–16 years) + n ↓ +

Adulthood (>16 years) + n ↓ +

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

+ ↑ ↑ ↓ ↓

Childhood (1.5–11 years) + + + ± + ± + + + + ↑ ↑ ↓ ↓

± ± ± ± ± ± + ± n-↑ n-↑ ↓ ↓

± ± ± ± ± ± + ± n-↑ n-↑ ↓-n ↓

↓-n ↑ ↓-n ↓-n n-↑

↓-n ↑ ↓-n ↓-n n-↑

↓-n ↑ ↓-n ↓-n n-↑

↓-n ↑ ↓-n ↓-n n-↑

n-↑ ↑

n-↑ ↑

n-↑ n-↑

n-↑ n-↑

On a fructose-containing diet

a

Table 39.15  Hereditary fructose intolerance System Digestive

Other Renal Laboratory findings

Symptoms and biomarkers Abdominal paina Feeding habits, abnormala Hepatomegalya Liver cirrhosisa Liver failurea Steatorrheaa Vomitinga Failure to thrivea No dental cariesb Renal tubulopathya ASAT/ALAT (plasma)a Bilirubin, conjugated (plasma)a Coagulation factors (plasma)a Fructose-1-phosphate aldolase (liver) Glucose (plasma) Glycerol (urine)a Magnesium (plasma)a Phosphate (plasma)a Sialotransferrins, type 1 pattern (serum)a Triglycerides (serum)a,c Uric acid (plasma)a

Neonatal Infancy (birth–1 month) (1–18 months) + + + + ± + +

↓

On a fructose-containing diet On fructose/sucrose restriction c Pseudo(!)-hypertriglyceridaemia due to glycerol accumulation a

b

Table 39.16  Haemolytic anaemia due to hexokinase 1 deficiency System Digestive Haematological Other

Laboratory findings

Symptoms and biomarkers Jaundice Splenomegaly Anaemia, hemolytic Chronic transfusion dependency Hydrops fetalis Bilirubin (plasma) Fetal haemoglobin (blood) Haemoglobin (blood) Hexokinase activity (red blood cells)a Reticulocytes (blood)

Neonatal (birth–1 month) + ± + ±

Infancy (1–18 months) + ± + ±

Childhood (1.5–11 years) + ± + ±

Adolescence (11–16 years) + ± + ±

Adulthood (>16 years) + ± + ±

± ↑ ↑

↑ ↑

↑ ↑

↑

↑

↓ to ↓↓↓ ↓-n

↓ to ↓↓↓ ↓-n

↓ to ↓↓↓ ↓-n

↓ to ↓↓↓ ↓-n

↓ to ↓↓↓ ↓-n

↑ to ↑↑↑

↑ to ↑↑↑

↑ to ↑↑↑

↑ to ↑↑↑

↑ to ↑↑↑

Enzyme testing might not be reliable after erythrocyte transfusion or when there is reticulocytosis (see also Jamwal et al. 2019)

a

666

T. G. J. Derks et al.

Table 39.17  Neurodevelopmental disorder wih visual defects and brain anomalies, NEDVIBA (see also Okur et al. 2019) System CNS

Digestive Eye

Musculoskeletal Laboratory findings

Symptoms and biomarkers Anomalies of corpus callosum Ataxia Brain anomalies Global developmental delay Hypotonia, axial Movement Disorder Feeding difficulties Optic atrophy Retinitis pigmentosa Visual impairment Dysmorphic features Hexokinase activity (red blood cells) No biochemical markers

Neonatal (birth–1 month) + + + + + + + + + + + n

Infancy (1–18 months) + + + + + + + + + + + n

Childhood (1.5–11 years)

+

+

+

Adolescence (11–16 years)

Adulthood (>16 years)

n

Table 39.18  Hereditary motor and sensory neuropathy, Russe type System CNS

Musculoskeletal

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Abnormal motor and sensory nerve conduction studies Cranial nerve involvement Distal sensory loss with areflexia Foot deformity (pes cavus), hand deformity (clawing), scoliosis Progressive weakness with onset in the distal lower limbs Hexokinase activity (red blood cells) No biochemical markers

Infancy (1–18 months)

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

±

±

±

+

++

+++

+

+

+

±

+

++

+++

n

n

n

n

+

+

+

+

±

Table 39.19  Retinitis pigmentosa type 79 System Eye

Laboratory findings

Symptoms and biomarkers Changes electroretinogram Macular atrophy Nyctalopia Optic disc pallor Pigmentary deposits of the retina Progressive (peripheral) vision loss Retinal vascular attenuation Hexokinase activity (red blood cells) No biochemical markers

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +a

Adolescence (11–16 years) +

Adulthood (>16 years) +

+a +a +a +a

+ + + +

+ + + +

+a

+

+

+a

+

+

n

n

n

+

+

+

A severe presentation in the first decade has been described in a patient with homozygosity for a HK1 variant

a

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

667

Table 39.20  Glucokinase deficiency Symptoms and biomarkers Diabetes mellitus Glucose (plasma) Glucose (urine) Insulin (serum) Ketones (urine)

System Endocrine Laboratory findings

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

↑ ↑ ↓ n

↑ ↑ ↓ n

↑ ↑ ↓ n

Adulthood (>16 years) + ↑ ↑ ↓ n

Adolescence (11–16 years) ± ± + ++ ++ ++

Adulthood (>16 years) ± ± ++ ++ ± ±

↓ ↓ - ↓↓↓ ↑ - ↑↑↑ ↓

↓-↑ ↓↓↓ - ↑↑↑ ↑ - ↑↑↑ ↓-↑

Table 39.21  Glucokinase superactivity System CNS Endocrine Metabolic

Laboratory findings

Symptoms and biomarkers Epilepsy Intellectual disability Diabetes mellitus, type 2 Hyperinsulinism Hypoglycaemia Hypoglycaemia, hypoketotic Free fatty acids (serum)a Glucose (plasma) Insulin (plasma)a Ketones (plasma, urine)a

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ++ ++ ++

++ ++ ++

Childhood (1.5–11 years) ± ± + ++ ++ ++

↓ ↓ - ↓↓↓ ↑ - ↑↑↑ ↓

↓ ↓ - ↓↓↓ ↑ - ↑↑↑ ↓

↓ ↓ - ↓↓↓ ↑ - ↑↑↑ ↓

During hypoglycaemia

a

Table 39.22  Glucose-6-phosphate isomerase deficiency (see also Fermo et al. 2019) System CNS Digestive Haematological

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Intelectual disability/ neurologic symptoms Pigment gallstones Splenomegaly Chronic haemolytic anaemia improving with age Haemolytic crisis Transfusion dependency Muscle weakness Hydrops fetalis Stillbirth Glucosephosphate isomerase activity (red blood cells, leukocytes) Haemoglobin (blood) Mean corpuscular volume (MCV) Osmotic fragility (red blood cells) Oxidative burst (leukocytes) Reticulocytes Unconjugated bilirubin

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ±

± + +

± + +

± + +

± + +

± ±

± ±

± ± ±

± ± ±

± ± ±

± ± ↓

↓

↓

↓

↓

↓-n n-↑

↓ to ↓↓↓ ↑

↓ to ↓↓↓ ↑

↓ to ↓↓↓ ↑

↓ to ↓↓↓ ↑

n

n

n

n

n

↓

↓

↓

↓

↓

n-↑ n-↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

668

T. G. J. Derks et al.

Table 39.23  Glycogen storage disease type VII (Muscle phosphofructokinase deficiency) System Digestive Haematological Musculoskeletal

Laboratory findings

Symptoms and biomarkers Gallstones Jaundice Anaemia, haemolytic Low RBC life span Exertion intolerance Muscle cramps Muscle pain Muscle weakness Second wind phenomenon 2,3-Diphosphoglycerate (red blood cells) Ammonia rise in forearm exercise test (blood) Bilirubin (plasma) Creatine kinase (plasma) Glycogen (muscle) Lactate rise in forearm exercise test (plasma) Myoglobin (urine) Phosphofructokinase (blood cells) Phosphofructokinase (fibroblasts) Phosphofructokinase (muscle) Reticulocytes (blood) Uric acid (plasma)

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years) ± + + + + ++ + ++ + ++ + ++ + − − ↓ ↓

↑

↓ ↓ ↓

Adolescence (11–16 years) + + + + + + + + − ↓

Adulthood (>16 years) + + + + + + + + − ↓

n

n

n

n ↑ ↑

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓

± ↓ ↓ ↓ n ↑

± ↓ ↓ ↓ ↑ ↑

± ↓ ↓ ↓ ↑ ↑

± ↓ ↓ ↓ ↑ ↑

Table 39.24  Glycogen storage disease type XII (Aldolase A deficiency) System CNS Haematological Musculoskeletal

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Intellectual disability Anaemia, haemolytic Dysmorphic features Muscle weakness Rhabdomyolysis Short stature Aldolase A (red blood cells) Bilirubin (plasma) Creatine kinase (plasma) Glycogen (liver) Glycogen (muscle) Reticulocytes (blood)

Infancy (1–18 months) ± + ± ± ± ± ↓

Childhood (1.5–11 years) ± + ± ± ± ± ↓

Adolescence (11–16 years) ± + ± ± ± ± ↓

Adulthood (>16 years) ± + ± ± ± ± ↓

↑ n-↑ n-↑ n-↑ ↑

↑ n-↑ n-↑ n-↑ ↑

↑ n-↑ n-↑ n-↑ ↑

↑ n-↑ n-↑ n-↑ ↑

Table 39.25  Triosephosphate isomerase deficiency System Cardiovascular CNS

Haematological Musculoskeletal Other Laboratory findings

Neonatal Infancy Symptoms and biomarkers (birth–1 month) (1–18 months) Cardiomyopathy ± Dystonia ± Intellectual disability ± Seizures ± Stroke ± Tremor ± Anaemia, haemolytic + Progressive muscle weakness ± Recurrent infections + Dihydroxyacetone phosphate ↑ (red blood cells) Triosephosphate isomerase ↓ ↓ (red blood cells)

Childhood (1.5–11 years) ± ± ± ± ± ± + ± + ↑

Adolescence (11–16 years) ± ± ± ± ± ± + ± + ↑

↓

↓

Adulthood (>16 years)

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

669

Table 39.26  Muscle phosphoglycerate kinase deficiency System CNS Eye Haematological Musculoskeletal

Laboratory findings

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ± ↓-n ± ± ± ± n-↑ n-↑ n-↑ ↓ ↓ n-↑

Symptoms and biomarkers Retardation, motor Seizures Retinal dystrophy Anaemia, haemolytic RBC life span Exertion intolerance Muscle cramps Muscle pain Muscle weakness Bilirubin (plasma) Creatine kinase (plasma) Myoglobin (urine) Phosphoglycerate kinase (blood cells) Phosphoglycerate kinase (muscle) Reticulocytes (blood)

Childhood (1.5–11 years) ± ± ± ± ↓-n ± ± ± ± n-↑ n-↑ n-↑ ↓ ↓ n-↑

Table 39.27  Glycogen storage disease type X (Muscle phosphoglycerate mutase deficiency) Symptoms and Neonatal Infancy Childhood System biomarkers (birth–1 month) (1–18 months) (1.5–11 years) Musculoskeletal Exertion intolerance Muscle cramps Muscle pain Muscle weakness Laboratory Creatine kinase findings (plasma) Glycogen (muscle) Myoglobin (urine) Phosphoglycerate mutase (muscle)

Adolescence (11–16 years) ± ± ± ± ↓-n ± ± ± ± n-↑ n-↑ n-↑ ↓ ↓ n-↑

Adulthood (>16 years) ± ± ± ± ↓-n ± ± ± ± n-↑ n-↑ n-↑ ↓ ↓ n-↑

Adolescence (11–16 years) + + + + ↑

Adulthood (>16 years) + + + + ↑

n-↑ ↑ ↓

n-↑ ↑ ↓

Table 39.28 Enolase β deficiency (GSD XIII) System Musculoskeletal

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Exertion intolerance Muscle cramps Muscle pain Muscle weakness Creatine kinase (plasma) Enolase beta (muscle) Glycogen (muscle)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + + + ↑ ↓ ↑

Table 39.29  Pyruvate kinase deficiency System Cardiovascular Digestive

Haematological

Symptoms and biomarkers Pulmonary hypertension Cholecystitis Cholelithiasis Liver cirrhosis Neonatal jaundice (severe) Neonatal liver failure Splenomegaly Anaemia, haemolytic Haemolytic crisis Post-splenectomy thrombosis Transfusion dependency

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years) ± ± ±

Adulthood (>16 years) ± ± ± +

± ± ± + to +++ ±

± + to +++ ±

±

±

± + to +++ ± ± ±

± + to +++ ± ± ±

± + to +++ ± ± ±

(continued)

670

T. G. J. Derks et al.

Table 39.29 (continued) System Other Laboratory findings

Symptoms and biomarkers Hydrops fetalis Intrauterine growth retardation Bilirubin, unconjugated (plasma) Ferritin Haemoglobin (blood) Mean corpuscular volume (MCV) Osmotic fragility Pyruvate kinase activity (spectrophotometric assay, red blood cell)a Reticulocytes (blood)

Neonatal (birth–1 month) ± ± ↑

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

↓ - ↓↓↓ n-↑ n-↑ +

↑ ↑ - ↑↑↑ ↓ - ↓↓↓ n-↑ n-↑ +

↑ ↑ - ↑↑↑ ↓ - ↓↓↓ n-↑ n-↑ +

↑ ↑ - ↑↑↑ ↓ - ↓↓↓ n-↑ n-↑ +

↑ ↑ - ↑↑↑ ↓ - ↓↓↓ n-↑ n-↑ +

↑

↑

↑

↑

↑

False normal values can be due to reticulocytosis or recent transfusion (Bianchi et al. 2019)

a

Table 39.30  Glycogen storage disease type XI (Lactate dehydrogenase A deficiency) System Dermatological Genitourinary Musculoskeletal

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Skin rasha Uterine muscle stiffness, in pregnancy Exertion intolerance Muscle cramps Muscle pain Muscle weakness Ammonia rise in forearm exercise test (blood) Creatine kinase (plasma) Glycogen (muscle) Lactate (plasma) Lactate dehydrogenase (muscle) Lactate dehydrogenase (red blood cells) Lactate rise in forearm exercise test (plasma) Myoglobin (urine)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ±

Adulthood (>16 years) ± +

+ + + + n

+ + + + n

↑ n-↑ ↑ ↓

↑ n-↑ ↑ ↓

↓

↓

↑

↑

↑

↑

Psoriasis-like lesions

a

Table 39.31  Lactate dehydrogenase B deficiency System Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Myoglobinuria No clinical significance Lactate dehydrogenase, LDH (plasma) Myoglobine (urine)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± + ↓ ↑

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

671

Table 39.32  D-Lactate dehydrogenase deficiency (see also Monroe et al. 2019) System Other Metabolic Laboratory findings

Symptoms and biomarkers Gout No clinical significancea Acidosis Anion gap (plasma) d-2-Hydroxyisocaproic acid (urine) d-2-Hydroxyisovaleric acid (urine) d-Lactate (plasma) d-Lactate (urine)c Lactate dehydrogenase, LDH (plasma) l-Lactate (plasma)b Uric Acid (P) Uric Acid (U)

Neonatal (birth–1 month) + ± ± n-↑

Infancy (1–18 months) ± + ± ± n-↑

Childhood (1.5–11 years) ± + ± ± n-↑

Adolescence (11–16 years) ± + ± ± n-↑

Adulthood (>16 years) + ± ± n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ n-↑ n

n-↑ n-↑ n

n-↑ n-↑ n

n-↑ n-↑ n

n-↑ n-↑ n

n

n n-↑ n-↑

n n-↑ n-↑

n n-↑ n-↑

n

Childhood (1.5–11 years)

Adolescence (11–16 years) +

Adulthood (>16 years) +

+

+

± ± ↓↓

+ + ↓↓

+ + ↓↓

Childhood (1.5–11 years) ± +

Adolescence (11–16 years) ± +

Adulthood (>16 years) ± +

± ± + + ↓↓↓ ↓

± ± + + ↓↓↓ ↓

± ± + + ↓↓↓ ↓

But may be relevant in bacterial overgrowth in short bowel patients Routine lactate (plasma) determinations are specific for l-lactate c Routine lactate (urine) determinations (by GC-MS) detect both l- and d-lactate a

b

Table 39.33  Glycogen storage disease type XV (Muscle glycogenin 1 deficiency) Symptoms and Neonatal Infancy System biomarkers (birth–1 month) (1–18 months) Cardiovascular Cardiomyopathy, hypertrophic Ventricular arrhythmia Musculoskeletal Exertion intolerance ± Muscle weakness ± Laboratory Glycogen (muscle) ↓↓ ↓↓ findings Table 39.34  Glycogen storage disease type 0b (Muscle glycogen synthase deficiency) System Cardiovascular

CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiac arrest, sudden Cardiomyopathy, hypertrophic Syncope Seizures Exertion intolerance Muscle weakness Glycogen (muscle) Glycogen synthase (muscle)

Neonatal (birth–1 month)

↓↓↓ ↓

Infancy (1–18 months)

↓↓↓ ↓

Table 39.35  Glycogen storage disease type 0a (Hepatic glycogen synthase deficiency) System CNS Digestive Metabolic Laboratory findings

Symptoms and biomarkers Seizures Hepatomegaly Hypoglycaemia (fasting) Glucose, fasted (plasma) Glucose, fed (plasma) Glycogen (liver) Glycogen synthase (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fed (plasma)

Neonatal (birth–1 month) ± n ± ↓ n-↑ ↓-n ↓ ↑ ↑ ↑

Infancy (1–18 months) ± n ± ↓ n-↑ ↓-n ↓ ↑ ↑ ↑

Childhood (1.5–11 years) ± n ± ↓ n-↑ ↓-n ↓ ↑ ↑ ↑

Adolescence (11–16 years)

Adulthood (>16 years)

n

n

↓-n n-↑ ↓-n ↓ n-↑ n-↑ n-↑

↓-n n-↑ ↓-n ↓ n-↑ n-↑ n-↑

672

T. G. J. Derks et al.

Table 39.36  Glycogen storage disease type IV (Glycogen branching enzyme deficiency) System Cardiovascular Digestive

Metabolic Musculoskeletal

Other

Laboratory findings

Symptoms and biomarkers Cardiomyopathy Hepatopathy Liver cirrhosis Splenomegaly Fasting intolerance Arthrogryposis multiplexa Hypotonia, muscular-axial Muscle weakness Muscular atrophy Adult polyglucosan body diseasea Early death Failure to thrive ASAT/ALAT (plasma) Bilirubin (plasma) Branching enzyme (fibroblasts) Branching enzyme (liver) Branching enzyme (muscle) Branching enzyme (red blood cells) Branching enzyme (white blood cells) Coagulation factors (plasma) Glycogen (liver) Prothrombin time

Neonatal (birth–1 month) ±

±

Infancy (1–18 months) ± + + + + ± + + +

Childhood (1.5–11 years) ± + + + +

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + +

n-↑ n-↑ ↓

+ + ↑ ↑ ↓

+ + ↑ ↑ ↓

↓ ↓ ↓

↓ ↓ ↓

↓ ↓ ↓

↓

↓

↓

↓-n ↑ n

↓ ↑ ↑

↓ ↑ ↑

↑

Allelic presentations to GSD-IV but rarely found with identical genetic variants

a

Table 39.37  Glycogen storage disease type IXd (Muscle phosphorylase kinase α1 subunit deficiency) (see also Kishnani et al. 2019) System Musculoskeletal

Laboratory findings

Symptoms and biomarkers Exertion intolerance Muscle cramps Muscle pain Muscle weakness Second wind phenomenon Ammonia rise in forearm exercise test (blood) Creatine kinase (plasma) Glycogen (muscle) Lactate rise in forearm exercise test (plasma) Myoglobin (urine) Phosphorylase kinase (muscle) Uric acid (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) +

± ± ± ±

± ± ± ±

+ + + +

n

n

↑

↑

↑ ↓

↑ ↓

n-↑ ↓

n-↑ ↓

↑

↑

↑

↑

↑

↓

↓

↓

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

673

Table 39.38  Glycogen storage disease type IXa (Hepatic phosphorylase kinase α2 subunit deficiency) (see also Kishnani et al. 2019) System Digestive Metabolic Musculoskeletal Other Laboratory findings

Neonatal (birth–1 month) ± ±

Symptoms and biomarkers Hepatomegaly Hypoglycaemia Short stature Adiposity (doll-like facies) ASAT/ALAT (plasma) Biotinidase (plasma) Cholesterol (serum) Glucose, fasted (plasma) Glycogen (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fasted (plasma) Lactate, fasted (urine) Phosphorylase kinase (blood cells) Phosphorylase kinase (liver) Triglyceride (serum) Uric acid (plasma) Uric acid (urine)

n-↑ n-↑ n-↑ ↓-n n-↑↑ ↑ ↑ n n n-↓ ↓ n-↑ n n

Infancy (1–18 months) ± ± ± ± n-↑ n-↑ n-↑ ↓-n ↑↑ ↑ ↑ n n n-↓ ↓ n-↑ n n

Childhood (1.5–11 years) ± ± + + n-↑ n-↑ n-↑ ↓-n ↑↑ ↑ ↑ n n n-↓ ↓ n-↑ n n

Adolescence (11–16 years)

Adulthood (>16 years)

± + + n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n n n-↓ ↓ n-↑ n n

±

n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n n n-↓ ↓ n-↑ n n

Table 39.39  Glycogen storage disease type IXb (Phosphorylase kinase β subunit deficiency) (see also Kishnani et al. 2019) System Digestive Metabolic Musculoskeletal Other Laboratory findings

Neonatal (birth–1 month) ± ±

Symptoms and biomarkers Hepatomegaly Hypoglycaemia Short stature Adiposity (doll-like facies) ASAT/ALAT (plasma) Biotinidase (plasma) Cholesterol (serum) Glucose, fasted (plasma) Glycogen (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fasted (plasma) Lactate, fasted (urine) Phosphorylase kinase (blood cells) Phosphorylase kinase (liver) Triglyceride (serum) Uric acid (plasma) Uric acid (urine)

n-↑ n-↑ n-↑ ↓-n n-↑↑ ↑ ↑ n n ↓ ↓ n-↑ n n

Infancy (1–18 months) ± ± ± ± n-↑ n-↑ n-↑ ↓-n ↑↑ ↑ ↑ n n ↓ ↓ n-↑ n n

Childhood (1.5–11 years) ± ± + + n-↑ n-↑ n-↑ ↓-n ↑↑ ↑ ↑ n n ↓ ↓ n-↑ n n

Adolescence (11–16 years)

Adulthood (>16 years)

± + + n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n n ↓ ↓ n-↑ n n

±

n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n n ↓ ↓ n-↑ n n

Table 39.40  Glycogen storage disease type IXc (Hepatic phosphorylase kinase γ2 subunit deficiency) (see also Kishnani et al. 2019) System Digestive

Metabolic Musculoskeletal Other

Symptoms and biomarkers Hepatomegaly Liver cirrhosis Liver fibrosis Splenomegaly Hypoglycaemia Short stature Adiposity (doll-like facies)

Neonatal (birth–1 month) ±

±

Infancy Childhood (1–18 months) (1.5–11 years) ± ± ± ± ± ± ± ± + ± +

Adolescence (11–16 years)

Adulthood (>16 years)

± ± ± ± + +

± ± ± ±

674

T. G. J. Derks et al.

Table 39.40 (continued) System Laboratory findings

Symptoms and biomarkers ASAT/ALAT (plasma) Biotinidase (plasma) Cholesterol (serum) Glucose, fasted (plasma) Glycogen (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fasted (plasma) Lactate, fasted (urine) Phosphorylase kinase (blood cells) Phosphorylase kinase (liver) Triglyceride (serum) Uric acid (plasma) Uric acid (urine)

Neonatal (birth–1 month) n-↑ n-↑ n-↑ ↓-n n-↑↑ ↑ ↑ n n ↓

Infancy (1–18 months) n-↑ n-↑ n-↑ ↓-n ↑↑ ↑ ↑ n n ↓

Childhood (1.5–11 years) n-↑ n-↑ n-↑ ↓-n ↑↑ ↑ ↑ n n ↓

Adolescence (11–16 years) n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n n ↓

Adulthood (>16 years) n-↑ n-↑ n-↑ ↓-n n-↑ n-↑ n-↑ n n ↓

↓ n-↑ n n

↓ n-↑ n n

↓ n-↑ n n

↓ n-↑ n n

↓ n-↑ n n

Table 39.41  Constitutional AMP-activated protein kinase activation System Cardiovascular

Metabolic Other Laboratory findings

Symptoms and biomarkers Cardiac preexcitation syndrome Cardiomyopathy, hypertrophic Heart block (variable types) Hypoglycaemia Early death Creatine kinase (plasma) Glucose (plasma) Glycogen (heart) Glycogen (muscle) Phosphorylase kinase (heart) Protein kinase, AMP-activated (heart) Protein kinase, AMP-activated (muscle)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+

+

+

+

+

+ + +a n-↑ ↓ ↑↑a n-↑ ↓a ↑↑a

+ + +a n-↑ ↓ ↑↑a n-↑ ↓a ↑↑a

+

+

+

n-↑

n-↑

n-↑

↑ n-↑

↑ n-↑

↑ n-↑

↑

↑

↑

↑↑a

↑↑a

↑

↑

↑

Severe neonatal type (‘fatal congenital heart glycogenosis’)

a

Table 39.42  Glycogen storage disease type V (Muscle glycogen phosphorylase deficiency) System Musculoskeletal

Laboratory findings

Symptoms and Neonatal biomarkers (birth–1 month) Exertion intolerance Muscle cramps Muscle pain Muscle weakness Second wind phenomenon Ammonia rise in forearm exercise test (blood) Creatine kinase (plasma) Glycogen (muscle) Lactate rise in forearm exercise test (plasma) Myoglobin (urine) Phosphorylase (muscle) ↓ Uric acid (plasma)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ± ± n

Adulthood (>16 years) + + + + + n

↑

↑

↑ ↑ ↓

↑ ↑ ↓

↓

↓

n-↑ ↓ ↑

n-↑ ↓ ↑

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

675

Table 39.43  Glycogen storage disease type VI (Hepatic glycogen phosphorylase deficiency) (see also Kishnani et al. 2019) System Digestive Metabolic Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Hepatomegaly Hypoglycaemia Short stature Adiposity (doll-like facies) ASAT/ALAT (plasma) Biotinidase (plasma) Cholesterol (serum) Glucose, fasted (plasma) Glycogen (liver) Glycogen phosphorylase (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fasted (plasma) Lactate, fasted (urine) Triglyceride (serum) Uric acid (plasma) Uric acid (urine)

Neonatal (birth–1 month) ± ±

Childhood (1.5–11 years) ± ± + + n-↑ n-↑ n-↑ ↓-n ↑↑ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

± + + n-↑ n-↑ n-↑ ↓-n n-↑ ↓

±

n-↑ n-↑ n-↑ ↓-n n-↑↑ ↓

Infancy (1–18 months) ± ± ± ± n-↑ n-↑ n-↑ ↓-n ↑↑ ↓

↑ ↑ n n ↑ n n

↑ ↑ n n ↑ n n

↑ ↑ n n ↑ n n

n-↑ n-↑ n n ↑ n n

n-↑ n-↑ n n ↑ n n

n-↑ n-↑ n-↑ ↓-n n-↑ ↓

Table 39.44  Glycogen storage disease type III (Glycogen debranching enzyme deficiency>) (see also Kishnani et al. 2010; Sentner et al. 2016) Neonatal Infancy Childhood Adolescence Adulthood System Symptoms and biomarkers (birth–1 month) (1–18 months) (1.5–11 years) (11–16 years) (>16 years) Cardiovascular Cardiomyopathy + + + + Digestive Biliary cirrhosis ± ± ± Hepatomegaly ± ++ + + Liver adenoma ± Liver carcinoma ± Liver fibrosis ± ± ± Metabolic Hypoglycaemia + + + ± ± Musculoskeletal Exertion intolerance ± ± + Muscle weakness + + ++ Osteopenia + Short stature ± + + + Other Adiposity (doll-like facies) ± + + + Laboratory Amylo-1,6-glucosidase (liver) ↓ ↓ ↓ ↓ ↓ findings Amylo-1,6-glucosidase (white ↓ ↓ ↓ ↓ ↓ blood cells) ASAT/ALAT (plasma) ↑↑ ↑↑ ↑↑ ↑↑ ↑↑ Biotinidase (plasma) n-↑ ↑-↑↑↑ ↑-↑↑↑ ↑-↑↑ n-↑ Cholesterol (serum) ↑ ↑ ↑ ↑ ↑ Creatine kinase (plasma) n-↑ n-↑ n-↑ n-↑ n-↑ Glucose, fasted (plasma) ↓ ↓ ↓ ↓-n ↓-n Glycogen (liver) n-↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑ Ketones, fasted (plasma) ↑↑ ↑↑ ↑↑ ↑↑ ↑↑ Ketones, fasted (urine) ↑↑ ↑↑ ↑↑ ↑↑ ↑↑ Lactate, fasted (plasma) n n n n n Lactate, fasted (urine) n n n n n Triglyceride (serum) ↑ ↑ ↑ ↑ ↑ Uric acid (plasma) n n n n n Uric acid (urine) n n n n n

676

T. G. J. Derks et al.

Table 39.45  Glycogen storage disease type Ia (Glucose-6-phosphatase deficiency) (see also Chen 2001; Rake et al. 2002; Kishnani et al. 2014) System Digestive

Haematological Metabolic Musculoskeletal Other Renal

Respiratory Laboratory findings

Symptoms and biomarkers Diarrhea Hepatomegaly Liver adenoma Liver carcinoma Pancreatitis Bleeding tendency Hypoglycaemia Osteopenia Short stature Adiposity (doll-like facies) Glomerulosclerosis Hyperfiltration Renal enlargement Tachypnea ASAT/ALAT (plasma) Biotinidase (plasma) Cholesterol (serum) Glucose, fasted (plasma) Glucose-6-phosphatase (liver) Glycogen (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fasted (plasma) Lactate, fasted (urine) Triglyceride (serum) Uric acid (plasma) Uric acid (urine)

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ++

Adolescence (11–16 years) ± +

± ± + + + + ± ± +

Adulthood (>16 years) ± + ± ± ± ± + + + + + + +

n-↑ ↑-↑↑ ↑ ↓ ↓ ↑↑↑ ↓ ↓ ↑ ↑ ↑ ↑ ↑

n-↑ n-↑ ↑ ↓ ↓ ↑↑↑ ↓ ↓ ↑ ↑ ↑ ↑ ↑

± + ±

± + ± ± ±

± ± + ± + +

+ + n-↑ n-↑ ↑ ↓ ↓ n-↑↑↑ ↓ ↓ ↑ ↑ ↑ ↑ ↑

+ + n-↑ ↑-↑↑↑ ↑ ↓ ↓ ↑↑↑ ↓ ↓ ↑ ↑ ↑ ↑ ↑

+ + n-↑ ↑-↑↑↑ ↑ ↓ ↓ ↑↑↑ ↓ ↓ ↑ ↑ ↑ ↑ ↑

Table 39.46  Glucose-6-phosphatase catalytic subunit 3 deficiency System Digestive

Haematological

Other Laboratory findings

Symptoms and biomarkers Diarrhea Inflammatory bowel disease Oral ulcerations Anaemia Leukocyte function impaired Neutropenia Failure to thrive Recurrent infections 1,5-Anhydroglucitol-6phosphate (plasma, urine) Neutrophil count Neutrophil function

Neonatal (birth–1 month) ± ± ± ± +

Infancy (1–18 months) ± ± ± ± +

Childhood (1.5–11 years) ± ± ± ± +

Adolescence (11–16 years) ± ± ± ± +

Adulthood (>16 years) ± ± ± ± +

+ ± + ↑-↑↑↑

+ ± + ↑-↑↑↑

+ ± + ↑-↑↑↑

+ ± + ↑-↑↑↑

+ ± + ↑-↑↑↑

↓ ↓

↓ ↓

↓ ↓

↓ ↓

↓ ↓

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

677

Table 39.47  Glycogen storage disease type I non-a (Glucose-6-phosphate translocase deficiency) (see also Visser et al. 2002) System Digestive

Haematological

Metabolic Musculoskeletal Other Renal Respiratory Laboratory findings

Symptoms and biomarkers Diarrhea Hepatomegaly Inflammatory bowel disease Liver adenoma Liver carcinoma Oral ulcerations Pancreatitis Anaemia Bleeding tendency Leukocyte function impaired Neutropenia Hypoglycaemia Osteopenia Short stature Adiposity (doll-like facies) Recurrent infections Glomerulosclerosis Hyperfiltration Tachypnea 1,5-Anhydroglucitol-6phosphate (plasma, urine) ASAT/ALAT (plasma) Biotinidase (plasma) Cholesterol (serum) Glucose, fasted (plasma) Glucose-6-phosphatase (liver, frozen) Glucose-6-phosphatase (liver, unfrozen) Glycogen (liver) Ketones, fasted (plasma) Ketones, fasted (urine) Lactate, fasted (plasma) Lactate, fasted (urine) Neutrophil count Triglyceride (serum) Uric acid (plasma) Uric acid (urine)

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± + + ± ± + +

Childhood (1.5–11 years) ± ++ + ++ ++ +

Adolescence (11–16 years) ± + + + + +

+ ± +

+ ± +

+ ± +

Adulthood (>16 years) ± + + + + + ± + ± +

+

+ + ± ± ± +

+ + ± + + +

+ + ± + + + ± ±

+ + ± + + + + +

+ ↑-↑↑↑

+ ↑-↑↑↑

+ ↑-↑↑↑

↑-↑↑↑

↑-↑↑↑

n-↑ n-↑ ↑ ↓ n

n-↑ ↑-↑↑↑ ↑ ↓ n

n-↑ ↑-↑↑↑ ↑ ↓ n

n-↑ ↑-↑↑ ↑ ↓ n

n-↑ n-↑ ↑ ↓ n

↓

↓

↓

↓

↓

n-↑↑↑ ↓ ↓ ↑ ↑ ↓ ↑ ↑ ↑

↑↑↑ ↓ ↓ ↑ ↑ ↓ ↑ ↑ ↑

↑↑↑ ↓ ↓ ↑ ↑ ↓ ↑ ↑ ↑

↑↑↑ ↓ ↓ ↑ ↑ ↓ ↑ ↑ ↑

↑↑↑ ↓ ↓ ↑ ↑ ↓ ↑ ↑ ↑

Neonatal (birth–1 month) + + ± ± ± ± + + + ± + ± n-↑ ↑ n-↑

Infancy (1–18 months) + + ± ± ± ± + + + ± + ± n-↑ ↑ n-↑

Childhood (1.5–11 years)

± + + + ±

Table 39.48  HOIL1 deficiency System Cardiovascular Dermatological Digestive Eye Haematological Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Amylopectinosis (biopsy) Cardiomyopathy, dilated Rash, eczematous Hepatomegaly Ptosis of eyelid Immunodeficiency Growth retardation Muscle weakness, proximal Myalgia Scoliosis Failure to thrive Recurrent infections ASAT/ALAT (plasma) Creatine kinase (plasma) IgA (serum)

Adolescence (11–16 years)

Adulthood (>16 years)

678

T. G. J. Derks et al.

Table 39.49  HOIL1 interacting protein deficiency System Haematological

Respiratory Laboratory findings

Neonatal Infancy (birth–1 month) (1–18 months)

Symptoms and biomarkers Anaemia Autoinflammation Immunodeficiency Immunodeficiency Lymphadenopathy Lymphangiectasia Respiratory distress Albumin (serum) Amylopectin (liver) IgG (serum) Iron (serum) Potassium (plasma) Vitamin D (plasma)

Childhood (1.5–11 years) + + + + + + + ↓ + ↓ ↓ ↓ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Table 39.50  Laforin deficiency System CNS

Other

Psychiatric

Symptoms and biomarkers Dementia EEG abnormalities Gait disturbances Hallucinations Mental retardation Myoclonic epilepsy, progressive Myoclonus Seizures, tonic-clonic, generalized Seizures, absence Seizures, partial PAS positive polyglucosan inclusions in brain, liver, muscle, heart, skin Rapidly progressive Short survival (16 years) + + + ± + +

± ±

± ±

± ± +

± ±

+ + ±

+ + ±

Table 39.51  Malin deficiency System CNS

Other

Psychiatric

Symptoms and biomarkers Demetia EEG abnormalities Gait disturbances Mental retardation Myoclonic epilepsy, progressive Myoclonus Seizures, tonic-clonic, generalized Seizures, absence Seizures, partial PAS positive polyglucosan inclusions in brain, liver, muscle, heart, skin Rapidly progressive Short survival (16 years) + + + + + ± ± ± ±

+ + ± ±

+ + ± ±

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

679

Table 39.52  Glycogen storage disease type IIa (Lysosomal α-1,4-glucosidase deficiency) (see also Kishnani et al. 2006; van der Ploeg et al. 2017) System Cardiovascular

CNS

Digestive Ear Haematological Musculoskeletal Other Respiratory Laboratory findings

Symptoms and biomarkers Cardiac failure Cardiac preexcitation syndrome Cardiomyopathy, dilated Cardiomyopathy, hypertrophic EEG, abnormal Intellectual disability Neuropathy, peripheral Hepatomegaly Macroglossia Hearing loss, sensorineural Vacuolated lymphocytes Hypotonia, muscular-axial Early death Orthopnea Sleep apnea Alpha-1,4-glucosidase (dried blood spot) Alpha-1,4-glucosidase (fibroblasts) Alpha-1,4-glucosidase (muscle) ASAT/ALAT (plasma) Creatine kinase (plasma) Glucotetrasaccharide (urine) Glycogen (all tissues) Lymphocytes, vacuolated Myocytes, vacuolated

Neonatal (birth–1 month) + +

Infancy (1–18 months) + +

++ ++

++ ++

+

± +

+ + + ± +

+ ++ ±

+ ++ ±

Childhood (1.5–11 years) +

Adolescence (11–16 years)

Adulthood (>16 years)

+ ±

±

±

+

+

+

++

++

++

+ + ↓

+ + ↓

↓

↓

+ + ↓

↓

↓

↓

↓

↓

↓ ↑ ↑ ↑ ↑

↓ ↑ ↑ ↑ ↑ n-↑

↓ ↑ ↑ ↑ n-↑ n-↑ n-↑

↓ ↑ ↑ ↑ n-↑ n-↑ n-↑

↓ ↑ ↑ ↑ n-↑ n-↑ n-↑

Table 39.53  Glycogen storage disease type IIb (Lysosome-associated membrane protein 2 deficiency) System Cardiovascular

CNS Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiac failure Cardiac preexcitation syndrome Cardiomyopathy, dilated Cardiomyopathy, hypertrophic EEG, abnormal Intellectual disability Lens changes Loss of central vision Loss of peripheral retinal pigment Myopia Hypotonia, muscular-axial Muscle cramps Sudden death Alpha-1,4-glucosidase (dried blood spot) Alpha-1,4-glucosidase (fibroblasts) Alpha-1,4-glucosidase (muscle) ASAT/ALAT (plasma) Creatine kinase (plasma) Glycogen (heart) Glycogen (muscle) Lymphocytes, vacuolated Myocytes, vacuolated

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years) ++ + ++ ++ + + + + + + + + n

n

n

Adolescence (11–16 years) ++ + ++ ++ + ++ + + + + + + + n

n n

n n

n n ↑ ↑ ↑ ↑ + +

n n ↑ ↑ ↑ ↑ + +

Adulthood (>16 years) +

+ ++ + + + + + + + n n n ↑ ↑ ↑ ↑ + +

680

T. G. J. Derks et al.

Table 39.54  Pyruvate carboxylase deficiency System CNS

Digestive

Metabolic Renal Laboratory findings

Symptoms and biomarkers Basal ganglia disease Global developmental retardation Hypoglycaemia Impaired myelination Leukodystrophy Muscular hypotonia Seizures Liver dysfunction Liver, fatty Renal tubular acidosis Hepatomegaly pH Acetoacetate/βhydroxybutyrate ratio Alanine (plasma) Ammonia (plasma) Citrullin (plasma) Glucose (plasma) Ketones (blood) Ketones (urine) Lactate (plasma) Lactate: pyruvate ratio Lysine (plasma) Pyruvate carboxylase (fibroblasts)

Neonatal (birth–1 month) + +

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

+ + + + + + + + + ↓ - ↓↓↓ ↑

+ + + + + + + + + ↓ - ↓↓↓ ↑

+ + + + + + + + + ↓ - ↓↓↓ ↑

+ + + + + + + + + ↓ - ↓↓ ↑

+ + + + + + + + + ↓ ↑

↑ ↑ ↑ ↓ ↑ ↑ ↑ - ↑↑↑ ↑ ↑ ↓

↑ ↑ ↑ ↓ ↑ ↑ ↑ - ↑↑↑ ↑ ↑ ↓

↑ n-↑ n-↑ ↓ ↑ ↑ ↑ - ↑↑↑ ↑ n-↑ ↓

↑ n-↑ n-↑ ↓ ↑ ↑ ↑ - ↑↑ ↑ n-↑ ↓

↑ n-↑ n-↑ ↓ ↑ ↑ ↑ ↑ n-↑ ↓

Table 39.55  Mitochondrial phosphoenolpyruvate carboxykinase deficiency Symptoms and Neonatal Infancy System biomarkers (birth–1 month) (1–18 months) Metabolic Hypoglycaemia + Digestive Liver dysfunction + Liver, fatty + Laboratory Glucose (plasma) ↓ findings Lactate (plasma) ↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 39.56  Cytosolic phosphoenolpyruvate carboxykinase deficiency System CNS Dermatological Digestive Eye Metabolic Respiratory

Symptoms and biomarkers Seizures Cyanosis Hepatomegaly Liver failure Optic nerve hypoplasia Hypoglycaemia, fasting Apnea

Neonatal (birth–1 month) ± + +

Infancy (1–18 months) ± + +

+ + ±

+ + ±

Childhood (1.5–11 years) ± + + ± + + ±

Adolescence (11–16 years)

Adulthood (>16 years)

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

681

Table 39.56 (continued) System Laboratory findings

Symptoms and biomarkers ALAT (plasma) Ammonia (blood) Arginine (plasma) Citrulline (plasma) Dicarboxylic acids (urine) Glucose, fasted (plasma) Glutamine (plasma) Ketones (urine)a Lactate (plasma) Lactate (urine)

Neonatal (birth–1 month) ↑ n-↑ ↓-n ↓-n ↑ ↓ n-↑ + ↑ ↑

Infancy (1–18 months) ↑ n-↑ ↓-n ↓-n ↑ ↓ n-↑ + ↑ ↑

Childhood (1.5–11 years) ↑ n-↑ ↓-n ↓-n ↑ ↓ n-↑ + ↑ ↑

Adolescence (11–16 years)

Adulthood (>16 years)

Pronounced during crises

a

Table 39.57  Fructose-1,6-bisphosphatase deficiency System Digestive Respiratory Metabolic Laboratory findings

Symptoms and biomarkers Hepatomegaly Tachypneaa Hypoglycemiaa Alanine (plasma)a Fructose-1,6bisphosphatase (liver) Glucose (plasma)a Glycerol (urine)a Ketones (plasma)a Ketones (urine)a Lactate (plasma)a Phosphate (plasma)a Triglyceride (serum)a,b Uric acid (plasma)a Uric acid (urine)a

Neonatal (birth–1 month) + + + ↑ ↓

Infancy (1–18 months) + + + ↑ ↓

Childhood (1.5–11 years) ± + + ↑ ↓

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ↑ ↓

±

↓ n-↑ ↑ ↑ ↑ ↓-n ↑ n-↑ n-↑

↓ n-↑ ↑ ↑ ↑ ↓-n ↑ n-↑ n-↑

↓ n-↑ ↑ ↑ ↑ ↓-n ↑ n-↑ n-↑

↓-n

↓-n

↑ n n-↑ n n

n n-↑ n n

↓

Disease features occur in the fasted state and can be exaggerated by fructose, sorbitol, or glycerol intake Pseudo(!)hypertriglyceridaemia

a

b

Diagnosis

• Drowsiness, lethargy, double vision, seizures (neuroglycopenia) Like in many other metabolic disorders, clinical hypothesis-­ • Morning anorexia can be a sign of nocturnal counterdriven pattern recognition is traditionally based on informaregulation with mobilisation of ketones that can even tion from history taking, physical examination and additional cause an abnormal, strong, penetrating smell in the (laboratory, imaging) investigations. For several disorders of bedroom. carbohydrate absorption, transmembrane transport and metab- • Muscle pain in the morning may indicate nocturnal counolism, the nutritional history is of utmost importance for cliniterregulatory proteolysis. cal reasoning and the following questions should be addressed: To approach the aetiology of fasting hypoglycaemia, the • Is there intolerance or avoidance of certain carbohydrates following information is helpful: (lactose, fruit, or fruit juice)? • Did symptoms occur with a change in diet? • The relationship between the time when the patient • When do symptoms occur in relation to the patient’s last meal? becomes symptomatic or hypoglycaemic and the last • How does the patient tolerate nocturnal fasting? meal • The presence of hepatomegaly The answers to these questions can lead to a new direction • The lactate concentration during hypoglycaemia of thinking in which the following signs and symptoms can • The ketone concentrations during hypoglycaemia point to fasting intolerance: Special laboratory tests (see Table  below) to come to a • Tremor, perspiration (adrenergic response, effective or diagnosis should be performed in laboratories with specific ineffective counterregulation) expertise. These procedures may include both in vivo clini-

682

T. G. J. Derks et al.

cal (loading or provocation) tests, in vitro functional studies in tissues expressing the affected protein (a transporter or an enzyme), prenatal diagnosis, and molecular genetic analysis of the relevant gene (usually in DNA samples from peripheral blood, but DNA can also be obtained from other sources, such as fibroblasts). Since in vivo and in vitro functional studies are laborious and may be invasive, nowadays a primary molecular genetic approach may be warranted. In that case, a working hypothesis has to be formulated on the basis of clinical and non-­ invasive paraclinical investigations. This is an option, particularly in disorders in which the affected gene is small or when few prevalent mutations are responsible for the cases of a population (see Table ‘Special conditions for enzymatic and/or molecular genetic diagnosis in disorders of carbohydrate metabolism’). Alternatively, genetic testing by (panel) DNA has become preferable to (invasive, laborious) enzymology and has replaced invasive in vivo testing in many situations. However, these traditional approaches may still be warranted when no

definite diagnosis can be made non-invasively, or to confirm the pathogenicity of genetic variants of unknown significance found by panel, whole exome, or whole genome sequencing.

Reference Values and Pathological Values The reference values for metabolites whose concentrations are altered in disorders of carbohydrate metabolism are shown in Table  below. Due to variable assay conditions, results of additional transport or enzymatic tests have to be interpreted in comparison to laboratory-specific reference values and can be presented as a percentage of the average of normal controls. For example, diagnostic values of monosaccharide uptake by enterocytes in SGLT1 deficiency (an autosomal recessive condition) usually fall below 10% of normal; diagnostic values of glucose uptake by erythrocytes in GLUT1 deficiency (an autosomal dominant condition) have been reported to be 46 ± 8% of controls.

Reference and pathological values for metabolites related to carbohydrate metabolism Metabolite Glucose (P)

Fasting

Glucose (CSF)

1 h after ingestion Fasting

Glucose (CSF/P ratio) Glucose (U) Reducing substances (stool) Galactose (P) Fasting After milk ingestion

Age group 1 d >1 d Child Adult Adult Child

Reference values 2.2–3.3 mmol/L 2.8–5.0 mmol/L 3.3–5.5 mmol/L 3.9–5.8 mmol/L 6.6–9.4 mmol/L 1.7–3.7 mmol/L

Child

65–85%xyx

Newborn Child Adult

Galactose-1phosphate (RBC) Galactose (U) Galactitol (U) Fructose (B) Fructose (U) Sorbitol (U) Lactic acid (P) Lactic acid (CSF) Lactic acid (U) Biotinidase (P) Glycogen (L) Glycogen (M)

Fasting

Child Child Child

Pathological values 40–60 mg/dL 50–90 mg/dL 60–100 mg/dL 70–105 mg/dL 120–170 mg/dL 32–68 mg/dL

10.6 mU/mL >5.0 g/100 g wet tissue >1.0 g/100 g wet tissue

n.d. Not detectable Lumbar punction should be performed after 4 h of fasting. For age-dependent cut-off values for CSF glucose and CSF to plasma glucose ratio see Leen et al. (2013)

a

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

Functional In Vivo Tests Functional in vivo (provocation and/or loading) tests can be helpful in certain conditions (Table below) and should only be performed by clinicians with expertise.

Functional tests glucose monitoring (CGM) Indication: Assessment of fasting intolerance, recurrent episodes of hypoglycaemia of unknown origin, determination of metabolic profile during hypoglycaemia, monitoring of the dietary management. Can be performed in hospital or at home. Stable clinical condition. Instruct on documentation of the use of CGM and alarming function. For patients with ketotic fasting intolerance or ketogenic diets, parallel documentation of ketones by a specific device may be helpful. Caution: Correlation between subcutaneous glucose and blood/plasma glucose concentrations may be poor. Thresholds for CGM-alarms and capillary blood glucose/ketone values should be discussed on an individual basis. Interpretation: Requires integration of symptoms and signs, documented diet history (including times), CGM (including the slope of the curves), and capillary blood glucose and ketone concentrations. Fasting test Indication: Assessment of fasting intolerance, recurrent episodes of hypoglycaemia of unknown origin, determination of metabolic profile during hypoglycaemia. Stable clinical condition. Plan maximal fasting time according to anamnestic tolerance. During test measure glucose (P), blood gases, lactate (P), ketones (P, U) every hour starting with the first meal that is missed. Terminate test in case of hypoglycaemia (A in Ashkenazi Jews p.E104D in Caucasians p.W78* in Afro-Americans (?)b p.R486W and p.R479H in Indians p.R510Q in Central Europe ex6 del20bp in Japanese (?)b Non-disease Reported only in two families

p.P1205L in Dutch

p.R302Q (?)b,e p.R531Q (?)b,f p.R50* in Japanese and Caucasians p.G205S in Japanese and Spanish p.L542T in Japanese c.1620+1G>A (heterozygosity in ~ 3% of the Mennonite population) c.16C>T [p.R6*]g c.17_18delAGf p.R408* in Norwegians and Faroese c.2039G>A (p.Trp680*) in Arubans c.4455delT in North African Jews p.R83C in Caucasians, Turks, Ashkenazi Jews p.Q347* in Caucasians c.648G>T [p.=] in Japanese, Chinese c.380insTA in Hispanics c.648G > T in Koreans p.R235H in Turks and Arabs p.W118R in Japanese p.G339C in Caucasians c.1042_3delCT in Caucasians

Reported only in two families

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

687

Enzymatic and molecular diagnosis (continued) 39.50

39.52

EPM2A-D (Laforin-D) EPM2B-D (Malin-D) GSD-IIa

39.53

GSD-IIb

LAMP2

(10 exons)

39.54 39.55 39.56 39.57

PC-D mtPCK-D cPCK-D FBP-D

PC PCK2 PCK1 FBP1

(19 exons) (10 exons) (10 exons) (7 exons)

39.51

↓

Enzyme act in WBC, dried blood spots

EPM2A

(5 exons)

NHLRC1

(1 exon)

p.C26S, p.P69A in Canadians

GAA

(20 exons)

IVS1-13T>G in Caucasiansi c.525delT in Caucasians ex18del in Caucasians p.D645E in Chinese and Taiwanese IVS5+1G>A (?)b in Japanese, Caucasians

1del in Turkey and Armeniaj c.960insG in Japan

Wada et al. (2019) Question mark refers to a small number of cases c Phosphorylase kinase activity in blood cells is diminished in types IXb and IXc but only in about 50% of GSD-IXa cases (=GSD-IXa-1 = XLG-1) d For PRKAG2b e In lethal congenital GSD of the heart f In hypertrophic cardiomyopathy and WPW syndrome g In GSD-IIIb patients h In unfrozen sample i With an adult-type variant of the disease k See Santer et al. (2016) a

b

Prenatal Diagnosis In principle, prenatal diagnosis is possible for all disorders by molecular genetic techniques with DNA samples from chorionic villi or amniotic fluid cells. For some disorders, prenatal enzymatic studies in amniotic fluid cells have been reported.

Treatment Summary Treatment depends on the underlying disorder and, for some disorders (highlighted in bold in Table  ‘Principles and measures of long-term treatment’), guidelines are published. In many of these disorders with symptomatic hypoglycaemia as part of the acute presentation, a rapid normalisation of blood glucose is important (see Table  ‘Initial treatment’). Longterm treatment aims and measures are summarised in Table  ‘Principles and measures of long-term treatment’; specific treatment in certain groups of disorders are given below. Many patients require personalised dietary measures prescribed by specialised dietitians, familiar with age-specific requirements, from the newborn period until late adulthood.

Emergency Treatment In some disorders, episodes of metabolic emergencies can be triggered by catabolism, evoked by combinations of fever,

decreased enteral intake and increased enteral losses by vomiting and/or diarrhea. To ensure safe shared care for patients with fasting intolerance in a subset of the disorders of carbohydrate absorption, transmembrane transport and metabolism, a written emergency protocol is warranted and should be personalised based on the age/body weight and specific disorder. If possible, the responsible metabolic centre should be contacted in advance in the case of a surgical procedure, to provide perioperative recommendations. Initial treatment of acute, symptomatic hypoglycaemia in patients with a disorder affecting endogenous glucose productiona Age

Immediate bolus (within 5–10 min) mg Glc/kg mL (Glc b.w. 10%)/kg b.w. 0–1 Years 500 5 1–6 Years 400 4 6–12 Years 350 3.5 Adolescents 300 3 Adults 250 2.5

Followed by continuous glucose infusionb mg glucose/kg b.w.per min 7–9 6–8 5–7 4–6 2–4

In patients with a confirmed metabolic disorder causing hypoglycaemia, treatment is challenged by (a) the risk of rebound hypoglycaemia due to hyperinsulinism, (b) the necessity of continuation of iv glucose, and/or (c) the careful reintroduction of enteral feeds. If possible, oral treatment is preferable to manage both symptomatic and asymptomatic hypoglycaemia, under clinical supervision. Based on symptoms and signs, the exogenous glucose intake should be titrated based on blood glucose values and secondary metabolic parameters, such as lactate concentrations and blood gas analyses in GSD-I patients. b Consider to adapt rate of glucose in case of fever a

688

T. G. J. Derks et al.

If galactose-1-phosphate uridyltransferase deficiency is suspected, for instance after positive newborn screening tests, a galactose-restricted diet should be started immediately, without waiting for confirmation of the diagnosis. Likewise, severe liver problems (e.g. a coagulation disor-

der) and a suitable dietary history justify to stop fructose intake with the diet. Severe postnatal osmotic diarrhoea and hypovolaemia should be treated by intravenous rehydration and omitting enteral carbohydrates prior to a definite diagnosis.

Standard Treatment Principles and measures of long-term treatment of disorders of carbohydrate metabolisma No. 39.1 39.2 39.3 39.4 39.5 39.6 39.7

Disorder CL-D CSI-D TREH-D SGLT1-D (GGM) SGLT2-D MAP17-D GLUT1-D

39.8 39.9

IDDNPF GLUT2-D (FBS)

39.10 39.11 39.12 39.13 39.14 39.15 39.16 39.17 39.18 39.19 39.20 39.21 39.22 39.23

GALM-D GALK-D GALT-D GALE-D FK-D ALDOB-D (HFI) HK1-D HK1 (NEDVIBA) HK1 (HMSNR) HK1 (RP79) GCK-D (MODY2) GCK-HI (HHF3) G6PI-D GSD-VII

39.24 39.25 39.26 39.27 39.28 39.29 39.30 39.31 39.32 39.33 39.34 39.35

ALDOA-D TPI-D PGK-D GSD-X GSD-XIII PK-D LDHA-D (GSD-XI) LDHB-D D-LDH-D GSD-XV (PGBM2) GSD-0b GSD-0a

39.36 39.37 39.38

GSD-IV GSD-IXd GSD-IXa

39.39 39.40 39.41 39.42

GSD-IXb GSD-IXc AMPK-A GSD-V

Principle Avoid non-absorbable lactose Avoid non-absorbable disaccharides, starch Avoid non-absorbable disaccharide Avoid non-absorbable monosaccharides

Improve energy supply to the brain: Use ketone bodies (transported by MCT1 at the BBB) as an alternative substrate as for 39.7 (?) Compensate for impaired hepatic Glc uptake and release Compensate for impaired hepatic Gal uptake Compensate for generalised impairment of proximal renal tubular cells secondary to Glc and glycogen overload Prevent accumulation of toxic galactitol in eye lens Prevent accumulation of toxic galactitol in eye lens Prevent accumulation of toxic Gal-1-P Prevent accumulation of toxic Gal-1-P

Measures Lac-free diet for life Sac-restricted diet, sucrase replacement with feeds Treh-restricted diet Glc- and Gal-restricted diet for life No specific Tx necessary No specific Tx necessary Avoid fasting, avoid valproic acid; low CH, high-fat (modified Atkins) diet, ketogenic diet as for 39.7 (?) Continuous enteral supply of slowly released CH to stabilise blood Glc and suppress gluconeogenesis Gal restriction Symptomatic Tx of renal Fanconi syndrome

Prevent accumulation of toxic Frc-1-P

Gal-restricted diet for life Gal-restricted diet for life Gal-restricted diet for life Gal-restricted diet for life No specific Tx necessary Strict Frc-restriction for life, avoid iv Frc/sorbitol

Normalise blood glucose Normalise blood glucose

Diet, antidiabetic drugs, insulin Diet, diazoxide

Compensate for diminished access to glycogen (M)

Symptoms can worsen if carbohydrates are taken before exercise

Compensate for diminished access to glycogen (M) Compensate for diminished access to glycogen (M) Compensate for diminished access to glycogen (M) Compensate for diminished access to glycogen (M) Compensate for diminished access to glycogen (M) Avoid accumulation of uric acid Compensate for diminished glycogen stores (M) Compensate for diminished glycogen stores (M) Provide exogenous CH that can compensate for diminished glycogen stores (L) Treat cirrhosis induced by abnormal glycogen (L) Compensate for diminished access to glycogen (M) Provide exogenous CH that can be metabolised despite impairment of glycogenolysis (L) See 39.38 See 39.38, treat cirrhosis Compensate for diminished access to glycogen (M)

No specific Tx necessary Allopurinol

Avoid fasting, frequent CH-rich feeds, continuous enteral supply of slowly released CH Symptomatic Tx (… liver Tpx) Avoid fasting, frequent CH-rich feeds, continuous enteral supply of slowly released CH See 39.38 See 39.38, symptomatic Tx of cirrhosis (… liver Tpx) No specific Tx available, symptomatic Tx (… heart Tpx) Diet rich in complex carbohydrates, exercise program

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

689

Standard Treatment (continued) No. 39.43

Disorder GSD-VI

39.44

GSD-III

39.45

GSD-Ia

39.46 39.47

G6PC3-D GSD-Ib

39.48 39.49 39.50 39.51 39.52 39.53 39.54

HOIL1-D (PGBM1) HOIL1-IP-D EPM2A-D (Laforin-D) EPM2B-D (Malin-D) GSD-IIa GSD-IIb PC-D

39.55 39.56 39.57

mtPCK-D cPCK-D FBP-D

Principle Provide exogenous CH that can be metabolised despite impairment of glycogenolysis (L) Provide exogenous CH that can be metabolised despite impairment of glycogenolysis (L) Treat cirrhosis Provide exogenous CH that can be metabolised despite impairment of glycogenolysis and gluconeogenesis (L) Avoid accumulation of uric acid Correct primary defect Treat adenoma complications (anaemia, tumour) Treat renal complications

Measures Avoid fasting, frequent CH-rich feeds, continuous enteral supply of slowly released CH Avoid fasting, frequent CH-rich feeds, continuous enteral supply of slowly released CH Symptomatic Tx (… liver Tpx) Avoid fasting, frequent CH-rich feeds, continuous enteral supply of slowly released CH, Gal- and Frc-restriction Allopurinol L-Tpx (?) L-Tpx Symptomatic Tx (… kidney Tpx)

See 39.45 plus Prophylaxis and Tx of bacterial infections

See 39.45 plus Antibiotic prophylaxis, G-CSF No specific Tx available, symptomatic No specific Tx available, symptomatic No specific Tx available, symptomatic

Replace missing enzyme in lysosomes Circumvent impaired gluconeogenesis, Anaplerosis; stimulate residual enzyme activity Circumvent impaired gluconeogenesis Circumvent impaired gluconeogenesis Circumvent impaired gluconeogenesis Avoid additional inhibition of glycogenolytic enzymes by accumulating Frc-1-P

No specific Tx available, symptomatic Enzyme replacement therapy No specific Tx available, symptomatic (… heart Tpx) Avoid fasting, supply citrate, triheptanoate; biotin, (… liver Tpx?) Avoid fasting Avoid fasting Avoid fasting, Frc-restricted diet for life, particularly during fasting

(L), in liver; (M) in muscle; Tx Treatment, CH Carbohydrates, BBB Blood brain barrier, Tpx Transplantation, G-CSF Granulocyte-colony stimulating factor aFor disorders presented in bold an international treatment guideline exists (see Kossoff et al. 2018; Welling et al. 2017; Rubio-Cabezas et al. 2014; Bianchi et al. 2019; Kishnani et al. 2019; Quinlivan et al. 2014; Rake et al. 2002; Kishnani et al. 2010; Kishnani et al. 2014; Visser et al. 2002; Kishnani et al. 2006; van der Ploeg et al. 2017)

Intestinal Carbohydrate Malabsorption Neonatal hypertonic dehydration frequently requires intravenous fluid therapy for which glucose-containing solutions with electrolytes can be used. Long-term enteral nutrition has to avoid the offending sugars: both glucose and galactose as monomers, as well as disaccharides and polymers of these sugars in GGM, and lactose in CL-D. Specialised commercial infant formulas containing fat and protein but free of a carbohydrate component can be used in GGM and fructose should be added according to the dietary allowances for carbohydrates to meet caloric needs. Small amounts of glucose and galactose are usually tolerated later in life. Patients with CL-D tolerate mono- and oligosaccharides. High fluid intake is recommended to prevent renal stone formation, which has repeatedly been reported in both conditions. Follow-up: Clinical monitoring (nutrient intake, growth, nutritional status, general health), biochemical and paraclinical monitoring (haemoglobin, total protein, general parameters of liver and kidney function, plasma osmolarity and electrolytes, urinary glucose, renal ultrasound) should be

planned depending on age, severity of initial decompensation and compliance.

Renal Glucosuria Allow free access to fluid. Caloric intake should compensate for renal losses in the severe cases. No specific treatment is necessary. Follow-up: Only the severe recessive types need systematic follow-up.

Glucose Transporter-1 Deficiency For most patients, an effective treatment is available by means of a modified Atkins diet or a ketogenic diet, both providing ketones as an alternative fuel for the brain. Ketones enter the brain via the facilitative MCT1 transporter. The diet should be introduced in a clinical setting and requires an experienced pediatrician and a dietitian. The classic ketogenic diet, with a

690

T. G. J. Derks et al.

3:1 ratio (fat vs non-fat intake in grams) using long-chain triglycerides is used for seizure control in infantile cases and preschool children. A modified Atkins diet, which is less restrictive, may be sufficient in milder cases with an isolated movement disorder. It can be considered in school-age children, adolescents and adults when the classic ketogenic diet is not tolerated. Fluids and calories are not restricted. Supplements (multivitamins, calcium and often carnitine) are required. Certain anticonvulsive drugs are relatively contraindicated: chloralhydrate, valproate and topiramate interfere with the diet, while others (phenobarbital, methylxanthines (caffeine), ethanol) have been shown to affect GLUT1 function. Experimental treatment: In individual patients, acetazolamide has shown good responses in movement disorders caused by GLUT1-D. However, when acetazolamide is given in combination with a ketogenic diet, there is an increased risk of nephrolithiasis and it may potentiate metabolic acidosis. Alpha-lipoic acid, an antioxidant, has been shown to increase glucose transport in cultured muscle cells but in vivo data is not available. Oral triheptanoin, an artificial tri-

glyceride composed of three seven-carbon fatty acids and potentially providing additional fuel for brain energy metabolism, is currently on clinical trial. Pitfalls/dangers of a ketogenic diet 1. Incorrect calculations: Note that the ratio of the ketogenic diet is defined in grams, not in calories or percentages! A 3:1 ratio means that, for 3 g of ingested fat, only 1 g of protein and carbohydrates is allowed. Thus, on a 3:1 ketogenic diet, 87% of kilocalories per day are supplied by fat. Percentages of protein and carbohydrates vary due to age-dependent protein requirements. 2. Non-compliance: Assess ketones in blood and urine. If ketones are inappropriately low, intensify dietary instructions and be aware that many medications have a high carbohydrate content! 3. Contraindications: β-oxidation defects, disorders of gluconeogenesis, ketolysis defects, porphyria, long QTc syndrome, relative contraindication concomitant use of propofol or pentobarbital coma 4.During intercurrent illness there is a risk of ketoacidosis and/or hypoglycaemia, provide an emergency protocol for these situations. Include a perioperative plan regarding intravenous fluids and monitoring of glucose/ketones in case surgery is necessary.

Nutritional requirements on a ketogenic diet Age 0–4 4–12 1–3 4–6 7–9 10–12 13–15 Adults

months months years years years years years

Fat requirements (g/kg bw per day) 9.0 9.0 8.7 7.8 7.0 5.8 5.0 5.0

Protein requirementsa (g/kg bw per day) 2.2 1.6 1.2 1.1 1.0 1.0 1.0 1.0

Carbohydrates (g/kg bw per day) 0.8 1.4 1.7 1.5 1.3 0.9 0.7 0.7

Energy demandb (g/kg bw per day) 93 91 90 80 72 60 52 52

Recommendations from the German Society for Nutrition (DGE; 1991) German-Austrian-Swiss (DACH) recommendations (2000)

a

b

Investigations on introduction and follow-up of a ketogenic diet On admission Clinicala Paraclinical   Glucose (P), OHB, BGA  Electrolytes   Liver/kidney parameters   Blood count, CRP   Fasting lipid profile   Essential fatty acids   Vitamin D level   Acylcarnitine profile   Serum amino acids and    Urine organic acids    (If diagnosis unclear)   Urine sediment and   calcium/creatinin ratio   Drug monitoring   EEG, EKG   Abdominal sonography on    Indication when there is    A risk of nephrolithiasis

Initiation of diet Clinicala Paraclinical   Glucose (P), OHB, BGA   Preferably bedside   2–4×/day;    If not possible,    Ketones in urine

On discharge Clinicala Paraclinical   Glucose (P), OHB, BGA  Electrolytes   Liver/kidney parameters  EEG   Abdominal sonography

Nutrient intake, growth, nutritional status, somatic findings, review medication for carbohydrate content

a

Follow-up   every 2–3(–6) months Clinicala Paraclinical   Glucose (P), OHB, BGA  Electrolytes   Liver/kidney parameters   Blood count, CRP   Acylcarnitine profile   Fasting lipid profile   Essential fatty acids   Vitamin D level   Selenium level   Urine sediment and   Calcium/creatinin ratio   Drug monitoring   EEG (seizure control?) EKG (long QT?)   Abdominal sonography   (Nephrolithiasis?)   DXA scan   after 2 years

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism Monitoring of ketosis on a ketogenic diet Sample Urine

Ketone body Acetoacetate

Test Test strips

Blood

Hydroxybutyrate

Test strips (hand devices) Enzymatic

Serum/plasma Total ketone bodies

Target value 80 (++)–160 (+++) mg/dL >2 mmol/L 3–5 mmol/L

Fanconi-Bickel syndrome Patients with FBS show signs of a hepatic GSD with impaired glycogenolysis and gluconeogenesis. Therefore, treatment should be similar to GSD-1 (see below) with frequent feeds and the use of slowly absorbed carbohydrates. Continuous nocturnal enteral nutrition may rescue growth failure (Pennisi et  al. 2020). Blood glucose concentrations should be in a range, so that gluconeogenesis is suppressed in order to avoid glycogen accumulation. This can be accomplished by a constant supply of slow release carbohydrates (frequent feeds, corn starch, nasogastric oligosaccharide drip feeding). In contrast to GSD-1, there is no evidence that a fructose-/ sucrose-restricted diet is beneficial to FBS patients. Likewise, there are patients with FBS that have ingested high amounts of galactose/lactose without developing cataracts. Therefore, galactose restriction is not generally recommended, but galactose and galactose-1-phosphate levels should be monitored. Due to the propensity to hypoglycaemia of FBS patients, the use of insulin for impaired glucose tolerance has to be considered with extreme caution and only after dietary measures have failed. There is no specific treatment for the Fanconi-type nephropathy. Symptomatic treatment is recommended to compensate for losses of water, sodium, potassium, calcium, phosphate, vitamin D and bicarbonate. Maintenance therapy should be monitored by urinary calcium excretion. Carnitine supplementation should only be performed at low plasma levels or when signs and symptoms of a secondary mitochondrial disorder are observed.

Disorders of Galactose Metabolism If a disorder of galactose metabolism is suspected in a newborn, dietary treatment consisting of a lactose-/galactose-­ free feeding regimen should be initiated without delay, even before the diagnosis has been confirmed enzymatically or by DNA analysis. In classical galactosaemia, supportive care depends on the severity of liver, renal and central nervous system disease and comprises intravenous fluids, plasma and vitamin K. Initiate treatment with broad-spectrum antibiotics without delay if suspicion of sepsis arises, since, in the event

691

of acute metabolic derangement, patients are at risk of infections due to the compromised response of the immune system. Long-term treatment requires a galactose-restricted diet for life in all four conditions. There is increasing evidence that small amounts of galactose are acceptable in GALK-D and GALT-D as long as it is in the range of endogenous galactose production. In the severe forms of GALE-D, some dietary galactose (1–2 g/d) and also N-acetyl-galactosamine intake is even necessary for the biosynthesis of complex carbohydrates and galactolipids. Excess, however, should be avoided, as this leads to accumulation of galactose-1-­ phosphate. Sufficient calcium intake and if necessary supplementation of vitamin D should be guaranteed to protect patients from osteoporosis. Ovarian dysfunction with hypergonadotropic hypogonadism is observed in almost all female patients with GALT-D.  Start ethinyl estradiol therapy from age 12–13 years, when gonadotropin levels are high and estradiol levels are low (first 6 months 2 μg daily; 6–12 months 2–5 μg daily; 12–24 months 5 μg daily; 24–36 months 10 μg daily; after 3 years, followed by an oral contraceptive preparation containing ethinyl estradiol and a progestagen daily for 21 days, 7 days abstinence) (Berry et al. 2016, Welling et al. 2017). Follow-up in patients with disorders of galactose and fructose metabolism Disorder Investigations GALM-D Ophthalmological investigation Paraclinical   Calcium metabolism, 25-OH-vitamin D   Galactose (P,U)   Galactitol (P,U) GALK-D Ophthalmological investigation Paraclinical   Calcium metabolism, 25-OH-vitamin D   Galactose (P,U)   Galactitol (P,U) GALT-D Clinicala,b Ophthalmological investigations Paraclinical   Liver/kidney parameters  Calcium metabolism, 25-OH-vitamin D   Gal-1-P (RBC)   Galactitol (P,U)  CDTd  LH, FSH, estradiol (in females, starting around 12 years)  Pelvic ultrasound (in females)e  X-ray (left hand for bone age)f  Bone mineral density assessmentg

Frequency 18 years: biannually

18 years: biannually

18 years: annuallyc

692 Disorder GALE-D

FK-D HFI

FBP-D

T. G. J. Derks et al. Investigations Clinicala,b Ophthalmological investigations Paraclinical   Liver/kidney parameters   Gal-1-P (RBC)   UDP-Gal (RBC)   Galactitol (U)   X-ray (left hand for bone age)f  Bone mineral density assessmentg None Clinicala Paraclinical   Liver/kidney parameters  CDTd   Folic acid (P), vitamin C (P)   Liver ultrasound Clinicala Paraclinical   Liver parameters  Glucose (P), Lactate (P) during infections

Frequency 18 years: annuallyh

18 years: biannually

Nutrient intake, growth, nutritional status, somatic findings (liver size) Neurological, psychological, cognitive functions, speech and language development c Follow-up of female GALT-D patients on hormone treatment should be done on a more regular interval d CDT, carbohydrate-deficient transferrin (abnormal glycosylation of transferrin) e Not routinely recommended f Depending on growth g Start at age 8–10 years, repeat at puberty with follow-ups every 5 years h In milder forms of GALE-D, follow-up can be less extensive a

b

Disorders of Fructose Metabolism If HFI or FBP-D is suspected, dietary treatment consisting of a sucrose-, fructose-, and sorbitol-free feeding regimen should be initiated without delay, even before the diagnosis has been confirmed enzymatically or by DNA analysis  (Steinmann and Santer 2016). Supportive care depends on the severity of liver and renal disease and comprises intravenous fluids, plasma and vitamin K. In the long term, fructose tolerance in HFI is highly variable. At least in infancy, fructose should be maximally restricted and intake should not be determined by subjective tolerance. For the maintenance of normal blood glucose concentrations, patients with FBP-D depend on glycogen breakdown and on exogenous glucose from intestinal absorption. Especially in young children, the relative amount of hepatic glycogen is limited. Only after a short period of fasting, patients may develop hypoglycaemia accompanied by accumulation of lactate. The most important aim of the dietary treatment is therefore maintenance of normoglycaemia by avoidance of fasting. In FBP-D, fructose intake should therefore be limited during periods of acute illness because ­ accumulating fructose-1-phosphate inhibits liver phosphorylase. Certain amounts of fructose, particularly when taken with other carbohydrates, are generally tolerated in non-catabolic periods.

In patients on a fructose-restricted diet, vitamin C and folic acid should be supplemented.

Glycogen Storage Diseases—Mainly Affecting Liver Patients with defects in hepatic glycogenolysis (FBS, GSD-­I, GSD-III, GSD-VI, GSD-IXa-c) but also with diminished hepatic glycogen formation (GSD-0a) may develop hypoglycaemia after only a short period of fasting. This holds especially true for younger patients and patients with GSD-­I.  A guideline for acute treatment of hypoglycaemia is given in Table ‘Initial treatment of acute, symptomatic hypoglycaemia in patients with a disorder affecting endogenous glucose production’, but amounts should be interpreted with caution because of the risk of overtreatment and iatrogenic hypoglycaemias. Hypoglycaemia may be accompanied by metabolic acidosis caused by accumulation of lactate (fasted in GSD-I, postprandial in so-called ‘ketotic’ GSDs) or ketones (GSD-III, GSD-VI, GSD-IXa-c, GSD-0, FBS). While lactic acidaemia will improve upon glucose administration in GSD I patients, in patients with a disorder affecting endogenous glucose production application of an excess of glucose in GSD-0a patients may lead to hyperglycaemia and/or lactacidaemia. The aim of long-term treatment in hepatic GSDs is the stabilisation of blood glucose with concentrations at which gluconeogenesis and secondary metabolic perturbations are suppressed as much as possible, in order to prevent long-­term complications and maximise quality of life. No consensus exists about the extent of avoiding lactate production in GSD-I from galactose, fructose and sucrose. Moderate hyperlactacidaemia may prevent cerebral symptoms if blood glucose concentration is low, as lactate may serve as an alternative fuel for the brain. On the other hand, some evidence exists that avoiding lactate production from endogenous sources or from galactose and fructose intake may favor long-term outcome. Since glycogenolysis is impaired in hepatic GSDs (with the additional involvement of gluconeogenesis in GSD-I), these patients depend on exogenous glucose from intestinal absorption for the maintenance of a normal blood glucose concentration. After a short period of fasting, especially younger patients and patients with GSD-I may develop hypoglycaemia. There is evidence that both the G6PC genotype and alternative pathways of glycogenolysis define the GSD-Ia phenotype severity. The most important aim of dietary treatment is avoidance of fasting. Intensive dietary treatment induces catch-up growth, reduces liver size and ameliorates secondary biochemical abnormalities. In GSD-I, life-long dietary treatment is necessary. In GSD-III, dietary treatment is often less demanding and in general, in types VI and IX therapy is markedly easier with only about 50% of patients being prone to hypoglycaemia. In the latter types, dietary treatment is generally limited to younger children.  In GSD-IV, dietary treatment may improve fasting intolerance related symptoms and signs, improve growth, normalize serum aminotransferases, and delay or prevent liver transplantation in a subset of patients (Derks et al. 2020).

39  Disorders of Carbohydrate Absorption, Transmembrane Transport and Metabolism

Intensive dietary treatment with carbohydrates slowly absorbed from the intestine and dietary protein enrichment may also ameliorate secondary myogenic symptoms in the group of hepatic GSDs by counteracting increased gluconeogenesis and avoiding a drain from muscle protein. Dietary treatment is based on frequent feedings during daytime depending on GSD type and individual fasting tolerance. For type I patients, the entire estimated endogenous glucose production has to be replaced by enteral feedings. The numbers given in the right column of Table ‘Initial treatment of acute, symptomatic hypoglycaemia in patients with a disorder affecting endogenous glucose production’ can serve as an orientation for a dietary prescription and have to be adapted individually and throughout life based on the age-­specific requirements. Fasting tolerance during daytime can be prolonged by using uncooked cornstarch from which glucose is only slowly released to the blood stream. During the night and at a younger age (especially in GSD-I and III), continuous gastric drip-feeding may be necessary for 8–12 h. Uncooked cornstarch should not be started in children less than 6 months and may be carefully introduced after the age of 6-12 months, when pancreatic amylase activity maturates. Alternatively, but only at a later age, uncooked cornstarch may be given during the night at 4- to 6-h intervals, in late adolescence or adulthood at 6- to 8-h intervals, depending on parameters of metabolic control (Chen 2001). In general, it is not necessary to replace breast milk in infants, except for those with GSD-I who may benefit from glucose-enriched lactose-/sucrose-free feedings or an oligosaccharide-­ based formula. In GSD-I for continuous gastric drip-feeding, a glucose/glucose polymer solution should be used; formulas enriched with maltodextrin are not recommended due to their high energy content. Dietary manipulations in hepatic glycogen storage diseases Disorder GSD-0a GSD-Ia GSD-Ib

GSD-III

All

Frequent feeds, prevention of fastinga Protein enriched diet (20%) Frequent feeds, prevention of fastinga High carbohydrate intake (55–70% of energy) Moderate fat restriction (20–30%) Predominantly polyunsaturated fatty acids Moderate protein restriction (10-15%) Sodium restriction Galactose/fructose restriction Frequent feeds, prevention of fastinga Carbohydrate enriched diet (50–55% of energy) Moderate fat restriction (20–30%) Predominantly polyunsaturated fatty acids Protein enriched diet (20%)b Frequent feeds, prevention of fastinga

Depending on GSD type, individual fasting tolerance and age consider frequent snacks or corn starch during daytime and continuous gastric drip feeding and use of corn starch during the night (see text) b In type IIIa with muscle involvement a

In adolescent patients with GSD-I, in analogy to proteinuric insulin-dependent diabetic mellitus, reduction of protein intake should be considered. Furthermore, a reduction in sodium intake may enhance the beneficial effects of angiotensin-­converting enzyme inhibitors.

693

Renoprotective treatment with an ACE inhibitor should be started in GSD-I patients as soon as microalbuminuria persists and before hypertension develops. Angiotensin II antagonists may elicit comparable results; however, clinical experience in GSD-I is more limited. In order to prevent urate nephropathy in patients with hepatic glycogenosis, allopurinol (10  mg/kg/d in 3 doses, max 900 mg/d) should be started if serum uric acid concentration exceeds the upper normal level for age despite optimal dietary treatment. As uric acid is regarded to be a potent radical scavenger (with a possible protective role against premature atherosclerosis), the targeted uric acid concentration is in the high normal range. Supplementation of vitamins should commence when WHO recommendations are not met. Furthermore, supplementation of calcium and vitamin D is important when intake of milk and milk-derived products is limited (GSD-I). Special attention is also needed regarding vitamin B1 intake as increased metabolism of carbohydrates needs sufficient vitamin B1. If GSD-I patients show persistence of a deficit of bases (base excess G mtDNA mutation is almost invariably associated with myoclonic epilepsy with ragged red fibers (MERRF). Likewise, patients presenting with mitochondrial neurogastrointestinal encephalopathy (MNGIE) most often have a mutation in the thymidine phosphorylase gene (TYMP). Nevertheless, as set out in the nomenclature table and discussed earlier in the introduction, different gene mutations in nuclear or mitochondrial DNA can produce similar symptoms. Since the costs of whole mitochondrial genome and whole exome/genome sequencing (WES/WGS) have fallen dramatically in recent years it is frequently cost effective to take this approach, rather than targeted gene sequencing, especially if the symptoms are compatible with many forms of mitochondrial disease. The small size of the mitochondrial genome means determining its sequence and integrity is an almost universal starting point for suspected mitochondrial diseases, particularly if the family history is compatible with maternal inheritance. Some specialist centres have developed PCR/sequencing arrays that screen the mitochondrial genome and around 100 nuclear genes linked to mitochondrial disorders, which provides an intermediate between sequencing one or a few targeted genes and WES/WGS and should have a lower false negative rate than the latter.

Mitochondrial depletion syndrome 2

Mitochondrial ribonucleotide reductase small subunit deficiency Mitochondrial depletion syndrome 1

45.11

45.12

Mitochondrial depletion syndrome 13

45.16

45.17

45.15

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 Mitochondrial DNA depletion syndrome 11

45.14

45.13

45.9

45.8

45.10

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 Mitochondrial depletion syndrome 3

Disorder Mitochondrial depletion syndrome 4A Mitochondrial depletion syndrome 4B Sensory ataxic neuropathy, dysarthria and ophthalmoparesis Progressive external ophthalmoplegia 1

Mitochondrial DNA depletion syndrome type 6 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 Mitochondrial DNA depletion syndrome type 7 Perrault syndrome 5

45.7

45.6

45.5

45.4

No. 45.1 45.2 45.3

Nomenclature Abbreviation MTDPS4A MTDPS4B SANDO

PEOB2

RNASEH1 defect

FBXL4 deficiency

MGME1 deficiency

PEOA6

MTDPS13

MTDPS11

MTDPS8A; MTDPS8B MTDPS1, MNGIE

FBXL4

MGME1

RNASEH1

DNA2

TYMP

RRM2B

TK2

MTDPS2; PEOB3

TWNK TWNK

MTDPS7

TWINKLE mitochondrial DNA helicase deficiency TWINKLE mitochondrial DNA helicase deficiency Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Mitochondrial DNA depletion syndrome 8A & 8B Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) DNA2 deficiency

TWNK

MPV17

DGUOK

POLG2

POLG

Gene symbol POLG POLG POLG

PRLTS5

PEOA3

MTDPS6

MTDPS3; PEOB4

TWINKLE mitochondrial DNA helicase deficiency

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 MPV17 deficiency

PEOA1; PEOB1 adPEO with mitochondrial DNA PEOA4 deletions type 4

Alternative name Alpers-Huttenlocher syndrome MNGIE, POLG-related Sensory ataxic neuropathy with mitochondrial DNA deletions

6q16.1-q16.2

20p11.23

2p25.3

AR

AR

AR

AD

AR

22q13.32-qter

10q21.3

AR

AR

16q21

8q22.3

AR

AR

AD

AR

10q24.31

10q24.31

10q24.31

2p23.3

AR

AD

17q23.3

2p13.1

AD, AR

Inheritance AR AR AR

15q26.1

Chromosomal localisation 15q26.1 15q26.1 15q26.1

131222; 603041

612075

617068; 609560

616138

271245

609286

256810

251880; 617070

157640; 258450 610131

OMIM No. 203700 613662 607459

616479

(continued)

Mitochondrial genome 615076 maintenance exonuclease 1 F-box and leucine-rich 615471 repeat protein 4

Ribonuclease H1

DNA replication helicase 2 615156

Ribonucleotide reductase small subunit 2-like Thymidine phosphorylase

Mitochondrial thymidine kinase (TK2)

Twinkle mtDNA helicase

Twinkle mtDNA helicase

Twinkle mtDNA helicase

MPV17

Deoxyguanosine kinase

DNA polymerase gamma 2, accessory subunit

Polymerase gamma

Affected protein Polymerase gamma Polymerase gamma Polymerase gamma

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA 847

Mitochondrial depletion syndrome 9

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 Mitochondrial DNA depletion syndrome type 12A (cardiomyopathic type) Mitochondrial DNA depletion syndrome type 12B (cardiomyopathic type) Mitochondrial RNA import protein deficiency

45.19

45.20

45.21

Spastic ataxia 4, autosomal recessive

CCA-adding tRNA-nucleotidyltransferase deficiency

Combined oxidative phosphorylation deficiency 15 tRNA 5-taurinomethyluridine modifier deficiency

45.27

45.29

45.30

45.31

tRNA 5-carboxymethylaminomethyl transferase deficiency

Myopathy lactic acidosis and sideroblastic anaemia tRNA isopentenyl transferase deficiency

tRNA methyltransferase 5 deficiency

45.33

45.34

45.35

45.36

45.32

45.26

Combined oxidative phosphorylation deficiency 30 Combined oxidative phosphorylation deficiency 17 Mitochondrial DNA depletion syndrome-15

45.25

45.24

45.23

45.22

Disorder Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 Mitochondrial depletion syndrome 5

No. 45.18

PNPT1

TRMT10C ELAC2

COXPD13

COXPD30 COXPD17

TRNT1

–

TRMT5

TRIT1

PUS1

MTO1

GTPBP3

MTFMT

MTPAP

SPAX4

TFAM

SLC25A4

MTDPS12B

MTDPS15

SLC25A4

SLC25A4

PEOA2

MTDPS12A

SUCLG1

SUCLA2

Gene symbol TOP3A

MTDPS9

MTDPS5

Abbreviation PEOB5

Mitochondrial methionyl-tRNA COXPD15 formyltransferase deficiency COXPD23 Combined oxidative phosphorylation deficiency type 23 COXPD10 Combined oxidative phosphorylation deficiency type 10 Pseudouridine synthase 1 MLASA1 deficiency Combined oxidative COXPD35 phosphorylation deficiency 35 COXPD26 Combined oxidative phosphorylation deficiency type 26

Combined oxidative phosphorylation deficiency type 13 Ribonuclease P 5′ tRNA processing enzyme deficiency Ribonuclease Z 3′ tRNA processing enzyme deficiency Mitochondrial transcription factor A deficiency Mitochondrial poly(A) polymerase deficiency Retinitis pigmentosa and erythrocytic microcytosis

ATP-specific succinyl-CoA ligase β subunit deficiency Encephalomyopathic type with methylmalonic aciduria

Alternative name

AR

6q13

AR AR

1p34.2 14q23.1

AR

AR

19p13.11

12q24.33

AR

AR

AR

AR

AR

AR

AR

AR

AD

AD

AR

AR

OMIM No. 618098

tRNA isopentenyl transferase 1 tRNA methyltransferase 5

Pseudouridine synthase 1

Mitochondrial translation optimization 1

Mitochondrial transcription factor A Mitochondrial poly(A) polymerase CCA-adding tRNAnucleotidyltransferase Methionyl-tRNA formyltransferase GTP-binding protein 3

Long form of RNase Z

RNA methyltransferase 10

Adenine nucleotide translocator 1 Adenine nucleotide translocator 1 Polyribonucleotide nucleotidyltransferase 1

616539

617873

600462

614702

616198

614947

616959; 616084

613672

617156

615440

616974

614932; 614934

615418

617184

ATP-specific succinyl-CoA 603921 ligase β subunit GTP-specific succinyl-CoA 245400 ligase α subunit Adenine nucleotide 609283 translocator 1

Inheritance Affected protein AR Topoisomerase 3α

15q22.31

3p26.2

10p11.23

10q21.1

17p12

3q12.3

2p16.1

4q35.1

4q35.1

4q35.1

2p11.2

13q14.2

Chromosomal localisation 17p11.2

848 I. J. Holt et al.

HSD10 mitochondrial disease

Mitochondrial ribosomal large subunit 3 deficiency

Mitochondrial ribosomal large subunit 12 deficiency Mitochondrial ribosomal large subunit 44 deficiency

45.39

45.40

45.41

45.53

45.52

45.51

45.50

45.49

45.48

No S&S* 45.47

45.46

45.45

45.44

45.43

Combined oxidative phosphorylation defect 1 Mitochondrial elongation factor G2 deficiency (unconfirmed) Combined oxidative phosphorylation defect 3 Combined oxidative phosphorylation defect 4

Combined oxidative phosphorylation defect 5 Mitochondrial ribosomal small subunit 23 deficiency Combined oxidative phosphorylation deficiency type 32 Mitochondrial ribosomal RNA 12S deficiency Combined oxidative phosphorylation deficiency 11

Combined oxidative phosphorylation deficiency 36 Combined oxidative phosphorylation deficiency 34 Combined oxidative phosphorylation defect 2

Mitochondrial RNA-processing endoribonuclease deficiency

45.38

45.42

Disorder Acute infantile liver failure

No. 45.37

Encephalomyopathy, respiratory COXPD3 failure and lactic acidosis Mitochondrial elongation factor COXPD4 Tu deficiency

TUFM

TSFM

GFM2

GFM1

RMND1

MTRNR1

MRPS34

MRPS23

MRPS22

MRPS16

COXPD2

COXPD5

MRPS7

MRPS2

MRPL44

MRPL12

MRPL3

COXPD34

COXPD36

COXPD16

COXPD9

16p11.2

12q14.1

5q13.3

AR

AR

AR

AR

AR

6q25.1

3q25.1-q26.2

Maternal

AR

AR

AR

AR

AR

AR

m.648–1601

16p13.3

17q22

3q23

10q22.1

17q25.1

9q34.3

AR

AR

17q25.3 2q36.1

AR

561000

617664

611985

611719

610498

617872

617950

615395

602375

614582

300438

250250

OMIM No. 613070

Elongation factor G1 (EFG1) Mitochondrial elongation factor G2 Mitochondrial elongation factor Ts Mitochondrial elongation factor Tu

(continued)

610678

610505

606544

609060

Required for meiotic 614922 nuclear division 1 homolog

Mitochondrial ribosomal protein S22 Mitochondrial ribosomal protein S23 Mitochondrial ribosomal protein S34 n.a.

Mitochondrial ribosomal protein S2 Mitochondrial ribosomal protein S7 Mitochondrial ribosomal protein S16

Mitochondrial ribosomal protein L12 Mitochondrial ribosomal protein L44

Mitochondrial ribosomal protein L3

Inheritance Affected protein AR tRNA 5-methylaminomethyl-2thiouridylate methyltransferase AR RNA component of mitochondrial RNAprocessing endoribonuclease AR 17-beta-hydroxysteroid dehydrogenase type 10

3q22.1

HSD17B10 Xp11.2

HSD10MD

9p13.3

Chromosomal localisation 22q13

RMRP

Gene symbol TRMU

CHH

Abbreviation

Mitochondrial ribosomal small COXPD32 subunit 34 deficiency Aminoglycoside-induced and nonsyndromic hearing loss COXPD11 Infantile encephaloneuromyopathy due to mitochondrial translation defect Early fatal progressive COXPD1 hepatoencephalopathy Putative Leigh-like syndrome

Combined oxidative phosphorylation deficiency type 16 Mitochondrial ribosomal small subunit 2 deficiency Mitochondrial ribosomal small subunit 7 deficiency Corpus callosum agenesis with dysmorphism and fatal lactic acidosis

17-beta-hydroxysteroid dehydrogenase type 10 deficiency Combined oxidative phosphorylation deficiency type 9

Cartilage-hair hypoplasia

Alternative name

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA 849

45.55

No S&S**

No. 45.54

Hypertrophic cardiomyopathy and sensorineural deafness Hypertrophic cardiomyopathy Multisystem disorder Progressive necrotizing encephalopathy Hypertension, hypercholesterolemiaand hypomagnesimia MELAS syndrome

Diabetes and deafness Mitochondrial myopathy Sensorineural deafness and migraine MELAS-like Hypertrophic cardiomyopathy Exercise intolerance Sudden death Dilated cardiomyopathy Pigmentary retinopathy and sensorineural deafness MERRF/MELAS overlap syndrome Sensorineural deafness Fatal cardiomyopathy

MT-TN MT-TN MT-TD MT-TC MT-TC MT-TE

Combined CI/CIV deficiency Chronic tubulointerstitial nephropathy Mitochondrial myopathy MELAS-like Mitochondrial dystonia Mitochondrial myopathy with diabetes mellitus Transient infantile mitochondrial myopathy

MT-TL1

Maternal

Maternal Maternal Maternal Maternal

m.4300A>G m.4284G>A m.4290T>C m.4291T>C MT-TI MT-TI MT-TI MT-TI

m.3243A>G, m.3271T>C

Maternal MT-TI

Maternal Maternal Maternal

Maternal Maternal Maternal Maternal Maternal Maternal Maternal Maternal Maternal

n.a.

n.a. n.a. n.a. n.a.

n.a.

n.a. n.a. n.a.

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.

n.a.

Maternal

m.12147G>A m.12201T>C m.4317A>G, m.4269A>G m.4295A>G

m.14674T>C, m.14674T>G m.14692A>G m.ins4366A m.4336A>G m.m4332G>A m.9997T>C m.10010T>C m.10044A>G m.12192G>A m.12183G>A

n.a. n.a. n.a. n.a. n.a. n.a.

n.a.

n.a. n.a. n.a.

Maternal Maternal Maternal Maternal Maternal Maternal

Maternal

Maternal Maternal Maternal

Inheritance Affected protein AR C12orf65 release factor

MT-TH MT-TH MT-TI

MT-TE MT-TQ MT-TQ MT-TQ MT-TG MT-TG MT-TG MT-TH MT-TH

MT-TE

MT-TN

m.5650G>A m.5591G>A m.10438A>G, m.10450A>G m.5703G>A, m.5692A>G m.5728A>G m.5656A>G m.7526A>G m.5814A>G m.5816A>G m.14709T>C

Gene Chromosomal symbol localisation C12ORF65 12q24.31

Ophthalmoplegia

Abbreviation COXPD7; SPG55 MT-TA MT-TA MT-TR

Alternative name C12orf65 release factor deficiency

Disorder Combined oxidative phosphorylation defect 7; spastic paraplegia 55 Myotonic dystrophy-like myopathy Mitochondrial myopathy Mitochondrial encephalomyopathy

590050

590045 590045 590045 590045

590045

590040 590040 590045

590025 590030 590030 590030 590035 590035 590035 590040 590040

590025

590010 590010 590015 590020 590020 590025

590010

OMIM No. 613559; 615035 590000 590000 590005

850 I. J. Holt et al.

45.56

Mitochondrial encephalopathy Tubulointerstitial nephropathy Mitochondrial myopathy Parkinson disease MERRF-like syndrome MERRF/MELAS overlap syndrome Palmoplantar keratoderma with deafness Mitochondrial cytochrome c oxidase deficiency with sensorineural deafness Mitochondrial sensorineural deafness

MERRF/MELAS overlap syndrome Cardiomyopathy and deafness Mitochondrial neurogastrointestinal encephalomyopathy syndrome Diabetes and deafness Progressive external ophthalmoplegia with myoclonus Mitochondrial myopathy MELAS-like syndrome MERRF-like syndrome Late onset mitochondrial myopathy Mitochondrial epilepsy

Mitochondrial encephalomyopathy Progressive external ophthalmoplegia, proximal myopathy and sudden death Mitochondrial myopathy Sudden infant death syndrome Kearns-Sayre like syndrome Myelodysplastic syndrome Mitochondrial encephalomyopathy Mitochondrial myopathy Mitochondrial cardiomyopathy MERRF syndrome

No S&S**

Disorder MERRF-like Cardiomyopathy and myopathy

No. No S&S**

MNGIE syndrome

Alternative name

Abbreviation

MT-TS1

MT-TF MT-TF MT-TP MT-TP MT-TP MT-TS1 MT-TS1 MT-TS1

m.7510T>C, m.7511T>C, m.7445A>C, m.7505T>C

n.a.

n.a. n.a. n.a. n.a. n.a.

Maternal

Maternal Maternal Maternal Maternal Maternal

m.4409T>C m.583G>A m.611G>A m.622G>A m.616T>C, m.616T>G m.586G>A m.608A>G m.15990G>A m.15965T>C m.15967G>A m.7512T>C m.7445A>G m.ins7472C MT-TM MT-TF MT-TF MT-TF MT-TF

n.a. n.a.

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.

Maternal Maternal

m.8296A>G m.8342G>A

MT-TK MT-TK

n.a. n.a. n.a.

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.

n.a. n.a.

Maternal Maternal Maternal Maternal Maternal Maternal Maternal Maternal

Maternal Maternal Maternal

MT-TK MT-TK MT-TK

Maternal Maternal Maternal Maternal Maternal Maternal Maternal Maternal

Maternal Maternal

Inheritance Affected protein Maternal n.a. Maternal n.a.

m.3250T>C m.3290T>C m.3249G>A m.3242G>A m.12315G>A m.12320A>G m.12297T>C m.8344A>G, m.8361G>A m.8356T>C m.8363G>A m.8313G>A

Chromosomal localisation m.3256C>T m.3303C>T, m.3260A>G m.3252T>C m.3251A>G

MT-TL1 MT-TL1 MT-TL1 MT-TL1 MT-TL2 MT-TL2 MT-TL2 MT-TK

MT-TL1 MT-TL1

Gene symbol MT-TL1 MT-TL1

(continued)

590080

590070 590070 590075 590075 590075 590080 590080 590080

590065 590070 590070 590070 590070

590060 590060

590060 590060 590060

590050 590050 590050 590050 590055 590055 590055 590060

590050 590050

OMIM No. 590050 590050

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA 851

45.64

45.63

45.62

45.61

45.60

45.59

45.58

45.57

No.

Alternative name

Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit B deficiency

Mitochondrial alanyl-tRNA synthetase deficiency Mitochondrial arginyl-tRNA synthetase deficiency Combined oxidative phosphorylation Mitochondrial asparaginyldeficiency 24 tRNA synthetase deficiency Leukoencephalopathy with brainstem and Mitochondrial aspartyl-tRNA spinal cord involvement and lactate elevation synthetase deficiency Combined oxidative phosphorylation Mitochondrial cysteinyl-tRNA deficiency 27 synthetase deficiency Combined oxidative phosphorylation Mitochondrial glutamyl-tRNA deficiency 12 synthetase deficiency Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit A deficiency

Mitochondrial myopathy Mitochondrial neurogastrointestinal syndrome Mitochondrial encephalocardiomyopathy Mitochondrial encephalomyopathy Exercise intolerance and complex III deficiency Chronic progressive external ophthalmoplegia with myopathy Focal segmental glomerulosclerosis and dilated cardiomyopathy Ataxia, progressive seizures, mental deterioration and hearing loss Neonatal death and Leigh syndrome Combined oxidative phosphorylation deficiency type 8 Pontocerebellar hypoplasia, type 6

Disorder Aminoglycoside-induced deafness Exercise intolerance, muscle pain and lactic acidemia Cerebellar ataxia, cataract and diabetes mellitus MERRF/MELAS overlap syndrome Parkinson disease Mitochondrial encephalopathy

COXPD12

COXPD27

LBSL

COXPD24

PCH6

COXPD8

Abbreviation

Maternal Maternal Maternal Maternal Maternal Maternal Maternal AR

m.5545C>T m.5556G>A m.5874A>G m.del5885T, m.5877G>A m.5843A>G m.1606A>G m.1624C>T 6p21.1

MT-TW MT-TW MT-TY MT-TY MT-TY MT-TV MT-TV AARS2

GATB

QRSL1

EARS2

CARS2

DARS2

NARS2

RARS2

4q31.3

6q21

16p12.2

13q34

1q25.1

11q14.1

AR

AR

AR

AR

AR

AR

AR

n.a.

Maternal Maternal

6q15

n.a.

Maternal Maternal Maternal

m.12207G>A m.15950G>A m.5549G>A, m.ins5537T m.5521G>A m.5532G>A

MT-TS2 MT-TT MT-TW MT-TW MT-TW

Maternal

m.12258C>A

MT-TS2

590105

590100

590100

590095 590095 590100

590095 590095

590085 590090 590095

590085

OMIM No. 590080 590080

Asparaginyl-tRNA synthetase 2 Aspartyl-tRNA synthetase 2 Cysteinyl-tRNA synthetase 2 Glutamyl-tRNA synthetase 2 Glutaminyl-tRNA synthase (glutamine-hydrolyzing)like protein 1 Glutamyl-tRNA amidotransferase, subunit B

603645

617209

614924

616672

611105

616239

590105 614096; 615889 Arginyl-tRNA synthetase 2 611523

n.a. Alanyl-tRNA synthetase 2

n.a.

n.a. n.a. n.a.

n.a. n.a.

n.a. n.a. n.a.

n.a.

Inheritance Affected protein Maternal n.a. Maternal n.a.

Chromosomal localisation m.7444G>A m.7497G>A

Gene symbol MT-TS1 MT-TS1

852 I. J. Holt et al.

Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia Perrault syndrome 4

Autosomal recessive spastic ataxia type 3

Combined oxidative phosphorylation deficiency 25 Spastic paraplegia 77, autosomal recessive

45.67

45.68

45.69

45.70

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease Perrault syndrome 6 NOP2/SUN RNA methyltransferase 3 deficiency Mitochondrial ribosomal small subunit 25 deficiency

45.80

Mitochondrial and cytoplasmic glycyl-tRNA synthetase deficiency Mitochondrial and cytoplasmic lysyl-tRNA synthetase deficiency Peptidyl-tRNA hydrolase 2 deficiency

Mitochondrial leucyl-tRNA synthetase deficiency Mitochondrial methionyl-tRNA synthetase deficiency Mitochondrial methionyl-tRNA synthetase deficiency Mitochondrial phenylalanyltRNA synthetase deficiency Mitochondrial phenylalanyltRNA synthetase deficiency Mitochondrial seryl-tRNA synthetase deficiency Mitochondrial threonyl-tRNA synthetase deficiency Mitochondrial tyrosyl-tRNA synthetase deficiency Mitochondrial valyl-tRNA synthetase deficiency Mitochondrial tryptophanyltRNA synthetase deficiency

Mitochondrial histidyl-tRNA synthetase deficiency Mitochondrial isoleucyl-tRNA synthetase deficiency

Alternative name

SARS2

HUPRA

WARS2

GARS

KARS

NEMMLAS

CMT2D; HMN5A DFNB89; CMTRIB(?)

PRLTS6

MRPS25

ERAL1 NSUN3

PTRH2

VARS2

COXPD20

IMNEPD

YARS2

MLASA2

TARS2

FARS2

COXPD14

COXPD21

FARS2

MARS2

COXPD25 SPG77

MARS2

LARS2

IARS2

CAGSSS

PRLTS4; HLASA(?) SPAX3

HARS2

Gene symbol GATC

PRLTS2

Abbreviation

3p25.1

17q11.2 3q11.2

17q23.1

16q23.1

7p14.3

1p12

6p21.33

12p11.21

1q21.2

19q13.2

6p25.1

6p25.1

2q33.1

2q33.1

3p21.31

1q41

5q31.3

Chromosomal localisation 12q24.31

AR

AR AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

613845

614946

617046

616430

615300; 617021(?) 611390

616007

613916; 613641(?)

601472; 600794

617710

615917

Era G-protein-like 1 NOP2/SUN RNA methyltransferase 3 Mitochondrial ribosomal protein S25

611987

617565 617491

Peptidyl-tRNA hydrolase 2 616263

Lysyl-tRNA synthetase

Glycyl-tRNA synthetase

Tryptophanyl-tRNA synthetase 2

Valyl-tRNA synthetase 2

Threonyl-tRNA synthetase 615918 2 Tyrosyl-tRNA synthetase 2 613561

Methionyl-tRNA synthetase 2 Methionyl-tRNA synthetase 2 Phenylalanyl-tRNA synthetase 2 Phenylalanyl-tRNA synthetase 2 Seryl-tRNA synthetase 2

Leucyl-tRNA synthetase 2

Isoleucyl-tRNA synthetase 2

Inheritance Affected protein OMIM No. 617210 AR Glutamyl-tRNA amidotransferase, subunit C AR Histidyl-tRNA synthetase 2 614926

No S&S*: rare single case patient, for which no OMIM disease record was yet available and no Signs and Symptoms table is provided; for most mitochondrial tRNA mutations, with the exception of the tRNA (LeuUUR) 3243A>G and the tRNA(Lys) 8344A>G mutations, for the MELAS and MERRF syndromes respectively, Signs and Symptoms tables are not provided

45.83

45.81 45.82

Deafness, autosomal recessive 89

45.79

45.78

45.77

45.76

45.75

45.74

45.73

45.72

Combined oxidative phosphorylation deficiency type 14 Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis Combined oxidative phosphorylation deficiency type 21 Myopathy lactic acidosis and Sideroblastic Anaemia type 2 Combined oxidative phosphorylation deficiency type 20 Mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with or without seizures Charcot-Marie-tooth disease type 2D; distal hereditary motor neuronopathy type 5A

Perrault syndrome type 2

45.66

45.71

Disorder Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit C deficiency

No. 45.65

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA 853

854

I. J. Holt et al.

Metabolic Pathway Nucleotide metabolism Tymp TK2 DGUOK RRM2B SUCLA2

Transcription

MPV17 SUCLG1 ANT1 CMPK2

5’

(2)

H-strand

HSP

12S rRNA (MT-RNR1)

disease associated mtDNA mutations

POLRMT TFB2M TFAM TEFM

(3)

F

3’

non-coding region

V

16S rRNA (MT-RNR2)

T

L-strand

L

LSP

cyt b

P

5’

Replication

Q

W HS

Pd

d LSP

er iv

ed

er i d ve

po

R G

l yc is

tr

ic

tra n

r ip

K

COX II t

ATPase6 ATPase8

ND1

3’ RNA turnover

RNase P RNase Z

PNPT1 SUPV3L1 GRSF1 SSBP1

ELAC2 tRNA 5’ and 3’ MRPP1 (TRMT10C) processing MRPP2 (4) (HSD17B10) MRPP3

12S rRNA 16S rRNA

NSUN4 TFB1m

MRM1 MRM3 RPUSD4 TRMT61B

(5)

Mitoribosome assembly 82 ribosomal proteins incl. MRPL3, MRPL12,MRPL44, MRPS2, MRPS7, MRPS16, MRPS22, MRPS23, MRPS25, MRPS34 Other proteins involved MTERF4 MTERF3 DDX28 AFG3L2 DHX30 SPG7 MTG1 FASTKD2 MTG2 ERAL1 MALSU1 MPV17L2 NOA1

tRNA modification PUS1 GTPBP3 RPUSD4 MTO1 TRMT1 YRDC TRMT5 OSGEPL1 MRPP1 NSUN3 MRPP2 ABH1 TRMU CDK5RAP1 TRIT1 TRNT1 PDE12

(5)

mRNA processing/ modification MTPAP FASTKD2 PDE12 FASTKD5 TRUB2(?) TRMT61B(?) RPUSD3(?) MRPP1(?) MRPP2(?)

AAAAAAAA Aminoacylation

(6) MRPs + 12S rRNA MRPs + 16S rRNA

19 aminoacyl-tRNA synthetases MTFMT QRSL1 GATB GATC

Complex I

Translation & translation control

mRNAs

rRNA modification 12S 16S

ND4L

ND3

COX III

D sc

S

ND4

S

16S rRNA

12S rRNA

H

p

COX I on

5’

L

yc

N C Y

ND5

mtND1-6, mtND4L +38 nuclear encoded subunits

LRPPRC SLIRP TACO1 RMND1 GFM1 GFM2 TSFM TUFM C12orf65 MTIF2 MTIF3 MTRF1 MTRF1L ICT1 PTCD3

OXPHOS enzyme complexes

A

ND2

(1)

ND6

ol

M

E a n s cr ipt

POLG POLG2 TWNK TFAM SSBP1 TOP3a MGME1 RNASEH1 POLRMT DNA2(?)

ic tr

I

ron

3’

ist

ND1

(7) (8)

AAAAAAAA

Complex II 4 nuclear subunits Complex III mtCyt b + 10 nuclear encoded subunits Complex IV mtCOX I-III + 11 nuclear encoded subunits Complex V mtATP6/8 + 12 nuclear encoded subunits

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

855

Signs and Symptoms Table 45.1  Mitochondrial depletion syndrome 4A System CNS

Digestive Eye Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Ataxia Developmental delay Epilepsy, intractable Hypotonia Intellectual disability Retardation, psychomotor Liver failure, progressive Vomiting Vision, impaired Death Valproate induced fatal liver toxicity 3-Methylglutaconic acid (urine) Lactate (plasma) Mitochondrial DNA (liver)

Infancy (1–18 months) ++ ++ +++ ++ ++ +++ +++ + + ++ +++ ↑ ↑ ↓↓↓

Childhood (1.5–11 years) ++ ++ +++ ++ ++ +++ +++ + + ++ +++ ↑ ↑ ↓↓↓

Adolescence (11–16 years)

Adulthood (>16 years)

Adulthood (>16 years)

Table 45.2  Mitochondrial depletion syndrome 4B System CNS Digestive

Ear

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Axonal sensory ataxic neuropathy Cachexia Chronic gastrointestinal dysmotility Liver failure, progressive Pseudo-obstruction Hearing loss Progressive external ophthalmoplegia Muscle weakness Death 3-Methylglutaconic acid (urine) Lactate (plasma) Mitochondrial DNA (liver) Mitochondrial DNA (muscle)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) +

+ +

+ ++

++ +++

+++ +++

+ ±

± ++ ±

± +++ ± ±

+

↓-n ↓↓↓

++ ++ ↑ ↑ ↓-n ↓↓↓

++ ++ ↑ ↑ ↓-n ↓↓↓

+++ + ++

↓↓↓

Fig. 45.1  Pathways and proteins involved in mitochondrial DNA replication, transcription and translation. Mitochondrial DNA (mtDNA) is a small double-stranded circular molecule that has a relatively simple machinery for its replication (1). Both strands serve as template for the transcription machinery (2) that initiates at the H-strand promoter (HSP) or the L-strand promoter (LSP), to give two large primary polycistronic transcripts here called ‘HSP derived polycistronic’ and ‘LSP derived polycistronic’ transcript. MtDNA replication requires deoxyribonucleotides provided by interconnected de novo and salvage pathways (3). Primary transcripts are interspersed with tRNA transcripts represented here by the standard tRNA cloverleaf structure. Endonucleolytic cleavage of the tRNAs at both ends by RNaseP and RNaseZ yields the two pre ribosomal RNAs (rRNA, 12S and 16S), pre tRNAs and pre mRNAs (4). These are all further processed (5) and in particular both rRNAs and all tRNAs are further modified at specific nucleoside positions, whilst all RNA types are also oligo/poly adenylated. Ribosomal RNAs together with mt tRNA(Val) (not indicated) are assembled into mature ribosomes (6) that include 82 nuclear encoded mitoribosomal proteins. This process involves approximately 15 so far identified additional ‘assembly’ factors, some of which have been associated with mitochondrial disease. The tRNAs after extensive modification are matured by 3′CCA addition (not indicated) and are now ready to be aminoacylated by 19 aminoacyl-­tRNA synthethases (7), all of which have been associated with mitochondrial disease. There is no dedicated enzyme to charge the glutamine (Q)-tRNA but instead it is charged with glutamate that is converted to glutamine by the trimeric Glu-tRNA (Gln) amidotransferase complex consisting of GATA (QRSL1), GATB and GATC subunits. All these various pathways come together so that the 11 mitochondrial mRNAs that direct the synthesis of 13 essential subunits of four of the five oxidative phosphorylation complexes can be translated by the dedicated mitochondrial ribosomes and charged tRNAs (as indicated, (8)). A considerable number of additional nuclear encoded factors are involved in this process, for example to recycle tRNAs, and to assist in the initiation, elongation and termination of protein synthesis. Mitochondria also have a machinery to degrade dysfunctional RNA as well as long non-coding RNAs that are mostly derived from LSP initiated transcription. In total almost 200 nuclear-encoded mitochondrial proteins are here indicated to be involved in the process of mtDNA maintenance and expression, of which some 80 (here indicated in red) have so far been associated with mitochondrial disease. In addition, all mitochondrial tRNA genes have been associated with disease (indicated here with a red dot on the tRNAs of the two polycistronic transcripts), whilst one rRNA mutation [m. 1555A>G in 12S (MT-RNR1); also indicated with a red dot on mtDNA] is known principally for its association with aminoglycoside-induced hearing loss

856

I. J. Holt et al.

Table 45.3  Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) Neonatal Infancy System Symptoms and biomarkers (birth–1 month) (1–18 months) CNS (Epileptic) seizures Dysarthria Headaches and/or migraine Mild cognitive impairment Sensory ataxic neuropathy Eye Ophthalmoparesis or ophthalmoplegia Laboratory Mitochondrial DNA findings deletions (muscle)

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

+ ±

+ ±

↑

↑

Adulthood (>16 years) + +++ + ± +++ ++ ↑

Table 45.4  Progressive external ophthalmoplegia 1 Symptoms and biomarkers Cardiac involvement Ataxia Parkinsonism Sensory ataxic neuropathy Ear Hearing loss Endocrine Hypogonadism Eye Ophthalmoparesis or ophthalmoplegia Metabolic Ragged red fibers Musculoskeletal Muscle weakness and/ or exercise intolerance Psychiatric Depression Laboratory findings Histochemical cytochrome c oxidase deficiency (muscle) Multiple mtDNA deletions (muscle) System Cardiovascular CNS

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± ± ± ± ± ± ++ + ++ ± ↑↑ ↑↑

Table 45.5  Mitochondrial DNA polymerase g accessory subunit deficiency (n = 1) System Cardiovascular CNS Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiac, anomalies, malformations Fatigue Ophthalmoplegia Ptosis of eyelid Muscle weakness, proximal Histochemical cytochrome c oxidase deficiency (muscle) Multiple mtDNA deletions (muscle)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + + + + ↑↑ ↑↑

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

857

Table 45.6  Mitochondrial deoxyguanosine kinase deficiency System Autonomic system CNS

Digestive

Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Noncirrhotic portal hypertension Hypotonia Neurologic abnormalities Regression, psychomotor Cholestasis Hepatomegaly Jaundice Liver failure Neonatal hemochromatosis Nystagmus Ophthalmoplegia Ptosis of eyelid Myopathy Death Activity respiratory chain complexes (I, III, IV, and V) Alpha-fetoprotein (serum) Cystathionine (urine) Ferritin (serum) Gamma-glutamyl transpeptidase, GGT (plasma) Glucose (plasma) Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitochondrial proliferation (muscle) Lactate (CSF) Lactate (plasma) mtDNA levels (liver & brain) Multiple mtDNA deletions Phenylalanine (plasma) Succinylacetone (urine) Transaminase (plasma) Tyrosine (plasma)

Neonatal (birth–1 month) +

Infancy (1–18 months) ±

+++ +++

+++ +++

+++

+++

+++ +++ +++ +++ ±

+++ +++ +++ +++

+++

++ ↓↓↓

+++ ± ± ± ++ ↓↓↓

↑↑

↑↑

↑↑ ↑↑

± ↑↑ ↑↑

↓↓↓

↓↓↓

Childhood (1.5–11 years) +

Adolescence (11–16 years)

Adulthood (>16 years)

++ ++ ++ ++

+ ++ ↓↓

↓

+

+

↑ ↑

↑↑ ↑↑ ↓↓↓

↑↑ ↑↑ ↓↓↓

↓↓ ↑

↑ n

↑ n

↑↑ ↑

↑↑ ↑

858

I. J. Holt et al.

Table 45.7  MPV17 deficiency System CNS

Digestive

Eye

Musculoskeletal Renal Other Laboratory findings

Symptoms and biomarkers Developmental delay Hypotonia Neurologic abnormalities Peripheral neuropathy Cholestasis Gastrointestinal dysmotility Hepatomegaly Jaundice Liver failure Corneal anesthesia & ulcers Ophthalmoplegia Ptosis of eyelid Myopathy Renal tubulopathy Death Failure to thrive Activity respiratory chain complexes (I, III, IV, and V) Gamma-glutamyl transpeptidase, GGT (plasma) Glucose (plasma) Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitochondrial proliferation (muscle) Lactate (CSF) Lactate (plasma) mtDNA levels Mutiple mtDNA deletions Transaminases (plasma)

Neonatal (birth–1 month) +++ +++ +++

Infancy (1–18 months) +++ +++ +++

+++ ±

+++ ±

+++ +++ +++

+++ +++ +++

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

± +

± +

±

+ + +

+ + + ±

± + + +

± +++ +++ ↓↓↓

± ++ +++ ↓↓↓

↑↑

↑↑

↓↓

↓↓

+

+

+

↓↓

↓

↑ ↑

↑ ↑ ↓↓↓

↑ ↑ ↓↓↓

↑↑

↑↑

↑ ↑ ↓↓

↑

Table 45.8  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 System Cardiovascular CNS

Endocrine Eye Musculoskeletal Psychiatric Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cardiac abnormalities Ataxia Fatigue Parkisonism Sensory neuropathy Endocrine abnormalities Ophthalmoplegia Ptosis of eyelid Proximal muscle weakness Depression Histochemical cytochrome c oxidase deficiency (muscle) Multiple mtDNA deletions (muscle)

Infancy (1–18 months)

Childhood (1.5–11 years)

n-↑

Adolescence (11–16 years) ± ± ± ± ± ± ± ± ± ± n-↑

Adulthood (>16 years) ± ± ± ± ± ± ++ ++ ± ± ↑↑

n-↑

n-↑

↑↑

± ±

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

859

Table 45.9  Mitochondrial DNA depletion syndrome type 7 System CNS

Digestive Ear Endocrine Eye

Other Laboratory findings

Symptoms and biomarkers Ataxia Athetosis Epileptic seizures Hypotonia Intellectual disability Peripheral sensory neuropathy Retardation, psychomotor Liver dysfunction Hearing loss Hypogonadism Abnormal eye movements Ophthamoplegia Optic atrophy Death Lactate (plasma) Mitochondrial DNA (liver)

Neonatal (birth–1 month)

Infancy (1–18 months)

±

± ± +

Childhood (1.5–11 years) ++ ++ ± + ±

Adolescence (11–16 years) ++ ++ ± + + +

Adulthood (>16 years) +++ + ± + + ++

± ±

+

+

+

+

±

+ ± n.a. + ±

++ ± n.a. + ±

± ++ + (F)

± +++ + (F) + + ±

↑ ↓↓↓

± ↑ ↓↓↓

+ + ± ↓-n

↓-n

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) +

Adulthood (>16 years) ++ ++

++

+++

+++

+++ ↓ ↑↑

+++ ↓ ↑↑

n-↑ ↑

n-↑ ↑

Table 45.10  Perrault syndrome 5 System CNS

Ear Genitourinary Laboratory findings

Symptoms and biomarkers Ataxia Neuropathy, sensory axonal Hearing loss, sensorineural Ovarian dysgenesis Estradiol (plasma) Follicle-stimulating hormone (plasma) Lactate (plasma) Luteinizing hormone (plasma)

Neonatal (birth–1 month)

Table 45.11  Mitochondrial thymidine kinase deficiency System CNS

Eye Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Central nervous system manifestation Hypotonia Neuropathy, peripheral Ophthalmoparesis Ophthalmoplegia Myopathy Spinal muscle atrophy-like phenotye (type 3) Death Creatine kinase (plasma) Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitocondrial proliferation (muscle) Lactate (plasma) mtDNA deletions (muscle) mtDNA levels (muscle)

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+++

+

+ ± ± ± +

±

+++

± ± ++ ±

++ ++ + ±

↑↑ ↑↑

+ ↑↑ ↑

+ ↑↑ ↑

↑↑ ↑

+ ↑↑ ↑

↑

↑

↑

↑

↑

↑ ↑ ↓

↑ ↑ ↓

↑ ↑ ↓

↑ ↓

↑ ↑ ↓

860

I. J. Holt et al.

Table 45.12  Mitochondrial DNA depletion syndrome 8 System CNS

Digestive Ear Eye Renal Other Laboratory findings

Symptoms and biomarkers Encephalomyopathy Hypotonia Neuropathy, peripheral Gastrointestinal dysmotility Hearing loss Ophthalmoplegia Renal tubulopathy Death Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitocondrial proliferation (muscle) Lactate (P/CSF) mtDNA deletions (muscle) mtDNA levels (muscle)

Neonatal (birth–1 month)

Infancy (1–18 months) + ± ±

Childhood (1.5–11 years) + + +

+

+

+ ↑

+ +++ ↑

+ +

↑

↑

↑

↑ ↑ ↓

↑ ↑ ↓

↑ ↑ ↓

+

Adolescence (11–16 years)

Adulthood (>16 years) ± ± ±

± + ↑

Table 45.13  Thymidine phosphorylase deficiency System CNS

Digestive

Metabolic Musculoskeletal Laboratory findings

Symptoms and biomarkers Areflexia Hypodense white matter Leukoencephalopathy Neuropathy, myelinating Abdominal pain Anorexia Diarrhea Gastrointestinal dysmotility Gastroparesis Intestinal pseudo obstruction Malabsorption Malnutrition, chronic Vomiting Ragged red fibers Muscle weakness Myopathy Deoxyuridine (plasma) Deoxyuridine (urine) Lactate (plasma) Thymidine (plasma) Thymidine (urine) Thymidine phosphorylase (white blood cells)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) + + + + + + + +

Adulthood (>16 years) + + + + + + + +

+ +

+ +

+ + + + + + ↑ ↑↑ ↑↑ ↑ ↑↑ ↓↓↓

+ + + + + + ↑ ↑↑ ↑↑ ↑ ↑↑ ↓↓↓

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

861

Table 45.14  DNA2 deficiency System CNS Eye Musculoskeletal Respiratory Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Fatigue Ophthalmoplegia Ptosis of eyelid Muscle weakness, proximal Dyspnea Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitochondrial proliferation (muscle) Multiple mtDNA deletions (muscle)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ±

Adulthood (>16 years) + + + +

± ↑

+ ↑

↑

↑

↑

↑

Table 45.15  RNASEH1 defect System CNS Digestive Eye Musculoskeletal Respiratory Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Ataxia Fatigue Dysphagia Ophthalmoplegia Ptosis of eyelid Muscle weakness, proximal Dyspnea Orthopnea Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitocondrial proliferation (muscle) Multiple mtDNA deletions (muscle)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ± ± ±

Adulthood (>16 years) ± ++ ± +++ ++ ++

n-↑

± ± n-↑

± ± ↑↑

±

±

↑↑

±

±

+

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ± ± ±

Adulthood (>16 years) + ++ ± +++ ++ ++

± ± ↑

+ + ± ↑

↑

↑

n-↑ n-↑

↑ ↑

± ±

Table 45.16  MGME1 deficiency System CNS

Eye Musculoskeletal Respiratory Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cerebellar atrophy (MRI) Fatigue Intellectual disability Ophthalmoplegia Ptosis of eyelid Muscle weakness, proximal Dyspnea Respiratory failure Death Histochemical cytochrome c oxidase deficiency (muscle) Histochemical mitocondrial proliferation (muscle) mtDNA levels (muscle) Multiple mtDNA deletions

Infancy (1–18 months)

862

I. J. Holt et al.

Table 45.17  FBXL4 deficiency System Cardiovascular CNS

Digestive Renal Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cardiomyopathy, hypertrophic Ataxia Cerebellar hypoplasia Cerebral atrophy (MRI) Developmental delay Encephalopathy Hypotonia Microcephaly Gastrointestinal dysmotility Renal tubular acidosis Death Lactate (plasma) mtDNA levels (muscle and fibroblasts) Respiratory chain enzymes (muscle and cells)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

+ + ++ + + +++ + + + + ↑ ↓↓

+ + ++ + + +++ + + + + ↑ ↓↓

↓

↓

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+

Table 45.18  TOP3A deficiency (n = 1) System Cardiovascular CNS Ear Eye Musculoskeletal

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cardiac, anomalies, malformations Ataxia Neuropathy, sensory Hearing loss, sensorineural Ophthalmoplegia Ptosis of eyelid Exercise intolerance Muscle weakness, proximal Histochemical cytochrome c oxidase deficiency (muscle) Multiple mtDNA deletions (muscle) Ragged red fibers

Adolescence (11–16 years)

Adulthood (>16 years) + + + + ++ ++ + + ↑↑ ↑↑ ↑↑

Table 45.19  ATP-specific succinyl-CoA ligase β subunit deficiency System CNS

Digestive Ear

Symptoms and biomarkers Axial hypotonia Choreoathetosis Dystonia Leigh syndrome Neurological symptoms Neuropathy, peripheral Pyramidal signs Retardation, psychomotor Feeding difficulties Deafness, sensorineural

Neonatal (birth–1 month) + ± − − ++ − − ±

Infancy (1–18 months) ++ ± ± ± ++ − ± ++

Childhood (1.5–11 years) ++ ± + + ++ ± + ++

Adolescence (11–16 years) + ± ++ ++ ++ ± ++ ++

Adulthood (>16 years) + ± ++ ++ ++ ± ++ ++

± ±

± ++

± ++

+ ++

+ ++ (continued)

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

863

Table 45.19 (continued) System Metabolic Other Laboratory findings

Symptoms and biomarkers Lactic acidosis Failure to thrive ASAT/ALAT (plasma) C4-DC Methylmalonylcarnitine (urine) C4-DC Succinylcarnitine (urine) Lactate (plasma) Lactate/pyruvate ratio Methylmalonic acid (urine) mtDNA levels Respiratory chain enzyme deficiencies (muscle)

Neonatal (birth–1 month) + + n-↑ ↑

Infancy (1–18 months) + + n-↑ ↑

Childhood (1.5–11 years) + + n-↑ ↑

Adolescence (11–16 years) + + n-↑ ↑

Adulthood (>16 years) + + n-↑ ↑

↑

↑

↑

↑

↑

↑ ↑ ↑ ↓

↑ ↑ ↑ ↓ ↓

↑ ↑ ↑ ↓ ↓

↑ ↑ ↑

↑ ↑ ↑

Infancy (1–18 months) ± ± ++ ± ± ++

Childhood (1.5–11 years) ± ± ++ ± + ++

Adolescence (11–16 years) ± ± + ± ++

++ ± ++

++ n-↑ ↑

± ++ ± ++ ± ± + + ++ n-↑ ↑

++ + ++ ± + ++ ± ++ ± ± + + ++ n-↑ ↑

++ ++ ++ ± ++ ++ ± ++ + ± + + ++ n-↑ ↑

↑

↑

↑

↑

↑

↑ ↑ ↑ ↓ ↓

↑ ↑ ↑ ↓ ↓

↑ ↑ ↑ ↓ ↓

↑ ↑ ↑

↑ ↑ ↑

Table 45.20  GTP-specific succinyl-CoA ligase α subunit deficiency System Cardiovascular CNS

Digestive Ear Metabolic Other Laboratory findings

Symptoms and biomarkers Congenital heart defects Ataxia Axial hypotonia Choreoathetosis Dystonia Encephalopathy, necrotizing Hypotonia Leigh syndrome Neurological symptoms Neuropathy, peripheral Pyramidal signs Retardation, psychomotor Seizures Feeding difficulties Liver dysfunction Deafness, sensorineural Lactic acidosis Death Failure to thrive ASAT/ALAT (plasma) C4-DC Methylmalonylcarnitine (urine) C4-DC Succinylcarnitine (urine) Lactate (plasma) Lactate/pyruvate ratio Methylmalonic acid (urine) mtDNA levels Respiratory chain enzymes (muscle)

Neonatal (birth–1 month) ± + ±

++

± ++ ± ± +

Adulthood (>16 years) ± + ± ++

++ ++ ± ++ ++ ++ + ± + ++ n-↑ ↑

864

I. J. Holt et al.

Table 45.21  Adenine nucleotide translocator deficiency, Ophthalmoplegia type System Eye

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Hearing loss, sensorineural Ophthalmoplegia Ptosis of eyelid Histochemical cytochrome c oxidase deficiency (muscle) Multiple mtDNA deletions (muscle)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± ++ ++ ↑ ↑

Table 45.22  Adenine nucleotide translocator deficiency, cardiomyopathic type System Cardiovascular CNS

Musculoskeletal Respiratory Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Hyporeflexia and/or paucity of movement Hypotonia Muscle weakness, proximal Respiratory dysfunction Death Lactate (cerebrospinal fluid) Lactate (plasma) mtDNA levels (muscle)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years)

Adulthood (>16 years)

++

++

++

+++

+++

+++ +

++ ++ ↑

++ ++ ↑

++

↑↑↑ ↓↓↓

↑↑ ↓↓↓

↓↓↓

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) +

+

+

Table 45.23  Adenine nucleotide translocator deficiency AD System Cardiovascular Musculoskeletal CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Exercise intolerance Fatigue Muscle atrophy Muscle weakness Histochemical cytochrome c oxidase deficiency (muscle) Lactate (plasma) Lactate (plasma) Multiple mitochondrial DNA deletions (muscle) Ragged red fibers

Neonatal (birth–1 month)

↑↑ ↑↑

+ + ± ± ↑↑ ↑↑ ↑↑ ↑↑

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

865

Table 45.24  PNPT1 deficiency System CNS Digestive Ear Eye Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Dystonia Hypotonia Dysphagia Feeding difficulties Deafness Nystagmus Muscle weakness Death Failure to thrive Lactate (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± ± ++ ± ± ± ± n-↑

Childhood (1.5–11 years) ± ± ± ± +++ ± ± ± ± n-↑

Adolescence (11–16 years) ± ± ± ± +++ ± ±

Adulthood (>16 years)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Infancy (1–18 months) +++

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

Adulthood (>16 years)

+

+

+

+ +

+ +

+

+ ↑↑

+ ↑↑

±

Table 45.25  Ribonuclease P 5′ tRNA processing enzyme deficiency (n = 1) System CNS Digestive Ear Other Laboratory findings

Symptoms and biomarkers Hypotonia Feeding difficulties Deafness, sensorineural Death Multi organ involvement Histochemical cytochrome c oxidase deficiency (muscle) Lactate (cerebrospinal fluid) Lactate (plasma) Ragged red fibers

Neonatal (birth–1 month) ++ + + ±

Infancy (1–18 months) ++ + + + ± ↑↑

↑↑

↑↑

↑↑

↑↑ ↑↑

Table 45.26  Ribonuclease Z 3′ tRNA processing enzyme deficiency System Cardiovascular CNS

Other

Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Delayed psychomotor development Hypotonia Death Intrauterine growth retardation Poor growth Lactate (plasma)

Neonatal (birth–1 month)

866

I. J. Holt et al.

Table 45.27  TFAM deficiency System Digestive Other Laboratory findings

Symptoms and biomarkers Liver failure Death mtDNA levels (liver and muscle)

Neonatal (birth–1 month)

Infancy (1–18 months) + + ↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Notes: Whilst this is undoubtedly a form of mtDNA depletion syndrome it is not yet certain that the TFAM variant is pathological, as low levels of TFAM protein are a feature of all forms of MTDPS

Table 45.28  PNPT1 deficiency System CNS

Ear Eye Respiratory Other

Neonatal Symptoms and biomarkers (birth–1 month) Encephalomyopathy Hypotonia Leukodystrophy Movement abnormalities Deafness Optic atrophy Respiratory chain enzymes Death

Infancy (1–18 months) + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + + ↓ ±

±

Infancy (1–18 months)

Childhood (1.5–11 years) ± ± ± ± ↓

Adolescence (11–16 years) + + + + ↓

Adulthood (>16 years) + + + + ↓

Neonatal (birth–1 month)

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

±

±

±

±

Adulthood (>16 years) ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ± + ↓-n

Adolescence (11–16 years) ± ± ± ± ± ±

Adulthood (>16 years) ± ± ± ± ± +

↓ +

Table 45.29  Mitochondrial Poly(A) Polymerase deficiency System CNS

Eye Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Ataxia, cerebellar Dysarthria Spastic paraparesis Optic atrophy Respiratory chain enzymes (I and IV)

Table 45.30  CCA-adding tRNA-nucleotidyltransferase deficiency System CNS Eye Hematological

Symptoms and biomarkers Developmental delay Intellectual disability Retinitis pigmentosa Microcytosis Sideroblastic anemia (with B-cell immunodeficiency)

Table 45.31  Mitochondrial methionyl-tRNA formyltransferase deficiency System CNS

Other Laboratory findings

Symptoms and biomarkers Ataxia Developmental delay Hypotonia Intellectual disability Leigh syndrome Death Respiratory chain enzymes

Neonatal (birth–1 month) ± ± ± ↓-n

Infancy (1–18 months) ± ± ± ± ± ± ↓-n

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

867

Table 45.32  tRNA 5-taurinomethyluridine modifier deficiency System Cardiovascular CNS Metabolic Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Hypotonia Intellectual disability Lactic acidosis Lactate (plasma) Mitochondrial complex I and IV activity (muscle) Protein levels of GTPBP3 in fibroblasts

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± n-↑ ↓

± ± ± n-↑ ↓

± ± ± n-↑ ↓

± ± ± n-↑ ↓

± ± ± n-↑ ↓

↓

↓

↓

↓

↓

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ↓

± ± ± ± ± ± ↓

± ± ± ± ± ± ↓

± ± ± ± ± ± ↓

± ± ± ± ± ± ↓

n-↑

n-↑

n-↑

n-↑

n-↑

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

±

±

↑

↑

++ ± + ↑↑ ↑

++ ± + ↑↑ ↑

++ ± + ↑↑ ↑

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

±

±

↑

↑

++ ± + ↑↑ ↑

++ ± + ↑↑ ↑

++ ± + ↑↑ ↑

Table 45.33  tRNA 5-carboxymethylaminomethyl transferase deficiency System Cardiovascular CNS

Digestive Eye Metabolic Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Ataxia Developmental delay Epilepsy Feeding difficulties Optic atrophy Lactic acidosis Complex I and IV acitvity in muscle Lactate (plasma)

Neonatal (birth–1 month)

± ±

Table 45.34  Pseudouridine synthase 1 deficiency System Cardiovascular Hematological Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Anemia, sideroblastic Dysmorphic features Exercise intolerance Lactate (plasma) Multiple mtDNA deletions (muscle)

Table 45.35  Pseudouridine synthase 1 deficiency System Cardiovascular Hematological Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Anemia, sideroblastic Dysmorphic features Exercise intolerance Lactate (plasma) Multiple mtDNA deletions (muscle)

868

I. J. Holt et al.

Table 45.36  tRNA methyltransferase 5 deficiency System Cardiovascular Endocrine Metabolic Musculoskeletal Renal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Glucose intolerance Lactic acidosis Exercise intolerance Renal tubulopathy Failure to thrive Lactate (plasma) Multiple oxidative phosphorylation enzymes (muscle)

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

± ±

± ±

± ± ± ±

± ± ± ±

± n-↑ ↓

± n-↑ ↓

n-↑ ↓

n-↑ ↓

n-↑ ↓

Neonatal (birth–1 month) ++ + +++ + ++ ++ ↓

Infancy (1–18 months) +++ + +++ + ++ ++ ↓

Childhood (1.5–11 years) n n ± n n n ↓

Adolescence (11–16 years) n n n n n n ↓

Adulthood (>16 years)

n

Childhood (1.5–11 years) +++ +++ +

Adolescence (11–16 years) +++ +++ ±

Adulthood (>16 years) +++ +++ ±

Table 45.37  Acute infantile liver failure TRMU System Digestive

Hematological Laboratory findings

Symptoms and biomarkers Hepatosplenomegaly Jaundice Liver failure Pancreatic failure Vomiting Coagulopathy Multiple oxidative phosphorylation enzymes

↓

Table 45.38  Mitochondrial RNA-processing endoribonuclease deficiency System Musculoskeletal Hematological

Symptoms and biomarkers Cartilage hypoplasia Chondrodysplasia Lymphopenia

Neonatal (birth–1 month) +++ +++ +

Infancy (1–18 months) +++ +++ +

Notes: Although some reports link this RNA to mtDNA replication, one study found a maximum of one molecule MRP per cell to reside in mitochondria, with the vast majority localizing to the nucleoli (PMID: 1377982). Therefore, it is not certain this is a mitochondrial disease, and the clinical features are not a good match for established mtDNA disorders.

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

869

Table 45.39  2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency System Cardiovascular CNS

Ear Eye Metabolic

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Basal ganglia lesions (MRI) Brain atrophy (MRI) Choreoathetosis Dysarthria Dystonia Frontotemporal atrophy (MRI) Frontotemporal atrophy (MRI) Movement disorder Periventricular white matter changes Regression, psychomotor Retardation, psychomotor Seizures Spasticity Hearing loss, sensorineural Vision, decreased Hypoglycemia Ketoacidosis Lactic acidosis Metabolic acidosis Rigidity Most patients are male 17-Beta-hydroxysteroid dehydrogenase type 10 (fibroblasts) 2-Methyl-3-hydroxybutyric acid (urine) C5:1 Tiglylcarnitine (blood) C5:1 Tiglylcarnitine (plasma) C5-OH 2-Methyl-3hydroxy-butyrylcarnitine (blood) C5-OH 2-Methyl-3hydroxy-butyrylcarnitine (plasma) Glucose (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Lactate (plasma) Tiglylglycine (urine)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) + ±

Childhood (1.5–11 years) + ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ±

± ± ± ± ±

± ± ± + ±

± ± + + ±

± ± + + ±

± ± + + ±

±

±

+

+

+

± ±

± ±

± ±

± ±

± ±

± ±

+ +

+ +

+ +

+ +

± ± ± ± ± ± ± ±

+ ± ± ± ± ± + ±

+ ↓

+ ↓

+ ± ± ± ± ± + ± ± + ↓

± ± ± ± ± ± ± ± ± + ↓

± ± ± ± ± ± ± ± ± + ↓

↑

↑

↑

↑

↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

↓-n n-↑

↓-n n-↑

↓-n n-↑

↓-n n-↑

↓-n n-↑

n-↑ n-↑ ↑

n-↑ ↑ ↑

n-↑ ↑ ↑

n-↑ n-↑ ↑

n-↑ n-↑ ↑

870

I. J. Holt et al.

Table 45.40  Mitochondrial ribosomal large subunit 3 deficiency MRPL3 System Cardiovascular Digestive Ear Metabolic Renal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Liver cirrhosis Hearing loss, sensorineural Lactic acidosis Tubulointerstitial nephritis Lactate (plasma) Multiple oxidative phosphorylation enzymes

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

± ± ± ± n-↑ ↓

± ± ± ± n-↑ ↓

± ± ± ± n-↑

Adolescence (11–16 years)

Adulthood (>16 years)

Table 45.41  Mitochondrial ribosomal large subunit 12 deficiency MRPL12 System CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Neurological deterioration Growth retardation Multiple oxidative phosphorylation enzymes (fibroblasts)

Neonatal (birth–1 month) ± ± ↓

Infancy (1–18 months) ± ± ↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ↓

± ± ± ↓

± ± ± ↓

± ± ± ↓

± ± ± ↓

Neonatal (birth–1 month)

Infancy (1–18 months) ± + ±

Childhood (1.5–11 years) ± ++ ± ++

Adolescence (11–16 years) ± ++ ± ++

Adulthood (>16 years)

±

±

+ ± ↓ ↑ ↓↓

+ ± ↓ ↑

Table 45.42  Mitochondrial ribosomal large subunit 44 deficiency System Cardiovascular Digestive Eye Renal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Liver steatosis Pigmentary retinopathy Renal insufficiency Mitochondrial complexes I and IV activity (heart and skeletal muscle)

Table 45.43  Mitochondrial ribosomal small subunit 2 deficiency System CNS Dermatological Ear Metabolic Musculoskeletal Laboratory findings

Symptoms and biomarkers Developmental delay Hypotonia Skin involvement Hearing loss, sensorineural Hypoglycemia Dysmorphic features Glucose (plasma) Lactate (plasma) Multiple oxidative phosphorylation enzymes (liver, muscle)

↓↓

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

871

Table 45.44  Mitochondrial ribosomal small subunit 7 deficiency System Ear Digestive Endocrine Metabolic Renal Laboratory findings

Symptoms and biomarkers Hearing loss, sensorineural Liver failure Hypogonadism Hypoglycemia Renal dysfunction Glucose (plasma) Lactate (plasma) Multiple oxidative phosphorylation enzymes (liver)

Neonatal (birth–1 month) +++

Infancy (1–18 months) +++

+

Childhood (1.5–11 years) +++

Adolescence (11–16 years) +++

Adulthood (>16 years) +++

±

± ±

± ±

±

±

↓ ↑ ↓↓

+ ± ↓ ↑ ↓↓

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month) ++

Infancy (1–18 months) ++

Childhood (1.5–11 years) ++

Adolescence (11–16 years)

Adulthood (>16 years)

++

++

++

++ ++ ++ ± ± + ↑↑ ↑↑↑ ↓↓

++ ++

++ ++

↑

Table 45.45  Combined oxidative phosphorylation defect 2 (n = 1) System CNS

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Agenesis, corpus callosum (MRI) Hypotonia Minimal spontaneous movements Facial dysmorphism Death Lactate (plasma) Multiple oxidative phosphorylation enzymes (liver, muscle)

Neonatal (birth–1 month) ++ ++ ++ ± +++ ↑↑↑ ↓↓↓

Table 45.46  Combined oxidative phosphorylation defect 5 System Cardiovascular CNS

Dermatological Digestive Renal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Agenesis or hypoplasia of the corpus callosum (MRI) Developmental delay Hypotonia Edema, generalized Ascites Renal tubulopathy Death Ammonia (blood) Lactate (plasma) Multiple oxidative phosphorylation enzymes (muscle, fibroblasts)

+

↓↓

↓↓

872

I. J. Holt et al.

Table 45.47  Mitochondrial ribosomal small subunit 34 deficiency System CNS

Digestive Other Laboratory findings

Symptoms and biomarkers Developmental delay Leigh or Leigh-like syndrome Microcephaly Dysphagia Death Lactate (plasma) One or multiple oxidative phosphorylation enzymes (muscle, liver, fibroblasts)

Neonatal (birth–1 month) ± ±

↑↑ ↓↓

Infancy (1–18 months) + +

Childhood (1.5–11 years) ++ +

Adolescence (11–16 years) ++ +

Adulthood (>16 years) ++ +

± + + ↑↑ ↓↓

± +

±

±

↑ ↓↓

↑ ↓↓

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

Infancy (1–18 months) + + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + ± +

+

+ + ± + ++a

Infancy (1–18 months) ± ± + ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years)

± ±

±

↑ ↓

↑ ↓

↑ ↓

Table 45.48  Mitochondrial ribosomal RNA 12S deficiency System Ear

Symptoms and biomarkers Deafness

Neonatal (birth–1 month)

Table 45.49  Combined oxidative phosphorylation deficiency 11 System Cardiovascular CNS

Ear Renal Other Laboratory findings

Symptoms and biomarkers Cardiac abnormalities Cerebral atrophy (MRI) Hypotonia Intellectual disability Seizures Deafness Renal failure Death Encephalomyopathy Lactate (plasma) Respiratory chain enzymes

Neonatal (birth–1 month)

+

+ +

+ ↑ ↓

+ + + +++ + ↑ ↓

Two cases, kidney transplant

a

Table 45.50  Mitochondrial elongation factor G1 deficiency System CNS Digestive Other

Laboratory findings

Symptoms and biomarkers Encephalopathy Liver failure Death Delayed growth and development Lactate (plasma) Respiratory chain enzymes

Neonatal (birth–1 month) ± ± +

↑ ↓

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

873

Table 45.51  Mitochondrial elongation factor G2 deficiency System CNS

Endocrine Other

Laboratory findings

Symptoms and biomarkers Cerebellar atrophy (MRI) Hypotonia Microcephaly Diabetes mellitus Death Delayed growth and development Lactate (plasma) Respiratory chain enzymes—fibroblasts

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

± ± ±

± ± ± ±

↑ ↓

↑ ↓

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ± ±

±

±

± ±

±

± ↑ ↓

++ ± ↑ ↓

± ↑ ↓

±

± + ±

Infancy (1–18 months) ± ± ± ↑↑ ↓

Childhood (1.5–11 years) ± ± ± ↑↑ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Infancy (1–18 months) ± ± +

Childhood (1.5–11 years) ± ± +

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

± ± ±

± ± ± ± ± ↑

± ±

± ± ± ±

↑ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

±

Table 45.52  Mitochondrial elongation factor Ts deficiency System Cardiovascular CNS

Eye Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Ataxia Dystonia Hypotonia Optic atrophy Death Encephalomyopathy Lactate (plasma) Respiratory chain enzymes

Table 45.53  Mitochondrial elongation factor Tu deficiency System CNS Other Laboratory findings

Symptoms and biomarkers Encephalopathy Leukodystrophy Death Lactate (plasma) Respiratory chain enzymes

Neonatal (birth–1 month) ± ± ± ↑↑ ↓

Table 45.54  Combined oxidative phosphorylation deficiency 7 C12ORF65 System CNS

Eye Other Laboratory findings

Symptoms and biomarkers Cerebral atrophy (MRI) Hypotonia Retardation, psychomotor Spastic paraplegia Nystagmus Optic atrophy Death Encephalomyopathy Lactate (cerebrospinal fluid) Respiratory chain enzymes

Neonatal (birth–1 month) ±

± ± ±

↓

↓

↓

±

874

I. J. Holt et al.

Table 45.55  Mitochondrial tRNA(Leu) 1 deficiency System Cardiovascular CNS

Ear Endocrine Musculoskeletal

Renal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Encephalopathy Epilepsy Stroke like episodes Hearing loss Diabetes mellitus Exercise intolerance Myopathy Rhabdomyolysis Renal insufficiency Failure to thrive Alanine (plasma) Creatine kinase (plasma) Lactate (plasma)

Neonatal (birth–1 month) ± ± ±

± ± ↑ ↑ ↑

Table 45.56  Mitochondrial tRNA(Lys) deficiency Neonatal System Symptoms and biomarkers (birth–1 month) Cardiovascular Cardiomyopathy CNS Ataxia Dementia Epilepsy, generalized Myoclonic epilepsy Ear Hearing loss Musculoskeletal Myopathy Laboratory Histochemical cytochrome findings c oxidase deficiency (muscle) Lactate (cerebrospinal fluid) Lactate (plasma) One or multiple oxidative phosphorylation enzymes (muscle) Ragged red fibers

Infancy (1–18 months)

± ± ± ± ± ↑ ↑ ↑

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± ± ± ± ↑ ↑ ↑

Adolescence (11–16 years) ± ± ± ± ± ± ± ± ± ± ± ↑ ↑ ↑

Adulthood (>16 years) ± ± ± ± ± ± ± ± ± ± ± ↑ ↑ ↑

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) + + + + + + + ↑

Adulthood (>16 years) + + + ++ +++ + ++ ↑↑

↑

↑↑

↑ ↓

↑↑ ↓↓

↑

↑↑

Adolescence (11–16 years)

Adulthood (>16 years)

±

+

+ ±

+ + +

± ±

Table 45.57  Mitochondrial alanyl-tRNA synthetase deficiency System Cardiovascular CNS

Eye Genitourinary Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Ataxia Cerebellar atrophy (MRI) Developmental delay Leukoencephalopathy Nystagmus Ovarian failure Death Cytochrome c oxidase activity (skeletal muscle) Respiratory chain enzymes (heart)

Neonatal (birth–1 month) ++

Infancy (1–18 months) +

Childhood (1.5–11 years)

+ ±

+

± +

+

++

± ↓

↓

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

875

Table 45.58  Mitochondrial arginine-tRNA synthetase deficiency System CNS

Other Laboratory findings

Symptoms and biomarkers Encephalopathy Hypotonia Intellectual disability Microcephaly Myoclonic epilepsy Pontocerebellar hypoplasia (MRI) Progressive loss of cerebral white matter Death Lactate (plasma) Respiratory chain enzymes

Neonatal (birth–1 month) + + ± ± ++

++ ↑ ↓

Infancy (1–18 months) ± + ±

Childhood (1.5–11 years) ± + ±

Adolescence (11–16 years) ±

Adulthood (>16 years)

±

±

±

±

±

±

+

+

+

+

+ ↑ ↓

+ ↑ ↓

+ ↑ ↓

+ ↑ ↓

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

±

± ±

±

±

± ± ↑

Table 45.59  Mitochondrial asparaginyl-tRNA synthetase deficiency System CNS

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Agenesis of the corpus callosum Epilepsy Hypomyelination of the white matter Intellectual disability, severe Microcephaly Psychomotor developmental delay Retardation, psychomotor Myopathy, severe Death Histochemical mitochondrial proliferation (muscle) Lactate (plasma) Respiratory chain enzymes

Neonatal (birth–1 month) ±

±

± ± ± ±

±

±

±

±

±

↑

↑

↑

↑

Infancy (1–18 months)

Childhood (1.5–11 years) ± ± + ± ± ± ↑

Adolescence (11–16 years) ± ± + ± ± ± ↑

↓

Table 45.60  Mitochondrial aspartyl-tRNA synthetase deficiency System CNS

Other Laboratory findings

Symptoms and biomarkers Ataxia, cerebellar Cognitive decline Leukoencephalopathy Neuropathy, axonal Spasticity Death Lactate (plasma)

Neonatal (birth–1 month)

Adulthood (>16 years) ± ± ++ ± ± ± ↑

876

I. J. Holt et al.

Table 45.61  Combined oxidative phosphorylation deficiency 27 System CNS

Ear Eye Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Brain atrophy (MRI) Cognitive decline Delayed psychomotor development Encephalopathy ± Hypotonia Myoclonic and generalized tonic-clonic seizures Tetraparesis, progressive Hearing impairment Visual impairment Death Failure to thrive Lactate (plasma) mtDNA levels Respiratory chain enzymes (muscle/liver)

Infancy (1–18 months)

±

Childhood (1.5–11 years) + + ±

± ±

+

+ ± ± ± ± ↑

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

Adulthood (>16 years)

↓

↑ ↓ ↓

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years)

± ↑ ↓

± ↑ ↓

±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Table 45.62  Combined oxidative phosphorylation deficiency 12 System CNS

Other Laboratory findings

Symptoms and biomarkers Cerebellar atrophy (MRI) Hypotonia Psychomotor developmental delay Death Lactate (plasma) Respiratory chain enzymes

Neonatal (birth–1 month) ± ±

↑ ↓

Table 45.63  Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit A deficiency System Cardiovascular Metabolic Hematological Laboratory findings

Symptoms and biomarkers Cardiomyopathy, severe Fatal lactic acidosis Anemia Lactate (plasma)

Neonatal (birth–1 month) + + + ↑

Infancy (1–18 months) + + + ↑

Adulthood (>16 years)

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

877

Table 45.64  Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit B deficiency System Cardiovascular Hematological Metabolic Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Anemia Lactic acidosis Neonatal death Lactate (plasma)

Neonatal (birth–1 month) + + + + ↑

Infancy (1–18 months) + + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Infancy (1–18 months) + + + + ↑ ↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) +

Adulthood (>16 years) ++

+

+

↑

Table 45.65  Mitochondrial glutamyl-tRNA(Gln) amidotransferase subunit C deficiency System Cardiovascular Digestive Hematological Metabolic Laboratory findings

Symptoms and biomarkers Cardiomyopathy Hepatic dysfunction Anemia Lactic acidosis Creatine kinase (plasma) Lactate (plasma)

Neonatal (birth–1 month) + + + + ↑ ↑

Table 45.66  Mitochondrial histidyl-tRNA synthetase deficiency System Ear Genitourinary

Symptoms and biomarkers Hearing loss, sensorineural Ovarian dysgenesis

Neonatal (birth–1 month)

Table 45.67  Mitochondrial isoleucyl-tRNA synthetase deficiency System CNS Ear Endocrine Eye Musculoskeletal Other

Symptoms and biomarkers Hypotonia Neuropathy, sensory Hearing loss, sensorineural Growth hormone deficiency Cataract Skeletal dysplasia Death

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years) ± ± ±

Adulthood (>16 years) ± ± ±

±

±

±

±

±

± ± ±

± ± ±

± ± ±

± ± ±

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

±

Adolescence (11–16 years) + + ±

Adulthood (>16 years) + + ±

↑

↑

↑

Table 45.68  Perrault syndrome 4 System Ear Endocrine Eye Hematological Renal Other Laboratory findings

Symptoms and biomarkers Hearing loss Ovarian dysfunction Ptosis of eyelid Anemia, sideroblastic Renal disease Death Hydrops Lactate (plasma)

+ ± + + ↑↑

+ ↑↑

878

I. J. Holt et al.

Table 45.69  Mitochondrial methionyl-tRNA synthetase deficiency System CNS

Eye Genitourinary Musculoskeletal

Symptoms and biomarkers Ataxia Dysarthria Dystonia Hyperreflexia Leukoencephalopathy (MRI) Spasticity Nystagmus Neurogenic bladder Scoliosis

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ± ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ±

Adulthood (>16 years) ++ ± ± ++ ±

± ± ± ±

± ± ± ±

++ ± ± ±

Infancy (1–18 months) + + + + + + + +

Childhood (1.5–11 years) ++ + ++ + + + + ++

Adolescence (11–16 years)

Adulthood (>16 years)

Infancy (1–18 months) +

Adolescence (11–16 years) + + + +

Adulthood (>16 years)

+ + ± ± ↑ ↑

+

↑ ↑

Childhood (1.5–11 years) + + + + ± + + ± ± ↑ ↑

Infancy (1–18 months) ++ +

Childhood (1.5–11 years) ++ +

Adolescence (11–16 years) ++ +

Adulthood (>16 years)

+ ± ±

+ ± ±

+ ±

+ +

++ +

++ +

Table 45.70  Mitochondrial methionyl-tRNA synthetase deficiency (n = 2) System CNS Digestive Ear Musculoskeletal Other

Symptoms and biomarkers Hypotonia Retardation, psychomotor Constipation Gastroesophageal reflux Hearing loss, sensorineural Dysmorphic features Growth retardation Pectus carinatum

Neonatal (birth–1 month)

+ + +

Table 45.71  Mitochondrial phenylalanyl-tRNA synthetase deficiency System CNS

Genitourinary Musculoskeletal Laboratory findings

Symptoms and biomarkers Developmental delay Dysarthria Hyperreflexia Hypotonia Seizures Spasticity Tremor Urinary incontinence Scoliosis Alanine (plasma) Lactate (plasma)

Neonatal (birth–1 month)

±

+ + ± + +

+ +

Table 45.72  Mitochondrial phenylalanyl-tRNA synthetase deficiency System CNS

Other

Symptoms and biomarkers Developmental delay Diverse & variable CNS pathology Hypotonia Microcephaly Retardation, psychomotor Seizures Death

Neonatal (birth–1 month) +

±

±

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

879

Table 45.73  Mitochondrial seryl-tRNA synthetase deficiency System Cardiovascular Endocrine Hematological Metabolic Renal

Other

Laboratory findings

Symptoms and biomarkers Hypertension, pulmonary Diabetes mellitus Pancytopenia Hypochloremic metabolic alkalosis High FeMg fractional excretion Polyuria Renal failure, progressive Salt wasting Death Failure to thrive Global developmental delay Preterm birth Creatine (plasma) Lactate (plasma) Magnesium (plasma) Uric acid (plasma) Uric acid (urine)

Neonatal (birth–1 month) ++ + ± +

Infancy (1–18 months) ++ + ± ++

+

++

+ + + + ++ ++

++ ++ ++ +++ ++ ++

n.a. ↑↑ ↑↑ ↓ ↑↑ ↑

↑↑ ↑↑ ↓ ↑↑ ↑↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

++ ± + ++ ↑↑

++ ± + ++ ↑↑

++ ± + ++ ↑↑

Table 45.74  Mitochondrial threonyl-tRNA synthetase deficiency System CSF

Other Laboratory findings

Symptoms and biomarkers Delayed psychomotor development Hypertonia, limb Hypotonia, axial Death (metabolic crisis) Lactate (plasma) Multiple oxidative phosphorylation enzymes (muscle)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

+ +

+ + + ↑↑ ↓↓

↑↑

Table 45.75  Mitochondrial tyrosyl-tRNA synthetase deficiency Neonatal System Symptoms and biomarkers (birth–1 month) Cardiovascular Cardiomyopathy, hypertrophic Hematological Anemia, sideroblastic Musculoskeletal Dysmorphic features ± Exercise intolerance Myopathy Laboratory Lactate (plasma) findings

Infancy (1–18 months)

±

880

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Table 45.76  Mitochondrial valyl-tRNA synthetase deficiency System Other

Symptoms and biomarkers Encephalomyopathy

Neonatal (birth–1 month) ?

Infancy (1–18 months) ?

Childhood (1.5–11 years) ?

Adolescence (11–16 years) ?

Adulthood (>16 years) ?

Infancy (1–18 months) ± ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± ↓-n n-↑

Adolescence (11–16 years) ± ± ± ± ± ± ± ± ↓-n n-↑

Adulthood (>16 years) ± ± ± ± ± ± ± ± ↓-n n-↑

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

±

±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

±

Adulthood (>16 years)

Table 45.77  Mitochondrial tryptophanyl-tRNA synthetase deficiency System CNS

Eye Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Ataxia Epilepsy Intellectual disability Leukoencephalopathy Retardation, psychomotor Optic atrophy Myopathy Multiorgan failure Glucose (plasma) Lactate (plasma)

Neonatal (birth–1 month) ± ±

± ± ↓-n n-↑

↓-n n-↑

Table 45.78  Mitochondrial and cytoplasmic glycil-tRNA synthetase deficiency System CNS

Neonatal Symptoms and biomarkers (birth–1 month) Charcot marie tooth disease Distal motor neuronopathy

Table 45.79  Mitochondrial and cytoplasmic lysyl-tRNA synthetase deficiency Neonatal Infancy System Symptoms and biomarkers (birth–1 month) (1–18 months) CNS Charcot marie tooth ± disease Ear Deafness ±

Table 45.80  Peptidyl-tRNA hydrolase 2 deficiency System CNS

Ear Endocrine

Musculoskeletal

Other

Symptoms and biomarkers Ataxia Cerebellar hypoplasia (progressive) Hypotonia Intellectual disability Microcephaly Motor delay Peripheral neuropathy Hearing loss, sensorineural Exocrine pancreatic insufficiency Hypothyroidism Brachycephaly Facial dysmorphism Growth retardation Hand and foot deformities Muscle weakness Failure to thrive

Neonatal (birth–1 month)

Infancy (1–18 months) + ±

Childhood (1.5–11 years) ++ ±

Adolescence (11–16 years) ++ ±

±

± ± ± + ± +

+ ± ± + ± ++

+ ± ± + ± ++

±

±

± ± ± + +

± ± ± + +

± ± ± + +

± +

+ +

+ +

±

± ± + ±

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

881

Table 45.81  Perrault syndrome 6 ERAL1 System Ear Endocrine Laboratory findings

Symptoms and biomarkers Hearing loss, sensorineural Ovarian dysgenesis Estradiol (plasma) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ++

Adolescence (11–16 years) ++

Adulthood (>16 years) +++

− n.a.

− n.a.

n.a.

++ ↓ ↑↑

+++ ↓ ↑↑

n.a.

n.a.

n.a.

↑

↑

Infancy (1–18 months) + + + + + ↑ ↓

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 45.82  NOP2/SUN RNA methyltransferase 3 deficiency (n = 1) System CNS Eye Musculoskeletal Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Developmental delay Microcephaly Nystagmus Ophthalmoplegia Muscle weakness Lactate (plasma) Respiratory chain enzymes (muscle)

Table 45.83  Mitochondrial ribosomal small subunit 25 deficiency (n = 1) System CNS

Musculoskeletal Laboratory findings

Symptoms and biomarkers Agenesis corpus callosum Dyskinetic cerebral palsy Psycomotor delay Myopathy Activity respiratory chain complexes IV in muscle Activity respiratory chain complexes (I, III, IV) in fibroblasts Lactate (cerebrospinal fluid) Lactate (plasma) Mitochondrial translation

Neonatal (birth–1 month)

Infancy (1–18 months) + +++ ++

+ ↓↓ ↓↓ n-↑ n-↑ ↓↓↓

882

I. J. Holt et al.

Reference Values Compound Lactate

Serum/blood (μmol/L) 450–1800 (B)

Pyruvate Lactate/pyruvate ratio Alanine

60–100 (B) 2 years)

>200 >17 >300 (150 (6 months–7 years) >100 (>7 years)

Protein (total) Ethylmalonic acid 3-Methylglutaconic acid B Blood, S Serum, P Plasma, M Male, F Female, U/L Units/liter

Cerebrospinal fluid (μmol/L) >2000

>1300 (650 (>1 month, mg/L) >25 >25

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

883

Diagnostic Flowchart Clinical profile

Defined mitochondrial syndrome

Laboratory & clinical tests

Other syndrome or feautures compatible with mitochondrial disease

Pearson Syndrome, MERRF, MELAS, MIDD KSS, CPEO, MNGIE, Alpers, IOSCA

Lactate , Pyruvate , Alanine MRI, CT or MRS aberrations

no abnormalities

Abnormal lactate in glucose loading test Abnormal change in ketone bodies after meal Abnormalities in31PNMR studies

e.g. Charcot-Marie-Tooth, spastic paraplegia, Perrault’s syndrome

yes

Opt

yes

no

iona

Inheritance maternal or sporadic

l Muscle/Liver biopsy (in specialised center)

Inheritance Mendelian

yes

Patient is very strongly suspected on clinical grounds

Biochemistry and Histochemistry Screen mtDNA for selected mutations, e.g. m.3243A>G

no

Screen selected genes, e.g. POLG for Alpers syndrome

Sequence mtDNA Screen for mtDNA deletion/ duplication

mtDNA depletion/ multiple deletions

no

Panels to screen a range of known disease genes such as TWNK or RNASEH1, OR consider WES/WGS

Mutation identified?

yes Known pathological?

yes Diagnosis established

yes no

Functional tests, complementation assays etc confirm likely pathogenicity

Mutation identified?

OXPHOS deficiency

Ragged red fibers

Mitochondrial disorder not established, WES/WGS recommended

Sequence mtDNA + Panels to screen a range of known disease genes such as TWNK or RNASEH1, OR consider WES/WGS

no Unconfirmed mitochondrial disorder

Fig. 45.2  Common practice diagnostic flowchart for mitochondrial oxidative phosphorylation defects caused by defects in replication, transcription or translation of mtDNA

884

Specimen Collection The remainder of this Chapter reflects similar information to that found in Chap. 44, since both Chaps. 44 and 45 deal with mitochondrial diseases directly or indirectly affecting the oxidative phosphorylation system. In order to reach a definite diagnosis, biochemical examination of tissue specimens is usually required, with the exception of a small number of well-defined mitochondrial syndromes that can be tested genetically. As a rule, the patient under investigation should not be on vitamin therapy, in order to avoid masking of possible enzyme deficiencies. For most biochemical determinations one should ask the diagnostic centre for information about specific requirements as to the practice of collecting and transporting material. Especially in the case of enzyme analysis in tissues or cells, one must consult the diagnostic laboratory in advance about the conditions for removal, preparation, storage (usually at −70 °C) and transport of the specimens. If fresh tissue is to be studied, samples have to be collected in a special, ice-cold but not frozen buffer and immediately transported to the laboratory. The biochemical tests of mitochondrial flux measurements, such as oxygen consumption, substrate oxidation and ATP production should be performed within 2 h of collection. Frozen tissue samples are suitable for the analysis of individual mitochondrial enzymes and histochemical tests. The physician should inform the laboratory about the clinical findings to ensure an adequate analysis and to aid data interpretation. It is important to discuss which type of tissue or cell is preferable in each case, thereby causing the patient as little inconvenience as possible. Tissue-specific expression of mitochondrial deficiencies renders fibroblasts and lymphocytes less universally appropriate than skeletal muscle, although fibroblast analysis does have an added diagnostic value when combined with a muscle sample examination, and it is surprising how often mitochondrial abnormalities are evident in cells cultured in the laboratory [e.g (Bugiardini et al. 2019)]. In the case of unexpected death, tissue, blood and urine specimens should be collected as soon as possible after death. They should be snap frozen (not fixed) immediately after collection using liquid nitrogen, and stored for possible additional studies. For enzymatic purposes tissues must be removed within 1–2 h after death and should be frozen immediately in liquid nitrogen. Skin biopsies can be performed as late as 48 h after death, and must be collected at room temperature in cell culture medium, after which the biopsy can be transported at room temperature to the cell culture laboratory. Because few reference values are generally available for neonates, it is recommended to perform a muscle biopsy

I. J. Holt et al.

beyond the first month of life, unless a life-threatening situation exists. MtDNA analysis can, in principle, be performed in all types of tissues or cells available. However, heteroplasmy varies from tissue to tissue, and partial deletions of mtDNA are not usually detectable in blood. Therefore, it is recommended to perform mtDNA studies in biopsies from affected tissue (usually skeletal muscle). However, some mutations can also be tested non-invasively, such as LHON mutations in blood and the MELAS/MIDD m.3243A>G mutation in urine. Test Lactate Pyruvate

Material Storage B, CSF, U −20 °C B, CSF −20 °C

Amino acids Blood gases

S, P, U, CSF B

Creatine kinase Acetoacetate

S B

−20 °C No storage allowed −20 °C −20 °C

Pitfalls Prevent glycolysis Prevent glycolysis and LDH activity – –

3-Hydroxybutyrate B

−20 °C

Carnitine

−20 °C

– Feeding state is important Feeding state is important –

−20 °C

–

Organic acids

S, M, L, FB U

Screening Amino acids

Material U

Pyruvate dehydrogenase 2-Oxoglutarate dehydrogenase Fumarase Respiratory chain enzymes ATPase ATP/ ADP-translocator Substrate oxidations

M, FB, L, −70 °C CV M, FB, L −70 °C M, FB, L M, FB, L, CV M, FB M, FB, L

ATP production

M, FB, FL M, FB

Oxygen consumption Coupling state

M, FB, BrF M, FB

DNA Respiratory chain enzymes

M, FB, B

Storage −70 °C

Pitfalls Anti epileptic drugs, antibiotic artefacts

−70 °C −70 °C −70 °C −70 °C No storage allowed No storage allowed No storage allowed No storage allowed

Maintain at 0 °C Maintain at 0 °C Maintain at 0 °C Maintain at 0 °C

−20 °C

M Muscle (fresh or frozen), L Liver (fresh or frozen), MF Fresh muscle required, LF Fresh liver required, BrF Brain (fresh), FB Fibroblasts, CV Chorionic villi

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA

885

Prenatal Diagnosis

Supportive Therapy

At present prenatal diagnosis, at the enzyme level, in mitochondrial disorders can be performed in families in which the proband is suffering (or has suffered) from a complex I, complex II, succinate:cytochrome c oxidoreductase, complex IV or pyruvate dehydrogenase deficiency (or combinations of these enzymes), at least in our centre. A prerequisite for prenatal diagnosis at the enzyme level is that mtDNA mutations must have been excluded in the proband. In case an mtDNA mutation has been identified, preimplantation genetic diagnosis (PGD) is possible. PGD is an IVF-based treatment that may be suitable for some women who are at risk of transmitting a mitochondrial DNA mutation to their children (Poulton et al. 2010). PGD for mtDNA disease is based on the principle that the level of mutated mitochondrial DNA can vary widely between eggs produced by a women who carries a mixture of mutated and normal mitochondrial DNA. PGD is only suitable for women who are expected to produce some eggs with low levels of mutated mitochondrial DNA. Prenatal diagnosis at the enzyme level is preferably performed in native chorionic villi because they can be obtained earlier in pregnancy as compared with amniocytes. Moreover, it is not necessary to cultivate chorionic villi in contrast with amniocytes, thus reducing the time of the diagnostic procedure considerably. In case the investigation of chorionic villi yields no conclusive result, amniocytes can also be ­investigated, although in practice this is hardly ever necessary. In case causative mutations in the nuclear DNA have been identified, prenatal diagnosis is possible using conventional prenatal genetic testing for all nuclear genetic defect. Because of the expanding possibilities of molecular genetic testing of suspected mitochondrial patients, nuclear DNA-based prenatal diagnosis is expected to increase in the future. However, for those families in which it has not (yet) been possible to identify the causative genetic defect, the measurement of enzyme activities in chorionic villi provides an alternative possibility for prenatal diagnostic testing.

• Central nervous system: Seizures should be treated adequately, and in many cases respond well to conventional anticonvulsants. Valproic acid should be used with great caution, and has strong contraindication in, for example, Alpers-Huttenlocher syndrome. • Heart: Timely placement of a pacemaker can be lifesaving in patients with cardiac conduction blocks. Cardiomyopathy can be treated with heart-failure therapy. Heart transplantation is controversial, but when cardiac involvement is the predominant problem, transplantation is justified. • Gastrointestinal: Patients often have complaints of vomiting, diarrhea, constipation or abdominal pain related to dysmotility, which can be treated with prokinetics and/or laxatives. Because of these problems the diet can be inadequate, and for this reason patients should be referred to a dietician for evaluation. Exocrine pancreatic dysfunction requires replacement therapy with pancreatic enzymes. • Kidney: Patients with proteinuria may be treated with ACE inhibitors. Renal tubular acidosis and Fanconi syndrome require therapy to readjust electrolyte balance. Patients with renal failure may also require dialysis or a renal transplant. Patients with a known mitochondrial disorder due to an mtDNA mutation should not be transplanted with a kidney from a maternal family member. • Endocrine: Diabetes can be treated with oral medication, but as the disease progresses usually insulin is required. Hypothyroidism can be treated with thyroid hormone. • Eye: Ptosis can be ameliorated by surgery, although the results of blepharoplasty are often transient. Congenital cataracts are also treated surgically. • Hearing: Hearing aids are often necessary. When hearing problems are progressive, cochlear implants may be useful. • Muscular: Aerobic exercise is useful in mitochondrial disease, improving work capacity, oxygen delivery to muscle (i.e. cardiac output), oxygen extraction and utilization by muscle and muscle energy metabolism. Sustained aerobic exercise is associated with mitochondrial proliferation (reflected by increased activity of citrate synthase) and improvement of respiratory chain activity (reflected by increased activity of COX) (Jeppesen et al. 2006). The specific questions that arise in those disorders associated with heteroplasmic mtDNA mutations are whether exercise preferentially promotes proliferation of normal mitochondria and, if not, whether proliferation of both normal mitochondria and abnormal mitochondria is beneficial. The former could increase ATP production, whereas the latter could increase production of reactive oxygen species. These questions have not yet been totally resolved but are being addressed in ongoing clinical trials.

Treatment In contrast to the progress in understanding biochemical and molecular aspects of mitochondrial disease, treatment is still limited. Many potentially therapeutic agents have been used to treat mitochondrial disorders, but few of these disorders have any proven effective therapy. The management of mitochondrial disease is largely supportive, therefore clinicians must have a thorough knowledge of the potential complications of mitochondrial disorders to prevent unnecessary morbidity and mortality.

886

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Vitamins and Cofactors Over the last 15  years several open-label and randomized control clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress. These include trials of administering dichloroacetate (an activator of PDHc), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine) and combined administration (of creatine, α-lipoate, and CoQ10). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (LHON, MELAS, Leigh). Trial designs varied from openlabel/uncontrolled to open-label/controlled or double-blind/ placebo-controlled/crossover. Primary outcomes ranged from single, clinically relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials (Glover et al. 2010). Of these only one (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in two subsequent trials with creatine with different patients. One trial (idebenone treatment of LHON) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients (Klopstock et al. 2013). Despite the paucity of benefits found so far, well-­ controlled clinical trials are essential in the continuing search for more effective treatment of mitochondrial disease (Pfeffer et al. 2013), and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicentre collaboration and the selection of very few, clinically relevant, primary outcomes.

Emergency Treatment Medication Sodium bicarbonate l-arginine

Indication Severe lactic acidosis (lactate >7 mmol/L) Acute stroke like episode

Dose (route) (0.33 mmol/kg) × base deficit 150–500 mg/kg/day (IV)

Funding AS is supported by UK Medical Research Council Senior Non-clinical Fellowship (MC_PC_13029), the Muscular Dystrophy UK and the Lily Foundation. IJH is supported by grants 2018111043 and 2018222031 Departamento de Salud, Euskadi and P17/00380, Carlos III Departamento de Salud. JNS was in part supported by the

“Prinses Beatrix Spierfonds” and the “Stichting Spieren voor Spieren” (W.OR15-05) and is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie SklodowskaCurie grant agreement No 721757.

References Amunts A, Brown A, Toots J, Scheres SH, Ramakrishnan V.  Ribosome. The structure of the human mitochondrial ribosome. Science. 2015;348(6230):95–8. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N.  Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.  Nat Genet. 1999;23(2):147. Bugiardini E, Poole OV, Manole A, Pittman AM, Horga A, Hargreaves I, et al. Clinicopathologic and molecular spectrum of RNASEH1-­ related mitochondrial disease. Neurol Genet. 2017;3(3):e149. Bugiardini E, Mitchell AL, Rosa ID, Horning-Do HT, Pitmann A, Poole OV, et al. MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy. Hum Mol Genet. 2019; Dalla Rosa I, Camara Y, Durigon R, Moss CF, Vidoni S, Akman G, et al. MPV17 loss causes deoxynucleotide insufficiency and slow DNA replication in mitochondria. PLoS Genet. 2016;12(1):e1005779. D’Souza AR, Minczuk M. Mitochondrial transcription and translation: overview. Essays Biochem. 2018;62(3):309–20. Glover EI, Martin J, Maher A, Thornhill RE, Moran GR, Tarnopolsky MA. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve. 2010;42(5):739–48. Gonzalez-Serrano LE, Chihade JW, Sissler M. When a common biological role does not imply common disease outcomes: disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases. J Biol Chem. 2019;294(14):5309–20. Goto Y-I, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348:651–3. Hensen F, Potter A, van Esveld SL, Tarres-Sole A, Chakraborty A, Sola M, et al. Mitochondrial RNA granules are critically dependent on mtDNA replication factors twinkle and mtSSB. Nucleic Acids Res. 2019;47(7):3680–98. Holt IJ, Harding AE, Morgan-Hughes JA.  Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988;331(6158):717–9. Jeppesen TD, Schwartz M, Olsen DB, Wibrand F, Krag T, Duno M, et al. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006;129(Pt 12):3402–12. Klopstock T, Metz G, Yu-Wai-Man P, Buchner B, Gallenmuller C, Bailie M, et  al. Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain. 2013;136(Pt 2):e230. de Laat P, Koene S, van den Heuvel LP, Rodenburg RJ, Janssen MC, Smeitink JA. Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation. J Inherit Metab Dis. 2012;35(6):1059–69. Martin CA, Sarlos K, Logan CV, Thakur RS, Parry DA, Bizard AH, et al. Mutations in TOP3A cause a bloom syndrome-like disorder. Am J Hum Genet. 2018;103(2):221–31. Nishino I, Spinazzola A, Hirano M.  Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999;283(5402):689–92. Ojala D, Montoya J, Attardi G. tRNA punctuation model of RNA processing in human mitochondria. Nature. 1981;290:470–4.

45  Disorders of Replication, Transcription and Translation of Mitochondrial DNA van den Ouweland JM, Lemkes HH, Trembath RC, Ross R, Velho G, Cohen D, et  al. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA(Leu(UUR)) gene. Diabetes. 1994;43(6):746–51. Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol. 2013;9(8):474–81. Pohjoismaki JLO, Forslund JME, Goffart S, Torregrosa-Munumer R, Wanrooij S. Known unknowns of mammalian mitochondrial DNA maintenance. BioEssays. 2018;40(9):e1800102.

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Poulton J, Chiaratti MR, Meirelles FV, Kennedy S, Wells D, Holt IJ. Transmission of mitochondrial DNA diseases and ways to prevent them. PLoS Genet. 2010;6(8) Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, et  al. Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001;28(3):223–31. Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C.  Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001;28(3):211–2.

Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

46

Lonneke de Boer, Maaike C. de Vries, Jan A. M. Smeitink, and Werner J. H. Koopman

Contents Introduction

 890

Nomenclature

 891

Metabolic Pathways

 894

Signs and Symptoms

 894

Reference Value

 909

Pathological Values

 909

Diagnostic Flowchart

 910

Specimen Collection

 910

Prenatal Diagnosis

 910

DNA Testing

 910

Treatment

 910

References

 911

Potential conflict of interest: JAMS is the founding CEO of the SME Khondrion B.V. (Nijmegen, The Netherlands). WJHK is a scientific advisor of Khondrion. This company had no involvement in this manuscript. L. de Boer · M. C. de Vries · J. A. M. Smeitink Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands e-mail: [email protected] W. J. H. Koopman (*) Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands e-mail: [email protected]

Summary

This chapter describes gene mutations and disorders linked to mitochondrial homeostasis, dynamics, protein import, and quality control. Although clinically highly variable, we here functionally categorized these mutations as impacting on mitochondrial biogenesis, mitochondrial morphology/motility (“mitochondrial dynamics”), and mitochondrial degradation (“mitophagy”). These three processes are described in more detail in the Introduction. In addition, several other mutations that affect mitochondrial function are presented. The gene mutations discussed in this chapter are all nuclear DNA

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_46

889

890

(nDNA) mutations. Most patients with mitochondrial disorders present with a multi-system disorder. The organs requiring the most energy, such as the brain, retina, heart, kidney, and skeletal muscle, are most commonly and severely affected. Onset of disease can be at any age and the symptoms are almost always progressive. A definitive diagnosis solely based on clinical signs and symptoms is very unlikely. Whole exome/genome sequencing (WES/ WGS) has greatly improved disease diagnosis and often simplified it, although in some cases has also resulted in new diagnostic challenges. Nonetheless, clinical diagnostic criteria, combined with brain imaging, metabolic, biochemical, and other functional tests are still needed. Since specific treatment options are still limited, the management of the described mitochondrial disorders is largely supportive. For diagnosis and treatment, patients should be referred to a specialized center.

Introduction Mitochondria consist of a double membrane system, the mitochondrial outer membrane (MOM) and mitochondrial inner membrane (MIM), which envelops the mitochondrial matrix compartment. The MIM is highly folded to accommodate the many proteins and protein complexes required for mitochondrial ATP production and other functions (Bulthuis et  al. 2019). Mitochondrial functioning requires about ~1500 proteins. Since the mitochondrial DNA (mtDNA) encodes only for 13 proteins the majority of mitochondrial proteins is encoded by the nuclear DNA (nDNA; Koopman et  al. 2012). These nDNA-encoded proteins are synthesized in the cytosol and are imported into mitochondria by a dedicated machinery consisting of translocases of the mitochondrial outer membrane (TOM) and translocases of the mitochondrial inner membrane (TIM). This TOM/ TIM system not only imports nDNA-encoded proteins, but also carries out posttranslational modifications and mediates the sorting of imported proteins to the correct mitochondrial subcompartment: MOM, MIM, matrix, or intermembrane space (IMS). In this sense (Fig.  46.1a), proper functioning of the TIM/TOM system is crucial for mitochondrial biogenesis and sustained mitochondrial functioning (Jackson et al. 2018). Inside cells, single mitochondria are motile and continuously fuse and divide. Although still incompletely understood, these “mitochondrial dynamics” are required for cell and organismal survival in allowing (Kluge et al. 2013): (1) individual mitochondria to reach

L. de Boer et al.

distant parts of the cell (e.g., for their local functioning in neurons), (2) mixing of mitochondrial content (e.g., to exchange mtDNA or damaged biomolecules), (3) distribution of mitochondria between daughter cells during cell division, and (4) degradation of dysfunctional mitochondria (see below). Three main proteins are currently described to be involved in mitochondrial fusion: Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), and Optic Atrophy Protein 1 (OPA1). With respect to mitochondrial fission, 6 main proteins were implicated: Dynamin-related protein 1 (Drp1/DNM1L), Dynamin 2 (Dyn2), Fission protein 1 (Fis1), Mitochondrial Elongation Factor 1 (MIEF1), Mitochondrial Elongation Factor 2 (MIEF2), and Mitochondrial fission factor (Mff). The function of mitochondrial fission/fusion proteins is interfaced with cellular regulatory pathways and redox signaling, primarily by posttranslational modifications like phosphorylation (Willems et al. 2015). As a consequence of mitochondrial dynamics, mitochondrial morphology can be highly heterogeneous within/between cells and ranges from “filamentous” (elongated) to fragmented phenotypes (Fig.  46.1b). Experimental evidence suggests that mitochondrial function and morphology are mutually dependent, giving rise to the concept of mitochondrial “morphofunction” (Bulthuis et al. 2019). Following biogenesis, it is believed that individual mitochondria can accumulate damage during their life cycle. This, for instance, could be due to the presence of mitochondrial protein-encoding gene mutations, increased reactive oxygen species (ROS) levels, or external influences like environmental toxins or off-target drug effects (Koopman et  al. 2012). As a homeostatic system, cells are equipped with a mitochondrial quality control mechanism that removes dysfunctional organelles by autophagy (Fig.  46.1c). The current evidence suggests that dysfunctional mitochondria are unable to maintain their transMIM inside-negative electrical potential (Δψ), and that this inability can trigger mitochondria-­specific autophagy (“mitophagy”). Depending on the extent of Δψ depolarization, mitochondrial dysfunction is associated with MOM rupture, reduced O2 consumption, and blocked ATP synthesis. In the mitophagy mechanism, Δψ depolarization activates MOM accumulation of PTEN-induced kinase 1 (PINK1). Next, PINK recruits and activates the protein Parkin to ultimately stimulate mitochondrial recognition by the autophagy machinery (Gustaffson and Dorn 2nd 2019). In addition to this “Parkin-­dependent pathway,” there are also various other mechanisms to recognize and remove dysfunction mitochondria, including receptor- and lipidmediated pathways (Yang et al. 2019).

GDAP1 deficiency

STAT2 deficiency

UGO-1 like protein deficiency Childhood-onset optic atrophy type 1 Optic Atrophy 1 and Deafness Costeff syndrome

Mitofusin 2 deficiency

MSTO1 deficiency

DNAJC19 deficiency

Mohr-Tranebjaerg syndrome TIMMDC1 deficiency

Mitochondrial epileptic encephalopathy TIMM50 GFER deficiency

MAGMAS deficiency

46.3

46.4

46.5

46.9

46.10

46.11

46.12

46.14

46.16

46.15

46.13

46.8

46.7

46.6

Mitochondrial fission factor deficiency

46.2

46.1

Disorder Peroxisomal and mitochondrial fission defect

Nomenclature

MSTO1 DNAJC19

MGCA5

Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay Spondylometaphyseal dysplasia, SMDMDM Megarbane-Dagher-Melike type

PAM16

GFER

TIMM50

Intellectual disability and seizure disorder due to TIMM50 variant

TIMM50

TIMMDC1

TIMM8A

MFN2

CMT2A2A; CMT2A2B MMYAT

MTS

OPA3

MGA3

OPA1

OPA1

OPA1 –­

SLC25A46

STAT2

GDAP1

MFF

AR

AR

16p13.3

16p13.3

AR

AR

X-linked

AR

AR, AD

AR, AD

AR, AD

AR, AD

AD

AR

AR

AR, AD

AR

125250

165500

616505

616636

607831 214400

617086

OMIM 614388

Presequence translocaseassociated motor 16

Growth factor, ERV1-like

Translocase of inner mitochondrial membrane 8A Translocase of inner mitochondrial membrane domain-containing protein 1 Translocase of inner mitochondrial membrane 50

(continued)

613320

613076

607381

252010

304700

Outer mitochondrial membrane 258501 lipid metabolism regulator Mitofusin 2 609260; 617087 Mitochondrial distribution and 617675 morphology regulator DNAJ/HSP40 homolog, 610198 subfamily C, member 19

Optic Atrophy 1

Ganglioside-induced differentiation-associated protein 1 Signal transducer and activator of transcription 2 Solute carrier family 25, member 46 Optic Atrophy 1

Mitochondrial fission factor 1

Inheritance Affected protein AR, AD Dynamin-like protein 1

19q13.2

3q13.33

Xq22.1

3q26.33

1q22

1p36.22

19q13.2-13.3

3q28-q29

3q28-q29

5q22.1

12q13.3

8q21.11

2q36.3

Chromosomal Gene symbol localization DNM1L 12p11.21

HMSN6B

IMD44

CMT2K; CMT4A

MFF deficiency

Abbreviation DLP1 deficiency

Mitochondrial complex I deficiency

Dilated cardiomyopathy with ataxia (DCMA syndrome); 3-Methylglutaconic aciduria type 5 Dystonia Deafness Syndrome

Axonal Charcot-Marie-Tooth type 2A2A and 2A2B Mitochondrial myopathy and ataxia

Methylglutaconic aciduria type III

Behr syndrome

Hereditary motor and sensory neuropathy type 6B Juvenile Optic Atrophy

Alternative name(s) Dynamin-like protein 1 deficiency; Encephalopahty, lethal, due to defective mitochondrial peroxisomal fission Encephalopathy due to defective mitochondrial and peroxisomal fission type 2 Axonal Charcot-Marie-Tooth type 2K Demyelinating Charcot-Marie-Tooth disease type 4A Immunodeficiency type 44

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control 891

CLPP deficiency

LONP1 deficiency

HSPA9 deficiency

HSP60 deficiency

Sacsin deficiency

m-AAA protease AFG3L2 subunit deficiency Paraplegin deficiency

HTRA2 deficiency Parkin deficiency

PINK1 deficiency

USP9X deficiency Valosin-containing protein superactivity

46.22

46.23

46.24

46.25

46.26

46.27

46.28

46.29 46.30

46.31

46.32 46.33

46.21

46.20

46.19

46.18

46.17

Disorder Acylglycerol kinase deficiency Mitochondrial processing peptidase alpha deficiency Mitochondrial processing peptidase beta deficiency Mitochondrial intermediate peptidase deficiency CLPB deficiency MMDS6

SCAR2

Abbreviation

X-linked mental retardation type 99 Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia type 1

Early-onset Parkinson disease type 6

3-methylglutaconic aciduria type 8 Early-onset Parkinson disease type 2

Cerebral, ocular, dental, auricular, and skeletal syndrome Sideroblastic anemia type 4; Epiphyseal, vertebral, ear, nose, plus associated malformations (EVENplus) syndrome Hypomyelinating leukodystrophy type 4 (recessive); Autosomal dominant spastic paraplegia type 13 Autosomal recessive spastic ataxia of Charlevoix-Saguenay Autosomal recessive spastic ataxia type 5; Spinocerebellar ataxia type 28 Spastic paraplegia type 7

MRX99 IBMPFD1

PARK6

MGCA8 PARK2

USP9X VCP

PINK1

HTRA2 PRKN

SPG7

AFG3L2

SPAX5; SCA28

SPG7

SACS

HSPD1

HSPA9

LONP1

CLPP

CLPB

MIPEP

PMPCB

PMPCA

Xp11.4 9p13.3

1p36.12

2p13.1 6q26

16q24.3

18p11.21

13q12.12

2q33.1

5q31.2

19p13.3

X-linked AD

AR

AR AR

AR, AD

AR

AR

AR, AD

AR

AR

AR

AR

11q13.4

19p13.3

AR

AR

AR

Paraplegin, a component of the m-AAA protease HTRA serine peptidase 2 Parkin, a RING domaincontaining E3 ubiquitin ligase PTEN-induced putative kinase 1 Ubiquitin-specific protease 9 Valosin-containing protein

Catalytic subunit of the m-AAA protease

Sacsin

Heat-shock 60-kDa protein 1

Heat-shock 70-kDa protein 9

Caseinolytic mitochondrial matrix peptidase proteolytic subunit LON peptidase 1

Caseinolytic peptidase B

Mitochondrial intermediate peptidase

Peptidase, mitochondrial processing, beta

Peptidase, mitochondrial processing, alpha

Inheritance Affected protein AR Acylglycerol kinase

13q12.12

7q22.1

9q34.3

Chromosomal Gene symbol localization AGK 7q34

SACS

HLD4; SPG13

SIDBA4

CODAS

Combined oxidative phosphorylation deficiency type 31; COXPD31 MEGCANN 3-methylglutaconic aciduria type 7, with cataracts, neurologic involvement and neutropenia Perrault syndrome type 3 PRLTS3

Multiple mitochondrial dysfunctions syndrome 6

Alternative name(s) Sengers syndrome; Cataract 38, autosomal recessive Autosomal recessive spinocerebellar ataxia type 2

300919 167320

605909

617248 600116

607259

614487; 610246

270550

612233; 605280

182170

600373

614129

616271

617228

617954

OMIM 212350; 614691 213200

892 L. de Boer et al.

Transmembrane protein 126A deficiency C1q-binding protein deficiency Trafficking kinesinbinding protein 1 deficiency Mitochondrial calcium uniporter deficiency Reticulon 4-interacting mitochondrial protein deficiency MICOS complex subunit MIC13 deficiency Mitochondrial thioredoxin 2 deficiency Mitochondrial thioredoxin reductase 2 deficiency MICU1

MPXPS OPA10

MIC13

Myopathy with extrapyramidal signs Optic atrophy type 10

QIL1 deficiency

Combined oxidative phosphorylation deficiency type 29 Selenoprotein Z deficiency; Glucocorticoid deficiency type 5

TRAK1

TXN2 TXNRD2

COXPD29 GCCD5

MICOS13

RTN4IP1

C1QBP

COXPD33

Combined oxidative phosphorylation deficiency type 33 –

TMEM126A

ATAD3A

OPA7

HAYOS

AIFM1

COXPD6

Optic atrophy type 7

Harel-Yoon syndrome

SFXN4

PPA2

YME1L1 XPNPEP3

22q11.21

22q12.3

19p13.3

6q21

AR

AR

AR

AR

AR

AR

3p22.1

10q22.1

AR

AR

AR, AD

X-linked

AR

AR

AR AR

617302 613159

OMIM 618211

Thioredoxin reductase 2

Mitochondrial contact site and cristae organizing system subunit 13 Thioredoxin 2

Mitochondrial calcium uptake 1 Reticulon 4-interacting protein 1

Complement C1q-binding protein Trafficking protein, kinesinbinding 1

ATPase family, AAA domaincontaining, member 3A Transmembrane protein 126A

Apoptosis inducing factor mitochondria associated 1

Sideroflexin 4

617825

616811

616658

616732

615673

608112

617713

612989

617183

300816

615578

Mitochondrial pyrophosphatase 617222 2

YME1-like 1 ATPase Aminopeptidase P3

Inheritance Affected protein AR Pitrilysin metallopeptidase 1

17p13.2

11q14.1

1p36.33

Xq25-q26

10q26.11

4q24

10p12.1 22q13.2

Chromosomal Gene symbol localization PITRM1 10p15.2

COXPD18

SCFI

Infantile sudden cardiac failure

Combined oxidative phosphorylation deficiency type 18 X-Linked Mitochondrial Myopathy

OPA11 NPHPL1

Abbreviation

Optic atrophy type 11 Nephronophthisis-like nephropathy type 1

Alternative name(s)

All info in this table was taken from the Inborn Errors of Metabolism Knowledgebase (IEMbase; www.iembase.org) except the parts highlighted in blue, which were compiled using information from the HUGO Gene Nomenclature Committee (HGCN; www.genenames.org) and/or from Online Mendelian Inheritance in Man (OMIM; www.omim.org)

46.48

46.47

46.46

46.45

46.44

46.43

46.42

46.41

46.40

46.39

46.38

46.37

46.35 46.36

46.34

Disorder Pitrilysin metallopeptidase 1 deficiency YME1L1 deficiency X-prolyl aminopeptidase 3 deficiency Mitochondrial inorganic pyrophosphatase 2 deficiency Sideroflexin 4 deficiency Combined Oxidative Phosphorylation Defect 6 ATAD3A deficiency

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control 893

894

L. de Boer et al.

Metabolic Pathways

a

Mitochondrial biogenesis

b

c

Mitochondrial degradation

Fragmented mitochondria

Filamentous mitochondria

Protein import, sorting and processing AFG3L2 AIFM1 AGK C1QBP CLPB CLPP DNAJC19 GFER HSPA9 HSPD1 HTRA2 LONP1

Mitochondrial dynamics

Mitochondrial dysfunction

MIPEP PAM16 PITRM1 PMPCA PMPCB SFXN4 SPG7 TIMM8A TIMM50 TIMMDC1 XNPEP3

+ Fusion

Fission

Mitophagy

MFN2 MSTO1? OPA1 OPA3? SLC25A46 YME1L1

DNM1L GDAP1 MFF STAT2

PINK1 PRKN SACS?

Degradation

Motility TRAK1

d

Mitochondrial function

Phosphate metabolism

PPA2

Redox metabolism

TXN2 TXNRD2

Fig. 46.1  Mechanisms involved in disorders of mitochondrial homeostasis, dynamics, protein import, and quality control. (a) Biogenesis of mitochondria and their sustained functioning require import of nuclear DNA-encoded proteins, sorting of these proteins to the correct mitochondrial compartment (i.e., mitochondrial outer membrane, mitochondrial intermembrane space, mitochondrial inner membrane, and mitochondrial matrix) and posttranslational processing of these proteins. (b) Within cells, individual mitochondria are motile and undergo continuous fusion/fission events. Proper mitochondrial dynamics is required for mitochondrial function and is mediated by a set of dedicated mito-

Contact site and cristae organization

ATAD3A MICOS13

Calcium uptake

MICU1

chondrial fusion, fission, and motility proteins. (c) When dysfunctional, mitochondria can be removed from the cell by a mitochondria-­specific autophagy process (“mitophagy”). (d) Aberrant mitochondrial function at the level of phosphate and redox metabolism, organization of mitochondrial contact sites, mitochondrial inner membrane folds (“cristae”), and mitochondrial calcium uptake. Within this figure, gene names linked to disease causing mutations are highlighted in bold italic. Since no exhaustive functional data was available, RTN4IP1, TMEM162A, USP9X, and VCP were not included in this figure

Signs and Symptoms Table 46.1  Peroxisomal and mitochondrial fission defect System CNS

Symptoms and biomarkers Abnormal gyral pattern (MRI) Areflexia Cerebral atorphy (MRI) Delayed myelination (MRI) Delayed psychomotor development Failure to thrive Hypotonia Microcephaly Neurologic decline Pyramidal signs Seizures

Neonatal (birth–1 month) + + +

+ + +

Infancy (1–18 months)

Childhood (1.5–11 years)

+ + +

+ + +

+ + + +

+ + + + + +

+

Adolescence (11–16 years)

Adulthood (>16 years)

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

895

Table 46.1 (continued) System Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Oculomtor apraxia Optic atrophy Poor visual fixation Muscle weakness Death Lactate (P) Very-long-chain fatty acids (P)

Neonatal (birth–1 month) + + + ↑ ↑

Infancy (1–18 months) + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

+

+ ↑

↑

Table 46.2  Mitochondrial fission factor deficiency System CNS

Eye

Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Basal ganglia lesions (MRI) Cerebellar atrophy (MRI) Delayed psychomotor development Failure to thrive Hypotonia Microcephaly Neurologic decline Neuropathy Poor head and trunk control Seizures Spasticity External ophthalmoparesis Optic atrophy Visual impairment Death Lactate (P) Very-long-chain fatty acids (P)

Infancy (1–18 months)

Childhood (1.5–11 years) + + +

+

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + +

+ + + + + +

+ + + + + + n-↑ n

+ n-↑

Table 46.3  GDAP1 deficiency System CNS

Musculoskeletal

Neonatal Symptoms and biomarkers (birth–1 month) Areflexia Delayed motor development Distal lower limb muscle weakness/atrophy Distal sensory impairment Hypotonia + Claw hand deformities Foot deformities Hand/upper limb weakness Kyphoscoliosis Proximal limb weakness Vocal cord paresis

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+

+

+

+

+ +

+ + + +

+

+

+ + + + + +

+ + + + + +

+

+

896

L. de Boer et al.

Table 46.4  STAT2 deficiency System Hematological

Laboratory findings

Symptoms and biomarkers Complicated viral infections Deficiencies Frequent infections Post-vaccination (MMR) complications Lactate (CSF) Lactate (P)

Neonatal (birth–1 month)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

± + +

± +

Adolescence (11–16 years)

Adulthood (>16 years)

n-↑ n-↑

Table 46.5  UGO-1 like protein deficiency System CNS

Ear Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Areflexia Ataxia Brain stem atrophy (MRI) Cerebellar atrophy (MRI) Cerebellar white matter changes (MRI) Developmental delay Diffuse brain atrophy (MRI) Hypertonia Hypotonia Irritability Loss of skills Lower limb muscle hypotrophy Myoclonus Neuropathy Thickened CC (MRI) Tremor Deafness Nystagmus Optic atrophy Visual impairment, progressive Flexion contractures Foot deformities Death Failure to thrive 3-methylglutaconic acid (U) Lactate (CSF) Lactate (P) Pyruvate

Neonatal (birth–1 month)

+ ++

Infancy (1–18 months) + + + ++

+ ++ +

Childhood (1.5–11 years)

Adolescence (11–16 years)

++

++

++ +

++

++ +

++ + + ±

++ + + ±

+

+

+ ++

+ ++

+

+ + + ++ +

+ +

++ ± ± + + +

++

+ ++ ±

+ ++

Adulthood (>16 years) + ++

++ +

+ ++ +

+ + ±

n-↑

± ± ↑ n-↑ n-↑ n-↑

± ↑

± ↑

Table 46.6  Childhood onset optic atrophy type 1 System Eye

Symptoms and biomarkers Color vision deficit Nystagmus Optic atrophy Scotoma Strabismus Temporal to diffuse optic nerve pallor Vision loss, onset

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + +++ + ± + +++

Adolescence (11–16 years) + ± +++ +

Adulthood (>16 years) +

+

+

++

+

+++ +

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

897

Table 46.7  Optic atrophy 1 and deafness System CNS

Digestive Ear Endocrine Eye

Musculoskeletal Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Areflexia/weak reflexes Ataxia Bilateral calcification basal ganglia (MRI) Brain stem atrophy (MRI) Cerebellar atrophy (MRI) Cortical atrophy (MRI) Developmental delay Hyperreflexia Migraine Neuropathy Spasticity White matter lesions (MRI) Dysmotility Hearing loss, progressive Diabetes Hypothyroidism Color vision deficit Glaucoma Ophthalmoplegia Ptosis Scotomata Temporal to diffuse optic nerve pallor Vision loss, onset Foot deformities Myopathy Lactate (P)

Infancy (1–18 months)

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years)

Adulthood (>16 years) + + ± ± ± ±

+

+ ± ±

+

+

+

+

± ± + ++

+ ++

+++

++

± n-↑

± ± + ± ± ± ++ ± ± + ± + + + ++ + ± + n-↑

Table 46.8  Costeff syndrome System CNS

Ear Eye

Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Chorea Developmental delay/loss of skills Extrapyramidal movement disorder Mild intellectual disability Movement disorder, complex, paroxysmal Neuropathy Non-specific white matter lesions (MRI) Nystagmus Spasticity Hearing loss Cataract Centrocecal scotomas Glaucoma Optic atrophy Visual disturbances 3-Methylglutaconic acid (U) 3-Methylglutaric acid (U)

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+

± +

+

+ +

±

±

+

+

± ±

+ ±

+ ± ± ±

±

+

±

↑ ↑

+ ± ↑ ↑

+ ±

+ ±

±

± ±

+ ± ± + +

+ + n-↑ ↑

+ + ↑ ↑

+ + n-↑ ↑

898

L. de Boer et al.

Table 46.9  Mitofusin 2 deficiency System CNS

Ear Eye Musculoskeletal

Symptoms and biomarkers Distal sensory loss Hyperreflexia Hypo/areflexia Hypotonia Periodic limb movement Hearing impairment Optic atrophy Club foot Distal muscular atrophy Finger contractures Muscle weakness, onset in lower extremitities Scoliosis

Neonatal (birth–1 month)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) + ±

± ± ± +

+

± ± ± + ±

+ +

+

+

Adulthood (>16 years) + ± ± ±

+ ± + ±

Table 46.10  MSTO1 deficiency System CNS

Eye Musculoskeletal

Other

Laboratory findings

Symptoms and biomarkers Ataxia Autism spectrum disorder Cerebellar hypotrophy (vermis) (MRI) Cerebral atrophy (MRI) Depression Developmental delay (motor) Dysdiadochokinesis Hyporeflexia Intellectual disability Non-specific white matter lesions (MRI) Schizophrenia Tremor Papillary pallor Pigmentary retinopathy Muscle weakness Scoliosis Thoracic deformities Growth retardation Short stature Citrulline (P) Creatine kinase (P) Vitamin D3

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +

±

+

Adulthood (>16 years) + ±

±

Adolescence (11–16 years) + ± ±

±

±

+

+

± ± +

+

+ ±

±

±

+

+ ± ± + ± ± +

+ ±

±

±

±

+

+ ± + +

± ± ±

↓ ↑

n-↑ ↓

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

899

Table 46.11  DNAJC19 deficiency System Cardiovascular CNS

Digestive Eye Hematological Other

Laboratory findings

Symptoms and biomarkers Dilated cardiomyopathy Long QT Ataxia Cerebellar atrophy (MRI) Intellectual disability Seizures Microvesicular steatosis Optic atrophy Anemia (microcytic, hypochrome, hemolytic) Death Growth retardation Male genital anomalies Recuperating disease course 3-Methylglutaconic acid (U) 3-Methylglutaric acid (U) Lactate (CSF) Lactate (P)

Neonatal (birth–1 month)

Infancy (1–18 months) +

± +

Childhood (1.5–11 years) ++ ± + ± + + ± ± +

+

± ++ +

+ ++ ±

n-↑↑ ↑-↑↑↑

↑ ↑ n-↑↑ ↑-↑↑↑

↑ ↑ n-↑↑ ↑-↑↑↑

+ + +

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

±

±

± ±

± ±

±

±

n-↑↑ ↑-↑↑↑

n-↑↑ ↑-↑↑↑

Table 46.12  Mohr-Tranebjaerg syndrome System CNS

Ear Eye Musculoskeletal Other

Symptoms and biomarkers Dementia Dystonia Intellectual disability Deafness, sensorineural Optic atrophy Vision, impaired Fractures Behavioural problems

Neonatal (birth–1 month)

+

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

+

+ + + ± +

++ + ++ ± +

+

+

Adulthood (>16 years) ± ++ ++ ++ + + ± +

Adolescence (11–16 years)

Adulthood (>16 years)

Table 46.13  TIMMDC1 deficiency System CNS

Ear Eye Other Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Bilateral basal ganglia hyperintensity (MRI) Developmental delay Dyskinesia Dysmetria Enlarged ventricles (MRI) Hypotonia ± Megacisterna magna (MRI) Neuropathy Seizures Deafness, sensorineural Nystagmus Death Failure to thrive Lactate (P)

Infancy (1–18 months) ±

Childhood (1.5–11 years)

+ ± ± ± + ± ±

+ ± ±

± ± + n-↑

+ ± ± ± ± + + n-↑

900

L. de Boer et al.

Table 46.14  Mitochondrial epileptic encephalopathy TIMM50 System CNS

Eye Other Laboratory findings

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ±

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +

+

+ + +

+

+ +

+ + + n-↓

Symptoms and biomarkers Behavior, aggressive Bilateral symmetric lesions globus pallidus and brain stem (MRI) Brain atrophy (MRI) Developmental delay Epilepsy Hypotonia Hypsarrhythmia (EEG) Optic atrophy Failure to thrive 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Lactate (cerebrospinal fluid) Lactate (plasma)

Table 46.15  GFER deficiency System CNS

Ear Eye Laboratory findings

Symptoms and biomarkers Areflexia Developmental delay Epilepsy Hypotonia Thin corpus callosum (MRI) Hearing loss, sensorineural Cataract Ptosis of eyelid Ferritin (S) Lactate (P)

+

↑

Adolescence (11–16 years) + + + + + + n-↓ n-↑

Adulthood (>16 years) +

+

n-↓ n-↑

Table 46.16  MAGMAS deficiency—PAM16 gene System Cardiovascular CNS Musculoskeletal

Other

Symptoms and biomarkers Cardiomegaly Developmental delay Hypotonia, axial Chrondrodysplasia Enlarged fontanel Facial dysmorphism Narrow chest Platyspondyly Short nose Death Short stature

Neonatal (birth–1 month) + + + + + + + + +

Infancy (1–18 months) + + + + + + + + + + +

Childhood (1.5–11 years)

+

+

Adolescence (11–16 years)

Adulthood (>16 years)

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

901

Table 46.17  Acylglycerol kinase deficiency—AGK gene System Cardiovascular Eye Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy hypertrophic Cataract Exercise intolerance Myopathy Death 3-Methylglutaconic acid (U) Lactate (P)

Neonatal (birth–1 month) + + ± + ± ↑ ↑

Infancy (1–18 months) + + + + ± ↑ ↑

Childhood (1.5–11 years) + + +

Adolescence (11–16 years) +

± ↑ ↑

± ↑ ↑

Adulthood (>16 years)

+ ±

Table 46.18  Mitochondrial processing peptidase alpha (PMPCA) deficiency System CNS

Ear Eye Other

Symptoms and biomarkers Ataxia Cerebellar vermis atrophy (MRI) Cerebral atrophy (MRI) Developmental delay Dysarthria Hyperreflexia Hypotonia Intellectual disability Muscle weakness Tremor Sensorineural hearing loss Cataract Nystagmus Short stature

Neonatal (birth–1 month)

Infancy (1–18 months)

+

±

±

±

±

±

Childhood (1.5–11 years) + ±

Adolescence (11–16 years) +

Adulthood (>16 years) +

± + +

+

+ +

+

+

+

± ± ± + ±

±

±

± + ±

± +

Table 46.19  Mitochondrial processing peptidase beta (PMPCB) deficiency System CNS

Eye Other Laboratory findings

Symptoms and biomarkers Ataxia Basal ganglia lesions (MRI) Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Dystonia Hypotonia Intellectual disability Loss of speech Seizures Spasticity Optic atrophy Death Lactate (P)

Neonatal (birth–1 month)

Infancy (1–18 months) + + + + + ±

+

↑

Childhood (1.5–11 years) + + + + + + ± + + + + + ± ↑

Adolescence (11–16 years)

Adulthood (>16 years)

902

L. de Boer et al.

Table 46.20  Mitochondrial intermediate peptidase deficiency—MIPEP gene System Cardiovascular CNS

Digestive Eye Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Developmental delay Dystonia Hypertonia Hypotonia Microcephaly Seizures Symmetric hyperintense lesions in basal ganglia (MRI) Intestinal dysmotility Cataract Death Poor growth Alanine (P) Lactate (P)

Neonatal (birth–1 month) ±

Infancy (1–18 months) + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + ± ±

± +

±

+ ± ±

± + ↑ ↑

± ↑ ↑

Infancy (1–18 months) ± + + ±

Childhood (1.5–11 years) ± + + ±

Adolescence (11–16 years) ± + + ±

Adulthood (>16 years) ± + + ±

± + + + ±

+ ± + + ±

+ ± + + ±

+ ± + + ±

± + +

± + +

± + +

± + +

± n

± n

± n

± n

± n

↑↑

↑↑

↑↑

↑↑

↑↑

↑

↑

↑

↑

↑

Table 46.21  CLPB deficiency System CNS

Endocrine Eye Hematological Other

Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Dystonia Hypereckplexia Hypertonia, extremities Hypotonia, muscular Intellectual disability Retardation Seizures Seizures, intra uterin Spasticity Stiffness Endocrine abnormalities Cataract Neutropenia Death Intrauterine growth retardation Ulcerations, oral, genital 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine)

Neonatal (birth–1 month) ± + + ± ± ± + + + ± ± ± ± + + ± ±

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

903

Table 46.22  CLPP deficiency System CNS

Ear Endocrine

Symptoms and biomarkers Ataxia Microcephaly Neuropathy Seizures Spasticity Sensorineural hearing loss Hypergonadotropic hypogonadism Ovarian failure Secundary amenorrhoea

Neonatal (birth–1 month)

Infancy (1–18 months) ±

+

+

Childhood (1.5–11 years) ± ± ± ± + +

Adolescence (11–16 years) ± ± ± ± + + +

+ +

+ +

Childhood (1.5–11 years) + ± ± ± + + + + + ± +

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

Table 46.23  LONP1 deficiency System CNS

Ear Eye Musculoskeletal

Other

Neonatal Symptoms and biomarkers (birth–1 month) Developmental delay Hypotonia Intellectual disability Microcephaly Hearing loss Cataract Ptosis eyelid Hip dysplasia, degenerative Short stature Teeth malposition Craniofacial dysmorphias

Infancy (1–18 months) + ± ± + + + + + ± +

Adulthood (>16 years)

±

Table 46.24  HSPA9 deficiency System Cardiovascular CNS

Hematological Musculoskeletal

Renal Other Laboratory findings

Symptoms and biomarkers Heart abnormalities Abnormal gait Agenesis of the corpus callosum Agenesis of the septum pellucidum Developmental delay Hypotonia Anemia, sideroblastic Anal atresia Aplasia cutis congenita on skull vertex Hypoplastic nose Microtia Short stature Shortened limbs Skeletal abnormalities Synophrys Hypoplastic kidney Vesicouretral reflux Low weight Teeth abonormalites Microcytic or macrocytic red blood cells Ringed sideroblasts in bone marrow

Neonatal (birth–1 month)

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) + ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

± ±

± ± +++

+ ++ + + +++ ++ + +

+++

±

+++ +++ +++

+

+++ +++ ± ± +++ ± +++ +++

904

L. de Boer et al.

Table 46.25  HSP60 deficiency System CNS

Other Laboratory findings

Symptoms and biomarkers Apnea Head circumference Hypotonia MRI cerebrum Psychomotor retardation Rotator nystagmus Seizures Spastic paraplegia Death Ethylmalonic acid (U) Lactate (P)

Neonatal (birth–1 month) ++ n +++ + +++ +++ + + ↑ n-↑

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

↓ +++ + +++ +++ + ++ + ↑ n-↑

↓ +++ + +++ + + ++ + ↑ n-↑

Infancy (1–18 months) ++ ±

Childhood (1.5–11 years) ++ ±

Adolescence (11–16 years) ++ +

Adulthood (>16 years) ++ ++

−

+ −

++ − + ++

++ − ++ ++ + +

Table 46.26  Sacsin deficiency System CNS

Digestive Eye Other

Symptoms and biomarkers Cereballar ataxia Cerebellar vermis atrophia (MRI) Dysarthria IQ 16 years) ++ + + ± ±

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) −

Adulthood (>16 years) − ± − +

Table 46.28  Paraplegin deficiency System CNS

Symptoms and biomarkers Ataxia Cerebellar atrophia (MRI) Peripheral neuropathy Spasticity lower limbs

− ±

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

905

Table 46.29  HTRA2 deficiency System CNS

Other Laboratory findings

Symptoms and biomarkers Brain atrophy (MRI) Hypertonia Hypotonia Seizures Death 3-Methylglutaconic (U) Lactate (P)

Neonatal (birth–1 month) ± + + + ± ↑ ↑

Infancy (1–18 months) +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + + +

+

Table 46.30  Parkin deficiency System CNS

Musculoskeletal

Symptoms and biomarkers Bradykinesia Dystonia Hyperreflexia Parkinsonism, hypokinetic features Retropulsion Tremor Postural instability Rigidity

Neonatal (birth–1 month)

Infancy (1–18 months)

+ + + + ±

+ ++ ± ±

Table 46.31  PINK1 deficiency System CNS

Musculoskeletal Genitourinary

Symptoms and biomarkers Anxiety Asymmetry Autonomic instability Bradykinesia Dementia Depression Dystonia Gait impairment Hyperreflexia Parkinsonism Psychiatric disturbances Sleep benefit Tremor Postural instability Rigidity Urinary urgency

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

Adulthood (>16 years) ± + ± + ± ± ± + + + ± ± + ± + ±

Neonatal (birth–1 month)

Infancy (1–18 months) + + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 46.32  USP9X deficiency System CNS Musculoskeletal

Symptoms and biomarkers Hypotonia Intelectual disability Short stature

+

906

L. de Boer et al.

Table 46.33  Valosin-containing protein superactivity System CNS Musculoskeletal

Symptoms and biomarkers Frontotemporal dementia Myopathy Paget bone disease

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± + +

Infancy (1–18 months) +

Childhood (1.5–11 years) ++ ± +/++ ±

Adolescence (11–16 years) ++ + +/++ ±

Adulthood (>16 years) ++ + + ±

Table 46.34  Pitrilysin metallopeptidase 1 deficiency System CNS

Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Intellectual disability Psychosis Creatine kinase (P)

Neonatal (birth–1 month)

+/++ ↑

Table 46.35  YME1L1 deficiency System CNS

Eye

Neonatal (birth–1 month)

Symptoms and biomarkers Intellectual disability Leukoencephalopathy (MRI) Motor development delay Optic nerve atrophy

Infancy (1–18 months) ++

Childhood (1.5–11 years) ++ + + +

+ +

Adolescence (11–16 years)

Adulthood (>16 years)

Table 46.36  X-prolyl aminopeptidase 3 deficiency System CNS Renal

Symptoms and biomarkers Tremor Nephronophtisis Renal insufficiency

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ± + ±

Adolescence (11–16 years) + + +

Adulthood (>16 years)

Infancy (1–18 months) + ± + + ↑

Childhood (1.5–11 years) + ± + + ↑

Adolescence (11–16 years) +

Adulthood (>16 years)

Infancy (1–18 months) + ± ±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Table 46.37  Mitochondrial inorganic pyrophosphatase 2 deficiency System Cardiovascular CNS Metabolic Other Laboratory findings

Symptoms and biomarkers Cardiac arrhythmia Seizures Lactic acidosis Sudden death Lactate (P)

Neonatal (birth–1 month)

+ + ↑

Table 46.38  Sideroflexin 4 deficiency System CNS Hematological Other Laboratory findings

Symptoms and biomarkers Microcephaly Speech delay Macrocytic anemia IUGR Lactate (P)

Neonatal (birth–1 month) +

+ ↑

↑

±

Adulthood (>16 years)

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

907

Table 46.39  Combined oxidative phosphorylation defect 6 System CNS

Other Laboratory findings

Symptoms and biomarkers Areflexia Hypotonia Neurologic deterioration Neuropathy Regression, psychomotor Seizures Death Lactate (CSF) Lactate (P)

Neonatal (birth–1 month)

Infancy (1–18 months) ++ ++ + ++ ++ + ++ ↑ ↑

Childhood (1.5–11 years) ++ ++ +++ ++ ++ ++ ++ ↑ ↑

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month)

Infancy (1–18 months) + + +a

Childhood (1.5–11 years) + + +a

Adolescence (11–16 years)

Adulthood (>16 years)

+ +a

+ +a

±

±

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) +

± ±

±

+

+

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

± ↑

↑

↑

n-↑

Adulthood (>16 years) ± ± ± ± n-↑

Infancy (1–18 months) ++ ++ +++ +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 46.40  ATAD3A deficiency System CNS

Eye Other

Symptoms and biomarkers Developmental delay Hypotonia Seizures Cataract Optic atrophy Death

±a +a ±a

Only bi-allelic mutations

a

Table 46.41  Transmembrane protein 126A deficiency System CNS Ear Eye

Symptoms and biomarkers Peripheral neuropathy Auditory neuropathy Optic atrophy

Neonatal (birth–1 month)

Table 46.42  C1q-binding protein deficiency System Cardiovascular Eye Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy CPEO Myopathy Death Lactate (P)

Table 46.43  Trafficking kinesin-binding protein 1 deficiency System CNS

Other

Symptoms and biomarkers Developmental delay Encephalopathy Seizures (myoclonic) Death

Neonatal (birth–1 month)

908

L. de Boer et al.

Table 46.44  Mitochondrial calcium uniporter deficiency System CNS

Musculoskeletal Laboratory findings

Symptoms and biomarkers Chorea Learning difficulties Motor delay Muscle weakness Creatine kinase (P)

Neonatal (birth–1 month)

Infancy (1–18 months) ± + + ± ↑

Childhood (1.5–11 years) ± + + ± ↑

Adolescence (11–16 years)

Adulthood (>16 years)

+ + ± ↑

+ + ± ↑

Infancy (1–18 months)

Childhood (1.5–11 years) ± +

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 46.45  Reticulon 4-interacting mitochondrial protein deficiency System CNS Eyes

Symptoms and biomarkers Learning disability Optic atrophy

Neonatal (birth–1 month)

±

Table 46.46  MICOS complex subunit MIC13 deficiency System CNS

Digestive Metabolic Other Laboratory findings

Symptoms and biomarkers Cortical atrophy (MRI) Epilepsy Hypotonia, muscular Microcephaly Regression Retardation, psychomotor Subcortical atrophy (MRI) White matter abnormalities (MRI) Liver dysfunction Liver failure, acute Hypoglycemia Deatha Failure to thrive 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Ammonia (blood) ASAT/ALAT (plasma) Bilirubin, conjugated (plasma) Disturbed clotting Glucose (plasma) Lactate (plasma)

Neonatal (birth–1 month) ± ± ± ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ± ± ± ±

+ + ± + ± n

+ + ± + ± n

↑↑

↑↑

↑

↑

n ↑ ↑

n ↑ ↑

↑ ↓-n ↑

↑ ↓-n ↑

All patients died (maximum age 13 months)

a

Table 46.47  Mitochondrial thioredoxin 2 deficiency System CNS

Eye Laboratory findings

Symptoms and biomarkers Developmental delay Microcephaly Peripheral neuropathy Seizures Optic neuropathy Lactate (P)

Neonatal (birth–1 month)

Infancy (1–18 months) ++

+

↑

+ + + ↑

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

909

Table 46.48  Mitochondrial thioredoxin reductase 2 deficiency System Endocrine

Symptoms and biomarkers Glucocorticoid deficiency Poor synacthen test

Neonatal (birth–1 month)

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

Reference Value Compound Lactate 3-Methylglutaconic acid

Serum/blood (μmol/L) 450–1800 (B)

Cerebrospinal fluid (μmol/L) 1100–1700

15 years male)

Ferritin

Alanine

Urine (mmol/mol creat)

150–450 (P, S)

Pathological Values No. 46.1 46.2 46.3 46.4 46.5 46.6 46.7 46.8 46.9 46.10 46.11 46.12 46.13 46.14 46.15 46.16 46.17 46.18 46.19 46.20 46.21 46.22 46.23 46.24 46.25

Disorder Peroxisomal and mitochondrial fission defect Mitochondrial fission factor deficiency GDAP1 deficiency STAT2 deficiency UGO-1 like protein deficiency Childhood-onset optic atrophy type 1 Optic atrophy 1 and deafness Costeff syndrome Mitofusin 2 deficiency MSTO1 deficiency DNAJC19 deficiency Mohr-Tranebjaerg syndrome TIMMDC1 deficiency Mitochondrial epileptic encephalopathy TIMM50 GFER deficiency MAGMAS deficiency Acylglycerol kinase deficiency Mitochondrial processing peptidase alpha deficiency Mitochondrial processing peptidase beta deficiency Mitochondrial intermediate peptidase deficiency CLPB deficiency CLPP deficiency LONP1 deficiency HSPA9 deficiency HSP60 deficiency

Lactate (P) ↑

Lactate (CSF)

3-MGA (U)

3-MG (U)

Ferritin (S)

Alanine (P)

n

n-↑

n-↑ n-↑

Very long chain fatty acids (P) ↑

n-↑ n-↑

↑

n-↑ n-↑

↑

↑

↑

n-↑ n-↑

n-↑

n-↑

n-↓

↑

↑

↑ ↑ ↑

n-↑

↑ ↑

↑

↑

CK (P)

910

No. 46.26 46.27 46.28 46.29 46.30 46.31 46.32 46.33 46.34 46.35 46.36 46.37 46.38 46.39 46.40 46.41 46.42 46.43 46.44 46.45 46.46 46.47 46.48

L. de Boer et al.

Disorder Sacsin deficiency m-AAA protease AFG3L2 subunit deficiency Paraplegin deficiency HTRA2 deficiency Parkin deficiency PINK1 deficiency USP9X deficiency Valosin-containing protein superactivity Pitrilysin metallopeptidase 1 deficiency YME1L1 deficiency X-prolyl aminopeptidase 3 deficiency Mitochondrial inorganic pyrophosphatase 2 deficiency Sideroflexin 4 deficiency Combined oxidative phosphorylation defect 6 ATAD3A deficiency Transmembrane protein 126A deficiency C1q-binding protein deficiency Trafficking kinesin-binding protein 1 deficiency Mitochondrial calcium uniporter deficiency Reticulon 4-interacting mitochondrial protein deficiency MICOS complex subunit MIC13 deficiency Mitochondrial thioredoxin 2 deficiency Mitochondrial thioredoxin reductase 2 deficiency

Lactate (P)

Lactate (CSF)

Very long chain fatty acids (P)

↑

3-MGA (U)

3-MG (U)

↑

↑

Ferritin (S)

Alanine (P)

CK (P)

↑

↑ ↑ ↑

↑

n-↑

↑

↑

↑

↑

Abbreviations: 3MGA 3-Methylglutaconic acid, 3MG 3-Methylglutaric acid, CK Creatine kinase P Plasma, CSF Cerebrospinal fluid, U Urine, S Serum

Diagnostic Flowchart

DNA Testing

See flowchart in Chap. 44.

If a nuclear-encoded mitochondrial syndrome is clinically suspected, then a sequence analysis of the relevant gene may be the appropriate first-line test. Although in these cases, exome sequencing will most probably also result in the identification of the defect, this approach does have a small chance of unsolicited genetic findings, and therefore specific gene sequencing is preferred over exome sequencing in the case of a strong clinical suspicion for such a specific gene defect.

Specimen Collection See Chap. 44.

Prenatal Diagnosis Prenatal DNA testing can be offered for the nDNA mutations after confirmation of parental carriage of the mutations.

Treatment See Chap. 44.

46  Disorders of Mitochondrial Homeostasis, Dynamics, Protein Import, and Quality Control

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Primary Coenzyme Q10 Deficiencies

47

Leonardo Salviati and Rafael Artuch

Contents Introduction

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Nomenclature

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Metabolic Pathway

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Signs and Symptoms

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Reference Values

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Diagnostic Flowchart

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Specimen Collection

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Prenatal Diagnosis

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DNA Testing

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Treatment

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References

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Summary

Coenzyme Q10(CoQ10) is a small lipophilic molecule which plays a number of crucial roles in cellular homeostasis. It is an electron carrier in the mitochondrial respiratory chain (MRC), and it is involved in other biochemical pathways such as mitochondrial fatty acid oxidation, sulfide detoxification, and pyrimidine biosynthesis. Moreover, it is modulator of the permeability transition L. Salviati (*) Clinical Genetics Unit, Department of Women and Children’s Health, University of Padova, and IRP Città della Speranza, Padova, Italy e-mail: [email protected] R. Artuch CIBERER, Instituto de Salud Carlos III, Madrid, Spain Clinical Chemistry Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain Pathology Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain e-mail: [email protected]

pore, and an essential antioxidant. CoQ10 biosynthesis is still incompletely understood and involves the products of at least 12 different genes (collectively known as COQ genes). Mutations in these genes cause primary CoQ10 deficiencies, a clinically and genetically heterogeneous group of conditions. To date mutations in nine genes (PDSS1, PDSS2, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, and COQ9) have been related to CoQ10 deficiency in humans, while the association of two other genes (ADCK2 and COQ5) must be confirmed. The age of onset can span from birth to the 6–7th decade of life. Manifestations range from catastrophic multiorgan failure, to isolated cerebellar ataxia or steroid resistant nephrotic syndrome (SRNS). SRNS is a peculiar manifestation of CoQ10 deficiency, since it is rarely seen in other mitochondrial disorders. Interestingly only some genetic defects cause SNRS (PDSS1, PDSS2, COQ2, COQ6, and COQ8B), while mutations in other genes (COQ4, COQ7, COQ8A, and COQ9) have never been observed in association with SRNS, but instead cause

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_47

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encephalomyopathy or multisystem disorders without glomerular involvement. CoQ10 deficiency is one of the few treatable mitochondrial disorders. In fact, many patients (especially those with milder forms, and who are treated soon after the onset of symptoms) respond well to high-dose oral CoQ10 supplementation. Therefore, it is essential to recognize promptly this condition to institute an appropriate treatment. Traditionally, the diagnosis relied on biochemical analysis of CoQ10 in muscle or cultured fibroblasts, while molecular studies were performed in a second time. Nowadays, NGS has revolutionized the diagnostic approach, and the molecular diagnosis generally precedes the biochemical one.

Introduction Coenzyme Q10 (CoQ10) is a small lipophilic molecule, comprised of a quinone group and an isoprenoid tail, which plays different crucial roles in cellular homeostasis. It is an electron carrier in the mitochondrial respiratory chain (MRC), where it shuttles electrons from respiratory complexes I and II to complex III; it is a cofactor of several other ­mitochondrial dehydrogenases (among which sulfide:quinone oxidoreductase which is essential for detoxification of H2S), a modulator of the permeability transition pore, and an essential antioxidant (Turunen et al. 2004). CoQ10 biosynthesis is still incompletely understood in eukaryotic cells where it involves the products of at least 12 genes (collectively known as COQ genes). The precursor of the quinone group, 4-hydoxybenzoate (4HB), is derived from tyrosine through a poorly characterized set of reactions (Payet et  al. 2016). The tail shares its initial biosynthetic steps with cholesterol through the cytosolic mevalonate pathway. Farnesyl-pyrophosphate is then condensed to form decaprenyl-pyrophosphate within mitochondria, by PDSS1 and PDSS2. Decaprenyl-pyrophosphate is then joined to 4HB by COQ2. The final biosynthetic steps are thought to be rate limiting and are carried out by a set of enzymes comprised of COQ3, COQ5, COQ6, and COQ7 located in the mitochondrial matrix associated to the inner membrane (Acosta et al. 2016). The proteins responsible for the decarboxylation and hydroxylation of position C1 of the ring, the first ring modifications to occur in mammals (Acosta Lopez et al. 2019), have not been identified yet. The process requires four other proteins, COQ9, which is required for the synthesis of COQ7, COQ8A, and COQ8B, which have a regulatory function, although their precise role is unclear, and COQ4,

L. Salviati and R. Artuch

which is thought to be essential for holding together the other COQ proteins in a complex (Marbois et al. 2009). CoQ10 deficiency can be defined as the presence of reduced levels of CoQ10 in tissues or cells of a patient (Acosta et al. 2016). The term primary CoQ10 deficiency comprises a clinically and genetically heterogeneous group of disorders caused by mutations in COQ genes. Primary deficiencies must be distinguished from secondary forms, in which reduction of CoQ10 is associated with mutations in genes unrelated to CoQ10 biosynthesis (or to non-genetic factors) (Sacconi et  al. 2010; Cordero et  al. 2009). In this chapter, we will focus exclusively on primary forms. To date mutations in nine genes (PDSS1, PDSS2, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, and COQ9) have been related to primary CoQ10 deficiency (Salviati et al. 2017), while the association with COQ5 and ADCK2 mutations must be confirmed. Primary CoQ10 deficiencies are associated with dramatically different clinical presentations, ranging from fatal neonatal multisystem disorders, to juvenile or adult-onset diseases with involvement of isolated organs. The genotype– phenotype correlations are only partially known. Most clinical symptoms are common to other respiratory chain disorders. However, a peculiar manifestation of CoQ10 deficiency is renal glomerular involvement, manifesting as steroid resistant nephrotic syndrome (SRNS), which is rarely seen in other mitochondrial disorders (Emma et al. 2016). The most severe forms are characterized by a catastrophic multiorgan failure, which leads to death at birth, or in the first days of life. Other forms may have a more subtle onset, and present in the first weeks of life with encephalomyopathic symptoms and features of Leigh syndrome on MRI. These forms are virtually indistinguishable from other severe MRC defects. Neonatal onset cases usually do not display glomerular involvement, although renal tubulopathy has been reported in patients with COQ9 defects (Duncan et al. 2009) and renal morphological abnormalities, that did not affect function, were reported in COQ7 patients (Kwong et al. 2019). SRNS may appear later in the course of the disease in long surviving early onset patients, or it can be the first manifestation in patients affected by intermediate forms, with disease onset occurring from the end of the first year of life through adolescence. In some cases, SRNS may be the only manifestation of CoQ10 deficiency, while other patients develop features of neurological involvement. Curiously, SRNS has been observed in patients with mutations in PDSS1, PDSS2, COQ2, COQ6, and COQ8B, while it has never been reported in those with COQ4, COQ7, COQ8A, and COQ9 mutations, which display only neuromuscular involvement (COQ8A) or neuromuscular involvement and multisystem dysfunction (COQ4, COQ7, and COQ9) (Acosta et  al. 2016; Kwong et  al. 2019). The reasons for these phenotypic differences are still unknown.

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The pathogenesis of CoQ10 deficiency involves deficient ATP production, increased ROS, impairment of pyrimidine metabolism (Lopez-Martin et al. 2007; Quinzii et al. 2010), and possibly impaired H2S clearance (Kleiner et al. 2018). At very low CoQ10 concentrations, the defect in energy production prevails, while ROS are not increased, and the clinical manifestations are those of classical MRC defects. With milder CoQ10 deficiency, ATP production is less impaired, and classical “mitochondrial” symptoms are less evident, whereas ROS production gradually increases causing the glomerular damage (Quinzii et al. 2008; Quinzii et al. 2013). For some genes, for example COQ2, the genotype–phenotype correlation is clear and depends on the presence of residual enzymatic activity (Desbats et al. 2016), while for others, such COQ8B, there is no clear genotype–phenotype correlation (Vazquez Fonseca et al. 2018). Traditionally, the diagnosis was based on direct biochemical measurements of CoQ10 in muscle biopsies or cultured fibroblasts, and then molecular genetics followed. NGS has revolutionized the diagnostic protocols, and it is simpler and cheaper to run the genetic analysis first, and then to confirm the findings with biochemical analyses on patients’ tissues (Yubero et al. 2018). Measurements of plasma CoQ10 levels are not indicated for diagnosis because they reflect dietary intake rather than tissue concentration of CoQ10. Furthermore, in our experience, patients with later-onset forms (who present in late childhood, adolescence or even later) may display

little or no reduction of CoQ10 in fibroblasts and even in skeletal muscle, despite harboring clearly pathogenic mutations. The suspicion of primary CoQ10 deficiency should arise in cases of early onset mitochondrial disorders, SRNS (even isolated), and unexplained ataxia (Trevisson et  al. 2011). NGS panels for these conditions routinely include COQ genes, but whole exome sequencing is becoming the first line investigation in these patients. Primary CoQ10 deficiency is one of the few treatable mitochondrial disorders. Many patients respond well to oral CoQ10 supplementation. Treatment can stop the progression of the encephalopathy and reverse the nephropathy. It must however be instituted before severe tissue damage has occurred, otherwise it is largely ineffective. Severe neonatal cases often do not respond (or respond only partially) to treatment (Alcazar-Fabra et al. 2018). Doses employed range from 10 to 30 or even 50 mg/kg per day of ubiquinone (the oxidized form of CoQ10). Ubiquinol (the reduced form) appears to be more effective than ubiquinone in animal models (Garcia-Corzo et al. 2014), but there is much less clinical experience. Moreover, long-term data about the efficacy of CoQ10 supplementation in patients are however scarce. Recently a novel approach, bypass therapy, has been proposed. It involves the use of specific analogues of the quinone ring which can bypass individual genetic defects (Pierrel 2017). Results are promising in cellular and animal models, but there is currently no experience in patients.

Nomenclature No. Disorder 47.1 Prenyl diphosphate synthase, subunit 1 (PDSS1) deficiency 47.2 Prenyl diphosphate synthase, subunit 2 (PDSS2) deficiency 47.3 COQ2 deficiency

Gene Abbreviation symbol COQ10D2 PDSS1

Chromosomal location Affected protein 10p12.1 Prenyl diphosphate synthase subunit 1

OMIM no. 614651

Decraprenyl diphosphate synthase (DPS) deficiency

COQ10D3

PDSS2

6q21

Prenyl diphosphate synthase subunit 2

614652

Mitochondrial 4-hydroxybenzoatepolyprenyltransferase deficiency

COQ10D1

COQ2

4q21-q22

4-hydroxybenzoate-polyprenyltransferase

607426

COQ4D7

COQ4

9q34.11

COQ4

616276

COQ6

14q24.3

COQ6 monooxygenase

614650

Alternative name Coenzyme Q10 deficiency, primary, 2

Alternative name-2 Decraprenyl diphosphate synthase (DPS) deficiency

Coenzyme Q10 deficiency, primary, 3

Coenzyme Q10 deficiency, primary, 1

47.4 COQ4 deficiency Coenzyme Q10 deficiency, primary, 7 47.5 COQ6 deficiency Coenzyme Q10 deficiency, primary, 6

COQ10D6 Early onset steroidresistant nephrosis with sensorineural deafness

(continued)

918

No. Disorder Alternative name 47.6 COQ7 deficiency Coenzyme Q10 deficiency, primary, 8 47.7 COQ8A Coenzyme Q10 deficiency deficiency, primary, 4 47.8 COQ8B Nephrotic deficiency syndrome type 9 47.9 COQ9 deficiency Coenzyme Q10 deficiency, primary, 5

Metabolic Pathway

L. Salviati and R. Artuch

Alternative name-2

Gene Abbreviation symbol COQ10D8 COQ7

ADCK3 deficiency

COQ10D4

ADCK4 deficiency

Chromosomal location Affected protein 16p12.3 COQ7, di-iron oxidase

COQ8A 1q42.13

COQ8B 19q13.2

COQ10D5

COQ9

16q21

OMIM no. 616733

AARF DOMAIN- 612016 CONTAINING KINASE 3 AARF DOMAIN- 615573 CONTAINING KINASE 4 COQ9 614654

for the stabilization of COQ7. The precise role of COQ4, COQ8A, COQ8B, and ADCK2 is still under investigation. The precursors of CoQ10, 4-hydroxybenzoate (4-HB) and Gene products in red have been definitely associated to farnesyl-pyrophosphate, are derived from tyrosine through a human CoQ10 deficiency (Fig. 47.1a and b). still poorly characterized set of reactions, and from acetylBesides being an electron carrier within the respiratory CoA, through the mevalonate pathway. Farnesyl- chain, where it shuttles electron from complex I (CI) and II pyrophosphate is joined by a heterotetrameric enzyme (CII) to complex III (CIII), CoQ is a cofactor of electron comprised of PDSS1 and PDSS2 to form decaprenyl-­ transfer flavoprotein dehydrogenase (ETFDH) (involved in pyrophosphate which is then joined to 4-HB by COQ2. The mitochondrial fatty acid oxidation), sulfide:quinone oxidonext two steps (the decarboxylation and hydroxylation of the reductase (SQOR) (involved in sulfide detoxification), and C1 carbon) are catalyzed by still unknown enzymes, while dihydroorotate dehydrogenase (DHODH) involved in the hydroxylation of the C5 carbon of the ring is carried out pyrimidine nucleotides b­iosynthesis. Moreover, it is a by COQ6. COQ3 then transfers a methyl group to this cofactor of uncoupling proteins (UCP), a modulator of the hydroxyl, and COQ5 transfers another methyl group directly permeability transition pore (PTP) thus controlling apoptoon the C2 carbon. Last, COQ7 hydroxylates the C6 carbon sis, and one of the most important cellular antioxidants and COQ3 adds the final methyl group. COQ9 is essential (Fig. 47.1c).

47  Primary Coenzyme Q10 Deficiencies

919

a

b

c

Fig. 47.1 (a) Structure of the reduced form of CoQ10. Carbons comprising the aromatic ring are numbered. (b) New model of the CoQ biosynthetic pathway in mammals based on the data of Acosta Lopez et al. 2019. (c) The central role of coenzyme Q10 (Q) in mitochondrial homeostasis

920

L. Salviati and R. Artuch

Signs and Symptoms Table 47.1  Prenyl diphosphate synthase, subunit 1 (PDSS1) deficiency System Cardiovascular CNS Digestive Ear Eye Musculoskeletal Renal Laboratory findings

Symptoms and biomarkers Cardiomyopathy Intellectual disability Neuropathy, peripheral Obesity Deafness Optic atrophy Macrocephaly Nephrotic syndrome CoQ10 (fibroblasts) Lactate (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

±

+

+ + + + + +

Adolescence (11–16 years) + + + + + + +

Adulthood (>16 years) + + + + + + +

↑

↓ ↑

↓ ↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+++

+

± ↑

Table 47.2  Prenyl diphosphate synthase, subunit 2 (PDSS2) deficiency System Cardiovascular CNS

Musculoskeletal Renal Laboratory findings

Symptoms and biomarkers Cardiomyopathy Epilepsy Leigh syndrome Stroke-like episodes Muscle weakness Nephrotic syndrome CoQ10 (fibroblasts) CoQ10 (muscle) Lactate (plasma)

Neonatal (birth–1 month) + + + +++ ↓ ↓ ↑

Infancy (1–18 months) + +++ +++ + +++ +++ ↓ ↓ n-↑

++ ++ ++ +++ ↓ ↓ n

n

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Table 47.3  COQ2 deficiency System CNS

Ear Eye Musculoskeletal Other Renal Laboratory findings

Symptoms and biomarkers Epilepsy Leigh syndrome Multiple system atrophylike encephalopathy Regression, psychomotor Stroke-like episodes Deafness Retinopathy Muscle weakness Severe multisystem disease Nephrotic syndrome CoQ10 (fibroblasts) CoQ10 (muscle) Lactate (plasma)

Neonatal (birth–1 month) +

Infancy (1–18 months) +++ ++

Adulthood (>16 years)

±

+++

++ ++ + ± +++

+ ↓ ↓ n-↑

++ ↓ ↓ n

+

±

±

+

+

+++ + ↓ ↓ ↑↑

n

47  Primary Coenzyme Q10 Deficiencies

921

Table 47.4  COQ4 deficiency System Cardiovascular

CNS Musculoskeletal Other

Respiratory Laboratory findings

Symptoms and biomarkers Bradycardia Cardiomyopathy, hypertrophic Left ventricular hypoplasia Patent ductus arteriosus Ataxia, cerebellar Encephalopathy, epileptic Hypotonia Neuropathy, sensory Regression, psychomotor Seizures Spasticity Swallowing difficulties Scoliosis Intrauterine growth retardation Multiorgan failure Respiratory insufficiency 2-Hydroxyglutarate (urine) CoQ10 (fibroblasts) CoQ10 (muscle) Lactate (plasma)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

± ±

± ±

± + ±

±

± ± + ±

± +

± ± ± + ±

± ± ± ± +

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

±

±

↓-n ↓-n n

n

+ +++ + n-↑ ↓ ↓ ↑

+ n-↑ ↓ ↓ ↑

n-↑ ↓-n ↓-n ↑

Neonatal (birth–1 month)

Infancy (1–18 months)

Adolescence (11–16 years)

Adulthood (>16 years)

±

+ ±

Childhood (1.5–11 years) ± ± + ++

+ ++

±

n

n

n

Table 47.5  COQ6 deficiency System CNS Ear Renal Laboratory findings

Symptoms and biomarkers Ataxia Epilepsy Deafness, sensorineural Nephrotic syndrome CoQ10 (fibroblasts) Lactate (plasma)

↓-n n

922

L. Salviati and R. Artuch

Table 47.6  COQ7 deficiency System Cardiovascular CNS

Digestive Ear Eye Musculoskeletal Other Psychiatric Renal Respiratory Laboratory findings

Symptoms and biomarkers Pulmonary hypertension Axonal sensory motor polyneuropathy, chronic Hypotonia Retardation, motor Feeding difficulties Hearing loss, sensorineural Visual impairment Growth retardation Joint contractures Intrauterine growth retardation Learning disabilities Kidney dysplasia Renal dysfunction Respiratory distress CoQ10 (fibroblasts) CoQ10 (muscle) Fumaric acid (urine) Lactate (cerebrospinal fluid) Lactate (plasma) Malic acid (urine)

Neonatal (birth–1 month) +

Infancy (1–18 months)

Childhood (1.5–11 years)

+

+

+ + + +

+ + + +

+ + + +

+ + +

+ +

Adolescence (11–16 years)

Adulthood (>16 years)

Adolescence (11–16 years) ++ ± ± + ± + ↓-n ↓-n n-↑

Adulthood (>16 years) ++ ± ± + ± + ↓-n ↓-n n-↑

+ +

+ + + ↓ ↓ ↑ ↑

+ +

+ +

↓ ↓ ↑ ↑

↓ ↓ ↑ ↑

n-↑ ↑

n-↑ ↑

n-↑ ↑

Neonatal (birth–1 month)

Infancy (1–18 months) + ± ± + ± + ↓-n ↓-n n-↑

Childhood (1.5–11 years) ++ ± ± + ± + ↓-n ↓-n n-↑

Table 47.7  COQ8A deficiency System CNS

Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia Cognitive dysfunction Dystonia Epilepsy Pyramidal signs Muscle weakness CoQ10 (fibroblasts) CoQ10 (muscle) Lactate (plasma)

↓-n ↓-n n-↑

47  Primary Coenzyme Q10 Deficiencies

923

Table 47.8  COQ8B deficiency System CNS Musculoskeletal Renal

Laboratory findings

Symptoms and biomarkers Epilepsy Intellectual disability Edema Nephrotic syndrome Proteinuria Renal failure, chronic Renal failure, end stage Albumin (serum) CoQ10 (lymphoblasts or fibroblasts) Proteins, total (urine)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± ± ± ± ± ↓

Childhood (1.5–11 years) ± ± + + + + + ↓ ↓

Adolescence (11–16 years) ± ± + + + + + ↓ ↓

↑

↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ± ± + + + + + ↓

Table 47.9  COQ9 deficiency System Autonomic system Cardiovascular CNS Digestive Metabolic Renal Laboratory findings

Symptoms and biomarkers Hypothermia Cardiomyopathy Epilepsy Regression, psychomotor Feeding difficulties Lactic acidosis Renal tubulopathy CoQ10 (fibroblasts) CoQ10 (muscle) Lactate (plasma)

Neonatal (birth–1 month) +++ + ++ +++ + ↓ ↓ ↑

It should be noted that relatively few patients have been described (for some genes less than 10), therefore clinical data are probably incomplete. Moreover, clinical presentations differ dramatically depending on the age of onset (see for example the case of COQ2) (Desbats et al. 2016). There are no pathognomonic manifestations, although the association of SRNS with other neurological manifestation should immediately raise the suspicion of CoQ10 deficiency.

Reference Values There are currently no universally accepted reference values for CoQ10 in muscle or fibroblasts, although most authors reported muscle CoQ10 values in a range between 110 and 580  nmol CoQ10/g protein and in fibroblasts between 39 and 112 nmol/g protein. It is important to refer the data to a set of in-house age matched controls and it is

Infancy (1–18 months)

Adulthood (>16 years)

++ +++ +++ ++ +++ + ↓ ↓ ↑

also useful to normalize data by citrate synthase activity (Yubero et al. 2014).

Diagnostic Flowchart The traditional approach privileged biochemical determinations, and genetic analyses, which were more complex and expensive, were performed only in a second stage. Nowadays, NGS allows analysis of very large numbers of genes for a fraction of the cost and of the time required by traditional Sanger sequencing. Targeted NGS gene panels are commonly used for SRNS, ataxias, and mitochondrial disorders. Whole Exome Sequencing (WES) is theoretically the best option, but costs are higher and coverage is inferior to targeted panels. Moreover CNV analysis is more efficient with targeted panels. Clinical exome panels include 5–7000 genes associated with Mendelian diseases. They may be a good compromise although they may lack some critical genes (see also Chap. 9).

924 Fig. 47.2  Traditional versus NGS-centered approaches for the diagnosis of primary CoQ10 deficiency

L. Salviati and R. Artuch Traditional approach

NGS-centered approach

Clinical Suspicion: SRNS±neurological symtoms Unexplained Ataxia Features suggestive of a mitochondrial disorder

Clinical Suspicion: SRNS Features suggestive of a mitochondrial disorder Ataxia, but also aspecific neurological symtoms

Muscle and skin biopsy Measurment of RC activities and CoQ10 determination

NGS Targeted panels Clinical exome WES

CoQ10 or c.II+III activity

Reduced

Sequencing of COQ genes

Normal If positive, one may consider biochemical assays to confirm diagnosis

STOP

Specimen Collection Plasma CoQ10 content determination is meaningless and should not be performed. Serum lactic acid should be measured with the precautions discussed for other mitochondrial disorders to avoid false positive results. If possible CoQ10 should be measured in muscle samples (which can be safely frozen at −80  °C or, better, in liquid nitrogen, and can be shipped in dry ice) and in cultured skin fibroblast.

Prenatal Diagnosis Prenatal diagnosis can be performed by molecular testing on standard chorionic villi or amniotic fluid cells, for all these forms, provided that the molecular defect in the index case has been unambiguously identified. Biochemical tests, such as CoQ10 determination in amniocytes, are not usually employed.

DNA Testing DNA testing is available for all forms of CoQ10 deficiency. Specific strategies have been described above.

In particular cases, RNA analysis from cultured fibroblasts can be performed.

Treatment The mainstay of treatment is oral supplementation with high dose CoQ10. Most reports refer to ubiquinone, the oxidized form of CoQ10. Dosages range from 5 to 50  mg/kg/day divided in three or more doses. Several formulations are available, but in general soluble forms, soft gel caps, or oily formulations should be preferred (Desbats et  al. 2015). Tablets should not be administered because of poor absorption (Bhagavan and Chopra 2007). Ubiquinol, the reduced form of CoQ10 is also available, but there is limited experience in patients. Idebenone is not effective and should not be employed in these patients. Patients with SRNS may also benefit of treatment with ACE inhibitors. Bypass therapy using analogues of the precursor of the quinone ring has been tested in cells and model organisms, but to date there are no data in patients. Renal transplantation is an option for patients with end-­ stage renal disease.

47  Primary Coenzyme Q10 Deficiencies

References Acosta Lopez MJ, Trevisson E, Canton M, Vazquez-Fonseca L, Morbidoni V, Baschiera E, Frasson C, Pelosi L, Rascalou B, Desbats MA, Alcazar-Fabra M, Rios JJ, Sanchez-Garcia A, Basso G, Navas P, Pierrel F, Brea-Calvo G, Salviati L. Vanillic acid restores coenzyme Q biosynthesis and ATP production in human cells lacking COQ6. Oxidative Med Cell Longev. 2019;2019:3904905. Acosta MJ, Vazquez Fonseca L, Desbats MA, Cerqua C, Zordan R, Trevisson E, Salviati L. Coenzyme Q biosynthesis in health and disease. Biochim Biophys Acta. 2016;1857(8):1079–85. Alcazar-Fabra M, Trevisson E, Brea-Calvo G.  Clinical syndromes associated with coenzyme Q10 deficiency. Essays Biochem. 2018;62(3):377–98. Bhagavan HN, Chopra RK.  Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion. 2007;7(Suppl):S78–88. Cordero MD, Moreno-Fernandez AM, deMiguel M, Bonal P, Campa F, Jimenez-Jimenez LM, Ruiz-Losada A, Sanchez-Dominguez B, Sanchez Alcazar JA, Salviati L, Navas P. Coenzyme Q10 distribution in blood is altered in patients with fibromyalgia. Clin Biochem. 2009;42(7–8):732–5. Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati L.  Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J Inherit Metab Dis. 2015;38(1):145–56. Desbats MA, Morbidoni V, Silic-Benussi M, Doimo M, Ciminale V, Cassina M, Sacconi S, Hirano M, Basso G, Pierrel F, Navas P, Salviati L, Trevisson E.  The COQ2 genotype predicts the severity of coenzyme Q10 deficiency. Hum Mol Genet. 2016;25(19): 4256–65. Duncan AJ, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves IP, Lopez LC, Hirano M, Quinzii CM, Sadowski MI, Hardy J, Singleton A, Clayton PT, Rahman S. A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet. 2009;84(5):558–66. Emma F, Montini G, Parikh SM, Salviati L. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol. 2016;12(5):267–80. Garcia-Corzo L, Luna-Sanchez M, Doerrier C, Ortiz F, Escames G, Acuna-Castroviejo D, Lopez LC.  Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency. Biochim Biophys Acta. 2014;1842(7):893–901. Kleiner G, Barca E, Ziosi M, Emmanuele V, Xu Y, Hidalgo-Gutierrez A, Qiao C, Tadesse S, Area-Gomez E, Lopez LC, Quinzii CM. CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. Biochim Biophys Acta Mol basis Dis. 2018;1864(11):3708–22. Kwong AK, Chiu AT, Tsang MH, Lun KS, Rodenburg RJT, Smeitink J, Chung BH, Fung CW. A fatal case of COQ7-associated primary coenzyme Q10 deficiency. JIMD Rep. 2019;47(1):23–9.

925 Lopez-Martin JM, Salviati L, Trevisson E, Montini G, DiMauro S, Quinzii C, Hirano M, Rodriguez-Hernandez A, Cordero MD, Sanchez-Alcazar JA, Santos-Ocana C, Navas P.  Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet. 2007;16(9):1091–7. Marbois B, Gin P, Gulmezian M, Clarke CF. The yeast Coq4 polypeptide organizes a mitochondrial protein complex essential for coenzyme Q biosynthesis. Biochim Biophys Acta. 2009;1791(1):69–75. Payet LA, Leroux M, Willison JC, Kihara A, Pelosi L, Pierrel F.  Mechanistic details of early steps in coenzyme Q biosynthesis pathway in yeast. Cell Chem Biol. 2016;23(10):1241–50. Pierrel F.  Impact of chemical analogs of 4-hydroxybenzoic acid on coenzyme Q biosynthesis: from inhibition to bypass of coenzyme Q deficiency. Front Physiol. 2017;8:436. Quinzii CM, Garone C, Emmanuele V, Tadesse S, Krishna S, Dorado B, Hirano M. Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice. FASEB J. 2013;27(2):612–21. Quinzii CM, Lopez LC, Gilkerson RW, Dorado B, Coku J, Naini AB, Lagier-Tourenne C, Schuelke M, Salviati L, Carrozzo R, Santorelli F, Rahman S, Tazir M, Koenig M, DiMauro S, Hirano M. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 2010;24(10):3733–43. Quinzii CM, Lopez LC, Von-Moltke J, Naini A, Krishna S, Schuelke M, Salviati L, Navas P, DiMauro S, Hirano M.  Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency. FASEB J. 2008;22(6):1874–85. Sacconi S, Trevisson E, Salviati L, Ayme S, Rigal O, Redondo AG, Mancuso M, Siciliano G, Tonin P, Angelini C, Aure K, Lombes A, Desnuelle C.  Coenzyme Q10 is frequently reduced in muscle of patients with mitochondrial myopathy. Neuromuscul Disord. 2010;20(1):44–8. Salviati L, Trevisson E, Doimo M, Navas P.  Primary coenzyme Q10 deficiency. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews(R). Seattle, WA: University of Seattle; 2017. Trevisson E, DiMauro S, Navas P, Salviati L. Coenzyme Q deficiency in muscle. Curr Opin Neurol. 2011;24(5):449–56. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660(1–2):171–99. Vazquez Fonseca L, Doimo M, Calderan C, Desbats MA, Acosta MJ, Cerqua C, Cassina M, Ashraf S, Hildebrandt F, Sartori G, Navas P, Trevisson E, Salviati L.  Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function. Hum Mutat. 2018;39(3):406–14. Yubero D, Montero R, Artuch R, Land JM, Heales SJ, Hargreaves IP.  Biochemical diagnosis of coenzyme q10 deficiency. Mol Syndromol. 2014;5(3–4):147–55. Yubero D, Montero R, Santos-Ocana C, Salviati L, Navas P, Artuch R.  Molecular diagnosis of coenzyme Q10 deficiency: an update. Expert Rev Mol Diagn. 2018;18(6):491–8.

Part VI Disorders of Lipids

Mitochondrial Fatty Acid Oxidation Disorders

48

Ute Spiekerkoetter and Jerry Vockley

Contents Introduction

 930

Nomenclature

 934

Metabolic Pathway

 935

Signs and Symptoms

 937

Reference Values

 950

Pathological Values

 950

Diagnostic Tools and Flowchart

 950

Specimen Collection

 951

Prenatal Diagnosis

 952

DNA Analysis

 952

Treatment

 953

Emergency Treatment

 954

Standard Treatment

 954

Experimental Treatment

 955

References

 955

U. Spiekerkoetter (*) Department of Pediatrics and Adolescent Medicine, University Children’s Hospital, Albert Ludwigs University, Freiburg, Germany e-mail: [email protected]

J. Vockley (*) Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA e-mail: [email protected]

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_48

929

930

Summary

Mitochondrial fatty acid oxidation disorders (FAODs) impair the ability of the body to utilize fats for energy production during times of physiologic stress such as fasting or illness, and thus can be asymptomatic and difficult to diagnose when a patient is well. Reducing equivalents from fatty acid oxidation (FAO) enzyme reactions directly enter the electron transfer chain (ETC) to support generation of adenosine triphosphate (ATP) through oxidative phosphorylation (oxphos), or by entry of its end product acetyl-coenzyme A (acetyl-CoA) into the tricarboxylic acid cycle (TCA or Krebs cycle). Acetyl-CoA from FAO can also be used to synthesize ketones, a fuel source that is used by some peripheral tissues and especially the brain during catabolic situations. Due to the ability to prevent life-threatening symptoms through early diagnosis, FAODs have been included in newborn screening (NBS) panels worldwide through tandem mass spectrometry-­ based screening. Acylcarnitine profiles are specific for the respective enzyme defects; however, the diagnosis should be confirmed by enzyme assay and/or molecular analysis as they may also offer insight into clinical severity. Metabolic profiles can be normal in the anabolic state and, consequently, newborn screening may miss the diagnosis when performed outside the catabolic state on days 2 and 3 of life. Mitochondrial fatty acid oxidation disorders are comprised of four groups: (1) disorders of the entry of long-chain fatty acids into mitochondria (often referred to as carnitine cycle defects), (2) intramitochondrial ß-oxidation defects of long-chain fatty acids, (3) β-oxidation defects of short- and medium-chain fatty acids affecting enzymes of the mitochondrial matrix, and (4) disorders of impaired electron transfer to the respiratory chain from mitochondrial β-oxidation. All told, more than 20 different genetic enzyme defects of FAO have now been identified, some with disease-specific characteristics that distinguish them from others in the group. The main pathophysiologic mechanism of all FAODs is an energy deficiency due to impaired fatty acid oxidation and ketone body formation. Toxic effects of accumulating acylcarnitine and acyl-CoA species may also play a role. FAODs present with heterogeneous phenotypes. Before addition of FAODs to newborn screening (NBS) panels in many countries, the commonest clinical presentations were hypoketotic hypoglycemia and sudden death, usually precipitated by an infection or fasting in the neonatal period or early childhood. With newborn screening, apparent disease incidence has significantly increased, while the proportion of milder phenotypes has grown. Newborn screening greatly reduces the morbidity and mortality, though it does not eliminate early neonatal death in severe phenotypes in some of the defects. Three major phenotypes are now recognized. Non-

U. Spiekerkoetter and J. Vockley

ketotic hypoglycemia predominates in the first few years of life, but is uncommon after age 4–6 years. Cardiomyopathy and arrhythmias are seen at any time, may be of acute onset, and can also be reversible. Exercise- or illness-induced rhabdomyolysis is a common presentation in adolescents or young adults, but muscle pain and elevated creatine kinase (CK) can occur in infancy. With some disorders, patients can remain asymptomatic throughout life if they have mild defects and are not exposed to the metabolic stress. Affected asymptomatic mothers have been identified due to pathological newborn screening in their child. Correlation of genotype and/or residual enzyme activity with disease phenotype has been reported for some defects but is imperfect, suggesting an additional role for disease modifiers and environment. Treatment must be tailored to the severity of the phenotype and the specific disorder, with a focus on avoidance of fasting, mitigation of stress, and fluid and caloric support through episodes of rhabdomyolysis. New therapies are in development and may change significantly the longterm prognosis for patients.

Introduction Fat is an important source of energy and the body’s principal fuel store. It is the main fuel for skeletal muscle during sustained exercise, and provides reducing equivalents to make ATP through oxidative phosphorylation during periods of fasting and physiologic stress. In postnatal life, fatty acids are used in preference to glucose by the heart regardless of caloric intake. Mitochondrial fatty acid oxidation involves four processes: (1) entry of fatty acids into mitochondria (the carnitine cycle), (2) mitochondrial ß-oxidation of long-chain fatty acids via a spiral pathway utilizing membrane-bound enzymes, (3) mitochondrial β-oxidation of chain-shortened fatty acids using matrix enzymes, and (4) electron transfer to the respiratory chain. The clinical presentation of these disorders is heterogeneous. FAODs have three characteristic clinical presentations: 1. Acute hypoketotic hypoglycemia and encephalopathy, accompanied by hepatomegaly and liver dysfunction precipitated by fasting or an infection, often described as the hepatic presentation or “Reye-like symptoms.” Presentation generally occurs in the first weeks and months of life, and the appearance and severity can be mitigated by early identification through newborn screening by mass ­spectrometry. Sudden death due to a first acute episode is reduced, but not eliminated by newborn screening. Intermittent recurrence of symptoms during intercurrent illness

48  Mitochondrial Fatty Acid Oxidation Disorders

is common in the first few years of life, but less common after age 4–6 years. 2. Cardiomyopathy (usually hypertrophic, but also dilated in later stages), arrhythmias, or conduction defects. The cardiac phenotype often occurs in the first weeks and months of life, but patients are at lifelong risk for acute or chronic symptoms. Cardiomyopathy is reversible without sequelae if treated early. 3 . Myopathy, presenting either with weakness, pain, or with acute rhabdomyolysis, precipitated by exercise or infection. The myopathic phenotype mainly occurs after the first few years of life, in later childhood and adolescence. Since implementation of newborn screening for FAODs, milder phenotypes (including asymptomatic) associated with specific genotypes have been recognized. It is not yet clear how many of the NBS-diagnosed patients will remain asymptomatic throughout life. Fasting hypoglycemia is due to increased peripheral glucose consumption, decreased production of glucose due to an intracellular ATP deficit, and a concomitant decreased production of glucose utilization sparing ketones (Brunengraber and Roe 2006; Herrema et al. 2008). While small amounts of ketone bodies can be synthesized, particularly in medium- or short-chain FAODs or if there is high residual enzyme activity, the plasma concentrations are lower than expected for the degree of hypoglycemia, and thus the classification as hypoketotic. Hyperammonemia occurs in some severe defects and lactic acidemia is seen particularly in long-chain 3-­hydroxyacyl-CoA dehydrogenase (LCHAD), mitochondrial trifunctional protein (MTP), and multiple acyl-CoA dehydrogenase (MAD) deficiencies. Rhabdomyolysis leads to elevated creatine kinase (CK), which can exceed 100.000  U/L (normal C mutation is essential in case of clinical suspicion. This common mutation alters the catalytic residue in the LCHAD domain of the MTP alpha subunit. Pregnant women who are heterozygous for LCHAD or MTP deficiencies have an increased risk of HELLP syndrome—Hemolysis, Elevated Liver enzymes and Low Platelets—and acute fatty liver of pregnancy (AFLP) during pregnancies when they are carrying an affected fetus (Wilcken et al. 1993).

Acyl-CoA Dehydrogenase 9 (ACAD9) Deficiency ACAD9 is homologous to VLCAD and has dehydrogenase activity toward various long-chain acyl-CoA esters in vitro. Its primary physiological role is in the assembly of the mitochondrial respiratory chain complex I, and it presents pre-

48  Mitochondrial Fatty Acid Oxidation Disorders

dominantly as a respiratory chain deficiency with cardiomyopathy (Repp et al. 2018) and therefore is treated in Table 44.36.

 edium-Chain Acyl-CoA Dehydrogenase (MCAD) M Deficiency MCAD deficiency (MCADD) has an incidence of approximately 1:10,000 in Europe, Australia, and the USA. Affected patients present clinically primarily if exposed to an appropriate environmental stress such as prolonged fasting or an intercurrent illness. The most common presentations before the era of newborn screening were sudden death or Reye-like symptoms, but many affected individuals identified through family screening were asymptomatic (Pourfarzam et  al. 2001; Wilcken et al. 2007). MCADD is readily identifiable by newborn screening and once diagnosed, sudden death is rare as preventive measures can be taken. The risk for hypoglycemia decreases in late childhood and adulthood, but is never zero. Blood octanoylcarnitine (C8) is a highly specific marker, but may be only moderately elevated in mild phenotypes. The excretion of hexanoyl- and phenylpropionylglycine is elevated in urine; however, in milder phenotypes they may not be detectable. Residual enzyme activity correlates with the genotype and the expected clinical phenotype. A common mutation accounts for 75% of the mutations in patients with MCADD.  A less common but recurrent c199T>C variant leads to sufficient residual activity to probably be protective from disease in combination with an inactivating mutation on the other allele.

933

 hort-Chain Acyl-CoA Dehydrogenase (SCAD) S Deficiency There are two polymorphisms in the SCAD gene (c.625G>A and c.511C>T). In northern Europe, 6% of the general population has one of these variants on both alleles. A common inactivating gene variant is present in Ashkenazi Jews. The biochemical diagnosis relies on the finding of increased blood butyrylcarnitine (C4) and/or urine ethylmalonic and methylsuccinic acids. A variety of clinical symptoms has been reported in patients with SCAD mutations, but patients identified through newborn screening have remained well. Thus, SCADD appears to be a biochemical phenotype rather than a clinically relevant disorder (Gallant et al. 2012). Nevertheless, it has been suggested that it may confer susceptibility to neuromuscular disease in combination with other impairments in mitochondrial function (Nochi et al. 2017).

 hort-Chain 3-Hydroxyacyl-CoA Dehydrogenase S (SCHAD) Deficiency SCHAD deficiency is associated with hypoglycemia but due to a different mechanism than the other FAODs. SCHAD has a second role independent of FAO, binding and inhibiting glutamate dehydrogenase (GDH). SCHAD mutations that prevent GDH binding lead to increased GDH activity and insulin secretion and subsequent hypoglycemia, particularly in response to leucine (Li et al. 2010). Increased plasma L-3-­ hydroxyl-C4-carnitine as well as urine 3-hydroxyglutaric acid are the accepted diagnostic markers.

48.18

48.17

48.16

48.15

48.14

48.13

48.12

48.11

48.10

48.9

48.5

48.4

Long-chain hydroxyacyl-CoA dehydrogenase or complete mitochondrial trifunctional protein deficiency Ichthyosis prematurity syndrome

Ethylmalonic aciduria

HADHA

HADHB

LCHAD

LKAT

MCPH15

ACAD9

MFSD2A

SLC27A4

mTFP, MTP HADHB

HADH

SCHAD

ACADM

ACADS

ACADVL

IPS

1p32

19q13.33

11q22.23

Chromosomal Localization 5q31.1

3q26

1p34.2

9q34.11

2p23.3

2p23

2p23

4q22–q26

17p13

1p31

12q24.31

SLC25A20 3p21.31

CPT2

VLCAD

MCAD

SCAD

Carnitine palmitoyl-CoA transferase 2 CPT2 deficiency CACT

CPT1C

CPT1A

Gene Abbreviation Symbol OCTN2 SLC22A5

Carnitine palmitoyl-CoA transferase 1 CPT1 deficiency Spastic paraplegia 73 (SPG73) SPG73

Alternative Disease Name Carnitine uptake defect

Fatty acid transport protein 4 deficiency Docosahexanoic acid transporter Autosomal recessive primary deficiency microcephaly type 15 Acyl-CoA dehydrogenase 9 Complex I assembly disorder deficiency

Carnitine palmitoyltransferase 1A deficiency Carnitine palmitoyl-transferase IC deficiency Carnitine palmitoyltransferase 2 deficiency Carnitine acylcarnitine translocase deficiency Short-chain acyl CoA dehydrogenase deficiency Medium-chain acyl CoA dehydrogenase deficiency Very long-chain acyl CoA dehydrogenase deficiency Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase Isolated deficiency of long-chain 3-ketoacyl CoA thiolase Trifunctional protein β subunit deficiency

48.2

48.3

Disease Name Carnitine transporter deficiency

No 48.1

Nomenclature

AR

AR

AR

AR

AR

AD

AR

AR

AR

AR

AR

AR

AD

AR

Mode of Inheritance AR

255120

OMIM# 212140

255110

600890

231530

201475

201450

201470

Major facilitator superfamily domain-containing protein 2a Acyl-CoA dehydrogenase 9

Fatty acid transport protein 4

611126

616486

608649

Long-chain 3-ketoacyl CoA 143450 thiolase Hydroxyacyl-CoA dehydrogenase 609015 trifunctional multienzyme complex subunit beta

Short-chain acyl CoA dehydrogenase Medium-chain acyl CoA dehydrogenase Very long-chain acyl CoA dehydrogenase Short-chain 3-hydroxyacyl-CoA dehydrogenase Long-chain 3-hydroxyacyl-CoA dehydrogenase

Carnitine acylcarnitine translocase 212138

Carnitine palmitoyltransferase 2

Carnitine palmitoyl-transferase IC 616282

Affected protein Organic cation carnitine transporter 2 Carnitine palmitoyltransferase

934 U. Spiekerkoetter and J. Vockley

48  Mitochondrial Fatty Acid Oxidation Disorders

Metabolic Pathway Fatty acids are released from tissue stores or from dietary fat, are transported to cells on carrier proteins, and enter cells in response to hormonal signals including dropping insulin. In the cytoplasm, they are activated to coenzyme A (CoA) esters by acyl-CoA synthases. Long-chain acyl-CoAs must be esterified with carnitine in order to cross the inner mitochondrial membrane, while medium- and short-chain acyl-­CoAs appear to enter the mitochondria independent of carnitine. Endogenous synthesis in the liver generally supplies about half of cellular needs and thus the remainder is derived from diet, largely meat. Endogenous production in vegans is enhanced, but in many cases still have clinically insignificant low levels in blood. Carnitine itself is actively transported into cells by the high-affinity organic cation carnitine transporter 2 (OCTN2) carnitine (Fig. 48.1). A low-affinity ­transporter provides some capacity to transport

935

carnitine into cells in the face of OCTN2 deficiency. At the outer mitochondrial membrane, carnitine palmitoyltransferase I (CPTI) catalyzes the formation of acylcarnitine esters. The carnitine esters are shuttled across the inner membrane by the carnitine acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPTII), which is attached to the inner mitochondrial membrane, catalyzes the release of CoA esters. Within the mitochondria, ß-oxidation is catalyzed by enzymes of different chain length specificities, and each turn of the β-oxidation spiral involves four enzymatic steps, shortening the acyl-­CoA by two carbons. The enzymes for the β-oxidation of long-chain substrates (C18C12 fatty acids) are also membrane-­associated, including very long-chain acyl-CoA dehydrogenase (VLCAD) and the mitochondrial trifunctional protein complex (mTFP or MTP) composed of three enzymatic activities on two different subunits. Long-chain enoyl-CoA hydratase (LCEH) and the long-chain 3-­ hydroxyacyl-CoA dehydrogenase

Fig. 48.1  Transport of fatty acids into the mitochondrion, mitochondrial β-oxidation, and electron transfer. Modified according to Bonnefont et al. (2010)

936

U. Spiekerkoetter and J. Vockley

(LCHAD) both are contained in the α-subunit, while the long-chain 3-ketoacyl-CoA thiolase (LKAT) is localized to the β-subunit. Medium- and short-chain-specific enzymes, including medium-chain acyl-­ CoA dehydrogenase (MCAD), short-chain acyl-CoA dehydrogenase (SCAD), enoyl-CoA hydratase or crotonase, and short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), are located in the mitochondrial matrix. The acyl-CoA dehydrogenase reaction produces two electrons, which are transferred sequentially to the electron transfer flavoprotein (ETF), ETF-ubiquinone oxidoreductase (ETF:QO), and ultimately to ubiquinone of the mitochondrial electron transfer chain. Flavin adenine dinucleotide (FAD), which is derived from riboflavin, acts as a cofactor in these reactions (see Chap.

4

11

ETF

ETF

TFP NADH

ETF ETF

Membrane ACADs

Inner membrane

Inner space

9

N1a 7 N1b N3

ETF

N6a

5

ETF

ETF

10 ETFDH

N6b

N2 CPTII

12 10

Matrix ACADs

N4

N5 3

2

TCA

ETF

8

6 Matrix

32). Acetyl-CoA produced by ß-oxidation can either enter the Krebs cycle or be utilized to synthesize ketone bodies in the liver (Fig. 48.1). The LCHAD reaction utilizes nicotinamide adenine dinucleotide (NAD) as an electron acceptor, which serves as a substrate for complex I of the electron transfer chain. The long-chain fatty acid oxidation enzymes VLCAD and LCHAD, along with electron transfer flavoprotein dehydrogenase (ETFDH), have been shown to interact with respiratory chain supercomplexes in a multiprotein enzyme complex that optimizes catalytic efficiency (Wang et al. 2010; Wang et al. 2019). The LCHAD (alpha) subunit of MTP interacts with the matrix arm of respiratory chain complex I and VLCAD, while ETFDH interacts with the coenzyme Q binding subunit of complex III (Fig. 48.2).

QH2

QH2

Com III

1 H+

Fig. 48.2  The model depicts the path of oxidation of long-chain fatty acids (Wang et al. 2019). Steps 1–3: Long-chain acyl-CoA substrates are transferred into VLCAD through CPTII, channeling its product to the MTP (Steps 6–7). Steps 4–5: Reduced ETF is released from VLCAD into the mitochondrial matrix, where it is free to find its redox partner, ETFDH, and shuttle its reducing equivalents (QH2) to ETC complex III. Step 8: In complex I, NADH is oxidized with channeling

H+

of electrons to complex III.  Medium- and short-chain acyl-CoA substrates produced by TFP are transferred to MCAD and SCAD in the matrix, or in amore weakly associating peripheral domain of the multifunctional FAO-ETC complex (Steps 9–10). ETFDH oxidizes reduced ETF by reducing CoQ to QH2 Finally, acetyl-CoA enters the TCA cycle or is utilized for ketone body production (Steps 12–13)

48  Mitochondrial Fatty Acid Oxidation Disorders

937

Signs and Symptoms Table 48.1  Carnitine transporter deficiency System Cardiovascular Digestive Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy Liver dysfunction Hypotonia, muscular-axial Rhabdomyolysis Skeletal myopathy Adipic acid (urine) C16:0-Acylcarnitine (dried blood spot) C16:0-Acylcarnitine (plasma) C18:0-Acylcarnitine (dried blood spot) C18:0-Acylcarnitine (plasma) C18:1-Acylcarnitine (dried blood spot) C18:1-Acylcarnitine (plasma) C18:2-Acylcarnitine (dried blood spot) C18:2-Acylcarnitine (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Carnitine, free (urine) Creatine kinase (plasma) Dicarboxylic acids (urine) Glucose (plasma) Ketones, during hypoglycemia Long-chain acylcarnitine (dried blood spot) Long-chain acylcarnitine (plasma) Sebacic acid (urine) Suberic acid (urine) Transaminase (plasma)

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ± ± ±

childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

± n-↑ ↓

± n-↑ ↓

± ± n-↑ ↓

± ±

± ±

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓ ↑ n-↑ n-↑ ↓-n ↓

↓ ↑ n-↑ n-↑ ↓-n ↓

↓ ↑ n-↑ n-↑ ↓-n ↓

↓ ↑ n-↑

↓ ↑ n-↑

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

n-↑ n-↑ n-↑

n-↑ n-↑ n-↑

n-↑ n-↑ n-↑

n-↑

n-↑

938

U. Spiekerkoetter and J. Vockley

Table 48.2  Carnitine palmitoyltransferase 1A deficiency System Digestive Renal Laboratory findings

Symptoms and biomarkers Liver dysfunction Renal tubular acidosis Adipic acid (urine) C16:0-Acylcarnitine (dried blood spot) C16:0-Acylcarnitine (plasma) C18:0-Acylcarnitine (dried blood spot) C18:0-Acylcarnitine (plasma) C18:1-Acylcarnitine (dried blood spot) C18:1-Acylcarnitine (plasma) C18:2-Acylcarnitine (dried blood spot) C18:2-Acylcarnitine (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Dicarboxylic acids (urine) Glucose (plasma) Ketones, during hypoglycemia Long-chain acylcarnitine (dried blood spot) Long-chain acylcarnitine (plasma) Sebacic acid (urine) Suberic acid (urine) Transaminase (plasma)

Neonatal (birth–1 month) ±

childhood (1.5–11 years) ± ± n-↑ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

n-↑ ↓

Infancy (1–18 months) ± ± n-↑ ↓

± n-↑ ↓

± n-↑ ↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↑-↑↑↑

↑-↑↑↑

↑-↑↑↑

↑-↑↑↑

↑-↑↑↑

n-↑ n-↑ ↓-n ↓

n-↑ n-↑ ↓-n ↓

n-↑ n-↑ ↓-n ↓

n-↑ n-↑

n-↑ n-↑

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

n-↑ n-↑ n-↑

n-↑ n-↑ n-↑

n-↑ n-↑ n-↑

n-↑ n-↑ n-↑

n-↑ n-↑ n-↑

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) +

Table 48.3  Carnitine palmitoyl-transferase IC deficiency Neonatal (birth–1 System Symptoms and biomarkers month) CNS Evoked potentials +/−, abnormal (EEG) Hyperreflexia Musculoskeletal Loss of ambulation Muscle atrophy Muscle weakness Spastic paraparesia/ paraplegia/tetraplegia Unable to walk

+ ± + + + +

48  Mitochondrial Fatty Acid Oxidation Disorders Table 48.4  Carnitine palmitoyltransferase 2 deficiency Neonatal System Symptoms and biomarkers (birth–1 month) Cardiovascular Cardiomyopathy ± CNS Coma ± Lethargy ± Digestive Liver dysfunction ± Musculoskeletal Hypotonia, ± muscular-axial Rhabdomyolysis, exercise induced Skeletal myopathy ± Other Malformations (brain) + Malformations (kidney) + Laboratory Adipic acid (urine) n-↑ findings C14:0-Acylcarnitine (dried n-↑ blood spot) C14:0-Acylcarnitine n-↑ (serum) C16:0-Acylcarnitine (dried n-↑ blood spot) C16:0-Acylcarnitine n-↑ (plasma) C16-C18 Acylcarnitine n-↑ C18:0-Acylcarnitine (dried n-↑ blood spot) C18:0-Acylcarnitine n-↑ (plasma) C18:1-Acylcarnitine (dried n-↑ blood spot) C18:1-Acylcarnitine n-↑ (plasma) C18:2-Acylcarnitine (dried n-↑ blood spot) C18:2-Acylcarnitine n-↑ (plasma) Carnitine, free (dried blood ↓-n spot) Carnitine, free (plasma) ↓-n Creatine kinase (plasma) n-↑ Dicarboxylic acids (urine) n-↑ Glucose (plasma) ↓-n Ketones, during ↓ hypoglycemia Long-chain acylcarnitine n-↑ Sebacic acid (urine) n-↑ Suberic acid (urine) n-↑ Transaminase (plasma) n-↑

939

Infancy (1–18 months) ± ± ± ± ±

childhood (1.5–11 years) ± ± ± ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

+++

+++

+++

±

±

±

±

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

↓-n

↓-n

↓-n

↓-n

↓-n n-↑ n-↑ ↓-n ↓

↓-n n-↑↑↑ n-↑ ↓-n ↓

↓-n n-↑↑↑ n-↑

↓-n n-↑↑↑ n-↑

n-↑ n-↑ n-↑ n-↑

n-↑ n-↑ n-↑ n-↑↑↑

n-↑ n-↑ n-↑ n-↑↑↑

n-↑ n-↑ n-↑ n-↑↑↑

940

U. Spiekerkoetter and J. Vockley

Table 48.5  Carnitine acylcarnitine translocase deficiency (30 patients) Neonatal Infancy System Symptoms and biomarkers (birth–1 month) (1–18 months) Cardiovascular Cardiac arrhythmias, +++ +++ severe Cardiomyopathy +++ +++ CNS Coma ± ± Lethargy ± ± Digestive Liver dysfunction ± ± Musculoskeletal Hypotonia, ± ± muscular-axial Skeletal myopathy ± ± Other Lethality of severe +++ +++ phenotypes, high Sudden death + + Laboratory Adipic acid (urine) n-↑ n-↑ findings C14:0-Acylcarnitine (dried ↑ ↑ blood spot) C14:0-Acylcarnitine ↑ ↑ (serum) C16:0-Acylcarnitine ↑ ↑ (plasma) C16-C18 Acylcarnitine ↑ ↑ C18:0-Acylcarnitine (dried ↑ ↑ blood spot) C18:0-Acylcarnitine ↑ ↑ (plasma) C18:1-Acylcarnitine (dried ↑ ↑ blood spot) C18:1-Acylcarnitine ↑ ↑ (plasma) C18:2-Acylcarnitine (dried ↑ ↑ blood spot) C18:2-Acylcarnitine ↑ ↑ (plasma) Carnitine, free (dried blood ↓-n ↓-n spot) Carnitine, free (plasma) ↓-n ↓-n Creatine kinase (plasma) ↑↑ ↑↑ Dicarboxylic acids (urine) n-↑ n-↑ Glucose (plasma) ↓-n ↓-n Ketones, during ↓ ↓ hypoglycemia Lactate (plasma) ↑ ↑ Long-chain acylcarnitine ↑ ↑ Sebacic acid (urine) n-↑ n-↑ Suberic acid (urine) n-↑ n-↑ Transaminase (plasma) ↑ ↑

Table 48.6  ε-N-trimethyllysine hydroxylase deficiency Neonatal (birth–1 System Symptoms and biomarkers month) Psychiatric Autistic spectrum disorder

Infancy (1–18 months)

childhood (1.5–11 years) +

Adolescence (11–16 years)

Adulthood (>16 years)

+ n-↑ ↑

n-↑ ↑

n-↑ ↑

↑

↑

↑

↑

↑

↑

↑ ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

n-↑ n-↑

n-↑ n-↑

Adolescence (11–16 years) +

Adulthood (>16 years) +

+ ± ± ± ± ± +

↓-n ↓-n ↑↑↑ n-↑ ↓-n ↓ ↑ ↑ n-↑ n-↑ ↑

Childhood (1.5–11 years) +

48  Mitochondrial Fatty Acid Oxidation Disorders

941

Table 48.7  γ-Butyrobetaine hydroxylase deficiency System Eye Musculoskeletal

Other Psychiatric Laboratory findings

Symptoms and biomarkers Long eye lashes Strabismus Facial dysmorphism Growth retardation High nasal bridge Microcephaly Epicanthal folds Epicanthal folds Behavior, psychotic Hyperactivity Carnitine, free (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months) + + + + + + + + ± +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ ↓-n

Table 48.8  Carnitine acetyltransferase deficiency System CNS

Symptoms and biomarkers Ataxia Consciousness disturbance Hypotonia Intellectual disability Oculomotor apraxia

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + + + + +

Adolescence (11-16 years)

Adulthood (>16 years)

Adulthood (>16 years) ±

±

±

+

± +

childhood (1.5–11 years) ± ± ± ± ± ± ± ± ± +

Adolescence (11–16 years) ±

± ±

Infancy (1–18 months) ± ± ± ±

+

+

+

+

+

n-↑ ↑

n-↑ ↑

n-↑ ↑

n-↑ ↑

n-↑ ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑ ↑↑ ↓-n ↑ ↓

↑ ↑↑ ↓-n ↑ ↓

↑ ↑↑ ↓-n ↑ ↓

↑ ↑

↑ n-↑

↑ ↓

↑ ↓

Table 48.9  Short-chain acyl-CoA dehydrogenase deficiency System CNS

Metabolic Musculoskeletal Psychiatric Other

Laboratory findings

Symptoms and biomarkers Developmental delay Epilepsy Hypotonia Hypoglycemia Hypoglycemia Dysmorphic features Exercise intolerance Behavioral disorder Failure to thrive Predisposition for symptomatic disease Second mitochondrial affection Butyrylglycine (urine) C4 Butyrylcarnitine (blood) C4 Butyrylcarnitine (plasma) C4-Acylcarnitine (dried blood spot) C4-Acylcarnitine (plasma) Ethylmalonic acid (urine) Glucose (plasma) Methylsuccinic acid (urine) Short-chain acyl-CoA dehydrogenase (fibroblasts)

Neonatal (birth–1 month)

± ± ± ± ± +

± ± ± +

942

U. Spiekerkoetter and J. Vockley

Table 48.10  Medium-chain acyl-CoA dehydrogenase deficiency System Digestive Other Laboratory findings

Symptoms and biomarkers Liver dysfunction Asymptomatic 5-Hydroxyhexanoic acid (urine) 7-Hydroxyoctanoic acid (urine) Adipic acid (urine) C10:0-Acylcarnitine (dried blood spot) C10:0-Acylcarnitine (plasma) C10:1-Acylcarnitine (dried blood spot) C10:1-Acylcarnitine (plasma) C6-Acylcarnitine (dried blood spot) C6-Acylcarnitine (plasma) C6-Acylcarnitine (urine) C8/C12 Acylcarnitines ratio C8/C2 Acylcarnitines ratio C8-Acylcarnitine (dried blood spot) C8-Acylcarnitine (plasma) C8-Acylcarnitine (urine) Carnitine, free (dried blood spot) Carnitine, free (plasma) Dicarboxylic acids (urine) Glucose (plasma) Hexanoylglycine (urine) Ketones, during hypoglycemia Octanoylglucuronide (urine) Phenylpropionylglycine (urine) Phenylpropionylglycine (urine) Sebacic acid (urine) Sebacic acid, unsaturated (urine) Suberic acid (urine) Suberic acid, unsaturated (urine) Suberylglycine (urine) Transaminase (plasma)

Neonatal (birth–1 month) ± ± n-↑

Infancy (1–18 months) ± ± n-↑

childhood (1.5–11 years) ± ± n-↑

Adolescence (11–16 years)

Adulthood (>16 years)

± n-↑

± n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ ↑

n-↑ ↑

n-↑ ↑

n-↑ ↑

n-↑ ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑ ↑ ↑

↑ ↑ ↑

↑ ↑ ↑

↑ ↑ ↑

↑ ↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑ ↓-n

↑ ↑ ↓-n

↑ ↑ ↓-n

↑ ↑ ↓-n

↑ ↑ ↓-n

↓-n n-↑ ↓-n n-↑ ↓

↓-n n-↑ ↓-n n-↑ ↓

↓-n n-↑ ↓-n n-↑ ↓

↓-n n-↑

↓-n n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

48  Mitochondrial Fatty Acid Oxidation Disorders Table 48.11  Very long-chain acyl-CoA dehydrogenase deficiency Neonatal System Symptoms and biomarkers (birth–1 month) Cardiovascular Cardiomyopathy ± CNS Coma ± Lethargy ± Digestive Liver dysfunction ± Musculoskeletal Rhabdomyolysis, exercise induced Musculoskeletal Skeletal myopathy ± Musculoskeletal Hypotonia, muscular-axial ± Laboratory Adipic acid (urine) n-↑ findings C14:0-Acylcarnitine (dried blood ↑ spot) C14:0-Acylcarnitine (serum) ↑ C14:1 Tetradecenoylcarnitine n-↑ (blood) C14:1 Tetradecenoylcarnitine n-↑ (plasma) C14:1/C12:1 Acylcarnitines ratio ↑ C14:1/C4 Acylcarnitines ratio ↑ C14:1-Acylcarnitine (dried blood ↑ spot) C14:1-Acylcarnitine (plasma) ↑ C16:0-Acylcarnitine (dried blood ↑ spot) C16:0-Acylcarnitine (plasma) ↑ C16:1-Acylcarnitine (dried blood ↑ spot) C16:1-Acylcarnitine (plasma) ↑ C18:0-Acylcarnitine (dried blood ↑ spot) C18:0-Acylcarnitine (plasma) ↑ C18:1-Acylcarnitine (dried blood ↑ spot) C18:1-Acylcarnitine (plasma) ↑ C18:2-Acylcarnitine (dried blood ↑ spot) C18:2-Acylcarnitine (plasma) ↑ Carnitine, free (dried blood spot) ↓-n Carnitine, free (plasma) ↓-n Creatine kinase (plasma) n-↑ Dicarboxylic acids (urine) n-↑ Glucose (plasma) ↓-n Ketones, during hypoglycemia ↓ Sebacic acid (urine) n-↑ Sebacic acid, unsaturated (urine) n-↑ Suberic acid (urine) n-↑ Suberic acid, unsaturated (urine) n-↑ Transaminase (plasma) n-↑

943

Infancy (1–18 months) ± ± ± ± ±

childhood (1.5–11 years) ± ± ± ± ++

Adolescence (11–16 years)

Adulthood (>16 years)

± ++

± ++

± ± n-↑ ↑

± ± n-↑ ↑

± ± n-↑ n-↑

± ± n-↑ n-↑

↑ n-↑

↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑

n-↑

n-↑

n-↑

↑ ↑ ↑

↑ ↑ ↑

↑ ↑ n-↑

↑ ↑ n-↑

↑ ↑

↑ ↑

n-↑ n-↑

n-↑ n-↑

↑ ↑

↑ ↑

n-↑ n-↑

↑n-↑ n-↑

↑ ↑

↑ ↑

n-↑ n-↑

n-↑ n-↑

↑ ↑

↑ ↑

n-↑ n-↑

n-↑ n-↑

↑ ↑

↑ ↑

n-↑ n-↑

n-↑ n-↑

↑ ↓-n ↓-n n-↑ n-↑ ↓-n ↓ n-↑ n-↑ n-↑ n-↑ n-↑

↑ ↓-n ↓-n n-↑↑ n-↑ ↓-n ↓ n-↑ n-↑ n-↑ n-↑ n-↑↑

n-↑ ↓-n ↓-n n-↑↑ n-↑

n-↑ ↓-n ↓-n n-↑↑ n-↑

n-↑ n-↑ n-↑ n-↑ n-↑↑

n-↑ n-↑ n-↑ n-↑ n-↑↑

944

U. Spiekerkoetter and J. Vockley

Table 48.12  Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (13 patients) Neonatal Infancy System Symptoms and biomarkers (birth–1 month) (1–18 months) Cardiovascular Cardiomyopathy ± CNS Intellectual disability ± ± Seizures ± ± Digestive Liver failure, Reye-like + Endocrine Hyperinsulinism + + Protein sensitivity + ++ Metabolic Hypoglycemia, + + hypoketotic 3-Hydroxydicarboxylic (↑) (↑) acid (urine) Laboratory 3-Hydroxyglutarate (urine) ↑ ↑ findings Ammonia (blood) ↑ C4-OH ↑ ↑ Hydroxybutyrylcarnitine (dried blood spot) C4-OH ↑ ↑ Hydroxybutyrylcarnitine (plasma) Glucose (plasma) ↓ ↓ Insulin, durig ↑ ↑ hypoglycemia Ketones (urine) ↓ ↓ Medium chain dicarboxylic (↑) (↑) acids (urine)

childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

±

+ + ++ +

++

(↑) ↑ ↑ ↑

↑

↑

↑

↑

↑

childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

± ± ± ± ± ±

± ± ±

± ± ±

(↑)

Table 48.13  Isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase System Cardiovascular CNS

Digestive Eye Metabolic Musculoskeletal

Other

Symptoms and biomarkers Cardiac arrhythmia Cardiomyopathy Coma Lethargy Neuropathy, peripheral Liver dysfunction Pigmentary retinopathy Lactic acidosis Hypotonia, muscular-axial Rhabdomyolysis, exercise induced Skeletal myopathy Intrauterine growth retardation Maternal HELLP syndrome

Neonatal (birth–1 month) ± ± ± ±

Infancy (1–18 months) ± ± ± ±

±

± ± ± +

+

+

+

±

++

++

++

+

+

+

+

± +

+ + +

48  Mitochondrial Fatty Acid Oxidation Disorders

945

Table 48.13 (continued) System Laboratory findings

Symptoms and biomarkers 3-Hydroxydicarboxylic acid (urine) Ammonia (blood) C14-OH 3-Hydroxy tetradecanoylcarnitine (plasma) C16-C18 Hydroxyacylcarnitine C16-OH 3-Hydroxy hexadecanoylcarnitine (plasma) C18:1-OH 3-Hydroxy octadecenoylcarnosine (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Creatine kinase (plasma) Dicarboxylic acids (urine) Glucose (plasma) Ketones, during hypoglycemia Lactate (plasma) Transaminase (plasma)

Neonatal (birth–1 month) n-↑

Infancy (1–18 months) n-↑

childhood (1.5–11 years) n-↑

Adolescence (11–16 years) n-↑

Adulthood (>16 years) n

(↑) n-↑

(↑) n-↑

(↑) n-↑

n n-↑

n-↑ n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

↓-n

↓-n

↓-n

↓-n

↓-n

↓-n n-↑ n-↑ ↓-n ↓

↓-n n-↑ n-↑ ↓-n ↓

↓-n n-↑↑ n-↑ ↓-n ↓

↓-n n-↑↑ n-↑

↓-n n-↑↑ n

n-↑ n-↑

n-↑ n-↑

n n-↑↑

n n-↑↑

n n-↑↑

Table 48.14  Isolated deficiency of long-chain 3-ketoacyl-CoA thiolase (1 patient) Neonatal Infancy System Symptoms and biomarkers (birth–1 month) (1–18 months) Cardiovascular Cardiac arrhythmia ± ± Cardiomyopathy + + Digestive Liver dysfunction + + Musculoskeletal Hypotonia, muscular-axial + + Skeletal myopathy + + Respiratory Pulmonary edema + + Other Lethality, high + + Laboratory 3-Hydroxyadipic acid (urine) ↑ ↑ findings 3-Hydroxyadipic acid lactone ↑ ↑ (urine) 3-Hydroxydicarboxylic acid ↑ ↑ (urine) 3-Hydroxysebacic acid (urine) ↑ ↑ 3-Hydroxysuberic acid (urine) ↑ ↑ Adipic acid (urine) ↑ ↑ C14:0-Hydroxyacylcarnitine ↑ ↑ (dried blood spot) C14:0-Hydroxyacylcarnitine ↑ ↑ (plasma) C14:1-Acylcarnitine (dried ↑ ↑ blood spot) C14:1-Acylcarnitine (plasma) ↑ ↑

childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

(continued)

946

U. Spiekerkoetter and J. Vockley

Table 48.14 (continued) System

Symptoms and biomarkers C14:1-Hydroxyacylcarnitine (dried blood spot) C14:1-Hydroxyacylcarnitine (plasma) C16:0-Hydroxyacylcarnitine (dried blood spot) C16:0-Hydroxyacylcarnitine (plasma) C16:0-Ketoacylcarnitine (dried blood spot) C16:0-Ketoacylcarnitine (plasma) C16:1-Hydroxyacylcarnitine (dried blood spot) C16:1-Hydroxyacylcarnitine (plasma) C16-C18 Hydroxyacylcarnitine C18:0-Hydroxyacylcarnitine (dried blood spot) C18:0-Hydroxyacylcarnitine (plasma) C18:1-Hydroxyacylcarnitine (dried blood spot) C18:1-Hydroxyacylcarnitine (plasma) C18:1-Ketoacylcarnitine (dried blood spot) C18:1-Ketoacylcarnitine (plasma) C18:2-Hydroxyacylcarnitine (dried blood spot) C18:2-Hydroxyacylcarnitine (plasma) C18:2-Ketoacylcarnitine (dried blood spot) C18:2-Ketoacylcarnitine (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Creatine kinase (plasma) Dicarboxylic acids (urine) Glucose (plasma) Ketones, during hypoglycemia Lactate (plasma) Sebacic acid (urine) Suberic acid (urine) Transaminase (plasma)

Neonatal (birth–1 month) ↑

Infancy (1–18 months) ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑ ↑

↑ ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

n

n

n n ↑ ± ± ↑↑ ↑ ↑ ↑

n n ↑ ± ± ↑ ↑ ↑ ↑

childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

48  Mitochondrial Fatty Acid Oxidation Disorders

947

Table 48.15  Trifunctional protein β subunit deficiency System Cardiovascular CNS

Digestive Eye Metabolic Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Cardiac arrhythmia Coma Lethargy Neuropathy, peripheral Liver dysfunction Pigmentary retinopathy Lactic acidosis Skeletal myopathy Intrauterine growth retardation Maternal HELLP syndrome 3-Hydroxyadipic acid (urine) 3-Hydroxydicarboxylic acid (urine) 3-Hydroxysebacic acid (urine) 3-Hydroxysuberic acid (urine) Adipic acid (urine) Ammonia (blood) C12-OH 3-Hydroxy dodecanoylcarnitine (plasma) C14:0-Hydroxyacylcarnitine (dried blood spot) C14:0-Hydroxyacylcarnitine (plasma) C14:1 Tetradecenoylcarnitine (plasma) C14:1-Acylcarnitine (dried blood spot) C14:1-Acylcarnitine (plasma) C14:1-Hydroxyacylcarnitine (dried blood spot) C14:1-Hydroxyacylcarnitine (plasma) C14-OH 3-Hydroxy tetradecanoylcarnitine (plasma) C16 Palmitoylcarnitine (plasma) C16:0-Hydroxyacylcarnitine (dried blood spot) C16:0-Hydroxyacylcarnitine (plasma) C16:1-Hydroxyacylcarnitine (dried blood spot) C16:1-Hydroxyacylcarnitine (plasma) C16-C18 Hydroxyacylcarnitine C18:0-Hydroxyacylcarnitine (dried blood spot)

Neonatal (birth–1 month) ± n - ↑↑↑ ± ± n ± n ± + + + n-↑ n-↑ n-↑ n-↑ n-↑ ↑ n-↑

Infancy (1–18 months) ± n - ↑↑↑ ± ± n ± ± ± + +

childhood (1.5–11 years) ±

Adolescence (11–16 years) n

Adulthood (>16 years) n

± ± ± ± ± n +

n n + ± ± n +

n n ++ ± ± n +

n-↑ n-↑ n-↑ n-↑ n-↑ ↑ n-↑

n-↑ n-↑ n-↑ n-↑ n-↑ ↑ n-↑

n-↑ n-↑ n-↑ n-↑ n-↑ n n-↑

n n n n n n n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑

n-↑ n-↑ (continued)

948

U. Spiekerkoetter and J. Vockley

Table 48.15 (continued) System

Symptoms and biomarkers C18:0-Hydroxyacylcarnitine (plasma) C18:1 Octadecenoylcarnitine (plasma) C18:1-Hydroxyacylcarnitine (dried blood spot) C18:1-Hydroxyacylcarnitine (plasma) C18:1-OH 3-Hydroxy octadecenoylcarnosine (plasma) C18:2 Octadecadienoylcarnitine (plasma) C18:2-Hydroxyacylcarnitine (dried blood spot) C18:2-Hydroxyacylcarnitine (plasma) C18-OH 3-Hydroxy octadecanoylcarnitine (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Creatine kinase (plasma) Dicarboxylic acids (urine) Glucose (plasma) Ketones, during hypoglycemia Lactate (plasma) Sebacic acid (urine) Suberic acid (urine) Transaminase (plasma)

Neonatal (birth–1 month) n-↑

Infancy (1–18 months) n-↑

childhood (1.5–11 years) n-↑

Adolescence (11–16 years) n-↑

Adulthood (>16 years) n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

↓-n ↓-n n-↑ n-↑ ↓-n ↓ n-↑ n-↑ n-↑ n-↑

↓-n ↓-n n-↑ n-↑ ↓-n ↓ n-↑ n-↑ n-↑ n-↑

↓-n ↓-n n-↑↑ n-↑ ↓-n ↓ n n-↑ n-↑ n-↑↑

↓-n ↓-n n-↑↑ n-↑

↓-n ↓-n n-↑↑ n

n n-↑ n-↑ n-↑↑

n n n n-↑↑

Table 48.16  Fatty acid transport protein 4 deficiency Neonatal (birth–1 System Symptoms and biomarkers month) Hematological Eosinophilia ± Dermatological Hyperkeratosis + Ichthyosis + Thick caseous +

Infancy (1–18 months) ± + + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 48.17  Docosahexanoic acid transporter deficiency System Autonomic system CNS

Eye Musculoskeletal Psychiatric Laboratory findings

Symptoms and biomarkers Talipes Cerebellar hypoplasia Hyperreflexia Hypotonia Intellectual disability Loss of speech Psychomotor delay Quadriparesis Seizures Thin corpus callosum Upslanting palpebral fissures Microcephaly Autistic spectrum disorder Lysophosphatidylcholines (plasma)

Neonatal (birth–1 month) ± ± ± ±

± ± ± + ↑

Infancy (1–18 months) ± ± + ± + + + + ± ± ± + ± ↑

Childhood Adolescence (1.5–11 years) (11–16 years) ± ± + ± + + + + ± ± ± + ± ↑

Adulthood (>16 years)

48  Mitochondrial Fatty Acid Oxidation Disorders

949

Table 48.18  Acyl-CoA Dehydrogenase 9 deficiency System Cardiovascular CNS Digestive

Ear Metabolic Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Encephalopathy Neurologic dysfunction Liver dysfunction Liver failure Liver failure, Reye-like Hearing loss Hypoglycemia Lactic acidosis Exercise intolerance Hypotonia, muscular-axial Rhabdomyolysis Skeletal myopathy Complex I assembly disorder Failure to thrive Transaminase (plasma) Glucose (plasma) Beta-hydroxybutyrate (urine) Ammonia (blood) Carnitine, free (dried blood spot) Carnitine, free (plasma) Long-chain acylcarnitine (dried blood spot) Long-chain acylcarnitine (plasma) Lactate (plasma) C14:0-Acylcarnitine (serum) C14:0-Acylcarnitine (dried blood spot) C16:0-Acylcarnitine (plasma) C16:0-Acylcarnitine (dried blood spot) C16:1-Acylcarnitine (plasma) C16:1-Acylcarnitine (dried blood spot) C18:0-Acylcarnitine (plasma) C18:0-Acylcarnitine (dried blood spot) C18:1-Acylcarnitine (plasma) C18:1-Acylcarnitine (dried blood spot) C18:2-Acylcarnitine (plasma) C18:2-Acylcarnitine (dried blood spot) Alanine (plasma) Alanine (urine) Adipic acid (urine) Suberic acid (urine) Suberic acid, unsaturated (urine) Sebacic acid (urine) Sebacic acid, unsaturated (urine) Lactate (urine) Lactate/pyruvate ratio Creatine kinase (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months) + + + + +

childhood Adolescence Adulthood (1.5–11 years) (11–16 years) (>16 years) +

+ + + + + + + + + ↑↑ ↓ ↑ (↑) ↓ ↓ ↑

+ + + + + + + + + ↑↑ ↓

↑ ↑ ↑ ↑

↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑

↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

+ + + +

↓

↑

↑ ↑

(↑) ↓ ↓ ↑

(↑)

↑ ↑

↑

950

U. Spiekerkoetter and J. Vockley

Reference Values

ing on single metabolite values improve testing accuracy (Marquardt et al. 2012).

Measured values of carnitine and acylcarnitines differ in dried blood spots and plasma (de Sain-van der Velden et al. 2013). They also change with age, especially in newborns over the first days of life. Catabolism increases acylcarnitine concentrations in patients and healthy individuals. Reference values are given in Chap. 5. Organic acid analysis in urine reveals a disease-specific profile distinct from healthy ­individuals; however, organic acids can also be normal in patients during anabolism and in milder phenotypes. Fasting significantly increases the excretion of disease-specific organic acids in patients.

Pathological Values An extremely wide variation in blood acylcarnitine values is observed in patients, related both to the specific diagnosis and timing of the most recent meal, and may normalize when the patient is well and not fasting (Smith and Matern 2010). Collecting diagnostic samples immediately prior to a meal or during acute illness maximizes the likelihood of making a diagnosis. In general, patients with milder disease have less dramatic changes in metabolite profiles than those with more severe neonatal/infantile presentations. Normal ketosis increases acylcarnitine levels even in healthy individuals and should not be confused with disease patterns. Acylcarnitine levels in newborn blood spot samples generally decrease in the first days of life and may normalize, even in patients with FAODs, and therefore late screening can lead to missed diagnoses (Lindner et  al. 2010). Importantly, healthy newborns and children may present with abnormal acylcarnitine profiles suggestive of a FAOD during severe catabolism. Pathological reference values taken from a large worldwide cohort have been reported (McHugh et  al. 2011). Consideration of the acylcarnitine pattern and calculation of metabolite ratios rather than relyFig. 48.3  Diagnostic flow chart

Diagnostic Tools and Flowchart Laboratory investigation of a suspected FAOD should begin with measurement of the acylcarnitine profile and includes consideration of individual metabolite values as well as the ratios of various acylcarnitines (Fig. 48.3). The acylcarnitine profiles in severe CPTII and CACT are indistinguishable, as are those in LCHAD and MTP deficiencies. In CPTI deficiency, carnitine concentration in dried blood spots is higher than in plasma, and diagnosis may be missed with measurement in plasma. Clinical circumstances have a major effect on the acylcarnitine profile. Abnormalities are usually more marked during catabolism but, if the plasma-free carnitine concentration is very low, abnormal acylcarnitines may be hard to detect. Abnormalities decrease with intravenous glucose or dietary treatment, and metabolites from medium-chain fat oxidation increase with the use of medium-chain triglycerides (MCTs). An interpretation is especially difficult for terminal or post-­mortem samples as they often show multiple raised acylcarnitine species, resembling MAD deficiency (MADD). In cases of very low free carnitine, diagnostic changes may be induced by overnight fasting or carnitine loading, respectively. However, these challenges can be dangerous and should only be considered in the inpatient setting, and the fasting period should be adjusted to the age of the patient. It is probably better to move to functional testing molecular analysis before considering challenge testing. While acylcarnitine analysis is often consistent with a specific diagnosis, enzyme and/or mutation analyses are required for confirmation. The in  vitro assays described below may be useful to reach a diagnosis when metabolite testing is normal in spite of a strong clinical suspicion.

Clinical signs suggestive for a defect of fatty acid oxidation

Newborn screening for a fatty acid oxidation disorder

Carnitine / Acylcarnitine analysis in blood (preferably during catabolism)

Abnormal result

Abnormal result on first screening (days 2 or 3 of life)

Normal result

With definite clinical suspicion,

In vitro acylcarnitine profiling / flux studies

Enzymology or molecular confirmation (in case of prevalent mutations)

48  Mitochondrial Fatty Acid Oxidation Disorders

Enzyme Testing Enzyme assays are generally performed in cultured fibroblasts or lymphocytes (Wanders et al. 2010) but are available in limited geographic areas. Enzymology in lymphocytes allows a rapid confirmation of diagnosis. Moreover, for VLCAD and MCAD deficiencies, residual activity may allow some predictions with respect to the expected severity of the defect (Hoffmann et al. 2012).

Fibroblast or Lymphocyte Acylcarnitine Profiling Fibroblast or lymphocyte acylcarnitine profiling may identify an enzymatic defect if a diagnosis is not clear from blood testing. Here, acylcarnitines are analyzed by tandem mass spectrometry after incubating fibroblasts or lymphocytes with fatty acids’ stable isotope-labeled substrates (2H or 13C) (Ventura et  al. 1999; Sim et  al. 2002). This technique can identify most FAODs except carnitine transporter and CPTI deficiencies. CACT and severe CPTII deficiencies cannot be distinguished and respiratory chain defects sometimes mimic FAODs (Sim et al. 2002).

Fatty Acid Oxidation Flux Fatty acid oxidation flux is measured by incubating cells with radio-labeled fatty acids and collecting the oxidation products (Olpin et  al. 1997). This technique identifies a

951

global defect in FAO, is useful in assessing the severity of a disorder, but is not as specific as acylcarnitines in arriving at a diagnosis.

Urinary Organic Acids and Acylglycines Urine organic acid analysis is normal in many FAODs when patients are well. Dicarboxylic acids are formed by ß-­oxidation in peroxisomes and ω-oxidation in microsomes when plasma-free fatty acid concentrations are increased, but normally they are accompanied by ketonuria. During fasting or illness, however, medium-chain (and sometimes longchain) dicarboxylic acids are elevated with little or no increase in ketone bodies. Dicarboxylic aciduria without ketonuria can also be seen in some respiratory chain defects. The analysis of acylcarnitines in the urine may identify carnitine esters of dicarboxylic acids that are of additional diagnostic significance. Defects of LCHAD and MTP deficiencies can accumulate unusual 3-hydroxydicarboxylic acids in urine. MCADD is characterized by an abnormal excretion of several acylglycines including hexanoylglycine, suberylglycine, and phenylpropionylglycine. These same acylglycines, in addition to short branched-chain acylcarnitines, are characteristic of MADD and, in general, are accompanied by a variety of dicarboxylic acids including as ethylmalonic acid, glutaric acid, and D-2-hydroxyglutaric acid. Unfortunately, normal organic acids do not exclude an FAO disorder since they can be normal in milder phenotypes and in anabolic situations.

Specimen Collection Test Acylcarnitines

Material Plasma; dried blood spot (DB)

Handling Room temperature (DB); Frozen (plasma)

Transport Normal mail

Carnitine

Plasma; dried blood spot (DB)

Room temperature (DB); Frozen (plasma)

Normal mail

Dicarboxylic acids Free fatty acids Enzyme assays in lymphocytes

Spot urine

Frozen for longer storage

Normal mail

Plasma Ethylenediamine tetraacetic acid (EDTA) plasma (2 mL)

Frozen Room temperature

Frozen Has to reach the laboratory within 48 hours after withdrawal; room temperature In culture medium

Enzyme assays in Skin biopsy fibroblasts Molecular analysis

EDTA blood; dried blood spot

Room temperature, in sterile 0.9% sodium chloride, fibroblast culture Room temperature

Normal mail

Pitfalls During anabolism eventually normal values; different profile with MCT diet; long-chain acylcarnitine accumulation also in healthy individuals during catabolism Blood and tissue concentrations do not correlate; in CPTI deficiency, carnitine is lower in plasma than in DB; it may be missed on analysis in plasma MCT diet and glucose infusion change the profile Determine before the next food intake Poor quality of the lymphocytes (due to transport conditions, low temperature, etc.) may result in lower residual enzyme activities

Fibroblast culture must grow 4–8 weeks until enzyme assays can be performed Delineation of only one mutation does not rule out deficiency of the enzyme

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Prenatal Diagnosis Prenatal diagnosis is available for all fatty acid oxidation disorders. Mutation analysis is the preferred technique if the molecular defect is known in the index case. Acylcarnitine and acylglycine assays of amniotic fluid have been reported for many FAODs, but are not routinely clinically available. These latter assays do not exclude the disease if metabolites are normal on prenatal diagnosis. All enzymes of fatty acid oxidation are expressed in chorionic villus biopsies and amniocytes and can be used for prenatal diagnosis. Chorionic villus biopsy can be performed at 11 gestational weeks, and amniotic fluid test at 14 + 0 weeks. Deficiency of OCTN2 CPTI CACT

Prenatal diagnosis suggested − − +

CPTII

+

VLCAD

– −

MTP

+ (+)

LCHAD

±

Remarks Very favorable clinical outcome Very favorable outcome Majority of patients die in the neonatal period due to severe cardiac arrhythmias Suggested for severe neonatal phenotypes with congenital anomalies Myopathic phenotypes Very favorable clinical outcome; many asymptomatic “patients”; skeletal myopathy needs to be discussed with the parents Suggested for severe phenotypes; neonatal phenotypes generally lethal; irreversible neuropathy/retinopathy needs to be discussed with the parents in milder phenotypes Irreversible retinopathy/neuropathy needs to be discussed with the parents

Prenatal Deficiency diagnosis suggested of LKAT + ACAD 9 MCAD

+ −

SCAD SCHAD

− ±

Remarks Only two patients so far; both died in the neonatal period Global mitochondrial dysfunction Very favorable clinical outcome since screening Only predisposition for disease Phenotypes of different severity and response to treatment

DNA Analysis All mitochondrial FAODs are inherited in an autosomal recessive pattern. There is molecular heterogeneity in all of the disorders but prevalent mutations have been identified in most. The relationship between genotype and phenotype varies among the different FAODs. In CPTII and VLCAD deficiencies, nonsense mutations on both alleles are generally associated with severe early onset disease, whereas adult onset rhabdomyolysis is associated with conservative missense mutations. A common mutation in VLCAD is found in nearly half of patients identified through newborn screening and is associated with a mild phenotype (c.848T>C). A common mutation accounts for 75% of the mutations in patients with MCADD and leads to complete deficiency, while a recurrent c.199T>C variant is associated with significant residual activity and appears to be benign. A common mutation in the HADHA gene alters the catalytic residue in the LCHAD domain and is the predominant cause of isolated LCHAD deficiency.

48  Mitochondrial Fatty Acid Oxidation Disorders

953

Prevalent mutations (Caucasian population) Mutation Amino acid change No prevalent mutation c.1436C>T p.P479L (Inuit population) No prevalent mutation c.338C>T p.S113L c.848T>C p.V243A No prevalent mutations

Enzyme name OCTN2 CPTI

Gene name SLC22A5 CPT1

CACT CPTII VLCAD MTP

SLC25A20 CPT2 ACADVL HADHA/HADHB

LCHAD LKAT ACAD9 MCAD

HADHA/HADHB HADHA/HADHB ACAD9 ACADM

c.1528G>C No prevalent mutation No prevalent mutation c.985A>G c.199G>C

p.E474Q

SCAD

ACADS

c.625G>A c.511C>T

p.G209S p.R171W

SCHAD

HADH

No prevalent mutation

p.K329E p.Y67H

Treatment Prolonged fasting should be avoided in all FAODs in order to prevent acute metabolic decompensation. Frequent, regular feeds are recommended, especially during the first year of life, but subsequently overnight fasting (8 h) will be tolerated in most disorders. Prolonged overnight fasting should be postponed until later childhood/adolescence, especially in MTP and LCHAD deficiencies, in order to reduce the risk of retinopathy and neuropathy as a consequence of accumulating toxic metabolites. Dietary fat restriction is not indicated in MCAD deficiency. In mild long-chain FAODs, the dietary fat intake does not have to be reduced if MCT oil is not prescribed; however, the fat intake should not exceed the dietary recommendation for healthy individuals. If MCT is used in severe long-chain FAODs, some restriction of long-chain fat will be necessary to maintain appropriate nutrient balance. Supplementation with 2–4 gm/kg of body weight per day of MCT oil may be used in young patients (T in the Inuit population (Canada and Greenland) Allele frequency (60%) Suggestive of mild VLCADD Many deletions and splice site mutations in the HADHA gene; Most compound heterozygotes for c.1528G>C and a second HADHA mutation have MTP deficiency Heterogeneous presentations despite one mutation Only two patients known Classical MCADD; before screening: 80% homozygosity Asymptomatic/(mild) variant; allele frequency: 6% of mutant alleles in screened population; not found in a clinically diagnosed patient before screening Polymorphisms with predisposition for disease; 625G > A: Allele frequency, 22%; c.511C > T: Allele frequency, 3%

FAODs (Gillingham et  al. 2006). Studies in VLCAD-­ deficient mice highlight the need to give MCT in accordance to the energy needs, since MCT are otherwise elongated and stored as saturated long-chain fatty acids (Tucci et al. 2015). Carnitine treatment is undisputedly effective in patients with carnitine transporter deficiency. With a dose of 100– 300 mg/kg/day, plasma concentrations may reach the lower normal range but muscle carnitine concentrations remain less than 5% of normal (Stanley et al. 1991). The value of carnitine supplementation in other FAODs is controversial. Plasma-free carnitine concentration is often low, particularly after an acute illness, but tissue concentrations have seldom been measured. In many patients, carnitine concentration in blood reach normal values when well, likely due to induced endogenous carnitine biosynthesis. Carnitine treatment has been hypothesized to be harmful in long-chain FAODs, as it increases the concentrations of potentially arrhythmogenic long-chain acylcarnitines (Primassin et al. 2008). However, this remains unproven and must be balanced against a potential benefit of providing some additional FAO capacity if the free carnitine is exceedingly low. Bezafibrates (PPARα and PPARδ agonists) may be promising in the treatment of patients with myopathic CPTII or VLCAD deficiencies, though a randomized controlled clinical trial failed to show a clinical effect (Bonnefont et  al. 2010). Triheptanoin (C7 odd-chain fatty acid) has been tested

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anecdotally and in clinical trials as a substitute for MCT (Vockley et al. 2019). It has been presumed that patients with long-chain FAODs have reduced levels of TCA cycle intermediates that is more effectively addressed by supplying both acetyl-CoA and propionyl-CoA from triheptanoin as compared to acetyl-CoA alone from MCT (Vockley et al. 2019). In a double-blind study of the two compounds in patients with long-chain FAODs, patients showed improvement in cardiac function on triheptanoin compared to MCT. A phase-2 openlabel trial of triheptanoin in long-­ chain FAOD patients showed an overall decrease in major clinical events defined as hypoglycemia, development and worsening of cardiomyopathy, and frequency and severity of rhabdomyolysis. A report on compassionate use of triheptanoin with acute onset or exacerbation of cardiomyopathy in long-chain FAOD patients while on MCT, showed rescue of critically ill patients in many cases (Vockley et al. 2016). The drug is being considered for approval in the USA, but has not been extensively tested in Europe. So far it is still considered an experimental treatment and has not been included in general treatment recommendations for FAO defects.

Deficiency of Emergency treatment SCHAD Glucose i.v.

Standard Treatment Deficiency of Dietary treatment OCTN2 Normal diet; regular meals; avoid catabolism CPTI CACT CPTII

Emergency Treatment Deficiency of Emergency treatment OCTN2 Glucose i.v.; oral glucose monomer (to avoid hypoglycemia) Reach anabolism CPTI Glucose i.v.; oral glucose monomer CACT (to avoid hypoglycemia) CPTII Reach anabolism: VLCAD 10 years: 5–8 mg/kg min Oral MCT; i.v. MCT generally not available (only special preparations) When severe decompensation, reach anabolism with use of insulin ACAD 9: Monitor lactate MCAD Glucose i.v.; oral glucose monomer (to avoid hypoglycemia) Reach anabolism No MCT SCAD Glucose i.v. in case of hypoglycemia

Pharmacological emergency treatment L-carnitine i.v. (100–300 mg/kg per day)

L-carnitine typically not needed unless free carnitine is very low (16 years) + + + + + + + +

+

+

+

+ +

+ +

+ +

Table 51.34  Perilipin 1 deficiency System Autonomic system CNS Dermatological Digestive Endocrine Genitourinary Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Hypertension Stroke Acanthosis nigricans Liver steatosis Cushing stigmata Diabetes mellitus Ovarian failure Lipodystrophy, partial Body fat percentage, low Body mass index, low Cholesterol (serum) Triglyceride (serum)

Neonatal (birth–1 month) ± ± ± ± ± ± ± ± ± ± ↑↑↑ ↑↑↑

skeletal muscle and liver, leading to insulin resistance and hypertriglyceridemia (Gandotra et  al. 2011). Interestingly, individuals with a heterozygous PLIN1 null allele were reported that do not display a partial lipodystrophy phenotype, suggesting that the initially reported heterozygous variants cause a specific disease mechanism leading to the reported partial lipodystrophy phenotype. The authors caution the interpretation of PLIN1 null allele in diagnostic gene testing for lipodystrophy, insulin resistance, and diabetes (Table 51.34) (Laver et al. 2018).  ormone-Sensitive Lipase Deficiency, Familial Partial H Lipodystrophy Type 6, LIPE

Function: LIPE encodes hormone-sensitive lipase (HSL) and is the predominant mediator of the hydrolysis of DG, cholesterol esters, and retinyl esters in human white adipose tissue (Fig.  51.2a). HSL is ubiquitously expressed and involved in lipolysis in adipocytes, steroidogenesis, and spermatogenesis (Albert et al. 2014). Clinical: Familial partial lipodystrophy type 6; heterozygous patients also show symptoms, but symptoms are more

Infancy (1–18 months) ± ± ± ± ± ± ± ± ± ± ↑↑↑ ↑↑↑

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± ± ± ↑↑↑ ↑↑↑

Adolescence (11–16 years) + + + + + + + + + + ↑↑↑ ↑↑↑

Adulthood (>16 years) + + + + + + + + + + ↑↑↑ ↑↑↑

prominent in homozygous individuals. Clinically characterized by partial lipodystrophy (reduced lower limb subcutaneous fat), dyslipidemia, hepatic steatosis, and systemic insulin resistance (Table 51.35) (Albert et al. 2014; Zolotov et al. 2017).

Sphingolipid Metabolism  erine Palmitoyltransferase Subunit 1 Deficiency, S Hereditary Sensory and Autonomic Neuropathy Type 1A, SPTLC1

Function: The de novo biosynthetic pathway is initiated in the ER by the action of serine palmitoyltransferase (SPT) which catalyzes the condensation of L-serine and an acyl-­CoA and generates 3-ketodihydrosphingosine (or 3-­ketosphinganine). Depending on the tissue/cell requirements, the acyl-CoA is palmitoyl-CoA (C16:0-CoA) or myristoyl- (C14:0), stearyl(C18:0) or lignoceryl- (C24:0)-CoA. SPTLC1 encodes serine palmitoyltransferase subunit 1, one of the three SPTLC genes (SPTLC1–3) that together with two separately encoded small

51  Disorders of Complex Lipids

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Table 51.35  Hormone-sensitive lipase deficiency System Dermatological Digestive Endocrine Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Acanthosis nigricans Liver steatosis Diabetes mellitus Lipodystrophy, partial Body fat percentage, low Body mass index, low Cholesterol (serum) Creatine kinase (plasma) Triglyceride (serum)

Neonatal Infancy (1–18 (birth–1 month) months)

Childhood Adolescence (1.5–11 years) (11–16 years)

↑↑↑ ↑ ↑↑↑

↑↑↑ ↑ ↑↑↑

↑↑↑ ↑ ↑↑↑

Adulthood (>16 years) + + + + + + ↑↑↑ ↑ ↑↑↑

↑↑↑ ↑ ↑↑↑

Table 51.36  Serine palmitoyltransferase subunit 1 deficiency System Autonomic system CNS

Dermatological Eye Laboratory findings

Symptoms and biomarkers Anhidrosis Axonal sensory motor polyneuropathy, chronic Neuropathy, myelinating Neuropathy, sensory Skin ulceration Maculopathy 1-Deoxymethylsphiganine (plasma) 1-Deoxysphinganine (plasma)

Neonatal Infancy (1–18 (birth–1 month) months) ± ±

subunits, SPTssa and SPTssb, forms different heterotrimeric complexes that have acyl-length specificity and thereby modulate the length of the sphingoid base (Fig. 51.4a). Hereditary sensory and autonomic neuropathy type 1A is caused by (missense) pathogenic variants that induce a shift in the substrate specificity of SPTs, which leads to the formation of the atypical deoxysphingoid bases 1-deoxysphinganine and 1-­deoxymethylsphinganine. These deoxysphingoid bases lack the 1-hydroxylgroup required for the coupling of headgroups which abrogates the creation of complex sphingolipids and cannot be degraded. Deoxysphingoid bases, especially deoxysphinganines, are neurotoxic and are elevated in plasma of these patients and can be used as a blood biomarker (Penno et al. 2010). Clinical: Hereditary sensory and autonomic neuropathy type 1A: autosomal and dominantly inherited-axonal neuropathy. Onset is usually in the second or third decade of life, and initial symptoms are sensory loss and pain in the feet and hands followed by distal muscle wasting and weakness caused by motor neuron degeneration. Loss of pain sensation leads to chronic skin ulcers and distal amputations (Dawkins et al. 2001). However, the age of onset can be quite variable

Childhood Adolescence (1.5–11 years) (11–16 years) ± ±

± ±

Adulthood (>16 years) +

↑

± + + ± ↑

↑

↑

± ±

(from infancy to late adulthood), disease penetrance is incomplete, and sensory loss may occur without pain (Houlden et  al. 2006). In some families, males presented with more severe and earlier onset, with significant motor involvement and demyelinating motor conduction velocities (Houlden et al. 2006). SPTLC1 variants have also been associated with macular telangiectasia type 2 (Gantner et  al. 2019). Most SPTLC1-deficient patients present with both sensory and autonomic neuropathy and macular telangiectasia. Treatment: L-serine has been tested as treatment for SPTLC1 deficiency (400 mg/kg/d L-serine, https://clinicaltrials.gov/ct2/show/NCT01733407) resulting in lower levels of deoxysphingolipids. L-serine treatment in mice and rat has shown positive effects on peripheral nerve function and should be considered a potential treatment in humans (Garofalo et al. 2011). A randomized controlled trial of 16 patients showed a significant improvement on the Charcot-­ Marie-­Tooth neuropathy score of patients treated by 400 mg/ kg/d L-serine compared to placebo, with evidence of continued improvement in the second year of treatment (Table 51.36) (Fridman et al. 2019).

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 erine Palmitoyltransferase Subunit 2 Deficiency, S Hereditary Sensory and Autonomic Neuropathy Type 1C, SPTLC2

Function: SPTLC2 encodes serine palmitoyltransferase subunit 2 (SPTLC2, Fig. 51.4a). Clinical: SPTLC2 pathogenic variants are a rarer cause of hereditary sensory and autonomic neuropathy (Rotthier et al. 2010). Age of onset and severity is very variable, from infancy to late adulthood (Suriyanarayanan et  al. 2016; Murphy et al. 2013). Patients have elevated plasma levels of deoxysphinganine. Treatment: A small study in one SPTLC2-deficient patient showed that L-serine treatment was well supported and also lowered deoxysphinganine levels in plasma, but there was no change in the Charcot-Marie-Tooth neuropathy score (Auranen et  al. 2017). Further studies are warranted in SPTLC2-deficient patients considering the benefit of L-serine supplementation in SPTLC1-deficient patients (Table 51.37).  eramide Synthase 1 Deficiency, Progressive C Myoclonic Epilepsy Type 8, CERS1

Function: CERS1 encodes ceramide synthase 1 (CERS1), a transmembrane ER protein that catalyzes the condensation of sphinganine with a fatty acyl-CoA, in case of CERS1 preferably C18-CoA, on the primary amino group yielding dihydroceramides (Fig.  51.4). CERS1 is highly expressed in the brain, especially in neurons (Kihara 2016b). Mouse models of the disease showed impaired exploration of novel objects, impaired locomotion and

motor coordination, neuronal apoptosis in the cerebellum, and dramatic changes in levels of cerebellar sphingolipids (Ginkel et al. 2012). Clinical: Only five patients reported, four from the same family (Ferlazzo et  al. 2009; Vanni et  al. 2014; Godeiro Junior et al. 2018). Patients presented with action myoclonus with onset in childhood or adolescence, generalized tonic-­ clonic seizures, and progressive cognitive deterioration up to dementia. Cerebellar ataxia was also present in one patient (Table 51.38) (Godeiro Junior et al. 2018).  eramide Synthase 3 Deficiency, Autosomal Recessive C Congenital Ichthyosis Type 9, CERS3

Function: CERS3 encodes ceramide synthase 3 (CERS3), a transmembrane ER protein that catalyzes the condensation of sphinganine with a fatty acyl-CoA to form dihydroceramides (Fig.  51.4). CERS3 has broad substrate specificity, exhibiting activity toward ≥C18-CoAs (Kihara 2016b). CERS3 is also responsible for creating ceramides containing ultra-long-chain fatty acids that are found in the epidermis (saturated and monounsaturated) and testis (polyunsaturated), which corresponds with the expression pattern of CERS3. Clinical: Pathogenic variants in CERS3 cause autosomal recessive congenital ichthyosis (ARCI). Patients are characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. Ceramides containing ≥C24 fatty acids, including ω-O-acylceramides, are reduced in the epidermis of Cers3 knockout mice and in CERS3 patients (Table 51.39) (Eckl et al. 2013).

Table 51.37  Serine palmitoyltransferase subunit 2 deficiency System Autonomic system CNS

Dermatological Laboratory findings

Symptoms and Neonatal (birth–1 biomarkers month) Anhidrosis Axonal sensory motor polyneuropathy, chronic Neuropathy, myelinating Neuropathy, sensory Skin ulceration 1-Deoxysphinganine (plasma)

Infancy (1–18 months)

Childhood (1.5–11 years) ±

Adolescence (11–16 years)

Adulthood (>16 years)

±

+

± ± ±

± ± ↑

+ + ↑

Table 51.38  Ceramide synthase 1 deficiency System CNS

Symptoms and biomarkers Ataxia, cerebellar Cognitive decline Dementia Myoclonic epilepsy Seizures, tonic clonic

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ± + + +

Adolescence (11–16 years) ± + ± + ±

Adulthood (>16 years) ± + ± + ±

51  Disorders of Complex Lipids

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Table 51.39  Ceramide synthase 3 deficiency System Dermatological

Symptoms and biomarkers Collodion skin, collodion baby Ichthyosis

Neonatal (birth–1 Infancy (1–18 month) months) + +

Dihydroceramide Desaturase Deficiency, DEGS1

Function: DEGS1 encodes Δ4-dihydroceramide desaturase that converts dihydroceramide to ceramide by creation of a Δ4,5 trans double bond into the sphinganine backbone (Karsai et al. 2019) (Fig. 51.4a). Clinical: Nineteen patients from 13 unrelated families were identified with DEGS1 pathogenic variants (Pant et al. 2019). Most of them presented with very poor psychomotor development, dystonia and severe spasticity, failure to thrive, and frequent seizures. A less severe phenotype was observed in some patients with capacity to sit or walk and to use verbal communication (Pant et al. 2019; Dolgin et al. 2019). Brain MRI was remarkable and showed hypomyelination, sometimes associated with atrophy of the thalami and hypointense T2/FLAIR of the pallidi (Pant et al. 2019). In fibroblasts, dihydroceramide accumulated, and the dihydroceramide/ceramide ratios in patients’ plasma, fibroblasts, and muscle were elevated (Karsai et al. 2019; Pant et al. 2019). Lipidomic analyses confirmed elevated levels of dihydroceramides, dihydrosphingosine, dihydro-S1P, and dihydrosphingomyelins in whole blood with concomitant reduced levels of ceramide (mild, still present), sphingosine, S1P, and monohexosylceramides (Table  51.40) (Karsai et al. 2019; Dolgin et al. 2019).  lkaline Ceramidase 3 Deficiency, Early ChildhoodA Onset Progressive Leukodystrophy, ACER3

Childhood (1.5–11 years)

Adolescence Adulthood (>16 (11–16 years) years)

+

+

+

 YP4F22 Omega Hydroxylase Deficiency, Autosomal C Recessive Congenital Ichthyosis Type 5, CYP4F22

Function: CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22, previously FLJ39501) encodes an ER localized ω-hydroxylase that catalyzes the NADPH and O2-­ dependent ω-hydroxylation of ultra-long-chain fatty acids longer than C26 and is most active toward species with ≥C28 carbon atoms (Ohno et  al. 2015) (Fig.  51.4b). These ω-hydroxylated ultra-long-chain fatty acids are used especially in the skin where they are needed for the synthesis of ω-O-acylceramides, which are important for skin permeability barrier formation. Clinical: Autosomal recessive congenital ichthyosis type 5: nonsyndromic autosomal recessive congenital ichthyosis (ARCI), generally mild to moderate ARCI phenotype (Hotz et al. 2018). In rare cases, the skin is minimally involved, the so-called self-healing collodion babies (Noguera-Morel et al. 2016). Pathogenic variants lead to considerably reduced ω-hydroxylase activity, decreased levels of ω-O-­ acylceramides, and concomitantly increased non-acylated ceramides (Table 51.42) (Ohno et al. 2015).  cylceramide Transacylase Deficiency, Autosomal A Recessive Congenital Ichthyosis Type 10, PNPLA1

Function: PNPLA1, also known as ARCI10, encodes patatin-­like phospholipase domain-containing 1 (PNPLA1) Function: ACER3 encodes alkaline ceramidase 3 (ACER3), which is a CoA-independent transacylase (Fig.  51.4b). localized to both the ER and Golgi, and catalyzes the hydro- Linoleate esterified in triglyceride is used as an acyl donor lysis of natural phytoceramide, dihydroceramide, and to acylate the ω-hydroxyl group of ω-hydroxyceramide. ceramides carrying an unsaturated fatty acid (C18:1, C20:1, PNPLA1 expression is highly restricted to the differentiand C20:4) (Fig. 51.4a). Its tissue expression is widespread, ated, stratified squamous epithelium of the skin but not evibut is highly expressed in the placenta (Hu et al. 2010). dent in most other tissues. PNPLA1 is involved in the Clinical: Only one paper reporting two patients (siblings) synthesis of ω-O-­acylceramides, which are important for from Ashkenazi Jewish origin suffering from developmental skin permeability barrier formation (Hirabayashi et  al. regression at 6–13 months, truncal hypotonia, appendicular 2018; Ohno et al. 2017). spasticity, dystonia, optic disc pallor, and peripheral neurop- Clinical: Autosomal recessive congenital ichthyosis type 10: athy. The disorder is progressive; both patients (at 11 and Most patients with biallelic PNPLA1 pathogenic variants are 13  years of age) are neurologically severely impaired. born as collodion babies and show a stable or improving Enzyme activity was measured in patients’ fibroblasts and course of the disease with age. Adult patients present with lymphoblasts using either C18:1-ceramide or NBD-C12-­ generalized fine lamellar ichthyosis with whitish or brownish phytoceramide as substrate and was (severely) reduced. scales and mild or moderate erythroderma. Differentiated Plasma analysis showed increased levels of ACER3 sub- keratinocytes prepared from a PNPLA1-mutated patient strates as well as upstream complex sphingolipids showed defective ω-O-acylceramide generation (Table 51.43) (Table 51.41) (Edvardson et al. 2016). (Hirabayashi et al. 2018; Pichery et al. 2017).

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Table 51.40  Dihydroceramide desaturase deficiency System CNS

Other Laboratory findings

Neonatal (birth–1 Symptoms and biomarkers month) Ataxia, cerebellar Basal ganglia abnormalities (MRI) Cerebral hypomyelination Dystonia Epileptic seizures Neuropathy, myelinating Retardation, psychomotor + Severe intellectual deficiency Spasticity Failure to thrive Dihydroceramide (plasma, fibroblasts) Dihydroceramide/ceramide ratio (plasma, fibroblasts)

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ±

+ + + ± + + + + ↑

+ + + ± + + + + ↑

+ + + ± + + + + ↑

+ + + ± + + + +

↑

↑

↑

Table 51.41  Alkaline ceramidase 3 deficiency System CNS

Laboratory findings

Symptoms and biomarkers Developmental regression Dystonia Neuropathy, peripheral Spasticity C(18:1)- and C(20:1)ceramides (plasma) C(18:1)- and C(20:1)dihydroceramides (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ↑

Adolescence (11–16 years)

Adulthood (>16 years)

↑

Table 51.42  CYP4F22 omega hydroxylase deficiency System Dermatological

Symptoms and biomarkers Collodion skin, collodion baby Ichthyosis

Neonatal (birth–1 month) +

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

+

+

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

+

+

Table 51.43  Acylceramide transacylase deficiency System Dermatological

Symptoms and biomarkers Collodion skin, collodion baby Ichthyosis

Neonatal (birth–1 month) ±

 DP-Glucose Ceramide Glucosyltransferase U Deficiency, Autosomal Recessive Congenital Ichthyosis, UGCG

Function: UGCG encodes UDP-glucose ceramide glucosyltransferase/glucosylceramide synthase (UGCG) that is localized in the ER (Fig. 51.4b). UGCG catalyzes the transfer of glucose to ceramide producing glucosylceramide (GlcCer) which is the precursor for the majority of complex sphingolipids. Production of GlcCer is also important for skin barrier

formation as ceramides and acylceramides are transported into the extracellular space of the stratum corneum in glucosylated form and liberated by the action of β-glucosidase 1 (encoded by GBA1, defective in Gaucher disease). Clinical: Autosomal recessive congenital ichthyosis: Only two patients from the same family presented with polyhydramnios during pregnancy, collodion membrane, joint contractures, hypernatremic dehydration, and death at 2 months of age. Another molecular event cannot be ruled out with

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Table 51.44  UDP-glucose ceramide glucosyltransferase deficiency System Dermatological Musculoskeletal Other

Symptoms and biomarkers Collodion skin, collodion baby Joint contractures Dehydration

Neonatal (birth–1 month) ±

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

± ±

Table 51.45  Nonlysosomal glucosylceramidase deficiency System CNS

Eye Laboratory findings

Symptoms and biomarkers Ataxia, cerebellar Cerebellar atrophy (MRI) Cognitive decline Intellectual disability Neuropathy, peripheral Retardation, psychomotor Spastic paraplegia Thin corpus callosum Cataract GBA2 activity in leuckocytes

Neonatal (birth–1 month)

±

respect to the contractures in these patients. In mice, complete UGCG deletion is early embryonic lethal, but the keratinocyte-specific conditional knockout displays a severely impaired skin barrier defect as seen in the two reported patients (Table 51.44) (Monies et al. 2018; Amen et al. 2013).  onlysosomal Glucosylceramidase Deficiency, N Autosomal Recessive Spastic Paraplegia Type 46, GBA2

Function: GBA2 encodes the ubiquitously expressed (highest expression levels found in the liver, brain, and testis) β-glucosidase 2 or nonlysosomal glucosylceramidase 2 (GBA2), an integral membrane protein located at the ER/ Golgi and close to the cell surface. The exact function of GBA2 is still under investigation. Clinical: GBA2 pathogenic variants have been associated predominantly with an early-onset spastic paraplegia, SPG46 (Martin et al. 2013), or cerebellar ataxia (Hammer et al. 2013). Overall, patients usually present with a spastic ataxia in childhood or adolescence, slowly progressive, often associated with intellectual disability and cataract (i.e., Marinesco-Sjögren-like syndrome, (Haugarvoll et  al. 2017)). Glucosylceramide levels were elevated in erythrocytes and plasma, in the range of untreated Gaucher patients. Enzyme activity can be measured in leukocytes (not in fibroblasts) by subtraction (with and without GBA2 inhibitor AMP-­deoxynojirimycin) to selectively measure GBA2 activity (Table  51.45) (Haugarvoll et al. 2017).

Infancy (1–18 months)

Childhood (1.5–11 years) ±

±

±

Adolescence Adulthood (11–16 years) (>16 years) ± + ± ± ± ± ±

±

±

±

±

±

±

+ ± ± ↓

 atty Acid 2-Hydroxylase Deficiency, Autosomal F Recessive Spastic Paraplegia Type 35 (SPG35); Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN), FA2H

Function: FA2H encodes fatty acid 2-hydroxylase (FA2H) which hydroxylates fatty acids at the 2 (or α)-position (Fig. 51.4a). This can subsequently be activated to its corresponding 2-OH-acyl-CoA and used by ceramide synthases to form 2-OH-ceramides and downstream complex sphingolipids. FA2H is highly expressed in the brain where it is involved in the formation of 2-hydroxy galactosylceramides and 2-hydroxy sulfatides which are critical for normal myelination and myelin function (Alderson et al. 2004). Clinical: Most patients with FA2H pathogenic variants present with a rather homogeneous and severe phenotype characterized by an early-onset spastic tetraparesis (SPG35), cerebellar ataxia with dysarthria, dysphagia, truncal hypotonia, and cognitive deficits, frequently accompanied by exotropia and dystonia/rigidity (Edvardson et al. 2008; Kruer et al. 2010; Rattay et al. 2019). Patients may also present with seizures and optic atrophy. Disease onset is usually around 4 years of age, with loss of ambulation within 7 years (Rattay et al. 2019). Rarely, adult-onset forms have been reported (Tonelli et  al. 2012). Brain MRI is rather evocative with a combination of periventricular white matter T2 hyperintensities, T2 hypointensity of the globus pallidus as seen in neurodegeneration with brain iron accumulation (NBIA), pontocerebellar atrophy, and thin corpus callosum (Kruer et al. 2010). These four imaging findings have been grouped under the acronym “WHAT”—white

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Table 51.46  Fatty acid 2-hydroxylase deficiency System CNS

Eye

Neonatal (birth–1 Symptoms and biomarkers month) Abnormalities in the globus pallidus (MRI) Ataxia, cerebellar Axial hypotonia Cerebellar hypoplasia Cognitive dysfunction Dystonia Hypoplasia of pons Periventricular white matter abnormalities Seizures Spastic tetraparesis Thin corpus callosum Exotropia Optic atrophy

matter changes, hypointensity of the globus pallidus, pontocerebellar atrophy, and thin corpus callosum (Rattay et al. 2019). The enzyme activity cannot be measured in fibroblasts due to other fatty acid hydroxylation activities (Edvardson et  al. 2008). Of note, uniparental disomy seems to be a rather frequent genetic mechanism for homozygous FA2H pathogenic variants in non-consanguineous families (Table 51.46) (Soehn et al. 2016).

Infancy (1–18 months)

± ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) +

Adulthood (>16 years) +

± ± ± ± ± ± ±

+ ± + ± ± + +

+ ± + ± ± + +

± ± ± ± ±

± + + ± ±

± + + ± ±

Nephrotic syndrome and adrenal insufficiency were variably associated with neurodevelopmental delay, microcephaly, brain malformations, ichthyosis, deafness, and adrenal calcifications (Bamborschke et  al. 2018). The levels of SGPL1 substrates, S1P, and sphingosine (latter differentiates best in blood, three- to sixfold elevated) were markedly increased in the patients’ blood and fibroblasts. Total serum ceramide levels and C24:0- and C16:0-lactosylceramides were also elevated (Table 51.47) (Lovric et al. 2017).

Sphingosine-1-Phosphate Lyase Deficiency, SGPL1

Function: SGPL1 encodes the ubiquitously expressed sphingosine-1-phosphate lyase (SGPL1) which cleaves sphingosine-1-phosphate (S1P) yielding a fatty aldehyde and phosphoethanolamine. SGPL1 is an essential enzyme in the sphingolipid catabolic pathway and regulator of S1P levels and other sphingoid bases (Fig. 51.4a). S1P is a bioactive lipid implicated in the regulation of cell survival, apoptosis, proliferation, and migration via both extracellular signaling of G-coupled protein receptors and intracellular signaling (Lovric et  al. 2017). Mouse work shows that SGPL1 is also involved in (neuronal) autophagy as the released phosphoethanolamine can be used for synthesis of PE that anchors LC3 to the phagophore membranes. Clinical: SGPL1 pathogenic variants were identified simultaneously in patients presenting with an atypical form of axonal peripheral neuropathy—characterized by acute or subacute onset and episodes of recurrent mononeuropathy during adolescence (Atkinson et  al. 2017)—and children presenting with nephrotic syndrome (NPHS14) and adrenal insufficiency (Lovric et  al. 2017; Prasad et  al. 2017).

 eramide Transfer Protein Superactivity, Autosomal C Dominant Mental Retardation Type 34, COL4A3BP

Function: COL4A3BP encodes collagen type IV alpha-­3-­ binding protein, also known as ceramide transfer protein (CERT) or StAR-related lipid transfer protein 11 (STARD11). In vitro assays show that this lipid transfercatalyzing domain specifically extracts ceramide from phospholipid bilayers and is suggested to mediate intracellular trafficking of ceramide in a non-vesicular manner (Hanada et al. 2003). Clinical: Only three patients in large-scale discovery of novel genetic causes of developmental disorders, The Deciphering Developmental Disorders Study: the three identical Ser132Leu pathogenic variants in CERT that remove a serine that when phosphorylated downregulates transporter activity from the ER to the Golgi. Authors suggest that this leads to superactivity of CERT and that this results in intracellular imbalances in ceramide and its downstream metabolic pathways (Deciphering Developmental Disorders Study 2015). As there is no functional proof, it should be considered a candidate gene awaiting confirmation (Table 51.48).

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Table 51.47  Sphingosine-1-phosphate lyase deficiency System CNS Dermatological Ear Endocrine Musculoskeletal Other Renal Laboratory findings

Symptoms and biomarkers Neuropathy, peripheral Retardation, psychomotor Ichthyosis Deafness, sensorineural Adrenal calcification Adrenal insufficiency Microcephaly Malformations (brain) Nephrotic syndrome C24:0 and C16:0 lactyosylceramides (serum) Ceramides (serum) Sphingosine-1-phosphate (plasma)

Neonatal (birth–1 month) ± ± ± ± ± ± ±

Infancy (1–18 Childhood months) (1.5–11 years) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ↑ ↑

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ±

±

±

±

↑

Table 51.48  Ceramide transfer protein superactivity System CNS

Symptoms and biomarkers Intellectual disability Retardation, psychomotor

Neonatal (birth–1 month)

 M3 Synthase Deficiency, Amish Infantile Epilepsy G Syndrome; Salt and Pepper Developmental Regression Syndrome, ST3GAL5 Now Also Called ST3GAL5-CDG

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence Adulthood (11–16 years) (>16 years)

 M2_GD2 Synthase Deficiency, Autosomal Recessive G Spastic Paraplegia Type 26 (SPG26), B4GALNT1

Function: B4GALNT1 encodes β-1,4-N-acetyl galactosaminyltransferase 1 (GalNAc-T), or GM2/GD2 synthase, a Function: ST3GAL5 encodes lactosylceramide α-2,3-­ Golgi enzyme which catalyzes the reaction GM3➔GM2 and sialyltransferase, or GM3 synthase, a Golgi enzyme which GD3➔GD2 in ganglioside synthesis of a-, b-, and c-series, catalyzes the formation of GM3 ganglioside from lactosylce- but also lactosylceramide➔GA2 and Gb3➔Gb4 of 0-series ramide, the first step in the synthesis of complex ganglioside and globo-series, respectively (Fig. 51.4c). species of the a-, b-, and c-series (Fig. 51.4c). Clinical: B4GALNT1 pathogenic variants were identified in Clinical: Autosomal recessive infantile-onset symptomatic patients with an early-onset but slowly progressive spastic epilepsy syndrome associated with microcephaly, choreoath- paraparesis (SPG26) associated with mild intellectual disetosis, blindness, and deafness and failure to thrive (Simpson ability and possibly pes cavus, cerebellar ataxia, peripheral et  al. 2004; Bowser et  al. 2019). Pathogenic variants in neuropathy, dystonia, cataract, and hypogonadism in males ST3GAL5 also have been found in the salt & pepper syn- (Boukhris et  al. 2013). Analysis of patient fibroblasts drome, a very similar neurodevelopmental disorder associ- revealed lack of GM2 production and increased levels of the ated with altered “salt & pepper” dermal pigmentation (= precursor GM3 (Table 51.50) (Harlalka et al. 2013). freckle-like hyperpigmented and depigmented macules). As ST3GAL5 deficiency also affects both N-linked and O-linked GD1a_GT1b Synthase Deficiency, ST3GAL3-CDG, glycosylation, this disorder is also known as ST3GAL5-­ ST3GAL3 CDG.  Plasma glycosphingolipids of ST3GAL5-deficient Function: ST3GAL3 encodes the Golgi enzyme patients completely lack GM3 and gangliosides derived from β-galactoside-α2,3-sialyltransferase-III (ST3Gal-III) that GM3 (GM2, GM1a, GD3, GD1a), and its precursor lactosyl- transfers sialic acid (N-acetylneuraminic acid) in α2,3-­ ceramide and its alternative derivatives (LacCer, Gb3, Gb4) linkage to galactose and is needed for the synthesis of GD1a are elevated (Simpson et  al. 2004). Secondary respiratory and GT1b in ganglioside a-, b-, and c-series but also takes chain dysfunction in fibroblasts and the liver was reported part in the formation of the sialyl-Lewis (sLea and sLex) epi(Fragaki et  al. 2013) as well as high blood lactate levels topes on proteins (Edvardson et al. 2013) (Fig. 51.4c). (Table 51.49) (Lee et al. 2016).

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Table 51.49  GM3 synthase deficiency System CNS

Dermatological Ear Eye Other Laboratory findings

Symptoms and biomarkers Acquired microcephaly Choreoathetosis Cortical atrophy (MRI) Epilepsy, intractable Regression, psychomotor Severe intellectual deficiency Pigmentation Deafness, sensorineural Visual impairment Failure to thrive GM3 activity (plasma) GM3 ganglioside (plasma) Lactate (plasma) Lactosylceramide (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months) + + ± + + ± ± + + ↓ ↓↓ ↑

Childhood (1.5–11 years) + + ± ± + + ± ± + + ↓ ↓↓ ↑ ↑

Adolescence (11–16 years) + + + ±

Adulthood (>16 years)

+ ± ± + + ↓ ↓↓ ↑

Table 51.50  GM2/GD2 synthase deficiency System CNS

Endocrine Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia, cerebellar Dystonia Intellectual disability, mild Neuropathy, peripheral Spastic paraparesis Hypogonadism Cataract Pes cavus GM2 gangliosides (fibroblasts) GM3 gangliosides (fibroblasts)

Neonatal Infancy (1–18 (birth–1 month) months) ± ± ±

Clinical: ST3GAL3 deficiency also affects protein glycosylation, therefore also called ST3GAL3-CDG.  Few patients have been reported so far with ST3GAL3 pathogenic variants: two families with nonsyndromic severe intellectual disabilities (Hu et  al. 2011) and two families with severe intellectual disability and epileptic encephalopathy (Table 51.51) (Edvardson et al. 2013).  b3 Synthase Deficiency, NOR Polyagglutination G Syndrome, A4GALT

Function: A4GALT encodes α-1,4-galactosyltransferase (A4GALT or Gb3 synthase) that uses UDP-galactose to add a galactose to lactosylceramide forming Gb3 (Fig. 51.4c) as well as reactions more downstream in the globo-series (not shown) that lead to the formation of the human P1PK blood group antigens P1, P(k), and P.  The antigen P(k) in fact is

±

Childhood (1.5–11 years) ± ± + ± ± ± ± ± ↓↓ ↑

Adolescence (11–16 years) ± ± + ± + ± ± ± ↓↓ ↑

Adulthood (>16 years) ± ± + ± + ± ± ± ↓↓ ↑

Gb3, which is also known as cluster of differentiation 77 (CD77). Clinical: Polyagglutination is the occurrence of red cell agglutination by virtually all human sera, but not by autologous serum or sera from newborns. NOR polyagglutination syndrome was designated “NOR” since the family where this phenomenon was first observed was from Norton, Virginia. The syndrome is transmitted in an autosomal dominant pattern of inheritance and results from a specific mutation in A4GALT, c.631C  >  G, and p. Q211E, which changes the substrate specificity of A4GALT, so it cannot only attach galactose to another galactose but also to N-acetylgalactosamine (GalNac). The latter reaction leads to synthesis of NOR antigens, which are glycosphingolipids with terminal Gal(α1–4)GalNAc sequence, which does not occur in mammals. The NOR-positive individuals do

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Table 51.51  GD1a/GT1b synthase deficiency System CNS

Symptoms and biomarkers Encephalopathy, epileptic Severe intellectual deficiency

Neonatal (birth–1 Infancy (1–18 month) months) ± + +

Childhood (1.5–11 years) ± +

Adolescence (11–16 years) ± +

Adulthood (>16 years)

Table 51.52  GB3 synthase deficiency System Other

Symptoms and biomarkers Polyagglutination syndrome (erythrocytes)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

not show any morbid symptoms, but their erythrocytes are agglutinated by most human sera, creating a risk of complications during transfusion of NOR erythrocytes. NOR-­ positive individuals should therefore be disqualified as blood donors (Table  51.52) (Suchanowska et  al. 2012; Kaczmarek et  al. 2016) (also see https://omim.org/ entry/111400).

Miscellaneous  hospholipid-Transporting ATPase IB Deficiency, P Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome Type 4, ATP8A2

Function: ATP8A2 encodes ATPase aminophospholipid transporter type 8A member 2 (ATP8A2) and belongs to the P4-ATPases subfamily of P-type ATPases, which are involved in the transport of aminophospholipids. ATP8A2 is involved in the transport of aminophospholipids (PE and PS) from the outer leaflet of the plasma membrane toward the inner leaflet (PS and to a lesser extent PE) in brain cells, retinal photoreceptors, and the testis. This is important to maintain membrane asymmetry in the plasma membrane (Cacciagli et al. 2010). Clinical: Cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4 (CAMRQ4): autosomal recessive condition with intellectual disability, developmental delay, ophthalmoplegia, movement disorder, hearing loss, epilepsy, and short stature (Table  51.53) (Guissart et  al. 2019).  YP2U1 Deficiency, Autosomal Recessive Spastic C Paraplegia Type 56, CYP2U1

Function: CYP2U1 encodes cytochrome P450 family 2 subfamily U member 1 (CYP2U1), is localized to both ER and mitochondria, and catalyzes the ω- and (ω-1)-hydroxylation

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

of arachidonic acid (C20:4ω6, AA) as well as hydroxylation of docosahexaenoic acid (C22:6ω3, DHA) and other long-­ chain fatty acids (saturated/monounsaturated C16-C22). This yields a series of oxygenated products including two bioactive metabolites 19- and 20-hydroxyeicosatetraenoic acid (so-called HETEs). CYP2U1 is highly expressed in the thymus and cerebellum and has been suggested to modulate the arachidonic acid signaling pathway and play a role in other fatty acid signaling processes (Chuang et al. 2004). Clinical: Autosomal recessive spastic paraplegia type 56. Patients with CYP2U1 pathogenic variants usually present with an infantile-onset but slowly progressive complicated spastic paraplegia (Tesson et al. 2012). Possible associated symptoms are dystonia, psychomotor retardation or regression, intellectual disability, and/or subclinical sensory motor neuropathy (Tesson et  al. 2012; Kariminejad et  al. 2016; Iodice et al. 2017). Brain MRI may show delayed myelination, white matter abnormalities, and/or thin corpus callosum (Tesson et al. 2012). CT scan may reveal basal ganglia calcifications (23176821). Adult-onset spastic paraplegia has been reported, associated with a pigmentary maculopathy (Table 51.54) (Leonardi et al. 2016).  BHD12 Deficiency, Polyneuropathy, Hearing Loss, A Ataxia, Retinitis Pigmentosa, and Cataract (PHARC) Syndrome, ABHD12

Function: ABHD12 encodes α−/β-hydrolase domain-­ containing protein 12 (ABHD12) which is an integral membrane plasma/ER membrane protein that was shown to hydrolyze the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid (C20:4ω6) and monoacylglycerol in vitro. More recently, ABHD12 was shown to be the major lipase acting on VLCFA-containing lysophosphatidylserine (LPS) (Blankman et al. 2013) in the brain and that it also hydrolyzes oxidized PS and LPS species. The oxidation of PS species due to elevated reactive oxygen species is

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Table 51.53  Phospholipid-transporting ATPase IB deficiency System CNS

Digestive Eye

Musculoskeletal Other

Symptoms and biomarkers Ataxia, cerebellar Bilateral sensory hearing loss Dysarthria Epileptic seizures Extrapyramidal movement disorder Gait, atactic Hypotonia, muscular-generalized Intellectual disability Interictal nystagmus Sleep disturbances Feeding difficulties Ophthalmoplegia Optic atrophy Ptosis of eyelid Microcephaly Short stature Failure to thrive

Neonatal (birth–1 month) + + + + +

Infancy (1–18 months) + + + + +

Childhood (1.5–11 years) + + + + +

Adolescence (11–16 years) + + + + +

Adulthood (>16 years) + + + + +

+

+

+ +

+ +

+ +

± + + + + ± + + + +

± + + + + + + + + +

+ + + + + + + + + +

+ + + + + + + + + +

+ + + + + + + + + +

Table 51.54  CYP2U1 deficiency System CNS

Eye

Neonatal Symptoms and biomarkers (birth–1 month) Basal ganglia calcifications (CT) Dystonia Intellectual disability Neuropathy, peripheral Regression, psychomotor Retardation, psychomotor ± Spastic paraplegia ± Thin corpus callosum White matter abnormalities (MRI) Pigmentary maculopathy

Infancy (1–18 months)

Childhood (1.5–11 years) ± ± ±

± ± ±

± ± ± ± ±

linked to their transmembrane migration to the exofacial membrane surface which is a pro-apoptotic signal (Kelkar et  al. 2019). LPS itself has been recognized as a signaling molecule (Makide et al. 2014), and ABHD12 therefore has been suggested to be involved in the regulation of (L)PS and oxidized (L)PS levels, thereby regulating immunological and neurological processes (Kelkar et al. 2019; Kamat et al. 2015). In Abhd12−/− mouse, accumulation of LPS, mainly VLCFA-containing as well as oxidized PS species, has been observed. Lipopolysaccharide challenge of Abhd12−/− mice showed a fivefold accumulation of oxidized PS levels in the brain. Reactive oxygen species and oxidative stress may play a role in PHARC pathology where deficient ABHD12 cannot mitigate the excess oxidized PS produced (Blankman et al. 2013; Kelkar et al. 2019).

Adolescence (11–16 years) ± ± ± ±

Adulthood (>16 years) ± ± ± ±

± ± ±

+ ± ± ±

Clinical: ABHD12 pathogenic variants have been associated with a pseudo-Refsum syndrome called PHARC: polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (Fiskerstrand et  al. 2010). Disease onset can be in childhood or adolescence, especially hearing loss and gait abnormalities that are related to sensory (i.e., demyelinating neuropathy) and/or cerebellar dysfunction. Visual impairment may occur in adolescence or adulthood due to bilateral cataracts and/or pigmentary retinopathy. ABHD12 pathogenic variants have also been reported in patients with Usher syndrome (deafness, retinopathy, and sometimes cataract), but neurological examination often revealed cerebellar ataxia or peripheral neuropathy (Eisenberger et  al. 2012). Still, some adult patients may present with isolated pigmentary retinopathy (Table 51.55) (Nishiguchi et al. 2014).

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Table 51.55  ABHD12 deficiency System CNS Ear Eye

Symptoms and biomarkers Ataxia, cerebellar Neuropathy, demyelinating Deafness, sensorineural Cataract Pigmentary retinopathy

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ±

Adulthood (>16 years) ± + + + ±

Diagnostic Flowchart

Prenatal Diagnosis

Given the heterogeneity of this group of disorders, no diagnostic flowcharts apply. Depending on the clinical symptoms—if available—specific biomarkers/tests can be measured, but the most common way of diagnosing these disorders is DNA diagnostics by whole-exome/whole-­ genome sequencing. At this time, lipidomics is not (yet) suited for clinical diagnostics as the measurement is not standardized, the optimal specimen type is variable, and no reference ranges have been established. Still, for disorders where a biomarker profile is known, this measurement can be used for the functional confirmation of the diagnosis. For uncharacterized disorders, however, it should be considered to perform lipidomics to search for new biomarkers that can be developed into targeted tests and/or panels for these types of disorders. To do this, it is crucial that specimens are collected from different cases (or if not available, at least sequential samples from the same patient) and suitable controls to allow comparative lipidomics in search of new biomarkers.

No specific biochemical tests exist at this time to perform prenatal testing. Like many disorders, if the index patient is known, DNA analysis can be used for prenatal testing if warranted.

Specimen Collection Test Preconditions DNA analysis

Lipidomics (blood)

Lipidomics (fibroblasts)

Lipidomics (tissues)

Material Whole blood (EDTA)

Handling RT or frozen (−20 °C) Frozen (−20 °C) Frozen (−20 °C) RT Frozen (−80 °C)

>4 h after last meal Whole blood or after overnight fast (EDTA) Plasma (EDTA) Fibroblasts: • Live cells • Cell pellets (from T-175) No formalin, rapid Tissue Frozen transfer to N2 and (−80 °C) then freezer

DNA Testing See Chapter structure.

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51  Disorders of Complex Lipids Pant DC, Dorboz I, Schluter A, et al. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J Clin Invest. 2019;129:1240–56. Payne F, Lim K, Girousse A, et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc Natl Acad Sci. 2014;111:8901–6. Penno A, Reilly MM, Houlden H, et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010;285:11178–87. Piccini M, Vitelli F, Bruttini M, Pober BR, Jonsson JJ, Villanova M, Zollo M, Borsani G, Ballabio A, Renieri A.  FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation. Genomics. 1998;47:350–8. Pichery M, Huchenq A, Sandhoff R, et al. PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-­ acylceramide synthesis and skin permeability barrier. Hum Mol Genet. 2017;26:1787–800. Prasad R, Hadjidemetriou I, Maharaj A, et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-­ resistant nephrotic syndrome. J Clin Invest. 2017;127:942–53. Quistad GB, Barlow C, Winrow CJ, Sparks SE, Casida JE. Evidence that mouse brain neuropathy target esterase is a lysophospholipase. Proc Natl Acad Sci U S A. 2003;100:7983–7. Ramanadham S, Ali T, Ashley JW, Bone RN, Hancock WD, Lei X. Calcium-independent phospholipases A2 and their roles in biological processes and diseases. J Lipid Res. 2015;56:1643–68. Rattay TW, Lindig T, Baets J, et al. FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. Brain. 2019;142:1561–72. Rotthier A, Auer-Grumbach M, Janssens K, et  al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet. 2010;87:513–22. Saunders CJ, Moon SH, Liu X, et al. Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 γ recapitulate the mitochondriopathy of the homologous null mouse. Hum Mutat. 2015;36:301–6. Shukla A, Saneto RP, Hebbar M, Mirzaa G, Girisha KM. A neurodegenerative mitochondrial disease phenotype due to biallelic loss-­ of-­ function variants in PNPLA8 encoding calcium-independent phospholipase A2γ. Am J Med Genet A. 2018;176:1232–7. Simpson MA, Cross H, Proukakis C, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet. 2004;36:1225–9. Soehn AS, Rattay TW, Beck-Wödl S, et  al. Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families. Neurology. 2016;87:186–91. Sohn M, Ivanova P, Brown HA, Toth DJ, Varnai P, Kim YJ, Balla T. Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions. Proc Natl Acad Sci U S A. 2016;113:4314–9. Suchanowska A, Kaczmarek R, Duk M, et al. A single point mutation in the gene encoding Gb3/CD77 synthase causes a rare inherited polyagglutination syndrome. J Biol Chem. 2012;287:38220–30. Suriyanarayanan S, Auranen M, Toppila J, et  al. The variant p.(Arg183Trp) in SPTLC2 causes late-onset hereditary sensory neuropathy. NeuroMolecular Med. 2016;18:81–90. Synofzik M, Gonzalez MA, Lourenco CM, et al. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2014;137:69–77.

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Disorders of Eicosanoid Metabolism

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Ertan Mayatepek

Contents Introduction

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Nomenclature

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Metabolic Pathways

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Signs and Symptoms

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Reference Values

 1032

Pathological Values

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Diagnostic Flowchart

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Specimen Collection

 1033

Prenatal Diagnosis

 1033

DNA Testing

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Treatment

 1034

References

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Summary

Eicosanoids, including prostaglandins and leukotrienes, are lipid mediators that have been implicated in various pathological processes. They are biologically active metabolites mainly derived from arachidonic acid, a membrane polyunsaturated fatty acid. Prostaglandins (PGs) and thromboxane A2 (TXA2) are formed when arachidonic acid is released from the plasma membrane by phospholipases and metabolized by sequential actions of prostaglandin G/H synthase, cyclooxygenase, or thromboxane synthase (TBXAS1). Leukotrienes (LTs) are synthesized from araE. Mayatepek (*) Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany e-mail: [email protected]

chidonic acid by 5-lipoxygnase. This chapter focuses on very rare disorders of eicosanoid metabolism caused by enzymatic defects in the synthesis of TXA2 or of the primary cysteinyl leukotriene C4 (LTC4) as well as defects in the degradation of PGE2. Thromboxane synthase deficiency (Ghosal hematodiaphyseal dysplasia (GHDD) syndrome) is caused by mutations in the TBXAS1 gene. This disorder is characterized by increased bone density (predominantly diaphyseal) and non-regenerative corticosteroid-sensitive anemia. A defect in the degradation of PGE2, primary hypertrophic osteoarthropathy (PHOAR), is – on the basis of the different pathogenetic genes – categorized into two subtypes. PHOAR type 1 is caused by mutations in the HPGD gene encoding for 15-hydroxyprostaglandin dehydroge-

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_52

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nase whereas PHOAR type 2 is caused by mutations in the SLCO2A1 gene which encodes for the prostaglandin transporter. Affected patients in both types are mainly characterized by digital clubbing, pachydermia, and periostosis. In the biosynthesis of leukotrienes, a primary defect has been described in the form of LTC4 synthase deficiency (LTC4SD) leading to decreased levels of cysteinyl leukotrienes in biological fluids. Affected patients seem to be severely affected with symptoms including muscular hypotonia, psychomotor retardation, microcephaly, and failure to thrive. A better understanding of the role of leukotrienes in the brain and their pathophysiological role is a prerequisite for the suggestion of therapeutical approaches. It is possible that this disorder is underdiagnosed since leukotrienes are usually not included in the metabolic workup.

Introduction Certain polyunsaturated fatty acids, such as arachidonic acid, are metabolized by oxygenation into a large family of biologically active substances, the eicosanoids. They comprise several compounds including most prominently prostaglandins, thromboxanes, and leukotrienes. Eicosanoids exert their functions through different mechanisms, e.g., by receptor binding and intracellular signaling pathway modulation. Their effects are diverse with a short half-life. A tight regulation on the processes of formation and inactivation is fundamental to prevent exacerbation of their effects. Their actions are primarily linked to inflammatory processes and cellular homeostasis. Thromboxane synthase deficiency (Ghosal hematodiaphyseal dysplasia (GHDD) syndrome) is an inherited disorder caused by homozygous mutation in the TBXAS1 gene, which encodes thromboxane synthase (Geneviève et al. 2008). This enzyme catalyzes the conversion of PGH2 to thromboxane A2 (TXA2). Deficiency of thromboxane synthase leads to abnormal bone remodeling and fibrosis of the bone marrow causing non-regenerative severe anemia. Patients, most have been from the Middle East and India, are characterized by sclerosis of long bones with widening of medullary cavities and cortical hyperostosis (Ghosal et  al. 1988; Arora et  al. 2015). The bone changes specifically affect both diaphysis and metaphysis. Moreover, anemia is a characteristic feature. In addition, defects in arachidonic acid-induced platelet

E. Mayatepek

aggregation in  vitro have been reported in some patients, although they do not show a clinically significant bleeding diathesis. Thromboxane synthase seems to be important for bone remodeling. TXA2 modulates the expression of TNFSF11 and TNFRSF11B that encode RANKL and osteoprotegerin in osteoblasts promoting osteosclerosis. Though mutational analysis is confirmatory, the clinical and radiological picture helps to differentiate from other sclerosing bony disorders. This is important since corticosteroids may lead to considerable improvement, at least with respect to anemia (Mondal et  al. 2015; John et al. 2015). Hypertrophic osteoarthropathy (HO) is a syndrome mainly involving bones and the skin (Martinez-Lavin et al. 1993). It is characterized by a distinct triad: digital clubbing, pachydermia, and periostosis. HO is classified either as primary or secondary. Secondary HO is the most common form and associated with an underlying pulmonary, cardiac, hepatic, or intestinal disease, or it may occur with systemic inflammatory or neoplastic processes (Castori et  al. 2005). Primary hypertrophic osteoarthropathy (PHOAR) represents about 3–5% of all cases of HO (Poormoghim et al. 2012). Two causative genes both encoding proteins participating in the degradation of PGE2 were identified. Based on these different pathogenic genes, PHOAR is categorized into two subtypes. Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene causes PHOAR type 1 (Uppal et  al. 2008). HPGD encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which is the main enzyme of prostaglandin degradation. In addition, mutations in the solute carrier organic anion transporter family, member 2A1 (SLCO2A1) gene, encoding the prostaglandin transporter (PGT), cause PHOAR type 2 (PGT deficiency) (Zhang et  al. 2012). Mutations in the SLCO2A1 gene are the major cause of PHOAR in the Japanese population, whereas mutations in the HPGD gene have not been identified in Japanese patients. The age of symptom onset has a bimodal distribution, peaking during the first year of life in type 1, with a higher frequency of patent ductus arteriosus and cranial suture defects, and at puberty in PHOAR type 2 (Castori et  al. 2005). It has a marked predominance in male, especially in PHOAR type 2. Diagnosis is based on the triad of digital clubbing, pachydermia, and periostosis of the tubular bones. Joint swelling, arthralgia or arthritis, and hyperhidrosis are other common symptoms. Peptic ulcers, chronic gastritis,

52  Disorders of Eicosanoid Metabolism

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anemia, and myelofibrosis occur only in patients with PHOAR type 2. Isolated digital clubbing can also be caused by homozygous mutation in the HPGD gene. Both causative genes of PHOAR encode proteins participating in the degradation of PGE2. PGE2 is degraded through two main steps: first, the PGT mediates the uptake of PGE2 across the plasma membrane; then PGE2 is degraded by 15-PGDH in the cell into PGEM. Elevated levels of PGE2 are present in affected patients of both subtypes. In addition, urinary levels of PGEM are elevated in PHOAR type 2 (Hou et al. 2018). Therefore, prostaglandins are considered to be involved in the pathogenesis of PHOAR (Uppal et al. 2008; Zhang et  al. 2012). Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in improving arthralgia or arthritis in majority of affected patients. Leukotrienes are derived from arachidonic acid via the 5-lipoxygenase pathway. They include the cysteinyl leukotrienes (LTC4, LTD4, LTE4) and LTB4 (Lewis et  al. 1990; Mayatepek and Hoffmann 1995). The role of leukotrienes in the CNS is poorly understood, but there is evidence that they are messengers or modulators of CNS activity. A few disorders have been identified causing secondary disturbances in leukotriene elimination and degradation

(Mayatepek et  al. 1993; Mayatepek and Lehmann 1996; Willemsen et al. 2000). In the synthesis of leukotrienes, a primary defect has been detected in the enzymatic step in the form of leukotriene C4 synthase deficiency (LTC4SD). So far, this defect has been identified in two independent patients (Mayatepek and Flock 1998; Mayatepek et  al. 1999). The clinical picture was mainly characterized by severe muscular hypotonia, psychomotor retardation, failure to thrive, microcephaly, and death in infancy. There was a complete absence of the primary cysteinyl leukotriene, LTC4, and its metabolites in the CSF (Mayatepek et  al. 2000). Absence of LTC4, especially in the brain, might at least in part be responsible for the neurological symptoms. Because of the very limited number of patients identified so far and due to the lack of profound understanding of the role of leukotrienes in the brain and their pathophysiological significance in deficiency states, there exist no therapeutic approaches. It is possible that this disorder is underdiagnosed, suggesting that leukotriene analysis might be included in the metabolic workup in patients with severe neurological symptoms who have no apparently other cause.

Nomenclature No. Disorder 52.1 Thromboxane synthase deficiency 52.2 15-Hydroxyprostaglandin dehydrogenase deficiency 52.3 Prostaglandin transporter deficiency 52.4 Leukotriene C4 synthase deficiency

Alternative name Ghosal hematodiaphyseal dysplasia syndrome Primary hypertrophic osteoarthropathy type 1 Primary hypertrophic osteoarthropathy type 2

Gene Abbreviation symbol GHDD TBXAS1

Chromosomal location 7q34

PHOAR1

HPGD

4q34.1

PHOAR2

SLCO2A1 3q22.1-q22.2

LTC4SD

LTC4S

5q35

Affected protein Thromboxane synthase

OMIM no. 231,095

15-Hydroxyprostaglandin dehydrogenase

259,100, 119,900

Organic anion transporter 2A1

259,100; 119,900

Leukotriene C4 synthase

246,530

1030

E. Mayatepek

Metabolic Pathways Diacylglycerol or phospholipid Phospholipase C

Phospholipase A2

5-Lipoxygenase

Arachidonic Acid

HPETE (hydroperoxyeicosatetraenoic acid)

Cyclooxygenase (COX-1 or COX-2)

Leukotriene A4

Prostaglandin H2(PGH2) PGE synthase

Glutathione

LTB4

LCT4 synthase

PGE2 PGD synthase

Prostaglandin transporter 15-hydroxyprostaglandin dehydrogenase PGEM

PGD2

Leukotriene C4 Thromboxane synthase

Prostacyclin synthase

Prostacyclin (PGI2)

Leukotriene D4

Thromboxane (TXA2)

Fig. 52.1  The arachidonic acid cascade. For simplicity, not all reactions are shown in detail. Prostaglandins (PGs) are derived from enzymatic metabolism of arachidonic acid to PGG2 and subsequently to PGH2 followed by the production of bioactive prostaglandins (e.g., PGE2, PGI2, PGD2) and thromboxane A2 (TXA2) by tissue-specific synthases. Cyclooxygenase (COX-1 or COX-2) is the rate-limiting enzyme responsible for the first two steps in the synthesis of prostaglandins. TXA2 is formed from PGH2 via the enzyme thromboxane synthase. PGE2 is

Leukotriene E4

degraded through two main steps: first, the prostaglandin transporter (PGT) mediates the uptake of PGE2 across the plasma membrane. Then PGE2 is degraded by 15-hydroxyprostaglandin dehydrogenase (15PGDH) in the cell into PGEM. Synthesis of the primary cysteinyl leukotriene (LT), LTC4, results from conjugation of the unstable LTA4 with glutathione and is mediated by LTC4 synthase. Stepwise cleavage of glutamate and glycine from LTC4 by γ-glutamyl transpeptidase membranebound dipeptidase yields LTD4 and LTE4, respectively

Signs and Symptoms Table 52.1  Thromboxane synthase deficiency (Ghosal hematodiaphyseal syndrome) System Digestive Hematological

Musculoskeletal

Symptoms and biomarkers Splenomegaly Anemia Leukopenia Thrombocytopenia Cutis verticis gyrata Diaphyseal thickening Metaphyseal thickening Swelling or pain of the large bones

Neonatal (birth–1 month) ± ± ± ±

Infancy (1–18 months) ± + ± ±

Childhood (1.5–11 years) ± + ± ±

+ + ±

+ + ±

+ + +

Adolescence (11–16 years) ± + ± ± + + + +

Adulthood (>16 years) ± + ± ± + + + +

52  Disorders of Eicosanoid Metabolism

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Table 52.2  15-Hydroxyprostaglandin dehydrogenase deficiency (primary hypertrophic osteoarthropathy type 1) System Autonomic system Cardiovascular Dermatological Musculoskeletal

Laboratory findings

Symptoms and biomarkers Hyperhidrosis Patent ductus arteriosus Thickened skin Arthralgia Arthritis Coarse facial features Cranial suture defects Digital clubbing Enlargement of hands/feet Pachydermia Periostitis Swollen joints Prostaglandin E2 (urine) Prostaglandin M (urine)

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ± ± ± ± ± ± ± ± ± ± + + ± ± + + + + ± ± ↑ ↑ n n

Childhood Adolescence Adulthood (1.5–11 years) (11–16 years) (>16 years) ± ± ± ± + + ± ± + ± + + ± ↑ n

± + + ±

± + + ±

+ ± + + ± ↑ n

+ ± + + ± ↑ n

Table 52.3  Prostaglandin transporter deficiency (primary hypertrophic osteoarthropathy type 2) System Autonomic system Dermatological Digestive Hematological Musculoskeletal

Laboratory findings

Symptoms and Biomarkers Hyperhidrosis Thickened skin Chronic gastritis Peptic ulcer Anemia Myelofibrosis Arthralgia Arthritis Coarse facial features Digital clubbing Enlargement of hands/feet Pachydermia Periostitis Swollen joints Prostaglandin E2 (urine) Prostaglandin M (urine)

Neonatal (birth–1 month) ±

Infancy (1-18 months) ± ±

± ± ± ± ± + ± + + ± ↑ ↑

± ± ± ± ± + ± + + ± ↑ ↑

childhood (1.5–11 years) ± ± ± ± ± ± + + ± + ± + + ± ↑ ↑

Adolescence (11–16 years) ± ± ± ± ± ± + + ± + ± + + ± ↑ ↑

Adulthood (>16 years) ± ± ± ± ± ± + + ± + ± + + ± ↑ ↑

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E. Mayatepek

Table 52.4  Leukotriene C4 synthase deficiency System CNS

Musculoskeletal

Other

Laboratory findings

Symptoms and biomarkers Absent head control EEG, abnormal Encephalopathy, progressive Hypotonia Lack of facial expression Minimal spontaneous movements No visual contact Retardation, psychomotor Tendon reflexes, decreased Dysmorphic features EMG, abnormal Microcephaly Death Failure to thrive Symmetric extension in the legs Glutathione (red blood cells) Leukotriene LTC4 (cerebrospinal fluid) Leukotriene LTC4 (plasma) Leukotriene LTD4 (cerebrospinal fluid) Leukotriene LTD4 (plasma) Leukotriene LTE4 (cerebrospinal fluid) Leukotriene LTE4 (urine) Leukotriene LTE4 (plasma) Leukotriene LTB4 (cerebrospinal fluid) Leukotriene LTB4 (plasma)

Neonatal (birth–1 month) + + + ± + + + + + ± + ± + ± n ↓ ↓ ↓ ↓ ↓ ↓ ↓ n-↑ n-↑

Reference Values Plasma (nmol/L) LTC4 LTD4 LTE4 LTB4 Urine (nmol/mol creatinine) PGE2 PGEM LTE4 CSF (pmol/L) LTC4 LTD4 LTE4 LTB4

14–17 23–28 27–33 27–35 103–242 70–161 27–64 37–100 32–70 46–124 56–183

There exists no significant age dependency in healthy individuals LT leukotriene, PG prostaglandin

Infancy childhood (1–18 months) (1.5–11 years) + + + + + + + + + ± + + + + + n ↓ ↓ ↓ ↓ ↓ ↓ ↓ n-↑ n-↑

Adolescence Adulthood (11–16 years) (>16 years)

52  Disorders of Eicosanoid Metabolism

1033

Pathological Values Disorder PGE2 (U) PGEM (U) LTC4 (CSF) LTC4 (P) LTD4 (CSF) LTD4 (P) LTE4 (CSF) LTE4 (P) LTE4 (U) LTB4 (CSF) LTB4 (P) PHOAR1 ↑-↑↑ N PHOAR2 ↑-↑↑ ↑-↑↑↑ LTC4SD ↓ ↓ ↓ ↓ ↓ ↓ ↓ n-↑ n-↑

Diagnostic Flowchart Diagnosis of thromboxane synthase deficiency as well as primary hypertrophic osteoarthropathy is primarily not made on the basis of specific metabolic analyses or profiles but instead based on typically clinical symptoms and especially in the first one on the basis of typical radiological findings. This is completely different in LTC4 synthase deficiency (see Fig. 52.2).

Specimen Collection

Leukotrienes are very susceptible to oxidative degradation. Collection of CSF, urine, or plasma (from heparinized blood after centrifugation) and storage should be done preferably in polypropylene tubes (if possible immediately kept in liquid nitrogen) and frozen immediately preferably at −70  °C.  Long-term storage may result in lower contents. Bacterial contamination may cause artificial higher contents. Leukotrienes are easily artificially generated and released from leukocytes during blood sampling. Prostaglandins and leukotrienes are analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). For mutational analysis, DNA is preferred.

For laboratory measurements of prostaglandins, a thorough drug history is mandatory since nonsteroidal anti-­ P  renatal Diagnosis inflammatory drugs or acetylsalicylic acid can affect such analyses. Prenatal diagnosis has not been performed yet.

Fig. 52.2  Diagnostic flow chart for a defect in the primary cysteinyl leukotriene C4 (LT leukotriene)

CSF Leukotrienes

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) ↓

LTC4 normal

LTE4 (U) ↓

Cysteinyl leukotrienes (P)↓

LTC4 synthase activity ↓

Leukotriene C4 synthase deficiency

NO Leukotriene C4 synthase deficiency

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E. Mayatepek

DNA Testing

References

Mutational analysis is feasible in GHDD as well as in PHOAR type 1 and type 2. It has not been performed yet in LTC4SD. DNA from peripheral blood leukocytes should be used for PCR and direct sequencing.

Arora R, Aggarwal S, Deme S. Ghosal hematodiaphyseal dysplasia— a concise review including an illustrative patient. Skelet Radiol. 2015;44:447–50. Castori M, Sinibaldi I, Mingarelli R, et al. Pachydermoperiostosis: an update. Clin Genet. 2005;6:477–86. Geneviève D, Proulle V, Isidor B, et al. Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome). Nat Genet. 2008;40:284–6. Ghosal SP, Mukherjee AK, Mukherjee D, et al. Diaphyseal dysplasia associated with anemia. J Pediatr. 1988;113:49–57. Erratum in: J Pediatr 113: 410 Hou Y, Lin Y, Qi X, et  al. Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): a single-center study. Bone. 2018;106:96–102. John RR, Boddu D, Chaudhary N, et al. Steroid-responsive anemia in patients of Ghosal hematodiaphyseal dysplasia: simple to diagnose and easy to treat. J Pediatr Hematol Oncol. 2015;37:285–9. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxygenase pathway: biochemistry and relation to pathophysiology in human diseases. N Engl J Med. 1990;323:646–55. Martinez-Lavin M, Matucci-Cerinic M, Jajic I, et  al. Hypertrophic osteoarthropathy: consensus on its definition, classification, assessment and diagnostic criteria. J Rheumatol. 1993;20:1386–7. Mayatepek E, Flock. Leukotriene C4-synthesisis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome. Lancet. 1998;352:1514–7. Mayatepek E, Hoffmann GF.  Leukotrienes: biosynthesis, metabolism and pathophysiological significance. Pediatr Res. 1995;37:1–9. Mayatepek E, Lehmann WD. Defective hepatobiliary leukotriene elimination in patients with the Dubin-Johnson syndrome. Clin Chim Acta. 1996;249:37–46. Mayatepek E, Lehmann WD, Fauler J, et al. Impaired degradation of leukotrienes in patients with peroxisome deficiency disorders. J Clin Invest. 1993;91:881–8. Mayatepek E, Lindner M, Zelezny R, et al. A severely affected infant with absence of cysteinyl leukotrienes in cerebrospinal fluid: further evidence that leukotriene C4-synthesis deficiency is a new neurometabolic disorder. Neuropediatrics. 1999;30:5–7. Mayatepek E, Zelezny R, Hoffmann GF.  Analysis of leukotrienes in cerebrospinal fluid of a reference population and patients with inborn errors of metabolism: further evidence for a pathognomonic profile in LTC4-synthesis deficiency. Clin Chim Acta. 2000;292:155–62. Mondal R, Sil A, Nag SS, et al. Ghosal syndrome—ten years follow-up. Indian J Pediatr. 2015;82:568–9. Poormoghim H, Hosseynian A, Javadi A. Primary hypertrophic osteoarthropathy. Rheumatol Int. 2012;32:607–10. Uppal S, Diggle CP, Carr IM, et al. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008;6:789–93. Willemsen MAAP, De Jong JGN, Van Domburg PHMF, et al. Defective inactivation of leukotriene B4 in patients with Sjögren-Larsson syndrome. J Pediatr. 2000;136:258–60. Zhang Z, Xia W, He J, et al. Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. Am J Hum Genet. 2012;90:125–32.

Treatment Summary In GHDD, steroid therapy is the mainstay of treatment especially for hypoplastic anemia negating the need for blood transfusions. No drug effectively treats PHOAR of both subtypes. NSAID, colchicine, or corticosteroids may be used for symptomatic relief. Bisphosphonates or infliximab has been attempted in patients refractory to these drugs. There exist no treatment options in LTC4SD.

Emergency Treatment No emergency treatment available.

Standard Treatment In GHDD, there exists no standard steroid regimen for this steroid-sensitive disorder. Most studies have reported good response to maintenance therapy with low-dose oral prednisolone throughout life. NSAIDs with their analgesic and anti-inflammatory activities via inhibition of COX activity and prostaglandin ­synthesis are reasonable in patients with painful osteoarthropathy in both subtypes. Colchicine may be helpful for the pain due to subperiosteal new bone formation. Corticosteroids have been given for rheumatologic symptoms. No standard treatment available in LTC4SD.

Experimental Treatment There exist no experimental treatment options for the disorders discussed here.

Disorders of Lipoprotein Metabolism

53

Amanda J. Hooper, Robert A. Hegele, and John R. Burnett

Contents Introduction

 1036

Nomenclature

 1038

Metabolic Pathways

 1040

Signs and Symptoms

 1040

Reference Values

 1046

Pathological Values

 1047

Diagnostic Flow Charts

 1048

Specimen Collection

 1051

Prenatal Diagnosis

 1051

DNA Testing

 1052

Treatment

 1052

Follow-Up and Monitoring

 1054

Online Resources

 1055

References

 1055

Summary A. J. Hooper · J. R. Burnett (*) Department of Clinical Biochemistry, Royal Perth Hospital and Fiona Stanley Hospital, PathWest Laboratory Medicine WA, Perth, WA, Australia School of Medicine, University of Western Australia, Perth, WA, Australia e-mail: [email protected]; [email protected] R. A. Hegele Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada e-mail: [email protected]

Disorders of lipoprotein metabolism-dyslipoproteinemiascan be classified based on the primary biochemical disturbance, such as high or low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride (TG), or some combination of these. Lipoproteins are physiological transporters of hydrophobic lipids and fat-soluble vitamins through plasma from their site of origin (intestine or liver) to their site of uptake and disposition. Abnormal levels of certain plasma lipids and lipoproteins increase the risk of

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_53

1035

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cardiovascular disease (CVD) end points, such as myocardial infarction and stroke, and other complications such as pancreatitis. Numerous genetic and environmental factors contribute to inter-individual variation in plasma concentrations of lipids and lipoproteins. Disorders with a monogenic basis typically present earlier in life, while those that present later in life also have genetic, mainly polygenic, determinants, but their expression further depends on interactions with nongenetic environmental or lifestyle factors. Early diagnosis is central to specific dietary, lifestyle, and pharmacological interventions to delay death, disability, and medical complications. For example, to prevent premature CVD in heterozygous familial hypercholesterolemia, it is important to screen subjects at risk, make the appropriate diagnosis (which may include DNA analysis), and initiate treatment, which includes diet, exercise, and lipid-lowering medications. Here we describe the current understanding of genetic determinants, clinical manifestations, and treatment of disorders of lipoprotein metabolism, focusing on defined monogenic disorders that are diagnosed throughout the lifespan.

Introduction Disorders of lipoprotein metabolism are usually diagnosed biochemically from a plasma lipid profile. The most important lipids clinically are cholesterol, a key component of cell membranes and a precursor for steroid hormones, and TG, a key energy source comprised of three fatty acids each linked to a glycerol backbone. Due to their hydrophobic nature, lipids are transported in plasma in spheroidal particles called lipoproteins. These consist of a core of cholesterol esters and TG, surrounded by a phospholipid and free cholesterol surface, along with associated proteins called apolipoproteins. Lipoproteins can be distinguished from each other by size, density, composition, and function. There are three major lipoprotein transport pathways: the exogenous, endogenous, and reverse cholesterol transport. In the exogenous pathway, dietary fats are packaged into large, TG-rich chylomicron particles and secreted from enterocytes via the lymphatic system into plasma. Chylomicrons are rapidly acted upon by lipoprotein lipase (LPL), which hydrolyzes TG to release free fatty acids and to form smaller remnant particles that are cleared by the liver. In the endogenous pathway, the liver produces TG-rich very-low-density

A. J. Hooper et al.

lipoproteins (VLDL) that are similarly metabolized by lipase activity to form intermediate-density lipoproteins (IDL) and then low-density lipoproteins (LDL). While the majority of LDL is cleared via the LDL receptor pathway by the liver or peripheral tissues, LDL can become modified, e.g., oxidized, and taken up by foam cells, forming a fatty streak in artery walls that is the early stage of atherosclerosis. This process is a function of atherogenic lipoprotein concentrations over time, with the fatty streak and accompanying inflammation progressing to an atherosclerotic plaque, which may eventually rupture, resulting in CVD end points, such as myocardial infarction or stroke. High-density lipoprotein (HDL) functions to, in part, reverse the process of atherosclerosis, by transporting cholesterol from cells and tissues back to the liver for excretion or reuse. Apolipoproteins provide lipoproteins with stability and also act as ligands for receptors or activators for enzymes. Apolipoprotein (apo) B forms an integral part of chylomicrons and VLDL and their remnants and, as there is only one molecule of apo B per particle, which stays with the lipoprotein for its circulating life, provides an estimate of atherogenic particle number. The other apolipoproteins are exchangeable between lipoproteins and include apo A-I, the main apolipoprotein of HDL; apo E, a ligand for receptormediated clearance particularly for IDL; and apo C-II and apo A-V, cofactors for LPL-mediated hydrolysis of TG. Plasma lipid and lipoprotein concentrations generally follow a right-skewed Gaussian distribution in the general population. Median levels vary by age and sex, with older age and male sex associated with a less favorable lipid profile. Increased plasma TG concentrations are associated with an increased risk of acute pancreatitis, while plasma concentrations of LDL cholesterol and apo B are directly related to the incidence of coronary events and cardiovascular deaths. Clinical trials using lipid-lowering drugs have unequivocally shown that lowering LDL cholesterol results in significant reductions in both morbidity and mortality in patients with or without established coronary heart disease. While there is an inverse association between HDL  cholesterol and CVD, genetic studies suggest that this relationship is not causal; in contrast, increased TG levels appear to have a causative association with CVD. Important genetic determinants of lipoprotein levels, and therefore targets for novel therapies, have been identified through studies of monogenic lipid disorders. These disorders are generally found at the extremes of the populationspecific lipoprotein distribution. While familial hypercholesterolemia (FH) affects ~1  in 250 individuals,

53  Disorders of Lipoprotein Metabolism

other monogenic disorders are classified as rare disorders, affecting less than 1  in 2000 individuals (Ng et  al. 2019). Many of these disorders are autosomal recessive, due to homozygous mutations in causative genes. Some affected patients are compound heterozygotes, a category implied whenever the term “homozygous” is used throughout this chapter. It is important to recognize that common dyslipidemias are often associated with other conditions and therefore are termed secondary. For example, untreated hypothyroidism, nephrotic syndrome, and cholestatic liver disease may cause a marked elevation of LDL cholesterol similar to levels seen in FH. Hypolipidemia may be caused by lipid-lowering therapy, cachexia, hyperthyroidism, or malnutrition/malabsorption. Hypertriglyceridemia is commonly associated with type 2 diabetes, obesity, and alcohol. However, secondary dyslipidemias may have a genetic component that is usually

1037

polygenic in nature; subjects who develop secondary dyslipidemia might have inherited one or more subtle metabolic defects that confer susceptibility. It is important to determine whether there is a strong secondary factor underlying the dyslipidemia, since this may guide the preferred means of intervention. This chapter will focus primarily on genetic disorders that affect the concentrations of the major circulating lipoproteins, indicated biochemically on a lipid profile. Each disorder has specific clinical features, including physical manifestations across a range of tissues and organ systems, a distinctive biochemical profile, and often a discrete molecular genetic basis. The increased availability of DNA sequencing means that this technology is often the most direct and cost-effective path to a diagnosis for monogenic dyslipoproteinemias (Berberich and Hegele 2019; Hegele et al. 2015).

Elevated lipoprotein(a) Dysbetalipoproteinemia Abetalipoproteinemia Homozygous familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia

PCSK9 deficiency

53.5 53.6 53.7 53.7

53.8

53.9

53.12 Apolipoprotein A5 deficiency

53.12 Apolipoprotein C2 deficiency

53.11 Chylomicron retention disease 53.12 Lipoprotein lipase deficiency

53.10 Familial combined hypolipidemia

53.4

53.3

53.2

53.1

53.1

Disorder Familial hypercholesterolemia Familial ligand-defective apolipoprotein B-100 Autosomal dominant hypercholesterolemia Homozygous familial hypercholesterolemia Autosomal recessive hypercholesterolemia Sitosterolemia

No. 53.1

Nomenclature

ARH

HoFH

Familial chylomicronemia syndrome; hyperlipoproteinemia type 1 Familial chylomicronemia syndrome; hyperlipoproteinemia type 1 Familial chylomicronemia syndrome; late-onset hyperchylomicronemia; hyperlipoproteinemia type 5

ANGPTL3 deficiency; familial hypobetalipoproteinemia type 2 Anderson disease

Hyperlipoproteinemia type 3 Bassen-Kornzweig syndrome ABL HoFHBL Familial hypobetalipoproteinemia type 1; normotriglyceridemic hypobetalipoproteinemia FHBL Familial hypobetalipoproteinemia type 1 Hypobetalipoproteinemia

LDL receptor adaptor protein 1 deficiency Phytosterolemia

Familial hypercholesterolemia 19p13.2

1p32.3

2p24.1

APOA5

APOC2

LPL

SAR1B

AR AR

AR

AR

5q31.1 8p21.3

19q13.32

11q23.3

AR

ANGPTL3 1p31.1

AD

2p24.1

AD

AD, AR AD, AR AR AR

AR

6q25-q26 19q13.32 4q23 2p24.1

2p21

1p32.3

PCSK9

APOB

ABCG5/ ABCG8 LPA APOE MTTP APOB

AR

AR

AD

AD

605019

607786

615558

152200 617347 200100 615558

210250

603813

143890

603776

144010

Disease OMIM 143890

Apolipoprotein A-V

Apolipoprotein C-II

144650

207750

Secretion-associated Ras related GTPase 246700 1B Lipoprotein lipase 238600

Proprotein convertase subtilisin/kexin type 9 Angiopoietin-like protein 3

Apolipoprotein B

ATP-binding cassette, subfamily G, members 5 and 8 Apolipoprotein(a) Apolipoprotein E Microsomal triglyceride transfer protein Apolipoprotein B

LDL receptor adaptor protein 1

Proprotein convertase subtilisin/kexin type 9 Low-density lipoprotein receptor

Apolipoprotein B

Chromosomal localization Mode of inheritance Affected protein 19p13.2 AD Low-density lipoprotein receptor

LDLRAP1 1p36.11

LDLR

PCSK9

Disease Gene Alternative name abbreviation symbol Autosomal dominant HeFH LDLR hypercholesterolemia Familial hypercholesterolemia FDB APOB

1038 A. J. Hooper et al.

APOA1 LCAT

CETP

Hypoalphalipoproteinemia Norum disease; fish-eye disease Hyperalphalipoproteinemia

53.15 Apolipoprotein A-I deficiency 53.16 Lecithin: cholesterol acyltransferase deficiency and 53.17 53.18 Cholesteryl ester transfer protein deficiency 16q13

16q22.1

11q23.3

15q21.3 9q31.1

AD

AR

AD

AR AR

Cholesteryl ester transfer protein

Lecithin: cholesterol acyltransferase

Hepatic lipase ATP-binding membrane cassette transporter A1 Apolipoprotein A-I

143470

136120, 245900

604091

614025 205400

Disease Gene Chromosomal abbreviation symbol localization Mode of inheritance Affected protein Disease OMIM GPIHBP1 8q24.3 AR Glycosylphosphatidylinositol-anchored 615947 high-density lipoprotein-binding protein 1 LMF1 16p13.3 AR Lipase maturation factor 1 246650

LIPC ABCA1

Alternative name Familial chylomicronemia syndrome; hyperlipoproteinemia type 1 Familial chylomicronemia syndrome; combined lipase deficiency

53.13 Hepatic lipase deficiency 53.14 Tangier disease Analphalipoproteinemia

53.12 Lipase maturation factor 1 deficiency

No. Disorder 53.12 GPIHBP1 deficiency

53  Disorders of Lipoprotein Metabolism 1039

1040

A. J. Hooper et al.

Metabolic Pathways

Dietary sterols

Intestine 53.4

LPL 53.12

MTTP

53.7 APOB 53.8 53.9 53.11

53.6

Remnant

Chylomicron

53.15

Cell

ABCA1 53.14

HL 53.13

A-I

53.16 53.17 LCAT

HDL 3

HL 53.13 53.6

LDL

Liver

A-I

HDL 2

CETP 53.18 53.7 53.8

LPL 53.12

IDL

Fig. 53.1  In enterocytes, dietary fats are loaded onto apoB-48 with the assistance of the microsomal triglyceride transfer protein (MTTP), forming large, triglyceride  (TG)-rich chylomicron particles, which enter the plasma via the lymphatic system. Chylomicron TG are hydrolyzed by lipoprotein lipase (LPL) to release free fatty acids and to form smaller remnant particles that are cleared by the liver. Similarly, the liver produces TG-rich very-low-density lipoproteins (VLDL) contain-

LDLR pathway 53.1 53.2 53.3

VLDL

ing apoB-100 that are metabolized by lipase activity to form intermediate-density lipoproteins (IDL) and then low-density lipoproteins (LDL), which is cleared via the LDL receptor pathway. The ATP-binding cassette transporter A1 (ABCA1) and lecithin: cholesterol acyltransferase (LCAT) facilitate the formation of mature high-density lipoprotein (HDL), while cholesteryl ester transfer protein (CETP) transfers cholesterol from HDL to apoB-containing lipoproteins

Signs and Symptoms Table 53.1  Familial hypercholesterolemia heterozygous (LDLR, APOB, PCSK9) System Cardiovascular Dermatological Eye Laboratory findings

Symptoms and biomarkers Carotid or femoral bruits Myocardial ischemia Xanthelasmas Xanthomas, tendon Arcus cornealis Apo B (plasma) HDL cholesterol (plasma) LDL cholesterol (plasma) LDLR, APOB or PCSK9 mutation, heterozygous, on DNA sequencing TG (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

↑↑ ↓-n ↑↑ +

↑↑ ↓-n ↑↑ +

↑↑ ↓-n ↑↑ +

↑↑ ↓-n ↑↑ +

Adulthood (>16 years) + ++ + ++ + ↑↑ ↓-n ↑↑ +

n

n

n

n

n

53  Disorders of Lipoprotein Metabolism

1041

Table 53.2  Familial hypercholesterolemia homozygous System Cardiovascular

Dermatological Eye Laboratory findings

Symptoms and Biomarkers Aortic valve (AV) disease Calcified AV Carotid bruits Carotid stenosis Coronary atherosclerosis Femoral bruits Myocardial ischemia Xanthelasmas Xanthomas, tendon Arcus cornealis Apo B (plasma) HDL cholesterol (plasma) LDL cholesterol (plasma) LDLR, APOB or PCSK9 mutation, homozygous, on DNA sequencing TG (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +

+ +

Adolescence (11–16 years) + + + + + + + ++ ++ ++ ↑↑↑ n ↑↑↑ +

Adulthood (>16 years) + +++ ++ + + ++ +++ +++ +++ +++ ↑↑↑ n ↑↑↑ +

↑↑↑ n ↑↑↑ +

↑↑↑ n ↑↑↑ +

+ + + + ↑↑↑ n ↑↑↑ +

n

n

n

n

n

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ++ ++ +++ +++ +++ +++ ↑↑↑ ↓-n ↑↑↑ +

Table 53.3  Autosomal recessive hypercholesterolemia (ARH) System Cardiovascular

Dermatological Eye Laboratory findings

Symptoms and biomarkers Carotid bruits Femoral bruits Myocardial ischemia Xanthelasmas Xanthomas, tendon Arcus cornealis Apo B (plasma) HDL cholesterol (plasma) LDL cholesterol (plasma) LDLRAP1 mutation, homozygous, on DNA sequencing TG (plasma)

Neonatal (birth–1 months)

↑↑ ↓-n ↑↑ +

↑↑ ↓-n ↑↑ +

↑↑ ↓-n ↑↑ +

+ ++ ++ + ↑↑↑ ↓-n ↑↑↑ +

n

n

n

n

n

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

n ↑↑ + n +

n ↑↑↑ + n +

+ n ↑ + n +

+ n ↑ + n +

Adulthood (>16 years) + + ++ + ++ n ↑ + n +

+ +

Table 53.4 Sitosterolemia System Cardiovascular

Dermatological Laboratory findings

Symptoms and biomarkers Carotid bruits Femoral bruits Myocardial ischemia Xanthelasmas Xanthomas HDL cholesterol (plasma) LDL cholesterol (plasma) Plant sterols (plasma) TG (serum) ABCG5 or ABCG8 mutation, homozygous, on DNA sequencing

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A. J. Hooper et al.

Table 53.5  Elevated lipoprotein(a) System Cardiovascular Laboratory findings

Symptoms and biomarkers Coronary artery disease Myocardial ischemia Cholesterol (plasma) HDL cholesterol (plasma) Lipoprotein (a) (plasma) Triglyceride (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

childhood (1.5–11 years)

Adolescence (11–16 years)

n-↑ n ↑↑ n

n-↑ n ↑↑ n

n-↑ n ↑↑ n

n-↑ n ↑↑ n

Adulthood (>16 years) + + n-↑ n ↑↑ n

Table 53.6 Dysbetalipoproteinemia System Cardiovascular

Dermatological Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Carotid bruits Claudication Femoral bruits Myocardial ischemia Xanthomas, palmar Xanthomas, tuberoeruptive APOE gene ε2/2 or rare mutation on sequencing Cholesterol (plasma) n HDL cholesterol (plasma) n Lipoprotein electrophoresis, n broad beta band TG (plasma) n

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

+

+

n n n

n n n

n n n

Adulthood (>16 years) + ++ + + ++ +++ + ↑↑ ↓-n +++

n

n

n

↑↑

Table 53.7  Abetalipoproteinemia; Homozygous familial hypobetalipoproteinemia System CNS Digestive Eye Hematological Other Laboratory findings

Symptoms and biomarkers Ataxia Deep tendon reflexes, low Malabsorption Atypical pigmentary retinopathy Acanthocytosis Bleeding tendency Failure to thrive Apo B (plasma) HDL cholesterol (plasma) INR LDL cholesterol (plasma) MTTP or APOB mutation, homozygous, on DNA sequencing Small intestinal biopsy, lipid-laden TG (plasma) Vitamin A (plasma) Vitamin E (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + + + +

Adolescence (11–16 years) ++ + + ++

Adulthood (>16 years) ++ + + ++

+

+

+

+

++ +

++ +

+ ↓↓↓ ↓-n ↑↑ ↓↓↓ +

++ + + ↓↓↓ ↓-n ↑↑ ↓↓↓ +

+ ↓↓↓ ↓-n ↑↑ ↓↓↓ +

↓↓↓ ↓-n ↑↑ ↓↓↓ +

↓↓↓ ↓-n ↑↑ ↓↓↓ +

↑

↑

↑

↑

↑

↓↓↓ ↓↓ ↓↓

↓↓↓ ↓↓ ↓↓

↓↓↓ ↓↓ ↓↓↓

↓↓↓ ↓↓ ↓↓↓

↓↓↓ ↓↓ ↓↓↓

53  Disorders of Lipoprotein Metabolism

1043

Table 53.8   Familial hypobetalipoproteinemia System Laboratory findings

Symptoms and biomarkers No clinical symptoms Apo B (plasma) APOB mutation, heterozygous, on DNA sequencing HDL cholesterol (plasma) LDL cholesterol (plasma) TG (plasma) Vitamin E (plasma)

Neonatal (birth–1 month) + ↓↓ +

Infancy (1–18 months) + ↓↓ +

Childhood (1.5–11 years) + ↓↓ +

Adolescence (11–16 years) + ↓↓ +

Adulthood (>16 years) + ↓↓ +

n ↓↓ ↓ n-↓

n ↓↓ ↓ n-↓

n ↓↓ ↓ n-↓

n ↓↓ ↓ n-↓

n ↓↓ ↓ n-↓

Neonatal (birth–1 month) + ↓↓ ↓ ↓↓ +

Infancy (1–18 months) + ↓↓ ↓ ↓↓ +

Childhood (1.5–11 years) + ↓↓ ↓ ↓↓ +

Adolescence (11-16 years) + ↓↓ ↓ ↓↓ +

Adulthood (>16 years) + ↓↓ ↓ ↓↓ +

↓

↓

↓

↓

↓

Neonatal (birth–1 month) + +

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

↓↓ ↓ ↓↓ ↓↓

↓↓ ↓ ↓↓ ↓↓

↓↓ ↓ ↓↓ ↓↓

↓↓ ↓ ↓↓ ↓↓

↓↓ ↓ ↓↓ ↓↓

Table 53.9  PCSK9 deficiency with low LDL cholesterol System Laboratory findings

Symptoms and biomarkers No clinical symptoms Apo B (plasma) HDL cholesterol (plasma) LDL cholesterol (plasma) PCSK9 mutation on DNA sequencing TG (plasma)

Table 53.10  Familial combined hypolipidemia System Laboratory findings

Symptoms and biomarkers No clinical symptoms ANGPTL3 mutation, homozygous, on DNA sequencing Apo B (plasma) HDL cholesterol (plasma) LDL cholesterol (plasma) TG (plasma)

1044

A. J. Hooper et al.

Table 53.11  Chylomicron retention disease System Cardiovascular Digestive

Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Abdominal distension Hepatomegaly Malabsorption Failure to thrive Apo B (plasma) Cholesterol (plasma) HDL cholesterol (plasma) SAR1B mutation, homozygous, on DNA sequencing TG (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) +

+ + + + ↓↓ ↓↓ ↓ +

+ + + + ↓↓ ↓↓ ↓ +

↓↓ ↓↓ ↓ +

↓↓ ↓↓ ↓ +

↓↓ ↓↓ ↓ +

n

n

n

n

n

Table 53.12  Lipoprotein lipase deficiency (LPL) and familial chylomicronemia syndrome System Dermatological Digestive Eye Laboratory findings

Symptoms and biomarkers Xanthomas, eruptive Abdominal pain Pancreatitis Lipemia retinalis Cholesterol (plasma) HDL cholesterol (plasma) LPL activity, post heparin LPL, APOC2, APOA5, LMF1, or GPIHBP1 mutation, homozygous, on DNA sequencing TG (plasma)

Neonatal (birth–1 month) + + + + ↑ ↓↓ ↓ +

Infancy (1–18 months) + + + + ↑ ↓↓ ↓ +

Childhood (1.5–11 years) + + + + ↑ ↓↓ ↓ +

Adolescence (11–16 years) + + ++ + ↑ ↓↓ ↓ +

Adulthood (>16 years) + + ++ + ↑↑ ↓↓ ↓ +

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

n n ↓

n n ↓

n n ↓

↑ n ↓

Adulthood (>16 years) + + ↑ ↑ ↓

+

+

+

+

+

n

n

n

n

+

n

n

n

↑

↑

Table 53.13  Hepatic lipase deficiency System Cardiovascular Laboratory findings

Symptoms and biomarkers Coronary artery disease Myocardial ischemia Cholesterol (plasma) HDL cholesterol (plasma) Hepatic lipase activity, post heparin LIPC mutation, homozygous, on DNA sequencing Lipoprotein electrophoresis, broad beta band TG (plasma)

53  Disorders of Lipoprotein Metabolism

1045

Table 53.14  Tangier disease System CNS Digestive Hematological Laboratory findings

Symptoms and Biomarkers Neuropathy, peripheral Hepatosplenomegaly Tonsils, enlarged yellow-orange ABCA1 mutation, homozygous, on DNA sequencing Apo A-I (plasma) Cholesterol (plasma) HDL cholesterol (plasma) TG (plasma)

Neonatal (birth–1 month)

Infancy (1-18 months)

Childhood (1.5–11 years)

+

Adolescence (11–16 years) + + +

Adulthood (>16 years) + + +

+

+

+

+

+

+

+

↓↓↓ ↓ ↓↓↓ n

↓↓↓ ↓ ↓↓↓ n

↓↓↓ ↓ ↓↓↓ ↑

↓↓↓ ↓ ↓↓↓ ↑

↓↓↓ ↓ ↓↓↓ ↑

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

↓↓ +

↓↓ +

↓↓ +

↓↓ +

Adulthood (>16 years) + + ↓↓ +

n ↓↓ n

n ↓↓ n

n ↓↓ n

n ↓↓ n-↑

n ↓↓ n-↑

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) +

Adulthood (>16 years) + +

Table 53.15  Apolipoprotein A-I deficiency System Cardiovascular Dermatological Laboratory findings

Symptoms and Biomarkers Coronary artery disease Xanthelasmas Apo A-I (plasma) APOA1 mutation, on DNA sequencing Cholesterol (plasma) HDL cholesterol (plasma) TG (plasma)

Table 53.16  Familial LCAT deficiency (complete) System Eye

Renal Laboratory findings

Symptoms and Biomarkers Arcus cornealis Corneal clouding, deposits Kidney disease Renal biopsy, abnormal Apo A-I (plasma) Cholesterol (plasma) Cholesterol esterification rate Cholesterol, unesterified (plasma) Creatinine (plasma) HDL cholesterol (plasma) LCAT activity (fibroblasts) LCAT mutation, homozygous, on DNA sequencing Protein, total (urine) TG (plasma)

Neonatal (birth–1 month)

↓↓ n ↓↓

↓↓ n ↓↓

↓↓ n ↓↓

↓↓ ↑ ↓↓

+ + ↓↓ ↑ ↓↓

↑

↑

↑

↑

↑

n ↓↓ ↓↓ +

n ↓↓ ↓↓ +

n ↓↓ ↓↓ +

n ↓↓ ↓↓ +

↑ ↓↓ ↓↓ +

n n

n n

n ↑

n ↑

↑ ↑

1046

A. J. Hooper et al.

Table 53.17  Familial LCAT deficiency (partial) System Eye Eye Laboratory findings

Symptoms and Biomarkers Arcus cornealis Corneal clouding, deposits Apo A-I (plasma) Cholesterol (serum) Cholesterol esterification rate Cholesterol, unesterified (plasma) Creatinine (plasma) HDL cholesterol (plasma) LCAT activity (fibroblasts) LCAT mutation, homozygous, on DNA sequencing Protein, total (urine) TG (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) +

Adulthood (>16 years) + +

↓↓ n n

↓↓ n n

↓↓ n n

↓↓ ↑ n

↓↓ ↑ n

n

n

n

n

n

n ↓↓ ↓ +

n ↓↓ ↓ +

n ↓↓ ↓ +

n ↓↓ ↓ +

n ↓↓ ↓ +

n n-↑

n n-↑

n n-↑

n n-↑

n n-↑

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

n ↑ n

n ↑ n

n ↑ n

n ↑↑ n-↑

↑ ↑↑↑ n-↑

Table 53.18  Cholesteryl ester transfer protein deficiency (CETP) System Laboratory findings

Symptoms and biomarkers CETP mutation, on DNA sequencing Cholesterol (plasma) HDL cholesterol (plasma) TG (plasma)

Reference Values Total cholesterol (mmol/L) Triglyceride (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Apo B (g/L) Apo A-I (g/L) Lp(a) (g/L)

Infant 2.0–3.5

Child 2.5–4.0

Adolescent 3.0–4.5

Adult 3.5–5.5

0.3–1.2

0.3–1.5

0.3–1.7

0.5–1.7

1.0–2.4

1.0–3.0

1.2–3.5

1.4–4.5

0.8–1.6

1.0–1.6

0.9–1.6

0.6–1.0 1.0–1.5 13 (adult) >10 (child) >13 (adult) >6.0

LDL-C (mmol/L) >4.0 (child) >5.0 (adult) >7.0 (child) >11 (adult) >7.0 (child) >11 (adult) >4.0

Triglyceride (mmol/L) n

HDL-C (mmol/L) n

Apo B (g/L) >1.8

n

↓-n

>2.4

n

↓-n

>2.4

53.4

Disorder name Familial hypercholesterolemia Homozygous familial hypercholesterolemia Autosomal recessive hypercholesterolemia Sitosterolemia

n

↓-n

53.5 53.6

Elevated lipoprotein(a) Dysbetalipoproteinemia

n >6.0

n Variable

n >3.0

n 1.5

53.7

Abetalipoproteinemia

16 years) ++ + ++ + ++ + ± ± + + ++ +

+++

++

+++ ++ +++ ± +++ +++ +++ ↓↓↓ ± ++ ++ ++ + ++

↓↓↓

+++ ↓↓↓

++ ++ ++ ± +++ ++ ++ ↓↓↓ ± ++ ++ ++ + ++ ++ +++ ↓↓↓

± ± + + +

± ± + + +

+ ++ ↓↓

+ ++ ↓

↓↓↓

↓↓↓

↓↓↓

↓↓

↓

↑ +

↑ + ↑↑↑

n-↑ + ↑↑↑

+ ↑↑↑

+ ↑↑↑

Enzyme activity is measured with synthetic substrates without need of GM2-activator

a

Table 60.3  Tay-Sachs disease System CNS

Digestive Eye Genitourinary Musculoskeletal

Symptoms and biomarkers Ataxia Dementia Dystonia Hypotonia Megalencephaly Mental deterioration Psychiatric symptoms Psychosis Seizuresa Spasticity Speech disturbances Startle response, exaggerated Hepatosplenomegaly Cherry-red spot Vision, impaired Urinary incontinence Macrocephaly Muscle weakness

Neonatal Infancy (birth–1 month) (1–18 months) ± +++

Childhood (1.5–11 years) ± ++

+++ ++ +++

++ + ++ +++

++ +++ +++ +++ ± ++ ++ ++

++ +++ ++ ++ ± ++ ++ ++ ++ +++

+++

Adolescence (11–16 years) ++ ± ++ ++

Adulthood (>16 years) ++ ± ++ ++

± ± ++ ± + ± ± ± ± ±

± ± ++ ± + ± ± ± ± ±

++

++ (continued)

1188

C. Hollak

Table 60.3 (continued) System Laboratory findings

Neonatal (birth–1 month) n-↑ ↓↓↓ ↑ + ↑↑

Symptoms and biomarkers Beta-hexosaminidase activity A + Bb Beta-hexosaminidase activity Ab LysoGM2 Molecular analysis Oligosaccharides (U)

Infancy (1–18 months) n-↑ ↓↓↓ ↑ + ↑↑↑

Childhood (1.5–11 years) n-↑ ↓↓↓ n-↑ + ↑↑↑

Adolescence (11–16 years) n-↑ ↓↓

Adulthood (>16 years) n-↑ ↓↓

+ ↑↑↑

+ ↑↑↑

There is no neonatal form of Tay-Sachs disease Chronic/adult form is clinical related to an atypical Friedreich’s ataxia (spinoqcerebellar ataxia); juvenile form is clinical related to juvenile spinal muscular atrophy (Kugelberg-Welander syndrome) a Seizures develop in infancy with disease duration time b Enzyme activity is measured with synthetic substrates without need of GM2-activator

Table 60.4  GM2-gangliosidosis AB variant System CNS

Eye Genitourinary Laboratory findings

Symptoms and biomarkers Megalencephaly Mental deterioration Muscular hypotonia Psychiatric symptoms Spasticity Speech disturbances Startle response, exaggerated Cherry-red spot Vision, impaired Urinary incontinence Beta-hexosaminidase activity A Molecular analysis Oligosaccharides (U) Oligosaccharides (U)

Neonatal (birth–1 month)

Infancy (1–18 months) ++ +++ ++

n-↑

++ +++ +++ ++ ++ ++ n-↑

Childhood (1.5–11 years) + ++ ++ +++ ++ ++ + ++ ++ ++ n-↑

+ n-↑ ↑↑

+ n-↑ ↑↑↑

+ n-↑ ↑↑↑

Adolescence (11–16 years)

Adulthood (>16 years)

All forms of GM2-gangliosidosis AB variant are infantile; no chronic forms described There is no possibility to measure the functionality of GM2-activator, so in clinical suspicion of GM2-gangliosidosis with normal activity of β-hexosaminidases, Molecular analysis of GM2A should be done

Table 60.5 Galactosialidosis System Cardiovascular CNS

Dermatological Digestive Eye

Hematological

Symptoms and biomarkers Cardiomyopathy Valvular thickening Ataxia Intellectual disability Myoclonus Seizures Spasticity Angiokeratoma Telangiectasia Hepatosplenomegaly Cherry-red spot Corneal clouding Vision, impaired Foam cells Vacuolated lymphocytes

Neonatal (birth–1 month) +++ ±

Infancy (1–18 months) ± +++

+++

±

±

±

± +++ +++ + + ± +++ +++

± ± +++ + + ± +++ +++

Childhood (1.5–11 years) +

Adolescence Adulthood (11–16 years) (>16 years) + +

+ + ++ + + + ± ++ +++ + +++ +++ +++

++ + ++ + + ++ ±

++ + ++ + + ++ ±

++ + +++ +++ +++

++ + +++ +++ +++

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

1189

Table 60.5 (continued) System Musculoskeletal

Renal Other Laboratory findings

Symptoms and biomarkers Coarse facial features Dysostosis multiplex Edema Growth retardation Hernias Renal failure, proteinuria Fetal hydrops Alpha-neuraminidase activity Beta-galactosidase activity Cathepsin A—activitya Molecular analysis Sialic acid-rich oligosaccharides (U)b

Neonatal (birth–1 month) + ++ ++ + + +++ ++ ↓↓↓ ↓↓↓ ↓-n + ↑↑↑

Infancy (1–18 months) + +++

Childhood (1.5–11 years) + +++

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

+++

++

++

++

↓↓ ↓↓ ↓-n + ↑↑↑

↓ ↓ ↓-n + ↑↑

↓ ↓ ↓-n + ↑↑

++ ↓↓↓ ↓↓↓ ↓-n + ↑↑↑

Catalytic activity of PPCA is an indication for galactosialidosis but is not needed for diagnosis of galactosialidosis, because not all mutations that avoid the interaction of the multienzyme complex lead to poor or absent catalytic activity of PPCA b Atypical forms with absence of sialyloligosacchariduria are described (Darin et al. 2009) a

Table 60.6  Krabbe disease and Krabbe disease-like disorder due to saposin A deficiency System CNS

Digestive Ear Eye Other Laboratory findings

Symptoms and biomarkers Ataxia Irritability Leukodystrophy Nerve conductive velocity Neurological deterioration Neuropathy Seizures Spasticity Feeding difficulties Deafness Blindness Fever Lysogalactosylceramidea Protein (CSF)

Neonatal (birth–1 month)

↑

Infancy (1–18 months)

Childhood (1.5–11 years)

+++ +++ ↓↓↓ +++ +++ +++ +++ +++ ++ +++ +++ ↑ ↑↑↑

++ +++ ↓↓↓ +++ +++ +++ +++ +++ +++ +++ ↑ (↑)

Adolescence (11–16 years) ++

Adulthood (>16 years) ++

++ ↓

++ ↓-n

↑ (↑)

↑ (↑)

Lysoglucosylceramide (glucosylsphingosine) are measured as lysohexosylceramide

a

Table 60.7  Metachromatic leukodystrophy and Metachromatic leukodystrophy-like disorder due to saposin B deficiency System CNS

Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia Dysarthria Emotion ability Gait disturbance Irritability Leukodystrophy Nerve conductive velocity Neurological deterioration Neuropathy Psychosis Seizures Spasticity Muscle weakness Protein (CSF) Sulfatide (U)

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years) +++ +++ + +++ +++ ↓↓↓ +++ +++ − +++ +++ +++ ↑↑↑ ↑↑↑

++ +++ ↓↓↓ +++ +++ − +++ +++ +++ ↑↑↑ ↑↑↑

Adolescence (11–16 years) ++ ++ ++ ++

Adulthood (>16 years) ++ ++ +++ ++

++ ↓↓↓

++ ↓↓↓

+ ± ±

+++ ± ±

↑↑↑ ↑↑↑

n ↑↑↑ (continued)

1190

C. Hollak

Table 60.8  Gaucher disease System CNS Dermatological Digestive Eye Hematological

Musculoskeletal

Respiratory Other Laboratory findings

Symptoms and biomarkers Developmental delay Seizures Collodion skin, collodion baby Hepatosplenomegaly Liver cirrhosis Eye movements, abnormal Anemia Foam cells Pancytopenia Thrombocytopenia Bone pain Kyphosis Osteoporosis Pathological fractures Restrictive lung disease Early death Beta-d-glucosidase Chitotriosidase Glucosylsphingosinea

Neonatal Infancy (birth–1 month) (1–18 months) +++ +++ +++

Childhood (1.5–11 years) ++ ++

Adolescence (11–16 years) ± ±

Adulthood (>16 years)

++

+++

+++

+++

+++ ±

++

+++ + +++ + +

++ +++ +++ + +++ + ± ± ± ++ ± ↓↓ ↑↑↑ ↑↑↑

± ++ +++ + +++ +++ ++ ++ + +

+ +++ + ++ ++ ± + ++ ±

↓↓ ↑↑↑ ↑↑↑

↓↓ ↑↑ ↑↑

++ +++ ↓↓ ↑↑ ↑↑

+++ ↓↓↓ ↑↑ ↑↑

Lysogalactosylceramide and lysoglucosylceramide (glucosylsphingosine) are measured as lysohexosylceramide

a

Table 60.9  Gaucher disease-like disorder due to saposin C deficiency System CNS Digestive Eye Hematological

Musculoskeletal Special laboratory

Symptoms and biomarkers Developmental delay Seizures, myoclonic Hepatosplenomegaly Eye movements, abnormal Anemia Foam cells Thrombocytopenia Bone pain Pathological fractures Beta-δ-glucosidase Chitotriosidase Glucosylsphingosinea

Neonatal Infancy (birth–1 month) (1–18 months) ++ ++

++

n ↑↑ ↑↑

+++ + +++ +

n ↑↑ ↑↑

Childhood (1.5–11 years) ++ ++ ++ ++ ++ +++ ++ ± ± n ↑↑↑ ↑↑↑

Adolescence (11–16 years) ± ± +++ ± ++ +++ +++ + + n ↑↑↑ ↑↑↑

Lysogalactosylceramide and lysoglucosylceramide (glucosylsphingosine) are measured as lysohexosylceramide

a

Adulthood (>16 years)

+++ +++ +++ +++ ++ ++ n ↑↑↑ ↑↑

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

1191

Table 60.10  Action myoclonus-renal failure syndrome System CNS

Heart Renal Laboratory findings

Symptoms and biomarkers Dementia Polyneuropathy Seizures, myoclonic Dilated cardiomyopathy Renal failure Beta-δ-glucosidase

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + + + n in leukocytes, decreased in fibroblasts

Adolescence (11–16 years) ± ++ ++ ± ++ n in leukocytes, decreased in fibroblasts

Adulthood (>16 years) ++ +++ +++ ± +++ n in leukocytes, decreased in fibroblasts

Adolescence (11–16 years)

Adulthood (>16 years)

Table 60.11  Combined saposin deficiency System CNS

Digestive Hematological Laboratory findings

Symptoms and biomarkers Cerebral and cerebellar atrophy Developmental delay Hyperkinesia Hypotonia Myoclonus Seizures, myoclonic Hepatosplenomegaly Foam cells Ceramidase (fibroblasts) Chitotriosidase— Glucosylsphingosine Galactosylceramidase (fibroblasts) Glycosylceramidase (fibroblasts)

Neonatal (birth–1 month) + ++ ++ ± ++ + ++ ++ ↓↓ ↑↑

Infancy (1–18 months) +++ +++ +++ ++ +++ ++ +++ +++ ↓↓↓ ↑↑

↓↓

↓↓

↓↓

↓↓↓

Childhood (1.5–11 years)

Table 60.12  Fabry disease System Cardiovascular CNS

Dermatological Digestive Ear Eye Renal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Cerebral infarction/stroke-like encephalopathy Neuropathic pain Angiokeratoma Abdominal pain Hearing loss, sensorineural Cornea verticillata Proteinuria Renal failure, chronic Globotriaosylceramide Globotriaosylsphingosine

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood Adolescence (1.5–11 years) (11–16 years) ± ± ± +

(↑) ↑

↑ ↑

+ ±

++ ++ + ± + ±

↑ ↑↑

↑ ↑↑

Adulthood (>16 years) ++ ++ + ++ + + + ++ ++ ↑ ↑↑

1192

C. Hollak

Table 60.13  Farber disease System CNS

Dermatological Digestive Eye Hematological Musculoskeletal Respiratory Other Laboratory findings

Symptoms and biomarkers Deep tendon reflexes Developmental delay Hypotonia Intellectual diasability Seizures Subcutaneous nodules Hepatosplenomegaly Cherry-red spot Foam cells Lymphadenopathy Arthritis Hoarseness Lung infiltrates Failure to thrive Acid ceramidase activity (LC) C26-ceramide Protein (CSF)

Neonatal Infancy (birth–1 month) (1–18 months) ↓↓ ++ ± ++ ++ ++ +++ +++ ++ + + ± ± + +++ +++ +++ +++ ++ ++ ↓↓↓ ↓↓↓ ↑ ↑ n-↑

Childhood (1.5–11 years) ↓ ±

Adolescence (11–16 years)

Adulthood (>16 years)

↑

↑

± + +++ + ± +++ +++ + ↓↓↓ ↑ n-↑

Table 60.14  Niemann-Pick disease type A or B System CNS

Digestive

Ear Eye Hematological

Respiratory Other Laboratory findings

Symptoms and biomarkers Developmental delay Hypotonia Seizures Feeding difficulties Hepatosplenomegaly Jaundice Liver cirrhosis Deafness Cherry-red spot Vision loss Foam cells Lymphadenopathy Pancytopenia Thrombocytopenia Hypoxia Pulmonary interstitial changes Failure to thrive Lysosphingomyelin Sphingomyelinase

Neonatal (birth–1 month) +++ +++ ± +++ +++ ↑↑ +++ +++ +++ +++ +++

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+++

+++

+++

+++

+++

+++

+++

+++

±

±

±

±

+++

+++

+++

+++

+

+

+

+

+++ +++

+++ +++

+++ +++

+++ +++

↑ ↓↓

↑↑ ↓↓

↑↑ ↓↓

↑↑ ↓↓

+++

+++ ↑ ↓↓↓

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

1193

Table 60.15  Niemann-Pick disease type C1 and Niemann-Pick disease type C2 System CNS

Digestive Hematological Laboratory findings

Symptoms and biomarkers Action dystonia Ataxia Behavioral disorder Clumsiness Cognitive dysfunction Dysarthria Dystonia Gait disturbance Gelastic cataplexy Language difficulties Psychosis School problems (difficulties in writing, attention) Seizures Vertical gaze palsy Hepatosplenomegaly Jaundice, cholestatic Foam cells Blue histiocytes Chitotriosidase Filipin test Oxysteroles, LysoSM-509/LysoSM Chitotriosidase

Neonatal Infancy (birth–1 month) (1–18 months) +

Childhood (1.5–11 years) + +++

Adolescence (11–16 years) + +++ + +++

± +

+++ +++ + + +++ + +++

+++ +++ + + +++ + +++

+++

+++

± + +++

± + ±

± + ±

+ + ↑↑↑ ↓↓↓ ↑

+ + ↑↑↑ ↓↓↓ ↑↑

+ + ↑↑↑ ↓↓↓ ↑↑

+ + ↑↑↑ ↓↓↓ ↑↑

Childhood (1.5–11 years) +

Adolescence (11–16 years) ++

Adulthood (>16 years) +++

+

+

+

n-↑ n-↑ ↓ +

n-↑ n-↑ ↓ +

n-↑ n-↑ ↓ +

+ +

± ±

+ +

+++ +++ + + ↑↑↑ ↓↓↓ ↑

Adulthood (>16 years)

+

Table 60.16  Lysosomal acid lipase deficiency System Cardiovascular CNS Digestive

Endocrine Routine laboratory Special laboratory

Symptoms and biomarkers Atherosclerosis, severe Developmental delay Abdominal distension Failure to thrive Hepatosplenomegaly Steatorrhea Vomiting Adrenal calcification Cholesterol (S) Triglycerides (S) Acid lipase activity Molecular analysis

Neonatal (birth–1 month)

Infancy (1–18 months)

+ + ++ +++ + + + n-↑ n-↑ ↓↓↓ +

+ + ++ +++ + + + n-↑ n-↑ ↓↓↓ +

Reference Values Reference values for fluorometric enzyme assays given as ratio enzyme/beta-galactosidase activity (normal ranges depend on assays and detection devices) No. 60.1 60.2 60.3 60.6 60.8 60.12 60.14

Disorder GM1 gangliosidosis Sandhoff disease Tay-Sachs disease Krabbe disease Gaucher disease Fabry disease Niemann-Pick disease type A or B

Enzyme Beta-galactosidase Beta-hexosaminidase A + B Beta-hexosaminidase A Galactocerebrosidase Beta-d-glucosidase Alpha-galactosidasea Sphingomyelinase

Enzyme/beta-galactosidase (%) 54–146 284–1345 46–171 0.2–3.2 2,2–22 5,9–59 0.2–0.8

Material Leukocytes Leukocytes Leukocytes Leukocytes Leukocytes Leukocytes Leukocytes

In females activities can be decreased or normal; family, clinical, biochemical, and genetic and sometimes histological studies are needed for confirmation

a

1194

C. Hollak

Reference values for spectrophotometric enzyme assays given as ratio enzyme/beta-hexosaminidase activity (normal ranges depend on assays and detection devices) No. 60.1 60.2 60.7

Disorder GM1 gangliosidosis Sandhoff disease Metachromatic leukodystrophy

Enzyme Beta-galactosidase Beta-hexosaminidase A + B Arylsulfatase A

Enzyme/beta-hexosaminidase (%) 6.6–33 53–147 1.7–8.5

Material Leukocytes Leukocytes Leukocytes

Laboratory Investigations Specific laboratory investigations for the diagnostic work-up of sphingolipidoses No. 60.1

Disorder GM1 gangliosidosis

60.2 60.3 60.4 60.5

Sandhoff disease Tay-Sachs disease GM2 gangliosidosis AB variant Galactosialidosis

60.6 60.6

Krabbe disease Krabbe disease-like disorder due to saposin A deficiency Metachromatic leukodystrophy Metachromatic leukodystrophy-like disorder due to saposin B deficiency Gaucher disease

60.7 60.7 60.8 60.9

60.11 60.12 60.13 60.14 60.15

Gaucher disease-like disorder due to saposin C deficiency Action myoclonus-renal failure syndrome Combined saposin deficiency Fabry disease Farber disease Niemann-Pick disease types A or B Niemann-Pick disease type C1

60.15

Niemann-Pick disease type C2

60.16

Lysosomal acid lipase deficiency

60.10

Enzyme assay L, FB

Molecular analysis L, FB

Prenatal diagnosis A, CV

L, S, FB L, S, FB – FB

L, FB L, FB L, FB L, FB

A, CV A, CV A, CV A, CV, oligoa

L, FB L

L, FB L, FB

A, CV A, CV

Sulfatides (U) Sulfatides (U)

L, FB –

L, FB L, FB

A, CV A, CV

Glucosylsphingosineb, chitotriosidase (S) Chitotriosidase (S)

L, FB

L, FB

A, CV

–

L, FB

A, CV

–

L, FB

L, FB

A, CV

– Globotriaosylsphingosine (lysoGb3) C26-ceramide Lysosphingomyelin (lysoSM) Oxysteroles, LysoSM-509/LysoSM Chitotriosidase (S), vacuolated lymphos Oxysteroles, LysoSM-509/LysoSM Chitotriosidase (S), vacuolated lymphos High LDL cholesterol, low HDL cholesterol; vacuolated lymphos

L, FB L, S FB FB L, FB –

L, FB L, FB L, FB L, FB L, FB

A, CV A, CV A, CV A, CV A, CV

–

L, FB

A, CV

L

L, FB

A, CV

Metabolite analysis diagnostic feature LysoGM1 (S); GAGs (U); oligosaccharides (U) LysoGM2 (S); oligosaccharides (U) LysoGM2 (S); oligosaccharides (U) lysoGM2 (S); oligosaccharides (U) Oligosaccharides (U), vacuolated lymphos Lysogalactosylceramideb Low galactocerebrosidase activity in L

GAGs Glycosaminoglycans, L Leukocytes, S Serum/plasma, FB Fibroblasts, A Amniotic fluid cells, CV Chorionic villi, EM Electron microscopy, lymphos lymphocytes a Sialyloligosaccharides in amniotic fluid supernatant b Lysogalactosylceramide and lysoglucosylceramide (glucosylsphingosine) are measured as lysohexosylceramide

Diagnosis and Reference Values The diagnostic work-up of the sphingolipidoses should begin with the clinical assessment of the patients and should consider the general classification. The characteristic combination of symptoms determines the further diagnostic investigations as outlined in the diagnostic flowcharts (see Fig. 60.2). Depending on the disorder and signs as shown in

the tables, these may comprise full blood count and smear, fundoscopy, cardiac assessment (ECG/ECHO), skeletal status (X-ray), cranial MRI, and electrophysiology (VEP, SEP, ERG). Specific tests for sphingolipidoses, LAL deficiency, and NPC should be performed in specialized laboratories. Diagnostic procedures include specific enzyme assays of lysosomal hydrolases in plasma, leukocytes, or fibroblasts as well as quantitative

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

analysis of metabolites, mostly in plasma, serum, urine, or CSF. In case the disorder is not associated with an enzyme deficiency or in order to confirm the diagnosis, DNA mutational analysis in the affected gene should be performed. DNA testing is also important in cases where enzymatic diagnosis is already made for counseling purposes, which may include prediction of phenotypes. For further details on specific investigations, see Table ‘Specific laboratory investigations for the diagnostic work-up of sphingolipidoses’. For reference values see corresponding lysosomal Tables.

Diagnostic Flowchart Figure 60.2 shows a diagnostic follow-up of patients presenting with visceral symptoms, mainly hepatosplenomegaly, and with or without neurological presentation. In the case of a multisystem disease with one or more of the specific symptoms in

Fig. 60.2  Diagnostic follow-up based upon presenting symptoms

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the figure, a further work-up can be performed with screening panels followed by specific enzyme and molecular analysis.

Pathological Values Specific laboratory investigations for the diagnostic workup of sphingolipidoses are given below. Of note, dried blood spots (DBS) are increasingly used for screening purposes. However, enzyme assays based upon DBS alone are not always reliable and should be confirmed with other specific tests including enzyme analysis in plasma, leukocytes, or fibroblasts and molecular analysis. Studies have shown that many of the biomarkers can also be determined from blood spots. Again, confirmation by state-of-the-art enzymatic and genetic studies is always necessary to avoid misdiagnosis resulting in erroneous treatment and counseling decisions.

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A screening panel consisting of the lysosphingolipids lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM), and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) and oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol by UPLC-MS/MS and chitotriosidase activity can be used for a rapid screening to identify lipid storage disorders (Voorink-Moret et  al. 2018). Specific elevations, i.e., without overlap between controls and other lipid storage disorders, can be used: LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease, and LysoHexCer (i.e., lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. In Niemann-Pick diseases, oxysterols were elevated, but LysoSM-509/LysoSM ratio was specifically abnormal in Niemann-Pick disease type C.  In Gaucher disease type I, chitotriosidase was grossly elevated while only mildly elevated in all other lipid storage disorders. For GM1 and GM2, lysolipids have also been found to be elevated but only in infantile cases (Pettazzoni et al. n,d). In Farber disease the ceramide C26:0 and especially its isoform 1 are a highly sensitive and specific biomarker (Cozma et al. 2017).

Treatment and Follow-Up  M1/GM2 Gangliosidosis, Galactosialidosis, G and Sandhoff and Tay-Sachs Diseases In order to replace the deficient enzyme, allogeneic hematopoietic stem cell transplantation has been attempted in both GM1 and GM2 gangliosidoses with disappointing results: in a child with infantile GM1 gangliosidosis. However, despite complete normalization of white blood cell β-galactosidase levels, the patient continued to deteriorate neurologically (Shield et  al. 2005). Also for galactosialidosis it has been shown that bone marrow transplantation in mice can fully correct the systemic organ pathology but not the neurological phenotype (Zhou et al. 1995). In some patients with GM1 gangliosidosis, treatment with the iminosugar N-butyldeoxynojirimycin, miglustat, an inhibitor of glycolipid synthesis, is reported to have some beneficial effect, but without a control group, it is difficult to ascertain its value (Deodato et al. 2017). Based upon its ability to reduce the generation of complex glycolipids, miglustat was also tried in GM2 gangliosidosis. However, no clear effect of miglustat in Sandhoff disease has been observed, and a clinical trial of late-onset TaySachs patients failed.

C. Hollak

The most promising therapeutic intervention at this moment is gene therapy: adeno-associated viruses (AAV) seem to have the greatest potential to treat the nervous system because most serotypes preferentially transduce neurons after intraparenchymal injection. Currently intravenous gene transfer with an AAV9 vector is studied for GM1 gangliosidosis, and gene therapy trials for Tay-Sachs and Sandhoff disease are underway. Similar gene transfer therapies are currently being studied for galactosialidosis. For late-onset patients with relatively milder mutations, pharmacological chaperones, such as pyrimethamine for GM2 gangliosidosis, which enhance residual enzyme activity may be an option. So far no clinical successes have been established (Clarke et al. 2011).

Krabbe Disease Hematopoietic stem cell transplantation appeared to be successful in asymptomatic infantile patients or slowly progressive later-onset forms of disease. Demyelination and neurological deterioration were prevented or arrested, respectively (Krivit et al. 1998; Escolar et al. 2005). While initially bone marrow was used as a source, nowadays umbilical cord blood is applied for transplants. Since only presymptomatic transplantation may lead to remyelination of the central nervous system, Krabbe disease has been implemented for newborn screening in New  York. However, HSCT is not a cure, and ethical issues towards newborn screening have been raised recently because of the identification of uncertain phenotypes based upon GALC enzyme levels (Ehmann and Lantos 2019). Therapeutic approaches using virus-mediated gene transfer and a combination of gene transfer and stem cell transplantation were performed in a mouse model of Krabbe disease (Biffi et  al. 2012). Currently preclinical studies are performed to investigate gene transfer for Krabbe disease using AAV-based vectors. No treatment is available for saposin A deficiency. Supportive care requires a multidisciplinary approach, including measures to manage pain, spasticity, and seizures, prevent infections, and support nutrition. Disease management recommendations are provided by Escolar ­ et al. (Escolar et al. 2016).

 etachromatic Leukodystrophy/Saposin B M Deficiency Only supportive treatment is available for late-infantile MLD caused by ASA deficiency. Stem cell transplantation, even at an early stage of disease, has been mainly proven ineffective. For juvenile and adult forms of MLD caused by ASA defi-

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

ciency, hematopoietic stem cell transplantation is able to stabilize cerebral demyelination and arrests or slows disease progression, but without influence on the peripheral nervous system. ERT trials are taking place in animal models (Batzios and Zafeiriou 2012; Matthes et al. 2012; Biffi et al. 2008). Gene therapy trials using a lentiviral vector to transfer a functional ARSA into hematopoietic stem cells are currently conducted with promising preliminary results (Sessa et  al. 2016). Additional gene therapy trials using AAV-based vectors are under investigation. Enzyme replacement therapy through intrathecal administration of the recombinant ARSA is piloted in a phase ½ study that was completed in 2017. Further results are awaited. There is no treatment available for MLD due to saposin B deficiency (Landrieu et al. 1998). As for Krabbe disease, supportive care managing pain and spasms as well as nutrition is the cornerstone of treatment of these patients, especially when they are not eligible for transplantation. A specific concern is the risk for gallbladder polyps that may evolve to carcinoma, even in transplanted patients, requiring follow-up and surgical intervention in some cases (van Rappard et al. 2016a, b).

Gaucher Disease Before enzyme replacement therapy became available, the treatment of a Gaucher disease patient has been symptomatic (Beutler 1988). Splenectomy was performed usually in case of grossly enlarged spleens, leading to infarcts, abdominal discomfort, or severe cytopenia secondary to hypersplenism. After splenectomy, cytopenia is usually immediately resolved. However, the patient is at risk for further liver involvement, hepatopulmonary syndrome, and pulmonary hypertension. In addition, splenectomized patients more frequently develop bone crises and pathological fractures (Mikosch and Hughes 2010). Also, absence of the spleen puts them at a higher risk of septicemia from pneumococci and other encapsulated bacteria. Thus, splenectomy should be avoided whenever possible. Bone crises usually present as acute, circumscript, severe, persistent pain in a long bone, pelvis, or spine, often with signs of inflammation. No other treatment than supportive care with bed rest and nonsteroidal anti-inflammatory drugs or morphine is available. Orthopedic procedures such as joint replacement in case of avascular necrosis are sometimes necessary. Bleeding has been a major problem related to thrombocytopenia, thrombocytopathy, and decreased clotting factors (Hollak et al. 1997). Coagulation studies, including PT and aPTT, need to be performed around every surgical procedure or pregnancy. Supplementation with coagulation factors or plasma may be indicated. For patients with severe skeletal disease, especially those with fractures and osteoporosis, bisphosphonates have

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been used. While they lead to an increase in bone density, the clinical relevance of this treatment is unclear. Also, new evidence points towards decreased osteoblast activity rather than increased bone loss, and prolonged bisphosphonate therapy may further impair bone remodelling (Van Dussen et al. 2011). Hematopoietic Stem Cell Transplantation (HSCT)

Allogeneic bone marrow transplantation or HSCT has been used specifically in the past to treat neuronopathic Gaucher disease (Ringdén et al. 1995). The aim of this approach is to replace hematopoietic stem cells with healthy donor cells secreting normal enzyme. Since enzyme replacement therapy does not reach the central nervous system, HSCT may still be an option for patients with chronic neuronopathic disease. However, this procedure is rarely performed nowadays considering the high risk and the beneficial effects of ERT. Updated outcomes of patients transplanted in the past showed that HSCT had no potential to completely prevent the development of neurological damage since patients developed epilepsy over time (Machaczka 2013). Enzyme Replacement Therapy (ERT)

The prospects of patients with type 1 Gaucher disease have improved dramatically with the advent of ERT. Intravenous administration, usually once every 2 weeks, of recombinant β-GCase (Cerezyme, Genzyme Corp., MA) has proven to result in reversal of most disease manifestations (Barton et  al. 1991). In patients with advanced liver, lung, or bone disease, the effectiveness is more limited. But in those initiating therapy before irreversible damage has occurred, the responses are very good. Many dosing regimens have been explored, with higher doses generally leading to more robust responses (Grabowski et al. 2009). However, individualization of dosing has become standard practice, since doses between 15 and 60  U/kg eow may all produce sustained responses. It needs to be emphasized that many patients do not need to be treated as they have very mild, nonprogressive disease manifestations (Beutler et al. 1995). The precise criteria to start ERT in type 1 Gaucher disease are not unequivocal. Some believe that most patients need ERT, while others tend to be more conservative. In general, children with symptoms are always treated, while adults with stable disease and mild splenomegaly without severe platelet count (e.g., below 60  ×  109/L) and without severe bone marrow infiltration may remain untreated. Currently, the risk factors for late complications, such as multiple myeloma, osteoporosis, or liver/lung disease, are unknown. Whether early initiation of ERT can prevent this is unclear and needs to be investigated. Patients with the acute neuronopathic form of Gaucher disease do not benefit from ERT, and it is now generally accepted that these should not be treated (Vellodi et al. 2009). In a very young patient with neurological symptoms,

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it may be difficult to decide whether this represents an acute or a chronic form. In such a case, it may be an option to discuss temporary treatment with the option to stop when the course of disease is rapidly progressive (Vellodi et al. 2009). In patients with the chronic neuronopathic form, ERT may certainly alleviate the symptoms related to hepatosplenomegaly and partially also skeletal disease. However, there is no evidence that ERT has reversed, stabilized, or slowed the progression of neurological involvement. Detailed recommendations for treatment are provided in the consensus paper by Vellodi et al. (2009). In type 3c, ERT is usually not indicated, as these patients do not have extensive visceral disease. Over the last years, new ERTs have been developed. Currently, velaglucerase (VPRIV, Shire HGT) has also received marketing authorization in the EU and the USA, whereas taliglucerase (Uplyso, Protalix/Pfizer) has been approved by the FDA only (Zimran et al. 2010, 2011). All these enzymes have shown effectiveness, and choices for treatment will probably depend on whether there are any potential differences in effectiveness or safety, as well as reimbursement strategies and costs. Substrate Reduction Therapy (SRT) and Gene Therapy

An alternative approach is based on small molecules that inhibit substrate synthesis. The authorized treatment is miglustat (N-butyl deoxynojirimycin, Zavesca, Actelion/Janssen). As mentioned before, this compound is an iminosugar, which inhibits the glucosyltransferase involved in the first step in the formation of complex glycosphingolipids. The rationale is that the reduction in substrate is balanced against the residual β-GCase activity, which ultimately results in degradation of stored glycolipids. Indeed, miglustat results in reductions in liver and spleen size and gradual improvements in hemoglobin and platelet counts (Cox et al. 2000). The limitations of miglustat are the inferior effects in relation to ERT and unpleasant, mainly gastrointestinal, side effects. With the authorization of a second-generation substrate inhibitor, eliglustat (Lukina et al. 2010), with a more favorable safety and efficacy profile, miglustat is rarely used for type 1 Gaucher disease. While miglustat failed in type 3 Gaucher disease (Schiffmann et  al. 2008), newer SRTs such as venglustat (Sanofi/Genzyme) are currently under development that have the ability to cross the bloodbrain barrier and can be used in neuropathic Gaucher disease. Preclinical data on gene therapy for type 1 Gaucher disease with lentiviral or liver-directed AAV-based vectors have been promising, and clinical trial programs are about to start. Follow-Up and Monitoring of Gaucher Disease

Follow-up should in principle be individualized, as the heterogeneity of the disease and a number of associated conditions precludes strict protocolized follow-up. However, recommendations for follow-up of patients with Gaucher

C. Hollak

disease have been previously published (Charrow et al. 2004; Baldellou et al. 2004; Grabowski 2004; Zimran 2011). For neuronopathic disease, a helpful scheme for follow-up of neurological symptoms has been published (Vellodi et  al. 2009). Some of the recommendations for follow-up in non-­ neuronopathic Gaucher disease refer to earlier-defined therapeutic goals (Pastores et al. 2004). It should be kept in mind that these goals are in fact mean responses in blood counts, liver and spleen volumes, and skeletal parameters, rather than clinically meaningful endpoints. Dose adjustment should be made on an individual basis rather than on achievement of these goals. For example, in patients with very large spleens, platelet responses will initially be very slow, and in the absence of clinically relevant bleeding episodes, there is no justification for a dose increase (Hollak et al. 2012a, b). In general, bleeding, severe anemia, and symptomatic organomegaly are alleviated within 12–24 months. Of importance is that good clinical responses are always accompanied by substantial decreases in chitotriosidase (Aerts et al. 2005) or in deficient patients, in CCL18/PARC, ACE, or ferritin levels. Absence of a response in these parameters indicates failure of treatment. Table ‘Follow-up and monitoring of non-neuronopathic (type 1) Gaucher disease’ shows the minimal recommended follow-up procedures. Because of the increased risk for multiple myeloma, pulmonary hypertension, Parkinson’s disease, and perhaps other conditions such as diabetes, it may be wise to include relevant physical, laboratory, or imaging parameters in the follow-up (Zimran 2011). Skeletal imaging should preferably be performed with MRI, as this allows the assessment of the degree of bone marrow involvement. Serial follow-up with skeletal X-rays is unnecessary and exposes patients at high levels of radiation (Poll et al. 2002). DEXA scanning has difficulties in interpreting results in pediatric patients and in adults with sclerotic lesions may also give false outcomes. However, in those with milder disease, regular follow-up to detect early osteopenia or osteoporosis is of importance (Hughes et al. 2019).

Fabry Disease Multidisciplinary care for a Fabry disease patient is usually required because of the complexity of the manifestations (Desnick et al. 2003). Since the natural disease course differs between man and women and classically and non-classically affected patients (Arends et al. 2017), management needs to be tailored to the patients’ needs. Adequate pain management and early treatment with ACE inhibitors or angiotensin receptor blockers may be needed in case of proteinuria or cardiac symptoms (Jain and Warnock 2011). The use of aspirin is mostly recommended, certainly after TIA or stroke, but whether use of antiplatelet therapy prevents new white mat-

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

ter lesions is unknown. Cardiovascular risk factors independent of Fabry disease are likely to influence the disease course and deserve adequate identification and strict treatment, including hypertension, diabetes, and hypercholesterolemia. Those with rhythm disturbances, frequently bradycardia and AV blocks with ventricular escape tachycardias, may experience syncope. Those patients carry a risk for acute cardiac death and need cardiological monitoring (Pierre-Louis et al. 2009). Patients with end-stage renal failure may benefit greatly from kidney transplantation. The graft survival is not different compared with other patients with renal failure (Ojo et al. 2000). Enzyme Replacement Therapy

In 2001, two recombinant enzymes were approved for use in Fabry disease: agalsidase alpha (Replagal®) and agalsidase beta (Fabrazyme®), referred to as enzyme replacement therapy (ERT). While these enzymes are produced in different cell systems, their biochemical properties are very similar. They have been investigated in different doses: agalsidase beta at 1.0  mg/kg eow and agalsidase alpha at 0.2  mg/kg eow. The first placebo-controlled trials showed some beneficial effect on reduction of storage in endothelial cells and improvement in pain, with stable parameters of renal and cardiac disease (Eng et  al. 2001; Schiffmann et  al. 2001; Hughes et al. 2008). In a phase IV placebo-controlled trial, treatment with agalsidase beta resulted in a reduction of Fabry-related complications in patients with advanced disease at baseline (Banikazemi et al. 2007). However, complications can still occur during treatment, specifically in patients with advanced disease (Schiffmann et  al. 2006; Germain et  al. 2007; Weidemann et  al. 2009). The occurrence of antibodies may also influence the clinical outcome, as has been recently shown (Lenders et  al. 2018; van der Veen et al. 2019). Antibodies almost exclusively emerge in male patients, in particular those without any residual enzyme activity. Their presence is frequently associated with infusion-associated reactions such as chills and fever. This can usually be managed by premedication with corticosteroids and/or slowing down of the infusion rate. Benefits of ERT have also been reported in children, but whether early treatment can prevent the occurrence of late complications is still unknown. There is increasing consensus that not all patients will benefit, and therefore start and stop criteria have been developed and should be regularly evaluated (Biegstraaten et al. 2015). More recently migalastat and oral chaperone treatment has been authorized for treatment of Fabry disease patients with amenable mutations (Germain et al. 2016). Only a subset of patients, mainly non-classical, have amenable mutations. For which patients this oral alternative is an effective option needs further study, including the reliability of the

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amenability assay, as some switch patients may show biochemical evidence of disease progression (Lenders et  al. 2019). Many questions are thus still unanswered regarding the appropriate use of Fabry treatments. A major concern in this respect is that screening initiatives (neonatal or screening in high-risk groups) may reveal many individuals with variants of unknown significance that may be misdiagnosed as Fabry cases. A diagnosis should be carefully considered before costly and burdensome treatments are recommended.  lternative or Investigational Treatments for Fabry A Disease

New enzyme replacement therapies are being developed that hopefully will have less immunological side effects and a better biodistribution. Of these, pegunigalsidase, a pegylated dimer of aGal-A, is a promising agent as shown in a phase 1/2 study (Schiffmann et al. 2019.) A moss-derived enzyme with a different glycosylation and therefore biodistribution, perhaps better targeting kidney cells, is also investigated in Fabry disease patients (Hennermann et al. 2019). Other small molecules, specifically substrate inhibitors (see Gaucher disease), are under investigation. Currently lucerastat (N-butyl deoxygalactonojirimycin, Idorsia) is investigated in Fabry disease and has shown to be safe (Guérard et  al. 2018). Its effectiveness is now studied in a phase 3 trial. In addition, a new oral substrate inhibitor is developed by Sanofi/Genzyme, venglustat, for treatment of Fabry disease but also for neuropathic Gaucher disease and Parkinson’s disease. Gene therapy has been successfully used in animal models of Fabry disease. As for Gaucher disease, lentiviral or liver-directed AAV-based vectors are currently explored in clinical trials of adult Fabry disease patients. All these developments hold great promise for the future, but results of safety and efficacy studies have to be awaited. Follow-Up and Monitoring of Fabry Disease

As discussed before, Fabry disease is extremely variable. Hence an individualized approach is the cornerstone of management and follow-up. ERT is usually initiated in symptomatic patients, but those who are asymptomatic should receive follow-up as well. Early recognition of organ failure and adequate and timely initiation of appropriate therapy are important. ERT is probably of limited effectiveness in advanced cases, and benefits should be outweighed against the burden of frequent intravenous administration and costs (Biegstraaten et  al. 2015). In advanced cases, follow-up schedules need to be extended based on the most severe end-­ organ damage, following general practice guidelines for patients with renal or cardiac failure. A proposal for follow­up measures is shown in Table ‘Follow-up and monitoring of Fabry disease’.

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Farber Disease There is no effective treatment for Farber disease at this moment. Hematopoietic stem cell transplantation (HSCT) has been explored in Farber disease showing some improvement in peripheral manifestations but without effect on the central nervous system (Ehlert et al. 2018). Enzyme replacement therapy with recombinant human ACDase (rhACDase) is not yet in clinical phase of development, but is currently being investigated as potential treatment. Finally, gene therapy strategies hold promise for the treatment of ACDase deficiency. Gene therapy was performed in mouse models showing long-term expression of ACDase for up to 13 weeks (Ramsubir et al. 2008). An ex vivo strategy with transduction of hematopoietic stem cells seems an attractive approach as well. No clinical trials have so far started in Farber disease.

Niemann-Pick Type a or B For patients with Niemann-Pick A and B, supportive therapy to treat the pulmonary manifestations or liver disease is still the mainstay of treatment. Splenectomy is rarely done as it aggravates the liver and lung disease, but may be required in case of extensive enlargement and infarcts or rupture. Standard lipid-lowering agents are indicated for the treatment of ASMD-associated lipid abnormalities in adult patients. Bronchoalveolar lavage has been tried in some cases of extreme pulmonary involvement to relieve symptoms, but its effect is unclear. Hematopoietic stem cell transplantation (HSCT) has not been very successful, with several patients succumbing due to peritransplant complications (Schuchman and Wasserstein et al. 2015). Enzyme replacement therapy (ERT) with recombinant human ASM (Sanofi/Genzyme) is currently explored in a phase 3 clinical study. In a 26-week phase 1 study, decreases in spleen and liver volumes and sphingomyelin accumulation in liver biopsies have been observed (Wasserstein et al. 2015).

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infantile-onset NPC presenting with jaundice and hepatosplenomegaly, liver transplantation can be a temporary lifesaving measure, but the outcome is poor due to neurological deterioration, despite miglustat therapy (Yamada et al. 2019). Substrate reduction therapy with miglustat is the only authorized treatment for NPC so far. A randomized controlled trial of 12-month duration reported improvements or stabilization of saccadic eye movements, and in later cohort studies, neurological symptoms including swallowing have been reported to improve or stabilize (Pineda et al. 2018). In a retrospective study in France, patients with less severe neurological disability had a better outcome while using miglustat. Since the disease course is very variable, and with the lack of an untreated comparator, it remains unclear whether this is due to a milder disease course or a neuroprotective effect of miglustat (Nadjar et  al. 2018). Current consensus states that only patients with milder phenotypes and early neurological disease should receive treatment (Geberhiwot et al. 2018). New treatments are arimoclomol, a small-molecule co-­ inducer of heatshock proteins, which is currently in phase 2/3 trial, and cyclodextrins. The latter compounds are small oligosaccharide rings that can capture cholesterol, a specific mixture of which was piloted in a phase 1/2a clinical trial with intrathecal administration followed by a phase 2/3 clinical trial. In addition, phase 1 clinical studies utilizing high-­ dose intravenous administration of different cyclodextrins are currently executed. N-Acetyl-L-leucine, which is an amino acid used traditionally for vertigo as well as several causes of ataxia, is also evaluated in NPC. The INPDR has proposed a schedule for follow-up on a regular basis including neurocognitive, ophthalmological, audiological, and swallowing assessments (Geberhiwot et al. 2018).

Lysosomal Acid Lipase Deficiency

HMG-CoA reductase inhibitors are given in cholesteryl ester storage disease to prevent early complications of atherosclerosis. HSCT and liver transplantation have been employed Niemann-Pick Disease Type C with successes in some patients but also with disease recurrence and complications in others (Bernstein et al. 2018). Treatment of NPC should involve symptom management, Currently, ERT with recombinant human acid lipase employing disease-modifying agent(s) when available. (Alexion) is authorized to treat patients of all ages, including Several supportive therapies for neurological symptoms are infants with Wolman disease, where it has shown to improve listed in an extensive review from the International Niemann-­ survival and growth (Jones et al. 2017). In attenuated phenoPick Disease Registry (INPDR) (Geberhiwot et  al. 2018). types with significant and progressive disease, ERT can Bone marrow transplantation in a child with NPC did not improve cholesterol profiles and liver enzymes and volume improve neurological deterioration (Hsu et al. 1999), whereas and hopefully prevent liver failure. Older patients with very trials with hematopoietic stem cell transplantation are in mild phenotypes and minimal symptoms may remain stable progress in an animal model of NPC (Seo et  al. 2011). In and probably do not require treatment (Burton et al. 2015).

60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C

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Follow-up and Monitoring Follow-up and monitoring of non-neuronopathic (type 1) Gaucher disease Assessment Schedule

Physical examination Laboratory

Imaging

QoL scores

Untreated Treated Every Every 3 months during the first Every 12 months during the first 12–24 months year, every 6 months thereafter 2–4 years, on an individual basis thereafter X X X Ab testingb X ACE X X CBC X X X X X Chitotriosidase or CCL18/PARCa X Ferritin X X Glucosylsphingosine X X X Liver enzymes X X M-protein X X X X DEXA scand Liver and spleen volume (MRI, US) Skeletal MRI X X Skeletal X-raysc X X X X

CCL18/PARC is recommended in case of chitotriosidase deficiency Testing for antibodies should be done at baseline and after 12 months. If negative, this should only be repeated in case of infusion-associated reactions or lack of response c Skeletal X-rays are recommended to be made only once, to serve as baseline; follow-up X-rays should only be made upon clinical indication (Maas et al. 2002) d DEXA scans should be performed at baseline and on an individual basis thereafter a

b

Follow-up and monitoring of Fabry disease Assessment

Physical examination Laboratory

Imaging

Others

General Neurologicala 24 h urinary protein Ab testing Cholesterol profileb Creatinine/eGFR Electrolytes Gb3/lysoGb3 Brain MRId Cardiac MRI or USd Audiogram EKG Ocular examination Qol scores

At first visit Untreated Treated Every 12–24 months Every 3 months during the first year, every 6 months thereafter X X X X X X

Every 12 months during the first 2–4 years, on an individual basis thereafter X Xc

X X X

X

X X X

X X X X X X

X X X X X

X X X

X

X

At first visit, the presence of angiokeratoma and small fiber neuropathy should be investigated b Cholesterol profile and other cardiovascular risk factors should be recorded carefully at first visit and followed on an individual basis c Testing for antibodies should be done at baseline and after 12 months. If negative, this should only be repeated in case of infusion-associated reactions or lack of response d MRI or US of the heart and MRI of the brain in adults only or upon clinical indication in children a

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60  Lipidoses: The Sphingolipidoses, Lysosomal Acid Lipase Deficiency, and Niemann-Pick Type C Schiffmann R, Kopp JB, Austin HA III, et  al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285(21):2743–9. Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrol Dial Transplant. 2006;21(2):345–54. Schiffmann R, Fitzgibbon EJ, Harris C, et  al. Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol. 2008;64(5):514–22. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, Packman S, Sorensen SA, Wilcox WR, Desnick RJ. Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant. 2009;24:2102–11. Schiffmann R. Fabry disease. Handb Clin Neurol. 2015;132:231–48. Schiffmann R, Goker-Alpan O, Holida M, Giraldo P, Barisoni L, Colvin RB, Jennette CJ, Maegawa G, Boyadjiev SA, Gonzalez D, Nicholls K, Tuffaha A, Atta MG, Rup B, Charney MR, Paz A, Szlaifer M, Alon S, Brill-Almon E, Chertkoff R, Hughes D.  Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: a 1-year phase 1/2 clinical trial. J Inherit Metab Dis. 2019;42(3):534–44. Schuchman EH.  The pathogenesis and treatment of acid sphingomyelinase-­deficient Niemann-pick disease. J Inherit Metab Dis. 2007;30(5):654–63. Schulze H, Kolter T, et al. Principles of lysosomal membrane degradation: cellular topology and biochemistry of lysosomal lipid degradation. Biochim Biophys Acta. 2009;1793(4):674–83. Scriver CR. The metabolic and molecular bases of inherited diseases. New York/London: McGraw-Hill; 2002. Seo Y, Yang SR, et al. Human umbilical cord blood-derived mesenchymal stem cells protect against neuronal cell death and ameliorate motor deficits in Niemann pick type C1 mice. Cell Transplant. 2011;20(7):1033–47. Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A, Fiori R, Silvani P, Rancoita PM, Gabaldo M, Benedicenti F, Antonioli G, Assanelli A, Cicalese MP, Del Carro U, Sora MG, Martino S, Quattrini A, Montini E, Di Serio C, Ciceri F, Roncarolo MG, Aiuti A, Naldini L, Biffi A. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-­ label, phase 1/2 trial. Lancet. 2016;388(10043):476–87. Shield JP, Stone J, et  al. Bone marrow transplantation correcting beta-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis. J Inherit Metab Dis. 2005;28(5):797–8. Smid BE, van der Tol L, et al. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. Int J Cardiol. 2014;177(2):400–8. Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79(1):31–40. Spiegel R, Bach G, et  al. A mutation in the saposin a coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin a deficiency in humans. Mol Genet Metab. 2005;84(2):160–6. Tiede S, Storch S, et  al. Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nat Med. 2005;11(10):1109–12. Tylki-Szymanska A, Czartoryska B, Vanier M-T, Poorthuis BJMH, Groener JAE, Lugowska A, Millat G, Vaccaro AM, Jurkiewicz E. Non-neuronopathic Gaucher disease due to saposin C deficiency. Clin Genet. 2007;72:538–42.

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Tylki-Szymańska A, Groener JE, Kamiński ML, Ługowska A, Jurkiewicz E, Czartoryska B.  Gaucher disease due to saposin C deficiency, previously described as non-neuronopathic form--no positive effects after 2-years of miglustat therapy. Mol Genet Metab. 2011;104(4):627–30. Van Dussen L, Lips P, Everts VE, Bravenboer N, Jansen ID, Groener JE, Maas M, Blokland JA, Aerts JM, Hollak CE. Markers of bone turnover in Gaucher disease: modeling the evolution of bone disease. J Clin Endocrinol Metab. 2011;96(7):2194–205. Vanier MT.  Niemann-pick diseases. Handb Clin Neurol. 2013;113:1717–21. van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE.  A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet. 2014;51(1):1–9. van der Veen SJ, van Kuilenburg ABP, Hollak CEM, Kaijen PHP, Voorberg J, Langeveld M.  Antibodies against recombinant alpha-­ galactosidase A in Fabry disease: subclass analysis and impact on response to treatment. Mol Genet Metab. 2019;126(2):162–8. Vellodi A, Tylki-Szymanska A, Davies EH, Kolodny E, Bembi B, Collin-Histed T, Mengel E, Erikson A, Schiffmann R, European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis. 2009;32(5):660–4. Vielhaber G, Hurwitz R, et al. Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP) precursor in cultured human fibroblasts. Mannose 6-phosphate receptor-independent endocytosis of SAP precursor. J Biol Chem. 1996;271(50):32,438–46. Voorink-Moret M, Goorden SMI, van Kuilenburg ABP, Wijburg FA, der Vlugt JMM G-v, Beers-Stet FS, Zoetekouw A, Kulik W, Hollak CEM, Vaz FM.  Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature. Mol Genet Metab. 2018;123(2):76–84. Wanner C, Oliveira JP, Ortiz A, Mauer M, Germain DP, Linthorst GE, Serra AL, Marodi L, Mignani R, Cianciaruso B, Vujkovac B, Lemay R, Beitner-Johnson D, Waldek S, Warnock DG. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry registry. Clin J Am Soc Nephrol. 2010;5(12):2220–8. Wasserstein MP, Jones SA, Soran H, Diaz GA, Lippa N, Thurberg BL, et  al. Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol Genet Metab. 2015;116:88–97. Weidemann F, Niemann M, Breunig F, et  al. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 2009;119(4):524–9. Wenger DA, Tarby TJ, et  al. Macular cherry-red spots and myoclonus with dementia: coexistent neuraminidase and betagalactosidase deficiencies. Biochem Biophys Res Commun. 1978;82(2):589–95. Wenger DA, Rafi MA, et al. Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70(1):1–9. Wheeler S, Schmid R, Sillence DJ.  Lipid–protein interactions in Niemann–pick type C disease: insights from molecular modeling. Int J Mol Sci. 2019;20:717. Yamada N, Inui A, Sanada Y, Ihara Y, Urahashi T, Fukuda A, Sakamoto S, Kasahara M, Yoshizawa A, Okamoto S, Okajima H, Fujisawa T, Mizuta K.  Pediatric liver transplantation for neonatal-onset Niemann-Pick disease type C: Japanese multicenter experience. Pediatr Transplant. 2019;23(5):e13462. Zhou XY, Morreau H, et al. Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with overexpressing erythroid precursor cells. Genes Dev. 1995;9(21):2623–34. Zimran A.  How I, treat Gaucher disease. Rev Blood. 2011;118(6):1463–71.

1206 Zimran A, Elstein D. Lipid storage diseases. In: Lichtman MA, Kipps T, Seligsohn U, Kaushansky K, Prchal JT, editors. Williams hematology. 8th ed. New York: McGraw-Hill; 2010. p. 1065–71. Zimran A, Altarescu G, Philips M, et al. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010;115(23): 4651–6.

C. Hollak Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Muñoz ET, Solorio-Meza SE, Amato D, Duran G, Giona F, Heitner R, Rosenbaum H, Giraldo P, Mehta A, Park G, Phillips M, Elstein D, Altarescu G, Szleifer M, Hashmueli S, Aviezer D. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood. 2011;118(22):5767–73.

The Neuronal Ceroid Lipofuscinoses

61

Maurizio Scarpa, Cinzia Maria Bellettato, and Annalisa Sechi

Contents Introduction

 1208

Nomenclature

 1209

NCL Phenotypes Classified by Age at Onset

 1211

Tripeptidyl-Peptidase 1 Deficiency (NCL2)

 1211

Neuronal Ceroid Lipofuscinosis Type 3

 1212

Neuronal Ceroid Lipofuscinosis Type 4 (Parry Type) (CLN4B)

 1214

Neuronal Ceroid Lipofuscinosis Type 5

 1214

Neuronal Ceroid Lipofuscinosis Type 6

 1216

Neuronal Ceroid Lipofuscinosis Type 7

 1216

Neuronal Ceroid Lipofuscinosis Type 8

 1216

Cathepsin D Deficiency (NCL Type 10)

 1220

Progranulin Deficiency (NCL Type 11 Recessive)

 1220

ATP13A2 Deficiency (NCL Type 12)

 1222

Cathepsin F Deficiency (NCL Type 13)

 1223

Neuronal Ceroid Lipofuscinosis Type 14

 1224

Ceroid Lipofuscinosis, Neuronal, 1

 1224

Current Treatment Strategies

 1227

Emerging Causal Treatment

 1231

Moving Towards Effective Therapeutic Strategies

 1232

References

 1232

M. Scarpa (*) · C. M. Bellettato Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy e-mail: [email protected] A. Sechi Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy © Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_61

1207

1208

Introduction Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of inherited neurodegenerative diseases characterized by the lysosomal accumulation of autofluorescent material, revealed upon electron microscopy of neurons and many other cell types. The autofluorescent storage material is most commonly represented by subunit c of mitochondrial ATP synthase and sphingolipid activator proteins A and C. Nearly all of the NCL diseases can be subdivided in different clinical forms by age of onset and severity due to residual activity of the corresponding enzyme. The overall incidence of the NCL is estimated to be 1:20.000. The disorders primarily affect the cerebral gray matter. Signs and symptoms vary widely between the forms, but generally the major clinical symptoms include psychomotor regression, movement disorder, myoclonic epilepsy, progressive loss of vision, behavioral disturbance, and cognitive decline leading to dementia. The early-onset forms of NCL are characterized by severe brain atrophy, decerebration, and premature death. Five

M. Scarpa et al.

clinical groups—congenital, infantile, late infantile, juvenile, and adult—refer to the age of disease onset and are caused by mutations in at least 13 different genes (see Table  61.1). Three enzymes have been recognized as responsible, when deficient, of NCL cases: palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl-­peptidase 1 (TPP1), and cathepsin D (CTSD). CLN9 is not genetically defined yet. SGSH gene mutations usually cause mucopolysaccharidosis type IIIA.  SGSH mutations that are associated with high residual sulfamidase activity may also cause adult onset of NCL. Most NCL diseases are inherited in an autosomal recessive manner. As by current knowledge, only the CLN4B follows an autosomal dominant inheritance. There is a rough genotype-phenotype correlation in the sense that several missense mutations with minor residual enzymatic activity in the palmitoyl protein thioesterase 1 (CLN1), the tripeptidyl peptidase 1 (CLN2), and cathepsin D (CLN10) are correlated with protracted clinical courses (Das et  al. 2001; Steinfeld et al. 2004, 2006).

Ceroid lipofuscinosis, neuronal, 2 Ceroid lipofuscinosis, neuronal, 3

61.2

Ceroid lipofuscinosis, neuronal, 8 Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant

61.9

61.10

61.8

61.7

61.6

61.5

Ceroid lipofuscinosis, neuronal, 4A Ceroid lipofuscinosis, neuronal, 4B Ceroid lipofuscinosis, neuronal, 5 Ceroid lipofuscinosis, neuronal, 6 Ceroid lipofuscinosis, neuronal, 7

61.4

61.3

Disorder Ceroid lipofuscinosis, neuronal, 1

No. 61.1

Nomenclature

CLN5

CLN6

Lysosomal CLN5 protein deficiency

CLN6 late infantile variant MFSD8

CLN8

CLN8

CLN7 Turkish variant CLN7

CLN8

CLN8

CLN8 disease, late infantile variant

CLN8 disease, progressive epilepsy with mental retardation

CLN6

CLN5

DNAJC5

CLN4B

Kufs disease dominant type A

CLN3

CLN6

CLN3

Batten-SpielmeyerVogt disease

TPP1

Kufs disease recessive CLN4A type A

CLN2

Gene Abbreviation symbol CLN1 PPT1

Jansky-Bielschowsky disease

Alternative names Santavuori-Haltia disease

8p23.3

8p23.3

4q28.2

15q23

13q22.3

20q13.33

15q23

16p11.2

11p15.4

CLN8

Major facilitator superfamily domaincontaining protein-8 (MFSD8) CLN8

CLN6

DNAJC5 Cysteine string protein alpha Lysosomal CLN5 protein

CLN6

Lysosomal tripeptidylpeptidase-1 Lysosomal transmembrane CLN3 protein

Chromosomal localization Affected protein 1p34.2 Lysosomal palmitoyl protein thioesterase-1 OMIN Subtypes 256730 All forms

CLN8 (ER-Golgi transmembrane protein) CLN8 (ER-Golgi transmembrane protein)

CLN6 (ER transmembrane protein) MFSD8 (lysosomal transporter)

CLN3 (Golgi lysosome transmembrane protein) CLN6 (ER transmembrane protein) Soluble cysteine string protein alpha (synaptic vesicle protein) CLN5 (soluble lysosomal protein)

Late infantile Late infantile

Late infantile

601780 All forms

610951 All forms

600143

610003 All forms

Late infantile

Adult

Juvenile

(continued)

Juvenile (EPMR)

Juvenile

Adult

Juvenile, adult

Typical NCL Atypical disease NCL disease Infantile Late infantile, juvenile, adult Late Juvenile infantile

256731 All forms

162350 Adult form

204300

204200 All forms

Tripeptidyl peptidase 1 204500 All forms (lysosomal enzyme)

Protein (type) Palmitoyl protein thioesterase 1 (lysosomal enzyme)

61  The Neuronal Ceroid Lipofuscinoses 1209

Ceroid lipofuscinosis, neuronal, 11 Ceroid lipofuscinosis, neuronal, 12 Ceroid lipofuscinosis, neuronal, 13 Ceroid lipofuscinosis, neuronal, 14

61.12

61.15

61.14

61.13

Disorder Ceroid lipofuscinosis, neuronal, 10

No. 61.11

CLN14/ EPM3

KCTD7

CTSF

Progressive myoclonic epilepsy type 3

Cathepsin F

ATP13A2 1p36.13

CLN12/ Kufor-Rakeb PARK9 syndrome, Parkinson’s disease 9 Kufs disease recessive CLN13 type B 7q11.22

11q13

Lysosomal type 5 P-type ATPase

17q21.31

GRN

Progranulin deficiency CLN11

Potassium channel tetramerization domaincontaining protein 7

Progranulin

Chromosomal localization Affected protein 11p15.5 Cathepsin D

Gene Alternative names Abbreviation symbol CTSD Ceroid lipofuscinosis, CLN10 neuronal, cathepsin D-deficient

Cathepsin F (lysosomal enzyme)

ATP13A2 (P-type ATPase, lysosomal cation transporter) KCTD7 (potassium channel) 611726 Juvenile form

615362 Adult form

606693 All forms

Infantile

Adult

Juvenile

Adult

Typical NCL OMIN Subtypes disease 610127 Late infantile Congenital form

Progranulin (autocrine 614706 Juvenile growth factor) form

Protein (type) Cathepsin D (lysosomal enzyme)

Atypical NCL disease Late infantile, juvenile, adult

1210 M. Scarpa et al.

61  The Neuronal Ceroid Lipofuscinoses

1211

NCL Phenotypes Classified by Age at Onset The congenital NCL (CLN10) begins in utero and is associated with intrauterine growth retardation and fetal microcephaly. At birth, affected infants show intractable seizures, spasticity, and central apnea. These newborns usually survive only days, seldom weeks. The infantile NCL is a rapidly progressive form and presents between 6 and 18 months with hyperexcitability, muscular hypotonia, psychomotor retardation, myoclonic seizures, visual failure, and microcephaly. Later, by the age of 3 years, loss of motor abilities, increasing spasticity, and lack of environmental contact comprise the clinical picture. The classical late infantile NCL is characterized by normal development to the age of 2 years, followed by developmental delay, motor regression, myoclonic seizures, and visual failure. After the onset of symptoms, the disease progresses in a program-like manner over 2–3 years leading to chair boundness, spasticity, blindness, and dementia (Steinfeld et al. 2002). The juvenile NCL is characterized by progressive visual failure beginning at the age of 4–9 years, followed by developmental delay, motor regression, myoclonic seizures, and visual failure. Cognitive decline and motor deterioration follow and finally lead to death in the third or fourth decades. Seizures are a variable feature. Atypical juvenile forms (CLN2 and CLN5) initially present with motor symptoms and behavioral problems before they develop visual disturbance. The variant forms of late infantile NCL have clinical presentations intermediate between the classical late infantile and juvenile forms. The adult NCL is distinguished from the other NCL types by the absence of visual failure and an onset at 20–30 years

of age with mild progression (Mole et  al. 2005, Mole and Williams 2010). The diagnostic work-up of the NCL should begin with the clinical assessment of the patients and should mainly consider the presence of major neurodegeneration (Mole and Williams 2001). The assessment of the specific combination of symptoms is important to determine the further diagnostic investigations that commonly comprise full blood count and smear, fundoscopy, cardiac assessment (ECG/ECHO), skeletal status (X-ray), brain MRI, and electrophysiology (VEP, SEP, ERG). Specific tests should be performed in specialized laboratories. Diagnostic procedures include quantitative analysis of metabolites in body fluids (urine, serum, CSF) and fibroblasts as well as specific assays of lysosomal hydrolases. DNA mutation analysis in the affected gene should be performed to confirm the diagnosis. DNA testing is particularly important for prenatal diagnosis. More specific information are available in the following specific sessions.

Tripeptidyl-Peptidase 1 Deficiency (NCL2) Physiopathology The lipopigment pattern seen most often in CLN2 consists of “curvilinear” profiles. Patients with CLN2 are deficient in a pepstatin-insensitive lysosomal peptidase called tripeptidyl peptidase 1 (TTP1). TTP1 removes tripeptides from the N-terminal of polypeptides. The mechanism by which failure to cleave these N-terminal peptides leads to neuronal degeneration of the hippocampus, cortical interneurons, cerebellum, and thalamocortical neurons with consequent neuronal death is still poorly understood.

Table 61.1  Ceroid lipofuscinosis, neuronal, 2 System CNS

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Developmental regression Dystonia EEG, abnormal ERG, abnormal Movement disorder Myoclonic epilepsy Myoclonus Neurodegenerative disease Seizures Seizures, myoclonic Seizures, tonic clonic Spasticity Speech delay SSEP, abnormal VEP, abnormal White matter abnormalities (MRI)

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ± ± ±

± ±

+ ± n ±

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ±

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ±

(continued)

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Table 61.1 (continued) System Eye

Metabolic Musculoskeletal Laboratory findings

Symptoms and biomarkers Optic atrophy Pigmentary retinopathy Retinal dystrophy Vision loss EM, Storage material Muscular atrophy Spinal muscular atrophy Lysosomal tripeptidyl-peptidase-1 (dried blood spot) Lysosomal tripeptidyl-peptidase-1 (fibroblasts) Lysosomal tripeptidyl-peptidase-1 (leukocytes)

Neonatal Infancy (birth–1 month) (1–18 months)

++ n n ↓↓↓

+++ + + ↓↓↓

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ ↓↓↓

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ ↓↓↓

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ ↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

Laboratory and instrumental examinations (NCL2) Histologic findings (electron microscopic findings) Enzyme activity

Molecular genetic testing Instrumental tests

Other tests

Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of the curvilinear profiles (CVB). Histologic findings include neuronal loss and the presence of distended neurons with granular PAS-positive material Tripeptidyl peptidase 1 (TPP1) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Fibroblast TPP1 activity is approximately 17,000 micromoles of amino acids produced per hour per mg of protein The TPP1 activity in CLN2 is less than 4% of normal Molecular genetic testing of TPP1 gene. More than 90 mutations of TPP1 are known. The common mutations are p. Arg208Ter and c.509-1G>C; the others are uncommon or private mutations Electroencephalography: Abnormal EEG with spikes in the occipital region in response to photic stimulation at 1–2 Hz Electroretinography: Electroretinogram (ERG) is usually abnormal at presentation and becomes undetectable soon thereafter. On occasion, the ERG may be normal at presentation Visual evoked potential: Abnormally enhanced for a long period and diminish in the final stage of the disease Somatosensory evoked potential: Progressive attenuation in all NCLs is seen in somatosensory evoked potential studies MRI and MR spectroscopy: Progressive cerebellar and cerebral atrophy with normal basal ganglia and thalami. In a study, Dyke et al. elaborate a multiparametric disease severity score, correlating with the patient’s age and disease duration; it is obtained from the combination of the whole-brain apparent diffusion coefficient (ADC), the volume percentage of CSF, and N-acetylaspartate-to-creatine metabolite ratios and const. They determined that children in the study with CLN2 began to differ from controls at age 5 years Positron emission tomography: a severe, generalized hypometabolism is seen Neurologic examination Developmental/cognitive and educational assessment Ophthalmic examination: Ophthalmic scale may serve as an objective marker of LINCL (late infantile neuronal ceroid lipofuscinosis) severity and disease progression A total disability score is derived by summing up the single scores for motor, visual, and verbal functions A Weill Cornell LINCL (late infantile neuronal ceroid lipofuscinosis) scale, based on neurologic, ophthalmologic, and CNS imaging, has been developed, which correlate with age and time since the onset of initial clinical manifestations

Prevention

Neuronal Ceroid Lipofuscinosis Type 3

Prenatal diagnosis is an option in patients with family history of CLN2 or known carriers. It can be done through electron microscopic examination of uncultured amniocytes for typical curvilinear bodies and through mutation analysis. Genetic counseling should be offered to family members, and the risk of CLN2 should be assessed for subsequent pregnancies.

Physiopathology In CLN3 NCL, mutations in CLN3 gene, coding for a protein involved in lysosomal function, in particular in microtubule-­ dependent, anterograde transport of late endosomes and lysosomes, have been found. These mutations result in a substantial decrease in mRNA expression and stability. Consequently, several cellular processes are affected, such as

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Table 61.2  Ceroid lipofuscinosis, neuronal, 3 System Cardiovascular CNS

Eye

Hematological Metabolic Musculoskeletal

Psychiatric

Symptoms and biomarkers Cardiac arrhythmia Cardiomyopathy Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Cognitive dysfunction Developmental regression Dysarthria EEG, abnormal ERG, abnormal Extrapyramidal movement disorder Gait disturbance Hallucinations Hypokinesia Movement disorder Neurodegenerative disease Psychiatric symptoms Seizures Seizures, complex partial Seizures, tonic clonic SSEP, abnormal VEP, abnormal White matter abnormalities (MRI) Optic atrophy Pigmentary retinopathy Retinal dystrophy Vision loss Vacuolated lymphocytes EM, Storage material Muscular atrophy Rigidity Spinal muscular atrophy Anxiety Behavior, aggressive Behavioral disorder Depression

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years)

n n + + + + ++

+ +

++ ++

+ ++ + + ++ ++ +++ ++ +++ ± ±

++

Adolescence (11–16 years) + + + + ++ ++ ++ ++ +++ ++ ++ ++ ++ ++ ++ ++ + + + ++ +++ + ++ +++ +++ +++ ++ +++ + ++ + ++ ++ +++ ++

Adulthood (>16 years) ++ ++ ++ ++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ +++ +++ ++ ++ ++ +++ +++ + +++ +++ +++ +++ ++ +++ ++ +++ ++ ++ ++ +++ ++

Laboratory and instrumental examinations (CLN3) Histologic findings (electron microscopic findings) and laboratory tests

Enzyme activity Molecular genetic testing

The analysis of blood smears through light microscopy reveals the presence of lymphocyte vacuoles Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of vacuoles and the storage of lipopigment with a “fingerprint” profile. The fingerprint profile can have three different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with CLN3 Histological studies reveal severe widespread neuronal degeneration resulting in retinal atrophy and in massive loss of brain substance, the selective necrosis of stellate cells in layers II and III and loss of pyramidal cells in layer V, and the accumulation of lipofuscin in neuronal perikaryon and in the thyroid Muscle biopsy: In muscle tissue, autophagic vacuoles and intermyofibrillar and subsarcolemmal accumulation of electrodense material are seen on biopsy (in some patients) Biochemical abnormalities include the accumulation of subunit C of the ATP synthase complex (SCMAS) in the lysosomes of patients Lymphoblast cell analysis: Enhanced levels of α-synuclein oligomers and gangliosides GM1, GM2, and GM3 and reduced levels of sphingomyelin and autophagy in CLN3 disease lymphoblast cells compared with normal cells CLN3-deficient cells display defects in the ARF1-Cdc42 pathway and actin-dependent events Not applicable Molecular genetic testing of CLN3 gene

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Instrumental tests

Other tests

Electroencephalography: The EEG shows nonspecific disorganization and spike-and-slow-wave complexes Electroretinography: Abnormal early ERG shows loss of photoreceptor function Visual evoked potential: Abnormal early with delayed latency Somatosensory evoked potential: Progressive attenuation Magnetic resonance imaging (MRI) and MR spectroscopy: Cerebral atrophy and cerebellar atrophy are seen usually after age 15 years. Progressive hippocampal atrophy is one of the characteristic features of brain atrophy in CLN3 in adolescence Longitudinal MRI shows that the annual rate of the gray matter loss in adolescent CLN3 patients is as high as 2.4% In voxel-based morphometric study, marked reduction in the gray matter volume of the dorsomedial thalami in particular and decreased white matter volume of the corona radiata are seen Positron emission tomography (PET): Hypometabolism, earliest in the calcarine area Neurologic examination Ophthalmologic examination (early in the course of disease may reveal macular changes only; gradually, typical signs of pan-retinal degeneration develop, such as pigmentary changes in the retinal periphery, vascular attenuation, and optic nerve pallor) Developmental/cognitive and educational assessment Use of the multimodal clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), to assess motor, behavioral, and functional capabilities of patients with juvenile onset

lysosomal pH, endocytosis, autophagy, transport of proteins from the TGN, cell proliferation, apoptosis, and synaptic transmission. Nevertheless, it is still not clear what precise biological function(s) CLN3 regulates and what is the mechanism of such regulation (Anil B. Mukherjee et al. 2019).

Prevention

Prevention

 euronal Ceroid Lipofuscinosis N Type 5

Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

Physiopathology The lipopigment patterns observed most often in CLN5 comprise mixed combinations of “granular,” “curvilinear,” and “fingerprint” profiles. The functions of these soluble lysosomal glycoproteins are still unknown, but it seems to play a role in endosomal sorting.

 euronal Ceroid Lipofuscinosis N Type 4 (Parry Type) (CLN4B) Physiopathology In CLN4B NCL, the DNAJ homolog subfamily C member 5 (DNAJC5) is deficient. DNAJC5 functions in many cellular processes by regulating the ATPase activity of 70-kd heat-­ shock proteins. In particular cysteine string protein alpha (CSPα) encoded by the DNAJC5 gene plays critical acting as a chaperone to facilitate correct folding of proteins.

Prevention Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

Table 61.3  Ceroid lipofuscinosis, neuronal, 4B System CNS

Metabolic Psychiatric

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Cognitive decline EEG, abnormal Extrapyramidal movement disorder Movement disorder Myoclonus Neurodegenerative disease Psychiatric symptoms Seizures Seizures, tonic clonic Spasticity EM, Storage material Behavioral disorder

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) ++ + + ++ ++ ++ ++ ++ +++ ++ ++ +++ ++ + ++

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Laboratory and instrumental examinations (CLN4B) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests

Enzyme activity Molecular genetic testing Instrumental tests Other tests

Histologic analysis: Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of mixed-type inclusions (curvilinear bodies, rectilinear complex, and granular osmiophilic deposits) In neural tissues, histopathologic features included neuronal loss, accumulation of lipopigment in remaining neurons, and PAS-positive intraneuronal storage material Biochemical tests: Abnormalities include the accumulation of subunit C of the ATP synthase complex (SCMAS) in the lysosomes of patients Not applicable Molecular genetic testing in DNAJC5 gene Electroencephalogram: Abnormal with recurrent burst of 4- to 6-Hz slow waves Somatosensory evoked potential: Progressive attenuation Neurologic examination Ophthalmologic examination Developmental/cognitive and educational assessment

Table 61.4  Ceroid lipofuscinosis, neuronal, 5 System CNS

Eye

Metabolic Musculoskeletal

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Dystonia EEG, abnormal ERG, abnormal Movement disorder Myoclonic epilepsy Myoclonus Neurodegenerative disease Seizures Seizures, myoclonic Seizures, tonic clonic Spasticity Speech delay SSEP, abnormal VEP, abnormal White matter abnormalities (MRI) Macular dystrophy Optic atrophy Retinal dystrophy Vision loss EM, Storage material Muscular atrophy Spinal muscular atrophy

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ± ± ±

± ±

± ±

++

+++ + +

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ + + +++ +++ + +++ ++ ++ +++ +++ +++ +++

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ ++ +++ +++ ± +++ +++ +++ +++ ++ +++ +++

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ± +++ +++ +++ +++ ++ +++ +++

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Laboratory and instrumental examinations (CLN5) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests

Enzyme activity Molecular genetic testing Instrumental tests

Other tests

Histologic analysis. Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of “fingerprint,” curvilinear,” and “rectilinear” profiles. No storage material is seen in lymphocytes. Histologic findings also include neuronal loss in the neocortex and cerebellum, laminar pattern of neuronal loss (most severe in layers III and V), meganeurites in layer III, extensive gliosis, and an almost complete loss of Purkinje and granule cells Accumulation of subunit C of the mitochondrial adenosine triphosphate (ATP) synthase complex in lysosomes Not applicable Molecular genetic testing on CLN5 gene Neurophysiologic inspection: Neurophysiologic abnormalities in electroencephalography and visual evoked potential MRI: Cerebral and cerebellar atrophy Somatosensory evoked potential: Enlarged SI (primary somatosensory cortex) and SII (secondary somatosensory cortex) somatosensory evoked responses Neurologic examination Ophthalmologic examination Developmental/cognitive and educational assessment

Neuronal Ceroid Lipofuscinosis Type 6 Physiopathology CLN6 encodes a protein of unknown function with seven transmembrane domains localizing to the endoplasmic reticulum (ER). It has been reported that CLN6 has a role in the regulation of cellular acidification, endocytosis, and autophagy, but how the altered function of this gene leads to the accumulation of biometals and how this defect leads to CLN6 disease pathogenesis must still be clarified.

of sugars, sugar phosphates, drugs, inorganic and organic cations, amino acids, and neurotransmitters across membranes, so mutations in gene cause depletion of soluble proteins in the lysosomes that in turn impairs the reactivation of mTOR signalling, thus being responsible for impaired anabolic regulator of cell growth and metabolism. The protein likely localizes to lysosomal membranes. MFSD8 is ubiquitously expressed at a very low level; only in the liver, heart, and pancreas its expression is consistently higher. Prevention

Prevention Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

Neuronal Ceroid Lipofuscinosis Type 7

Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

Neuronal Ceroid Lipofuscinosis Type 8 Physiopathology

Physiopathology In NCL 7, the major facilitator superfamily domain of the CLN7 gene containing protein-8 (MFSD8), an acid membrane protein that belongs to the major facilitator superfamily of transporter proteins (active permeases), is deficient. The precise role of this protein is still not well understood, but active permeases function as transporters

The CLN8 gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER) and may recycle between the ER and ER-Golgi intermediate compartment. The exact function is still not clear, but it is known that CLN8 protein belongs to the TRAM-

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Table 61.5  Ceroid lipofuscinosis, neuronal, 6 System CNS

Eye

Musculoskeletal

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Dystonia EEG, abnormal ERG, abnormal Movement disorder Myoclonic epilepsy Myoclonus Neurodegenerative disease Seizures Seizures, myoclonic Seizures, tonic clonic Spasticity Speech delay SSEP, abnormal VEP, abnormal White matter abnormalities (MRI) Optic atrophy Pigmentary retinopathy Retinal dystrophy Vision loss Muscular atrophy Spinal muscular atrophy

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± ± ± ±

± n ±

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ +

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ ±

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ±

+ +

++ ++ ++ +++ +++ +++

+++ +++ +++ +++ +++ +++

+++ +++ +++ +++ +++ +++

± ±

Laboratory and instrumental examinations (CLN6) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests

Enzyme activity Molecular genetic testing Instrumental tests

Other tests

Histologic analysis: Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of mixed-type inclusions (curvilinear bodies, fingerprint profiles, rectilinear complex, and granular osmiophilic deposits). In neural tissues, histologic findings also include the presence of autofluorescent lipopigment in neurons; neuronal loss, especially layer V; and loss of granule cells, with relative preservation of Purkinje cells Subunit C of the mitochondrial adenosine triphosphate (ATP) synthase complex accumulates in the lysosomes of patients Not applicable Genetic variants in CLN6 gene associated with CLN6 disease, late infantile Electroencephalogram: Abnormal patterns of electrical activity MRI and MR spectroscopy: Severe cerebral and cerebellar atrophy Somatosensory evoked potential: Progressive attenuation Neurologic examination Ophthalmologic examination Developmental/cognitive and educational assessment

Lag1p-­CLN8 (TLC) family. Members of this family are involved in the biosynthesis, metabolisms, transport, and sensing of lipids. However, the specific function of the CLN8 is not known.

Prevention Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

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Table 61.6  Ceroid lipofuscinosis, neuronal, 7 System CNS

Eye

Musculoskeletal Psychiatric

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Dystonia EEG, abnormal ERG, abnormal Movement disorder Myoclonic epilepsy Myoclonus Neurodegenerative disease Seizures Seizures, myoclonic Seizures, tonic clonic Spasticity Speech delay SSEP, abnormal VEP, abnormal White matter abnormalities (MRI) Optic atrophy Pigmentary retinopathy Retinal dystrophy Vision loss Muscular atrophy Spinal muscular atrophy Behavioral disorder

Neonatal Infancy (birth–1 month) (1–18 months) ± ± ± ± ± ± n ± ±

± ±

+ +

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ + ++ ++ ++ +++ +++ +++ +

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ ± +++ +++ +++ +++ +++ +++ ++

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ± +++ +++ +++ +++ +++ +++ +++

Laboratory and instrumental examinations (CLN7) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests

Enzyme activity Molecular genetic testing Instrumental tests

Other tests

Histologic analysis: Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of “curvilinear profiles,” “fingerprint profiles” (FP), and “rectilinear complex.” Intracellular accumulation of material can occur in neuronal and nonneuronal cells and may not always be apparent Histologic findings also include neurodegeneration Storage of subunit C of the mitochondrial adenosine triphosphate (ATP) synthase complex in lysosomes Not applicable Molecular genetic testing of MFSD8 gene Electroencephalography: Shows EEG abnormalities with diffuse slowing and frequent, multifocal sharp waves Brain magnetic resonance imaging (MRI) shows atrophic changes which are more in the occipital lobe Neurologic examination Ophthalmologic examination Developmental/cognitive and educational assessment

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Table 61.7  Ceroid lipofuscinosis, neuronal, 8 System CNS

Eye

Musculoskeletal Psychiatric

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Dystonia EEG, abnormal ERG, abnormal Movement disorder Myoclonic epilepsy Myoclonus Neurodegenerative disease Seizures Seizures, complex partial Seizures, tonic clonic Spasticity Speech delay SSEP, abnormal VEP, abnormal White matter abnormalities (MRI) Optic atrophy Pigmentary retinopathy Retinal dystrophy Vision loss Muscular atrophy Spinal muscular atrophy Behavioral disorder

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ± ± ± ±

± ±

± ±

+ +

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ + ++ ++ ++ ++ +++ +++ +

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ ± +++ +++ +++ +++ +++ +++ ++

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ± +++ +++ +++ +++ +++ +++ +++

Table 61.8  Ceroid lipofuscinosis, neuronal, 8, Northern Epilepsy variant (CLN8) System CNS

Metabolic Psychiatric

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Cognitive decline EEG, abnormal Movement disorder Myoclonus Neurodegenerative disease Seizures Seizures, complex partial Seizures, tonic clonic Speech delay EM, Storage material Behavioral disorder

Neonatal Infancy (birth–1 month) (1–18 months)

Childhood (1.5–11 years) +

+

±

++

++

+ ++ ++ +++ +++ +++ ++ ++ +

Adolescence (11–16 years) ++ ± ± ++ +++ ++ ++ + +++ +++ +++ ++ ++ ++

Adulthood (>16 years) ++ + + ++ +++ ++ ++ + +++ +++ +++ +++ ++ ++

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Laboratory and instrumental examinations (CLN8) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests

Enzyme activity Molecular genetic testing Instrumental tests

Other tests

Electron microscopy studies of tissue specimens (5–10 mL of heparinized whole blood (lymphocytes)) or tissue biopsies (now usually of skin, but previously of conjunctiva or other tissues) show intracellular accumulation of granular storage material and autofluorescent lipopigment in neurons Intracellular curvilinear profiles on ultrastructural analysis Lymphocytes are not usually vacuolated Not applicable Molecular analysis to confirm the diagnosis Neurologic examination with developmental/cognitive and educational assessment EEG shows abnormalities MRI shows cerebral and cerebellar atrophy, progressive Somatosensory evoked magnetic field (SEF) studies within normal limits Magnetic resonance imaging shows slight to moderate cerebellar atrophy and might reveal slightly enlarged cerebral sulci Clinical examination Family history

Cathepsin D Deficiency (NCL Type 10) Physiopathology The CLN10 gene encodes cathepsin D, a lysosomal aspartic protease belonging to the pepsin superfamily. Cathepsin D is important for neuronal stability and maintenance of the extracellular environment. It is associated with several physiological processes such as protein degradation, autophagy, and apoptosis since it hydrolyzes a wide variety of substrates including the extracellular matrix proteins fibronectin and laminin. So far, the in vivo substrates of this enzyme have not been clearly identified although it has been reported that CTSD catalyzes the cleavage of α-synuclein, a protein associated with Parkinson’s disease. Alterations in a macroautophagy-lysosomal degradation pathway appear to mediate neurodegeneration in this disease.

Prevention Prenatal testing is possible in pregnancies at increased risk if biochemical studies in the proband have revealed deficient activity of the enzyme CTSD, or if the disease-causing mutation(s) have been identified in the proband and parents. In these instances, testing is performed on fetal cells obtained by chorionic villus sampling (CVS) at about 10–12  weeks’ gestation or amniocentesis usually performed at about 15–18 weeks’ gestation. (Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.)

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

 rogranulin Deficiency (NCL Type 11 P Recessive) Physiopathology The CLN11 gene encodes progranulin (PGRN), originally described as a growth factor that regulates wound healing, vasculogenesis, and tumor growth. Within the central nervous system, GRN-mRNA is expressed in a variety of cell types including neuron, microglia, astrocytes, and endothelial cells. It has been suggested that signaling pathways downstream of Akt may also be activated by progranulin. In macrophages, granulins, cleaved from PGRN, bind to CpG oligodeoxynucleotides in lysosomes, enabling Toll-like receptor-9 signaling. Mutations in the PGRN gene are responsible for frontotemporal lobar degeneration with distinct neuropathological features consisting of ubiquitin-­positive protein aggregates in the nucleus and cytoplasm of cortical neurons related to the lysosomal dysfunction. The role of PGRN in this disease is anyway still not clear, and more research is needed to advance our understanding of the induced pathogenesis.

Prevention Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

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Table 61.9  Ceroid lipofuscinosis, neuronal, 10 System CNS

Eye

Metabolic Musculoskeletal

Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Congenital encephalopathy Developmental regression EEG, abnormal Epilepsy ERG, abnormal Language difficulties Movement disorder Myoclonus Neurodegenerative disease Seizures Spasticity SSEP, abnormal VEP, abnormal Optic atrophy Pigmentary retinopathy Retinal dystrophy Vision loss EM, Storage material Microcephaly Microcephaly Muscular atrophy Spinal muscular atrophy Cathepsin D (dried blood spot) Cathepsin D (fibroblasts) Cathepsin D (leukocytes)

Neonatal Infancy (birth–1 month) (1–18 months) + +++ +++ +++ +++ +++ +++ +++ +++

+++ +++

+++

+++

+++ +++ +++

+++ +++ +++

+++ +++ +++ +++ +++ ↓↓↓ ↓↓↓ ↓↓↓

+++ +++ +++ +++ +++ ↓↓↓ ↓↓↓ ↓↓↓

Childhood (1.5–11 years) +++ + +

Adolescence (11–16 years) +++ ++ ++

Adulthood (>16 years) +++ + +

+ + + +++ ++ + + ++ + + ++ +++ + +++ ++ ++ +++

++ + + +++ +++ ++ + ++ + + ++ +++ ++ +++ +++ +++ +++

++ + + +++ +++ ++ + ++ + + + +++ ++ +++ ++ +++ +++

+ + ↓↓↓ ↓↓↓ ↓↓↓

++ ++ ↓↓↓ ↓↓↓ ↓↓↓

+ + ↓↓↓ ↓↓↓ ↓↓↓

Laboratory and instrumental examinations (CLN10) Histologic findings and laboratory Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of autofluorescent granular osmiophilic deposits (GRODs). This tests (electron microscopic granular lipopigment material can be identified in astrocytes, macrophages, and residual neurons. Similar findings) and laboratory tests material can be observed in cells from the liver, spleen, thymus, and lung. Histologic findings also include severe neuronal loss in the cerebrum and cerebellum, extensive gliosis, and white matter almost devoid of axons and myelin Neuropathologic examination showed severe cerebral atrophy and diffuse ballooning of neurons with autofluorescent lipid accumulation Decrease or absence of cathepsin D (CTSD) protein immunostaining in brain tissue Presence of non-vacuolated lymphocytes Enzyme activity Measurement of enzymatic activity of cathepsin D (CTSD) in leukocytes and cultured skin fibroblast cells Molecular genetic testing Molecular genetic testing of CTSD gene Instrumental tests Magnetic resonance imaging (MRI) shows cerebral and cerebellar atrophy Other tests

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Table 61.10  Ceroid lipofuscinosis, neuronal, 11 System CNS

Eye Metabolic Musculoskeletal

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) EEG, abnormal ERG, abnormal Language difficulties Movement disorder Seizures Retinal dystrophy Vision loss EM, Storage material Muscular atrophy Spinal muscular atrophy

Neonatal (birth–1 month)

Infancy Childhood (1–18 months) (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + + ++ + + + ++ ++ +++ + +

Laboratory and instrumental examinations (CLN11) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests Enzyme activity Molecular genetic testing Instrumental tests

Other tests

Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of numerous “fingerprint profiles” Measurement of plasma progranulin levels: undetectable in the homozygous patients and about 50% decreased in the heterozygous parents Presence of non-vacuolated lymphocytes Not applicable Molecular genetic testing of GRN gene Electroencephalography showed generalized polyspike wave discharges Electroretinography showed severe attenuation of both rod and cone responses Magnetic resonance imaging (MRI) showed cerebellar atrophy Visual evoked potential (VEP): polyphasic VEP waveform suggesting hyperexcitability of the occipital cortex Somatosensory evoked potential: progressive attenuation in all NCLs Visual evoked potential (VEP): polyphasic VEP waveform suggesting hyperexcitability of the occipital cortex Neurologic examination Ophthalmologic examination Developmental/cognitive and educational assessment

ATP13A2 Deficiency (NCL Type 12) Physiopathology The ATP13A2 gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. In most human tissues, ATP13A2-mRNA is detectable, but it is expressed at a high level in the ventral midbrain, including substantia nigra, and to a lesser extent in the kidney and skeletal muscle. Interestingly, oxidative stress is found to increase the expression of the CLN12/ATP13A2-­mRNA. This protein is highly expressed in neurons and is predicted to function as a cation pump, playing a role as a cation transporter regulating Mn2+, Zn2+, and Mg2+ homeostasis with H+ ion concentration in the cell. Being cation regulation and homeostasis vital for neuronal function including intra- and intercel-

lular signaling, dysfunction of the ATP13A2 may be responsible for the dysregulated neurotransmission and eventual dementia characteristic of this ­disease. Indeed, accumulation of zinc and mitochondrial dysfunction are established etiological factors that contribute to Parkinson’s disease; however, their underlying molecular mechanisms are largely unknown. Mitochondrial dysfunction and autophagy are centrally implicated in Parkinson’s disease (PD). It has been suggested that ATP13A2 helps maintain optimal pH in lysosomes where ceramide is also metabolized. The apoptosis that appears to cause NCLs is associated with increased levels of ceramide, which might have also been linked to α-synuclein deposition, contributing to PD pathogenesis. It may be that ATP13A2 helps regulate ceramide metabolism, such that significant changes inATP13A2 activity may contribute to the pathogenesis of both PD and NCLs.

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Table 61.11  Ceroid lipofuscinosis, neuronal, 12 System CNS

Metabolic Musculoskeletal Psychiatric

Symptoms and biomarkers Akinesia Cognitive dysfunction Dysarthria Extrapyramidal movement disorder Gait disturbance Movement disorder Myoclonus Neurodegenerative disease EM, Storage material Rigidity Behavioral disorder

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) +

Adolescence (11–16 years) ++ ++ + + ++ + + + +++ ++ +

Adulthood (>16 years) +++ +++ ++ ++ +++ ++ +++ ++ +++ +++ ++

Laboratory and instrumental examinations (CLN12/PARK9) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests Enzyme activity Molecular genetic testing Instrumental tests

Other tests

Light and electron microscopy ultrastructural studies: Light and electron microscopic investigations of intracellular storage that, when performed in the logical order shown, lead straight and economically to adequate molecular genetic confirmation Presence of non-vacuolated lymphocytes Not applicable Sequences analysis ATP13A2 EEG shows nonspecific disorganization and spike-and-slow-wave complexes Computed tomography and MRI reveal cerebral and, to a lesser degree, cerebellar atrophy in the later stages (age > 15 years) Ophthalmologic examination may reveal macular changes only; gradually, typical signs of pan-retinal degeneration develop: pigmentary changes in the retinal periphery, vascular attenuation, and optic nerve pallor ERG shows loss of photoreceptor function early on Developmental/cognitive and educational assessment: Speech disturbances (festinating stuttering, often mislabelled as echolalia) and slow decline in cognition occur around the time of onset of seizures. Behavioral problems, extrapyramidal signs, and sleep disturbance occur in the second decade Cardiological assessment: Cardiac involvement late in the disease, progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus node dysfunction Medical genetics consultation Psychiatric examination: Psychiatric problems including disturbed thoughts, attention problems, somatic complaints, and aggressive behavior

Prevention Prenatal testing is possible in pregnancies at increased risk if the disease-causing mutation(s) have been identified in the proband and parents. In these instances, testing is performed on fetal cells obtained by chorionic villus sampling (CVS) at about 10–12 weeks’ gestation or amniocentesis usually performed at about 15–18 weeks’ gestation.

Cathepsin F Deficiency (NCL Type 13)

recently identified. When the CTSF gene is mutated, it cannot produce cathepsin F, an enzyme that cuts proteins in the lysozyme. CTSF is a cysteine protease synthesized in the ER.  CTSF is tagged with mannose 6-phosphate residues in the cis-Golgi and transported by CI-M6PR to the late endosomal/lysosomal compartment. CTSF is highly expressed in cerebrocortical, hippocampal, and cerebellar neurons. By cutting proteins, cathepsin F can modify the function of the proteins as well as help break them down. Dysfunction leads to incomplete breakdown of proteins. Once again, lipopigments build up, and brain function is decreased as the neuron cells.

Physiopathology Kufs disease type B can be due to variants to the DNAJC5 and cathepsin F (CTSF) genes with CTSF mutations accounting for a minority of cases of type B Kufs. Mutations in cathepsin F as the causative gene for autosomal recessive Kufs disease type B have been only

Prevention Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

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Table 61.12  Ceroid lipofuscinosis, neuronal, 13 System CNS

Metabolic Musculoskeletal Psychiatric

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Cognitive decline Dysarthria Extrapyramidal movement disorder Movement disorder Neurodegenerative disease Seizures Seizures, tonic clonic EM, Storage material Muscular atrophy Spinal muscular atrophy Behavioral disorder

Neonatal (birth–1 month)

Laboratory and instrumental examinations (CLN13) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests

Enzyme activity

Molecular genetic testing Instrumental tests Other tests

Histologic findings: Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) often show the presence of fingerprint profiles Abundant autofluorescent material is found in the cytoplasm of neurons of the cerebral cortex, thalamus, striatum, brainstem nuclei, and Purkinje cells. This storage material is immunoreactive for ubiquitin and contained fingerprint profiles Measurement of enzymatic activity of cathepsin F (CTSF) in leukocytes and cultured skin fibroblast cells Molecular genetic testing on CTSF gene Brain MRI showed diffuse cerebral atrophy

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + + ++ + ++ + ++ + + ± + + +

a highly conserved soluble cytosolic protein localized in various organs indicating that it plays a role in the hyperpolarization of the cell membrane via interaction with a component of the ubiquitin ligase complex. It also directly interacts with Cullin-3, a component of E3 ubiquitin-protein ligases, for degradation by ubiquitin proteasome system. Missense mutations in the KCTD gene found in CLN14 disease disrupt KCTD7-­Cullin-­3 interactions, suggesting a role in the impairment of the cellular degradative process.

Prevention No data.

Ceroid Lipofuscinosis, Neuronal, 1 Neuronal Ceroid Lipofuscinosis Type 14 Physiopathology KCTD7 gene (potassium channel tetramerization domain containing 7) encodes a member of the potassium channel tetramerization domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. Mutations in this gene have been associated with progressive myoclonic epilepsy-3, a clinically defined epileptic syndrome that manifests as myoclonic seizures and progressive neurological dysfunction before age 2  years and accompanied by developmental regression. Alternative splicing results in multiple transcript variants. KCTD7 encoded protein is

Physiopathology The neuronal ceroid lipofuscinoses (NCLs; CLNs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns. The lipopigment pattern seen most often in CLN1 is referred to as granular osmiophilic deposits (GROD), with characteristic accumulation of saposins A and D. In CLN1 NCL, a lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), is deficient. PPT1, which removes fatty acyl groups from cysteine residues on fatty acid-­ modified proteins, remains in the endoplasmic reticulum, where it is inactive, causing saposins A and D to accumulate in the lysosomes.

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Table 61.13  Ceroid lipofuscinosis, neuronal, 14 System CNS

Eye Metabolic Musculoskeletal

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression EEG, abnormal Epilepsy Hypokinesia Language difficulties Movement disorder Myoclonic epilepsy Neurodegenerative disease Seizures, myoclonic Speech delay Optic atrophy Vision loss EM, Storage material Microcephaly Muscular atrophy Spinal muscular atrophy

Neonatal Infancy Childhood (birth–1 month) (1–18 months) (1.5–11 years) ++ + ++ + ++ +++ + +++ + +++ ++ +++ +++ + +++ +++ + +++ +++ +++ +++

± ±

++ ++

+++ +++ +++

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

Laboratory and instrumental examinations (CLN14/EPM3) Histologic findings and laboratory tests (electron microscopic findings) and laboratory tests Enzyme activity Molecular genetic testing

Instrumental tests

Other tests

Electron microscopy ultrastructural studies: Presence of granular osmiophilic deposits with fingerprint profiles Lymphocytes’ vacuolation is absent Not applicable KCTD7 mutation screening should be considered in progressive myoclonus epilepsies (PME) patients with onset around 2 years of age followed by rapid mental and motor deterioration Metabolic screening and normal routine blood test including lactate, chromatography of amino acids in plasma and urine, organic acids in urine Genetic variations associated with progressive myoclonic epilepsy type 3 EEG shows slowed dysrhythmia and multifocal discharges EEG with photic stimulation to provoke frequency-dependent spike-wave activity with increase of myoclonic seizures raising Cerebral morphological magnetic resonance imaging can show cerebral and cerebellar atrophy, thinning of the corpus callosum Evoked potential of nervus tibialis and medianus on both sides might present a slightly delayed cortical answer to stimulation with normal amplitude (no giant potentials) Fundoscopy Abdominal ultrasonography Family pedigree

Prevention Prenatal testing is possible in pregnancies at increased risk if biochemical studies in the proband have revealed deficient activity of the enzyme PPT-1, or if the disease-causing mutation(s) have been identified in the proband and parents. In these instances, testing is performed on fetal cells obtained by chorionic villus sampling (CVS) at about

10–12  weeks’ gestation or amniocentesis usually performed at about 15 to 18 weeks’ gestation. (Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.) Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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Table 61.14  Ceroid lipofuscinosis, neuronal, 1 System CNS

Eye

Metabolic Musculoskeletal

Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Developmental regression Dystonia EEG, abnormal Epilepsy ERG, abnormal Language difficulties Movement disorder Myoclonic epilepsy Myoclonus Neurodegenerative disease Seizures, myoclonic Seizures, tonic clonic Spasticity Speech delay SSEP, abnormal VEP, abnormal White matter abnormalities (MRI) Maculopathy Optic atrophy Retinopathy Vision loss EM, Storage material Microcephaly Muscular atrophy Spinal muscular atrophy Lysosomal palmitoyl protein thioesterase-1 (dried blood spot) Lysosomal palmitoyl protein thioesterase-1 (fibroblasts) Lysosomal palmitoyl protein thioesterase-1 (leukocytes)

Neonatal (birth–1 month)

± ++ ± ± ± ↓↓↓

Infancy (1–18 months) + ++ ++ ++ + + ± + + + ± + ++ ± ± ± + ± ± ++ ± + ± + +++ ++ ++ ++ ↓↓↓

Childhood (1.5–11 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ +++ +++ +++ +++ +++ +++ ↓↓↓

Adolescence (11–16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ± +++ +++ +++ +++ +++ +++ +++ +++ ↓↓↓

Adulthood (>16 years) +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ ± +++ +++ +++ +++ +++ +++ +++ +++ ↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

↓↓↓

± ±

Laboratory and instrumental examinations (CLN1) Histologic findings (electron microscopic findings) Enzyme activity

Molecular genetic testing Instrumental tests

Electron microscopy ultrastructural studies in peripheral blood lymphocytes or other tissues (conjunctiva, skin, or other tissues) show the presence of autofluorescent granular osmiophilic deposits (GROD) with characteristic accumulation of saposins A and D Not vacuolated lymphocytes Almost complete loss of cortical neurons Deficient activity of palmitoyl-protein thioesterase 1 (PPT-1) encoded by PPT1 evidenced by fluorimetric assay based on the fluorochrome 4-methylumbelliferone in leukocytes, dry blood samples, cultured skin fibroblast cells, amniotic fluid cells, or chorionic villi Targeted analysis for pathogenic variants Sequence analysis for assessment of sequence variants Deletion/duplication analysis Electroencephalography: Electroencephalographic characteristics seen in CLN1 NCL include lack of attenuation of posterior dominant rhythm to eye opening, loss of sleep spindles, progressive background abnormality, and attenuation with the background flat by age 3 years Electroretinography: Unrecordable at age 3 years Visual evoked potential: Unrecordable at age 4 years Somatosensory evoked potential: Progressive attenuation in all NCLs Magnetic resonance imaging (MRI): Mild cerebral atrophy that progresses after 4 years, decreased T2 signal intensity in the thalami, callosal thinning, periventricular rims of hyperintensity that progress to diffuse white matter hyperintensity on T2, and cerebellar atrophy after age 3 years Magnetic resonance (MR) spectroscopy: Almost complete loss of N-acetylaspartate (metabolite present only in neurons), reduction in creatine- and choline-containing compounds (i.e., markers for glial membrane turnover), elevation of myoinositol (i.e., a glial marker), elevation of lactate in gray and white matter

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Current Treatment Strategies Being the NCL inherited metabolic disorders, any therapeutic approach will need to be strictly connected to the primary metabolic defect. For the majority of NCLs, so far, there is no specific treatment, and current disease management is mainly aimed at controlling the symptoms rather than “curing” the disease. The only specific treatment available for NCL is cerliponase alfa for neuronal ceroid lipofuscinosis type 2 (CLN2, also known as tripeptidyl peptidase 1 [TPP1] deficiency). Cerliponase alfa is an enzyme replacement ther-

apy (ERT) approved by the FDA in April 2017 and by the CE in June 2017, to slow the loss of ambulation in symptomatic pediatric patients aged 3  years or older with late infantile neuronal CLN2. Recent studies confirm that the decline in motor and language functions is decreased in patients treated with alfa cerliponase compared to their historical controls (Schulz et al. 2018). The drug requires weekly intraventricular administration via a reservoir surgically implanted under the scalp. The recommended dosage for cerliponase alfa is 300  mg (10  mL solution) administered every other week by intraventricular infusion.

Standard anticonvulsant drugs to control seizures in NCLs to terminate clinical and electrical seizure activity as rapidly as possible and to prevent seizure recurrence (from Goldenberg 2010) Drug Chemical name Carbamazepine 5H-Dibenz[b, f] azepine-5-­ carboxamide

Oxcarbazepine 10,11-Dihydro-10-­ oxo-5H-dibenz[b,f] aze-pine-5-­ carboxamide

Molecular Brand and weight other names 236.27 (Tegretol, Carbatrol, Epitol, Equetro)

252.27

(Trileptal)

Indication Treatment of complex partial seizures (To control generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and for preventing and treating seizures occurring during or following neurosurgery) Anticonvulsant Monotherapy for adults and in children 4 to 16 years of age with partial seizures and as adjunctive therapy for children 2 years of age and older and for adults and children 2 to 16 years of age with partial seizures

Action May reduce polysynaptic responses and block post-tetanic potentiation

Mechanism of action Reduction of sustained, high-frequency, repetitive neural firing

May block voltage-­ sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation

Increased potassium conductance and modulation of high-­ voltage activated calcium channels

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Drug Valproic

Chemical name -N-propyl acetic acid

Gabapentin

1-(Aminomethyl) cyclohexaneacetic acid

171.24

(Neurontin)

Topiramate

2,3:4,5-Di-O-­ isopropylidene-β-dfructopyranose sulfamate

339.36

(Topamax)

Tiagabine

(−)-(R)-1-[4,4-Bis(3-­ 412.0 methyl-­2-thienyl)-3-­ butenyl]nipecotic acid HCl

(Gabitril)

Indication Status epilepticus: primary generalized tonic-clonic seizures Partial and generalized seizures and is indicated as monotherapy and adjunctive therapy for complex partial seizures, which begin in a limited area of the brain. These seizures may occur either in isolation or in association with other types of seizures Status epilepticus: Adjunctive therapy for patients older than 12 years of age with partial seizures with and without secondary generalization Adjunctive therapy for pediatric patients 3–12 years of age with partial seizures Nerve pain Primary generalized tonic-clonic seizures Adjunctive therapy for adult and pediatric patients 2 to 16 years of age with partial-onset seizures Initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures

Action Increase brain concentrations of GABA.1

Mechanism of action Not established

Mimic the Not established neurotransmitter GABA

Potentiate the inhibitory activity of the neurotransmitter GABA. In addition, topiramate may block glutamate activity

Adjunctive therapy Enhanced activity of GABA in adults and children 12 years of age and older with partial seizures

Not well established: Probable inhibition of voltage-dependent sodium channels; may increase activity of the neurotransmitter GABA at some subtypes of the GABAA receptor, and antagonize the AMPA/ kainate subtype of the glutamate receptor, and inhibit the carbonic anhydrase enzyme, particularly isozymes II and IV Not well established: It is believed to be related to recognition sites associated with the GABA uptake carrier, therefore blocking GABA uptake into presynaptic neurons and thus increasing the quantity of GABA available for receptor binding on the surfaces of postsynaptic cells

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Molecular Brand and weight other names Indication 238.24 (Felbatol)

Drug Felbamate

Chemical name 2-Phenyl-1,3-­ propanediol dicarbamate

Midazolam

8-Chloro-6-(2-­ fluorophenyl)-1-­ methyl-­4H-­ imidazo[1,5-a][1,4] benzodiazepine

325.8

(Versed)

Emergency management of seizures Sleep problems

Phenobarbital

5-Ethyl-5-­ phenylpyrimidine2,4,6(1H,3H,5H)trione

232.24

(Solfoton, Luminal)

Valproate

2-Propylpentanoic acid

144.21

(Convulex, Depakote, Epilim, Stavzor, and others)

Seizures that occur Potentiated inhibitory neurotransmission in neonates and in the first year of life Both generalized tonic-clonic seizures and partial seizures in patients of all ages Phenobarbital is used to treat status epilepticus (continuous seizures with impaired consciousness between episodes) Anticonvulsant effect Tonic-clonic seizures Mioclonus

Zonisamide

1,2-Benzisoxazole-3-­ 212.23 methanesulfonamide

(Zonegran)

Adjunctive therapy for treating partial seizures in adults

Action Weak inhibitory effects on GABA receptor binding and benzodiazepine receptor binding Anxiolytic, amnestic, hypnotic, anticonvulsant, and sedative action

Mechanism of action Antagonist at the strychnine-insensitive glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor-­ ionophore complex Binding to the benzodiazepine receptor at the GABA receptor-­ chloride ionophore complex in the central nervous system (CNS). It induces an increase in the opening of chloride channels and membrane hyperpolarization and increases the inhibitory effect of GABA in the CNS. Midazolam may also interfere with the reuptake of GABA, thereby causing accumulation of GABA in the synaptic cleft Increased duration of time that GABA-mediated chloride channels remain open and reduced neurotransmitter release from nerve terminals, probably due to effect on calcium channels Decreased excitatory neurotransmission due to a reduced effect of glutamate

Not well established: It seems to be due to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA) Not well established, Reduces sustained probable inactivation of high-frequency voltage-sensitive sodium repetitive firing of channels and inhibition of action potentials and low-threshold T-type prevents the spread of seizure discharge across calcium channels in neurons cells

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Drug Levetiracetam

Chemical name (−)-(S)-α-Ethyl-2-­ oxo-1-pyrrolidine acetamide

Molecular Brand and weight other names 170.21 (Keppra, Keppra XR, Spritam)

Indication Adjunctive therapy for partial-onset seizures and epilepsy in adults and children 4 years of age and older Myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy And primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy

Action May selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity

Mechanism of action Modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain

Drugs used to control myoclonia and spasticity

Drug Baclofen

Molecular Chemical name weight 4-Amino-3-(4-chlorophenyl) 213.661 butyric acid

Tizanidine 5-Chloro-4-(2-imidazolin-2-­ 253.71 yl-amino)-2,1,3-­ benzothiadiazole monohydrochloride Piracetam 2-(2-Oxopyrrolidin-1-yl) 142.156 acetamide

Brand and other names Lioresal

Indication Myoclonia and spasticity

Action GABA agonist used as a skeletal muscle relaxant

Zanaflex

Myoclonia and spasticity

Central alpha-2-­ adrenergic receptor agonist

Nootropil

Adult patients suffering from myoclonus of cortical origin

Neuroprotective and Piracetam’s mode of action in anticonvulsant cortical myoclonus is as yet unknown

Other helping supportive means of utmost importance in these chronic diseases characterized by a multiplicity of symptoms and affected systems include chest physiotherapy, nasogastric or gastric tube feeding in the later stages of the disease, orthopedic treatment, speech therapy, and psychological and transition (Kohlschütter et al. 2019). In particular physical and occupational therapies are routinely used to aid in the retention of physical abilities (Neverman et al. 2015).

Mechanism of action Reduces the release of excitatory neurotransmitters and substance P by binding to the GABA-B receptor Reduces spasticity by increasing presynaptic inhibition of motor neurons

Some antiepileptic drugs like carbamazepine, phenytoin, and vigabatrin can exacerbate myoclonia. These drugs should therefore be avoided especially in the late infantile NCL types that commonly manifest a high prevalence of myoclonic seizures, although they can improve control of tonic-clonic seizures when these are refractory to other medications. Clinical distinction among NCL forms is therefore important for the therapeutic choice (Augustine et al. 2015).

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Drug to be avoided Drug Chemical name Carbamazepine 5H-Dibenz[b, f] azepine-5-­ carboxamide

Molecular Brand and weight other names 236.27 (Tegretol, Carbatrol, Epitol, Equetro)

Phenytoin

Sodium 5,5-diphenyl-2, 4-imidazolidinedione

274.3

(Dilantin, Phenytek)

Vigabatrin

4-Amino-5-hexenoic acid

129.16

(Sabril, Vigadrone)

Indication Treatment of complex partial seizures (To control generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and for preventing and treating seizures occurring during or following neurosurgery) Status epilepticus: For controlling generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and for preventing and treating seizures occurring during or following neurosurgery It is used in patients who have already been treated with other medicines that did not work well. For treating complex partial seizures in adults and children 10 years of age and older and infantile spasms in children

Recently also the use and effectiveness of Lamotrigine have been debated since it may worsen myoclonus in the Lamotrigine 3,5-Diamino-6-(2,3-­ dichlorophenyl)-as-­ triazine

Several major therapeutic options are under investigations: The majority - enzyme replacement therapy; gene therapy; bone marrow transplantation; neural stem cell therapy; and molecular or pharmacological chaperone therapy—are aimed at reducing the levels of the compounds that accumulate in the lysosomes. • Enzyme replacement therapy (ERT): It usually consists in the regular intravenous infusions of a recombinant form of the defective enzyme which is then scavenged by affected cells, endocytosed, and incorporated into lysosomes restoring functional activity. Unfortunately, ERT

Mechanism of action Reduction of sustained, high-frequency, repetitive neural firing

Selective block of high-­ frequency neuronal activity

Suppression of the sodium action potential through a voltage-dependent blockade of membrane sodium channels (Yaari et al. 1986)

Increased concentrations of GABA in the CNS

The precise mechanism of the antiseizure effect is unknown, but it is believed to result from its action as an irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA

early stages of CLN2 disease, late infantile (Shorvon, et al. 2019).

256.09 (Lamictal) Adjunctive therapy for partial seizures, and primary generalized tonic-clonic seizures Neuralgic pain

Emerging Causal Treatment

Action May reduce polysynaptic responses and block post-­ tetanic potentiation

Diminished neuronal activity

Inhibition of the release of glutamate and also inactivation of voltage-­ sensitive sodium channels, with stabilization of the neuronal membrane

does not cross the blood-brain barrier, thus hindering effective treatment of CLNs with CNS involvement. Therefore, it is necessary to inject the enzyme to the cerebrospinal fluid, either directly into the lateral ventricles or by intrathecal injection (needle in the back). ERT is currently available for CLN2 and under study for CLN1. • Gene therapy is currently only utilized in animal models. Multiple viral vectors have been used to accomplish in vivo gene transfer, such as herpesviruses, lentiviruses, adeno-associated viruses (AAV), adenoviruses (Ad), and others. Gene therapy approaches have shown promising results in animal models of various NCLs with improvements already made in vectors used for delivery of the genes. Importantly recent findings indicate that early ther-

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•

•

•

•

apy (i.e., presymptomatic) provides best results (Kohlschütter et al. 2019). Bone marrow transplant (BMT): It consists in using donor bone marrow-derived cells as a source of enzyme. Studies in animal models as well as in a few infants have so far not showed satisfactory results. Nevertheless, BMT in combination with gene therapy provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters (Macauley et al. 2012). Molecular or pharmacological chaperone therapy (protein chaperone therapy, PCT): It consists in the use of small molecule compounds to assist the folding of mutated enzymes, therefore restoring their catalytic activity. This type of therapy is still highly experimental, but testing in cell culture models has shown promising results. Currently, no pharmacological chaperones have been tested in NCL cell lines or animal models except one study in lymphoblast lines from patients with CLN1where increase in PPT1 activity was showed (Dawson et  al. 2010). Currently, no other pharmacological chaperones have been tested in NCL cell lines or animal models. Stem cell transplant (SCT): It is useful for the enzymatic deficiencies and it can intravenous transplantation of different types of donor cells. Generally it consists of healthy hematopoietic stem cells (usually from bone marrow, sometimes from cord blood) or neural stem cells (nerve cells). The newly produced enzymes can be taken up by the enzyme-deficient cells (cross-correction), or in certain cases stem cells can also have the capacity to differentiate and replace the person’s own (diseased) cells. Both types have been used in animal models and clinical trials. Unfortunately, this therapy showed to have minimal effects on disease progression and to be largely ineffective against LINCL and JNCL. Nevertheless, this is not an approach to be eliminated since more promising outcomes have been obtained using HSC, specifically bone marrow treatment, in combination with gene therapy in Ppt1 −/− mice where neurodegeneration in the brain was attenuated, even if not in the retina (Arrant et al. 2018). Substrate reduction therapy (SRT): It consists in the oral administration of a drug capable of inhibiting/reducing the rate of production of the substrate reducing the metabolic load on the lysosome. Clinical trials that studied the effect of combining cysteamine bitartrate and N-acetylcysteine to treat INCL have been performed, but no effect on the progression of the disease was shown even if the treatment succeeded in reducing the amount of storage material in peripheral leucocytes and parents reported less irritability and increased concentration.

M. Scarpa et al.

Nowadays CLN1, CLN2, CLN3, and CLN6 are the diseases for which the current therapeutic approaches have reached preclinical or clinical trials (see Table below). Both small and large animal models of various forms of NCLs are being developed. These animal models are likely to be very useful for the preclinical evaluation of novel therapeutic strategies.

 oving Towards Effective Therapeutic M Strategies For ongoing trial for NCL see ClinicalTrials.gov. Acknowledgments  We thank Carla E Hollak for her help in the preparation of the paper. Funding This work was generated within the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), cofunded by the European Union within the framework of the Third Health Programme ERN-2016  - Framework Partnership Agreement 2017–2021, Project ID No. 739543.

References Arrant AE, et  al. Progranulin gene therapy improves lysosomal dysfunction and microglial pathology associated with frontotemporal dementia and neuronal ceroid lipofuscinosis. J Neurosci. 2018;38:2341e. Augustine EF, Adams HR, Beck CA, et  al. Standardized assessment of seizures in patients with juvenile neuronal ceroid lipofuscinosis. Dev Med Child Neurol. 2015;57(4):366–71. Das AK, Lu JY, et al. Biochemical analysis of mutations in palmitoyl-­ protein thioesterase causing infantile and late-onset forms of neuronal ceroid neuronal ceroid lipofuscinosis. Hum Mol Genet. 2001;10(13):1431–9. Dawson G, Schroeder C, Dawson PE.  Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease. Biochem Biophys Res Commun. 2010;395:66–9. Goldenberg MM.  Overview of drugs used for epilepsy and seizures: etiology, diagnosis, and treatment. P T. 2010;35(7):392–415. Kohlschütter A, et  al. Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS drugs vol. 2019;33(4):315–25. Macauley SL, Roberts MS, Wong AM, McSloy F, Reddy AS, Cooper JD, Sands MS.  Synergistic effects of central nervous system-­ directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis. Ann Neurol. 2012;71(6):797–804. Mole SE, Williams RE. Neuronal ceroid-lipofuscinoses. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2019; 2001. [Updated 2013 Aug 1]. Mole SE, Williams RE, Goebel HH.  Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107–26. Mole SE, Williams RE.  Neuronal Ceroid-Lipofuscinoses. Gene Reviews; 2010.

61  The Neuronal Ceroid Lipofuscinoses Mukherjee AB, Appu AP, Sadhukhan T, Casey S, Mondal A, Zhang Z, Bagh MB. Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses. Mol Neurodegener. 2019;14(1):4. Neverman NJ, Best HL, et al. Experimental therapies in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta. 2015;1852(10 Pt B):2292–300. Schulz A, Ajayi T, et  al. CLN2 study group. Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med. 2018;378(20): 1898–907. Shorvon S, Guerrini R, Trinka E, Schachter S. The causes of epilepsy: diagnosis and investigation. Cambridge: Cambridge University Press; 2019.

1233 Steinfeld R, Heim P, et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002;112:347–54. Steinfeld R, Steinke HB, et  al. Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes. Hum Mol Genet. 2004;13(20): 2483. Steinfeld R, Reinhardt K, et  al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78(6):988–98. Yaari Y, Selzer ME, Pincus JH. Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol. 1986;20(2):171–84.

Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

62

Hidde H. Huidekoper and Esmee Oussoren

Contents Introduction

 1236

Nomenclature

 1238

Metabolic Pathways

 1239

Signs and Symptoms

 1240

Reference Values

 1243

Pathological Values

 1243

Diagnostic Flowchart

 1244

Treatment and Follow-Up

 1245

References

 1246

Summary

Mucolipidosis type II/III (ML II/III) and multiple sulfatase deficiency (MSD) share clinical features with the mucopolysaccharidoses. Both ML II/III and MSD result from enzymatic defects that affect the post-translational modification of lysosomal enzymes. In ML II/III the mannose-­6-phosphate marker, essential for routing lysosomal enzymes towards the lysosomes, is lacking. This leads to the excretion of lysosomal enzymes in plasma where they are unable to execute their function. In MSD lysosomal sulfatases, as well as sulfatases from the endoplasmic reticulum and Golgi complex, cannot be activated due to the inability to modify a conserved cysteine residue

H. H. Huidekoper (*) · E. Oussoren (*) Center for Lysosomal and Metabolic diseases, Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands e-mail: [email protected]; [email protected]

at the active site. In mucolipidosis type IV (ML IV), lysosomal dysfunction is caused by the deficiency of transient receptor potential channel mucolipin-1 (TRPML1), a nonselective cation channel present in late endosomal and lysosomal membranes necessary for autophagy, vesicular trafficking, and mTOR and TFEB signaling. Neurological dysfunction and visual impairment are the most predominant clinical features; skeletal abnormalities are not seen in ML IV. Deficiency of the lysosomal enzymes cathepsin K (pycnodysostosis) and C (Papillon–Lefèvre or Haim– Munk syndrome) presents both with a very distinct clinical picture. Cathepsin K is important for bone resorption and extracellular matrix remodeling. Its deficiency results in stunted growth, facial dysmorphism, osteopetrosis, and dental abnormalities. In cathepsin C deficiency, premature loss of both deciduous and permanent teeth due to periodontitis in combination with palmoplantar keratosis is the main clinical feature. All disorders are ultra-rare and have autosomal recessive inheritance. Their clinical spectrum is not yet fully

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_62

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known, and patients are likely still underdiagnosed. No specific biomarkers are available that can lead to the diagnosis. All disorders have in common that no curative treatments are available and specialized multidisciplinary supportive care is needed to minimize the disease burden and provide an adequate quality of life.

H. H. Huidekoper and E. Oussoren

and develop rapidly progressive airway, cardiac, skeletal, and nervous system disease, resulting in death in early childhood. The ML III α/β patients present with a broader clinical phenotype ranging from severely affected patients that die in childhood to milder affected patients displaying primarily skeletal symptoms, who survive into adulthood (Cathey et al. 2010). ML III γ patients have a milder phenotype with onset in early school age, but are phenotypically not distinguishable from the ML III α/β patients (Nampoothiri et al. 2019). Introduction In mucolipidosis type IV (ML VI; OMIM#252650), another ultra-rare autosomal recessive disorder predomiIn this chapter different lysosomal storage disorders are nantly present among Ashkenazi Jews (Bargal et al. 2001), described that do not necessarily share a mutual pathophysi- mutations in MCOLN1, which encodes for the transient ological mechanism, but do cause lysosomal dysfunction receptor potential cation channel, mucolipin-1 subfamily and have overlap in clinical presentation. In both mucolipi- member 1 (TRPML1), lead to lysosomal dysfunction dosis type II and III (ML II/III) and in multiple sulfatase defi- (Clapham et  al. 2001). This channel is distributed in the ciency (MSD), the deficiency of an extra-lysosomal enzyme membranes of late endosomes and lysosomes in all tissues, results in the deficiency of lysosomal enzymes. In mucolipi- with the highest expression in the brain, kidney, liver, spleen, dosis type IV, lysosomal dysfunction is caused by a defect in and heart (Cheng et al. 2010). It is nonselective permeable to a cation channel in the membrane of lysosomes, and both several cations. Abnormal flux of calcium probably is the cathepsin K and C deficiency are lysosomal proteases whose most important in the lysosomal dysfunction in ML IV, deficiency results in a distinct clinical picture. We will briefly resulting in dysregulation of autophagy, vesicular traffickintroduce all disorders separately. ing, and mammalian target of rapamycin (mTOR) and tranMucolipidoses: mucolipidosis type II (ML II; I-cell dis- scription factor EB (TFEB) signaling (Boudewyn and ease OMIM#252500) and mucolipidosis type III α/β or γ Walkley 2019). Patients with ML IV do not have the typical (pseudo-Hurler dystrophy, ML III α/β; OMIM#252600, dysmorphic features, as seen in ML II/III. Patients can have ML III γ; OMIM#252605) are rare autosomal recessive lyso- severe psychomotor delay (slowly progressive over time) somal storage disorders (Maroteaux and Lamy 1966; Leroy due to neuronal dysmyelination, hypotonia which gradually and Martin 1975). The birth prevalence in the Netherlands is progresses to spasticity during childhood, speech deficits, less than 1 per 100.000. In ML II and ML III, there is absent retinal degeneration, and optic atrophy causing visual impairor reduced activity of the membrane-bound enzyme UDP-N-­ ment. Other symptoms are cornea clouding, achlorhydria acetyl glucosamine-1-phosphotransferase (GlcNAc-1-­ with increased gastrin secretion and iron deficiency anemia, phosphotransferase), a hexameric complex, with three and kidney disease and failure, which finally leads to a shortsubunits; α2, β2 (GNPTAB), and γ2 (GNPTG). GlcNAc-1-­ ened life span in the patients (Boudewyn and Walkley 2019). phosphotransferase is responsible for the first step in the Most of them are still alive at least in the first two to three phosphorylation of enzyme-conjugated mannose residues to decades; thereafter, it is still unknown. From the patients that form mannose-6-phosphate (Reitman and Kornfeld 1981). died in the second decade, the cause of death was not exactly Mannose-6-phosphate serves as the recognition marker for known (Bargal et al. 2001). the targeting of more than 70 newly synthesized soluble Multiple sulfatase deficiency: multiple sulfatase defilysosomal enzymes to the lysosome. Absence or reduced ciency (MSD; OMIM #272200), an ultra-rare disorder with presence of this marker results in secretion of lysosomal autosomal recessive inheritance, was first described in 1964 enzymes in the plasma, where they are unable to execute by Austin et al. (Austin et al. 1964) and results from the defitheir function and substrates, such as glycosaminoglycans ciency of formylglycine-generating enzyme (FGE) due to (GAGs) and (glyco)sphingolipids, accumulate in the lyso- mutations in SUMF1 (sulfatase-modifying factor 1). Only some. The clinical picture of ML II and ML III mostly approximately 100 cases have been described to date, but resembles that of the mucopolysaccharidoses and much less MSD is most likely still underdiagnosed due to the broad that of the sphingolipidoses and other lysosomal storage dis- clinical spectrum seen in patients. FGE plays a crucial role in orders. There is a clinical spectrum with severely affected the post-translational activation of sulfatases by modifying a patients (MLII) at one end of the spectrum and milder conserved cysteine residue into formylglycine at the active patients at the other end (ML III). There is also an “interme- site, necessary for the catalytic activity of sulfatases. Its defidiate” phenotype with features of both ML II and ML III ciency therefore affects the activity of all known 17 sulfapatients (Cathey et  al. 2010). The patients with the most tases, including 8 lysosomal sulfatases, of which 6 are severe form of ML II are already severely affected at birth associated with well-characterized lysosomal storage

62  Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

disorders (i.e., metachromatic leukodystrophy (OMIM #250100), mucopolysaccharidoses types II (OMIM #309900), III A (OMIM #252900) and D (OMIM #252940), IV A (OMIM #253000), and VI (OMIM #253200)), 1 in the endoplasmatic reticulum associated with X-linked ichthyosis (OMIM #308100), and 1 in the Golgi complex associated with chondrodysplasia punctata type I (OMIM #302950). The clinical phenotype of MSD can be very heterogeneous and is dependent on FGE protein stability and residual enzyme activity and the degree the different sulfatases are affected. Four clinical subtypes can be distinguished based on the main presenting symptoms and age of symptom onset: a neonatal, severe late infantile, mild late infantile, and juvenile form of MSD (Ahrens-Nicklas et al. 2018). Cathepsin K deficiency (pycnodysostosis): pycnodysostosis (OMIM #265800) is an ultra-rare, prevalence is estimated at one to three per million, osteochondrodysplasia with autosomal recessive inheritance (Bizaoui et al. 2019). It was first described in 1962 (Maroteaux and Lamy 1962), and since a few hundred cases have been published, the most well-known being the French painter Henri de Toulouse-­ Lautrec (Markatos et al. 2018). Pycnodysostosis is caused by the deficiency of lysosomal cathepsin K encoded by CTSK. Cathepsin K belongs to the papain-like cysteine protease family and is mainly expressed in osteoclasts where it plays a central role in bone resorption by degrading collagen type I. Cathepsin K is also expressed in other tissues where it is involved in extracellular matrix remodeling, adipogenesis, thyroxine liberation, and peptide hormone regulation (Novinec and Lenarcic 2013). Its deficiency causes a distinct clinical phenotype characterized by short stature and the formation of hard and dense bones with thick cortices (osteope-

1237

trosis), resulting in frequent fractures and skeletal problems including dysplasia of the cranium, mandible, clavicle, and distal phalanges. In addition, dental abnormalities are frequently seen including dental crowding, delayed eruption of permanent teeth, enamel hypoplasia, and hypercementosis (Xue et al. 2011; Wen et al. 2016). Cathepsin C deficiency: cathepsin C deficiency is best known as Papillon–Lefèvre syndrome (PLS; OMIM #245000) characterized by a severe early-onset periodontitis, resulting in the premature loss of both deciduous and permanent teeth, and palmoplantar keratosis. It is also associated with Haim–Munk syndrome (HMS; OMIM #245010), which resembles PLS but in addition also exhibits arachnodactyly, acro-osteolysis, and onychogryphosis (Hart TC et al. 2000). PLS is an ultra-rare disorder with an estimated prevalence of approximately one to four per million and autosomal recessive inheritance (Machado et  al. 2019). Cathepsin C, encoded by CTSC and also known as dipeptidyl peptidase 1, also belongs to the papain-like cysteine protease family and is ubiquitously expressed. By removing dipeptides from the N-terminus of its substrates, it has a major role in the activation of pro-inflammatory granule-associated serine proteases, which degrade various extracellular matrix compounds causing tissue damage and chronic inflammation. It also has been suggested to play an important role in epithelial differentiation and desquamation, which could explain the palmoplantar keratosis seen in patients (Korkmaz et al. 2018). Besides the characteristic severe periodontitis and palmoplantar keratosis, patients have a higher susceptibility to infections, especially skin, respiratory, and urinary tract infections, and may exhibit a delay in somatic development, keratosis pilaris, and hyperhidrosis.

Disorder Mucolipidosis type II

Mucolipidosis type III alpha, beta

Mucolipidosis type III, gamma

Mucolipidosis type IV

Multiple sulfatase deficiency

Cathepsin K deficiency Cathepsin C deficiency

No. 62.1

62.2

62.2

62.3

62.4

62.5 62.6

Nomenclature

Mucosulfatidosis Austin disease Pycnodysostosis Papillon–Lefèvre syndrome Haim–Munk syndrome

Pseudo-hurler

Pseudo-hurler

Alternative name I-cell disease

PLS/HMS

MSD

ML IV

CTSK CTSC

SUMF1

MCOLN1

GNPTG

GNPTAB

ML III α, β ML III ƴ

Gene symbol GNPTAB

Abbreviation ML II

1q21.3 11q14.2

3p26.1

19p13.2

16p13.3

12q23.3

Chromosomal localization 12q23.3

AR AR

AR

AR

AR

AR

Inheritance AR

Affected protein UDP-N-acetyl glucosamine-1-­ phosphotransferase (GlcNAc-PTase) UDP-N-acetyl glucosamine-1-­ phosphotransferase (GlcNAc-PTase) UDP-N-acetyl glucosamine-1-­ phosphotransferase (GlcNAc-PTase) Transient receptor potential channel mucolipin-1 (TRPML1) Formylglycine-generating enzyme (FGE) Cathepsin K Cathepsin C

265800 245000/245010

272200

252650

252605

252600

OMIM no. 252500

1238 H. H. Huidekoper and E. Oussoren

62  Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

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Metabolic Pathways

endosome GlcNAc-1phosohotransferase FGE 1

ML

P TR

Iysosome

Golgi

ER

MSD: defective sulfatase activation

ML II/III: defective mannose-6 phosphate (M6P) transport

inactive sulfatase

M6P

active sulfatase

M6P receptor

Iysosomal hydrolase

M6P-containing Iysosomal enzyme

Fig. 62.1  Intracellular lysosomal enzyme processing and trafficking. After production more than 70 lysosomal enzymes are transported from the ER to the Golgi complex where a mannose-6-phosphate residue is added by UDP-N-acetyl glucosamine-1-phosphotransferase (GlcNAc-1-­phosphotransferase), defective in mucolipidosis type II/III (ML II/III), which serves as a key targeting signal for the intracellular routing of enzymes towards lysosomes. In addition, lysosomal sulfatases need to be activated by

ML IV: defective cation channel

formylglycine-generating enzyme (FGE), defective in multiple sulfatase deficiency (MSD), in the ER before transportation to the Golgi complex. The TRPML1 cation channel present in the membranes of late endosomes and lysosomes, defective in mucolipidosis type IV, is essential for the nonselective flux of cations, necessary for regulation of lysosomal autophagy and vesicular trafficking and mammalian target of rapamycin (mTOR) and transcription factor EB (TFEB) signaling

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H. H. Huidekoper and E. Oussoren

Signs and Symptoms Table 62.1  Mucolipidosis II alpha-beta System Cardiovascular CNS

Digestive Ear Endocrine Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Cardiomyopathy Valvular thickening Cortical atrophy (MRI) Cortical atrophy (MRI) Hypomyelination, CNS Intellectual disability Retardation, motor Speech disturbances Spinal cord compression Subcortical atrophy (MRI) Hepatosplenomegaly Recurrent otitis media Hyperparathyroidism Corneal clouding Carpal and tarsal syndrome Coarse facial features Craniosynostosis Dysostosis multiplex Gingival hypertrophy Hernias (umbilical, inguinalis) Hip dislocation Hypotonia, muscular-axial Joint contractures Glycosaminoglycans Lysosomal enzyme activities (fibroblast) Lysosomal enzyme activities (serum) Oligosaccharide (urine)

Neonatal (birth–1 month) ± ± + ± + + +

Childhood (1.5–11 years) + ++ ++ ++ +++ +++ +++ ++ ++ ++

Adolescence (11–16 years) + ++ + + ± ± ++

±

Infancy (1–18 months) ± + + + ++ ++ ++ + + +

Adulthood (>16 years)

± + ± + n

+ ++ ± ++ ±

++ +++ n ++ +

++ ± n ++ ++

+ + + + +

++ + ++ ++ +

+++ + +++ +++ +

++ ± +++ ++ +

± +

+ +

++ ±

+++ ±

+ n-↑ ↓↓↓

++ n-↑ ↓↓↓

++ n-↑ ↓↓↓

++

↑↑↑

↑↑↑

↑↑↑

↑↑

↑↑

↑↑

Infancy (1–18 months) ±

Childhood (1.5–11 years) + ± ++ ± ±

Adolescence (11–16 years) + ± ++ + ±

Adulthood (>16 years) ± + ++ + ±

+ ++

+ ++ +

+ ++ ++

n-↑ ↓↓

n-↑ ↓↓

n-↑ ↓↓

↑↑ n-↑

↑↑ n-↑

↑↑ n-↑

++ +

Table 62.2  Mucolipidosis III alpha-beta-gamma System CNS Ear Musculoskeletal

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Intellectual disability Spinal cord compression Recurrent otitis media Carpal tunnel syndrome Coarse facial features (puffy cheeks) Dysostosis multiplex Joint contractures Osteoarthritis (all joints can be involved) Glycosaminoglycans Lysosomal enzymes (fibroblasts) Lysosomal enzymes (serum) Oligosaccharide (urine)

+

± ±

62  Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

1241

Table 62.3  Mucolipin 1 deficiency System CNS

Eye

Digestive Hematological Renal Musculoskeletal Laboratory findings

Symptoms and biomarkers Bilateral tract pyramidal tract signs Cerebellar atrophy Epilepsy Hypotonia Intellectual disability Motor delay Reduced size of corpus callosum Spasticity Speech delay Cornea clouding Myopia Optic nerve atrophy Photophobia Retinal degeneration Strabismus Visual impairment Achlorhydria Iron deficiency anemia Kidney disease (failure) Growth retardation Blood gastrin Blood Iron (iron deficiency anemia)

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years)

±

+ ± + + + +

+ ± + ++ ++ +

++ ±

++ ±

++ ++ +

++ +++ +

+

++ + ± ± + ± + + +++ + ± ± + ↑ ↓-n

+++ ++ ± ± ++

+++ ++ ± ± +++

++ + +++ + ± + ± ↑ ↓-n

+++ + +++ + ± ++ ±

± ± ± ±

± ±

± ± ±

± + + + ±

± + ++ + ±

↑ ↓-n

± ↑ ↓-n

Table 62.4  Multiple sulfatase deficiency System CNS

Dermatological Digestive Eye Musculoskeletal

Respiratory

Symptoms and biomarkers Gait disturbance Hypomyelination, CNS Intellectual disability Leukodystrophy Slow nerve conductive velocity Cortical atrophy (MRI) Hydrocephalus Neurologic deterioration Retardation, psychomotor Seizures Spasticity Speech disturbances Ichthyosis Hepatosplenomegaly Ophthalmological anomalies Coarse facial features Dysostosis multiplex Growth retardation Hypotonia, muscular-axial Cardiopulmonary involvement

Neonatal (birth-1 month)

Infancy (1–18 months) +++ + +++ +++ +

Childhood (1.5–11 years) +++ + ++ + +

++ +++ +

+ ± ++ +++ ± +++ +++ + ± ±

+ ± ++ ++ ± +++ +++ + ± ±

+++ +++ +++ +++

+ ± + ±

+ ± ± ±

++

±

±

+++

± +++ ±

Adolescence (11–16 years)

+

+ ++

+

Adulthood (>16 years)

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H. H. Huidekoper and E. Oussoren

Table 62.5  Cathepsin K deficiency System Digestive

Eye Musculoskeletal

Respiratory

Symptoms and biomarkers Dental crowding/ displacement Delayed eruption of permanent teeth Enamel hypoplasia Hypercementosis Obliteration of pulp chambers Periodontitis Persistant desiduous teeth Blue sclera Abnormal cranial suture closure Acro-osteolysis Aquiline nose Growth retardation Increased bone density (osteopetrosis) Mandibular and/or maxillary hypoplasia Short stature Skull deformity Upper airway obstruction

Neonatal (birth to 1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

±

±

±

± ± ±

± ± ±

± ± ±

±

± ±

± ±

± ±

−

± +

± +

± +

± +

± ± ± +

+ ± ++ ++

++ ± +++ +++

++ ± +++ +++

++ ± +++ +++

+

++

++

++

++

±

++ + ±

+++ + ±

+++ + ±

+++ + ±

−

±

Table 62.6  Cathepsin C deficiency System Autonomic system Dermatological

Digestive

Musculoskeletal Other

Symptoms and biomarkers Hyperhidrosis

Neonatal Infancy (birth–1 month) (1–18 months)

Keratosis pilaris Onychogryphosis* Palmoplantar hyperkeratosis ± Periodontitis Loss of deciduous teeth Loss of permanent teeth Acro-osteolysis* Arachnodactyly* Delay in somatic development Increased susceptibility to infections

* Characteristic for Haim-Munk syndrome (HMS)

+ + ±

± ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± + +++ +++ ± ± ± ± ±

± ++ ++ +++

± ++ ++ +

+++ ++ ++ ± ±

+ ++ ++ ± ±

62  Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

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Reference Values For the diagnosis of mucolipidosis type II/III and cathepsin C deficiency, the following enzymatic assays are used (normal ranges may vary between laboratories). Please see Chaps. 60 “Lipidoses” and 64 “Mucopolysaccharidoses” for details on the different sulfatase assays which can be used for the diagnosis of multiple sulfatase deficiency. No. 62.1

Disorder Mucolipidosis type II

Enzyme(s) β-Hexosaminidase A β-Hexosaminidase A+B α-l-Fucosidase β-d-Glucuronidase α-d-Mannosidase β-D-Galactosidase

Material Plasma/fibroblasts

62.2 62.2 62.4 62.6

Mucolipidosis type III alpha, beta Mucolipidosis type III, gamma Multiple sulfatase deficiency Cathepsin C deficiency

See 62.1 See 62.1 See Chaps. 60 and 64 Cathepsin C

See 62.1 See 62.1 See Chaps. 60 and 64 Leucocytes Fibroblasts

Normal range In nmol/h/mg: 22–63/292–1,200 620–3,700/4,000–23,900 80–800/35–160 12–160/78–270 20–120/39–180 N.A./320–1,900 See 62.1 See 62.1 See Chaps. 60 and 64 685–1,200 μmol/min/mg 4030–11,700 nmol/h/mg 1,180–9,610 nmol/h/mg

Reference Erasmus MCa

See 62.1 See 62.1 See Chaps. 60 and 64 Hart PS et al. (2000) Erasmus MCa Erasmus MCa

N.A. Not applicable a Control values obtained in the laboratory of Clinical Genetics at the Erasmus MC University Medical Center, Rotterdam, The Netherlands

Pathological Values

the variable expressivity in patients carrying the same mutation (Velho et al. 2019). The diagnosis of mucolipidoses (ML), multiple sulfatase ML IV can only be diagnosed by molecular analysis of deficiency (MSD), and cathepsin K and C deficiency is based MCOLN1. Increased gastrin secretion and iron deficiency on enzymatic analysis and/or molecular analysis. No specific anemia are indicative for ML IV and can support the diagnostic biomarkers are known for these disorders, diagnosis. although biochemical abnormalities are seen: urinary glyMultiple sulfatase deficiency: the diagnosis of MSD is cosaminoglycans (GAGs) excretion can be increased in ML based on demonstrating reduced activity of at least two sulII and III as well as in MSD.  Urinary sulfatides may be fatases in leucocytes or fibroblasts as patients can be missed increased in MSD, in ML II, bound sialic acid is elevated in if only one sulfatase is assayed (Schlotawa et  al. 2011). urine. As these can also be normal in ML and MSD, they Hereafter, the diagnosis should be confirmed with molecular cannot be used to exclude these disorders. In ML and MSD, analysis by demonstrating a pathogenic alteration on both as well as in attenuated forms of cathepsin K and C defi- alleles of SUMF1. Several specific genotype–phenotype corciency, the clinical phenotype may be less distinct. These relations have been established, where mutations strongly forms are more likely to be diagnosed through untargeted affecting protein stability and residual enzyme activity are molecular analysis, especially with exome sequencing since associated with a more severe clinical phenotype (Sabourdy this is now more widely used in patients with an unexplained et al. 2015). clinical phenotype. Cathepsin K deficiency (pycnodysostosis): the distinct Mucolipidoses: for ML II/III first-level diagnostic clinical and radiographic features of pycnodysostosis are the procedures include measurement of the activity of sev- most important clues towards diagnosis. Detecting acro-­ eral lysosomal enzymes including β-hexosaminidase A, osteolysis in combination with increased bone density upon β-hexosaminidase A+B, α-l-fucosidase, β-d-glucuronidase, radiological evaluation is almost pathognomonic of the disα-d-mannosidase, and β-d-galactosidase in plasma and/or order. The diagnosis can only be confirmed by molecular fibroblasts, where these enzymes are elevated in plasma analysis of CTSK demonstrating pathologic alterations on and decreased in fibroblasts. In addition, GlcNAc-1-­ both alleles. Until now genotype–phenotype relations have phophotransferase activity can be measured in fibroblasts. not been established (Bizaoui et al. 2019). CTSK mutations Finally, molecular analysis of GNPTAB (ML II and III α, have also been detected in patients with a more attenuated β) or GNPTG (ML III γ) can be performed. Genotype-­ osteopetrosis phenotype without the distinct clinical features phenotype correlations in the MLII/III are difficult to estab- of pycnodysostosis and should therefore be considered in all lish due to the high proportion of individual mutations and patients with unexplained osteopetrosis (Schlotawa et  al.

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H. H. Huidekoper and E. Oussoren

2011). Differentiating pycnodysostosis from other forms of osteopetrosis is important as the latter may benefit from early hematopoietic stem cell transplantation whereas this has no proven benefit in pycnodysostosis (Bizaoui et al. 2019). Cathepsin C deficiency: as with cathepsin K deficiency, the distinct clinical features of palmoplantar hyperkeratosis and periodontitis seen in Papillon–Lefèvre syndrome offer the most important clues for cathepsin C deficiency. An

enzymatic assay for cathepsin C has been described (Hart PS et al. 2000), but is not widely available. Diagnosis should be confirmed with molecular analysis of CTSC. To date 89 disease-­causing mutations have been described, all affecting the heavy chain of cathepsin C which is essential for its tetramer formation and protein function. No consistent genotype–phenotype relations have been established (Machado et al. 2019).

Diagnostic Flowchart

Predominant clinical phenotype

MPS work-up (see chapter 64). Diagnosis of MPS?

MPS-like phenotype

Yes

Urinary GAGs increased?

No

No

Developmental delay & corneal clouding

Short stature & facial dysmorphism*

Periodontitis & palmoplantar keratosis

Laboratory findings: • iron deficiency anemia • increased blood gastrin level

Radiological findings: • increased bone density • acro-osteolysis • non-pneumatized mastoids • abnormal cranial suture closure

Skin abnormalities: • keratotic plaques on palmar and plantar regions • keratosis pilaris

Ichthyosis Urinary sulfatides increased? Yes

Multiple sulfatase deficiency molecular analysis of SUMF1

No

Increased activity of Iysosomal enzymes in plasma?

No Consider other genetic disorders consultation of clinical geneticist; WES#

Dental abnormalities: • dental crowding • malocclusion • enamel hypoplasia • obliteration of pulp chambers • hypercementosis

Yes

Mucolipidosis type II / III molecular analysis of GNPTAB and GNPTG

Mucolipidosis type IV molecular analysis of MCOLN1

Cathepsin K def,; Pycnodysostosis molecular analysis of CTSK

Fig. 62.2  Diagnostic flowchart based on predominant clinical features *Frontal bossing, mandibular and/or maxillary hypoplasia, aquiline nose, proptosis, blue sclera # Whole exome sequencing

Dental abnormalities: • premature loss of deciduous and permanent teeth (due to periodontitis)

Higher susceptibility to infections: • skin • respiratory • urinary tract

Cathepsin C def,; Papillon Lefèvre syndr. molecular analysis of CTSC

62  Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

Treatment and Follow-Up

1245

culoskeletal problems, including dysostosis multiplex, contractures, and muscle tone dysregulation and/or muscle All lysosomal disorders discussed in this chapter are multi-­ weakness, requiring the involvement of a physiotherapist system diseases for which no curative treatments are avail- and rehabilitation specialist as well as pharmacological manable. Multidisciplinary supportive treatment is therefore agement of tone abnormalities. A specialized dermatologist essential, as well as palliative care for the patients with a is needed to treat ichthyosis. Other potential clinical issues shortened life span. Supportive treatment and develop- requiring specialized care include symptoms related to GAG ments in innovative treatment approaches are discussed accumulation in different tissues as seen in MPS; see details below. in Chap. 64. Patients should be seen at regular time intervals (every 3–6  months is suggested depending on the disease burden) to monitor the progression of the disease and its Supportive Treatment complications, preferably using standardized outcome measures in order to obtain more knowledge about the natural Mucolipidoses: as the clinical phenotype of ML II/III patients course of MSD.  For more details and a comprehensive is similar to the patients with mucopolysaccharidosis (MPS), guideline on treatment and follow-up in MSD, see Ahrens-­ the multidisciplinary supportive care described for MPS Nicklas et al. 2018 (Ahrens-Nicklas et al. 2018). patients in Chap. 64 can also be used for patients with ML II/ Cathepsin K deficiency (pycnodysostosis): as pycnodysIII. Patients with ML II are poor feeders with stunted growth ostosis is primarily a bone disease and patients are prone to and are often overfed. Most children need nasogastric tube fractures, (parents of) patients should be instructed to avoid feeding and dietary support. Patients with ML III have skele- activities that increase the risk of fractures. Nevertheless, tal problems and often develop secondary osteoarthritis (more most patients require at least one surgical intervention in severe than observed in MPS patients), necessitating surgical their life span (Bizaoui et al. 2019). As bone remodeling is orthopedic interventions relatively early in life. impaired due to the osteoclastic dysfunction, open reduction Orthopedic follow-up is necessary, with involvement of with internal fixation (direct bone healing) is advised over the care of a rehabilitation specialist and occupational thera- external fixation with casting (indirect bone healing) in fracpist. ML III patients experience bone pain due to secondary ture management (Grewal et  al. 2019). It should be noted osteoarthritis and osteopenia causing microfractures. there is an increased risk of developing osteomyelitis with all Adequate pain management is important in this patient surgical procedures as bone blood supply in pycnodysostosis group, which may require an expert in pain management. is decreased. An important aspect of the disease is upper airBisphosphonates have been given to ML III patients way obstruction due to the mandibular and/or maxillary (Robinson et al. 2002; Zolkipli et al. 2005; Kerr et al. 2011; hypoplasia, the long soft palate, and possible laryngomalaKobayashi et  al. 2011). Their effect on bone pain remains cia. This can lead to severe obstructive apnea requiring a unclear. Since long-term use of these drugs suppresses bone nasopharyngeal tube and/or noninvasive ventilation and posturnover and consequently may have a negative effect on sibly surgical interventions, during childhood. Patients can final height, they may be of limited use in ML III. be very difficult to intubate, and airway management should For patients with ML IV, neurological and pediatric fol- be carefully evaluated before any procedure requiring genlow-­up is important. There is a psychomotor delay in all the eral anesthesia is scheduled. Dental hygiene and managepatients, and in infancy patients are hypotonic, which gradu- ment are essential as patients are prone to develop severe ally progresses to spasticity during childhood. All patients caries with the dental abnormalities seen in pycnodysostosis; develop visual impairment due to corneal clouding, strabis- patients should be seen by a (specialized) dentist at least mus, myopia, retinal degeneration, and/or optic atrophy, for once a year. Patients may exhibit a Chiari malformation which they need ophthalmologic follow-up. It has been noted related to the cranial dysplasia; it is therefore advised to do a that many patients in the second to third decades of life suffer cerebral MRI in all patients after diagnosis. Finally, as from kidney disease and kidney failure, which needs follow- stunted growth is important in pycnodysostosis, supplemen­up by a nephrologist (Boudewyn and Walkley 2019). Patient tation of growth hormone can be considered and was with ML IV can have iron deficiency anemia for which they reported to be effective in 40% of the patients (Bizaoui et al. need iron supplementation, which must be monitored over 2019). time by measuring iron and hemoglobin levels in the blood. Cathepsin C deficiency: management in Papillon–Lefèvre Multiple sulfatase deficiency: the clinical spectrum in syndrome focuses on the preservation of permanent teeth in MSD is highly variable. Therefore, a tailor-made multidisci- young patient by controlling factors that contribute to the plinary approach is required in each patient in order to sup- destruction of the periodontium. This requires frequent port motor function, prevent secondary complications, and (every 3 months) specialized dentist care aimed at prevention maintain an adequate quality of life. Most patients have mus- and early treatment of periodontitis with oral hygiene instruc-

1246

tions using chlorhexidine gluconate 0.2% mouth rinses and antibiotic treatment when necessary. Development of pyogenic liver and skin abscesses due to bacteremia is a complication of periodontitis seen in PLS because of impairment of the immune system. Renal and cerebral abscesses have also been described. Deciduous teeth should be extracted when they have a poor prognosis and cause a potential problem for the eruption of permanent teeth. Extraction of permanent teeth with advanced periodontal disease is also required. In order to preserve chewing function, dental prostheses are needed involving fabrication of partial or complete dentures with an age-specific approach. Management of the dermatological manifestations seen in PLS requires the involvement of a specialized dermatologist. The mainstay of treatment is anti-inflammatory emollients; keratolytics, such as salicylic acid and topical steroids; and oral retinoids, which have been shown to improve both dental and cutaneous lesions of PLS. Retinoids decrease the total keratin content of keratinocytes, are involved in the regulation of growth and differentiation of epithelial cells, and may have a positive effect on inflammation by stimulating both humoral and cellular immunity. Prescribers should be aware of adverse effects which include dryness of lips, mild pruritus, transient hair loss, and elevated serum triglycerides and liver enzymes due to liver toxicity and teratogenicity. Long-term use of retinoids can cause bone toxicity with growth disturbances due to premature epiphyseal closure and traumatic fractures (Sreeramulu et al. 2015; Korkmaz et al. 2018).

H. H. Huidekoper and E. Oussoren

Multiple sulfatase deficiency: combined rAAV9 gene therapy, where a single injection of this vector was given both systemic and in the cerebral ventricles, was shown to result in a widespread transduction of tissues, leading to the activation of sulfatases, a near complete clearance of glycosaminoglycans (GAGs), a decrease in inflammation in both the central nervous system and visceral organs, and an improvement in behavior and survival of SUMF1 knockout mice (Spampanato et al. 2011). Further work on the development of gene therapy for MSD has not been reported. Currently, there is no evidence to support the use of HSCT in MSD (Tan et al. 2019). Cathepsin K deficiency (pycnodysostosis): to our knowledge no innovative treatment approaches for pycnodysostosis are under development. This may be related to the fact that enzyme replacement treatment strategies are known to be less effective for skeletal disease manifestations. Hematopoietic stem cell transplantation has been proven effective in several genetic forms of osteopetrosis, but its therapeutic potential in pycnodysostosis remains yet to be shown (Bizaoui et al. 2019). Cathepsin C deficiency: autophagic flux has been shown to be impaired in Papillon–Lefèvre syndrome and is suggested to play an important role in PLS pathophysiology. Providing recombinant cathepsin C to fibroblasts of PLS patients partially restored autophagic flux, reduced lysosomal membrane permeability, and improved the fibroblast growth rate (Bullon et al. 2018). This suggests that enzyme replacement therapy and gene therapy approaches may be of interest in PLS.

Innovative Treatments Mucolipidoses: in ML II patients, hematopoietic stem cell transplantation (HSCT) has been explored but was proven ineffective (Lund et al. 2014). As in both ML II/III and ML IV, a transmembrane protein is involved, it is highly unlikely that this approach would be effective (Boudewyn and Walkley 2019). In patients with lysosomal storage diseases, an inflammatory component, arising from the accumulation of lysosomal storage products, contributes to the pathophysiology. Reducing this inflammatory response could be a possible target of treatment. This may be achieved by drugs such as pentosan polysulfate (PPS), as this drug has shown to improve range of motion and reduce pain in MPS I patients in a short-term study (Hennermann et al. 2016). Recently, a proof of concept for the development of an anti-sense oligonucleotide to induce exon skipping of exon 19 in GNPTAB, in order to overcome the deleterious effect of the most common c.3503_3504del mutation in ML II, was reported (Matos et al. 2020). Some clinical aspects, like bone disease, in ML II are less likely to be treated with this approach, as they have their origin in fetal development.

References Ahrens-Nicklas R, Schlotawa L, Ballabio A, et  al. Complex care of individuals with multiple sulfatase deficiency: clinical cases and consensus statement. Mol Genet Metab. 2018;123:337–46. Austin J, McAfee D, Armstrong D, O’Rourke M, Shearer L, Bachhawat B.  Abnormal sulphatase activities in two human diseases (metachromatic leucodystrophy and gargoylism). Biochem J. 1964;93:15C–7C. Bargal R, Avidan N, Olender T, et  al. Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat. 2001;17:397–402. Bizaoui V, Michot C, Baujat G, et al. Pycnodysostosis: natural history and management guidelines from 27 French cases and a literature review. Clin Genet. 2019;96:309–16. Boudewyn LC, Walkley SU. Current concepts in the neuropathogenesis of mucolipidosis type IV. J Neurochem. 2019;148:669–89. Bullon P, Castejon-Vega B, Roman-Malo L, et  al. Autophagic dysfunction in patients with Papillon-Lefevre syndrome is restored by recombinant cathepsin C treatment. J Allergy Clin Immunol. 2018;142:1131–1143.e1137. Cathey SS, Leroy JG, Wood T, et al. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet. 2010;47:38–48.

62  Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency Cheng X, Shen D, Samie M, Xu H. Mucolipins: intracellular TRPML1-3 channels. FEBS Lett. 2010;584:2013–21. Clapham DE, Runnels LW, Strubing C. The TRP ion channel family. Nat Rev Neurosci. 2001;2:387–96. Grewal S, Kilic O, Savci-Heijink CD, Kloen P. Disturbed remodeling and delayed fracture healing in pediatric pycnodysostosis patients. J Orthop. 2019;16:373–7. Hart PS, Zhang Y, Firatli E, et al. Identification of cathepsin C mutations in ethnically diverse papillon-Lefevre syndrome patients. J Med Genet. 2000;37:927–32. Hennermann JB, Gokce S, Solyom A, Mengel E, Schuchman EH, Simonaro CM.  Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study. J Inherit Metab Dis. 2016;39:831–7. Kerr DA, Memoli VA, Cathey SS, Harris BT.  Mucolipidosis type III alpha/beta: the first characterization of this rare disease by autopsy. Arch Pathol Lab Med. 2011;135:503–10. Kobayashi H, Takahashi-Fujigasaki J, Fukuda T, et  al. Pathology of the first autopsy case diagnosed as mucolipidosis type III alpha/ beta suggesting autophagic dysfunction. Mol Genet Metab. 2011;102:170–5. Korkmaz B, Caughey GH, Chapple I, et  al. Therapeutic targeting of cathepsin C: from pathophysiology to treatment. Pharmacol Ther. 2018;190:202–36. Leroy JG, Martin JJ. Mucolipidosis II (I-cell disease): present status of knowledge. Birth Defects Orig Artic Ser. 1975;11:283–93. Lund TC, Cathey SS, Miller WP, et al. Outcomes after hematopoietic stem cell transplantation for children with I-cell disease. Biol Blood Marrow Transplant. 2014;20:1847–51. Machado RA, Cuadra-Zelaya FJM, Martelli-Junior H, et  al. Clinical and molecular analysis in Papillon-Lefevre syndrome. Am J Med Genet A. 2019;179:2124–31. Markatos K, Mavrogenis AF, Karamanou M, Androutsos G. Pycnodysostosis: the disease of Henri de Toulouse-Lautrec. Eur J Orthop Surg Traumatol. 2018;28:1569–72. Maroteaux P, Lamy M.  Pyknodysostosis. Presse Med. 1962;70:999–1002. Maroteaux P, Lamy M. [Hurler’s pseudo-polydystrophy] La pseudo-­ polydystrophie de Hurler. Presse Med. 1966;74:2889–92. Matos L, Vilela R, Rocha M, et  al. Development of an antisense oligonucleotide-­ mediated exon skipping therapeutic strategy for mucolipidosis II: validation at RNA level. Hum Gene Ther. 2020;31:775–83.

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Nampoothiri S, Elcioglu NH, Koca SS, et al. Does the clinical phenotype of mucolipidosis-IIIgamma differ from its alphabeta counterpart?: Supporting facts in a cohort of 18 patients. Clin Dysmorphol. 2019;28:7–16. Novinec M, Lenarcic B. Cathepsin K: a unique collagenolytic cysteine peptidase. Biol Chem. 2013;394:1163–79. Reitman ML, Kornfeld S.  UDP-N-acetylglucosamine:glycoprotein N-acetylglucosamine-1-phosphotransferase. Proposed enzyme for the phosphorylation of the high mannose oligosaccharide units of lysosomal enzymes. J Biol Chem. 1981;256:4275–81. Robinson C, Baker N, Noble J, et al. The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment. J Inherit Metab Dis. 2002;25:681–93. Sabourdy F, Mourey L, Le Trionnaire E, et al. Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency. Orphanet J Rare Dis. 2015;10:31. Schlotawa L, Ennemann EC, Radhakrishnan K, et  al. SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Hum Genet. 2011;19:253–61. Spampanato C, De Leonibus E, Dama P, et al. Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder. Mol Ther. 2011;19:860–9. Sreeramulu B, Shyam ND, Ajay P, Suman P.  Papillon-Lefevre syndrome: clinical presentation and management options. Clin Cosmet Investig Dent. 2015;7:75–81. Tan EY, Boelens JJ, Jones SA, Wynn RF.  Hematopoietic stem cell transplantation in inborn errors of metabolism. Front Pediatr. 2019;7:433. Velho RV, Harms FL, Danyukova T, et  al. The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: update on GNPTAB and GNPTG mutations. Hum Mutat. 2019;40:842–64. Wen X, Yi LZ, Liu F, Wei JH, Xue Y. The role of cathepsin K in oral and maxillofacial disorders. Oral Dis. 2016;22:109–15. Xue Y, Cai T, Shi S, et al. Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. Orphanet J Rare Dis. 2011;6:20. Zolkipli Z, Noimark L, Cleary MA, Owens C, Vellodi A. Temporomandibular joint destruction in mucolipidosis type III necessitating gastrostomy insertion. Eur J Pediatr. 2005;164:772–4.

Oligosaccharidoses and Sialic Acid Disorders

63

Michael Beck and Zoltan Lukacs

Contents Introduction

 1250

Nomenclature

 1252

Signs and Symptoms

 1253

Metabolic Pathways

 1258

Reference Values

 1259

Pathological Values

 1259

Diagnostic Flowcharts

 1260

Specimen Collection

 1261

Prenatal Diagnosis

 1262

DNA Testing

 1262

Treatment Summary

 1262

Standard Treatment

 1262

Experimental Treatment

 1263

References

 1264

Summary Zoltan Lukacs was deceased on 13. August 2020. M. Beck (*) SphinCS GmbH–Clinical Science for LSD, Hochheim, Germany e-mail: [email protected] Z. Lukacs Newborn Screening and Metabolic Diagnostics Unit, Hamburg University Medical Center, Hamburg, Germany

Oligosaccharidoses comprise a group of disorders which show glycoprotein excretion in urine and diminished activity of lysosomal enzymes that are involved in the degradation of sugar side chains (Tables 63.1–63.14). Among those are glycosylasparaginase deficiency (aspartylglucosaminuria), α-L-fucosidase deficiency (fucosidosis), αand β-mannosidase deficiency (α- and β-mannosidosis), α-N-­ acetylgalactosaminidase deficiency (Kanzaki and Schindler disease), and neuraminidase deficiency (siali-

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_63

1249

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dosis) (Fig. 63.1). In contrast to the latter, where the degradation of glycosides is impaired, disorders of sialic acid (= N-acetyl neuraminic acid, Neu5Ac) metabolism are based on different mechanisms: A defect of sialin, a transporter protein of the lysosomal membrane, leads to accumulation of sialic acid within the lysosomes and clinical consequences, namely to Salla disease and the more severe form, free sialic acid storage disorder (Fig.  63.2). Sialuria, inclusion body myopathy and a defect of N-acetylneuraminic acid synthase (NANS) are due to a disturbance of sialic acid biosynthesis. In patients with a deficiency of N-acetylneuraminate pyruvate lyase (NPL) the degradation of sialic acid is impaired. Oligosaccharidoses and sialic acid disorders are rare and present a wide phenotypic spectrum. Detection of oligosaccharides in urine and enzyme activity measurements in leukocytes or fibroblasts is usually diagnostic. Free sialic acid has to be assessed by HPLC. For final confirmation a molecular genetic test should be carried out. To date mainly palliative therapies can be provided.

Introduction The term oligosaccharidoses comprises a group of disorders that are caused by defective degradation of protein-bound sugar side chains as a result of deficiency in certain lysosomal enzymes. Hurler-like symptoms, skeletal abnormalities, hearing impairment, and neurological symptoms are common features of most of these conditions. As it is common to all lysosomal storage disorders, a broad phenotypic heterogeneity is observed within each of the o­ ligosaccharidoses, ranging from a severe neonatal to a milder adult form, making the clinical diagnosis often difficult. In sialidosis the enzyme neuraminidase is deficient. In vivo this enzyme is found within a multienzyme complex consisting of protective protein/cathepsin A (PPCA), neuraminidase and β-galactosidase. Cathepsin A stabilizes this structure, and a defect of that protein leads to the disease galactosialidosis in which both neuraminidase and ß-­ galactosidase are deficient. Clinically galactosialidosis resembles sialidosis.

M. Beck and Z. Lukacs

The diseases named after Schindler and Kanzaki represent different phenotypic expressions of α-N-­acetylgalactosaminidase (α-NAGA) deficiency. However, it seems that α-NAGA deficiency alone cannot explain the phenotypic variation among patients with the same mutation. The first two brothers described by Schindler et al. (Schindler et al. 1989) had clinical signs of neuroaxonal dystrophy, a neurodegenerative disorder that is now known to be caused by mutations of the PLA2G6 gene. Therefore it must be suggested that mutations in this gene have caused neuroaxonal dystrophy in the original patients with Schindler disease (Westaway et  al. 2007). And also in other patients with α-NAGA deficiency, no clear correlation between residual enzyme activity and the severity of symptoms exists. Therefore, most likely other factors or genes contribute to this clinical heterogeneity (Bakker et al. 2001). In contrast to oligosaccharidoses, where the degradation of sugar side chains is impaired, other pathogenetic mechanisms are responsible for sialic acid disorders. A defect of sialin, a specific carrier protein of the lysosomal membrane that transports sialic acid out of the lysosomes, leads to progressive accumulation of this compound in the cell, resulting in the allelic disorders free sialic acid storage disease and Salla disease. Free sialic acid storage disease represents the severe infantile form, characterized by global developmental delay, hepatosplenomegaly, cardiomegaly, and early death. The less severe adult form is named Salla disease after a geographic region in Finland where the patients’ families have lived. Patients with Salla disease show a broad phenotypic spectrum ranging from mild cognitive dysfunction and ataxia to an intermediate severe form characterized by coarse facial features, intellectual disability, hypotonia, and hepatosplenomegaly (Barmherzig et al. 2017). The biosynthesis of sialic acid is a complex process in which the enzyme UDP-GlcNac 2-epimerase/ManNAc kinase (GNE) plays an essential role as the master regulator. This enzyme consists of two independent functional domains, an N-terminal domain covering the epimerase activity and a C-terminal domain responsible for ManNAc kinase activity. In the initial step of sialic acid synthesis, the active site of UDP-GlcNac 2-epimerase converts UDP-GlcNAc into ManNAc. The activity of UDP-GlcNac 2-epimerase is regulated by allosteric feed-

63  Oligosaccharidoses and Sialic Acid Disorders

back inhibition by CMP-sialic acid, the final product of the synthetic pathway. Two disorders are known in GNE deficiency: hereditary inclusion body myopathy (or Nonaka myopathy; autosomal recessive) and sialuria (autosomal dominant). Sialuria is a genetic defect of the feedback inhibition of UDPGlcNac 2-epimerase resulting in cytoplasmic accumulation and urinary excretion of large amounts of free sialic acid. Characteristic clinical signs of sialuria include developmental delay, mildly coarse features, hepatomegaly, and prolonged neonatal jaundice (Ferreira et  al. 2018). Until now, only nine patients with sialuria have been described (Martinez et al. 2018). The C-terminal domain of UDP-GlcNac 2-epimerase/ManNAc kinase converts ManNAc into ManNAc-6-­ phosphate. Mutations of this domain, but in some cases also of the epimerase domain, lead to the autosomal recessive adult-onset hereditary inclusion body myopathy (HIBM), also called distal myopathy with rimmed vacuoles or Nonaka myopathy. In affected patients progressive muscle weakness and limb atrophy are the leading clinical signs. This is associated with muscle hyposialylation. A unique feature of hereditary inclusion body myopathy is the sparing of the quadriceps muscles, even in advanced stages of the disease. Since both disorders hereditary inclusion body myopathy and sialuria represent defects in the biosynthesis of sialic acid, an important component of the glycosylation machinery, they are also classified as congenital disorders of glycosylation (CDG) (Ferreira et al. 2018). As the next step in the sialic acid biosynthetic pathway, ManNAc-6-phosphate is converted to N-acetylneuraminic acid (Neu5Ac) by N-acetylneuraminic acid synthase (NANS) and N‑acetylneuraminic acid phosphatase (NANP), respectively. Finally, Neu5Ac is transported to the nucleus and there activated to CMP-sialic acid by the enzyme cytidine monophosphate N-acetylneuraminic acid synthase (CMAS). CMP-sialic acid is transferred to the Golgi apparatus by the specific transporter SLC35A1 for sialylation of gangliosides and glycoproteins (Willems et al. 2016). A genetic defect of the enzyme N-acetylneuraminic acid synthase (NANS) leads to a disorder characterized by severe

1251

developmental delay, intellectual disability, skeletal dysplasia, and coarse facial features (van Karnebeek et al. 2016; van Karnebeek et  al. 2017). In the affected patients, the urine concentration of N-acetylmannosamine is increased, but not of sialic acid. Wen et  al. have detected a defect not in the biosynthesis, but in the degradation of sialic acid in two siblings who presented with dilated cardiomyopathy, proximal myopathy, and sensorineural hearing loss. In these patients compound heterozygous mutations in the gene NPL have been found that codes for the enzyme N‑acetylneuraminate pyruvate lyase NPL (Wen et al. 2018). And a defect of this enzyme that is responsible for the degradation of sialic acid to N-acetylmannosamine and pyruvate leads to significant sialic aciduria, but not to accumulation of sialic acid in fibroblasts. For the diagnosis of oligosaccharidoses and sialic acid disorders usually thin-layer chromatography (TLC) combined with enzyme measurement and/or mutation analysis is employed. Free sialic acid will not prominently show on thin-layer chromatography, and therefore a dedicated high-­performance-­liquid-chromatography method is necessary to assess the concentration of sialic acid in urine and possibly fibroblasts. More recently, tandem-mass spectrometry (TMS) has been applied for the determination of oligosaccharides and sialic acid. However, as the differentiation of sugar moieties by TMS is difficult, TLC will probably remain the screening method of choice for the time being. N-Acetylmannosamine has been measured by NMR-spectroscopy. Finally, molecular genetic testing by using modern methods such as next-generation sequencing will become more important for the diagnosis of these rare disorders. Unfortunately, despite progress in therapies for many lysosomal storage diseases, the oligosaccharidoses and sialic acid disorders still lack an effective treatment; only for patients affected by alpha-mannosidosis enzyme replacement therapy has become available. However, further understanding of disease mechanism and phenotypic differences between patients with the same mutation may help to pave the way to novel therapies and better care for the patients.

UDP-GlcNAc 2-epimerase/ManNac kinase superactivity ∅ Spondyloepimetaphyseal dysplasia Geneviève type

NPL deficiency

Sialic acid synthase deficiency

63.13 Neuraminic acid pyruvate-lyase deficiency 63.14 N-Acetylneuraminic acid synthase deficiency

SLC17A5

Sialuria, French type

SLC17A5

63.12 Sialuria

SLC17A5 6q13

FUCO AGU

∅ Aspartylglucosaminidase deficiency Solute carrier family 17 member 5 (SLC17A5) deficiency Solute carrier family 17 member 5 (SLC17A5) deficiency Hereditary inclusion body myopathy 2

Nonaka myopathy

SLC17A5 6q13

NAGA

∅

63.11 GNE myopathy

FUCA1 AGA

NAGA

GNE

GNE

NPL

NANS

HIBM ∅ ∅ ∅

NAGA

NAGA

9q22.33

1q25.3

9p13.3

9p13.3

1p36.11 4q34.3

22q13.2

22q13.2

4q24

Schindler disease type II

MANBA

LBMAN

∅

MAN2B1 19p13.13

LAMAN

Chromosomal localization 6p21.3 20q13.12

∅

Alternative name 2 Abbreviation Gene Neuraminidase deficiency NEU NEU1 Goldberg syndrome GSL CTSA

Sialuria, Finnish type

Alternative name 1 Mucolipidosis type I Protective protein/ cathepsin A deficiency α-Mannosidosis α-mannosidase B deficiency ß-Mannosidosis ß-mannosidase deficiency Kanzaki disease α-NAcetylgalactosaminidase deficiency II Schindler disease type α-NIII Acetylgalactosaminidase deficiency III Fucosidosis α-Fucosidase deficiency Aspartylglucosaminuria Glycosylasparaginase deficiency Infantile sialic acid ISSD storage disease

Disorder name Sialidosis Galactosialidosis

63.10 Salla disease

63.9

63.7 63.8

63.6

63.5

63.4

63.3

No. 63.1 63.2

Nomenclature

AR

AR

AD

AR

AR

AR

AR AR

AR

AR

AR

248510

248500

OMIM no. 256550 256540

N-Acetylneuraminic acid synthase

UDP-GlcNAc 2-epimerase/ManNac kinase UDP-GlcNAc 2-epimerase/ManNac kinase N-Acetylneuraminate pyruvate lyase

Sialin

Sialin

α-Fucosidase Glycosylasparaginase

605202

611412

Infantile/ adult form

Infantile/ adult form

Infantile form

Adult form

605820

269921

Juvenile/ adult form

Infantile form

All forms All forms

Juvenile form

Adult form

All forms

All forms

Phenotype All forms All forms

604369

269920

230000 208400

609241 α-NAcetylgalactosaminidase

609242 α-NAcetylgalactosaminidase

ß-mannosidase

Mode of inheritance Affected protein AR Neuraminidase AR Protective protein/ cathepsin A AR α-mannosidase B

1252 M. Beck and Z. Lukacs

63  Oligosaccharidoses and Sialic Acid Disorders

1253

Signs and Symptoms Table 63.1 Sialidosis System CNS

Dermatological Digestive Ear Eye Hematological Musculoskeletal

Other Renal Laboratory findings

Symptoms and biomarkers Ataxia Developmental delay Intellectual disability Myoclonic epilepsy Seizures Spasticity Startle response, exaggerated Angiokeratoma Hepatosplenomegaly Hearing loss Cherry red spot Corneal clouding Vacuolated lymphocytes Coarse facial features Dysostosis multiplex Hernias Macrocephaly Short stature Fetal hydrops Renal failure, chronic Alpha-neuraminidase activity Sialic acid-rich oligosaccharide (urine)

Neonatal (birth–1 month)

Infancy (1–18 months)

Adolescence (11–16 years) ++ + + ++ ± +

Adulthood (>16 years) ++ + + +++ ± +

± ±

± ±

++ + + ++ ++ + ± ±

Childhood (1.5–11 years) ± +++ ++ ± + ++ + ± ++ + ++ ± ++ ++ ++ + ± ++

++ ± ±

++ ± ±

±

+ ±

± ↓ ↑

± ↓ ↑

± ↓ ↑

± ↓ ↑

+++ ++ ± + +

++

+++

++

± ++ + ± +++ ↓ ↑

Table 63.2 Galactosialidosis System Cardiovascular

Symptoms and biomarkers Cardiomyopathy Valvular thickening

CNS

Ataxia Intellectual deterioration Myoclonus Seizures Spasticity Angiokeratoma Telangiectasia Hepatosplenomegaly Cherry red spot Corneal clouding Vision, impaired Foam cells Vacuolated lymphocytes Coarse facial features Dysostosis multiplex Edema Growth retardation Hernias Fetal hydrops Proteinuria Renal failure Alpha-neuraminidase activity Beta-galactosidase Cathepsin A activity Sialic acid-rich oligosaccharide (urine)

Dermatological Digestive Eye

Hematological Musculoskeletal

Other Renal Laboratory findings

Neonatal (birth–1 month) +++ ±

Infancy (1–18 months) ± +++

+++

±

±

±

± +++ +++ + + ± +++ +++ + ++ ++ + + ++ +++ +++ ↓↓↓ ↓↓↓ ↓-n ↑↑↑

± ± +++ + + ± +++ +++ + +++ ± +++ − ± ++ ++ ↓↓↓ ↓↓↓ ↓-n ↑↑↑

Childhood (1.5–11 years) + −

Adolescence (11–16 years) + −

Adulthood (>16 years) + −

+ + ++ + + + ± ++ +++ + +++ +++ +++ + +++ − ++ −

++ + ++ + + ++ ±

++ + ++ + + ++ ±

++ + +++ +++ +++ + +

++ + +++ +++ +++ + +

++ −

++ −

± ± ↓ ↓ ↓-n ↑↑

± ± ↓ ↓ ↓-n ↑↑

± ± ↓↓ ↓↓ ↓-n ↑↑↑

1254

M. Beck and Z. Lukacs

Table 63.3 Alpha-mannosidosis System CNS

Digestive Ear Eye Hematological Musculoskeletal

Other Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Intellectual disability Spasticity Hepatomegaly Deafness, sensorineural Corneal clouding Corneal deposits Vacuolated lymphocytes Coarse facial features Dysostosis multiplex Hernias Macrocephaly Immunodeficiency Psychosis Alpha-mannosidase B (fibroblasts) Alpha-mannosidase B (white blood cells) Mannose-oligosaccharides (urine)

Neonatal (birth–1 month)

Infancy Childhood (1–18 months) (1.5–11 years) + ± + ±

Adolescence (11–16 years) ++ ++ ±

Adulthood (>16 years) +++ +++ ±

++

+++ ± ± + + ± ± ± + + ↓ ↓ ↑

++

+ ++ + + + ++

+++ ± ± + ++ + + + ++

↓ ↓

↓ ↓

↓ ↓

+++ ± ± + + ± + + ++ + ↓ ↓

↑

↑

↑

↑

±

±

Table 63.4  β-Mannosidase deficiency System CNS

Dermatological Ear Musculoskeletal

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Ataxia Intellectual disability Polyneuropathy Spasticity Angiokeratoma Hearing loss Coarse facial features Dysostosis multiplex Short stature Beta-mannosidase (fibroblasts) ↓ Beta-mannosidase (white blood ↓ cells)

Infancy (1–18 months)

Childhood (1.5–11 years)

+

+

± ± +

± ± ++ + ± ± ↓ ↓

± ± ↓ ↓

Adolescence (11–16 years) ± + ± ± ± +++ + ± ± ↓ ↓

Adulthood (>16 years) ± ++ ± ± ± +++ ± ± ↓ ↓

63  Oligosaccharidoses and Sialic Acid Disorders

1255

Table 63.5  Kanzaki disease Neonatal Symptoms and biomarkers (birth–1 month) Cardiomyopathy, hypertrophic Intellectual disability, mild Neuropathy, sensory Dermatological Angiokeratoma Lymphedema Eye Corneal clouding Musculoskeletal Coarse facial features Laboratory Alpha-N↓ findings acetylgalactosaminidase (fibroblasts) Alpha-N↓ acetylgalactosaminidase (white blood cells)

System Cardiovascular CNS

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

±

Adulthood (>16 years) + ± ± ++ ±

↓

↓

↓

± ↓

↓

↓

↓

↓

Table 63.6  Schindler disease System CNS

Symptoms and biomarkers Autism Developmental delay Intellectual disability Seizures Eye Cataract Cardiovascular Cardiomyopathy Digestive Hepatomegaly Laboratory Alpha-Nfindings acetylgalactosaminidase (fibroblasts) Alpha-Nacetylgalactosaminidase (white blood cells)

Neonatal (birth–1 month)

Infancy (1–18 months)

↓

± + ± ± ± ± ↓

↓

↓

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

↓

↓

↓

↓

↓

↓

±

Table 63.7 Fucosidosis System Autonomic system CNS

Dermatological Digestive Ear Eye Hematological Musculoskeletal

Laboratory findings

Symptoms and biomarkers Sweating Epileptic seizures Intellectual disability Spasticity Angiokeratoma Hepatosplenomegaly Hearing loss Corneal clouding Vacuolated lymphocytes Coarse facial features Dysostosis multiplex Hernias Short stature Alpha-L-fucosidase (fibroblasts) Alpha-L-fucosidase (white blood cells) Fucose (urine)

Neonatal Infancy (birth–1 month) (1–18 months)

±

± ± ± ± ±

↓

↓

Childhood (1.5–11 years) ± + ++ ++ + ± ± ± ± + + ± + ↓

↓

↓

↓

↓

↓

↑

↑

↑

↑

↑

± ± ± ± ±

Adolescence (11–16 years) ± + ++ ++ + ± ± ± ± + + ± + ↓

Adulthood (>16 years) ± ± + +++ + ± ± ± ± + ± ± ± ↓

1256

M. Beck and Z. Lukacs

Table 63.8 Aspartylglucosaminuria System Cardiovascular CNS

Dermatological Digestive Hematological Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Epileptic seizures Intellectual disability Spasticity Angiokeratoma Hepatosplenomegaly Vacuolated lymphocytes Club foot Coarse facial features Dysostosis multiplex Hernias Hypotonia, muscular-axial Macrocephaly Short stature Accelerated growth Aspartylglucosamine (urine) Aspartylglucosaminidase (fibroblasts) Aspartylglucosaminidase (lymphocytes) Aspartylglucosaminidase (white blood cells)

Neonatal (birth–1 month)

Infancy (1–18 months) − ± − ± ± +

Childhood (1.5–11 years) ± ± + ± ± ± ±

Adolescence (11–16 years) ± ± ++ + ± ± ±

Adulthood (>16 years) ± ± ++ + ± ± ±

± + ±

+ + ±

+ + ±

±

± ±

±

± ± + ± − ± ± ++ ±

− ± ± ± ±

++ ↑ ↓

+ ↑ ↓

↑ ↓

↑ ↓

↑ ↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

Table 63.9  Free sialic acid storage disease System CNS

Digestive Eye Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Ataxia Developmental delay Hypotonia Spasticity Hepatosplenomegaly Nystagmus Coarse facial features Growth retardation Hernias Fetal hydrops N-Acetylneuraminic acid (urine) Sialic acid, free (urine)

Neonatal (birth–1 month)

Infancy (1–18 months)

± ±

+++ ± + ++

+ ± ± ± ↑ ↑

Adolescence (11–16 years)

Adulthood (>16 years)

± + ±

Childhood (1.5–11 years) ± +++ + + ++ + ± ++ ±

↑

↑

↑

↑

↑

↑

↑

↑

63  Oligosaccharidoses and Sialic Acid Disorders

1257

Table 63.10  Salla disease Neonatal (birth–1 month)

System CNS

Symptoms and biomarkers Ataxia Developmental delay Hypotonia Intellectual disability Seizures Spasticity Digestive Hepatosplenomegaly Eye Nystagmus Optic atrophy Musculoskeletal Coarse facial features Growth retardation Hernias Laboratory N-Acetylneuraminic acid findings (urine) Sialic acid, free (urine)

Infancy (1–18 months) +

+ ±

±

Childhood (1.5–11 years) ± + + ++ + + ± + ± ± +

Adolescence (11–16 years) +++ + ± ++ + ++ ± + ± ± +

Adulthood (>16 years) +++ + ± +++ + +++ ± + ± ± +

↑

± ↑

↑

↑

↑

↑

↑

↑

↑

↑

Table 63.11  UDP-GlcNAc epimerase-kinase deficiency System Cardiovascular Musculoskeletal

Respiratory Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Cardiomyopathy Foot drop Muscle dystrophy, progressive Muscle histopathology, rimmed vacuoles Muscle histopathology, tubulofilaments Muscle wasting of limbs with sparing of quadriceps muscles Respiratory dysfunction Creatine kinase (plasma) n Sialotransferrins (serum) n

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence Adulthood (11–16 years) (>16 years) ± ± ± ± ++ ± + ±

+

±

+++ + n-↑ n

n n

n n

n-↑ n

Infancy (1–18 months) ++

Childhood (1.5–11 years) +

Adolescence (11–16 years) ± ±

++

+

±

↑↑↑

+ + ↑↑↑

+ + ↑↑↑

+ ± ↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

Table 63.12  UDP-GlcNAc epimerase-kinase superactivity System CNS

Digestive Musculoskeletal Laboratory findings

Symptoms and biomarkers Cognitive decline Intellectual disability, mild Jaundice, prolonged neonatal Motor developmental delay Hepatomegaly Coarse facial features N-Acetylneuraminic acid (urine) Sialic acid, free (urine)

Neonatal (birth–1 month)

Adulthood (>16 years)

±

1258

M. Beck and Z. Lukacs

Table 63.13  Neuraminic acid pyruvate-lyase deficiencya System Cardiovascular Ear Musculoskeletal Other Laboratory findings

Neonatal (birth–1 month)

Symptoms and biomarkers Cardiomyopathy, dilated Fetal arrhythmia Hearing loss, sensorineural Proximal myopathy Fetal hydrops N-Acetylneuraminic acid (urine) Sialic acid, free (urine)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) +

± + + ± ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

Wen et al. (2018)

a

Table 63.14  N-acetylneuraminic acid synthase deficiencya System CNS

Musculoskeletal

Laboratory findings

Symptoms and biomarkers Developmental delay Epileptic seizures Hydrocephalus Intellectual disability Muscle hypotonia Coarse facial features Short limbs Short stature N-acetylmannosamine (urine) Sialic acid, free (urine)

Neonatal (birth–1 month)

Infancy (1–18 months) +++

Childhood (1.5–11 years) +++

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

+++

+++

+++ +++ +++ ↑↑ n

+++ +++ +++ ↑↑ n

± +

+

+

+

+

Not known n

Not known n

↑↑ n

van Karnebeek et al. (2017)

a

Metabolic Pathways Lysosomal enzymes that cleave sugar residues from glycoproteins are deficient in oligosaccharidoses (Fig.  63.1). In aspartylglucosaminuria, glycosylasparaginase shows diminished activity (Fig. 63.1, step 2). This enzyme requires prior hydrolysis of both peptide bonds joined to the asparagine (Asn). This is achieved by lysosomal cathepsins. In addition, the enzyme is inhibited by fucose that is bound to the core reducing end of N-acetylglucosamine (Fig. 63.1, step 1). This special property explains why most of fragments that accumulate in fucosidosis are glycopeptides that retain the Asn residue (Aronson Jr. 1999). In α-mannosidosis oligosaccharides containing α-1–3 and α-1–6 linkages accumulate, while in β-mannosidosis the disaccharide Man-β1-4GlcNAc is the major storage material (Fig.  63.1, step 4α/β). For α-NAGA deficiency the major compounds are sialylglycopeptides of the O-linked type. However, they seem not to be the primary lysosomal storage product (Keulemans et al. 1996). Sialidosis is characterized by increased amounts of sialylated oligosaccharides and glycoproteins (Fig. 63.1, step 3).

Protein

3 4a

4b

1 2

3

Asn

4a

sialic acid

N-acetylglucosamine fucose

galactose

a–/b-mannose

Fig. 63.1  Degradation of complex oligosaccharides. Liberation of the glycoside from the protein by lysosomal cathepsins is followed by a sequential degradation of the sugar moieties (steps 1–4). Galactose and N-acetylglucosamine are cleaved by β-galactosidase and hexosaminidase, respectively, between steps 3 and 4

63  Oligosaccharidoses and Sialic Acid Disorders

HO

1259

OH –

COO O

OH

NH O

HO HO

Fig. 63.2  Sialic acid (N-acetyl neuraminic acid, Neu5Ac)

In Salla disease, a defect in the membrane transporter protein, sialin, impairs efflux of sialic acid (Fig.  63.2) from the lysosomes, so that this compound accumulates in the cell.

Entry 16

Protein LBMAN

Method MUBMf

17

LBMAN

MUBMf

18

LBMAN

MUBMf

18

NAGA

MUNACg

19

NAGA

MUNACg

20

NAGA

MUNACg

21

NEU

MUNEUh

22

Sialini

HPLC

23

Sialini

HPLC

24

N-Acetylmannosaminej

NMR spectroscopy

Reference Values

Material Leukocytes

Range (unit) 245–467 (μM/h*g) Fibroblasts 58–389 (μM/h*g) DBS 0.92–2.89 (nmol/ spot*21 h) Fibroblasts 40–130 (nmol/h*mg) Plasma 4–8.33 (nmol/ s*L) Lymphoblasts 10.5–27.2 (nmol/s*g) Fibroblasts 17.6–189 (nmol/h*mg) Fibroblasts < 1.3 (nmol/mg protein) Urine 30 umol/L (chronic RF)

Oxalate (P) 70 umol/L (PD, pre-HD)

Oxalate (P) 16 years) ±

± ± ± ± ± + ± ± ± ± ± ± ±

± ± ± ± ± + ± ±

±

±

±

± ± ± + ±

± ± ± + ±

± ± ± +

± ±

± ±

±

±

±

± ±

±

±

±

− ±

±

±

68  Congenital Disorders of Glycosylation

1347

Table 68.3 (continued) System Other Laboratory findings

Symptoms and biomarkers Dysmorphism Fatal outcome Antithrombin III (plasma) Asialotransferrin (serum) Creatine kinase (plasma) Disialotransferrin (serum) Lipid-linked Man9GlcNAc2 (fibroblasts) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Transaminase (plasma)

Neonatal (birth–1 month) ± ± ↓ n-↑ n-↑ n-↑ ↓-n

Infancy (1–18 months) ± ± ↓ n-↑ n-↑ n-↑ ↓-n

Childhood (1.5–11 years) ± ± ↓ n-↑ n-↑ n-↑ ↓-n

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

n-↑

n-↑

±

±

±

±

↓-n n-↑

↓-n n-↑

↓-n n-↑

n-↑

↓-n

n-↑

Table 68.4  X-linked recessive UDP-N-acetylglucosamine transferase catalytic subunit deficiency X-linked recessive ALG13-CDG System CNS

Digestive Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Developmental regression Epilepsy, refractory Extrapyramidal signs Intellectual disability Pyramidal signs Feeding difficulties Hepatomegaly Delayed visual maturation Dysmorphic features Microcephaly Asialotransferrin (serum) Disialotransferrin (serum) Tetrasialotransferrin (serum) Thromboplastin time (blood)

Neonatal (birth–1 month) – – – – – ± – ± + ± n-↑ n-↑ ↓-n n-↑

Infancy (1–18 months) ± + ± + ± ± ± ± + ± n-↑ n-↑ ↓-n n-↑

Childhood (1.5–11 years) ± + ± + ± ± ± ± + ± n-↑ n-↑ ↓-n n-↑

Adolescence (11–16 years)

Adulthood (>16 years)

Table 68.5  X-linked dominant UDP-N-acetylglucosamine transferase catalytic subunit deficiency X-linked dominant ALG13-CDG System CNS

Digestive Eye Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Developmental regression Epilepsy, refractory Extrapyramidal signs Intellectual disability Pyramidal signs Feeding difficulties Hepatomegaly Delayed visual maturation Microcephaly Dysmorphism Asialotransferrin (serum) Disialotransferrin (serum) Tetrasialotransferrin (serum) Thromboplastin time (blood)

Neonatal (birth–1 month) − − − − − ± − ± ± + n-↑ n-↑ ↓-n n-↑

Infancy (1–18 months) ± + ± + ± ± ± ± ± + n-↑ n-↑ ↓-n n-↑

Childhood (1.5–11 years) ± + ± + ± ± ± ± ± + n-↑ n-↑ ↓-n n-↑

Adolescence (11–16 years)

Adulthood (>16 years)

1348

J. Jaeken and L. van den Heuvel

Table 68.6  Congenital myasthenic syndrome, without tubular aggregates-15 ALG14-CDG System CNS

Musculoskeletal Other Psychiatric Laboratory findings

Symptoms and biomarkers Congenital myasthenic syndrome Developmental delay Epilepsy Hypotonia Contractures Fetal hydrops Behavioral abnormalities Creatine kinase (plasma) Sialotransferrin type 1 (serum)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ±

± ± ± ±

± ± ± ±

± ± ±

n ±

± n ±

± n ±

± n ±

Neonatal (birth–1 month) ± ± ± ± + + ± ± ± ± ± ± ± ± ± ± ± ↓-n ↑ ↑ ↑

Infancy (1–18 months) ± ± ± ± + + ± ± ± ± ± ± ± ± ± ± ± ↓-n ↑ ↑ ↑

Childhood (1.5–11 years) ± ± ± ± + + ± ± ± ± ± ± ± + ± ± ± ↓-n ↑ ↑ ↑

Adolescence (11–16 years)

Adulthood (>16 years)

↑

↑

↑

↓-n +

↓-n +

↓-n +

↓ n-↑ ±

↓ n-↑ ±

↓ n-↑

± ± ± ± n ±

Table 68.7  Mannosyltransferase 1 deficiency ALG1-CDG System Cardiovascular CNS

Digestive Eye Hematological Musculoskeletal

Other Renal Laboratory findings

Symptoms and biomarkers Cardiomyopathy Axial hypotonia Cerebellar hypoplasia (MRI) Cortical atrophy (MRI) Epilepsy Retardation, psychomotor Diarrhea, chronic Feeding difficulties Poor visual fixation Strabismus Thrombocytopenia Contractures Facial dysmorphism Microcephaly Scoliosis Fatal outcome Nephrotic syndrome Albumin (serum) Asialotransferrin (serum) Disialotransferrin (serum) Dolichol-linked GlcNAc2 (serum) Lipid-linked GlcNAc2 (fibroblasts) Protein C (plasma) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Transaminase (plasma) Xeno-tetrasaccharide (serum, fibroblasts)

68  Congenital Disorders of Glycosylation

1349

Table 68.8  Mannosyltransferase 2 deficiency ALG2-CDG System CNS

Eye Laboratory findings

Symptoms and biomarkers Abnormal jitter Bulbar dysfunction Congenital myasthenic syndrome Demyelination Epilepsy Facial weakness, mild Hyperreflexia Hypotonia Motor developmental delay Cataract Coloboma Asialotransferrin (serum) Creatine kinase (plasma) Disialotransferrin (serum) Dolichol-linked Man1GlcNAc2 (serum) Dolichol-linked Man2GlcNAc2 (serum) Factor XI (blood) Lipid-linked Man1GlcNAc2 (fibroblasts) Lipid-linked Man2GlcNAc2 (fibroblasts) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Thromboplastin time

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

±

±

±

+ + ± + + + + + ↑ n-↑ ↑ ↑

+ + ± + + + + + ↑ n-↑ ↑ ↑

+ + ± + + + + + ↑ n-↑ ↑ ↑

↑

↑

↑

↓ ↑

↓ ↑

↓ ↑

↑

↑

↑

+

+

+

↓ ↑

↓ ↑

↓ ↑

Infancy (1–18 months) + ± ± + ± ± ± + ± ± ± ± ± ± + + ± ± ± ±

Childhood (1.5–11 years) + ± ± + ± ± ± + ± ± ± ± ± ± + + ± ± ± ±

Adolescence (11–16 years) + ±

Adulthood (>16 years) + ±

±

±

+

+

±

±

n-↑

n-↑

Adolescence (11–16 years)

Adulthood (>16 years)

−

−

Table 68.9  Mannosyltransferase 4–5 deficiency ALG11-CDG System CNS

Dermatological Digestive Eye

Hematological Musculoskeletal Other Respiratory

Symptoms and biomarkers Axial hypotonia Cerebral atrophy (MRI) Demyelination Epilepsy Hearing, impaired Hyperreflexia Hypertonia, extremities Retardation, psychomotor Fat pads Inverted nipples Feeding difficulties Vomiting, episodic Optic atrophy Retinal dystrophy Strabismus Leukocytosis Facial dysmorphism Microcephaly Early death Stridor, inspiratory

Neonatal (birth–1 month) + ± ± ± ± ± ± + ± ± ± ± ± ± + + ± ± ± ±

(continued)

1350

J. Jaeken and L. van den Heuvel

Table 68.9 (continued) System Laboratory findings

Symptoms and biomarkers Albumin (serum) Antithrombin III (plasma) APTT Asialotransferrin (serum) Disialotransferrin (serum) Dolichol-linked Man3GlcNAc2 (serum) Dolichol-linked Man4GlcNAc2 (serum) Factor XI (blood) Lactate (plasma) Lipid-linked Man3GlcNAc2 (fibroblasts) Lipid-linked Man4GlcNAc2 (fibroblasts) Prolactin (plasma) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum)

Neonatal (birth–1 month) ↓-n ↓ ↑ ↑ ↑ ↑

Infancy (1–18 months) ↓-n ↓ ↑ ↑ ↑ ↑

Childhood (1.5–11 years) ↓-n ↓ ↑ ↑ ↑ ↑

Adolescence (11–16 years)

Adulthood (>16 years)

↑

↑

↑

↓-n n-↑ ↑

↓-n n-↑ ↑

↓-n n-↑ ↑

↑

↑

↑

↑ +

↑ +

↑ +

↓

↓

↓

Neonatal (birth–1 month) ± ± ± ± + + ± ± ± ± ± ± ± ± ↓ ↑ n ↑ ↑

Infancy (1–18 months) ± ± ± ± + + ± ± ± ± ± ± ± ± ↓ ↑ n ↑ ↑

Childhood (1.5–11 years) ± ± ± ± + + ± ± ± ± ± ± ± ± ↓ ↑ n ↑ ↑

Adolescence (11–16 years) ± ± ± ± + + ± ± ± ± ± − ± − ↓ ↑ n ↑ ↑

Adulthood (>16 years) ± − ± ± + + − − ± − − − ± − ↓ ↑ n ↑

↓ ↑

↓ ↑

↓ ↑

↓ ↑

↓

↓ ↑

↓ ↑

↓ ↑

↓ ↑

↓ ↑

↓ n

↓ n

↓ n

↓ n

↓ n

Table 68.10  Flippase of Man5GlcNAc2-PP-Dol deficiency RFT1-CDG System CNS

Dermatological Digestive Eye Hematological Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Ataxia Cerebral atrophy (MRI) Epilepsy Hearing, impaired Hypotonia Retardation, psychomotor Inverted nipples Feeding difficulties Hepatomegaly Vision, impaired Thrombosis Microcephaly Dysmorphism Failure to thrive Antithrombin III (plasma) Asialotransferrin (serum) Creatine kinase (plasma) Disialotransferrin (serum) Dolichol-linked Man5GlcNAc2 (serum) Factor XI (blood) Lipid-linked Man5GlcNAc2 (fibroblasts) Protein C (serum) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Transaminase (plasma)

68  Congenital Disorders of Glycosylation

1351

Table 68.11  Mannosyltransferase 6 deficiency ALG3-CDG System Cardiovascular CNS

Digestive Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Congenital heart defects Axial hypotonia Cerebral atrophy (MRI) Epilepsy Hypertonia, extremities Retardation, psychomotor Hypsarrhythmia (EEG) Microcephaly Feeding difficulties Optic atrophy Strabismus Arachnodactyly Club foot Facial dysmorphism Microcephaly Micrognathia Skeletal dysplasia Antithrombin III (plasma) Apolipoprotein B (serum) Asialotransferrin (serum) Disialotransferrin (serum) Lipid-linked Man5GlcNAc2 (fibroblasts) Protein S (serum) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Glucose (plasma) Free fatty acids (serum), during hypoglycemia Ketones, during hypoglycemia Insulin, durig hypoglycemia

Neonatal (birth–1 month) ± + ± ++ + +++ + + ± ± ± ± ± ± ± ± ± ↓ ↓ ↑ ↑ ↑↑

Infancy (1–18 months) ± ++ ± ++ + +++ + + ± ± ± ± ± + + ± ± ↓ ↓ ↑ ↑ ↑↑

Childhood (1.5–11 years) ± ++ ± ++ + +++ + + ± ± ± ± ± + ++ ± ± ↓ ↓ ↑ ↑ ↑↑

Adolescence (11–16 years) ± + + ++ + +++ + + ± ± ± ± ± + + ± ±

Adulthood (>16 years) ± + + ++ + +++ + + ±

± ±

↑ ↑ ↑↑

↑ ↑ ↑↑

↓ +

↓ +

↓ +

+

+

↓ ↓ ↓↓↓

↓ ↓ ↓↓↓

↓

↓

↓

↓↓↓ ↑

↓↓↓ ↑

Childhood (1.5–11 years) ± ± ± + + + ± ± ± ± ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ± + ± ± ± ± ± ± ± +

Adulthood (>16 years)

± ± ± +

Table 68.12  Mannosyltransferase 7–9 deficiency ALG9-CDG System Cardiovascular CNS

Dermatological Digestive Eye Musculoskeletal

Other

Symptoms and biomarkers Pericardial effusion Brain atrophy (MRI) Demyelination Epilepsy Hypotonia Retardation, psychomotor Inverted nipples Hepatomegaly Splenomegaly Strabismus Facial dysmorphism Microcephaly Skeletal dysplasia Failure to thrive

Neonatal (birth–1 month) ± ± ± + + + ± ± ± ± ± ± + ±

Infancy (1–18 months) ± ± ± + + + ± ± ± ± ± ± + ±

(continued)

1352

J. Jaeken and L. van den Heuvel

Table 68.12 (continued) System Renal Laboratory findings

Symptoms and biomarkers Renal cysts Albumin (serum) Asialotransferrin (serum) Cholesterol (serum) Disialotransferrin (serum) Dolichol-linked Man6GlcNAc2 (serum) Dolichol-linked Man8GlcNAc2 (serum) Factor XI (blood) Lipid-linked Man6GlcNA2 Lipid-linked Man8GlcNA2 Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum)

Neonatal (birth–1 month) ± ↓-n ↑ ↓-n ↑ ↑

Infancy (1–18 months) ± ↓-n ↑ ↓-n ↑ ↑

Childhood (1.5–11 years) ± ↓-n ↑ ↓-n ↑ ↑

Adolescence (11–16 years) ±

↑

↑

↑

↓-n ↑ ↑ +

↓-n ↑ ↑ +

↓-n ↑ + +

+

↓

↓

↓

↓

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years)

± ± ± ++ ±

± ± ± ++ ±

± ± ± ++ ±

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± − ± ± ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± − ± ± − ± ± ± ± ±

Adulthood (>16 years)

↑ ↑

Table 68.13  Mannosyltransferase 8 deficiency ALG12-CDG System Cardiovascular CNS

Dermatological Digestive

Eye Genitourinary

Hematological Metabolic Musculoskeletal

Other

Symptoms and biomarkers Cardiomyopathy, hypertrophic Ventricular septal defect Agenesis, corpus callosum (MRI) Cerebellar hypoplasia Hearing, impaired Hypotonia Retardation, psychomotor Temporal hypoplasia, dilated external CSF spaces Hypoplastic nails Inverted nipples Feeding difficulties Gastric tube feeding Gastrointestinal dysmotility Malrotation Retinal detachment Strabismus Hypospadias Male genital hypoplasia Micropenis Thrombocytopenia Hypoglycemia Club foot Dwarfism Edema Facial dysmorphism Microcephaly Skeletal dysplasia Early death Failure to thrive Maternal HELLP syndrome Prematurity

Adulthood (>16 years)

68  Congenital Disorders of Glycosylation

1353

Table 68.13 (continued) System Laboratory findings

Symptoms and biomarkers Antithrombin III (plasma) Asialotransferrin (serum) Cholesterol (serum) Disialotransferrin (serum) Dolichol-linked Man7GlcNAc2 (serum) Glucose (plasma) IGF BP3 IGF1 Immunoglobulins (serum) Lipid-linked Man7GlcNA2 (fibroblasts) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Transaminase (plasma)

Neonatal (birth–1 month) ↓ ↑ ↓-n ↑ ↑

Infancy (1–18 months) ↓ ↑ ↓-n ↑ ↑

Childhood (1.5–11 years) ↓ ↑ ↓-n ↑

Adolescence (11–16 years)

Adulthood (>16 years)

↓-n ↓-n ↓-n ↓-n ↑

↓-n ↓-n ↓-n ↓-n ↑

↓-n ↓-n ↓-n ↑

+

+

+

↓ n-↑

↓ n-↑

↓ n-↑

Neonatal (birth–1 month) ± ++ + ++ ± ++ ± ± ↓ ↑ ↑ ↓↓ ↑ ↑

Infancy (1–18 months) ± ++ ++ ++ ± ++ ± ± ↓ ↑ ↑ ↓↓ ↑ ↑

Childhood (1.5–11 years) ± + + ++ ± ++ ± ± ↓ ↑ ↑ ↓↓ ↑ ↑

Adolescence (11–16 years) ± ± ± ++ ± ++ ± ±

Adulthood (>16 years) ± − ± ++ ± ++ ± ±

n-↑

n-↑

↓↓

↓↓

↓ ↓ ↓↓↓

↓ ↓ ↓↓↓

↓ ↓ ↓↓

↓

↓

↓↓

↓↓

↓ ↑ ↓↓↓ ↑

↓ ↑ ↓↓↓ ↑

↓ ↑ ↓↓ ↑

↓ ↑ ↓↓ ↑

↓ ↑ ↓↓ ↑

+

+

+

+

−/+

↓ ↓

↓ ↓

↓ ↓

↓-n

↓-n

↑

↑

↑

n-↑

n-↑

Table 68.14  Glucosyltransferase 1 deficiency ALG6-CDG System CNS

Eye Musculoskeletal Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Axial hypotonia Epileptic seizures Retardation, psychomotor Nystagmus Strabismus Skeletal abnormalities Behaviour difficulties Antithrombin III (plasma) Arylsulfatase A (serum) Asialotransferrin (serum) Cholesterol (serum) Disialotransferrin (serum) Dolichol-linked Man9GlcNAc2 (serum) Factor XI (blood) Factor XI (blood) Free fatty acids (serum), during hypoglycemia Glucose (plasma) Insulin, during hypoglycemia Ketones, during hypoglycemia Lipid-linked Man9GlcNAc2 (fibroblasts) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum) Thyroxin-binding globulin (serum) Transaminase (plasma)

1354

J. Jaeken and L. van den Heuvel

Table 68.15  Glucosyltransferase 2 deficiency ALG8-CDG System Cardiovascular CNS

Dermatological

Digestive

Endocrine Eye Genitourinary Hematological

Musculoskeletal

Other Renal Laboratory findings

Symptoms and biomarkers Ventricular septal defect Cerebellar hypoplasia Cerebral atrophy (MRI) Hypotonia Retardation, psychomotor Seizures Edema, generalized Excess skin Inverted nipples Cholestasis Feeding difficulties Hepatomegaly Protein-losing enteropathy Hypothyroidism Cataract Optic atrophy Cryptorchidism Anemia Coagulopathy Thrombocytopenia Camptodactyly Closure of fontanels, delayed Facial dysmorphism Macrocephaly Microcephaly Osteopenia Early death Renal cysts Renal tubulopathy Albumin (serum) Antithrombin III (plasma) Asialotransferrin (serum) Disialotransferrin (serum) Dolichol-linked Glc1Man9GlcNAc2 (serum) Factor XI (blood) Lipid-linked Glc1Man9GlcNAc2 (fibroblasts) Protein C (serum) Sialotransferrins, type 1 pattern (serum) Tetrasialotransferrin (serum)

Neonatal (birth–1 month) ± ± ± + ++ ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ↓↓ ↓ ↑ ↑ ↑

Infancy (1–18 months) ± ± ± + ++ ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ↓↓ ↓ ↑ ↑ ↑

Childhood (1.5–11 years) ± ± ± + ++ ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± − ± ± ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

± ± ↓↓ ↓ ↑ ↑ ↑

↓ ↑

↓ ↑

↓ ↑

↓

↓ +

↓ +

↓ +

↓ +

↓

↓

↓

↓

+ ±

± ± ±

+ +

↓ ↓ ↑ ↑

Table 68.16  Oligosaccharyltransferase subunit tusc 3 deficiency TUSC3-CDG System CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Retardation, psychomotor Facial dysmorphism Short stature Sialotransferrins (serum)

Neonatal (birth–1 month) ± ± n

Infancy (1–18 months) ++ ± ± n

Childhood (1.5–11 years) ++ ± ± n

Adolescence (11–16 years) ++ ± ± n

Adulthood (>16 years) ++ ± ± n

68  Congenital Disorders of Glycosylation

1355

Table 68.17  Congenital disorder of glycosylation DDOST-CDG System CNS

Digestive

Ear Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Delayed myelination Developmental delay Hypotonia Intellectual disability Oromotor dysfunction Constipation Gastroesophageal reflux Liver dysfunction, mild to moderate Ear infections Strabismus Osteopenia Failure to thrive Antithrombin (blood) Asialotransferrin (serum) Disialotransferrin (serum) Factor XI (blood) Monosialotransferrin (serum) Protein C (serum) Protein S (serum) Tetrasialotransferrin (serum)

Neonatal (birth–1 month)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

+

+

+

+

+

+

±

±

Infancy (1–18 months) ± + + + + + ± ± n-↑ n-↑ ↓-n ↓-n ↓-n

Childhood (1.5–11 years) ± + + + + + ± ± n-↑ n-↑ ↓-n ↓-n ↓-n

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + + +

+ + ↓ ↑ ↑ ↓ ↑ ↓ ↓ ↓

Table 68.18  Congenital disorder of glycosylation STT3A-CDG System CNS

Digestive Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cerebellar atrophy (MRI) Developmental delay Hypotonia Intellectual disability Seizures Gastrointestinal dysmotility Microcephaly Failure to thrive Asialotransferrin (serum) Disialotransferrin (serum) Factor VIII (plasma) Tetrasialotransferrin (serum) von Willebrand factor (plasma)

Neonatal (birth–1 month)

Adolescence (11–16 years) ± + + + +

Adulthood (>16 years)

± ± n-↑ n-↑ ↓-n ↓-n ↓-n

± − n-↑ n-↑ ↓-n ↓-n ↓-n

+ − + +

1356

J. Jaeken and L. van den Heuvel

Table 68.19  Congenital disorder of glycosylation STT3B-CDG System CNS

Digestive Eye Genitourinary

Hematological Musculoskeletal Other Respiratory Laboratory findings

Symptoms and biomarkers Intellectual disability Cerebral atrophy (MRI) Seizures Hypotonia Developmental delay Gastrointestinal dysmotility Hepatopathy Optic atrophy External genitalia abnormality Scrotum, hypoplastic Testes, undescended Thrombocytopenia Microcephaly Failure to thrive Respiratory failure Disialotransferrin (serum) Asialotransferrin (serum) Tetrasialotransferrin (serum)

Neonatal (birth–1 month) + + + + + + + + +

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

±

±

+ +

+ +

±

±

+

+

+ + + + + + ↑ ↑ ↓

Table 68.20  Magnesium transporter 1 deficiency MAGT1-CDG System CNS Hematological Other

Symptoms and biomarkers Sialotransferrin type 1 pattern (serum) Epstein-Barr virus infection Neoplasm Immunodeficiency, T-cell Magnesium transport defect Retardation, psychomotor

Table 68.21  Congenital disorder of glycosylation SSR4-CDG System CNS

Dermatological

Eye Genitourinary Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Developmental delay Failure to thrive Hypotonia Microcephaly Hypospadias Subcutaneous fat distribution, abnormal Skeletal malformations Clinodactyly Facial dysmorphism Intellectual disability Micrognathia Seizures Subcutaneous fat distribution, abnormal Strabismus Disialotransferrin (serum) Tetrasialotransferrin (serum)

Neonatal (birth–1 month) + + + + ± + ± + + + + + + ↑ ↓

68  Congenital Disorders of Glycosylation

1357

Table 68.22  Glucosidase 1 deficiency GCS1-CDG System CNS

Digestive Eye Genitourinary Hair Musculoskeletal

Respiratory Laboratory findings

Symptoms and biomarkers Apnea BAER, abnormal Burst-suppression (EEG) Developmental delay Epilepsy Hypokinesia Hypotonia Neuropathy, myelinating VEP, abnormal Gastric tube feeding Hepatomegaly Long eye lashes Short palpebral fissures Hypoplastic labia majora Alopecia areata Arched palate, high Facial dysmorphism Fingers, overlapping Respiratory failure Immunoglobulins (serum) Sialotransferrin abnormal pattern (serum) Tetrasaccharide (urine)

Neonatal (birth–1 month) ++ + +

± + + + ↓ ±

Infancy (1–18 months) ++ + + + + + + + +++ + + + + + ± ± + + + ↓ ±

↑

↑

+ + + + +++ + + + + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Adolescence (11–16 years)

Adulthood (>16 years) + ± n

+ + + +

+

+

↓ ±

Table 68.23  Polycyctic kidney disease 3 GANAB-CDG System Renal Digestive Laboratory findings

Neonatal (birth–1 month)

Symptoms and biomarkers Polycystic kidney Polycystic liver disease Sialotransferrins (serum)

Infancy Childhood (1–18 months) (1.5–11 years)

Table 68.24  α-1,3-glucosidase II subunit β deficiency System Digestive Renal Laboratory findings

Neonatal (birth–1 month)

Symptoms and biomarkers Polycystic liver disease 1 Kidney cysts Sialotransferrins (serum)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + ± n

Table 68.25  Mental retardation, autosomal recessive 15 MAN1B1-CDG System CNS

Dermatological Digestive Eye Musculoskeletal

Psychiatric Laboratory findings

Symptoms and biomarkers Hypotonia Intellectual disability Seizures Speech delay Inverted nipples Obesity Strabismus Bulbous nose Flat oval face Macrocephaly Tin upper lips Behaviour difficulties Tetrasialotransferrin (serum) Transaminase (plasma) Trisialotransferrin (serum)

Neonatal (birth–1 month) +

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

± ± ± ± + ± ±

+ ± ± ± ± + ± ±

↓ n-↑ ↑

↓ n-↑ ↑

+ ± ± ± ± + ± + ± ↓ n-↑ ↑

Adolescence (11–16 years) ± + ± +

Adulthood (>16 years) ± + ± +

± ± ± + ± ± ± ↓ n-↑ ↑

+ ± ± + ± ± ± ↓ n ↑

1358

J. Jaeken and L. van den Heuvel

Table 68.26  N-acetylglucosaminyltransferase 2 deficiency MGAT2-CDG System Cardiovascular CNS

Digestive

Ear Endocrine Eye Genitourinary Hematological

Musculoskeletal

Respiratory Other

Laboratory findings

Symptoms and biomarkers Ventricular septal defect Cortical atrophy (MRI) Epilepsy, intractable Hypotonia Movement, abnormal Retardation, psychomotor Big open mouth Diarrhea, chronic Everted lower lip Feeding difficulties Gastroesophageal reflux Gastrointestinal bleeding Volvulus of the stomach Dysplastic ears Hearing loss Absent puberty Decreased body height Delayed visual maturation Myopia Male genital hypoplasia Bleeding tendency Problematic lymphocyte growth Facial dysmorphism Foot deformity Kyphosis Microcephaly Muscular dystrophy Osteoporosis Pectus excavatum Radius dislocation Scoliosis Vertebral anomalies Respiratory insufficiency Beaked nose Drug reactions Fatal evolution before 1 year Gum hypertrophy Recurrent infections Teeth malposition Antithrombin III (plasma) Arylsulfatase A (serum) ASAT (plasma) Factor IX (blood) Factor XI (blood) Haptoglobin (serum) Immunoglobulin G (serum) Sialotransferrins, type 2 pattern (serum) Thyroxin-binding globulin (serum)

Neonatal (birth–1 month) ± ± ± + ± ++ + ± ± ± ± ± ± + ±

Infancy (1–18 months) ± ± ± + ± ++ + ± ± ± ± ± ± + ±

Childhood (1.5–11 years) ± ± ± + ± ++ + ± ± ± ± ± ± + ±

±

+ ± ± ± ± ±

+ ± ± ± ± ±

+ ± ± ± ± ± ± ± ± ±

+ ± ± ± ± ± ± ± ± ± ± ±

↓ n ↑ ↓ ↓ ↓ ↓ +

± ± ± ± ± ± ↓ n ↑ ↓ ↓ ↓ ↓ +

± ± ± ↓ n ↑ ↓ ↓ ↓ ↓ +

↓

↓

↓

± ± ± ± + ± ± ±

± ± ± ± ± ± ± ±

Adolescence (11–16 years) ± ± ± + ± ++ +

Adulthood (>16 years) ± ± ± + ± ++ +

± ±

± ±

+ ± ± +

+ ± ± +

± ± ± ±

± ± ± ±

+ ± ± ± ± ± ± ± ± ± ± ± ±

+ ± ± ± ± ± ± ± ± ± ± ± ±

± ± ±

± ± ±

n ↑

n ↑

↓ n +

↓ n +

↓

↓

68  Congenital Disorders of Glycosylation

1359

Table 68.27  Beta-1,4-galactosyltransferase 1 deficiency B4GALT1-CDG System CNS Eye Digestive Hematological Musculoskeletal Laboratory findings

Symptoms and biomarkers Axial hypotonia Myopia Diarrhea, recurrent episodes Perinatal bleeding diathesis Facial dysmorphism Antithrombin (blood) Antithrombin III (plasma) APTT ASAT (plasma) Asialotransferrin (serum) Cholinesterase (plasma) Creatine kinase (plasma) Disialotransferrin (serum) Factor XI (blood) Fibrinogen Hypogalactosylation Tf glycans Monosialotransferrin (serum) Sialotransferrins, type 2 pattern (serum) Tetrasialotransferrin (serum) Trisialotransferrin (serum)

Neonatal (birth–1 month) + + ± ± + ↓ ↓ ↑ ↑↑ ↑ ↓ ↑ ↑ ↓ ↓ +

Infancy (1–18 months) + + ±

Childhood (1.5–11 years)

+ ↓ ↓ ↑ ↑↑ ↑ ↓ ↑ ↑ ↓ ↓ +

+ ↓ ↓ ↑ ↑↑ ↑ ↓ ↑ ↑ ↓ ↓ +

↑ +

↑ +

↑ +

↓ ↑

↓ ↑

↓ ↑

Infancy (1–18 months) ++ + + + + ± ± ± ± + + + ± ± ± ++ n

Childhood (1.5–11 years) ++ + + + + ± ± ± ± + + + ± ± ± ++ n

Adolescence (11–16 years)

Adulthood (>16 years)

+

↑↑

Table 68.28  α-1,6-fucosyltransferase deficiency FUT8-CDG System CNS

Digestive Endocrine Eye Musculoskeletal

Renal Respiratory Other Laboratory findings

Symptoms and biomarkers Developmental delay Epilepsy Hypotonia Intellectual disability Feeding difficulties Hypothyroidism Buphthalmos Glaucoma Contractures Facial dysmorphism Microcephaly Short stature Nephrocalcinosis Recurrent bronchopneumonia Tracheostomy Failure to thrive Sialotransferrins (serum)

Neonatal (birth–1 month) + + + ± ± ± ± + + + ± ± ± ++ n

Adolescence (11–16 years)

Adulthood (>16 years)

1360

J. Jaeken and L. van den Heuvel

Table 68.29  O-Mannosyltransferase 1 deficiency POMT1-CDG System CNS

Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Agenesis, corpus callosum (MRI) Cerebellar abnormalities Cerebral cortical malformations Cobblestone lissencephaly Encephalocele Epilepsy Hydrocephalus Retardation, psychomotor Buphthalmos Cataract Exophthalmia Glaucoma Megalocornea Microphthalmia Pigmentary retinopathy Dysmorphic features Muscular dystrophy Fatal evolution before 1 year Walker-Warburg syndrome Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ±

± ±

± ±

± ±

± ±

± ± ± ± +++ ± ± ± ± ± ± ± ± + ± ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + ± ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + − ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + − ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + − ± ↑↑ n

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ±

± ±

± ±

± ±

± ±

± ± ± ± +++ ± ± ± ± ± ± ± ± + ± ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + ± ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + − ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + − ± ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± + − ± ↑↑ n

Table 68.30  O-Mannosyltransferase 2 deficiency POMT2-CDG System CNS

Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Agenesis, corpus callosum (MRI) Cerebellar abnormalities Cerebral cortical malformations Cobblestone lissencephaly Encephalocele Epilepsy Hydrocephalus Retardation, psychomotor Buphthalmos Cataract Exophthalmia Glaucoma Megalocornea Microphthalmia Pigmentary retinopathy Dysmorphic features Muscular dystrophy Fatal evolution before 1 year Walker-Warburg syndrome Creatine kinase (plasma) Sialotransferrins (serum)

68  Congenital Disorders of Glycosylation

1361

Table 68.31  O-Mannose beta-1,2-N-acetyglucosaminyltransferase deficiency POMGNT1-CDG System CNS

Eye

Musculoskeletal

Laboratory findings

Symptoms and biomarkers Agenesis, corpus callosum (MRI) Cerebellar abnormalities Cerebral cortical malformations Cobblestone lissencephaly Encephalocele Epilepsy Hydrocephalus Retardation, psychomotor Buphthalmos Cataract Exophthalmia Glaucoma Megalocornea Microphthalmia Myopia Pigmentary retinopathy Dysmorphic features Muscle-eye-brain disease Muscular dystrophy Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ±

± ±

± ±

± ±

± ±

± ± ± ± +++ ± ± ± ± ± ± ± ± ± ± + ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± ± ± + ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± ± ± + ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± ± ± + ↑↑ n

± ± ± ± +++ ± ± ± ± ± ± ± ± ± ± + ↑↑ n

Table 68.32  Protein O-mannose β-1,4-N-acetylglucosaminyltransferase deficiency POMGNT2-CDG System CNS

Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cerebellar hypoplasia Cobblestone lissencephaly Hydrocephalus Hypotonia Retardation, psychomotor Macrophthalmia Microphthalmia Retinal dysplasia Limb-girdl muscular dystrophy Death Walker-Warburg syndrome Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth-1 month) ± ± ± ± ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ± ± ± ± ±

Adulthood (>16 years) ± ± ± ± ± ± ± ± ±

± ± ↑↑ n

± ± ↑↑ n

± ↑↑ n

± ↑↑ n

± ↑↑ n

1362

J. Jaeken and L. van den Heuvel

Table 68.33  β-1,3-galactosaminyltransferase 2 deficiency B3GALNT2-CDG System CNS

Eye

Musculoskeletal Psychiatric Other Laboratory findings

Symptoms and biomarkers Cortical malformation/ dysplasia Epilepsy Hydrocephalus Hypotonia Intellectual disability Pontocerebellar abnormalities Retardation, psychomotor Speech disorder Cataract Glaucoma Microphthalmia Optic nerve hypoplasia Muscular dystrophy Behaviour difficulties Walker-Warburg syndrome/ muscle-eye-brain disease Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ±

↑↑ n

↑↑ n

↑↑ n

↑↑ n

↑↑ n

Neonatal (birth–1 month) ± ± ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ± ± ±

Adulthood (>16 years) ± ± ± ± ± ± ±

± ± ± ± ±

± ± ± ± ± ±

± ± ± ± ± ±

± ± ± ± ± ±

± ± ± ± ± ±

± ± ± ±

± ± ± ±

± ± ± ±

± ± ± ±

± ± ± ±

↑↑ n

↑↑ n

↑↑ n

↑↑ n

↑↑ n

Table 68.34  Protein O-mannose kinase deficiency POMK-CDG System CNS

Ear Eye Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cerebellar hypoplasia Cobblestone lissencephaly Cognitive disability Hydrocephalus Hyporeflexia Hypotonia Mirror movements, upper limbs Retardation, motor Hearing loss, sensorineural Glaucoma Retinal dystrophy Calf pseudohypertrophy Limb-girdle congenital muscular dystrophy Macrocephaly Muscle cramps Muscle weakness, proximal Walker Warburg syndrome/ muscle-eye-brain disease Creatine kinase (plasma) Sialotransferrins (serum)

68  Congenital Disorders of Glycosylation

1363

Table 68.35  Muscular dystrophy-dystroglycanopathy type A7 and C7 CRPPA-CDG System Cardiovascular CNS

Endocrine Eye

Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cardiac dysfunction Agenesis, corpus callosum (MRI) Anterior chamber abnormalities Brain stem hypoplasia Brain vascular anomalies Cerebellar dys/hypoplasia Cobblestone lissencephaly Hydrocephalus Hypotonia Neural tube defects Gonadal dysgenesis Agyria Cataract Chorioretinal degeneration Corneal clouding Microphthalmia Optic nerve hypoplasia Pachygyria Vitreous, persistent hyperplastic primary Calf pseudohypertrophy Limb deformities Muscular dystrophy Walker-Warburg syndrome/ muscle-eye-brain disease Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ±

±

±

±

±

±

+ ± + + ± ± ±

± ± ± ± ± ± ±

± ± ± ± ± ± ±

± + ± ± ± ± ± ±

± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

± ± ± ±

± ± ± ±

± ± ± ±

± ± ± ±

± ± ± ±

n-↑ n

n-↑ n

n-↑ n

n-↑ n

n-↑ n

Table 68.36  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 FKTN-CDG A System Cardiovascular CNS

Eye

Musculoskeletal

Respiratory Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Brainstem hypoplasia Cerebellar abnormalities Cobblestone lissencephaly Corpus callosum abnormalities Epilepsy Hydrocephalus Hypotonia Polymicrogyria Regression, psychomotor Agyria Cataract Chorioretinal degeneration Microphthalmia Optic atrophy Pachygyria Calf muscle hypertrophy Contractures, progressive Muscular dystrophy Scoliosis Respiratory insufficiency Walker-Warburg syndrome/ muscle-eye-brain disease Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ±

Adolescence (11–16 years) ± ± ± ± ±

Adulthood (>16 years) ± ± ± ± ±

± ± ± ±

±

± ± ± ± ± ± ± ± ± ± ± ± ± + ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± + ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± + ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± + ± ± ±

↑↑ n

↑↑ n

↑↑ n

↑↑ n

↑↑ n

± ± ± ± ± ± ± ± +

1364

J. Jaeken and L. van den Heuvel

Table 68.37  Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 FKTN-CDG B System CNS Musculoskeletal Laboratory findings Laboratory findings

Symptoms and biomarkers Hypotonia Muscular dystrophy Creatine kinase (plasma)

Neonatal (birth–1 month) + + ↑↑

Infancy (1–18 months) + + ↑↑

Childhood (1.5–11 years) + + ↑↑

Sialotransferrins (serum)

n

n

n

Adolescence (11–16 years)

Adulthood (>16 years)

Table 68.38  Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 FKTN-CDG C System Cardiovascular CNS Musculoskeletal

Laboratory findings

Symptoms and biomarkers Cardiomyopathy Hypotonia Limb-girdle muscular dystrophy Rigid spine Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± ± +

Infancy (1–18 months) ± ± +

Childhood (1.5–11 years) ± ± +

Adolescence (11–16 years) ± ± +

Adulthood (>16 years) ± ± +

↑↑ n

↑↑ n

± ↑↑ n

± ↑↑ n

± ↑↑ n

Table 68.39  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 FKRP-CDG A System Cardiovascular CNS

Eye

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy Brainstem hypoplasia Cerebellar abnormalities Cobblestone lissencephaly Corpus callosum abnormalities Dandy-Walker malformation Hydrocephalus Hypotonia Regression, psychomotor Agyria Cataract Coloboma Corneal clouding Eye movements, roving Microphthalmos Pachygyria Retinal abnormalities Calf pseudohypertrophy Muscular dystrophy Walker-Warburg syndrome/ muscle-eye-brain disease Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± ± + + +

Infancy (1–18 months) ± ± + + +

Childhood (1.5–11 years) ± ± + + +

± ± + ± ± ± ± ± ± ± + ± + +

± ± + ++ ± ± ± ± ± ± ± + ± + +

± ± + ++ ± ± ± ± ± ± ± + ± + +

↑↑ n

↑↑ n

↑↑ n

Adolescence (11–16 years)

Adulthood (>16 years)

68  Congenital Disorders of Glycosylation

1365

Table 68.40  Muscular dystrophy-dystroglycanopathy (congenital with or without mental retardation), type B, 5 FKRP-CDG B System CNS

Digestive Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Cerebellar abnormalities Hypotonia Intellectual disability Nodular heterotopia Spinal abnormalities White matter abnormalities Feeding difficulties Pachygyria Microcephaly Muscular dystrophy Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± + ± ± ± ± ± ± + ↑↑ n

Infancy (1–18 months) ± + ± ± ± ± ± ± ± + ↑↑ n

Childhood (1.5–11 years) ± + ± ± ± ± ± ± ± + ↑↑ n

Adolescence (11–16 years) ± + ± ± ± ± ± ± ± + ↑↑ n

Adulthood (>16 years) ± + ± ± ± ± ± ± ± + ↑↑ n

Table 68.41  Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 FKRP-CDG C System Cardiovascular CNS Musculoskeletal

Respiratory Laboratory findings

Symptoms and biomarkers Cardiomyopathy Spinal abnormalities Calf muscle hypertrophy Limb-girdle muscular dystrophy Myoglobinuria Tongue hypertrophy Respiratory failure Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ±

+ ±

↑↑ n

Infancy (1–18 months) ± ± ± +

Childhood (1.5–11 years) ± ± ± +

Adolescence (11–16 years) ± ± + +

Adulthood (>16 years) ± ± + +

± ± ± ↑↑ n

± ± ± ↑↑ n

± ± ± ↑↑ n

± ± ± ↑↑ n

Table 68.42  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10 TMEM5-CDG System CNS

Endocrine Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Cerebellar dysplasia Cobblestone lissencephaly Hypotonia Intellectual disability Neural tube defect Gonadal dysgenesis Retinal dysplasia Muscular dystrophy Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± ± + ± ± ± + ↑↑ n

Infancy (1–18 months) ± ± + ±

Childhood (1.5–11 years) ± ± + ±

Adolescence (11–16 years) ± ± + ±

± ± + ↑↑ n

± ± + ↑↑ n

± ± + ↑↑ n

Adulthood (>16 years)

1366

J. Jaeken and L. van den Heuvel

Table 68.43  β-1,4-glucuronyltransferase 1 deficiency B4GAT1-CDG System CNS

Eye

Genitourinary Musculoskeletal

Renal

Other Laboratory findings

Symptoms and biomarkers Brainstem hypoplasia Cerebellar hypoplasia Cobblestone lissencephaly Corpus callosum hypogenesis Cortical dysplasia Epilepsy Hydrocephalus Hypotonia Nodular heterotopia Psychomotor development, absent Corneal clouding Optic nerve dysplasia Retinal dysplasia Micropenis Testicular hypoplasia Anencephaly Encephalocoele, occipital Muscular dystrophy Hydronephrosis Kidney dysplasia Renal cysts Dandy-Walker malformation Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) + + + +

Infancy (1–18 months) + + + +

+ ± + + ± +

+ ± + + ± +

± + + ± ± ± ± + ± ± ± ± ↑↑ n

± + + ± ±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Adulthood (>16 years)

± + ± ± ± ± ↑↑ n

Table 68.44  β-1,3-glucuronyltransferase/α-1,3-xylosyltransferase deficiency LARGE1-CDG System CNS

Musculoskeletal

Laboratory findings

Symptoms and biomarkers Brainstem hypoplasia Cerebellar hypoplasia Developmental regression Hypotonia Neuronal migration abnormalities Nystagmus, horizontal Pachygyria, frontoparietal White matter changes (MRI) Camptodactyly Muscle dystrophy, progressive Muscle hypertrophy Creatine kinase (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ± + + +

Infancy (1–18 months) ± + + + +

Childhood (1.5–11 years) ± + + + +

Adolescence (11–16 years) ± + + + +

± ± ± ± +

± ± ± ± +

± ± ± ± +

± ± ± ± +

± ↑↑ n

+ ↑↑ n

+ ↑↑ n

+ ↑↑ n

68  Congenital Disorders of Glycosylation

1367

Table 68.45  XYLT1 deficiency XYLT1-CDG System CNS Digestive Eye Musculoskeletal

Radiographic findings

Symptoms and biomarkers Intellectual disability Obesity Myopia Brachydactyly Cleft palate Clubfoot Depressed nasal bridge Flat midface Joint laxity Patellar dislocation Short stature Synophrys Advanced bone age Coronal clefts Monkey wrench appearance of femora Short femoral necks Short metacarpals Short phalanges

Neonatal (birth–1 month)

+ ± ± + + +

Infancy (1–18 months) + ± ± + ±

Childhood (1.5–11 years) + ± ± + ±

+ +

Adolescence (11–16 years) + ±

Adulthood (>16 years) +

+

+

+

+

+ + ±

+ + ±

+ ± + + +

+ ± +

+ + + + ± +

+

+

+ + +

+ + +

+ + +

+ +

+ +

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

+ +

+ ±

±

± + +

± + +

Table 68.46  XYLT2 deficiency XYLT2-CDG System Cardiovascular CNS Ear Eye Musculoskeletal

Radiographic findings

Symptoms and biomarkers Atrial septal defect Intellectual disability Hearing loss Cataract Retinal detachment Kyphosis Long bone fractures Short stature Low bone mineral density Vertebral compression fractures

+

± + + + ± + ± + +

+ + +

Table 68.47  Beta-1,4-galactosyltransferase 7 deficiency B4GALT7-CDG System CNS Dermatological Eye Musculoskeletal

Laboratory findings Radiographic findings

Symptoms and biomarkers Developmental delay Atrophic scars Hyperelastic, loose skin Cataracts Proptosis Arachnodactyly Dental defects Flat midface Frontal bossing Joint laxity Overlapping fingers Scoliosis Short stature Talipes equinovarus Sialotransferrins (serum) Advanced bone age Large joint dislocations Low bone mineral density Radioulnar synostosis

Neonatal (birth–1 month) ±

+ + n ± +

Infancy (1–18 months) ± + + ± + + + + + ++ + + + + n ± +

+

+

+ ± + + + + ++ +

Childhood (1.5–11 years) ± + + ± + + + + + ++ + + + + n ± + + +

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

+ +

+ + + + + ++ + + + + n

+ + + + + ++ + + + + n

+ + +

+ + +

1368

J. Jaeken and L. van den Heuvel

Table 68.48  Beta-1,3-galactosyltransferase 6 deficiency B3GALT6-CDG System Cardiovascular CNS Dermatological Eye Musculoskeletal

Other Radiographic findings

Symptoms and biomarkers Congenital heart defects Hypotonia Hyperelastic skin Corneal clouding Cleft palate Flat midface Joint laxity Kyphoscoliosis Short stature Spatulate distal phalanges Talipes equinovarus Pectus carinatum Epiphyseal dysplasia Hip dislocation Long bone fractures Platyspondyly Radial head dislocation

Neonatal (birth–1 month) ± ± ± ± ± + ++ + + + + ± + + ± + +

Infancy (1–18 months) ± ± ± ± ± + ++ + + + + ± + + ± + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

++ ++ +

++ ++ +

± ± ± ± + ++ ++ + + + ± + + ±

±

±

+

+

+

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

± ± ± ± + + + ± ± + +

+

+

+

+

+ ± +

+ ± +

+ ± +

Childhood (1.5–11 years) ± ± ± ++ n

Adolescence (11–16 years) ± ± ± ++ n

Adulthood (>16 years) ± ± ± ++ n

+

Table 68.49  Beta-1,3-glucuronyltransferase 3 deficiency B3GAT3-CDG System Cardiovascular CNS Eye Musculoskeletal

Radiographic findings

Neonatal (birth–1 month) ± ± ± ± ± + + + ± ± + + ± ± + ± +

Infancy (1–18 months) ± ± ± ± ± + + + ± ± + + ± ± + ± +

Neonatal Symptoms and biomarkers (birth–1 month) Bone deformity Chondrosarcoma Functional joint impairment Osteochondroma Sialotransferrins (serum) n

Infancy (1–18 months)

Symptoms and biomarkers Congenital heart defects Hypotonia Proptosis Cleft palate Clubfoot Flat midface Joint laxity Kyphoscoliosis Overlapping, long fingers Pectus carinatum Scoliosis Short stature Bowing of long bones Craniosynostosis Joint dislocations Long bone fractures Radioulnar synostosis

Table 68.50  Exostosin 1 deficiency EXT1-CDG System Musculoskeletal

Laboratory findings

+ n

68  Congenital Disorders of Glycosylation

1369

Table 68.51  Exostosin 2 deficiency EXT2-CDG System Musculoskeletal

Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Bone deformity Chondrosarcoma Functional joint impairment Osteochondroma Sialotransferrins (serum) n

Infancy (1–18 months)

+ n

Childhood (1.5–11 years) ± ± ± ++ n

Adolescence (11–16 years) ± ± ± ++ n

Adulthood (>16 years) ± ± ± ++ n

Childhood (1.5–11 years) + + + + + ±

Adolescence (11–16 years) + + + + + + ±

Adulthood (>16 years) + + + + + + ±

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+

+

+ +

+ +

+ + + +

+ + +

+ + +

+ + +

+ + +

+ +

Table 68.52  Autosomal recessive exostosin 2 deficiency autosomal recessive EXT2-CDG System CNS

Musculoskeletal

Radiographic findings

Symptoms and biomarkers Hypotonia Intellectual disability Seizures Hypertelorism Kyphoscoliosis Macrocephaly Low bone mineral density

Neonatal (birth–1 month) +

+

Infancy (1–18 months) + + + +

Table 68.53  Exostosin-like glycosyltransferase 3 deficiency EXTL3-CDG System CNS

Digestive Hematological Musculoskeletal Radiographic findings

Symptoms and biomarkers Developmental delay Intellectual disability Opisthotonus Hyperreflexia Seizures Spinal cord compression Liver cysts Hypogammaglobulinemia Immunodeficiency, T-cell Kyphosis Short stature Brachydactyly Craniosynostosis Dislocated radial heads Platyspondyly Small capital femoral epiphyses

Neonatal (birth–1 month) + + ± ± ± + + ± + + + + ±

Infancy (1–18 months) + + ± ± ± + + ± + + + + ±

+

+ +

1370

J. Jaeken and L. van den Heuvel

Table 68.54  Chondroitin sulfate synthase 1 deficiency CHSY1-CDG System CNS

Ear Eye Musculoskeletal

Radiographic findings

Symptoms and biomarkers Cerebellar vermis hypoplasia Developmental delay Sensorineural hearing loss Optic atrophy Abducted thumbs Clinodactyly Kyphoscoliosis Medial deviations of fingers Medial deviations of toes Pectus excavatum Preaxial brachydactyly Syndactyly Carpal/tarsal fusion Delta-shaped phalanges Hyperphalangism Radioulnar synostosis Symphalangism

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± + + ± +

± ± ± + + ± +

± ± ± + + ± +

± ± ± + + ± +

± ± + + ± +

+ ± + +

+ ± + +

+ + ± +

+ + ± +

+ ± + + + + + ± +

+ ± + + + + + ± +

+ ± + + + + + ± +

Table 68.55  Chondroitin 4-sulfotransferase 1 deficiency CHST11-CDG Neonatal System Symptoms and biomarkers (birth–1 month) Musculoskeletal Clinodactyly + Kyphoscoliosis Medial deviations of fingers + Medial deviations of toes + Pectus excavatum Preaxial brachydactyly + Syndactyly + `Radiographic Delta-shaped phalanges + findings Dislocated patellae Hyperphalangism + Symphalangism +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) + + + + + + + + + +

Adulthood (>16 years) + + + + ± + + + + + +

+ +

+ +

+ + +

+ + +

+ +

+ +

Infancy (1–18 months) ± ± + + + + ±

Childhood (1.5–11 years) ± ± + + + +

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

+ +

±

±

±

Table 68.56  Chondroitin 6-sulfotransferase deficiency CHST3-CDG System Cardiovascular Ear Musculoskeletal

Radiographic findings

Symptoms and biomarkers Heart valve dysplasia Hearing loss Clubfoot Joint dislocations Kyphoscoliosis Short stature Bifid distal humerus Coronal clefts Small epiphyses

Neonatal (birth–1 month) ± ± + + + ± +

68  Congenital Disorders of Glycosylation

1371

Table 68.57  Dermatan 4-sulfotransferase 1 deficiency CHST14-CDG System Hematological Dermatological

Eye Musculoskeletal

Symptoms and biomarkers Large subcutaneous hematomas Atrophic scars Excessively wrinkled palms Hyperextensible skin Glaucoma Adducted thumbs Downslanted palpebral fissures Joint laxity Long tapered fingers and toes Myopathy Scoliosis Short stature Talipes equinovarus

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+ +

+ + +

+ + +

+ + +

+ + + +

± +

± +

+

+

+

+ +

+ +

+ +

+ +

+ +

+

+

+ + +

+ + +

+ + +

+

+

Table 68.58  Dermatan sulfate epimerase deficiency DSE-CDG System Hematological Dermatological

CNS Musculoskeletal

Symptoms and biomarkers Large subcutaneous hematomas Atrophic scars Excessively wrinkled palms Hyperextensible skin Hypotonia Adducted thumbs Downslanted palpebral fissures Joint laxity Long tapered fingers and toes Scoliosis Short stature Talipes equinovarus

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+ + + ± +

+ + + + ± +

+ + + +

+ + +

+ + + +

+

+

+

+ +

+ +

+ +

+ +

+ +

+ +

+ +

+ +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + +

+ + +

+

+

+

+

Table 68.59  Chondroitin sulfate N-acetylgalactosaminyltransferase 1 deficiency CSGALNACT1-CDG System Cardiovascular CNS Musculoskeletal

Radiographic findings

Symptoms and biomarkers Congenital heart defect Hypotonia Flat midface Genu valgum Joint laxity Short stature Advanced bone age Coronal clefts Enlarged lesser trochanter Mild tibial bowing

Neonatal (birth–1 month) ± ± +

+ + + +

Infancy (1–18 months)

+ + + + +

1372

J. Jaeken and L. van den Heuvel

Table 68.60  Corneal N-acetylglucosamine 6-O-sulfotransferase deficiency CHST6-CDG System Eye

Symptoms and biomarkers Corneal erosion Corneal opacities Macular corneal dystrophy Photophobia

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + + + +

Adolescence (11–16 years) + + + +

Adulthood (>16 years) + + + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

±

±

±

+ + + ± ± ±

+ + + ± ± ±

+ + +

Childhood (1.5–11 years) ± ± +

Adolescence (11–16 years) ± ± +

± ↓ ↓

+ ± ↓ ↓

Table 68.61  Heparan sulfate N-deacetylase N-sulfotransferase 1 deficiency NDST1-CDG System Respiratory CNS

Psychiatric

Symptoms and biomarkers Apnea Ataxia Cranial nerve dysfunction Epilepsy Hypotonia Intellectual disability Sleep disturbances Aggressive behavior Self-injury

Neonatal (birth–1 month) ± ± + +

Infancy (1–18 months)

+ + + ± ± ±

± ±

Table 68.62  Heparan sulfate 6-O-sulfate transferase 1 deficiency HS6ST1-CDG System CNS Ear Endocrine

Musculoskeletal Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Anosmia Sensorineural hearing loss Hypogonadotropic hypogonadism Self-limited delayed puberty Cleft palate Gonadotropins (plasma) Testosterone (plasma)

Infancy (1–18 months)

Adulthood (>16 years)

+

Table 68.63  Calcium-activated nucleotidase 1 deficiency CANT1-CDG System CNS Eye

Musculoskeletal

Radiographic findings

Symptoms and biomarkers Motor developmental delay Glaucoma Myopia Prominent eyes Clubfoot Finger deviation Joint laxity Microretrognathia Midface hypoplasia Round face Short stature Advanced bone age Coronal clefts Hyperphalangy Joint dislocations Prominent lesser trochanters Short metacarpals Small epiphyses

Neonatal (birth–1 month) ± + + + + + + + + + + ± ± + ±

Infancy (1–18 months) ± ± + + + + + + + + + + + ± ± + ±

Childhood (1.5–11 years) ± ± + + +

Adolescence (11–16 years)

Adulthood (>16 years)

± + +

+ + + + + +

+ + + + + +

±

±

+ ± +

± +

+

68  Congenital Disorders of Glycosylation

1373

Table 68.64  Sulfate transporter deficiency SLC26A2-CDG System Ear Musculoskeletal

Radiographic findings

Other Respiratory

Symptoms and biomarkers Cauliflower ear Cystic ear Abducted (“hitchhiker”) thumbs Cleft palate Joint contractures Kyphoscoliosis Short stature Talipes equinovarus Advanced carpal bone age Bowing of radius and ulna Delta-shaped phalanges Flat epiphyses Multilayered patellae Short long bones Fetal hydrops Intrauterine death Respiratory insufficiency

Neonatal (birth–1 month)

Infancy (1–18 months)

± + ± + + + + ± + + + ± ± ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± +

+

+

+

± + + + + +

+ + + + +

+ + + + +

+ + + +

+ + ± +

+ + ± +

Adolescence (11–16 years) + + ± + + ± + + + + ±

± + + ± ↑ n-↑

+ + +

± +

Table 68.65  Phosphoadenosine 5′-phosphosulfate synthetase 2 deficiency PAPSS2-CDG System Dermatological Endocrine Musculoskeletal

Radiographic findings

Laboratory findings

Symptoms and biomarkers Acne, severe Hirsutism Premature pubarche Secondary amenorrhea Bowed limbs Brachydactyly Enlarged knee joints Kyphosis Short stature Advanced bone age Delayed epiphyseal ossification Platyspondyly Precocious osteoarthropathy Short metacarpals Androstenedione (plasma) Dehydroepiandrosterone DHEA (plasma) Dehydroepiandrosterone sulfate DHEAS (plasma) Testosterone (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + + ±

±

+ ± +

Adulthood (>16 years)

+ + ± + + +

±

±

+ ± + + + + ±

+

+

+

±

±

± ↑ n-↑

+ + ± ↑ n-↑

↓

↓

↓

↑

↑

↑

+

1374

J. Jaeken and L. van den Heuvel

Table 68.66  Inositol monophosphate domain-containing protein 1 deficiency IMPAD1-CDG System Ear

Musculoskeletal Radiographic findings

Symptoms and biomarkers Brachydactyly Cleft palate Hearing loss Joint dislocations Joint laxity Lateral deviation of the fifth toe Micrognathia Short stature Accesory ossification centers of hands and feet Advanced carpal bone age Carpal fusion Dislocated patellae Short metacarpals

Neonatal (birth–1 month) + +

Infancy (1–18 months) + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + +

+ + +

+ + +

± + + +

± + + +

+ + ±

+ + ±

+

+

+

±

± + + +

± +

+

+

+ +

Table 68.67  TDP-D-glucose 4,6-dehydrogenase deficiency—Catel–Manzke syndrome TGDS-CDG System Cardiovascular Musculoskeletal

Symptoms and biomarkers Ventricular septal defect Cleft palate Hyperphalangy of index finger Joint laxity Micrognathia Radial deviation of the index finger Short stature

Neonatal (birth–1 month) ± + + ± + +

Infancy (1–18 months) ± + + ± + +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + ± + +

+ +

+

+ +

+ +

±

±

±

Childhood (1.5–11 years) ++ ++ ± ± + ± ↑↑ n

Adolescence (11–16 years) ++ ++ ± ± + ± ↑↑ n

Adulthood (>16 years) ++ ++ ± ± + ± ↑↑ n

Childhood (1.5–11 years) ± ± + ↓ ↓ ↓

Adolescence (11–16 years) ± ± + ↓ ↓ ↓

Adulthood (>16 years) ± ± + ↓ ↓ ↓

Table 68.68  Polypeptide N-acetylgalactosaminyltransferase 3 deficiency GALTNT3-CDG System Dermatological Digestive Musculoskeletal

Laboratory findings

Symptoms and biomarkers Cutaneous calcifications Subcutaneous calcifications Visceral calcifications Bone pain Ectopic calcifications Hyperostosis Phosphate (plasma) Sialotransferrins (serum)

Neonatal (birth–1 month) ++ ++ ± ± + ± ↑↑ n

Infancy (1–18 months) ++ ++ ± ± + ± ↑↑ n

Table 68.69  Core 1 β-1,3-galactosyltransferase chaperone deficiency C1GALT1C1-CDG System Hematological

Laboratory findings

Symptoms and biomarkers Leukemia Myelodysplasia Polyagglutination syndrome Hemoglobin (blood) Neutrophils (blood) Platelets (blood)

Neonatal (birth–1 month) ± ± + ↓ ↓ ↓

Infancy (1–18 months) ± ± + ↓ ↓ ↓

68  Congenital Disorders of Glycosylation

1375

Table 68.70  O-linked N-acetylglucosamine transferase deficiency OGT-CDG System CNS Eye

Genitourinary Musculoskeletal Laboratory findings

Symptoms and biomarkers Intellectual disability Psychomotor disability Amblyopia Hypermetropia Nystagmus Hypogenitalism Hypospadias Facial dysmorphism, minor Sialotransferrins (serum)

Neonatal (birth–1 month)

± ± ± ± ± + n

Infancy (1–18 months) + + ± ± ± ± ± + n

Childhood (1.5–11 years) + + ± ± ± ± ± + n

Adolescence (11–16 years) + + ± ± ± ± ± + n

Adulthood (>16 years) + + ± ± ± ± ± + n

Adolescence (11–16 years) ± ± ± + + + + ± ± n

Adulthood (>16 years)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years) + + + n

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years)

+ ± n

+ ± n

Table 68.71  EGF domain-specific O-linked N-acetylglucosamine transferase deficiency EOGT-CDG System Cardiovascular CNS Dermatological Musculoskeletal

Laboratory findings

Symptoms and biomarkers Heart defects Epilepsy Periventricular calcifications Nail abnormalities Scalp skin defects Distal phalanges hypoplasia Facial dysmorphism Skull defects Syndactyly Sialotransferrins (serum)

Neonatal (birth-1 month) ± ± ± + + + + ± ± n

Infancy (1–18 months) ± ± ± + + + + ± ± n

Childhood (1.5–11 years) ± ± ± + + + + ± ± n

Table 68.72  Muscular dystrophy, limb-girdle, type 2Z autosomal recessive POGLUT1-CDG System Musculoskeletal

Laboratory findings

Symptoms and biomarkers Muscular dystrophy Muscle weakness, proximal Scapular winging Sialotransferrins (serum)

Neonatal (birth–1 month)

Infancy (1–18 months)

Table 68.73  Dowling–Degos disease 4 autosomal dominant POGLUT1-CDG System Dermatological

Laboratory findings

Symptoms and biomarkers Hyperkeratotic dark-brown papules Hyperpigmentation Pruritus Sialotransferrins (serum)

Neonatal (birth–1 month)

Infancy (1–18 months)

1376

J. Jaeken and L. van den Heuvel

Table 68.74  Protein O-fucosyltransferase deficiency POFUT1-CDG System Dermatological

Eye Laboratory findings

Neonatal Symptoms and biomarkers (birth–1 month) Hyperkeratotic papules Hyperpigmentation Hypopigmented macules Hypopigmentation, reticular Sialotransferrins (serum)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years) + + + + n

Adulthood (>16 years) + + + + n

Table 68.75  O-Fucose-specific beta-1,3-N-acetylglucosaminyltransferase deficiency LFNG-CDG System Endocrine Musculoskeletal

Laboratory findings

Symptoms and biomarkers Decreased body height Long, slender fingers Scoliosis Vertebral anomalies of the whole spine Sialotransferrins (serum)

Neonatal (birth–1 month) + + + +

Infancy (1–18 months) + + + +

Childhood (1.5–11 years) + + + +

Adolescence (11–16 years) + + + +

Adulthood (>16 years) + + + +

n

n

n

n

n

Table 68.76  O-Fucose-specific beta-1,3-N-glucosyltransferase deficiency B3GALTL-CDG System Cardiovascular CNS Digestive

Ear

Genitourinary Musculoskeletal

Renal Laboratory findings

Symptoms and biomarkers Cardiac, anomalies, malformations Hydrocephalus Retardation, psychomotor Anteriorly placed anus Gastroesophageal reflux Malrotation Anterior eye chamber anomalies Hearing loss Cryptorchidism Hydroureter Brachydactyly Facial dysmorphism Growth retardation Hydronephrosis Sialotransferrins (serum)

Neonatal (birth-1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± ± ± +

± ± ± ± ± +

± ± ± ± ± +

± ± ± ± ± +

± ± ± ± ± +

± ± ± ± + ± ± n

± ± ± ± + ± ± n

± ± ± ± + ± ± n

± ± ± ± + ± ± n

± ± ± ± + ± ± n

Neonatal (birth–1 month) + + + ± ± + ±

Infancy (1–18 months) + + + ± ± + ±

Childhood (1.5–11 years) + + + ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

±

↓

↓

↓

Table 68.77 PIGA-CDG System CNS

Musculoskeletal Gastrointestinal Laboratory findings

Symptoms and biomarkers Hypotonia Intellectual disability Seizures Broad nasal bridge Coarse face Feeding difficulty Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

68  Congenital Disorders of Glycosylation

1377

Table 68.78  Developmental disability, severe intellectual disability, and drug-responsive epilepsy PIGC-CDG System CNS

Laboratory findings

Symptoms and biomarkers Developmental delay Epilepsy Intellectual disability Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month) + +

Childhood (1.5–11 years) + + + ↓

Adolescence (11–16 years)

Adulthood (>16 years)

↓

Infancy (1–18 months) + + + ↓

Neonatal (birth–1 month) ± + + + + ± ± ↑

Infancy (1–18 months) ± + + + + ± ± ↑

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month) + + + + ± ↓

Infancy (1–18 months) + + + + ± ↓

Childhood (1.5–11 years) + + + + ± ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month) ±

Childhood (1.5–11 years) ± + ± + ↑-↑↑

Adolescence (11–16 years)

Adulthood (>16 years)

± + ↑-↑↑

Infancy (1–18 months) ± + ± + ↑-↑↑

↓

↓

↓

Neonatal (birth–1 month)

Infancy (1–18 months) + ± ± + + ↓

Childhood (1.5–11 years) + ± ± + + ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Table 68.79 PIGQ-CDG System CNS

Eye Laboratory findings

Symptoms and biomarkers Delayed myelination Developmental delay Encephalopathy, epileptic Hypotonia Seizures, refractory Alacrima Optic atrophy Alkaline phosphatase (plasma)

Table 68.80 PIGP-CDG System CNS

Laboratory findings

Symptoms and biomarkers Dyskinesias Epileptic seizures Hypotonia Intellectual disability Microcephaly Flow cytometry of GPI markers (granulocytes)

Table 68.81 PIGY-CDG System CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Epilepsy Intellectual disability Brachytelephalangy Large, fleshy earlobes Alkaline phosphatase (plasma) Flow cytometry of GPI markers (fibroblasts)

Table 68.82 PIGH-CDG System CNS

Psychiatric Laboratory findings

Symptoms and biomarkers Developmental delay Hypotonia Seizures Autism Behavior, aggressive Flow cytometry of GPI markers (granulocytes)

↓

1378

J. Jaeken and L. van den Heuvel

Table 68.83 PIGL-CDG System Cardiovascular CNS Dermatological Ear Eye Laboratory findings

Symptoms and biomarkers Congenital heart defects Intellectual disability Ichthyosis Hearing loss Coloboma Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month) + + + + ±

Infancy (1–18 months) + + + + + ±

Childhood (1.5–11 years) + + + + ±

↓

↓

↓

Neonatal (birth–1 month) + + ± n-↑

Infancy (1–18 months) + + ± n-↑

Childhood (1.5–11 years) + + ± n-↑

↓

↓

↓

Neonatal (birth-1 month)

Infancy (1–18 months)

± ↓

± ± + + ± ↓

Childhood (1.5–11 years) + ± ± + + ± ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Adolescence (11–16 years) +

Adulthood (>16 years)

Table 68.84 PIGW-CDG System CNS

Laboratory findings

Symptoms and biomarkers Developmental delay Epilepsy Hypotonia Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

Table 68.85 PIGM-CDG System CNS Hematological

Dermatologic Laboratory findings

Symptoms and biomarkers Absence seizures Developmental delay Cerebral vein thrombosis Hepatic vein thrombosis Portal vein thrombosis Prominent superficial veins Flow cytometry of GPI markers (granulocytes)

+ +

Table 68.86 PIGV-CDG System CNS

Dermatological Digestive

Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Hearing, impaired Hypotonia Intellectual disability Seizures Hypoplastic nails Anorectal anomalies Feeding difficulties Megacolon Upslanted palpebral fissures Brachytelephalangy Broad nasal bridge Hypertelorism Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month)

+ ± ± + ± + + + + ↑

Infancy (1–18 months) + + ++ + ± ± + ± + + + + ↑

+ ± + + + + ↑

+ + + + ↑

↓

↓

↓

↑

+

Childhood (1.5–11 years) + + ++ + ±

Adolescence (11–16 years) + ++ +

Adulthood (>16 years)

68  Congenital Disorders of Glycosylation

1379

Table 68.87 PIGN-CDG System Cardiovascular Gastrointestinal CNS Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiac anomalies Diaphragmatic defect Hypotonia Seizures Brachytelephalangy Dysmorphic features Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month) ± ± + + ± + ↑

Infancy (1–18 months) ± ± + + ± + ↑

Childhood (1.5–11 years) ± ± + + ± + ↑

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month) ± +

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

+ + + ± ↑

Infancy (1–18 months) ± + + + + + + ± ↑

↑

↓

↓

↓

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± + + + ↓

Childhood (1.5–11 years) ± ± + + + ↓

Adolescence (11–16 years)

Adulthood (>16 years)

n

n

Infancy (1–18 months) + + + ±

Childhood (1.5–11 years) + + + ±

Adolescence (11–16 years)

Adulthood (>16 years)

Table 68.88 PIGO-CDG System Cardiovascular CNS

Dermatological Musculoskeletal Gastrointestinal Laboratory findings

Symptoms and biomarkers Cardiac anomalies Hypotonia Intellectual disability Seizures Hypoplastic nails Brachytelephalangy Facial dysmorphism Anal stenosis Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

+ + + + + +

Table 68.89 PIGG-CDG System CNS

Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar hypoplasia Epilepsy Hypotonia Intellectual disability Flow cytometry of GPI markers (fibroblasts) Flow cytometry of GPI markers (granulocytes)

Table 68.90 PIGT-CDG System CNS

Musculoskeletal Hematologic Immunologic Laboratory findings

Symptoms and biomarkers Hypotonia Intellectual disability Seizures Dysmorphic features Intravascular hemolysis Autoinflammation Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month) + + ±

± ± ↓

↓

↓

↓

↓

1380

J. Jaeken and L. van den Heuvel

Table 68.91 GPAA1-CDG System CNS

Eye Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Developmental delay Hypotonia Intellectual disability Seizures Nystagmus Osteopenia Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years) + + + + + ± + ± ↓

Adolescence (11–16 years) + + + + + ± + ± ↓

Adulthood (>16 years) + + + + + ± + ± ↓

Neonatal (birth-1 month)

Infancy (1–18 months) + + + + + + + ±

Childhood (1.5–11 years) + + + + + + + ±

Adolescence (11–16 years)

Adulthood (>16 years)

Neonatal (birth–1 month)

Infancy (1–18 months) ± + + + ± ± ↑

Childhood (1.5–11 years) ± + + + ± ± ↑

Adolescence (11–16 years)

Adulthood (>16 years)

↓

↓

Infancy (1–18 months) + ± + ± ± ± ↑-↑↑

Childhood (1.5–11 years) + ± + ± ± ± ↑-↑↑

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

+ +

Table 68.92 PGAP1-CDG System CNS

Musculoskeletal Respiratory

Symptoms and biomarkers Brain atrophy (MRI) Delayed myelination Epilepsy Hypotonia Intellectual disability Movement disorder Facial dysmorphism Apnea

Table 68.93 PGAP3–CDG System CNS

Musculoskeletal Respiratory Laboratory findings

Symptoms and biomarkers Ataxia Epilepsy Hypotonia Intellectual disability Micrognathia Cleft palate Alkaline phosphatase (plasma) Flow cytometry of GPI markers (granulocytes)

+ ± ±

Table 68.94 PGAP2-CDG System CNS

Ear Musculoskeletal Laboratory findings

Symptoms and biomarkers Developmental delay Hypotonia Intellectual disability Seizures Hearing loss, sensorineural Microcephaly Alkaline phosphatase (plasma)

Neonatal (birth–1 month) ± ± ± ±

68  Congenital Disorders of Glycosylation

1381

Table 68.95 PIGS-CDG System CNS

Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Hypotonia Intellectual disability Seizures, intractable Coarse facial features Flow cytometry of GPI markers (granulocytes)

Neonatal (birth–1 month) ± + + + ↓

Infancy (1–18 months) + ± + + + + ↓

Childhood (1.5–11 years) + ± + + + + ↓

Adolescence (11–16 years)

Adulthood (>16 years)

Infancy (1–18 months) ± ± ± ± ± ± ± ± n

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± n

Adolescence (11–16 years) ± ± ± ± ± ± ± ± n

Adulthood (>16 years) ± ± ± ± ± ± ± ± n

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Table 68.96  Dehydrodolichyl diphosphate synthase deficiency DHDDS-CDG System CNS

Genitourinary Renal Laboratory findings

Symptoms and biomarkers Ataxia Dystonia Epilepsy Hypotonia Intellectual disability Retinitis pigmentosa Micropenis Renal failure, acute Sialotransferrins (serum)

Neonatal (birth–1 month) ± ± ± ±

± ± n

Table 68.97  Nogo-B receptor deficiency NgBR-CDG System CNS

Eye Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Cortical atrophy (MRI) Developmental delay Epilepsy Hypotonia, axial Spasticity, acral Retinitis pigmentosa Microcephaly Scoliosis Failure to thrive Cholesterol (fibroblasts) Dolichols (fibroblasts)

Neonatal (birth–1 month) +

+ + + + + + + + ↑ ↓

1382

J. Jaeken and L. van den Heuvel

Table 68.98  Steroid 5 alpha-reductase 3 deficiency SRD5A3-CDG System CNS

Dermatological

Endocrine Eye

Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cerebellar abnormalities Hypotonia Midline brain malformations Dry skin Erythroderma Ichthyosis Growth hormone deficiency Cataract Coloboma Microphthalmia Nystagmus Optic atrophy Facial dysmorphism Hypotonia, muscular-axial Kyphosis Failure to thrive Antithrombin III (plasma) Dolichol-linked Glc3Man9GlcNAc2 (serum) Dolichol-phosphate (serum) Partial thromboplastin time (PTT) Protein C (serum) Protein S (serum) Sialotransferrins, type 1 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years) ± ± ±

Adulthood (>16 years) ± ± ±

± ± ± ± ± ± ± ± ± + +

± ± ± ± ± ± ± ± ± + +

± ± ± ± ± ± ± ± ± + +

± ↓ ↓

± ↓ ↓

± ↓ ↓

± ± ± ± ± ± ± ± ± + + ± ±

± ± ± ± ± ± ± ± ± + + ± ±

↓ ↑

↓ ↑

↓ ↑

↓ ↓ ±

↓ ↓ ±

↓ ↓ ±

±

±

↑

↑

↑

Neonatal (birth–1 month) ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ±

Adulthood (>16 years) ±

± ±

±

±

Adolescence (11–16 years) ± ± ± ± ± ± ±

–

– ±

– ±

± ↓

– ± ± ± ↓

± ↓

± ↓

+

+

+

+

n-↑

n-↑

n-↑

n-↑

Table 68.99  Dolichol kinase deficiency DK1-CDG System Cardiovascular CNS Dermatological Endocrine Eye Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Epilepsy Hypotonia Hair abnormality Ichthyosiform erythroderma Puberty, delayed Nystagmus Digital necrosis (distal phalanges) Facial dysmorphism Microcephaly Early death Failure to thrive Lipid-linked oligosaccharides (fibroblasts) Sialotransferrins, type 1 pattern (serum) Transaminase (plasma)

± ±

– ±

68  Congenital Disorders of Glycosylation

1383

Table 68.100  GDP-Man:Dol-P mannosyltransferase subunit 1 deficiency DPM1-CDG System CNS

Digestive Eye

Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia Cerebral atrophy (MRI) Dentate nucleus lesions (MRI) Epilepsy Hypotonia Intellectual disability Neuropathy, peripheral Tremor Feeding difficulties Hepatosplenomegaly Nystagmus Retinal dystrophy Strabismus Microcephaly Creatine kinase (plasma) Dolichol-linked Man5GlcNAc2 (serum) Factor XI (blood) Sialotransferrins, type 1 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month) ±

↑

Infancy (1–18 months) ± ± ± ± + ++ ± ± ± ± ± ± + + ↑ ↑

Childhood (1.5–11 years) ± ± ± ± + ++ ± ± ± ± ± ± + + ↑ ↑

↑ +

↑ +

↑ +

↑

↑

Neonatal (birth–1 month) + + +++ + + + + + + + ↑ ↑

Infancy (1–18 months) + + +++ + + + + + + + ↑ ↑

Childhood (1.5–11 years)

+

+

↑

↑

± + ++ ± ± ± ± ± + −

Adolescence (11–16 years) ± ± ± + ++ ± ±

Adulthood (>16 years) ±

±

+

+

Adolescence (11–16 years)

Adulthood (>16 years)

Table 68.101  Dolichol-P-mannose synthase-2 deficiency DPM2-CDG System CNS

Digestive Musculoskeletal

Respiratory Laboratory findings

Symptoms and biomarkers Cerebral atrophy (MRI) Epilepsy Hypotonia Hepatomegaly Dysmorphic features Joint contractures Microcephaly Muscular dystrophy Scoliosis Respiratory infections/distress Creatine kinase (plasma) Dolichol-linked Man5GlcNAc2 (fibroblasts) Sialotransferrin type 1 pattern (serum) Transaminases (serum)

1384

J. Jaeken and L. van den Heuvel

Table 68.102  GDP-Man:Dol-P mannosyltransferase 3 deficiency DPM3-CDG System Cardiovascular CNS

Musculoskeletal

Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Gait disturbance Retardation, psychomotor Stroke-like episode Dysmorphic features Limb girdle muscular dystrophy Muscle weakness, proximal Pes planus Creatine kinase (plasma) Dolichol-linked Man5GlcNAc2 (serum) Dolichol-P-mannose (serum) Factor XI (blood) Sialotransferrins, type 1 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

n − n

n − n

n − n +

+ n − n +

n

n

+

+ +

↑

↑

↓ n

↓ n

Adulthood (>16 years) ± + n + n + + + ↑↑ ↑ ↓ n ± ↑

Table 68.103  Dol-P-Man utilization 1 deficiency MPDU1-CDG System CNS

Dermatological

Digestive Endocrine Eye

Musculoskeletal Laboratory findings

Symptoms and biomarkers Cerebral atrophy (MRI) Hypotonia Retardation, psychomotor Seizures Tendon reflexes Erythroderma Hyperkeratosis Ichthyosis Feeding difficulties Growth hormone deficiency Optic atrophy Strabismus Vision, impaired Dysmorphic features Antithrombin III (plasma) Creatine kinase (plasma) Dolichol-linked Man5GlcNAc2 (serum) Dolichol-linked Man9GlcNAc2 (serum) Lipid-linked Man5GlcNAc2 (fibroblasts) Lipid-linked Man9GlcNAc2 (fibroblasts) Sialotransferrins, type 1 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month) ± ±

± ↓ n-↑ ↑

± ± ± ± ↓ n-↑ ↑

Childhood (1.5–11 years) ± ± ++ ± n ± ± ± ± ± ± ± ± ± ↓ n-↑ ↑

Adolescence (11–16 years) ± ± ++ ± n ± ± ± ± ± ± ± ± ± ↓ n-↑ ↑

Adulthood (>16 years) ± ± ++ ± n ± ± ± ± ± ± ± ± ± ↓ n-↑ ↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

+

+

+

+

+

n

n

n

n

n

± n ± ± ± ± ± ±

Infancy (1–18 months) ± ± ++ ± n ± ± ± ±

68  Congenital Disorders of Glycosylation

1385

Table 68.104  Glutamine:fructose-6-phosphate transaminase deficiency GFPT1-CDG System CNS

Eye Other Laboratory findings

Symptoms and biomarkers Cerebral white matter involvement (MRI) Congenital myasthenic syndrome Ophthalmoparesis Retinoschizis Response to anticholinesterase therapy Creatine kinase (plasma) Sialotransferrin, type 1 pattern (serum)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

+

+

+

+

+

– ± +

– ± +

– ± +

– ± +

– ± +

± +

± +

± +

± +

± +

± ± + ± ± ±

Infancy (1–18 months) ± ± ± ± + ± ± ±

Childhood (1.5–11 years) ± ± ± ± + ±

Adolescence (11–16 years) ± ± ± ± + ±

Adulthood (>16 years) ± ± ± ± + ±

±

±

±

± ± ± ± ± ± ±

± ± ± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

± ± ± ± ±

±

±

±

↑ ↓ ↑ ↑ ↑ ↓↓↓

↑ ↓ ↑ ↑ ↑ ↓↓↓

↑ ↓ ↑ ↑ ↑

↑ ↓ ↑ ↑ ↑

↑ ↓ ↑ ↑ ↑

↓ ↑ ↓↓↓ ↑ ↓ ↑ ↑

↓ ↑ ↓↓↓ ↑ ↓ ↑ ↑

↑

↑

↑

↑ ↓ ↑ ↑

↑ ↓ ↑ ↑

↑ ↓ ↑ ↑

Table 68.105  Phosphoglucomutase 1 deficiency PGM1-CDG System Cardiovascular CNS Digestive Endocrine

Musculoskeletal

Metabolic Other Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Fatigue Thrombosis, cerebral Bifid uvula Hepatopathy Growth hormone deficiency Hyperinsulinism Hypogonadotropic hypogonadism Cleft palate First arch syndrome Muscle weakness Rhabdomyolysis Short stature Hypoglycemia (episodic) Increased susceptibility to malignant hyperthermia Ammonia (blood) Antithrombin (plasma) Asialotransferrin (serum) Creatine kinase (plasma) Disialotransferrin (serum) Free fatty acids (serum), during hypoglycemia Glucose (plasma) Insulin, durig hypoglycemia Ketones, during hypoglycemia Monosialotransferrin (serum) Tetrasialotransferrin (serum) Transaminase (plasma) Trisialotransferrin (serum)

Neonatal (birth–1 month) ±

1386

J. Jaeken and L. van den Heuvel

Table 68.106  Immunodeficiency-23 PGM3-CDG System CNS Hematological Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Intellectual disability Immunodeficiency, T-cell Neutropenia Brachydactyly Facial dysmorphism Short stature Skeletal dysplasia Atopy Recurrent infections B-cells IgE (serum) Sialotransferrins (serum)

Neonatal (birth–1 month) + + ± ± ± + + ↓ n-↑ n

Infancy (1–18 months) ± + + ± ± ± ± + + ↓ n-↑ n

Childhood (1.5–11 years) ± + + ± ± ± ± + + ↓ n-↑ n

Adolescence (11–16 years) ± + + ± ± ± ± + + ↓ n-↑ n

Adulthood (>16 years) ± + + ± ± ± ± + + ↓ n-↑ n

Table 68.107  Glucose-6-phosphatase catalytic subunit 3 deficiency G6PC3-CDG System Cardiovascular

CNS Digestive Genitourinary Hematological

Musculoskeletal Other

Symptoms and biomarkers Atrial septal defect Patent ductus arteriosus Pulmonary arterial hypertension Skin veins, prominent Intellectual disability Inflammatory bowel disease Urogenital abnormalities Anemia, mild Neutropenia Neutrophil hypoglycosylation Thrombocytopenia Facial dysmorphism Respiratory infections, recurrent

Neonatal (birth–1 month) ± ± ±

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

Adolescence (11–16 years) ± ± ±

Adulthood (>16 years) ± ± ±

+ ± ± ± ± ++ + ± ± ±

+ ± ± ± ± ++ + ± ± ±

+ ± ± ± ± ++ + ± ± ±

+ ± ± ± ± ++ + ± ± ±

+ ± ± ± ± ++ + ± ± ±

Childhood (1.5–11 years) ± + ± ± ± + + + + ± + ± ± n

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± ± ± +

± ± ± +

+ ± + ± ± n

+ ± + ± ± n

Table 68.108  GDP–mannose pyrophosphorylase B deficiency GMPPA-CDG System Cardiovascular CNS

Digestive Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Hypotension, postural Developmental delay Gait disturbance Hearing, impaired Hypotonia Intellectual disability Dysphagia Regurgitation Alacrima Ocular abnormalities Achalasia Facial dysmorphism Growth retardation Sialotransferrins (serum)

Neonatal (birth–1 month)

± ± + + + + ± ± n

Infancy (1–18 months) + ± ± ± + + + + ± + ± ± n

68  Congenital Disorders of Glycosylation

1387

Table 68.109  Muscular dystrophy-dystroglycanopathy GMPPB-CDG System CNS

Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Cerebellar hypoplasia (MRI) Congenital myasthenic syndrome Epilepsy Hypotonia Intellectual disability Cataract Microcephaly Muscle weakness Muscular dystrophy, limb-girdle Myoglobinuria Creatine kinase (plasma) Hypoglycosylation of α-dystroglycan (muscle)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

±

±

±

±

±

± +

± + ± ± ± + ±

± + ± ± ± + ±

± + ± ± ± + ±

± + ± ± ± + ±

↑ +

± ↑ +

± ↑ +

± ↑ +

Infancy (1–18 months) + + ± + + + n n n

Childhood (1.5–11 years) + + ± + + + n n n

Adolescence (11–16 years)

Adulthood (>16 years)

+

Infancy (1–18 months) + + ± + ± + ± ± +

Childhood (1.5–11 years) + + ± + ± + ± ± +

Adolescence (11–16 years) + + ± + ± + ± ± +

Adulthood (>16 years) + + ± + ± + ± ± +

↓

↓

↓

↓

↓

± ± +

↑ +

Table 68.110  Epileptic encephalopathy, early infantile, 50 CAD-CDG System CNS

Hematological

Laboratory findings

Symptoms and biomarkers Developmental regression Epilepsy Swallowing difficulties Anemia (dyserythropoietic) Anisocytosis Poikilocytosis Orotic acid (urine) Pyrimidines (urine) Sialotransferrins (serum)

Neonatal (birth-1 month)

Table 68.111  CMP–sialic acid transporter deficiency SLC35A1-CDG System CNS

Hematological Musculoskeletal Psychiatric Laboratory findings

Symptoms and biomarkers Ataxia Epilepsy Hypotonia Intellectual disability Bleeding, easy Macrothrombocytopenia Microcephaly Behaviour difficulties Sialotransferrins, type 2 pattern (serum) Sialylation of platelet glycoproteins

Neonatal (birth–1 month) + ± ± + ±

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Table 68.112  Congenital disorder of glycosylation SLC35A2-CDG System CNS

Digestive Eye

Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cerebellar abnormalities Cerebral abnormalities Corpus callosum abnormalities Developmental disability Epilepsy Hypotonia Intellectual disability Feeding difficulties Cortical visual impairment Nystagmus Retinitis pigmentosa Dysmorphic features Hand/finger abnormalities Microcephaly Shortened limbs Frequent infections Sialotransferrins, type 2 pattern (serum)

Neonatal (birth–1 month) ± ± ±

+ + ±

+ ± ± ± ± ±

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) ± ± ±

+ + + + ± ± ± ± + ± ± ± ± ±

+ + + + ± ± ± ± + ± ± ± ± ±

Adolescence (11–16 years) ± ± ±

Adulthood (>16 years) ± ± ±

+

+

+ ± ± ± ± + ± ± ± ± ±

+ ± ± ± ± + ± ± ± ± ±

Table 68.113  UDP-N-acetylglucosamine transporter deficiency SLC35A3-CDG System CNS

Musculoskeletal

Laboratory findings

Symptoms and biomarkers Autistic spectrum disorder Epilepsy Hypotonia Intellectual disability Arthrogryposis Facial dysmorphism Skeletal abnormalities Vertebral abnormalities Sialotransferrins (serum)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± + + + + + + ?

Childhood (1.5–11 years) ± ± + + + + + + ?

Adolescence (11–16 years)

Adulthood (>16 years)

+ +

Infancy (1–18 months) +++ ++ + +

Childhood (1.5–11 years) +++ ++ + +

Adolescence (11–16 years) +++ ++ + +

Adulthood (>16 years) +++ ++ + +

−

−

−

−

−

++ ++ + + n ↓↓↓ ↓↓↓ n ↓ n

++ ++ + + n ↓↓↓ ↓↓↓ n ↓ n

++ ++ + + n ↓↓↓ ↓↓↓ n ↓ n

++ ++ + + n ↓↓↓ ↓↓↓ n

++ ++ + + n ↓↓↓ ↓↓↓ n

n

n

± + + + + ?

Table 68.114  GDP-fucose transporter deficiency SLC35C1-CDG System CNS Digestive Endocrine Hematological

Musculoskeletal Other Laboratory findings

Symptoms and biomarkers Retardation, psychomotor Periodontitis Decreased body height Bombay blood group phenotype Delayed separation umbilical cord Neutrophilia Facial dysmorphism Pus formation, inability to Recurrent infections B-cell function Neutrophil motility Neutrophil rolling Sialotransferrins (serum) Sialyl-Lewis on neutrophils T-cell function

Neonatal (birth–1 month)

68  Congenital Disorders of Glycosylation

1389

Table 68.115  UDP–glucuronic acid/UDP-N-acetylgalactosamine dual transporter deficiency SLC35D1-CDG System Digestive Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Abdominal distension Advanced ossification Club foot Dwarfism Nasal hypoplasia Platyspondyly Shortening of long bones Small ilia with snail-like appearance Thoracic hypoplasia Hydrops Perinatal lethality Sialotransferrins (serum)

Neonatal (birth–1 month) ++ + + ++ + ++ +++ ++

Infancy (1–18 months)

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

Adolescence (11–16 years) ± ± ± + ++ ± + ± ± ± ± ↓↓ n-↑ +

Adulthood (>16 years) ± ±

↓↓ n-↑ +

Childhood (1.5–11 years) ± ± ± + ++ ± + ± ± ± ± ↓↓ n-↑ +

↓ n

↓ n

↓ n

+++ ++ + n

Table 68.116  Solute carrier family 39 (Zn transporter) deficiency SLC39A8-CDG System CNS

Eye Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Hyperreflexia Hypotonia Intellectual disability Seizures Strabismus Osteopenia Scoliosis Short stature Recurent infections Manganese (blood) Manganese (urine) Sialotransferrins, type 2 pattern (serum) Zinc (serum) Zinc (urine)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ±

+

+ ++ ± + ± ±

+

+ ++ ± + ± ± ±

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Table 68.117  V0 subunit a2 of vesicular H(+)-ATPase deficiency ATP6V0A2-CDG System CNS

Dermatological

Eye

Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Cerebral cortical malformations Intellectual disability Cutis laxa Skin histology, abnormal elastin fibers Amblyopia Myopia Strabismus Closure of fontanels, delayed Facial dysmorphism Fat distribution, subcutaneous, abnormal Growth retardation Joint laxity Microcephaly Osteoporosis Aged appearance Apolipoproteine C-III isoelectrofocusing, abnormal (serum) Sialotransferrins, type 2 pattern (serum)

Neonatal (birth–1 month) ±

Infancy (1–18 months) ±

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years) ±

± + +

± + +

± ± ±

± ± ±

± ± ±

± ± ± − + ±

± ± ± − + ±

± ± ± ± + ±

± ± ± − + ±

± ± ± − + ±

± + ± ± + +

± + ± ± + +

± + ± ± + +

± + ± ± + +

± + ± ± + +

n-↑

n-↑

n-↑

n-↑

n-↑

Childhood (1.5–11 years) ±

Adolescence (11–16 years) ±

Adulthood (>16 years)

± + ± + ± ± ± ± ± ±

± + ± + ±

Table 68.118  Cutis laxa, autosomal recessive, type IID ATP6V1A-CDG Neonatal Infancy System Symptoms and biomarkers (birth–1 month) (1–18mths) Cardiovascular Cardiovascular ± abnormalities CNS Brain, abnormal (MRI) ± Hypotonia + Intellectual disability ± Seizures + Dermatological Cutis laxa ± Musculoskeletal Contractures ± Facial dysmorphism ± Kyphoscoliosis ± Marfanoid features ± Laboratory Sialotransferrins, type 2 ± findings pattern

±

Table 68.119  Cutis laxa, autosomal recessive, type IIC ATP6V1E1-CDG System Cardiovascular CNS Dermatological Eye Musculoskeletal

Laboratory findings

Symptoms and biomarkers Cardiovascular abnormalities Hypotonia Cutis laxa Entropion Contractures Facial dysmorphism Hip dysplasia Kyphoscoliosis Marfanoid habitus Sialotransferrins, type 2 pattern (serum)

Neonatal (birth–1 month)

Infancy (1–18 months) +

Childhood (1.5–11 years) +

+ + ± ± + ± ± ± +

+ + ± ± + ± ± ± +

Adolescence (11–16 years)

Adulthood (>16 years)

68  Congenital Disorders of Glycosylation

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Table 68.120  Immunodeficiency 47 ATP6AP1-CDG System CNS Dermatological Digestive

Hematological Other Laboratory findings

Symptoms and biomarkers Neurological symptoms Cutis laxa, improving with age Hepatosplenomegaly Pancreatic insufficiency, exocrine Leukopenia Recurrent infections Alkaline phosphatase (plasma) Apolipoprotein C-III, abnormal IEF (serum) Ceruloplasmin (serum) Copper (serum) IgA (serum) IgG (serum) IgM (serum) Sialotransferrins, type 2 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± −

+ ±

+ ±

+ ±

+ ±

+

± + n-↑

± + n-↑

± + n-↑

±

±

±

±

+

↓ ↓ ↓-n ↓ ↓-n +

↓ ↓ ↓-n ↓ ↓-n +

↓ ↓ ↓-n ↓ ↓-n +

n-↑

n-↑

n-↑

↓ ↓ +

Infancy (1–18 months) ± + + ± + ↓ ↓ +

Childhood (1.5–11 years) ± + + ± + ↓ ↓ +

Adolescence (11–16 years) ± + + ± + ↓ ↓ +

Adulthood (>16 years) ± + + ± + ↓ ↓ +

↑

↑

↑

↑

↑

Adolescence (11–16 years)

Adulthood (>16 years)

↑↑

n-↑

±

Table 68.121 ATP6AP2-CDG System CNS Dermatological Digestive Other Laboratory findings

Symptoms and biomarkers Cognitive impairment, mild Cutis laxa Liver involvement Dysmorphism Recurrent infections Factor IX (blood) Gammaglobulins (serum) Sialotransferrins, type 2 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month) + + ±

Table 68.122  Congenital disorder of glycosylation, type IIp TMEM199-CDG System Digestive Laboratory findings

Symptoms and biomarkers Hepatomegaly Alkaline phosphatase (plasma) Ceruloplasmin (serum) Hypoglycosylation of apolipoprotein CIII (serum) Sialotransferrins, type 2 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month)

Infancy (1–18 months)

↑↑

↑↑

Childhood (1.5–11 years) ± ↑↑

↓ ±

↓ ±

↓ ±

↓ ±

↓ ±

+

+

+

+

+

↑

↑

↑

↑

n

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Table 68.123  CCDC115 deficiency CCDC115-CDG System CNS

Digestive

Musculoskeletal Psychiatric Laboratory findings

Symptoms and biomarkers Hypotonia Retardation, psychomotor Seizures Cholestasis Hepatosplenomegaly Liver failure Facial dysmorphism Behaviour difficulties Alkaline phosphatase (plasma) Apolipoprotein CIII hypoglycosylation (serum) Ceruloplasmin (serum) Cholesterol (serum) LDL cholesterol (serum) Sialotransferrins, type 2 pattern (serum) Transaminase (plasma)

Neonatal (birth–1 month)

± ± ± ±

Infancy (1–18 months) ± + ± ± ± ± ±

Childhood (1.5–11 years) ± + ± ± ± ± ±

Adolescence (11–16 years)

Adulthood (>16 years)

↑↑

+ ± ± ± ± ± ± ↑↑

+ ± ± ± ± ± ± ↑↑

↑↑ +

+

+

+

↓ ↑ ↑ +

↓ ↑ ↑ +

↓ ↑ ↑ +

↓ ↑ ↑ +

↑

↑

↑

↑

Infancy (1–18 months) + + + + + ++ + + + ++ + ± ↑ ↑ +

Childhood (1.5–11 years) + + + + + ++ + + + ++ + ± ↑ ↑ +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+ + + ++

+ + ++

+

+

++

++

± ↑ ↑ +

± ↑ ↑ +

Table 68.124  Congenital disorder of glycosylation TMEM165-CDG System CNS Digestive Endocrine Musculoskeletal

Other Laboratory findings

Symptoms and biomarkers Retardation, psychomotor Hepatomegaly Obesity Growth hormone deficiency Dysmorphic features Growth retardation Joint laxity Midface hypoplasia Muscle weakness Skeletal abnormalities Failure to thrive Fever of unknown origin ASAT:ALAT ratio (plasma) Creatine kinase (plasma) Sialotransferrins, type 2 pattern (serum)

Neonatal (birth–1 month) + + + ++ + + + ++ ± ↑ ↑ +

68  Congenital Disorders of Glycosylation

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Table 68.125  N-glycanase 1 deficiency System CNS

Digestive Endocrine Eye

Musculoskeletal Other

Laboratory findings

Symptoms and biomarkers Developmental/intellectual disability Epilepsy Hyporeflexia Hypotonia Microcephaly, acquired Movement abnormalities Peripheral neuropathy Feeding difficulties Liver storage Adrenal insufficiency Alacrima, hypolacrima Corneal ulceration, scarring Ocular apraxia Strabismus Hands/feet, small Scoliosis Anhydrosis Dysmorphism Mortality increased Pain sensation diminished Sialotransferrins (serum) Transaminase (plasma)

Neonatal (birth–1 month)

+

± ±

+ ± ± ±

Childhood (1.5–11 years) ++

Adolescence (11–16 years) ++

Adulthood (>16 years) ++

± + + ± ± ± ± + ± + ±

± + + ± ± ± ± + ± + ± ± ± ± ± ± ± + ± n n-↑

± + + ± ± ±

− + + + ± ±

+ ± + ± ± ± ± ±

+

±

± + ± n n-↑

n n-↑

± ± ±

±

± + ± n ↑

n ↑

Reference Values *Serum sialotransferrins (isoelectrofocusing) (P3–P97 centiles, n = 96, all ages) Monosialotransferrins Disialotransferrins Trisialotransferrins Tetrasialotransferrins Pentasialotransferrins Hexasialotransferrins

Infancy (1–18 months) ++

+ − ± ±

Pathological Values Disease 68.1–68.15 68.17–68.21 68.96–68.104 68.25–68.27 68.105, 68.111, 68.112 68.116–68.124 All other CDG

0.0–3.7 2.0–6.1 5.5–15.1 48.5–65.3 14.9–28.7 2.3–8.1

Sialotransferrin IEF pattern (S) Type 1 patterna

Type 2 pattern°

Normal pattern

Type 1 pattern, increase of di- and asialotransferrin and decrease of tetra-, penta-, and hexasialotransferrin; °type 2 pattern, increase of tri-, di-, mono-, and/or asialotransferrin and decrease of tetra-, penta-, and hexasialotransferrin

a

*Enzyme analyses Phosphomannose mutase (mU/mg protein) Leukocytes 1.8–3.2 (range); 2.2 (median) Fibroblasts 3.8 ± 0.9 (mean ± 1 SD) Phosphomannose isomerase (mU/mg protein) Leukocytes 860–1800 (nmol/h/mg protein, range) Fibroblasts 6.8 ± 1.0 (mean ± 1 SD)

Disease 68.117–68.124 All other CDG

Apolipoprotein C-III IEF pattern (S) Cathodal shift Normal pattern

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Diagnostic Flowchart Fig. 68.2  Flowchart for the diagnosis of CDG

Isoelectrofocusing and/or capillary zone electrophoresis of serum transferrin1

Abnormal

Normal

Protein variant Artefact Isoelectrofocusing of Type 1 pattern

Type 2 pattern

Secondary

Primary

serum apolipoprotein C-III

Normal3

Abnormal

(galactosemia, fructose intolerance, alcohol abuse,.......)

Enzymatic tests (PMM, MPI)2

Deficient

Normal

Mutation analysis of PMM2 or MPI

Mutation analysis by gene panels, WES or WGS

WES: whole exome sequencing (checking first established genes for CDG defects and afterwards candidate genes for CDG defects and/or all other genes). WGS: whole genome sequencing (checking first established genes for CDG defects and afterwards candidate genes for CDG defects and/or all other genes). 1: In specialized centers for CDG diagnostics, glycomics MS assays have been developed and may be used for initial screening as well (Bakar et al 2018; Ashikov et al 2018). 2: Enzymatic tests may be performed when there is a typical PMM2-CDG or MPI-CDG phenotype. 3: In case of strong clinical suspicion of CDG, genetic testing is advocated.

68  Congenital Disorders of Glycosylation

1395

Specimen Collection Test Precondition Sialotransferrins

Material S

Apolipoprotein C-III Phosphomannomutase Phosphomannose isomerase

S WBC, FB WBC, FB

Handling Pitfalls Frozen No EDTA (−20 °C) plasma Frozen (−20 °C) Frozen (−20 °C) Frozen (−20 °C)

Prenatal Diagnosis Disorder Material Timing, trimester All (68.1–68.125) CV sampling or cultured AFC I, II

Prenatal diagnosis is performed by DNA diagnostics on genomic DNA when the genetic defect has been established in a particular family. Maternal contamination has to be excluded by haplotype (CA repeat) testing of the AFC and maternal blood.

DNA Testing Disorder Material All (68.1–68.125) F, WBC

Methodology Direct sequencing of genomic DNA

• •

• •

nases. Oral mannose, 0.2 g/kg of body weight per 4 h, is recommended. The clinical symptoms usually disappear rapidly, but it takes several months for the serum transferrin isoform pattern to improve or normalize. 68.114 GDP-fucose transporter deficiency Oral fucose, 150 mg/kg of body weight, five times a day, abolishes or prevents infections and normalizes neutrophil counts in some patients (depending on genotype). 68.85 PIGM deficiency Oral sodium phenylbutyrate (a histone deacetylase inhibitor), 20–30  mg/kg body weight, three times a day, has been given to three patients with a clearly beneficial effect on seizures and psychomotor development.

Dangers/Pitfalls • 68.2 Higher mannose doses can induce osmotic diarrhea. Some patients develop hemolytic jaundice under mannose therapy. The alternative is then liver transplantation. • 68.114 Higher fucose doses can induce autoimmune neutropenia.

Experimental Treatment

• 68.105 Phosphoglucomutase 1 deficiency • In pilot studies, oral galactose administration (1 g/kg per day) caused an improvement of liver transaminases, antiTreatment thrombin and factor XI, endocrine parameters (to a variable degree), and glycosylation and a decreased frequency Besides the well-established symptomatic and supportive of rhabdomyolysis (review in Witters et al. 2017). therapies for all CDG, there are very few specific/curative • 68.110 CAD trifunctional protein deficiency treatments: mannose for MPI-CDG, fucose for some patients • Oral uridine administration (100  mg/kg per day) abolwith SLC35C1-CDG, benzoate for the neurological sympished the epilepsy and the anemia, improved psychomotoms of PIGM-CDG, and uridine for CAD-CDG. Galactose tor development, and normalized UDP sugars in is on trial for several CDG mainly PGM1-CDG, SLC35A2-­ fibroblasts (Koch et al. 2017). CDG, and TMEM165-CDG. Also on trial is manganese for • 68.112 UDP-galactose transporter deficiency SLC39A8-CDG.  A minority of patients with PMM2-CDG • On oral galactose, seizures tend to improve. In one patient, present recurrent stroke-like episodes, thromboses (probably glycosylation was nearly completely restored, but serum at least in part due to hyperaggregability of blood platelets), transaminases remained elevated (review in Witters et al. and/or bleeding episodes. Guidelines for the preventive and 2017). curative treatment of these features are being established by • 68.116 SLC39A8 deficiency the Paris MetabERN center. The same center also prepares • In two patients, oral MnSO4 administration (15 and 20 mg/kg per day) considerably improved motor abiliguidelines for the hormonal treatment of pubertal problems ties, hearing, and other neurological functions and comin PMM2-CDG. pletely normalized enzyme dysfunctions (Park et  al. 2018). Standard Treatment • 68.124 Transmembrane protein 165 deficiency • In two patients, oral galactose administration caused a • 68.2 Phosphomannose isomerase deficiency substantial improvement of N-glycosylation, endocrine • Mannose circumvents the defective step because it can be function, and some coagulation parameters (Morelle et al. directly converted to mannose-6-phosphate by hexoki2017).

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Marques-da-Silva D, Dos Reis Ferreira V, Monticelli M, et al. Liver involvement in congenital disorders of glycosylation (CDG): a systematic review. J Inherit Metab Dis. 2017a;40:195–207. Abu Bakar N, Lefeber DJ, van Scherpenzeel M.  Clinical glycomics Marques-da-Silva D, Francisco R, Webster D, Dos Reis Ferreira V, for the diagnosis of congenital disorders of glycosylation. J Inherit Jaeken J, Pulinilkunnil T. Cardiac complications of congenital disMetab Dis. 2018;41:499–513. orders of glycosylation (CDG): a systematic literature review. J Carchon H, Chevigné R, Falmagne JB, Jaeken J. Diagnosis of congeniInherit Metab Dis. 2017b;40:657–72. tal disorders of glycosylation by capillary zone electrophoresis of Matthijs G, Schollen E, Pardon E, et al. Mutations in PMM2, a phosserum transferrin. Clin Chem. 2004;50:101–11. phomannomutase gene on chromosome 16p13, in carbohydrateComan D, Irving M, Kannu P, Jaeken J, Savarirayan R.  The skeletal deficient glycoprotein type I syndrome (Jaeken syndrome). Nat manifestations of the congenital disorders of glycosylation. Clin Genet. 1997;16:88–92. (erratum in Nat Genet 1997 Jul; 16(3): 316) Genet. 2008;73:507–15. Monticelli M, Ferro T, Jaeken J, Dos Reis Ferreira V, Videira PA. Ferreira CR, Altassan R, Marques-Da-Silva D, Francisco R, Jaeken J, Immunological aspects of congenital disorders of glycosylation Morava E. Recognizable phenotypes in CDG. J Inherit Metab Dis. (CDG): a review. J Inherit Metab Dis. 2016;39:765–80. 2018;41:541–53. Morava E, Thiemes V, Thiel C, et al. ALG6-CDG: a recognizable pheFrancisco R, Marques-da-Silva D, Brasil S, et  al. The challenge of notype with epilepsy, proximal muscle weakness, ataxia and behavCDG diagnosis. Mol Genet Metab. 2018a; https://doi.org/10.1016/j. ioral and limb anomalies. J Inherit Metab Dis. 2016;39:713–23. ymgme.2018.11.003. Morava E, Wosik HN, Sykut-Cegielska J, et  al. Ophthalmological Francisco R, Pascoal C, Marques-da-Silva D, et  al. Keeping an eye abnormalities in children with congenital disorders of glycosylation on congenital disorders of O-glycosylation: a systematic literature type I. Br J Ophthalmol. 2009;93:350–4. review. J Inherit Metab Dis doi. 2018b; https://doi.org/10.1007/ Morelle W, Potelle S, Witters P, et  al. Galactose supplementation in s10545-­017-­0119-­2. patients with TMEM165-CDG rescues the glycosylation defects. J Grünewald S.  The clinical spectrum of phosphomannomutase 2 defiClin Endocrinol Metab. 2017;102:1375–86. ciency (CDG-Ia). Biochim Biophys Acta. 2009;1792:827–34. Ng BG, Freeze HH.  Perspectives on glycosylation and its congenital Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time disorders. Trends Genet. 2018;34:466–76. for a change! Biochim Biophys Acta. 2009;1792:825–6. Ng BG, Shiryaev SA, Rymen D, et  al. ALG1-CDG: clinical and Jaeken J, Lefeber D, Matthijs G. Clinical utility gene card for : phosmolecular characterization of 39 unreported patients. Hum Mutat. phomannose isomerase deficiency. Eur J Hum Genet. 2014; https:// 2016;37:653–60. doi.org/10.1038/ejhg.2014.29. Park JH, Hogrebe M, Fobker M, et al. SLC39A8 deficiency: biochemiJaeken J, Péanne R.  What is new in CDG? J Inherit Metab Dis. cal correction and major clinical improvement by manganese ther2017;40:569–86. apy. Genet Med. 2018;20:259–68. Jaeken J, van Eijk HG, van der Heul C, et al. Sialic acid-deficient serum Van Schaftingen E, Jaeken J.  Phosphomannomutase deficiency is and cerebrospinal fluid transferrin in a newly recognized syndrome. a cause of carbohydrate-deficient glycoprotein syndrome type Clin Chim Acta. 1984;144:245–7. I. FEBS Lett. 1995;370:318–20. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et  al. Familial Witters P, Cassiman D, Morava E.  Nutritional therapies in congenipsychomotor retardation with markedly fluctuating serum proteins, tal disorders of glycosylation (CDG). Nutrients. 2017; https://doi. FSH and GH levels, partial TBG-deficiency, increased serum arylorg/10.3390/nu9111222. sulphatase a and increased CSF protein: a new syndrome? Pediatr Wopereis S, Grünewald S, Morava E, et al. Apolipoprotein C-III isofoRes. 1980;14:179. cusing in the diagnosis of genetic defects in O-glycan biosynthesis. Koch J, Mayr JA, Alhaddad B, et  al. CAD mutations and uridine-­ Clin Chem. 2003;49:1839–5. responsive epileptic encephalopathy. Brain. 2017;140:279–86.

Part XI Various

Cerebral Organic Acidurias

69

Stefan Kölker

Contents Introduction

 1400

Nomenclature

 1402

Metabolic Pathways

 1402

Signs and Symptoms

 1405

Reference Values

 1407

Pathological Values

 1407

Diagnostic Flowchart(s)

 1408

Specimen Collection

 1411

Prenatal Diagnosis

 1412

DNA Testing

 1412

Treatment Summary

 1412

Experimental Treatment

 1414

References

 1414

Summary

A group of organic acidurias, including Canavan disease (N-acetylaspartic aciduria), glutaric aciduria type I, L-2-­ hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria types I and II, are characterised by a predominantly or even exclusively neurological presentation and have therefore been termed ‘cerebral’. The clinical presentation frequently includes developmental delay, cognitive disability, movement disorder and epilepsy, resulting from acute and/or chronic pathological changes in various brain regions including grey matter (cortex, basal ganglia, cerebellum) and white matter (periventricular and subcor-

S. Kölker (*) Division of Pediatric Neurology and Metabolic Medicine, Clinic I, Center for Pediatric and Adolescent Medicine, Heidelberg, Germany e-mail: [email protected]

tical). Unlike ‘classic’ organic acidurias (e.g. propionic and methylmalonic aciduria), acute metabolic decompensations with hyperammonaemia, metabolic acidosis and elevated concentrations of lactate and ketone bodies are uncommon for cerebral organic acidurias. Biochemically, these diseases are characterised by accumulation of characteristic organic acids, mostly dicarboxylic acids, in body fluids. At high concentrations, some of these may become neurotoxic. Since the blood–brain barrier has a low transport capacity for dicarboxylic acids, cerebral accumulation of dicarboxylic acids is facilitated. Impairment of brain energy metabolism is suggested to play a central role in the pathophysiology of this disease group. Metabolic treatment initiated in neonatally diagnosed patients with glutaric aciduria type I has significantly improved the neurological outcome, whereas current treatment strategies for the other cerebral organic acidurias are ineffective.

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_69

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Introduction Canavan disease (Van Bogaert–Bertrand disease, N-acetylaspartic aciduria), a debilitating and lethal leukodystrophy, is caused by an autosomal recessively inherited deficiency of aspartoacylase (aminoacylase 2) which is exclusively expressed in oligodendrocytes. Most patients have the infantile form which generally manifests at 2–4 months of age with head lag, muscular hypotonia and macrocephaly, progressing to marked developmental delay, seizures, optic nerve atrophy, progressive spasticity and opisthotonic posturing (Matalon et  al. 1995). Death usually occurs in a few years. However, the initial symptoms may already start at or shortly after birth (neonatal form) or after the age of 5 years (juvenile form). Cranial MRI studies show diffuse or exclusively subcortical involvement of the white matter due to spongiform myelinopathy and involvement of the thalamus and globus pallidus. Diagnosis can be made by finding elevated Nacetylaspartate concentrations in urine using GC/MS analysis of organic acids. A decreased aspartoacylase activity in cultured skin fibroblasts and/or the identification of two disease-causing mutations in the ASPA gene localised on 17p13.2 confirms the diagnosis. N-Acetylaspartate is formed in neurons and hydrolysed to L-aspartate and acetate by oligodendrocytes. No effective treatment exists for Canavan disease. Lithium citrate decreases brain N-acetylaspartate concentrations (Assadi et al. 2010), and glyceryl triacetate treatment supplies the brain with acetate (Segel et al. 2011). Although this treatment is considered as safe, there is no proof for its t­herapeutic efficacy. Initial attempts of ASPA gene therapy have not met expectations (Leone et al. 2000). Recombinant adeno-­associated virusbased gene therapy targeting astrocytes (Gessler et  al. 2017), however, achieved complete and sustained rescue of the lethal phenotype in a mouse model of Canavan disease. Translation into clinical studies is pending. Glutaric aciduria type I (glutaric acidaemia type I) is caused by an autosomal recessively inherited deficiency of glutaryl-CoA dehydrogenase, an FAD-dependent mitochondrial matrix enzyme. This enzyme is involved in the catabolic pathways of lysine, hydroxylysine and tryptophan, catalysing the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA.  Transient muscular hypotonia and macrocephaly are often found in newborns. At this age, cranial MRI of affected individuals reveals temporal hypoplasia, dilated external CSF spaces, subependymal pseudocysts, myelination delay and an immature gyral pattern which all

S. Kölker

may improve or even resolve in early treated children (Harting et al. 2009). In the time interval between 3 and 36 (−72) months, however, most untreated patients develop a complex movement disorder best described as generalised dystonia superimposed on axial hypotonia (Gitiaux et  al. 2008). These symptoms are the consequence of bilateral striatal injury which may occur acutely during acute encephalopathic crises precipitated by catabolism or insidiously without preceding crises (Kölker et  al. 2006). Aside from striatal injury, MRI may show additional frontal atrophy and subdural haemorrhage. A few adolescent and adult patients with a late-onset form have been reported presenting with headaches, vertigo, reduced fine motor skills and white matter abnormalities (Harting et al. 2009). Patients can be identified in the first week of life by newborn screening using glutarylcarnitine as a diagnostic parameter. Glutarate and 3-hydroxyglutarate concentrations are increased in urine and other body fluids but may be (intermittently) normal in patients with a low-excreter phenotype. Therefore, a normal organic acid analysis result does not unequivocally exclude the diagnosis. Suspected diagnosis is confirmed by significantly decreased glutaryl-CoA dehydrogenase activity in leucocytes or fibroblasts and/or the identification of two disease-­causing mutations in the GCDH gene localised on 19p13.13. Glutarate and 3-hydroxyglutarate concentrations are 100–1000-fold higher in the brain than in plasma which is caused by the very low efflux transport of dicarboxylic acids across brain capillary endothelial cells (Sauer et  al. 2006). At high concentrations, accumulating dicarboxylic acids may become neurotoxic inhibiting energy metabolism (2-oxoglutarate dehydrogenase, dicarboxylate shuttle between astrocytes and neurons) and activating N-methyl-D-­ aspartate receptors. The development of prognostic relevant striatal injury can be prevented in the majority of children if the diagnosis is made and metabolic treatment is started neonatally (Heringer et  al. 2010; Boy et  al. 2018). Metabolic treatment according to a recently revised guideline includes a low lysine diet, carnitine supplementation and emergency treatment to counteract catabolism (Kölker et al. 2011; Boy et al. 2017a, b). Patients with a high- and low-excreter phenotype have the same risk of developing striatal injury and thus receive the same treatment (Kölker et al. 2006); however, the neurological long-term risk of individuals with high-excreter phenotype might be increased (Boy et  al. 2017a, b). Regardless of therapy, some individuals develop mild to moderate degree chronic kidney disease starting at school age. The prognosis of this renal manifestation needs to be elucidated.

69  Cerebral Organic Acidurias

L-2-Hydroxyglutaric aciduria (L2HGA) is an autosomal recessive inborn error of metabolism, caused by mutations in the L2HG dehydrogenase (L2HGDH) gene. The L2HGDH gene product, i.e. L2HGDH, is an FAD-dependent membrane-bound enzyme responsible for the conversion of L-2hydroxyglutarate (L2HG) into 2-ketoglutaric acid (2KG). The current opinion is that nonspecific mitochondrial formation of L2HG out of 2KG by L-malic dehydrogenase is the sole source of L2HG and that L2HGDH is an enzyme for metabolite repair (Van Schaftingen et al. 2009). L2HGA has an insidious onset starting in childhood with developmental delay, macrocephaly, epilepsy and cerebellar ataxia as clinical signs. In a minority of patients, the diagnosis is established in adulthood, but retrospective evaluation of the clinical course reveals an earlier subtle onset (Steenweg et al. 2010). MRI reveals disease-specific alterations characterised by predominantly subcortical cerebral white matter abnormalities and abnormalities of the dentate nucleus, globus pallidus, putamen and caudate nucleus (Steenweg et  al. 2009). Metabolic investigations will reveal increased 2HG in the urinary organic acid screening, and subsequent chiral differentiation shows the increased excretion of exclusively L2HG. Apart from the massive increase of L2HG in all body fluids, a modest increase of CSF lysine is observed, while plasma lysine levels may be normal. Since the massive increase of L2HG is the major biochemical finding, pathology is likely to be explained by the pathologic levels of L2HG; however, lowered (peripheral) 2KG levels might also attribute to the disease. Currently, there is no established treatment protocol for L2HGA apart from two anecdotic reports mentioning positive effects of treatment with riboflavin and/or FAD. D-2-Hydroxyglutaric aciduria (D2HGA) type I is one of the two subtypes of D2HGA and has an autosomal recessive pattern of inheritance. The disease is caused by mutations in the D2HG dehydrogenase (D2HGDH) gene, resulting in a deficiency of D-2-hydroxyglutarate (D2HG) dehydrogenase (Struys et  al. 2005). This FAD-dependent mitochondrial

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enzyme converts D2HG, most likely formed by the action of hydroxyacid-oxoacid transhydrogenase (HOT), into 2KG. Although several hypothetical metabolic pathways for D2HG have been proposed, there is strong evidence that D2HG is directly and exclusively formed out of 2KG (Struys et al. 2004). The disease displays a strong clinical heterogeneity from severely affected individuals to asymptomatic individuals. However, frequently reported clinical findings are developmental delay, hypotonia and epilepsy. Usually, patients are first recognised by an increase of 2HG in the urinary organic acid screening. In contrast with L2HGA, these elevations can be modest. The increase of D2HG in all body fluids is the sole biochemical alteration in this disease, and the pathophysiology of the disease is likely to be explained by this. Currently, there is no treatment. However, it can be hypothesised that in individual cases, riboflavin supplementation might be beneficial. D-2-Hydroxyglutaric aciduria (D2HGA) type II is the second form of D2HGA and is caused by a gain-of-function mutation in the isocitrate dehydrogenase 2 (IDH2) gene (Kranendijk et al. 2010). Heterozygous mutations in IDH2 result in the formation of a neomorph enzyme which is able to efficiently convert 2KG into D2HG. This is in contrast with the normal action of IDH2, i.e. the conversion of isocitrate into 2KG. D2HGA type II has an autosomal dominant trait, and in the vast majority of patients, the mutation arose de novo. The degree of D2HG accumulation in D2HGA type II is higher than in type I, despite properly functioning D2HG dehydrogenase. Patients affected with D2HGA type II suffer from developmental delay, muscular hypotonia and epilepsy, and their clinical presentation is generally more severe than that of patients with D2HGA type I. Cardiomyopathy is frequently observed in D2HGA type II and absent in type I. Specific inhibition of the neomorph enzyme by a small molecule rescued cardiomyopathy and improved survival in a mouse model for D2HGA type II (Wang et al. 2016).

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Nomenclature No. Disorder 69.1 Canavan disease 69.2 Glutaric aciduria type I 69.3 L-2-Hydroxyglutaric aciduria 69.4 D-2-Hydroxyglutaric aciduria type I 69.5 D-2-Hydroxyglutaric aciduria type II

Alternative name Van Bogaert–Bertrand disease Glutaric acidaemia type I L-2-Hydroxyglutarate dehydrogenase deficiency D-2-Hydroxyglutarate dehydrogenase deficiency Isocitrate dehydrogenase 2 deficiency

Abbreviation CD

Chromosomal Gene symbol localisation ASPA 17p13.2

GA-I

GCDH

19p13.13

L2HGA

L2HGDH

14q21.3

D2HGA type I

D2HGDH

D2HGA type II

IDH2

Metabolic Pathways Canavan Disease (Aspartoacylase Deficiency)

Aspartate Acetyl-CoA

CoA N-Acetylaspartate 69.1

Aspartate + Acetyl-CoA

Fig. 69.1  Metabolic pathway of Canavan disease. N-Acetylaspartate is produced in neurons from L-aspartate and acetyl-CoA and is transported to oligodendrocytes where it is hydrolysed to L-aspartate and acetyl-­CoA by aspartate aminoacylase 2. Inherited deficiency of this enzyme results in accumulation of N-acetylaspartate in patients with Canavan disease

Affected protein Aspartoacylase (aminoacylase 2) Glutaryl-CoA dehydrogenase L-2-Hydroxyglutarate dehydrogenase

OMIM no. 271900

2q37.3

D-2-Hydroxyglutarate dehydrogenase

600721

15q26.1

Isocitrate dehydrogenase 2

613657

231670 236792

69  Cerebral Organic Acidurias

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 lutaric Aciduria Type I (Glutaryl-CoA G Dehydrogenase Deficiency) Lysine 2-Oxoglutarate Saccharopine pathway

Hydroxylysine

Pipecolic acid pathway

2-Aminoadipic semialdehyde 1 2-Aminoadipic acid 2

Tryptophan

2-Oxoadipic acid 3

–

Glutaric acid

Glutaryl-CoA 4 Glutaconyl-CoA 4 Crotonyl-CoA

Glutarylcarnitine Glutaconic acid 3-Hydroxyglutaryl-CoA

3-Hydroxyglutaric acid

Acetyl-CoA

Fig. 69.2  Metabolic pathway of glutaric aciduria type I. Glutaryl-CoA is formed within the catabolic pathways of lysine, tryptophan and hydroxylysine. The quantitatively major precursor is lysine. Deficient activity of glutaryl-CoA dehydrogenase (4) results in variable accumulation of glutaric, 3-hydroxyglutaric and glutaconic acid as well as glutarylcarnitine, which are important for the diagnosis and can be determined in body fluids. Elevated glutaryl-CoA—similar to homologous succinyl-CoA—results in feedback inhibition of the TCA cycle enzyme 2-oxoglutarate dehydrogenase complex (3). 1, 2-aminoadipic semialdehyde dehydrogenase (enzyme is deficient in pyridoxine-­dependent epilepsy), 2, 2-aminoadipate aminotransferase, 3,

2-­ oxoglutarate dehydrogenase-like complex (enzyme complex contains three subunits: DHTKD1, a E1 component with substrate specificity for 2-oxoadipate, is deficient in 2-aminoadipic/2-oxoadipic aciduria; the E2 subunit is deficient in 2-oxoglutarate dehydrogenase complex deficiency; E3 subunit (lipoamide dehydrogenase), which is shared with pyruvate dehydrogenase and branched-chain oxoacid dehydrogenase complexes, is deficient in E3 deficiency, biochemically resembling maple syrup urine disease, 2-oxoglutarate dehydrogenase complex deficiency and pyruvate dehydrogenase complex deficiency, 4, glutaryl-CoA dehydrogenase

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 -2-Hydroxyglutaric Aciduria (L-2L Hydroxyglutarate Dehydrogenase Deficiency)

 -2-Hydroxyglutaric Aciduria Type II (Isocitrate D Dehydrogenase 2 Deficiency) D-2-HGDH

NADH + H+

NAD+

L-malDH

TCA cycle

L-2-HG FAD L-2-HGDH

2-KG

TCA cycle

NADPH + H+ 2-KG

NADPH+ IDH 2 mut D-2-HG

FADH2 HOT

Fig. 69.3 Metabolic pathway of L-2-hydroxyglutaric aciduria. L-2-­ Hydroxyglutaric acid is formed by a nonspecific conversion of mitochondrial 2KG into L-2-hydroxyglutaric acid by the action of NADH-dependent Fig. 69.5  Metabolic pathway of D-2-hydroxyglutaric aciduria type l-malic acid dehydrogenase. L2HG dehydrogenase corrects for this meta- II.  As a consequence of a heterozygous mutation in IDH2, the neomorph IDH2 enzyme produces vast amounts of D2HG, which exceed bolic imperfection by reconverting L2HG into 2KG the capacity of D2HG dehydrogenase, an enzyme with a low Km, and as a net result, D2HG accumulates. The neomorph IDH2 enzyme consumes both 2KG and NADPH, which might lead to their shortages

D-2-Hydroxyglutaric Aciduria Type I (D-Hydroxyglutarate Dehydrogenase Deficiency)

TCA cycle

D-2-HGDH 2-KG

D-2-HG HOT

Fig. 69.4  Metabolic pathway of D-2-hydroxyglutaric aciduria type I. D-2-Hydroxyglutaric acid is formed out of mitochondrial 2KG by the action of hydroxyacid-oxoacid transhydrogenase (HOT). D2HG is reconverted into 2KG by D2HG dehydrogenase. This pathway is thought to play a role in GABA/GHB homeostasis

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Signs and Symptoms Table 69.1  Canavan disease System CNS

Ear Eye

Musculoskeletal Laboratory findings

Symptoms and biomarkers Decerebrate posture Dysarthria Epilepsy Extrapyramidal movement disorder Loss of very early milestones Mental retardation Motor retardation Muscular hypotonia Opisthotonos Spasticity Deafness Blindness Nystagmus Optic atrophy Macrocephaly MRI: bilateral subcortical leukodystrophy + involvement of globus pallidus N-acetylaspartic acid (CSF, P) N-acetylaspartic acid (U)

Neonatal (birth–1 month)

Infancy (1–18 months)

± ± ±

+ + ± ± ± ± + ±

Most patients follow the infantile form which mostly manifests at 2–4 months of age with head lag, muscular hypotonia and macrocephaly, progressing to marked developmental delay, seizures, optic nerve atrophy, progressive spasticity and opisthotonic posturing (Matalon et al. 1995).

± ± ±

Childhood (1.5–11 years) ± ± ± ±

Adolescence (11–16 years) ± ± ± ±

Adulthood (>16 years) ± ± ± ±

+ + + + ± ± ± + ± + + +

+ + + + ± + ± + ± + + +

+ + + ± ± + ± + ± + + +

+ + + ± ± + ± + ± + + +

↑ ↑

↑ ↑

↑ ↑

↑ ↑

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Table 69.2  Glutaric aciduria type I System CNS

Symptoms and Biomarkers Abasia Astasia Ataxia Chorea Dysarthria Dystonia Encephalopathic crisis, acute Headache Hypokinesia Hypotonia, axial Spasticity Swallowing difficulties Vertigo Digestive Feeding difficulties Vomiting Musculoskeletal Macrocephaly Respiratory Pneumonia Kidney Chronic kidney disease Routine laboratory ASAT/ALAT (P) Creatine kinase (P) Laboratory 3-Hydroxyglutaric acid (U) findings C5DC glutarylcarnitine (P, B) Glutaconic acid (U) Glutaric acid (U) MRI: periventricular white matter and other extrastriatal MR abnormalities MRI: striatal atrophy MRI: temporal hypoplasia, dilated external CSF spaces

Neonatal (birth–1 month)

Infancy (1–18 months) ±

Adolescence (11–16 years) ± ± ± ± ± ±

Adulthood (>16 years) ± ± ± ± ± ±

± ±

± ±

(↑) (↑) n-↑ n-↑ n-↑ n-↑ ±

± ± ± ± ± (↑) (↑) n-↑ n-↑ n-↑ n-↑ ±

± ± ± ± ± ± ± ± (↑) (↑) n-↑ n-↑ n-↑ n-↑ +

± ± ± ± ± ± ± ± (↑) (↑) n-↑ n-↑ n-↑ n-↑ +

± +

± ±

± ±

± ±

Infancy (1–18 months) ±

Adolescence (11–16 years) + ± ± ± ± + ± ± ± ±

Adulthood (>16 years) + ± ± ± ± + ± ± ± ±

± ± ± ±

±

± ± ±

±

n-↑ n-↑ n-↑ n-↑

+

± ± + ±

Childhood (1.5–11 years) ± ± ± ± ± ± ±

± ± ± ±

Table 69.3  L-2-Hydroxyglutaric aciduria System CNS

Musculoskeletal Laboratory findings

Symptoms and biomarkers Ataxia Choreoathetosis Dysarthria Dystonia Hypotonia Mental retardation Seizures Spasticity Tremor Macrocephaly Ammonia (B) L-2-hydroxyglutaric acid (U, P, CSF) Lactate (P) Lysine (P, CSF) MRI/CT: white matter abnormalities MRI: globus pallidus and dentate nudeus lesions Protein (CSF)

Neonatal (birth–1 month)

±

Childhood (1.5–11 years) + ± ± ± ± + ± ± ± ±

n-↑ ↑

↑

↑

↑

↑

n-↑ n ±

n-↑ +

n-↑ +

n-↑ +

n-↑ +

±

+

+

+

+

↑

↑

± ±

± ± ±

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Table 69.4  D-2-Hydroxyglutaric aciduria type I System Cardiovascular CNS

Laboratory findings

Symptoms and Biomarkers Cardiomyopathy Developmental delay Epilepsy Hypotonia D2HG (U, P, CSF)

Neonatal (birth–1 month) n + ± + ↑

Infancy (1–18 months) n + ± + ↑

Childhood (1.5–11 years) n + ± + ↑

Adolescence (11–16 years) n + ± ± ↑

Adulthood (>16 years) n + ± ± ↑

Neonatal (birth–1 month) ± + + + ↑

Infancy (1–18 months) ± + + + ↑

Childhood (1.5–11 years) ± + + + ↑

Adolescence (11–16 years) ± + + ± ↑

Adulthood (>16 years) ± + + ± ↑

Table 69.5  D-2-Hydroxyglutaric aciduria type II System Cardiovascular CNS

Laboratory findings

Symptoms and Biomarkers Cardiomyopathy Developmental delay Epilepsy Hypotonia D2HG (U, P, CSF)

Reference Values

L-2-Hydroxyglutaric acid (L2HG)

N-Acetylaspartic acid (NAA) Age

NAA (U) mmol/mol creatinine 6–36

Age NAA (P) μmol/L 0.17–0.84

NAA (CSF) μmol/L 0.25–2.8

Gas chromatography/mass spectrometry (preferably with stable isotope dilution assay)

Age

GA (P) μmol/L 0.5–2.9

GA (CSF) μmol/L 0.18–0.63

Gas chromatography/mass spectrometry (preferably with stable isotope dilution assay)

L2HG (P) μmol/L 0.5–1

L2HG (CSF) μmol/L 0.3–2.3

Separation and individual quantification of the D- and L-isomer of 2HG by gas chromatography–mass spectrometry or liquid chromatography-­ tandem mass spectrometry

D-2-Hydroxyglutaric acid (D2HG)

Glutaric acid (GA) GA (U) mmol/mol creatinine < 10

L2HG (U) mmol/mol creatinine 1–19

Age

D2HG (U) mmol/mol creatinine 3–17

D2HG (P) μmol/L 0.3–0.9

D2HG (CSF) μmol/L 0.07–0.3

Separation and individual quantification of the D- and L-isomer of 2HG by gas chromatography–mass spectrometry or liquid chromatography-­ tandem mass spectrometry

3-Hydroxyglutaric acid (3-OH-GA) Age

3-OH-GA (U) mmol/mol creatinine cut-off?

No

Targeted diagnostic work-up

Yes

No

Suggestive clinical and/or neuroradiological signs? Quantitative analysis of 3-OH-GA and GA (urine, blood)

3-OH-GA (and GA) elevated?

No diagnostic work-up recommended

Yes

No*

Yes Start treatment

GCDH gene mutation analysis

Two disease-causing mutations?

No

GCDH enzyme analysis (leukocytes or fibroblasts)

Yes Low or deficient GCDH activity?

No

Stop treatment

Yes GA I established

Fig. 69.6 Diagnostic flowchart for glutaric aciduria type I. (a) Newborn screening for glutaric aciduria type I (GA-I) is performed using tandem mass spectrometry (MS/MS). (b) Targeted diagnostic work-up should be started if diagnosis of GA-I is suspected or a positive family history is known. Note that a few patients with a low-excreting phenotype may show (intermittently) normal urinary excretion of

GA I excluded

GA I not suggestive **

3-hydroxyglutaric acid (3-OH-GA) and glutaric acid (GA) (*). If an individual shows normal 3-OH-GA (and GA) concentrations in urine but presents with highly suspicious signs and symptoms for GA-I, it should be decided individually whether diagnostic work-up is continued (**)

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 -2-Hydroxyglutaric Aciduria, D-2-Hydroxyglutaric L Aciduria Type I and D-2-Hydroxyglutaric Aciduria Type II Targeted diagnostic work-up

Suggestive clinical and/or neuroradiological signs? Yes Organic acids in urine (GC/MS)

2HG elevated? Consider separation of D2HG and L2HG

No

No

Yes Molecular genetic testing (L2HGDH, D2HGDH, IDH2) Known disease-causing mutation(s)? Yes

Consider SLC25A1 and somatic IDH1/2 mutations

Disease confirmed

Fig. 69.7  Flowchart for diseases 69.3, 69.4 and 69.5. Elevated 2HG in GC/MS analysis of urinary organic acids is the biochemical hallmark of these diseases. According to discriminating biochemical (elevated CSF lysine and protein in L-2-hydroxyglutaric aciduria, elevated CSF GABA and elevated urinary 2-ketoglutarate in D-2-hydroxyglutaric aciduria), clinical (cardiomyopathy in D-2-hydroxyglutaric aciduria type II, progressive spasticity in L-2-hydroxyglutaric aciduria) and neuroradiologic parameters (pathognomonic MRI pattern of L-2-­ hydroxyglutaric aciduria), molecular genetic testing of L2HGDH,

Consider other neurologic diseases

D2HGDH and IDH2, respectively, are often the next steps. However, enantiomeric separation and individual quantification of D2HG and L2HG may help to direct diagnostic work-up (dotted line). In case of negative molecular genetic tests, alternative diseases should also be considered including D-2−/L-2-hydroxyglutaric aciduria (caused by SLC25A1 deficiency), somatic gain-of-function mutations of the IDH1 and IDH2 genes in adult patients with gliomas or acute myeloid leukaemia or secondary increased D2HG in SSADH deficiency and GA-I

69  Cerebral Organic Acidurias

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Specimen Collection Disease no. 69.1

Symbol CD

69.2

GA-I

Test Organic acids (NAA) Quantitative amino acids

Tryptophan

Organic acids (3-OH-GA, GA)

Pitfalls Compound has poor recovery in organic solvent extraction

3.5–4 h postprandially, no dietary changes prior to the test 3.5–4 h postprandially, no dietary changes prior to the test None

Plasma

Plasma

Keep frozen (−20 °C)

Losses due to inappropriate deproteinisation

Urine

Keep frozen (−20 °C)

Reliable identification of 3-OH-GA may require the use of a quantitative GC/MS method; differential diagnoses of elevated GA and 3-OH-GA include GA-II and GA-III, SCHAD deficiency and ketosis

Enzyme activity (GCDH)

None

L2HGA

Organic acids

None

Fibroblasts Leucocytes from heparinised blood Urine

RT Keep frozen (−20 °C) Keep frozen (−20 °C)

L2HGA

L2HG dehydrogenase activity Organic acids

Isolation of cells according to specific protocol None

Fibroblasts, lymphoblasts, lymphocytes Urine

RT, pellets should be frozen

D2HG dehydrogenase activity Organic acids

Isolation of cells according to specific protocol None

Fibroblasts, lymphoblasts

RT, pellets should be frozen

Urine

Keep frozen (−20 °C)

IDH2 gain-offunction assay

Isolation of cells according to specific protocol

Lymphoblasts

RT, pellets should be frozen

D2HGA type I

D2HGA type I 69.5

Handling Keep frozen (−20 °C) Keep frozen (−20 °C)

Keep frozen (−20 °C)

Acylcarnitine profile (C5DC)

69.4

Material Urine

None, also informs Plasma serum on adherence to carnitine supplementation None Dried blood spots Plasma

Carnitine status

69.3

Preconditions None

D2HGA type II

D2HGA type II

Plasma; keep frozen (−20 °C)

Keep frozen (−20 °C)

C5DC may be also elevated in GA-II, renal insufficiency, MCAD deficiency (pseudoglutarylcarnitinemia)

For specific quantification of L2HG, enantiomeric separation, hyphenated to mass spectrometry, is required

For specific quantification of D2HG, enantiomeric separation, hyphenated to mass spectrometry, is required

For specific quantification of D2HG, enantiomeric separation, hyphenated to mass spectrometry, is required. D2HG also accumulates GA-I and SSADH

3-OH-GA 3-hydroxyglutarate, C5DC glutarylcarnitine, GA glutarate, GA-II glutaric aciduria type II, GA-III glutaric aciduria type III, GCDH glutaryl-CoA dehydrogenase, GC/MS gas chromatography/mass spectrometry, MCAD medium-chain acyl-CoA dehydrogenase, NAA N-acetylaspartate, SCHAD short-chain 3-hydroxyacyl-CoA, SSADH succinic semialdehyde dehydrogenase deficiency

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Prenatal Diagnosis Disease no. Symbol Material 69.1 CD Chorionic villi (accomplished) Amniotic fluid, amniocytes (accomplished)

69.2

69.3

69.4

69.5

GA-I

Chorionic villi Amniocytes, amniotic fluid L2HGA Chorionic villi Amniocytes, amniotic fluid D2HGA Chorionic villi type I Amniocytes, amniotic fluid D2HGA Chorionic villi type II Amniocytes, amniotic fluid

Treatment Summary Timing trimester Pitfalls I Assay of aspartoacylase in amniocytes is not II reliable. A combination of mutation analysis together with the exact quantitation of N-acetylaspartate in the amniotic fluid is recommended I II I II I II I II

Disease is usually caused by a heterozygous de novo mutation. Somatic and germline mosaicism in the parents cannot be excluded; thus, the recurrence risk for the parents is not zero. Therefore, prenatal diagnosis should always be offered

In case of DNA-based prenatal diagnosis, maternal contamination should be excluded by VNTR marker analysis. Trimester one: only mutation analysis. Trimester two: a combination of metabolite and DNA investigations is recommended

DNA Testing Disease no. 69.1

Symbol CD

69.2

GA-I

69.3

L2HGA

69.4

D2HGA type I

69.5

D2HGA type II

Tissue Lymphocytes, fibroblasts Lymphocytes, fibroblasts Blood, lymphocytes, fibroblasts, lymphoblasts Blood, lymphocytes, fibroblasts, lymphoblasts Blood, lymphocytes, fibroblasts, lymphoblasts

Methodology Sequencing Sequencing Sequencing

Sequencing

Sequencing, targeted mutation analysis

Effective metabolic treatment has only been described for glutaric aciduria type I (low lysine diet, carnitine supplementation, emergency treatment). Riboflavin should be considered as a treatment option for patients with L-2-hydroxyglutaric aciduria aiming to activate residual enzyme activity. Treatment of patients’ Canavan disease with lithium citrate, lowering brain N-acetylaspartate concentrations, and glycerol triacetate, supplying the brain with acetate, is considered as safe; however, it is yet unknown whether it improves the clinical outcome. Metabolic treatment for D-2-­ hydroxyglutaric aciduria types I and II has not yet been described. Although effective treatment is only known for some cerebral organic acidurias, symptomatic and supportive treatment is important. This includes adequate supply with nutrient, minerals and micronutrients, physiotherapy, occupational therapy and pharmacotherapy of epilepsy and extrapyramidal movement disorder, among others. The therapeutic concept should be implemented after the assessment of individual needs and, subsequently, monitored and evaluated by an interdisciplinary team of specialists. Emergency Treatment Table for All Disorders of Your Chapter (If Applicable) and Medication Requirements (A. Including Box After the Table, with Pitfalls and Important Information).

Diseases 69.1 and 69.3–69.5 No emergency treatment is available.

Disease 69.2 (GA-I) Emergency treatment is thought to be the most effective component of the current treatment strategies to prevent acute striatal injury during infectious disease and for other causes of catabolism in glutaric aciduria type I (Heringer et al. 2010; Boy et al. 2018). It must be initiated before the onset of severe neurological signs, which already indicate the manifestation of neuronal damage. Therefore, during episodes that are likely to induce catabolism (e.g. infectious disease), emergency treatment should start without delay. Treatment should consist of frequent high carbohydrate feeds and increased carnitine supplementation, followed by high-dose intravenous glucose and carnitine (Kölker et  al. 2011; Boy et al. 2017a, b). All patients with glutaric aciduria type I should be supplied with an emergency card. This concept should be strictly followed for the first 6 years of life. After this age, emergency treatment is individually adjusted.

69  Cerebral Organic Acidurias

Emergency treatment at home A. Oral carbohydratesa Maltodextrin Age (years) % Kcal/100 mL KJ/100 mL Volume (mL) per day orally Up to 0.5 10 40 167 Min. 150/kg 0.5–1 12 48 202 120/kg 1–2 15 60 250 100/kg 2–6 20 80 334 1200– 1500 B. Protein intake Natural protein Stop for max. 24 (−48) h, and then reintroduce and increase stepwise until the amount of maintenance treatment is reached within 48 (−72) h AAM If tolerated, AAM should be administered according to maintenance therapy C. Pharmacotherapy l-carnitine Double oral carnitine supplementations

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AAM lysine-free, tryptophan-reduced amino acid mixtures. Standard Treatment Table for All Disorders of Your Chapter (If Applicable) and Medication Requirements (A. Including Box After the Table, with Pitfalls and Important Information).

Diseases 69.1, 69.3, 69.4 and 69.5 No specific treatment is available.

Disease 69.2 (GA-I) Disorder Symno. bol 69.2 GA-I

According to Kölker et al. 2011; Boy et al. 2017a, b a Solutions should be administered every 2  h  day and night. Patients should be reassessed every 2 h. AAM, lysine-free, tryptophan-reduced amino acid mixtures

Emergency treatment in hospital (according to Kölker et al. 2011; Boy et al. 2017a, b). A. Intravenous infusions Glucose Age (years)

Glucose (g/ kg per day IV) 0–1 (12–)15 1–3 (10–)12 3–6 (8–)10 Insulin If persistent hyperglycaemia >150 mg/dL (>8 mmol/L) and/or glucosuria occurs, start with 0.05 IE insulin/kg per h IV, and adjust the infusion rate according to serum glucose B. Protein intake Natural Stop for max. 24 (−48) h, and then reintroduce and protein increase stepwise until the amount of maintenance treatment is reached within 48 (−72) h AAM If tolerated, AAM should be administered orally or by nasogastric tube according to maintenance therapy C. Pharmacotherapy l-carnitine 100(−200) mg/kg per day IV

Doses/ day (n) Age Medication/diet Dosage 6 years Carnitine (30–)50 mg/ 3 kg per day Riboflavina 100 mg 2 Treatment of extrapyramidal movement disordersb Antiepileptic treatmentc Diet (see below)

Riboflavin is not a recommended therapy in glutaric aciduria type I since riboflavin responsiveness seems to be very rare (if at all present) and no standard protocol exists to test it. There is no proven clinical benefit of riboflavin supplementation (Kölker et al. 2006) b The complex movement disorder of symptomatic patients with glutaric aciduria type I is difficult to treat. Baclofen and benzodiazepines as monotherapy or in combination are often used as first-line drug treatment for focal and generalised dystonia. Intrathecal baclofen is used for additional therapy in individuals with generalised dystonia and spasticity. Trihexyphenidyl can be considered as second-line treatment for dystonia, particularly in adolescents and adults, and botulinum toxin A injections as additional therapy for severe focal dystonia (according to Kölker et al. 2011; Boy et al. 2017a, b) c The risk of epilepsy is mildly elevated in glutaric aciduria type I. Dystonic and epileptic movements, however, may be confused with seizures. Indication, prescription and monitoring of antiepileptic treatment should be performed by a child neurologist or neurologist. Valproate is not recommended due to the theoretical risk of mitochondrial dysfunction and secondary carnitine depletion a

1414

S. Kölker

Dietary treatment (low lysine diet, according to Kölker et al. 2011; Boy et al. 2017a, b). Treatment Lysine (from natural protein)a Protein from amino acid mixturesb Energy Micronutrientsc

Dosage mg/kg per day g/kg per day Kcal/kg per day %

Age 0–6 months 7–12 months 1–3 years 4–6 years >6 years 100 90 80–60 60–50 Controlled protein intake using natural protein with a low lysine content and avoiding lysine-rich food 1.3–0.8 1.0–0.8 0.8 0.8 100–80

80

94–81

86–63

≥100

≥100

≥100

≥100

≥100

The lysine/protein ratio (i.e. 2–9 mg lysine/100 mg protein) varies in natural food, and thus natural protein intake in children on a low lysine diet is dependent on the natural protein source b Lysine-free, tryptophan-reduced amino acid mixtures should be supplemented with minerals and micronutrients as required to maintain normal levels. Safe intakes of essential amino acids are provided from natural protein and lysine-free, tryptophan-reduced amino acid supplements c According to dietary recommendations a

Dangers/Pitfalls

1. Dietary treatment needs to be adapted to the individual needs, in particular in dystonic patients. Overtreatment by protein restriction may result in malnutrition with essential nutrients. 2. Dysphagia is a frequent problem in dystonic patients. Tube feeding (via nasogastric tube or percutaneous gastrostomy) should be considered if oral food intake is inadequate.

Experimental Treatment Disease no. Symbol 69.1 CD

69.2

GA-I

69.3 69.4

L2HGA D2HGA type I

69.5

D2HGA type II

Alternative therapies/experimental trials Lithium citrate Glycerol triacetate rAAV-based gene therapy (translational and preclinical studies) Arginine or homoarginine supplementation has yet only been studied in Gcdh-deficient mice, an animal model for GA-I, and in a small number of patients (arginine). The safety and efficacy of arginine supplementation as well as optimal dosage are unknown Riboflavin supplementation On the basis that D2HG dehydrogenase is an FAD-dependent enzyme, riboflavin supplementation is a therapeutic option AGI-026, a mutant IDH2 protein inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy and provided a survival benefit in Idh2R140Q mice (translational and preclinical studies)

References Assadi M, Janson C, Wan DJ, et al. Lithium citrate reduces excessive intracerebral N-acetylaspartate in Canavan disease. Eur J Paediatr Neurol. 2010;14:354–9. Boy N, Heringer J, Brackmann R, et al. Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of longterm neurotoxicity. Orphanet J Rare Dis. 2017a;12:77. PMID: 28438223 Boy N, Mengler K, Thimm E, et  al. Newborn screening: a disease-­ changing intervention for glutaric aciduria type 1. Ann Neurol. 2018;83:970–9. PMID: 29665094 Boy N, Mühlhausen C, Maier EM, et  al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017b;40:75–101. PMID: 27853989 Gessler DJ, Li D, Su Q, et al. Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease. JCI Insight. 2017;2:e9087. PMID: 28194442 Gitiaux C, Roze E, Kinugawa K, et al. Spectrum of movement disorders associated with glutaric aciduria type 1: a study of 16 patients. Mov Disord. 2008;23:2392–7. Harting I, Neumaier-Probst E, Seitz A, et al. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain. 2009;132:1764–82. Heringer J, Boy SPN, Ensenauer R, et al. Use of guidelines improves the neurological outcome in glutaric aciduria type I.  Ann Neurol. 2010;68:743–52. Kölker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I—revised recommendations. J Inherit Metab Dis. 2011;34:677–94. Kölker S, Garbade S, Greenberg CR, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res. 2006;59:840–7. Kranendijk M, Struys EA, Van Schaftingen E, et  al. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010; 330:336. Leone P, Janson CG, Bilanuk L, et al. Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol. 2000;48:27–38. Matalon R, Michals K, Kaul R. Canavan disease: from spongy degeneration to molecular analysis. J Pediatr. 1995;127:511–7.

69  Cerebral Organic Acidurias Sauer SW, Okun JG, Fricker G, et  al. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood–brain barrier constitutes a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem. 2006;97:899–910. Segel R, Anikster Y, Zevin S, et al. A safety trial of high glucose triacetate for Canavan disease. Mol Genet Metab. 2011;103:203–6. Steenweg ME, Jakobs C, Errami A, et  al. An overview of L-2-­ hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-­phenotype study. Hum Mutat. 2010;31:380–90. Steenweg ME, Salomons GS, Yapici Z, et al. L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology. 2009;2009(251):856–65.

1415 Struys EA, Salomons GS, Achouri Y, et  al. Mutations in the D-2-­ hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet. 2005;76:358–60. Struys EA, Verhoeven NM, Brunengraber H, et al. Investigations by mass isotopomer analysis of the formation of D-2-hydroxyglutarate by cultured lymphoblasts from two patients with D-2-hydroxyglutaric aciduria. FEBS Lett. 2004;557(1–3):115–20. Van Schaftingen E, Rzem R, Veiga-da-Cunha M. L-2-hydroxyglutaric aciduria, a disorder of metabolite repair. J Inherit Metab Dis. 2009;32:135–42. Wang F, Travins J, Lin Z, et al. A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model. J Inherit Metab Dis. 2016;39:807–20.

3-Methylglutaconic Acidurias

70

Saskia B. Wortmann and Johannes A. Mayr

Contents Introduction

 1418

Nomenclature

 1419

Metabolic Pathways

 1420

Signs and Symptoms

 1421

Reference Values

 1428

Pathological Values

 1428

Leucine Loading Test

 1428

Specimen Collection

 1429

DNA Testing

 1429

Treatment Summary

 1429

References

 1429

Summary

Increased urinary 3-methylglutaconic acid excretion is a relatively common finding in inborn errors of metabolism, especially in mitochondrial disorders. In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease-specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallS. B. Wortmann (*) University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria

mark of the phenotype and the key to diagnosis: inborn errors with 3-methylglutaconic aciduria as a discriminative feature (3-MGA-IEM). One should distinguish between “primary 3-methylglutaconic acidurias” formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the—currently known— 11 “secondary 3-methylglutaconic acidurias.” The latter should be further classified and named by their defective protein or the historical name as follows: TAZ-defect or Barth syndrome, SERAC1-defect or MEGDEL syndrome, AGK-­defect or Sengers syndrome, OPA3-defect or Costeff syndrome, TMEM70, MICOS13, DNAJC19, TIMM50, and HTRA2 defect.

Institute for Human Genetics, Technische Universität München, Munich, Germany e-mail: [email protected] J. A. Mayr University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria e-mail: [email protected] © Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_70

1417

1418

Introduction The branched-chain organic acid 3-methylglutaconic acid (3-MGA) is an intermediate of the mitochondrial leucine catabolism. In the urine of healthy individuals, 3-MGA is found only in traces (40 umol/mmol creat.) and repeatedly increased

=3-MGA-urla as minor finding

=3-MGA-urla as major finding

cis:trans isoforms 1:1 3-HIVA normal Other metabolic disorder Fatty acid oxidation disorder (FAOD) Methylmalonic aciduria (MMA) Propionic aciduria (PA) Glycogen storage disorder (GSD) Urea cycle disorder (UCD)

Defective phospholipid remodeling SERAC1 AGK TAZ

Consider: OXPHOS disorder, Hematological disorder, neuromuscular disorder, Genetic syndrome/ chromosomal abnormality

Mitochondrial (membrane) associated fusion/fission OPA3 membrane TMEM70 MICOS13 ATAD3A protein import DNAJC19 TIMM50 AGK chaperone CLPB ?apoptosis signalling HTRA2

cis:trans isoforms 2:1 3-HIVA elevated

Organic aciduria/ mitochondrial leucine catabolism 3-metylglutaconyl-CoA hydratase deficiency (AUH)

Not otherwise soecified (NOS) 3-MGA-uria Secondary 3-MGA –uria

Primary 3-MGA –uria

Fig. 70.1  Inborn errors with 3-methylglutaconic aciduria as discriminative feature (3-MGA-IEM). (Updated from Wortmann et al. 2013a, b)

Fig. 70.2 Leucine metabolism (Updated from Wortmann et al. 2013a, b)

Leucine Transaminase 2-Oxo-isocaproic Acid Branched Chain 2-Oxo-Acid Dehydrogenase Isovaleryl-CoA Isovaleryl-CoA Dehydrogenase 3-Methylcrotonyl-CoA

3-HYDROXYISOVALERIC ACID

3-Methylcrotonyl-CoA Carboxylase 3-METHYLGLUTACONIC ACID 3-Methylglutaconyl-CoA 3-METHYLGLUTARIC ACID 3-Methylglutarylcamitine 3-Methylglutaconyl-CoAHydratase 3-Hydroxy-3-Methyl-glutaric acid

HMG-CoA HMG-CoA-Synthase

Acetyl-CoA

HMG-CoA Lyase

Acetoacetate

70  3-Methylglutaconic Acidurias

1421

Signs and Symptoms

MIM # Gene 3-MGA-uria Mode of inheritence Typical age at onset Developmental delay Intellectual disability Movement disorder Central hypopnea Optic atrophy Deafness Epilepsy Cataracts Cardiomyopathy Neutropenia Growth failure Liver involvement

AUHdef. 250950 AUH x AR 4-5th decade

TAZ-def. 302060 TAZ x XLR

SERAC1def. 614739 SERAC1 x AR

Neonatal Neonatalfirst year (x) x

AGK-def. 212350 AGK x AR

OPA3-def. 258501 OPA3 x AR

TMEM70def. 614052 TMEM70 x AR

MIC13defect 618329 MIC13 x AR

Neonatal

Neonatal

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x) x

x

x

x

x

x

x x

x x

TIMM50def. 617698 TIMM50 x AR Neonatal

(x) x (x)

x x

HTRA2def. 617248 HTRA2 x AR

Neonatal Neonatal

x

x

CLPBdef. 616271 CLPB x AR

Childhood Childhood Childhood

x x

DNAJC19def 610198 DNAJC19 x AR

x

x

x

x

x

x

x x x

x x

x

x

x x

Table 70.1  AUH deficiency System CNS

Digestive Eye

Symptoms and Bbomarkers Ataxia Athetosis Basal ganglia lesions (MRI) Cerebellar abnormalities Cerebellar abnormalities Cerebral atrophy (MRI) Dementia Fits Leukoencephalopathy Regression Retardation Retardation, psychomotor Seizures, febrile Spasticity, limbs White matter changes (MRI) Hepatomegaly Liver dysfunction Nystagmus Optic atrophy

Neonatal (birth-1 month) ± ± ± ± ± ± ± ± ± + + ± ± ± ± ± ± ± ±

Infancy (1–18 months) ± ± ± ± ± ± ± ± ± + + + ± ± ± ± ± ± ±

Childhood (1.5–11 years) ± ± ± ± ± ± ± ± + + + + ± ± ± ± ± ± ±

Adolescence (11–16 years) + ± ± ± ± ± ±

Adulthood (>16 years) + ± ± ± ± ± ±

+ + + ±

+ + + ±

± ± ± ± ± ±

+ ± ± ± ± ± (continued)

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S. B. Wortmann and J. A. Mayr

Table 70.1 (continued) System Hematological Metabolic Laboratory findings

Symptoms and Bbomarkers Thrombocytopenia Metabolic acidosis Hypoglycemia 3-Hydroxyisovaleric acid (MRS) 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaconyl-CoA hydratase (fibroblasts) 3-Methylglutaric acid (urine) Ammonia (blood) ASAT/ALAT (plasma) C5-OH Acylcarnitine (dried blood spot) C5-OH Acylcarnitine (plasma) C6-unsaturated acylcarnitine (blood) C6-unsaturated acylcarnitine (plasma) Carnitine, esterified (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Creatine kinase (plasma) Glucose (plasma) N-acetylaspartate (MRS)

Neonatal (birth-1 month) ± ± ± n-↑ ↑-↑↑↑ ↑-↑↑↑ ↓

Infancy (1–18 months) ± ± ± n-↑ ↑-↑↑↑ ↑-↑↑↑ ↓

Childhood (1.5–11 years) ± ± ± n-↑ ↑-↑↑↑ ↑-↑↑↑ ↓

Adolescence (11–16 years)

Adulthood (>16 years)

n-↑ ↑-↑↑↑ ↑-↑↑↑ ↓

n-↑ ↑-↑↑↑ ↑-↑↑↑ ↓

↑-↑↑ n-↑ n-↑ ↑-↑↑↑

↑-↑↑ n-↑ n-↑ ↑-↑↑↑

↑-↑↑ n-↑ n-↑ ↑-↑↑↑

↑-↑↑ n-↑ n-↑ ↑-↑↑↑

↑-↑↑ n-↑ n-↑ ↑-↑↑↑

↑-↑↑↑ ↑-↑↑

↑-↑↑↑ ↑-↑↑

↑-↑↑↑ ↑-↑↑

↑-↑↑↑ ↑-↑↑

↑-↑↑↑ ↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

n-↑ ↓-n ↓-n n-↑ ↓-n ↓-n

n-↑ ↓-n ↓-n n-↑ ↓-n ↓-n

n-↑ ↓-n ↓-n n-↑ ↓-n ↓-n

n-↑ ↓-n ↓-n

n-↑ ↓-n ↓-n

↓-n

↓-n

Table 70.2  TAZ deficiency System Cardiovascular

Dermatological Digestive Hematological Musculoskeletal

Respiratory Other Laboratory findings

Symptoms and biomarkers Cardiac arrhythmia Cardiomyopathy Cardiomyopathy, dilated Heart failure Left ventricular non-compaction Chronic aphthous ulceration Feeding difficulties Neutropenia Sepsis Exercise intolerance Growth retardation Hypotonia, muscular-axial Myopathy Respiratory distress Mild dysmorphic features 2-Ethylhydracrylic acid (urine) 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Abnormal cardiolipin profile (DBS) Cholesterol (serum)

Neonatal (birth–1 month) ± + ± ± ±

Infancy (1–18 months) ± + ± ± ±

Childhood (1.5–11 years) ± + ± ± ±

Adolescence (11–16 years) ± + ± ± ±

Adulthood (>16 years) ± + ± ± ±

± ± + ± ± + ± ± ± ± n-↑

± ± + ± ± + ± ± ± ± n-↑

± ± + ± ± + ± ± ± ± n-↑

± ± + ± ± + ± ± ± ± n-↑

± ± + ± ± + ± ± ± ± n-↑

n

n

n

n

n

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑ +

↑ +

↑ +

↑ +

↑ +

↓-n

↓-n

↓-n

↓-n

↓-n

70  3-Methylglutaconic Acidurias

1423

Table 70.3  SERAC1 deficiency System CNS

Digestive

Laboratory findings Metabolic Other Laboratory findings

Symptoms and biomarkers Bilateral sensory hearing loss Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Dystonia Encephalopathy Epilepsy Extrapyramidal signs Hypotonia Leigh-like lesions (MRI) Regression Retardation Spasticity Feeding difficulties Jaundice Liver dysfunction ASAT/ALAT (plasma) Hypoglycemia Failure to thrive 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Cholestasis Filipin test Glucose (plasma) Lactate (cerebrospinal fluid) Lactate (plasma)

Neonatal (birth–1 month) +

Infancy (1-18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

+ + + + ± ± ± + + + ± ± ± ± n-↑↑

+ + + + ± ± ± + + + + ± ±

+ + + + ± ± + + + + + ±

+ + + + ± ± + + + + + ±

+ + + + ± ± + + + + + ±

n-↑↑

n-↑↑

n-↑↑

n-↑↑

± ± n

± ± n

± ± n

± ± n

± ± n

↑↑

↑↑

↑↑

↑↑

↑↑

↑ n-↑↑↑ n-↑ ↓-n n-↑↑ n-↑↑↑

↑ n-↑↑↑ n-↑ n n-↑↑ n-↑↑↑

↑ n n-↑ n n-↑↑ n-↑↑↑

↑ n n-↑ n n-↑↑ n-↑↑↑

↑ n n-↑ n n-↑↑ n-↑↑↑

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S. B. Wortmann and J. A. Mayr

Table 70.4  AGK deficiency System Cardiovascular Eye Metabolic Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, hypertrophic Cataract Lactic acidosis Metabolic acidosis Hypotonia, muscular-axial 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Lactate (plasma)

Neonatal (birth–1 month) +

Infancy (1–18 months) +

Childhood (1.5–11 years) +

Adolescence (11–16 years) +

Adulthood (>16 years) +

± + + + n

± + + + n

± ± + + n

± ± + + n

± ± ± + n

↑↑

↑↑

↑↑

↑↑

↑↑

↑ ↑-↑↑↑

↑ ↑-↑↑↑

↑ ↑-↑↑↑

↑ ↑-↑↑↑

↑ ↑-↑↑↑

Neonatal (birth–1 month)

Infancy (1–18 months) ± ± ±

Childhood (1.5–11 years) + ± +

Adolescence (11–16 years) + ± +

Adulthood (>16 years) + ± +

± ± n

+ ± ± + + n

+ + + + + n

+ + + + + n

+ + + + + n

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

Neonatal (birth–1 month) + +

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years) + +

Adulthood (>16 years) + +

± ± ± ± ± ± ± ± + + n

+ ± ± ± ± ± ± ± + + n

+ ± ± ± ± ± ± ± + + n

+ ± ± ± ± ± ± ± + + n

+ ± ± ± ± ± ± ± + + n

↑↑

↑↑

↑↑

↑↑

↑↑

↑ n-↑↑ ↑-↑↑↑

↑ n-↑↑ ↑-↑↑↑

↑ n-↑↑ ↑-↑↑↑

↑ n-↑↑ ↑-↑↑↑

↑ n-↑↑ ↑-↑↑↑

Table 70.5  OPA3 deficiency System CNS

Eye Laboratory findings

Symptoms and biomarkers Ataxia Cerebral atrophy (MRI) Extrapyramidal movement disorder No intellectual disability Spastic paraplegia Spasticity Nystagmus Optic atrophy 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine)

±

+

Table 70.6  DNAJC19 deficiency System Cardiovascular

CNS

Digestive Ear Eye Genitourinary Hematological Musculoskeletal Laboratory findings

Symptoms and biomarkers Cardiomyopathy, dilated Cardiac conduction defect/ long QT Ataxia Intellectual disability Seizures Liver steatosis Hearing loss Optic atrophy Genitourital anomalies Testicular dysgenesis Anemia, microcytic Growth retardation 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Lactate (cerebrospinal fluid) Lactate (plasma)

70  3-Methylglutaconic Acidurias

1425

Table 70.7  CLPB deficiency System CNS

Endocrine Eye Hematological Other

Laboratory findings

Symptoms and biomarkers Ataxia Cerebellar atrophy (MRI) Cerebral atrophy (MRI) Dystonia Hyperekplexia Hypertonia, extremities Hypotonia, muscular Intellectual disability Retardation Seizures Seizures, intrauterine Spasticity Stiffness Endocrine abnormalities Cataract Neutropenia Death Intrauterine growth retardation Ulcerations, oral, genital 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) 3-Hydroxyisovaleric acid (urine)

Neonatal (birth–1 month) ± + + ± ± ± + + + ± ±

Infancy (1–18 months) ± + + ±

Childhood (1.5–11 years) ± + + ±

Adolescence (11–16 years) ± + + ±

Adulthood (>16 years) ± + + ±

± + + + ±

+ ± + + ±

+ ± + + ±

+ ± + + ±

± + +

± + +

± + +

± + +

± ↑↑

± ↑↑

± ↑↑

± ↑↑

± ↑↑

↑ n

↑ n

↑ n

↑ n

↑ n

± ± + + ± ±

Table 70.8  HTRA2 deficiency System CNS

Digestive Hematological Other

Laboratory findings

Symptoms and Biomarkers Apnea Brain atrophy (MRI) Central hypopnea Developmental delay Hypertonia, extremities Hypotonia, muscular Intellectual disability Jitteriness Neurodegeneration Seizures Tremor Dysphagia Neutropenia Death Loss of skills Intrauterine growth retardation Lactate (plasma) Lactate (cerebrospinal fluid) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) 3-Hydroxyisovaleric acid (urine)

Neonatal (birth–1 month) + + + + + + + + + + + + + + + + ↑-↑↑↑ n-↑↑ ↑↑ ↑ n

Infancy (1–18 months) + + + + + + + + + + + + + + + + ↑-↑↑↑ n-↑↑ ↑↑ ↑ n

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

↑-↑↑↑ n-↑↑ ↑↑ ↑ n

↑-↑↑↑ n-↑↑ ↑↑ ↑ n

↑-↑↑↑ n-↑↑ ↑↑ ↑ n

1426

S. B. Wortmann and J. A. Mayr

Table 70.9  TMEM70 deficiency System Cardiovascular CNS

Digestive

Eye Genitourinary Metabolic

Musculoskeletal Renal Respiratory

Other

Laboratory findings

Symptoms and Biomarkers Cardiomyopathy, hypertrophic Wolf-Parkinson-white syndrome Apnea Basal ganglia lesions (MRI) Cerebellar hypoplasia, mild Cortical atrophy (MRI) Encephalopathy Hypotonia, muscular-axial Microcephaly Retardation, psychomotor Subcortical atrophy (MRI) Gastrointestinal dysmotility Hepatomegaly Liver dysfunction Cataract Cryptorchidism Hypospadias Hyperammonemia, during crisis Hyperuricemia, during crisis Ketonuria, pronounced during crisis Lactic acidosis Metabolic acidosis Contractures Facial dysmorphism Renal tubulopathy Persistent pulmonary hypertension of the newborn Respiratory insufficiency Failure to thrive Growth retardation, postnatal Low birth weight Alanine (plasma) Ammonia (blood and plasma) Anion gap Uric acid Citrulline (plasma) Complex V activity (skeletal muscle) Creatine kinase (plasma) Glutamine (plasma) Lactate (cerebrospinal fluid) Lactate (plasma) Orotate (urine) 3-Methylglutaconic acid (urine)

Neonatal (birth–1 month) + ± ± ± ± ± + + ± ± ± ± + ± ± ± ± + + +

Infancy (1–18 months) + ± ± ± ± ± + + ± + ± ± + ± ± ± ± + + +

Childhood (1.5–11 years) + ± ± ± ± ± + + ± + ± ± ± ± ± ± ± + + +

Adolescence (11–16 years) + ± ± ± ± ± + + ± + ± ± ± ± ± ± ± + + +

Adulthood (>16 years) + ± ± ± ± ± + + ± + ± ± ± ± ± ± ± ± ± +

+ + ± ± ± ±

+ + ± ± ±

± + ± ± ±

± + ± ± ±

± ± ± ± ±

± + ± ± ↑-↑↑ n-↑↑ ↑ n-↑↑ n-↑ ↓

± + ±

± + ±

± + ±

± + ±

↑-↑↑ n-↑↑ ↑ n-↑↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑↑ n-↑ ↓

↑-↑↑ n-↑↑ ↑ n-↑↑ n-↑ ↓

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ ↑-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ ↑-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ ↑-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ ↑-↑↑

n-↑↑ n-↑ n-↑↑ ↑-↑↑↑ n-↑ ↑-↑↑

70  3-Methylglutaconic Acidurias

1427

Table 70.10  TIMM50 deficiency System CNS

Eye Other Laboratory findings

Symptoms and biomarkers Behavior, aggressive Bilateral symmetric lesions globus pallidus and brain stem (MRI) Brain atrophy (MRI) Developmental delay Epilepsy Hypotonia Hypsarrhythmia (EEG) Optic atrophy Failure to thrive 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Lactate (cerebrospinal fluid) Lactate (plasma)

Neonatal (birth–1 month) ± ±

Infancy (1–18 months) ± ±

Childhood (1.5–11 years) ± ±

Adolescence (11–16 years) ± ±

Adulthood (>16 years) ± ±

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

± + + + + + + n ↑↑ ↑ n-↑↑ ↑-↑↑↑

Neonatal (birth–1 month) ± ± ± ± ± ± ± ± + + ± + ± n ↑↑ ↑ n ↑ ↑ ↑ ↓-n ↑

Infancy (1–18 months) ± ± ± ± ± ± ± ± + + ± + ± n ↑↑ ↑ n ↑ ↑ ↑ ↓-n ↑

Table 70.11  MICOS13 deficiency System CNS

Digestive Metabolic Other Laboratory findings

Symptoms and biomarkers Cortical atrophy (MRI) Epilepsy Hypotonia, muscular Microcephaly Regression Retardation, psychomotor Subcortical atrophy (MRI) White matter abnormalities (MRI) Liver failure, acute Liver dysfunction Hypoglycemia Death Failure to thrive 3-Hydroxyisovaleric acid (urine) 3-Methylglutaconic acid (urine) 3-Methylglutaric acid (urine) Ammonia (blood) ASAT/ALAT (plasma) Bilirubin, conjugated (plasma) Disturbed clotting Glucose (plasma) Lactate (plasma)

All patients died (maximum age 13 months)

a

Childhood (1.5–11 years)

Adolescence (11–16 years)

Adulthood (>16 years)

1428

S. B. Wortmann and J. A. Mayr

Reference Values Metabolite 3-Hydroxyisovaleric acid (U)

3-Methylglutaconic acid (U)

3-Methylglutaric acid (U)

Reference value 0–25 mmol/mol creatinine (0–2 month) 0–50 mmol/mol creatinine (2 months–2 years) 0–45 mmol/mol creatinine (2–10 years) 0–15 mmol/mol creatinine (10–18 years) 0–20 mmol/mol creatinine (> 18 years) (GCMS, TML laboratory, Radboud university, Nijmegen, NL) 0–20 mmol/mol creatinine (0–2 month) 0–15 mmol/mol creatinine (2 months–2 years) 0–10 mmol/mol creatinine (>2 years) (GCMS, TML laboratory, Radboud university, Nijmegen, NL) Absent, if present not quantified (GCMS, TML lab, Radboud University, Nijmegen, NL)

Pathological Values Metabolite 3-Methylglutaconic acid (U)

Pathological value 20–40 mmol/mol creatinine: Suggestive for mitochondrial dysfunction as it can be seen in numerous inborn errors of metabolism > 40 mmol/mol creatinine: Suggestive for inborn error of metabolism with 3-methylglutaconic aciduria as discriminative feature

Leucine Loading Test Indication: To distinguish between primary and secondary 3-methylglutaconic aciduria. Procedure: Collect a urine portion for urinary organic acid analysis and a venous blood sample for serum amino acids. Give 100 mg/kg (max. 6 g) leucine powder orally, and

repeat listed investigations 1 h after the leucine gift. Collect a 24-h urine sample for another urinary organic acid analysis. Interpretation: Table below lists the typical findings before and after leucine loading in several 3-methylglutaconic acidurias. Only in primary 3-MGA_uria due to AU deficiency a clear increase in urinary 3-MGA occurs.

Results of the leucine loading tests in different 3-­methylglutaconic acidurias

Defect AUH TAZ OPA3 SERAC1 CLPB NOS

Elevated urinary 3-HIVA + − − − − −

Lowest urinary 3-MGA before loading (Ref 16 years) ±

Table 71.15  Cystathionase deficiency System Other Laboratory findings

Symptoms and biomarkers No clinical significance Cystathionine (plasma) Cystathionine (urine) Cysteine (plasma) Homocysteine, total (plasma) Methionine-to-cystathionine ratio (plasma)

Adulthood (>16 years) + ↑↑↑ ↑↑↑ n n-↑ ↓↓

Table 71.16 3-Methylcrotonylglycinuria System Other Laboratory findings

Symptoms and biomarkers No clinical significance 3-Hydroxyisovaleric acid (urine) 3-Methylcrotonylcarnitine 3-Methylcrotonylglycine (urine) Ammonia (blood) Anion gap ASAT/ALAT (plasma) Base excess C5-OH Acylcarnitine (dried blood spot) C5-OH Acylcarnitine (plasma) Carnitine, esterified (plasma) Carnitine, free (dried blood spot) Carnitine, free (plasma) Glucose (plasma) Methylcrotonyl-CoA carboxylase (fibroblasts) Uric acid (plasma)

Neonatal (birth–1 month) + ↑-↑↑↑ n-↑↑ ↑-↑↑↑ n-↑ ± n-↑ ± ↑-↑↑↑

Infancy (1–18 months) + ↑-↑↑↑ n-↑↑ ↑-↑↑↑ n-↑ ± n-↑ ± ↑-↑↑↑

Childhood (1.5–11 years) + ↑-↑↑↑ n-↑↑ ↑-↑↑↑ n-↑ ± n-↑ ± ↑-↑↑↑

Adolescence (11–16 years) + ↑-↑↑↑ n-↑↑ ↑-↑↑↑ n-↑ ± n-↑ ± ↑-↑↑↑

Adulthood (>16 years) ↑-↑↑↑ n-↑↑ ↑-↑↑↑ n-↑ ± n-↑ ± ↑-↑↑↑

↑-↑↑↑ n-↑ ↓-n ↓-n ↓-n ↓

↑-↑↑↑ n-↑ ↓-n ↓-n ↓-n ↓

↑-↑↑↑ n-↑ ↓-n ↓-n ↓-n ↓

↑-↑↑↑ n-↑ ↓-n ↓-n ↓-n ↓

↑-↑↑↑ n-↑ ↓-n ↓-n ↓-n ↓

n-↑

n-↑

n-↑

n-↑

n-↑

1444

S. I. Goodman

Table 71.17 2-Methylbutyrylglycinuria System Other Laboratory findings

Symptoms and biomarkers No clinical significance 2-Ethylhydracrylic acid (blood) 2-Ethylhydracrylic acid (plasma) 2-Methylbutyric acid (urine) 2-Methylbutyryl-CoA dehydrogenase (fibroblasts) 2-Methylbutyrylglycine (urine) Anion gap C5 2-Methylbutyrylcarnitine (blood) C5 2-Methylbutyrylcarnitine (plasma) C5/C2 Acylcarnitines ratio Glucose (plasma) Isobutyrylglycine (urine)

Neonatal (birth–1 month) ± n-↑

Infancy (1–18 months) ± n-↑

Childhood (1.5–11 years) ± n-↑

Adolescence (11–16 years) ± n-↑

Adulthood (>16 years) ± n-↑

n-↑

n-↑

n-↑

n-↑

n-↑

↑↑ ↓

↑↑ ↓

↑↑ ↓

↑↑ ↓

↑↑ ↓

↑↑

↑↑

↑↑

↑↑

↑↑

± ↑-↑↑

± ↑-↑↑

± ↑-↑↑

± ↑-↑↑

± ↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑-↑↑

↑ ↓-n n-↑

↑ ↓-n n-↑

↑ ↓-n n-↑

↑

↑

n-↑

n-↑

Neonatal (birth–1 month) + ± ↑ ↓ ↓

Infancy (1–18 months) + ± ↑ ↓ ↓

Childhood (1.5–11 years) + ± ↑ ↓ ↓

Adolescence (11–16 years) + ± ↑ ↓ ↓

Adulthood (>16 years)

Neonatal (birth–1 month) + ↓-n ↑ ↑ ↑

Infancy (1–18 months) + ↓-n ↑ ↑ ↑

Childhood (1.5–11 years) + ↓-n ↑ ↑ ↑

Adolescence (11–16 years) + ↓-n ↑ ↑ ↑

Infancy (1–18 months) + ↑

Childhood (1.5–11 years) + ↑

Adolescence (11–16 years) + ↑

Table 71.18 Oxoprolinuria System Other CNS Laboratory findings

Symptoms and biomarkers No clinical significance Retardation, psychomotor 5-Oxoproline (urine) 5-Oxoprolinase (fibroblasts) 5-Oxoprolinase (white blood cells)

± ↑ ↓ ↓

Table 71.19  Glycerol kinase deficiency System Other Laboratory findings

Symptoms and biomarkers No clinical significance Glucose (plasma) Glycerol (plasma) Glycerol (urine) Triglyceride, pseudo (plasma)

Adulthood (>16 years) ↓-n ↑ ↑ ↑

Table 71.20  Methionine adenosyltransferase deficiency System Other Laboratory findings

Symptoms and biomarkers No clinical significance Methionine (plasma)

Neonatal (birth–1 month) + ↑

Adulthood (>16 years)

71  Biochemical Phenotypes of Questionable Clinical Significance

1445

Table 71.21  Methylmalonyl-CoA epimerase deficiency System Other Laboratory findings

Symptoms and biomarkers No clinical significance Methylmalonic acid (urine)

Neonatal (birth–1 month) + ↑

Infancy (1–18 months) + ↑

Childhood (1.5–11 years) + ↑

Adolescence (11–16 years) + ↑

Adulthood (>16 years)

Neonatal (birth–1 month) + +

Infancy (1–18 months) + +

Childhood (1.5–11 years) + +

Adolescence (11–16 years) + +

Adulthood (>16 years) +

+

+

+

+

+

n-↑ ↑ ↑ ↑

n-↑ ↑ ↑ ↑

n-↑ ↑ ↑ ↑

n-↑ ↑ ↑ ↑

n-↑ ↑ ↑ ↑

↑ ↑↑ ↓-n ↑ ↓

↑ ↑↑ ↓-n ↑ ↓

↑ ↑↑ ↓-n ↑ ↓

↑ ↑

↑ n-↑

↑ ↓

↑ ↓

Table 71.22  Short-chain acyl CoA dehydrogenase deficiency System Other

Laboratory findings

Symptoms and biomarkers No clinical significance Predisposition for symptomatic disease Second mitochondrial affection Butyrylglycine (urine) C4 Butyrylcarnitine (blood) C4 Butyrylcarnitine (plasma) C4-Acylcarnitine (dried blood spot) C4-Acylcarnitine (plasma) Ethylmalonic acid (urine) Glucose (plasma) Methylsuccinic acid (urine) Short-chain acyl-CoA dehydrogenase (fibroblasts)

defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am J Hum Genet. 2000;67:1095–103. The list of inborn errors of questionable clinical significance Arnold GL, Koeberl DD, Matern D, et al. A Delphi-based consensus clinical practice protocol for the diagnosis and management of provided is almost certainly incomplete, as future clinical 3-methylcrotonyl CoA carboxylase deficiency. Mol Genet Metab. studies of patients detected by selective or newborn screen2008;93:363–70. ing will show that some disorders do in fact cause disease in Bar-Joseph I, Pras E, Reznik-Wolf H, et al. Mutations in the sarcosine dehydrogenase gene in patients with sarcosinemia. Hum Genet. some patients, and that others do not. Further, newer diag2012;131:1805–10. nostic methods like whole genome analysis or exome Bennett MJ, Pollitt RJ, Goodman SI, et  al. Atypical riboflavin-­ sequencing will add novel disorders to the mix, and these too responsive glutaric aciduria, and deficient peroxisomal glutaryl-­ will have to undergo intensive analysis to decide if they are CoA oxidase activity: a new peroxisomal disorder. J Inherit Metab Dis. 1991;14:165–73. indeed clinically relevant. Bikker H, Bakker HD, Abeling NGGM, et  al. A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria. Hum Mutat. 2006;27:640–3. References Binzak BA, Wevers RA, Moolenaar SH, et al. Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. Am J Hum Genet. Alfardan J, Al-Walid M, Copeland S, et  al. Characterization of new 2001;68:839–47. ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn Blom HJ, Davidson AJ, Finkelstein JD, et  al. Persistent hypermethioninemia with dominant inheritance. J Inherit Metab Dis. screening. Mol Genet Metab. 2010;100:333–8. 1992;15:188–97. Almaghlouth IA, Mohamed JY, Al-Amoudi M, et  al. 5-Oxoprolinase deficiency: report of the first human OPLAH mutation. Clin Genet. Carson NAJ, Scally BG, Neill DW, Carre IJ. Saccharopinuria—a new inborn error of lysine metabolism. Nature. 1968;218:679. 2011; https://doi.org/10.1111/j.1399-­0004.2011.01728.x. Andresen BS, Christensen E, Corydon TJ, et  al. Isolated Christensen M, Duno M, Lund AM, et al. Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase. J Inherit Metab Dis. 2-­ methylbutyrylglycinuria caused by short/branched chain acyl-­ 2007;30:248–55. CoA dehydrogenase deficiency: identification of a new enzyme

Concluding Remarks

1446 Crawhall JC, Parker R, Sneddon W, et al. Beta mercaptolactate-­cysteine disulfide: Analog of cystine in the urine of a mentally retarded patient. Science. 1968;160:419–20. Dancis J, Hutzler J, Ampola MG, et al. The prognosis of hyperlysinemia: an interim report. Am J Hum Genet. 1983;35:438–42. Danhauser K, Sauer SW, Haack TB, et al. DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. Am J Hum Genet. 2012;91:1082–7. Dobson CM, Gradinger A, Longo N, et al. Homozygous nonsense mutation in the MCEE gene and sRNA suppression of methylmalonyl-­ CoA epimerase expression: a novel cause of methylmalonic aciduria. Mol Genet Metab. 2006;88:327–33. Dorland L, Duran M, de Bree PK, et al. O-Phosphohydroxylysinuria: a new inborn error of metabolism. Clin Chim Acta. 1990;188:221–6. Efron ML.  Familial hyperprolinemia: report of a second case associated with congenital renal malformations, hereditary hematuria, and mild mental retardation, with demonstration of an enzyme defect. N Engl J Med. 1965;272:1243–54. Efron ML, Bixby EM, Palattao LG, Pryles CV.  Hydroxyprolinemia associated with mental deficiency. N Engl J Med. 1962;267:1193–4. Elpeleg ON, Christensen E, Hurvitz H, Branski D. Recurrent, familial Reye-like syndrome with a new complex amino and organic aciduria. Eur J Pediatr. 1990;149:709–12. Espinós C, Pineda M, Martinez-Rubio D, et al. Mutations in the urocanase gene (UROC1) are associated with urocanic aciduria. J Med Genet. 2009;46:407–11. Fontaine G, Farriaux JP, Dautrevaux M. Type I hyperprolinemia. Study of a familial case. Helv Paediatr Acta. 1970;25:165–75. Gaull GE, Tallan HH, Lonsdale D, et al. Hypermethioninemia associated with methionine adenosyltransferase deficiency: clinical, morphologic, and biochemical obervations on four patients. J Pediatr. 1981;98:734–41. Gerritsen T, Waisman HA.  Hypersarcosinemia: an inborn error of metabolism. N Engl J Med. 1966;275:66–9. Ghadimi H, Partington W, Hunter A. A familial disturbance of histidine metabolism. N Engl J Med. 1961;265:221–4. Goodman SI, Browder JA, Hiles RA, Miles BS. Hydroxylysinemia, a disorder due to a defect in the metabolism of free hydroxylysine. Biochem Med. 1972;6:344–54. Goodman SI, Mace JW, Miles BS, et  al. Defective hydroxyproline metabolism in type II hyperprolinemia. Biochem Med. 1974;10:329–36. Guggenheim MA, McCabe ERB, Roig M, et al. Glycerol kinase deficiency with neuromuscular, skeletal, and adrenal abnormalities. Ann Neurol. 1980;7:441–9. Hagen J, te Brink H, Wanders RJ, et  al. Genetic basis of alpha-­ aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis. 2015;38:873–9. Harris H, Penrose LS, Thomas DHH.  Cystathioninuria. Ann Hum Genet. 1959;23:442–53. Hernandez D, Addou S, Lee D, et al. Trimethylaminuria and a human FMO3 mutation database. Hum Mutat. 2003;22:209–13. Hilton JF, Christensen KE, Watkins D, et  al. The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat. 2003;22:67–73. Hirashima M, Hayakawa T, Koike M. Mammalian alpha-keto acid dehydrogenase complexes. II. An improved procedure for the preparation of 2-oxoglutarate dehydrogenase complex from pig heart muscle. J Biol Chem. 1967;242(5):902–7. Houten SM, Denis S, Te Brinke H, Jongejan A, van Kampen AH, Bradley EJ, Baas F, Hennekam RC, Millington DS, Young SP, Frazier DM, Gucsavas-Calikoglu M, Wanders R. Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoylCoA reductase deficiency with hyperlysinemia. Hum Mol Genet. 2014;23(18):5009–16.

S. I. Goodman Huang CS, Sadre-Bazzaz K, Shen Y, et  al. Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme a carboxylase. Nature. 2010;466:1001–5. Ishikawa M.  Developmental disorders in histidinemia: follow-up study of language development in histidinemia. Acta Paediatr Jpn. 1987;29:224–8. Johnson DW.  A flow injection electrospray ionization tandem mass spectrometric method for the simultaneous measurement of trimethylamine and trimethylamine N-oxide in urine. J Mass Spectrom. 2008;43:495–9. Kawai Y, Moriyama A, Asai K, et al. Molecular characterization of histidinemia: identification of four missense mutations. Hum Genet. 2005;116:340–6. Kim SZ, Varvogli L, Waisbren SE, Levy HL.  Hydroxyprolinemia: comparison of a patient and her unaffected twin sister. J Pediatr. 1997;130:437–41. Komrower GM, Wilson V, Clamp JR, Westall RG. Hydroxykynureninuria, a case of abnormal tryptophan metabolism probably due to a deficiency of kynureninase. Arch Dis Child. 1964;39:250–6. Kuracka L, Kalnovicova T, Liska B, Turcani P. HPLC method for measurement of purine nucleotide degradation products in cerebrospinal fluid. Clin Chem. 1996;42:756–60. Larsson A, Mattsson B, Wauters EA, et  al. 5-Oxoprolinuria due to hereditary 5-oxoprolinase deficiency in two brothers—a new inborn error of the gamma-glutamyl cycle. Acta Paediatr Scand. 1981;70:301–8. Levy HL, Coulombe JT, Benjamin R. Massachusetts metabolic disorders screening program: III. Sarcosinemia. Pediatrics. 1984;74:509–13. Malvagia S, La Marca G, Casetta B, et al. Falsely elevated C4-carnitine as expression of glutamate formiminotransferase deficiency in tandem mass spectrometry newborn screening. J Mass Spectrom. 2006;41:263–5. McCabe ERB.  Disorders of glycerol metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 2217–37. Moolenaar SH, Poggi-Bach J, Engelke UF, et al. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin Chem. 1999;45:459–64. Mourmans J, Bakkeren J, de Jong J, et  al. Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase deficiency: four sibs devoid of pathology. J Inherit Metab Dis. 1995;18:643–5. Mudd SH. Hypermethioninemias of genetic and non-genetic origin: a review. Am J Med Genet C Semin Med Genet. 2011;157:3–32. Mudd SH, Levy HL, Kraus JP. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Valle D, Sly WS, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-­ Hill; 2001. p. 2007–56. Perry TL, Hansen S, Tischler B, et al. Carnosinemia: a new metabolic disorder associated with neurologic disease and mental defect. N Engl J Med. 1967;277:1219–27. Roe CR, Ding J.  Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 2297–326. Schafer IA, Scriver CR, Efron ML. Familial hyperprolinemia, cerebral dysfunction and renal anomalies occurring in a family with hereditary nephritis and deafness. N Engl J Med. 1962;267:51–60. Sherman EA, Strauss KA, Tortorelli S, et al. Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in C7orf10. Am J Hum Genet. 2008;83:604–9. Sjaastad O, Blau N, Rydning SL, et  al. Homocarnosinosis: a historical update and findings in the SPG11 gene. Acta Neurol Scand. 2018;138:245–50.

71  Biochemical Phenotypes of Questionable Clinical Significance Sjarif D, Dorland L, Sperl W, et al. Hyperketonaemia in glycerol kinase deficiency. J Inherit Metab Dis. 2000;23:760–4. Stiles AR, Venturoni L, Mucci G, et  al. New cases of DHTKD1 mutations in patients with 2-ketoadipic aciduria. JIMD Rep. 2016;25:15–9. Teufel M, Saudek V, Ledig J-P, et al. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J Biol Chem. 2003;278:6521–31. Waisbren SE, Levy HL, Noble M, et al. Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms. Mol Genet Metab. 2008;95:39–45. Wang J, Hegele RA. Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH). Hum Genet. 2003;112:404–8.

1447 Wilcken B, Haas M, Joy P, et  al. Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics. 2009;124:e241–8. Wolfe LA, Finegold DN, Vockley J, et  al. Potential misdiagnosis of 3-methylcrotonyl-coenzyme a carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. Pediatrics. 2007;120:e1335–40. Woody NC. Hyperlysinemia. Am J Dis Child. 1964;108:543–53. Xu WY, Gu MM, Sun LH, et  al. A nonsense mutation in DHTKD1 causes Charcot-Marie-tooth disease type 2 in a large Chinese pedigree. Am J Hum Genet. 2012;91:1088–94. Xu WY, Zhu H, Shen Y, et  al. DHTKD1 deficiency causes Charcot-­ Marie-­tooth disease in mice. Mol Cell Biol. 2018;38:e00085–18.

Knowledge Base of Inborn Errors of Metabolism (IEMbase): A Practical Approach

72

Tamar V. Av-Shalom, Jessica J. Y. Lee, Carlos R. Ferreira, Nenad Blau, Clara D. M. van Karnebeek, and Wyeth W. Wasserman

Contents Introduction 

 1449

Knowledge Base 

 1450

Mini-Expert 

 1450

Application Walkthrough 

 1450

Future Directions 

 1453

References 

 1455

Summary

Here we give an overview of the inborn errors of metabolism knowledge base, or IEMbase, a comprehensive electronic repository of the IEMs described in this book. Developed as a companion application to this textbook, IEMbase provides two key functions: first, it is a free and

T. V. Av-Shalom · J. J. Y. Lee · W. W. Wasserman (*) Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada e-mail: [email protected] C. R. Ferreira Division of Genetics and Metabolism, Children’s National Health System, Washington, DC, USA e-mail: [email protected] N. Blau Division of Metabolism, University Children’s Hospital, Zürich, Switzerland e-mail: [email protected] C. D. M. van Karnebeek Department of Pediatrics, Emma Children’s Hospital, Amsterdam University Medical Centres, Amsterdam, The Netherlands

openly available repository of the features characterizing the different IEMs; second, it has an artificial intelligence (AI) search tool to aid the diagnosis of IEMs. Given the highly specialized knowledge necessary to accurately diagnose IEMs and the necessity for timely diagnosis, it is essential that all clinicians involved in IEM diagnoses have quick access to the disease-characterizing features of known IEMs. IEMbase fills this gap by providing a highly accessible tool to aid clinicians in overcoming the barriers to IEM diagnosis.

Introduction Inborn errors of metabolism (IEMs) represent a large class of rare genetic disorders that result from congenital defects in metabolic pathways. While individually rare, as a group IEMs have a collective incidence rate higher than 1:1000. Early timely diagnosis is crucial for these disorders as early intervention has proven to be effective in improving the quality of life and preventing serious sequelae that if left untreated, can lead to end-organ damage and death. Technological advances

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_72

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in DNA sequencing and metabolomics have greatly improved our ability to detect, diagnose, and manage IEMs in recent years (Vernon 2015). However, with the large number of these disorders as well as the associated genetic and phenotypic heterogeneity, timely diagnosis can often be delayed (Hawkes et  al. 2011). Nonspecialists often have challenges with the diagnosis and management of these disorders due to the large amount of specialist knowledge required (Hawkes et al. 2011). IEMbase was created as an accessible digital application to store standardized information about IEMs taken from the IEM community knowledge base (Lee et al. 2018). The system is implemented as two complementary parts: a digital knowledge base of IEMs and a mini-expert AI to aid diagnosis. The regularly updated knowledge base is compiled by experts from the IEM community consisting of clinicians, geneticists, and scientists. It houses over 1000 disorders and their associated profiles, including information on relevant genomic, biochemical, and clinical markers. The mini-expert AI is designed to help with the diagnosis of IEMs. It allows users to input lists of biochemical and clinical phenotypes and to compare them quickly with the database of disorder profiles.

Knowledge Base The specific steps regarding compilation and assembly of IEMbase have been previously described (Lee et al. 2018). For the purpose of this chapter, we will describe the components and content making up IEMbase, with a focus on the facilitating use of the system by potential users. In its essence, IEMbase is a collection of disorder characterizing profiles for known IEMs. Each disorder profile stores known disorder names, causal gene information, and links to external databases. The links to external databases include OMIM (OMIM 2020), UniProt (UniProt Consortium 2019), NCBI Gene (Brown et  al. 2015), GeneCards (Stelzer et  al. 2016), Kyoto Encyclopedia of Genes and Genomes (KEGG 2020), National Institutes of Health Genetic Testing Registry (NIH 2020), and GeneReviews (Adam et al. 1993). Each disorder profile also contains a list of associated symptoms and biomarkers, information regarding the age of onset and severity of symptoms, as well as the pathological level(s) of associated biomarkers (Lee et  al. 2018). Onset information is organized into five developmental categories: neonatal, infancy, childhood, adolescence, and adulthood. Severities of symptoms are denoted by plus signs, and pathological levels of biochemical markers are denoted by up/down arrows.

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In the “backend” of the system, the disorder profiles and associated symptoms/biochemical markers are stored in a PostgreSQL database as three tables: disorders, biochemical/ clinical phenotypes, and disorder-phenotype associations. As of April 2020, there are 1342 disorders, 3424 biochemical/clinical phenotypes, and 18,672 disorder-phenotype associations. IEMbase is actively updated to reflect new information in the field. The first version of IEMbase was compiled as version 1.0.0. Regular updates have yielded new versions of the database, with the latest version at the time of writing (April 2020) being 1.4.3. Mobile Apps for Android and iOS are available in corresponding stores.

Mini-Expert With over 1000 distinct IEMs in our database, several of which have overlapping symptoms and/or biochemical marker profiles, IEMbase includes an AI tool for diagnosing IEMs called the mini-expert. The mini-expert takes as input, a list of biochemical and clinical phenotypes. The system then uses a two-step algorithm to identify IEMs with matching profiles and presents them in ranked order (Fig.  72.1). Specific information regarding the algorithm for the mini-­ expert system is previously published (Lee et al. 2018).

Application Walkthrough The IEMbase application is made of three parts: a search feature, a browsing feature, and the mini-expert. When the user enters the site at http://iembase.org they are presented a disclaimer. Once the user agrees, they are then redirected to the main page (Fig.  72.2); this page features a search bar and three buttons: browse, search, and mini-expert. This main page is identical to the search page.

Search The search bar feature is found both on the main page and the search page. Using the search bar, the user can enter a disorder name, symptom, or gene name. The search feature will bring up a results page with all disorders that have a partial match with the search term entered (Fig.  72.3). Clicking the “more” button on a disorder from the results list will bring the user to the disorder view page, which will be discussed later in this walkthrough.

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Biochemical - ↑ Creatine kinase (plasma)

User input (Signs and Symptoms) - ↑ Creatine kinase (plasma) - Muscle cramps - Muscle pain

1 Biochemical phenotype comparison (cosine similarity)

Output (disorders)

2 Clinical phenotype comparison (semantic similarity and HPO)

1. Glycogen storage disease type VII 2. Glycogen storage disease type X 3 ....

Clinical - Muscle cramps - Muscle pain

Fig. 72.1  Mini-expert algorithm flowchart. The user enters a list of signs and symptoms into the mini-expert. The biochemical signs entered are used in step 1 for comparison with the disorder profiles in the system using a cosine similarity measurement, while the clinical

symptoms are compared in step 2 using a semantic similarity measurement. The mini-expert then outputs a ranked list of disorders matching the user input

Fig. 72.2  Main page and search page. This page allows users to search IEMbase for a disorder but entering a partial name, gene symbol, or symptom

Browse By clicking the browse button, the user navigates to the browsing page (Fig.  72.4). This page displays a dropdown list of all the IEMs stored in IEMbase organized by the disorder group, where the groupings are consistent with the textbook chapters. The user can expand different disorder

groups and subgroups to look for specific disorders. By clicking a specific disorder, the user is redirected to that disorder’s view page, which will be discussed in the next section. The browse section also contains a search bar, which connects to a simplified search that only looks for substrings of a specific disorder name or disorder group name.

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Fig. 72.3  Search results. After users enter a search term, the results returned include all disorders that have that search term in their summary. The summary consists of the disorder name and alternate names, associated gene(s), affected protein, and associated symptoms

Disorder View

Mini-Expert

When a user selects a disorder, either through the search or browse functions, they are redirected to that disorder’s view page. This page has four sections: disorder information, clinical symptoms, biochemical markers, and gene information. The user can expand or hide each of these individual sections. Some parts of these sections have clickable features, such as the OMIM number, which redirect the user to relevant external databases.

When the user clicks on the mini-expert button, they are redirected to the mini-expert AI. The first page prompts the user to enter biochemical markers of clinical symptoms (Fig. 72.5). For biochemical markers the user can also specify the relative level by clicking on the up or down arrows. The user can then press the match button, which runs the AI and returns a ranked list of disorders that match the inputted features. The match-

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Fig. 72.4  Browse feature. The user is presented with a dropdown list of disorder groups. Clicking on any of these groups will expand them to show the specific subgroups and disorders under that category

ing algorithm prioritizes biochemical markers and will only work if at least one biochemical marker is input. The result page (Fig. 72.6) has on the top a summary of the query and then panel options: results, differential diagnosis (DDX), biochemical tests, and gene panel. The DDX, biochemical tests, and gene panel options allow the user to select any subset of disorders from the results of the mini-­ expert, and it will then create a summary of the selected disorders depending on the option.

Future Directions Over the long-term, IEMbase benefits most from the continuous effort of editors and experts to maintain the currency of the disorder characterizing profiles, and we are committed to continuous renewal.

Excluding technical updates, which are necessary for any informatics resource, we are exploring several innovations that may enhance the utility of IEMbase for users. We are attempting to incorporate the embedded display of information from external resources, such as the display within IEMbase of pathway diagrams from pathway databases. The system has largely focused on aiding diagnosis, but we are exploring how we could display information that is useful for clinicians planning treatment of patients. Finally, we are exploring improved AI and search functions that would allow results to be generated based on either verbal description of patient characteristics or submission of a transcribed medical record note. Users are encouraged to provide feedback, particularly if there are features that would improve the utility of the IEMbase system.

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Fig. 72.5  Mini-expert input. The user can search for biochemical markers or clinical symptoms and can add them to the search query. For biochemical markers, the user can specify a level by selecting the up/down arrow or normal

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Fig. 72.6  Mini-expert results. The results from the mini-expert query consist of a summary of the query and a ranked list of matching disorders. There are three additional tabs, DDX, biochemical tests, and gene panel, which allow the user to create summary tables from the ranked results

References Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A, editors. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993. Brown GR, Hem V, Katz KS, et al. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res. 2015;43:D36–42. Hawkes CP, Walsh A, O’Sullivan S, Crushell E. Doctors’ knowledge of the acute management of inborn errors of metabolism. Acta Paediatr 1992. 2011;100:461–3. KEGG as a reference resource for gene and protein annotation.  – PubMed – NCBI. https://www.ncbi.nlm.nih.gov/pubmed/26476454. Accessed 21 Apr 2020. Lee JJY, Wasserman WW, Hoffmann GF, van Karnebeek CDM, Blau N. Knowledge base and mini-expert platform for the diagnosis of inborn errors of metabolism. Genet Med. 2018;20:151–8.

OMIM  - Online Mendelian Inheritance in Man. https://omim.org/. Accessed 21 Apr 2020. Stelzer G, Rosen N, Plaschkes I, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics. 2016;54:1.30.1–1.30.33. The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3531155/. Accessed 21 Apr 2020. UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47:D506–15. Vernon HJ.  Inborn errors of metabolism: advances in diagnosis and therapy. JAMA Pediatr. 2015;169:778–82.

WikiPathways: Integrating Pathway Knowledge with Clinical Data

73

Denise N. Slenter, Martina Kutmon, and Egon L. Willighagen

Contents Introduction 

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IEMBase and WikiPathways 

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Machine-Readable Metabolic Pathway Models 

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Using Pathway Models to Analyze Clinical Data 

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Limitations 

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Conclusions 

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References 

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Summary

Throughout the chapters in this book, pathways are used to visualize how genetically inheritable metabolic disorders are related. These pathways provide common conceptual models which explain groups of chemical reactions within their biological context. Visual representations of the reactions in biological pathway diagrams provide intuitive ways to study the complex metabolic processes. In order to link (clinical) data to these path-

ways, they have to be understood by computers. Understanding how to move from a regular pathway drawing to its machine-readable counterpart is pertinent for creating proper models. This chapter outlines the various aspects of the digital counterparts of the pathway diagrams in this book, connecting them to databases and using them in data integration and analysis. This is followed by three examples of bioinformatics applications including a pathway enrichment analysis, a biological network extension, and a final example that integrates pathways with clinical biomarker data.

The original version of this chapter was previously published non-open access. A Correction to this chapter is available at https://doi. org/10.1007/978-3-030-67727-5_74 D. N. Slenter (*) · E. L. Willighagen Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands e-mail: [email protected]; [email protected] M. Kutmon Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands Maastricht Centre for Systems Biology – MaCSBio, Maastricht University, Maastricht, The Netherlands e-mail: [email protected] © The Author(s) 2022, corrected publication 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_73

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2012; Kutmon et al. 2016; Slenter et al. 2018). This database allows researchers to add machine-readable pathways, includThe metabolic pathways in this book are common concep- ing literature references, and creates a traceable history of tual models which help us understand groups of chemical edits. The results are freely accessible and reusable by everyreactions within their biological context. These conversion one in the world. Furthermore, adding a pathway to reactions are catalyzed by enzymes and triggered by recep- WikiPathways exposes the biological knowledge captured in tors or transporters, causing a wide variety of metabolites to the model via various other data formats (http://help.wikipathbe present in bodily fluids and tissues. Visual representations ways.org) and tools (http://tools.wikipathways.org), allowing of the reactions in biological pathway diagrams provide intu- researchers to directly integrating the new knowledge within itive ways to study complex metabolic processes. If we want their tool of choice. to link clinical data to these pathways, we need pathways We aim to provide all pathways in the chapters of this that can be understood by computers. By creating machine-­ book as machine-readable pathway models in WikiPathways. readable versions of the pathways relevant for (rare) disor- You can find the currently available pathways on http://iem. ders, clinical data can be processed and analyzed in an wikipathways.org. automated fashion, allowing fast and visual interpretation (Kutmon et al. 2014a; Villaveces et al. 2015). However, modeling these pathways for data analysis comes with some Machine-Readable Metabolic Pathway challenges and limitations (Howe et  al. 2008; Khare et  al. Models 2016), which are discussed in this chapter in more detail. Even though there is still a substantial amount of unex- Researchers can use different tools to model machine-­ plored territory in human molecular biology, data on bio- readable pathways from schematic drawings in publications. logical mechanisms, pathways, and related diseases has WikiPathways stores all pathways in the graphical pathway increasingly become available due to improvements in markup language (GPML), which can be drawn in PathVisio measurement and computational techniques. A crucial step (www.pathvisio.org) (Kutmon et  al. 2015). This format is to enable advanced data analysis is structuring and sharing flexible enough to allow modeling of detailed biological the knowledge obtained from biological experiments. This phenomena, while relying on a machine-readable structured chapter provides some examples of what types of data anal- backbone for automated data analysis. In the following subysis can be performed with machine-readable pathways sections, we highlight relevant topics for creating pathways and related knowledge. More examples are available in lit- on genetically inheritable metabolic rare diseases. This inforerature, e.g., visualization of drug metabolism related ex- mation is complemented with an online step-by-step tutorial pression changes (Jennen et al. 2010), integrating molecular (academy.wikipathways.org). interaction data (Herwig et al. 2016), and fully automatable processing steps of metabolomics data (Stanstrup et  al. 2019). We hope to inspire the metabolic rare disease com- Modeling Biological Entities munity to aid our quest in transforming, structuring, and collecting knowledge about molecular processes in ma- The biological entities in GPML-encoded pathways (e.g., gene chine-readable pathway models and databases. Finally, all products, proteins, and metabolites) are captured as DataNodes these data acquisition and modeling steps will lead to a bet- (Fig. 73.1a). These nodes have a textual label and biological ter understanding of the phenotype of a patient. type and can contain the following additional information: literature references, free text comments, and a unique database identifier (Fig. 73.1b). The textual label is the visible name of IEMBase and WikiPathways the entity while the type represents which biological entity is modeled: genes are modeled as GeneProducts, proteins and The knowledge captured in the chapters of this book holds enzymes as Proteins and chemicals as Metabolites (Fig. 73.1a). vital information on genetically inheritable metabolic dis- Additional modeling options include Complexes, Groups, eases, genes, and proteins involved, metabolic biomarkers, RNAs, (full) Pathways, and States such as posttranslational pathways, relevant literature, diagnosis, and treatment. A great modifications (Fig. 73.1c). DataNodes can be connected to liteffort has been done digitizing most of this information in the erature, ideally using PubMed identifiers. Another section IEMBase (www.iembase.org) (Lee et al. 2018), but one key allows users to add free text in the comment field, to explain element missing were machine-readable pathways, which are additional details relevant for the pathway. Finally, a database being added through a collaboration with the WikiPathways identifier and the accompanying database (Fig. 73.1b) provides pathway database (www.wikipathways.org) (Kelder et  al. the framework required for data integration later (Figs. 73.4

73  WikiPathways: Integrating Pathway Knowledge with Clinical Data

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Fig. 73.1  Visualization of modeling properties for biological entities in PathVisio. (a) Main DataNodes, where the GeneProduct is selected (indicated with small yellow blocks). (b) Pop-up menu allowing connecting a DataNode to literature, identifier, and database. (c) Additional

modeling options, where multiple DataNodes can be used to form Complexes and Groups. Nodes can also be used to point to other Pathways (including identifier) and RNA. DataNodes can also be extended with a State like posttranslational modifications

and 73.5). An online database identifier allows the retrieval of additional facts about the entity in the pathway. PathVisio makes use of the BridgeDb identifier mapping framework (www.bridgedb.org) (van Iersel et al. 2010) and can therefore support a variety of databases and mappings between them. Since these identifiers are crucial for data analysis, the next two sections discuss them in more detail.

regarding identification of biological entities, the more specifically the identifier points to one entity, the more straightforward data can be connected to GeneProduct (Ensembl, NCBI Gene) and Protein (UniProt) DataNodes. For Complexes with multiple enzymes, each individual enzyme should receive a unique identifier from UniProt. In addition, distinctive isoforms could also have unique identifiers and be drawn as separate DataNodes. Metabolites can be annotated with over 25 databases, where most of these databases have their own focus (nutrition, toxicology, human metabolism, medication) and ­possess different levels of chemical detail. These different levels can be quite relevant for the biological implications of these compounds and corresponding interactions, such as stereochemistry (e.g., chirality, isomers), protonation state, (de) phosphorylation, and tautomerization. For several pathways and reactions, the specific level can also be unknown, which is particularly the case for lipid pathways. These are more often considered to behave biologically similar when the head and tail of the lipid are comparable; however a small difference in number of double bonds or location thereof could lead to distinct biological behavior. Identifiers exist to be able to add groups of compounds as Metabolite DataNodes in pathways. Nevertheless, this does not solve the issue of straightforward data analysis as discussed for genes and proteins. We would therefore advise to use chemical identifiers which correspond to the known level of chemical detail, e.g., ChEBI (Hastings et  al. 2016) for metabolites, DrugBank (Wishart et al. 2018) for drugs, and LIPID MAPS (Fahy et al. 2009) for lipids. Interactions can currently be annotated with 14 databases, for which some allow easy integration with other resources. A good coverage of metabolic conversions between metabolites is provided by the Rhea database (Lombardot et al. 2019).

Identifiers for Pathway Entities There are many online resources storing information about the proteins, molecules, and interactions in pathways. Ideally, each element in the pathway is annotated with a specific identifier from one of the online databases. Because there are many different databases to choose from, we provide some general guidelines for the annotations of DataNodes and interactions in pathways. Genes and proteins can be annotated with over 60 different databases. However, there are some subtle differences between what type of information is modeled in these databases. Ensembl (Cunningham et  al. 2019) and NCBI (Entrez) Gene (Agarwala et  al. 2018) focus on gene and transcript identifiers, while UniProt (UniProt Consortium 2019) models their data at a protein level. Therefore, one gene identifier in Ensembl could point to multiple UniProt entries. Enzyme commission numbers (EC-codes) (McDonald and Tipton 2014) can be very useful to annotate a group of enzymes which serve a similar biological function or to classify a chemical conversion to a specific reaction mechanism, without knowing the actual protein structure or gene involved. However, since this classification is not specific for one gene or protein, numerous mappings can be created which complicates data analysis. Thus,

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Interaction Types

Modeling Diseases and Interactions

As mentioned previously, interactions are separate elements within the pathway model. An interaction clearly connects two or more biological entities to depict a relationship between them. Understanding the biological meaning of a connection between different entities is needed to create accurate machine-readable models. PathVisio supports several types of interaction (standards): basic interactions, molecular interaction map (MIM) interactions (Luna et  al. 2011), and the interaction types described in the systems biology graphical notation (SBGN) (van Iersel et al. 2012). For the pathways in this book, we advise the application of MIM interactions, which include conversion and catalysis for reactions between metabolites and related enzyme(s) (Fig.  73.2a); stimulation and inhibition for signaling functions (Fig. 73.2b); transcription/translation for GeneProduct to Protein (Fig. 73.2c); modification for posttranslational or other modifications and binding for complex formation (Fig.  73.2d); and translocation for transport of metabolites between different cellular compartments (Fig. 73.2e).

Most pathways in this book clearly indicate which step(s) in a pathway are disease causing. This disease information can be added to pathways in several manners. First, diseases can be added to a pathway as text labels and connected to the related gene or protein. Second, a pathway can be tagged with terms from the Human Disease Ontology (Köhler et al. 2019) Pathway Ontology (Petri et al. 2014) and Cell Type Ontology (Diehl et al. 2016) on WikiPathways. The information enables systematic search and browse functionalities with clearly defined child-parent relationships; for example find all pathways, which are linked to the term “inborn error of metabolism pathway” (purl.bioontology.org/ontology/PW/ PW:0001589) or all pathways linked to possible child terms. Third, genes and proteins are often linked to OMIM gene entries (Amberger et  al. 2015) through BridgeDb, allowing navigation from a specific pathway to disease databases. Finally, including the disease name or class in the title of the pathway or description also helps searching for relevant pathways.

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Fig. 73.2  Overview of MIM interaction types and how these can be used to connect biological entities in PathVisio. (a) Metabolite 1 is enzymatically converted to Metabolite 2, which is catalysed by a Protein. (b) Protein 1 stimulates Protein 2; Protein 2 is inhibited by a Metabolite. (c) A GeneProduct is transcribed and/or translated to a

Protein. (d) top: A Protein undergoing a phosphorylation (P) PostTranslational-Modification (PTM); bottom: two Proteins binding together to form a complex. (e) A translocation from cytosol to nucleus for a Metabolite

73  WikiPathways: Integrating Pathway Knowledge with Clinical Data

 enetically Inheritable Metabolic Disorder G Pathways on WikiPathways

(GWAS), metabolomics, or targeted chemical assay data. In this section, we provide several examples on how the created pathway models can be used for data analysis. Scripts and instructions for performing these analyses can be found online (bigcat-um.github.io/IEMPathwayAnalysis).

A majority of the pathways in the chapters of this book are already available on WikiPathways (iem.wikipathways.org). As an example, Fig.  73.3 visualizes a complete example of a machine-readable version of the purine pathway (Chap. 13, WikiPathways:WP4792, www.wikipathways.org/instance/ WP4792), which is linked to over 20 genetically inheritable diseases (available at WikiPathways:WP4224). Even though at first glance, this figure resembles the original drawing quite closely, all the individual metabolites, proteins, and biomarkers are annotated with identifiers and linked to databases, all interactions connect these elements together and have the appropriate MIM types. The following sections provide several examples on how these pathways can now be used for data analysis.

Pathway Analysis The availability of pathways as machine-readable models enables us to visualize molecular data on the elements in the pathways and to perform advanced computational analysis including gene set enrichment and network analysis. While whole-genome sequencing is already well established in clinical practice, transcriptome analysis seems promising for diagnosing rare disease patients (Gonorazky et al. 2019). Pathway analysis for transcriptomics data is a powerful tool to put the data into a biological context. As an example, we selected a publicly available transcriptomic dataset of patients with Lesch-Nyhan disease (LND) (geo:GSE24345, omim:300322) (Kang et  al. 2011). The disease is caused by mutations in the HPRT1 gene (ensemb l:ENSG00000165704), producing the hypoxanthine phos-

 sing Pathway Models to Analyze Clinical U Data Pathways can be used to analyze various types of clinical data including whole exome sequencing (WES), transcriptomics and proteomics, genome-wide association studies

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phoribosyltransferase 1 enzyme (uniprot:P00492) which enables cells to recycle purines. After statistical analysis with GEO2R (Davis and Meltzer 2007), the differential gene expression data was visualized on the previously described purine pathway (Fig.  73.3) using the WikiPathways app in Cytoscape (apps.cytoscape.org/apps/ wikipathways) (Kutmon et  al. 2014b); see Fig.  73.4. Cytoscape (www.cytoscape.org) (Shannon et al. 2003) is a widely adopted network analysis and visualization software tool, and the WikiPathways app provides direct access to the WikiPathways pathway content. The log2 fold changes (difference in gene expression between patients and control group) are visualized as a gradient from blue (less expressed) over white (not changed) to red (more expressed). A strong downregulation of the HPRT1 gene is immediately visible by the corresponding blue gene boxes. Based on this dataset, it seems that several of the other enzymes in the pathway (PNP, APRT, PRPS1) attempt to compensate for the lower transcript availability of HPRT1 and are upregulated in LND patients. Other enzymes, which are up- or downstream from the affected purine pathway, could also show changes relevant for the phenotype of the

patient. Therefore, enrichment analysis on other pathway models can be used to assess the relevance of these pathways and find interesting affected processes in a certain dataset. Enrichment analysis showed several immunerelated processes including the complement system as well as the Wnt signaling pathway affected in LND patients. Reimand et al. published a protocol that provides a description of pathway enrichment analysis and a practical stepby-step guide (Reimand et al. 2019). Tutorial videos and R scripts for the data visualization (1A, Fig. 73.4) and pathway enrichment analysis (1B) can be found in the PathwayAnalysis folder on GitHub ­(bigcat-um. github.io/IEMPathwayAnalysis).

Pathways as a Source for Network Biology Well-annotated pathway models are also an immensely useful source for network biology approaches. They can be used to extend biological pathways and networks (combinations of pathways) with additional knowledge, such as drug targets.

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Fig. 73.4  Visualization of changes in gene expression in patients with Lesch-Nyhan disease in the purine metabolism pathway (WikiPathways: WP4792)

73  WikiPathways: Integrating Pathway Knowledge with Clinical Data

Using the WikiPathways app in Cytoscape, pathways can be visualized in two different views: the pathway view and the network view. The network view retains the existing biological interactions in the pathway only and applies an automatic layout allowing the pathways to be used for network analysis. Pathways can then be automatically enriched with additional information, e.g., regulatory mechanisms, known drugs, or disease annotations. The CyTargetLinker app for Cytoscape was specifically designed for this purpose (cytargetlinker.github.io) (Kutmon et  al. 2019). In the following example, we will extend the purine metabolism pathway with approved drugs from DrugBank; see Fig.  73.5. The pathway contains fifteen enzymes, shown as rounded rectangles. In

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DrugBank, 21 drugs (shown as green diamonds) are reported to target one or more of these enzymes. Nine of the 15 enzymes are targeted by at least one drug, as shown in orange. The LND-causing gene HPRT1 (highlighted with the red rectangle) is targeted by three drugs, azathioprine, mercaptopurine, and ɑ-phosphoribosyl pyrophosphoric acid. The first two are immunosuppressants and inhibit HPRT1. The last molecule is a key substance in the biosynthesis of histidine, tryptophan, purine, and pyrimidine nucleotides and has unknown pharmacological action on HPRT1. Tutorial videos and R scripts for the following example can be found in the Network Analysis folder on GitHub (bigcat-um.github.io/IEMPathwayAnalysis).

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Legend: Protein Metabolite Biomarker Drug Enzyme targeted by drug

Didanosine dAMP

Inosine Cladribine GTP

2-Deoxyguanosine

RR

dADP dGDP dGMP dATP

dGTP

Fig. 73.5  Known drug-target interactions (from DrugBank) for the purine metabolism pathway

DGUOK

Febuxostat

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Linking Chemical (Biomarker) Data with RDF The two examples in the previous sections work well for transcriptomics data. However, connecting metabolomics or chemical biomarker data to pathways can be challenging with the methods presented above, since the amount of data is significantly lower. Furthermore, as previously mentioned in Sect. 73.3.2, various levels of chemical detail exist within pathway models. To overcome these problems, we want to highlight another method to connect biomarkers data with pathways using an automated approach. The workflow for this example is visualized in Fig. 73.6a. One starts with chemical data from targeted (clinically validated) assays or with (un) targeted metabolomics data from mass spectrometry (MS) and/or nuclear magnetic resonance (NMR). After preprocessing of this data, for example, in R (Stanstrup et al. 2019), and annotation of relevant peaks with the corresponding chemical structure, one can also add an identifier from a (supported) database to the data. For subsequent data analysis steps, we used BridgeDb to link these identifiers to their corresponding InChIKey (a shortened version of the InChI) (Heller et  al. 2015), which links the chemical structure to the original compound identifier in a machine-readable manner. The InChIKey consists of three parts (separated by a bar “-”); the first describes the general structure of a molecule, the second its stereochemistry, and the third the charge of the molecule. For example, “CKLJMWTZIZZHCS-REOHCLBHSA-M” is the InChIKey for L-aspartic acid monoanion, where the “M” stands for a −1 charge. In order to link these compounds to (metabolic) pathways, we will use a SPARQL query (Galgonek

a

et al. 2016). This query is a structured method to ask questions to a database such as WikiPathways, which has been converted to the Resource Description Framework (RDF) format (Waagmeester et al. 2016). This RDF format unifies and harmonizes pathway data over all models, with several filtering and search options; data can be queried for specific species, DataNodes, literature, and more. Figure  73.6b provides an example of a SPARQL query where we investigated the occurrence of five compounds within the pathway models of WikiPathways. More details on the structure of the WikiPathways RDF and example queries are available on the Semantic Web portal: rdf.wikipathways.org. We also provide a beginners’ tutorial on how to write SPARQL queries in the SPARQL folder on GitHub (bigcat-um.github.io/ IEMPathwayAnalysis). To visualize the concepts of SPARQL and data mapping, we chose the five naturally charged proteinogenic amino acids (positive charge: aspartic acid (Asp, D) and glutamic acid (Glu, E); negative charge: arginine (Arg, R), histidine (His, H), and lysine (Lys, K)). Lines 6–10 in Fig. 73.6b provide the InChIKeys for these compounds, which we will link to pathway data in line 15 (wp:bdbInChIKey ?inchikey). The results of the example query reveal in which pathways these compounds can be found, which are listed from lowest to highest (line 22) occurrence counts (line 4) in pathways, to find the most relevant pathways for further analysis. This results in 15 pathways, which all have one of these compounds present (RDF data release 2021-­03-­10). However, since pathways can be annotated with the uncharged form of these amino acids as well, we can also query all compounds

b

Fig. 73.6  Proposed workflow for data analysis of metabolic biomarkers with semantic web technologies. (a) Moving from chemical assay data to data interpretation using BridgeDb, SPARQL and Cytoscape. (b) Example of a SPARQL query on metabolic data in the WikiPathways RDF

73  WikiPathways: Integrating Pathway Knowledge with Clinical Data

with the same stereochemistry independent of change status, obtaining a more complete result. By changing the end of each compounds InChIKey to their neutral counterpart (“CKLJMWTZIZZHCS-REOHCLBHSA-M” becomes “CKLJMWTZIZZHCS-REOHCLBHSA-N”) and changing line 15 to “rdfs:seeAlso ?inchikey,” we obtain a total of 38 pathways, with 15 pathways containing 2 of the 5 amino acids (either in their neutral or charged form). This example is explained in more detail in the SPARQL folder on GitHub (bigcat-um.github.io/IEMPathwayAnalysis). The next step in this workflow downloads the relevant pathways from WikiPathways in Cytoscape; see Sect. 73.4.1 and 73.4.2 for further details. When moving to a network tool, more advanced analysis approaches can be used. The chemical data can be visualized on the nodes in the network, while the edges (interactions between nodes) can be used to visualize fluxomic data (if available). After the data has been added, interpretation can be facilitated by additional features in Cytoscape, such as visualizing the chemical structure of the compounds, connecting several pathways (as networks) to obtain a more complete overview, adding other experimental data (e.g., transcriptomics; see Sect. 73.4.1), or expanding the network with biological knowledge from other databases (see Sect. 73.4.2).

Limitations Every type of data analysis comes with its own set of limitations. For pathway analysis, the results depend on the coverage of the selected database (s), the mappings between identifiers from the dataset to the pathway knowledge, the statistics, and cut-off value used for the fold change to discover significant findings. Especially regarding this first issue, WikiPathways is a useful resource, since users can add missing information on pathways and interaction themselves, allowing them and others to use them directly in data analysis. Furthermore, the machine-readable model behind this database is flexible enough to accommodate the needs of researchers from the genetic inheritable metabolic disease research area. We hope that this chapter, as well as the created examples of machine-readable pathways from the figures in this book, provides other users inspiration to add more biological knowledge to databases. For more information on how to model these pathways, please visit help.wikipathways.org.

Conclusions While regular pathway drawings are a great resource to visualize relevant biological interactions, these figures are not interactive and not directly reusable for data analysis. Understanding how to move from a regular pathway drawing to its machine-readable counterpart is pertinent for creating

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proper models. As shown in this chapter, having a digital pathway can link to reference databases and allows us to preform data integration and analysis. This will require some time and effort from the side of the user; however once these skills are mastered, adding new information is relatively easy, will decrease other research time needed for data analysis, and aid the research community as a whole.

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Open Access  This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons. org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Correction to: Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

Correction to: N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5 The original version of the book was published with errors and was updated with the following corrections: 1. Chapter 73, WikiPathways: Integrating Pathway Knowledge with Clinical Data was previously published non-open access. It has now been changed to open access under a CC BY 4.0 license and the copyright holder updated to ‘The Author(s)’. The book has also been updated with this change. 2. The affiliation of the fifth editor Dr. Clara D. M. van Karnebeek was updated to ‘Departments of Pediatrics and Human Genetics, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands’.

The updated version of this book can be found at https://doi.org/10.1007/978-3-030-67727-5

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5_74

C1

Disorder Index

A AADC deficiency. See Aromatic L-amino acid decarboxylase (AADC) deficiency AARF domain-containing kinase 3 (ADCK3) deficiency, 918 ABCB7 deficiency, 36, 482, 488, 492 ABCC6 deficiency, 216, 218, 229 ABCD3 deficiency, 1305 ABCG5 deficiency, 30 ABCG8 deficiency, 30 Abetalipoproteinemia (MTP), 1042 ABHD12 deficiency, 1019, 1021 ACAD9 deficiency. See Acyl-CoA Dehydrogenase 9 (ACAD9) deficiency ACBD5 deficiency, 1300, 1307, 1309 Aceruloplasminemia, 35, 608, 627 N-Acetyl-alpha-D-glucosaminidase deficiency, 1269 N-Acetylaspartic aciduria, 1400 Acetyl-CoA alpha-glucosaminide acetyltransferase deficiency, 1269 Acetyl-CoA carboxylase deficiency 1 (ACACA), 1001 2 (ACACB), 1002, 1003 Acetyl-CoA transporter deficiency, 610, 611, 616, 620, 621 N-Acetylgalactosamine-4-sulfatase deficiency, 1269 N-Acetylgalactosamine-6-sulfatase deficiency, 1269 N-Acetylglucosamine-6-sulfatase deficiency, 1269 N-Acetylglucosaminyltransferase 2 congenital defects of glycosylation (MGAT2-CDG), 1336, 1337, 1339 N-Acetylglucosaminyltransferase 2 deficiency, 1358 N-Acetylglutamate synthase deficiency, 22, 266, 268 N-Acetylglutamate synthetase deficiency, 176 N-Acetylneuraminic acid synthase deficiency, 1252, 1258 Acid sphingomyelinase deficiency, 30, 38 Acrodermatitis enteropathica, 34, 610, 611, 616, 619–622 Activation-induced cytidine deaminase deficiency, 214, 216–218, 221, 231 Acute hyperammonemia, 263–265 Acute hypoketotic hypoglycemia and encephalopathy, 930–931 Acute intermittent porphyria, 1119 Acute symptomatic hyperammonemia, 286 Acylceramide transacylase deficiency, 1013 Acyl-CoA dehydrogenase 9 (ACAD9) deficiency, 21, 22, 24, 32, 799, 815, 932–934, 953, 954 Acyl-CoA oxidase 1 deficiency, 1309, 1313 Acyl-CoA oxidase 2 deficiency, 1306, 1310 Acyl-CoA synthetase family member 3 deficiency, 396 Acylglycerol kinase deficiency (AGK), 26, 892, 901, 909, 992, 1417, 1419, 1421, 1424 ADCK4 deficiency, 918 Adenine nucleotide translocator deficiency, 767, 773, 786, 787 cardiomyopathic type, 865 ophthalmoplegia type, 865 Adenine nucleotide translocator deficiency AD, 865

Adenine nucleotide translocator deficiency AR, 24 Adenine phosphoribosyl transferase deficiency, 194, 195, 205 Adenosine deaminase deficiency, 195, 203 1, 194 2, 115, 194, 203 Adenosine kinase deficiency, 20, 30, 32, 366, 368–370, 381, 382, 388, 717, 724, 731, 732 Adenosine monophosphate deaminase deficiency, 32, 194, 202 Adenosine monophosphate deaminase 2 deficiency, 115, 194, 202 Adenosylcobalamin and methylcobalamin synthesis defect -cblC, 500, 504, 510 -cblD-MMA/HC, 500, 504, 510 -cblF, 500, 504, 510 -cblJ, 500, 504 -epi-cblC, 500, 504, 510, 511 Adenosylcobalamin synthesis defect -cblA, 501, 504, 506–507, 510, 511 -cbl A/B, 22, 28 -cblB, 501, 504, 506–507, 510, 511 -cblD-MMA, 22, 28, 500, 504, 506–507, 511 Adenylate kinase 1 deficiency, 36, 194, 205 Adenylate kinase 2 deficiency, 194, 205 Adenylosuccinase deficiency, 194 Adenylosuccinate lyase (ADSL) deficiency, 115, 172, 173, 194, 195, 201 Adipose triglyceride lipase deficiency, 33, 1009, 1010 AdPEO with mitochondrial DNA deletions type 2, 767 type 4, 849 Adrenal corticosterone methyl oxidase II deficiency, 1079 Adrenoleukodystrophy, 1307–1308 ADSL. See Adenylosuccinate lyase (ADSL) deficiency AGK. See Acylglycerol kinase deficiency (AGK) AGS. See Aicardi-Goutières syndrome (AGS) AGT. See Alanine-glyoxylate aminotransferase (AGT) deficiency AHCY deficiency, 383, 388 Aicardi-Goutières syndrome (AGS), 109, 111, 115, 214–215, 231, 232 type 1, 217, 222 type 2, 217 type 3, 217 type 4, 217 type 5, 217, 224 type 6, 217, 225 type 7, 217, 226 AICA-riabosiduria, 194 AICAR transformylase/IMP cyclohydrolase deficiency, 194, 202 AKR1C2/4 deficiency, 1088 AKT2 superactivity, 21, 718, 728, 731, 733 AKT3 superactivity, 718, 728, 731 AKU. See Alkaptonuria (AKU) Alanine-glyoxylate aminotransferase (AGT) deficiency, 27, 55, 1322 ALDOB-D (HFI), 686, 688

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5

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1468 Aldolase A deficiency (ALDOA-D), 32, 37, 39, 652, 686, 688 Aldolase B deficiency, 651 ALG6 α-1,3-glucosyltransferase deficiency, 717 ALG3 α-1,3-mannosyltransferase deficiency, 717 ALG1-CDG, 1338, 1344, 1348 ALG2-CDG, 33, 1338, 1344, 1349 ALG3-CDG, 31, 717, 731, 732, 1338, 1344, 1351 ALG6-CDG, 29, 717, 731, 732, 1338, 1344, 1353 ALG8-CDG, 37, 38, 1338, 1344, 1354 ALG9-CDG, 29, 1338, 1344, 1351–1352 ALG11-CDG, 1338, 1344, 1349–1350 ALG12-CDG, 29, 1338, 1344, 1352–1353 ALG13-CDG, 1338, 1344 ALG14-CDG, 33, 1338, 1344 Alkaline ceramidase 3 deficiency, 1013 Alkaptonuria (AKU), 17–19, 53, 355, 358, 362 Allan-Hernon-Dudley syndrome, 702 Alpers-Huttenlocher syndrome, 849 α-Aminoadipic semialdehyde dehydrogenase deficiency, 48, 123 α-fucosidase deficiency, 141, 1252 α-1,6-fucosyltransferase deficiency, 1359 α-galactosidase A deficiency, 140 α-1,3-glucosidase II subunit β deficiency, 1357 17 α-hydroxylase deficiency, 1078, 1079, 1081 α-ketoadipic aciduria, 48 α-ketoglutarate dehydrogenase deficiency, 744 α-mannosidase B deficiency, 1252 α-mannosidase deficiency, 141 α-mannosidosis, 1252 α-methylacetoacetic aciduria, 427 α-methylacyl-CoA racemase (AMACR) deficiency, 138, 1096, 1103 Alpha-amino adipic semialdehyde (AASA) dehydrogenase deficiency (AASADHD), 20, 579, 581, 584, 586–588 α-NAcetylgalactosaminidase deficiency II, 1252 α-NAcetylgalactosaminidase deficiency III, 1252 Alpha dystroglycanopathies, 142 Alpha-Iduronidase deficiency, 1269 Alpha-L-fucosidase deficiency, 76, 81 Alpha-mannosidosis, 1254 Alpha-methylacetoacetic aciduria, 23, 393 Alpha-methylacyl-CoA racemase deficiency, 1300 5-Alpha-reductase type II deficiency, 1086 AMACR deficiency, 1310, 1315 Amino acid N-acyltransferase deficiency, 1105 Aminoacidopathies, 11 Amino acid synthesis deficiencies, 453–465 Amino acid synthesis disorders, 458 Aminoacidurias, 86, 307 2-Aminoadipic aciduria, 1436 2-Aminoadipic 2-oxoadipic aciduria, 27 Aminoglycoside-induced and nonsyndromic hearing loss, 851 Aminoglycoside-induced deafness, 854 5-Aminolevulinate dehydratase deficiency, 1118 2-Amioadipic and 2-ketoadipic aciduria, 54 Amish infantile epilepsy syndrome, 1017 Amish lethal microcephaly, 540, 745 Amish microcephaly, 537–539, 545, 766, 768 Ammonia detoxification, 263, 264 Amnionless deficiency, 36, 500, 502 Amylo-1,6-glucosidase (debrancher) deficiency, 31, 32, 35 Amyotrophic lateral sclerosis (ALS), 1156–1157, 1160 2 (ALS2), 1168 3 (SQSTM1), 1164 4 (TBK1), 1162 11 (FIG4), 1170 17 (CHMP2B), 1173

Disorder Index Andersen disease, 653 Androgen insensitivity syndrome, 1087 Angiopoietin-like 3 deficiency, 30 Antiquitin (ATQ) deficiency, 578, 579, 583, 584, 587–589 Apnea, 474 Apolipoprotein A5 deficiency, 30 Apolipoprotein A-I binding protein deficiency, 566 Apolipoprotein A-I deficiency, 1045 Apolipoprotein C2 deficiency, 30, 137 Apolipoprotein E deficiency, 30 Apolipoprotein E superactivity, 30, 38 APOPT1 deficiency, 131, 803, 826 Apparent mineralocorticoid excess, 1085 Aquaporin 7 deficiency, 959, 961–965 Arachnodactyly, 463 Arginase deficiency, 11, 48, 117 Arginase 1(ARG1) deficiency, 22, 30, 34, 264, 266, 270, 282, 284, 285, 287, 288 Arginine:glycine amidinotransferase aggregation syndrome, 236, 238, 239, 241, 242 Arginine:glycine amidinotransferase deficiency, 27, 236, 237 Argininemia, 266 Argininosuccinate lyase (ASL) deficiency, 22, 30, 34, 42, 48, 116, 266, 270, 282, 284, 285, 287, 288 Argininosuccinate synthetase (ASS) deficiency, 22, 30, 34, 42, 48, 116, 266, 269, 282, 284, 285, 287, 288 Argininosuccinic acidemia, 11 Argininosuccinic aciduria, 48, 58, 176, 266 Arias Syndrome. See Crigler-Najjar syndrome, type 2 (CN2) Aromatase deficiency, 1086 Aromatic L-amino acid decarboxylase (AADC) deficiency, 315, 316, 319, 325–327 Aromatic L-amino acid descarboxylase (AADC) deficiency, 56 Arylsulfatase A deficiency, 139 ASCT1 transporter deficiency, 296, 301, 302, 305, 306 Asparagine deficiency, 455 Asparagine synthase deficiency, 48 Asparagine synthetase deficiency, 456, 457, 464 Aspartate-glutamate carrier 1 deficiency, 24, 767, 773, 786, 788 Aspartoacylase deficiency, 111, 143, 1402 Aspartylglucosamidase deficiency, 48 Aspartylglucosaminidase deficiency, 141 Aspartylglucosaminuria, 76, 81, 1252, 1256 Asymptomatic familial hyperzincemia, 611, 612, 618, 619 ATAD3A deficiency, 893, 907, 910 Ataxia, 442, 456, 1019 Ataxia, progressive seizures, mental deterioration and hearing loss, 854 Ataxia with lactic acidosis II, 744 ATP13A2 deficiency, 1222–1223 ATPAF2 deficiency, 804 ATP6AP1-CDG, 30, 31, 34, 1343, 1344, 1391 ATP6AP2-CDG, 1343, 1344, 1391 ATP7A-related distal hereditary neuropathy, 608 ATP5E deficiency, mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, 804 ATP-sensitive potassium channel pore-forming subunit deficiency, 20, 716, 720, 731, 732 ATP-sensitive potassium channel pore-forming subunit superactivity, 22 ATP-sensitive potassium channel regulatory subunit deficiency, 20, 716, 720, 731, 732 ATP-sensitive potassium channel regulatory subunit superactivity, 22 ATP-specific succinyl-CoA ligase β subunit deficiency, 24, 28, 55, 126, 744, 752, 850, 863–864 ATP6V0A2-CDG, 1343, 1344, 1390 ATP6V1A-CDG, 1343, 1344, 1390 ATP6V1E1-CDG, 1343, 1344, 1390

Disorder Index Atransferrinemia, 36, 628, 631 Atypical hemolytic uremic syndrome type 7, 1001 Auditory neuropathy and optic atrophy (ANOA), 482 AUH deficiency, 1419, 1421–1422, 1428, 1429 Autism, 437 Autism spectrum disorder (ASD), 292 Autosomal dominant GTPCH deficiency, 332, 338, 349 Autosomal dominant inherited hyperinsulinism-hyperammonemia (HIHA) syndrome, 265, 284, 285, 288 Autosomal dominant MATI/III deficiency, 382 Autosomal dominant mental retardation type 34, 1016 Autosomal dominant spastic paraplegia type 13, 892 Autosomal recessive congenital ichthyosis type 5, 1013 type 9, 1012 type 10, 1013 Autosomal recessive cutis laxa syndromes, 455 Autosomal recessive dilated cardiomyopathy, 566 Autosomal recessive exostosin 2 deficiency, 1369 Autosomal recessive EXT2-CDG, 1369 Autosomal recessive GTP cyclohydrolase I deficiency, 335 Autosomal recessive hypercholesterolemia (ARH), 1041 Autosomal recessive 15 MAN1B1-CDG, 1357 Autosomal recessive mental retardation type 14, 1003 Autosomal recessive POGLUT1-CDG, 1375 Autosomal recessive spastic ataxia of Charlevoix-Saguenay, 892 Autosomal recessive spastic ataxia type 3, 855 Autosomal recessive spastic ataxia type 5, 892 Autosomal recessive spastic paraplegia type 26 (SPG26), 1017 type 28 (SPG28), 998 type 35 (SPG35), 1015 type 39, 1000–1001 type 46, 1015 type 54 (SPG54), 999 type 56, 1019 Autosomal recessive spinocerebellar ataxia type 2, 892 Axial hypotonia, 456 Axonal Charcot-Marie-Tooth type 2A2A and 2A2B, 891 type 2K, 891 B Barth syndrome, 21, 56, 157, 173, 992, 1417 Barth (MGA2) syndrome, 392 Batten-Spielmeyer-Vogt disease, 1209 BBGD, 540 BCKDC phosphatase deficiency, 392 Beckwith-Wiedemann syndrome, 717, 723, 731, 732 Behr syndrome, 891 Benign recurrent intrahepatic cholestasis (BRIC), 1142 Berardinelli-Seip syndrome, 1006 Beta amino acid degradation, disorders of, 437 Beta amino acid disorders, 445–447 Beta amino acid synthesis, disorders of, 436 β-aminoisobutyric acid aminotransferase deficiency, 48 Beta-aminoisobutyric aciduria, 437–438 Beta and gamma amino acid dipeptide metabolism, disorders of, 438 β-alaninemia, β-aminoisobutyric acid aminotransferase deficiency, 48 β-1,3-galactosaminyltransferase 2 deficiency, 1362 β-galactosylceramidase deficiency, 139 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency, 1100 11 β-hydroxylase deficiency, 1078, 1085 3 β-hydroxysteroid dehydrogenase deficiency, 1078, 1084, 1086

1469 β-ketothiolase deficiency, 54, 61, 136, 417 prenatal diagnosis, 420 β-mannosidase deficiency, 1252, 1254 β-mannosidosis deficiency, 1252 Beta-enolase deficiency, 32, 36 Beta-galactosidase deficiency, 1269 Beta-1,3-galactosyltransferase 6 deficiency, 1368 Beta-1,4-galactosyltransferase 1 deficiency, 1359 Beta-1,4-galactosyltransferase 7 deficiency, 1367 Beta-glucosidase deficiency, 76 Beta-glucuronidase deficiency, 1269 Beta-1,3-glucuronyltransferase 3 deficiency, 1368 17-beta-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency, 393, 851 Beta-ketothiolase deficiency, 11, 14, 29, 173, 393, 423 Beta-mannosidosis, 76, 81 Beta-ureidopropionase deficiency, 194, 196, 200, 435, 437, 445, 450, 451 B3GALNT2-CDG, 33, 1339, 1362 B3GALT6-CDG, 1340, 1368 B4GALT1-CDG, 29, 33, 1337, 1339, 1344, 1359 B4GALT7-CDG, 1337, 1340, 1367 B3GALTL-CDG, 1337, 1376 B3GAT3-CDG, 1340, 1368 B4GAT1-CDG, 33, 1339 B3GLCT-CDG, 1341 β-1,3-glucuronyltransferase/α-1,3-xylosyltransferase deficiency LARGE1-CDG, 1366 β-1,4-glucuronyltransferase 1 deficiency B4GAT1-CDG, 1366 BH4 deficiencies, 332, 333, 342, 351 Bilateral striatal necrosis (SLC25A19), 537–540, 768, 779, 787, 789 Bile acid biosynthesis, disorders of, 1306 Bile acid-CoA:amino acid N-acyltransferase (BAAT) deficiency, 34, 1305, 1306, 1310, 1315 Bile acid-CoA ligase deficiency, 1105 Bile acid deficiency, 1096 Biotin and thiamine basal ganglia disease, 23 Biotine and thiamine responsive basal ganglia disease, 122 Biotinidase deficiency, 4, 9, 12, 23, 61, 67, 121, 173, 174, 178, 529–536 Biotin-thiamine-responsive basal ganglia disease (BTBGD), 537, 538, 540, 544, 545 Biotin transporter defect, 530, 534 Birk-Landau-Perez syndrome, 608, 611, 612, 618–620 Bitemporal narrowing, 463 Blood-brain barrier glucose transporter 1 deficiency (GLUT1-D), 651 Blue sclerae, 462 BOLA3 deficiency, 23, 119, 482, 485, 490, 491 Boucher-Neuhauser syndrome, 1000–1001 Brain dopamine-serotonin vesicular transport disease, 314 Brain glucose transporter SLC45A1 deficiency, 651 Branched-chain amino acid metabolism disorders, 391–430 Branched-Chain Amino Acid (BCAA) Transferase (BCAT1 and BCAT2) Deficiency, 392, 395, 416, 418, 419, 424 signs and symptoms, 397 Branched-chain amino transferase 2 deficiency, 50, 118, 420 Branched-chain ketoacid dehydrogenase E1α deficiency, 118, 424 Branched-chain ketoacid dehydrogenase E1β deficiency, 118, 424 Branched-chain ketoacid dehydrogenase kinase deficiency, 395, 399, 419, 420, 422 Branched-chain ketoacid dehydrogenase phosphatase deficiency, 395, 399, 419, 420, 424 Branched-chain organic acidemias (BCOAs), 172–174, 176 Brown-Vialetto-Van Laere syndrome, 122, 548–550, 553 type 1, 551 type 2, 551

1470 BTBGD. See Biotin-thiamine-responsive basal ganglia disease (BTBGD) Bulbar syndrome, 640 Bulbous nose, 463 Burst-suppression, 473, 474 γ-Butyrobetaine hydroxylase deficiency, 941 C Cabbage-like breath odor, 370 CABC1/ADCK3 deficiency, 26 CACT deficiency. See Carnitine-acylcarnitine translocase (CACT) deficiency CAD-CDG, 1343, 1395 CAD trifunctional protein deficiency, 36, 193, 1395 Canavan disease, 56, 91, 111, 113, 143, 1402, 1405, 1412 CANT1-CDG, 1340 Carbamoyl phosphate synthetase (CPS) deficiency, 49, 176 Carbamoyl phosphate synthetase I (CPS1) deficiency, 22, 30, 48, 116, 264, 266, 268, 282, 284, 285, 287, 288 Carbohydrate disorders, 185, 186 Carbohydrate metabolism, 682, 684, 685 Carbohydrates disorders, 38 Carbonic anhydrase VA (CAVA) deficiency, 20, 22, 23, 266, 273, 282, 285, 286, 288 Cardiomyopathy, 931 Cardiomyopathy and deafness, 853 Cardiomyopathy and myopathy, 853 CARKD deficiency, 566 Carnitine acetyltransferase deficiency, 941 Carnitine/acylcarnitine deficiency, 766 Carnitine-acylcarnitine translocase (CACT) deficiency, 21, 23, 27, 32, 36, 67, 70, 71, 73, 135, 932, 934, 940, 950, 952, 954 Carnitine palmitoyl-CoA transferase 1 deficiency, 934 Carnitine palmitoyl-CoA transferase 2 deficiency, 934 Carnitine palmitoyltransferase 1A deficiency, 135, 934 Carnitine palmitoyltransferase 2 deficiency, 21, 32, 36, 135, 934, 939, 950 Carnitine palmitoyltransferase 2 deficiency, severe, 23 Carnitine palmitoyltransferase IC deficiency, 934, 938 Carnitine palmitoyltransferase I (CPT I) deficiency, 21, 66, 67, 71, 73, 931–932, 938, 952, 954 Carnitine palmitoyltransferase II (CPT II) deficiency, 65–67, 70, 73, 932, 952, 954 Carnitine transporter deficiency, 12, 14, 931, 934, 937 Carnitine uptake defect, 934 Carnosinase deficiency, 1434, 1441 Carnosinemia, 48 Cartilage-hair hypoplasia, 851 Catalytic phosphatidylinositol 3-kinase α subunit superactivity, 21, 126, 718, 729 Cataract 38, autosomal recessive, 892 Cataract syndrome, 458, 460, 461, 854, 855, 1019 Catel-Manzke syndrome, 1374 Cathepsin A deficiency, 140 Cathepsin C deficiency, 1235, 1237, 1238, 1242–1246 Cathepsin D deficiency (NCL Type 10), 1220 Cathepsin F deficiency, 1223–1224 Cathepsin K deficiency, 1237, 1238, 1242, 1244–1246 Cationic amino acid transporter 2 deficiency, 296, 300, 302, 304, 306 CAVA deficiency. See Carbonic anhydrase VA (CAVA) deficiency cblC-like adensoylcobalamin and methylcobalamin defect —HCFC1, 510, 511 —THAP11, 505 —ZNF143, 505 cblD disease, 36

Disorder Index Cbl deficiency, 507 cblC, 511 cblF, 511 cblJ, 511 cblX, 500 cblD-MMA/ HC, 511 CCA-adding tRNA-nucleotidyltransferase deficiency, 37, 850, 867 CCDC115-CDG, 30, 31, 34, 1343, 1344, 1392 CCDC115 deficiency, 1392 CCS deficiency, 608, 609, 619, 620 CDG. See Congenital disorder of glycosylation (CDG) CDPX2. See X-linked dominant sterol Δ8,Δ7-isomerase deficiency Centronuclear myopathy 1, 1172 CEP89 deficiency, 25, 803, 824 Ceramide synthase deficiency, 1012 Ceramide transfer protein superactivity, 1016 Cerebellar ataxia, 854, 1019 Cerebellar hypoplasia, 464 Cerebral Cr deficiency syndrome, 111–113 type 1, 116 type 2, 115 Cerebral folate deficiency (CFD), 516–519 Cerebral gigantism, 717 Cerebral, ocular, dental, auricular, and skeletal syndrome, 892 Cerebral tetrahydrobiopterin deficiency, 517 Cerebro-renal disease, 612 Cerebrotendinous xanthomatosis (CTX), 1096 Ceroid lipofuscinosis neuronal, 1, 1209, 1226 neuronal, 2, 1209, 1211–1212 neuronal, 3, 1209, 1213 neuronal, 5, 1209, 1215 neuronal, 6, 1209, 1217 neuronal, 7, 1209, 1218 neuronal, 8, 1209, 1219–1220 neuronal, 10, 1210, 1221 neuronal, 11, 1210, 1222 neuronal, 12, 1210, 1223 neuronal, 13, 1210, 1224 neuronal, 14, 1210, 1225 neuronal, 4A, 1209 neuronal, 4B, 1209, 1214–1215 neuronal, cathepsin D-deficient, 1209 neuronal, 8, Northern epilepsy variant, 1209, 1219 C1GALT1C1-CDG, 1374 C1GATLT1C1-CDG, 1341 CGI-58 deficiency, 1008 Chanarin-Dorfman syndrome, 31, 33, 1008 Charcot-Marie-Tooth (CMT) disease, 1155 4A, 1301 2B (RAB7A), 1163 4 J (FIG4), 1170 2 M (DNM2), 1173 type 2D, 855 type 4G, 652 X-linked dominant, 744 CHCHD10 deficiency, 32 Childhood-onset lethal metabolic disorder, 564 Childhood-onset optic atrophy type 1, 891, 896, 909 CHILD syndrome. See X-linked dominant sterol-4 α-carboxylate 3-dehydrogenase deficiency Cholesterol 7 alpha-hydroxylase deficiency, 30, 1083 Cholesterol side-chain cleavage deficiency, 1083 Cholesteryl ester transfer protein deficiency (CETP), 1046 Choline kinase β deficiency (CHKB), 995, 996 Chondrodysplasia punctata, 1073

Disorder Index Chondroitin sulfate N-acetylgalactosaminyltransferase 1 deficiency, 1371 Chondroitin sulfate synthase 1 deficiency, 1370 Chondroitin 4-sulfotransferase 1 deficiency, 1370 Chondroitin 6-sulfotransferase deficiency, 1370 Chorioretinal degeneration, 464 Chromosomal abnormality, 1420 Chronic progressive external ophthalmoplegia with myopathy, 854 Chronic tubulointerstitial nephropathy, 852 CHST3-CDG, 1340, 1370 CHST6-CDG, 1340, 1372 CHST11-CDG, 1340, 1370 CHST14-CDG, 1340, 1371 CHSY1-CDG, 1337, 1340, 1370 Chylomicron retention disease, 29, 30, 33, 1044 Citrin deficiency, 19, 22, 30, 48, 50, 266, 272, 282, 284–288, 767, 777–778, 787, 789 Citrullinemia, 11, 14, 766 type I, 42, 48, 266 type II, 48, 50, 767 CK syndrome. See X-linked recessive sterol-4 α-carboxylate 3-dehydrogenase deficiency Classical iron deficiency anemia, 634 Classical phenylketonuria, 17, 19, 20 Classic galactosemia, 48 Classic homocystinuria, 117 CLN8 disease, late infantile variant, 1209 CLN8 disease, progressive epilepsy with mental retardation, 1209 CLN6 late infantile variant, 1209 CLN7 Turkish variant, 1209 CLOVE syndrome, 731, 733 CLPB deficiency, 26, 38, 892, 902, 909, 1419, 1421, 1425, 1428 CLPP deficiency, 892, 903, 909 CMD2C, 566 CMP–sialic acid transporter deficiency, 1387 COA3 deficiency, 801 COA7 deficiency, 802 COA5 deficiency, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, 801 COA6 deficiency, cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4, 802 CoA synthase protein-associated neurodegeneration (CoPAN), 566 Cobalamin E/G defect, 11 Cobalamin metabolism disorders, 14 Coenzyme A synthase deficiency, 123, 566, 574 Coenzyme Q10 deficiency primary, 1, 917 primary, 2, 917 primary, 3, 917 primary, 4, 918 primary, 5, 918 primary, 6, 917 primary, 7, 917 primary, 8, 917 COG4-CDG, 31 COG6-CDG, 33 COG7-CDG, 33 COG8-CDG, 33 Cohen syndrome, 38, 139 Cole disease, 216, 218 Collodion-like skin, 454 Combined CI/CIV deficiency, 852 Combined d-2-And l-2-hydroxyglutaric aciduria, 767 Combined malonic and methylmalonic aciduria (CMAMMA), 394, 410, 420, 424, 429 Combined methylmalonic and malonic aciduria, 420 Combined MMA and MA, 20, 23, 27

1471 Combined oxidative phosphorylation deficiency type 1, 26, 851 type 2, 25, 851, 872 type 3, 26, 851 type 4, 26, 851 type 5, 23, 25, 851, 872 type 6, 26, 893, 907 type 7, 26, 852, 874 type 8, 854 type 9, 851 type 10, 850 type 11, 851, 873 type 12, 854, 877 type 13, 850 type 14, 855 type 15, 850 type 16, 851 type 17, 850 type 18, 893 type 19, 482 type 20, 855 type 21, 855 type 22, 803 type 23, 850 type 24, 854 type 25, 855 type 26, 850 type 27, 854, 877 type 28, 767, 774, 786, 788 type 29, 893 type 30, 850 type 31, 892 type 32, 851 type 33, 893 type 34, 851 type 35, 850 type 36, 851 Combined saposin deficiency, 1181 Complete and partial androgen insensitivity syndrome, 1079 Complex I assembly disorder, 799, 934 Congenital adrenal hyperplasia, 4, 9, 12 Congenital adrenal hyperplasia, 17-alpha-hydroxylase deficiency, 29 Congenital adrenal hyperplasia, 11-β-hydroxylase deficiency, 29 Congenital alactasia, 651 Congenital atransferrinemia, 627 Congenital bile acid synthesis defect, 31 Congenital cataracts, hearing loss, and low serum copper and ceruloplasmin, 611 Congenital central hypoventilation syndrome, 718 Congenital diarrhea type 7, 985, 1008 Congenital disorder of glycosylation (CDG), 21, 27, 29–31, 33, 34, 36–38, 104–105, 126, 185, 186, 1251, 1355, 1356, 1388, 1392 Congenital disorder of glycosylation SSR4-CDG, 1356 Congenital disorder of glycosylation, type IIn, 640 Congenital disorder of glycosylation, type IIp, 1391 Congenital erythropoietic porphyria, 1119, 1128 Congenital generalized lipodystrophy type 1, 1006 Congenital hyperinsulinism (CHI), 714, 723 Congenital hypophosphatasia, 34, 578, 580, 581, 584–586, 588 Congenital hypothyroidism, 12 Congenital lactase deficiency (CL-D), 651, 660, 685, 688 Congenital microcephaly, 455 Congenital muscular dystrophy, 995 Congenital myasthenic syndrome, 1348 Congenital myasthenic syndrome, without tubular aggregates-15 ALG14-CDG, 1348

1472 Congenital pernicious anaemia, 500 Congenital sucrase-isomaltase deficiency (CSI-D), 651, 661, 685, 688 Connective tissue disorder, 609 Constitutional AMP-activated protein kinase activation (AMPK-A), 21, 32, 653, 674, 686, 688 Copper metabolism disorders, 608 Copper-transporting ATPase α subunit deficiency, 124 Copper-transporting ATPase β subunit deficiency, 123 COQ8A deficiency, 918, 922 COQ8B deficiency, 918, 923 COQ10 deficiencies, 915–924 COQ2 deficiency, 917, 920 CoQ2 deficiency, 26, 32 COQ4 deficiency, 917, 921 COQ6 deficiency, 917, 921 COQ7 deficiency, 917, 922 COQ9 deficiency, 26, 29, 918, 923 Core 1 β-1,3-galactosyltransferase chaperone deficiency, 1374 C12orf65 release factor deficiency, 852 Cori disease, 653 Corneal N-acetylglucosamine 6-O-sulfotransferase deficiency, 1372 Corpus callosum agenesis with dysmorphism and fatal lactic acidosis, 851 Cortical atrophy, 458, 462, 464 Corticosterone methyl oxidase deficiency, 1085 Cortisone reductase deficiency (CRD), 1079, 1086 Costeff syndrome (MGA3), 56, 392–393, 891, 897, 909, 1417 Costello syndrome, 718, 731, 733 COX8A deficiency, 801 COX6A1 deficiency, Charcot-Marie-Tooth disease, recessive intermediate D, 801 COX6B1 deficiency, 801 COX7B deficiency linear skin defects with multiple congenital anomalies 2, 801 COX14 deficiency, 802 COX20 deficiency, 802 COX10 deficiency, Leigh syndrome due to mitochondrial COX4 deficiency, 802 COXFA4 deficiency, NDUFA4 deficiency, mitochondrial complex IV deficiency, nuclear type 21, 803 COX4I2 deficiency, Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis, 801 COXPD31, 892 CPT-I deficiency, 6, 12, 14 CPT-II deficiency, 12, 14 C1q-binding protein deficiency, 26, 32, 893, 907, 910 Creatine metabolism disorders, 12 Creatine transporter deficiency, 116, 236, 238 Crigler-Najjar syndrome type 1 (CN1), 1133–1135 type 2 (CN2), 1136 Crotonase deficiency, 417–420, 423, 427 CRPPA-CDG, 1339 CrT or SLC6A8 deficiency, 236, 243, 244 CSGALNACT1-CDG, 1340, 1371 CTH deficiency, 386 Cubilin deficiency, 36, 500, 502 Cutis laxa, 461, 462, 1390 Cutis laxa, autosomal recessive, type IID, 1390 Cutis laxa in proline defects, 454 CYP4F22 omega hydroxylase deficiency, 1013 CYP2U1 deficiency, 1019 Cystathionase deficiency, 49, 368–370, 374, 382 Cystathionine beta-synthase (CBS) deficiency, 49, 117, 368–370, 373, 379, 381, 384, 387, 388 Cystathioninuria, 20, 1437

Disorder Index Cysteinylglycine dipeptidase deficiency, 253 Cystinosis, 1287–1293 Cystinuria, 18–20, 41, 42, 45, 48, 49, 292, 310 type A, 295, 297, 302, 304, 305, 308, 309 type B, 295, 297, 302, 304, 305, 308, 309 Cytochrome c oxidase subunit 5A deficiency, 25 Cytochrome c oxidase subunit 6B1 deficiency, 130 Cytochrome c oxidase subunit 1 deficiency, 130 Cytosolic acetoacetyl-CoA thiolase deficiency, 27, 968, 969 Cytosolic acetyl-CoA carboxylase 1 deficiency, 1002 Cytosolic glycerol-3-phosphate deficiency, 963–965 Cytosolic glycerol-3-phosphate dehydrogenase deficiency, 767, 774, 786, 788, 959–961, 963 Cytosolic phosphoenolpyruvate carboxykinase deficiency (cPCK-D), 656, 680, 687, 689 Cytosolic phospholipase A2 α deficiency, 37 Cytosolic pyrimidine 5ʹ-nucleotidase deficiency, 193, 198 D Danon disease, 76, 654 DAPIT deficiency, 25, 804, 830 D βH deficiency. See Dopamine β-hydroxylase (DβH) deficiency D-bifunctional protein (DBP) deficiency, 1300, 1307–1309, 1313 DDOST-CDG, 1338, 1344, 1355 DDX58 superactivity, 218, 227 Deafness, autosomal recessive 89, 855 De Barsy syndrome, 266 7-Dehydrocholesterol reductase deficiency, 137, 1060, 1069 24-Dehydrocholesterol reductase deficiency, 1060, 1061, 1068, 1074 Dehydrodolichyl diphosphate synthase deficiency, 1381 Delayed myelination, 458, 464 Demyelinating Charcot-Marie-Tooth disease type 4A, 891 Deoxyguanosine kinase deficiency, 192, 195 Dermatan sulfate epimerase deficiency, 1371 Dermatan 4-sulfotransferase 1 deficiency, 1371 Desmosterolosis. See 24-Dehydrocholesterol reductase deficiency Developmental delay, 460–462, 474 DHDDS-CDG, 1342, 1344, 1381 DHPR deficiency. See Dihydropteridine reductase (DHPR) deficiency D-hydroxyglutarate dehydrogenase deficiency, 1404 D-2-hydroxyglutarate dehydrogenase deficiency, 1402 D-2-hydroxyglutaric aciduria (D2HGA) type I, 1401, 1402, 1404, 1407, 1412 type II, 744, 1401, 1402, 1404, 1407, 1412 Diabetes and deafness, 852, 853 Diabetes-associated protein deficiency, 804 Diabetes mellitus, 19, 854 Diabetes mellitus type I, 13 Diacylglycerol acyltransferase deficiency, 1008 Diacylglycerol kinase ε deficiency, 1001, 1002 Dibasic aminoaciduria, 48, 49 type 1, 292, 295, 299, 302, 304, 306 type 2, 266, 295 Dicarboxylic aminoaciduria, 48, 49, 292, 295, 298, 302, 304, 305 2,4-Dienoyl-CoA reductase deficiency, 67 2,4-Dienoyl-CoA reductase deficiency with hyperlysinemia (DECRD), 28, 566 Dietary hyperoxaluria, 1320 DiGeorge syndrome, 456 Dihydroceramide desaturase deficiency, 1013, 1014 Dihydrofolate reductase (DHFR) deficiency, 33, 36, 121, 517–518, 522, 525, 526 Dihydrolipoamide acetyltransferase deficiency, 126, 744 Dihydrolipoamide dehydrogenase deficiency, 422, 744 Dihydrolipoyl transacetylase deficiency, 24

Disorder Index Dihydrolipoyl transacylase deficiency, 424 Dihydroorotate dehydrogenase deficiency, 192, 193, 196, 197, 208 Dihydropteridine reductase (DHPR) deficiency, 117, 334, 337, 343, 346, 348 Dihydropyrimidinase deficiency, 193, 200, 435–437, 440, 450, 451 Dihydropyrimidine dehydrogenase deficiency, 193, 199, 210, 435, 436, 440, 450, 451 Dihydropyrimidinuria, 58, 193 Dilated cardiomyopathy, 852 Dilated cardiomyopathy with ataxia (DCMA syndrome), 891 Dimethylglycine (DMG), 1435, 1442 Dimethylglycine dehydrogenase deficiency, 86 Dimethylglycinuria, 19 Dipeptidase (DPEP) deficiency, 252, 254 Distal hereditary motor neuronopathy type 5A, 855 Divalent metal transporter 1 deficiency, 628, 632 Diverse organic acid disorders, 56 DK1-CDG, 1342, 1344, 1382 DLD deficiency, 744 DLP1 deficiency, 1307 DNA2 deficiency, 849, 862 DNA2 helicase deficiency, 32 DNAJC12 deficiency, 334, 339, 349 DNAJC19 deficiency, 37, 891, 899, 909, 1417, 1419, 1421, 1424 Docosahexanoic acid transporter deficiency, 934 Dolichol kinase deficiency, 1382 Dolichol-P-mannose synthase-2 deficiency, 31, 1383 Dol-P-Man utilization 1 deficiency MPDU1-CDG, 1342, 1384 Dopamine β-hydroxylase (DβH) deficiency, 20, 314–316, 320, 325–327 Dopamine-serotonin vesicular transport defect, 321 Dopamine transporter deficiency syndrome (DTDS), 316, 321, 325–327 Dopa-responsive dystonia (DRD) deficiency, 344, 346, 349 Dowling–Degos disease 4, 1375 DPAGT1-CDG, 33, 1338, 1344, 1346–1347 DPM1-CDG, 33, 1342, 1344, 1383 DPM2-CDG, 33, 1342, 1344, 1383 DPM3-CDG, 33, 1342, 1344, 1384 DRD deficiency. See Dopa-responsive dystonia (DRD) deficiency Drooling, 608 Drug-resistant seizures, 456 Drummond syndrome, 18 DSE-CDG, 1340, 1371 DTDS. See Dopamine transporter deficiency syndrome (DTDS) Dubin-Johnson syndrome, 1137–1139 Dursun syndrome, 653 Dynamin-like protein 1 deficiency, 891, 1301 Dysarthria, 608 Dysbetalipoproteinemia, 1042 Dyschromatosis symmetrica hereditaria, 215, 217, 225 Dysequilibrium syndrome type 4, 1019 Dysgraphia, 608 Dysmorphism, 456 Dystonia, 455 Dystonia deafness syndrome, 891 Dystonic rigidity, 608 E EAAT1 deficiency, 296, 302, 306, 308, 310 Early childhood-onset progressive leukodystrophy, 1013 Early fatal progressive hepatoencephalopathy, 851 Early infantile epileptic encephalopathy-3, 768 Early infantile epileptic encephalopathy type, 767 Early-onset encephalopathy with brain oedema, 564

1473 Early-onset Parkinson disease type 2, 892 type 6, 892 Early-onset seizures, 454 Ecto-5ʹ-nucleotidase deficiency, 216, 218, 230 Ectonucleotide pyrophosphatase/phosphodiesterase 1 deficiency, 216, 218, 229 Ectonucleotide pyrophosphatase/phosphodiesterase 1 dimerization deficiency, 218, 230 E3 (lipoamide dehydrogenase) deficiency, 392, 419, 420, 424 EGF domain-specific O-linked N-acetylglucosamine transferase deficiency, 1375 Ehlers-Danlos syndrome, 612 Electron transfer flavoprotein (ETF) deficiency, 70, 551 Electron transfer flavoprotein dehydrogenase deficiency, 551 Electron transfer flavoprotein subunit or dehydrogenase deficiency, 122 Elevated lipoprotein(a), 1042 Encephalomyopathic type with methylmalonic aciduria, 850 Encephalomyopathy, respiratory failure and lactic acidosis, 851 Encephalomyopathy with methyl malonic aciduria, 745 Encephalopathy, 992 Encephalopathy due to defective mitochondrial and peroxisomal fission type 2, 891 Encephalopathy, epileptic, 460 Encephalopathy, progressive, 464 Endocrinopathies, 12 End-stage renal failure (ESRF), 1324 Enolase β deficiency (GSD XIII), 652, 669 Enoyl-CoA reductase deficiency, 1004 Enteric, absorptive hyperoxaluria, 1322 ε-N-trimethyllysine hydroxylase deficiency, 940 EOGT-CDG, 1341, 1375 EPG5 deficiency, 138 E1-phosphatase deficiency, 741 Epilepsy, intractable, 460 Epileptic encephalomyopathy, 766 Epileptic encephalopathy, early infantile, 745, 1387 Epileptic encephalopathy, early infantile, 50 CAD-CDG, 193, 196, 1387 Epileptic encephalopathy with intractable seizures, 456 Epiphyseal, vertebral, ear, nose, plus associated malformations (EVEN-plus) syndrome, 482, 490, 892 Episodic ataxia type 6, 292, 296, 310 EPM2A-D (Laforin-D), 687, 689 EPM2B-D (Malin-D), 687, 689 Equilibrative nucleoside transporter 1 deficiency, 216, 218, 230 Equilibrative nucleoside transporter 3 deficiency, 214, 216, 218, 230 Erythrocyte adenosine monophosphate deaminase 3 deficiency, 194, 202 Erythrocyte ITPase deficiency, 195 Erythrocytic microcytosis, 850 Erythroid 5-aminolevulinate synthase deficiency, 35, 37 Erythropoietic protoporphyria, 1122, 1127–1128 Erythropoietic protoporphyria type 2, 37 Essential fructosuria (FK-D), 19, 651, 665 Estrogen resistance, 22, 1079, 1087 Ethanolaminephosphotransferase 1 deficiency, 994, 995 Ethylmalonic aciduria, 54, 934 Ethylmalonic encephalopathy (ETHE1 deficiency), 56, 67, 368, 383, 386, 388, 597 experimental treatment, 387 Exercise induced hyperinsulinemic hypoglycaemia, 716, 722, 731, 732 Exercise intolerance, 852 Exercise intolerance and complex III deficiency, 854 Exercise intolerance, muscle pain and lactic acidemia, 854

1474 Exomphalos–macroglossia–Gogantism syndrome, 717 Exostosin 1 congenital defects of glycosylation (EXT1-CDG), 1336–1337 Exostosin 2 congenital defects of glycosylation (EXT2-CDG), 1336–1337 Exostosin 1 deficiency, 1368 Exostosin 2 deficiency, 1369 Exostosin-like glycosyltransferase 3 deficiency, 1369 EXT1-CDG, 1340, 1368 EXT2-CDG, 1340, 1369 EXTL3-CDG, 1340, 1369 F Fabry disease, 27, 76, 82, 140, 1181, 1183, 1185, 1191, 1199 Facial dysmorphism, 463 Facio-cutaneo-skeletal syndrome, 718 FAD transporter deficiency, 560 Faisalabad histiocytosis, 216, 218 Familial chilblain lupus, 215, 218, 232 type 1, 217, 222 type 2, 217, 224 Familial chylomicronemia syndrome, 1044 Familial combined hypolipidemia, 1043 Familial dysalbuminemic hyperzincemia, 611, 620 Familial glucocorticoid deficiency, 1080 Familial hypercholesterolemia heterozygous (LDLR), 1040 Familial hypercholesterolemia homozygous, 1041 Familial hyperinsulinemic hypoglycaemia type 1, 716 type 2, 716 type 3, 652, 716 type 4, 716 type 5, 716 type 6, 266, 716 type 7, 716 Familial hypobetalipoproteinemia, 1043 type 1, 29, 37 type 2, 29, 37 Familial LCAT deficiency complete, 1045 partial, 1046 Familial LCAT deficiency (complete), 30 Familial partial lipodystrophy type 4, 1009 type 6, 1010 Familial renal glucosuria type 1, 651 type 2, 651 Familial renal iminoglycinuria, 49, 50 Fanconi-Bickel syndrome (FBS), 19, 20, 22, 30, 31, 34, 174, 651, 662–663, 691, 694 Farber disease, 76, 1181–1182 Farber lipogranulomatosis, 76 Fasting hypoglycemia, 931 FASTKD2 deficiency, 25, 803, 826 Fatal cardiomyopathy, 852 Fatty acid hydroxylase-associated neurodegeneration (FAHN), 1015 Fatty acid 2-hydroxylase deficiency, 136, 1015 Fatty acid oxidation disorder (FAOD), 1420 Fatty acid transport protein 4 deficiency, 948 Fatty aldehyde dehydrogenase deficiency, 135 Fazio-Londe syndrome, 57, 548, 550, 553 Fazio Londe syndrome with RFVT2 and RFVT3 deficiency, 549 FBP-D. See Fructose-1,6-bisphosphatase deficiency (FBP-D) FBS. See Fanconi-Bickel syndrome (FBS)

Disorder Index FBXL4 deficiency, 23, 25, 28, 38, 849, 863 Feeding difficulties, 474 Fellman disease; Björnstad syndrome Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis and Early death syndrome, 800 Ferredoxin 2 (FDX2) deficiency, 23, 32, 35, 36, 482, 488, 491 Ferredoxin reductase (FDXR) deficiency, 482, 489, 492 Ferritin heavy chain dysregulation, 627, 631 Ferritin light chain deficiency, 627 Ferritin light chain dysregulation, 627, 631 Ferritin light chain superactivity, 124, 627 Ferrochelatase deficiency, 35, 37 Ferroportin deficiency, 627 Ferroportin 1 deficiency, 630 FIS1 deficiency, 1301, 1307 FKRP-CDG, 33 FKRP-CDG A, 1339 FKRP-CDG B, 1339 FKRP-CDG C, 1339 FKTN-CDG, 33 FKTN-CDG A, 1339 FKTN-CDG B, 1339 FKTN-CDG C, 1339 Flavin adenine dinucleotide synthase (FADS) deficiency, 548, 550, 551, 557, 560, 561 early-onset form, 551, 554, 560 late-onset form, 548, 551, 554, 560 Flavin adenine dinucleotide synthetase deficiency, 57 Flippase of Man5GlcNAc2-PP-Dol deficiency, 1350 Focal segmental glomerulosclerosis and dilated cardiomyopathy, 854 Folate-dependent recurrent megaloblastic anemia, 518 Folate receptor alpha (FRα) deficiency, 121, 173 Folate receptor alpha deficiency (FOLR1), 516, 518, 520, 524–526 Fontaine syndrome, 766, 767 Formiminoglutamic aciduria, 49, 57, 518 5-Formyltetrahydrofolate cycloligase, 518 FOXA2, 718 FOXA2/HNF3, 731, 733 FOXRED1 deficiency, 799 Frataxin deficiency, 120 Frataxin (FXN) deficiency, 482, 490 Free sialic acid storage disease, 1256 Friedreich ataxia, 120, 479, 482, 490 Frontotemporal dementia, 1162, 1164 Frontotemporal dementia chromosome 3 linked (CHMP2B), 1173 Fructokinase deficiency (FK-D), 651, 655, 684, 685, 688, 692 Fructose-1,6-bisphosphatase deficiency (FBP-D), 21, 23, 30, 35, 654–656, 684, 687, 689, 692 Fructose metabolism, 655, 659, 691 Fructose-1-phosphate aldolase deficiency, 20, 30, 31, 34, 651, 655 Fucosidosis, 76, 81, 141, 1252, 1255 Fumarase deficiency, 24, 28, 38, 740, 745, 755, 756, 758–760 Fumarase deficiency, tumoral phenotype, 756 Fumarate hydratase deficiency, 745 Fumarate hydratase deficiency, tumoral phenotype, 745 Fumaric aciduria, 55, 745 Fumarylacetoacetase deficiency type I, 355 FUT8-CDG, 1339, 1344, 1359 G GABA disorders, 448 GABA receptor subunit deficiencies, 439 GABA transaminase deficiency, 48, 49, 173, 180, 435, 438, 441, 450, 451 GABA transporter deficiency, 435, 439, 442, 450, 451

Disorder Index GABA type A receptor α1 subunit deficiency, 435, 442, 450, 451 GABA type A receptor α6 subunit deficiency, 435, 443, 450, 451 GABA type A receptor β1 subunit deficiency, 435, 443, 450, 451 GABA type A receptor β2 subunit deficiency, 435, 443, 450, 451 GABA type A receptor β3 subunit deficiency, 435, 443, 450, 451 GABA type A receptor δ subunit deficiency, 435, 443, 450, 451 GABA type A receptor γ2 subunit deficiency, 435, 443, 450, 451 GABA type B receptor subunit 2 deficiency, 435, 444 Galactokinase deficiency (GALK-D), 19, 651, 655, 663, 685, 688, 691 Galactosaemia, 664 type 1, 651 type 2, 651 type 4, 651 Galactose and fructose metabolism disorders, 651 Galactose epimerase deficiency (GALE-D), 651, 685, 688, 691, 692 Galactose metabolism, 655, 658, 691–692 Galactosemia, 9, 12, 17, 19, 125 Galactose mutarotase (GALM) deficiency, 5 Galactose mutarotase deficiency (GALM-D), 651, 663, 685, 688, 691 Galactose-1-phosphate uridyltransferase deficiency (GALT-D), 22, 31, 36, 651, 655, 685, 688, 691, 696 Galactosialidosis, 27, 76, 81, 173, 1201, 1252, 1253 GALK-D. See Galactokinase deficiency (GALK-D) GALT-D. See Galactose-1-phosphate uridyltransferase deficiency (GALT-D) GALTNT3-CDG, 1341, 1374 Gamma amino acids disorders, 438 Gamma-glutamylcysteine synthetase deficiency, 36, 38, 256 Gamma glutamyl transpeptidase deficiency, 47 GANAB-CDG, 1339, 1344, 1357 Gangliosidoses, 1178 GATA1 deficiency, 37–39 Gaucher disease, 29, 35, 37, 38, 76, 81, 82, 173, 174, 1178–1180, 1197 Gaucher disease-like disorder due to saposin C deficiency, 1190 Gb3 synthase deficiency, 1018 GCK-HI (HHF3), 686, 688 GCS1-CDG. See Glucosidase 1 deficiency GCS1-CDG GD1a_GT1b synthase deficiency, 1017 GDAP1 deficiency, 134, 891, 895, 909, 1307 GDP-fucose transporter deficiency, 1388 GDP-Man:Dol-P mannosyltransferase 3 deficiency, 1384 GDP-Man:Dol-P mannosyltransferase subunit 1 deficiency, 1383 GDP–mannose pyrophosphorylase B deficiency, 1386 Genée-Wiedemann syndrome, 193 General arterial calcification of infancy type 1, 216, 218, 232 type 2, 216, 218, 228, 232 Generalized edema, 596 Generalized hypoxic-ischemic encephalopathy, 596 Genetic syndrome, 1420 Geranylgeranyl pyrophosphate synthase deficiency, 1060 GFER deficiency, 26, 891, 900, 909 GFPT1-CDG, 33, 1342, 1385 γ-Glutamylcysteine (GCLC) deficiency, 252 γ-Glutamylcysteine synthetase (GCLC) deficiency, 252, 254, 260 γ-Glutamyl transpeptidase (GGT1) deficiency, 252–254 Ghosal hematodiaphyseal dysplasia (GHDD) syndrome. See Thromboxane synthase deficiency Gilbert syndrome, 1136 GKD. See Glycerol kinase deficiency (GKD) Global cerebral hypomyelination, 292 Global cerebral hypomyelination due to AGC1 defect, 292 Globoid cell leukodystrophy. See Krabbe disease Glucagon receptor defect, 48 Glucocorticoid and mineralocorticoid deficiency, 960 Glucocorticoid deficiency type 4, 566

1475 Glucocorticoid deficiency type 5, 893 Glucocorticoid deficiency type 4 with or without mineralocorticoid deficiency (GCCD4), 565, 566 Glucocorticoid receptor deficiency, 29 Glucocorticoid resistance, 1080, 1088 Glucocorticoid-suppressible hyperaldosteronism, 1079, 1085 Glucokinase deficiency (GCK-D) (MODY2), 22, 667, 686, 688 Glucokinase superactivity (HHF3), 21, 652, 667, 716, 720, 731, 732 Gluconeogenesis disorder, 654, 656 Glucose-galactose malabsorption, 651 Glucose-6-phosphatase catalytic subunit-3 deficiency, 37, 38, 656, 676, 1386 Glucose-6-phosphatase deficiency, 23, 29–31, 35, 653 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 12, 33, 36, 701 Glucose-6-phosphate isomerase deficiency (G6PI-D), 652, 667 Glucose-6-phosphate translocase deficiency, 21, 23, 30, 34, 38, 653 Glucose-6-phosphate transporter deficiency, 29, 125 Glucose transporter-1 deficiency (GLUT1-D), 36, 651, 662, 682, 685, 688–691, 696 Glucose transporter 2 deficiency (FBS), 651, 662–663, 683 Glucosidase 1 deficiency GCS1-CDG, 1339, 1357 Glucosyltransferase 2 deficiency, 1354 Glucosyltransferase 1 deficiency ALG6-CDG, 727, 1353 Glutamate aspartate transporter deficiency, 296, 301 Glutamate-cysteine ligase deficiency, 254 Glutamate dehydrogenase superactivity, 20, 22, 266, 278, 716, 721, 731, 732 Glutamate formiminotransferase-cyclodeaminase deficiency (FIGLUUria), 1434, 1441 Glutamate formimino transferase deficiency (FTCD), 67, 72, 516–519, 522, 526 Glutaminase deficiency, 49, 166, 454, 455, 457, 460 Glutaminase hyperactivity, 455, 457, 460 Glutamine deficiency, 455, 458 Glutamine:fructose-6-phosphate transaminase deficiency, 1385 Glutamine synthase deficiency, 49 Glutamine synthetase (GS) deficiency, 22, 265, 266, 278, 282, 285, 288, 457, 460 Glutaredoxin 5 deficiency (GLRX5), 23, 35, 36, 120, 482, 486, 490, 491 Glutaric acidaemia type I, 1402 Glutaric acidemia type I, 67 Glutaric aciduria type I, 10, 11, 54, 100, 101, 143, 1400, 1402, 1403, 1406, 1409, 1412 type II, 19, 122, 549, 1411 type III, 54, 1411, 1436–1437, 1443 Glutaryl-CoA dehydrogenase deficiency, 67, 143, 1403 Glutathione metabolism disorders, 11, 252 Glutathione peroxidase 4 deficiency, 254, 258 Glutathione reductase deficiency, 252, 254, 258 Glutathione synthetase (GSS) deficiency, 36, 38, 251, 252, 260, 261, 1438 Glutathione synthetase (GSS) deficiency, mild, 254, 256, 259 Glutathione synthetase (GSS) deficiency, severe, 23, 27, 252, 254, 257, 259 Glutathionuria, 20, 254, 255 GLUT2-D (FBS), 688 Glycerate kinase deficiency (GLYCTK-D), 655, 960–965 D-Glyceric acidemia, 961 D-Glyceric aciduria, 56 Glycerol kinase deficiency (GKD), 56, 959–961, 963–965, 1438– 1439, 1444 Glycerol kinase deficiency, isolated, 962 Glycerol kinase deficiency, isolated GK, 21 Glycine encephalopathy, 41, 42, 49

1476 Glycine metabolism, disorders of, 469–477 Glycine N-methyltransferase (GNMT) deficiency, 30, 49, 367–368, 370, 371, 381–383, 388 Glycine transporter defect, 471 Glycine transporter 1 deficiency, 474 Glycine transporter GLYT1 encephalopathy, 472 Glycogen branching enzyme deficiency, 31, 125, 653 Glycogen debranching enzyme deficiency, 653 Glycogenolysis, 655–656 Glycogen storage disease type 14, 717, 731, 732 type I, 21 type I a, 21 type II b, 31 type III, 21, 30 Glycogen storage disorders (GSDs), 655–657, 684, 691, 692, 694, 695, 1420, 1451 ALDOA-D, 695 G6PC3-D, 697 GSD-0a (GSD-0a), 653, 671, 686, 688, 692 GSD-0b (GSD-0b), 653, 671, 686, 688, 695, 696 GSD-I, 677, 690, 694 GSD-I non-a, 653 GSD-Ia, 653, 676, 686, 689, 692, 697 GSD-Ib, 653, 686, 689, 692–694, 697 GSD-IIa, 654, 679, 686, 689, 696–698 GSD-IIb, 654, 679, 687, 689, 698 GSD-III, 653, 675, 686, 689, 692, 693, 695–697 GSD-IIIa, 694 GSD-IV, 653, 672, 686, 688, 696 GSD-IXa, 653, 673, 686, 688, 697 GSD-IXa-c, 694 GSD-IXb, 653, 673, 686, 688, 695, 697 GSD-IXc, 653, 673–674, 686, 688, 693, 697 GSD-IXd, 653, 672, 686, 688, 695, 696 GSD-V, 653, 674, 686, 688, 695–697 GSD-VI, 653, 675, 686, 689, 694, 697 GSD-VII, 668, 686, 688, 695, 696 GSD-X, 652, 669, 686, 688, 695, 696 GSD-XI, 652, 670 GSD-XII, 668 GSD-XIII, 652, 686, 688, 695, 696 GSD-XIV, 695 GSD-XV (PGBM2), 653, 671, 686, 688, 695, 696 LDHA-D, 695, 696 PGK-D, 695, 696 Glycolate oxidase 1 deficiency, 1325 Glycolysis disorder, 655 Glycosylasparaginase deficiency, 1252 Glycosylphosphatidylinositol deficiency, 1335–1337 Glyoxylate reductase/hydroxypyruvate reductase (GRHPR) deficiency, 27, 34, 1320 GLYT2 transporter deficiency, 302 GM1 gangliosidosis, 76, 139, 1186 GM2 gangliosidosis, 139, 1178, 1288 AB variant, 1183, 1185, 1188, 1194 B-variant, 1183 O-variant, 1183 type I, 76, 81 type II, 76, 81 GM2/GD2 synthase deficiency, 1017, 1018 GMPPA-CDG, 1343, 1344, 1386 GMPPB-CDG, 33, 36, 1343, 1344, 1387 GM3 synthase deficiency, 1017, 1018 GNE-CDG, 1336, 1337 GNE myopathy, 33, 1252

Disorder Index Goldberg syndrome, 76 Gorlin–Chaudhry–Moss syndrome, 766, 767 GPAA1-CDG, 34, 1342, 1380 G6PC3-CDG, 1343, 1386 G6PC3-D, 686, 689 G6PI-D, 686, 688 GPIHBP1 deficiency, 30 GRACILE syndrome, 24, 28, 35, 800, 819 Growth hormone deficiency, 855 Growth retardation, 463 GS deficiency. See Glutamine synthetase (GS) deficiency GSDs. See Glycogen storage disorders (GSDs) GTP cyclohydrolase I (GTPCH) deficiency, 332, 334, 346, 347 GTP-specific succinyl-CoA ligase α subunit deficiency, 24, 28, 31, 55, 127, 744, 753, 864 Guanidinoacetate methyltransferase deficiency, 27, 115, 236, 237 Gyrate atrophy of the choroid and retina, 236, 238, 239 H Haemolytic anaemia due to hexokinase deficiency (HK1-D), 652, 665, 686, 688 Haemolytic anaemia due to triosephosphate isomerase deficiency, 652 Haemolytic anaemia, nonspheric, due to GPI deficiency, 652 Haim–Munk syndrome (HMS), 1237, 1238 Haptocorrin deficiency (HCD), 500, 502, 511 Harel-Yoon syndrome, 893 Hartnup disorder, 18, 41, 42, 45, 48, 292, 295, 296, 302, 305, 309, 565, 566, 569, 574 Hawkinsinuria (HAWK), 19, 49, 53, 355, 357, 358, 363 Hematological disorder, 1420 Heme oxygenase 1 deficiency, 37 Hemoglobin, 12 Hemoglobin H, 12 Hemoglobinopathies, 12 Hemoglobin SC disease, 12 Hemojuvelin deficiency, 627 Hemolytic anemia due to glutathione reductase deficiency, 254 Heparan-N-sulfatase deficiency, 78, 80, 1269 Heparan sulfate N-deacetylase N-sulfotransferase 1 deficiency NDST1-CDG, 1340, 1372 Heparan sulfate 6-O-sulfate transferase 1 deficiency, 1372 Heparan sulfate 6-O-sulfotransferase 2 deficiency, 27 Hepatic glycogen phosphorylase deficiency, 653 Hepatic glycogen synthase deficiency, 653 Hepatic lipase deficiency, 30, 1044 Hepatic phenylalanine-4-hydroxylase (PAH) deficiency, 332, 333, 342 Hepatic phosphorylase kinase α2 subunit deficiency, 21, 29–31, 653 Hepatic phosphorylase kinase γ2 subunit deficiency, 21, 30, 31, 653 Hepatocyte nuclear factor-1α deficiency, 716, 731, 732 Hepatocyte nuclear factor-4α deficiency, 716, 731, 732 Hepatocyte nuclear factor 4-alpha loss-of-function mutations, 716, 722 Hepatoerythropoietic porphyria, 1120 Hepatolenticular degeneration, 611 Hepatomegaly, 930–931 Hepatorenal tyrosinemia, 355 Hepcidin deficiency, 627 Heredetary hemachromatosis, 124 Hereditary ceruloplasmin deficiency, 124, 627, 631 Hereditary coproporphyria, 1120 Hereditary D-lactic aciduria, 652 Hereditary dopamine transporter deficiency syndrome, 314 Hereditary folate malabsorption, 516, 518, 520, 524, 525 Hereditary fructose intolerance (HFI), 19, 48, 172, 174, 179, 651, 655, 665, 692, 696 Hereditary glutathione reductase (GSR) deficiency, 252

Disorder Index Hereditary hemochromatosis (HH), 35, 625 type 1, 22, 31, 627, 629 type 2A, 627 type 2a, 22, 630 type 2B, 627 type 2b, 22, 630 type 3, 22, 627, 630 type 4, 627 type 5, 627 Hereditary inclusion body myopathy, 1251 Hereditary intrinsic factor deficiency (IFD), 500, 502 Hereditary L-ferritin deficiency, 627 Hereditary motor and sensory neuropathy, Russe type, 666 Hereditary motor and sensory neuropathy type 6B, 891 Hereditary myopathy with lactic acidosis, Swedish type myopathy with exercise intolerance (HML), 482 Hereditary orotic aciduria, 193 Hereditary paraganglioma syndrome type 2, 799 type 3, 799 type 5, 799 Hereditary paraganglioma syndrome type 1 Cowden syndrome type 3, 799 Hereditary paraganglioma syndrome type Cowden syndrome type 2, 799 Hereditary spastic paraplegia 9, 266 Hereditary spastic paraplegias (HSPs), 1156 Hereditary transferrin deficiency, 628 Hereditary tyrosinemia, 355 Hereditery Leiomyomatosis, 745 Hers disease, 653 Hexokinase 1 mutation, 716 HFI. See Hereditary fructose intolerance (HFI) High-dose pantothenate therapy, 574 HIHA syndrome. See Autosomal dominant inherited hyperinsulinismhyperammonemia (HIHA) syndrome Histidinemia, 11, 19, 20, 49, 1433, 1441 Histiocytosis lymphadenopathy plus syndrome, 218 HMGL deficiency, 971 HNF1a deficiency, 722 HNF1-alpha deficiency, 20 HNF4-alpha deficiency, 20 HNF3B, 718 HOIL1 interacting protein deficiency (HOIL1-IP-D), 37, 654, 677, 678, 686, 689 Holocarboxylase synthase deficiency, 11 Holocarboxylase synthetase deficiency (HCSD), 23, 173, 174, 178, 529–536 Holocytochrome c synthase deficiency (HCCS), 804, 831 Homocarnosinosis, 49, 435 , 438, 444, 450, 451, 1434, 1441 Homocysteine remethylation disorders, 49 Homocystinuria, 9, 11, 14, 18, 20, 120 Homocystinuria, cblD-HC type, 500 Homocystinuria due to deficiency of MTHFR activity, 518, 526 Homogentisate 1,2-dioxygenase deficiency, 355 Homozygous familial hypobetalipoproteinemia, 1042 Hormone-sensitive lipase deficiency, 1010 HSD10 mitochondrial deficiency, 395 HSD10 mitochondrial disease, 20, 23, 27, 851 HSPA9 deficiency, 37, 482, 490, 491, 892, 903, 909 HSP60 deficiency, 26, 134, 892, 904, 909 HS6ST1-CDG, 1340, 1372 H syndrome, 216, 218 HTRA2 deficiency, 26, 38, 892, 905, 910, 1417, 1419, 1421, 1425 Hunter disease (MPS II), 1268, 1272 Hunter syndrome, 76

1477 Huppke-Brendel syndrome, 608–610, 619 Hurler–Scheie disease (MPS I), 1268, 1271 Hyaluronidase deficiency (MPS IX), 76, 78, 80, 1269, 1276 Hydrogen sulfide metabolism, disorders of, 365–389 Hydroxyacid oxidase 1 (HAO1) deficiency, 1321, 1325 3-Hydroxyacyl-CoA dehydratase 1 deficiency (HACD1), 1003 3-Hydroxyanthranilate 3,4-dioxygenase deficiency, 565, 566, 570, 574 4-Hydroxybutyric aciduria, 56 3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency, 29, 31, 34 3-Hydroxyisobutyrate dehydrogenase deficiency, 23, 27, 395, 404, 418, 420, 423, 427 3-Hydroxyisobutyric aciduria, 54, 393 3-Hydroxyisobutyryl-CoA deacylase deficiency, 27, 393, 404, 423, 427 β-Hydroxyisobutyryl-CoA deacylase deficiency, 418, 420 3-Hydroxyisobutyryl-CoA hydrolase deficiency, 395 3-Hydroxykynureninase deficiency, 569, 574 Hydroxykynureninuria, 1437 21-Hydroxylase deficiency, 137, 1078, 1084 3-Hydroxy-3-methylglutaric acidemia (HMG-CoA lyase deficiency), 393 Hydroxymethylglutaric aciduria, 418, 420, 422, 427 3-Hydroxy-3-methylglutaric aciduria, 19, 53, 405–406 3-Hydroxymethylglutaryl-CoA lyase deficiency, 11, 14 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency, 20, 22, 23, 27, 30, 61, 395, 968, 972 3-Hydroxy-3-methylglutaryl-CoA synthase deficiency, 21, 31, 968, 971 4-Hydroxy-2-oxoglutarate aldolase deficiency, 27 4-Hydroxy-2-oxoglutarate aldolase 1 (HOGA1) deficiency, 1322–1323 4-Hydroxyphenylpyruvate dioxygenase change of function, 355 4-Hydroxyphenylpyruvate dioxygenase deficiency, 355 Hydroxyproline dehydrogenase deficiency, 1440 Hydroxyprolinemia, 11, 49, 1433 15-Hydroxyprostaglandin dehydrogenase deficiency, 1029, 1031 11-β-Hydroxysteroid dehydrogenase type 2 deficiency, 29 Hyperammonemia, 264 Hyperammonemia–hyperornithinemia–homocitrullinuria (HHH) syndrome, 11, 48, 49, 58, 266, 282, 284, 285, 287, 288, 766, 767 Hyper-β-alaninemia, 435, 441 diagnosis, 450 signs and symptoms, 440–441 treatment of, 451 Hyper-β-aminoisobutyric aciduria, 435, 441 diagnosis, 450 signs and symptoms, 441 treatment of, 451 Hyper-beta-alaninemia, 437 Hyperbilirubinemia syndromes, 1133 Hyperbiliverdinemia, 18 Hypercalciuria, 18 Hypercalprotectinemia, 608, 611, 612, 618–621 Hypercholesterolemia due to ligand-defective apoB, 29 Hyperekplexia, 292, 305, 307, 310, 464, 474, 477 Hyperekplexia due to glycine transporter GLYT2 defect, 296, 302, 308 Hyperferritinemia-cataract syndrome, 35, 627 Hyperglycerolemia, 961 Hyperglyceroluria with mild platelet secretion defect, 961 Hyperglycinemia, lactic acidosis, and seizures (GCLAS), 482 Hyperglycinuria, 292, 295, 297, 302, 304, 305 Hyperhomocysteinemia, 379, 380 Hyper-IgD syndrome, 56, 1063

1478 Hyper-IgM syndrome type 2, 216–218, 232 type 5, 216–218, 232 Hyperinsulinemic hypoglycaemia-4, 720–721 Hyperinsulinemic hypoglycaemia-5, 721 Hyperinsulinemic hypoglycaemia (HI), 714 Hyperinsulinemic hypoglycaemia, exercise induced, 716, 722, 731 Hyperinsulinemic hypoglycemia 5, 20 Hyperinsulinism-hyperammonemia syndrome, 266, 716 Hyperintensities (T2) of the globus pallidus, 442 Hyperkinesia, 462 Hyperkinetic movement disorders, 456 Hyperlysinemia, 1435–1436, 1442 Hypermanganesaemia with dystonia 1 (HMNDYT1) (SLC30A10 deficiency), 637–641, 643 Hypermanganesaemia with dystonia 2 (HMNDYT2) (SLC39A14 deficiency), 639, 640, 643 Hypermanganesemia with dystonia type 1, 31, 35, 124 Hypermethioninemia, 366, 379, 381 Hyperornithinemia, 14 Hyperornithinemia (OAT deficiency and HHH syndrome), 11 Hyperoxaluria, 18, 19 Hyperoxaluria type 1, 1306, 1309, 1315 Hyperphenylalaninemia (HPA), 332, 333 Hyperprolinaemia type II, 58, 578, 579, 581–587 Hyperprolinemia, 456 type I, 49, 50, 454, 456, 1432–1433, 1440 type II, 49, 50, 454, 456 Hyperreflexia, 462 Hypertension, hypercholesterolemia and hypomagnesimia, 852 Hypertrophic cardiomyopathy, 852 Hypertrophic cardiomyopathy and sensorineural deafness, 852 Hypertrophic osteoarthropathy (HO), 1028 Hypertyrosinemia, 354 Hyperuricaemic nephropathy, familial juvenile 1, 195, 207 Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, 855 Hyperuricosuria, 18, 19 Hyperzincemia, 608, 611, 612, 618–621 Hypochromic microcytic anemia with iron overload type 1, 628 Hypohomocysteinemia, 252, 379, 380 Hypomyelinating leukodystrophy type 4 (recessive), 892 Hypomyelination, 455, 462, 1004 Hypophosphatasia, 49 Hypoplasia, corpus callosum, 473, 474 Hypotonia, 440, 441, 473, 474 Hypotransferrinemia, 627 Hypoxanthine guanine phosphoribosyltransferase deficiency, 34, 194, 204 Hypoxic ischemic encephalopathy, 101 Hypsarrhythmia, 458, 464, 473 I IBA57 deficiency, 23, 120, 482, 486, 491 IBD deficiency. See Isobutyryl-CoA dehydrogenase deficiency I-cell disease, 76, 81, 173, 1238 Ichthyotic keratoderma, 1004 Iduronate 2-sulfatase deficiency, 76, 78, 80, 1269 IEMbase disorder, 598–600 IFD. See Intrinsic factor deficiency (IFD) IMD disease, 166–168 Imerslund-Najman-Gräsbeck syndrome (IGS), 499–502, 511 Imerslund-Najman-Gräsbeck syndrome (IGS) due to AMN, 500 Imerslund-Najman-Gräsbeck syndrome (IGS) due to CUBN, 500 Iminoglycinuria, 292, 295, 296, 302, 303, 305, 1432, 1440

Disorder Index Immunodeficiency, 252 Immunodeficiency, developmental delay, and hypohomocysteinemia (IEMDHH), 254 Immunodeficiency-23 PGM3-CDG, 1386 Immunodeficiency type 44, 891 Immunodeficiency type 46, 628 Immunodeficiency type 47, 1391 IMPAD1-CDG, 1341 Inborn errors of metabolism (IEMs), 1449–1455 Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia type 1, 892 Infantile encephaloneuromyopathy due to mitochondrial translation defect, 851 Infantile mitochondrial complex II/III deficiency (IMC23D), 482 Infantile nephropathic cystinosis, 1287–1293 Infantile neuroaxonal dystrophy, 998 Infantile-onset multiple carboxylase deficiency, 530 Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, 855 Infantile sialic acid storage disease, 1252 Infantile sudden cardiac failure, 893 Inheritable metabolic diseases, 1458 Inherited manganese deficiency, 638 Inosine monophosphate dehydrogenase deficiency, 194, 195, 205 Inosine triphosphatase deficiency, 194, 195, 206 Inosine triphosphatase deficiency (erythrocyte), 195, 206 Inositol monophosphate domain-containing protein 1 deficiency IMPAD1-CDF, 1374 Insulin receptor dysregulation, 716, 731, 732 Intellectual developmental disorder with neuropsychiatric features, 651 Intellectual developmental disorder with neuropsychiatric features (SLC45A1 deficiency), 662 Intellectual disability and seizure disorder due to TIMM50 variant, 891 Intestinal glucose-galactose malabsorption, 661 Intestinal malabsorption, 18, 19 Intestinal sodium-glucose cotransporter 1 deficiency (GGM), 651 Intracellular disorder, 502–505 Intrinsic factor deficiency (IFD), 36, 499–501, 511 Iron deficiency anemia, 629 Iron-refractory iron deficiency anemia (IRIDA), 625, 628 ISCA1 deficiency, 23, 32, 120, 482, 487, 491 ISCA2 deficiency, 23, 482, 487, 491 ISCU deficiency, 23, 32, 35, 482, 488 ISD11 deficiency, 23, 31, 482, 489, 491 Isobutyryl-CoA dehydrogenase deficiency, 36, 67, 70, 393, 395, 401, 417–420, 423, 427 Isobutyrylglycinuria, 54 Isocitrate dehydrogenase 2 deficiency, 1402, 1404 Isolated congenital HI, 715–716 Isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, 934, 944–945 Isolated deficiency of long-chain 3-ketoacyl CoA thiolase, 934, 945–946 Isolated methylmalonic aciduria, 54 Isolated mitochondrial ATP synthase deficiency, 393 Isolated sulfite oxidase deficiency, 118, 368, 382, 386, 388 Isovaleric acidemia, 11, 19, 23, 61, 67, 70, 172, 392, 395, 400, 416, 418–420, 422, 425–426 Isovaleryl-CoA dehydrogenase deficiency, 20, 22, 27, 37, 38, 67 ISPD-CDG, 33 J Jagunal 1 deficiency, 38 Jansky-Bielschowsky disease, 1209 Juvenile Cbl deficiency (JCD), 499 Juvenile cystinosis, 1289

Disorder Index Juvenile/hereditary megaloblastic anaemia, 499 Juvenile optic atrophy, 891 K Kabuki syndrome, 717, 723, 731, 732 Kanzaki disease, 81, 1252, 1255 Kearns-Sayre like syndrome, 853 Kearns-Sayre syndrome, 174 Kennedy disease, 33, 137 2-Ketoadipic aciduria, 20, 1436, 1442 2-Ketoglutarate dehydrogenase deficiency, 55, 744, 752 Ketohexokinase deficiency, 651 Kinky (steely) hair disease, 611 Krabbe disease, 76, 81, 109, 112, 139, 1178–1179, 1196 Krabbe disease-like disorder due to saposin A deficiency, 1189, 1194 Krebs cycle disorders, 739–741 Kufor-Rakeb syndrome, 638, 640, 1210 Kufs disease dominant type A, 1209 Kufs disease recessive type A, 1209 Kufs disease recessive type B, 1210 Kynureninase deficiency, 565, 566, 574 L Lactate dehydrogenase A deficiency (LDHA-D), 32, 35, 36, 652 Lactate dehydrogenase B deficiency (LDHB-D), 652, 670 D-Lactate dehydrogenase deficiency, 23, 652, 671, 686, 688 Lactic acidosis, 795 D-Lactic aciduria, 56 Laforin deficiency (EPM2A-D), 654, 678 LAMP2 deficiency, 32 Language difficulties, 442 Lanosterol 14 α-demethylase deficiency, 1058, 1064 Lanosterol synthase deficiency, 1058, 1064 L-arabinosuria, 703 LARGE1-CDG, 33, 1339 Large malformed ears, 462 Large neutral amino acid transporter deficiency, 296, 300, 302, 305, 306, 396, 420 Late onset mitochondrial myopathy, 853 Late-onset multiple carboxylase deficiency, 530 Lathosterolosis. See Sterol Δ5-desaturase deficiency Laurence-Moon syndrome, 1000–1001 LCFA-CoA ligase 4 deficiency, 1006 LCHAD deficiency. See Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency L-cysteine deficiency, 596 LDHA-D (GSD-XI), 686, 688 LDHB-D, 686, 688 LDL receptor adaptor protein 1 deficiency, 29 LDL receptor deficiency, 29 Leber congenital amaurosis (LCA), 564 Leber congenital amaurosis 9 (LCA9), 566 Lecithin cholesterol acyl transferase deficiency (LCAT), 27, 34, 173 Leigh disease, 106, 107, 119 Leigh-like disease, 393 Leigh-like encephalomyopathy, 759 Leigh-like mitochondrial disease, 638, 639 Leigh-like syndrome, 992 Leigh syndrome, 148, 165, 538, 744 Leigh syndrome, due to COX IV deficiency, Charcot-Marie-Tooth disease, type 4K, 803 Leigh syndrome due to cytochrome c oxidase deficiency, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 802

1479 Leigh Syndrome with French-Canadian Ethnicity, 25, 803, 825 Leloir pathway: galactose mutarotase deficiency (GALM-D), 655 Lennox-Gastaut syndrome, 458 Lenz-Majewski syndrome, 997 Lesch-Nyhan disease, 1461 Lesch-Nyhan syndrome, 191, 194 Leucoencephalopathy, 564 Leukodystrophy, 108, 111, 117–120, 125, 127, 128, 130, 132, 133, 135, 139, 142, 143 Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, 26, 854 Leukotriene C4 synthase deficiency, 1029, 1032 Leukotrienes, 1029 LFNG-CDG, 1341, 1376 L-2-Hydroxyglutarate dehydrogenase deficiency, 24, 143, 1402, 1404 L-2-Hydroxyglutaric aciduria (L2HGA), 100, 101, 143, 1399, 1401, 1402, 1404, 1406, 1412 Limp2 deficiency, 1180–1181 Linear skin defects with multiple congenital anomalies type 1, 804 Lipase maturation factor 1 deficiency, 30 Lipids disorders, 21–23, 27, 29–32, 34, 36–38, 185, 186 Lipiduria, 18 Lipin 1 deficiency (LPIN1), 33, 36, 1007 Lipin 2 deficiency, 1007 Lipoate deficiency, 471 Lipodystrophy phenotype, 996 Lipoic acid synthase (LIAS) deficiency, 23, 482, 483, 491 Lipoid adrenal hyperplasia, 1078, 1083 Lipoprotein glomerulopathy, 27, 30 Lipoprotein lipase deficiency (LPL), 30, 174, 1044 Lipoyltransferase 1 deficiency (LIPT1D), 23, 482, 484 Lipoyltransferase 2 deficiency (LIPT2), 23, 482, 483, 491 Liver disease, 638, 710, 711 Liver dysfunction, 930–931 Liver glycogen phosphorylase deficiency, 21, 29–31, 35 Liver glycogen synthase deficiency, 21, 22 Long-chain hydroxyacyl-CoA dehydrogenase, 934 Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, 12, 14, 21, 23, 27, 29, 32, 36, 55, 67, 70–73, 932, 935–936, 952, 954 Long-chain 3-ketoacyl-CoA thiolase (LKAT) deficiency, 932, 952, 954 Long QT syndrome with syndactily, 717 LONP1 deficiency, 892, 903, 909 Lowe syndrome, 48 LRPPRC deficiency, 131 17,20-Lyase deficiency, 1086 Lysine malabsorption syndrome, 292, 295, 299, 302, 304, 306 Lysinuric protein intolerance, 22, 27, 30, 33, 35–38, 41, 42, 45, 48, 49, 58, 266, 274, 282, 284, 285, 287, 288, 292, 295, 298, 302, 304, 305, 309, 310 Lysophosphatidic acid acyltransferase deficiency, 1006, 1007 Lysosomal acid lipase deficiency (LAL-D), 30, 76, 1182, 1200 lysosomal alpha-glucosidase deficiency, 650 Lysosomal alpha-1,4-glucosidase deficiency, 32, 654 Lysosomal CLN5 protein deficiency, 1209 Lysosomal storage disorders, 12, 1264 Lysosome-associated membrane protein 2 deficiency, 654 M m-AAA protease AFG3L2 subunit deficiency, 892, 904, 910 MAAI. See Maleylacetoacetate isomerase (MAAI) deficiency MADD. See Multiple acyl-CoA dehydrogenase deficiency (MADD) MAGMAS deficiency, 891, 900, 909 Magnesium transporter 1 deficiency (MAGT1-CDG), 1336–1337, 1339, 1344, 1356

1480 Majeed syndrome, 1007 Malar hypoplasia, 463 Malate dehydrogenase deficiency, 55 Maleylacetoacetate isomerase (MAAI) deficiency, 354, 355, 358, 361, 363 Malin deficiency (EPM2B-D), 654, 678 Malonic aciduria, 54, 67, 394, 410–412, 420, 424, 429 Malonyl-CoA decarboxylase deficiency, 11, 14, 20, 23, 27, 29, 396 MAN1B1-CDG, 1339, 1344 Manganese deficiency, 638 Mannosephosphate isomerase deficiency, 717 Mannosyltransferase 1 deficiency, 1348 Mannosyltransferase 2 deficiency, 1349 Mannosyltransferase 4–5 deficiency, 1349–1350 Mannosyltransferase 6 deficiency, 21, 1351 Mannosyltransferase 7–9 deficiency, 1351–1352 Mannosyltransferase 8 deficiency, 22, 1352–1353 Mannosyltransferase 6 deficiency ALG3-CDG, 726 MAP17 deficiency (MAP17-D), 651, 662, 685, 688 Maple syrup urine disease (MSUD), 4, 9–11, 14, 18–20, 27, 42, 45–50, 53, 97–99, 172–174, 177–178, 392, 395, 416, 418, 419 type 2, 420 type 1a, 118, 420 type1b, 118 type 1b, 420 Maroteaux-Lamy disease (MPS VI), 1269, 1275 Martinelli syndrome, 609, 611 Maternal dietary riboflavin deficiency, 549 Matriptrase 2 deficiency, 628, 631 MCAD deficiency. See Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency MCAP syndrome, 731, 733 McArdle disease, 653 MCHAD deficiency, 12 MCPHA, 540 MDA5 superactivity Aicardi-Goutières syndrome type 7, 217, 226 Singleton-Merten syndrome type 1, 217, 226 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, 9, 12, 14, 18, 21, 55, 67, 70, 71, 135, 550, 933, 934, 942, 952–954 MEDNIK-like syndrome, 608, 610, 619, 620, 622 MEDNIK syndrome, 31, 610, 611, 616, 619–621 MEDNIK syndrome plus hepatopathy (MEDNIK-HC), 609 Megaconial type, 995 Megalencephaly-micropolygyria-polydactily-hydrocephalus syndrome, 718, 733 Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 733 Megaloblastic anemia due to DHFR deficiency, 516–518 Megarbane-Dagher-Melike type, 891 MEGDEL syndrome, 21, 26, 56, 136, 393, 1417 MELAS-like syndrome, 852, 853 MELAS syndrome. See Mitochondrial encephalopathy with lactate acidosis and stroke-like episodes (MELAS) syndrome Membrane-bound dipeptidase deficiency, 254, 257 Membrane-bound O-acyltransferase domain-containing 7 deficiency (MBOAT7), 1001, 1002 Mendelian diseases, 93 MEND syndrome. See X-linked dominant sterol Δ8,Δ7-isomerase deficiency Menkes disease, 104, 124, 173, 607–610, 615, 619–622 Mental retardation, 454, 1019, 1357 Mental retardation, Enteropathy, Deafness, Neuropathy, Ichthyosis, and Keratoderma (MEDNIK), 608, 609 Mercaptopyruvate sulfur transferase (MPST) deficiency, 368–370, 376, 381, 382, 386, 388 MERRF-like syndrome, 853

Disorder Index MERRF/MELAS overlap syndrome, 852–854 MERRF syndrome, 853 Metachromatic leukodystrophy (MLD), 76, 109, 111, 113, 139, 1179, 1196–1197 Metachromatic leukodystrophy-like disorder due to saposin B deficiency, 1189, 1194 Methacrylic aciduria, 54, 393 Methanethiol oxidase (MTO) deficiency, 19, 368–370, 374, 381, 382, 386, 388 5,10-Methenyltetrahydrofolate synthetase deficiency (MTHFS), 516, 518, 522, 525, 526 Methionine adenosyltransferase deficiency, 19, 49, 1439, 1444 Methionine adenosyltransferase (MAT) II deficiency, 366–368, 370, 383, 388 Methionine adenosyltransferase (MAT) I/III deficiency, 366–368, 370, 381–383, 387 Methionine malabsorption syndrome, 292, 295, 300, 302, 304, 306 Methionine synthase deficiency, 36 Methionine synthase deficiency-cblG, 501, 510, 511 Methionine synthase reductase deficiency, 36 Methionine synthase reductase deficiency—cblE, 501, 511 Methioninuria, 295 2-Methylacetoacetic aciduria, 54 Methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, 21, 393, 969 2-Methylbutyryl-CoA dehydrogenase (MBD) deficiency, 20, 393, 395 2-Methylbutyrylglycinuria, 54, 70, 393, 401, 418–420, 423, 427, 1438, 1444 Methylcobalamin deficiency cblE type, 501, 510 cblG type, 501 Methylcobalamin synthesis defect —cblD-HC, 500, 506, 511 —cblE-HC, 506 —cblG, 506 3-Methylcrotonyl-CoA carboxylase 1 and 2 deficiency, 20, 27 Methylcrotonyl-CoA carboxylase deficiency, 530 3-Methylcrotonyl-CoA carboxylase deficiency, 529, 536 3-Methylcrotonyl-CoA carboxylase (3MCCC) deficiency, 5, 11, 14, 67, 71, 392, 395 3-Methylcrotonylglycinuria, 19, 53, 174, 1437–1438, 1443 Methylcrotonylglycinuria A and B, 401–402 3-Methylcrotonylglycinuria type 1, 419, 420, 422, 426 3-Methylcrotonylglycinuria type 2, 419, 420, 422 5,10-Methylene-tetrahydrofolate dehydrogenase deficiency (MTHFD1), 36, 37, 517, 518, 521 Methylene tetrahydrofolate reductase deficiency, 20 5,10-Methylenetetrahydrofolate reductase deficiency, 121 Methylenetetrahydrofolate reductase deficiency (MTHFR), 516, 517, 521, 526 Methylglutaconic aciduria type I, 402–403 type III, 891 3-Methylglutaconic aciduria, 392–393, 416, 1417–1429 type 1 (MGA1), 53, 118, 418–420, 422, 426 type 5, 891 type 7, 892 type 8, 892 3-Methylglutaconic aciduria with deafness, 992 3-Methylglutaconyl-CoA hydratase deficiency, 20, 27, 32, 118, 395 2-Methyl-3-hydroxybutyryl-CoA deficiency, 417 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, 405, 418, 420, 423, 427, 870 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency, 54, 59, 61, 393 Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency, 23, 48, 393–394, 396, 406, 420, 423, 427, 435, 438, 444, 450, 451

Disorder Index Methylmalonic acidemia, 9, 11, 49, 394, 1452 Methylmalonic aciduria (MAA), 14, 18, 100, 119–121, 420, 424, 1420 cblA type, 501 cblB type, 27, 34, 501 cblD type, 500 Methylmalonic aciduria and homocystinuria cblC type, 27, 34, 36, 500 cblC type, digenic, 500 cblD type, 500 cblF type, 36, 500 cblJ type, 36, 500, 510 cblX type, 500 Methylmalonic aciduria and homocystinuria due to Ronin deficiency, 500 Methylmalonic aciduria and homocystinuria due to ZNF143 deficiency, 500 Methylmalonic aciduria due to methylmalonyl-CoA epimerase deficiency, 394, 423, 428 Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, 27, 34, 396, 409–410, 420, 423, 428 Methylmalonic semialdehyde dehydrogenase deficiency, 54 Methylmalonyl-CoA epimerase deficiency, 396, 408, 420, 1439, 1445 Methylmalonyl-CoA mutase deficiency, 20, 22, 23, 27, 34, 36–38, 119 Mevalonate kinase deficiency, 29, 33, 37, 38, 61 Mevalonic aciduria, 56, 173 Mevalonic kinase deficiency (MKD), 1058, 1063 MFT deficiency. See Mitochondrial flavin adenine dinucleotide transporter (MFT) deficiency MGA1 or juvenile pernicious anaemia with proteinuria, 499 MGAT2-CDG, 1339, 1344, 1358 MGME1 deficiency, 849, 862 MICOS complex subunit MIC13 deficiency, 21, 26, 893, 908, 910 MICOS13 deficiency, 1417, 1419, 1427, 1445 Microcephaly, 399, 454, 456, 458, 460–463, 717 Microcytic iron deficiency anemia, 627 Micrognathia, 464 Microsomal triglyceride transfer protein deficiency, 29 Mild hypohomocysteinemia, 380 Mild methylmalonic aciduria, 759 Miller syndrome, 193, 197 Mitochondrial acetoacetyl-CoA thiolase deficiency, 136, 396, 420 Mitochondrial acetyl-CoA carboxylase 2 deficiency, 27, 29 Mitochondrial aconitase deficiency, 744, 751 Mitochondrial alanyl-tRNA synthetase deficiency, 854, 875 Mitochondrial and cytoplasmic glycyl-tRNA synthetase deficiency, 855, 881 Mitochondrial and cytoplasmic lysyl-tRNA synthetase deficiency (KARS), 133, 855, 881 Mitochondrial arginine-tRNA synthetase deficiency (AARS2), 26, 132, 876 Mitochondrial arginyl-tRNA synthetase deficiency, 854 Mitochondrial asparaginyl-tRNA synthetase deficiency, 26, 854, 876 Mitochondrial aspartate aminotransferase deficiency, 767, 776, 787, 788 Mitochondrial aspartyl-tRNA synthetase deficiency (DARS2), 132, 854, 876 Mitochondrial ATP-Mg2+/phosphate transporter deficiency, 767, 775–776, 787, 788 Mitochondrial ATP synthase F1 subunit a deficiency, 25, 803, 826 Mitochondrial ATP synthase F1 subunit δ deficiency, 21, 22, 25, 28, 803, 827 Mitochondrial ATP synthase F0 subunit 6 deficiency, 37, 131 Mitochondrial ATP synthase F1 subunit e deficiency, 25, 28, 803, 827 Mitochondrial calcium uniporter deficiency, 32, 893, 908, 910 Mitochondrial cardiomyopathy, 853 Mitochondrial citrate carrier deficiency, 767–772, 774, 783, 787, 788

1481 Mitochondrial coenzyme A transporter deficiency, 22, 23, 28, 32, 566, 571, 574, 768, 779, 787, 789 Mitochondrial complex (ATP synthase) deficiency, nuclear type 4, 803 Mitochondrial complex I assembly deficiency FOXRED1, 24, 28, 799, 814 NDUFAF1, 24, 28, 798, 813 NDUFAF2, 24, 798, 813 NDUFAF3, 24, 799, 813 NDUFAF4, 24, 28, 799, 813 NDUFAF5, 24, 28, 799, 814 NDUFAF6, 24, 28, 799, 814 TMEM126B, 799, 816 Mitochondrial complex I deficiency, 891 Mitochondrial complex II deficiency, 745 nuclear type 1, 799 nuclear type 2, 800 Mitochondrial complex III assembly deficiency, 24 LYRM7, 24, 801, 820 TTC19, 21, 24 UQCC2, 24, 801, 820 UQCC3, 21, 28, 800, 819 UQCRC2, 21, 22, 24, 28, 31 Mitochondrial complex III deficiency (TTC19), 130 Mitochondrial complex III deficiency, nuclear type 2 (TTC19), 800 Mitochondrial complex III deficiency, nuclear type 6, 804 Mitochondrial complex III deficiency, nuclear type 7 (UQCC2), 801 Mitochondrial complex III deficiency, nuclear type 8 LYRM7, 130, 801 Mitochondrial complex III subunit deficiency (TTC19), 800, 819 Mitochondrial complex III subunit deficiency (UQCRB), 21, 24, 28, 800, 818 Mitochondrial complex III subunit deficiency (UQCRC2), 800, 818 Mitochondrial complex III subunit deficiency (UQCRQ), 24, 130, 800, 819 nuclear type 3, 800 nuclear type 4, 800 nuclear type 5, 800 nuclear type 7, 801 nuclear type 9, 800 Mitochondrial complex I subunit deficiency COXFA4, 824 MTND1, 798, 811 MTND2, 24, 798, 811 MTND3, 24, 798, 811 MTND4, 24, 798, 812 MTND5, 24, 798, 812 MTND6, 24, 28, 798, 812 MTND4L, 798, 812 NDUFA1, 24, 28, 797, 808 NDUFA2, 24, 797, 808 NDUFA4, 25 NDUFA9, 24, 28, 797, 809 NDUFA10, 24, 797, 809 NDUFA11, 24, 28, 797, 809 NDUFA12, 798, 809 NDUFA13, 24, 798, 810 NDUFB3, 24, 28, 798, 810 NDUFB9, 24, 28, 798, 810 NDUFB11, 24, 28, 798, 811 NDUFS1, 24, 28, 797, 806 NDUFS2, 24, 797, 807 NDUFS3, 24, 797, 807 NDUFS4, 24, 28, 797, 808 NDUFS6, 24, 28, 32, 797, 808 NDUFS7, 24, 797, 807 NDUFS8, 797, 807 NDUFV1, 24, 797, 806 NDUFV2, 24, 28, 797, 806

1482 Mitochondrial complex IV assembly deficiency COA3, 801, 821 COA5, 802, 822 COA6, 25, 802, 822 COA7, 802, 822 COX10, 25, 37, 802, 822 COX14, 25, 802, 822 COX15, 25, 802, 822 COX20, 25, 802, 823 SCO1, 25, 802, 823 SCO2, 25, 802, 823 SURF1, 25, 803, 824 Mitochondrial complex IV deficiency nuclear type 5, 803 nuclear type 8, 803 nuclear type 12, 803 nuclear type 17, 803 Mitochondrial complex IV subunit deficiency COX6A1, 801, 821 COX8A, 801, 821 COX6B1, 25, 801, 821 COX7B, 25, 801, 821 COXFA4, 802 COX4I2, 801, 821 MTCO1, 25, 801, 820 MTCO2, 25, 801, 820 MTCO3, 25, 801, 820 Mitochondrial complex V assembly deficiency (ATPAF2), 25, 804, 829 Mitochondrial complex V (ATP synthase) deficiency, 266 Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, 804 Mitochondrial complex V subunit deficiency (MTATP6), 25, 803, 827 Mitochondrial complex V subunit deficiency (MTATP8), 803, 828 Mitochondrial cysteinyl-tRNA synthetase deficiency, 26, 854 Mitochondrial cytochrome b deficiency MTCYB, 25, 32, 36, 804, 830 Mitochondrial cytochrome beta deficiency, 21 Mitochondrial cytochrome c1 deficiency CYC1, 23, 25, 28, 804, 831 Mitochondrial cytochrome c deficiency CYCS, 38, 804, 831 Mitochondrial cytochrome c oxidase deficiency with sensorineural deafness, 853 Mitochondrial deoxyguanosine kinase deficiency, 21, 25, 31, 35, 858 Mitochondrial depletion syndrome 1, 849 2, 849 3, 849 4A, 25, 849, 856 4B, 849, 856 5, 850 9, 850 13, 849 Mitochondrial dicarboxylate transporter deficiency, 37, 767, 776, 787, 788 Mitochondrial disorders of energy metabolism, 21–23, 28, 29, 31–33, 35–38, 185, 186 Mitochondrial DNA depletion syndrome, 132, 192 5, 744 6, 849 7, 849, 860 8, 861 8A & 8B, 849 9, 744 11, 849 12, 767 12A (cardiomyopathic type), 850 12B (cardiomyopathic type), 850 15, 850

Disorder Index Mitochondrial DNA polymerase g accessory subunit deficiency, 25, 32, 857 Mitochondrial dysfunction, 794, 833 Mitochondrial dystonia, 852 Mitochondrial elongation factor G1 deficiency, 873 Mitochondrial elongation factor G2 deficiency, 851, 874 Mitochondrial elongation factor Ts deficiency, 32, 874 Mitochondrial elongation factor Tu deficiency, 851, 874 Mitochondrial encephalocardiomyopathy, 854 Mitochondrial encephalomyopathy, 795, 852–854 Mitochondrial encephalopathy, 853, 854 Mitochondrial encephalopathy with lactate acidosis and stroke-like episodes (MELAS) syndrome, 106, 108, 111, 128, 134, 852 Mitochondrial enoyl-CoA reductase deficiency, 136 Mitochondrial epilepsy, 853 Mitochondrial epileptic encephalopathy TIMM50, 891, 900, 909 Mitochondrial fatty acid beta-oxidation defect, 39 Mitochondrial fatty acid oxidation disorders (FAODs), 933–955 Mitochondrial fission factor deficiency, 26, 133, 891, 895, 909 Mitochondrial flavin adenine dinucleotide transporter (MFT) deficiency, 550, 551, 555, 557, 560, 561, 768, 779, 787, 789, 1307 Mitochondrial 10-formyltetrahydrofolate dehydrogenase deficiency (ALDH1L2), 518, 523, 526 Mitochondrial glutamate carrier 1 deficiency, 768, 778, 787, 789 Mitochondrial glutamyl-tRNA(Gln) amidotransferase deficiency subunit A, 26, 32, 37, 854, 877 subunit B, 21, 26, 37, 854, 878 subunit C, 26, 28, 32, 37, 855, 878 Mitochondrial glutamyl-tRNA synthetase deficiency (EARS2), 26, 133, 854 Mitochondrial glycine transporter deficiency, 35, 36, 768, 778, 787, 789 Mitochondrial histidyl-tRNA synthetase deficiency, 855, 878 Mitochondrial 4-hydroxy-2-oxoglutarate aldolase deficiency, 34 Mitochondrial inorganic pyrophosphatase 2 deficiency, 26, 29, 893, 906, 910 Mitochondrial intermediate peptidase deficiency, 26, 28, 892, 902, 909 Mitochondrial isoleucyl-tRNA synthetase deficiency, 855, 878 Mitochondrial leucyl-tRNA synthetase deficiency, 26, 28, 37, 38, 855 Mitochondrial malate dehydrogenase deficiency, 24, 745, 757 Mitochondrial malate dehydrogenase deficiency, tumoral phenotype, 745, 757 Mitochondrial methionyl-tRNA formyltransferase deficiency, 25, 132, 850, 867 Mitochondrial methionyl-tRNA synthetase deficiency, 855, 879 Mitochondrial myopathy, 852–854 Mitochondrial myopathy and ataxia, 891 Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy (MEOAL), 482 Mitochondrial myopathy with diabetes mellitus, 852 Mitochondrial myopathy with lactic acidosis, 993 Mitochondrial NADH-dependent isocitrate dehydrogenase 2 superactivity, 744 Mitochondrial NAD kinase 2 deficiency, 23, 566, 568, 574 Mitochondrial NADPH-dependent isocitrate dehydrogenase 3β subunit deficiency, 744, 752 Mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with or without seizures, 855 Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome, 58, 853 Mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome, 174, 193, 848, 849 Mitochondrial neurogastrointestinal syndrome, 854 Mitochondrial ornithine transporter deficiency, 22, 30, 34, 271, 767, 776–777, 787, 788

Disorder Index Mitochondrial oxodicarboxylate carrier deficiency, 37 Mitochondrial phenylalanyl-tRNA synthetase deficiency (FARS2), 26, 28, 37, 133, 855, 879 Mitochondrial phosphate carrier deficiency, 24, 767, 773, 786, 788, 803, 826 Mitochondrial phosphoenolpyruvate carboxykinase deficiency, 21, 654, 680 Mitochondrial poly(A) exoribonuclease deficiency, 25, 28 Mitochondrial poly(A) polymerase deficiency, 850, 867 Mitochondrial processing peptidase alpha deficiency, 134, 909 Mitochondrial processing peptidase alpha (PMPCA) deficiency, 892, 901 Mitochondrial processing peptidase beta (PMPCB) deficiency, 26, 134, 892, 901, 909 Mitochondrial pyruvate carrier deficiency, 744, 750 Mitochondrial respiratory chain complex II deficiency, 745 Mitochondrial respiratory chain disorders, 106 Mitochondrial ribonucelotide reductase subunit 2 deficiency, 25 Mitochondrial ribonuclease H1 deficiency, 25, 32 Mitochondrial ribonucleotide reductase small subunit deficiency, 849 Mitochondrial ribosomal large subunit 3 deficiency, 25, 31, 851 Mitochondrial ribosomal large subunit 12 deficiency, 25, 851 Mitochondrial ribosomal large subunit 44 deficiency, 851, 871 Mitochondrial ribosomal large subunit 3 deficiency MRPL3, 871 Mitochondrial ribosomal large subunit 12 deficiency MRPL12, 871 Mitochondrial ribosomal RNA 12S deficiency, 851, 873 Mitochondrial ribosomal small subunit 2 deficiency, 21, 25, 31, 851, 871 Mitochondrial ribosomal small subunit 7 deficiency, 21, 25, 851, 872 Mitochondrial ribosomal small subunit 14 deficiency, 25 Mitochondrial ribosomal small subunit 16 deficiency, 31 Mitochondrial ribosomal small subunit 23 deficiency, 21, 851 Mitochondrial ribosomal small subunit 25 deficiency, 855, 882 Mitochondrial ribosomal small subunit 28 deficiency, 21, 25, 28, 31 Mitochondrial ribosomal small subunit 34 deficiency, 851, 873 Mitochondrial RNA import protein deficiency, 25, 132, 850 Mitochondrial RNA-processing endoribonuclease deficiency, 851, 869 Mitochondrial sensorineural deafness, 853 Mitochondrial seryl-tRNA synthetase deficiency, 26, 29, 35, 37, 38, 855, 880 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, 23, 54, 395, 403 Mitochondrial sulfur dioxygenase deficiency, 23, 27, 369, 370, 376 Mitochondrial thiamine pyrophosphate carrier deficiency, 537, 539, 540, 543–545, 768 Mitochondrial thiamine pyrophosphate transporter deficiency, 122 Mitochondrial thioredoxin 2 deficiency, 26, 893, 908, 910 Mitochondrial thioredoxin reductase 2 deficiency, 893, 909, 910 Mitochondrial threonyl-tRNA synthetase deficiency, 26, 855, 880 Mitochondrial thymidine kinase deficiency, 860 Mitochondrial thymidine kinase 2 deficiency, 25, 32 Mitochondrial transcription factor A deficiency, 21, 31, 850 Mitochondrial trans-2-enoyl-CoA reductase protein-associated neurodegeneration (MEPAN), 1004 Mitochondrial trifunctional protein (MTP) deficiency, 55, 67, 70–73, 932, 934, 952, 954 Mitochondrial tRNA deficiencies, 132 Mitochondrial tRNA(Ala) deficiency, 32 Mitochondrial tRNA(Arg) deficiency, 26 Mitochondrial tRNA(Asn) deficiency, 26 Mitochondrial tRNA(Asp) deficiency, 32 Mitochondrial tRNA(Cys) deficiency, 26, 28 Mitochondrial tRNA(Glu) deficiency, 26, 32 Mitochondrial tRNA(Gly) deficiency, 26, 32 Mitochondrial tRNA(Ile) deficiency, 26 Mitochondrial tRNA(Leu) 1 deficiency, 26, 32, 875

1483 Mitochondrial tRNA(Lys) deficiency, 26, 875 Mitochondrial tRNA(Met) deficiency, 26, 28 Mitochondrial tRNA(Phe) deficiency, 26 Mitochondrial tRNA(Ser) 2 deficiency, 22 Mitochondrial tRNA(Thr) deficiency, 26 Mitochondrial tRNA(Trp) deficiency, 26 Mitochondrial tryptophanyl-tRNA synthetase deficiency, 21, 26, 28, 855, 881 Mitochondrial tyrosyl-tRNA synthetase deficiency, 26, 37, 855, 880 Mitochondrial valyl-tRNA synthetase deficiency, 31, 855, 881 Mitofusin 2 deficiency, 891, 898, 909 MMSDH. See Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency MNGIE syndrome, 849, 853 MODY1, 716 MODY3, 716 MOGS-CDG, 1339, 1344 Mohr-Tranebjaerg syndrome, 891, 899, 909 Molybdenum cofactor deficiency, 49, 50, 102, 103, 123 A, 35, 597 B, 35, 597 C, 35, 597 sulfurase, 35, 597, 601 Monoamine oxidase A deficiency, 315, 316, 320, 325–327 Monocarboxylate transporter-1 (MCT1) deficiency, 29, 412–413, 968, 973 Monocarboxylate transporter gain-of-function, 21 Monocarboxylate transporter 1 superactivity, 969 Monomethylglycine. See Sarcosinemia Morquio A disease (MPS IVA), 1269, 1274 Morquio B disease (MPS IVB), 1269, 1274 MPDU1-CDG, 33. See Dol-P-Man utilization 1 deficiency MPDU1-CDG MPI-CDG, 29, 31. See Phosphomannose isomerase deficiency MPI-CDG MPS. See Mucopolysacharidoses (MPS) MPV17 deficiency, 21, 25, 849, 859 MSD. See Multiple sulfatase deficiency (MSD) MSSGM1 syndrome, 717, 731, 733 MSTO1 deficiency, 32, 134, 891, 898, 909 MSUD. See Maple syrup urine disease (MSUD) MTATP6 deficiency, 804 MTATP8 deficiency, 804 MTCO1 deficiency, 801 MTCO2 deficiency, 801 MTCO3 deficiency, 801 MTF deficiency, 548 MTND1 deficiency, 798 MTND2 deficiency, 798 MTND3 deficiency, 798 MTND4 deficiency, 798 MTND5 deficiency, 798 MTND6 deficiency, 798 MTND4L deficiency, 798 MTP. See Mitochondrial trifunctional protein (MTP) deficiency mtPCK-D, 687, 689 Mucolipidosis tyep I, 76, 81, 1252 type II, 76, 81, 1235, 1236, 1238, 1239, 1243 type II alpha-beta, 1240 type III, 76, 81, 1235, 1236, 1238, 1239, 1243 type III alpha, beta, 1236, 1238, 1243 type III alpha-beta-gamma, 1240 type III, gamma, 1238, 1243 type IV, 76, 140, 1235, 1236, 1238, 1239 Mucolipin 1 deficiency, 140, 1241

1484 Mucopolysaccharidosis Plus (MPSPS), 1269, 1276, 1280, 1283 Mucopolysacharidoses (MPS), 105–106 type I (Hurler disease), 76, 141, 1280, 1283 type II (Hunter disease), 76, 141, 1280, 1283 type IIIA, 76, 141, 1280, 1283 type IIIB, 76, 141, 1280, 1283 type IIIC, 76, 1280, 1283 type IIID, 76, 1280, 1283 type IVA, 76, 1280, 1283 type IVB (Morquio disease, type B), 76, 1283 type IX, 76, 1280, 1283 type VI (Maroteaux-Lamy disease), 76, 141, 1280, 1283 type VIB, 1280 type VII (Sly disease), 76, 1280, 1283 Mucosulfatidosis Austin disease, 1238 Mudd disease, 19 Multifocal epilepsy, 458, 473 Multiple acyl-CoA dehydrogenase deficiency (MADD), 14, 19, 20, 31, 32, 50, 55, 57, 67, 70, 173, 174, 178, 547–549, 551, 557, 559–561 Multiple acyl-CoA dehydrogenase deficiency DH, 28 Multiple acyl-CoA dehydrogenase deficiency (MADD)—Electron transfer flavoprotein (ETF) deficiency, 551, 555 Multiple acyl-CoA dehydrogenase deficiency (MADD)—Electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO) deficiency, 556 early-onset form, 560 late onset form, 560 Multiple carboxylase deficiency, 19, 57 Multiple mitochondrial dysfunction syndrome type 1 (MMDS1), 482 type 2 (MMDS2), 482 type 3 (MMDS3), 482 type 4 (MMDS4), 482 type 5 (MMDS5), 482 type 6 (MMDS6), 892 Multiple sulfatase deficiency (MSD), 1235–1239, 1241, 1243–1246 Multiple sulfite oxidase deficiency, 180 Multisystem disorder, 852 Muscle adenosine monophosphate deaminase 1 deficiency, 194 Muscle disease with high creatine kinase, 368 Muscle glycogenin 1 deficiency, 653 Muscle glycogen phosphorylase deficiency, 653 Muscle glycogen storage disorders, 655 Muscle glycogen synthase deficiency, 653 Muscle phosphofructokinase deficiency, 32, 35, 37, 38, 652 Muscle phosphoglycerate kinase deficiency, 32, 36, 37, 39, 669 Muscle phosphoglycerate mutase deficiency, 32, 35, 36 Muscle phosphorylase deficiency, 32, 35 Muscle phosphorylase kinase α1 subunit deficiency, 653 Muscle phosphorylase kinase deficiency, 32, 35 Muscular dystrophy-dystroglycanopathy, 1387 type A7 and C7 CRPPA-CDG, 1363 type A, 5 FKRP-CDG A, 1364 type A, 4 FKTN-CDG A, 1363 type A, 10 TMEM5-CDG, 1365 type B, 5 FKRP-CDG B, 1365 type B, 4 FKTN-CDG B, 1364 type C, 5 FKRP-CDG C, 1365 type C, 4 FKTN-CDG C, 1364 Muscular dystrophy, limb-girdle, type 2Z autosomal recessive POGLUT1-CDG, 1375 Myelodysplastic syndrome, 853 Myoadenylate deaminase deficiency, 194 Myoclonic atonic epilepsy (MAE), 439 Myopathy, 399, 891, 931

Disorder Index Myopathy distal with rimmed vacuoles (SQSTM1), 1164 Myopathy lactic acidosis and sideroblastic anaemia, 850 Myopathy lactic acidosis and sideroblastic anaemia type 2, 855 Myopathy with extrapyramidal signs, 893 Myopathy with lactic acidosis, 744 Myopathy with lactic acidosis and exercise intolerance (ISCU), 479, 490 Myopia, 464 Myopia 6, cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 802 Myotonic dystrophy-like myopathy, 852 N N-acetylaspartic acid (NAA), 1407 NADH dehydrogenase α subcomplex assembly factor 2 deficiency, 128 NADH dehydrogenase α subcomplex assembly factor 3 deficiency, 129 NADH dehydrogenase α subcomplex assembly factor 5 deficiency, 129 NADH dehydrogenase α subcomplex assembly factor 6 deficiency, 129 NADH dehydrogenase α subcomplex subunit 1 deficiency, 127 NADH dehydrogenase α subcomplex subunit 6 deficiency, 24, 28 NADH dehydrogenase α subcomplex subunit 9 deficiency, 128 NADH dehydrogenase α subcomplex subunit 12 deficiency, 128 NADH dehydrogenase β subcomplex subunit 8 deficiency, 24, 28, 128, 798, 810 NADH dehydrogenase β subcomplex subunit 10 deficiency, 24 NADH dehydrogenase β subcomplex subunit 11 deficiency, 37 NADH dehydrogenase core subunit deficiency 1, 128 3, 128 5, 128 6, 128 4L, 128 NADH dehydrogenase flavoprotein 1 and/or 2 deficiency, 127 NADH dehydrogenase iron-sulfur protein 1 and/or 2 deficiency, 127 NADH dehydrogenase iron-sulfur protein 3 deficiency, 127 NAD(P)HX dehydratase deficiency, 566, 568, 574 NAD(P)HX epimerase deficiency, 566, 568, 574 NADK2 deficiency, 574 NAD metabolism, 564–574 NAGS deficiency, 48, 49, 265, 266, 282, 284–288 NANS deficiency, 88, 90, 91, 166 Natowicz disease, 1269 NDST1-CDG. See Heparan sulfate N-deacetylase N-sulfotransferase 1 deficiency NDST1-CDG NDUFA1 deficiency, 797 NDUFA2 deficiency, 797 NDUFA9 deficiency, 797 NDUFA10 deficiency, 797 NDUFA11 deficiency, 797 NDUFA12 deficiency, 798 NDUFA13 deficiency, 798 NDUFAF1 deficiency, 798 NDUFAF2 deficiency, 798 NDUFAF3 deficiency, 799 NDUFAF4 deficiency, 799 NDUFAF5 deficiency, 799 NDUFAF6 deficiency, 799 NDUFB3 deficiency, 798 NDUFB8 deficiency, 798 NDUFB9 deficiency, 798 NDUFB11 deficiency, 798

Disorder Index NDUFS1 deficiency, 797 NDUFS2 deficiency, 797 NDUFS3 deficiency, 797 NDUFS4 deficiency, 797 NDUFS6 deficiency, 797 NDUFS7 deficiency, 797 NDUFS8 deficiency, 797 NDUFV1 deficiency, 797 NDUFV2 deficiency, 797 Necrolytic erythema in glutamine deficiency, 454 Neonatal death and Leigh syndrome, 854 Neonatal mitochondrial encephalocardiomyopathy, 804 Neonatal myoclonic epilepsy, 766 Neonatal severe encephalopathy with lactic acidosis and brain abnormalities (NELABA), 482 Nephronophthisis-like nephropathy type 1, 893 Nephropathic cystinosis, 22, 27, 35, 702, 1290 Nephrotic syndrome type 7, 1001 type 9, 918 Neu-Laxova syndrome, 455, 458–459 Neuraminic acid pyruvate-lyase deficiency, 1252, 1258 Neuroblastoma, 19 Neurodegeneration with ataxia, dystonia, and gaze palsy (SQSTM1), 1165 Neurodegeneration with brain iron accumulation (NBIA), 1157, 1159 type 1, 566, 570 type 2B, 998 type 6, 566, 571 Neurodegenerative disease, 643 Neurodevelopmental abnormalities, 252 Neurodevelopmental disorder, 655 Neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA), 652, 665 Neuroferritinopathy, 124, 627 Neuromuscular disorder, 1420 Neuronal ceroid lipofuscinosis, 105, 139 type 2, 1227 type 3, 1212, 1214 type 4 (CLN4B), 1214 type 5, 1214 type 6, 1216 type 7, 1216 type 8, 1216–1217 type 12, 640 type 14, 1224 Neuronal glucose transporter deficiency (IDDNPF), 651, 685, 688 Neuronal system A amino acid transporter deficiency, 296, 301, 306 Neuronal system A SNAT8 transporter deficiency, 302, 305 Neuropathy, 537 Neuropathy, distal hereditary motor, type VIIB (DCTN1), 1169 Neurotransmitter disorders, 314 Neurotransmitter related diseases, 439 Neutropenia, severe, congenital, type 4, 653 NFS1 deficiency, 20, 23, 32, 482, 490, 491 NFU1 deficiency, 23, 119, 482, 484–485, 490, 491 NgBR-CDG, 1342, 1344, 1381 N-glycanase 1 deficiency, 31, 1337, 1343, 1393 NGLY1-CDDG, 1343 Niacin disorder, 564–574 Nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1) deficiency, 564, 566, 568, 574 Nicotinamide nucleotide transhydrogenase deficiency, 20, 566, 569, 574 Niemann-Pick disease, 1182 type A, 76, 82, 173, 1182

1485 type B, 76, 82, 173, 1182 type C, 140, 173, 1182 type C1, 76 type C2, 76 Niikawa-Kuroki syndrome, 717 Nitrogen-containing compound disorders, 38, 184–186 NKH. See Nonketotic hyperglycinemia (NKH) Nogo-B receptor deficiency, 1381 Nonaka myopathy, 1252 Non-CBS hypermethioninemias, 380 Nonketotic hyperglycinemia, 11, 14, 470–473, 477 attenuated phenotype, 474 severe phenotype, 473 Nonketotic hyperglycinemia (NKH), 99, 119, 172, 173, 180 Nonlysosomal glucosylceramidase deficiency, 1015 Non-nephropathic cystinosis, 1289 NOP2/SUN RNA methyltransferase 3 deficiency, 855, 882 NOR polyagglutination syndrome, 1018 NPL deficiency. See Neuraminic acid pyruvate-lyase deficiency Nrf2 superactivity, 251–254, 258, 260 NT5E deficiency, 216 NUBPL deficiency, 24, 129, 799, 814 Nystagmus, 440 O Oasthouse disease, 295 Oasthouse syndrome, 19 OAT. See Ornithine aminotransferase (OAT) deficiency Occipital horn syndrome (OHS), 607, 609, 611, 615, 619–621 O-Fucose-specific beta-1,3-N-acetylglucosaminyltransferase deficiency, 1376 O-Fucose-specific beta-1,3-N-glucosyltransferase deficiency, 1376 OGT-CDG. See O-linked N-acetylglucosamine transferase deficiency OGT-CDG OHS. See Occipital horn syndrome (OHS) 2ʹ, 5ʹ-Oligoadenylate synthetase 1 (OAS1) deficiency, 215–216, 218, 228, 231, 232 Oligosaccharyltransferase subunit tusc 3 deficiency, 1354 O-linked N-acetylglucosamine transferase deficiency OGT-CDG, 1341, 1375 Oliver-McFarlane syndrome, 1000–1001 O-Mannose beta-1,2-N-acetyglucosaminyltransferase deficiency, 1361 O-Mannosyltransferase 1 deficiency, 1360 O-Mannosyltransferase 2 deficiency, 1360 Ondine syndrome, 718, 731, 733 OPA3 deficiency, 1417, 1419, 1421, 1424, 1454. See also Costeff syndrome (MGA3) O-phosphoseryl-tRNA(Sec) selenium transferase deficiency, 612, 619 Ophthalmoplegia, 852 Optic atrophy type 7, 893 type 10, 893 type 11, 893 Optic atrophy 1 and deafness, 26, 891, 897, 909 Organic acidemias, 9, 11, 41, 42, 48 Organic aciduria, 86, 171, 174–178 Organic cation carnitine transporter 2 (OCTN2) deficiency, 21, 952, 954 Ornithine aminotransferase (OAT) deficiency, 22, 27, 48, 49, 236, 238, 239, 241–243, 264–266, 277, 282, 284, 285, 287, 288, 454, 456–458, 464–465 Ornithine carbamoyltransferase deficiency, 160, 266 Ornithine transcarbamylase (OTC) deficiency, 22, 30, 34, 58, 116, 264, 266, 269, 282, 284, 285, 287, 288 Orotate phosphoribosyltransferase deficiency, 36, 196

1486 Orotic aciduria, 58, 173, 184 Osteopenia, 462 OTC deficiency. See Ornithine transcarbamylase (OTC) deficiency Oxalate metabolism, disorders of, 1319–1329 Oxalate transporter deficiency, 1320, 1323, 1329 2-Oxoglutarate dehydrogenase deficiency, 21, 24, 28 2-Oxoglutaric acid excretion, 759 Oxoglutaric Aciduria, 744 2-Oxoglutaric aciduria, 745, 758, 761 Oxoprolinase deficiency, 61, 1438, 1444 5-Oxoprolinase (OPLAH) deficiency, 27, 253, 254 Oxoprolinuria, 256 5-Oxoprolinuria, 251 Δ4-3-Oxosteroid-5β-reductase deficiency, 1101 Δ4-3-Oxosteroid-5β-reductase deficiency, 31, 34 3-Oxothiolase deficiency, 19, 20, 22, 38, 393 OXPHOS disorder, 1420 Oxysterol 7 α-hydroxylase deficiency, 31, 34, 1101 P Paget disease of bone 3 (SQSTM1), 1165 PAH deficiency. See Hepatic phenylalanine-4-hydroxylase (PAH) deficiency Palmoplantar keratoderma with deafness, 853 Pantothenate kinase-associated neurodegeneration (PKAN), 103–104, 566 Pantothenate kinase 2 deficiency, 122, 564–574 Pantothenate metabolism, 565 Papillon–Lefèvre syndrome (PLS). See Cathepsin C deficiency Papillon–Lefèvre syndrome Haim–Munk syndrome, 1238 PAPSS2-CDG, 1341, 1373 Paragangliomas 1, 745 3, 745 4, 745 5, 745 Paraplegin deficiency, 892, 904, 910 Parkin deficiency, 892, 905, 910 Parkinson disease, 638, 640, 644, 853, 854, 1157 2 (PRKN), 1163 6 early onset (PINK1), 1164 type 9, 640, 643, 1210 PASNA. See Primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome PC-D. See Pyruvate carboxylase deficiency (PC-D) P5CS deficiency. See Pyrroline-5-carboxylate synthetase (P5CS) deficiency PCSK9 deficiency with low LDL cholesterol, 1043 PCSK9 superactivity, 29 PDHc deficiency, 740, 760, 761 Pearson syndrome, 173, 174 PEBEL, 566 PEBEL2, 566 Pentosuria, 19, 703 PEPCK deficiency cytosolic, 654 mitochondrial, 654 Peptidyl-tRNA hydrolase 2 deficiency, 855, 881 Perilipin 1 deficiency, 1009, 1010 Perinatal stress HI, 731, 732 Perlman syndrome, 718, 731, 733 Permanent neonatal diabetes mellitus; MODY type 2 (MODY2), 652 Peroxin 1 deficiency, 142 Peroxisomal acyl-CoA oxidase 2 deficiency, 1104, 1300

Disorder Index Peroxisomal acyl-CoA oxidase type 1 (ACOX1) deficiency, 1300, 1307–1308 Peroxisomal alanine-glyoxylate aminotransferase deficiency, 34 Peroxisomal and mitochondrial fission defect, 26, 891, 894–895, 909 Peroxisomal bile acid biosynthesis, disorders of, 1310, 1315 Peroxisomal biosynthesis disorders, 142 Peroxisomal branched-chain acyl-CoA oxidase deficiency, 29, 34 Peroxisomal disorders, 49, 1298–1316 Peroxisomal fission defects, 1307 Peroxisomes and oxalate disorders, 185, 186 Perrault syndrome 6 ERAL1, 882 type 2, 855 type 3, 892 type 4, 855, 878 type 5, 849, 860 type 6, 855 Perry syndrome (DCTN1), 1170 Persulfide dioxygenase (PDO) deficiency, 368 PET100 deficiency, 25, 803, 825 PEX11 beta deficiency, 1301, 1307, 1309 PGAP1-CDG, 34, 1342, 1380 PGAP2-CDG, 34, 1342, 1380 PGAP3-CDG, 34, 1342, 1380 PGM1-CDG, 33, 36, 717, 731, 732, 1343, 1385 PGM3-CDG, 38, 1343 Phenylalanine hydroxylase deficiency, 117, 334, 346, 347, 350 classic PKU, 334, 335 Phenylketonuria (PKU), 4, 5, 9, 11, 14, 20, 50, 53, 92, 102, 103, 148, 154 Pheochromocytoma, 19, 745 Phosphatidic acid-preferring phospholipase 1 deficiency, 998, 1000 2 deficiency, 999, 1000 Phosphatidylserine decarboxylase deficiency (PISD), 996, 998 Phosphatidylserine synthase 1 superactivity, 997, 998 Phosphaturia, 18 Phosphoadenosine 5'-phosphosulfate synthetase 2 deficiency, 1373 Phosphocholine cytidylyltransferase 1α deficiency (PCYT1A), 996, 997 Phosphoenolpyruvate carboxykinase deficiency, 656 Phosphoethanolamine cytidylyltransferase 2 deficiency (PCYT2), 995 Phosphoethanolaminuria, 581 Phosphoglucomutase deficiency, 12 Phosphoglucomutase 1 deficiency PGM1-CDG, 22, 31, 717, 727–728, 1385, 1395 Phosphoglycerate dehydrogenase deficiency, 458 3-Phosphoglycerate dehydrogenase deficiency, 457 Phosphoglycerate kinase deficiency (PGK-D), 652, 686, 688 Phospholipase A2 group 6 deficiency (INAD), 136, 998, 999 Phospholipid-transporting ATPase IB deficiency, 1019 Phosphomannomutase 2 deficiency PMM2-CDG, 21, 717, 724–725, 1345 CDG type 1a, 126 Phosphomannose isomerase deficiency MPI-CDG, 21, 717, 725–726, 731, 732, 1337, 1338, 1344, 1346, 1395 Phosphopantothenoylcysteine synthetase deficiency, 23, 566, 570, 574 Phosphoribosylpyro-phosphate synthetase 1 deficiency, 194, 201 superactivity, 194, 200–201 Phosphoribosyl pyrophosphate synthetase 1 superactivity, 34 Phosphorylase kinase β subunit deficiency, 21, 30, 31, 653 Phosphoserine aminotransferase deficiency, 459 3-Phosphoserine aminotransferase deficiency, 457 Phosphoserine phosphatase deficiency, 457, 459

Disorder Index PIGA-CDG, 30, 34, 1341, 1376 PIGB-CDG, 34 PIGC-CDG, 1341, 1377 PIGG-CDG, 1342, 1379 PIGH-CDG, 34, 1341, 1377 PIGL-CDG, 1342, 1378 PIGM-CDG, 1342, 1378, 1395 PIGM deficiency, 1395 Pigmentary retinopathy and sensorineural deafness, 852 PIGN-CDG, 34, 1342, 1379 PIGO-CDG, 34, 1342, 1379 PIGP-CDG, 1341, 1377 PIGQ-CDG, 1341, 1377 PIGS-CDG, 1342, 1381 PIGT-CDG, 34, 1342, 1379 PIGV-CDG, 1342, 1378 PIGW-CDG, 34, 1342, 1378 PIGY-CDG, 34, 1341, 1377 PINK1 deficiency, 892, 905, 910 Pitrilysin metallopeptidase 1 deficiency, 26, 32, 33, 893, 906, 910 PK-D. See Pyruvate kinase deficiency (PK-D) PKU. See Phenylketonuria (PKU) PMM2-CDG, 29, 31, 717, 731, 732, 1337, 1338, 1344, 1345, 1395 PMP70/ABCD3 deficiency, 1103 PMP70 deficiency, 37, 1306, 1315 PNPLA6 deficiency, 1000–1001 PNPLA8 deficiency, 993, 995 PNPT1 deficiency, 866, 867 POFUT1-CDG, 1341, 1376 POGLUT1-CDG, 1341, 1375 POGLUT2-CDG, 1341 Polycyctic kidney disease 3, 1357 Polyglucosan body myopathy type 1, 654 type 2, 653 Polymicrogyria bilateral temporo-occipital (FIG4), 1170 Polyneuropathy, 458, 1019 Polypeptide N-acetylgalactosaminyltransferase 3 deficiency, 1374 POMGNT1-CDG, 33, 1339, 1361 POMGNT2-CDG, 1339, 1361 POMK-CDG, 33, 1339, 1362 Pompe disease, 76, 81–83, 172, 654 POMT1-CDG, 33, 1339, 1360 POMT2-CDG, 33, 1339, 1360 Pontocerebellar hypoplasia type 6, 854 type 2D, 612 Porokeratosis (PK), 1060 Porphobilinogen deaminase deficiency, 138 Porphyria cutanea tarda type I, II, 1120, 1127 Porphyria variegata, 1121 Postaxial acrofacial dysostosis, 193 P450 oxidoreductase deficiency, 1087 Prenyl diphosphate synthase subunit 1 (PDSS1) deficiency, 917, 920 subunit 2 (PDSS2) deficiency, 917, 920 Primapterinuria, 334 Primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome, 717, 731, 732 Primary carnitine deficiency, 32, 134 Primary cerebral folate deficiency, 180 Primary coenzyme Q10 deficiency, 134 Primary hyperammonemia, 263, 264 Primary hyperoxaluria type 1, 1300 type I, 55, 1320, 1324, 1329

1487 type II, 55, 1320, 1321, 1329 type III, 55, 1320, 1322, 1329 Primary hypertrophic osteoarthropathy type 1, 1031 type 2, 1031 Primary inherited aminoacidurias cystinuria, 292 Primary lateral sclerosis juvenile (PLSJ), 1169 PRKCSH-CDG, 1339, 1344 Profound psychomotor retardation, 456 Progesterone resistance, 1088 Progranulin deficiency, 1210, 1220 Progressive cerebello-cerebral atrophy, 611, 619 Progressive external ophthalmoplegia 1, 849, 857 Progressive external ophthalmoplegia, proximal myopathy and sudden death, 853 Progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant 2, 850 autosomal dominant 3, 849, 859 autosomal dominant 4, 849 autosomal dominant 6, 849 autosomal recessive 2, 849 autosomal recessive 3, 849 autosomal recessive 4, 849 autosomal recessive 5, 850 Progressive external ophthalmoplegia with myoclonus, 853 Progressive familial intrahepatic cholestasis type 1 (PFIC-1), 1140–1141 type 2 (PFIC-2), 1141–1142 type 3 (PFIC-3), 1142 type 4 (PFIC-4), 1143 type 5 (PFIC-5), 1143 Progressive microcephaly, 296 Progressive (congenital) microcephaly, 456 Progressive myoclonic epilepsy type 3, 1210 type 8, 1012 type 2A, 654 type 2B, 654 Progressive necrotizing encephalopathy, 852 Progressive peripheral spasticity with axial hypotonia, 470 Progressive polyneuropathy, 540 Prolidase deficiency, 27, 36, 37, 45, 49, 173 Proline dehydrogenase deficiency, 456, 457, 463 Proline disorders, 455–456 Prominent ears, 462 Propionic academia (α subunit), 423, 428 Propionic academia (β subunit), 423, 428 Propionic acidemia, 11, 49, 61, 67, 71, 119, 394, 407–408 Propionic acidemia (α subunit) DNA analysis, 420 prenatal diagnosis, 420 Propionic acidemia (β subunit) DNA analysis, 420 prenatal diagnosis, 420 Propionic aciduria, 18, 54, 1420 Propionyl-CoA carboxylase deficiency, 20, 22, 23, 27, 36–38, 67, 119, 396, 529, 536 Prosaposin deficiency. See Saposin C deficiency PROSC-deficient B6-dependent epilepsy, 23 Prostaglandin transporter deficiency, 37, 1029, 1031 Protective protein/cathepsin A deficiency, 1252 Protein O-fucosyltransferase deficiency, 1376 Protein O-mannose β-1,4-N-acetylglucosaminyltransferase deficiency, 1361 Protein O-mannose kinase deficiency, 1362

1488 Proton-coupled folate transporter (PCFT) deficiency, 36, 515, 518 Pseudo-hurler, 1238 Pseudo-Hurler polydystrophy, 76 Pseudohypoaldosteronism (type I), 1080, 1088 Pseudo-Sjögren-Larsson syndrome (recessive), 1004 Pseudouridine synthase 1 deficiency, 25, 37, 850, 868 Pseudoxanthoma elasticum (PXE), 216, 218, 229, 231 Pterin-4 α-carbinolamine dehydratase deficiency, 334, 348 Pterin carbinolamine-4 α-dehydratase deficiency, 22, 338 Pterin disorders, 49, 50 Purine nucleoside phosphorylase deficiency, 35, 194, 203 Purple urine bag syndrome, 18 Putative Leigh-like syndrome, 851 Pycnodysostosis, 1238 Pyluria, 18 Pyridoxal-binding protein (PLPBP) deficiency, 578–581, 585, 588, 589 Pyridoxal 5´-phosphate (PLP) dependent epilepsy (PNPO) deficiency, 579–580, 586, 588, 589 Pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, 180 Pyridoxine-dependent epilepsy (PDE), 581 Pyridox(am)ine oxidase deficiency, 475, 476 Pyridox(am)ine 5'-phosphate oxidase deficiency, 20, 579–585, 587–589 Pyridox(am)ine-5-phosphate oxidase deficiency, 57 Pyridoxine-refractory sideroblastic anemia type 2, 768 Pyridoxine-refractory sideroblastic anemia type 3 (SIDBA3), 482 Pyrimidine disorders, 48 Pyrimidine-5'-nucleotidase I deficiency, 36 Pyrimidine 5'-nucleotidase superactivity, 35 Pyroglutamic aciduria, 57, 173 Pyrroline-5-carboxylate dehydrogenase deficiency (PSCDH), 457, 463, 581 Pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, 455, 457, 462 Pyrroline-5-carboxylate reductase 2 (PYCR2) deficiency, 455–457, 462–463 Pyrroline-5-carboxylate synthase (P5CS) deficiency, 455–457, 461 Δ-Pyrroline-5-carboxylate synthase deficiency, 49 Pyrroline-5-carboxylate synthetase (P5CS) deficiency, 22, 264, 266, 282, 284, 285, 287, 288 cutis laxa phenotype 3, 275 spastic paraplegia type 9A, 276 spastic paraplegia type 9B, 276 Pyruvate carboxylase deficiency, 21–23, 49, 56, 117, 266, 279, 284–286, 288, 529, 536, 654, 680, 740, 744, 747 type B, 265 Pyruvate carboxylase deficiency (PC-D), 687, 689, 698 Pyruvate carboxylase deficiency type B, 48, 49 Pyruvate decarboxylase deficiency, 744 Pyruvate dehydrogenase complex deficiency E2, 28, 744, 748 E3, 399 E1a, 23, 28, 747 E1b, 24, 28, 748 E3 X, 24, 28, 749 PDHP, 24, 28, 749 Pyruvate dehydrogenase deficiency, 56, 157 E1-α, 126, 744 E1-β, 126, 744 E3-binding protein, 126, 744 Pyruvate dehydrogenase kinase isoenzyme 3 superactivity, 744, 750 Pyruvate dehydrogenase phosphatase deficiency, 744 Pyruvate kinase deficiency (PK-D), 37, 39, 652, 669–670, 686, 688, 696 Pyruvate metabolism disorders, 48, 739–761 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, 334, 336, 346–348

Disorder Index Q QIL1 deficiency, 893 R Racemase deficiency, 1306 RCDP. See Rhizomelic chondrodysplasia punctata (RCDP) Reduced folate carrier deficiency, 516, 523, 525, 526 Refsum disease, 58, 1300, 1306–1309, 1314–1315 Renal cell cancer, 745 Renal Fanconi syndrome, 17, 19, 48 Renal glucosuria, 18, 661, 689 Renal sodium-glucose cotransporter 2 deficiency (SGLT2-D), 651 3' Repair exonuclease 1 deficiency Aicardi-Goutières syndrome type 1, 217, 222 familial chilblain lupus type 1, 217, 222 retinal vasculopathy with cerebral leukodystrophy, 217, 223 Reticular dysgenesis, 194 Reticulon 4-interacting mitochondrial protein deficiency, 893, 908, 910 Retinal vasculopathy with cerebral leukodystrophy, 215, 217, 223 Retinitis pigmentosa, 744, 850, 1019 Retinitis pigmentosa type 79 (RP79), 652, 666 Retinoskeletal phenotype, 996 Reversible leukoencephalopathy, 57 RFT1-CDG, 33, 1338, 1344, 1350 Rhizomelic chondrodysplasia punctata (RCDP), 1307–1309, 1314–1316 type 1, 1311, 1326 type 2, 1300, 1311 type 3, 1300, 1311 type 4, 1300, 1311 type 5, 1300, 1311 Riboflavin-responsive electron transfer flavoprotein dehydrogenase deficiency, 551 Riboflavin-responsive exercise intolerance, 551, 768 Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (ETFDH), 551 Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD), 551, 560 Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD)—Electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO) deficiency, 556–557 Riboflavin transporter deficiency (RTD), 122, 550, 559 type 1 (RFVT1), 57, 549, 551, 560 type 2 (RFVT2), 548, 550, 551, 553, 560 type 3 (RFVT3), 548, 550, 551, 560 type 3—RTD3-RFVT3 deficiency, 553–554 Ribonuclease H2, 214 subunit A deficiency, 217, 223 subunit B deficiency, 217, 223 subunit C deficiency, 217, 223 Ribonuclease P 5' tRNA processing enzyme deficiency, 25, 850, 866 Ribonuclease T2 deficiency, 215, 218, 228 Ribonuclease Z 3' tRNA processing enzyme deficiency, 25, 850, 866 Ribose-5-phosphate isomerase (RPI), 702, 703, 705, 709–711 RMND1 deficiency, 26, 28 RNASEH1 defect, 849, 862 RNA-specific adenosine deaminase deficiency Aicardi-Goutières syndrome type 6, 217, 225 dyschromatosis symmetrica hereditaria, 217, 225 Rogers syndrome, 537, 538, 540 Rotor syndrome, 1137, 1139–1140 RTD. See Riboflavin transporter deficiency (RTD) Rubinstein-Taybi syndrome, 718, 731, 733 RXYLT1-CDG, 33, 1339

Disorder Index S Saccharopinuria, 50, 1435–1436, 1442 Sacsin deficiency, 892, 904, 910 S-adenosylhomocysteine hydrolase (SAHH) deficiency, 30, 32, 49, 366, 368, 370, 371, 382, 383 Sagging cheeks, 462 SAHH deficiency, 380 Salla disease, 76, 81, 141, 1250, 1252, 1257, 1259, 1262 Salt and pepper developmental regression syndrome, 1017 SAMHD1 deficiency Aicardi-Goutières syndrome type 5, 217, 224 familial chilblain lupus type 2, 217, 224 SAM transporter deficiency, 28, 767 Sandhoff disease, 76, 79, 1196 Sanfilippo disease A, 76, 1268, 1272 B, 76, 1268, 1273 C, 76, 1268, 1273 D, 76, 1268, 1273 Santavuori-Haltia disease, 1209 Saposin C deficiency, 1179, 1180, 1183 Saposin deficiency B, 1196–1197 C, 37, 38, 1180 Sarcosinemia, 50, 1435, 1442 Sarcosine oxidase deficiency, 27 SCAD. See Short-chain acyl-CoA dehydrogenase (SCAD) deficiency SCD-EDS. See Spondylocheirodysplastic Ehlers-Danlos Syndrome (SCD-EDS) SCHAD. See Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency Schindler disease, 76, 81, 1249, 1250, 1255 type II, 1252 type III, 1252 Schizophrenia susceptibility, 463 SCO1 deficiency, 802 SCS deficiency SUCLA2, 745 SCS deficiency SUCLG1, 745 SEC23B-CDG, 37, 1336 Secondary cerebral folate deficiency, 180 Secondary hyperammonemias, 264 Secondary hyperoxaluria, 1322, 1324, 1326, 1329 Secondary mitochondrial respiratory chain deficiencies, 394 Sedaghatian type, 254 Sedaghatian-type spondylometaphyseal dysplasia, 253 Sedoheptulokinase deficiency (SHPK), 702, 703, 707, 709, 710 Segawa disease, 334 Seitelberger disease, 998 Selenocysteine insertion sequence-binding protein 2 (SBP2) deficiency, 611, 612, 618, 619, 621 SELENOI, 994 Selenoprotein Z deficiency, 893 Sengers syndrome, 892, 992, 1417 Sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), 849, 857 Sensory ataxic neuropathy with mitochondrial DNA deletions, 849 Sensory neuropathy, 855 Sepiapterin reductase (SR) deficiency, 332–334, 339, 340, 346, 349 SERAC1-defect, 1417 SERAC1 deficiency, 136, 992, 993, 1419, 1421, 1423, 1428 Serin deficiency, 11 Serine deficiency, 50, 454, 455, 458 Serine palmitoyltransferase subunit 1 deficiency, 1010 2 deficiency, 1012

1489 Serum carnosinase deficiency, 435, 438, 444, 450, 451 Severe combined immunodeficiency (SCID), 9, 192, 194, 203, 209 SGLT1-D, 685, 688 SGLT2-D, 685, 688 SGLT1 deficiency, 651, 682 SGLT2 deficiency, 651, 655 Short-chain acyl-CoA dehydrogenase (SCAD) deficiency, 5, 12, 21, 54, 55, 62, 67, 70, 73, 93, 135, 933, 934, 941, 952, 954, 1439–1440, 1445 Short-chain enoyl-CoA hydratase or crotonase deficiency (SCEH/ ECHS1 deficiency), 393 Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency, 55, 716, 731, 732, 933, 934, 944, 952, 954 Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency, 21 Short stature, developmental delay, and congenital heart defects, 703 Sialic acid synthase deficiency, 1252 Sialidosis, 1252, 1253, 1262 Sialidosis type II, 76, 81, 173 Sialin deficiency, 141 Sialolipidosis, 76 Sialuria, 1251, 1252, 1261 Sialuria, Finnish type, 1252 Sialuria, French type, 1252 Sickle cell anemia, 12 Sideroblastic anemia, 766 Sideroblastic anemia and spinocerebellar ataxia (ASAT), 482 Sideroblastic anemia type 4 (SIDBA4), 482, 892 Sideroflexin 4 deficiency, 26, 29, 37, 893, 906, 910 Simpson-Golabi-Behmel syndrome, 718, 731, 733 Single enzyme deficiencies, 1311 Singleton-Merten syndrome (SGMRT), 215 type 1, 215, 217, 226 type 2, 215, 218, 227 Sitosterolemia, 30, 137, 1041 Sjögren-Larsson syndrome, 135 Skeletal dysplasia, 855 Skin abnormalities, 460 SLC26A2-CDG, 1340, 1373 SLC35A1-CDG, 38, 1343, 1344, 1387 SLC35A2-CDG, 1343, 1344, 1388 SLC35A3-CDG, 1343, 1344, 1388 SLC39A8-CDG, 1343, 1344, 1389 SLC7A5 deficiency, 296 SLC29A1 deficiency, 216 SLC29A3 deficiency, 216 SLC39A8 deficiency, 125, 638–640, 1395 SLC39A14 deficiency, 125 SLC25A42-related disorders, 574 SLC35C1-CDG, 1343, 1344, 1388, 1395 SLC35D1-CDG, 1343, 1344, 1389 Sly disease (MPS VII), 1268, 1275 Smith-Lemli-Opitz syndrome, 29, 137 Smith-Strang disease, 295 Snyder-Robinson syndrome (SRS), 92, 457 Sodium-dependent multivitamin transporter (SMVT) deficiency, 33, 530, 533 Solute carrier family 39 (Zn transporter) deficiency, 1389 Sorbitol dehydrogenase (SORD) deficiency, 703, 707, 709, 710 Sotos syndrome, 717, 731, 732 SOX deficiency, 597 Spastic ataxia 4, autosomal recessive, 850 Spasticity, childhood-onset, with hyperglycinemia (SPAHGC), 482 Spastic paralysis, infantile onset ascending (IAHSP), 1169

1490 Spastic paraplegia, 455 7, 892 11 (SPG11), 1159 15 (ZFYVE26), 1161 47 (AP4B1), 1166 49 (TECPR2), 1162 50 (AP4M1), 1166 51 (AP4E1), 1167 52 (AP4S1), 1165 73 (SPG73), 934 74, autosomal recessive (SPG74), 482 77, autosomal recessive, 855 Spastic tetraplegia, 296, 456, 464 Speech disturbances, 440 Sphingosine-1-phosphate lyase deficiency, 1016, 1017 Spike wave discharges, 442 Spinocerebellar ataxia type 20 (SCARS20), 1155, 1159 type 25 (ATG5), 1163 type 28, 892 type 34 (Dominant), 1004 type 38, 1005 Spondylocheirodysplastic Ehlers-Danlos Syndrome (SCD-EDS), 608, 610–611, 617, 619, 620 Spondylometaphyseal dysplasia, 254, 891 Squalene synthase deficiency, 29, 86, 1058, 1064 SRD5A3-CDG, 1342, 1344, 1382 SSADH. See Succinic semialdehyde dehydrogenase (SSADH) deficiency SSR4-CDG, 1339 S/ß-thalassemia, 12 STAP1 deficiency, 29 StAR deficiency. See Lipoid adrenal hyperplasia Stargardt disease type 3, 1005 Startle disease, familial, 296 STAT2 deficiency, 26, 891, 896, 909 Steroid 5 alpha-reductase 3 deficiency, 1382 Steroid resistant nephrotic syndrome (SRNS), 915, 923 Steroid sulfatase deficiency, 138 Sterol C4-methyl oxidase deficiency, 1059, 1065 Sterol C14-reductase deficiency, 1058, 1065 Sterol Δ5-desaturase deficiency, 1060, 1068 Sterol 27-hydroxylase deficiency, 138, 1102 ST3GAL3, 1017 ST3GAL3-CDG, 1017 STING-associated vasculopathy with onset in infancy (SAVI), 215, 218, 231, 232 STING superactivity, 227 Storage disorders, 38, 185, 186 Striatonigral degeneration, childhood-onset (VAC14), 1172 STT3A-CDG, 1338, 1344, 1355 STT3B-CDG, 38, 1339, 1344, 1356 Subcortical atrophy, 458 Succinate dehydrogenase complex assembly factor 1 deficiency, 130, 800, 818 Succinate dehydrogenase complex assembly factor 2 deficiency, tumoral phenotype, 800, 818 Succinate dehydrogenase subunit A deficiency, 127, 745, 754, 799, 816 tumoral phenotype, 745, 799, 816 Succinate dehydrogenase subunit B deficiency, 127, 745, 754, 799, 816 tumoral phenotype, 745, 799, 817 Succinate dehydrogenase subunit C deficiency, tumoral phenotype, 745, 754, 799, 817 Succinate dehydrogenase subunit D deficiency, 745, 799, 817 tumoral phenotype, 745, 799, 818

Disorder Index Succinic semialdehyde dehydrogenase (SSADH) deficiency, 173, 435, 438–439, 442, 450, 451, 1410 Succinyl-CoA:3-ketoacid-CoA transferase deficiency, 20, 21, 29, 55 Succinyl-CoA:3-oxoacid CoA transferase deficiency, 21, 29, 969, 974 SUCLA2 deficiency, 758, 760, 761 SUCLG1 deficiency, 758, 760, 761 Sudden death, 852 Sudden infant death syndrome, 853 Sulfate transporter deficiency, 1373 Sulfite oxidase deficiency, 49, 50, 369, 370, 375, 579 Sulfur amino acid, disorders of, 365–389 SURF1 deficiency, 131 Syndromic CHI, 714–715, 717 T TACO1 deficiency, 25, 131, 803, 825 Tafazzin deficiency, 26, 28, 29, 32, 38, 992, 994, 1417, 1419, 1421–1423, 1428 Tangier disease, 30, 137, 1045 TANGO2 deficiency, 21, 23, 27, 33, 36 Tarui disease, 652 Tay-Sachs disease, 76, 1196 TBCK deficiency, 1155 T-cell deficiency, 9 T cell immunodeficiency, 194, 197, 203 TCN2 deficiency. See Transcobalamin deficiency, transcobalamin II (TC II) deficiency TCR/CD320 defect, 500 TDP-D-glucose 4,6-dehydrogenase deficiency, 1374 Tetrahydrobiopterin (BH4) metabolism, 314 Tetrapyrroles disorders, 35, 37–39, 185, 186 TFAM deficiency, 867 TFP deficiency, 12 TGDS-CDG, 1341, 1374 TH. See Tyrosine hydroxylase (TH) deficiency THAP11, 510, 511 Thiamine metabolism disorders, 537, 544 Thiamine metabolism dysfunction syndrome type 1 (THMD1), 540 type 2 (THMD2), 538, 540 type 3 (THMD3), 540 type 4 (THMD4), 540 type 5 (THMD5), 23, 540, 542 Thiamine phosphokinase (TPK1) deficiency, 544, 545 Thiamine pyrophosphokinase deficiency, 122, 537, 539, 544 Thiamine-responsive megaloblastic anemia (TRMA) syndrome, 22, 36, 38, 173, 537, 538, 540, 542–545 Thiamine transporter 2 deficiency, 122 Thin corpus callosum, 296 Thiopurine S-methyltransferase deficiency, 195, 206, 210 Thoracic aortic aneurysms, 370 Thrombocytopenia type 4, 804 Thromboxane synthase deficiency, 37, 38, 1028, 1030 THTR1 deficiency, 540 Thymidine kinase 2 deficiency, 192 Thymidine phosphorylase deficiency, 25, 192, 193, 198, 861 Thymine-uraciluria, 58, 193 TIMMDC1 deficiency, 24, 891, 899, 909 TIMM50 deficiency, 26, 891, 1417, 1419, 1421, 1427 Timothy syndrome, 717, 731, 732 TMEM126B deficiency, 37, 799 TMEM165-CDG, 33, 1343, 1344, 1392, 1395 TMEM199-CDG, 30, 31, 34, 1343, 1344, 1391 TOP3A deficiency, 863 TPI-D. See Triosephosphate isomerase deficiency (TPI-D)

Disorder Index

1491

Trafficking kinesin-binding protein 1 deficiency, 893, 907, 9410 Transaldolase (TALDO) deficiency, 20, 27, 31, 33, 34, 36, 38, 173, 174, 701, 703, 705, 709–711 Transcobalamin deficiency, 500, 501, 503, 511 transcobalamin I (TC I) (TCN1) deficiency, 500 transcobalamin II (TC II) deficiency, 36, 120, 500 transcobalamin III, 500 transcobalamin receptor defect, 500, 503, 511 Trans-2-enoyl-CoA reductase deficiency (TECR), 1003 Transferrin receptor 1 deficiency, 628, 632 Transferrin receptor 2 deficiency, 627 Transient infantile hypertriglyceridemia, 766, 767, 961 Transient infantile mitochondrial myopathy, 852 Transient neonatal HI, 714 Transient neonatal zinc deficiency, 610, 611 Transient nonketotic hyperglycinemia, 471 Transient riboflavin deficiency, 549, 551 Transient tyrosinemia, 354 Transketolase (TKT) deficiency, 701, 703, 709, 710 Translocase deficiency, 12 Transmembrane protein 126A deficiency, 893, 907, 910 Transmembrane protein 70 (TMEM70) deficiency, 22, 25, 28, 32, 266, 280, 282, 285–288, 804, 828–829, 1417, 1419, 1421, 1426 Transmembrane protein 165 deficiency, 1395 TRAPPC11-CDG, 33 Treatment-resistant epilepsy, 470 Trehalase deficiency (TREH-D), 651, 661, 685, 688 Trehalose intolerance, 651 Tremor, 455, 608 Trifunctional dehydrogenase/cyclohydrolase/synthetase, 518 Trifunctional protein β subunit deficiency, 31, 934, 947–948 Trifunctional protein deficiency, 21, 23, 27, 29, 33, 36 Trimethylaminuria, 19, 174, 1434–1435, 1441 Triosephosphate isomerase deficiency (TPI-D), 37, 39, 652, 668, 686, 688 Tripeptidyl-peptidase 1 deficiency (NCL2), 1211–1212 TRMA syndrome. See Thiamine-responsive megaloblastic anemia (TRMA) syndrome tRNA 5-carboxymethylaminomethyl transferase deficiency, 21, 25, 28, 850, 868 tRNA isopentenyl transferase deficiency, 850 tRNA methyltransferase 5 deficiency, 25, 28, 850, 869 tRNA synthetase disorders, 111, 132, 133 tRNA 5-taurinomethyluridine modifier deficiency, 25, 850, 868 Tryptophanuria, 50 Tubulointerstitial nephropathy, 853 Turner syndrome, 717, 723, 731, 732 TUSC3-CDG, 1336, 1338, 1344, 1354 TWINKLE mitochondrial DNA helicase deficiency, 849 Tyrosine aminotransferase deficiency, 355 Tyrosine hydroxylase (TH) deficiency, 314–318, 325–327 Tyrosinemia, 117 type I (TYR1), 10, 11, 14, 19, 20, 30, 48–50, 53, 172–174, 178, 354–358, 361 type II (TYR2), 14, 19, 20, 50, 53, 354, 355, 357, 358, 361, 362 type III (TYR3), 14, 50, 53, 355, 357, 358, 361, 362

UDP-N-acetylglucosamine transporter deficiency, 1388 UGO-1 like protein deficiency, 28, 891, 896, 909 Uncoupling protein 2 deficiency, 20, 716, 722, 731, 732 Upslanting palpebral fissures, 462 Uracil-DNA glycosylase (UNG) deficiency, 214, 216, 218, 231 Urate transporter 1 deficiency, 35, 195, 207 Urate voltage-driven efflux transporter 1 deficiency, 35, 195, 207 Urea cycle defects, 41, 42, 48, 49 Urea cycle disorder, 9, 14, 19, 29, 100–102, 171–177, 1420 Uridine diphosphate galactose-4-epimerase deficiency, 22, 31, 655, 664 Uridine 5ʹ-monophosphate hydrolase 1 deficiency, 193 Uridine monophosphate synthase deficiency, 193, 197–198 Urocanic aciduria, 1433, 1441 Uroporphyrinogen cosynthase deficiency, 37 USP9X deficiency, 892, 905, 910

U UDP-galactose transporter deficiency, 1395 UDP–GlcNAc:Dol-P-GlcNac-P transferase deficiency, 1346–1347 UDP-GlcNAc epimerase-kinase deficiency, 1257 UDP-GlcNAc epimerase-kinase superactivity, 1257 UDP-glucose ceramide glucosyltransferase deficiency, 1014 UDP–glucuronic acid/UDP-N-acetylgalactosamine dual transporter deficiency, 1389

X X-ALD. See X-linked adrenoleukodystrophy (X-ALD) Xanthine dehydrogenase deficiency, 204 Xanthine oxidase deficiency, 35, 194, 195 Xanthinuria, 191, 192 type 1, 194 type I, 594, 601 type II, 594, 595, 597, 601

V Vacuolating myelinopathy, 367 Vacuolating myelopathy, 370 Valosin-containing protein superactivity, 32, 33, 910 Van Bogaert–Bertrand disease, 1400, 1402 Ventriculomegaly, 464 Vertebral, cardiac, renal, and limb defects syndrome type 1 (VCRL1), 566 Vertebral, cardiac, renal, and limb defects syndrome type 2 (VCRL2), 566 Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 5, 12, 14, 21, 32, 36, 55, 67, 70, 73, 932, 934, 943, 952, 954 Very long-chain fatty acid (VLCFA) elongase deficiency 1, 136, 1004 4, 1004, 1005 5, 1005 Vesicular monoamine transporter 2 deficiency, 316, 325–327 Vici syndrome, 1155, 1158 Vitamin B12 deficiency, 45, 52, 59, 379 cobalamin (Cbl), 498, 499 Vitamins, cofactors, metals, and minerals disorders, 20, 22, 23, 27, 28, 31–37, 39, 184–186 VLCAD. See Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency VLCFA. See Very long-chain fatty acid (VLCFA) elongase deficiency von Gierke disease, 653 V0 subunit a2 of vesicular H(+)-ATPase deficiency, 1390 W WDR45 deficiency (BPAN), 139 Wernicke-like encephalopathy and BRBG, 542 White matter disorders, 108 Wilson disease, 31, 36, 38, 39, 123, 173, 174, 607, 608, 610, 614, 619–622 Wolman disease, 76, 173, 174 Wrinkly skin, 461, 462

1492 Xanthurenic aciduria, 19, 566 X-linked adrenoleukodystrophy (X-ALD), 108, 109, 142, 1300, 1306, 1309, 1314–1316 X-linked Charcot-Marie-Tooth disease-5, 194 X-linked creatine deficiency syndrome, 236 X-linked cutis laxa, 611 X-linked distal hereditary neuropathy, 609 X-linked distal spinal muscular atrophy, 611, 615, 619 X-linked dominant ALG13-CDG, 1347 X-linked dominant Conradi-Hünermann syndrome. See X-linked dominant sterol Δ8,Δ7-isomerase deficiency X-linked dominant sterol-4 α-carboxylate 3-dehydrogenase deficiency, 1059, 1066 X-linked dominant sterol Δ8,Δ7-isomerase deficiency, 1059, 1067 X-linked dominant UDP-N-acetylglucosamine transferase catalytic subunit deficiency, 1347 X-linked mental retardation Hedera type, 1343 type 99, 892 X-linked mental retardation 63, 985, 1006 X-Linked Mitochondrial Myopathy, 893 X-linked multi-system disorder with cardiomyopathy, 392 X-linked OTC deficiency (ornithine carbamoyltransferase deficiency), 160 X-linked protoporphyria, 1118 X-linked recessive ALG13-CDG, 1347 X-linked recessive sterol-4 α-carboxylate 3-dehydrogenase deficiency, 1059, 1066 X-linked recessive sterol Δ8,Δ7-isomerase deficiency, 1059, 1067

Disorder Index X-linked recessive UDP-N-acetylglucosamine transferase catalytic subunit deficiency, 1347 X-linked sideroblastic anemia, 1118 X-linked sideroblastic anemia with ataxia (ABCB7), 479, 490 X-linked spinal and bulbar muscular atrophy, 33, 137 X-prolyl aminopeptidase 3 deficiency, 893, 906, 910 45,X syndrome, 717 Xylitol dehydrogenase deficiency, 703 XYLT1-CDG, 1340, 1367 XYLT2-CDG, 1340, 1367 XYLT1 deficiency, 1367 XYLT2 deficiency, 1367 L-Xylulose reductase deficiency, 702, 703, 707, 709 L-Xylulosuria, 703 Y YME1L1 deficiency, 26, 893, 906, 910 Yunis-Varon syndrome, 1155, 1171, 1172 Z Zellweger spectrum disorders, 31, 1298, 1299, 1306, 1307, 1309, 1311, 1313–1315 Zellweger syndrome, 108–110, 142 Zinc-deficiency type (AEZ), 611 Zinc metabolism disorders, 608 Zinc transporternnn deficiency, 611, 617 ZNF143, 510, 511

Test and Medication Index: Strange Association

A AAA domain-containing, member 3A, 893 AARF domain containing kinase 3, 918 AARF domain containing kinase 4, 918 Abdominal ultrasonography, 1225 Abetalipoproteinemia, 173 Abnormal holocarboxylase synthetase, 533 ACAD9, 953 Accessory subunit 1 of the vacuolar-ATPase protein, 1343 2-Acetamido-N-(L-aspart-4'-oyl)-2-deoxy-β-glucopyranosylamine, 1259, 1260 Acetoacetate, 20, 413, 832, 883, 884 Acetoacetic acid, 19, 971–974 Acetone, 20 Acetyl carnitine, 14 Acetyl-CoA alpha-glucosaminide acetyltransferase, 78–80, 1269 alpha-glucosaminide N-acetyltransferase, 1280 alpha-N-glucosaminide-N-acetyl transferase, 1273 carboxylase (ACC), 530 Acetylglucosaminyltransferase-like protein, 1339 Acidosis, 175 Acids ceramidase, 1192 sphingomyelinase, 76 Aconitase, 488 ACRE inhibitors, 697 ACTH, 569 Activation-induced cytidine deaminase, 218 Acylcarnitines, 4, 5, 10–12, 52, 60, 61, 63, 65–73, 172, 177, 179, 377, 381, 413, 415, 418, 419, 550, 557, 559, 571, 683, 784, 950, 951, 971, 973, 1411 Acyl carrier protein (ACP), 987 Acyl-CoA binding domain-containing protein 5, 1300 Acyl-CoA dehydrogenase, 552, 799, 934 Acylglycerol kinase, 892 Acylglycine conjugates, 557 Acylglycine derivatives, 550 Acylglycines, 52, 63, 68, 71, 419, 554, 559, 784, 951, 973, 974 Adaptor-related complex protein 1, 608, 611 Adenine, 205 Adenine nucleotide translocator 1, 767, 850 Adenine phosphoribosyl transferase, 194, 205 Adenosine, 372, 378, 724 deaminase, 9, 203, 214 deaminase 1, 194 deaminase 2, 194 kinase, 49, 192, 369 monophosphate deaminase, 202 monophosphate deaminase 1, 194 monophosphate deaminase 2, 194 monophosphate deaminase 3, 194

triphosphatase carnitine uptake, 173 Adenosylcobalamin (AdoCbl), 501 Adenosylhomocysteinase, 368 Adenosyltransferase, 49, 501 Adenylate kinase, 173, 205 Adenylate kinase 1, 194 Adenylate kinase 2, 173, 194 Adenylosuccinate, 760 Adenylosuccinate lyase, 194, 201 Adipic acid, 60, 406, 411, 553, 555–557, 780, 781, 785, 815, 937–940, 942, 943, 945, 947, 971 Adrenal androgens, 1086 Adrenocorticotropic hormone (ACTH), 964 AG-348, 696 AGU, 1259 AICAR, 519 AICA riboside, 202 AICAR transformylase, 194, 202 AKR1D1 gene sequencing, 1101 AKU. See Alkaptonuria (AKU) 5-ALA dehydratase, 1124 Alanine, 14, 42–45, 48, 86, 484, 542, 543, 585, 680, 681, 696, 747–749, 815, 820, 823, 824, 826, 829, 832, 875, 879, 883, 902, 909, 949, 1426 Alanine-glyoxylate aminotransferase, 55, 1321 Alanineglyoxylate and serine-pyruvate aminotransferase, 1300 Alanyl-tRNA synthetase 2, 854 ALAT, 371, 372, 629, 632, 663–665, 672–677, 679, 706, 724, 774, 778, 785 Albumin, 59, 69, 371, 608, 611, 614, 618, 678, 706, 725, 726, 778, 923, 1009, 1100, 1101, 1129, 1291, 1293, 1345, 1346, 1348, 1350, 1352, 1354 Albuterol, 698 Alcohol dehydrogenase, 612 Aldolase A, 651, 652, 655, 666, 668 Aldosterone, 569, 1084, 1085, 1088 ALD protein, 1300 Alglucosidase alfa, 697 Alkaline phosphatase, 33, 34, 580, 581, 585, 612, 616, 621, 706, 711, 1100–1103, 1105, 1165, 1376–1380, 1392 Alkalosis, 1083 Alkaptonuria (AKU), 183, 355, 358, 362 Alkylglycerol, 1315 Alkylglycerone-3-synthase, 1304 ALLN-177, 1329 Allochenodeoxycholic acid, 1101 Allocholic acid, 1101 Allo-isoleucine, 8, 42, 46–48, 398, 414, 416 Allopurinol, 204 Alpha-AASA dehydrogenase, 584 α-Aminoadipate, 42 Alpha-aminoadipic semialdehyde, 375

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5

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1494 Alpha-aminoadipic semialdehyde dehydrogenase, 579, 581, 583, 587 Alpha-aminoadipic semialdehyde synthase, 564 α-Aminobutyrate, 42 α-Aminoisobutyric acid, 243, 248 Alpha-aminosemialdehyde, 375, 379, 598–600 4-alpha-carboxymethyl sterol, 1066 4α-dimethyl sterols, 1065 Alpha-fetoprotein, 778, 858, 1141 α-fucosidase, 1252 Alpha-L-fucosidase, 76, 81, 1243, 1255 Alpha-galactosidase, 76, 83, 1193 Alpha-1,4-glucosidase, 654, 679 7α-hydroxycholesterol dehydrogenase, 1100 Alpha-iduronidase, 1269, 1271 Alpha-ketoglutarate, 542–544, 715, 721, 779–781, 785 α-ketoglutarate dehydrogenase, 744 Alpha-ketoglutaric acid, 774 α2-macroglobulin, 608 Alpha-mannosidase, 76, 81 Alpha-mannosidase B, 1252, 1254 α-D-mannosidase, 1264 4-Alpha-methyl sterols, 1065, 1066 Alpha-N-acetylgalactosaminidase, 76, 81, 1252, 1255 Alpha-N-acetylglucosaminidase, 78, 80, 1273, 1298 Alpha-neuraminidase, 81 Alpha-neuraminidase activity, 1189, 1253 Alpha subunit of glucosidase II, 1339 AMACR gene, 1103 Amino acid N-acyltransferase, 1096 Amino acids, 4, 10, 18, 20, 41–53, 60, 61, 63, 65, 66, 68, 69, 175, 239, 241, 252, 256, 381, 419, 449, 508, 515, 587, 656, 661, 663, 664, 683, 691, 695, 766, 784, 795, 884, 1310, 1413, 1414 Amino acid transporter, 42, 76 Amino acid tryptophan, 563, 567 Aminoacidurias, 307 5-Aminoimidazole-N-succinylcarboxamide ribotide, 760 2-Aminoisobutyrate, 406, 443 3-Aminoisobutyric acid, 406, 443 5-Aminolevulinic acid, 1118, 1121, 1125 δ-Aminolevulinic acid, 48 Aminopeptidase P3, 893 3-Amino-2-piperidone, 240, 465 Amish microcephaly, 768 Ammonia, 17, 19, 42–44, 49, 177, 179, 240, 398, 400, 402, 403, 406, 408, 409, 411, 413, 460, 461, 465, 506, 555, 556, 571, 668, 670, 672, 674, 680, 681, 684, 720–722, 728, 747, 778–781, 785, 815, 818, 827, 829, 834, 836, 872, 883, 908, 944, 945, 947, 954, 972–974, 976, 994, 1385, 1406, 1418, 1448, 1426, 1427 detoxification, 263, 264 scavengers, 176 Amniocytes, 535 Amnionless, 498–500 AMP-activated protein kinase ã2 subunit, 653 Amylase, 693, 694 Amylo-1,6-glucosidase, 653, 660, 675 Amylopectin, 677, 678 Androgens, 1084, 1085, 1087 Androstenedione, 1373 Androsterone/etiocholanolone ratio, 1088 Anion gap, 43, 51, 52, 177, 506, 671, 829, 993, 1444 Anserine, 45, 444 Antibody testing, 1284 Anti-epileptic drugs, 787, 1313, 1314 Anti-Mullerian hormone (AMH), 1087 Antinuclear antibodies, 222

Test and Medication Index: Strange Association Antioxidants, 834 Antiquitin, 579 Antithrombin, 1385 Antithrombin III, 725–728, 1346, 1347, 1350, 1351, 1353, 1354, 1358, 1359, 1382, 1384 Apo A-I, 1046 Apo B, 1040–1044 Apo-ceruloplasmin, 608 Apolipoprotein A-I binding protein, 566 B, 726, 1351 C-III, 1389, 1392, 1395 Apoptogenic protein 1, 803 Apoptosis inducing factor mitochondria associated 1, 893 Aquaglyceroporin family, 960 Aquaporin 7 (AQP7), 960, 961 L-Arabinose, 707 Arabitol, 705–707 L-Arabitol, 707 L-Arabitol dehydrogenase, 703 Arachidonic acid, 1006 Arginase 1 deficiency, 264, 266, 270, 282, 284, 285, 287, 288 Arginine, 14, 18, 42–46, 48, 102, 117, 236, 240, 247, 461, 465, 681, 696, 778, 780, 781, 784, 1414 L-Arginine, 176, 242, 248, 886 Arginine aspartate, 696 Arginine/glycine amidinotransferase, 236 L-Arginine:glycine amidinotransferase, 112 L-Arginine hydrochloride, 511 Argininemia, 266 Argininosuccinate, 44, 48 lyase, 42, 48, 266, 270, 282, 284, 285, 287, 288 synthetase, 42, 48, 266, 269, 282, 284, 285, 287, 288 Argininosuccinic acid, 18 Argininosuccinic aciduria, 266 Arginyl-tRNA synthetase 2, 854 Aromatic acid decarboxylase (AADC), 578 Aromatic acids (4-hydroxyphenyl), 59 Aromatic L-amino acid decarboxylase, 56, 315, 316, 319, 325–327 Arylsulfatase A, 76, 725–727, 1194, 1346, 1353, 1358 ASAT, 371, 629, 632, 664, 665, 672–675, 679, 774, 778, 785 ASAT/ALAT, 175, 177, 484, 489, 490, 614, 616, 753, 756, 830, 864, 908, 963, 971, 972, 1008, 1009, 1103, 1392 Ascorbic acid, 19, 261 ASCT1 transporter deficiency, 296, 301, 302, 305, 306 Asialotransferrin, 725–728, 1346–1356, 1359, 1385 Asparagine, 42–44, 48, 454, 456, 464 Asparagine synthetase, 457 Asparaginyl-tRNA synthetase 2, 854 Aspartate aminotransferase (AAT), 596, 597 Aspartate-glutamate carrier, 767, 786 Aspartate transcarbamoylase, 193, 1343 Aspartic acid, 42, 43, 48 Aspartoacylase, 56, 1400, 1402, 1408, 1412 Aspartoacylase deficiency, 111 Aspartylglucosamine, 1256 Aspartylglucosaminidase, 1256 Aspartylglucosaminuria, 1252 Aspartyl-tRNA synthetase 2, 854 AT2221, 698 Ataluren, 1282 ATB200, 698 ATP7A, 611 ATP13A2, 1223 ATP13A2, 638–640, 643, 644 ATP/ADP-translocator, 884

Test and Medication Index: Strange Association ATPase, 884 ATPase family, 893 ATPase subunit E, 1343 ATP7B, 611 ATP-binding cassette, 218 ATP6E, 1343 ATP production, 773, 785, 884 ATP-specific succinyl-CoA ligase β subunit, 744, 850 ATP synthase F1 complex assembly factor 1, 804 ATP synthase F1 complex H+ transporter epsilon subunit, 804 ATP synthase F1 complex H+ transporter subunit 1, 803 ATP synthase (complex V) subunit 6, 804 ATP synthase (complex V) subunit 8, 804 Autism spectrum disorder (ASD), 292 Autoantibodies, 227 B Baclofen, 1230 Barbiturates, 834 Base excess, 411 B(0)AT1, 566 B12-binding alpha-globulin, 500 BCS1L assembly of complex III of the mitochondrial respiratory chain, 800 Beets, 18 Benzoate, 176, 476, 477 Benzodiazepine, 477 Benzodiazepine receptor antagonist of the GABA(A) receptor, 451 Benzoic acid, 59 Beta-alanine, 46, 48, 406, 434, 444 Beta amino acid, 437 Beta-aminoisobutyrate, 43, 434 Beta-aminoisobutyric acid, 441, 450 Beta and gamma amino acid dipeptides, 434 β-aminoisobutyric acid, 48 β-D-galactosidase, 1269 β-D-glucuronidase, 1269 β-galactosidase, 1185 β-1,4-galactosyltransferase, 638, 639 β-GCase, 1180 β-hexosaminidase A, 1183, 1258 3β-hydroxy-5-cholestenoic acid, 1102 Beta-δ-glucosidase, 1190, 1191 Beta-galactosidase, 76, 78, 80, 81, 1189, 1193, 1194, 1253, 1269, 1274, 1299 Beta-1,3-galactosyltransferase 6, 1340 Beta-1,4-galactosyltransferase 1, 1339 Beta-glucuronidase, 76, 78–80, 1269, 1275, 1300 Beta-1,4-glucuronyltransferase 1, 1339 Beta-hexosaminidase, 76, 81, 1187, 1188, 1193, 1194 Beta-hydroxybutyrate, 815, 949 17-Beta-hydroxysteroid dehydrogenase type 10, 405, 870 17-beta-hydroxysteroid dehydrogenase type 10, 851 Betaine, 248, 382, 384, 385, 510, 511, 524–526 Beta-ketothiolase (BKT), 11, 14, 54, 61, 67 Beta-mannosidase, 76, 81, 1252, 1254 Beta-mercaptolactate cysteine disulfide, 376 Beta-1,3-N-acetylgalactosaminyltransferase 2, 1339 Beta-ureidopropionase, 194 Bezafibrate, 955 Bezafibrates, 953 BH4. See Tetrahydrobiopterin (BH4) Bicarbonate, 786, 1291, 1293 Bicarbonate supplementation, 761 Bicarbonate therapy, 740

1495 D-Bifunctional protein, 1300 Bile acid(s), 46, 616 Bilirubin, 18, 19, 153, 156, 258, 614, 629, 664, 665, 668–670, 672, 706, 724, 756, 1100, 1101, 1105, 1129, 1131, 1134, 1137, 1143, 1427 conjugated, 372, 908 glucuronides, 1131 total/direct, 778 Biotin, 57, 178, 529–536, 545, 789 Biotinidase, 4, 9, 12, 23, 57, 61, 67, 173, 178, 530, 532, 673–677, 682 Bisphosphonates, 232, 1245 Blood gas, 179, 683, 694, 884 Blood gastrin, 1241 Blood iron, 1241 Blood propionylcarnitine, 508 Bloodspot acylcarnitine, 179 Blue histiocytes, 1193 BolA family member 3 (BOLA3), 481, 482, 490, 491 Bone density, 694 Bone marrow transplant (BMT), 1232 Brain dopamine-serotonin vesicular transport disease, 314 Brain MRI, 638–640, 643, 644 Branched-chain, 19 Branched-chain dicarboxylic acids, 1064 Branched-chain ketoacid dehydrogenase, 481, 486 Branched-chain oxoacids, 19, 398 Branching enzyme, 653, 672 2-Butanone, 20 Butyrylcarnitine, 14, 71, 72 Butyrylglycine, 408, 941 C Ca++, 585 CACT. See Carnitine acylcarnitine translocase (CACT) C2 acylcarnitine, 971 C3-acylcarnitine, 498 C4-acylcarnitine, 67, 70–73, 401, 403, 780, 782, 784, 941 C5-acylcarnitine, 67, 70, 71, 73, 400, 780, 782, 784 C6-acylcarnitine, 942 C6:1 acylcarnitine, 406 C8-acylcarnitine, 942 C10 acylcarnitine, 782 C10-acylcarnitine, 780, 784 C10:0-acylcarnitine, 942 C10:1-acylcarnitine, 942 C10:2 acylcarnitine, 568 C12:0-acylcarnitine, 780, 782, 784 C14:0-acylcarnitine, 780, 782, 784, 815, 939, 940, 943, 949 C14:1-acylcarnitine, 943, 945, 947 C16:0 acylcarnitine, 571 C16:0-acylcarnitine, 780, 782, 784, 815, 937–940, 943, 949 C16:1-acylcarnitine, 815, 943, 949 C18:0 acylcarnitine, 571 C18:0-acylcarnitine, 780, 782, 784, 815, 937–940, 943, 949 C18:1-acylcarnitine, 815, 937–940, 943, 949 C18:2-acylcarnitine, 815, 937–940, 943, 949 Calcium, 400, 663, 664, 691–694, 719, 1100, 1291, 1324 Calcium-activated nucleotidase 1, 1340 Calcium-binding carrier, 767 Calcium oxalate, 1330 Calprotectin, 618 Carbamazepine, 1227, 1231, 1263 Carbamoyl phosphate synthetase, 193, 1343 Carbamoyl phosphate synthetase I, 264, 266, 268, 282, 284, 285, 287, 288

1496 Carbohydrate, 51, 52 Carbohydrate kinase domain-containing protein, 566 Carbohydrate sulfotransferase 11, 1340 Carbohydrate sulfotransferase 14, 1340 Carbonic anhydrase, 612 Carbonic anhydrase VA (CAVA), 266, 273, 282, 285, 286, 288 Carboxylase assays, 535 Carboxylic acid, 51 Cardiac glycogenosis, 173 Cardiolipin, 994 Carnitine, 7, 9, 12, 19, 52, 61, 62, 65–68, 70, 71, 178, 419, 421, 422, 424, 559, 692, 694, 780, 782, 789, 884, 950, 951, 971–974, 994, 1401, 1411–1413 esterified, 1443 free, 8, 12, 14, 66, 67, 71, 1443 free/total, 1291 palmitoyltransferase, 70 palmitoyltransferase I, 21, 66, 67, 71, 73 palmitoyltransferase II, 21, 23, 32, 36, 65, 67, 70, 71, 73 total and free, 1291 L-Carnitine, 69, 71, 176, 425–428, 511 Carnitine acylcarnitine translocase (CACT), 66, 67, 70, 71, 73, 934, 935, 953 Carnitine, esterified, 400–404, 408, 410, 413 Carnitine, free, 400–404, 406, 408, 410, 411, 413, 506, 553–557, 571, 779, 785, 815, 830, 937–943, 945, 946, 950, 951 Carnitine palmitoyltransferase, 934, 935 Carnitine palmitoyltransferase 2, 934 Carnitine treatment, 953 Carnosine, 444 Carvedilol, 788 Caseinolytic mitochondrial matrix peptidase proteolytic subunit, 892 Caseinolytic peptidase B, 892 Cataract, 1102 Catecholamines, 19, 609, 754, 817, 818 Cathepsin A, 76, 81, 1183, 1189, 1253 C, 1238, 1264 D, 77, 1210, 1221 F, 1210 K, 1235–1270 Cationic amino acid transporter 2 deficiency, 296, 300, 302, 304, 306 CAVA. See Carbonic anhydrase VA (CAVA) C27-bile acid, 1103 C4 butyrylcarnitine, 376, 378, 941 CCA-adding tRNA-nucleotidyltransferase, 850 C4-C18 acylcarnitine, 553–557 C16-C18 acylcarnitine, 939, 940 C4-C10 acylcarnitines, 555, 779 C4-C18 acylcarnitines, 554 C3/C0 acylcarnitines ratio, 408, 506 C3/C2 acylcarnitines ratio, 408, 506 C5/C2 acylcarnitines ratio, 400, 401, 1444 C8/C12 acylcarnitines ratio, 942 C14:1/C4 acylcarnitines ratio, 943 C14:1/C12:1 acylcarnitines ratio, 943 C27-carboxylic acid, 1096 C8 carnitine, 67, 70–73 C10 carnitine, 67, 70, 71 C0/C16 + C18 acylcarnitines ratio, 571 C3/C4DC acylcarnitines ratio, 408, 506 C6-C10 dicarboxylic acids, 553–557 C26-ceramide, 1192, 1194 C16-C18 hydroxyacylcarnitine, 945–947 C6DC acylcarnitine, 406, 972 C5-DC glutarylcarnitine, 376

Test and Medication Index: Strange Association C3-DC malonylcarnitine, 411 C3-DC methylmalonylcarnitine, 409, 410 C4-DC methylmalonylcarnitine, 411, 752, 753, 864 C4-DC succinylcarnitine, 752, 753, 864 CDG2N, 637, 639–641, 643, 644 CD320 receptor, 500 Cell-free amniotic fluid, 510 Centrosomal protein, 89-KD, 803 Ceramidase, 1191 Ceramide, 989, 1016 Cerebroside beta-galactosidase, 1185 Cerebrospinal fluid, special assays in, 379 Ceruloplasmin, 608, 609, 614–616, 627, 631, 1392 C26:0 fatty acid, 222–224 C1GALT1-specific chaperone 1, 1341 Chaperones, 1287–1288 Chelating agents, 622 Chenodeoxycholic acid, 1100 Childhood-onset, 638, 643 Chitotriosidase, 77, 1190, 1191, 1193, 1198 Chlorhexidine gluconate, 1246 Cholesta-8,14-dien-3β-ol, 1065 Cholestane pentol glucuronide, 1102 Cholestanol, 1102 8(9)-Cholestenol, 1067 Cholesterol, 29, 411, 673–677, 696, 725–727, 774, 780, 782, 785, 962, 963, 994, 997, 1010, 1011, 1036, 1040–1044, 1063, 1068, 1069, 1102–1104, 1193, 1346, 1352, 1353, 1381, 1392, 1422 Cholesterol 7α-hydroxylase, 30 Cholesteryl esters, 1183 Cholic acid, 1313, 1314 Choline, 103, 106, 413, 516, 520, 523, 525 Choline/creatine ratio, 458 Cholinesterase, 725, 726, 1346 Chondroitin sulfate, 1274, 1275 Chondroitin sulfate N-acetylgalactosaminyltransferase 1, 1340 Chondroitin sulfate synthase 1, 1340 Chondroitin 6-sulfotransferase 3, 1340 Chorionic villous sampling (CVS) DNA, 510 C14:0-hydroxyacylcarnitine, 945, 947 C14:1-hydroxyacylcarnitine, 946, 947 C16:0-hydroxyacylcarnitine, 946, 947 C16:1-hydroxyacylcarnitine, 946, 947 C18:0-hydroxyacylcarnitine, 946–952 C18:1-hydroxyacylcarnitine, 946, 952 C18:2-hydroxyacylcarnitine, 946, 952 Cis-aconitic acid, 60 C4 isobutyrylcarnitine, 376, 378 C5 isovalerylcarnitine, 376, 378, 400 Citrate, 132, 1326 Citric acid, 55, 60, 66, 1325 Citric acid cycle intermediates, 823, 827 Citrin, 266, 272, 282, 284–288 Citrullin, 680, 681 Citrulline, 14, 19, 42–44, 47–49, 240, 461, 465, 747, 778, 780, 782, 784, 829, 1426 Citrullinemia, 11, 14, 42, 48, 50, 102 Citrullinemia type I, 266 C18:1-Ketoacylcarnitine, 946 C18:2-Ketoacylcarnitine, 946 Clenbuterol, 698 CLN3, 1209 CLN5, 1209 CLN6, 1209 CLN8, 1209

Test and Medication Index: Strange Association Clonazepam, 574 C5 2-Methylbutyrylcarnitine, 376, 401, 1444 C5 2-methylbutyrylcarnitine, 378 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, 1339 CMP-sialic acid transporter, 1343 Coagulation factors, 664, 672, 675 Cobalamins, 8, 11, 14, 49, 382, 385, 497–512, 548 C18:2 Octadecadienoylcarnitine, 948 C18:1 Octadecenoylcarnitine, 948 Coenzyme A, 563–565 Coenzyme A synthetase, 567 Coenzyme-Q, 548 Coenzyme Q10, 915–924 C5-OH acylcarnitine, 402, 403, 406, 532, 972, 1443 C4-OH hydroxybutyrylcarnitine, 720, 721, 944 C12-OH 3-hydroxy dodecanoylcarnitine, 947 C4-OH 3-hydroxyisobutyryl-carnitine, 404 C18-OH 3-hydroxy octadecanoylcarnitine, 948 C18:1-OH 3-hydroxy octadecenoylcarnosine, 945, 948 C14-OH 3-hydroxy tetradecanoylcarnitine, 945, 947 C5-OH 2-methyl-3-hydroxy-butyrylcarnitine, 405, 413, 870 Coiled-coil domain-containing protein 115, 1343 Colestipol, 46 Complement C1q-binding protein, 893 Complexes I–II, 485 Complexes I–III, 485, 486, 488 Complexes I–IV, 483, 486–490 Complex I activity, 807–814, 816, 868 Complex II activity, 816, 818 Complex III activity, 808, 818 Complex IV activity, 868 Complex IV cytochrome C oxidase subunit 1, 801 subunit 2, 801 subunit 3, 801 Complex V activity, 829 Complex V assembly protein, 804 Copper, 607–622 Copper-binding cytochrome C oxidase assembly protein 1, 802 Copper chloride, 621 Copper-dependent enzymes, 609 Copper histidine, 621 Coproporphyrin, 1124 Coproporphyrin I, 1119, 1124 Coproporphyrin III, 1119–1121, 1124 COQ4, 917 COQ9, 918 CoQ10, 561, 920–923 COQ7, di-iron oxidase, 917 COQ6 monooxygenase, 917 C12orf65 release factor, 852 14 C-ornithine incorporation, 785 Cortisol, 179, 569, 714, 1084, 1088 cortisol, 683 Coupling state M, FB, 884 C16 palmitoylcarnitine, 947 C-peptide, 179, 729 14C-Propionate incorporation assay, 409 C3 propionylcarnitine, 408, 409, 411, 504–506, 508 CPTI, 953 CPTII, 953 C-reactive protein, 1063 Creatine, 103, 235–248, 384, 461, 465, 574, 780, 782, 785, 880 kinase, 17, 32, 68, 172, 202, 371, 372, 403, 487, 488, 490, 555–557, 561, 571, 668–670, 672, 674, 677, 679, 696, 697, 724, 728, 779, 780, 782, 785, 795, 815, 829, 830, 836, 860,

1497 875, 878, 883, 884, 898, 906, 908, 937, 939, 940, 943, 945, 946, 952, 954, 994, 996, 1007, 1010, 1011, 1063, 1164, 1257, 1347–1350, 1359–1366, 1383–1385, 1387, 1392, 1406, 1448, 1426, 1451 monohydrate, 247, 248, 458 ratio, 458 Creatine/phosphocreatine ratio, 465 Creatinine, 17, 19, 20, 27, 43–45, 60, 61, 69, 73, 79, 80, 258, 259, 1045, 1322, 1326, 1407, 1408 Crotonylglycine, 971 CRP,690 CSF-plasma glycine ratio, 475, 476 C14:1 tetradecenoylcarnitine, 943, 947 C5:1 tiglylcarnitine, 405, 413, 870 Cubilin, 498–500 Cu-histidinate, 622 Cultured amniocytes—Enzymatic assays, 510 C6-unsaturated acylcarnitine, 403, 1422 Cu/Zn superoxide dismutase (SOD1), 609 Cyanocobalamin, 524 Cyclic GMP-AMP synthase, 215 Cyclic NADHX, 564 Cyclic pyranopterin monophosphate (cPMP), 594, 595, 598–601, 603, 605 3' 8-Cyclo 7,8-dihydro-GTP, 595 CYP27A1 gene, 1102, 1103 CYP7B1 gene, 1102 Cystathionine, 45, 46, 48, 49, 369, 370, 373, 374, 377, 378, 858 Cystathionine beta-synthase (CBS), 49, 369, 596, 597 Cystathionine gamma-lyase, 369, 596, 597 Cysteamine treatment, 1288 Cysteine, 596 dioxygenase, 596, 597 string protein alpha, 1209 sulfinate decarboxylase, 597 total, 373, 374, 377, 378, 381 Cysteine-homocysteine mixed disulfide, 20 Cysteinylglycine dipeptidase, 253 Cysteinyl-tRNA synthetase 2, 854 Cystine, 20, 42–46, 49, 239, 257, 258, 373, 598–600, 602, 824, 1292–1293 L-Cystine, 596 Cystinosin, 76, 1288, 1289 Cystinuria, 292, 310 type A, 295, 297, 302, 304, 305, 308, 309 type B, 295, 297, 302, 304, 305, 308, 309 Cystinylglycine, 257 Cytochrome b complex III, 804 Cytochrome c, 804 Cytochrome c1, 804 Cytochrome c oxidase, 609 subunit 6A1, 801 subunit 8A, 801 subunit 6B1, 801 subunit 7B, 801 subunit FA4, 803 subunit 4I2, 801 Cytochrome c oxidase activity, 875 Cytochrome c oxidase assembly factor 3, 801 Cytochrome c oxidase assembly factor 5, 802 Cytochrome c oxidase assembly factor 6, 802 Cytochrome c oxidase assembly factor 7, 802 Cytochrome c oxidase assembly factor 10, 802 Cytochrome c oxidase assembly factor 14, 802 Cytochrome c oxidase assembly factor 15, 802 Cytochrome c oxidase assembly factor 20, 802

1498 Cytochrome oxidase, 607 Cytosolic bile acid-CoA, 1096 Cytosolic deoxyribonuclease, 219 Cytosolic glycerol-3-phosphate dehydrogenase, 960 Cytosolic NADH levels, 788 Cytosolic phosphoenolpyruvate carboxykinase, 654, 680 D DCR-PHXC/Nedosiran®, 1329 De Barsy syndrome, 266 Decanoylcarnitine, 14 Decaprenyl-pyrophosphate, 916 Decenoylcarnitine, 14 Decreased complex I activity, 806, 807, 813 Deep brain stimulation, 574 Deferiprone, 574 7-Dehydrocholesterol, 1059, 1069 8-Dehydrocholesterol, 1067, 1069 Dehydrodolichyl diphosphate synthase, 1342 Dehydroepiandrosterone DHEA, 1373 Dehydroepiandrosterone sulfate DHEAS, 1373 Deiodinases, 612 Delta-ALA, 1119 Delta-ALA dehydratase, 1119 Delta-ALA synthase, 1118 Deoxyadenosine, 203 Deoxyadenosine triphosphate, 203 Deoxycorticosterone, 1085 11-Deoxycortisol, 1085 Deoxyguanosine, 204 Deoxyguanosine kinase, 845, 849 Deoxyinosine, 204 1-Deoxymethylsphiganine, 1011 1-Deoxysphinganine, 1011, 1012 Deoxythymidine, 519 Deoxyuridine, 199, 861 Dermatan sulfate, 78–80, 1269, 1271, 1272, 1275, 1276 Dermatan sulfate epimerase, 1340 Desmosterol, 1068 Developmental/cognitive and educational assessment, 1217–1218, 1222, 1223 Dexamethasone, 1090, 1092 Dextromethorphan, 386, 477 Dextrose, 67, 733, 734 DHEA sulfate, 1084 Diabetes-associated protein in insulin-sensitive tissues, 804 Di-and trihydroxycholestanoic acid (DHCA and THCA), 1303 Diazoxide, 714, 715, 733, 734 Dibasic amino aciduria type 1, 292, 295, 299, 302, 304, 306 Dibasic amino aciduria type 2, 266, 295 Dicarbonyl (diacetyl)/l-Xylulose reductase, 703 Dicarboxylic acids, 52, 54, 55, 57, 59, 62, 413, 557, 681, 774, 780, 782, 937–940, 942, 943, 945, 946, 951, 951, 963, 972–974, 1400–1401 3-Hydroxy (Dicarboxylic acids), 55, 59, 62 Dicarboxylic aciduria, 68 Dicarboxylic aminoaciduria, 292, 295, 298, 302, 304, 305 2,4-Dienoyl-CoA reductase, 564, 566 Dietary fat restriction, 953 Dietary folate, 515 Dietary therapy, 789 Dihydroceramide, 1014 Dihydrofolate, 519 Dihydrofolate reductase, 518 Dihydrolanosterol, 1064

Test and Medication Index: Strange Association Dihydrolipoamide acetyltransferase, 744 Dihydrolipoamide dehydrogenase, 744 Dihydroorotase trifunctional protein, 193, 1343 Dihydroorotate dehydrogenase, 192, 193 Dihydroorotic acid, 197 Dihydropteridine reductase, 334, 337, 343, 346, 348 Dihydropyrimidinase, 193 Dihydropyrimidine dehydrogenase, 193, 199, 436 Dihydrotestosterone, 1082, 1086 Dihydrothymine, 58, 61, 62, 200, 436 Dihydrouracil, 58, 61, 62, 200, 436 Dihydroxyacetone phosphate, 668 2,8-Dihydroxyadenine, 205 Dihydroxycholestanoic acid, 1310, 1311 7α,12α-Dihydroxy-3-oxo-cholenoic acids, 1098 Dihydroxyphenylacetic acid, 609, 620 Dihydroxyphenylglycol, 609, 620 Dimethylglycine, 87, 555–557 Dimethylglycine dehydrogenase, 174 Dimethylsulfide, 19, 374, 377–379 Dimethylsulfoxide, 377, 378 Dinitrophenylhydrazine (DNPH), 18, 20 2,4-Dinitrophenylhydrazine test, 398, 414, 416, 419 3,4-Dioxygenase, 566 2,3-Diphosphoglycerate, 668 Disialotransferrin, 725–728, 1346–1356, 1359, 1385, 1393 Disodium calcium edetate, 644 Disseminated intravascular coagulation, 490 Disturbed clotting, 908 DMT1, 625–629 DNA, 884 DNAJC5 Cysteine string protein alpha, 1214 DNAJC12 deficiency, 334, 339, 349 DNAJ homolog subfamily C member 5, 1214 DNAJ/HSP40 homolog subfamily C, 891 DNA polymerase, 612 DNA polymerase gamma 2, accessory subunit, 849 DNA replication helicase 2, 849 DNA sequencing, 1040 DNA testing, 786, 964 Docosahexaenoic acid, 1006, 1314 Dodecanoylcarnitine, 14 Dolichol kinase, 1342 Dolichol-linked Glc3Man9GlcNAc2, 1382 Dolichol-linked GlcNAc1, 1347 Dolichol-linked GlcNAc2, 1348–1350 Dolichol-linked Man5GlcNAc2, 1383 Dolichol-linked Man6GlcNAc2, 1352–1354, 1382–1384 Dolichol-linked Man9GlcNAc2, 727, 1384 Dolichol-P-glucose: Glc1Man9GlcNAc2-PPdolichol-α1,3glucosyltransferase, 1338 Dolichol-P-glucose: Man9GlcNAc2-PPdolichol glucosyltransferase, 1338 Dolichol-phosphate, 1382 Dolichol-P-mannose, 1384 Dolichol-P-mannose:α1,2 mannosyltransferase, 1338 Dolichol-P-mannose: Man5GlcNAc2-PP-dolichol mannosyltransferase, 1338 Dolichol-P-mannose: Man7GlcNAc2-PP-dolichol mannosyltransferase, 1338 Dolichol-P-mannose synthase-2, 1342 Dolichol-P-mannose synthase-3, 1342 Dolichols, 1381 Dol-P-Man utilization 1, 1342 Dopamine, 609, 620

Test and Medication Index: Strange Association β-hydroxylase (DβH), 314–316, 320, 325–327, 609 beta monooxygenase, 607 transporter, 316, 321, 325–327 Dopamine–serotonin, 321 D-penicillamine, 622 Dynamin 2, 890 Dynamin-like protein 1, 891, 1301 Dynamin-related protein 1, 890 E EAAT1 deficiency, 296, 302, 306, 308, 310 Ecto-5'-nucleotidase, 216 Ectonucleotide pyrophosphatase/ phosphodiesterase, 218 Ecto-5-prime nucleotidase, 218 EGF domain-specific O-linked N-acetylglucosamine transferase, 1341 Electroencephalography, 1214, 1216, 1222, 1226 Electron microscopy ultrastructural studies, 1213, 1218, 1220–1224, 1226 Electron transfer flavoprotein (ETF), 70, 551, 552, 936 Electron transfer flavoprotein dehydrogenase (ETFDH), 936 Electroretinography, 1212, 1214, 1226 Elevated pyridoxamine, 580 Elevated serum alanine, 538 Elongation factor G1, 851 Elosulfase alfa, 1283 Empagliflozin, 694, 697 Encoded amino acid, 157 Endoplasmic reticulum glucosidase I, 1339 Endoplasmic reticulum O-glucosyltransferase, 1341 Enolase, 652, 669 Enolase beta, 652, 669 Enoyl-CoA hydratase or crotonase, 936 Enzymatic activity, 1006 Enzyme assay, 381, 951, 1284 in fibroblasts, 951 in lymphocytes, 951 Enzyme replacement therapy, 1231, 1282, 1284, 1282 Episodic ataxia type 6, 292, 296, 310 Equilibrative nucleoside transporter 1, 218 Equilibrative nucleoside transporter 3, 218 Era G-protein-like 1, 855 Erythritol, 706, 707 Erythrocyte count, 778 Erythrocyte sedimentation rate, 1008, 1063 Erythronic acid, 706 Estradiol, 860, 882, 1087 ETF-ubiquinone oxidoreductase (ETF-QO), 551, 552 Ethosuximide metabolites, 59 2-Ethyl-hexanedioic acid, 1002 2-Ethylhydracrylic acid, 54, 401, 412, 994, 1444 2-Ethyl-3-hydroxy-hexanoic acid, 1002 2-Ethyl-3-keto-hexanoic acid, 1002 Ethylmalonic acid, 54–57, 59, 60, 62, 376, 378, 406, 411, 443, 550, 553–557, 779, 780, 782, 785, 832, 883, 904, 941 Everolimus, 735 Exhaled air, 377, 379 Exostosin glycosyltransferase 1, 1340 Exostosin glycosyltransferase 2, 1340 Exostosin glycosyltransferase 3, 1340 F Factor IX, 1391 Factor VII, 780, 785 Factor X, 780, 785

1499 Factor XI, 725–727, 1346, 1349, 1350, 1352–1355, 1358, 1359, 1383, 1384, 1395 FAD, 557 FAD-dependent oxidoreductese domain-containing protein 1, 799 FAD synthase, 549, 551, 559 Familial hyperinsulinemic hypoglycemia type 6, 266 Farnesol, 1064 Farnesyl-pyrophosphate, 916 Fast kinase domain-containing protein 3, 803 Fat, 934 Fatty acid oxidation, 794 Fatty acid oxidation flux, 951 Fatty acids, 1184, 1303 Fatty acyl-CoA reductase 1, 1300 F-box and leucine-rich repeat protein 4, 849 Fecal α1-antitrypsin, 696 Felbamate, 1229 Ferredoxin 2 (FDX2), 482 Ferredoxin reductase (FDXR), 482 Ferric chloride, 17, 19 Ferric chloride test, 398, 414, 416, 419 Ferritin, 35, 486, 629–632, 639, 642–644, 670, 706, 778, 780, 782, 785, 858, 900, 909, 1118, 1122 L-Ferritin, 627 Ferroportin, 625–628, 630, 633, 634 Ferrous sulphate/fumarate, 644 Fetal DNA sequencing, 1293 Fetal haemoglobin, 665 FFAs. See Free fatty acids (FFAs) Fibroblast or lymphocyte acylcarnitine profiling, 951 Filipin test, 993, 1193 Fission protein 1, 890 Flavin adenine dinucleotide (FAD), 553, 936 Flavin mononucleotide (FMN), 549, 553, 557 Flavins, 553, 554, 559 Flavokinase, 549 Flippase of Man5GlcNAc2-PP-Dol, 1338 Fludrocortisone, 1092 Flumazenil, 451 5-Fluorouracil, 451 Folate(s), 45, 49, 382, 384, 385, 516–526, 548, 789 Folic acid, 511, 522, 524–526, 693 Folinic acid, 180, 511, 516, 517, 524–526, 588 Folinic acid/methylfolinic acid, 510 Follicle-stimulating hormone, 860, 882 FOLR1 transporter, 518 Formiminoglutamate, 67, 70, 72 Formiminoglutamic acid (FIGLU), 49, 516, 518, 520, 522–524 Formimino transferase, 518 Formylglycine-generating enzyme, 1238 Formyl-5'-phosphoribosyl-5-aminoimidazole-4-carboxamide, 519 Formyl-5'-phosphoribosylglycinamide, 519 5-Formyltetrahydrofolate, 518, 525 Formyltetrahydrofolate dehydrogenase, 519 Formyl-tetrahydrofolate synthase, 518 Frataxin, 482 Frc-1-P aldolase, 685 Frc-1,6-P bisphosphatase, 685 Free carnitine, 66, 67, 71 Free fatty acids (FFAs), 39, 68, 179, 406, 413, 720–723, 725–729, 951, 971, 972, 974–976, 1346 during hypoglycemia, 1351, 1353, 1385 Free sulfide, 377, 378, 381 Fructokinase, 651, 652, 655, 668 Fructose, 19, 48, 141, 649–651, 654–657, 661, 665, 681, 682, 684, 689, 690, 692–693, 965

1500 Fructose-1,6-bisphosphatase, 654, 681 Fructose loading test, 661, 684 Fructose-1-phosphate aldolase, 651, 655, 665 FUCO, 1259, 1260 Fucose, 1255 Fucosyltransferase 8, 1339 Fukutin, 1339 Fukutin-related protein, 1339 Fumarase, 24, 28, 38, 55, 745, 884 Fumarate, 757, 761 Fumarate hydratase, 745 Fumaric acid, 55, 57, 411, 740, 756, 758, 758, 759, 829, 922 Fumarylacetoacetase, 53, 355 Functional tests in cultured fibroblasts, 559 lymphocytes, 559 Furane-2,5-dicarboxylic acid, 52, 59 Furoylglycine, 59 G GABA. See Gamma-aminobutyric acid (GABA) Gabapentin, 1228 GABA transaminase, 48, 49, 173 Galactitol, 125, 655, 658, 663, 664, 682, 684, 688, 691 Galactocerebrosidase, 1193 Galactokinase, 19, 651, 655, 663, 683 Galactose, 5, 17–19, 39, 650, 651, 655, 663–665, 683, 688, 778, 780, 782, 785 Galactose epimerase, 651 Galactose loading test, 651, 661 Galactosemia, 173 Galactose mutarotase, 651, 655, 663 Galactose mutarotase activity, 663 Galactose-1-phosphate, 651, 655, 663, 664, 682, 688, 691 Galactose-1-phosphate uridyltransferase, 651 Galactose uptake by enterocyte, 661 Galactosylceramidase, 1191 Gal-1-P, 685, 688, 691 Galsulfase, 1283 GALT, 651, 655, 685, 688, 691 692, 696 Gamma-aminobutyric acid (GABA), 44–46, 48, 49, 135, 434, 449 γ-Glutamylcysteine, 36, 38, 252, 254 γ-Glutamylcysteine synthetase, 251–255, 257, 260, 261 γ-Glutamyl transpeptidase, 252–254, 1104, 1105, 1140 Gammaglobulins, 227, 230, 1391 Gamma-glutamylcysteine synthetase, 36, 38, 173, 256 Gamma-glutamyl transferase, 778 Gamma-glutamyl transpeptidase, 255, 489, 706, 711, 858, 859, 1096, 1100, 1105 Ganglioside-induced differentiation-associated protein 1, 891, 1302 GBA2 activity, 1015 GDP-fucose transporter, 1343 GDP-Man:Dol-P mannosyltransferase subunit, 1342 GDP-Man:Dol-P mannosyltransferase subunit 1, 1342 GDP-Man:GlcNAc2-PPdolichol mannosyltransferase, 1338 GDP-mannose, 1336 GDP-mannose:Man1GlcNAc2-PP-dolichol mannosyltransferase, 1338 GDP-mannose pyrophosphorylase subunit A, 1343 subunit B, 1343 Gene editing, 1288 Gene therapy, 838, 1231–1232, 1246, 1268, 1282, 1283 Genetic testing, 796 Genistein, 1282 Genome editing, 1283

Test and Medication Index: Strange Association Gephyrin, 597 Globotriaosylceramide, 1191 Globotriaosylsphingosine, 1188, 1191, 1198 GLP1 receptor inhibitor, 735 GLRX5, 491 Glucagon, 733, 734 Glucagon loading test, 730 Glucokinase, 652, 667, 716, 720, 731, 732 Glucose, 177–179, 239, 372, 398, 400–403, 405, 406, 408, 410, 411, 413, 490, 542, 543, 555, 556, 569, 584, 585, 629, 630, 650–668, 673–678, 680–697, 706, 720–729, 747–749, 751, 758, 778, 815, 818, 819, 858, 859, 870–872, 881, 908, 937–946, 952, 954, 954, 962, 971–976, 993, 994, 1103, 1288, 1291, 1346, 1351, 1412, 1413, 1418, 1444, 1445, 1427, 1444 -6-phosphatase, 653, 655, 656, 660, 676, 677 catalytic subunit 3, 653, 1343 -6-phosphate dehydrogenase, 8, 12, 253, 255, 258, 260, 261 translocase, 653 phosphate isomerase, 652, 667 phosphate isomerase activity, 667 Glucose transporter 1, 651 Glucose transporter-2, 651 Glucose uptake, 661, 662, 682 Glucosidase alfa, 697 Glucosylsphingosine, 1189, 1190, 1191 Glucotetrasaccharide, 679 GLUT1, 682 Glutaconic acid, 1403, 1406 Glutamate, 44, 45, 67, 102, 454, 455, 460 aspartate transporter, 296, 301 decarboxylase, 578 dehydrogenase, 716, 721, 731, 732 dehydrogenase superactivity, 266, 278 oxaloacetate transaminase, 767 oxidation, 751, 778 Glutamate-cysteine ligase deficiency, 254 Glutamateformimino-transferase, 57 Glutamic acid, 42–44, 49, 62, 460, 484, 485, 569 Glutamic acid γ semialdehyde, 583 Glutaminase, 457 Glutamine, 42–45, 48, 49, 59, 61, 102, 175, 408, 410, 454, 455, 460, 681, 778, 780, 782, 784, 829, 1426 L-Glutamine, 458 Glutamine-dependent NAD(+) synthetase (NADS), 567 Glutamine:fructose-6-phosphate transaminase 1, 1342 Glutamine/glutamate ratio, 408 Glutamine synthase, 49 Glutamine synthetase, 265, 266, 278, 282, 285, 288, 457 Glutaminyl-tRNA synthase (glutaminehydrolyzing)-like protein 1, 854 Glutamyl-tRNA amidotransferase subunit B, 854 subunit C, 855 Glutamyl-tRNA synthetase 2, 854 Glutarate, 1400 Glutaredoxin 5, 482 Glutaric acid, 10, 53, 54, 56, 57, 59, 60, 62, 100, 143, 406, 411, 550, 553–557, 779, 780, 782, 785, 1003, 1403, 1406–1409, 1411 Glutarylcarnitine, 14, 378, 554–557, 779, 1400, 1403, 1406–1408 Glutaryl-CoA dehydrogenase, 54, 67, 1400, 1402, 1403, 1411 Glutathione, 20, 198, 251–261, 1036 Glutathione metabolism, 252 Glutathione peroxidase, 612 Glutathione peroxidase 4 deficiency, 254, 258 Glutathione persulfide dioxygenase, 597

Test and Medication Index: Strange Association Glutathione reductase, 252, 254, 258 Glutathione synthetase, 23, 27, 36, 38, 251–257, 259–261 mild, 254, 256 severe, 254, 257 Glutathionuria, 254, 255 GLUT1 in RBC, 662 GLXR5, 481 Glycaemic control, 734 Glycans, 167 Glycemia, 175 Glyceol, 789 Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 567 Glycerate, 1328 D-Glycerate, 962 L-Glycerate, 1326 D-Glycerate dehydrogenase, 1322 Glycerate kinase, 961 Glyceric acid, 55, 56, 1325 Glycerol, 52, 56, 59, 656, 665, 681, 962, 1444 kinase, 21, 56, 961 triacetate, 1412, 1414 Glycerol-3-phosphate dehydrogenase, 767, 961 Glycerol plasma, 963 Glycerol urine, 963, 964 Glycerone-3-phosphate acyltransferase, 1300 Glycerophospholipids, 983 Glycine, 41–44, 47, 49, 52, 62, 119, 132, 400, 408, 410, 422, 425, 426, 458, 459, 463, 471–477, 483–487, 492, 505, 585, 789, 975 L-Glycine, 242, 248 Glycine cleavage enzyme (GCE), 470 Glycine (CSF)-glycine (P) ratio, 474 Glycine N-methyltransferase, 49, 368 Glycocholic acid, 1315 Glycogen, 21, 30, 31, 76, 668, 670–676, 679, 682, 684, 730 Glycogen branching enzyme, 653 Glycogenin 1, 653, 656 Glycogen phosphorylase, 653, 675 Glycogen synthase, 653, 671 Glycogen synthase 1, 653 Glycogen synthase 2, 653 Glycolate, 1326, 1328 Glycolic acid, 55, 59, 60, 1325 Glycolipids, 141 Glycolytic and pentose-phosphate enzyme, 173 Glycosaminoglycans, 77–80, 1240 Glycosphingolipids, 989 Glycosylasparaginase, 76, 81, 1252 Glycosylation, 167 Glycosylceramidase, 1191 Glycosylphosphatidylinositol anchor attachment protein 1, 1342 Glycosylphosphatidylinositol glycan anchor biosynthesis G protein, 1342 Glycylproline, 49 Glycyl-tRNA synthetase, 855 GLYT1-protein, 472 GLYT2 transporter deficiency, 302 GM3 activity, 1018 GM3 ganglioside, 1018 Golgi N-acetylglucosaminyltransferase II, 1339 Golgi UDP-galactose N-acetylglucosamine β-1,4-galactosyltransferase, 1340 transporter, 1343 Gonadotropins, 1087, 1372 GPI deacylase, 1342 Growth factor, ERV1-like, 891

1501 GRPEL1, 481 GSH synthetase, 173 GTP-binding protein 3, 850 GTPCH, 346 GTP cyclohydrolase I, 334, 347 GTP-specific succinyl-CoA ligase α subunit, 744, 850 Guanadinoacetate, 115, 116 Guanidinoacetate, 102, 236–238, 240, 242, 244–246, 465 Guanidinoacetate methyltransferase, 111, 236 H 5-Halogenated pyrimidines, 451 Haptocorrin (HC), 498, 501 Haptoglobin, 1358 Hartnup disorder, 292, 295, 296, 302, 305, 309 HAWK. See Hawkinsinuria (HAWK) Hawkinsin, 49 Hawkinsinuria (HAWK), 355, 357, 358, 363 HDL cholesterol, 778, 997 Heat-shock 60-kDa protein 1, 892 Heat-shock 70-kDa protein 9, 482, 892 Hematopoietic stem cell transplantation (HSCT), 1264, 1282 Heme, 548 Hemochromatosis, 173 Hemoglobin, 36, 256, 257, 522, 523, 542, 629, 632, 642–644, 667, 670, 706, 822, 1008 Hemojuvelin, 625–627 Hemolytic anemia due to glutathione reductase deficiency, 254 Heparan-N-sulfatase, 78–80, 1269, 1272, 1280 Heparan sulfate (HS), 78–80, 1269, 1271–1273, 1275, 1276 Heparan sulfate 6-O-sulfotransferase 1, 1340 Hepatic and muscle phosphorylase kinase â subunit, 653 Hepatic lipase activity, 1044 Hepatic phosphorylase kinase α2 subunit, 653 Hepatic phosphorylase kinase γ2 subunit, 653 Hepatocyte nuclear factor 1α (HNF1α), 716, 731, 732 Hepatocyte nuclear factor 4α (HNF4α), 716, 722, 731, 732 Hepatorenal tyrosinemia, 355 Hepcidin, 625–629, 631, 634 Heptacarboxyporphyrin, 1123 Hereditary dopamine transporter deficiency syndrome, 314 Hereditary glutathione reductase, 252 Hereditary spastic paraplegia 9, 266 Hereditary tyrosinemia, 355 Hexacarboxyporphyrin, 1123 Hexacosanoic acid, 1303 Hexanoylcarnitine, 14 Hexanoylglycine, 55, 554–557, 779, 780, 782, 784, 942 Hexasialotransferrins, 1393 Hexokinase 1, 652, 655, 665 Hexokinase activity, 665, 666 High-affinity urate transporter, 195 Hippuric acid, 19, 59, 60 Histidyl-tRNA synthetase 2, 855 Histochemical cytochrome c oxidase deficiency, 857–863, 865, 866, 875 Histochemical mitochondrial proliferation, 858–862, 876 Histological studies, 1213–1218, 1224 HMNDYT1, 637–642, 644.643 HMNDYT2, 637–641, 643, 644 Holocarboxylase synthetase, 23, 57, 61, 173, 178, 530 Holocytochrome c synthase, 804 Holotranscobalamin, 498, 502, 503, 508, 510 Homoarginine, 49 Homocarnosine, 49, 441, 442

1502 Homocitrulline, 43, 45, 47, 49, 780, 782, 785 Homocysteine, 252, 255, 258–260, 369, 373, 377, 400, 498, 502–504, 506, 508, 598–600, 724 total, 370–375, 377, 378, 381, 388, 502–506 Homocysteine-cysteine, 49 Homocysteine/homocyst(e)ine (Hcy), 18, 46, 49, 517, 519–524, 526 Homocystine, 20, 377, 378 Homocyst(e)ine, 508 Homocystinuria, 4, 8–11, 14, 18, 20, 27, 34, 36, 45, 173, 518 Homogentisate 1,2-dioxygenase deficiency, 355 Homogentisic acid, 18, 19, 53, 183 Homogentisic acid oxidase, 53 Homovanillic acid (HVA), 59, 60, 521–524, 585, 586 Host cell factor C1, 500 H-protein, 472 HS. See Heparan sulfate (HS) HSCB, 481 HSPA, 481 hTHTR1, 537, 541 hTHTR2, 537, 541 HTRA serine peptidase 2, 892 Hyaluronan, 78, 1276 Hyaluronidase, 76, 78, 80, 1269, 1276, 1280 Hydantoin-5-propionic acid, 522 4-Hydoxybenzoate, 916, 918 Hydoxytetradecanoylcarnitine, 14 Hydrating creams, 1314 Hydration, 740 Hydrocortisone, 1092 Hydrogen sulfide, 376 Hydroxo-Cbl, 511, 512 Hydroxocobalamin, 178, 384, 524, 525 Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta, 934 2-Hydroxy acyl-CoA lyase (HACL1), 538 2-Hydroxyadipate, 485 3-Hydroxyadipic acid, 945, 947 3-Hydroxyadipic acid lactone, 945 3-Hydroxyanthranilate, 566 3-Hydroxyanthranilate 3,4-dioxygenase (HAAO), 567 3-Hydroxyanthranilic acid, 569 4-Hydroxybenzoatepolyprenyltransferase, 917 3-Hydroxybutyrate, 179, 413, 561, 683, 729, 832, 883, 884 3-Hydroxybutyrate + acetoacetate ratio, 883 3-Hydroxybutyrate/acetoacetate ratio, 883 3-Hydroxybutyric acid, 56, 411 4-Hydroxybutyric acid, 56, 59, 62, 442, 449 Hydroxybutyrylcarnitine, 721 27-Hydroxycholesterol, 1101 4-Hydroxycyclohexanecarboxylic acid, 59 3-Hydroxydicarboxylic acid, 55, 59, 62, 720, 721, 945, 947 2-Hydroxyglutarate, 485, 921 3-Hydroxyglutarate, 720, 721, 944, 1400, 1411 D-2-Hydroxyglutarate dehydrogenase, 1402, 1404 Hydroxyglutaric acid, 56, 57 2-Hydroxyglutaric acid, 550, 554, 555, 557, 779, 785 3-Hydroxyglutaric acid, 10, 54, 55, 1403, 1406–1409 D-2-Hydroxyglutaric acid, 56, 57, 555–557, 774, 780, 782 D-2-Hydroxyglutaric aciduria, 173 Hydroxyhexadecenoylcarnitine, 14 5-Hydroxyhexanoic acid, 942 Hydroxyhexanoylcarnitine, 14 5-Hydroxyindoleacetic acid (5-HIAA), 59, 521–524, 585, 586 3-Hydroxyisobutyrate dehydrogenase, 54, 404 3-Hydroxyisobutyric acid, 54, 404, 406, 444 3-Hydroxyisobutyryl-CoA deacylase, 54, 404

Test and Medication Index: Strange Association D-2-Hydroxyisocaproic acid, 671 2-Hydroxyisovaleric acid, 53, 404 3-Hydroxyisovaleric acid, 19, 53, 57, 59, 60, 62, 400, 402, 403, 406, 532, 534–536, 900, 902, 908, 972, 993, 1418, 1442–1425, 1427, 1428 D-2-Hydroxyisovaleric acid, 671 Hydroxyisovalerylcarnitine, 14 3-Hydroxykynurenine, 565, 569 27-Hydroxylase, 1102 Hydroxylysine, 49 3-Hydroxy-3-methylglutaric acid, 53, 60, 406, 972 3-Hydroxy-3-methylglutaryl-CoA lyase (HMGL), 20, 22, 23, 27, 30, 53, 406 3-Hydroxy-3-methylglutaryl-CoA lyase activity, 972 4-Hydroxy-6-methyl-2-pyrone, 971 3-Hydroxy-n-butyric acid, 412, 971–974 Hydroxyoctadecenoylcarnitine, 14 7-Hydroxyoctanoic acid, 942 Hydroxy-oxoglutarate, 1324, 1326 4-Hydroxy-2-oxoglutarate aldolase, 1320 Hydroxypalmitoylcarnitine, 14 4-Hydroxyphenylacetate, 19 4-Hydroxyphenyllactate, 19 4-Hydroxyphenylpyruvate, 19 4-Hydroxyphenylpyruvate dioxygenase, 53, 355 4-Hydroxyphenylpyruvic acid, 19, 20 Hydroxyproline, 42–46, 49, 463, 585 3-Hydroxypropionic acid, 54, 57, 59, 60, 406, 408, 409, 498, 504, 507, 508, 532, 534, 535, 1003 3-Hydroxysebacic acid, 945, 947 3-Hydroxysuberic acid, 945, 947 25-Hydroxy-vitamin D, 1100, 1102, 1103 Hyperammonemia, 17, 22, 42, 44, 68, 100, 172, 174, 175, 239, 264, 931, 1143 Hyperekplexia, 292, 305, 307, 310 Hyperglycinuria, 292, 295, 297, 302, 304, 305 Hyperinsulinism, 39, 46, 173, 713–735 Hyperintensity globus pallidus, 643 Hyperlactataemia, 550 Hyperphenylalaninemia, 332, 333 Hypertyrosinemia, 354 Hypoglycaemia, 720, 722 Hypoglycemia, 172, 179, 1101 Hypoglycosylation of α-dystroglycan, 1387 Hypohomocysteinemia, 252 Hypophosphatasia, 587 Hypotonia, muscular-axial, 937 Hypoxanthine, 201, 204 Hypoxanthine guanine phosphoribosyltransferase, 194, 204 I Idebenone, 574 Iduronate sulfatase, 78, 80 Iduronate-2-sulfatase, 76, 79, 83, 1269, 1272, 1280 Idursulfase, 1283 IgA, 677 IgE, 1386 IgG, 1009 Imidazolepyruvic acid, 19, 20 Iminoglycinuria, 292, 295, 296, 302, 303, 305 Immunoglobulin(s), 520 Immunoglobulin D, 1063 Immunoglobulin G, 1358 IMP cyclohydrolase, 194, 202 Increased prothrombin time (INR), 1143

Test and Medication Index: Strange Association Indoleamine 2,3-dioxygenase (IDO), 567 Inosine monophosphate dehydrogenase, 194 Inosine 5'-triphosphate pyrophosphohydrolase, 194, 195 Inositol, 516, 520, 523, 524 Inositol monophosphatase domain-containing protein 1, 1341 Insulin, 179, 650, 652, 657, 667, 683, 684,688, 691, 695, 714, 716, 720–723, 725–729, 733, 734, 944, 1346, 1351, 1353 Insulin receptor, 714, 731, 735 Interferon-α, 222, 224, 226, 228 Interferon-induced helicase C domaincontaining protein, 217 Interferon signature, 222–228 Interferon-stimulated genes, 222–228 Intestinal phosphatases, 578 Intracellular lysosomal enzyme processing and trafficking, 1239 Intrathecal and intraventricular baclofen, 574 Intravenous fructose loading test, 684 Intravenous glucagon test, 684 Intrinsic factor (IF), 498 Iron, 569, 571, 625, 626, 629–632, 678, 819, 999, 1000, 1008, 1103, 1122, 1159 Iron-sulfur cluster assembly 1, 482 Iron-sulfur cluster assembly 2, 482 Iron-sulfur cluster assembly enzyme, 482 Iron-sulfur cluster assembly factor IBA57, 482 Iron-sulfur (Fe-S) clusters, 479–493 2Fe-2S, 480 3Fe-4S, 480 4Fe-4S, 480 Iron-sulfur cluster scaffold protein, 744 Ischaemic muscle exercise tolerance test, 202 ISCU, 481 ISD11, 482 Isobutyryl-CoA dehydrogenase, 54, 67, 70, 71, 401 Isobutyrylglycine, 54, 401, 408, 555–557, 779, 780, 782, 784, 1444 Isocitrate dehydrogenase 2, 56, 1401, 1402, 1404 Isocoproporphyrin, 1120, 1123 Isoleucine, 8, 42–44, 48, 49, 71, 87, 397–399, 414, 416, 425, 427, 428, 538, 474 Isoleucyl-tRNA synthetase 2, 855 Isomaltase, 660, 685 Isomaltase activity, 660, 661 Isovaleric acid, 19, 400 Isovalerylcarnitine, 14, 71 Isovaleryl-CoA dehydrogenase, 53, 67, 400 Isovalerylglycine, 53, 56, 376, 378, 400, 554–557, 779, 781, 782, 784 K KCTD7, 31210 KCTD7 mutation screening, 1225 Keppra, 59 Keratan sulfate, 78, 79, 1269, 1274 Ketamine, 477 Ketoacidosis, 27 Keto acids, 177 2-Ketoadipate, 485 Ketogenic diet, 761 2-Ketoglutarate, 484, 485 2-Ketoglutarate dehydrogenase, 55, 481, 483–487 2-Ketoglutaric acid, 1401 Ketohexokinase, 651, 665 Ketolysis, 173 Ketone bodies, 177, 179 Ketones, 18–20, 39, 55, 62, 406, 408, 410, 413, 555, 556, 671–675, 677, 720–723, 725–729, 747–749, 759, 937–940, 942–946, 948, 971–976, 1346, 1351, 1385

1503 Ketonuria, 175 Kidney function myoglobin, 695 KYN-F kynurenine formamidase, 567 Kynunerinase, 567 Kynurenine, 569 Kynurenine 3-monoxygenase, 567 L Lactase, 650, 651, 660, 684 Lactase activity in intestinal biopsy, 660 Lactate, 23, 86, 104, 111, 116, 118–134, 136, 139–142, 175, 177, 179, 199, 376, 378, 399, 400, 403–406, 408, 410–413, 443, 483–490, 492, 506, 532, 542–544, 555, 568, 569, 571, 584, 585, 652, 656, 662, 663, 670–677, 680–683, 687, 692–694, 719, 747–749, 747, 751, 752, 753, 773, 779, 781, 782, 785, 806–830, 831, 856, 858–861, 863–866, 868–884, 895–897, 899–902, 904–909, 920–923, 940, 945, 946, 947, 949, 1400, 1406, 1418, 1423–1427 D-Lactate, 654, 671 Lactate dehydrogenase, 17, 33, 522, 612, 652, 670, 671 subunit H, 652 subunit M, 652 D-Lactate dehydrogenase, 652, 671 Lactate/lactic acid, 972–974, 992–995, 1003, 1004, 1018 Lactate/N-acetylaspartic acid (NAA) ratio, 400 Lactate/pyruvate ratio, 399, 403, 815, 832, 864, 883, 949 Lactate rise in forearm exercise test, 668, 670, 672, 674 Lactic acid, 55, 56, 60, 177, 535, 543, 550, 667, 670, 682, 685 Lactic acid (LA), 758 Lactic acidosis, 19, 20, 48, 50, 538, 795 Lactose, 789 Lactosylceramide, 1018 Laforin glucan phosphatase, 654 Lanosterol, 1064 Lanreotide, 734 Large neutral amino acid transporter deficiency, 296, 300, 302, 305, 306 Laronidase, 1283 Lathosterol, 1068 LCAT activity, 1045 LCHAD. See Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) LDL cholesterol, 778, 1392 L-D1-pyrroline-5-carboxylate, 579, 585 Lecithin cholesterol acyl transferase, 27, 34 Leptin, 1007 Leucine, 8, 14, 42–44, 46, 48, 49, 71, 87, 397–399, 414, 416, 538, 715, 721, 747, 1417–1420, 1428, 1429 Leucine-rich PPR Motif-containing protein, 803 Leucyl-tRNA synthetase 2, 855 Leukocyte cystine measurement, 1292 Leukotriene, 1036, 1037 Leukotriene E4, 1063 Levetiracetam, 1230 Levodopa, 640 L-2-Hydroxyglutarate dehydrogenase, 1402 L-2-Hydroxyglutaric acid (L2HG), 56, 143, 774, 781, 782, 1404, 1406, 1407 L-2-Hydroxyglutaric aciduria, 100, 101 Light and electron microscopy ultrastructural studies, 1223 Linear ubiquitin chain assembly complex, 654 Lipase, 76, 694 Lipase activity, 1193 Lipid-linked GlcNAc2, 1348 Lipid-linked Man6GlcNA2, 1352 Lipid-linked Man8GlcNA2, 1352

1504 Lipid-linked Man1GlcNAc2, 1349, 1350 Lipid-linked Man2GlcNAc2, 1349 Lipid-linked Man5GlcNAc2, 726, 1351, 1384 Lipid-linked Man9GlcNAc2, 727, 1347, 1384 Lipid-linked oligosaccharides, 1382 Lipids, 21–23, 27, 29–32, 34, 36–38, 51, 52, 76, 135, 137, 142, 167 Lipid storage myopathy, 555–557 Lipid storage myopathy with ragged-red fibres, 555 Lipoate, 534, 742 Lipoic acid (LA), 759 Lipoic acid synthase (LIAS), 481, 482 Lipoprotein, 774, 781, 782, 785, 963 Lipoprotein lipase (LPL), 30 Lipoyltransferase 1 (LIPT1), 482, 491 Lipoyl(octanoyl)transferase 2 (LIPT2), 482 Lithium citrate, 1400, 1412, 1414 Liver copper, 619 Liver function tests, 643 Liver glycogen phosphorylase, 653, 675 Liver GSD enzymes, 685 Liver ultrasound, 692 L-kynurenine hydrolase, 566 L-Lysine, 243, 248 Long-chain acylcarnitine, 66, 69, 71, 779, 781, 782, 815, 932, 937–940, 949 Long-chain enoyl-CoA hydratase (LCEH), 935 Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), 12, 21, 23, 27, 29, 32, 36, 55, 67, 70–73, 931, 934–936, 953 Long-chain 3-ketoacyl-CoA thiolase, 934, 936, 953 Long form of RNase Z, 850 LON peptidase 1, 892 L-ornithine, 236, 242 L-ornithine:2-oxoacid aminotransferase, 238 Low alkaline phosphatase, 610 LPL. See Lipoprotein lipase (LPL) L-Proline, 248, 583 L-serine, 455, 458 Luteinizing hormone, 860, 882 Lymphoblast cell analysis, 1213 Lymphocyte, 679 LYR motif-containing protein 7, 801 Lysine, 42–44, 46, 49, 54, 66, 240, 465, 680, 1400, 1401, 1403, 1406, 1410, 1412–1414 Lysinuric protein intolerance (LPI), 266, 274, 282, 284, 285, 287, 288, 292, 295, 298, 302, 304, 305, 309, 310 Lysogalactosylceramide, 1189 LysoGM1, 1186 LysoGM2, 1187, 1188 LysoSM-509/LysoSM, 1193 Lysosomal acid lipase, 76 Lysosomal CLN5 protein, 1209 Lysosomal enzyme activities, 1240 Lysosomal enzymes, 1240 Lysosomal export of cobalamin, 500 Lysosomal hydrolase acid ceramidase, 1185 Lysosomal hydrolases, 1268 Lysosomal palmitoyl protein thioesterase-1, 1209, 1226 Lysosomal transmembrane CLN3 protein, 1209 Lysosomal tripeptidyl-peptidase-1, 1211, 1212 Lysosomal type 5 P-type ATPase, 1210 Lysosome-associated membrane protein 2, 654 Lysosphingomyelin, 1192, 1194 Lysyl hydroxylase activity, 617 Lysyl oxidase, 607 Lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP) ratio, 617 Lysyl-tRNA synthetase, 855

Test and Medication Index: Strange Association M Magnesium, 665, 880, 1119–1121 Magnesium transporter 1, 1339 Major facilitator superfamily domain-containing protein-8, 1216 Malate, 757 Maleylacetoacetate isomerase, 354, 355, 358, 361, 363 Malic acid, 55, 56, 922 Malin, 654, 656, 674, 687, 689 Malonic acid, 54, 411, 412 Malonylcarnitine, 14, 71 Malonyl-CoA decarboxylase, 20, 23, 27, 29, 54 Malonyl-CoA decarboxylase activity, 412 Maltase activity, 660 Mandelic acid, 53, 59 Manganese, 637–644, 1389 Manganese sulphate, 644 Manganese superoxide dismutase, 638 Mannoheptulose, 706 Mannose-oligosaccharides, 1254 Massive lipid storage myopathy, 554 MAT activity, 975 Matriptase 2, 625, 626, 628 Medium-chain acylcarnitine, 779, 781, 782 Medium-chain acyl CoA, 9, 21, 55, 67, 70 Medium-chain acyl-CoA dehydrogenase, 552, 934, 936, 953 Medium-chain dicarboxylic acids, 721, 944 Medium chain triglycerides (MCT) milk, 789 Melanin, 18, 19 Membrane-associated protein (MAP17), 651, 655, 662, 685, 688 Membrane-bound dipeptidase deficiency, 254, 257 Mercaptocysteine disulfide, 379 Mercaptolactate, 376 3-Mercaptolactatecysteine disulfide, 20 Mercaptolactate, mercaptopyruvate, 379 Mercaptopyruvate, 376 Mercaptopyruvate sulfurtransferase, 369 3-Mercaptopyruvate sulfurtransferase, 596, 597 Metabolic acidosis, 172, 555, 556 Metal binding pterin (MPT), 595 Methacrylic acid conjugates, 404 Methanethiol, 374, 377, 379 Methanethiol and dimethylsulfide in exhaled air, 381 Methanethiol oxidase, 369 Methemoglobin, 18 Methenyltetrahydrofolate cyclohydrolase, 519 5,10-Methenyltetrahydrofolate cyclohydrolase, 518 5,10-Methenyltetrahydrofolate synthetase, 518 Methionine, 8, 10, 11, 14, 19, 20, 42–44, 49, 66, 369–373, 375, 377, 378, 381, 406, 414, 428, 444, 497, 504, 506, 508, 516, 517, 521, 524–526, 724, 778, 781, 782, 784, 1444 adenosyltransferase, 49 adenosyltransferase I/III, 368 sulfoxide, 49 Methionine and cysteine-free amino acid mixture, 382 Methionine malabsorption syndrome, 292, 295, 300, 302, 304, 306 Methionine/phenylalanine, 378 Methionine sulfoxide, 370 Methionine synthase, 501 Methionine synthase reductase, 501 Methionine-to-cystathionine ratio, 370, 373, 374, 377, 378 Methionine-to-phenylalanine ratio, 373 Methionine-to-total homocysteine, 378 Methionine-to-total homocysteine ratio, 370, 373, 377 Methioninuria, 295 Methionyl-tRNA formyltransferase, 850 Methionyl-tRNA synthetase 2, 855

Test and Medication Index: Strange Association Methotrexate, 46 3-Methoxytyrosine, 585, 586 2-Methylacetoacetate, 20 2-Methylacetoacetic acid, 412 2-Methylbutyric acid, 401, 1444 2-Methylbutyrylcarnitine, 71 2-Methylbutyryl-CoA dehydrogenase, 54, 401, 1444 2-Methylbutyrylglycine, 54, 56, 376, 378, 401, 408, 555–557, 779, 781, 782, 784, 1444 Methylcitric acid, 54, 57, 62, 408, 410, 498, 504, 506, 508, 532, 535, 1003 Methylcobalamin, 499, 501, 517, 521, 524, 525 3-Methylcrotonic acid, 19 3-Methylcrotonylcarnitine, 402 Methylcrotonyl-CoA carboxylase, 402, 529, 530, 536 3-Methylcrotonyl-CoA carboxylase, 20, 27, 53, 67, 530 3-Methylcrotonylglycine, 53, 57, 62, 402, 406, 408, 972, 1003 3-Methylcrotonylglycine acid, 532, 534–536 2-Methyl-2,3-dihydroxybutyrate, 403 Methylene-tetrahydrofolate, 518 5,10-Methylenetetrahydrofolate dehydrogenase, 518 5,10-Methylenetetrahydrofolate reductase, 518 3-Methylglutaconic acid, 53, 54, 56, 62, 403, 406, 488, 827, 829, 830, 856, 883, 896, 897, 899–902, 905, 908, 909, 972, 992–994, 1003, 1417, 1418, 1421–1428 Methylglutaconic aciduria, 67 3-Methylglutaconic aciduria, 53, 62, 1417–1429 3-Methylglutaconyl-CoA hydratase, 53, 67, 403, 1422 3-Methylglutaric acid, 53, 62, 403, 406, 897, 899, 900, 902, 908, 972, 994, 1418, 1422–1425, 1427, 1428 Methylglutarylcarnitine, 14 3-Methylhistidine, 43 2-Methyl-3-hydroxybutyric acid, 54, 405, 412, 870, 1003 Methylmalonate semialdehyde dehydrogenase, 48 Methylmalonic acid, 52, 54, 55, 57, 59, 60, 408, 410–412, 498, 502–506, 508, 510, 517, 521, 522, 752, 753, 758, 864 Methylmalonic aciduria, 100, 499 Methylmalonic semialdehyde dehydrogenase, 54, 406, 445 Methylmalonylcarnitine, 14, 71 Methylmalonyl-CoA epimerase, 54 Methylmalonyl-CoA mutase activity, 410 Methylsuccinic acid, 55, 62, 376, 378, 941 Methyltetrahydrofolate (MTHF), 498 5-Methyltetrahydrofolate (5MTHF), 515, 516, 520–526 5-Methyltetrahydrofolate-homocysteine methyltransferase reductase, 501 5-Methyl-THF, 458 Metronidazole, 382, 383, 386, 388, 428 Mevalonate kinase, 56, 61 Mevalonate/mevalonic acid, 1058, 1063, 1064 Mevalonic acid, 56, 60, 61 MFSD8, 1209 Microalbumin, 693, 694 Microsomal uridinediphosphoglucuronate glucuronosyltransferase type 1 (UGT1A1), 1131 Midazolam, 834, 1229 Miglustat in co-administration with ERT, 698 Mitochondrial aspartate aminotransferase, 786 Mitochondrial calcium uptake 1, 893 Mitochondrial carboxylase, 530 Mitochondrial CoA transporter, 565 Mitochondrial coenzyme A transporter, 566 Mitochondrial complexes I and IV activity, 871 Mitochondrial complex I and IV activity, 868 Mitochondrial DNA, 856, 860 Mitochondrial DNA deletions, 857

1505 Mitochondrial elongation factor 1, 890 2, 890 G2, 851 Ts, 851 Tu, 851 Mitochondrial FAD transporter, 551, 553, 559 Mitochondrial F1Fo-ATP synthase complex delta subunit, 803 Mitochondrial fission factor, 890, 1301 Mitochondrial fission factor 1, 891, 1301 Mitochondrial flavin adenine dinucleotide transporter, 768 Mitochondrial 10-formyltetrahydrofolate dehydrogenase, 518 Mitochondrial genome maintenance exonuclease 1, 849 Mitochondrial glutamate/ H+ symporter 1, 768 Mitochondrial intermediate peptidase, 892 Mitochondrial kinase, 564 Mitochondrial malate dehydrogenase, 745 Mitochondrial NADH-dependent isocitrate dehydrogenase 2, 744 Mitochondrial NADH-dependent isocitrate dehydrogenase 2 superactivity, 752 Mitochondrial NADPH-dependent isocitrate dehydrogenase 3β subunit, 744 Mitochondrial ornithine transporter, 767 Mitochondrial ornithine transporter deficiency, 271 Mitochondrial persulfide dioxygenase, 369 Mitochondrial phosphoenolpyruvate carboxykinase, 654 Mitochondrial poly(A) polymerase, 850 Mitochondrial pyrophosphatase 2, 893 Mitochondrial pyruvate carrier, 744 Mitochondrial ribosomal protein L3, 851 L12, 851 L44, 851 S2, 851 S7, 851 S16, 851 S22, 851 S23, 851 S25, 855 S34, 851 Mitochondrial thiamine pyrophosphate carrier, 540 Mitochondrial thymidine kinase, 849 Mitochondrial transcription factor A, 850 Mitochondrial translation, 882 Mitochondrial translational activator, 803 Mitochondrial translation optimization 1, 850 Mitochondrial tricarboxylate transporter, 767 Mitochondrial trifunctional protein (MTP), 932 Mitochondrial tyrosyl-tRNA synthetase, 173 Mitofusin 1, 890 Mitofusin 2, 890, 891 MOCOS, 597 MOCS1A, 597 MOCS2A, 597 MOCS1AB, 597 MOCS1AB fusion protein, 594 MOCS2B, 597 Modified Johns Hopkins diet, 788 Molecular analysis, 559, 951 Molecular genetic testing, 1251 of CLN3 gene, 1212 of CLN5 gene, 1216 of CTSD gene, 1221 on CTSF gene, 1223 of DNAJC5 gene, 1214 of GRN gene, 1220 of MFSD8 gene, 1218

1506 Molecular or pharmacological chaperone therapy, 1232 Molybdenum cofactor (Moco)-dependent enzymes, 594 Molybdopterin (MPT), 594 Monoamine oxidase A deficiency, 315, 316, 320, 325–327 Monosialotransferrin, 728, 1355 Monosialotransferrins, 1393 MPV17, 845, 846, 849 MRS: N-acetyl aspartate, 773 MR spectroscopy, 1214, 1215, 1226 MSPT, 596 mtDNA content, 487 mtDNA deletions, 860, 861 mtDNA levels, 752, 753, 858–865, 867, 877 mTOR inhibitor, 735 MTP, 953 Mucolipidoses, 1235–1246 Mucopolysaccharides, 1186 Multiple carboxylase, 173 Multiple mitochondrial DNA deletions, 865 Multiple mtDNA deletions, 857–859, 862, 863, 865, 868 Multiple oxidative phosphorylation enzymes, 869, 871, 872, 880 Muscle glycogen phosphorylase, 653 Muscle GSD enzymes, 685 Muscle phosphofructokinase, 652 Muscle phosphoglycerate mutase, 652 Muscle phosphorylase kinase α1 subunit, 653 Mutation analysis on DNA, 731–733, 964 Mutiple mtDNA deletions, 859 Myoglobin, 18, 35, 488, 668–670, 672, 674, 1007 Myoinositol, 102, 106, 144 N N-acetyl-alpha-D-glucosaminidase, 1269 N-acetylaspartate, 97, 103, 104, 106, 121, 125, 127, 129, 131, 132, 139, 140, 142, 143, 403, 408, 410, 458, 1400, 1402, 1408, 1412, 1422 N-acetylaspartic acid, 52, 56, 57, 60, 398 N-acetylcysteine, 382–384 N-Acetylgalactosamine-4-sulfatase, 78–80, 83, 1269, 1275, 1280 N-Acetylgalactosamine-6-sulfatase, 76, 78, 80, 83, 1269, 1274, 1280 N-Acetylglucosamine 6-O-sulfotransferase, 1340 N-Acetylglucosamine-1-phosphotransferase, 76, 81 N-Acetylglucosamine-6-sulfatase, 76, 78, 1269, 1273, 1280 N-Acetylglucosaminidase, 78–80 N-Acetylglutamate synthase, 265, 266, 268, 282, 284–288 N-Acetylmannosamine, 168, 1258–1260 N-Acetylneuraminate pyruvate lyase, 1252 N-Acetylneuraminic acid, 1256–1258 N-Acetylneuraminic acid synthase, 1250–1252 NAD, 563, 565, 567 NAD+, 569 NAD(H), 565 NADH, 563 ubiquinone oxidoreductase 1 alpha subcomplex 1, 797 ubiquinone oxidoreductase 1 alpha subcomplex 2, 797 ubiquinone oxidoreductase 1 alpha subcomplex 9, 797 ubiquinone oxidoreductase 1 alpha subcomplex 10, 797 ubiquinone oxidoreductase 1 alpha subcomplex 11, 797 ubiquinone oxidoreductase 1 alpha subcomplex 12, 798 ubiquinone oxidoreductase 1 alpha subcomplex 13, 798 ubiquinone oxidoreductase 1 beta subcomplex 3, 798 ubiquinone oxidoreductase 1 beta subcomplex 9, 798 ubiquinone oxidoreductase Fe-S protein 1, 797 ubiquinone oxidoreductase Fe-S protein 2, 797 ubiquinone oxidoreductase Fe-S protein 3, 797

Test and Medication Index: Strange Association ubiquinone oxidoreductase Fe-S protein 4, 797 ubiquinone oxidoreductase Fe-S protein 6, 797 ubiquinone oxidoreductase Fe-S protein 7, 797 ubiquinone oxidoreductase Fe-S protein 8, 797 ubiquinone oxidoreductase flavoprotein 1, 797 ubiquinone oxidoreductase flavoprotein 2, 797 ubiquinone oxidoreductase subunit ND1, 798 ubiquinone oxidoreductase subunit ND2, 798 ubiquinone oxidoreductase subunit ND3, 798 ubiquinone oxidoreductase subunit ND4, 798 ubiquinone oxidoreductase subunit ND5, 798 ubiquinone oxidoreductase subunit ND6, 798 ubiquinone oxidoreductase subunit ND4L, 798 NADH dehydrogenase 1 beta subcomplex 11, 798 NADH dehydrogenase β subcomplex subunit 8, 798 NADH dehydrogenase (ubiquinone) complex I assembly factor 1, 798 assembly factor 2, 798 assembly factor 3, 799 assembly factor 4, 799 assembly factor 5, 799 assembly factor 6, 799 NADHX, 567 NADK2 NAD kinase 2, 567 NADP, 563, 564 NADP(H), 565 NADP-dependent mitochondrial enzymes, 564 NADPH, 567, 574 NAGA, 1259, 1262 NAM, 564 NAXD NAD(P)HX dehydratase, 567 NAXE NAD(P)HX epimerase, 567 N-Carbamoyl asparate, 197 N-Carbamyl-β-alanine, 200, 440, 450 N-Carbamyl-β-aminoisobutyric acid, 440, 450 N-carbamylglutamate, 176 N-deacetylase/Nsulfotransferase 1, 1340 Neopterin, 222, 224, 226 NEU, 1259, 1260 Neuraminidase, 1250, 1252 Neurodevelopmental abnormalities, 252 Neurologic examination, 1212, 1214–1218, 1220–1222 Neuronal-and musclespecific mitochondrial aspartate/glutamate transporter 1, 767 Neuronal ceroid lipofuscinoses (NCLs), 1211 Neuronal system A amino acid transporter deficiency, 296, 301, 306 Neuronal system A SNAT8 transporter deficiency, 302, 305 Neurophysiologic inspection, 1216 Neurotransmitter disorders, 314 Neurotransmitters, 449, 449 Neutral amino acids, 46, 48, 569 Neutropenia, 17, 38, 734 Neutrophil count, 676, 677 Neutrophil function, 676 NFS1 cysteine desulfurase (NFS1), 482 NFU1, 481, 490, 491 NFU1 Iron-sulfur cluster scaffold (NFU1), 482 N-glycanase 1, 1343 Niacin, 46, 563–574 Nicotinamide, 458, 563, 567 Nicotinamide adenine dinucleotide (NAD), 563, 936 Nicotinamide mononucleotide (NMN), 563–564 Nicotinamide mononucleotide adenyltransferase 1 (NMNAT1), 567 Nicotinamide nucleotide adenylyltransferase 1, 566 Nicotinamide nucleotide transhydrogenase (NNT), 566, 567 Nicotinamide phosphoribosyltransferase (NAMPT), 567

Test and Medication Index: Strange Association Nicotinamide riboside (NR), 563, 564 Nicotinamide riboside kinase (NRK), 567 Nicotinate phosphoribosyltransferase (NAPRT), 567 Nicotinic acid, 563, 564, 574 Nicotinic acid mononucleotide (NAMN), 564, 567 Nifedipine, 733 Nitrogen scavenger, 175 Nitroprusside test, 373, 376, 377, 379 NMDA receptor, 477 NMDA receptor antagonist memantine, 596 N-methyl-D-aspartate receptors, 1401 NMR-spectroscopy, 1251 NOP2/SUN RNA methyltransferase 3, 855 Norepinephrine, 609, 620 NPC1 protein, 76 Nrf2 superactivity, 252–254, 258, 260 Nucleoside diphosphate kinase (NDPK), 742–743 Nucleotide-binding protein-like protein, 799 O Octanoylcarnitine, 14, 67 Octanoylglucuronide, 62, 942 OCTN2. See Organic cation carnitine transporter 2 (OCTN2) Octreotide, 734 Odiparcil, 1282 O-Fucose-specific beta-1,3-N-acetylglucosaminyltransferase, 1341 O-Fucose-specific beta-1,3-N-glucosyltransferase, 1341 3-OH-butyrate/acetoacetate, 747 OH-butyrylcarnitin, 71 5-OH-Methyluracil, 440 17-OH-Pregnenolone, 1084, 1085 17-OH-Progesterone, 1087 2',5'-Oligoadenylate synthetase 1, 216–218 Oligosaccharides, 77, 80–81, 167–168, 1174, 1186, 1187, 1240, 1276, 11922 Oligosaccharidoses, 1249–1264 Oligosacharide, 141 O-linked N-acetylglucosamine transferase, 1341 O-Mannose beta-1,2-Nacetyglucosaminyltransferase, 1339 O-mannosyltransferase 1, 1339 O-mannosyltransferase 2, 1339 O-phosphoseryl-tRNA(sec) selenium transferase, 612 Ophthalmic examination, 1212, 1211–1218 Optic atrophy, 1101 Optic atrophy 1, 890, 891 Oral baclofen, 574 Oral cysteamine bitartrate, 1293 Oral galactose loading test, 683 Oral glucose loading test, 683 Oral iron chelation therapy, 787, 789 Oral nicotinamide treatment, 574 Oral pantethine supplementation, 574 Oral protein tolerance test, 730 Organic acids, 177, 377, 378, 381, 414, 419, 449, 535, 550, 559, 683, 785, 884 Organic aciduria, 171, 176 Organic cation carnitine transporter 2 (OCTN2), 931, 934, 953 Organic or inorganic selenium supplementation, 611 Ornithine, 14, 42–45, 49, 240, 241, 244–246, 461, 465, 781, 782, 784 aminotransferase, 48, 49, 236, 241, 264–266, 277, 282, 284, 285, 287, 288, 457 ornithine transcarbamylase (OTC), 22, 27, 30, 34, 48, 49 Ornithine aspartate, 247 Ornithine carbamoyltransferase deficiency, 266

1507 Ornithine transcarbamylase (OTC), 264, 266, 269, 282, 284, 285, 287, 288, 612 Orotate, 829, 1426 Orotic acid, 52, 58, 61, 62, 172, 196–198, 460, 522, 781, 782, 785, 1387 Orotic aciduria, 173 Orotidine, 197 Osmolality, 398 Osmotic fragility, 667 3-O-sulfogalactosyl-containing glycolipids, 1185 Outer mitochondrial membrane lipid metabolism regulator, 891 Oxabact®, 1329 Oxalate, 1326, 1328, 1329 Oxalic acid, 19, 55, 60, 1325, 1326 Oxcarbazepine, 1227 Oxidative burst, 667 Oxidative phosphorylation enzymes, 873, 875 Oxlumo®, 1329 2-Oxoadipate, 399, 751 2-Oxoadipate dehydrogenase, 481 2-Oxobutyric acid, 19, 20 18-Oxocorticosterone, 1085 18-Oxocortisol, 1085 2-Oxoglutarate dehydrogenase, 21, 24, 28, 745, 760, 884, 1401, 1403 2-Oxoglutaric acid, 399, 751, 756, 758, 759 2-Oxoglutaric aciduria, 742 2-Oxoisocaproic acid, 20 2-Oxo-3-methylvaleric acid, 20 6-Oxo-pipecolate, 579 Oxoprolinase, 61 5-Oxoprolinase, 57, 252–256, 260, 261, 1444 5-Oxoproline, 255–257, 259, 260, 1444 5-Oxoproline/Pyroglutamate, 14 Oxoprolinuria, 256 5-Oxoprolinuria, 252 3-Oxothiolase activity, 413 OXPHOS enzyme activity, 757 Oxygen consumption, 785, 884 Oxypurinol, 204 Oxysteroles, 1193, 1194 P Palmitoylcarnitine, 12, 14 Palmitoyl-protein thioesterase 1, 1211 Pantothenate, 563, 574 Pantothenate-derived CoA, 563 Pantothenate kinase, 566 Pantothenate kinase 2 (PANK2), 567 Pantothenate kinase-associated neurodegeneration, 103–104 Pantothenic acid, 534, 565 Paraplegin, 892 Parenteral cyano-Cbl, 510 Parenteral hydroxo-Cbl, 510 PARK9 Carbidopa/levodopa, 644 Parkin, 892 Partial thromboplastin time (PTT), 1382 Patatin-like phospholipase domain-containing lipase A (PNPLA), 991 PBG deaminase, 1119, 1124 Penicillamine, 48, 621 Pentacarboxyporphyrin, 1123 Pentasialotransferrins, 1393 Pentenoylcarnitine, 14 Pentosan polysulfate, 1246, 1282 Pent(ul)ose 5 phophates, 706 Peptidase, 892

1508 Peptidyl glycine mono-oxygenase, 609 Peptidyl-tRNA hydrolase 2, 855 Periportal inflammation, 1101 PER1-like domain-containing protein 1, 1342 Peroxisomal bile acid-CoA:Amino acid N-acyl transferase, 1300 Peroxisomal branched-chain acyl-CoA oxidase, 1300 Peroxisomal straight-chain acyl-CoA oxidase, 1300 Perseitol, 706 Persulfide dioxygenase (PSD), 597 PET100 protein involved in the biogenesis of mitochondrial complex IV, 803 Phenobarbital, 1229 Phenolphthalein, 18 Phenothiazines, 18, 19 Phenylacetic acid, 19, 53 Phenylalanine, 4, 10, 14, 17, 42–44, 49, 53, 88, 144, 778, 858 Phenylalanine hydroxylase (PKU), 4–5, 53, 102, 334, 346, 347, 350 classic, 334, 335 Phenylalanyl-tRNA synthetase 2, 855 Phenylbutyrate, 176 Phenylpropionylglycine, 55, 942 Phenylpyruvic acid, 19, 20, 53 Phenytoin, 59, 1231 Phosphate, 228, 229, 585, 650–653, 655, 656, 663–665, 667, 669, 676, 682, 684, 688, 692, 694, 696, 1103, 1290, 1292, 1374 Phosphate kinase, 582 Phosphatidylcholine, 384, 996 Phosphatidylethanolamine ratio, 996 Phosphatidylinositol glycan anchor biosynthesis class A protein, 1341 class C protein, 1341 class H protein, 1341 class L protein, 1342 class M protein, 1342 class N protein, 1342 class O protein, 1342 class P protein, 1341 class Q protein, 1341 class S protein, 1342 class T protein, 1342 class V protein, 1342 class W protein, 1342 class Y protein, 1341 Phosphoethanolamine, 43, 45, 49 Phosphofructokinase, 668 Phosphoglucomutase 1, 1343 Phosphoglucomutase 3, 1343 Phosphoglycerate dehydrogenase, 457 Phosphoglycerate kinase, 652, 668, 669 Phosphoglycerate mutase, 669 Phospholipids, 983 Phosphomannomutase, 1395 Phosphomannomutase 2, 1338 Phosphomannose isomerase, 1338, 1395 Phosphopantetheine adenylytransferase/dephosphocoenzyme A, 566 Phosphopantothenoylcysteine decarboxylase, 567 Phosphopantothenoylcysteine synthetase, 566, 567 Phosphoribose pyrophosphate, 201 Phosphoribosyl, 201 5'-Phosphoribosyl-5-aminoimidazole-4-carboxamide, 519 5'-Phosphoribosylglycinamide, 519 Phosphoribosyl pyrophosphate synthetase, 194 Phosphoribosyl pyrophosphate synthetase 1, 34, 194 Phosphorylase, 21, 25, 29–32, 35 Phosphorylase kinase, 673, 674 5'-phosphorylated esters, 578

Test and Medication Index: Strange Association Phosphoserine aminotransferase, 457 Phosphoserine phosphatase, 173, 457 Phototherapy, 1135 Phytanic acid, 1103, 1104, 1310, 1311, 1313, 1316 Phytanoyl-CoA hydroxylase, 1309 Pipecolic acid, 49, 375, 379, 579, 586, 587, 598–600, 1310, 1311 Piperideine-6-carboxylate, 583 Piracetam, 1230 Pitrilysin metallopeptidase 1, 893 Plasma, 419 Plasma acylcarnitines, 378, 535 Plasma amino acids, 172, 377, 378, 388 Plasma/blood acylcarnitine profile, 561 Plasma/DBS acylcarnitine, 557 Plasma glycine, 475 Plasma propionylcarnitine, 508 Plasma quantitative amino acids, 508 Plasma renin activity/renin, 1088 Plasma/serum isovaleric acid, 415 Plasma triglyceride levels, 788 PLP. See Pyridoxal 5'-phosphate (PLP) PLP-binding protein (PLBBP), 578, 581 Polyadenylation, 845 Polymerase gamma, 849 Polyoles, 705 Polypeptide N-acetylgalactosaminyltransferase 3, 1341 Poly(ADP-ribose) polymerases (PARPs), 567 Polyribonucleotide nucleotidyltransferase 1, 850 Porphobilinogen, 19, 1119–1121, 1125 Porphyria, 173 Porphyrin, 18, 1118–1121, 1125 Porphyrin I isomers, 1123 Potassium, 239, 618, 678, 716, 1083–1085, 1088, 1291, 1291 Potassium channel tetramerization domaincontaining protein 7, 1210 P-protein, 472 Pre-albumin, 695 Prednisone, 1092 Prenatal DNA testing, 910 Prenyl diphosphate synthase subunit 1, 917 Prenyl diphosphate synthase subunit 2, 917 Presequence translocaseassociated motor 16, 891 Primapterinuria, 334 Primary hyperammonemia, 263, 264 Primary inherited aminoacidurias cystinuria, 292 3-Prime-phosphoadenosine 5-prime-phosphosulfate synthase 2, 1341 3-Prime repair exonuclease 1, 217 Pristanic acid, 1103, 1104, 1303, 1310, 1311 Progesterone, 1084, 1088 Progranulin, 1210 Prolactin, 1350 Prolidase, 45, 49 Proline, 42–46, 49, 50, 240, 456, 461, 463, 465, 484, 585, 586, 781, 782, 784 Proline dehydrogenase, 457 Proline-serine-threonine phosphatase-interacting protein 1, 611, 612 Prolyl 4-hydroxylase activity, 617 Propionic acid, 1131 Propionylcarnitine, 11, 14, 62, 71 Propionyl-CoA carboxylase, 62, 67, 529, 530, 534 β-subunit, 54 α-subunit, 54 Propionyl-CoA-carboxylase activity, 408 Propionylglycine, 54, 408, 1003 Propofol, 834 Prostaglandin, 1035, 1037 Protective protein/cathepsin A, 1178, 1252

Test and Medication Index: Strange Association Protein, 166, 167, 239, 502, 650, 656–658, 664, 685, 831, 883, 923, 1045, 1189, 1192, 1406, 1413, 1414 Protein-bound lipoic acid, 483–487 Protein C, 725, 726, 1346, 1348, 1350, 1355, 1382 Protein kinase, 718 AMP-activated, 674 C substrate, 1339 Protein levels of GTPBP3 in fibroblasts, 868 Protein O-fucosyltransferase 1, 1341 Protein O-mannose beta-1,4-N-acetylglucosaminyltransferase 2, 1339 Protein-O-mannose kinase, 1339 Protein S, 726, 1351, 1355, 1382 Prothrombin ratio, 614, 1100, 1101, 1105 Prothrombin time, 371, 372, 672, 706, 724, 778 Protoporphyrin, 488, 1117–1119, 1124 Protoporphyrin-Zn, 1118 PRPP synthase, 201 Pseudouridine synthase 1, 850 PTEN-induced kinase 1, 890 PTEN-induced putative kinase 1, 892 Pterin-4α-carbinolamine dehydratase, 334, 338, 348 PTH, 694 PTPS, 346 Purine nucleoside phosphorylase, 35, 194, 204 Purines, 192, 449, 449 Pyrazolones, 18 Pyridine nucleotide transhydrogenase, 565 Pyridoxal kinase, 578 Pyridoxal phosphate, 180, 477, 596, 598–600, 602 Pyridoxal 5'-phosphate (PLP), 375, 379, 516, 524–526, 548, 577, 578, 580, 582, 584–588 Pyridoxal phosphatedependent epilepsy, 173 Pyridoxal 5'-phosphate-dependent epilepsy, 580 Pyridoxamine, 578, 582, 585, 587 Pyridoxic acid, 585, 587 Pyridoxine, 180, 384, 458, 578, 580, 587, 588 Pyridoxine-dependent epilepsy, 173 Pyridoxine-glucoside, 578 Pyridoxine hydrochloride, 247 Pyridox(am)ine 5'-phosphate oxidase, 578, 581, 582, 588 Pyridoxine responsiveness test, 379 Pyridoxine test, 382 Pyrimidine-5'-nucleotidase I, 36, 193, 198 Pyrimidine nucleotides, 198 Pyrimidines, 192, 449, 449, 1387 Pyroglutamic acid, 57, 59, 61 Pyrophosphate synthetase activity, 201 Pyrroline-5-carboxylate, 454–456, 463 dehydrogenase, 457, 581 reductase 1, 457 reductase 2, 457 Δ1-Pyrroline 5-carboxylate dehydrogenase, 579, 583, 587 Pyrroline-5-carboxylate synthase, 457 Pyrroline-5-carboxylate synthetase, 264, 266, 282, 284, 285, 287, 288 cutis laxa phenotype 3, 275 spastic paraplegia type 9A, 276 spastic paraplegia type 9B, 276 Pyruvate, 20, 48, 49, 122, 126, 403, 542, 719, 747–749, 758, 759, 774, 781, 782, 785, 831, 883, 884, 896, 995 carboxylase, 21–23, 48, 49, 266, 279, 284–286, 288, 529, 530, 654, 656, 680, 744 dehydrogenase, 481, 483–488, 740–742, 884 dehydrogenase E1, 744 dehydrogenase E3, 744 dehydrogenase kinase isoenzyme 3, 744 dehydrogenase phosphatase, 744

1509 Pyruvate kinase, 652, 669, 670 Pyruvate kinase activity, 670 Pyruvate test, 722 6-Pyruvoyl-tetrahydropterin synthase, 334 Q QPRT nicotinate-nucleotide pyrophosphorylase, 567 Qualitative test, 377 Quinone oxidoreductase (SQR), 597 R rAAV1-CMV-GAA, 697 Ragged red fibers, 863, 865, 866, 875 Receptor, 9, 516, 525 Recombinant growth hormone, 1293 Reduced folate carrier, 518 Reducing substances, 663–665, 682, 683, 684, 707 REN001, 697 Renin, 569, 1084 Respiratory chain activity, 706, 773, 774 Respiratory chain enzymes, 753, 785, 863, 864, 867, 873–877, 882, 884 Reticulocytes, 665–670 Reticulocytosis, 17, 38 Reticulon 4-interacting protein 1, 893 Retinoic acidi-nducible gene I, 218 Rhabdomyolysis, 937 RhGAA, 697 Ribitol, 705, 706 Ribitol β1,4-xylosyltransferase, 1339 Riboflavin, 18, 55, 57, 178, 387, 422, 789, 1401, 1412–1414 Riboflavin kinase, 549, 553 Riboflavin transporter, 553 1, 551 2, 551 3, 551 Riboflavin/vitamin B2, 547–562 Ribonuclease H1, 849 Ribonuclease H2 subunit A, 217 subunit B, 217 subunit C, 217 Ribonuclease T2, 218 Ribonucleotide reductase small subunit 2-like, 849 Ribose-5-phosphate isomerase, 701–705, 709 Ringed sideroblasts in bone marrow, 491 Ring finger protein 31, 654 R-NADHX, 564 RNA methyltransferase 10, 850 RNA polymerase, 612 Ronin, 500 S Saccharopine, 50 Sacsin, 892 S-Adenosylhomocysteine, 49, 370–373, 377, 378, 381, 724 S-Adenosylhomocysteine hydrolase, 368 S-Adenosylmethionine (SAM), 242, 248, 370–373, 377, 378, 381, 383, 504, 506, 508, 510, 517, 594, 724, 767 SAICA riboside, 201 Salicylates, 19 SAM domain-and HD domain-containing protein 1, 217 Saposin A, 1179

1510 Sarcosine, 42, 43, 50, 371, 373, 377, 378, 555–557 SCAD. See Short-chain acyl CoA dehydrogenase (SCAD) S-2-carboxypropyl-cysteamine, 404 S-2-carboxypropyl-cysteine, 403, 404 SCHAD. See Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) SCO2 cytochrome C oxidase assembly protein, 802 SCOT. See Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) Sebacic acid, 406, 412, 553, 555–557, 781, 783, 785, 815, 937–940, 942, 943, 946, 948, 949 unsaturated, 815, 942, 943 SECIS-binding protein 2 (SBP2), 612 SECIS-binding protein 2 (SECISBP2), 613 Sedoheptitol, 706 Sedoheptulokinase, 702–704, 709 Sedoheptulose, 706, 707 Sedoheptulose-7-P, 706 Selenium, 607–622 Selenocysteine, 612 Selenomethionine, 612 Sepiapterin reductase, 332–334, 339, 340, 346, 349 Serine, 41–45, 50, 458, 459, 776, 781, 783–785, 788, 965 Serum alkaline phosphatase, 586 Serum ceruloplasmin, 619 Serum copper, 608, 619 Serum holotranscobalamin, 508 Serum selenium, 611 Seryl-tRNA synthetase 2, 855 SGLT1, 685 Short-chain acyl CoA dehydrogenase (SCAD), 12, 21, 55, 62, 67, 70, 73, 552, 934, 936, 941, 953, 1445 Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), 55, 67, 71, 73, 934, 936, 953 Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD)-HI, 716, 731, 732 Short-chain L-3-hydroxyacyl-CoA dehydrogenase, 21 Sialic acid, 77, 80–82, 1249–1264, 1276 free, 1256–1258 Sialic acid-rich oligosaccharide, 1253 Sialic acid-rich oligosaccharides, 1189 Sialin, 1252, 1259, 1260 Sialotransferrins, 664, 665, 725, 726, 1257, 1357, 1359–1369, 1375, 1381, 1386, 1387, 1389, 1395 type 1, 1348, 1351 type 2, 642, 1358, 1359, 1388–1392 type 1 pattern, 726, 727, 1346–1350, 1352–1354, 1382–1384 Sialylation of platelet glycoproteins, 1387 Sideroflexin 4, 893 Simvastatin, 1058 Sirolimus, 735 Sirtuins, 567 SLC5A6, 530 SLC25A3, 767, 803 SLC30A10, 637–641, 643, 644 SLC33A1, 611 SLC39A8, 637–641, 643, 644 SLC39A14, 637–641, 643, 644 SLC7A5 deficiency, 296 SLC27A5 gene, 1105 SLC25A42 mitochondrial coenzyme A transporter, 567 SLC46A1 transporter, 518 S-NADHX, 564 Sodium, 398, 660, 661, 689, 693, 696, 697, 734, 1083–1085, 1090, 1119–1121, 1291 benzoate, 19, 242, 247, 477, 511, 787 bicarbonate, 178, 788, 886 phenylacetate, 787

Test and Medication Index: Strange Association phenylbutyrate, 177 valproate, 697, 834 Sodium-dependent multivitamin transporter (SMVT), 530 Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19), 567 Sodium-glucose cotransporter-1, 651 Sodium-glucose cotransporter-2, 651 Soluble cysteine string protein alpha, 1209 Solute carrier family, 651 Solute carrier family 25, 767, 768, 891 Solute carrier family 26, 1340 Solute carrier family 35, 1343 Somatosensory evoked potential, 1212, 1214–1217, 1226 Somatostatin analogues, 735 Sorbitol, 658, 681, 682, 684, 688, 691, 707 Sorbitol dehydrogenase, 702–704, 707, 709 Spasmolytics, 1314 Spastic tetraplegia, 296 SPH-binding factor, 500 Sphingolipids, 987 Sphingomyelinase, 1192, 1193 Sphingosine-1-phosphate, 1017 Spondylometaphyseal dysplasia, 254 S-Sulfocysteine, 45, 50, 375–378, 594, 596, 602, 604 S-Sulfohomocysteine, 596 Startle disease, familial, 296 Stearylcarnitine, 12, 14 Stem cell transplant (SCT), 1232 Steroid 5 alpha-reductase 3, 1342 Steroids, 51, 1083 Sterol, 1058 Sterol-Δ8, Δ7-isomerase, 1059 Suberic acid, 60, 406, 412, 553, 556, 557, 781, 783, 785, 815, 937–940, 942, 943, 946, 948, 949 unsaturated, 815, 942, 943, 949 Suberylglycine, 55, 59, 555, 779, 942 Substrate oxidations, 884 Substrate reduction therapy (SRT), 1232 Substrate supplementation, 1263 Subunit of cisprenyltransferase, 1342 Subunit of ferritin, 627, 629 Succinate, 127, 130 Succinate-CoA ligase α-subunit deficiency, 745 Succinate-CoA ligase β-subunit deficiency, 745 Succinate dehydrogenase, 754 Succinate dehydrogenase 5, 800 Succinate dehydrogenase complex assembly factor 1, 800 Succinate dehydrogenase complex, subunit a, flavoprotein, 799 Succinate dehydrogenase subunit A, 745 Succinate dehydrogenase subunit B, 745, 799 Succinate dehydrogenase subunit C, 745, 799 Succinate dehydrogenase subunit D, 745, 799 Succinic acid, 55–57, 59, 60, 756, 758 Succinic-semialdehyde, 56 Succinic-semialdehyde dehydrogenase, 56 Succinylacetone, 59–61, 778, 858 Succinyladenosine, 115, 201 Succinylaminoimidazole carboxamide riboside, 115 Succinylcarnitine, 14 Succinyl-CoA:3-oxoacid CoA transferase (SCOT), 21, 29 Succinyl-CoA synthetase (SCS), 742–743 Sucrase, 660, 661, 684 Sucrase-isomaltase, 651, 661 4-Sulfatase, 78–80, 83 Sulfated 3α,7α,12α-trihydroxy-5-cholenoic acids, 1100 Sulfatide, 109, 1189, 1194

Test and Medication Index: Strange Association Sulfhydryl oxidase, 609 Sulfite, 19, 375–378, 381, 598–600 Sulfite dipstick, 19, 604 Sulfite oxidase, 369, 597 Sulfocysteine, 587, 598–600 Superoxide dismutase, 607, 612 Surfeit 1, 803 T Taurine, 42–45, 47, 50, 375–378, 598–600, 602 Tauro-tetrahydroxycholestanoic acid, 1311 TDP-D-glucose 4,6-dehydrogenase, 1341 Testosterone, 569, 1086, 1088, 1372, 1373 Tetracosahexaenoic acid, 1303 Tetradecadienoylcarnitine, 14 Tetradecanoylcarnitine, 14 Tetradecenoylcarnitine, 14 Tetrahydrobiopterin (BH4), 332, 333, 342, 351 Tetrahydrobiopterine (BH4), 5, 314, 522, 524 Tetrahydrocortisol/tetrahydrocortisone ratio, 1085, 1086 Tetrahydrofolate, 519 5,6,7,8-Tetrahydrofolate, 515 Tetrahydrofolate (THF), 498 Tetrahydroxycholestanoic acid, 1310, 1311 2,6,10,14-Tetramethylpentadecanoic acid, 1303 Tetrasaccharide, 695, 1357 Tetrasialotransferrin, 725–728, 1346–1357, 1359, 1385, 1393 Tetratricopeptide repeat domain-containing protein 19, 801 Thiamine, 422, 537–546, 761, 789 Thiamine phosphokinase, 537, 538 Thiamine pyrophosphate, 537, 538, 786 Thiamine pyrophosphokinase, 540 thiamine supplementation, 789 Thin corpus callosum, 296 Thin-layer chromatography (TLC), 1278 Thiopurine S-methyltransferase, 195 Thioredoxin 2, 893 Thioredoxin reductase, 612 Thioredoxin reductase 2, 893 Thiosulfate, 375–378, 381, 594, 602 Thiosulfate sulfur transferase (TST), 597 Threonine, 42–44, 50, 414, 428, 585, 586, 778, 781, 783, 784 Threonyl-tRNA synthetase 2, 855 Thrombocytes, 545 Thrombocytopenia, 17, 37 Thromboplastin time, 1347, 1349 THTR1 transporter, 540 THTR2 transporter, 540 Thymidine, 199, 515, 861 Thymidine kinase, 845 Thymidine phosphorylase, 193, 199, 849, 861 Thymine, 52, 58, 61, 62, 440 Thyroid-stimulating hormone (TSH), 1291 Thyrotropin, 618 Thyroxin-binding globulin, 725–727, 1346 Thyroxine T4, 618, 1291 Tiagabine, 1228 Tiglylglycine, 54, 405, 408, 413, 535, 870, 1003 Tissue non-specific alkaline phosphatase (TNSALP), 578, 580, 582 Tizanidine, 1230 Topiramate, 1228 Topoisomerase 3, 850 Total GAGs, 1271–1276 Total homocysteine, 45, 46, 49, 499, 508, 510, 602 Total iron binding capacity (TIBC), 642–644

1511 T-protein, 472, 778 Trafficking protein, 893 Transaldolase, 701–705, 709, 711 Transaminases, 48, 49, 555, 556, 561, 725–728, 815, 818, 858, 859, 937–940, 942, 943, 945, 946, 943, 945, 1063, 1103–1105, 1346–1348, 1350, 1353, 1357, 1382–1385, 1391–1393 Transaminases plasma, 963 Transcobalamin, 498, 501 Transcobalamin III, 500 Transferrin, 486, 626–634 Transferrin receptor 2, 626, 627 Transferrin saturation, 627, 629–634, 1118 Transient receptor potential channel mucolipin-1, 1238 Transient tyrosinemia, 354 Transketolase, 701–704, 706, 709 Translocase of inner mitochondrial membrane 50, 891 Translocase of inner mitochondrial membrane 8A, 891 Translocase of inner mitochondrial membrane domain-containing protein 1, 891 Transmembrane protein 70, 266, 280, 282, 285–288 Transmembrane protein 173, 218 Transmembrane protein 199, 1343 Transmembrane protein 126A, 893 Transmembrane protein 126B, 799 Transporter assays, 685 Treahalase activity in intestinal biopsy, 661 Trehalase, 650, 651, 661, 685 Trientine, 622 Triglycerides, 30, 179, 663, 665, 673–677, 681, 690, 694, 694, 774, 781, 783, 785, 962, 963, 997, 1007, 1010, 1011, 1040–1044, 1193, 1444, 6921 pseudo, 962 Triglylglycine, 975 Triheptanoin, 690, 696,697, 955 Trihexyphenidyl, 574 Trihydroxycholestanoic acid, 1311 Triiodothyronine, reverse rT3, 618 Triiodothyronin T3, 618 Trimethylamine, 599 Triosephosphate isomerase, 173, 652, 668 Tripeptidylpeptidase 1, 1211, 1212, 1214 Trisialotransferrin, 728, 1359, 1385, 1393 Trisialotransferrins, 1393 tRNA isopentenyl transferase 1, 850 tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, 851 tRNA methyltransferase, 850 Tryptophan, 564, 565 Tryptophan 2,3-dioxygenase, 567 Tryptophanyl-tRNA synthetase 2, 855 Twinkle mtDNA helicase, 849 Tyrosinase, 607 Tyrosine, 10, 14, 42–44, 46, 50, 53, 88, 778, 781, 783, 784, 858 aminotransferase, 53, 355 Tyrosine hydroxylase (TH) deficiency, 314–318, 325–327 Tyrosinemia type I, 354–358, 361 type II, 354, 355, 357, 358, 361, 362 type III, 355, 357, 358, 361, 362 Tyrosyl-tRNA synthetase 2, 855 U Uberic acid, 555 Ubidecarenone, 574 Ubiquinol-cytochrome c oxidoreductase-binding protein, 800 Ubiquinol-cytochrome C reductase complex assembly factor 2, 801

1512 Ubiquinol-cytochrome C reductase complex assembly factor 3, 800 Ubiquinol-cytochrome C reductase complex III subunit VII, 800 Ubiquinol-cytochrome C reductase core protein II, 800 Ubiquinone, 387, 917 Ubiquinone-50, 1063 Ubiquitin-specific protease 9, 892 UDPGal-4-epimerase, 685 UDP-GlcNAc dolicholphosphate-N-Acetylglucosamine-1-phosphotransferase, 1338 dolichol pyrophosphate N-acetylglucosamine transferase, 1338 UDP-GlcNAc 2-epimerase/ManNAc kinase, 1251, 1252 UDP-glucuronic acid-UDPN-acetylgalactosamine dual transporter, 1343 UDP-N-acetyl glucosamine-1-phosphotransferase, 1238 Unconjugated bilirubin, 667, 670 UPD-Gal epimerase, 664 Uracil, 52, 58, 61, 62, 440 Uracil-DNA glycosylase, 218 Urates, 18 Urate transporter 1, 195 Urea, 9, 17, 19, 34, 41, 42, 44, 48, 49, 781, 783, 785, 1326 Uric acid, 19, 34, 35, 172, 175, 177, 179, 180, 201, 204, 207, 372, 375, 400, 402, 408, 410, 413, 598–601, 604, 663, 665, 668, 670–677, 681, 684, 688, 689, 693, 694, 695, 724, 829, 880, 994, 1290, 1292, 1426 Uridine monophosphate synthase, 193, 198 Urinary amino acids, 377, 378 Urinary copper, 619 Urinary GAG level, 1284 Urinary glucose, 689, 695 Urinary organic acid, 413, 550, 557 Urinary quantitative amino acids, 508 Urinary special assays, 377, 378 Urine analysis, 1284 Urine lactate, 415 Urine MMA/MA ratio, 411, 412 Urine organic acid, 172, 951 Uromodulin, 195 Uroporphyrin, 1123, 1124 Uroporphyrin I, 1123 Uroporphyrinogen-decarboxylase, 1124 Urothione, 598–600 Ursodeoxycholic acid, 1141 V Vacuolar protein sorting-associated protein 33A, 1269 Valine, 14, 42–44, 48, 50, 71, 397–399, 414, 416, 425, 427, 428, 585, 751 Valosin-containing protein, 892 Valproate, 43, 46, 47, 59, 451, 474, 477, 1229 Valproic acid, 171, 1228 Valyl-tRNA synthetase 2, 855

Test and Medication Index: Strange Association Vanillactic acid (VLA), 585, 586 V-ATPase A subunit 1, 1343 Venous blood lactate, 415 Very long-chain acyl-CoA dehydrogenase (VLCAD), 12, 21, 32, 36, 55, 67, 70, 73, 552, 934, 935 Very-long-chain fatty acids (VLCFA), 616, 895, 1103 Vesicular excitatory amino acid transporter, 76 Vesicular monoamine transporter 2 deficiency, 316, 325–327 Vestronidase alfa, 1283 Vigabatrin, 1231 Visual evoked potential, 1215, 1217, 1225, 1226 Vitamin, 548, 788, 789, 886 A, 1102, 1105, 1313 B3, 563–574 B5, 563 B6, 45, 238, 242, 243, 247, 524–526, 577–589 B12, 8, 45, 59, 60, 497–512, 517, 523 binding protein, 500 C, 260, 261 D, 678, 691–694, 696, 1105, 1313 D3, 898 E, 260, 261, 574, 1102, 1103, 1104, 1105, 1313 K, 1313 VLA. See Vanillactic acid (VLA) VLCAD. See Very long-chain acyl-CoA dehydrogenase (VLCAD) VLCFA. See Very-long-chain fatty acids (VLCFA) X Xanthine, 204, 598–601, 604, 605 Xanthine dehydrogenase, 194 Xanthine oxidoreductase, 594 Xanthinuria type II, 595 Xanthurenic acid, 19, 569 Xeno-tetrasaccharide, 1348 Xylitol, 707 Xylose, 19 Xylosyltransferase 1, 1340 Xylosyltransferase 2, 1366 Xylulose, 705, 707 L-Xylulose, 707 Z Zinc, 607–622, 642, 643, 1389 acetate, 622 protoporphyrin, 1124, 1125 salts, 622 sulphate, 622 ZIP4, 611 ZIP13, 611 ZnT2, 611 ZnT9, 611 Zonisamide, 1229

Sign and Symptoms Index

A Abasia, 1406 Abdominal, 734 Abdominal distension, 1044, 1193, 1389 Abdominal pain, 172, 198, 629, 630, 661, 665, 684, 776, 864, 1044, 1118–1121, 1185 Abducted thumbs, 1370, 1373 Aberrant splicing, 155 Abnormal jitter, 1349 Abnormal mitochondria with paracrystalline inclusions, 755 Absence seizures, 1378 Absent clavicle, 1171 Absent head control, 278, 319, 321, 461 Absent puberty, 1358 Absent pubic and axillary hair, 1087 Absent speech, 757 Absent spontaneous movements, 825 Absent tendon reflexes, 371, 615 Absent uterus, 1087 Acanthocytosis, 1042 ACBD5 deficiency, 1307 Accelerated growth, 1256 Accelerated iron deposition dentate nucleus, 120 Accessory ossification centers of hands and feet, 1374 Accessory nipples, 197 Aceruloplasminemia, 104 Achalasia, 1325, 1386 Achlorhydria, 1236, 1241 Acidosis, 507, 671, 971, 974, 975 metabolic, 507 Acne, severe, 1373 Acrodermatitis enteropathica, 617 Acro-osteolysis, 1242 Actionability, 160 Action dystonia, 1193 Acute cardiorespiratory, 173 Acute hematological and vascular signs, 173 Acute hemiplegia, 375 Acute hypoketotic hypoglycemia, 930–931 Acute liver and digestive signs, 173 Acute liver failure, 174 Acute neurological signs, 173 Acute peripheral neuropathy, 173 Acute renal failure, 174 Acute rhabdomyolysis episodes, 554 Acyl-CoA oxidase deficiency, 1306 Adaptation, dark impaired/night blindness, 465 Addison crisis, 569 Adducted thumbs, 459, 1371 Adenylosuccinase deficiency, 194 Adiposity (doll-like facies), 673, 675–677 Adrenal failure, 1309

Adrenal hyperplasia, 4, 9, 12, 29, 1083–1086 Adrenal insufficiency, 174, 1083–1085, 1102, 1307, 1393 Adulthood neurological developmental delay, 1308 Adult polyglucosan body disease, 672 Advanced bone age, 1367, 1371–1373 Advanced carpal bone age, 1373, 1374 Advanced ossification, 1389 Aged appearance, 1390 Agenesis cingulate gyrus, 404 corpus callosum, 399, 404, 463, 491, 584, 747–749, 751, 872, 876, 882, 903, 1067, 1069, 1158, 1160, 1171, 1352, 1360, 1361, 1363 septum pellucidum, 491, 903 Aggressive behavior, 1372 Agyria, 1363, 1364 AICA-riabosiduria, 194 Akinesia, 643, 1223 Alaaxia, 705 Alacrima, 1325, 1377, 1386 hypolacrima, 1393 Albinism, 183 Alkaptonuria, 183 Allelic expression imbalance, 167 Alopecia, 400, 532, 533, 610, 616, 617, 1066, 1067 areata, 1357 Altered consciousness, 400, 756 Ambiguous genitalia, 1069, 1083, 1084, 1086, 1087 Amblyopia, 1375, 1390 Amicable character, 1165, 1167 Amino acidopathy, 99 Aminoaciduria, 239 Amylopectinosis, 677 Amyotrophic lateral sclerosis, 1162, 1164 Amyotrophy, 1160–1162, 1164, 1168, 1170 Anal atresia, 491, 903 Anal stenosis, 1379 Anarthria, 1168, 1169 Anemia, 173, 196–198, 206, 272, 401, 407, 409, 517, 521, 526, 614, 615, 618, 625, 627, 628, 631, 632, 634, 650, 652, 655, 662, 664, 665, 667–669, 676–678, 690, 695, 705, 777, 877, 878, 991, 1030, 1031, 1063, 1103, 1122, 1190, 1276, 1354, 1387 hemolytic, 252–254, 256–259, 899, 1119 hypochromic, 776, 778, 899, 1118, 1119 macrocytic, 522 megaloblastic, 459, 499, 501–506, 508, 516–518, 520–523 microcytic, 488, 776, 899, 1119, 1424 mild, 1386 non-spherocytic, 205 sideroblastic, 479, 486, 490, 491, 542, 778, 811, 827, 868, 878, 880, 903 transfusion dependent, 822

© Springer Nature Switzerland AG 2022 N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, https://doi.org/10.1007/978-3-030-67727-5

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1514 Anencephaly, 1366 Aneurysms, 132 Angina, 1102 Angiokeratoma, 1188, 1253–1256 Anhydrosis, 1393 Anisocoria, 1325 Anisocytosis, 196, 197, 521, 1387 Anophthalmia, uni-or bilateral, 831 Anorectal anomalies, 1378 Anorexia, 198, 490, 501, 502, 616, 664, 724, 861, 1345 Anosmia, 1309, 1372 Anterior eye chamber anomalies, 1363, 1376 Anteverted nares, 1068, 1069, 1168, 1171 Anticholinesterase therapy, 1385 Antley-Bixler syndrome, 1087 Anus, anteriorly placed, 569, 1376 Anxiety, 442, 662, 905, 1164, 1213 Aortic ectasia, 775 Aortic valve (AV) disease, 1041 Aortic valvulitis, 358 Apathy, 501–503, 610, 616, 1162, 1164, 1173 Aplasia cutis congenita on skull vertex, 491, 903 Apnea, 68, 280, 308, 398, 403, 473, 474, 521, 588, 596, 598–600, 603, 680, 773, 828, 904, 1162, 1357, 1372, 1425, 1426 Aquiline nose, 1242 Aquired microcephaly, 662 Arachnodactyly, 373, 464, 726, 1242, 1351, 1367 Arched eyebrows, 1168 Arched palate, 1065, 1346 high, 776, 1166, 1357 Arcus cornealis, 1040, 1041, 1045, 1046 Areflexia, 198, 571, 751, 861, 894–897, 900, 907, 1159, 1162, 1163, 1170, 1172, 1173 Arrhythmia, 68, 173, 407, 831 Arterial ruptures, 615 Arterial stenoses, 134, 135 Arterialthrombosis, 121 Arthralgia, 1031 Arthritis, 81, 355, 358, 362, 1031, 1192 Arthrogryposis, 1068, 1388 multiplex, 672 Arthrophaty, 630 Arts syndrome, 194 Ascites, 614, 872, 1101, 1345 edema, 1186 Astasia, 1406 Asterixis, 269, 271, 776 Astrocyte swelling, 175 Astrocytosis, 1173 Asymmetric white matter lesions, 826 Asymmetry, 905, 1164 Asymptomatic, 942 Ataxia, 173, 200, 201, 256, 257, 269–272, 291, 292, 294, 296, 301, 302, 305–308, 310, 321, 398, 400, 402, 407, 409, 412, 441, 459, 474, 489, 490, 505, 506, 520, 532, 533, 537–539, 542, 548, 553, 568, 569, 571, 573, 614, 618, 619, 662, 666, 727, 751–753, 776, 777, 795, 806, 807, 813, 814, 817, 822, 824–828, 830, 847, 856, 857, 859, 860, 862–864, 867, 868, 874, 875, 879, 881, 896–899, 901–904, 906, 921, 922, 941, 1042, 1063, 1102–1104, 1157, 1159–1161, 1187–1189, 1193, 1211, 1214, 1215, 1217–1219, 1221, 1222, 1224– 1226, 1253, 1254, 1256, 1257, 1308, 1350, 1353, 1372, 1379–1381, 1383, 1387, 1406, 1421, 1424, 1425, 1429 cerebellar, 565, 867, 876, 921, 996, 1101 Atherosclerosis, 167 severe, 1193

Sign and Symptoms Index Athetosis, 319, 402, 534, 751, 756, 860, 1421 Atlantoaxial instability, 1271, 1272, 1274, 1281 Atopy, 1386 Atrial septal defect, 570, 775, 1386 Atrophic scars, 1367, 1371 Atrophy, 3, 9, 13, 43, 115, 120, 133, 238, 239, 336, 337, 517, 520, 522, 593, 595 cortical, 239, 596 generalized, 534 grey and white matter, 579 gyrate of choroid and retina, 239, 266, 277, 465 hyperornithinemia-associated gyrate, 238 Attention deficit disorder, 371 Attention disorder, 442, 523 Attenuated retinal vessels/pigmentary retinal changes, 568 Atypical pigmentary retinopathy, 1042 Auditory brainstem potential, abnormal, 750 Auditory neuropathy, 907 Autism, 199, 201, 237, 238, 335, 339, 399, 436, 437, 440, 464, 517, 662, 756, 1255, 1377 Autistic spectrum disorder, 401, 410, 520, 898, 940, 1388 Autoamputation, 1163 Autoinflammation, 618, 678, 1379 Autonomic instability, 905, 1164 Autonomic symptoms, 344, 345 Autosomal recessive spastic paraplegia type 63, 194 Avascular necrosis, 1179 Axial hypotonia, 316, 321, 332, 337, 339, 375, 487, 726, 727, 752, 753, 862, 863, 864, 1069, 1165, 1348, 1349, 1351, 1353, 1359 Axonal neuropathy, 571, 572 Axonal sensorimotor neuropathy, 488 Axonal sensorimotor polyneuropathy, 750 Axonal sensory ataxic neuropathy, 856 Axonal sensory motor polyneuropathy, chronic, 398, 459, 922 Axonal spheroids, 1170 Azoospermia, 569 B BAAT deficiency, 1306 BAER, abnormal, 1357 Basal ganglia, 98–104, 106, 107, 109, 110, 113, 124, 128, 144 abnormalities, 98–103, 107, 109, 124, 237, 407, 409, 412, 571, 596, 779, 806, 808, 809, 813, 814, 819, 822, 824, 975, 993 atrophy, 829 calcifications, 337 lesions, 124, 173, 280, 402, 403, 405, 407, 409, 411, 412, 506, 542, 543, 614, 779, 828, 870, 895, 901, 1421, 1426 Basilar artery ectasia, 140 Basilar ecasia, 140 Beaked nose, 1358 Behavior abnormalities, 271, 319, 324, 643, 662, 705, 706, 1066, 1348 aggressive, 320, 371, 442, 520, 900, 1069, 1170, 1173, 1213, 1272, 1273, 1377, 1427 changes, 1308 cognitive deterioration, 1308 disorder, 941, 993, 1162, 1164, 1170, 1193, 1213, 1214, 1218, 1219, 1223, 1224, 1271, 1272 difficulties, 462, 571, 727, 824, 899, 941, 1281, 1353, 1357, 1362, 1387, 1392 psychotic, 298, 339 Benign polymorphisms, 153 Beta-propellar protein-associated neurodegeneration, 104 Bicuspid aortic valve, 775

Sign and Symptoms Index Bifid distal humerus, 1370 Bifid uvula, 617, 727, 995, 1385 Big open mouth, 1165, 1358 Bilateral basal ganglia hyperintensity, 899 Bilateral calcification basal ganglia, 897 Bilateral hyperintensities of basal ganglia, 825, 993 Bilateral schizencephaly, 1158 Bilateral sensory hearing loss, 993, 1423 Bilateral symmetric lesions globus pallidus and brain stem, 900, 1427 Bilateral tract pyramidal tract signs, 1241 Bile duct proliferation, 1101 Biliary cirrhosis, 675 Birth asphyxia, 714 Bitemporal narrowing, 464, 1068, 1166–1168 Black toenail sign, 106 Bladder diverticula, 609, 615 Bleeding, 362, 1387 tendency, 676, 677, 1042, 1358 Blended phenotype, 166, 168 Blindness, 106, 202, 238, 239, 277, 564, 568, 827, 1189, 1405 cortical, 465, 774 Blisters, 357, 1120, 1121 Blood ammonia, 533 Blue sclerae, 463, 617 Body mass index, low, 997 Bombay blood group phenotype, 1388 Bone abnormalities, 991 Bone deformity, 1368, 1369 Bone density, increased, 1242 Bone fractures, 1165 Bone marrow hypoplasia, 1276 Bone pain, 1165, 1190, 1323–1326, 1374 Bowed limbs, 997, 1373 long bones, 1368 radius and ulna, 1373 Brachycephaly, 775, 881, 1162 Brachydactyly, 1367, 1369, 1373, 1374, 1376, 1386 Brachytelephalangy, 1377–1379 Bradycardia, 68, 484, 921 Bradykinesia, 316, 317, 321, 332, 338, 571, 905, 1163, 1164 Brain, abnormal, 368, 403, 705, 1170 Brain anomalies, 651, 654, 664 Brain atrophy, 301, 405, 593, 823, 870, 877, 900, 905, 1161, 1186, 1187, 1351, 1380, 1425, 1427 hemispheral, 826 white matter, 483 Brain changes on MRI atrophy, 533 polymicrogyria, 533 Brain edema, 97, 101, 175, 264, 398, 407, 409, 412, 664 cytotoxic, 398 Brain hypoplasia, 123 Brain malformations, 135 Brainstem abnormal, 809 atrophy, 830, 896, 897 and cerebellum hypoplasia/dysplasia, 143 edema, 398 hypoplasia, 1363, 1364, 1366 lesions, 806, 824 Brain underdevelopment, 123 Brain vascular anomalies, 1363 Brain volume, decreased, 121 Breathing difficulty, 1169 Bridging fibrosis, 1100, 1101, 1105 Brisk reflexes, 275

1515 Broad alveolar ridges, 1068, 1069 Broad nasal bridge, 1165, 1166, 1376, 1378 Bulbar dysfunction, 321, 532, 596, 1160, 1162, 1164, 1169, 1170, 1173, 1349 Bulbar palsy, 550 Bulbous nose, 463, 464, 1165–1168, 1357 Buphthalmos, 1359–1361 Burning sensation after sun exposure, 1118 Burst-suppression, 465, 473, 474, 1357 C Cabbage-like breath odor, 370, 374 Cachexia, 856, 1037 Café au lait spot, 489 Calcification, 96, 97, 102, 109, 111, 133, 144, 337, 355 Calcified AV, 1041 Calcinosis cutis, 1323–1326 Calcium, abnormal flux of, 1236 Calf muscle hypertrophy, 1363, 1365 Calf pseudohypertrophy, 1362–1364 Callosum, 99, 101, 108, 110, 111, 113, 144, 1241 Camptodactyly, 1354, 1366 Cardiac, 701, 705 abnormalities, 859, 873 anomalies, 372, 504, 724, 831, 1376, 1379 malformations, 372, 504, 857, 863, 1376 Cardiac arrest, sudden, 671 Cardiac arrhythmia, 176, 400, 906, 944, 945, 947, 994, 1213, 1309, 1422 severe, 940 Cardiac conduction abnormalities, 1308 defect, 1424 Cardiac dysfunction, 1363 Cardiac failure, 490, 679 Cardiac involvement, 857 Cardiac oxalate deposition, 1323–1326 Cardiac preexcitation syndrome, 674, 679 Cardiac rhythm disorder, 629 Cardiomegaly, 779, 900, 974, 1250 Cardiomyopathy, 68, 166, 173, 176, 206, 401, 405, 407, 409–412, 485, 488, 490, 504, 506, 542, 547–550, 554–556, 565, 568, 571, 629, 630, 632, 668, 671, 672, 674, 675, 720, 724, 807, 809, 811, 813, 818, 820–822, 830, 870, 874, 875, 878, 902, 907, 920, 923, 931, 937, 939, 940, 943–945, 947, 972, 974, 992, 994–996, 1044, 1171, 1186, 1188, 1213, 1240, 1253, 1255, 1257, 1271, 1272, 1275, 1281, 1323–1326, 1345, 1348, 1364, 1365, 1401, 1407, 1422 dilated, 401, 405, 407, 570, 677, 679, 727, 815, 817, 827, 949, 1158, 1258, 1363, 1382, 1384, 1385, 1422, 1424 hypertrophic, 403, 671, 674, 679, 714, 773, 806–811, 814, 816, 817, 822–824, 826–828, 830, 863, 865, 866, 868, 869, 871, 872, 880, 901, 921, 1255, 1256, 1352, 1424, 1426 severe, 877 Cardiopathy, 630 Cardiopulmonal congenital heart defects, 1307, 1308 Cardiopulmonary failure, 774 Cardiopulmonary involvement, 1241 Cardiovascular abnormalities, 1390 Cardiovascular tachycardia, 1119, 1120 Caries, dental abscess, 1281 Carotid body tumors, 754, 817 Carotid bruits, 1041, 1042 Carotid/femoral bruits, 1040 Carotid stenosis, 1041

1516 Carpal and tarsal syndrome, 1240 Carpal fusion, 1374 Carpal/tarsal fusion, 1370 Carpal tunnel syndrome, 1240, 1271, 1272, 1275, 1281 Cartilage hypoplasia, 869 Cataract, 206, 252, 275–277, 280, 459–462, 554, 610, 611, 614, 616, 627, 631, 661–664, 702, 703, 706, 707, 773, 824, 825, 828, 830, 831, 878, 897, 900–903, 907, 992, 998, 1063–1065, 1067–1069, 1101, 1102, 1158, 1171, 1255, 1310, 1346, 1349, 1354, 1360–1364, 1367, 1382, 1387, 1424–1426 bilateral, 258 posterior subcapsular, 239, 277, 465 risk in dysregulated, 707 Cauliflower ear, 1373 Cavitating leukodystrophy, 119, 120, 126, 127, 129–131, 135, 820, 826 CC dysgenesis, 829 CC malformation, 123 Cellular lipidome, 167 Cellular stress and inactivity, 794 Cenal calcium oxalate stones, 1314 Central cerebral predominant injury, 116 Central hypopnea, 1425 Central nervous system, 1133 abnormalities, 253, 258 manifestation, 860 Centrocecal scotomas, 897 Cerebellar, 98–100, 105, 111, 119, 702, 705 abnormalities, 402, 1360, 1361, 1363–1365, 1382, 1388, 1421 ataxia, 488, 565, 823, 904, 1309 nonprogressive, 488 atrophy, 121, 134, 139, 141, 375, 441, 517, 520, 610, 616, 638, 639, 642–644, 751, 757, 810, 814, 827, 830, 862, 874, 875, 877, 895–897, 899, 901, 902, 904, 906, 993, 996, 1165– 1167, 1211, 1213–1215, 1217–1219, 1221, 1222, 1224– 1226, 1241, 1355, 1380, 1381, 1389, 1423, 1425 and brainstem hypoplasia, 596 cortical encephalomalacia, 120 dys/hypoplasia, 1363 dysplasia, 1365 edema, 398 hypoplasia, 139, 141, 201, 278, 280, 371, 460, 461, 465, 724, 774, 775, 863, 1063, 1069, 1157, 1163, 1168, 1345, 1348, 1352, 1354, 1361, 1362, 1366, 1379, 1387 mild, 828, 1426 progressive, 881 hypotrophy (vermis), 898 vermis agenesis, hypoplasia, 1158 atrophy, 901, 904 hypoplasia, 460, 1370 volume loss, 104 white matter abnormalities, 487 changes, 896 Cerebral abnormalities, 1388 anteroposterior gradient, 135 atrophy, 199, 206, 375, 398, 401, 402, 405, 407, 409, 440, 441, 463, 484, 486, 489, 504–506, 517, 522, 611, 612, 616, 619, 621, 638, 639, 642–644, 726, 751, 778, 863, 873, 874, 894, 897, 898, 901, 902, 993, 1159, 1162, 1168, 1211, 1213– 1215, 1217–1219, 1221, 1224–1226, 1349–1351, 1354, 1356, 1383, 1384, 1389, 1421, 1423–1425 cortical malformations, 1066, 1068, 1360, 1361, 1390 creatine deficiency, 237, 238

Sign and Symptoms Index hypomyelination, 773 infarction, 134, 135, 137, 405, 490, 972 neoplasm, 143 palsy, 204, 339, 344, 345, 756 vein thrombosis, 1378 visual impairment, 596, 598–600 volume, 773 white matter involvement, 118, 134, 996, 1385 without edema, 118 Cervical compressive myelopathy, 725, 1067, 1345 Cervical myelopathy, 1271, 1272, 1274, 1281 Cervical spinal cord lesions, 486 Changes electroretinogram, 666 Charcot Marie tooth disease, 881 Chemodectomas, 754, 817 Cherry-red spot, 1186–1188, 1192, 1253 Cherubic face, 994 Chiari I, 123, 126 Childhood death, 206 Childhood-onset disorder with walking difficulties, 1157 Choanal atresia, 197 Cholecystitis, 669 Cholelithiasis, 669 Cholestasis, 372, 703, 705, 724, 819, 858, 859, 1100–1101, 1103– 1105, 1354, 1392 intrahepatic, 272, 777, 854 jaundice, 174 Cholesterol gallstones, 1142 Chondrodysplasia, 869 punctata, 1065, 1067 Chondro-osseous mineralization, 1065 Chondrosarcoma, 1368, 1369 Chorea, 316, 319, 321, 324, 474, 568, 897, 908, 1406 Choreoathetoid movements, 1133 Choreoathetosis, 204, 336, 337, 405, 407, 409, 438, 505, 618, 752, 753, 863, 864, 870, 1187, 1406 Chorioretinal degeneration, 236, 238, 239, 242, 277, 465, 1363 Chrondrodysplasia, 900 Chronic, 81, 96, 97, 100, 103, 104, 106, 108, 265, 270, 286, 297, 309, 355, 356, 524, 1399, 1400 aphthous ulceration, 994, 1422 fatigue, 629, 634 gastritis, 1031 gastrointestinal dysmotility, 856 haemolytic anaemia improving with age, 666 interstitial nephritis, 207 metabolic encephalopathies, 102 mucocutaneous candidiasis, 1158 transfusion dependency, 665 Citric acid cycle intermediates, 827 Citrulline, 898 Clasped thumb, 463 Claudication, 1042 Clava hypertrophy, 136 Claw hand deformities, 895 Cleft lip, 197, 1158 Cleft palate, 197, 1068, 1069, 1158, 1367, 1368, 1372–1374, 1380, 1385 Clinodactyly, 1356, 1370 Clitoral hypertrophy, 705 Clitoromegaly, 1084 Closure of fontanels, delayed, 1354, 1390 Clots, stroke, 994 Clubfoot, 726, 898, 1069, 1166, 1256, 1351, 1352, 1367, 1368, 1370, 1372, 1389 Clumsiness, 614, 1193

Sign and Symptoms Index CMV infection, 13 CNS ataxia, 256, 257, 269–272, 296, 301, 520, 532, 533 Coagulopathy, 173, 354, 359, 371, 614, 869, 1307, 1308, 1354 Coarse facial features, 756, 1031, 1159, 1165–1168, 1186, 1189, 1240, 1241, 1253–1258, 1271–1276, 1376, 1381 Coarse scalp hair, 775 Cobblestone complex, 142 Cobblestone lissencephaly, 1360–1366 Coeliac disease, 59 Cognitive decline, 827, 876, 877, 1097, 1103, 1161, 1165, 1214, 1219, 1224, 1257 Cognitive disability, 1362 Cognitive dysfunction, 321, 370, 643, 922, 1066, 1104, 1193, 1213, 1223, 1290, 1291 Cognitive impairment, 368, 755, 817, 826 mild, 830, 1391 Cold cyanotic extremities, 740 Colitis, 256 Collodion skin, 1190 Coloboma, 197, 199, 440, 1349, 1364, 1378, 1382 Colored red-brown urine, 1118–1121 Color vision deficit, 896, 897 Coma, 43, 68, 173, 265, 268–274, 410, 474, 533, 555, 556, 714, 776, 777, 939, 940, 943, 944, 947, 971, 972, 974, 975, 1118–1121 during crisis, 405 hyperammonemic, 274, 298, 305 during ketoacidotic episodes, 398, 400, 407, 409, 412 Complete epipheseal closure, 1087 Complex I assembly disorder, 815, 949 Complicated viral infections, 896 Cone-rod dystrophy, 995, 997 Confusion, episodic, 269–272, 776, 777 Congenital agranulocytosis, 205 anomalies, 555, 556 encephalopathy, 1221 heart abnormalities, 462 heart defects, 4, 6, 10, 460, 702, 703, 706, 726, 753, 864, 1171, 1276, 1351, 1368, 1371, 1378 hip dislocation, 197 muscular dystrophy, 995 myasthenic syndrome, 1346, 1348, 1349, 1385, 1387 Conical teeth, 197 Conjunctivitis, 706 Connective tissue abnormalities, 615 Consciousness decreased, 596 disturbance, 272, 777, 941 Constipation, 238, 757, 879, 1118–1121, 1355 Constricted visual fields, 205 Contractures, 280, 474, 828, 1159, 1166, 1170, 1172, 1348, 1359, 1390, 1426 progressive, 1363 rhizomelia, 1307, 1308 Convulsions, 278, 299, 300, 405, 615, 720, 721, 1133 Cornea clouding, 1236, 1241 Corneal anesthesia & ulcers, 859 Corneal clouding, 257, 275, 462, 1045, 1046, 1186, 1188, 1240, 1253–1255, 1271, 1274, 1275, 1281, 1363, 1364, 1366, 1368 Corneal cystine crystals, 1289, 1291 Corneal deposits, 1254 Corneal erosion, 356, 357, 532, 1372 Corneal ulceration, scarring, 1393 Coronal clefts, 1367, 1370–1372

1517 Coronary artery disease, 1042, 1045, 1271, 1281 Coronary atherosclerosis, 1041 Corpus callosum, 99, 101, 103, 107–111, 114, 140, 144, 596, 748 abnormalities, 1363, 1364, 1388 absent, 462 agenesis, 748, 749 anomalies, 666 hypogenesis, 748, 1366 hypoplasia, 757, 831 Cortical atrophy, 239, 277, 280, 336, 337, 459, 463, 465, 483, 484, 596, 828–830, 897, 908, 1160, 1162, 1167, 1169, 1173, 1240, 1241, 1348, 1358, 1381, 1426, 1427 with white matter abnormalities and cysts, 483 Cortical blindness, 470, 473 Cortical dysplasia, 579, 1366 Cortical infarction, 138 Cortical malformation, 505, 1362 Cortical visual impairment, 1388 Corticospinal tract abnormalities, 1170 Course, episodic, 756 CPEO, 907 Cramps, 173, 247 Cranial nerve dysfunction, 1372 involvement, 666 Cranial suture closure, abnormal, 1242 defects, 1031 Craniofacial dysmorphias, 903 Craniosynostosis, 1240, 1368, 1369 Cryptorchidism, 197, 280, 569, 705, 711, 775, 828, 1067, 1069, 1083, 1084, 1086–1088, 1171, 1354, 1376, 1426 Cup-shaped ears, 197 Cushing’s stigmata, 1088 Cutaneous albinism, 1158 Cutaneous calcifications, 1374 Cutaneous nodules and swelling, 1276 Cutis laxa, 462, 463, 611, 615, 616, 701, 705, 1390, 1391 Cutis verticis gyrata, 1030 Cyanosis, 680 Cystic encephalomalacia, 123 Cystic fibrosis, 3, 9, 13 Cystic hygroma, 1065 Cystic leukoencephalopathy, 484 Cystic necrosis, 102 Cystic white matter changes, 375 Cytoplasmic accumulation, 1251 D Dandy-Walker malformation, 1067, 1364, 1366 D-bifunctional protein deficiency, 1306 Deafness, 538, 542, 609, 610, 616, 866, 867, 873, 881, 896, 920, 993, 1165, 1189, 1192, 1405 conductive, 197 sensorineural, 200, 201, 553, 752, 753, 819, 824, 830, 863, 864, 866, 899, 921, 1069, 1254 Death, 3, 5, 65, 66, 68, 180, 302, 308, 336, 337, 464, 517, 595, 753, 773, 774, 776, 810, 811, 813, 820, 822–827, 829, 831, 856, 858–867, 872–880, 895, 896, 899–902, 904, 905, 907, 908, 1361, 1425, 1427 Decerebrate posture, 1405 Decreased body height, 407, 409, 1358 Decreased cortical sulci, 401 Decreased fertility, 1084 Decreased mitochondrial ATP production, 766

1518 Deep cerebellar lesions, 132 Deep cerebral gray, 140 Deep cerebrum, 126, 127, 129–131, 133, 138, 142 Deep gray matter structural lesions, 398 Deep gray nuclear iron deposition, 124 Deeply set eyes, 463, 775, 1168 Deep tendon reflexes, 487, 502, 503, 1042, 1159, 1192 Degenerative hip dysplasia, 1271, 1272, 1274–1276, 1281 Dehydration, 20, 172, 484, 505, 507, 533, 660, 661, 688, 740, 1083–1085 Delayed epiphyseal ossification, 1373 Delayed eruption of permanent teeth, 1242 Delayed growth and development, 873, 874 Delayed gyration, 119, 774 Delayed motor development, 895 learning disability, 488 and mental development, 483, 488 Delayed myelination, 121, 124, 206, 371, 398, 407, 409, 459, 461, 465, 484, 522, 757, 774, 894, 1170, 1355, 1377, 1380 Delayed psychomotor development, 741, 866, 877, 880, 894, 895 severe, 751 Delayed puberty, 1083 Delayed separation umbilical cord, 1388 Delayed tooth eruption, 617 Delayed visual maturation, 1347, 1358 Delta-shaped phalanges, 1370 Demarcation retinal nerve fibres, 904 Dementia, 173, 402, 502–504, 564, 678, 773, 816, 875, 899, 905, 1102, 1159, 1164, 1187, 1423 Demyelination, 108, 370, 517, 724, 1102, 1345, 1349, 1351 with edema of subcortical, 367 Dental abnormalities, 1314 Dental crowding, 1162 displacement, 1242 Dental defects, 1291, 1367 Dentate calcifications, 138 Dentate nucleus lesions, 412, 1383 Dentatorubrothalamic tract involvement, 123, 138 Depression, 570, 610, 616, 857, 859, 898, 905, 1164, 1170, 1213 Derangement of trabecular structure, 1323–1326 Dermal fibroblasts, 166 Dermal translucency, 775 Dermatitis, 608, 610–612, 616, 617, 619–622 psoriasiform, 1065 Developmental and gross motor delay, 490 Developmental arrest, 196 Developmental delay, 197, 200, 203, 236–238, 268–272, 278, 279, 300, 305, 306, 314, 315, 332, 339, 345, 354, 361, 362, 368, 370–373, 397, 399, 400, 404, 406, 410, 411, 436–439, 444, 461–464, 474, 485, 487, 489, 491, 502–506, 516, 517, 532, 533, 564, 571, 584, 585, 655, 662, 666, 701–703, 706, 724, 747–749, 751, 774, 776, 777, 779, 807, 810, 814, 818–822, 824–827, 831, 856, 859, 863, 867, 868, 871–873, 875, 879, 882, 896, 897, 899–903, 907, 908, 941, 968, 995, 996, 998, 1064, 1065, 1067, 1069, 1102, 1103, 1168, 1171, 1190, 1192, 1193, 1251, 1253, 1255–1258, 1276, 1307, 1308, 1310, 1348, 1355–1357, 1359, 1367, 1369, 1370, 1377, 1378, 1380, 1381, 1386, 1407, 1425, 1427 global, 275, 276 loss of skills, 897 mild, 827 mild-moderate, 824 motor, 301, 773, 826, 830, 898 severe, 829 Developmental disability, 1388 Developmental impairment, mild-moderate, 973

Sign and Symptoms Index Developmental/intellectual disability, 1393 Developmental regression, 501, 502, 517, 520, 521, 795, 847, 901, 995, 1172, 1211, 1213, 1215, 1217–1219, 1221, 1225, 1226, 1308, 1347, 1366, 1387 Diabetes, 13, 46, 106, 167, 174, 338, 490, 627, 629–632, 897 Diabetes mellitus, 19, 183, 537, 538, 542, 629, 650, 654, 667, 714, 720, 722, 723, 733, 874, 875, 880, 997, 1289, 1290 type 2, 667 Diabetes MODY3, 338 Diaphragmatic defect, 1379 Diaphragm dysfunction, 1289, 1290 paralysis, 550, 553, 554, 558 Diaphyseal thickening, 1030 Diarrhea, 197, 198, 256, 298, 300, 315, 319, 516, 520, 564, 608, 610, 611, 615, 616, 660, 661, 676, 677, 683, 687, 724, 861, 971, 1063, 1102, 1111, 1140, 1271–1273, 1281, 1345, 1346 chronic, 503, 1348, 1358 recurrent episodes, 1359 Dicarboxylic aciduria without ketonuria, 951 Diffuse bilateral cerebral white matter abnormalities, 487 Diffuse brain atrophy, 896 Diffuse cerebral edema, 116 Diffuse hyperintense brain lesions, 824 Diffusion restriction in external capsule, 441 in subcortical white matter, 441 Digital clubbing, 1028, 1031 Digital necrosis, 1382 Dihydropyrimidinuria, 193 Dilated cardiomyopathy, 755, 899, 1251 Dilated ventricles, 596 Dimorphism (red blood cells), 1118 Disinhibition, 1162, 1164, 1173 Dislocated patellae, 1374 Dislocated radial heads, 1369 Dislocation, 43, 302 hip, 275, 302 Disorganized chondroosseous proliferation, 1065 Distal, 607, 609, 611, 615, 619 Distal lower limb muscle weakness/atrophy, 895 Distal motor neuropathy, 881 Distal muscular atrophy, 898 Distal phalanges hypoplasia, 1375 Distal sensory impairment, 895 Distal sensory loss, 898, 1170, 1173 with areflexia, 666 Distressed facial expression, 596 Diurnal fluctuation of symptoms, 338, 339, 344, 345 Diverse & variable CNS pathology, 879 DLP1 deficiency, 1307 Dolichocephaly, 1171 Doll-like face, 1187 Downslanting palpebral fissures, 463, 617, 775, 1167, 1371 Drooling, 318, 319, 321, 335–337, 608, 614, 1167, 1172, 1281 Drowsiness, 305 high-pitched crying, 1133 Drug reactions, 1358 Dry skin, 1382 Dwarfism, 1352, 1389 Dysarthria, 276, 299, 319, 321, 339, 405, 488–490, 550, 555, 608, 614, 642, 643, 779, 807, 809, 825, 826, 828, 857, 867, 870, 879, 901, 904, 995, 1103, 1160–1162, 1164–1166, 1168, 1169, 1173, 1189, 1193, 1213, 1223, 1224, 1405, 1406 Dyscalculia, 1173 Dysdiadochokinesis, 321, 370, 898, 1165

Sign and Symptoms Index Dyskinesia, 316, 321, 324, 327, 338, 346, 517, 899, 1377 Dyskinetic cerebral palsy, 882 Dysmetria, 370, 826, 899, 995, 1161–1163, 1165 Dysmorphic features, 197, 200, 202, 404, 436–438, 440, 504, 505, 570, 598–600, 662, 666, 668, 702, 705–707, 725, 747, 756, 817, 829, 868, 871, 879, 880, 941, 1063, 1066, 1307, 1345, 1347, 1360, 1361, 1379, 1383, 1384, 1388, 1392 Dysmorphism, 168, 305, 404, 703, 705, 1064, 1347, 1350, 1391, 1393 Dysmotility, 897 Dysmyelination, 306 Dysostosis multiplex, 141, 142, 725, 1186, 1189, 1240, 1241, 1253–1256, 1271–1276, 1345 Dysphagia, 338, 809, 862, 866, 873, 904, 1160, 1162, 1164, 1168, 1169, 1172, 1173, 1386, 1414, 1425 Dysplasia, 135, 142, 1362 Dysplastic ears, 775, 1358 Dyspnea, 728, 774, 862 Dystonia, 68, 173, 200, 315–317, 319, 321, 324, 332, 333, 338, 339, 346, 370, 398, 403–405, 407, 409–411, 437, 438, 440, 462, 483–485, 534, 537–539, 542, 543, 568, 570, 571, 574, 614, 618, 637–644, 662, 668, 748, 752, 753, 755–757, 779, 809, 811, 812, 814, 817, 818, 823–827, 863, 864, 866, 870, 874, 879, 899, 901, 902, 905, 922, 993, 995, 1159, 1163–1166, 1172, 1173, 1186, 1187, 1193, 1211, 1215, 1217–1219, 1226, 1381, 1406, 1413, 1423 cerebral palsy, 598–600 crisis, 317, 321 deafness, 992 movements, 593 Dystostosis multiplex, 105 Dystroglycanopathies, 109 Dystrophic nails, 1066, 1067 Dystrophic toenail changes, 1163 E Ear creases, 723 Ear infections, 1355 Early childhood neurological developmental regression, 1307 Early death, 664, 665, 672, 674, 679, 706, 819, 962, 1250, 1349, 1352, 1354, 1382 Early infantile encephalopathy, 444 Early infantile epileptic encephalopathy type 35, 194 Early myoclonic encephalopathy, 596 Early-onset encephalopathy, 564 Early onset hearing loss, 795, 847 Early-onset retinitis pigmentosa, 1309 Ectatic arteries, 118 Ectopia lentis, 373 Edema, 97, 247, 923, 1101, 1189, 1253, 1352 generalized, 596, 872, 1354 in light-exposed areas, 1122 EEG, abnormal, 483, 520, 678, 679, 756, 776, 778, 1211, 1213–1215, 1217–1219, 1221, 1222, 1225, 1226 Electrocardiogram, 206 Elevated sweat chloride, 1140 EM, abnormal mitochondria, 239, 465, 466 Emesis, 1111 Emotion ability, 1189 EM, storage material, 643, 1212–1215, 1219, 1221–1226 EM, type 2 fiber atrophy, 239, 466 EM, type 2 fiber tubular aggregates, 239, 466 Enamel hypoplasia, 1242 Encephalocele, 1360, 1361 occipital, 1366

1519 Encephalomyopathy, 813, 861, 867, 873, 874, 881 Encephalopathic crisis, acute, 398, 400, 506, 542, 543, 1406 Encephalopathy, 68, 106, 206, 263, 268–273, 280, 437, 441, 483, 615, 757, 774, 776, 777, 795, 806, 807, 809–811, 813, 815, 816, 818, 821, 828, 830, 847, 863, 873–877, 907, 930–931, 949, 962, 992, 993, 1032, 1103, 1423, 1426 acute, 543 acute, episodic, 831 acute, precipitated by infection, 401, 404, 407, 409, 411, 779 epileptic, 180, 194, 278, 461, 517, 921, 1377 episodic, 344, 537, 539, 542, 556, 831 necrotizing, 753, 864 progressive, 465, 489, 778 Encephalopmyopathy, 874 Endocrine abnormalities, 859, 902, 1425 Endocrinological adrenal insufficiency, 1307, 1308 Endometrium, 1088 Enlarged fontanel, 900 Enlarged knee joints, 1373 Enlarged lesser trochanter, 1371 Enlarged ventricles, 899 Enlargement of hands/feet, 1031 Entropion, 1390 Eosinophilia, 948 Epicanthal folds, 941, 1069 Epilepsy, 196, 199, 201, 237, 238, 292, 301, 368, 372, 411, 436–440, 464, 483, 489, 522, 542, 568, 654, 655, 667, 678, 702, 705, 724, 726, 807, 808, 810–812, 814, 818, 820–827, 831, 868, 875, 876, 881, 900, 908, 920–923, 941, 993, 995, 1103, 1221, 1225, 1226, 1241, 1345, 1346, 1348–1351, 1357, 1359–1363, 1366, 1372, 1375, 1377–1383, 1387, 1388, 1393, 1407, 1423, 1427 focal, 542 generalized, 278, 721, 875 intractable, 278, 461, 542, 856, 1358 pyridoxal 5′-phosphate-dependent, 580 refractory, 1347 vitamin B6-dependent, 581 Epileptic encephalopathy, 180, 194 Epileptic seizures, 317, 484, 486, 727, 860, 995, 996, 1255, 1256, 1258, 1262, 1353, 1377 Epileptic spikes, 301 Epiphyseal dysplasia, 1368 Episodic ataxia, 291, 292, 294, 296, 301, 302, 305–308, 310 Episodic decompensation, 827 Episodic lethargy, 474 Episodic vomiting, 1083, 1085 Epstein-Barr virus infection, 1356 Equinovarus, 338 ERG, abnormal, 778, 1211, 1213, 1215, 1217–1219, 1221, 1222, 1226 Erythema, 1064, 1066 necrotizing, 278, 461 Erythrocyte ITP accumulation, 206 Erythroderma, 616, 1382, 1384 Esophageal varices, ascites, 1140 Everted lower lip, 1358 Exaggerated startle response, 598–600 Excess digital whorls, 1069 Excessively wrinkled palms, 1371 Excess skin, 1354 Exercise-induced acute renal failure, 207 Exercise intolerance, 202, 320, 479, 488, 547–550, 554, 558, 773, 813, 815, 818, 821, 826–828, 830, 863, 865, 868, 869, 875, 880, 901, 941, 949, 992, 994, 1422 muscle pain, 556 with nausea/vomiting during exercise, 555, 779

1520 Exertion intolerance, 668–672, 674, 675 Exocrine pancreatic insufficiency, 821, 881 Exomphalos, 723 Exophthalmia, 1360, 1361 Exostosis, 615 Exotropia, 1346 Expressive dysphasia, 1102 Extensor plantar responses, 1160, 1161, 1165–1169, 1173 External genitalia abnormality, 1356 External ophthalmoparesis, 895 Extrapyramidal movement disorder, 505, 506, 638, 643, 897, 1213, 1214, 1223, 1224, 1412, 1424 Extrapyramidal signs, 407, 409, 504–506, 570, 819, 993, 1159, 1347, 1423 Eye abnormal movement, 199, 319, 339, 440, 522, 570, 811, 830, 860, 1133, 1190 delayed opening, 320, 1169 movements, roving, 1364 optic atrophy, 1323 unable to track visual, 489 Eye-of-the-tiger-sign, 103, 104, 122, 123, 570 F Face disfiguration, 1119 Facial dysmorphism, 275, 276, 280, 305, 464, 523, 723, 726, 828, 872, 881, 900, 941, 1067, 1068, 1159, 1166, 1268, 1348, 1349, 1351, 1352, 1354, 1356–1359, 1375, 1376, 1379, 1382, 1386, 1388, 1390, 1392, 1426 mild, 825 minor, 1375 Facial dystonia, 1172 Facial flushing, 596 Facial naevus simplex, 723 Facial pallor, 740 Facial weakness, mild, 1349 Failure to thrive, 43, 68, 199, 203, 237, 252, 253, 268, 269, 271, 272, 275, 279, 280, 354, 355, 357, 359, 368, 371, 372, 398, 400, 402, 404, 406, 407, 410, 444, 462–465, 485, 489, 501–507, 516, 520, 522, 533, 534, 610, 616–618, 660, 661, 665, 672, 676, 677, 747–749, 751–757, 773, 776, 777, 806, 808, 810, 813, 815, 817, 821, 823–831, 859, 864, 866, 869, 875, 877, 880, 881, 894–896, 899, 900, 908, 941, 949, 962, 993, 1032, 1042, 1044, 1065, 1085, 1105, 1158, 1171, 1192, 1193, 1288, 1291, 1292, 1307, 1323–1326, 1345, 1350–1352, 1355, 1356, 1359, 1381, 1382, 1392, 1426, 1427 acidosis, 354, 355, 357, 359, 363 Fanconi syndrome, 17–20, 42, 48, 174, 359 Fasciculations, 1160, 1162, 1164, 1173 Fasting intolerance, 171, 672 Fat distribution, abnormal subcutaneous, 1390 malabsorption, 1096 pads, 1349 Fatal lactic acidosis, 877 Fatal outcome, 1347, 1348 Fatigue, 272, 629, 630, 634, 777, 857, 859, 862, 865, 995, 1385 Fatty infiltration of muscles, 618 Favism, 252, 258 Features, 43, 85, 87–89, 97, 99, 100, 102–106, 109, 115, 236–238, 252, 253, 316, 344, 516, 517, 525, 596 Febrile episodes, 174 Febrile seizures, 461 Feeding, 333

Sign and Symptoms Index difficulties, 68, 199, 206, 268, 269, 273, 275, 318, 319, 321, 324, 335, 398, 400, 404, 407, 409, 410, 440–442, 462, 465, 473, 474, 483–487, 489, 504, 521, 522, 598–600, 615, 666, 726, 752, 753, 756, 757, 774, 775, 807, 810, 823–825, 827, 829, 863, 864, 866, 868, 922, 923, 993, 994, 1069, 1168, 1189, 1192, 1346–1352, 1354, 1358, 1359, 1365, 1376, 1378, 1383, 1384, 1388, 1393, 1406, 1422, 1423 habits, abnormal, 665 protein aversion, 269, 270, 777 Female external genitalia abnormality, 1356 Female infertility, 1088 Female to ambiguous genitalia in XY, 1086, 1088 Femoral bruits, 1041, 1042 Fertility, decreased, 1085 Fetal arrhythmia, 1258 Fetal hydrop, 173, 371, 706, 725, 756, 1189, 1253, 1256, 1258, 1275, 1345, 1348 Fetal hypokinesia phenotype, 1346 Fetal pads, 723 Fever, 61, 309, 1189 Fever of unknown origin, 1392 Fibrillations, 1160, 1162, 1164 Fibrosis, 3, 9, 13 Fingers contractures, 898 deviation, 1372 flexion contractures, 617 overlapping, 1357 First arch syndrome, 1385 FIS1 deficiency, 1307 Fish odor urine, 174, 1441, 1442 Fits, 402, 1421 Flat epiphyses, 1373 Flat midface, 1367, 1368, 1371 Flat oval face, 1357 Flat philtrum, 775 Flexion contractures, 896 Foam cells, 1188, 1190, 1192, 1193, 1253, 1276 Focal epilepsy, 542 Focal seizures with eye deviation, 596 Focal white matter lesions, 404 Foetal distress, 714 Follicular atrophoderma, 1067 Fontanel enlarged, 463 Food consumption reduction, 1111 Foot deformities, 666, 895–897, 1163, 1358 Foot drop, 1164, 1257 Foveal hypoplasia, 296, 301, 306, 308 Frameshift variants, 153 Frequent infections, 516, 520, 610, 616, 618, 896, 1388 Frequent myoclonus, 596 Frontal bossing, 368, 372, 724, 1367 Frontalhypoplasia, 122 Frontal lobe atrophy, 1170 Frontotemporal atrophy, 405, 411, 870 Frontotemporal dementia, 906, 1162, 1164, 1170, 1173 Functional joint impairment, 1368, 1369 G Gait abnormal, 491, 903 ataxia, 819, 1162, 1165 disturbance, 276, 520, 521, 571, 643, 678, 1159, 1161, 1164, 1165, 1170, 1186, 1189, 1193, 1213, 1223, 1241, 1384, 1386 impairment, 905, 1164

Sign and Symptoms Index Gallstones, 667, 668, 1102 Gastric tube feeding, 1352, 1357 Gastroesophageal reflux, 275, 276, 463, 487, 489, 756, 775, 879, 1162, 1355, 1358, 1376 Gastrointestinal bleeding, 1358 Gastrointestinal cholestasis, 1307 Gastrointestinal diarrhea, 1307, 1308 Gastrointestinal dysmotility, 198, 280, 339, 437, 828, 830, 859, 861, 863, 1352, 1355, 1356, 1426 Gastrointestinal side effect, 347, 348 Gastrointestinal stromal tumor, 754, 816 Gastroparesis, 198, 861 GDAP1 deficiency, 1307 Gelastic cataplexy, 1193 Genée-Wiedemann syndrome, 193 Generalized atrophy, 460, 534 Generalized edema, 596 Generalized hypoxic-ischemic encephalopathy, 596 Generalized seizures, 593 Generalized slowing, 441 Genetic defect, 157 Genetic heterogeneity, 148 Genetic modifiers, 154 Genitourital anomalies, 1424 Genu valgum, 373, 1271, 1274, 1291, 1371 deformities, 1281 Germinolytic cysts, 109, 123, 142 Germinoma, 137 Giant cell hepatitis, 1100–1101, 1103 Gingival hyperplasia, 1168 Gingival hypertrophy, 1240 macroglossia, 1186 Glaucoma, 897, 1271, 1275, 1281, 1308, 1359–1362, 1372 retinitis pigmentosa, 1307 Gliosis, 1166 Global developmental delay, 275, 276, 319, 666, 752, 880 Global developmental retardation, 680 Globus pallidus abnormalities, 400, 404 hyperintensity, 115 lesions, 117 Glomerulonephritis, 81, 298, 309 Glomerulosclerosis, 676, 677 Glomus jugular tumors, 754 Glossitis, 532 Glucocorticoid deficiency, 909 Glucose intolerance, 869, 937, 1087 Glucose tolerance, abnormal, 490 GNE myopathy, 168 Gonadal dysgenesis, 1363, 1365 Gout, 200, 207, 210–211, 671 Gower sign, 995 GP infarction, 120, 121 GP lesions, 126 Granulation in lymphocytes, 1276 Growth hormone deficiency, 878, 1382, 1384, 1385, 1392 Growth restriction, 436, 437, 1241 Growth retardation, 272, 276, 309, 318, 460, 464, 608, 617, 627, 631, 632, 677, 702, 706, 777, 809, 818, 871, 879, 881, 898, 899, 922, 941, 994, 1068, 1069, 1096, 1158, 1189, 1241, 1242, 1253, 1256, 1257, 1323–1325, 1376, 1386, 1390, 1392, 1422, 1424 intrauterine, 275 postnatal, 280, 829, 1426 Gum hypertrophy, 1358 Gynecomastia, 728, 729

1521 at puberty, 1086 Gyral pattern, abnormal, 894 Gyration, 119, 239 H Haematuria, 198 Haemolysis, 650, 651, 655, 662, 664, 665, 667–669 Haemolytic anaemia, 194 Haemolytic crisis, 667, 669 Haemolytic uraemic syndrome, 504 Hair abnormality, 615, 1382 Hallucination, 678, 1213 Halo, 104 Hammer toes, 1163 Hand and feet abnormalities, 1388 anomalies, 1159 deformities, 881 edema, 723 Hand tremor (females), 750 Hand/upper limb weakness, 895 Handwriting, 614 Headache, 370, 1083, 1085, 1103, 1406 and/or migraine, 857 Head circumference, 299, 335, 904 Head control, 278, 319, 321 Head-retraction reflex, 302 Hearing impaired, 490, 831, 877, 898, 1349, 1350, 1352, 1378, 1386 and visual impairment, 1314 Hearing loss, 106, 201, 403, 463, 532, 533, 550, 610, 611, 616, 679, 705, 773, 815, 821, 826, 856, 857, 860, 861, 875, 878, 897, 903, 949, 1133, 1165, 1171, 1253–1255, 1271–1275, 1358, 1370, 1374, 1376, 1378, 1424 conductive, 775 progressive, 897 sensorineural, 372, 405, 407, 489, 570, 679, 750, 751, 773, 827, 860, 863, 865, 870–872, 878, 879, 881, 882, 900, 922, 1158, 1258, 1307, 1308, 1362, 1380 Heart abnormalities, 491, 903 block, 674 defects, 1375 failure, 258, 520, 629, 634, 994, 1158, 1276, 1422 septal defect, 723 valve dysplasia, 1370 HELLP syndrome, 68 Hematological pancytopenia, 1323–1326 Hematuria, 204, 205, 297 Hemihypertrophy, 718, 728, 729 Hemiparesis, 1103 Hemiplegia, 826 Hemiplegic migraine, 301 Hemolysis, 1261 Hemolytic anemia, 173, 252–254, 256–259 Hemolytic uremic syndrome, 174, 517, 521 Hemophagocytic lymphohistiocytosis, 298, 309 Hemorrhage, 97, 105, 135 Hemorrhagic pancreatitis, 490 Hemosiderosis, 631, 819 Hepatic disease, 46 Hepatic dysfunction, 878 Hepatic steatosis, 68, 968 Hepatic vein thrombosis, 1378 Hepatitis, chronic, 727

1522 Hepatocellular carcinoma, 371, 629 Hepatomegaly, 43, 68, 272, 280, 371, 400, 402, 406, 407, 409, 411, 412, 444, 485, 489, 629, 642, 650, 655, 656, 662, 664, 665, 671, 673, 675–677, 679–682, 702, 705, 715, 774, 777, 821, 823, 828, 829, 857, 858, 859, 963, 972, 975, 1044, 1100, 1105, 1254, 1255, 1257, 1290, 1347, 1350, 1351, 1354, 1357, 1383, 1391, 1392, 1421 jaundice, 1307 liver dysfunction, 1307, 1308 Hepatopathy, 357, 630, 672, 673, 727, 795, 847, 992, 1356, 1385 Hepatosplenomegaly, 274, 298, 611, 614, 618, 756, 778, 869, 1045, 1063, 1101, 1103, 1105, 1186–1188, 1190, 1192, 1193, 1240, 1241, 1250, 1253, 1255–1257, 1268, 1271, 1272, 1275, 1276, 1281, 1383, 1391, 1392 Hereditary orotic aciduria, 193 Hereditary renal hypouricaemia type 1, 195 type 2, 195 Hernia(s), 275, 302, 462, 615, 1189, 1240, 1253–1257, 1271, 1272, 1275, 1276 Heterogeneity, 148 Heterotopia, 135, 138 5HIAA, 521 Hiccups, 473, 474 High FeMg fractional excretion, 880 High nasal bridge, 941, 1168 High palate, 617 Hip dislocation, 275, 302, 462, 463, 1171, 1240, 1368 Hip dysplasia, 470, 473, 1390 degenerative, 903 Hippocampal dysgenesis, 137 Hirschsprung disease, 1069 Hirsutism, 1276, 1373 mild, 825 Histochemical cytochrome c oxidase deficiency (muscle), 857 Hoarseness, 1192 Holoprosencephaly, 1069 Homocarnosinosis, 1434 Hydrocephalus, 105, 109, 117, 119, 121, 135, 141, 143, 173, 463, 473, 474, 517, 521, 579, 775, 1241, 1258, 1271, 1272, 1281, 1360–1364, 1366, 1376 ex vacuo, 596 Hydronephrosis, 1366, 1376 Hydrops, 474, 774, 878, 1389 fetalis, 665, 667, 670 Hydroureter, 1376 Hyperactivity, 199, 299, 371, 440, 442, 474, 523, 941, 1272, 1273 Hyperammonemia, 100, 827 during crisis, 828, 1426 episodic, 270, 830 symptomatic, 239 Hypercementosis, 1242 Hyperekplexia, 291, 292, 296, 302, 305, 307, 308, 310, 465, 474, 902, 1425 Hyperelastic, 610, 617 loose skin, 1367 skin, 1368 Hyperesthesia, 1118–1121 Hyperexcitability, 459 Hyperextensible skin, 1371 Hyperfiltration, 662, 676, 677 Hyperglycemia, 409, 1432 insuline treatment, 831 Hyperglycinuria, 1432 Hypergonadotropic hypogonadism, 664, 691, 725, 903 female, 407, 1345 Hyperhidrosis, 1031, 1242

Sign and Symptoms Index Hyperinsulinemic hypoglycemia, 174 Hyperinsulinism, 39, 46, 178, 278, 667, 687, 713–735, 944, 976, 1346, 1385 Hyperintensities (T2) of globus pallidus, 412, 441, 542 T2, 410 Hyperkeratosis, 354, 616, 948, 1384 palms and soles, 357 Hyperkeratotic dark-brown papules, 1375 Hyperkeratotic papules, 1376 Hyperkinesia, 314, 319, 321, 463 Hyperlipidemia, 298, 309 Hypermetropia, 1375 Hypernasal speech, 321 Hyperopia, 568, 775 Hyperostosis, 1374 Hyperoxaluria, 1323–1325 type 1, 1306 Hyperparathyreoidy, 1240 Hyperphalangism, 1370 Hyperphalangy, 1372 of index finger, 1374 Hyperpigmentation, 569, 629, 630, 705, 721, 1375, 1376 retina, 995 Hyperreflexia, 463, 465, 642, 755, 757, 817, 827, 879, 897, 898, 901, 905, 938, 1160–1169, 1172, 1173, 1349, 1369, 1389 Hypersalivation, 1172 Hypersomnolence, 438 Hypertelorism, 368, 756, 775, 1158, 1165, 1171, 1369, 1378 Hypertension, 210, 211, 274, 298, 356, 618, 824, 1083, 1085, 1088, 1118–1121 pulmonary, 880 Hyperthermia, 321, 522, 1385 Hyperthyroidism, 1037, 1102 Hypertonia, 199, 257, 324, 338, 398, 400, 401, 407, 409, 412, 440, 460, 484, 505, 506, 520, 534, 726, 829, 896, 902, 905, 1165, 1166, 1346 extremities, 321, 335, 336, 902, 1349, 1351, 1425 limb, 598–600, 880 limbs, 319 Hypertrichosis, 734, 775, 824, 1120 Hypertriglyceridemia, 1037 Hypertrophic cardiomyopathy, 714, 755, 1276 Hyperuricaemic nephropathy, 195 Hyperuricemia during crisis, 828, 1426 Hypo/areflexia, 898 Hypocalcemic, 1100 Hypochloremic metabolic alkalosis, 880 Hypochromic, 197, 627, 628, 631 Hypodense white matter, 198, 861 Hypodontia, 615, 617 Hypogammaglobulinemia, 1369 Hypogenesis, 748 corpus callosum, 399, 748, 751, 1068, 1069 Hypogenitalism, 1375 Hypoglycemia, 17, 18, 20–39, 46, 68, 178–179, 279, 315, 320, 326, 398, 400–403, 405, 407, 410, 411, 490, 569, 667, 673–677, 714, 720–722, 747, 815, 818, 819, 830, 870–872, 908, 941, 949, 962, 971, 973, 974, 976, 993, 994, 1101, 1352, 1385, 1422, 1427 brain injury pattern, 125, 134 fasting, 671, 680, 681 hypoketotic, 278, 406, 944, 1346 leucine sensitivity causing, 278 Hypogonadism, 459, 629, 630, 632, 857, 860, 872, 1290, 1293 Hypogonadotropic hypogonadism, 705, 1372, 1385 Hypokalemic alkalosis, 1088

Sign and Symptoms Index Hypoketotic, 667 Hypokinesia, 279, 314, 317, 319, 321, 338, 339, 747, 1213, 1225, 1357, 1406 Hypomimia, 316, 321, 1162 Hypomyelinating leukodystrophy, 134 diffuse, 136 Hypomyelination, 111, 115, 119, 121, 138, 140, 292, 301, 463, 517, 520, 523, 610, 616 CNS, 1240, 1241 global, 773 of white matter, 876 Hypophosphatemic rickets, 239 Hypopigmentation, 335, 1064 hair, 336, 337 macules, 1376 reticular, 1376 retinal, 1158 Hypopituitarism, 629 Hypoplasia, 99, 102, 104, 105, 107, 109, 110, 119, 121, 126, 130, 131, 143, 144, 275, 276, 296, 301, 306, 308, 876, 1065 corpus callosum, 371, 473, 474 limbs, 197 pons, 371, 533 unilateral, 1066 Hypoplastic corpus callosum, 596, 1064 Hypoplastic kidney, 491, 903 Hypoplastic labia majora, 775, 1357 Hypoplastic left heart, 569, 570 Hypoplastic nails, 1067, 1352, 1378, 1379 Hypoplastic nose, 491, 903 Hyporeflexia, 751, 828, 898, 1159, 1162–1164, 1168, 1173, 1362, 1393 and/or paucity of movement, 865 Hypospadias, 280, 828, 1067–1069, 1158, 1171, 1352, 1356, 1375, 1426 Hypotelorism, 463 Hypotension, 315, 615 orthostatic, 315, 320, 324, 326 postural, 1386 Hypothalamic dysfunction, 1102 Hypothalamic hamartoma, 137 Hypothalamic involvement, 141 Hypothermia, 315, 320, 615, 923 during crisis, 398, 400, 409 Hypothyroidism, 4, 9, 12, 258, 881, 897, 1102, 1103, 1290, 1293, 1354, 1359 Hypotonia, 68, 199–201, 237, 257, 275, 279, 305, 317, 321, 338, 344, 345, 368, 372, 398, 400, 401, 403, 407, 409, 412, 436–442, 461, 462, 473, 474, 483–486, 489–491, 502–506, 523, 548–550, 558, 568, 584, 585, 609, 616, 642, 662, 672, 679, 702, 705, 706, 724, 725, 747–749, 751–757, 773–776, 778, 806–810, 813, 814, 817, 819, 820, 822–827, 829, 830, 856, 858–861, 863–868, 871–874, 876–879, 881, 894–896, 898–905, 907, 921, 922, 941, 995, 1032, 1063–1065, 1067, 1068, 1157–1159, 1162, 1166–1168, 1171, 1186, 1187, 1192, 1241, 1256, 1257, 1307, 1345, 1346, 1348–1352, 1354–1359, 1361–1366, 1368, 1369, 1371, 1372, 1376– 1384, 1386–1390, 1392, 1393, 1406, 1407, 1423, 1427 axial, 316, 321, 332, 337, 339, 666, 825, 880, 900, 1381, 1406 generalized, 996 intermittent, 315 mild, 338 muscular, 534, 570, 902, 908, 1400, 1401, 1405, 1425, 1427 muscular-axial, 280, 335–337, 398, 400, 401, 404, 406, 407, 409–412, 555, 556, 598–600, 672, 679, 773, 815, 828, 937, 939, 940, 943–945, 949, 962, 994, 1240, 1241, 1256, 1382, 1422, 1424, 1426

1523 peripheral, 314 progressive generalized, 399, 751 severe, 206, 258 truncal, 275, 319, 324 Hypoventilation, central, 1170 Hypovolaemic shock, 660, 661 Hypoxia, 48, 1192 Hypsarrhythmia, 301, 459, 465, 473, 474, 726, 900, 1351, 1427 I Ichthyosiform erythroderma, 1067, 1382 Ichthyosiform skin lesions, 1066 Ichthyosis, 523, 609, 610, 616, 948, 991, 1067, 1241, 1309, 1378, 1382, 1384 dermatological, 1307, 1308 Immunodeficiency, 197, 252, 253, 258, 520, 533, 534, 677, 678, 1158, 1254 severe combined, 3, 9, 13, 192, 194, 203, 209, 517, 521 T-cell, 203, 1356, 1369, 1386 variable, 533 Impaired coagulation, 777 Impaired ejaculation, 320 Impaired myelination, 680 Impaired vision, 755 Inability to gaze upward, 1133 Inability to walk, 464, 1165, 1172 Incomplete epiphyseal closure, 1087 Incomplete penetrance, 154 Incontinence, 1309 Increased startle, 474 Increased T2 signal in brain stem, 441 In-curving forearms, 197 Infantile spasms, 521, 533, 776 with hypsarrhythmia, 505 Infantile transient temporal lobe tumafactive edema, 124 Infantile uterus, 1087 Infections, 13, 46, 171, 174, 260, 261, 345, 734, 1388, 1389, 1391 pneumonia, otitis, 1307, 1308 recurrent, 198, 203, 1358, 1386 recurrent bacterial, 252, 257 Inferior olives, 132 Infertility, 1290 Inflammatory bowel disease, 676, 677, 1386 Inheritance pattern, 157 Insomnia, 319, 1170 Insulin resistance, 962, 991 Intellectual deterioration, 1253 Intellectual development, 971 Intellectual disability, 168, 199–202, 204, 236, 237, 239, 252, 255, 298–302, 306, 317, 333, 335–337, 339, 373, 399, 440, 442, 464, 465, 484, 486, 502, 503, 506, 516, 517, 520–522, 570, 571, 609, 611, 615, 618, 619, 642, 662, 664, 668, 679, 702, 705, 729, 740, 779, 814, 818, 819, 824, 825, 856, 860, 862, 867, 868, 873, 876, 881, 898, 899, 901–903, 905, 906, 920, 923, 941, 944, 962, 995, 996, 1068, 1157, 1160, 1161, 1165–1167, 1186, 1188, 1192, 1240, 1241, 1251, 1253–1258, 1307, 1308, 1310, 1346, 1347, 1355–1357, 1359, 1362, 1365, 1367, 1369, 1372, 1375–1381, 1383, 1386–1390, 1424, 1425 mild, 302, 320, 995, 1161, 1255, 1257 severe, 876 severe to profound, 751 Interictal nystagmus, 301 Intermittent encephalopathy, 1308 Intermittent hypotonia, 315 Interstitial changes, 298

1524 Intestinal dysmotility, 902, 1069 Intestinal pseudo, 616 Intestinal pseudo-obstruction, 174, 198, 584, 861 Intracerebral calcification, 404 Intractable seizures, 461 Intradural extramedullary enhancing masse, 137 Intramyelinic edema, 97, 102, 117, 118, 122, 134 Intrauterine cardiomyopathy, 947 Intrauterine death, 1373 Intrauterine growth retardation, 275, 462, 463, 486, 670, 706, 776, 819, 820, 866, 902, 906, 921, 922, 944, 947, 1171, 1425 Intravascular hemolysis, 1379 Inverted nipples, 1349–1352, 1354, 1357 Involuntary movements, 483, 1172 Iridodonesis, 373 Iron deficiency anemia, 1236, 1241 Iron deposition in basal ganglia, 1165 Irritability, 319, 327, 332, 335, 484, 485, 489, 501, 502, 608, 610, 614, 616, 756, 774, 825, 826, 896, 1064, 1069, 1189 crisis, 317 episodic, 398 neonatal, 321 Ischemic heart disease, 1102 Itching, 1100, 1105 J Jaundice, 256, 257, 272, 614, 642, 665, 668, 777, 858, 859, 869, 1100–1103, 1105, 1140–1143, 1192, 1423 cholestatic, 1193 prolonged neonatal, 1257 severe neonatal, 252, 258 Jitteriness, 1425 Join pain, 629 Joint contractures, 275, 461, 725, 817, 922, 1165, 1167, 1240, 1271, 1272, 1275, 1276, 1281, 1345, 1373, 1383 Joint dislocations, 1370, 1372, 1374 Joint hyperextensibility, 462, 463 Joint hypermobility, 1166 Joint laxity, 275, 276, 461, 609, 617, 1274, 1367, 1368, 1371, 1372, 1374, 1390, 1392 K Kayser-Fleischer ring, 608, 614, 620 Kearns-Sayre syndrome, 755, 816–818 Keratosis pilaris, 1242 Ketoacidosis, 398, 400, 402, 404, 405, 407, 409, 410, 412, 870, 973, 975 Ketones, during hypoglycemia, 937 Ketonuria, pronounced during crisis, 828, 1426 Ketosis, 507 Ketotic hypoglycemia, 46 Kidney cysts, 1357 Kidney disease, 1045, 1241 Kidney dysplasia, 922, 1366 Kidney stones, 43, 1313, 1325 Kinky hair, 615 Kussmaul breathing, 533 Kyphoscoliosis, 460, 895, 1159, 1368–1370, 1373, 1390 Kyphosis, 373, 1190, 1271, 1272, 1274, 1275, 1281, 1358, 1369, 1373, 1382 L Lack of developmental progress, 593 Lack of facial expression, 1032 Lack of speech, 595

Sign and Symptoms Index Lacrimation, 356, 357 Lactate, 824, 827 Lactic acidosis, 257, 405, 406, 564, 568, 747–749, 752, 753, 756, 774, 806–815, 818–820, 822, 828, 864, 868–871, 878, 906, 923, 944, 947, 949, 992, 993, 995, 1424, 1426 episodic, 830 Language delay, 442 Language difficulties, 339, 370, 441, 1164, 1193, 1221, 1222, 1225, 1226 Large anterior fontanel, 776 Large feet, 464 Large hands, 464 Large malformed ears, 462, 464 Large subcutaneous hematomas, 1371 Lateral deviation of the fifth toe, 1374 Laterally upslanting eyebrows, 775 Lateral ventricular enlargement, 774, 775 Learning difficulties, 908 Learning disabilities, 828, 908, 922, 1160 Leber congenital amaurosis type 11, 194 Leber hereditary optic neuropathy, 811, 812 Left ventricular hypertrophy, 775, 1158 Left ventricular hypoplasia, 921 Left ventricular non-compaction, 817, 994, 1422 Leigh disease, 106, 119, 125–128, 130–136, 144 Leigh-like syndrome, 825, 827, 873, 992, 993, 1423 Leigh syndrome, 148, 399, 484, 747, 748, 751–753, 755, 806–814, 816–818, 820, 822–824, 830, 863, 864, 867, 920, 993 Lennox-Gastaut syndrome, 458 Lens changes, 679 dislocation, 43, 368, 593, 596, 598–600 Lenticular myopia, 368 Lethality high, 945 of severe phenotypes, high, 940 Lethal, male, 831 Lethargy, 68, 265, 410, 437, 441, 473, 474, 484, 485, 489, 490, 505, 506, 555, 556, 823, 827, 939, 940, 943, 944, 947, 971, 972, 974, 975 coma, 43 during crisis, 405 during ketoacidotic episodes, 398, 400, 407, 409, 412 Leucencepahloathy, 881 Leucopenia, 309 Leukemia, 1374 Leukocyte function impaired, 676, 677 Leukocytosis, 1063, 1349 Leukodystrophy, 76, 108, 111, 113, 117–120, 125–127, 129–133, 135, 139, 142, 143, 484–487, 491, 680, 806, 814, 818, 821, 822, 867, 874, 1186, 1187, 1189, 1241 cerebrum, 136 Leukoencephalopathy, 105, 109, 115, 121, 134, 138, 140, 141, 143, 198, 402, 485, 702, 705, 808, 861, 875, 876, 879, 906, 1421 progressive, 759 Leukomalacia, diffuse, 813 Leukonecephalopathy, 141 Leukopenia, 205, 400, 614, 705, 1030, 1391 Life-threatening illness, 504, 505, 507 Limb defects, 458, 459, 1068, 1363 Limb-girdle muscular dystrophy, 1361, 1362, 1364, 1365, 1384 Linear skin defects, 821, 831 Lipemia retinalis, 1044 Lipid deposition, 1102 Lipid storage myopathy with ragged-red fibres, 779 Lipodystrophy, 991 partial, 997

Sign and Symptoms Index Lissencephaly, 122, 459 Livedo reticularis, 1323–1326 Liver adenoma, 675–677 Liver adenomatosis, 717 Liver cancer, 354, 361, 362 Liver carcinoma, 356, 675–677 Liver cirrhosis, 630, 632, 638, 641, 642, 664, 665, 669, 672, 673, 705, 871, 1064, 1100, 1105, 1190, 1192 hepatocellular carcinoma, 1308 Liver cysts, 1369 Liver disease, 14, 17, 19, 20, 59, 270, 354, 359–362 chronic, 270 with elevated aminotransferases, 368 Liver dysfunction, 271, 272, 280, 354, 371, 372, 402, 406, 407, 409, 410, 412, 504, 555, 556, 614, 616, 680, 724, 753, 777, 806, 807, 815, 828, 860, 864, 908, 937–940, 942–945, 947, 949, 971, 1069, 1120, 1122, 1272–1274, 1345, 1421, 1423, 1426, 1427 mild to moderate, 1355 Liver failure, 48, 361, 664, 665, 680, 815, 831, 858, 859, 867, 869, 872, 873, 949, 1101, 1103, 1140, 1392 acute, 269, 271, 356, 608, 614, 621, 705, 777, 908, 1427 acute recurrent, 399, 751 progressive, 705, 856 Reye-like, 720, 815, 944, 949 Liver, fatty, 680 Liver fibrosis, 629, 630, 673, 675, 705, 725, 774, 963, 1103, 1104, 1290, 1346 Liver involvement, 1391 Liver steatosis, 272, 372, 724, 774, 777, 871, 963, 997 Liver storage, 1393 Lobular inflammation, 1101 Long bone fractures, 1368 Long digits, 462 Long eye lashes, 941, 1357 Long philtrum, 463, 775 Long QT, 899 Long tapered fingers and toes, 1371 Loose skin, 617 Loose stools, 662, 706 Loss of ambulation, 938 Loss of central vision, 679 Loss of deciduous teeth, 1242 Loss-of-function variants, 153 Loss of peripheral retinal pigment, 679 Loss of permanent teeth, 1242 Loss of purposeful hand movements, 444 Loss of skills, 824, 896, 1425 regression, 824, 826, 827 Loss of speech, 410, 460, 462, 618, 819, 901, 1159, 1165, 1173 Loss of very early milestones, 1405 Loss of white matter with cyst formation, 596 Low anterior hairline, 1162 Low birth weight, 280, 502, 504, 617, 829, 1426 Low body temperature during crisis, 407 Low carbohydrate, high protein and high fat intake, 777 Lower limb muscle hypotrophy, 896 reflexes, absent, 490 Low frontal hairline, 775 Low levels of fat-soluble vitamins A, D, and E, 1313 Low RBC life span, 668 Low-set ears, 197, 462, 775, 1158, 1171 Low weight, 491, 903 gain, 489 Lumbosacral disc degeneration ochronosis, 358 Lung hypoplasia, 459

1525 Lung infiltrates, 1192 Lymphadenopathy, 678, 1192 Lymphangiectasia, 678 Lymphedema, 1255 Lymphohistiocytosis, 298, 309 Lymphopenia, 203, 205, 869 M Macrocephaly, 368, 372, 817, 818, 920, 1068, 1159, 1187, 1253, 1254, 1256, 1271, 1272, 1275, 1276, 1354, 1357, 1362, 1369, 1405, 1406 Macrocytic anemia, 906 Macrocytosis, 505 Macroglossia, 679, 719, 723, 1168, 1276 Macrophage, 173 activation, 298 Macrophthalmia, 1361 Macrosomia, 720, 722–723, 728, 729 Macrothrombocytopenia, 1387 Macular atrophy, 568, 666 Macular corneal dystrophy, 1372 Macular dystrophy, 1160, 1215 Maculopathy, 504, 1226 Malabsorption, 18, 19, 198, 661, 662, 861, 1037, 1042, 1044, 1063 Malar flush, 373 Malar hypoplasia, 197, 463 Male genital anomalies, 899 hypoplasia, 1352, 1358 Malformation, 123, 705, 939 Malnutrition, 1037, 1414 chronic, 198, 756, 861 Malocclusion, 617 Malrotation, 1352, 1376 Mandibular and/or maxillary hypoplasia, 1242 Maple syrup odor, 174 Marfanoid features, 373, 1390 Marfanoid habitus, 1390 Maternal eclampsia, 716 Maternal HELLP syndrome, 944, 947, 1352 MCP hyperintensity, 122 Medial deviations of fingers, 1370 of toes, 1370 Mega cisterna magna, 579, 584, 596 Megacisterna magna (MRI), 899 Megacolon, 1378 Megalencephaly, 1187, 1188 Megalocornea, 1360, 1361 Melanoderma, 629 MELAS syndrome, 128, 132, 134, 811–813 Memory problems, 410, 1173 Mental deterioration, 1187, 1188 Mental development, 333 Mental retardation, 3, 4, 252, 253, 294, 305, 332, 333, 346, 355, 357, 359, 368, 516, 585, 678, 717, 724–727, 1281, 1405, 1406 MERFF syndrome, 812 Metabolic acidosis, 398, 400, 402–407, 409–412, 507, 741, 751, 755, 756, 817–819, 828, 870, 962, 994, 1424, 1426 Metabolic crisis, 565, 571, 574 Metabolic stroke, 111, 116, 401, 407, 409, 505, 506, 512, 993 Metabolite toxicity, 100 Metabolome, 92 Metachromatic leukodystrophy, 76 Metaphyseal thickening, 1030 3-Methylglutaconic aciduria, 992

1526 MFF deficiency, 1307 Microcephaly, 199, 202, 206, 256, 275, 276, 280, 294, 300, 301, 306, 308, 335–337, 375, 399, 404, 410, 436–438, 440, 458–464, 483, 489, 505, 517, 520–522, 533, 534, 585, 598–600, 706, 719, 726, 741, 743, 747–751, 756, 774–776, 778, 806, 821, 826, 828, 831, 863, 873, 874, 876, 879, 881, 882, 894, 895, 902, 903, 906, 908, 941, 962, 995, 996, 1032, 1064–1069, 1158, 1162, 1165–1168, 1171, 1221, 1225, 1226, 1346– 1352, 1354–1356, 1358, 1359, 1365, 1377, 1380–1383, 1387, 1388, 1390, 1426, 1427 acquired, 1393 Microcytic, 627, 628, 631, 632 Microcytosis, 867, 1122 Microdontia, 776 Micrognathia, 197, 464, 726, 775, 1067–1069, 1158, 1171, 1346, 1351, 1356, 1374, 1380 Microhemorrhages, 140 Micropenis, 197, 705, 775, 1171, 1352, 1366, 1381 Microphthalmia, 811, 1067, 1360–1363, 1382 uni-/bilateral, 831 Microphthalmos, 1364 Microretrognathia, 1372 Microtia, 491, 903 Microvesicular steatosis, 899 Midbrain abnormalities, 404 Midface hypoplasia, 462, 775, 1067, 1372, 1392 Midgut malrotation, 197 Midline brain malformations, 1382 Migraine, 106, 258, 897 ocular, 410 Mild cognitive impairment, 857 Mild dysmorphic features, 410, 1422 Mild intellectual disability, 897 Mild tibial bowing, 1371 Miller syndrome, 193, 197 Minimal spontaneous movements, 872 Minor allele frequency, 153 Mirror movements, upper limbs, 1362 Mitochondrial DNA deletions, 857 Mitochondrial DNA depletion, 996 Mitochondrial neurogastrointestinal encephalopathy syndrome, 193 Mitral valvulitis, 358 MODY, 716–718, 722, 731, 732 Monkey wrench appearance of femora, 1367 Mono-allelic expression, 155 Mood swings, 1161 Most patients are male, 870 Motor and sensory nerve conduction studies, abnormal, 666 Motor developmental delay, 300, 301, 489, 596, 881, 906, 908, 1169, 1170, 1172, 1241, 1257, 1349, 1372 Motor dysfunction, 1157 Motor neuropathy, 1118–1121 Motor retardation, 1405 Movement abnormal, 375, 614, 1358 abnormalities, 867, 1393 disorder, 236, 237, 242, 405, 412, 441, 502, 505, 520, 534, 564, 571, 638, 643, 662, 666, 779, 870, 1097, 1208, 1213–1215, 1217–1219, 1221–1226, 1380, 1400 complex, 897 extrapyramidal, 505, 506 paroxysmal, 897 stereotyped hand, 315, 320 Moyamoya, 125 mtDNA variants, 152, 845, 846, 867 Multifocal epilepsy, 458, 473, 474

Sign and Symptoms Index Multilayered patellae, 1373 Multiorgan failure, 881, 921 Multi organ involvement, 866 Multiple mtDNA deletions (muscle), 857 Multiple system atrophy like encephalopathy, 920 Muscle atrophy, 617, 773, 865, 938, 1160, 1164, 1169, 1173 Muscle cramps, 202, 247, 488, 668–670, 672, 830, 1362, 1451 Muscle dystrophy, progressive, 1257, 1366 Muscle-eye-brain disease, 1361–1364 Muscle histopathology rimmed vacuoles, 1257 tubulofilaments, 1257 Muscle hypertrophy, 1366 Muscle hypotonia, 1258 Muscle mass, low, 238 Muscle pain, 402, 668–670, 672, 1118–1121, 1451 and rhabdomyolysis, 172 Muscle wasting of limbs with sparing of quadriceps muscles, 1257 Muscle weakness, 199, 276, 277, 339, 371, 402, 465, 488, 489, 521, 548–550, 553–556, 558, 615, 667–672, 674, 675, 724, 727, 750, 757, 773–775, 779, 817, 820, 823, 827, 828, 856, 861, 865, 866, 881, 882, 895, 898, 901, 908, 920, 922, 938, 1162, 1164, 1169, 1172, 1173, 1187, 1189, 1291, 1385, 1387, 1392 and/ or exercise intolerance, 857 distal, 751, 1159, 1160, 1163, 1164 facial, 1169, 1172 lower extremities, 826 mild proximal, 237, 239 onset in lower extremities, 898 progressive, 239, 372 proximal, 677, 830, 857, 862, 863, 865, 995, 1170, 1362, 1375, 1384 Muscular atrophy, 3, 9, 13, 672, 1212, 1213, 1215, 1217–1219, 1221, 1222, 1224–1226 distal, 823 Muscular-axial, 616, 662 Muscular dystrophy, 996, 1358, 1360–1366, 1375, 1383 limb-girdle, 1387 Muscular hypotonia, 237, 534, 1188, 1400, 1401, 1405 Musculoskeletal bone pain, 1323 Musculoskeletal cleft palate, 995 Musculoskeletal dysmorphic features, 1308 Musculoskeletal enlarged fontanel, 1307 Musculoskeletal spasticity, 301 Musty odor, 174 Mutilation, 1119 Mutism, 1162, 1164, 1173 Myalgia, 677 Myelination abnormal, 142 absent, 458, 460 Myelodysplasia, 407, 1374 Myelofibrosis, 1031 Myelopathy, 504, 506 Myoadenylate deaminase deficiency, 194 Myocardial infarction, 1102 Myocardial ischemia, 1040–1042, 1044 Myoclonic and generalized tonic-clonic seizures, 877 Myoclonic epilepsy, 292, 473, 516, 678, 778, 795, 847, 875, 876, 1211, 1215, 1217–1219, 1225, 1226, 1253 progressive, 678 Myoclonus, 593, 596, 598–600, 602, 603, 643, 678, 751, 757, 817, 896, 1161, 1173, 1188, 1211, 1214, 1215, 1217–1219, 1221, 1223, 1226, 1253 Myoglobinuria, 17, 18, 173, 198, 399, 488, 670, 741, 751, 1365, 1387

Sign and Symptoms Index Myokymia, 306 Myopathy, 68, 204, 237, 256, 257, 371, 399, 479, 488, 490, 491, 549, 550, 554, 556, 565, 571, 601, 741, 751, 773, 779, 806, 807, 810–812, 814, 816, 818, 820, 821, 824, 826, 858–861, 875, 880–882, 897, 901, 906, 907, 931, 992, 994, 1371, 1442 peripheral, 1290, 1291 severe, 876 Myopia, 238, 239, 277, 373, 464, 679, 1241, 1358, 1359, 1361, 1367, 1372 N Nail abnormalities, 775, 1375 Narrow chest, 900 Narrow, elongated face, 1167 Narrow palate, 1171 Nasal bridge, depressed, 1367 Nasal congestion, 319, 321 Nasal hypoplasia, 1389 Nausea, 1118–1121 Nausea/vomiting, 301, 724, 734 Necrosis, 108, 120 Neonatal death, 878 encephalopathy, 97 epileptic encephalopathy, 470 hemochromatosis, 858 irritability, 321 jaundice, 368, 669, 1121 liver failure, 669 seizures, 586 Neoplasm, 1356 Nephrocalcinosis, 356, 706, 1290, 1291, 1323–1326, 1359 Nephrolithiasis, 596, 598–600, 1290, 1291, 1323–1326 Nephromegaly, 662 Nephropathy, 207 Nephrotic syndrome, 174, 920, 921, 923, 1348 Nerve conductive velocity, 1189 Neural tube defect, 459, 1363, 1365 Neuroaxonal dystrophy, 76, 1250 Neurodegeneration, 1425 Neurodegenerative disease, 643, 1211, 1213–1215, 1217–1219, 1221, 1223–1226 Neurodevelopmental regression, 487, 533 Neuroferritonopathy, 104 Neurogenic bladder, 879 Neurologic abnormalities, 858, 859 Neurological deterioration, 333, 871, 1189 Neurological manifestation, 565 Neurological regression, 484, 485 Neurological symptoms, 51, 252, 253, 257, 314, 315, 326, 343, 355, 503, 506, 510, 614, 621, 752, 753, 756, 863, 864, 1391, 1408 Neurologic crisis, 354 Neurologic decline, 894, 895 Neurologic deterioration, 474, 487, 520, 907, 1241 Neurologic dysfunction, 503–505, 815, 949 Neurologic symptoms, 667 Neuronal loss, 105, 106 Neuronal migration abnormalities, 1366 Neuropathy, 198, 256, 257, 608, 609, 616, 620, 679, 702, 705, 811, 821, 827, 895–897, 899, 903, 907, 1102, 1103, 1161, 1189, 1308, 1310 axonal, 571, 876 axonal motor, 1159, 1161 demyelinating, 995

1527 myelinating, 861, 1357 peripheral, 201, 247, 486, 520, 521, 568, 679, 747, 752, 753, 822, 823, 827, 860, 861, 863, 864, 920, 944, 947, 995, 1045, 1310, 1383 sensory, 239, 277, 863, 878, 921, 1160, 1255 sensory axonal, 489, 860 Neuropsychiatric, 631 Neuropsychiatric manifestations, sudden onset, 777 Neutropenia, 17, 38, 173, 400, 402, 407, 409, 412, 488, 615, 676, 677, 734, 756, 902, 994, 1386, 1422, 1425 Neutrophil hypoglycosylation, 1386 Neutrophilia, 1388 Neutrophils, hypersegmented, 502–504 Night blindness, 205, 239, 277, 464, 827 Nipples, absent, 1171 Nodular heterotopia, 1365, 1366 Non ambulant, 819 Noncirrhotic portal hypertension, 858 Nonhemolytic anemia, 173 Nonketotic hyperglycinemia, 99 Non-macrocytic anemia, 173 Non-specific white matter lesions, 897, 898 No voluntary activity, 826 Nyctalopia, 666 Nystagmus, 199, 205, 301, 306, 370, 402, 440, 458, 462, 486, 487, 489, 504–506, 568, 705, 727, 751, 813, 814, 817, 823, 824, 826, 827, 858, 866, 874, 875, 879, 882, 896, 897, 899, 901, 996, 1158, 1160, 1163, 1165, 1167, 1256, 1257, 1346, 1353, 1375, 1380, 1382, 1383, 1388, 1405, 1422, 1424 horizontal, 1366 optic atrophy, 488 O Obesity, 45, 167, 821, 920, 1086, 1160, 1357, 1367, 1392 Obliteration of pulp chambers, 1242 Obsessive-Compulsive Disorder (OCD), 706 Obstruction, 616 Obstructive sleep apnea, 1271, 1272, 1275, 1281 Obstructive uropathy, 297 Occipital cortex, 132 Occipital horn, 607, 609, 611, 615, 619–621 Occipital lesions, 405 Ocular abnormalities, 1169, 1386 Ocular albinism, 1158 Ocular apraxia, 1393 Ocular malformations, 143 Oculo-digital sign, 568 Oculogyric crisis, 173, 318, 319, 321, 339, 522 Oculomotor apraxia, 895, 941, 1159, 1165 Oculomotor dyspraxia, 441 Odontoid hypoplasia, 1274 Odor acrid, 402 of maple syrup, 398 of sweaty feet, 19, 400 Olfaction anosmia, 1308 Olfactory hypoplasia, 138 Oligodontia, 776 Oligohydramnios, prenatally, 705 Omphalocele, 1065 Onychogryphosis, 1242 Ophthalmologic, 1241 abnormalities, 436, 438 involvement, 1241 Ophthalmoparesis, 857, 860, 1172, 1385

1528 Ophthalmoplegia, 755, 773, 795, 806, 817, 824, 827, 828, 830, 847, 857–863, 865, 882, 897 progressive external, 807 Opisthotonus, 398, 534, 596, 1369, 1405 Optic atrophy, 43, 122, 132, 199, 201, 402, 403, 407, 437, 440, 485–487, 489, 532, 533, 568, 570, 666, 705, 726, 751, 755–756, 811–813, 817, 824–827, 860, 867, 868, 874, 881, 895–901, 907, 908, 920, 1101, 1186, 1212, 1213, 1215, 1217–1219, 1221, 1225, 1226, 1257, 1276, 1323–1324, 1349, 1351, 1354, 1356, 1363, 1370, 1377, 1382, 1384, 1405, 1422, 1424, 1427 Optic disc pallor, 666 Optic nerve atrophy, 795, 847, 906, 1241 dysplasia, 1366 enlargement, 139 hypoplasia, 680, 1064, 1362, 1363 Optic neuritis, 128 Optic neuropathy, 409, 505, 506, 542, 806, 908 Oral ulcerations, 676, 677 Orobulbar dysfunction, 598–600, 602 Orofacial apraxia, 1164 Orofacial dyskinesia, 1173 Oromotor dysfunction, 1355 Orotic acid crystalluria, 198 Orthopnea, 679, 862 Orthostatic, 615 acrocyanosis, 368 cyanosis, petechiae, 174 Osmotic, 660, 661 Osteoarthritis, 1240 Osteoarthrosis, 1165 Osteochondroma, 1368, 1369 Osteomalacia, 239 Osteopenia, 275, 407, 409, 461, 462, 610, 617, 642, 676, 677, 725, 1290, 1291, 1308, 1345, 1354, 1355, 1380, 1389 Osteoporosis, 237, 274, 275, 298, 299, 310, 368, 373, 461, 533, 534, 629, 1102, 1190, 1290, 1291, 1358, 1390 Osteosclerosis, 1165 Ovarian cysts in 46,XX, 1083 Ovarian dysfunction, 878 Ovarian dysgenesis, 723, 860, 878, 882 Ovarian failure, 664, 875, 903 Overlapping fingers, 1367 long fingers, 1368 Overweight, 723 P Pachydermia, 1028, 1031 Pachygyria, 122, 131, 142, 1171, 1363–1365 frontoparietal, 1366 Paget bone disease, 906 Pain, 173, 354, 362 Painful bone, 1179 Pain sensation, 1393 Palmoplantar hyperkeratosis, 1242 Pancreatic, 677 dysfunction, endocrine, 1290, 1291 failure, 869 insufficiency, 1140 exocrine, 1391 Pancreatitis, 174, 398, 400, 406, 407, 409, 506, 676, 972, 1044 recurrent, 272, 777

Sign and Symptoms Index Pancytopenia, 173, 400, 501–503, 506, 517, 520, 522, 526, 568, 880, 1190, 1192, 1323–1326 Papillary pallor, 898 Papilloma, 817 Paraganglioma, 754, 755, 757, 816–818 Parenchymal volume loss, 111 Paresis, 271 Parkinsonism, 324, 333, 338, 339, 570, 571, 638–640, 642–644, 806, 807, 857, 859, 905, 1102, 1161, 1164, 1170 hypokinetic, 279, 321 hypokinetic features, 747, 905, 1163 PAS positive polyglucosan inclusions in brain, 678 Patellar dislocation, 1367 Patent ductus arteriosus, 569, 705, 775, 921, 1031, 1386 Pathogenicity, 153, 156 Pathogenic variants, 151, 153, 155 Pathological fractures, 534, 1190, 1323–1326 Paucity of white matter, 461 Pectus carinatum, 879, 1368 Pectus excavatum, 197, 1358, 1370 Peculiar facies, 615 Peculiar pigmented skin rash, 564 Pellagra, 565 Penetrance, 154 Peptic ulcer, 1031 Pericardial effusion, 724, 1345, 1351 Perinatal bleeding diathesis, 1359 Perinatal death, 486 Perinatal lethality, 1389 Perinatal stress, 716 Periodic limb movement, 898 during sleep, 302 Periodontitis, 1242, 1388 Periostitis, 1031 Peripheral, 616, 620 Peripheral demyelinating neuropathy, 751 Peripheral hypotonia, 314 Peripheral neuropathy, 172, 247, 824, 859, 881, 904, 907, 908, 1290, 1393 Peripheral sensory neuropathy, 860 Periportal inflammation, 1100–1101 Perisylvian, 142 Periventricular calcifications, 1375 Periventricular cysts, 117 Periventricular white matter changes, 405, 870 Persistant desiduous teeth, 1242 Persistent hyperexcitability, 596 Persistent pulmonary hypertension of the newborn, 829, 1426 Personality changes, 1162, 1164, 1173 Pes cavus, 373, 490, 751, 1102, 1160, 1161, 1163, 1169, 1173 Pes equinovarus, 338 Pes planus, 275, 461, 617, 1163, 1166, 1290, 1291, 1384 Petechia due to vasodilation, 368 PEX11 beta deficiency, 1307 pH, 680 Pheochromocytoma, 756, 816–818 Photodermatitis, 305, 308, 309 Photophobia, 301, 356, 357, 1241, 1290, 1291, 1372 Photosensitivity, 296, 569, 1118 acute painful, 1122 Pigmentary deposits of the retina, 666 Pigmentary retinopathies, 205, 257, 725, 757, 817, 871, 898, 944, 947, 991, 1103, 1212, 1213, 1217–1219, 1221, 1323–1326, 1345, 1360, 1361 Pigmentation, 355, 358

Sign and Symptoms Index Pigment gallstones, 667 Pili torti, 819 Pitched cry, high, 441 Pituitary dysfunction, 1102 Pituitary hyperplasia, 137 Plasmalogens deficiency, 1309 Platyspondyly, 610, 617, 900, 1065, 1368, 1369, 1373, 1389 PMP70 deficiency, 1306 Pneumonia, 336, 337, 1406 Poikilocytosis, 196, 197, 1387 Polyagglutination syndrome, 1374 Polyarteritis nodosa, 194, 203 Polycystic kidney, 68, 1357 Polycystic liver disease, 1357 Polydactyly, 1067 postaxial, 1065, 1068, 1069 Polyhydramnios, 474, 486 Polymicrogyria, 142, 1170, 1363 Polyneuropathy, 474, 539, 543, 545, 779, 821, 826–828, 830, 1254, 1309 Polyuria, 880, 1290, 1291 Pontobulbar palsy, 553 Pontocerebellar, 876 abnormalities, 1362 hypoplasia, 102, 104 type 9, 194 Poor, 43, 96, 176, 264, 319, 321, 346, 596, 1411 airway maintenance, 470 growth, 866, 902, 1140 head and trunk control, 895 head control, 319, 321, 487 swallowing requiring gastric tube feeding, 470 synacthen test, 909 visual fixation, 774, 895, 1160, 1348 Porphyria-like neurological crisis, 354, 356, 363 Portal hypertension, 1140, 1142 Portal vein thrombosis, 1378 Postaxial acrofacial dysostosis, 193 Posterior fossa anomalies, 473, 775 Posteriorly rotated ears, 775 Postnatal virilization (XX), 1084 Post-splenectomy thrombosis, 669 Postural instability, 905, 1163, 1164 Post-vaccination (MMR) complications, 896 Preaxial brachydactyly, 1370 Precocious osteoarthropathy, 1373 Precocious pseudopuberty (46,XY), 1086 Precocious puberty, 569 Predisposition for symptomatic disease, 941 Premature death, 564 Premature loss of teeth, 1171 Premature pubarche, 1373 Prematurity, 332, 1352 PRESS, 138 Preterm birth, 880 Primary hyperoxaluria, 183 Problematic lymphocyte growth, 1358 Profound global developmental delay, 598–600 Profuse, 660, 661 Progeroid appearance, 275, 461, 776 Prognathia, 775 Progressive, 609, 611, 612, 615, 619, 621 ataxia, 460 cerebral atrophy, 118 deterioration of joint, 1309 external ophthalmoplegia, 856

1529 gait disorder, 1309 leukodystrophy, 1309 loss of cerebral white matter, 876 muscle weakness, 668 peripheral spasticity with axial hypotonia, 470 psychomotor regression, 106 renal impairment, 409 spastic paraplegia, 995, 996, 1101 (peripheral) vision loss, 666 weakness with onset in the distal lower limbs, 666 Prominent antihelix, 1167 ears, 462 eyes, 1372 lesser trochanters, 1372 superficial veins, 1378 Proptosis, 1367, 1368 Protein intolerance, 274, 292, 293, 295, 298, 302, 304–307, 309, 310 Protein-losing enteropathy, 725, 991, 1346, 1354 Protein sensitivity, 944 Protein synthesis reduced, 371 Proteinuria, 309, 725, 923, 1253, 1276, 1345 Protruding eyes, 1171 Protruding tongue, 776 Protuberant eyes, 617 Proximal limb weakness, 895 Proximal muscle weakness, 859 Proximal myopathy, 1251, 1258 Proximal tubular acidosis, renal, 824 Proximal weakness, mild, 827 Pruritus, 1140–1143, 1375 Pseudoacinar transformation, 1101 Pseudo-hypertriglyceridem, 960 Pseudo-obstruction, 856 Pseudotumor cerebri, 663 Psychiatric disturbances, 568, 905, 1164 Psychiatric signs, 173 Psychiatric symptoms, 373, 502, 504, 506, 521, 608, 614, 678, 830, 1170, 1187, 1188, 1213, 1214 Psychomotor, 611, 615, 616, 705 delay, 882 impairment, 975 regression, 568, 755 retardation, 368, 741, 904 Psychomotor developmental absent, 1366 delay, 484, 757, 876, 877 Psychosis, 255, 256, 296, 502, 503, 569, 906, 1161, 1187, 1189, 1193, 1254 Ptosis of eyelid, 318–321, 335, 336, 554, 618, 677, 755, 773, 823, 827, 847, 857–859, 862, 863, 865, 878, 897, 900, 903, 904, 1068, 1069, 1172 Pubertal sex development, lack of, 1083 Puberty, delayed, 1290, 1291, 1382 Pulmonary alveolar proteinosis (PAP), 298, 309, 310 Pulmonary arterial hypertension, 775, 1386 Pulmonary edema, 945 Pulmonary hypertension, 173, 484, 669, 814, 821, 922, 1171 Pulmonary hypoplasia, 775, 1068, 1069 Pulmonary interstitial changes, 1192 Pulmonary lobation, abnormal, 1069 Punctate calcification, 1066, 1067 Pus formation, inability to, 1388 Putamen abnormalities, 412 PVWM hyperintensity, 116, 126 Pycnodysostosis, 1237, 1244

1530 Pyloric stenosis, 197, 1069, 1171 Pyramidal signs, 204, 271, 275, 276, 279, 321, 412, 461, 747, 748, 752, 753, 756, 776, 814, 863, 864, 894, 922, 1102, 1157, 1160, 1165, 1173, 1276, 1290, 1291, 1347 Pyridoxal 5′-phosphate-dependent, 586 epilepsy, 580, 586 seizures, 579 Pyrimidine metabolism impairment, 917 Q Quadriparesis, 776 R Racemase deficiency, 1306 Radial deviation of the index finger, 1374 Radial head dislocation, 1368 Radiolucent metaphyseal bands, 1323–1326 Radioulnar synostosis, 197, 1368, 1370 Radius dislocation, 1358 Ragged red fibers, 779, 811, 857, 861 Rapidly progressive, 678 Rash, eczematous, 336, 337, 677 RBC life span, 669 Rectal flatulence, 661 Recuperating disease course, 899 Recurrent bacterial infections, 252, 257, 1158 bronchopneumonia, 1359 encephalophatic periods, 820 infections, 522, 631, 642, 668, 676, 677 otitis media, 1240, 1271, 1272, 1275, 1281 rhabdomyolysis, 991 vomiting, 68 Red fibres, ragged, 199 Reduced consciousness, 598–600 Reduced glomerular filtration rate, 409 Reduced muscle tone /muscle stiffness, 1133 Reduced size of corpus, 1241 Refsum disease, 1306 Regression, 702, 705, 908, 993, 996, 1102, 1421, 1423 acute, 830 motor, 523, 756 psychomotor, 403, 405, 774, 775, 806, 817, 858, 870, 907, 920, 921, 923, 1162, 1363, 1364 Regurgitation, 1386 Renal agenesis, 1066, 1068, 1069 Renal anomalies, 197 Renal cancer, 754, 816 Renal colic, 205, 256, 1323–1326 Renal cysts, 1354, 1366 Renal disease, 59, 878 Renal dysfunction, 872, 922 Renal enlargement, 356, 676, 725, 1345 Renal failure, 46, 207, 239, 354, 490, 662, 812, 873, 1253 acute, 204, 205, 601, 1381 chronic, 205, 297, 356, 407, 505, 507, 706, 923, 1253, 1290, 1291, 1323–1326, 1328 end stage (ESRF), 298, 923 progressive, 880 proteinuria, 1189 Renal Fanconi syndrome, 17–20, 42, 48, 819, 1290, 1291 Renal hypoplasia, 569, 570, 829, 1066, 1068, 1069 Renal insufficiency, 871, 875, 906 Renal nephrocalcinosis, 1323

Sign and Symptoms Index Renal osteodystrophy, 1290, 1291 Renal salt loss, 1088 Renal stones, 204 Renal tubular acidosis, 68, 174, 239, 614, 680, 813, 816, 863, 938, 1158 Renal tubular dysfunction, 825 Renal tubulopathy, 280, 354, 356, 361, 409, 662, 665, 706, 820, 828, 859, 861, 869, 872, 923, 1354, 1426 proximal, 819 Respiratory chain enzymes, 867 Respiratory disturbance, 1276 Respiratory dysfunction, 865, 1257 Respiratory failure, 247, 490, 568, 573, 585, 813, 823, 824, 830, 862, 1102, 1160, 1356, 1357, 1365 Respiratory infections/distress, 46, 68, 406, 412, 483–485, 489, 823, 922, 994, 1276, 1383, 1386, 1422 Respiratory insufficiency, 274, 280, 298, 371, 407, 409, 460, 464, 486, 548, 550, 553, 554, 774, 775, 813, 829, 921, 1168, 1170, 1173, 1358, 1363, 1373, 1426 Restrictive lung disease, 1190, 1271, 1272, 1274, 1281 Retardation, 3, 4, 199, 200, 252, 253, 294, 305, 332, 333, 346, 355, 357, 359, 516, 608, 609, 615–617, 702, 705, 706, 717, 724–727, 773, 866, 902, 993, 1032, 1423–1425 mental, 1405 motor, 202, 440, 669, 922, 1240, 1241, 1346, 1362 psychomotor, 201, 202, 205, 206, 256, 257, 280, 336, 337, 339, 398, 400–402, 405, 407, 409, 412, 440, 441, 458, 459, 462, 473, 474, 516, 726, 750, 752, 753, 756, 773, 778, 808–810, 814, 818, 820, 823–825, 827, 828, 856, 860, 863, 864, 870, 874, 876, 879, 881, 908, 1063, 1158, 1159, 1161, 1165– 1168, 1325, 1345, 1346, 1348–1354, 1358, 1360–1362, 1376, 1384, 1388, 1392, 1421, 1426, 1427 and regression, 1271–1273, 1275 Retinal abnormalities, 1364 Retinal degeneration, 631, 795, 847, 1241 Retinal detachment, 239, 277, 464, 1352 Retinal dysfunction, 205 Retinal dysplasia, 1361, 1365, 1366 Retinal dystrophy, 205, 669, 751, 1160, 1212, 1213, 1215, 1217–1219, 1221, 1222, 1271, 1272, 1281, 1349, 1362, 1383 Retinal pigmentary abnormalities, 437 Retinal vascular attenuation, 666 Retinitis pigmentosa, 43, 205, 489, 666, 705, 752, 809, 827, 867, 1308, 1310, 1381, 1388 type 10, 194 Retinopathy, 257, 504, 521, 570, 572, 820, 920, 1161, 1226, 1290, 1291 Retinoschizis, 1385 Retrocerebellar cyst, 119 Retrognathia, 775 Retropulsion, 905, 1163 Rett like phenotype, 444 Reversible leukoencephalopathy, 488 Reye-like, liver failure, 68, 720 Rhabdomyolysis, 68, 668, 727, 815, 820, 827, 875, 937, 949, 1103, 1308, 1310, 1385 exercise induced, 555, 556, 939, 943, 944 Rheumatoid arthritis, 81, 355 Rhizomelia, 461, 569, 1067, 1069 chondrodysplasia punctata spectrum, 1306 shortness, 1065 Rib defects, 197 Riboflavin responsiveness, 553–556, 779 Rickets, 46, 48, 354, 356, 359, 662, 1100, 1105, 1290, 1291 Rigidity, 318, 338, 570, 572, 638, 643, 870, 905, 1163, 1164, 1173, 1213, 1223

Sign and Symptoms Index Ringed sideroblasts one marrow, 488 Rotator nystagmus, 904 Round face, 1162, 1372 S Sagging cheeks, 462 Salt wasting, 880 Scalp skin defects, 1375 Scapular winging, 1375 Schizophrenia, 898 susceptibility, 463 School problems (difficulties in writing, attention), 1193 Scleral pigmentation, 355, 358 Sclerocornea, 831, 1171 Scoliosis, 338, 373, 462, 470, 473, 484, 490, 554, 642, 666, 677, 879, 898, 921, 1067, 1276, 1290, 1291, 1348, 1358, 1363, 1367, 1371, 1376, 1381, 1383, 1389, 1393 Scotomata, 897 Scrotum, hypoplastic, 1356 Sebacic acid (urine), 937 Secondary amenorrhea, 903, 1373 Second mitochondrial affection, 941 Second wind phenomenon, 668, 672 Seizures, 43, 68, 106, 173, 179–180, 199, 200, 206, 237, 239, 242, 247, 252, 257, 258, 265, 268–271, 275–279, 301, 306, 310, 335, 368, 373, 398–400, 403, 405, 407, 409, 410, 412, 440, 441, 458–465461462464, 473, 474, 483, 484, 487, 489, 490, 502–506, 522, 532, 533, 569–572, 579, 585, 638, 639, 642, 662, 669, 671, 678, 680, 720, 721, 728, 729, 741, 747, 749, 751–753, 755–757, 774, 776, 817, 829, 830, 857, 864, 870, 873, 879, 894, 895, 899, 901–908, 921, 944, 962, 971, 972, 975, 1064, 1066–1068, 1100, 1102, 1103, 1118–1121, 1158, 1159, 1162, 1165–1168, 1170, 1186–1190, 1192, 1193, 1213–1215, 1217–1219, 1221, 1222, 1224, 1241, 1253, 1255, 1257, 1271–1273, 1281, 1307, 1308, 1310, 1314, 1354–1357, 1369, 1376–1380, 1384, 1389, 1390, 1392, 1406, 1425 absence, 678 clonic, 579 complex partial, 995, 1213, 1219 febrile, 402, 463, 585, 1421 folinic acid-responsive, 579 generalized, 678 intractable, 459, 505, 1381 intrauterine, 902, 1425 myoclonic, 335–337, 485, 516, 521, 579, 907, 1190, 1211, 1215, 1217, 1218, 1225, 1226 myoclonic-astatic, 516, 520 myoclonic-atonic, 442 neonatal, 305 neonatal myoclonic, 580 partial, 678 pharmacoresistant, 463, 584, 585 primary generalised, 579 pyridoxal 5′-phosphate-dependent, 579 refractory, 1377 tonic, 579 tonic clonic, 336, 337, 520, 521, 598–600, 678, 1211, 1213–1215, 1217–1219, 1224, 1226 Self-injury, 706, 1372 Self-limited delayed puberty, 1372 Self-mutilation, 204 Sensorimotor axial neuropathy, 550 Sensorineural deafness, 1140, 1281 Sensorineural hearing impairment, 740

1531 Sensorineural hearing loss, 901, 903, 1251, 1309, 1370, 1372 Sensory ataxic neuropathy, 857 Sensory neuropathy, 859 Sepsis, 354, 993, 994, 1422 Severe brain hypoplasia, 122 Severe combined immunodeficiency (SCID), 3, 9, 13, 192, 194, 203, 209, 517, 521 Severe denutrition, 59 Severe 5-fluorouracil toxicity, 199 heterogotes, 440 homozygotes, 440 Severe gastroesophageal reflux, 533 Severe hyperoxalemia, 1321 Severe multisystem disease, 808, 920 Severe psychomotor delay, 1236 Shortened limbs, 491, 903, 1388 Shortening of long bones, 1389 Short femoral necks, 1367 Short limbs, 1258 Short long bones, 1373 Short metacarpals, 617, 1367, 1373, 1374 Short nose, 463, 900 Short palpebral fissures, 775, 1357 Short phalanges, 617, 1367 Short philtrum, 1165–1167, 1171 Short stature, 372, 461, 491, 522, 569, 570, 610, 617, 618, 638, 639, 642, 662, 668, 673, 675–677, 723, 727, 755, 774, 775, 816, 817, 819, 821, 824, 827, 831, 898, 900, 901, 903, 905, 963, 997, 1064, 1065, 1084, 1085, 1140, 1162, 1165–1167, 1242, 1253–1256, 1258, 1274–1276, 1359, 1367–1374, 1385, 1386, 1389 Short, wide femoral neck, 617 Shrunken, bright cerebellar sign, 104 Shy character, 1165–1167 Sialorrhea, 1168 Sialotransferrin type 1 pattern, 1356 Sideroblastic anemia (with B-cell immunodeficiency), 867 Single transverse palmar crease, 1171 Skeletal abnormalities, 491, 727, 903, 1309, 1353, 1388, 1392 Skeletal dysplasia, 168, 726, 878, 1251, 1351, 1352, 1386 Skeletal hypomineralisation, 585 Skeletal malformations, 1356 Skeletal myopathy, 555, 556, 815, 937, 939, 940, 943–945, 947, 949, 992 Skin, abnormal, 701, 705 Skin abnormalities, 460 Skin blisters, 1119, 1120 Skin dryness, 629 Skin fragility, 1119, 1120 Skin histology, abnormal elastin fibers, 1390 Skin involvement, 871 Skin lesions, 354, 355, 361, 533, 568, 573 Skin rash, 174, 532, 670 Skin scarring, 1119 Skin veins, 617 prominent, 1386 Skull defects, 1375 Skull deform, 1242 Sleep apnea, 679 Sleep benefit, 905, 1164 Sleep disturbance, 317, 344, 345, 441, 489, 776, 1272, 1273, 1281, 1372 Slender, 617 fingers, long, 1376 hands and feet, 372 Slow/near-absent pupillary reactions, 568

1532 Slow nerve conductive velocity, 1241 Small basal ganglia, 1168 Small canaliculi, few microvilli, 1101 Small capital femoral epiphyses, 1369 Small epiphyses, 1370, 1372 Small ilia with snail-like appearance, 617, 1389 Small medullary cysts, 207 Small nipples, 776 Small nose, 776 Smooth skin, 617 Sneddon syndrome, 203 Somatic development, delayed, 1086, 1087, 1242 Somnolence, 265 Spares posterior putamen putamen eye sign, 136 Sparse eyebrows and eyelashes, 1171 Sparse hair, 274, 298, 461, 1171 Spasms, 521 Spastic diplegia, 203, 270, 1064 Spasticity, 204, 252, 301, 338, 399, 405, 441, 462, 473, 474, 484–487, 489, 491, 570, 572, 593, 596, 611, 615, 638, 642, 701, 705, 741, 751, 757, 773, 776, 778, 811, 814, 817, 825–827, 830, 870, 876, 879, 895, 897, 901–904, 921, 993, 995, 1157, 1160, 1161, 1165, 1166, 1168, 1169, 1186–1189, 1196, 1211, 1215, 1217–1219, 1221, 1226, 1241, 1253–1257, 1400, 1405, 1406, 1410–1425, 1429 acral, 1381 limbs, 402, 487, 1161, 1421 lower limbs, 904 Spastic paraparesia/ paraplegia/tetraplegia, 276, 458, 464, 484, 486, 571, 867, 874, 904, 938, 1102, 1103, 1169, 1424 Spastic paresis, 776, 1102, 1307, 1308, 1310 Spastic quadriplegia, 818, 1166, 1167 Spastic tetraparesis, 484, 486, 1168, 1169 Spatulate distal phalanges, 1368 Speech delay, 237, 238, 275, 399, 522, 569, 706, 756, 825, 906, 962, 1166–1168, 1211, 1215, 1217–1219, 1225, 1226, 1241, 1357 disorder, 1362 disturbances, 440, 442, 445, 614, 1172, 1186–1188, 1240, 1241 impairment, 237 Sphincter control problems, 490, 1160 Spike wave discharges, 337, 441 Spinal cord abnormalities, 487, 1365 and/or cerebellomedullary angle xanthogranulomas, 136 atrophy, 120, 490 compression, 1240, 1275, 1309, 1369 myelopathy, 1102 Spinal muscle atrophy-like phenotype (type 3), 860 Spinal muscular atrophy (SMA), 3, 9, 13, 1212, 1213, 1215, 1217– 1219, 1221, 1222, 1224–1226 Spinocerebellar ataxias, 306 Splenomegaly, 198, 203, 665, 667, 672, 673, 701, 702, 705, 774, 821, 963, 1030, 1290, 1291, 1351 Spongiform encephalomyelopathy, 755 Spongiotic dysmyelination, 97 Sporadic tonic seizures, 773 SSEP, abnormal, 1212, 1213, 1215, 1217–1219, 1221, 1226 Startle reflex, 302 Startle response, exaggerated, 1186–1188, 1253 Static cerebral palsy, 593 Static encephalopathy, 439 Statin resistant hyperlipidemia, 1100 Status epilepticus, 579 Steatorrhea, 1100, 1104, 1105, 1193

Sign and Symptoms Index Steatosis liver, microvesicular, 825 Stereotyped hand movement, 315, 320, 399, 662, 706 Stereotypic behaviors, 1165–1167, 1173 Sternal bulging, 1274, 1275 Sternal deformities, 373 Stiffness, 302, 308, 310, 902, 1169, 1425 Stillbirth, 667 STN lesions, 131 Stomatitis, 520, 532 Strabismus, 371, 442, 487, 489, 618, 642, 706, 725–727, 751, 757, 896, 941, 1069, 1166, 1241, 1345, 1346, 1348, 1349, 1351–1353, 1355–1357, 1383, 1384, 1389, 1390, 1393 Strenuous exercise, 171 Stress-induced deterioration, 485 Striatal necrosis, isolated bilateral, 814 Striatum lesions, 132 Stridor, 173 inspiratory, 489, 532, 774, 1349 Stroke, 111, 116, 140, 373, 668 Stroke-like encephalopathy, 405, 972 Stroke-like episode, 106, 173, 269–271, 724, 776, 795, 812, 820, 826, 827, 830, 847, 875, 920, 1290, 1291, 1345, 1384 Structural transport mechanism, 766 Subacute demyelinating mixed motor sensory neuropathy, 484 Subcortical atrophy, 280, 336, 337, 458, 828, 829, 908, 1240, 1426, 1427 Subcutaneous calcifications, 1374 Subcutaneous fat distribution, abnormal, 1345, 1356 Subcutaneous nodules, 1192 Subdural hematoma, 173 Subdural hemorrhages, 104 Suberic acid (urine), 937 Subtype with isolated retinopathy, 997 Sudden death, 336, 337, 679, 756, 906, 940 Sudden hearing loss, 173 Sudden infant death, 180, 302, 308 Sudden visual loss, 173 Supernumerary vertebrae, 197 Supernumery nipples, 757 Swallowing difficulties, 196, 319, 335, 336, 489, 490, 550, 555, 779, 921, 1162, 1164, 1271–1273, 1290, 1291, 1387, 1406 problems, 1281 Sweating, 317, 319, 321, 324, 1255 Sweaty feet odor, 174 Swollen joints, 1031 Syderoblasts, 1118 Symmetric hyperintense lesions in basal ganglia, 902 Symphalangism, 1370 Symptoms, 6, 43, 51, 61, 68, 75, 76, 171–174, 178, 196–208, 252, 253, 255–258, 314–321, 326, 332, 333, 335–339, 343–345, 354–359, 362, 363 Syncope, 315, 320, 671, 976 Syndactyly, 197, 569, 1171, 1370, 1375 Synophrys, 491, 776, 903, 1367 Syphilis infection, 13 T Tachycardia, 1118, 1121 Tachypnea, 505, 533, 676, 677, 681, 740, 974, 975 Talipes, 569, 570 equinovarus, 1165, 1167, 1367, 1368, 1371, 1373 Tall stature, 1086, 1087 Tapered fingers, 617 Taste loss, 309 T-cell immunodeficiency, 194

Sign and Symptoms Index Teeth abnormalities, 491, 903 malposition, 903, 1358 Telangiectasia, 1188, 1253 Temperature instability, 265, 268–271, 273, 317, 319, 324, 335–337, 776, 1133 Temporal hypoplasia, dilated, 1352 Temporal to diffuse optic nerve pallor, 896, 897 Temporary impairment of renal function, 407 Tendon reflexes, 1384 decreased, 441, 1345 increased, 338, 339, 370, 441, 520, 773 Testicular hypoplasia, 1366 Testicular nodules, 569 Testicular tumour, 569 Tetany, 1100 Tetralogy of Fallot, 1171 Tetraparesis, 203, 483 progressive, 877 Thalamic hypointensity, 139, 140 Thick caseous, 948 Thickened skin, 1031 Thick lips, 1168 Thin body habitus, 995 Thin corpus callosum, 372, 461, 462, 464, 474, 533, 534, 571, 579, 724, 775, 900, 1159–1162, 1166, 1168 Thin skin, 617 Thin upper lips, 776 Thoracic aortic aneurysms, 370 Thoracic deformities, 898 Thoracic hypoplasia, 1389 Thrombocytopenia, 17, 37, 173, 309, 354, 400, 402, 407, 409, 412, 521, 542, 614, 701, 705, 734, 1030, 1063, 1190, 1192, 1276, 1348, 1352, 1354, 1356, 1386, 1422 mild, 830 Thromboembolic episodes, 521 Thromboembolism, 173, 373 Thromboses, infarcts, 373 Thrombosis, 725, 1346, 1350 cerebral, 727, 1385 Thumb hypoplasia, 197 Thymine-uraciluria, 193 T1 hyperintensity brain, 642 Tigroid white matter signal, 140 Tin upper lips, 1171, 1357 Toe syndactyly, 1067–1069 Toe-walking, 995 Tongue hypertrophy, 1365 Tonic spasms, 596 Tonsils, 1045 Tortuous arteries, 615 Tortuous blood vessels, 275, 461 Toxoplasmosis infection, 13 Tracheostomy, 1359 Track-like spinal cord calcifications, 133 Transferrin, 626–634 saturation, 627, 629–631, 633, 634 Transfusion dependency, 667, 669 Transient alteration in tone, 338 Transient vasospasm, 138 Treatment-resistant epilepsy, 470 Tremor, 255, 316, 317, 321, 332, 338, 370, 520, 668, 879, 896, 898, 901, 905, 906, 1103, 1159, 1163–1165, 1383, 1406, 1425 intentional, 824, 825 Triangular face, 462, 463, 775 Tricuspid insufficiency, 775

1533 Truncal ataxia, 404, 1163 Truncal hypotonia, 462, 464 Tubular atrophy, 207 Tubulointerstitial nephritis, 409, 618, 871 Tubulopathy, 180 Tumors, 723 Turricephaly, 775 Typical minor dysmorphic facial features, 596 U Ulcerations, 1425 genital, 902 oral, 902 Ulcers, distal, 1163 Ulegyria, 102, 118 Umbilical hernia, 723, 776 and inguinal hernias, 1281 Unable to walk, 938 Unclear clinical features-possibly benign, 707 Unclear clinical significance, 707 Unilateral limb defects, 1066 Untargeted metabolomics, 85–93 Upper airway obstruction, 1242, 1271, 1272, 1275, 1281 Upslanted palpebral fissures, 462, 1378 Upturned nose, 463 Uridine 5'-monophosphate hydrolase 1 deficiency, 193 Urinary dysfunction, 904 Urinary incontinence, 879, 1159–1161, 1165, 1169, 1173, 1187, 1188 Urinary infections, 204, 297, 305, 1323–1326 Urinary urgency, 905, 1164 Urogenital abnormalities, 1386 Urolithiasis, 198, 200, 204, 207, 256, 297, 305, 601, 660, 661 cystine stones, 297 glutamate stones, 298 xanthine stones, 204, 601 Uterine muscle stiffnessn pregnancy, 670 Uveitis, 706 V Vacuolated lymphocytes, 679, 1186–1188, 1213, 1253–1256 Vacuolating myelinopathy, 398 Vacuolating myelopathy, 370 Vague upper abdominal pain, 1137 Valproate induced fatal liver toxicity, 856 Valve lesions, 1281 Valvular thickening, 1188, 1240, 1253, 1271, 1272, 1274, 1275 Valvulitis, mitral, 358, 461, 532 Variable immunodeficiency, 533, 534 Variant annotation, 152 Variant prioritisation, 152–154 Variants, 151, 152, 154 Vascular thromboses, 121 Vasculopathy, 105, 140 Vasogenic edema, 97 Vegetative state, 778 Venous thrombosis, 121 Ventricular, 671 Ventricular arrhythmia, 68, 671 Ventricular dilatation, 483 Ventricular septal defect, 1171, 1352, 1354, 1358, 1374 Ventriculomegaly, 464, 474, 487, 831, 1068, 1166, 1170 Vermian hypoplasia, 135 Vermishypoplasia, 119 Vertebral abnormalities, 1388

1534 Vertebral anomalies, 725, 1066, 1067, 1345, 1358 of whole spine, 1376 Vertical gaze palsy, 1170, 1193 Vertigo, 1406 Vesicouretral reflux, 491, 903 Vestibular nuclei lesions, 128 Virilization, 1084, 1086, 1088 at puberty (XY), 1088 Visceral calcifications, 1374 Vision cataract, 1307, 1308 decreased, 405, 490, 870 impaired, 269, 271, 504–506, 755, 756, 777, 817, 856, 899, 1187, 1188, 1253, 1290, 1291, 1350, 1384 progressive loss, 201 tunnel, 239, 277, 464 Vision loss, 205, 826, 828, 1168, 1192, 1212, 1213, 1215, 1217–1219, 1221, 1222, 1225, 1226 onset, 896, 897 optic atrophy, 553 progressive loss, 1103 Visual disturbances, 505, 897 Visual evoked potential, 1187 abnormal, 1212, 1213, 1215, 1217–1219, 1221, 1226, 1357 Visual fixation, 319 Visual hallucinations, 1170 Visual impairment, 489, 491, 666, 701, 705, 825, 830, 877, 895, 922, 1241 progressive, 896 Vitamin D3, 898 Vitamin K-dependent coagulopathy, 1313 Vitamin K responsive bleeding, 1100, 1101, 1103 Vitreous, persistent hyperplastic primary, 1363 Vocal cord paresis, 895 Volvulus of the stomach, 1358 Vomiting, 43, 45, 48, 68, 171, 198, 265, 268–271, 273, 274, 276, 279, 298, 301, 407, 409–411, 484, 490, 505, 506, 534, 548, 550, 555, 556, 558, 584, 585, 664, 665, 724, 734, 740, 747, 777, 824, 856, 861, 869, 971, 973, 994, 1118–1121, 1193, 1345, 1406 episodic, 398, 400, 401, 406, 412, 444, 1349 frequent, 275 recurrent, 174 W Waddling gait, 1166 Walker-Warburg syndrome, 1360–1364

Sign and Symptoms Index Walking difficulty, 1172 on tiptoes, 1160 Weakness, 484 muscle, 488, 489 Weak tendon reflexes, 371 Webbed neck, 723 Weight loss, 830, 1111, 1170 Wernicke-encephalopathy, 122 Wheelchair bound, 489 White matter abnormalities, 239, 405, 411, 440, 464, 908, 995, 1101, 1161, 1166, 1167, 1173, 1212, 1213, 1215, 1217–1219, 1226, 1365, 1427 changes, 398, 400–402, 407, 409, 504, 1366, 1421 disease, 751 lesions, 97, 99, 101, 102, 108, 111, 117, 897 loss, 1064 microstructural defects, 137 Wide forehead, 462 Widely spaced nipples, 776 Wide mouth, 1166, 1167 Wide nasal bridge, 1166, 1167 Widened metaphyses, 617 Widespread gray matter iron deposition, 124 Wolf-Parkinson-White syndrome, 828, 1426 Wormian bones, 124, 461 Wrinkled skin, 275, 276, 461, 462, 775 X X-adrenoleukodystrophy, 68 Xanthelasma, 1040, 1041, 1045 Xanthomas palmar, 1042 tendon, 1040, 1041, 1102 tuberoeruptive, 1042 X-linked adrenoleukodystrophy, 1306 X-linked Charcot-Marie-Tooth disease, 194 XXY karyotype, male, 831 Y Yellow discoloration (jaundice), 1133, 1137, 1138 Z Zellweger spectrum disorders, 1306