Inborn Metabolic Diseases: Diagnosis and Treatment 3662631229, 9783662631225

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Jean-Marie Saudubray · Matthias R. Baumgartner Ángeles García-Cazorla · John H. Walter Eds.

Inborn Metabolic Diseases Diagnosis and Treatment 7th Edition

Inborn Metabolic Diseases

Jean-Marie Saudubray • Matthias R. Baumgartner Ángeles García-Cazorla • John H. Walter Editors

Inborn Metabolic Diseases Diagnosis and Treatment Seventh Edition

Editors Jean-Marie Saudubray Paris, France Ángeles García-Cazorla Servicio de Neurologia Hospital Sant Joan de Deu Barcelona, Barcelona, Spain

Matthias R. Baumgartner Division of Metabolism University Children’s Hospital University of Zurich Zurich, Switzerland John H. Walter Developmental Biology and Medicine School of Medical Sciences University of Manchester Manchester, UK

ISBN 978-3-662-63122-5 ISBN 978-3-662-63123-2 https://doi.org/10.1007/978-3-662-63123-2

(eBook)

© Springer-Verlag GmbH Germany, part of Springer Nature 1990, 1995, 2000, 2006, 2012, 2016, 2022 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. Editorial Contact: Christine Lerche This Springer imprint is published by the registered company Springer-Verlag GmbH, DE part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

V

Preface This 7th edition is a milestone in the series of Inborn Metabolic Diseases (IMD): Diagnosis and Treatment, first published in 1990. Within the last 6 years a Copernican revolution in our understanding of IMD has changed the definition, concepts, paradigms, and classification. This new edition confirms the ubiquity of biochemical reactions in cellular biological processes, disturbances of which cause the large majority of human genetic disorders, many not classically labelled as metabolic diseases. While previous editions remained largely focused on disorders of intermediary metabolism and organelles, mostly diagnosed with metabolic markers, this edition extends the concept of IMD to include disturbances of molecular machinery, diagnosed by molecular techniques but which currently may not have measurable metabolic markers. About 600 new disorders are described in this 7th edition. Many are included in two new chapters: 7 Chap. 39, Disorders of nucleic acid metabolism, tRNA metabolism and ribosomal biogenesis, and 7 Chap. 44, Disorders of Cellular Trafficking. Defects in complex molecule synthesis and remodelling, many disorders of cellular or organelles transporters involving small or complex molecules, and new disorders involving energetic processes have also been considerably expanded. Up to 85% of IMDs impact on neurodevelopment or are responsible for neurodegeneration. Acute, chronic or progressive neurological syndromes, psychiatric presentations, developmental delay, intellectual disability, neurodevelopment disturbances and neurodegeneration at any age deserve special attention. A new editor with a special expertise in neurology has joined us for the purpose of describing these disorders. The description of neurological presentations, with about 35 tables and algorithms, now accounts for about 50% of 7 Chap. 1. The new concept of synaptic vesicle disorders is developed in 7 Chap. 30. While the most recent international classification of inborn errors of metabolism (IEM) encompasses >1400 disorders, from a clinical point of view, all IEM can be maintained in a simplified classification that mixes elements from a clinical diagnostic perspective and a pathophysiological approach based on three large groups. Our general clinical approach and algorithms are based upon this simplified classification and presented in 7 Chap. 1 which should be read first. In this era of genome sequencing, powerful computerized programs, and emerging artificial intelligence, we remain convinced that metabolic physicians must have a sound clinical training. As biochemical and molecular investigations grow in complexity, there is a risk that these effective but complex, time consuming, and expensive methods will be used in an uncontrolled and uncritical way. In view of the major improvements in treatment, it is crucial that clinicians do not miss IMD for which specific and effective treatment may be available. Physicians should be able to initiate a simple method of clinical screening, particularly in the emergency room, not only for children but also for adults. While this new edition highlights recent findings, it continues to provide a comprehensive review of all IEM, with a particular focus on the clinical and biochemical approach to recognition, diagnosis and treatment at all ages. The clinical algorithms of 7 Chaps. 1 and 2 incorporate both ‘old’ and ‘new’ disorders, and there are now many more algorithms detailing neurological presentations. An updated listing of metabolic markers and profiles and a section on molecular techniques including next generation sequencing and gene panels are included in 7 Chap. 3. As before, we continue to advocate referral to specialist centres for the diagnosis and treatment of inherited metabolic disorders. For countries in the Europe a list of such centres is compiled by the Society for the Study of Inborn Errors of Metabolism (SSIEM), while for the United States and Canada, Japan, Australia, South American

VI

Preface

and Middle East countries, comparable lists are compiled by the American (SIMD), Japanese (JIMD), Australian (AIMD) South Latin America (SLEIMPN) and Middle East societies for the study of inherited metabolic diseases, respectively. We welcome new authors and thank those previous authors who, while not involved with this edition, have helped to lay the foundation for this book. Jean-Marie Saudubray

Paris, France Matthias R. Baumgartner

Zurich, Switzerland Ángeles García-Cazorla

Barcelona, Spain John H. Walter

Manchester, UK

VII

Contents I 1

Diagnosis and Treatment: General Principles Clinical Approach to Inborn Errors of Metabolism in Paediatrics .....................

3

Jean-Marie Saudubray and Ángeles García-Cazorla 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.2 1.2.1 1.2.2 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7 1.3.8 1.3.9 1.3.10 1.4 1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 1.4.6 1.4.7 1.4.8 1.4.9 1.4.10 1.4.11 1.4.12 1.4.13 1.4.14 1.4.15 1.4.16 1.4.17 1.4.18 1.4.19 1.5

Simplified Classification of IEM in 3 Groups .................................................................................... Group 1. Small Molecule Disorders (7 Chaps. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, and 34)..................................................................................... Group 2. Complex Molecule Disorders (7 Chaps. 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44) ................................................................................................................................................... Group 3: Disorders Involving Energy Metabolism (7 Chaps. 5, 6, 7, 8, 9, 10, 11, 12, and 13) ................................................................................................................................................... Clinical Approach ............................................................................................................................................. Antenatal and Congenital Presentations ......................................................................................... Classification of Antenatal Manifestations in Three Major Clinical Categories .......................... Clinical Circumstances of Presentations .................................................................................................. Presentation in Neonates and Infants (1 year to 18 years) ....................................................................... Onset in Adulthood (>15 years to >70 years) ........................................................................................ Deafness .............................................................................................................................................................. Head Circumference, Cephalhematomas, Subdural Hematomas (. Table 1.22) .................... Neuroimaging Signs........................................................................................................................................ Neuro-ophthalmological Signs (. Tables 1.28 and 1.29) ................................................................. Neurophysiological Signs.............................................................................................................................. Recommended Laboratory Tests in Neurological Syndromes......................................................... Specific Organ Signs and Symptoms ................................................................................................. Cardiology........................................................................................................................................................... Dermatology ...................................................................................................................................................... Endocrinology (. Table 1.35) ..................................................................................................................... Gastroenterology and Nutritional Findings............................................................................................ Haematology ..................................................................................................................................................... Hepatology ......................................................................................................................................................... Immunology (See Also Neutropenia . Table 1.38) ............................................................................ Myology ............................................................................................................................................................... Nephrology (. Table 1.40) ........................................................................................................................... Neurology and Psychiatry ............................................................................................................................. Ophthalmologic Signs .................................................................................................................................... Orthopaedic Signs (. Table 1.43) ............................................................................................................. Pneumology ....................................................................................................................................................... Psychiatry ............................................................................................................................................................ Rheumatology ................................................................................................................................................... Stomatology....................................................................................................................................................... References............................................................................................................................................................

49 55 87 89 89 89 89 95 98 98 98 98 104 107 107 112 114 115 115 117 117 117 120 120 120 121 121

2

Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations ......................................

125

Fanny Mochel and Frédéric Sedel 2.1 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.3.9 2.3.10 2.3.11

3

Differences Between Paediatric and Adult Phenotypes ............................................................. General Approach to IEM in Adulthood ........................................................................................... Accumulation of Small Molecules .............................................................................................................. Deficiency of Small Molecules ..................................................................................................................... Accumulation of Complex Molecules ....................................................................................................... Deficiency of Complex Molecules .............................................................................................................. Disorders of Energy Metabolism ................................................................................................................ Specific Approaches to Neurometabolic Presentations in Adults ........................................... Encephalopathies/Comas ............................................................................................................................. Strokes and Pseudo-Strokes ......................................................................................................................... Movement Disorders ...................................................................................................................................... Peripheral Neuropathies................................................................................................................................ Leukoencephalopathies ................................................................................................................................ Epilepsy................................................................................................................................................................ Psychiatric Disorders ....................................................................................................................................... Spastic Paraparesis........................................................................................................................................... Cerebellar Ataxia .............................................................................................................................................. Myopathy ............................................................................................................................................................ Sensorial Disorders .......................................................................................................................................... References............................................................................................................................................................

126 128 128 130 130 130 130 131 131 131 132 134 136 136 136 138 140 140 143 144

Diagnostic Procedures....................................................................................................................

147

Guy Touati, Fanny Mochel, and Rafael Artuch 3.1 3.1.1

Basal Metabolic Investigation .............................................................................................................. Amino and Organic Acids .............................................................................................................................

148 148

IX Contents

3.1.2 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.3 3.4 3.5 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5

4

Metabolic Profile over the Course of the Day ........................................................................................ Functional Tests ........................................................................................................................................ Fasting Test ......................................................................................................................................................... Oral Glucose Loading Test ............................................................................................................................. Glucagon Test .................................................................................................................................................... Exercise Test........................................................................................................................................................ Metabolomic Analyses for Diagnosis of IEM ................................................................................... Next Generation Sequencing and Gene Panels ............................................................................. Postmortem Protocol .............................................................................................................................. Cells and Tissues for Enzyme Assays ......................................................................................................... Cells and Tissues for Chromosome and DNA Investigations ............................................................ Skin Fibroblasts ................................................................................................................................................. Body Fluids for Chemical Investigations .................................................................................................. Autopsy ................................................................................................................................................................ References............................................................................................................................................................

148 158 158 161 161 162 162 163 164 164 164 164 164 164 165

Emergency Treatments ..................................................................................................................

167

Manuel Schiff, Fanny Mochel, and Carlo Dionisi-Vici 4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.3

General Principles .................................................................................................................................... Supportive Care ................................................................................................................................................ Nutrition .............................................................................................................................................................. Specific Therapies............................................................................................................................................. Extracorporeal Procedures for Toxin Removal ....................................................................................... Emergency Management of Particular Clinical Presentations ................................................. Neurological Deterioration ........................................................................................................................... Liver Failure ........................................................................................................................................................ Neonatal Hypoglycaemia .............................................................................................................................. Cardiac Failure ................................................................................................................................................... Primary Hyperlactataemia ............................................................................................................................ Intractable Seizures ......................................................................................................................................... Final Considerations ................................................................................................................................ References............................................................................................................................................................

II

Disorders of Energy Metabolism

5

The Glycogen Storage Diseases and Related Disorders ...........................................

168 168 168 168 169 169 169 173 173 174 174 174 175 175

179

John H. Walter, Philippe Labrune, and Pascal Laforêt 5.1 5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.1.7 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6 5.2.7

Hepatic Glycogenoses ............................................................................................................................ Glycogen Synthase 2 Deficiency (GSD 0a) .............................................................................................. Glycogen Storage Disease Type I (GSD I) ................................................................................................. Glycogen Storage Disease Type III (GSD III) ............................................................................................ Glycogen Storage Disease Type IV (GSD IV) ........................................................................................... Glycogen Storage Disease Type VI (GSD VI) ............................................................................................ Glycogen Storage Disease Type IX (GSD IX)............................................................................................ Fanconi-Bickel Syndrome .............................................................................................................................. Muscle and Cardiac Glycogenoses ..................................................................................................... Glycogen Storage Disease Type V (Myophosphorylase Deficiency, McArdle Disease) ........... Disorders of Glycolysis.................................................................................................................................... Glycogen Storage Disease Type II (Pompe Disease) ............................................................................ Danon Disease (LAMP-2 Deficiency) ......................................................................................................... Glycogen Depletion Syndromes: Muscle Glycogen Synthase Deficiency (Muscle GSD Type 0, GSD 0b) and Glycogenin 1 Deficiency ............................................................ Muscle and Cardiac Glycogenosis with Polyglucosan Bodies Due to RBCK1 and GYG1 Mutations ........................................................................................................... AMP-Activated Protein Kinase (AMPK) Deficiency ...............................................................................

181 181 183 186 187 188 189 190 190 190 191 191 193 193 195 195

X

Contents

5.3 5.3.1 5.3.2

Brain Glycogenoses ................................................................................................................................. Lafora Disease (Neuronal Laforin/Malin Defects) ................................................................................. Adult Polyglucosan Body Disease .............................................................................................................. References............................................................................................................................................................

196 196 196 197

6

Congenital Hyperinsulinism and Genetic Disorders of Insulin Resistance and Signalling .....................................................................................

201

Jean-Baptiste Arnoux and Pascale de Lonlay 6.1 6.2 6.3 6.4 6.5 6.6

7

Clinical Presentation ............................................................................................................................... Metabolic Derangement........................................................................................................................ Genetics ....................................................................................................................................................... Diagnostic Tests ........................................................................................................................................ Treatment.................................................................................................................................................... Prognosis..................................................................................................................................................... References............................................................................................................................................................

203 204 204 205 206 207 207

Disorders of Glycolysis and the Pentose Phosphate Pathway .............................

209

Mirjam M. C. Wamelink, Vassili Valayannopoulos, and Barbara Garavaglia 7.1 7.1.1 7.1.2 7.1.3 7.1.4 7.1.5 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.3 7.3.1 7.3.2 7.3.3 7.3.4 7.3.5 7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5 7.5 7.5.1 7.5.2 7.5.3 7.5.4 7.5.5 7.6 7.6.1 7.6.2 7.6.3 7.6.4 7.6.5 7.7

Muscle Phosphofructokinase (PFKM) Deficiency .......................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Aldolase A (ALDOA) Deficiency ........................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Triosephosphate Isomerase (TPI) Deficiency .................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Phosphoglycerate Kinase (PGK) Deficiency .................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Phosphoglycerate Mutase (PGAM) Deficiency............................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Enolase Deficiency ................................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Lactate Dehydrogenase (LDH) Deficiency .......................................................................................

212 212 212 214 214 214 214 214 214 214 214 214 215 215 215 215 215 215 215 215 215 216 216 216 216 216 216 216 217 217 217 217 217 217 217 217 217

XI Contents

7.7.1 7.7.2 7.7.3 7.7.4 7.7.5 7.8 7.8.1 7.8.2 7.8.3 7.8.4 7.8.5 7.9 7.9.1 7.9.2 7.9.3 7.9.4 7.9.5 7.10 7.10.1 7.10.2 7.10.3 7.10.4 7.10.5 7.11 7.11.1 7.11.2 7.11.3 7.11.4 7.11.5 7.12 7.12.1 7.12.2 7.12.3 7.12.4 7.12.5

8

Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Glycerol Kinase Deficiency (GKD)........................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Ribose-5-Phosphate Isomerase (RPI) Deficiency ........................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Transaldolase (TALDO) Deficiency...................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Transketolase (TKT) Deficiency ........................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Sedoheptulokinase (SHPK) Deficiency ............................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. References............................................................................................................................................................

217 217 217 218 218 218 218 218 218 218 219 219 219 219 219 220 220 220 220 220 220 220 221 221 221 221 221 222 222 222 222 222 222 222 222 222

Disorders of Glucose and Monocarboxylate Transporters .....................................

225

René Santer and Joerg Klepper 8.1 8.1.1 8.1.2 8.1.3 8.1.4 8.1.5 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 8.3 8.3.1 8.3.2 8.3.3 8.3.4

Congenital Glucose/Galactose Malabsorption (SGLT1 Deficiency)......................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Renal Glucosuria (SGLT2 Deficiency) ................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Glucose Transporter-1 Deficiency Syndrome (GLUT1DS) ........................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................

228 228 228 228 229 229 229 229 229 229 229 229 230 230 230 230 230

XII

Contents

8.3.5 8.4

Treatment and Prognosis .............................................................................................................................. Intellectual Developmental Disorder with Neuropsychiatric Features (PAST-A Deficiency)................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Fanconi-Bickel Syndrome (GLUT2 Deficiency) ............................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Other Defects of Glucose Transporters ............................................................................................. Monocarboxylate Transporter-1 Deficiency (MCT1 Deficiency) .............................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Exercise-Induced Hyperinsulinism (β-Cell MCT1 Overexpression) ......................................... Allan-Herndon-Dudley Syndrome (MCT8 Deficiency)................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Familial Cataract, Microcornea Syndrome (MCT12 Deficiency) ............................................... References............................................................................................................................................................

231 231 231 232 232 232 232 232 232 233 233 233 233 234 234 234 235 235 235 235 235 235 235 235 235 236 236 236

Disorders of Creatine Metabolism ..........................................................................................

239

8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.5 8.5.1 8.5.2 8.5.3 8.5.4 8.5.5 8.6 8.7 8.7.1 8.7.2 8.7.3 8.7.4 8.7.5 8.8 8.9 8.9.1 8.9.2 8.9.3 8.9.4 8.9.5 8.10

9

231

Sylvia Stöckler-Ipsiroglu, Saadet Mercimek-Andrews, and Gajja S. Salomons 9.1 9.1.1 9.1.2 9.1.3 9.1.4 9.2 9.3 9.4 9.4.1 9.4.2 9.4.3 9.4.4 9.4.5 9.4.6 9.5 9.5.1 9.5.2 9.5.3 9.5.4

Clinical Presentation ............................................................................................................................... Arginine: Glycine Amidinotransferase (AGAT) Deficiency ................................................................. Guanidinoacetate Methyltransferase (GAMT) Deficiency ................................................................. Creatine Transporter (CRTR) Deficiency ................................................................................................... Autosomal Dominant Renal Fanconi syndrome and Kidney Failure Due to Partial AGAT Deficiency ................................................................................................................... Metabolic Derangement........................................................................................................................ Genetics ....................................................................................................................................................... Diagnostic Tests ........................................................................................................................................ In Vivo Brain MRS and MRI ............................................................................................................................ Metabolite Analysis ......................................................................................................................................... Molecular Genetic Investigations............................................................................................................... Biochemical Functional Investigations..................................................................................................... Prenatal Diagnosis ........................................................................................................................................... Newborn Screening ........................................................................................................................................ Treatment and Prognosis ...................................................................................................................... AGAT Deficiency ............................................................................................................................................... GAMT Deficiency .............................................................................................................................................. CRTR Deficiency ................................................................................................................................................ Autosomal Dominant Renal Fanconi syndrome and Kidney Failure Due to Dominant GATM Variants.................................................................................................. References............................................................................................................................................................

241 241 241 241 242 242 242 243 243 243 243 243 243 243 244 244 244 244 244 244

XIII Contents

10

Disorders of Oxidative Phosphorylation............................................................................

247

Shamima Rahman and Johannes A. Mayr 10.1 10.1.1 10.1.2 10.1.3 10.2 10.3 10.3.1 10.3.2 10.3.3 10.4 10.4.1 10.4.2 10.4.3 10.5 10.5.1 10.5.2 10.5.3 10.5.4 10.5.5 10.5.6

11

Clinical Presentation ............................................................................................................................... Neonatal and Infantile Presentations ....................................................................................................... Presentation in Childhood and Adolescence......................................................................................... Adult-Onset Disorders .................................................................................................................................... Metabolic Derangement........................................................................................................................ Genetics ....................................................................................................................................................... Mitochondrial DNA Mutations .................................................................................................................... Nuclear Gene Defects ..................................................................................................................................... Frequency of Mutations................................................................................................................................. Diagnostic Tests ........................................................................................................................................ Screening Tests.................................................................................................................................................. Muscle and Other Tissue Biopsies .............................................................................................................. Molecular Genetic Investigations............................................................................................................... Treatment and Prognosis ...................................................................................................................... Treatable Disorders.......................................................................................................................................... Supportive Management .............................................................................................................................. Vitamin and Cofactor Cocktails ................................................................................................................... Experimental Approaches............................................................................................................................. Genetic Counselling and Prenatal and Preimplantation Genetic Diagnosis .............................. Prognosis ............................................................................................................................................................. References............................................................................................................................................................

249 250 255 256 257 258 258 258 261 261 261 262 264 265 265 265 265 266 266 266 266

Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle ..............

269

Michèle Brivet, Pauline Gaignard, and Manuel Schiff 11.1 11.1.1 11.1.2 11.1.3 11.1.4 11.1.5 11.2 11.3 11.3.1 11.3.2 11.3.3 11.3.4 11.3.5 11.4 11.4.1 11.4.2 11.4.3 11.4.4 11.4.5 11.5 11.5.1 11.5.2 11.5.3 11.5.4 11.5.5 11.6 11.7 11.8 11.9 11.10

Pyruvate Carboxylase (PC) Deficiency .............................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Phosphoenolpyruvate Carboxykinase (PEPCK) Deficiency ....................................................... Pyruvate Dehydrogenase Complex (PDHC) Deficiency .............................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Dihydrolipoamide Dehydrogenase (DLD) Deficiency.................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. 2-Ketoglutarate Dehydrogenase Complex (KDHC) Deficiency................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Succinyl-CoA Ligase (SUCL) Deficiency............................................................................................. Succinate Dehydrogenase (SDH) Deficiency .................................................................................. Fumarase (FH) Deficiency ...................................................................................................................... Mitochondrial Aconitase (ACO) deficiency ...................................................................................... Mitochondrial Isocitrate Dehydrogenase (IDH) deficiency........................................................

273 273 273 274 274 275 275 276 276 277 277 278 278 279 279 279 279 279 279 279 279 280 280 280 280 280 280 281 281 282

XIV

Contents

11.11 11.12 11.13 11.14 11.15

Malate-Aspartate Shuttle (MAS) defects .......................................................................................... Mitochondrial Citrate Carrier Deficiency ......................................................................................... Mitochondrial Pyruvate Carrier (MPC) deficiency......................................................................... NAD(P)HX System Repair Defects ....................................................................................................... Protein-Bound Lipoic Acid Defects and Defects in Cofactors ................................................... References............................................................................................................................................................

282 282 282 283 283 283

12

Disorders of Mitochondrial Fatty Acid Oxidation & Riboflavin Metabolism...............................................................................................................

287

Andrew A. M. Morris and Ute Spiekerkoetter 12.1 12.1.1 12.1.2 12.1.3 12.1.4 12.1.5 12.2 12.2.1 12.2.2 12.2.3

13

Disorders of Mitochondrial Fatty Acid Oxidation.......................................................................... Clinical Presentations...................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Defects of Riboflavin Transport & Metabolism .............................................................................. Riboflavin Transporter Deficiencies ........................................................................................................... RFVT1 Deficiency.............................................................................................................................................. FAD Synthase and Mitochondrial FAD Transporter Deficiencies .................................................... References............................................................................................................................................................

288 288 293 293 294 296 298 299 299 299 300

Disorders of Ketogenesis and Ketolysis ..............................................................................

303

Andrew A. M. Morris 13.1 13.1.1 13.1.2 13.1.3 13.1.4 13.1.5 13.2 13.2.1 13.2.2 13.2.3 13.2.4 13.2.5 13.3 13.4 13.4.1 13.4.2 13.4.3 13.4.4 13.5 13.6

Ketogenesis Defects ................................................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Defects of Ketone Body Utilisation or Transport ........................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Cytosolic Acetoacetyl-CoA Thiolase Deficiency ............................................................................. “Idiopathic“ Ketotic Hypoglycaemia ................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Ketogenic Diets ......................................................................................................................................... Therapeutic Use of Ketone Bodies and Ketone Esters ................................................................. References............................................................................................................................................................

III

Small Molecule Disorders

14

Disorders of Galactose Metabolism ......................................................................................

304 304 304 305 306 306 306 306 307 307 307 308 308 308 308 309 309 309 309 310 310

315

Gerard T. Berry, John H. Walter, and Judith L. Fridovich-Keil 14.1 14.1.1 14.1.2 14.1.3

Galactose-1-Phosphate Uridylyltransferase (GALT) Deficiency ............................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ...............................................................................................................................................................

317 317 318 318

XV Contents

14.1.4 14.1.5 14.2 14.2.1 14.2.2 14.2.3 14.2.4 14.2.5 14.3 14.3.1 14.3.2 14.3.3 14.3.4 14.3.5 14.4 14.5 14.6

15

Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Uridine Diphosphate Galactose 4′-Epimerase (GALE) Deficiency ........................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Galactokinase (GALK) Deficiency........................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Galactose Mutarotase (GALM) Deficiency ....................................................................................... Fanconi-Bickel Syndrome ...................................................................................................................... Portosystemic Venous Shunting and Hepatic Arteriovenous Malformations ..................... References............................................................................................................................................................

318 319 321 321 321 322 322 322 322 322 322 322 323 323 323 324 324 324

Disorders of Fructose Metabolism .........................................................................................

327

Beat Steinmann and René Santer 15.1 15.1.1 15.1.2 15.1.3 15.1.4 15.1.5 15.1.6 15.2 15.2.1 15.2.2 15.2.3 15.2.4 15.2.5 15.2.6 15.3 15.3.1 15.3.2 15.3.3 15.3.4 15.3.5 15.3.6 15.4 15.4.1 15.4.2 15.4.3 15.4.4 15.4.5

16

Essential Fructosuria ............................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnosis ............................................................................................................................................................. Differential Diagnosis ..................................................................................................................................... Treatment and Prognosis .............................................................................................................................. Hereditary Fructose Intolerance ......................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnosis ............................................................................................................................................................. Differential Diagnosis ..................................................................................................................................... Treatment and Prognosis .............................................................................................................................. Fructose-1,6-Bisphosphatase Deficiency ......................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnosis ............................................................................................................................................................. Differential Diagnosis ..................................................................................................................................... Treatment and Prognosis .............................................................................................................................. Sorbitol Dehydrogenase Deficiency .................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnosis ............................................................................................................................................................. Treatment and Prognosis .............................................................................................................................. References............................................................................................................................................................

329 329 329 329 329 329 330 330 330 330 330 331 331 332 332 332 333 333 334 334 334 334 335 335 335 335 335 335

Hyperphenylalaninaemia .............................................................................................................

337

Peter Burgard, Robin H. Lachmann, and John H. Walter 16.1 16.1.1 16.1.2 16.1.3

Phenylalanine Hydroxylase Deficiency............................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ...............................................................................................................................................................

339 339 339 339

XVI

Contents

16.1.4 16.1.5 16.2 16.2.1 16.2.2 16.2.3 16.2.4 16.2.5 16.3 16.3.1 16.3.2 16.3.3 16.4 16.4.1 16.4.2 16.4.3 16.4.4 16.4.5

Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. DNAJC12 Deficiency................................................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic and Confirmatory Tests............................................................................................................ Treatment and Prognosis .............................................................................................................................. Maternal PKU ............................................................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Treatment and Prognosis .............................................................................................................................. HPA and Disorders of Biopterin Metabolism .................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic and Confirmatory Tests............................................................................................................ Treatment and Prognosis .............................................................................................................................. References............................................................................................................................................................

340 340 346 346 346 346 346 346 346 346 347 347 348 348 348 348 348 349 351

Disorders of Tyrosine Metabolism ..........................................................................................

355

17

Anupam Chakrapani, Paul Gissen, and Patrick McKiernan 17.1 17.1.1 17.1.2 17.1.3 17.1.4 17.1.5 17.2 17.2.1 17.2.2 17.2.3 17.2.4 17.3 17.3.1 17.3.2 17.3.3 17.3.4 17.3.5 17.4 17.4.1 17.4.2 17.4.3 17.4.4 17.4.5 17.5 17.6 17.6.1 17.6.2 17.6.3 17.6.4 17.6.5

Hereditary Tyrosinaemia Type I (Hepatorenal Tyrosinaemia): Fumarylacetoacetate Hydrolase Deficiency.................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Maleylacetoacetate Isomerase Deficiency (Mild Hypersuccinylacetonaemia, MHSA) ..... Clinical Presentation ....................................................................................................................................... Metabolic Derangement and Genetics .................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Hereditary Tyrosinaemia Type II (Oculocutaneous Tyrosinaemia, Richner-Hanhart Syndrome): Hepatic Cytosolic Tyrosine Aminotransferase Deficiency .................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Hereditary Tyrosinaemia Type III: 4-hydroxyphenylpyruvate Dioxygenase Deficiency......................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Transient Tyrosinaemia .......................................................................................................................... Alkaptonuria: Homogentisate Dioxygenase Deficiency............................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis ..............................................................................................................................

357 357 358 359 359 360 361 361 361 362 362 362 362 362 363 363 363 363 363 363 363 364 364 364 364 364 365 365 365 365

XVII Contents

17.7 17.7.1 17.7.2 17.7.3 17.7.4 17.7.5

18

Hawkinsinuria............................................................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. References............................................................................................................................................................

365 365 365 366 366 366 366

Branched-Chain Organic Acidurias/Acidaemias ...........................................................

369

Manuel Schiff, Anaïs Brassier, and Carlo Dionisi-Vici 18.1 18.1.1 18.1.2 18.1.3 18.1.4 18.1.5 18.2 18.2.1 18.2.2 18.2.3 18.2.4 18.2.5 18.3 18.4 18.5 18.6 18.7 18.8 18.9 18.10

19

Maple Syrup Urine Disease, Isovaleric Aciduria, Propionic Aciduria, Methylmalonic Aciduria ......................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. 3-Methylcrotonyl Glycinuria ................................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. 3-Methylglutaconic Aciduria ................................................................................................................ Short/Branched Chain Acyl-CoA Dehydrogenase Deficiency ................................................... 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency .................................................. Isobutyryl-CoA Dehydrogenase Deficiency .................................................................................... 3-Hydroxyisobutyric Aciduria .............................................................................................................. Malonyl-CoA Decarboxylase Deficiency........................................................................................... ACSF3 Deficiency...................................................................................................................................... Short-Chain Enoyl-CoA Hydratase 1 (ECHS1) Deficiency ........................................................... References............................................................................................................................................................

371 371 374 375 376 376 382 382 382 382 382 382 383 384 384 384 384 385 385 385 386

Disorders of the Urea Cycle and Related Enzymes ......................................................

391

Johannes Häberle and Vicente Rubio 19.1 19.2 19.3 19.3.1 19.3.2 19.4 19.4.1 19.4.2 19.5

Mitochondrial Urea Cycle Disorders .................................................................................................. Cytosolic Urea Cycle Disorders ............................................................................................................ Urea Cycle Mitochondrial Transporter Defects .............................................................................. Hyperornithinemia, Hyperammonaemia and Homocitrullinuria (HHH) Syndrome ................ Citrin Deficiency ............................................................................................................................................... Urea Cycle Defects Due to Deficiencies of Ancillary Enzymes .................................................. Δ1-Pyrroline-5-Carboxylate Synthetase (P5CS) Deficiency............................................................... Carbonic Anhydrase Va (CAVA) Deficiency.............................................................................................. Transient Hyperammonaemia of the Newborn (THAN).............................................................. References............................................................................................................................................................

392 397 400 400 400 402 402 402 403 403

20

Disorders of Sulfur Amino Acid Metabolism ...................................................................

407

20.1 20.1.1 20.1.2 20.1.3 20.1.4 20.1.5

Methionine S-Adenosyltransferase Deficiency (Mudd’s Disease) ........................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis ..............................................................................................................................

Viktor Kožich, Andrew A. M. Morris, and Henk J. Blom 409 409 411 411 411 412

XVIII

Contents

20.2 20.2.1 20.2.2 20.2.3 20.2.4 20.2.5 20.3 20.3.1 20.3.2 20.3.3 20.3.4 20.3.5 20.4 20.4.1 20.4.2 20.4.3 20.4.4 20.4.5 20.5 20.6 20.6.1 20.6.2 20.6.3 20.6.4 20.6.5 20.7 20.7.1 20.7.2 20.7.3 20.7.4 20.7.5 20.8 20.8.1 20.8.2 20.8.3 20.8.4 20.8.5 20.9 20.9.1 20.9.2 20.9.3 20.9.4 20.9.5 20.10 20.10.1 20.10.2 20.10.3 20.10.4 20.10.5 20.11 20.11.1 20.11.2 20.11.3 20.11.4 20.11.5

Methanethiol Oxidase Deficiency ...................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Glycine N-Methyltransferase Deficiency .......................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. S-Adenosylhomocysteine Hydrolase Deficiency ........................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Adenosine Kinase Deficiency ............................................................................................................... Cystathionine β-Synthase Deficiency ................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Cystathionine γ-Lyase Deficiency ....................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Sulfide:Quinone Oxidoreductase Deficiency.................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Ethylmalonic Encephalopathy ............................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Molybdenum Cofactor Deficiency...................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Isolated Sulfite Oxidase Deficiency .................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. References............................................................................................................................................................

413 413 413 413 413 413 413 413 413 413 413 413 414 414 414 414 414 414 414 414 414 415 415 416 416 418 418 418 418 418 418 418 418 418 419 419 419 419 419 419 419 419 419 419 419 420 420 420 420 420 420 421 421 421 421 421

XIX Contents

21

Disorders of Ornithine and Proline Metabolism ...........................................................

423

Matthias R. Baumgartner, David Valle, and Carlo Dionisi-Vici 21.1 21.1.1 21.1.2 21.1.3 21.1.4 21.1.5 21.2 21.2.1 21.2.2 21.2.3 21.2.4 21.2.5 21.3 21.3.1 21.3.2 21.3.3 21.3.4 21.3.5 21.4 21.5 21.5.1 21.5.2 21.5.3 21.5.4 21.5.5 21.6 21.6.1 21.6.2 21.6.3 21.6.4 21.6.5 21.7 21.8 21.9

22

Hyperornithinaemia Due to Ornithine Aminotransferase Deficiency (Gyrate Atrophy of the Choroid and Retina) ................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Hyperornithinaemia, Hyperammonaemia and Homocitrullinuria (HHH) Syndrome ....... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Δ1-Pyrroline-5-Carboxylate Synthetase Deficiency .................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Δ1-Pyrroline-5-Carboxylate Reductase Deficiency 1 (PYCR1) and 2 (PYCR2) ..................... Proline Dehydrogenase (Proline Oxidase) Deficiency (Hyperprolinaemia Type I)............. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Δ1-Pyrroline-5-Carboxylate Dehydrogenase Deficiency (Hyperprolinaemia Type II) ..... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Polyamine Synthetic Defects................................................................................................................ Ornithine Decarboxylase (ODC) Superactivity Syndrome ......................................................... Spermine Synthase Deficiency (Snyder Robinson Syndrome) ................................................. References............................................................................................................................................................

426 426 427 427 427 428 428 428 430 430 430 430 431 431 431 432 432 432 432 432 432 432 433 433 433 433 433 433 433 433 433 433 434 434 434

Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism..............................................................................................................................................

437

Stefan Kölker and Georg F. Hoffmann 22.1 22.1.1 22.1.2 22.1.3 22.1.4 22.1.5 22.2 22.3 22.3.1 22.3.2 22.3.3 22.3.4 22.3.5

Hyperlysinaemia (2-Aminoadipic Semialdehyde Synthase Deficiency)/Saccharopinuria ................................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Hydroxylysinuria (Hydroxylysine Kinase Deficiency) .................................................................. 2-Aminoadipic and 2-Oxoadipic Aciduria (DHTKD1 Deficiency) ............................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis ..............................................................................................................................

443 443 443 443 443 446 446 446 446 446 446 446 446

XX

Contents

22.4 22.4.1 22.4.2 22.4.3 22.4.4 22.4.5 22.5 22.6

Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase Deficiency) ....................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Glutaric Aciduria Type II (Multiple Acyl-CoA Dehydrogenase Deficiency) ........................... Glutaric Aciduria Type III (Succinate Hydroxymethylglutarate CoA-Transferase Deficiency) ................................................................................................................. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. L-2-Hydroxyglutaric Aciduria (L-2-Hydroxyglutaric Dehydrogenase Deficiency).............. Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. D-2-Hydroxyglutaric Aciduria Type I (D-2-Hydroxyglutarate Dehydrogenase Deficiency) and Type II (Isocitrate Dehydrogenase 2 Deficiency) ........... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. D-2- and L-2-Hydroxyglutaric Aciduria (Mitochondrial Citrate Carrier or SLC25A1 Deficiency) .......................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. N-Acetylaspartic Aciduria (Aspartoacylase or Aminoacylase 2 Deficiency) (Canavan Disease) .................................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Aminoacylase 1 Deficiency ................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Hypoacetylaspartia (L-Aspartate N-Acetyltransferase Deficiency) ......................................... Malate-Aspartate Shuttle Defects ...................................................................................................... References............................................................................................................................................................

22.6.1 22.6.2 22.6.3 22.6.4 22.6.5 22.7 22.7.1 22.7.2 22.7.3 22.7.4 22.7.5 22.8 22.8.1 22.8.2 22.8.3 22.8.4 22.8.5 22.9 22.9.1 22.9.2 22.9.3 22.9.4 22.9.5 22.10 22.10.1 22.10.2 22.10.3 22.10.4 22.10.5 22.11 22.11.1 22.11.2 22.12 22.13

23

Nonketotic Hyperglycinaemia and Lipoate Deficiency Disorders ....................

447 447 448 448 448 449 450 450 450 451 451 451 451 451 451 451 451 451 452 452 452 452 452 452 452 453 453 453 453 453 453 453 453 454 454 455 455 455 455 455 455 455 456 459

Johan L. K. Van Hove and Rudy Van Coster 23.1 23.2 23.2.1 23.2.2 23.2.3 23.3

Definition .................................................................................................................................................... Clinical Presentation ............................................................................................................................... Severe Classic NKH........................................................................................................................................... Attenuated Classic NKH ................................................................................................................................. Lipoate Disorders Including Variant NKH ................................................................................................ Metabolic Abnormalities .......................................................................................................................

460 461 461 463 463 464

XXI Contents

23.4 23.5 23.6 23.7

24

Genetics ....................................................................................................................................................... Diagnostic Tests ........................................................................................................................................ Treatment.................................................................................................................................................... Prognosis..................................................................................................................................................... References............................................................................................................................................................

465 466 467 468 468

Disorders of Glutamine, Serine and Asparagine Metabolism ..............................

471

Jaak Jaeken, Johannes Häberle, and Olivier Dulac 24.1 24.1.1 24.1.2 24.1.3 24.1.4 24.2 24.2.1 24.2.2 24.2.3 24.2.4 24.2.5 24.3 24.3.1

25

Inborn Errors of Glutamine Metabolism .......................................................................................... Glutamine Synthetase Deficiency .............................................................................................................. NAD Synthesis Defect ..................................................................................................................................... Glutaminase Deficiency ................................................................................................................................. Glutaminase Hyperactivity ........................................................................................................................... Inborn Errors of Serine Metabolism ................................................................................................... 3-Phosphoglycerate Dehydrogenase Deficiency ................................................................................. Phosphoserine Aminotransferase Deficiency ........................................................................................ 3-Phosphoserine Phosphatase Deficiency ............................................................................................. Brain Serine Transporter Deficiency .......................................................................................................... Serine Palmitoyltransferase Defects .......................................................................................................... Inborn Errors of Asparagine Metabolism ......................................................................................... Asparagine Synthetase Deficiency ............................................................................................................ References............................................................................................................................................................

474 474 475 475 475 475 475 476 476 476 477 477 477 478

Disorders of Amino Acid Transport at the Cell Membrane .....................................

481

Harri Niinikoski, Manuel Schiff, and Laura Tanner 25.1 25.1.1 25.1.2 25.1.3 25.1.4 25.1.5 25.2 25.3 25.3.1 25.3.2 25.3.3 25.3.4 25.3.5 25.4 25.4.1 25.4.2 25.4.3 25.4.4 25.4.5 25.5 25.6 25.7 25.8

Cystinuria .................................................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Asymptomatic Amino Acidurias: Iminoglycinuria and Dicarboxylic Amino Aciduria ...... Lysinuric Protein Intolerance................................................................................................................ Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Hartnup Disease ....................................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Collectrin Deficiency ............................................................................................................................... SLC7A5/Brain Neutral Amino Acid Transporter Deficiency........................................................ SLC7A8/LAT2 Neutral Amino Acid Transporter Deficiency ........................................................ SLC6A6/Taurine Transporter Deficiency ........................................................................................... References............................................................................................................................................................

483 483 483 483 485 485 486 486 486 487 487 488 488 489 489 489 489 489 490 490 490 490 490 490

26

Cystinosis.................................................................................................................................................

493

26.1 26.1.1 26.1.2 26.1.3

Infantile Cystinosis ................................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ...............................................................................................................................................................

Patrick Niaudet 494 494 496 496

XXII

Contents

26.1.4 26.1.5 26.2 26.3

Diagnostic Tests ................................................................................................................................................ Treatment............................................................................................................................................................ Late-Onset Cystinosis ............................................................................................................................. Ocular Cystinosis ...................................................................................................................................... References............................................................................................................................................................

496 497 498 498 498

Biotin-Responsive Disorders ......................................................................................................

501

27

D. Sean Froese and Matthias R. Baumgartner 27.1 27.1.1 27.1.2 27.1.3 27.1.4 27.2 27.3 27.3.1 27.3.2 27.3.3 27.4 27.4.1 27.4.2 27.4.3 27.4.4 27.5 27.5.1 27.5.2 27.5.3

28

Clinical Presentation ............................................................................................................................... Holocarboxylase Synthetase Deficiency.................................................................................................. Biotinidase Deficiency .................................................................................................................................... Sodium-Dependent Multivitamin Transporter Deficiency (SLC5A6)............................................. Acquired Biotin Deficiency ........................................................................................................................... Metabolic Derangement........................................................................................................................ Genetics ....................................................................................................................................................... Holocarboxylase Synthetase Deficiency.................................................................................................. Biotinidase Deficiency .................................................................................................................................... SLC5A6 Deficiency ........................................................................................................................................... Diagnostic Tests ........................................................................................................................................ Holocarboxylase Synthetase Deficiency.................................................................................................. Biotinidase Deficiency .................................................................................................................................... SLC5A6 Deficiency ........................................................................................................................................... Prenatal Diagnosis ........................................................................................................................................... Treatment and Prognosis ...................................................................................................................... Holocarboxylase Synthetase Deficiency.................................................................................................. Biotinidase Deficiency .................................................................................................................................... SLC5A6 Deficiency ........................................................................................................................................... References............................................................................................................................................................

503 503 504 504 505 505 505 505 506 506 506 506 507 507 507 507 507 508 508 508

Disorders of Cobalamin and Folate Transport and Metabolism .........................

511

Brian Fowler, D. Sean Froese, and David Watkins 28.1 28.1.1 28.1.2 28.1.3 28.1.4 28.1.5 28.2 28.2.1 28.2.2 28.2.3 28.3 28.3.1 28.3.2 28.3.3 28.3.4 28.3.5 28.3.6 28.3.7 28.3.8 28.3.9 28.3.10

Disorders of Absorption and Transport of Cobalamin ................................................................ Hereditary Intrinsic Factor Deficiency ...................................................................................................... Defective Transport of Cobalamin by Enterocytes (Imerslund-Gräsbeck Syndrome) ............. Haptocorrin (R Binder) Deficiency.............................................................................................................. Transcobalamin Deficiency .......................................................................................................................... Transcobalamin Receptor Deficiency ....................................................................................................... Disorders of Intracellular Utilisation of Cobalamin ...................................................................... Combined Deficiencies of Adenosylcobalamin and Methylcobalamin ....................................... Adenosylcobalamin Deficiency: CblA (MMAA) & CblB (MMAB) ....................................................... Methylcobalamin Deficiency: CblE (MTRR) & CblG (MTR) .................................................................. Disorders of Absorption and Metabolism of Folate ..................................................................... Hereditary Folate Malabsorption (Proton-Coupled Folate Transporter Deficiency, SLC46A1) ....................................................................................................................................... Cerebral Folate Deficiency (Folate Receptor α Deficiency, FOLR1) ................................................. Reduced Folate Carrier Deficiency (SLC19A1) ........................................................................................ Methylenetetrahydrofolate Dehydrogenase Deficiency (MTHFD1)............................................... Dihydrofolate Reductase Deficiency (DHFR) .......................................................................................... Glutamate Formiminotransferase Deficiency (FTCD) .......................................................................... Methylenetetrahydrofolate Reductase Deficiency (MTHFR)............................................................. Methenyltetrahydrofolate Synthetase Deficiency (MTHFS) .............................................................. 10-Formyltetrahydrofolate Dehydrogenase Deficiency (ALDH1L2) ............................................... Serine Hydroxymethyltransferase 2 Deficiency (SHMT2)................................................................... References............................................................................................................................................................

513 513 513 514 514 515 516 516 519 520 522 522 522 523 523 523 524 524 525 526 526 526

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29

Disorders of Thiamine and Pyridoxine Metabolism ...................................................

531

Garry Brown and Barbara Plecko 29.1 29.1.1 29.1.2 29.1.3

29.1.4 29.1.5 29.1.6 29.1.7 29.2 29.2.1 29.2.2 29.2.3 29.2.4 29.2.5 29.2.6 29.2.7

30

Disorders of Thiamine (vitamin B1) Metabolism ............................................................................ Thiamine Metabolism Dysfunction Syndrome 1 (SLC19A2, THTR1 Deficiency)......................... Thiamine Metabolism Dysfunction Syndrome 2 (SLC19A3, THTR2 Deficiency)......................... Thiamine Metabolism Dysfunction Syndrome 3 (Microcephaly, Amish Type) and Thiamine Metabolism Dysfunction Syndrome 4 (Bilateral Striatal Degeneration and Progressive Polyneuropathy Type): Mitochondrial TPP Transporter deficiency (SLC25A19) .................................................................................................... Thiamine Metabolism Dysfunction Syndrome 5 (Episodic Encephalopathy Type, TPK1 Deficiency) ............................................................................................................................................... Thiamine-Responsive α-ketoacid Dehydrogenase Deficiencies ..................................................... Thiamine-Responsive Pyruvate Dehydrogenase Deficiency............................................................ Thiamine-Responsive Maple Syrup Urine Disease ............................................................................... Disorders of Pyridoxine Metabolism ................................................................................................. Antiquitin Deficiency (ALDH7A1) ................................................................................................................ Hyperprolinemia Type II................................................................................................................................. Pyridox(am)ine 5’-phosphate Oxidase (PNPO) Deficiency................................................................ Congenital Hypophosphatasia (Tissue Non Specific Alkaline Phosphatase) ............................. Hyperphosphatasia-Mental Retardation Syndrome (HPMRS) ......................................................... PLP Binding protein (PLPBP, Formerly PROSC) Deficiency ................................................................ Other B6 Responsive Disorders .................................................................................................................... References............................................................................................................................................................

532 533 534

Disorders of Neurotransmission ..............................................................................................

547

535 535 536 536 536 537 539 541 541 542 542 542 543 543

Ángeles García-Cazorla, Rafael Artuch, and Phillip L. Pearl 30.1 30.1.1 30.1.2 30.1.3 30.1.4 30.1.5 30.2 30.2.1 30.2.2 30.3 30.4 30.5 30.5.1 30.5.2 30.5.3 30.5.4 30.5.5 30.5.6 30.5.7 30.5.8 30.5.9 30.6 30.6.1 30.6.2

Gamma Amino Butyric Acid (GABA) Neurotransmitter Disorders........................................... Gamma Amino Butyric Acid Transaminase Deficiency....................................................................... Succinic Semialdehyde Dehydrogenase Deficiency ........................................................................... Glutamic Acid Decarboxylase (GAD) Deficiency ................................................................................... GABA Receptor Mutations ............................................................................................................................ GABA Transporter Deficiency....................................................................................................................... Glutamate Neurotransmitter Disorders ........................................................................................... Glutamate Receptor Mutations................................................................................................................... Mitochondrial Glutamate Transporter Defect ....................................................................................... Glycine Neurotransmitter Disorders.................................................................................................. Choline Neurotransmitter Disorders ................................................................................................. Monoamine Neurotransmitter Disorders ........................................................................................ Tyrosine Hydroxylase Deficiency ................................................................................................................ Aromatic L-Amino Acid Decarboxylase Deficiency.............................................................................. Dopamine β-Hydroxylase Deficiency........................................................................................................ Monoamine Oxidase-A Deficiency ............................................................................................................ Guanosine Triphosphate Cyclohydrolase I-Deficiency ....................................................................... Sepiapterin Reductase Deficiency ............................................................................................................. Dopamine Transporter Defect ..................................................................................................................... Brain Dopamine-Serotonin Vesicular Transport Defect ..................................................................... Other Defects..................................................................................................................................................... Synaptic Vesicle Disorders (see also 7 Chap. 44).......................................................................... Disorders of SV Exocytosis ............................................................................................................................ Disorders of SV Endocytosis ......................................................................................................................... References............................................................................................................................................................

549 549 549 550 551 551 551 551 553 553 555 556 558 558 560 560 561 562 562 562 562 563 563 567 567

XXIV

31

Contents

Disorders of Peptide and Amine Metabolism .................................................................

571

Ron A. Wevers, Ertan Mayatepek, and Valerie Walker 31.1 31.1.1 31.2 31.2.1 31.2.2 31.3 31.3.1 31.3.2 31.3.3 31.3.4 31.3.5 31.3.6 31.3.7 31.3.8 31.4 31.4.1 31.4.2 31.4.3 31.4.4

32

Disorders of Trimethylamine Metabolism ....................................................................................... Trimethylaminuria (Fish Malodour Syndrome) ..................................................................................... Disorders of Choline Metabolism ....................................................................................................... Dimethylglycine Dehydrogenase Deficiency......................................................................................... Sarcosine Dehydrogenase Deficiency ...................................................................................................... Disorders of Glutathione Metabolism............................................................................................... γ-Glutamylcysteine Synthetase Deficiency (Synonym: Glutamate-Cysteine Ligase Deficiency) ............................................................................................................................................ Glutathione Synthetase Deficiency ........................................................................................................... γ-Glutamyl Transpeptidase Deficiency (Synonym: Glutathionuria) ............................................... Dipeptidase Deficiency (Synonym: Cysteinylglycinuria) ................................................................... 5-Oxoprolinase Deficiency............................................................................................................................ Glutathione Reductase Deficiency ............................................................................................................ Glutathione Peroxidase 4 Deficiency (Synonym: Spondylometaphyseal Dysplasia, Sedaghatian Type) ...................................................................................................................... NRF2 Superactivity (Synonym: Immunodeficiency, Developmental Delay, and Hyperhomocysteinaemia).................................................................................................................... Other Disorders of Peptide Metabolism........................................................................................... Prolidase Deficiency ........................................................................................................................................ X-Prolyl Aminopeptidase 3 Deficiency (Synonym: Nephronophthisis-like Nephropathy Type 1) ...................................................................................................................................... Serum Carnosinase Deficiency (Synonym: Carnosinemia) ............................................................... Homocarnosinosis ........................................................................................................................................... References............................................................................................................................................................

Disorders of Purine and Pyrimidine Metabolism .........................................................

572 572 575 575 576 578 578 578 579 580 580 581 581 581 582 582 582 583 583 583 587

Sandrine Marie, Joseph P. Dewulf, and Marie-Cécile Nassogne 32.1 32.1.1 32.1.2 32.1.3 32.1.4 32.1.5 32.1.6 32.1.7 32.1.8 32.1.9 32.1.10 32.1.11 32.1.12 32.1.13 32.1.14 32.1.15 32.2 32.2.1 32.2.2 32.2.3 32.2.4 32.3 32.3.1 32.3.2

Diseases with Birth Defects, Prenatal or Early Onset of Severe Symptoms with Malformations or Neurological Impairment ......................................................................... Bifunctional Enzyme Phosphoribosyl-Aminoimidazole Carboxylase/Phosphoribosyl-Aminoimidazole-Succinocarboxamide Synthetase Deficiency ...................................................... Adenylosuccinate Lyase Deficiency........................................................................................................... AICAR Transformylase/IMP Cyclohydrolase Deficiency ...................................................................... Phosphoribosylpyrophosphate Synthetase 1 Deficiency ................................................................. AMP Deaminase-2 Deficiency ..................................................................................................................... Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency..................................................... Adenylate Cyclase 5-Related Dyskinesia.................................................................................................. IMP Dehydrogenase Mutations .................................................................................................................. Inosine Triphosphate Pyrophosphatase (ITPase) Deficiency............................................................ Carbamoylphosphate Synthetase II, Aspartate Transcarbamylase, Dihydroorotase Deficiency ........................................................................................................................... Dihydroorotate Dehydrogenase Deficiency........................................................................................... Dihydropyrimidine Dehydrogenase Deficiency ................................................................................... Dihydropyrimidinase Deficiency ................................................................................................................ β-Ureidopropionase Deficiency .................................................................................................................. Cytosolic 5’-Nucleotidase Superactivity .................................................................................................. Diseases with Predominant Kidney Stones or Kidney Involvement ....................................... PRPS1 Overactivity........................................................................................................................................... Hereditary Xanthinuria................................................................................................................................... Adenine Phosphoribosyltransferase Deficiency ................................................................................... Uric Acid Transport Defects: Hypo- and Hyperuricemia .................................................................... Diseases with Predominant Immunologic or Hematological Symptoms ............................. Adenosine Deaminase 1 Deficiency .......................................................................................................... Adenosine Deaminase 2 Deficiency ..........................................................................................................

597 597 597 598 598 598 598 599 600 600 600 600 600 601 601 601 601 601 602 602 602 603 603 604

XXV Contents

32.3.3 32.3.4 32.3.5 32.3.6 32.3.7 32.3.8 32.3.9 32.4 32.4.1 32.4.2 32.5 32.5.1 32.5.2 32.6 32.6.1 32.6.2 32.6.3 32.6.4 32.7 32.7.1 32.7.2

33

Purine Nucleoside Phosphorylase Deficiency ....................................................................................... Adenylate Kinase Deficiencies..................................................................................................................... Adenosine Deaminase 1 Overactivity....................................................................................................... Uridine Monophosphate Synthase Deficiency...................................................................................... Cytosolic 5’-Nucleotidase 3A Deficiency ................................................................................................. Hyper-IgM Syndromes ................................................................................................................................... Ecto-5’-Nucleotidase (NT5E) Deficiency .................................................................................................. Diseases with Predominant Muscular Involvement ..................................................................... AMP Deaminase 1 Deficiency ...................................................................................................................... Muscle-Specific Adenylosuccinate Synthase Deficiency ................................................................... Diseases with Predominant Liver Involvement ............................................................................. Adenosine Kinase Deficiency....................................................................................................................... Deoxyguanosine Kinase Deficiency .......................................................................................................... Mitochondrial DNA Depletion Syndromes ...................................................................................... Deoxyguanosine Kinase Deficiency .......................................................................................................... Ribonucleotide Reductase Deficiency...................................................................................................... Thymidine Kinase 2 Deficiency ................................................................................................................... Thymidine Phosphorylase Deficiency ...................................................................................................... Pharmacogenetics ................................................................................................................................... Thiopurine S-Methyltransferase and Nudix Hydroxylase 15 Deficiencies ................................... Dihydropyrimidine Dehydrogenase Dihydropyrimidinase and Cytidine Deaminase Deficiencies ................................................................................................................................. References............................................................................................................................................................

604 605 605 605 606 606 606 606 606 607 607 607 607 607 607 608 608 608 609 609

Disorders of Haem Biosynthesis ..............................................................................................

615

609 609

Charles Marques Lourenço and Karl E. Anderson 33.1 33.2 33.2.1 33.2.2 33.2.3 33.2.4 33.2.5 33.2.6 33.2.7

X-Linked Sideroblastic Anaemia ......................................................................................................... The Porphyrias .......................................................................................................................................... 5-Aminolevulinic Acid Dehydratase Porphyria...................................................................................... Acute Intermittent Porphyria (AIP) ............................................................................................................ Congenital Erythropoietic Porphyria (CEP) (Gunther Disease) ........................................................ Porphyria Cutanea Tarda (PCT) ................................................................................................................... Hepatoerythropoietic Porphyria ................................................................................................................ Hereditary Coproporphyria and Variegate Porphyria ......................................................................... Erythropoietic Protoporphyria and X-Linked Protoporphyria ......................................................... References............................................................................................................................................................

617 617 619 620 622 623 624 624 625 627

34

Disorders in the Transport of Copper, Iron, Magnesium, Manganese, Selenium and Zinc................................................................................................

631

Peter M. van Hasselt, Peter T. Clayton, and Roderick H. J. Houwen 34.1 34.1.1 34.1.2 34.1.3 34.1.4 34.2 34.2.1 34.2.2 34.2.3 34.3 34.3.1 34.3.2 34.3.3

Copper.......................................................................................................................................................... Wilson Disease................................................................................................................................................... Menkes Disease ................................................................................................................................................ Other Copper Storage Disorders ................................................................................................................ Other Disturbances of Copper Metabolism with a Low Serum Copper....................................... Iron ................................................................................................................................................................ Systemic Iron Overload Syndromes (Haemochromatosis) ............................................................... Iron Deficiency and Distribution Disorders ............................................................................................ Neurodegeneration with Brain Iron Accumulation (NBIA)................................................................ Magnesium ................................................................................................................................................. Primary Hypomagnesaemia with Secondary Hypocalcaemia ........................................................ Isolated Dominant Hypomagnesemia ..................................................................................................... Isolated Autosomal Recessive Hypomagnesaemia .............................................................................

633 634 636 637 637 638 640 641 642 643 643 644 644

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Contents

34.3.4 Hypomagnesaemia with Other Serum Electrolyte Abnormalities and/or Congenital Malformations or with Nephrocalcinosis ......................................................................... 34.4 Manganese ................................................................................................................................................. 34.4.1 Hypermanganesaemia with Dystonia Type 1 (HMNDYT1) ............................................................... 34.4.2 Hypermanganesaemia with Dystonia Type 2 (HMNDYT2) ............................................................... 34.4.3 CDG2N-SLC39A8 Deficiency ........................................................................................................................ 34.5 Selenium ..................................................................................................................................................... 34.6 Zinc ................................................................................................................................................................ 34.6.1 Acrodermatitis Enteropathica...................................................................................................................... 34.6.2 Spondylocheirodysplastic Ehlers-Danlos Syndrome .......................................................................... 34.6.3 Birk-Landau-Perez Syndrome ...................................................................................................................... 34.6.4 Transient Neonatal Zinc Deficiency ........................................................................................................... 34.6.5 Hyperzincaemia with Hypercalprotectinaemia .................................................................................... 34.6.6 Familial Hyperzincaemia Without Symptoms ........................................................................................ References............................................................................................................................................................

IV 35

645 645 645 646 646 646 646 647 648 648 648 648 648 648

Complex Molecule Disorders and Cellular Trafficking Disorders Disorders of Intracellular Triglyceride and Phospholipid Metabolism ..........

655

Foudil Lamari, Francis Rossignol, and Grant A. Mitchell 35.1 35.1.1 35.1.2 35.1.3 35.1.4 35.1.5 35.2 35.2.1 35.2.2 35.2.3 35.2.4 35.3 35.3.1 35.3.2 35.3.3 35.3.4 35.3.5 35.3.6 35.3.7 35.3.8 35.4 35.4.1 35.4.2 35.4.3 35.4.4 35.4.5 35.4.6 35.4.7 35.5

Inborn Errors of the Common Pathway and of Triglyceride Synthesis and Degradation ...................................................................................................................................... Glycerol-3-Phosphate Dehydrogenase 1 (GPD1) Deficiency ........................................................... Glycerol Kinase Deficiency ............................................................................................................................ 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) Deficiency ........................................ Phosphatidic Acid Phosphatase (PAP; Lipin) Deficiencies ................................................................. Diacylglycerol Kinase Epsilon (DGKE) Deficiency.................................................................................. Inborn Errors of Cytoplasmic Triglyceride Synthesis, Storage and Degradation ............... Diacylglycerol O-Acyltransferase (DGAT) Deficiencies ....................................................................... Diseases Related to Structural Proteins of Lipid Droplet (LD) Production, Fusion and Maintenance ............................................................................................................................... Neutral Lipid Storage Diseases (NLSDs): ATGL and CGI-58 Deficiencies ...................................... Hormone-Sensitive Lipase (HSL, LIPE) Deficiency ................................................................................ Inborn Errors of Phospholipid Biosynthesis and Mitochondrial Phospholipid Metabolism ..................................................................................................................... Choline Kinase β (CHKβ) Deficiency........................................................................................................... Choline-Phosphate Cytidylyltransferase α (CCTα, PCYT1A) Deficiency ........................................ Phosphatidylserine Synthase 1 (PSS1, PTDSS1) Gain of Function................................................... Ethanolamine Phosphotransferase (EPT1, SELENOI) Deficiency ..................................................... Phosphatidylserine Decarboxylase (PISD) Deficiency......................................................................... Acylglycerol Kinase (AGK) Deficiency: Sengers Syndrome ............................................................... SERAC1 Mutations: MEGDEL Syndrome ................................................................................................... Cardiolipin Remodelling Enzyme (TAZ) Deficiency: Barth Syndrome ........................................... Inborn Errors of Phospholipid Remodelling ................................................................................... α/β Hydrolase Domain-Containing Protein 12 (ABHD12) Deficiency ........................................... Phospholipase A2 (PLA2G6, PNPLA9) Deficiency .................................................................................. Mitochondrial Calcium Independent Phospholipase A2γ (iPLA2γ, PNPLA8) ............................... Deficiency of Neuropathy Target Esterase (NTE, PNPLA6) ................................................................. DDHD1 and DDHD2 Mutations.................................................................................................................... CYP2U1 Mutations (SPG56) ........................................................................................................................... Lysophosphatidylinositol Acyltransferase (LPIAT1, MBOAT7) Deficiency .................................... Inborn Errors of Phosphoinositide Phosphorylation ................................................................... References............................................................................................................................................................

657 657 657 657 659 660 660 660 660 661 662 662 662 662 663 664 664 664 665 665 666 666 666 667 667 668 668 668 669 671

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36

Inborn Errors of Lipoprotein Metabolism Presenting in Childhood ................

677

Uma Ramaswami and Steve E. Humphries 36.1 36.2 36.3 36.4 36.5

37

Disorders of Low Density Lipoprotein Metabolism ...................................................................... Disorders of Triglyceride (TG) Metabolism ...................................................................................... Disorders of High Density Lipoprotein Metabolism .................................................................... Disorders of Sterol Storage ................................................................................................................... Conclusion .................................................................................................................................................. References............................................................................................................................................................

679 688 689 690 690 690

Disorders of Isoprenoid/Cholesterol Synthesis .............................................................

693

Hans R. Waterham and Peter T. Clayton 37.1 37.2 37.3 37.4 37.5 37.6 37.7 37.7.1 37.7.2 37.8 37.8.1 37.8.2 37.9 37.10 37.11

38

Mevalonate Kinase Deficiency ............................................................................................................. Porokeratosis ............................................................................................................................................. Squalene Synthase Deficiency............................................................................................................. Desmosterol Reductase Deficiency (Desmosterolosis) ............................................................... Lanosterol C14-Demethylase Deficiency ......................................................................................... Sterol β14-Reductase Deficiency (Hydrops – Ectopic Calcification – Moth-Eaten (HEM) Skeletal Dysplasia or Greenberg Skeletal Dysplasia) ............................. Deficiency of the C4-Demethylase Complex .................................................................................. C4-Methyl Sterol Oxidase Deficiency (SMO Deficiency) .................................................................... Sterol 4α-Carboxylate 3-Dehydrogenase Deficiency .......................................................................... Sterol ∆8-∆7 Isomerase Deficiency .................................................................................................... X-Linked Dominant Chondrodysplasia Punctata 2 or Conradi-Hünermann Syndrome in Females ..................................................................................................................................... Hemizygous EBP Deficiency in Males ....................................................................................................... Sterol ∆5-Desaturase Deficiency (Lathosterolosis) ...................................................................... Smith-Lemli-Opitz Syndrome (7-Dehydrocholesterol Reductase Deficiency) .................... Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) Syndrome .............................. References............................................................................................................................................................

694 696 696 696 697

Disorders of Bile Acid Synthesis ...............................................................................................

705

697 698 698 698 699 699 699 700 700 701 702

Peter T. Clayton 38.1 38.2 38.3 38.4 38.5

3β-Hydroxy-∆5-C27-Steroid Dehydrogenase Deficiency........................................................... ∆4-3-Oxosteroid 5β-Reductase Deficiency ..................................................................................... Cerebrotendinous Xanthomatosis (Sterol 27-Hydroxylase Deficiency) ................................ Oxysterol 7α-Hydroxylase Deficiency ............................................................................................... Bile Acid Amidation Defect 1: Bile Acid CoA: Amino Acid N-Acyl Transferase Deficiency............................................................................................................................ 38.6 Bile Acid Amidation Defect 2: Bile Acid CoA Ligase Deficiency ................................................ 38.7 Cholesterol 7α-Hydroxylase Deficiency ........................................................................................... 38.8 Disorders of Peroxisome Biogenesis, Peroxisomal Import and Peroxisomal β-Oxidation ................................................................................................................................................ 38.8.1 PMP70 Deficiency: ABCD3 Mutations ....................................................................................................... 38.8.2 α-Methylacyl-CoA Racemase Deficiency ................................................................................................. 38.8.3 Acyl-CoA Oxidase 2 Deficiency ................................................................................................................... References............................................................................................................................................................ 39

Disorders of Nucleic Acid Metabolism, tRNA Metabolism and Ribosomal Biogenesis ...........................................................................................................

708 709 711 712 713 714 714 715 715 715 716 716

719

Carlos R. Ferreira, Alejandra Darling, and Jerry Vockley 39.1 Nucleotide and Nucleic Acid metabolism ........................................................................................ 39.1.1 Disorders of Ectonucleotide Metabolism – Prototype: Ectopic Calcification ............................. 39.1.2 Disorders of Nucleic Acids: Autoinflammatory Phenotype – Prototype: Aicardi-Goutières Syndrome ........................................................................................................................

720 720 728

XXVIII

Contents

39.2 39.2.1 39.2.2 39.2.3 39.3 39.3.1 39.3.2

tRNA Processing Disorders ................................................................................................................... Disorders of Pre-tRNA Splicing – Prototype: Pontocerebellar Hypoplasia .................................. Disorders of tRNA Modification – Prototype: Non-syndromic Intellectual disability .............. Disorders of tRNA Aminoacylation: Neurodegenerative and Systemic Disorders ................... Ribosomal Biogenesis............................................................................................................................. Disorders of Pre-rRNA Transcription: Craniofacial Anomalies .......................................................... Disorders of 5S rRNA and tRNA Transcription: Neurodegeneration, Leukodystrophy and Systemic Disorders ................................................................................................ 39.3.3 Disorders of Pre-rRNA Processing: Skeletal Dysplasia and Systemic Disorders ......................... 39.3.4 Disorders of Maturation of 40S and 60S Ribosomal Subunits – Prototype: Diamond-Blackfan Syndrome...................................................................................................................... 39.3.5 Disorders of Active 80S Ribosome Assembly: Shwachman-Diamond Syndrome .................... References............................................................................................................................................................ 40

Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses ...............

729 729 730 730 731 731 731 732 732 732 733

735

Marie T. Vanier, Catherine Caillaud, and Thierry Levade 40.1 40.1.1 40.1.2 40.1.3 40.1.4 40.1.5 40.1.6 40.1.7 40.1.8 40.1.9 40.1.10 40.2 40.2.1 40.2.2 40.2.3 40.2.4 40.2.5 40.2.6 40.2.7 40.2.8 40.2.9 40.3 40.3.1 40.3.2 40.3.3 40.3.4 40.4 40.5

Disorders of Sphingolipid Synthesis.................................................................................................. Serine Palmitoyltransferase (Subunit 1 or 2) Deficiency and HSAN1 ............................................ Ketosphinganine Reductase Deficiency and Hyperkeratosis .......................................................... Defects in Ceramide Synthases 1 and 2 and Myoclonic Epilepsy ................................................... Dihydroceramide Δ4-Desaturase Deficiency and Leukodystrophy ............................................... Fatty Acid 2-Hydroxylase Deficiency (SPG35/FAHN) ........................................................................... GM3 Synthase Deficiency and Amish Epilepsy Syndrome................................................................ GM2/GD2 Synthase Deficiency (SPG26) .................................................................................................. Defects in Skin Ceramide Synthesis: Autosomal Recessive Congenital Ichthyoses (ARCI) .............................................................................................................................................. Sphingomyelin Synthase 2 Mutations and Osteoporosis ................................................................. Mutations in Ceramide Kinase-Like (CERKL) Gene and Retinal Dystrophy ................................. Disorders of Lysosomal Sphingolipid Degradation: Sphingolipidoses ................................. Gaucher Disease ............................................................................................................................................... Acid Sphingomyelinase-Deficient Niemann-Pick Disease (Type A, Type B and Intermediate Forms) ............................................................................................................................... GM1 Gangliosidosis ......................................................................................................................................... GM2 Gangliosidoses ....................................................................................................................................... Krabbe Disease.................................................................................................................................................. Metachromatic Leukodystrophy ................................................................................................................ Fabry Disease ..................................................................................................................................................... Farber Disease/Acid Ceramidase Deficiency .......................................................................................... Prosaposin Deficiency .................................................................................................................................... Disorders of Non-Lysosomal Sphingolipid Degradation ............................................................ Non-lysosomal β-Glucosidase (GBA2) Deficiency: SPG46 and Ataxia ........................................... Neutral Sphingomyelinase-3 Deficiency ................................................................................................. Alkaline Ceramidase 3 (ACER3) Deficiency: Infantile Leukodystrophy ......................................... Sphingosine-1-phosphate Lyase (SGPL1) Deficiency: A Multisystemic Disorder ..................... Niemann-Pick Disease Type C .............................................................................................................. Neuronal Ceroid Lipofuscinoses ......................................................................................................... References............................................................................................................................................................

737 739 740 740 740 740 741 741 741 742 742 742 743 745 746 747 749 750 751 753 753 754 754 754 754 754 755 757 761

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41

Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects, Mucopolysaccharidoses, Oligosaccharidoses and Sialic Acid Disorders ................................................................

765

Simon Jones and Frits A. Wijburg 41.1 41.2 41.2.1 41.2.2 41.2.3 41.2.4 41.2.5 41.3 41.3.1 41.3.2 41.3.3 41.3.4 41.3.5

Glycosaminoglycans Synthesis Defects............................................................................................ Mucopolysaccharidoses ......................................................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Oligosaccharidoses and Mucolipidoses ........................................................................................... Clinical Presentation ....................................................................................................................................... Metabolic Derangements ............................................................................................................................. Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. References............................................................................................................................................................

767 767 767 774 774 774 774 777 777 779 779 779 780 780

42

Inborn Errors of Non-Mitochondrial Fatty Acid Metabolism Including Peroxisomal Disorders ............................................................................................

785

Ronald J. A. Wanders, Marc Engelen, and Frédéric M. Vaz 42.1 42.1.1 42.1.2 42.1.3 42.1.4 42.1.5 42.2 42.2.1 42.2.2 42.2.3 42.2.4 42.2.5 42.2.6 42.2.7 42.2.8 42.2.9 42.3 42.4 42.4.1 42.4.2 42.4.3 42.4.4 42.4.5 42.4.6 42.4.7 42.4.8 42.4.9 42.4.10 42.4.11 42.4.12

Disorders of Ether Lipid Biosynthesis................................................................................................ Peroxin 7 (PEX7) Deficiency (RCDP Type 1) ............................................................................................. Glycerone-3-Phosphate Acyltransferase (GNPAT) deficiency (RCDP Type 2) ............................. Alkylglycerone-3-Phosphate Synthase (AGPS) Deficiency (RCDP Type 3)................................... FAR1 Deficiency (RCDP Type 4) ................................................................................................................... PEX5L Deficiency (RCDP Type 5) ................................................................................................................. Disorders of Peroxisomal Fatty Acid β-Oxidation ......................................................................... X-Linked Adrenoleukodystrophy (ALD) ................................................................................................... D-Bifunctional Protein (DBP) Deficiency.................................................................................................. Acyl-CoA Oxidase 1 (ACOX1) Deficiency.................................................................................................. 2-Methylacyl-CoA Racemase (AMACR) Deficiency .............................................................................. Sterol Carrier Protein 2 Deficiency ............................................................................................................. PMP70 (ABCD3) Deficiency........................................................................................................................... Acyl-CoA Oxidase 2 (ACOX2) Deficiency.................................................................................................. Contiguous ABCD1, DXS1357A-Deletion Syndrome (CADDS) ........................................................ Generalized Peroxisomal Fatty Acid Oxidation Deficiencies: Zellweger Spectrum Disorders......................................................................................................................................... Disorders of Peroxisomal Fatty Acid α-Oxidation: Adult Refsum Disease ............................ Disorders of Fatty Acid Chain Elongation and Fatty Acid/Alcohol/Aldehyde Homeostasis ............................................................................................................................................... FACL4 Deficiency .............................................................................................................................................. FATP4/ACSVL4/SLC27A4 Deficiency .......................................................................................................... Fatty Acid 2-Hydroxylase (FA2H) Deficiency .......................................................................................... CYP4F22 Deficiency......................................................................................................................................... Sjögren Larsson Syndrome (SLS) ................................................................................................................ Fatty Acid Chain-Elongation Disorders .................................................................................................... Acetyl-CoA Carboxylase 1 Deficiency ....................................................................................................... ELOVL4 Deficiency ........................................................................................................................................... ELOVL5 Deficiency ........................................................................................................................................... ELOVL1 Deficiency ........................................................................................................................................... Trans-2,3-Enoyl-CoA Reductase Deficiency ............................................................................................ 3-Hydroxyacyl-CoA Dehydratase Deficiency .........................................................................................

788 790 791 791 791 791 791 792 793 794 794 795 795 795 795 796 797 798 798 798 798 798 798 799 799 800 800 800 800 801

XXX

Contents

42.4.13 42.5 42.5.1 42.5.2

MFSD2A Brain DHA Transporter Deficiency ........................................................................................... Disorders of Eicosanoid Metabolism ................................................................................................. Cytosolic Phospholipase A2∝ Deficiency ................................................................................................ 15-Hydroxyprostaglandin Dehydrogenase and Prostaglandin Transporter Deficiency Causing Primary Hypertrophic Osteoarthropathy (PHOAR) ...................................... 42.5.3 Leukotriene C4 Synthase (LTC4) Deficiency............................................................................................ References............................................................................................................................................................ 43

Congenital Disorders of Glycosylation, Dolichol and Glycosylphosphatidylinositol Metabolism.............................................................

801 801 801 801 803 803

811

Jaak Jaeken and Eva Morava 43.1 43.1.1 43.1.2 43.1.3 43.1.4 43.1.5 43.1.6 43.1.7 43.1.8 43.1.9 43.1.10 43.2 43.2.1 43.2.2 43.2.3 43.2.4 43.2.5 43.2.6 43.3 43.3.1 43.3.2 43.3.3 43.4 43.4.1 43.4.2 43.4.3 43.4.4 43.4.5 43.4.6 43.4.7 43.4.8 43.5 43.5.1 43.5.2

Congenital Disorders of Protein N-Glycosylation ......................................................................... Phosphomannomutase 2 Deficiency (PMM2-CDG) ............................................................................ Mannose-Phosphate-Isomerase Deficiency (MPI-CDG)..................................................................... Glucosyltransferase 1 Deficiency (ALG6-CDG)....................................................................................... Mannosyltransferase 1 Deficiency (ALG1-CDG) .................................................................................... UDP-GlcNAc:Dol-P-GlcNAc-P Transferase Deficiency (DPAGT1-CDG) ........................................... Metabolic Derangement ............................................................................................................................... Genetics ............................................................................................................................................................... Diagnostic Tests ................................................................................................................................................ Treatment and Prognosis .............................................................................................................................. Golgi α1-2 Mannosidase 1 Deficiency (MAN1B1-CDG) ...................................................................... Congenital Disorders of Protein O-Glycosylation ......................................................................... Progeroid Variant of Ehlers-Danlos Syndrome (B4GALT7-CDG) ...................................................... GALNT3 Deficiency (GALNT3-CDG) ........................................................................................................... Hereditary Multiple Exostoses (EXT1/EXT2-CDG)................................................................................. Cerebro-Ocular Dysplasia-Muscular Dystrophy Syndromes, Types A1, B1, C1/A2, B2, C2 (POMT1-CDG/POMT2-CDG) .................................................................. Muscle-Eye-Brain Disease, Types A3, B3, C3, RP76/A8,C8 (POMGNT1-CDG/POMGNT2-CDG) ............................................................................................................. O-Fucose-Specific β-1,3-Glucosyltransferase Deficiency (B3GLCT-CDG) ..................................... Defects in Lipid Glycosylation and in Glycosylphosphatidylinositol Anchor Biosynthesis ................................................................................................................................ GM3 Synthase Deficiency (ST3GAL5-CDG) ............................................................................................. GM2 Synthase Deficiency (B4GALNT1- CDG)......................................................................................... PIGA Deficiency (PIGA-CDG) ........................................................................................................................ Defects in Multiple Glycosylation Pathways and in Other Pathways Including Dolicholphosphate Biosynthesis .................................................................................... Hereditary Inclusion Body Myopathy (GNE-CDG) ................................................................................ Congenital Myasthenic Syndrome-12 (GFPT1-CDG)........................................................................... Steroid 5-α-Reductase Deficiency (SRD5A3-CDG) ............................................................................... COG6 Deficiency (COG6-CDG)..................................................................................................................... Autosomal Recessive Cutis Laxa Type 2 (ATP6V0A2-CDG) ................................................................ Phosphoglucomutase 1 Deficiency (PGM1-CDG) ................................................................................ Golgi Homeostasis Disorders: TMEM199 and CCDC115 Deficiencies ........................................... Manganese and Zinc Transporter Defect: SLC39A8 Deficiency ...................................................... Congenital Disorders of Deglycosylation (CDDG)......................................................................... N-glycanase 1 (NGLY1) Deficiency ............................................................................................................. Lysosomal Storage Disorders....................................................................................................................... References............................................................................................................................................................

823 823 824 824 825 825 826 826 826 826 826 826 826 827 827 827 827 828 828 828 828 828 828 828 828 829 829 829 830 830 830 830 830 830 831

XXXI Contents

44

Disorders of Cellular Trafficking...............................................................................................

833

Ángeles García-Cazorla, Carlo Dionisi-Vici, and Jean-Marie Saudubray 44.1 44.1.1 44.1.2 44.1.3 44.2 44.2.1 44.2.2 44.2.3 44.2.4 44.2.5 44.3 44.3.1 44.3.2

V 45

Cellular Mechanisms of Trafficking .................................................................................................... Membrane Trafficking .................................................................................................................................... Membrane Contact Sites ............................................................................................................................... Other Types of Cellular Trafficking ............................................................................................................. Cellular Trafficking in the Nervous System: Polarization and Compartmentalization .................................................................................................................. Trafficking Defects in the Neuronal Soma (ER-Golgi-PM-Endosome-Lysosome-Autophagosome) ............................................................................................................................................. Axonal and Other Cytoskeleton Related Trafficking Defects ........................................................... Synaptic Vesicle Cycle Disorders ................................................................................................................. Dendrites and Post-synaptic Neuron Compartment Traffic Defects ............................................. Glia Trafficking Disorders ............................................................................................................................... Main Clinical Presentations of Cellular Trafficking Disorders.................................................... Neurological Manifestations ........................................................................................................................ Extra-Neurological Manifestations ............................................................................................................ References............................................................................................................................................................

834 834 837 838 850 850 852 852 852 852 853 853 855 856

Appendices Medications Used in the Treatment of Inborn Errors of Metabolism ..............

861

Andrew A. M. Morris and Simon Jones

Supplementary Information Index .............................................................................................................................................................

875

XXXIII

Editors and Contributors Editors Jean-Marie Saudubray Paris, France [email protected] Matthias R. Baumgartner Division of Metabolism and Children’s Research Center, University Children’s Hospital, University of Zurich, Zurich, Switzerland [email protected] Ángeles García-Cazorla Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain [email protected] John H. Walter Developmental Biology and Medicine, School of Medical Sciences, University of Manchester, Manchester, UK

Contributors Karl  E.  Anderson Department of Internal Medicine, Division of Gastroenterology and Hepatology, The University of Texas Medical Branch, Galveston, Texas, USA [email protected] Jean-Baptiste  Arnoux Reference Centre for Inherited Metabolic Diseases, Necker-Enfants Malades University Hospital, APHP, and Paris Cité University, Paris, France [email protected] Rafael Artuch Clinical Biochemistry Department, Hospital Sant Joan de Déu and CIBERERISCIII, Barcelona, Spain [email protected] Matthias R. Baumgartner Division of Metabolism and Children’s Research Center, University Children’s Hospital, University of Zurich, Zurich, Switzerland [email protected] Gerard  T.  Berry Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA [email protected] Henk J. Blom Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands [email protected] Anaïs Brassier Reference Centre for Inherited Metabolic Diseases, Necker-Enfants Malades University Hospital, APHP, and Paris Cité University, Paris, France [email protected] Michèle Brivet

Service de Biochimie, Hôpital Bicêtre, Le Kremlin Bicêtre, France

Garry Brown Oxford, UK [email protected]

XXXIV

Editors and Contributors

Peter  Burgard Centre for Pediatric and Adolescent Medicine, Division for Neuropediatrics and Metabolic Medicine, Dietmar-Hopp-Metabolic Centre, Heidelberg, Germany [email protected] Catherine  Caillaud Laboratoire de Biochimie Métabolique, Hôpital Universitaire Necker Enfants Malades, Paris, France [email protected] Anupam  Chakrapani Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK [email protected] Peter T.  Clayton Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK [email protected] Alejandra Darling Inherited Metabolic Diseases Unit and Movement Disorders Unit, Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain [email protected] Pascale  de Lonlay Reference Centre for Inherited Metabolic Diseases, Necker-Enfants Malades University Hospital, APHP, and Paris Cité University, Paris, France [email protected] Joseph P. Dewulf Laboratoire des Maladies Métaboliques Héréditaires/Biochimie Génétique et Centre de Dépistage Néonatal, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium Department of Biochemistry, de Duve Institute, UCLouvain, Brussels, Belgium [email protected] Carlo Dionisi-Vici Division of Metabolism, Bambino Gesù Children’s Hospital, Rome, Italy [email protected] Olivier Dulac

AdPuerivitam, Antony, France

Marc Engelen Department of Pediatric Neurology, Emma Children’s Hospital & Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands [email protected] Carlos R. Ferreira National Institutes of Health, Bethesda, Maryland, United States [email protected] Brian Fowler University Children’s Hospital, UKBB, Basel, Switzerland [email protected] Judith L. Fridovich-Keil Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, GA, USA [email protected] D. Sean Froese Division of Metabolism and Children’s Research Center, University Children’s Hospital, University of Zurich, Zurich, Switzerland [email protected] Pauline Gaignard Service de Biochimie, Hôpital Bicêtre, Le Kremlin Bicêtre, France [email protected]

XXXV Editors and Contributors

Barbara Garavaglia Fondazione IRCCS Istituto Neurologico “C.Besta”, Milan, Italy [email protected] Ángeles García-Cazorla

Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain

[email protected] Paul Gissen Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK [email protected] Johannes  Häberle Division of Metabolism and Children’s Research Center, University Children’s Hospital, University of Zurich, Zurich, Switzerland [email protected] Georg  F.  Hoffmann University Children’s Hospital, Ruprecht-Karls University, Heidelberg, Germany [email protected] Roderick  H.  J.  Houwen Department of Paediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands [email protected] Steve  E.  Humphries Institute Cardiovascular Science, University College London, London, UK [email protected] Jaak  Jaeken Centre for Metabolic Diseases, Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium [email protected] Simon  Jones Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS, Foundation Trust St Marys Hospital, Manchester, UK [email protected] Joerg Klepper Children’s Hospital, Aschaffenburg, Germany [email protected] Stefan Kölker Heidelberg University Hospital Center for Child and Adolescent Medicine, Heidelberg, Germany [email protected] Viktor  Kožich Department of Pediatrics and Inherited Metabolic Disorders, Charles University-First Faculty of Medicine and General University Hospital, Praha, Czech Republic [email protected] Philippe  Labrune Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Hôpital Antoine Béclère, Service de Pédiatrie, Clamart, France [email protected] Robin H. Lachmann Charles Dent Metabolic Unit, The National Hospital for Neurology and Neurosurgery, London, UK [email protected] Pascal Laforêt Neurology Department, Raymond Poincaré Hospital, Nord/Est/Ile de France neuromuscular center, FHU PHENIX, APHP, Garches. U 1179 INSERM, Université Versailles Saint Quentin en Yvelines, Paris-Saclay, France [email protected]

XXXVI

Editors and Contributors

Foudil Lamari Hôpital Pitié Salpêtrière, Department of Biochemistry, Neurometabolic Unit, Paris, France [email protected] Thierry Levade Laboratoire de Biochimie, CHU Toulouse, Toulouse, France [email protected] Charles  Marques  Lourenço Neurogenetics Unit - Inborn Errors of Metabolism Clinics, National Reference Center for Rare Diseases, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, Brazil [email protected] Sandrine Marie Laboratoire des Maladies Métaboliques Héréditaires/Biochimie Génétique et Centre de Dépistage Néonatal, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium [email protected] Ertan  Mayatepek University Children’s Hospital, Heinrich-Heine-University, Düsseldorf, Germany [email protected] Johannes A. Mayr University Children’s Hospital, Paracelsus Medical University, Salzburger Landeskliniken Universitätsklinikum (SALK), Salzburg, Austria [email protected] Patrick  McKiernan Gastroenterology/Hepatology/Nutrition, UPMC Children’s Hospital of Pittsburgh, PA, USA [email protected] Saadet Mercimek-Andrews Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada [email protected] Grant  A.  Mitchell Division of Medical Genetics, Department of Pediatrics, University of Montreal, Montreal, QC, Canada [email protected] Fanny Mochel Reference Center for Adult Neurometabolic Diseases, Department of Genetics, La Pitié-Salpêtrière University Hospital, Paris, France [email protected] Eva Morava Department of Clinical Genetics, Mayo Clinic, Rochester, MN, USA [email protected] Andrew  A.  M.  Morris Willink Metabolic Unit, Manchester Centre for Genomic Medicine, St Mary’s Hospital and University of Manchester, Manchester, UK [email protected] Marie-Cécile Nassogne Service de Neurologie Pédiatrique & Centre de référence des maladies héréditaires du métabolisme, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium [email protected] Patrick Niaudet

Pediatric Nephrology Unit, Hôpital Necker Enfants Malades, Paris, France

Harri Niinikoski Department of Pediatrics, University of Turku, Turku, Finland [email protected]

XXXVII Editors and Contributors

Phillip  L.  Pearl Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA [email protected] Barbara Plecko Universitätsklinik für Kinder- und Jugendheilkunde, Graz, Austria [email protected] Shamima Rahman Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK [email protected] Uma  Ramaswami Inherited Metabolic Disorders, Lysosomal Disorders Unit, Institute of Immunity and Transplantation, Royal Free Hospital, London, UK [email protected] Francis Rossignol National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA [email protected] Vicente  Rubio Structural Enzyme Pathology Laboratory, Instituto de Biomedicina de Valencia, IBV-CSIC & CIBERER-ISCIII, Valencia, Spain [email protected] Gajja  S.  Salomons Amsterdam UMC location University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children’s Hospital, Amsterdam, The Netherlands Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology & Metabolism, Amsterdam, The Netherlands [email protected] René  Santer Department of Pediatrics, University Medical Centre Hamburg Eppendorf, Hamburg, Germany [email protected] Jean-Marie Saudubray Paris, France [email protected] Manuel  Schiff Reference Centre for Inherited Metabolic Diseases, Necker-Enfants Malades University Hospital, APHP, and Paris Cité University, Paris, France [email protected] Frédéric Sedel MedDay Pharmaceuticals, Paris, France [email protected] Ute Spiekerkoetter Department of Pediatrics, Adolescent Medicine and Neonatology, University Medical Center, Albert Ludwigs University, Freiburg, Germany [email protected] Beat Steinmann Division of Metabolism, University Children’s Hospital, Zürich, Switzerland [email protected] Sylvia  Stöckler-Ipsiroglu Division of Biochemical Genetics, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada [email protected]

XXXVIII Editors and Contributors

Laura Tanner Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland [email protected] Guy Touati France

Reference Center for Inborn errors of Metabolism, Children’s Hospital, Toulouse,

Vassili Valayannopoulos Clinical Development, Gene Therapy, Ultragenyx Pharmaceuticals, Cambridge, MA, USA [email protected] David Valle Institute of Genetic Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA [email protected] Rudy Van Coster NMRC UZ Gent, Ghent University Hospital – UZ Gent, Gent, Belgium [email protected] Peter M. van Hasselt Department of Metabolic diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands [email protected] Johan  L.  K. Van Hove Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA [email protected] Marie  T.  Vanier Former INSERM U820; Laboratoire Gillet-Mérieux, GHE, Hôpitaux de Lyon, Lyon, France [email protected] Frédéric  M.  Vaz Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands [email protected] Marie-Françoise Vincent Laboratory for Inherited Metabolic Diseases, Saint-Luc University Hospital, University of Louvain Medical School, Brussels, France [email protected] Jerry Vockley University of Pittsburgh School of Medicine, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Valerie Walker Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton, UK [email protected] John H. Walter Developmental Biology and Medicine, School of Medical Sciences, University of Manchester, Manchester, UK Mirjam  M.  C.  Wamelink Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, The Netherlands [email protected] Ronald J. A. Wanders Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, Netherlands [email protected]

XXXIX Editors and Contributors

Hans R. Waterham Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, Netherlands Amsterdam Reproduction & Development, Amsterdam, Netherlands [email protected] David Watkins Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada [email protected] Ron  A.  Wevers Department of Laboratory Medicine, Translational Metabolic Laboratory (830), Radboud University Medical Center, Nijmegen, Netherlands [email protected] Frits  A.  Wijburg Amsterdam UMC, University of Amsterdam, Academic Medical Centre, Department of Pediatrics, Amsterdam, Netherlands [email protected]

1

Diagnosis and Treatment: General Principles Contents Chapter 1

Clinical Approach to Inborn Errors of Metabolism in Paediatrics – 3 Jean-Marie Saudubray and Ángeles Garcia-Cazorla

Chapter 2

Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations – 125 Fanny Mochel and Frédéric Sedel

Chapter 3

Diagnostic Procedures – 147 Guy Touati, Fanny Mochel, and Rafael Artuch

Chapter 4

Emergency Treatments – 167 Manuel Schiff, Fanny Mochel, and Carlo Dionisi-Vici

I

3

Clinical Approach to Inborn Errors of Metabolism in Paediatrics Jean-Marie Saudubray and Ángeles García-Cazorla Contents 1.1

Simplified Classification of IEM in 3 Groups – 6

1.1.1

1.1.4

Group 1. Small Molecule Disorders (7 Chaps. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, and 34) – 6 Group 2. Complex Molecule Disorders (7 Chaps. 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44) – 7 Group 3: Disorders Involving Energy Metabolism (7 Chaps. 5, 6, 7, 8, 9, 10, 11, 12, and 13) – 8 Clinical Approach – 9

1.2

Antenatal and Congenital Presentations – 9

1.2.1 1.2.2

Classification of Antenatal Manifestations in Three Major Clinical Categories – 9 Clinical Circumstances of Presentations – 14

1.3

Presentation in Neonates and Infants (1 year to 18 years) – 55 Onset in Adulthood (>15 years to >70 years) – 87 Deafness – 89 Head Circumference, Cephalhematomas, Subdural Hematomas (. Table 1.22) – 89 Neuroimaging Signs – 89 Neuro-ophthalmological Signs (. Tables 1.28 and 1.29) – 89 Neurophysiological Signs – 95 Recommended Laboratory Tests in Neurological Syndromes – 98

1.5.6 1.5.7 1.5.8 1.5.9

1.6

Specific Organ Signs and Symptoms – 98

1.6.1 1.6.2 1.6.3 1.6.4 1.6.5 1.6.6 1.6.7 1.6.8 1.6.9 1.6.10 1.6.11 1.6.12 1.6.13 1.6.14 1.6.15 1.6.16

Cardiology – 98 Dermatology – 98 Endocrinology (. Table 1.35) – 104 Gastroenterology and Nutritional Findings – 107 Haematology – 107 Hepatology – 112 Immunology (See Also Neutropenia . Table 1.38) – 114 Myology – 115 Nephrology (. Table 1.40) – 115 Neurology and Psychiatry – 117 Ophthalmologic Signs – 117 Orthopaedic Signs (. Table 1.43) – 117 Pneumology – 120 Psychiatry – 120 Rheumatology – 120 Stomatology – 121

References – 121

6

1

z

J.-M. Saudubray and Á. Garcia-Cazorla

Introduction

Inborn errors of metabolism (IEM) are individually rare, but collectively numerous. The application of tandem mass spectrometry (tandem MS) to newborn screening and prenatal diagnosis has enabled presymptomatic diagnosis for some IEM. However, for most, neonatal screening tests are either too slow, expensive or unreliable and, as a consequence, a simple method of clinical screening is mandatory before initiating sophisticated biochemical or molecular investigations. The clinical diagnosis of IEM relies upon a limited number of principles: 5 In the appropriate clinical context consider IEM in parallel with other more common conditions. 5 Be aware of symptoms that persist and remain unexplained after the initial treatment and usual investigations have been performed for more common disorders, may be due to an IEM. 5 Suspect that any neonatal death may possibly be due to an IEM, particularly those that have been attributed to sepsis. Additionaly, true sepsis can trigger acute decompensation when there is an underlying IEM. Carefully review all autopsy findings. 5 Do not confuse a symptom or a syndrome with aetiology- the underlying cause may be an IEM yet to be defined. 5 Remember that IEM can present at any age, from fetal life to old age. 5 Be aware that because most IEM have a recessive inheritance (although some have dominant, X-linked, or maternal inheritance), the majority of individual cases may appear sporadic. 5 In the acute emergency situation first consider those IEM that are most amenable to treatment. 5 Get help from specialized centers. Until recently IEM were considered as a speciality of paediatricians. Indeed, the term ‘inborn’ in the mind of clinicians has for a long time meant a disease which starts in the newborn period or at least in childhood. Although paediatricians have learned with time that in addition to severe neonatal forms most IEM can have mild forms with first clinical signs starting in adolescence or very late in adulthood, this concept of ‘adult onset IEM’ only recently reached the adult medical community (7 Chap. 2). Since these late onset forms are often unrecognized, their exact prevalence is unknown. Based mainly upon personal experience over 40 years, the content of chapters in this book, and on the literature analysis, this chapter gives an overview of clinical clues to the diagnosis of IEM in paediatrics. In the following pages, inborn errors amenable to treatment are printed in bold. > Do not miss a treatable disorder!

1.1

Simplified Classification of IEM in 3 Groups

Metabolism involves thousands of proteins mostly enzymes, receptors and transporters, deficits of which cause IEM that effect small or complex molecules. No matter their size, metabolites involved in IEM can behave as signalling molecules, structural components and fuels, and many metabolites have more than one role. According to Morava et al., the classification of a disorder as an IEM requires only that “impairment of specific enzymes or biochemical pathways is intrinsic to the pathomechanism” [1]. DNA testing has recently revolutionized the diagnostic approach of IEM [2]. Using this extended definition and this new diagnostic approach, the more recent international classification of IEM currently encompasses more than 1400 disorders, provisionally divided into 23 groups [3]. However, from a clinical point of view, all IEM can be maintained in a simplified classification that mixes elements from clinical diagnostic perspective and a pathophysiological approach based on three large groups [4]. We highlight the increasing importance of complex molecule metabolism, and their connection with cell biology processes and intracellular trafficking [5]. Transporters, such as those of SLC25A mitochondrial family, play a crucial role in transporting molecules and ions across membrane to link cytosolic and mitochondrial metabolism and to provide compounds for building and maintenance of the mitochondrion and the cell [6].

1.1.1

Group 1. Small Molecule Disorders (7 Chaps. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, and 34)

Almost all these IEM have plasma and urines metabolic marker(s) (small diffusible water-soluble molecules) that can be easily and rapidly measured in an emergency in a single chromatographic run (amino acids, organic acids, acylcarnitines…), or by using specific methods (metals or galactose metabolites.). There are two subcategories in small molecule disorders defined by whether the phenotype primarily results from an acute or progressive “intoxication” caused by accumulation of toxic compounds proximal to the metabolic block or a deficiency where symptoms are primarily due to the defective synthesis of compounds distal from the block or from the defective transportation of an essential molecule through membranes. The “deficiency” subgroup shares many characteristics with defects in the complex molecule disorders group 2 (see below).

7 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

1.1.1.1

Accumulation of Small Molecules

This includes inborn errors of intermediary metabolism (IEIM) that lead to an acute or progressive intoxication from the accumulation of small molecules proximal to the metabolic block. In this group are the inborn errors of amino acid (AA) catabolism (phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia etc.), most organic acidurias (OA) (methylmalonic, propionic, isovaleric etc.), congenital urea cycle defects (UCD), sugar intolerances (galactosaemia: 7 Chap. 14) hereditary fructose intolerance (7 Chap. 15), metal intoxication (Wilson, Menkes, haemochromatosis…) (7 Chap. 34), and porphyrias (7 Chap. 33). Many purine and a few pyrimidine disorders may be classified in this group. Indeed, most that involve either nucleotide synthesis, catabolism or salvage pathways may be screened by the plasma/urine purines and pyrimidines profile (7 Chap. 32). Some metabolite repair defects like D/L-2-OHglutaric (7 Chap. 22) and NAXE deficiency (7 Sect. 11.14) are also included in this group. Hyperglycinaemias (7 Chap. 23) behave more as neurotransmitters disorders (7 Chap. 30) than as an intoxication (see later 7 Sect. 1.2). Vitamins interfere with many different metabolic pathways (transport, and intracellular processing) where they act as enzymatic cofactor, chaperone, or signalling molecules. Therefore, IEM of vitamins may manifest as a treatable intoxication disorder or a complex severe congenital encephalopathy (7 Chaps. 27, 28, and 29). All the conditions in this group share clinical similarities: they do not interfere with the embryo-fetal development; they present with a symptom-free interval and clinical signs of intoxication, which may be acute (vomiting, coma, liver failure, thromboembolic complications etc.) or chronic (failure to thrive, developmental delay, ectopia lentis, cardiomyopathy etc.). Circumstances that can provoke acute metabolic attacks include catabolism, fever, intercurrent illness and food intake. Clinical expression is often both late in onset and intermittent. The diagnosis is straightforward and most commonly relies on plasma and urine AA, OA and acylcarnitine chromatography. Most of these disorders are treatable and require urgent removal of the toxin by special diets, extra-corporeal procedures, or ‘cleansing’ drugs (carnitine, sodium benzoate, penicillamine, etc.) chaperons and vitamins. 1.1.1.2

Deficiency of Small Molecules

Symptoms result primarily from the defective synthesis of compounds that are distal from the block or from the defective transportation of an essential molecule through intestinal epithelium, blood-brain barrier, and cytoplasmic or organelle membranes. Clinical signs are, at least in theory, treatable by providing the missing compound. Most of these defects cause a neurodevelopmental disruption, have a congenital presentation

(antenatal), and may present as birth defects (see 7 Sect. 1.2, . Table 1.1). They share many characteristics with disorders in the complex molecules group (see later). This group encompasses all carrier defects of essential molecules (AA, FA, Metals, Vitamins) that must be transported through cellular membranes, inborn errors in the synthesis of nonessential amino acids (7 Chap. 24) and fatty acids, (7 Chap. 42) and several pyrimidine disorders that affects the synthesis of cytidine, uridine and thymidine nucleosides and are treatable, such as CAD deficiency, or the congenital orotic aciduria (7 Chap. 32). Severe defects affect early developmental stages and behave as brain malformations whereas mild forms may present as ‘synaptopathies’ [7]. In addition to amino acid and fatty acid metabolism defects, the small molecules group defects also encompass the IEM of neurotransmitters. Hyperglycinaemias and dopamine transporter defect behave more as neurotransmitter disorders and signalling molecule defects than as intoxication disorders (7 Chap. 30). In summary, most small molecule defect disorders produce major neurodevelopmental disruptions, thereby leading to severe global encephalopathies where almost all neurological functions are chronically altered. These defects mimic early ‘non-metabolic’ genetic encephalopathies. 1.1.2

Group 2. Complex Molecule Disorders (7 Chaps. 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44)

This expanding group encompasses diseases that disturb the metabolism of complex molecules that are neither water-soluble nor diffusible. The main chemical categories of such complex molecules are glycogen, sphingolipids (SPL), triglycerides (TG) phospholipids (PL), complex long chain fatty acids (LCFA), cholesterol and bile acids, glycosaminoglycans (GAGs), oligosaccharides (OLS), glycoproteins, glycolipids and nucleic acids. These complex metabolic processes of synthesis and recycling take place in organelles (mitochondria, lysosomes, peroxisomes, endoplasmic reticulum and Golgi apparatus) and most pathways involve several organelles and require transporters. Congenital disorders of glycosylation (CDG) (7 Chap. 43) and trafficking, processing and quality control disorders, belong also to this category (7 Chap. 44). Clinical symptoms are permanent, very often progressive, independent of intercurrent events, and unrelated to food intake. Most disorders do not present with acute crises. Similar to the small molecule disorders there are also two subcategories in complex molecule disorders, defined by whether the phenotype primarily results from an accumulation or a deficiency.

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Accumulation of Complex Molecules

Catabolism defects lead to storage of compounds visible in the cytoplasm or in lysosomes causing classical lysosomal storage disorders (LSD) (7 Chaps. 40 and 41) or glycogenosis (GSD) (7 Chap. 5). The neurological presentations consist of progressive disorders with late onset neurodegeneration with or without obvious ‘storage’ signs. Intracellular cytoplasmic TG disorders display noncerebral presentations including hepatic steatosis with hypertriglyceridemia, neutral lipid storage disorders, congenital lipodystrophy with insulin resistance and diabetes and several other tissue specific disorders (7 Chap. 35). 1.1.2.2

Deficiency of Complex Molecules

TG, PL, SPL, cholesterol and bile acids, GAGs, and OLS synthesis/remodeling disorders comprise a new rapidly expanding group of IEM without storage signs. Defects of non mitochondrial fatty acid metabolism including peroxisomal disorders, congenital disorders of glycosylation, nucleic acid metabolism, trafficking, processing and quality control disorders also belong to this category. PL (7 Chap. 35) and SPL (7 Chap. 40) synthesis and remodeling defects display a variety of neurodegenerative symptoms, orthopaedic signs (bone and chondrodysplasia, malformation), syndromic ichthyosis, and retinal dystrophy. Phosphatidylinositides (P-ins) metabolism mutations are responsible for neurodevelopment and neurodegenerative disorders (7 Chap. 35). Overall, there are not readily measurable metabolic markers for these diseases and diagnosis relies on NGS. Most peroxisomal disorders involve complex lipids. They should be reclassified as non-mitochondrial fatty acid metabolism disorders in a vast complex lipid category (7 Chap. 42). Many present at birth with a polymalformative syndrome, severe neurologic signs and hepatic involvement such as the Zellweger syndrome and chondrodysplasia punctata. Others present later between the first and second decade of life or in adulthood with neurodegenerative disorders. Inborn errors of cholesterol (7 Chap. 37) and bile acid synthesis (7 Chap. 38) present either with polymalformative syndromes (such as Smith-Lemli-Opitz syndrome), neonatal cholestasis, or with late onset neurodegenerative disorders. GAGs and oligosaccharides synthesis disorders do not present with preponderant neurological symptoms but rather should be suspected in patients with a combination of characteristic clinical features in more than one connective tissue compartment: bone and cartilage, ligaments, and subepithelial (skin, sclerae). Some produce distinct clinical syndromes with bone dysplasias (7 Chap. 41). Many are usually classified in CDG syndromes (7 Chap. 43).

1.1.2.3

Cellular Trafficking and Processing Disorders (7 Chap. 44)

This is a new and growing category that encompasses CDG syndromes and many other defects affecting systems involved in intracellular vesiculation, trafficking, processing of complex molecules, and quality control processes (such as protein folding and autophagy). They should be considered with any unexplained clinical condition, particularly in multiorgan disease with neurological involvement but also with non-specific developmental disability (7 Chap. 44). The concept of ‘synaptic metabolism’ has been recently introduced; it can be defined as the specific chemical composition and metabolic functions occurring at the synapse [8]. Mutations coding for different proteins that regulate the synaptic vesicle (SV) exocyticendocytic pathway have been described as responsible of a variety of disorders (7 Chap. 30). This oversimplified classification does not take into account the complexity of cellular biology and the more recent trafficking breakthroughs like the membrane contact sites and the membraneless organelles (7 Chap. 44). The newly described metabolic disorders affecting cytoplasmic and mitochondrial tRNA synthetases, nucleic acid metabolism (7 Chap. 39) and other factors related to cytoplasmic protein synthesis, transporters, channels and enzymes implicated in the signaling, logistics and regulation of the cell, challenge our current classification based on organelles. The same is true for nuclear factors related to gene expression and splicing. All these “new IEM” form a bridge between “classic” metabolic diseases with metabolic markers and those caused by structural proteins mutations without such markers and which are most often diagnosed by molecular techniques.

1.1.3

Group 3: Disorders Involving Energy Metabolism (7 Chaps. 5, 6, 7, 8, 9, 10, 11, 12, and 13)

These consist of IEM with symptoms due, at least in part, to a deficiency in energy production or utilisation within the liver, myocardium, muscle, brain, and other tissues. Common symptoms in this group include hypoglycaemia, hyperlactataemia, hepatomegaly, severe generalized hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collapse, sudden unexpected death in infancy, and brain involvement. These diseases present an overlapping clinical spectrum, and manifestations sometimes result from accumulation of toxic compounds as well as from the deficiency in energy production or abnormal signaling.

9 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

Group 3 disorders can be divided in 3 sub-categories: energetic molecule transporter, cytoplasmic and mitochondrial defects. Diagnosis is difficult and relies on functional tests, enzymatic analyses requiring biopsies or cell culture, and increasingly on molecular analyses. Mitochondrial diseases are the most common group of IEM and are among the most common forms of inherited neurological disorders (7 Chap. 10). 1.1.3.1

Membrane Carriers of Energetic Molecules

Membrane carriers of energetic molecules include many tissue specific isozymes. The solute carrier (SLC) SLC2 and SLC5 gene families encode for the glucose carriers GLUT and GLT respectively while the SLC16 gene family encodes for FA, ketone bodies, and monocarboxylic acid (MCT) carriers (7 Chap. 8). 1.1.3.2

Mitochondrial Defects

Mitochondrial defects encompass aerobic glucose oxidation defects presenting with congenital lactic acidemias (pyruvate transporter, pyruvate carboxylase, pyruvate dehydrogenase system, Krebs cycle and malate-aspartate shuttle defects) (7 Chap. 11), mitochondrial respiratory-chain disorders, mitochondrial transporters of energetic and other indispensable molecules (mostly belonging to the SLC25A family [6]), coenzyme Q biosynthesis (7 Chap. 10), β-oxidation, (7 Chap. 12) and ketone body defects (7 Chap. 13). A large and growing group of disorders, already more than 110, involve mitochondrial machinery (7 Chap. 10). Some of the mitochondrial disorders and pentose phosphate pathway (PPP) defects can interfere with the embryofetal development and give rise to dysmorphism, dysplasia and malformations. NAXE deficiency causes a severe neonatal encephalopathy (7 Sect. 11.14). 1.1.3.3

1.2

Antenatal and Congenital Presentations

Dysmorphism is often combined with a neurodevelopmental disorder and other manifestations. About 30%–40% of genetic disorders manifest craniofacial abnormalities but only a few IEM present with antenatal symptoms. Metabolic disorders change the cellular environment and impact on gene expression and regulation. Those alterations affecting morphogenesis (during the embryonic period lasting the first 6–8 weeks) result in malformations, while those affecting growth and cellular differentiation of a tissue (during the fetal period starting after 8–9 weeks) result in dysplasias.

Cytoplasmic Energy Defects

Cytoplasmic energy defects are generally less severe. They include: disorders of glycolysis (7 Chap. 7), glycogen metabolism (7 Chap. 5), gluconeogenesis (7 Sects. 11.2 and 15.3) and hyperinsulinism (7 Chap. 6), all of which are treatable; disorders of creatine metabolism (7 Chap. 9), which are partially treatable; and inborn errors of the pentose phosphate pathways, with a phenotype mostly linked to defective NADP/ NADPH production and which are largely untreatable [9] (7 Chap. 7).

1.1.4

(e.g., metabolomics and lipidomic approaches) and genetic (e.g., next generation sequencing) investigations. Besides newborn screening in the general population or in at-risk families, the clinical diagnostic circumstances observed in IEM are divided in this chapter into five categories numbered 1.2–1.6: 5 1.2 Antenatal and congenital presentations 5 1.3 Neonatal presentations 5 1.4 Later-onset emergencies (from early childhood to adulthood) with acute (and recurrent) manifestations such as coma, ataxia, acidosis, exercise intolerance, or visceral failure… 5 1.5 Chronic and progressive neurological presentation (from early childhood to adulthood) (developmental delay, intellectual disability, epilepsy, neurological deterioration, psychiatric signs). 5 1.6 Specific and permanent organ/system presentations that may concern all medical specialities (cardiology, dermatology, endocrinology, gastroenterology, hematology … etc.).

Clinical Approach

The careful grouping of patients in well-defined clinical entities may provide algorithms for orientating metabolic

1.2.1

Classification of Antenatal Manifestations in Three Major Clinical Categories

1. True malformations (such as skeletal malformations, congenital heart disease, visceral aplasias and neural tube defects), 2. Dysplasias (such as brain malformations, polycystic kidneys, liver cysts), 3. Functional signs (such as intrauterine growth retardation, hydrops fetalis, hepatosplenomegaly, microcephaly). Neurodevelopment may be disrupted in IEM at different stages producing a wide repertoire of clinical manifestations that range from severe brain malformations

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with early complex encephalopathies to mild neurological signs such as learning difficulties [10]. True irreversible central nervous system (CNS) anomalies are observed in disorders of cellular trafficking (7 Chap. 44) O-glycosylation disorders (7 Chap. 43), cholesterol synthesis defects (7 Chap. 37), amino acid synthesis (7 Chap. 24) and transport defects (7 Chap. 25), NKH (7 Chap. 23), MFSD2A defect (DHA transporter) (7 Sect. 42.4.13), congenital Amish microcephaly due to mutations in SLC25A19 (7 Sect. 29.1.3), congenital lipofuscinosis (brain shrinking at birth) (7 Chap. 40), receptor neurotransmitter defects (in particu-

lar ionotropic receptors) (7 Chap. 30), rarely in glutaric aciduria type II and in respiratory chain disorders (. Table 1.1). Congenital NAD deficiency disorders have also been recently identified as an important potential cause of major congenital malformations that could be potentially prevented by niacin supplementation (7 Sect. 24.1.2). Of note the congenital microcephaly observed in serine synthesis defects is partially reversible with early treatment (7 Sect. 24.2). Lysosomal, peroxisomal and N-glycosylation defects are responsible for dysplasia and in the less severe cases partially reversible functional abnormalities. Ciliopathies (such

. Table 1.1 Clinical, imaging, macroscopic and microscopic features in fetuses and neonates with IEM Clinical feature Bones

Disorder Stippled epiphyses chondrodysplasia punctata)

Lysosomal disorders Peroxisomal disorders Cholesterol synthesis defects ALG3-CDG

Shortening of the limbs

Small molecules defects Glutamine synthetase deficiency, PAICS mutation (purine defect), SLC39A8 mutations (Mn transporter) Complex molecules defects ML II; RCDP; cholesterol synthesis defects Phospholipids synthesis defects (7 Chap. 35) PLCB3 mutations leading to phosphoinositide signalling defect CDG syndromes: ALG3-CDG, ALG12-CDG, SLC39A8-CDG Other: Hypophosphatasia (alkaline phosphatase)

Shortening of the extremities and malformations

Cholesterol synthesis defects CDG syndromes: ALG12-CDG, SLC39A8-CDG, COG7-CDG (7 Chap. 43) Phosphoinositide synthesis defects (7 Sect. 35.5) Other disorders: Arylsulfatase E deficiency, Refsum disease, PAICS mutation

Joint contractures, arthrogryposis

Lysosomal storage diseases (LSD) and related disorders Gaucher type II, Mucopolysaccharidosis and Prosaposin deficiency Multiple sulfatase deficiency, Neutral sphingomyelinase-3 deficiency Complex molecules synthesis and trafficking defects: RCDP types I-III, Cholesterol synthesis defects, COASY deficiency Cellular trafficking disorders such as SLC35A3-CDG, ERG1C1, KIAA1109, Biallelic deletion of SOX 10 (associated with blond hair) Other disorders: Glycogenosis type IV, respiratory chain defects, Hyperekplexia type 4, glycine transporter 1 deficiency (7 Chap. 30), Glutamate decarboxylase (GAD1) (with cleft palate and omphalocele), severe fetal neuromuscular diseases and congenital myopathies

Dysostosis multiplex: LSD (see 7 Chap. 41)

MPS types I, II, IV, VI, VII, multiple sulfatase deficiency, ML types I, II (with fractures), III, Pycnodysostosis, ISSD Alpha mannosidosis

Vertebral defects Vertebral defects in VACTERL association Thoraco lumbar kyphosis

Congenital NAD synthesis defects (7 Sect. 24.1.2) PAICS mutation (purine defect) 3-hydroxyisobutyrylCoA deacylase deficiency MPS IH (at birth)

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11 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.1 (continued) Clinical feature Head /face

Disorder Coarse facies Coarse facies appears later in life in many progressive storage disorders

At birth: Galactosialidosis, I-cell disease, GM1 gangliosidosis, Sialidosis type 2, MPS VII. In many other LSDs facial coarsening starts later in infancy as it is also observed in AIFM1 mutations (see below) Onset in infancy/early childhood: Multiple sulfatase deficiency, Fucosidosis type I, Mannosidosis, MPS type IH, V, VII), Salla disease, Sialidosis type II, AIFM1 mutation (with Spondyloepimetaphyseal dysplasia) Onset in childhood: Aspartylglucosaminuria, MPSs types I, III, & X Pseudo-Hurler polydystrophy

Facial dysmorphism can be found in a large number of diseases. Some may have characteristic metabolic markers, such as Zelwegger syndrome, Smith Lemli Opitz (SLO) syndrome, PMM2-CDG or PDH deficiency

Maternal metabolic disturbances: PKU, Foetal alcohol syndrome, diabetes, drugs, riboflavin deficiency Defects of small molecules synthesis and transport: Amino acids synthesis defects; serine (including Neu Laxova syndrome), glutamine, asparagine synthesis defects Large neutral amino acid transporter (SLC7A5) and branched chain dehydrogenase kinase (BCDK) overactivity syndrome Purines (PAICS mutations, AICA ribosiduria) pyrimidines (CAD and DHODH mutations causing Miller syndrome) Molybdenum cofactor / Sulfite oxidase deficiency, metal transporter defects Complex molecules synthesis, transport and processing: Lysophosphatidylcholine LPC symporter 1: (MFSD2A) Cholesterol synthesis defects (mostly SLO) Phospholipids synthesis defects (several types including plasmalogens and polyphosphoinositides defects) CDG (many types including PMM2-CDG, SLC39A8 and Phosphoglucomutase defects (with cleft uvula and palate) Peroxisomal disorders (many types including Zellweger and RCDP) Defects in trafficking (see 7 Chap. 44, 7 Table 44.1) Defects in energy availability: mtDNA depletion, respiratory chain defects, PPP defects, MADD, CPT2 deficiency, PDH deficiency, Malate-aspartate shuttle defects (7 Chap. 11) Defects of post translational modifications and signalling Ralopathies (RALGAPA1) PPP1R21 mutations (PP1 regulatory proteins) Many new syndromes without markers have been found with the use of NEGS as diagnostic tool …

Craniosynostosis

I-cell disease, Antley-Bixler, SLC39A8, KAT6A mutations

Cleft palate, Bifida uvula

GAD (cleft palate), PGM1-CDG, Ethanolaminephosphotransferase 1 Congenital NAD synthesis defects (7 Sect. 24.1.2)

Macrocephaly

See below 7 Sect. 1.5.5

Cephalhematomas

See below 7 Sect. 1.5.5

Microcephaly

See below 7 Sect. 1.5.5

Midface hypoplasia

Sly disease (MPS type VII) Peroxisomal biogenesis disorders (continued)

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. Table 1.1 (continued) Clinical feature Growth

Disorder Overgrowth

PIK3CA-related segmental overgrowth disorders (with lipomatosis) Child syndrome (congenital hemidysplasia) Congenital hyperinsulinism and INSR/PI3K/AKT signalling pathway AIFM1 mutation (with Spondyloepimetaphyseal dysplasia and severe neurodegeneration)

Intra uterine growth restriction (IUGR)

Fetal alcohol syndrome, infants born to mothers with untreated PKU Complex molecules defects: Cholesterol biosynthesis defects (mostly with malformations) CDG (several types) and N-Glycanase defect Lysosomal storage disorders, peroxisomal disorders Neutral sphingomyelinase-3 deficiency Cytosolic isoleucyl-tRNA synthetase (IARS) ATAD3 locus duplication (with cardiac failure) (see 7 Sect. 1.3.7) Others: Respiratory chain disorders (isolated or with mild signs) TMEM70 Transaldolase deficiency (with hydrops and pseudo cutis laxa) Many polymalformative syndromes Microcephalic primordial dwarfism

Ascites and hydrops fetalis polyhydramnios NIHF (defined by the presence of fetal ascites, pleural or pericardial effusions, skin oedema, cystic hygroma, increased nuchal translucency, or a combination of these conditions)

Storage disorders Niemann Pick type C disease (with hepatosplenomegaly), Sphingosine-1-phosphate lyase (SGPL1) deficiency MLP type 2 (with multiple dysostosis), Wolman disease (with adrenal calcifications). MPS type VII, sialidosis, galactosialidosis Glycogenosis type IV (with fetal akinesia and arthrogryposis) Complex molecules synthesis and trafficking Cholesterol (Greenberg skeletal dysplasia: sterol C14 reductase) CDG: PMM2-CDG, ALG1-CDG, ALG8-CDG, and ALG12-CDG Ichthyosis prematurity syndrome (fatty acid transport protein 4) (7 Sect. 42.4.2) Plasmalemma vesicle-associated protein (PLVAP) hydrops with facial dysmorphic features, and cardiac and renal abnormalities RAS–MAPK cell-signalling pathway (RASopathies) Miscellaneous TALDO deficiency, Pearson (with anemia), Barth (with myocardiopathy) Fumarase deficiency S-adenosylhomocysteine hydrolase deficiency (SAHH) (7 Chap. 20) De novo purine synthesis: PAICS deficiency (with malformations) Thrombospondin-1 domain containing protein 1 defects (see 7 Sect. 1.3.5.2) INSR/PI3K/AKT signalling pathway defects (with severe hypoglycaemia, megalencephaly and multiple malformations) (7 Chap. 6) Ornithine decarboxylase overactivity Growth and differentiation factor 2 (GDF2) mutations

Liver

Hepatomegaly/splenomegaly

See later 7 Sect. 1.3.5

Hemosiderosis

Neonatal hemochromatosis, Respiratory chain disorders, TALDO, Zellweger

Steatosis

See later 7 Sect. 1.3.5

Bile ducts anomalies

Zellweger, PMM2-CDG, ALG3-CDG Respiratory chain disorders

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13 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.1 (continued) Clinical feature

Disorder

Kidneys

Cysts

Zellweger, MADD, CPTII, promotor mutation in phosphomannomutase II (with hyperinsulinaemic hypoglycaemia: HIPCKD) Ciliopathies (TMEM67)

Heart

Hypertrophic cardiomyopathy

See 7 Sects. 1.3.7 and 1.4.8

Malformations (only few examples are cited)

Baby born to mother with untreated PKU Several trafficking disorders (7 Chap. 44): Vesicular trafficking (RAB23, STRADA, VPS13B, WFS1) Organelles and interorganelles trafficking (COG1, PACS1, SLC35A1, ARCN1) Cytoskeleton (DYNC2H1, FLNA) Miscellaneous KAT6A mutations CNNM2 homozygous mutations Congenital NAD synthesis defects PLVAP mutations

Digestive system

Oesophageal atresia, tracheoesophageal fistula Choanal stenosis/atresia

PAICS mutation (purine defect) Cobalamin C and F disorders

Omphalocele

Glutamate decarboxylase (GAD) deficiency

Hyperechogenic colon (cysteine crystals)

Cystinuria

Skin

Ichthyosis See later 7 Sect. 1.6.2

Nail

Nail hypoplasia

Glycosylphosphatidylinositol (GPI) deficiency

Genitalia

Hypospadias, sexual ambiguity

Smith Lemli Opitz, Antley Bixler, Desmosterolosis, Respiratory chain Disorders of adrenal steroid metabolism RAB18 related Warburg micro syndrome PAICS mutations (small penis with hypospadias, cryptorchidism)

Brain (only a few disorders are cited) See 7 Sect. 1.5.6

Hydrocephalus, Ventriculomegaly

Brain essential fatty acid transporter (MFSD2A) (7 Sect. 42.4.13) INSR/PI3K/AKT signalling pathway defects (Arnold Chiari malformation) WDR45B mutations

Gyration anomalies

Peroxisome defects (Zellweger spectrum), Amino acid synthesis defects, Congenital Amish microcephaly, O-CDG, tubulin defects, Congenital lipofuscinosis, Glutaric aciduria type II, Respiratory chain disorders, SCHIP1/IQCJ-SCHIP1 mutations, Several cell trafficking disorders in particular Golgipathies GRINpathies Lissencephaly: Tubulin disorders, MAPS (microtubule associated proteins), ACTB genes (actin related) Severe pachygyria: Glutathione peroxidase 4 deficiency

Corpus callosum agenesis/hypoplasia

Many disorders: NKH, PDH, Respiratory chain, Complex molecules synthesis defects, most Trafficking disorders (7 Chap. 44). Corpus callosum thickening: Neurofibromatosis, syndromes with hyperactivation of PI3K/AKT3/mT MAST1 mutations

Posterior fossa anomalies

CDG, peroxisomal disorders, pontocerebellar hypoplasia (ribosomopathies, tRNA synthetase deficiencies, Golgipathies), (7 Chap. 39) Respiratory chain disorders.

Neural tube defects

Folate disorders

Calcifications

See later 7 Sect. 1.5.6 (continued)

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. Table 1.1 (continued) Clinical feature Cells

Disorder Overloaded cells

Most lysosomal disorders Neutral lipid storage disorders (Jordan’s anomaly)

Adapted from Collardeau and Guibaud [14] ARCI autosomal recessive congenital ichthyosis, CDG congenital disorder of glycosylation, CPT carnitine palmityl transferase, FA fatty acid, HIPCKD hyperinsulinism polycystic kidney disease syndrome, ISSD infantile sialic acid storage disease, LSD lysosome storage disorder, MADD multiple acyl-CoA dehydrogenase, MLII mucolipidosis II, MPS mucopolysaccharidosis, NBIA neurodegeneration with brain iron accumulation, NIHF non immune hydrops fetalis, NKH non ketotic hyperglycinaemia, PAICS bifunctional purine enzyme (7 Chap. 36). PDH pyruvate deshydrogenase, PPP pentose phosphate pathway, RCDP rhizomelic chondrodysplasia punctata. TALDO transaldolase

as TMEM67 mutations) and cytoskeleton disorders are cell trafficking defects that may display a wide range of presentations from lethal phenotypes to specific organ involvement only (7 Chap. 44). SLC35A2 (encoding a UDP-galactose transporter) brain mosaicism has been very recently described in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) [11]. The vast majority of “true intoxication” disorders (amino acid and organic acid catabolism disorders) do not interfere with the embryo-fetal development and do not give rise to dysmorphism and antenatal manifestations despite the presence of some toxic compounds prenatally. Coarse facies is seen in relatively few lysosomal disorders at birth but when present is an important diagnostic feature. Untreated maternal PKU (and possible tyrosinemia type II) can cause fetal dysplasia with intrauterine growth retardation (IUGR), mimicking foetal alcoholic syndrome (. Table 1.1) (7 Sects. 16.3.1 and 17.3). Non immune hydrops fetalis and severe IUGR are frequent findings in a large number of inborn errors that disturb the synthesis or the catabolism of complex molecules, including some LSDs, peroxisomal disorders and cholesterol biosynthesis defects and in trafficking disorders such as those affecting the RAS–MAPK cell-signalling pathway (rasopathies) [12]. In most of these cases, many other significant clinical symptoms, such as facial dysmorphism, malformations, visceral or neurologic manifestations, lactic acidosis, and liver hemosiderosis, are present. IUGR is also a very frequent finding in a number of polymalformative syndromes of genetic and non-genetic origin. It is a preponderant symptom in respiratory chain disorders such as TMEM79 deficiency [13] and ATAD3 locus mutations (see below 7 Sect. 1.3.7).

1.2.2

Clinical Circumstances of Presentations

Antenatal manifestations of IEM can be suggested and should be investigated when facing some prenatal imaging findings, especially in cases of consanguinity and/or recurrence of symptoms, after exclusion of the most frequent non-metabolic aetiologies. Most imaging findings suggestive of IEM in the prenatal period are non-specific. They comprise ascites and hydrops fetalis, IUGR, CNS anomalies, echogenic kidneys, visceromegaly and a wide spectrum of dysostosis [14]. These anomalies can be isolated, but a combination of findings can be more suggestive of an IEM. An autopsy is essential when an IEM is suspected after an abortion [15]. It also allows the collection of fluid and tissue samples required for biochemical investigations to confirm the diagnosis [16]. The concept of a metabolic autopsy’has been recently developed [17]. A clinical examination in the delivery room often remains the difficult circumstance in which an IEM is suspected. The most important clinical, imaging, macroscopic and microscopic pathological findings reported in fetuses and neonates with IEM are listed in . Table 1.1.

1.3

Presentation in Neonates and Infants (18 mmol/). Elevated lactic acid levels in the absence of infection or tissue hypoxia are a significant finding (7 Sect. 1.4.13). An elevated ammonia level in itself can induce respiratory alkalosis (7 Sect. 1.4.16). PA, MMA and IVA may induce granulocytopenia and thrombocytopenia (bone marrow suppression), which may be mistaken for sepsis. Transaldolase deficiency and early onset forms of mevalonate kinase deficiency present with severe recurrent hemolytic anemia.

25 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.3 Protocol for emergency investigations Immediate investigations

Storage of samples

Urine

Smell (special odour) Look (special colour) Ketones (Acetest, ketostick, Ames) Reducing substances (multisticks pH: pHstix Merck) Sulfitest (Merck) Electrolytes (Na, K), urea, creatinine Uric acid

Urine collection: collect fresh samples before and after treatment and freeze at −20 °C. Do not use the samples without expert metabolic advice. Specialist metabolic investigation include: OAC, AAC, orotic acid, porphyrins

Blood

Blood cell count Electrolytes (search for anion gap) Glucose, calcium Blood gases (pH, pCO2, HCO3, pO2) Uric acid Prothrombin time Transaminases (and other liver tests) Ammonia Lactic acid 3-hydroxybutyratea Free fatty acids (FFA)a

Plasma (5 ml) heparinized at −20 °C Blood on filter paper: 2 spots (as ‘Guthrie’ test) Whole blood (1–5 ml) collected on EDTA and frozen (for molecular biology studies) Specialist metabolic investigations include: Total homocysteine, AAC (P) Acylcarnitine (tandem MS) (P, blood spot) Purines, pyrimidines Neurotransmitters (P, CSF, U) (HPLC, tandem MS) Peroxisome investigations (VLCFA, plasmalogen, phytanic acid CDG screening tests Specific markers (eg galactose markers, metals …)

Miscellaneous

Lumbar puncture Chest X-ray Cardiac echography, ECG Cerebral ultrasound, EEG

Skin biopsy (fibroblast culture) CSF (1 ml), frozen (neurotransmitters, AA) Postmortem: liver, muscle biopsies (7 Chap. 3)

AA amino acid, AAC amino acid chromatography, CSF cerebrospinal fluid, DNPH dinitrophenylhydrazine; the dinitrophenylhydrasine (DNPH) test screens for the presence of alpha-keto acids as occur in MSUD (however, it has now largely been abandoned.), ECG electrocardiogram, EDTA ethylenediaminetetra-acetic acid, EEG electroencephalogram, MS mass spectrometry, HPLC high performance liquid chromatography, OAC organic acid chromatography, P plasma, U urine, VLCFA very long chain fatty acids aBlood ketone analysis is available using a bedside meter. 3-hydroxybutyrate and FFA data are generally not obtained in an emergency but are useful for interpreting the metabolic profile. Similarly, pyruvate and acetoacetate are not included in this emergency protocol

The storage of adequate amounts of plasma, urine, blood on filter paper, and CSF, is an important element in reaching a diagnosis. The utilization of these precious samples should be carefully planned after taking advice from specialists in IEM.

1.3.10

According to this Bedside Protocol Most Patients with Neurological Findings Can Be Classified into One of Six Metabolic Types (. Table 1.4)

Once the above clinical and laboratory data have been collected, first line therapeutic recommendations can be made. This process is completed within 2–4 h and often precludes waiting long periods for the results of sophisticated diagnostic investigations. On the basis of this evaluation, most patients can be classified into one of six types that may overlap (. Table 1.4).

1.3.10.1

With First Line Metabolic Disturbances

The experienced clinician will, of course, have to carefully interpret the metabolic data, particularly in relation to time of collection and ongoing treatment. At the same time, it is important to collect all the first line data listed in . Table 1.3. Some very significant symptoms (such as metabolic acidosis and especially ketosis) can be moderate and transient, largely depending on the symptomatic therapy. Conversely, at an advanced state, many non-specific abnormalities (such as respiratory acidosis, severe hyperlactataemia, secondary hyperammonaemia) can disturb the original metabolic profile. This applies particularly to IEM with a rapidly fatal course such as severe urea cycle defects, in which the initial characteristic presentation of hyperammonaemia with respiratory alkalosis shifts rapidly to a rather non-specific picture of acidosis and hyperlactataemia.

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. Table 1.4 Classification of inborn errors with neurological deterioration presenting in the neonatal period and in early infancy (according to preponderant first line metabolic disturbance) Clinical types

Acidosis/Ketosis

Other signs

Most likely diagnosis (disorder/enzyme deficiency)

Metabolic test

I

With ketosis “Intoxication” type, 4–8 days of “well” period Slow abnormal movements Hypertonia

Acidosis 0/± Ketone urine test 0/±

NH3 N or ↑ ± Lactate N Blood count N Glucose N Calcium N

MSUD (7 Chap. 18) (abnormal odour) Mild forms of OA (see below)

AAC (P, U) Blood spot for tandem MS-MS OAC (U)

II

With ketoacidosis “Intoxication” type 1–3 days of ‘well’ period Fast abnormal movements Dehydration

Acidosis ++ Ketone urine test ++ Ketoacidosis

NH3 ↑ +/++ Lactate N or ↑ ± Blood count: leucopenia, Thrombopenia (BMS) Glucose N or ↑ + Calcium N or ↓ +

OA (7 Chap. 18) Ketolysis defect (7 Chap. 13)

OAC (U, P) Carnitine (P) AcylCarnitin (U, P, DBS) By tandem MS-MS

With non (hypo) ketotic acidosis “Energy deficiency” type, with liver or cardiac signs

Acidosis ++/± Ketone urine test 0 (no ketosis)

NH3 ↑ ±/++ Lactate ↑ ±/++ Blood count N Glucose ↓ +/++ (hypoketotic hypoglycaemia)

FAO and ketogenesis defects (7 Chap. 12)

Idem above Metabolic profile FAO studies Lymphocytes fibroblasts, DNA tests

III

With hyperlactataemia “Energy deficiency” type, Polypnea, Hypotonia Lactic acidosis may be sometimes well tolerated

Acidosis +++/+ Ketone urine test++/0 Lactate ++

NH3 N or ↑ ± Blood count: Anemia /N Glucose N or ↓ ± Calcium N

Pyruvate oxidation and TCA cycle defects (7 Chap. 11) Respiratory chain, (7 Chap. 14) Lipoylation defects (7 Sect. 23.2.3)

(L:P 3OHB: AA) OAC (U), AAC (P) PolarographEnzyme test DNA tests

IV

With Hyperammonaemia Hyperammonaemia, without ketoacidosis “Intoxication” type, 0–3 days “well” period Moderate liver findings High blood pressure

Alkalosis Ketone urine test 0/+

NH3 ↑ +/+++ lactate N↑/ + Blood count N Glucose N (low in CAVAS) Calcium N

UCD, CAVA, HHH (7 Chap. 19), LPI (7 Chap. 25), GS deficiency (7 Chap. 24)

AAC, OAC Orotic acid Carbaglu test DNA tests

Hyperammonaemia with ketoacidosis “Intoxication” type, 0–3 days “well” period, dehydration.

Acidosis +/+++ Ketone urine test +/+++

NH3 ↑ +/+++ Lactate +/ ++ Blood count: BMS

OA (7 Chap. 18), PC (7 Chap. 11), MCD (7 Chap. 27)

AAC, OAC Carbaglu test + (OA) Biotin test + (MCD)

Hyperammonaemia with hypoketotic hypoglycaemia Moderate liver findings Cardiac failure, cardiac arrythmias, muscle involvement

Acidosis 0/++ Ketone urine test 0/+/−

NH3 ↑ +/+++ Lactate N or ↑ + Blood count N Glucose ↓ +/+++

FAO defects HI/HH syndrome (7 Chap. 12)

OAC carnitine Acylcarnitine FAO studies DNA tests Insulin

Hyperammonaemia with elevated lactate Cardiomyopathy (TMEM 70)

Acidosis 0/++ Ketone urine test ++/0

NH3 ↑ +/++ Lactate ↑ +/+++ Citrulline↑ +

PC, MCD, MAS TMEM70, (with high citrulline PDH, Krebs cycle defects

L/Pyr (P) OAC (U) Enzyme test DNA tests

27 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.4 (continued) Clinical types

V

Acidosis/Ketosis

Other signs

Metabolic test

CHI and CHI like (7 Chap. 9) FAO GSD I and III FBPase deficiency HFI, galactosemia, Tyr I, TALDO, hemochromatosis, Mito DNA depletion

See later 7 Chap. 3

With severe hypoglycaemia Recurrent seizures, hypotonia, and lethargy are mostly linked to hypoglycaemia and improve quickly after blood glucose comes back to normal (but in FAO)

VI

Most likely diagnosis (disorder/enzyme deficiency)

With no first line metabolic disturbances (see . Table 1.5)

N normal (normal values = NH3 100 times upper limit of normal), recurrent pigmenturia, and sometimes acute renal failure. In the last instance, or when the patient is in a comatose state, clinical muscular symptoms can be missed. An important rule is to check serum CK and for myoglobinuria in such conditions. Rhabdomyolysis may be also observed in acute intermittent porphyrias. The spectrum of genetic susceptibility for rhabdomyolysis has not yet been completely clarified and the following criteria have been listed to trigger an extensive genetic investigation [45]: RHABDO. 5 R – Recurrent episodes of exertional rhabdomyolysis 5 H – HyperCKaemia more than 8 weeks after event 5 A – Accustomed to exercise 5 B – Blood creatine kinase (CK) >50 × upper limit of normal 5 D – Drug ingestion insufficient to explain exertional rhabdomyolysis 5 O – Other family members affected or other exertional symptoms (e.g., cramps or myalgia) The disorders of muscle energy metabolism present in two ways: 1.4.6.1

Glycolytic Disorders

In the glycolytic disorders, exercising muscle is most vulnerable during the initial stages of exercise and during intense exercise. A ‘second-wind’ phenomenon

sometimes develops. Clinically, the glycolytic disorders are mostly observed in late childhood, adolescence, or adulthood. The CK levels remain elevated in most patients. The most frequent and typical disorder in this group is McArdle disease (7 Sect. 5.2.1). 1.4.6.2

FAO Disorders

In the FAO disorders, attacks of myoglobinuria occur typically after mild to moderate prolonged exercise and are particularly likely when patients are additionally stressed by fasting, cold, or infection. This group is largely dominated by muscle CPT II, VLCAD, LCHAD and trifunctional (TF) deficiencies, which may occur in childhood, in adolescence, or later. Recurrent rhabdomyolysis has been described in a child with GAI (7 Chap. 22) and recently in one patient with an FAD transporter defect (7 Sect. 12.2). Deficiencies of VLCAD and SCHAD may also present with a myopathy. 1.4.6.3

Complex Molecules Disorders

Mutations in TANGO2 (7 Sect. 44.3.1) present in infants and children with episodic rhabdomyolysis, hypoglycaemia, hyperammonaemia, and susceptibility to lifethreatening cardiac tachyarrhythmias mimicking a FAO. Similarly, mutations in TRAPPC2L may present with the combination of febrile illness-induced encephalopathy and rhabdomyolysis [46] (7 Sect. 44.3.1). Mutations in RYR 1 encoding the ryanodine receptor present with muscle rigidity and rhabdomyolysis when affected individuals are exposed to general anaesthesia from infancy (recessive mutations) to adults (dominant mutations) [47]. LPIN1 gene mutations should be regarded as a major cause of severe fever induced myoglobinuria in infancy and rarely in adults (7 Sect. 35.1.4). Recurrent rhabdomyolysis and stroke like episodes has been described in a single adult patient with racemase deficiency (AMACR) (7 Sect. 42.2.4). 1.4.6.4

Other Causes

Adenylate deaminase deficiency has been suspected to cause exercise intolerance and cramps in a few patients, but the relationship between clinical symptoms and the enzyme defect is uncertain (7 Sect. 32.4.1). Respiratory chain disorders (RCD) can present with recurrent muscle pain and myoglobinuria from neonatal period to adolescence often associated with cardiomyopathy or diverse neurologic signs (encephalomyopathy) (7 Chap. 10). A case of lipoamide dehydrogenase deficiency presenting with recurrent myoglobinuria has been described in an adult. It is not clear whether normo- and hyperkalaemic paralysis due to sodium channel gene mutations may present with attacks of exercise intolerance. Attention has been directed toward myoglobinuria associated with Xp21-linked myopathies. (Becker syndrome). Dystonic

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1

crises occurring in GLUT1DS and PDH deficiency may clinically mimic cramping. Cramp fasciculations syndrome is a rare muscular hyperexcitability disorder characterized by spontaneous, painful muscle cramps and diffuse fasciculations, predominantly in the lower extremities. This syndrome has been recently shown to be linked to mutations in Transient receptor potential ankyrin 1 (TRPA1) a plasmalemmal cation channel and is carbamazepine responsive [48]. Chvostek and Trousseau’s signs, spasticity and tetany, cramps, paraesthesia or even cardiac arrest are common presenting signs in congenital hypomagnesemias (7 Sect. 34.3). 1.4.7

Abdominal Pain (Recurrent Attacks)

. Table 1.10 contains all pertinent information on recurrent attacks of abdominal pain. Mevalonic aciduria due to mevalonate kinase deficiency can present as recurrent attacks of abdominal pain with fever, skin rashes, arthralgias, and inflammatory syndrome and hyper IgD mimicking Mediterranean fever (7 Sect. 37.1).

1.4.8

Cardiac Failure, Cardiac Arrhythmias and Cardiomyopathy (. Tables 1.11 and 1.12)

Acute cardiac failure, arrythmia and cardiomyopathy non obstructive (CMNO) can be the first signs in many IEM. 1.4.8.1

With flatulence, diarrhoea, loose stools

Diacylglycerol acyltransferase 1 deficiency Lactose malabsorption Congenital sucrase isomaltase deficiency

With vomiting, lethargy, ketoacidosis

Urea cycle defects (OTC, ASA) Organic acidurias (MMA, PA, IVA) Ketolysis defects Respiratory chain disorders Diabetes

With neuropathy, psychiatric symptoms

Porphyrias Tyrosinemia type I acute crisis OTC (late onset) MNGIE syndrome (intestinal obstruction)

With fatigue, weakness

Hemochromatosis

With hepatomegaly and splenomegaly

Cholesterol ester storage disease Lipoprotein lipase deficiency Lysinuric protein intolerance MPI-CDG (protein losing enteropathy) Hemochromatosis Mevalonate kinase deficiency

With pain in extremities

Fabry disease δ-aminolevulinate dehydratase deficiency Sickle cell anaemia

With hemolytic anemia

Acute intermittent porphyria, Coproporphyria Hereditary spherocytosis Sickle cell anemia Nocturnal paroxysmal hemoglobinuria

With Crohn/Pseudo Crohn disease

Trifunctional enzyme deficiency(?) Carnitine transporter deficiency (?) Glycogenosis type Ib

With inflammatory syndrome (fever rash, IC reactive protein)

Hyper IgD syndrome (mevalonate kinase deficiency)

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is a preponderant presenting sign in (1) several glycogen disorders (Pompe and Danon disease, AMP activated protein kinase, GSD III, GSD 0b, RBCK1 and GYG1 (Glycogenin) mutations (7 Sect. 5.2) (2) all long-chain FAO disorders except CPT I deficiency, and MADD (7 Chap. 12), (3) some RCD (7 Chap. 10), and Barth and Sengers syndromes (7 Sects. 35.3.6 and 35.3.8). Fatal congenital heart glycogenosis due to mutation in PRKAG2 can initially mimic RCD, or trifunctional enzyme deficiency when generalized hypotonia is associated with cardiomyopathy. In adults PRKAG2/AMPK clinical phenotype displays a hypertrophic cardiomyopathy and preexcitation syndrome (Wolf Parkinson White and atrioventricular block) (7 Sect. 5.2). Many other IEM cause syndromic CMNO including lysosomal storage diseases and trafficking disorders (7 Chap. 44) (. Table 1.12). 1.4.8.2

. Table 1.10 Abdominal pain

Dilated Cardiomyopathy

Dilated cardiomyopathy is a major sign in several dolichol synthesis/recycling defects and in COG7-CDG (7 Chap. 43). PMM2-CDG may at times present in infancy

as tamponade with pericardial effusion, multiorgan failure, and characteristic cutaneous and neurologic features. Pericardial effusion associated with severe fatty liver has been observed in late onset type II glutaric aciduria. Isolated isobutyryl CoA dehydrogenase deficiency presenting with dilated cardiomyopathy has been recently described (7 Sect. 18.6). 1.4.8.3

Arrhytmias and Conduction

Alternatively, heart failure may result from disturbed cardiac rhythm. In congenital hypoparathyroidism and pseudohypoparathyroidism, cardiac failure can be the

39 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.11 Arrhythmias, conduction defects Primary or preponderant dysrhythmias

Secondary to ion disturbances Adrenal dysfunction (hyperkalemia) Hypoparathyroidism (hypocalcemia): prolonged QT interval Congenital hypomagnesemias: prolonged QT interval (especially with concomitant hypokalemia) Cardiac sodium and potassium channels genes mutations SCN5A, KVLQT1, and HERG Cardiac glycogenosis (7 Sect. 5.2) Pompe, Danon disease (short PR interval, high QRS complexes) AMP activated protein kinase (PRKAG2: WPW, supraventricular arrhythmias Primary and secondary energy deficiency+/− intoxication process FAO (7 Chap. 12), TANGO2 mutations (7 Sect. 44.3.1) Carnitine transporter defect (only in adults) Phytanyl CoA hydroxylase deficiency (Adult Refsum disease) (7 Sect. 42.3) Triose phosphate isomerase deficiency (7 Sect. 7.3) Kearns-Sayre syndrome (7 Sect. 10.1, . Table 10.2) Propionic acidaemia (prolonged QTc) (7 Sect. 18.1.1) Thiamine deficiency/dependent states (7 Sect. 29.1) D2-hydroxyglutaric aciduria (AV block) (7 Sect. 22.8)

With cardiac/ multiorgan failure

PMM2-CDG (Ia) (with tam 7 Sect. 43.1.1) Timothy syndrome (de novo CaV1.2 missense mutation G406R.)

WPW Wolf Parkinson White, AV auriculoventricular, CPT carnitine palmitoyl transferase, LCAD/LCHAD/VLCAD long/3hydroxy long/very long chain acyl-CoA dehydrogenase, TF trifunctional enzyme, CDG congenital disorders of glycosylation

. Table 1.12 Cardiomyopathies Complex molecules accumulation disorders (accumulated compounds in parenthesis) Glycogenosis (7 Chap. 5) (glycogen)

AMP activated protein kinase (presenting sign) Glycogenosis type III, and IV (can be presenting sign) Glycogenin 1 and RBCK1 (adult presenting sign) Muscular glycogen synthetase (GSD0b) (presenting sign) NO glycogen accumulation Pompe disease, Danon disease (with eye fundus abnormality) (presenting sign in both)

LSD (7 Chaps. 40 and 41) (sphingolipids, GAGs) Lipopigments

Fabry disease (may be presenting sign with myocardial infarction) or conduction defects GM1 gangliosidosis MPS cardiac valve disease with thickening of valves is common in MPS with accumulation of dermatan sulfate and MLIII Infantile free sialic acid storage disease (ISSD), MLII, MLIII CLN3 (adolescents to adults)

Complex lipids (7 Chap. 35) (phospholipids, neutral lipids)

Neutral lipid storage myopathy (Chanarin Dorfman and PNPLA2) Lipin1

Disorders involving energy metabolism

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J.-M. Saudubray and Á. Garcia-Cazorla

. Table 1.12 (continued) Mitochondrial disorders (7 Chap. 10)

Primary respiratory chain defects Barth (3 methylglutaconic aciduria) Sengers syndrome Friedreich ataxia (presenting sign) Mitochondrial DNA depletion syndrome Dilated cardiomyopathy with ataxia syndrome (DNAJC19 mutations) BOLA3 deficiency (with severe neurological dysfunction in infancy) TMEM70 mutations (complex V)

CoA synthesis defect (7 Sect. 34.2.3)

PPCS mutations

FAO disorders (presenting sign) (7 Chap. 12)

Carnitine transport defect and all FAO disorders except CPT1

Thiamine metabolism defect (7 Chap. 29)

Thiamine responsive anaemia Thiamine deficiency states (BeriBeri)

TCA Krebs cycle deficiency

Succinate dehydrogenase deficiency (7 Sect. 11.7)

Small molecules catabolism defects (secondary energy deficiency, +/− intoxication) Branched chain amino acid (7 Chap. 18)

MMA (Cbl C) and rarely MMCoA mutase, malonic aciduria Propionic aciduria 3-Ketothiolase deficiency Isobutyryl-CoA dehydrogenase Short-chain enoyl-CoA hydratase deficiency (with Leigh like syndrome)

Disorders of intracellular trafficking CDG syndromes (7 Chap. 43)

PMM2-CDG (with pericardial effusion, can be the presenting sign) (COG7-CDG) defects (CDG IIe: dilated cardiomyopathy) Dolichol synthesis/recycling disorders (SRD5A3, DOLK, and DPM3-CDG): dilated cardiomyopathy

Vesicular, organelles and cytoskeleton trafficking disorders (7 Chap. 44)

Familial hypertrophic cardiomyopathy (CAV3) Martsolf syndrome (RAB3GAP2) Vici syndrome (EPG5) Wolfram syndrome (WFS1) ATAD3A mutations (hypertrophic CMNO with neurodegeneration)

Miscellaneous

Congenital muscle dystrophies Steinert disease myotonic dystrophy Selenium deficiency Taurine transporter deficiency (SLC6A6) (7 Sect. 25.8) [49] Tyrosinemia type 1 (long term complication)

consequence of severe hypocalcemia with a prolonged QT interval on ECG. Several arrhythmia susceptibility genes which encode cardiac sodium and potassium channels, such as SCN5A, KVLQT1, and HERG mutations, have been described. In the vast majority of such arrhythmia syndromes, individuals appear normal except for subtle electrocardiographic abnormalities.

Timothy syndrome is due to mutations in CACNA1C encoding CaV1.2, the cardiac L-type calcium channel causing nearly complete loss of voltage-dependent channel inactivation. It is a multiorgan disorder including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycaemia, cognitive abnormalities, and autism [50].

41 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

In Kearns-Sayre syndrome (KSS) (7 Sect. 10.2), as in PRKAG2/AMPK (7 Sect. 5.2), atrioventricular block with syncope is a classic sign. In the rare disorder triosephosphate isomerase deficiency, which presents early in infancy as hemolytic anemia and progressive neurologic dysfunction, arrhythmia may cause sudden cardiac death (7 Sect. 7.3). A hyperkinetic hemodynamic state with sinus tachycardia, a classic finding in hyperthyroidism is also an early presenting sign in thiamine-deficient and dependent states associated with lactic acidosis which can be dramatically relieved by thiamine administration (7 Sect. 29.1). Finally, all long-chain FAO disorders except CPT I deficiency can present in early infancy, even in the neonatal period, with cardiac arrest or hypotension, which is readily misdiagnosed as toxic shock or malignant hyperthermia. Disorders of heart rhythm (premature ventricular complexes, atrioventricular block, and ventricular tachycardia) are frequent features (7 Chap. 12). Mechanisms of cardiac conduction defects observed in Adult Refsum disease are not fully elucidated (7 Sect. 42.3). Extreme sinus tachycardia with acute hypertension are hallmarks of an acute intermittent porphyria crisis (7 Sect. 33.2.2).

1.4.9

Age at onset

Disorder

Congenital, neonatal 15 h).

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This timing may vary with age and nutritional state (7 Chap. 3). The clinical approach to hypoglycaemia is based on four major clinical criteria: 5 the liver size, 5 the characteristic timing of hypoglycaemia, 5 the association with lactic acidosis (suggesting impairment of gluconeogenesis), and 5 the association with hyperketosis or hypoketosis (the latter suggesting FAO or ketogenesis disorders, hyperinsulinism and INSR/PI3K/AKT signalling pathway defects) (7 Chap. 6). Crucial information comes from the timing of hypoglycaemia which can be: 5 unpredictable and only postprandial: 2.5 h to 8 hours (suggests glycogenosis type I, III or 0), 5 after a moderate to long fast >8 h to 24 h (suggests gluconeogenesis defects: ‘enzymatic’ causes such as FBPase and PEPCKC deficiency or of ‘energetic’ causes, mostly FAO and ketogenesis defects and RCD). Other clinical findings of interest are hepatic failure, vascular hypotension, dehydration, short stature, neonatal body size (head circumference, weight and height), and evidence of encephalopathy, myopathy, or cardiomyopathy. Based on the liver size, hypoglycaemia s can be classified into two major groups: 5 Hypoglycaemia with permanent hepatomegaly. Hypoglycaemia associated with permanent hepatomegaly is usually due to an IEM. When hepatomegaly is the most prominent feature without liver failure, GSD type I and type III are the most likely diagnoses. FBPase deficiency and mitochondrial FAO defects may present with a major to moderate hepatomegaly during hypoglycaemic attacks. Disorders presenting with hepatic fibrosis and cirrhosis, such as hereditary tyrosinemia type I, also can give rise to hypoglycaemia. The late-onset form of HFI rarely, if ever, presents with isolated postprandial fructose induced hypoglycemic attacks (7 Sect. 15.2). S-adenosyl homocysteine hydrolase deficiency presents with fasting hypoglycaemia and liver failure, often triggered by high protein or methionine ingestion, and is associated with marked hypermethioninemia (7 Sect. 20.4). RCD (complex III deficiency UQCRB mutation) can present with liver failure, hypoglycaemia and fasting lactic acidosis which can mimic FBPase deficiency (7 Chap. 10). PMM2 and MPICDG (phosphomannose isomerase deficiency) with

hepatic fibrosis and exudative enteropathy can cause hypoglycaemia early in infancy (7 Sect. 43.1.2) 5 Hypoglycaemia without permanent hepatomegaly. It is important to determine the timing of hypoglycaemia and to look for metabolic acidosis and ketosis when the patient is hypoglycaemic. Unpredictable hypoglycaemic attacks occurring postprandial or after a very short fast and without ketosis are mostly due to hyperinsulinism (congenital or Munchausen by proxy) (7 Chap. 6) at any age, or to growth hormone deficiency or related disorders in early infancy. Adenosine kinase deficiency may also present early in infancy with hyperinsulinaemic hypoglycaemia (7 Sect. 32.5.1). Most episodes of hypoglycaemia, due to IEM that are not accompanied by permanent hepatomegaly, appear after at least 8 h of fasting. This is particularly true for inherited FAO disorders except in the neonatal period. Severe fasting Hypoglycaemia without ketosis, strongly suggests FAO disorders (without severe acidosis) (7 Chap. 12), HMG-CoA lyase deficiency, or HMG-CoA synthetase deficiency (with acidosis) (7 Sect. 13.1) and PEPCKC (7 Sect. 11.2). When ketoacidosis is present at the time of hypoglycaemia, ketolytic defects (7 Chap. 13), OA, late-onset MSUD (7 Sect. 18.1), and glycerol kinase deficiencies (7 Sect. 7.8) should be considered but hypoglycaemia is very rarely the presenting metabolic abnormality in these disorders. Adrenal insufficiencies (including those presenting undiagnosed X-ALD) should be systematically considered in the differential diagnosis, especially when vascular hypotension, dehydration, and hyponatremia are present. Fasting Hypoglycaemia with ketosis occurring mainly in the morning and in the absence of metabolic acidosis suggests recurrent “idiopathic” ketotic hypoglycaemia, which presents mostly in late infancy or childhood in those who were small for gestational age or with macrocephaly. This pattern is rarely associated with IEM but glycogen synthetase deficiency with intermittent glycosuria that is underrecognized (see below 7 Sect. 1.4.19) (7 Sect. 5.1.1). All types of adrenal insufficiencies (peripheral or central) can share this presentation. SCHAD and MCAD deficiency can rarely present as recurrent attacks of ketotic Hypoglycaemia (7 Chap. 12) as can glycogen synthetase deficiency. . Figure 1.4 summarizes the simplified diagnostic approach to hypoglycaemia. Although not a constant finding, some neurotransmitter defects (aminoacid decarboxylase deficiency (AADC) and dopamine beta-hydroxylase deficiency) can also present with hypoketotic hypoglycaemia, especially in stressful situations (7 Sect. 30.5). Additionally, pyridoxine-dependent epilepsy can present with profound hypoglycaemia associated with hyperlactataemia (7 Sect. 29.2.1).

47 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

Timing

Liver size

Metabolit es

Hyperinsulinism Factitious

Hec tic, Permanen t

At fast Permanent Hepatomegaly

High Lac tate

Sho rt fast: GSD Ia and b Long fast: FBP, FAO with acidosis

Post prandial HYPOGLYCEMIA

No acidosi s

At fast

Yes Post prandial Exposur e

Without Hepatomegaly

Hereditar y fruc tose intoleranc e Hyperinsulinism Galac tosemia

. Fig. 1.4 Diagnostic approach to hypoglycaemia in paediatrics based on the timing of hypoglycaemia, the size of the liver and the metabolic profile. GSD glycogen storage disease, FBP fructose

1.4.16

Hyperammonaemia

Many IEM can give rise to hyperammonaemia. In the context of acute neonatal encephalopathy, (see . Table 1.4) severe hyperammonaemia (>500 μmol/l) is generally caused either by a UCD (with respiratory alkalosis, no ketosis and no bone marrow suppression) or by an OA (PA, MMA, IVA with metabolic acidosis, ketosis and leuco-thrombocytopenia) (7 Sect. 18.1.1). Plasma glutamine is generally elevated in UCD (>1000 μmol/l) and LPI while it is close to normal or low (6 mmol/l) and hyperketosis suggests PC (with low glutamine and high citrulline), GOT2 (with high citrulline and low serine) (7 Sect. 11.11), MCD (7 Chap. 27), or carbonic anhydrase VA deficiencies (7 Sect. 19.4.2), both with suggestive organic acid profiles.

GSD III (hig h CK ) GSD VI, IX

Ketosis

No or lo w

Ketotic hypoglycemia Glycogen synthase MCAD , SCAD TANGO2 mutations (with ketoacidosis)

Fatty acid o xidation Ketogenesis def ects PEPC KC deficienc y Hyperinsulinism

biphosphatase, FAO fatty acid oxidation, MCAD medium chain acyl CoA dehydrogenase, SCAD short chain acyl CoA dehydrogenase

In a context of severe hypoketotic hypoglycaemia, hyperammonaemia (in general NH3 60 mg/l (360 μmol/l) must be always considered abnormal. Hyperuricaemia can result from excessive input, decreased output or both, with regard to the uric acid (UA) pool. Input derives from cellular catabolism of the nucleic acids, purine synthesis and degradation of purines in food. Output results from bacterial intestinal destruction and renal elimination. UA filtered by glomeruli is reabsorbed in the proximal tubule; urinary UA comes from distal secretion which is competitive with organic acids (lactic, MMA, PA…). Several tubular UA transporters have been already described, SLC22A12 (type I), SLC2A9 (type II) and GLUT9 acting probably in a multimolecular complex ‘transportosome’ allowing cooperation between multiple transporters [55, 56]. Secondary hyperuricaemias with low to very low UA excretion are observed in transient neonatal hyperuricaemia and in renal failure from all causes and can be caused by a variety of other disorders: hyperlactataemia s, GSD1, OAs such as MMA (in which gout crisis and hyperuricaemic nephropathy can be a presenting sign), muscular GSDs and FAO defects in acute crisis and during treatment with dichloroacetate, and after a fructose load. Hyperuricaemia is a prominent finding in the recently described HUPRA syndrome (Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis) linked to SARS 2 mutations (7 Chap. 39). Primary hyperuricaemias with high UA excretion are seen in primary classic gout and in the rare disorders PRPP synthetase superactivity and Lesch-Nyhan syndrome (HGPRT deficiency). Primary hypouricaemias can result from decreased UA production, as observed in xanthine oxidase and molybdenum co-factor deficiency (with almost no UA in urine) and purine nucleoside phosphorylase, PRPPsynthetase and guanine desaminase deficiency (with low UA excretion), but is more commonly due to decreased renal tubular UA reabsorption. Cytosolic 5′ nucleotidase superactivity results in marked hypouricosuria (7 Chap. 32). Renal hypouricaemia is constant in cystinosis (Fanconi syndrome) (7 Chap. 26). It is also due to renal UA transporter defects characterised by blood uric acid 1 year to 18 years)

In this period, diagnosis becomes easier. Symptoms tend to express in a different manner depending on the age ranges: early childhood (up to 2 years of age), mid to late childhood (2–12 years), adolescence (12–18 years). Six general categories can be defined according to the accompanying signs and leading symptom: 1-with extraneurological/somatic abnormalities (. Table 1.16) 2- with predominant epilepsy (. Tables 1.17 and 1.18) 3- with abnormal movements (. Table 1.19) 4- with complex motor disorders (. Table 1.20) 5- with predominant intellectual disability and/or behavioural and neuropsychiatric manifestations, 6- with predominant neuroregression.

1.5.2.1

Category 1: With Visceral, Craniovertebral, Ocular, or Other Somatic Abnormalities (. Table 1.16)

These symptoms associated with a slowing or regression of development, suggest MPS types I and II, mucolipidosis type III, oligosaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease type C, Gaucher disease type III, and lactosyl ceramidosis, all disorders which are usually easy to recognize. Mucolipidosis type

. Table 1.16 Prominent neurological involvement with extraneurological signs >1 year to 18 years Symptoms

Diagnosis (disorder/enzyme deficiency)

With visceral, craniovertebral, or other somatic abnormalities Coarse facies, skeletal change

MPS I, MPS II, MPS III, MLP III, (hirsutism, corneal opacities) AIFM1 mutation (Spondyloepimetaphyseal dysplasia with severe neurodegeneration)

Coarse facies, subtle bone changes, lens/corneal opacities, hepatosplenomegaly, vacuolated lymphocytes

Mannosidosis (gingival hyperplasia) Fucosidosis (angiokeratoma) Aspartylglucosaminuria (joint laxity) Multiple sulfatase deficiency (ichthyosis)

Hepatosplenomegaly, progressive dementia, myoclonic jerks

Niemann-Pick type C and related disorders (vertical supranuclear ophthalmoplegia)

Splenomegaly + hepatomegaly, osseous lesions, (ataxia, myoclonus)

Gaucher disease type III (supranuclear ophthalmoplegia)

Major visual impairment, blindness

Mucolipidosis type IV (corneal clouding)

Retinitis pigmentosa, deafness

Peroxisomal defects, Usher syndrome type II

Cataract, joint laxity, hypotonia

Pyrroline-5-carboxylase synthetase

Cutis laxa, hypotonia

PI4K2A mutation

Congenital cataracts multiple respiratory illnesses, progressive short stature and mild global developmental delay

Phosphatidyl serine decarboxylase deficiency

Recurrent lung infections with developmental delay, failure to thrive, immunodeficiency, leukoencephalopathy

NFE2L2 mutations causing NRF2 accumulation that leads to overtranscription of genes involved in cytosolic redox balance

1

56

1

J.-M. Saudubray and Á. Garcia-Cazorla

IV, which causes major visual impairment by the end of the first year of life, sometimes associated with dystonia, presents with characteristic cytoplasmic membranous bodies in cells. In MPS III, coarse facies and bone changes may be very subtle or absent with only abundant and hirsute hair. Peroxisomal disorders may present at this age, with progressive mental deterioration, retinitis pigmentosa, and deafness, and in a very similar manner to Usher syndrome type II. Pyrroline5-carboxylate-synthase deficiency presents with slowly progressive neurological and mental deterioration, severe hypotonia, joint laxity, and congenital cataracts (7 Sect. 21.3). Sjogren Larsson syndrome and ELOVL4 deficiency present with ichthyosis and spastic paraplegia (7 Sect. 42.4). 1.5.2.2

Category 2: With Predominant Epilepsy (. Tables 1.17 and 1.18)

Epilepsy is an important sign of many neurometabolic disorders and reflects the excitatory/inhibitory imbalance of neuronal activity caused by these conditions. In most cases, the semiology of seizures and EEG patterns are determined by the age of presentation: (i) Early myoclonic epilepsy in the neonatal period (7 Sect. 1.3.2); (ii) Infantile spasms, West syndrome, in severe epilepsies of early and late infancy; (iii) Progressive myoclonic epilepsy phenotype in late childhood, adolescence or young patients. A large number of diseases may cause epilepsy as a major clinical feature beyond the neonatal period and include all pathophysiological categories of IEM (. Table 1.17). Epileptic encephalopathies (refractory seizures leading to neurological deterioration) may be a relevant form of presentation during the first 2 years of life. Some of them are late-onset forms of diseases that are typically seen in the neonatal period. In these severe forms, the EEG may show slow background, multi-focal spikes and burst-suppression pattern. Attenuated forms of pyridoxine dependent seizures, PNPO deficiency and other vitamin dependent epilepsies should be considered also at these onset ages. In childhood and adolescence, mitochondrial disorders and late infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL), are amongst the most common neurometabolic conditions with prominent seizures. Progressive myoclonic epilepsies (PMEs) are more likely to appear during these periods of life. They are characterized by progressive myoclonus, epileptic seizures and in most cases, dementia and ataxia. PMEs include Lafora disease, NCLs, sialidosis type I, myoclonus epilepsy and ragged red fibres (MERRF), Gaucher disease type 3, ASAH1 (N-Acylsphingosine amidohydrolase) associated to spinal muscle atrophy (a specific form of Farber disease), some complex lipid defects such as ceramide synthetase deficiency, and SCARB

mutations that encodes a cell trafficking protein (LMP2) and causes action myoclonus renal failure syndrome. Other non-metabolic diseases such as UnverrichtLundborg disease, dentatorubral-pallidoluysian atrophy (DRPLA), neuroserpinosis, and KCNC1 related diseases [61] are also causes of PMEs. Other types of seizures occasionally raise suspicion for a specific disorder. This is the case with epilepsia partialis continua in POLG-related disorder and acute intermittent porphyria, migrating partial seizures of infancy in some CDG syndromes and mitochondrial glutamate transporter defect, drop attacks and LennoxGastaut syndrome in GAMT deficiency, and myoclonicastatic seizures in cerebral folate deficiency. By contrast, in most cases, the aetiology of seizures cannot be predicted from its semiology. This is the case of many mitochondrial disorders and GLUT1DS that present with a wide repertoire of seizure types [62]. Other than treatable disorders (. Table 1.17), emerging non-treatable new categories of IEM with prominent epilepsy are complex lipid defects, aminoacyl-tRNA synthetases and cell trafficking disorders, in particular GPI-anchor biosynthesis defects and synaptic vesicle disorders that in general, associate intellectual disability, abnormal movements and neuropsychiatric manifestations. In infants and children up to 3 years of age, also consider the possibility of genetic epilepsies, such as some forms of KCNQ2, with an excellent response to specific antiepileptic drugs [63]. Other than . Table 1.17 key symptoms that may help in the differential diagnosis are in the . Table 1.18. 1.5.2.3

z

Category 3: With Predominant Abnormal Movements: Ataxia, Hyper and Hypokinetic Movements (. Table 1.19)

Movement disorders (MD)

Are among the most usual neurological symptoms in children with IEMs, present in about 70% of these diseases. MD are classified in hyperkinetic and hypokinetic. Hyperkinetic MD refers to an unwanted excess of movements and include dystonia, choreoathetosis, tremor, myoclonus, tics, and stereotypies. Hypokinetic movements are called hypokinetic-rigid syndrome or Parkinsonism. Ataxia, not initially considered in this classification, is now progressively being included as hyperkinetic MD. Most IEMs that present with MD exhibit more than one abnormal movement and all types can be present in IEM. However, tics, that are the most prevalent MD in the general population, are almost absent in IEM although can appear in two neurodegenerative disorders: neuroacanthocytosis and Hungtinton’s disease.

Onset age

EEG

Other neurological and clinical features

Brain image

Hypsarrhythmia (infantile spasms), variable EEG patterns

Multifocal, partial spikes, variable

Slow background, multi-focal spikes, burst-suppression pattern Multi-focal spikes Multi-focal spikes, variable Slow background, multifocal spikes Multi-focal spikes, variable. Myoclonicastatic seizures Multi-focal and partial spikes, variable

1

1,2

1, 2 (attenuated)

1 1

1

1,2 1

1,2,3 1,2,3

Serine synthesis and transport def. (7 Sect. 24.2)

BCAA transport def. SLCA5 (7 Sect. 25.6)

Pyridoxine-dependent PNPO (7 Sect. 29.2) Hypophosphatasia (7 Sect. 29.2.4)

Biotinidase, HCS deficiency (7 Sect. 27.1.1)

SLC5A6 (7 Sect. 27.1.3)

Folate defects (7 Sect. 28.3) FOLR deficiency SLC46A1 (absorption)

Cbl C disease (7 Sect. 28.2.1) MTHFR deficiency (7 Sect. 28.3.7)

Slow background due to encephalopathy

1 1,2

Urea cycle disorders Organic acidurias

DD, ID, psychiatric symptoms, abnormal movements, parkinsonism.

FOLR: DD, hypotonia, abnormal movements SLC46A1: anaemia, diarrhoea, stomatitis

DD, regression, 1 child with peripheral neuropathy

Abnormal movements, developmental delay, myelopathy, dermatitis, alopecia

Abnormal movements (myoclonus, segmentary), developmental delay. Mild hyperlactataemia and hypoglycaemia.

Microcephaly, autistic-like and aggressive behaviour, growth retardation

DD, pyramidal signs, microcephaly, peripheral neuropathy, may have ichthyosis. Progressive microcephaly and spasticity: transport defect

Abnormal movements, hypotonia, developmental delay

Vascular stroke, BBGGa may appear. MTHFR: Normal to hydrocephalus

Normal to BBGG calcification, delayed myelination. SLC46A1: brain calcifications

Ca, WM hyperintensity

Normal to WMa, BBGGa and myelopathy changes

From normal to posterior fossa abnormalities and cortical malformations, dysgenetic CC

Delayed myelination

Delayed myelination, atrophy, may have cortical malformations.

Cortical and subcortical oedema, BBGG hyperintensities

I. Small molecule defects. Some disturb first line metabolic investigations (acidosis, hyperammonaemia, glucose, lactate). Most have plasma, urines or CSF metabolic markers either elevated or lowered with a typical or suggestive metabolic signature. Metabolomics for diagnostic purpose is available in some specialized centres.

Disease group

. Table 1.17 IEM with epilepsy as a prominent symptom

(continued)

Organic acids, total homocysteine, folate

FOLR: CSF folate SLC46A1: Plasma folate

Ca, WM hyperintensity

Plasma biotinidase activity, organic acids

PDE: High AASA and pipecolic acid; PNPO: Low PLP, high glycine, low NTs, alkaline phosphatase, phosphate, calcium

Low BCAA in plasma and CSF Only in CSF in transport def (?)

Low serine in plasma and CSF

Ammonia, AA

First line markers (. Table 1.3) Second line: AA, OA, acylcarnitine, metals, porphyrins, purines, pyrimidines, biopterins

Biomarkers

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 57

1

Multi-focal and partial spikes, variable

Irregular slowing, multifocal sharp waves and a periodic sharp wave pattern Slow background, multifocal waves Partial spikes (the most common)

Focal and generalized spikes. status epilepticus, epilepsia partialis continua Slow background, multifocal waves Slow background, multi-focal spikes, burst-suppression pattern Slow background, burst-suppression, multifocal abnormalities Slow background, multifocal spikes, burst-suppression pattern

1,2,3 TH, AADC, DHPR, PTPS

1,2

1

3

3

1

1 1

1,2 (attenuated)

1,2,3 SSADH 1 GABAT

Monoamine-BH4 def. (7 Sect. 30.5)

CAD deficiency (7 Sect. 32.1.10)

Menkes disease (7 Sect. 34.1.2)

Wilson (7 Sect. 34.1.1)

Porphyria (AIP) (7 Sect. 33.2.2)

MOCS1, isolated SUOX (7 Sects. 20.10 and 20.11)

GS deficiency (7 Sect. 24.1) AS deficiency (7 Sect. 24.3)

NKH chapter (7 Sect. 23.2)

GABA disorders (7 Sect. 30.1)

Hypersomnolence, choreoathetosis, DD, behavioural abnormalities. GABAT: macrocephaly

Lethargy, hypotonia, hiccup, myoclonus

Severe encephalopathy, microcephaly, erythema, necrotizing (GS)

Hypertonia, hyperekplexia, microcephaly, lethargy

Abdominal pain, sympathetic overactivity, psychiatric manifestations, peripheral neuropathy

Extrapyramidal syndrome, depression, 6% patients present with seizures. Sometimes, status epilepticus.

DD, pyramidal signs, hypotonia, kinky hair

Global encephalopathy, swallowing difficulties

Dopa-responsive MD, hypotonia, neonatal hypoglycaemia

Other neurological and clinical features

T2 hyperintensities of globi pallidi, dentate and subthalamic nucleus (SSADH)

Dysgenesis of the CC. T2 hyperintensities and DWI restriction of myelinated tracts

Cerebellar hypoplasia, cortical malformations

Hypoxic encephalopathy like, ventriculomegaly, BBGa, Ca

Posterior reversible encephalopathy signs may appear

BBGGa

Vessel tortuosity, subdural collections

Global brain atrophy

In general, normal. Myelination delay and cortical atrophy has been reported. BBGG calcifications in some BH4 defects.

Brain image

Hydroxybutyric acid (SSADH); GABA, beta-alanine and homocarnosine (GABAT)

High CSF glycine and CSF/ plasma glycine ratio

High ammonia, low glutamine, high asparagine

Uric acid, sulfite, sulfocysteine, total homocysteine

Porphyrins

Copper, ceruloplasmin

Copper, ceruloplasmin

Anaemia, acanthocytosis

CSF NT, biopterins plasma phenylalanine

Biomarkers

1

Other small molecule disorders with epilepsy as a prominent feature: AA and related disorders: Canavan disease (7 Sect. 22.10), adenosine kinase deficiency (high CPK, hypoglycaemia, liver dysfunction, S-adenosylhomocysteine) (7 Sect. 32.5.1), HSD10 disease, (7 Sect. 18.5), pyrroline-5-carboxylate dehydrogenase deficiency (hyperprolinaemia type 2) (7 Sect. 21.3), combined D-2- and L-2-HGA (7 Sect. 22.10), folate metabolism: MTHFS (7 Sect. 28.3.8), purine defects: ADSL deficiency (7 Sect. 32.1.2), ATIC deficiency (7 Sect. 32.1.3), ITPAse deficiency (7 Sect. 32.1.9), neurotransmitter disorders: GABA and glutamate receptor mutations (7 Sect. 30.1), synaptic vesicle disorders (7 Sect. 30.6) (see also cell trafficking diseases)

EEG

Onset age

Disease group

. Table 1.17 (continued)

58 J.-M. Saudubray and Á. Garcia-Cazorla

Variable, as well as the seizure type GAMT: Drop attacks, Lennox-Gastaut Multifocal spikes, myoclonic-absence Diffuse or focal slowing, focal and generalized spikes, hypsarrhythmia

Multifocal spikes; hypsarrhythmia in early onset presentations

1,2

1,2,3

1,2

1, 2 SLC19A3 1 SLC25A19

1 1,2

1,2,3

Creatine deficiency (7 Chap. 9)

HH syndrome (7 Chap. 6)

PDH (7 Sect. 11.3)

BRBG SLC19A3 (7 Sect. 29.1.2) SLC25A19 (7 Sect. 29.1.3)

Fumarase deficiency (FD)a (7 Sect. 11.8) Aconitase def (7 Sect. 11.9) GOT2 def (7 Sect. 11.11)

Mitochondrial defects (multiple genes) primary CoQ10 deficiency (7 Table 10.4) Various EEG patterns mainly slowing, multifocal or diffuse epileptic abnormalities, or hypsarrhythmia. POLG pattern: RHADS, epilepsia partialis continua

FD, ACO2: Infantile spasms, hypsarrhythmia, variable GOT2: focal, temporal spikes (generalized, tonic, myoclonic seizures)

Atypical absence EEG pattern, multifocal and partial spikes

1,2

GLUT1D (7 Sect. 8.3)

Early-onset cases may have up to 50% of epilepsy Seizure type are diverse and myoclonus is frequent. MERFF (2,3): characteristic myoclonic epilepsy POLG (1,2,3): liver involvement, parkinsonism MELAS (2,3): often, focal epilepsy starts before strokes

FD: Hypotonia, irritability, cerebral-palsy mimic. High fat, low carbohydrate diet may modify the disease course. ACO2: from neonatal encephalopathy to attenuated forms, optic atrophy, retinopathy, deafness, ataxia. GOT2: hypotonia, progressive microcephaly

Wernicke like encephalopathy and BRBG (SLC19A3); Amish microcephaly (SLC25A19)

Leigh syndrome, DD, ID, abnormal movements PDH deficiency is one of the most epileptogenic mitochondrial disorders

ID, leucine sensitive hyperinsulinism

ID, autism, speech disorders, abnormal movements

DD, ID (mild in general), movement disorders

BBGGa, cerebellar atrophy, WMa, POLG: progressive atrophy MELAS: stroke-like images

FD: May have cortical malformations: polymicrogyria, thin/absent CC ACO2: progressive cortical and cerebellar atrophy; GOT2; cystic encephalomalacia, cerebellar hypoplasia, thin CC

BBGG abnormalities

Normal to CC agenesis, periventricular cysts BBGGa

No specific pattern

BBGGa. (GAMT). Low Creatine peak: MRS

Normal

II. Energy metabolism defects. In mitochondrial disorders lactate and other markers may be disturbed mostly in children but often remain normal in adult cases. Diagnosis is complex more and more based on molecular investigations (7 Sect. 14.5)

(continued)

Lactate, pyruvate, AA, organic acids, coenzyme Q10 (muscle, plasma)

FD: Fumaric acid, lactate, amino acids GOT: Hyperlactataemia, mild hyperammonaemia and citrullinemia

Lactate, amino acids, alpha-ketoglutarate, CSF thiamine

High lactate, pyruvate, normal L/P

High ammonia, low glucose

Creatine, guanidinoacetate, MRS

Low CSF glucose and lactate; low CSF/serum glucose ratio

First line markers (. Table 1.3) (lactate…) AA OA function tests

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 59

1

Onset age

EEG

Other neurological and clinical features

Brain image

Biomarkers

1 VLCFA, plasmalogens, phytanic acid, oxysterols, MPS, oligosaccharides, sulfatides, sialic acid, lipidomics

Peroxisomal defects PBD (7 Sect. 42.2.9), DBP (7 Sect. 42.2.2) RCDP, FAR1, (7 Sect. 42.1) ACOX1 def; (7 Sect. 42.2.3), ELOVL4 (AR);(7 Sect. 42.4.6) X-ALD (7 Sect. 42.2.1)

All starting in infancy-early childhood (1) except X-ALD (2,3) and FAR1 (AD) (2)

Peroxisomal biogenesis disorders: Multifocal spikes; hypsarrhythmia Other diseases: variable EEG patterns

RCDP: ID, skeletal dysplasia, cataracts, seizures ELOVL4 (AR): ichthyosis, retinopathy, spasticity, ID mimicking SLS FAR1: cataract, spasticity

X-ALD: pathognomonic confluent WMa with gadolinium enhancement Perisylvian polymicrogyria and pachygyria; hypomyelination; subependymal cysts

VLCFA, plasmalogens, pristanic, phytanic acid Acylcarnitines

Lysosomal disorders: many can cause epilepsy, in particular at advanced stages of the disease. In most cases progressive myoclonus epilepsy with a slow EEG. The most frequent lysosomal disorders with prominent epilepsy according to age of presentation are: GM1 gangliosidosis (1) (7 Sect. 40.2.3), Gaucher disease type 2 (1) (7 Sect. 40.2.1), Sialidosis type 2 (1), Prosaposin deficiency (1) (7 Sect. 40.2.9), GM2 gangliosidosis (2) (7 Sect. 40.2.4), juvenile GM1 gangliosidosis (2), sialidosis type 1 (3) (7 Sect. 41.3.1), Gaucher disease type 3 (3), Niemann-Pick type C (3) (7 Sect. 40.2.2); and NCLs (1,2,3) (7 Sect. 40.5); acid ceramidase deficiency: spinal muscular atrophy and progressive myoclonic epilepsy (SMA-PME) (1,2,3) (7 Sect. 40.3.3); in infantile NCL: photic stimulation leads to occipital spikes and may trigger seizures. In CLN2 epilepsy may mimic Lennox-Gastaut syndrome (akinetic myoclonic petit mal)

III. Complex molecules defects. Many complex molecules accumulation defects like sphingolipidosis, sterols and some peroxisomal disorders may be suspected on clinical grounds and have robust metabolic markers. Most complex molecules synthesis and remodelling defects like complex lipids have no easy to reach metabolic markers and diagnosis is based on molecular investigations. Lipidomics become more and more accessible

Other energy metabolism defects with epilepsy as a prominent feature: mitochondrial glutamate transporter def (early migrating epilepsy), different genes involved in persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) (7 Chap. 9); lipoylation disorders: in particular lipoyltransferase 2 def, lipoic acid synthase def, ISCA1 def (high lactate, glycine, WM cavitation) (7 Sect. 23.2.3); aspartate-glutamate carrier 1 (SLC25A19) def (sporadic tonic seizures) (7 Sect. 11.11); FBXL4 deficiency (mitochondrial DNA deletion) (Table 14.2); disorders of glycolysis: Triosephosphate isomerase def (7 Sect. 7.3); phosphoglycerate kinase def (7 Sect. 7.4); pentose pathway defects: ribose 5-phosphate isomerase def (7 Sect. 7.9); ketone body utilization defects: homozygous MCT1 mutations (7 Sect. 13.3)

Disease group

. Table 1.17 (continued)

60 J.-M. Saudubray and Á. Garcia-Cazorla

DEGS1 (1,2) CERS1,2 (2, 3) GM3 synthase def (1) PLA2G6 (1,2,3) FA2H (1,2), PNPLA8 (1) Squalene synthase def (1) CTX (3, adult) CK (1) BSCL2 (1,2) DHA transport (1)

Lafora disease (2,3) (7 Sect. 5.3.1)

All (1)

Lipid metabolism defects Sphingolipid defects: (7 Sect. 40.1) DEGS1, CERS1, CERS2 GM3 synthase def Phospholipids: (7 Sect. 35.4) PLA2G6, PNPLA8 FA2H (7 Sect. 40.1.5) Cholesterol metabolism Squalene synthase def (7 Sect. 37.3) Sterol and bile acid metabolism: CTX (7 Sect. 38.4) CK syndrome, (7 Sect. 37.7.2.2) Others: BSCL2 (7 Sect. 35.2.2), Mfsd2a (7 Sect. 42.4.13), CK syndrome

Glycogen storage disease

Aminoacyl-tRNA synthetases and tRNA metabolism defects (7 Sect. 39.2.3 7 Table 39.1) Variable pattern DALRD3: includes myoclonic epilepsy

Slow background Progressive myoclonic epilepsy

Variable patterns PLA2G6: In the infantile neuroaxonal dystrophy type, diffuse fast beta-activity in stage I and II of sleep CERS1, 2: progressive myoclonic epilepsy

DALRD3: ID, severe seizures (including myoclonic), microcephaly, hypotonia, dystonia YRDC, GON7, LAGE3, OSGEP, TP53RK, TPRKB, WDR4: Galloway-Mowat syndrome SARS1: ID, microcephaly, seizures, ataxia CARS2, TARS2, NARS2, PARS2: complex encephalopathy

Neurodegeneration, dementia, ataxia, photosensitive seizures, cortical blindness, apraxia

DEGS1 (1,2):DD, ID, nystagmus, spasticity CERS1, 2: progressive myoclonic epilepsy, ataxia, ID GM3 synthase (1): Early severe epileptic encephalopathy, pharmacoresistant, with choreoathetosis, DD, optic atrophy and hyperpigmented lesions PLA2G6: infantile neuroaxonal dystrophy PNPLA8 (1,2): microcephaly, dystonia, spasticity Squalene synthase deficiency (1): brain malformations, dysmorphy, DD CTX: ID, cataracts, ataxia, abnormal movements, peripheral neuropathy CK syndrome: microcephaly, brain malformation, X-linked ID. Mfsd2 DHA transport (1): microcephaly, brain malformation BSCL2 (1,2): cardiomyopathy, spasticity, DD, ID

Hypomyelination, cerebellar and brainstem atrophy are frequent findings (7 Chap. 37)

Brain atrophy

DEGS1: hypomyelinating leukodystrophy FA2H (2): NBIA features PLA2G6: NBIA, cerebellar atrophy CERS1,2: cerebellar and/or brainstem atrophy PNPLA8: simplification of the gyral pattern, diffuse atrophy and Ca

(continued)

High lactate (not constant)

Skin biopsy: PAS + inclusions

DEGS1: increased dihydrosphingolipids in plasma CTX: cholesterol, sterols

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 61

1

Variable patterns

UBTF1 (2) SNORD118 (1)

Ribosomal biogenesis (7 Sect. 39.3)

UBTF1: Cognitive regression after a period of normal development; eventual severe ID SNORD118: neurodegeneration, spasticity, dystonia

Other neurological and clinical features

Neonatal: CNPNY3 (ER/cochaperone), HCFC1 (ER, nucleus, ATAD1: AMPA receptor trafficking defect. KIF5A (kinesin, anterograde transport): intractable neonatal myoclonus. PACS2: ER-mitochondria MCS defect. Seizures difficult to treat during the first year. Dysmorphism+cerebellar dysgenesis. SCARB encodes LMP2 causes action myoclonus renal failure syndrome (AMRF) Most golgipathies and tubulinopathies cause early-onset epilepsy (1,2) and often associate microcephaly, cortical malformation and hypomyelination Epilepsy (onset-age: 1,2) with high CPK levels: TANGO2 and TRAPPC related disorders

Cellular trafficking disorders (7 Chap. 44)

Sialotransferrin in some CDG forms, hyperphosphatasia

Biomarkers

Onset age: 1 newborn to infancy (up to 1 year), 2 early to mid-childhood (from 2 to 12 years), 3 adolescence AA amino acids, AADC L-amino acid decarboxylase deficiency, ABHD12 monoglycerol lipase, ACAT1 acetoacetyl-CoA thiolase deficiency, AD autosomal dominant, ADCY5 adenylate cyclase deficiency, ADL-X X-linked adrenoleukodystrophy, ADSL adenylosuccinate lyase deficiency, AIP acute intermittent porphyria, ALS amyotrophic lateral sclerosis, AMACR α-methylacyl-CoA racemase, AMPD AMP deaminase-2 deficiency, AR autosomal recessive, ARALAR mitochondrial protein involved in glutamate aspartate exchange encoded by SLC25A12, ARD (adult Refsum disease) phytanoyl-CoA 2-hydroxylase, ARG arginine, ARSA arylsulfatase A deficiency, AS asparagine synthetase, ATIC 5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria, Atten attenuated forms, ATIC 5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH, ATP8A2 encodes for a P4-ATPase that actively transports phospholipids across cell membranes (‘flipping’), BBGGa basal ganglia abnormalities, B4GALNT1 GM2/GD2 synthase deficiency, BCAA branched chain amino acids, C cerebellum, Ca cerebellar atrophy, CAD CAD trifunctional protein, carbamoylphosphate synthetase/aspartate transcarbamylase/dydroorotase, CC corpus callosum, CDG congenital disorders of glycosylation, CERS ceramide synthase, CIT citrulline, CK syndrome X-linked recessive sterol-4-alpha-carboxylate 3-dehydrogenase deficiency, CLBP mitochondrial quality protein control, CMH congenital methemoglobinemia, CMNO cardiomyopathy, CP cerebral palsy, CPTII carnitine palmitoyltransferase II deficiency, CTX cerebrotendinous xanthomatosis, CSF cerebrospinal fluid, CP cerebral palsy, DBP D-bifunctional protein, DD developmental delay, DEF deficit, DHPR dihydropyrimidine reductase deficiency, DEGS dihydroceramide delta4-desaturase, DHFR dihydrofolate reductase deficiency, DLP1 dynamin related protein 1. EAAT1 glutamate aspartate transporter deficiency (SLC25A22), DWI diffusion, ECHS1 mitochondrial short-chain enoyl-CoA hydratase deficiency, ELOVL elongation of very long chain fatty acids, encephalop encephalopathy, ENTPD ectonucleoside trisphosphate diphosphohydrolase I, EPT1 ethanolamine phosphotransferase, ETHE1 sulfur dioxygenase deficiency, FA2H fatty acid 2-hydroxylase deficiency, FAR1 fatty-acyl CoA reductase 1 deficiency, FHD fumarate hydratase deficiency, FOLR1 folate receptor alpha deficiency, GAMT guanidinoacetate methyltransferase, GA1 glutaric aciduria type 1, GABAR GABA receptor mutations, GABAT GABA transaminase deficiency, GALC galactocerebrosidase, GLUT1DS glut-1 deficiency syndrome, GORS Golgi SNAP receptor complex member 2, GOT2 glutamate oxaloacetate transaminase deficiency, GRIN mutations in NMDA glutamatergic receptors, GS glutamine synthetase, GSS glutathione synthetase deficiency, GTPCH guanosine triphosphate cyclohydroxylase, HCS deficiency holocarboxylase synthetase deficiency, HH hyperinsulinism-hyperammonaemia syndrome, HHH hyperornithinaemia-hyperammonaemia-homocitrullinaemia syndrome,

Epilepsy may appear in different CDG subtypes. PIGOPATHIES, defects in the GPI-anchor-biosynthesis pathway, are amongst the most representative causes of epilepsy (multiple types, dysmorphy, onset-age:1,2); HPMRS: Hyperphosphatasia and Mental Retardation Syndrome (global developmental delay with marked involvement of expressive language, coarse facial features, malformations, anorectal abnormalities and other malformations may be present). In PIGW (1 case described) the patient developed West syndrome. SLC35-A2-CDG: may respond to D-galactose supplementation

UBTF1: cerebellar and brain atrophy SNORD118: angiomatous-like blood vessels, leukoencephalopathy with calcifications

Brain image

1

CDG (1,2) (7 Chap. 43)

IV. Cellular trafficking disorders- In general without specific metabolic markers; diagnosis is based on DNA analysis.

EEG

Onset age

Disease group

. Table 1.17 (continued)

62 J.-M. Saudubray and Á. Garcia-Cazorla

HIBCH 3-hydroxyisobutyryl-CoA hydrolase deficiency, Homocyst homocysteine, HRS hypokinetic-rigid syndrome, HSD10 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, ID intellectual disability, INAD infantile neuroaxonal dystrophy, ITPase Inosine triphosphatase, ITPR1 inositol 1,4,5-triphosphate receptor, type1, IVA isovaleric aciduria, L2-HGA L2-hydroxyglutaric aciduria, L2HGDH L-2-hydroxyglutarate dehydrogenase deficiency, L,D2-HGA L and 2-D-hydroxyglutaric aciduria, LBSL leukodystrophy with brainstem and spinal cord involvement and lactate elevation, LN Lesch-Nyhan, MCGA1 3-methylglutaconic aciduria type 1, MECR Trans-Enoyl-CoA reductase, MELAS lactic acidosis, and strokelike episodes, MEGDEL 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MEPAN mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, MERRF mitochondrial encephalopathy and ragged red syndrome, MD movement disorders, MDH malate dehydrogenase deficiency, MLD metachromatic leukodystrophy, MMA methylmalonic aciduria, MOCS molybdenum cofactor deficiency, MPS mucopolysaccharides, MRS brain MRI with spectroscopy, MSD multiple sulfatase deficiency, MSUD maple syrup urine disease, MTHFR methylenetetrahydrofolate reductase deficiency, MTHFS 5,10-methenyltetrahydrofolate synthetase, NADK2 Mitochondrial NAD kinase 2 deficiency, NARP neuropathy, ataxia and retinitis pigmentosa, NAXE NAD(P)HX epimerase deficiency, NBIA neuronal brain iron accumulation, NCL neuronal ceroid lipofuscinosis, NKH non-ketotic hyperglycinaemia, NPS neuropsychiatric symptoms, NRL neurological, NT neurotransmitter, NT5C2 5-prime-nucleotidase, cytosolic II, ORN ornithine, OA organic acids, P5CS δ-1-pyrroline-5-carboxylate synthase deficiency, PA propionic aciduria, PHARC polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, PC pyruvate carboxylase, PCH pontocerebellar hypoplasia, PDH pyruvate dehydrogenase, PERIV periventricular, PLA2G6 phospholipase A2, PKAN pantothenate kinase 2 deficiency, PGK1 phosphoglycerate kinase 1, PHARC peripheral neuropathy hearing loss retinitis pigmentosa, cataract, PME progressive myoclonic epilepsy, PMPCA peptidase, mitochondrial processing, alpha, PN peripheral neuropathy, PNPO pyridoxamine 5′-phosphate oxidase, PNP purine nucleoside phosphorylase deficiency, PMM2 phosphomannomutase 2 deficiency, PRO proline, PSAP prosaposin, RALF recurrent acute liver failure, RCDP rhizomelic chondrodysplasia punctata, RHADS rhythmic high amplitude delta with superimposed polyspikes, RP retinitis pigmentosa, RPIA ribose-5-phosphate isomerase deficiency, SACS sacsin, SCA spinocerebellar atrophy, SCP2 sterol carrier protein 2 deficiency, SDE syndrome, SLC25A19 thiamine pyrophosphate transporter, SHMT2 serine hydroxymethyltransferase type 2, SLS Sjögren Larsson syndrome, SORD sorbitol dehydrogenase, SP spastic paraparesis, SR sepiapterin reductase deficiency, SSADH succinic semialdehyde dehydrogenase (aldehyde dehydrogenase 5a1, SUCLA2 succinyl-CoA lyase subunit, SUCLG1 succinyl-CoA ligase alpha subunit, SUMF1 gene responsible for multiple sulfatase deficiency, SUOX sulphite oxidase deficiency, SV synaptic vesicle, TH tyrosine hydroxylase deficiency, TPK1 thiamine pyrophosphokinase deficiency, UCD urea cycle disorders, VLCFA very long chain fatty acids, WM white matter, WMa white matter abnormalities, X-ALD X-linked adrenoleukodystrophy aPartially treatable; diet modifies the clinical course

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 63

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64

1

J.-M. Saudubray and Á. Garcia-Cazorla

. Table 1.18 Clinical approach to metabolic epilepsies as the most prominent symptom Seizures and progressive deterioration Rapid regression, myoclonic seizures, spasticity

Schindler disease (optic atrophy, severe osteoporosis), INCL, MERFF, NiemannPick disease type C, Gaucher disease type III (ophthalmoplegia, hepatosplenomegaly), Alpers syndrome (hepatic symptoms, hyperlactataemia)

Macular cherry-red spot and myoclonus

Sialidosis, other lysosomal diseases

With spinal muscle atrophy

ASAH1 mutations (new phenotype of Farber disease)

With +/− microcephaly, spasticity, movement disorders

Golgipathies, tubulinopathies, TRAPCC related disorders and TANGO2 (with high CPK)

Without clear degeneration, often static, other neurological signs associated Autistic signs, movement disorders

Creatine defects (GAMT, CTD), synaptic vesicle disorders, GABA and glutamate signalling defects, BCAA defects (BCKDK)

Ataxia, abnormal movements, worse before meals

GLUT1DS (low glycorrhachia)

Late onset pyridoxine dependent seizures

Antiquitin defect (elevated pipecolic acid (CSF, plasma, urine) and alpha-aminoadipic semialdehyde (urine).

Intellectual disability, dysmorphia (not constant)

GPI-anchor biosynthesis pathway defects, other cell trafficking disorders

NCL neuronal ceroid lipofuscinosis

MD may have different characteristics according to the age of presentation. In infancy and early childhood, a spectrum or continuum of symptoms is often more common than an isolated sign. In fact, the younger the patients the higher likelihood of detecting combinations of different MD. Hyperkinetic MD are very frequent in infancy and childhood whereas hypokinetic are rare and tend to be complex (associated with other neurological sings). In children with IEM, dystonia is often a prelude to parkinsonism in later childhood and adolescence. Children with a MD that appear acutely may have an acute injury to the basal ganglia or the cerebral cor-

tex, in most cases with accompanying encephalopathy/ coma, as is often seen in Leigh syndrome, glutaric aciduria type 1, and other organic acidurias, and energy defect disorders. Most IEM with extrapyramidal symptoms exhibit an abnormal brain MRI, although this is usually normal in neurotransmitter defects, GLUT1DS and genetic primary dystonias. Specific features of MD such as triggers, anatomic localization and the particular characteristics of MD semiology may help in the detection of some particular IEMs (algorithm specific features of MD, . Fig. 1.7). z

Ataxia

Ataxia, the most frequent MD found in IEM [64], is defined as an inability to maintain normal posture and smoothness of movement while force and sensation are intact. Most IEM cause cerebellar dysfunction and cerebellar hypoplasia or atrophy (. Table 1.19). Autosomal recessive cerebellar ataxia (ARCA) with onset in childhood to young adulthood age is the most common type of ataxia [65]. It is important to first consider treatable disorders (most of them partially treatable) such as vitamin E deficiency, biotinidase deficiency, folate metabolism defects, Hartnup disease, CAD deficiency, some forms of porphyrias, PDH deficiency, cerebrotendinous xanthomatosis, Refsum disease, GLUT-1 deficiency, Niemann-Pick type C, and coenzyme Q10 deficiency (. Table 1.19). 5 Intermittent/episodic ataxias are mostly caused by channelopathies [66] and have been already addressed at 7 1.3.2 (. Table 1.7) 5 Progressive ataxias is the most common form of ataxia in IEM: the treatable (or partially treatable) conditions vitamin E-responsive ataxias, Refsum disease, cerebrotendinous xanthomatosis, Niemann-Pick C and Coenzyme Q10 deficiency (in which the phenotype ataxia with oculomotor apraxia deserves special attention) belong to this category. Other disorders frequently associated with progressive ataxia are mitochondrial syndromes such as MERRF, MELAS, NARP, MILS and KSS. Mitochondrial homeostasis defects, including mtDNA replication and repair are also an important cause of progressive ataxia such as: Frataxin (Friedreich ataxia), POLG (sensory ataxic neuropathy with dysarthria and ophthalmoparesis), TWNK/ C10ORF2 (infantile-onset spinocerebellar ataxia) (7 Chap. 10). The emerging categories of IEM that cause progressive ataxias are: (i) complex lipid synthesis and remodelling disorders (7 Chap. 35) such as ABHD5 (ChanarinDorfmann syndrome), PNPLA6 (Laurence-Moon and

Ataxia

Dystonia

Chorea/athetosis

Myoclonus

Tremor (T)/ Parkinsonism (P)

Other neurological features

(1,2) MMA, GA1 IVA (2,3) (7 Chap. 18) L/D2-HGA (7 Sects. 22.8 and 22.9)

(1,2) Hartnup (7 Sect. 25.4) MSUD (7 Sect. 18.1) (2) ECHS1, (7 Sect. 18.10) HIBCH (7 Sect. 18.7) HSD10 (7 Sect. 18.5) SlC25A22 (7 Sect. 30.2)

Arginase def. All UCD: in decompensations

Organic acidurias (in particular MMA, PA ((7 Sect. 18.1) and GA1) (7 Sect. 22.5)

BCAA defects (7 Chap. 18) and AA transport defects (1,2) (7 Chap. 25) Partially treatable, not all of them

Urea cycle defects (2,3) (7 Chap. 19)

Monoamine-BH4 deficiencies (1, 2, 3) (7 Sect. 30.5)

All

(2) HSD10 (7 Sect. 18.5)

(1,2) MSUD, ECHS1, HIBCH, HSD10 (2) Malonyl-CoA carboxylase def

All

All of them

All of them (3) isolated dystonia may

HHH (7 Sect. 21.2)

(2) HSD10

(2,3) L2-HGA (7 Sect. 22.8)

TH, SR, AADC

T: (1,2) MSUD P: (2,3) HSD10

T: (2,3) IVA D-2-HGA (7 Sect. 22.9) P: may appear at late stages

T: All of them. May be isolated in GTPCH (AR) P: All of them (3). Isolated HRS may appear

Spasticity in arginase def and HHH: CP-mimic. BBGGa with thalamic sparing

Hartnup and MSUD: intermittent ataxia Abrupt dyskinesia, DD, ataxia Leigh-like phenotype (excluding MSUD); SlC25A22: episodic edema

Acute decompensations, In (3): Perioral dyskinesia, tremor dyskinesia may be unilateral.

Oculogyric crises, dysautonomy, fluctuating SP mimic BBGG calcifications in DHPR def

I. Small molecule defects. Some result in abnormalities in first line metabolic investigations (acidosis, hyperammonaemia, glucose, lactate). Most disorders have abnormal plasma, urine or CSF metabolic markers with a typical or suggestive metabolic signature. Metabolomics for diagnostic purpose is available in some specialized centres.

Disease group

. Table 1.19 IEM with abnormal movements as prominent clinical manifestation

(continued)

Ammonia, AA

Lactate, AA acylcarnitines, OA Urine AA: Hartnup

Organic acids, acylcarnitines Plasma AA

CSF specific patterns of monoamines and pterins DR

First line markers (. Table 1.3) second line: AA, OA, acylcarnitines, metals, porphyrins, purines, pyrimidines, biopterins

Biomarkers /L-Dopa responsive (DR)

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 65

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SLC19A3: (7 Sect. 29.1.2) Biotin metabolism def FOLR1 Vitamin E deficiency (TTPA)

Biotinidase def (7 Sect. 27.1.2) SLC46A1 (7 Sect. 28.1.1) FOLR1 (7 Sect. 28.3.2) DHFR (7 Sect. 28.3.5) TPK1, (7 Sect. 29.1.4) SLC25A19 (7 Sect. 29.1.3) NADK2, NAXE (7 Sect. 11.14) MTHFR (7 Sect. 28.3.7)

ATP7A (Menkes) (7 Sect. 34.1.2) ATP7B (Wilson) (7 Sect. 34.1.1) SLC30A9 (7 Sect. 34.6.3) (7 Chaps. 2 and 3) NBIA

(2) HMBS (7 Sect. 33.4)

Vitamin related diseases (7 Chaps. 27, 28, and 29) All (2) except: MTHRF (3) (2,3) Biotinidase def (3) Vitamin E def (TTPA) (2,3) Disorders of thiamine

Metal related disorders (1) SLC39A14; SLC30A10 (7 Sect. 34.4) Hypermanganesemia (2) Menkes, Wilson, SLC39A14; SLC30A10, SLC30A9 (3) NBIA, Wilson

Hem disorders (1, 2) (7 Chap. 33)

(1) CMH (caused by CYB5R3 mutations)

SLC39A8 (CDG type) SLC39A14 SLC30A10 (7 Sect. 34.4) NBIA (7 Sect. 34.2.3) ATP7B (Wilson) SLC30A9 (7 Sect. 34.6.3)

(3)

Galactosemia (2,3) (7 Chap. 14)

(1) CMH

FOLR1

(3)

Wilson

(2)

HMBS: Vertical gaze palsy, nystagmus. SP CYB5R3: torticollis, opisthotonos, spasticity, headache, hypomyelination, microcephaly

Generalized drug-resistant dystonia, suggestive brain MRI finding SLC39A1: progressive spasticity and dystonia

SLC19A3: Abrupt dystonia in catabolic states. TTPA: ataxia, retinopathy SLC25A19: bilateral striatal necrosis, polyneuropathy Basal calcifications in SLC46A1 FOLR1 and DHFR

T: Head tremor in Vitamin E def

T: SLC39A14, SLC30A10 Wilson P: SLC39A14, SLC30A10 NBIA, Wilson

Learning difficulties Inconstant WM changes

ETHE1: BBGGa SUOX: extrapyramidal and cerebellar signs, (2,3) cystic leukomalacia

(2) CblD: spasticity

Other neurological features

T: (3)

T: (1,2) ETHE1 (7 Sect. 20.9)

Methionine adenosyltransferase I/III deficiency. ETHE1, SUOX

(1,2) ETHE1 (7 Sect. 20.9) (2,3) SUOX (7 Sect. 20.11)

Sulfur AA defects (7 Chap. 20) (1,2, 3)

(1,2,3) SUOX (7 Sect. 20.11)

T: (2,3) CblC P: (2,3) CblD

(2,3) CBS (7 Sect. 20.6) (1,2,3) intracellular Cbl defects

Tremor (T)/ Parkinsonism (P)

(1,2,3) CblD, (2) Cubulin def (7 Sect. 28.1.2) (3) CBS (7 Sect. 20.6), CblG

Myoclonus

Homocystinurias (7 Sect. 20.6) and Cobalamin (Cbl) related disorders (1,2,3) (7 Sect. 28.2)

Chorea/athetosis

Dystonia

Ataxia

Congenital: methemoglobin (B) porphobilinogen, aminolevulinic acid, porphyrins

Sialotransferrin, manganese Copper, Ceruloplasmin, ASAT/ALAT, blood count

OA, lactate, free thiamine, folate, blood count, 5-MTHF in the CSF, vitamin E, triglycerides

Galactose-1-P (RBC), GALT enzyme activity

Lactate, OA, acylcarnitines, thiosulfate, homocysteine

Homocysteine, AA, B12, OA, acylcarnitines

Biomarkers /L-Dopa responsive (DR)

1

Disease group

. Table 1.19 (continued)

66 J.-M. Saudubray and Á. Garcia-Cazorla

All (2): PNP (7 Sect. 32.3.3) ADSL (7 Sect. 32.1.2)

Purine disorders (1,2,3) (7 Chap. 32)

L2HGDH

L2HGDH

P5CS

(1,2) LN disease (7 Sect. 32.1.6) (2,3) ADCY5

LN disease (1) All (2): β-ureidopropionase deficiency (7 Sect. 32.1.14) ADCY5 (7 Sect. 32.1.7) P5CS (7 Sect. 21.3)

(1,2) NKH (1) GRIN, GABAR GABAT

All of them (1) SSADH, NKH GRIN related disorders (7 Sect. 30.2)

(1) SSADH (7 Sect. 30.1)

T and P: L2HGDH

Epilepsy, DD, leukoencephalopathy

Epilepsy, extensive WM disease, spasticity

P5CS: Prominent spasticity, vessel tortuosity

LN: self-aggressive behaviour ADCY5: myokymia, paroxysmal chorea, alternating hemiplegia PNP: immunodeficiency. diplegia ADSL: autism, Rett-like

SSADH: ID, behavioural abnormalities NKH: DD, seizures GRIN1A: oculogyric crises GABAT: hypersomnolence

Developmental encephalopathy, epilepsy

GLUT1DS (1,2,3) (7 Sect. 8.3)

At any age At any age

At any age

At any age

T: Head tremor may appear in particular in (3) and adults P: Rare although described in (3) and adults

Paroxysmal dystonia, learning disabilities Ataxic-dyspraxic gait, ataxic-spastic gait distal spasticity. Abnormal, pathognomonic eye movements in early infancy

II. Energy metabolism defects. In mitochondrial disorders lactate and other markers may be disturbed mostly in children but often remain normal in adult cases. Diagnosis is complex more and more based on molecular investigations (7 Sect. 14.5)

Metabolite repair (3) (7 Sect. 22.8)

Polyol metabolism def (2)

RPIA (7 Sect. 7.9)

(2) SSADH (7 Sect. 30.1) SLC25A22 (7 Sect. 30.5) (2, 3) NKH (7 Sect. 23.2) GRIN, GABAR (7 Sect. 30.1)

Amino acid neurotransmitter disorders (1, 2, 3) (7 Chap. 30)

Proline/Ornithine defect (1)

CAD deficiency (7 Sect. 32.1.10)

Pyrimidine metabolism (1,2) (7 Chap. 32)

(continued)

Low glycorrhachia

First line markers (. Table 1.3) (lactate…) AA OA function tests

Organic acids, aminoacids / lysine

Polyols

Ammonia, amino acids

Uric acid, purines PNP: T-lymphocyte deficiency Purines in urine

OA, AA

Anisopoikilocyto-sis / anaemia

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 67

1

Dystonia

(2,3) SLC6A8 (2,3) Creatine synth. (3) GAMT

ACAT1

(1) PC; diverse Leigh genes. (7 Table 10.2) PDH; FHD; citrate transporter def; CLBP def. tWARS.SUCLA2, SUCLG1; (7 Sect.11.6) other genes (2) Diverse Leigh genes. FHD, PDH, MDH, citrate transporter def, ARALAR1 COQ8A, DNAJC19, POLG, FBXL4, OPA3 (3) Protein import: TIMM8A, POLG, FARS2, MT-ND6, MT-TI, MERRF

Ataxia

SLC6A8 (Creatine transporter) (2,3) (7 Sect. 9.1.3) GAMT (3) (7 Sect. 9.1.2)

ACAT1 (7 Sect. 13.3)

(1) PC, (7 Sect. 11.1) PDH (7 Sect. 11.3) NARP (7 Table 10.2) Plasma membrane citrate transport, other genes Leigh related, (7 Table 10.4, 7 Sect. 10.2.1) twinkle, CLPB, SACS 2) NARP, twinkle COQ6, COQ8A C12orf65 release factor def MSTO1, DNAJC19 FBXL4, OPA3 (3) Diverse genes PMPCA

Creatine defects (2,3) (7 Chap. 9)

Ketone body metabolism (2) (7 Chap. 13)

(1) Mitochondrial/ pyruvate metabolism/ Krebs cycle (7 Chap. 11) (PDH may be treatable) CoQ10 synthesis def (2,3) Mitochondrial carriers, protein import, quality control, fusion, DNA depletion (7 Chap. 10)

(1) Aconitase def, (2) FBXL4, OPA3 MECR: (3) Diverse genes

(2,3) SLC6A8 (3) GAMT

Chorea/athetosis

(1) CLBP def, (2) CoQ10 def, MERRF (3) Diverse genes MERRF 7 Table 10.2)

ACAT1

Myoclonus

T: (1) ATAD3A (high amplitude tremor (2) DNAJC19, MSTO1 (3) POLG P: (1) tWARS, DLP1, PC (2) POLG; (3) POLG, MTCYB (complex III), FARS2, MT-ND6 (complex I), MT-TI, Mitophagy genes

Tremor (T)/ Parkinsonism (P)

Aconitase def: cerebellar signs, progressive. SUCLA2: deafness (7 Sect. 11.6) SACS: Spastic ataxia, Charlevoix-Saguenay type MERRF: myoclonic epilepsy. Progressive spasticity ARALAR1: epilepsy (7 Sect. 11.11) DNAJC19: Dilated cardiomyopathy with ataxia 3-methylglutaconic aciduria type 5 POLG: epilepsy, ID OPA3: spasticity TIMM8A: MohrTranebjaerg syndrome: dystonia+deafness-optic neuronopathy PMPCA: Autosomal recessive spinocerebellar ataxia type 2

Brain MRI: Normal to BBGG T2 hyperintensity

Epilepsy, autism, DD, ID, microcephaly SLC6A8: Mild cerebellar atrophy +/ WMa GAMT: BBGG T2 hyperintensity (pallidum)

Other neurological features

Lactate, organic acids, plasma amino acids, citrate Lactate (brain), N-acetylaspartic acid (brain), POLG may be DR

OA, acylcarnitines, ketone bodies, glucose

Creatine, guanidine compounds, brain MRS

Biomarkers /L-Dopa responsive (DR)

1

Disease group

. Table 1.19 (continued)

68 J.-M. Saudubray and Á. Garcia-Cazorla

PGK1 (7 Sect. 7.4)

T y P: PGK1

Haemolytic anaemia, myopathy

(2) CLN subtypes: 2, 3, 5,6,7,8,14 (7 Sect. 40.5) Sphingolipidosis (7 Sect. 40.2) Gaucher type 3, Sandhoff (HEXA), Krabbe SUMF1; Sialidosis (Salla disease); Β-mannosidosis, NEU (7 Sect. 41.3) (3) CLN10, CTSD Gaucher. Sandhoff, NPC, SCARB2, MAN2B1 (oligosaccharidosis)

Lafora disease: EPM2A, EPM2B

Lysosomal storage disorders (2,3) (7 Chaps. 40 and 41)

Glycogen metabolism (2,3) (7 Sect. 5.3.1) Lafora disease

(2) CLN2,3,6, (NLC) Niemann-Pick type C (NPC) 1 and 2 (7 Sect. 40.4) Gaucher type 3, GM1 Krabbe, α-fucosidase, FUCA (7 Sect. 41.3) (Oligosaccharide accumulation) (3) Sphingolipidosis: Gaucher, GM1 Niemann-Pick C NLC, others (7 Sect. 41.3)

Lafora disease

(2) NPC Gaucher 3 NLC

(2) Sialidosis CLN2, 8 Sandhoff Krabbe NEU (3) Gaucher HEXB

T: Lafora disease

T: (2) ATP13A2 Sandhoff, Sialidosis (3) HEXB P: (2) CLN2,3,6, NPC, Gaucher 3, GM1, Sandhoff (3) Gaucher, GM1, NLC, HEXB

Myoclonic epilepsy, Neurodegneration

NLC: retinal degeneration, PME NPC: vertical ophthalmoplegia, gelastic cataplexy Gaucher: horizontal ophthalmoplegia. β-mannosidosis: mimics SCA Sialidosis: hypotonia at 6 months followed by ataxia, tremor CLN2, Sandhoff: spasticity FUCA: generalised and painful dystonia Oromandibular dystonia CTSD: prominent spasticity; GM1. Cherry red spot. SCARB2: PME, action myoclonusrenal failure syndrome

III. Complex molecules defects. Many complex molecules accumulation defects like sphingolipidosis, sterols and some peroxisomal disorders may be suspected on clinical grounds and have robust metabolic markers. Most complex molecules synthesis and remodelling defects like complex lipids have no easy to reach metabolic markers and diagnosis is based on molecular investigations. Lipidomics become more and more accessible

Glycolysis metabolism (3)

(continued)

Skin biopsy: PAS + inclusions

Sialidosis, CLN3, GM1, Sandhoff: Enzymatic activity, genetic test GM1, FUCA, NEU: vacuolated lymphocytes SUMF1: Sulfatides, glycosaminoglycans, urine oligosaccharides, enzymatic activity

VLCFA, plasmalogen, phytanic acid, oxysterols, MPS, oligosaccharides, sulfatides, sialic acid, lipidomics

Blood count

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 69

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Nucleotide and nucleic acid metabolism disorders (1,2) (7 Chap. 39)

TREX1, RNASEH2A, RNASEH2B, C SAMHD1, ADAR1 and IFIH1, RNASET2

(2) ACOX1, SCP2 (2) SCP2, X-ALD

FA β-oxidation (7 Sect. 42.2) (2) ACOX1, ACOX2 (7 Sect. 42.2.7), SCP2, ABCD1 (3) HSD17B4, AMACR Diverse PEX genes

Peroxisomal disorders (7 Chap. 42)

(1) PI4K2A ATP8A2

(1) PLA2G6 (PLAN) (7 Sect. 35.4.2) PI4K2A (dyskinesia) SERAC1 (7 Sect. 35.3.7) (2) MECR BSCL2 (seipin) (7 Sect. 35.2.2) PLA2G6 (7 Sect. 35.4.2) FA2H (7 Sect. 40.1.5) (NBIA) (7 Sect. 34.2.3)

(1) ITPR1 (2) Celia’s encephalopathy (See . Table 35.1) Mevalonate kinase deficiency (MK) (7 Sect. 37.1) NBIA (7 Sect. 34.2.3) PL remodelling (7 Sect. 35.4) ABHD5, PNPLA6 ABHD12, CYP7B1 CERS1,2 (7 Sect. 40.1.3)

Lipid metabolism: Phospholipid defects (7 Chap. 35) Phosphatidylinositol def Phospholipid (PL) remodeling (7 Sect. 35.4) Fatty acid synthesis elongation (7 Sect. 42.4) Triglyceride metabolism (7 Sect. 35.2.3) NBIA syndromes (7 Sect. 34.2.3)

Chorea/athetosis

Dystonia

Ataxia

(1) PI4K2A (2) MECR Celia’s

Myoclonus

P: Rigidity, HRS-like is common in different genes

T: (2) SCP2, AMACR

T: (2) ABHD12 (7 Sect. 42.4) P: (1) PLA2G6 (1) PI4K2A (7 Table 35.1)

Tremor (T)/ Parkinsonism (P)

Aicardi-Goutières syndrome (7 Sect. 39.1.2) (emergency treatment: Baricitinib) Leukodystrophy, basal ganglia calcification

SCP2: spasmodic torticollis, head tremor ABCD1: regression, progressive spasticity AMACR: Leukoencephalopathy with dystonia and neuropathy HSD17B4: PseudoZellweger (severe) Perrault syndrome type 1 (milder) (7 Sect. 42.2.2)

ITPR1; congenital non progressive SCA PLA2G6: INAD, NBIA2 PI4K2A akathisia, epilepsy, cutis laxa SERAC1: MEGDEL syndrome MEPAN, MECR, FA2H and Celia’s encephalopathy: spasticity CERS1,2: PME ABHD5: ChanarinDorfman PNPLA6: retinopathy, hypogonadotropic hypogonadism ABHD12: PHARC syndrome CYP7B1: sensory ataxia, optic atrophy

Other neurological features

Increased CSF lymphocytes, thrombocytopenia, interpheron signature

VLCFA, pristanic acid, phytanic acid, plasmalogens, pipecolic acid, bile acids

OA, lactate, liver enzymes Lactate (brain) ACOX2: Bile acid intermediates CYP7B1: hydroxycholesterol PLA2G6 mutations may present as DR parkinsonism

Biomarkers /L-Dopa responsive (DR)

1

Disease group

. Table 1.19 (continued)

70 J.-M. Saudubray and Á. Garcia-Cazorla

(1) PMM2 (7 Sect. 43.2.1) (2,3) Diverse CDG syndromes

(1,2) PMM2 (2) Dolichol metabolism def (7 Sect. 43.5)

PMM2

(2) NGLY1 (7 Sect. 43.5.1)

T: (1) GPI anchor defects (7 Sect. 43.4) (2) NGLY1

Multisystem involvement (7 Chap. 43) Often cerebellar hypoplasia/atrophy

Hypomyelinating leukodystrophy (type 11) with hypodontia, hypogonadotropic hypogonadism POLR3A: spastic-ataxia UBTF1: cerebellar atrophy, regression

Some of them with combined oxidative phosphorylation (see also mitochondria) SARS1: seizures DARS1, 2, RARS1,2, EPRS1: spastic-ataxia, spastic paraparesis (. Table 39.1) PCH and hypomyelination are common Lactic acidosis may be present DR has been described in tWARS

(continued)

Sialotransferins, ASAT/ALAT, coagulation factors

T: (2) DARS1 P: (1) tWARS

CDG syndromes (1,2,3) (7 Chap. 43)

(1) tWARS (2) WARS2

Only in some CDG syndromes

(1) POLR1C (type 11) (1) POL3B (type 8) (3) POLR3A (type 7) (2) UBTF1

Ribosomal biogenesis (7 Sect. 39.3)

(1) EPRS1, EPRS1, SEPSECS Other genes (2) MARS2, WARS2, EPRS1

IV. Cellular trafficking disorders: in general, there is no metabolic marker so far but in some CDG. Diagnosis is based on DNA test.

tRNA aminoacylation (7 Sect. 39.2.3) (2) DARS1,2, MARS2 SARS1, RARS1,2 EPRS1

Aminoacyl-tRNA synthetases and tRNA processing metabolism disorders (7 Sect. 39.2) 7 Table 39.1

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 71

1

(1) SNX14 (disorders of autophagy, 7 Sect. 44.2.1) SCYL1 (SCA21) KIF1C (2) SNX14 (autophagy defect) TRAPPC11 TANGO2, VPS13D RUBCN, SIL1, SCYL1, SPTBN2 (3) WDR45 (autophagy) VPS13D SIL1

Cell trafficking disorders (1,2,3) (7 Chap. 44)

(1) Synaptic vesicle disorders (7 Sect. 30.6) (2) TRAPPC (diverse subunits) VPS16, VPS4: early-onset dystonia ATP1A3 TUBB4A (3) Autophagy disorder: WDR45 ATP13A2: RuforRakeb syndrome VPS16 ACTB

Dystonia

(1) SNX14 ATP8A2 (flippase)

Chorea/athetosis

(1) SNX14 (2) GORS2 (action myoclonus)

Myoclonus

T: (1) SNX14, KIF1C (dystonic tremor) (2) GORS2 (rest tremor) P: (1) FIG4 PARKIN deficiency (2) Autophagy disorder: WDR45, SV endocytic disorders, ATP6AP2 VPS13D: SCA4 (3) WDR45, ATP13A2 KIAA1840; ZFYVE26 STXBP1, TUBB4A VAC14, VPS13C, VPS13D

Tremor (T)/ Parkinsonism (P) BCAP31: deafness, dystonia, hypomyelination ATP8A2: hypotonia, optic atrophy SCYL1: RALF, peripheral Neuropathy KIF1C: may also cause spastic ataxia, adultonset ataxia WDR45: β-propeller protein-associated neurodegeneration (BPAN) (7 Sect. 39.2.3) TUBB4A: torsion dystonia TANGO2: arrythmias, rhabdomyolysis, SP VPS13D: Cohen disease, spastic-ataxia RUBCN: SCA4; SIL1: cataracts, myopathy SPTBN2: may cause adult onset SCA KIAA1840; ZFYVE26, VPS13D: spastic paraparesis SYNJ1, DNAJC6, STXBP1 may appear as refractory epilepsy in early childhood and progressively evolve towards parkinsonism

Other neurological features

SYNJ1, DNAJC6, CLCT, VPS35 may be DR

Biomarkers /L-Dopa responsive (DR)

In black bold: treatable disorders Onset age: 1 infancy to early childhood, 2 childhood (from 2 years until adolescence), 3 adolescence AA amino acids, AADC L-amino acid decarboxylase deficiency, ABHD12 monoglycerol lipase, ACAT1 acetoacetyl-CoA thiolase deficiency, AD autosomal dominant, ADCY5 adenylate cyclase deficiency, ADL-X X-linked adrenoleukodystrophy, ADSL adenylosuccinate lyase deficiency, AIP acute intermittent porphyria, ALS amyotrophic lateral sclerosis, AMACR α-methylacyl-CoA racemase, AMPD AMP deaminase-2 deficiency, AR autosomal recessive, ARALAR mitochondrial protein involved in glutamate aspartate exchange encoded by SLC25A12, ARD (adult Refsum disease) phytanoyl-CoA 2-hydroxylase, ARG arginine, ARSA arylsulfatase A deficiency, AS asparagine synthetase, ATIC 5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria, Atten attenuated forms, ATIC 5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive

Ataxia

1

Disease group

. Table 1.19 (continued)

72 J.-M. Saudubray and Á. Garcia-Cazorla

condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH, ATP8A2 encodes for a P4-ATPase that actively transports phospholipids across cell membranes (‘flipping’), BBGGa basal ganglia abnormalities, B4GALNT1 GM2/GD2 synthase deficiency, BCAA branched chain amino acids, C cerebellum, Ca cerebellar atrophy, CAD CAD trifunctional protein, carbamoylphosphate synthetase/aspartate transcarbamylase/dydroorotase, CC corpus callosum, CDG congenital disorders of glycosylation, CERS ceramide synthase, CIT citrulline, CK syndrome X-linked recessive sterol-4-alpha-carboxylate 3-dehydrogenase deficiency, CLBP mitochondrial quality protein control, CMH congenital methemoglobinemia, CMNO cardiomyopathy, CP cerebral palsy, CPTII carnitine palmitoyltransferase II deficiency, CTX cerebrotendinous xanthomatosis, CSF cerebrospinal fluid, CP cerebral palsy, DBP D-bifunctional protein, DD developmental delay, DEF deficit, DHPR dihydropyrimidine reductase deficiency, DEGS dihydroceramide delta4-desaturase, DHFR dihydrofolate reductase deficiency, DLP1 dynamin related protein 1. EAAT1, glutamate aspartate transporter deficiency (SLC25A22), DWI diffusion, ECHS1 mitochondrial short-chain enoyl-CoA hydratase deficiency, ELOVL elongation of very long chain fatty acids, encephalop encephalopathy, ENTPD ectonucleoside trisphosphate diphosphohydrolase I, EPT1 ethanolamine phosphotransferase, ETHE1 sulfur dioxygenase deficiency, FA2H fatty acid 2-hydroxylase deficiency, FAR1 fatty-acyl CoA reductase 1 deficiency, FHD fumarate hydratase deficiency, FOLR1 folate receptor alpha deficiency, GAMT guanidinoacetate methyltransferase, GA1 glutaric aciduria type 1, GABAR GABA receptor mutations, GABAT GABA transaminase deficiency, GALC galactocerebrosidase, GLUT1DS glut-1 deficiency syndrome, GORS Golgi SNAP receptor complex member 2, GOT2 glutamate oxaloacetate transaminase deficiency, GRIN mutations in NMDA glutamatergic receptors, GS glutamine synthetase, GSS glutathione synthetase deficiency, GTPCH guanosine triphosphate cyclohydroxylase, HCS deficiency holocarboxylase synthetase deficiency, HH hyperinsulinism-hyperammonaemia syndrome, HHH hyperornithinaemia-hyperammonaemia-homocitrullinaemia syndrome, HIBCH 3-hydroxyisobutyryl-CoA hydrolase deficiency, Homocyst homocysteine, HRS hypokinetic-rigid syndrome, HSD10 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, ID intellectual disability, INAD infantile neuroaxonal dystrophy, ITPase Inosine triphosphatase, ITPR1 inositol 1,4,5-triphosphate receptor, type1, IVA isovaleric aciduria, L2-HGA L2-hydroxyglutaric aciduria, L2HGDH L-2-hydroxyglutarate dehydrogenase deficiency, L,D2-HGA L and 2-D-hydroxyglutaric aciduria, LBSL leukodystrophy with brainstem and spinal cord involvement and lactate elevation, LN Lesch-Nyhan, MCGA1 3-methylglutaconic aciduria type 1, MECR Trans-Enoyl-CoA reductase, MELAS lactic acidosis, and strokelike episodes, MEGDEL 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MEPAN mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, MERRF mitochondrial encephalopathy and ragged red syndrome, MD movement disorders, MDH malate dehydrogenase deficiency, MLD metachromatic leukodystrophy, MMA methylmalonic aciduria, MOCS molybdenum cofactor deficiency, MPS mucopolysaccharides, MRS brain MRI with spectroscopy, MSD multiple sulfatase deficiency, MSUD maple syrup urine disease, MTHFR methylenetetrahydrofolate reductase deficiency, MTHFS 5,10-methenyltetrahydrofolate synthetase, NADK2 mitochondrial NAD kinase 2 deficiency, NARP neuropathy, ataxia and retinitis pigmentosa, NAXE NAD(P)HX epimerase deficiency, NBIA neuronal brain iron accumulation, NCL neuronal ceroid lipofuscinosis, NKH nonketotic hyperglycinaemia, NPS neuropsychiatric symptoms, NRL neurological, NT neurotransmitter, NT5C2 5-prime-nucleotidase, cytosolic II, ORN ornithine, OA organic acids, P5CS δ-1-pyrroline-5-carboxylate synthase deficiency, PA propionic aciduria, PHARC polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, PC pyruvate carboxylase, PCH pontocerebellar hypoplasia, PDH pyruvate dehydrogenase, PERIV periventricular, PLA2G6 phospholipase A2, PKAN pantothenate kinase 2 deficiency, PGK1 phosphoglycerate kinase 1, PHARC peripheral neuropathy hearing loss retinitis pigmentosa, cataract, PME progressive myoclonic epilepsy, PMPCA peptidase, mitochondrial processing, alpha, PN peripheral neuropathy, PNPO pyridoxamine 5′-phosphate oxidase, PNP purine nucleoside phosphorylase deficiency, PMM2 phosphomannomutase 2 deficiency, PRO proline, PSAP prosaposin, RALF recurrent acute liver failure, RCDP rhizomelic chondrodysplasia punctata, RHADS rhythmic high amplitude delta with superimposed polyspikes, RP retinitis pigmentosa, RPIA ribose-5-phosphate isomerase deficiency, SACS sacsin, SCA spinocerebellar atrophy, SCP2 sterol carrier protein 2 deficiency, SDE syndrome, SLC25A19 thiamine pyrophosphate transporter, SHMT2 serine hydroxymethyltransferase type 2, SLS Sjögren Larsson syndrome, SORD sorbitol dehydrogenase, SP spastic paraparesis, SR sepiapterin reductase deficiency, SSADH succinic semialdehyde dehydrogenase (aldehyde dehydrogenase 5a1, SUCLA2 succinyl-CoA lyase subunit, SUCLG1 succinyl-CoA ligase alpha subunit, SUMF1 gene responsible for multiple sulfatase deficiency, SUOX sulphite oxidase deficiency, SV synaptic vesicle, TH tyrosine hydroxylase deficiency, TPK1 thiamine pyrophosphokinase deficiency, UCD urea cycle disorders, VLCFA very long chain fatty acids, WM white matter, WMa white matter abnormalities, X-ALD X-linked adrenoleukodystrophy

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Boucher-Neuhauser syndrome), ABHD12 (PHARC), or ceramide synthase deficiency (with myoclonic epilepsy) amongst others; (ii) Cell trafficking disorders (7 Chap. 44) such as several disorders of autophagy (SNX14, WDR45); (iii) Disorders of aminoacyl-tRNA synthetases and ribosome metabolism disorders (7 Chap. 39) which are associated with early-onset encephalopathies with cerebellar and brainstem atrophy and hypomyelination. Hypogonadotropic hypogonadism is a key sign of the neuropathy target esterase (NTE) spectrum that includes Boucher-Neuhäuser syndrome (with chorioretinal dystrophy) and Gordon Holmes syndrome (with peripheral neuropathy) (7 Sect. 35.4.4). 5 Non-progressive ataxias are typically found in CDG syndromes, SSADH deficiency and ITPR signalling defects. In these diseases, ataxia can even improve over time [67].

MOST COMMON GENETIC ATAXIAS -

Friedrich ataxia (accounts for ~25% of all SCARs) Autosomal-recessive spastic ataxia of Charlevoix-Saguenay SPG7: paraplegin mutations; SYNE1 mutations Ataxia telangiectasia (PI3K-family kinase) Ataxia with oculomotor apraxia type 1 and 2 POLG and other mitochondrial diseases such as PDH, OPA1 ITPR1 (inositol 1,4,5-triphosphate (IP3) receptor)

ATAXIA WITH SPASTICITY Ataxia and spasticity usually coexist as a spectrum of clinical manifestations that correspond to similar mechanisms of disease. See Table 1.20 “Complex Motor Signs”

ATAXIA WITH PROMINENT EPILEPSY CAD deficiency, GLUT1D, Creatine defects, PDH, Biotinidase deficiency, Cerebral folate deficiency, COQ10 defects, Niemann-Pick C - NKH, SSADH. GABA receptor mutations and GRINpathies cause ataxic-dyspraxic-uncoordinated gait more than pure ataxia - Several mitochondrial disorders - Lysosomal disorders, and in particular NLCs (neuronal lipofuscinosis) - Complex lipid disorders such as PI4K2A, PLA2G6 mutations - Aminoacyl-tRNA synthetases such as SARS mutations. - UBTF1 mutations (ribosomopathy) with regression - Cell trafficking disorders and in particular synaptic vesicle defects such as SYNJ1, DNAJC6, STXBP1 mutations - Progressive Myoclonic Epilepsies: Lafora disease, NCLs, sialidosis type I, MERRF), Gaucher disease type 3, ASAH1, ceramide synthetase deficiency, SCARB mutations, Unverricht-Lundborg disease, dentatorubral-pallidoluysian atrophy (DRPLA), neuroserpinosis, and KCNC1 related diseases.

. Fig. 1.5 Ataxia algorithm

Other than . Table 1.19 key symptoms that may help in the differential diagnosis are depicted in the ataxia algorithm (. Fig. 1.5). z

Dystonia

Dystonia is defined by the occurrence of sustained/intermittent muscle contractions, causing aberrant, repetitive twisting movements, and abnormal postures. In many different metabolic diseases, dystonia is a major feature. In fact, almost all neurometabolic disorders can cause dystonia at some stage. However, glutaric aciduria type I, Leigh syndrome, metal disorders, neurotransmitter defects and some lysosomal disorders such as NiemannPick C are among the most relevant (dystonia algorithm, . Fig. 1.6). Neurodegeneration with Brain Iron Accumulation (NBIA) is a growing group of disorders that is characterized by progressive dystonia and parkinsonism [68] (7 Sect. 34.2.3).

ATAXIA WITH OTHER ABNORMAL MOVEMENTS - With dystonia: organic acidurias, BCAA disorders, intracellular Cbl defects, creatine defects, biotinidase deficiency, cerebral folate deficiency, vitamin E deficiency, Wilson, GLUT1DS, PDH, CoQ10 defects, Niemann-Pick C, sulfur amino acid disorders such as ETHE1, SUOX mutations, SLC30A9, NBIA, SSADH, NKH, GRIN related disorders, several mitochondrial disorders, CLN2,3,6, Niemann-Pick type C 1 and 2, Gaucher type 3, Lafora disease, NBIA syndromes, peroxisomal disorders: ACOX1, SCP2, X-ALD, Aminoacyl-tRNA synthetases such as EPRS1 mutations, diverse CDG subtypes, cell trafficking disorders such as TRAPPCpathies - With choreoathetosis: organic acidurias, creatine defects, cerebral folate deficiency, Wilson, GLUT1DS, Niemann-Pick C. Diverse mitochondrial disorders such as: Aconitase deficiency, FBXL4, OPA3, MECR. Lysosomal disorders: Gaucher 3, NLC, Lafora disease. CDG syndrome: PMM2. Cell trafficking disorders such as SNX14 mutations - With myoclonus: HHH, ACAT1 (ketone body metabolism defect), Wilson, CoQ10 defects, GLUT1D, L2-HGA, SSADH, sialidosis, CLN2, 8, Sandhoff, Krabbe, NEU, Gaucher, HEXB mutations. Cell trafficking disorders such as SNX14 mutations - With tremor: Isovaleric aciduria, MSUD, CblC, Wilson, vitamin E deficiency and GLUT1D (head tremor), D-2-HGA, L2HGDH, sulfur metabolism defect such as ETHE1, metal disorders such as SLC39A14, SLC30A10, several mitochondrial disorders such as ATAD3A, DNAJC19, MSTO1., POLG. Sialidosis, Lafora disease. Complex lipid disorders such as ABHD12 mutations. Peroxisomal disorders such as: SCP2, AMACR. Aminoacyl-tRNA synthetases such as DARS1, GPI anchor defects, cell trafficking disorders such as: SNX14, KIF1C, GORS2 mutations. - With parkinsonism: Wilson, CblD, GLUT1DS (rare, and more common in adults), HSD10 (BCAA defect), metal disorders: SLC39A14, SLC30A10 mutations, NBIA syndromes, L2HGDH, in several mitochondrial disorders: tWARS, DLP1, POLG, MTCYB (complex III), FARS2, MT-ND6 (complex I), MT-TI, mitophagy genes. Lysosomal disorders such as: CLN2,3,6, NPC, Gaucher 3, GM1, Sandhoff, Gaucher, GM1, NLC, HEXB mutations. Aminoacyl-tRNA synthetases such as tWARS. Cell trafficking disorders such as WDR45, FIG4, VPS13D

ATAXIA WITH POLYNEUROPATHY: see table 1.20 “Complex Motor Signs”

75 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

ISOLATED DYSTONIA - DYT-THAP1: young-onset generalized dystonia with predominant craniocervical symptoms - The GAG deletion in TOR1A: generalized dystonia with onset in childhood in the lower limbs - De novo mutations in GNAL and ANO3: isolated focal and/or segmental dystonia with preference for the upper half of the body and older ages at onset. IEM with isolated dystonia are rare and in most cases dystonia remains isolated for some time but later on, other symptomos appear. This is the case for: Neurotransmitter defects, homocystinurias, early stages of NBIA syndromes and lysosomal disorders.

MOST COMMON IEM WITH DYSTONIA -

-

-

OTHER GENETIC CAUSES OF EARLY-ONSET DYSTONIA (related to developmental encephalopathies) Relatively high frequency of the following genetic variants: KMT2B (complex childhood onset dystonia), SGCE (myoclonusdystonia), ADCY5 (dystonia associated with other movement disorders), ATP1A3 (rapid onset dystonia parkinsonism), PANK2, and ATM (ataxia-telangiectasia). Early infancy until 2 years: – Complex hyperkinetic movements: ADCY5, GNAO1 (may have also epilepsy), PDE10. All these disorders dysregulate cAMP signaling. PDE10A: dominant forms: early onset generalized chorea and t2 striatal hyperintensity; recessive: generalized chorea first months of life, normal brain MRI. Other genes involved in early complex hyperkinetic movements: SCNA2, SCN8A; PNKP deficiency (chorea): DNA damage response gene; microcephaly, DD, seizures, oculomotor apraxia and polyneuropathy, AUTS2, CHD8, ZEB2, DHCR24, GRID2, MORC2, MSL3, PAK1, PPP2R5D, TECPR2, ZMYND1

Neurotransmitter defects Classic homocystinuria, Cbl and remethylation defects Maple syrup urine disease Organic acidurias (propionic academia, methylmalonic aciduria, malonic aciduria, glutaric aciduria type 1) Vitamin related disorders: Pyridoxine-dependent epilepsy, PNPO deficiency, biotin-thiamine-responsive basal ganglia disease, thiamine pyrophosphokinase deficiency, mitochondrial thiamine pyrophosphate transporter deficiency Other treatable disorders: GLUT1DS, classic galactosaemia, pyruvate dehydrogenase complex deficiency, COQ8A deficiency, beta-ketothiolase deficiency, Wilson disease, cerebrotendinous xantomatosis Metal related disorders: Aceruloplasminemia, SLC30A10, SLC39A14, SLC39A8 mutations Complex molecule defects: CLN2 disease, Gaucher disease, metachromatic leukodystrophy, X-ADL, Celia’s encephalopathy (seipinopathy)

MOST COMMON IEM WITH CHOREOATHETOSIS Aromatic L-amino acid decarboxylase deficiency, 6-pyruvoyltetrahydropterin synthase deficiency, sepiapterin reductase deficiency, dihydropteridine reductase deficiency propionic academia, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, glutaric aciduria type 1, hereditary folate malabsorption, folate receptor alpha deficiency, classic galactosemia, Wilson disease, glucose transporter 1 deficiency, pyruvate dehydrogenase complex deficiency, beta-ketothiolase deficiency, cerebrotendinous xanthomatosis Dopamine transporter deficiency, glycine encephalopathy due to glycine decarboxylase deficiency, glycine encephalopathy due to aminomethyltransferase deficiency, molybdenum cofactor deficiency, aceruloplasminemia CLN2 disease Benign hereditary chorea: NRX2/TITF-1 (genetic, non metabolic disease). May improve with L-Dopa

. Fig. 1.6 Algorithm for IEM with dystonia and choreoathetosis

Specific characteristics of dystonia and dyskinetic movements may suggest some particular IEM. Some of the most common IEM in abrupt with an acute onset of dystonia are OA (such as GA1) and mitochondrial disorders. GLUT1DS can cause paroxysmal exerciseinduced dyskinesia and also complex MD even without epilepsy. Oromandibular dystonia is common in creatine deficiency, PKAN and other IEMs, whereas head tremor is a typical feature of Vitamin E, GLUT1DS and a few other diseases [64] (specific features of MD algorithm, . Fig. 1.7). New and emerging categories of IEM that cause dystonia as a relevant feature are: (i) complex lipid defects such as PI4K2A (dyskinesia and parkinsonism), SERAC1 (MEGDEL syndrome with progressive painful dystonia and specific brain MRI images), ATP8A2 (with optic atrophy), MECR (with associated spasticity)

and, BSCL2 (seipin defect, that may also cause spasticity and epilepsy) (ii) Nucleotide metabolism disorders, such as diverse genes that cause Aicardi-Goutières syndrome (dystonia-rigidity) [69]; (iii) Cell trafficking disorders such as synaptic vesicle diseases, VPS16, VPS4 as forms of early-onset dystonia, TRAPPCpathies and many other genes (. Table 1.19). In all cases it is important to consider first those IEM for which some effective therapeutic intervention is possible, such as dopa-responsive dystonia syndromes (Segawa disease and other neurotransmitter related deficiencies), creatine deficiency syndromes, cerebral folate deficiency, Wilson disease, homocystinuria, biotinidase, thiamine defects, vitamin E and GLUT1 deficiencies. Other than . Table 1.19, key symptoms that may help in the differential diagnosis are in the dystonia and choreoathetosis algorithm, . Fig. 1.6.

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PAROXYSMAL MOVEMENT DISORDERS Triggers: exercise, fever, other stimuli, unknown - Energy defects (dyskinesias, dystonia, ataxia, chorea) GLUT1D, PDH, biotinidase deficiency - Amino acid catabolism + energy metabolism defects (dystonia, choreoathetosis) ECHS1-mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, HIBCH-3-hydroxyisobutyryl-CoA hydrolase deficiency - Neurotransmitter amino acids (ataxia, chorea, dyskinesias) - Non-ketotic Hyperglycinaemia, GABA transaminase deficiency, succinic semialdehyde dehydrogenase - Other amino acids: HTD-tyrosinemia type III (dystonia): Hartnup disease (ataxia) - T3 transport defect (Allan-Herndon-Dudley syndrome) - PARK2-Parkin deficiency (dyskinesia) - B4GALNT1 (GM2/GD2 synthase): fever-induced ataxia with myokymia - FOLR1 – sensory stimulus sensitive drop attacks - Niemann-Pick C-cataplexy while laughing - ADCY5 – nocturnal - ATP1A3 – painful tonic spasms - SLC16A2 – shivering tremor like episodes - KCNMA1 – complex PNKD (*) with epilepsy

ANATOMIC LOCATION Oromandibular dystonia Cerebral creatine deficiency, Segawa disease, NBIA syndromes, aceruloplasminemia, fucosidosis, oligosaccharidosis, hypermanganesemia due to SLC39A14, CLN3, GM1, TIMM8A-Deafness-Dystonia-Optic Neuronopathy Syndrome, biotin-thiamine responsive basal ganglia disease. Jaw opening dystonia: PKAN2 Dystonic posturing of the jaw and tongue: ETHE1 Head tremor GLUT1D, diverse spino cerebellar ataxias, PEX6, PEX16, VitE deficiency, Niemann Pick type C disease, NAXE-NAD(P)HX epimerase deficiency, SCP2-sterol carrier protein-2 deficiency Palatal myoclonus, myoclonus of the tongue: Krabbe Facial chorea: MECR Facial dystonia: GM1 Facial dyskinesia: ATP8A2

SPECIFIC TYPE OF MOVEMENTS Status dystonicus: PKAN2, GNAO, Wilson, AADC and dopamine transporter deficiency Tics: neuroacanthocytosis, Huntington disease; Starting as action dystonia in one limb: Niemann-Pick C; Micrographia: Wilson’s disease; Spasmodic torticollis: SPC2; Startle myoclonus: ST3GAL5; Ballismus: Lesch-Nyhan disease; Opisthotonos: Lesch-Nyhan disease, CYB5R3; Facial-faucial-finger mini-myoclonus: ATP13A2; Stereotypies: CDG syndromes, syndromes with prominent autism such as BPAN, purine disorders, creatine defects, SSADH, synaptic vesicle disorders, amino acid neurotransmitter signalling disorders, MAO deficiency

(*) PNKD paroxysmal non-kinesigenic dyskinesia

. Fig. 1.7 Movement disorders depending on specific features that may help in the differential diagnosis

z

Chorea/Choreoathetosis

The term chorea is a derived from the Greek word “choreia” for dancing and refers to involuntary, brief, random, rapid, spasmodic movements of the face, neck and proximal limb muscles. It can migrate from one side of the body to the other. Choreic movements are a prominent feature of GA1, GLUT-1 deficiency, LeschNyhan disease, cerebral folate deficiency, PKAN and other NBIA syndromes, homocystinuria and NiemannPick C among others [64, 67] (. Fig. 1.6). z

Parkinsonism (Rigid Akinetic Syndrome)

IEM constitute an important group amongst the genetic causes of parkinsonism at any age. However, early forms of parkinsonism have distinctive features as compared to parkinsonism in adolescents and adults. Most early forms of parkinsonism lack crucial classical signs like tremor and tend to be associated to other kind of abnormal movements and neurological manifestations such as pyramidal signs. Therefore, the concept “hypokineticrigid syndrome” (HRS), “dystonia-parkinsonism”, “parkinsonism-plus”, or “parkinsonism-like” are more accurate in children [70].

The main IEM causing parkinsonism are (. Table 1.19, . Fig. 1.8 algorithm parkinsonism): (i) metal-storage diseases such as Wilson’s disease, manganese transporter deficiency and NBIA syndromes; (ii) Neurotransmitter defects (as already discussed as causes of early onset dystonia and dystonia-parkinsonism); (iii) Lysosomal and complex molecule disorders. In this group, special consideration should be given to ceroid lipofuscinosis (CNL), GM1, NiemannPick C and cerebrotendinous xanthomatosis (CTX) 4) Energy metabolism defects. POLG and different mitochondrial diseases may exhibit parkinsonism features. Characteristically they can respond to low L-dopa+carbidopa doses, especially in adolescents and adults [71]. New diseases and emerging categories of IEM that cause prominent parkinsonism are cell trafficking disorders, in particular endocytotic defects of the synaptic vesicle cycle and autophagy disorders such as WDR45 mutations (7 Chap. 44), and some aminoacyl tRNA synthetase deficiencies such as tWARS [72]. Some of these IEM may be also doparesponsive (. Table 1.19).

77 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

PARKINSONISM-HYPOKINETIC RIGID SYNDROME often associated with DYSTONIA and other abnormal movements

Early infancy until 2 years 1-Small molecule disorders - Neurotransmitter defects (monoamine and BH4 defects) 2-Energy metabolism defects - Pyruvate carboxylase: has been described during the neonatal period - DLP1 mutations: during the first months of life 3-Complex molecule defects - Lipid metabolism defects: PLA2G6, PI4K2A - Aminoacyl tRNA synthetases: tWARS, FARS2 - Nucleotide and nucleic acid metabolism: FIG4, Parkin deficiency - Cell trafficking disorders: AMPA trafficking defects

Childhood (2–12 years)

Adolescence (12–18 years)

1-Small molecule disorders: - Neurotransmitter defects (monoamine and BH4 defects) - BCAA disorders: HSD10 deficiency - CbLD: described in one 10 year-old patient - Metal disorders: SLC39A14, SLC30A10, NBIA, Wilson 2-Energy metabolism defects Mitochondrial defects may cause rigidity, bradykinesia and other signs of parkinsonism 3-Complex molecule defects - Lysosomal disorders: CLN2,3,6, NPC, Gaucher 3, GM1, Sandhoff - Aminoacyl tRNA synthetases: tWARS - Nucleotide and nucleic acid metabolism: Rigidity, hypokinetic-rigid syndrome-like is common in different genes - Cell trafficking defects: Autophagy disorder: WDR45, synaptic vesicle endocytotic disorders, ATP6AP2 VPS13D: SCA4

1-Small molecule disorders: - Organic acidurias: may appear at late stages of the disease - BCAA disorders: HSD10 deficiency - Metal disorders: SLC39A14, SLC30A10, NBIA, Wilson - Metabolite repair: L2HGDH deficiency 2-Energy metabolism defects - GLUT1DS: although parkinsonism is rare, rigidity and hypokinesia may appear during adolescence and adulthood - Glycolysis defect: PGK1 mutations - Mitochondrial disorders: POLG, MTCYB (complex III), MT-ND6 (complex I), MT-TI, mitophagy genes 3-Complex molecule defects - Lysosomal disorders: NCL, Gaucher, GM1, NLC, HEXB mutations - Cell trafficking defects WDR45, ATP13A2, KIAA1840; ZFYVE26 STXBP1, TUBB4A, VAC14, VPS13C, VPS13D, synaptic vesicle endocytotic disorders, All neurodegenerative disorders may present parkinsonism features over time

. Fig. 1.8 Algorithm for parkinsonism

1.5.2.4

Category 4: With Complex Motor Disorders: Ataxic-Spastic Gait, Predominant Spasticity, and/or Peripheral Nerve/Motor Neuron Involvement [. Table 1.20, . Fig. 1.9 (Spasticity) and . Fig. 1.10 (Peripheral Neuropathy/Motor Neuron Diseases)]

In this category of complex motor disorders, we will include diseases with major involvement of the pyramidal system, which is often connected with the cerebellum, as well as the motor neuron and peripheral nerves. z

Ataxic-Spastic Spectrum

Purkinke cells and spinocerebellar tracts (ataxias) and corticospinal tracts (spastic paraparesis, spasticity in general), are often damaged by the same mutated genes causing a continuum spectrum. Ataxia may appear before spasticity or both signs could be detected simultaneously. The classical system of neurogenetic classification of spastic paraplegia (SPG) and autosomal recessive ataxias (ARCAs) were traditionally separated. However, the coincidence of both phenotypes in many genetic conditions has raised awareness about the common mechanisms of disease in these neurological

manifestations. Therefore, the concept “spastic-ataxic” disease is being increasingly used [73] The same occurs in IEMs that cause this motor phenomenology and that are included in . Table 1.20. z

Spasticity

Spasticity is a very common clinical situation in paediatric and adult neurology and is the result of damage to upper motor neurons or to the corticospinal tract. Symptoms may vary from mild stiffness to severe muscle spasms and include hypertonia, brisk deep tendon reflexes, pathological reflexes, clonus and weakness. Depending on the affected anatomical region, spasticity may be more evident or restricted to the lower extremities (spastic diplegia or paraplegia: spastic paraparesis) to one side of the body (spastic hemiplegia) or affecting all four limbs (spastic quadriplegia or tetraparesis). Recent advances in the molecular characterization of spastic paraplegias (SPGs) have described more than 60 genes that show considerable overlap with other clinical manifestations and share pathophysiological mechanisms as intracellular trafficking, mitochondrial function and lipid metabolism [74]. Regarding IEM, disorders that interfere with myelin metabolism (leukodystrophies), synthesis and remodelling of complex lipids, defects in energy production

1

Ataxia-SP spectrum

Spasticity (pure/complex)

Peripheral neuropathy/ motor neuron disease

Other clinical features

Brain image

Axonal neuropathy

Mild cerebellar signs may be present

Proline, ornithine defect: ALDH18A1 (P5CS) (7 Sect. 21.3) Pure or with cataracts, skeletal abnormalities, other NRL features AR: 1,2; AD: 3

(2,3) GTPCH (AD), (1,2,3) TH: complex; also pure in TH

(1,2,3) SR

Monoamine-BH4 def. (7 Sect. 30.5)

Microcephaly, tremor, seizures, ID

Dopa-responsive MD

CblD: seizures, psychiatric symptoms, parkinsonism. TTPA: head tremor, nystagmus, retinopathy; Biotinidase def: hypoacusia, dermatitis, myelopathy, seizures. SHMT2: myocardiopathy, ID, congenital microcephaly. Riboflavin transport: deafness, pontobulbar palsy

Riboflavin transport (2,3): motor and sensory neuropathy, distal motor neuropathy, multineuritis with cranial nerve involvement, GuillenBarré syndrome, ALS mimic SHMT2 (1): axonal neuropathy

Pure spasticity has been described in biotinidase deficiency. All other are complex

(1,2,3) CblD (7 Sect. 28.2) (1,2,3) Biotinidase deficiency (7 Sect. 27.1.2) (3) TTPA: Vit E def (1) SHMT2 (7 Sect. 28.3.10)

Vitamin related diseases including folate metabolism

ID, seizures

MCGA1 (1), L,D-2HGA (1,2): complex

MCGA1 (1,2,3) (7 Sect. 18.3) L,D-2HGA (1,2) (7 Sects. 22.8 and 22.9)

Organic acidurias (7 Chaps. 18 and 22)

Acute decompensations, DD, ID. Arginase def: CP-like, microcephaly

(1,2) Arginase def (complex) (2,3) HHH: pure or complex

(2,3) HHH (7 Sect. 21.2)

Urea cycle disorders (7 Chap. 19)

Normal, thin/absent CC. C may be affected Atrophy and/or vessel tortuosity

Usually normal

CblD: Vascular stroke BBGGa may appear. SHMT2: perisylvian polymicrogyria, thin CC

MCGA: WMa, BBGGa, Ca; L,D2HGA: Table X

Cortical and subcortical edema. BBGGa

AA: low ORN, CIT, ARG, PRO

CSF NT

Organic acids, homocysteine, biotinidase, VitE acylcarnitines

Organic acids

Ammonia, AA

First line markers (. Table 1.3) Second line: AA, OA, acylcarnitine, metals, porphyrins, purines, pyrimidines, biopterins

Biomarkers

1

I. Small molecule defects. Some cause abnormalities in first line metabolic investigations (acidosis, hyperammonaemia, glucose, lactate …). In most, plasma, urine or CSF metabolic markers are abnormal with a typical or suggestive metabolic signature. Metabolomics for diagnostic purpose is available in some specialized centres.

Disease group

. Table 1.20 IEM with complex motor clinical manifestations

78 J.-M. Saudubray and Á. Garcia-Cazorla

Porphobilinogen, aminolevulinic acid, porphyrins, blood count

Purines

Ataxic-spastic gait

(1,2,3) OPA1, 3 (1,2,3) PDH (7 Chap. 11) (1) POLR3A, POLR3B (1) SACS, (2,3) TTC19, (2,3) Paraplegin, (1) Aconitase def

Glut-1 deficiency (1,2,3) (7 Sect. 8.3)

Mitochondrial defects (7 Chap. 10) (2,3) C12orf65, (2) IBA57: complex (2,3) Paraplegin: pure or complex (2,3) MERFF: complex

Complex: ataxia, other MD (1) SACS: axonal demyelinating sensorimotor PN (2,3) C12orf65, (2) IBA57 (2,3) Paraplegin: axonal PN

POLR3A, POLR3B: hypodontia, hypogonadism C12orf65: optic atrophy, PN IBA57: optic atrophy, PN Paraplegin: optic atrophy, PN MERFF: myoclonic epilepsy

DD, ID, tremor, parkinsonism

POLR3A, POLR3: hypomyelination TTC19: BBGGa Aconitase def: Cerebellar atrophy

Normal

(continued)

Lactate, pyruvate, AA, organic acids

Low glycorrhachia

First line markers (. Table 1.3) (lactate…) AA, OA, function tests

NBIA: Eye of the tiger

HMBS: Leukodystrophy, later cerebellar atrophy CYB5R3: Decreased WM volume, hypomyelination

ENTPD1: WMa NT5C2: WMa, thin CC

High plasma glycine levels

II. Energy metabolism defects. In mitochondrial disorders lactate and other markers may be disturbed mostly in children but often remain normal in adult cases. Diagnosis is complex and increasingly reliant on molecular investigations (7 Sect. 14.5).

Axonal (CMT2) and motor neuropathy

NBIA: other MD, neurodegeneration

HMBS: Acute intermittent porphyria. Vertical gaze palsy, nystagmus. CYB5R3: Decreased WM volume, hypomyelination

AMPD2: short stature, amyotrophy; ENTPD1:ID, microcephaly; NT5C2: ID; ATIC: epilepsy, CP-like

Leukodystrophy, upper spinal cord lesions

High levels plasma sorbitol

1 patient with spastic-ataxia

Polyol defects: SORD (2,3) (7 Sect. 15.4)

(1) AMPD2, (2,3) ENTPD1: axonal neuropathy

ID, tonic upgaze (occasional or persistent)

1 patient with cerebellar atrophy

(2,3) SLC30A9 progressive complex spasticity

(1,2,3) NBIA; SLC30A9 (7 Sect. 34.6.3) (Zinc metabolism) (2,3)

(1), AMPD2, (2,3) ENTPD. (1) NT5C2, (1) ATIC: all complex

Metal defects

(2,3) ENTPD1

Purine defects (7 Chap. 32)

(2) HMBS: complex (7 Sect. 38.3) (2) CYB5R3 (2): complex

(1) GLRX5

Lipoylation defect (7 Chap. 23)

Hem disorders (porphyrias) (7 Chap. 33)

(1) GRID2

Glutamatergic signaling (7 Sect. 30.1)

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 79

1

(2) ABCD1, (1) RCDP, (1,2) SLS, (1) ELOVL4 biallelic mutations: complex Several PEX genes (7 Chaps. 10, 14, and 19): infantile; (2,3) AMACR (2) FAR1 AD inheritance All are complex

(1,2) ARSA: complex (1,2) GALC: complex (1,2) GM2: complex (1,2) SUMF: complex (2) PSAP: complex (1,2) Sialidosis: complex

(2) ABCD1: demyelinating (2,3) PN. DBP: sensorimotor neuropathy (3) ARD (Refsum): demyelinating motor and sensory PN (2,3) AMACR: demyelinating

(1,2) ARSA, GALC, (2) PSAP, (1,2) SLC17A5: demyelinating PN

RCDP: ID, skeletal dysplasia, cataracts, seizures ARD: RP, cerebellar ataxia, and chronic polyneuropathy; SLS: ID, retinopathy, ichthyosis; ELOVL4: ichthyosis, seizures; FAR1: cataracts, seizures; AMACR: PR

ARSA, GALC, GM2: neuroregression, irritability NPC1,2: visceral involvement, early Cholestasis, vertical supranuclear gaze palsy SUMF1: visceral involvement GM2, SLC17A5, PSAP, Sialidosis: Cherry red spot, myoclonus ABCD1: pathognomonic confluent WMa with gadolinium enhancement SLS: periventricular WMa Several PEX genes (7 Chaps. 10, 14, and 19): demyelination

ARSA, PSAP: metachromatic leukodystrophy GALC: calcifications, leukodystrophy, optic nerve thickness NPC1,2: cerebellar atrophy SLC17A5: hypomyelination

VLCFA, plasmalogens, pristanic, phytanic acid acylcarnitines

(2) ABCD1: X-ADL (2,3) AMACR

Biomarkers

Peroxisomal defects (7 Chap. 42)

Brain image

ARSA, GALC: high CSF proteins Enzymatic tests, peripheral cell blood inclusions, vacuolations SLC17A: CSF, urine sialic acid

Other clinical features

(1,2) ARSA (1,2) GALC (1,2) GM2 (1,2,3) NPC1,2 (2) PSAP (1,2) SLC17A5

Peripheral neuropathy/ motor neuron disease

Lysosomal storage disorders (7 Chaps. 40 and 41) ARSA (MLD) GALC (Krabbe) GM2 (Gangliosidoses) NPC (Niemann-Pick C) SUMF1 (MSD) SLC17A5 (sialin transport)

Spasticity (pure/complex)

VLCFA, plasmalogens, phytanic acid, oxysterols, MPS, oligosaccharides, sulfatides, sialic acid, lipidomics

Ataxia-SP spectrum

1

III. Complex molecules defects. Many complex molecules accumulation defects such as sphingolipidosis, sterols and some peroxisomal disorders may be suspected on clinical grounds and have robust metabolic markers. Most complex molecules synthesis and remodelling defects such as complex lipids have no readily measured metabolic markers and diagnosis is based on molecular investigations. Lipidomics is becoming increasingly accessible.

Disease group

. Table 1.20 (continued)

80 J.-M. Saudubray and Á. Garcia-Cazorla

(2) DARS1, 2, RARS1,2, EPRS1

(1) EXOSC3, UCHL1

Aminoacyl-tRNA synthetases and tRNA metabolism defects (7 Sect. 39.2)

Nucleotide metabolism (7 Chap. 39) (1) UCHL1: complex (3) ENTPD1: complex; (1) ADAR: pure or complex

(2) DARS1, 2, RARS1,2, EPRS1 (1) FARS (2), MARS2 (1): all are complex

(1,2) DEGS1: complex (2) FA2H: complex (1,2) B4GALNT1: complex (2,3) CTX: complex (1,2,3) CYP7B1: pure or with cerebellar signs, ID and nystagmus (1,2,3) GBA2: complex (1,2,3) PLA2G6: complex (3) DDHD2: pure or complex (1) DDHD2: complex (1,2) CYP2UI: complex (1,2,3) ERLIN: pure (1,2,3) BSCL2: complex (2,3) ABHD5: complex (1) EPT1: complex (1) CYP51A1: complex

(1) UCHL1: Axonal sensorimotor PN

(2) KARS1, (1) AARS1, GARS1, HARS1 YARS1: Axonal motor PN

(1,2) DEGS1: demyelinating PN. (1,2) B4GALNT1: axonal PN (2,3) ABHD12: demyelinating sensory motor polyneuropathy (2,3) CTX: axonal PN GBA2: polyneuropathy (1,2,3) PLA2G6: neuroaxonal dystrophy (1,2,3) PNPLA6: axonal motor PN, (1,2) BSCL2: axonal neuropathy, ALS DDHD1: axonal neuropathy with distal sensory loss CYP2UI: axonal PN

UCHL1: optic atrophy, nystagmus; ENTPD1: ID

DD, ID, cerebellar atrophy, seizures KARS1: deafness HARS1 (AD); Usher syndrome

DEGS1:DD, ID, nystagmus, seizures; ABHD12: PHARC B4GALNT1: cataracts, PN CTX: cataracts, ID, diarrhoea GBA2:ID, nystagmus, cataracts, male infertility PNPLA6: retinopathy, cerebellar atrophy DDHD2: DD, ID, nystagmus, dysarthria; DDHD1: RP CYP2UI: DD, ID, nystagmus, dysarthria BSCL2: cardiomyopathy, epilepsy, DD, ID ABHD5: ChanarinDorfman (deafness, cataract, cardiomyopathy) EPT1: ID, RP CYP51A1: cataract, liver disease

Onset-age Pure/complex SP

Cellular trafficking disorders (7 Chap. 44)

Ataxia-SP spectrum disease Peripheral neuropathy/motor neuron disease

Ataxia and Spastic-Ataxia spectrum are common. Peripheral axonal and mixed neuropathies are also frequent

CDG syndromes (7 Chap. 42)

IV. Cellular trafficking disorders: in general, there are, as yet no metabolic markers. Diagnosis is based on DNA testing.

(2) FA2H (1,2) B4GALNT1 (2,3) ABHD12 (2,3) CTX (1,2,3) CYP7B1 (1,2,3) GBA2 (1,2,3) PLA2G6 (2,3) PNPLA6 (2,3) ABHD5

Lipid metabolism defects Sphingolipid defects (7 Chap. 40): DEGS1, FA2H, B4GALNT1 Phospholipids (7 Chap. 35): BHD12, PLA2G6, EPT1, ABHD12, PNPLA6, DDHD1,2 Sterols: CYAP27A1 CTX CYP7B1, CYP51A1 Others: GBA2, ERLIN1, BSCL2, ABHD12, ABHD5

Only in some CDG syndromes

ADAR: interferon signature

High lactate

DEGS1: increased dihydrosphingolipids in plasma CTX, CYP51A1: Cholesterol, sterols ABHD5: CPKs, Jordan’s anomaly

Other symptoms Genetic syndromes

(continued)

Disialotransferrins. Some forms do not have markers

PCH type 1B

DARS: LBSL

DEGS1: hypomyelinating leukodystrophy FA2H (2): NBIA features GBA2: thin CC, cerebellar atrophy PLA2G6: NBIA, cerebellar atrophy DDHD1: thin CC, NBIA DDHD2: thin CC, WMa CYP2UI (1,2): thin CC, WMa

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 81

1

Ataxia-SP spectrum

Spasticity (pure/complex)

Other clinical features

Biomarkers

Cognitive impairment: most of them except pure forms Early-onset complex encephalopathy: AP4B1, TECPR2, AP4M1, AP4E1, AP4S1, VPS37A, TFG, KLC2 Parkinsonism: KIF5A, ATP13A2 Ocular symptoms: Cataract: RAG3GAP2 Nystagmus: KLC2, ZFYVE26, SPART, GJC2, TECPR2, AP4M1, KIF1C, ATP13A2, KIF1A, TUBB4A Deafness: RAG3GAP2 Genetic syndromes: Kjellin syndrome: ZFYVE26, Troyer syndrome: SPART

Brain image

In black bold: treatable disorders. Onset age: 1 infancy to early childhood, 2 childhood (from 2 years until adolescence), 3 adolescence AA amino acids, AADC L-amino acid decarboxylase deficiency, ABHD12 monoglycerol lipase, ACAT1 acetoacetyl-CoA thiolase deficiency, AD autosomal dominant, ADCY5 adenylate cyclase deficiency, ADL-X X-linked adrenoleukodystrophy, ADSL adenylosuccinate lyase deficiency, AIP acute intermittent porphyria, ALS amyotrophic lateral sclerosis, AMACR α-methylacyl-CoA racemase, AMPD AMP deaminase-2 deficiency, AR autosomal recessive, ARALAR mitochondrial protein involved in glutamate aspartate exchange encoded by SLC25A12, ARD (adult Refsum disease) phytanoyl-CoA 2-hydroxylase, ARG arginine, ARSA arylsulfatase A deficiency, AS asparagine synthetase, ATIC 5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria, Atten attenuated forms, ATIC 5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH, ATP8A2 encodes for a P4-ATPase that actively transports phospholipids across cell membranes (‘flipping’), BBGGa basal ganglia abnormalities, B4GALNT1 GM2/GD2 synthase deficiency, BCAA branched chain amino acids, C cerebellum, Ca cerebellar atrophy, CAD CAD trifunctional protein, carbamoylphosphate synthetase/aspartate transcarbamylase/dydroorotase, CC corpus callosum, CDG congenital disorders of glycosylation, CERS ceramide synthase, CIT citrulline, CK syndrome X-linked recessive sterol-4-alpha-carboxylate 3-dehydrogenase deficiency, CLBP mitochondrial quality protein control, CMH congenital methemoglobinemia, CMNO cardiomyopathy, CP cerebral palsy, CPTII carnitine palmitoyltransferase II deficiency, CTX cerebrotendinous xanthomatosis, CSF cerebrospinal fluid, CP cerebral palsy, DBP D-bifunctional protein, DD developmental delay, DEF deficit, DHPR dihydropyrimidine reductase deficiency, DEGS dihydroceramide delta4-desaturase, DHFR dihydrofolate reductase deficiency, DLP1 dynamin related protein 1. EAAT1, glutamate aspartate transporter deficiency (SLC25A22), DWI diffusion, ECHS1 mitochondrial short-chain enoyl-CoA hydratase deficiency, ELOVL elongation of very long chain fatty acids, encephalop encephalopathy, ENTPD ectonucleoside trisphosphate diphosphohydrolase I, EPT1 ethanolamine phosphotransferase ETHE1, sulfur dioxygenase deficiency, FA2H fatty acid 2-hydroxylase deficiency, FAR1 fatty-acyl CoA reductase 1 deficiency, FHD fumarate hydratase deficiency, FOLR1 folate receptor alpha deficiency, GAMT guanidinoacetate methyltransferase, GA1 glutaric aciduria type 1, GABAR GABA receptor mutations, GABAT GABA transaminase deficiency, GALC galactocerebrosidase, GLUT1DS glut-1 deficiency syndrome, GORS Golgi SNAP receptor complex member 2, GOT2 glutamate oxaloacetate transaminase deficiency, GRIN mutations in NMDA glutamatergic receptors, GS glutamine synthetase, GSS glutathione synthetase deficiency, GTPCH guanosine triphosphate cyclohydroxylase, HCS deficiency holocarboxylase synthetase deficiency, HH hyperinsulinism-hyperammonaemia syndrome, HHH hyperornithinaemia-hyperammonaemia-homocitrullinaemia syndrome, HIBCH 3-hydroxyisobutyryl-CoA hydrolase deficiency, Homocyst homocysteine, HRS hypokinetic-rigid syndrome, HSD10 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, ID intellectual disability, INAD infantile neuroaxonal dystrophy, ITPase inosine triphosphatase, ITPR1 inositol 1,4,5-triphosphate receptor, type1, IVA isovaleric aciduria, L2-HGA L2-hydroxyglutaric aciduria, L2HGDH L-2-hydroxyglutarate dehydrogenase deficiency, L,D2-HGA L and 2-D-hydroxyglutaric aciduria, LBSL leukodystrophy with brainstem and spinal cord involvement and lactate elevation, LN Lesch-Nyhan, MCGA1 3-methylglutaconic aciduria type 1, MECR Trans-Enoyl-CoA reductase, MELAS lactic acidosis, and stroke-

Ataxia-SP spectrum disease: ZFYVE26, SPART, GJC2, TECPR2, AP4M1, KIF1C, ATP13A2, KIF1A, TUBB4A Axonal neuropathy: KIF5A, SPG11, ZFYVE26, GJC2, TFG, WDR48, ATP13A2, KLC2, ATL1, TMR13, LITAF, MTMR2, 5, SH3TC2, ARL6IP1, ATP13A2, ATP7, TGF, DGAT2 -Demyelinating neuropathy: FIG, EGR2, NEFL, FBLN5 ARHGEF Sensory and autonomic neuropathy: FAM134B, RAB7, ATL1, DNMT1, ATL3, SCN11A, PRNP, WNK1, KIF1A, IKBKAP, SCN9A, NTRK1, NGF-B, DST, CCT5 ALS: CHMP2B, Spactasin, FIG4, C9orf72, OPTN1, VAP9, VAPB, SigR1, KIF5A, BICAUDAL; DYNC1H1, ATP7

Peripheral neuropathy/ motor neuron disease

1

Onset age: (1): SPAST, SPART, AP4B1, TECPR2, AP4M1, AP4E1, AP4S1, VPS37A, TFG, USP8, WDR48, ARL6IP1, RAG3GAP2, KLC2, ATL1, KIF1A, REEP2, TUBB4A. (2): SPAST, NIPA1, KIF5A, RTN2, REEP1, SLC33A1, SPG11, ZFYVE26, SPART, GJC2, KIF1C, ATL1, KIF1A, REEP2, TANGO2; (3): SPAST, NIPA1, WASHC5, KIF5A, RTN2, REEP1, SLC33A1, SPG11, ZFYVE26, GJC2, KIF1C, ATP13A2, KIF1A, TANGO2 -adult onset: SPAST, NIPA, WASHC51, KIF5A, RTN2, REEP1, SLC33A1, SPG11, ZFYVE26, KIF1C, ATP13A2, KIF1A Pure: SPAST, NIPA1, WASHC5, KIF5A, RTN2, REEP1, SLC33A1, SPG1, ZFYVE26, ATL1, KIF1A, REEP2 Complex: KIF5A, REEP1, SPG11, ZFYVE26, SPART, GJC2, AP4B1, TECPR2, AP4M1, AP4E1, AP4S1, VPS37A, TFG, KIF1C, USP8, ARL6IP1, ATP13A2, KLC2, ATL1, KIF1A, TANGO2

Disease group

. Table 1.20 (continued)

82 J.-M. Saudubray and Á. Garcia-Cazorla

like episodes, MEGDEL 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MEPAN mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, MERRF mitochondrial encephalopathy and ragged red syndrome, MD movement disorders, MDH malate dehydrogenase deficiency, MLD metachromatic leukodystrophy, MMA methylmalonic aciduria, MOCS molybdenum cofactor deficiency, MPS mucopolysaccharides, MRS brain MRI with spectroscopy, MSD multiple sulfatase deficiency, MSUD maple syrup urine disease, MTHFR methylenetetrahydrofolate reductase deficiency, MTHFS 5,10-methenyltetrahydrofolate synthetase, NADK2 mitochondrial NAD kinase 2 deficiency, NARP neuropathy, ataxia and retinitis pigmentosa, NAXE NAD(P)HX epimerase deficiency, NBIA neuronal brain iron accumulation, NCL neuronal ceroid lipofuscinosis, NKH nonketotic hyperglycinaemia, NPS neuropsychiatric symptoms, NRL neurological, NT neurotransmitter, NT5C2 5-prime-nucleotidase, cytosolic II, ORN ornithine, OA organic acids, P5CS δ-1-pyrroline-5-carboxylate synthase deficiency, PA propionic aciduria, PHARC polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, PC pyruvate carboxylase, PCH pontocerebellar hypoplasia, PDH pyruvate dehydrogenase, PERIV periventricular, PLA2G6 phospholipase A2, PKAN pantothenate kinase 2 deficiency, PGK1 phosphoglycerate kinase 1, PHARC peripheral neuropathy hearing loss retinitis pigmentosa, cataract, PME progressive myoclonic epilepsy, PMPCA peptidase, mitochondrial processing, alpha, PN peripheral neuropathy, PNPO pyridoxamine 5′-phosphate oxidase, PNP purine nucleoside phosphorylase deficiency, PMM2 phosphomannomutase 2 deficiency, PRO proline, PSAP prosaposin, RALF recurrent acute liver failure, RCDP rhizomelic chondrodysplasia punctata, RHADS rhythmic high amplitude delta with superimposed polyspikes, RP retinitis pigmentosa, RPIA ribose-5-phosphate isomerase deficiency, SACS sacsin, SCA spinocerebellar atrophy, SCP2 sterol carrier protein 2 deficiency, SDE syndrome, SLC25A19 thiamine pyrophosphate transporter, SHMT2 serine hydroxymethyltransferase type 2, SLS Sjögren Larsson syndrome, SORD sorbitol dehydrogenase, SP spastic paraparesis, SR sepiapterin reductase deficiency, SSADH succinic semialdehyde dehydrogenase (aldehyde dehydrogenase 5a1, SUCLA2 succinyl-CoA lyase subunit, SUCLG1 succinyl-CoA ligase alpha subunit, SUMF1 gene responsible for multiple sulfatase deficiency, SUOX sulphite oxidase deficiency, SV synaptic vesicle, TH tyrosine hydroxylase deficiency, TPK1 thiamine pyrophosphokinase deficiency, UCD urea cycle disorders, VLCFA very long chain fatty acids, WM white matter, WMa white matter abnormalities, X-ALD X-linked adrenoleukodystrophy

Clinical Approach to Inborn Errors of Metabolism in Paediatrics 83

1

. Fig. 1.9 Algorithm for spasticity

CELL TRAFFICKING DISORDERS SPAST, NIPA1, WASHC5, KIF5A, RTN2, REEP1, SLC33A1, SPG1, ZFYVE26, ATL1, KIF1A, REEP2

COMPLEX MOLECULE DEFECTS - Lipid defects: CYP7B1, DDHD2 - Nucleotide defects: ADAR

ENERGY DEFECTS - Mitochondrial disorders: paraplegin

SMALL MOLECULE DEFECTS - Urea cycle defect: HHH - Biotinidase deficiency - Neurotransmitter defect: TH - Ornithine/proline: P5CS

Although these IMD can present as pure forms, they often have associated signs

PURE EPILEPSY (see Table 1.17)

HYPERKINETIC MOVEMENTS (see Table 1.19)

Organic acidurias: MCGA1, L,D-2HGA; CblD; biotinidase deficiency; -P5CS Purine defects: ATIC, others Mitochondrial defects: MERRF: myoclonic epilepsy Lysosomal disorders: diverse lysosomal diseases cause myoclonic epilepsy Peroxisomal defects: FAR1, ELOVL4, diverse PEX genes Aminoacyl-tRNA synthetases : diverse genes Cell trafficking disorders: in particular synaptic vesicle cycle defects

Many diseases that present prominent spasticity associate ATAXIA: spastic-ataxia spectrum (see Table 1.20)

PERIPHERAL NEUROPATHY/MOTOR NEURON DISEASE:

see table

- Neurotransmitter disorders: TH, GTPCH, SR; - metal disorders: SLC39A14, SLC30A10; - Lysosomal disorders: Tay-Sachs, Gaucher types 2, 3; CLN2,3,6; NPC, GM1, Sandhoff; - Nucleotide metabolism: several causes of Aicardi-Goutières syndrome; - Cell trafficking disorders: VPS13D, several synaptic vesicle disorders

HYPOKINETIC MOVEMENTS: parkinsonism often dystonia-parkinsonism (see Figure 1.8)

- Tremor: GTPCH, D-2-HGA, VitE deficiency, SLC39A14, SLC30A10, Glut1D, Tay-Sachs, Sandhoff, sialidosis, DARS1, PHARC, KIF1C - Dystonia: SLC39A8 (CDG type), SLC39A14, SLC30A10, homocystinurias, Lesch-Nyhan disease, Glut1D, SERAC1, lysosomal disorders, CLN14, several sphingolipidosis, several nucleotide metabolism defects. - Chorea: ADCY5, NKH, Lesch-Nyhan disease Glut1D, aconitase deficiency, sialidosis, MLD - Myoclonus: Neurotransmitter defects (TH, SR), L2-HGA, CLN14, Tay-Sachs, Krabbe, Sandof, sialidosis, MERRF, PHARC, DARS1

-

WITH ASSOCIATED NRL SYMPTOMS

- Several complex molecule disorders: Lysosomal, complex lipid defects - Arginase and HHH deficiency

VISCERAL

- Plasmalogen defects; - P-Inositides defects; - Cholesterol defects; - P-Cho, P-Eth, P-Ser defects

BONE

- Nystagmus: CblD, HMBS (porphyria), many diseases with cerebellar involvement and hypomyelination - Retinopathy: CblD, several lysosomal disorders (GM2, SLC17A5, PSAP, sialidosis) - Cataract: several disorders of complex lipid defects, peroxisomal defects and cell trafficking - Optic atrophy: botinidase, several mitochondrial defects (C12orf65, IBA57: optic atrophy, Paraplegin) - Cherry red spot: lysosomal disorders - Pigmentary retinitis: peroxisomal disorders, some NBIA syndromes, VitE deficiency

EYE

- Ichthyosis: complex lipid disorders such as ELOVL4, Sjögren-Larsson; peroxisomal defects: FAR1, ARD, RCD; lysosomal disorders: Gaucher II, MSD; -Others: serine deficiency - Melanoderma: X-ADL; - Angiokeratoma: sialidosis II

SKIN

WITH ASSOCIATED NRL SYMPTOMS

84 J.-M. Saudubray and Á. Garcia-Cazorla

1

- Mitochondrial: MNGIE, SACS, SURF1, MPV17; Sacsinopathies - Homocysteine remethylation defects - Lysosomal: Krabbe, MLD, Beta-mannosidase, Sandhoff disease, PSAP, SLC17A5, SUMF1, Farber, Krabbe - Peroxisomal: Zellweger, Adrenoleucodystrophy Refsum, AMACR, several PEX mutations, X-ADL, AMN - Lipid disorders: DEGS1, ABHD12 (PHARC), CTX, Tangier disease - Cell trafficking: FIG, EGR2, NEFL, FBLN5, ARHGEF - Fatty acid oxidation: LCHAD, TP - Other genes: GDAP1, MTMR2, SBF3, MTMR5, SH3TC2, NDGR1, HK1, Neurofascin

- Mitochondrial: NARP, POLG, MELAS, MERRF. From 35–45% of mitochondrial patients have axonal neuropathy, mostly nuclear, PDH; Sacsinopathies - Fatty acid oxydation: LCHAD, trifunctional protein. - Lysosomal: Nieman Pick type-C, Gaucher disease, ceroid lipofuscinosis, Pompe disease, Schindler disease, GM2 (*) - Peroxisomal: Bifunctional protein (neuropathy may be isolated as presentation), peroxisome biogénesis defects, racemase (*) - Porphyrias: DOSS porphyria; acute intermittent porphyria Hereditary coproporphyria, Variegate porphyria - Lipid disorders: B4GALNT1, CTX, BSCL2, DDHD1, Neuronal Target Enterase, INAD - Cell traffic: KIF5A, SPG11, ZFYVE26, GJC2, TFG, WDR48, ATP13A2, KLC2, ATL1, TMR13, LITAF, MTMR2, 5, SH3TC2, ARL6IP1, ATP13A2, ATP7, TGF, DGAT2 - CDGs: in general, axonal neuropathies - Purine disorders: PRPS, AMPD2, ENTPD1 - Aminoacyl-tRNA and nucleotide metabolism: KARS1, AARS1, GARS1, HARS1, YARS1, UCHL1, MARS1 - Triose phosphate isomerase; - Choline presynaptic defect - Polyol defect: sorbitol dehydrogenase deficiency - Ornithine/proline metabolism: P5CS; - OAT deficiency (late complications) - Serine synthesis deficiency - Polyglucosan body disease (*), pyroglutamic aciduria (*)

. Fig. 1.10 Algorithm for peripheral neuropathy and motor neuron disease

- Lysosomal: Galactosialidosis, mucolipidosis, others - Fatty acid oxydation: LCHAD, trifunctional protein. - Many other complex molecule defects, in particular those with WM involvement may have mixed neuropathies, also CDG syndromes

MIXED

DEMYELINATING

AXONAL

HEREDITARY MOTOR AND SENSORY NEUROPATHY (HMSN)

HEREDITARY SENSORY NEUROPATHY (HSN) and autonomic (HSAN)

VITAMIN RELATED

Mitochondrial: MELAS, MERRF, other genes Lipid disorders: SPTLC1 or SPTLC2, DDHD Cell traffic disorders: REEP1, KIF1A, FAM134B Other genes involved in HSN and/or HSAN (most cell traffic disorders): ELP1, FAM134B, RAB7, ATL1, DNMT1, ATL3, SCN11A, PRNP, WNK1, KIF1A, IKBKAP, SCN9A, NTRK1, NGF-B, DST, CCT5 ; - Painful small fiber neuropathy: Fabry disease

Neonatal, early infancy SMA-like - Mitochondrial defects: TK2, other genes leading to mtDNA depletion, ACO2; - Peroxisomal disorders; - Traffic defects: BICD2, VAPB, ATP7; - Others: PCH1, AGTPBP1. Late SMA with progressive myoclonic epilepsy: acid ceramidase deficiency ALS: - Traffic defects: CHMP2B, spactasin, FIG4, C9orf72, OPTN1, VAP9, VAPB, SigR1, KIF5A, BICAUDAL, DYNC1H1, ATP7; - DNA/RNA metabolism: FUS, TARDBP; Others: SOD1, riboflavin transport defects (ALS mimic) HMN, distal SMA: - Polyol defect: SORD; - Glycolitic defect: TPI; - Cell traffic disorders: DCTN1, FIG, SPG11, RAB7, DNM2, RAB18, 39B, RAB7, RAB18, 39B, RAB7, RAB3GAP1, connexin32 (C32), BSCL2, REEP1, SIGMAR1, DCTN1, SPTAN1, PLEKHG5, SYT2; - Lipid disorders: PNPLA6, presynaptic choline transporter (CHT), GM2 synthase deficiency; - RNA and DNA metabolism: FBX038, SETX, IGHMBP2, AIFM1 - tRNA aminoacylation: AARS, HARS, GARS, WARS, HINT1; - Ion channels and transporters: SLC12A6, SLC25A21, TRPV4, SLC5A7, ATP7A Others: ABCD1 (adrenomyeloneuropathy), combined spinal cord degeneration in homocysteine remethylation defects, PNPLA6 (spinal cord atrophy)

HEREDITARY MOTOR NEUROPATHY (HMN) Lower motor neuron disease: SMA-like, ALS

VitB12: myelopathy, funicular myelosis, proprioceptive dysfunction Folate related: progressive distal sensory neuropathy. Thiamine: distal axonal sensory motor. VitB6: distal axonal sensory motor. Biotin: myelopathy: VitE/abetalipoproteinemia: distal symmetric with severe sensory ataxia. Riboflavin transport: motor and sensory neuropathy, distal motor neuropathy, cranial nerve involvement, Guillan-Barré, ALS

-

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or small toxic molecules often cause pyramidal tract lesions. In fact, almost all progressive neurometabolic diseases end up manifesting different degrees of spasticity. Only those IEM in which spasticity is the dominant or one of the most prominent signs in the clinical picture are depicted in . Table 1.20 (complex motor disorders). Metachromatic leukodystrophy and infantile neuroaxonal dystrophy (INAD) (PLA2G6 mutations) present between 12 and 24 months of age with flaccid paraparesis, hypotonia, and weakness (7 Sect. 35.4.2). CSF protein content and nerve conduction velocity are disturbed in the former but normal in the latter (however axonal neuropathy can be present). Schindler disease is roughly similar to neuroaxonal dystrophy, though it is often associated with myoclonic jerks (7 Sect. 41.3). Spasticity in IEMs is in general associated with involvement of additional neurological functions or organs (. Fig. 1.9 spasticity algorithm). However, some disorders can start with isolated spastic paraparesis such as X-linked adrenoleukodystrophy, remethylation defects of homocysteine metabolism, biotinidase deficiency, HHH syndrome (hyperammonaemia, hyperornithinemia, homocitrullinuria), arginase deficiency, Segawa disease and some lipid metabolism disorders, in particular phospholipid synthesis and remodeling defects (. Table 1.20 complex motor disorders, . Fig. 1.9 spasticity algorithm). New IEMs with prominent spasticity belong to cell trafficking disorders, most of them included in classical genetic spastic paraparesis and complex lipid defects. z

for a demyelinating polyneuropathy (7 Sect. 32.6.4). Some lipid storage disorders such as cerebrotendinous xanthomatosis (7 Sect. 38.3), adrenomyeloneuropathy and other peroxisomal diseases (7 Chap. 42) may cause polyneuropathies that can be axonal, demyelinating or both (algorithm peripheral neuropathy). Peripheral neuropathies in IEM are in most cases syndromic opposite to non-syndromic classic CMT (Charcot-Marie-tooth disease). In fact, they are often found in IEM that show other motor manifestations involving first motorneuron and the spinal cord. However, there are some particular IEMs in which peripheral neuropathy is the only clinical manifestation. This is the case of the recently described SORD (sorbitol dehydrogenase) deficiency (7 Sect. 14.4), some late-onset riboflavin metabolism defects, some forms of trifunctional protein defects and those related to cell trafficking disorders. Porphyrias and tyrosinemia type I can present with acute attacks of polyneuropathy mimicking Guillain-Barre syndrome. Patients with sphingosine-1-P lyase deficiency (7 Sect. 40.3.4) are distinct from other AR-CMT2 subtypes and are characterized by acute/subacute onset, unilateral motor deficit (one patient), and episodes of mononeuropathy with a tendency for improvement. The deterioration pattern is atypical for axonal CMT. Rather, it is observed in acquired neuropathies, hereditary neuropathies with liability to pressure palsies, or hereditary neuralgic amyotrophy [75] (7 Chap. 40). EM (Electromyography) can reveal myotonia-like discharges as typical finding in juvenile type II glycogenosis.

Peripheral Neuropathy

The diagnosis of peripheral neuropathies rely on clinical and electrophysiological criteria. The general classification depends on whether there is an involvement of large fibers (motor weakness, loss of deep reflexes, muscle atrophy, sensory ataxia), or small fibers (autonomic dysfunction, abnormal temperature, sensibility pinprick loss) and whether the neuropathy is predominantly demyelinating or axonal (. Fig. 1.10 algorithm neuropathies). Although peripheral neuropathies can be found in all IEM categories, complex molecule defects, and in particular, lipid storage disorders, and energy metabolism defects are the most common. In lipid storage disorders, both the peripheral and central myelin can be involved, leading to a low nerve conduction velocity (NCV) and leukoencephalopathy on brain MRI. In contrast, defects of energy metabolism are mostly responsible for axonal peripheral neuropathies with normal NCV and are usually associated with other signs of energy metabolism defects (optic atrophy and cerebellar ataxia in the case of respiratory chain disorders). Many exceptions to this schematic view however exist. MNGIE syndrome (myoneurogastrointestinal neuropathy) caused by thymidine phosphorylase deficiency is typically responsible

z

Motor Neuron Disease

Motor neuron diseases refer to lower motor neuron dysfunction (second motor neuron). These are hereditary motor neuropathies (HMN) and may present as distal SMA (spinal muscle atrophy) with peroneal muscular atrophy and weakness without involvement of sensory dysfunction, or more complex and severe SMA-like clinical pictures. A few metabolic diseases cause HMN and tend to be complex or atypical, that means that they may have predominance in the upper limbs or involvement of upper motor neurons, and vocal cord and/or diaphragm paralysis, among other features. Lipid disorders and cell trafficking defects are the most representative IEM with this clinical manifestation. SMA-like are found in energy, peroxisomal and complex lipid defects (. Table 1.20 complex motor disorders, and . Fig. 1.10 neuropathy/motor neuron algorithm). On the other hand, Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of the lower and upper motor neurons and is the most prevalent motor neuron disease in the general population. This disease is characterized by muscle weakness, stiffness, and hyperreflexia. Most cases are sporadic, with only 10% of the

87 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

cases being genetic. Only a few IEM may present with ALS and they include SORD deficiency, Riboflavin transport defects, cell trafficking and DNA/RNA metabolism defects and dominantly acting SPTLC1 (7 Chap. 40 note added in proof) (. Fig. 1.20). 1.5.2.5

Category 5: With Predominant Intellectual Disability and/or Behavioural, Neuropsyhiatric Manifestations (Algorithm)

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptative behaviour, that originates before the age of 18 [76] and affects about 2.5% of the population. It is defined by an IQ below 70 at 5 years of age or older. Developmental delay (DD) is the term used below 5 years, defined as deficits in two or more developmental domains (e.g. motor skills and speech) [77]. It is estimated that IEMs account for 1–5% of non-specific ID, although no recent systematic studies have been performed to validate these numbers. Almost all IEMs that affect the nervous system at paediatric ages will cause DD or ID. However, in the great majority of cases, this is a syndromic ID that associates other neurological and extra-neurological symptoms. In this section we discuss IEM with isolated or predominant ID, although most of them are accompanied by behavioural problems (autistic features, hyperactivity, aggressive and self-injurious behaviours, executive dysfunction problems) (. Fig. 1.11 ID algorithm). All pathophysiological categories of IEM may cause isolated or predominant ID and some are treatable (. Fig. 1.11). In most of them DD/ID remains the only sign for a certain period of time before the appearance of more evocative signs such as in small molecule disorders (AA related disorders, OAs) and mitochondrial defects. Autism is a frequent sign in disorders with predominant ID. This is the case with AA and creatine defects, mitochondrial disorders, attenuated forms of Smith-LemliOpitz syndrome, and other diseases that mimic genetic conditions. Disorders that mimic Rett syndrome are BPAN (beta-propeller associated neurodegeneration, an autophagy disorder) [78] (7 Sect. 44.3.1), choline kinase deficiency (7 Sect. 35.3.1), disorders of the Synaptic Vesicle and GABA/Glutamate signalling diseases (7 Chap. 44). Choline kinase deficiency may also mimic Angelman syndrome. Behavioural disturbances, psychosis, and schizophrenia-like syndrome can be also the first clinical signs of a metabolic disorder even in the absence of ID [79]. This is more frequent in late childhood, adolescence and adulthood. OTC deficiency can present with episodes of abnormal behaviour and personality change until hyperammonaemia and coma reveal the true situation (see 7 Sect. 1.4.1). Homocystinuria due to MTHFR deficiency has presented as isolated schizophrenia. Searching for

these treatable disorders is mandatory including also CTX and Wilson disease (see . Fig. 1.11). 1.5.2.6

Category 6: With Neuroregression

Most diseases that cause progressive intellectual and neurological deterioration (PIND) present in childhood: 81% before the age of 5 years [80]. Most of these IEMs represent storage disorders, but other categories are represented as well. In a recent review over half were categorized in the group “storage disorders” mainly due to different types of MPS (type I, II, IIIA, IIIB, IIIC, IIID, VII) and NCL (neuronal ceroid lipofuscinosis) which represent about half of the storage diseases [81]. Sanfilippo disease is the classic example with regression of high-level achievements, loss of speech, and agitation usually beginning later than 5 years. Other complex molecule disorders such as peroxisomal diseases (in particular X-ALD, where regression appears in childhood but can also starts at early adolescence, in particular in frontal forms), complex lipid defects, cell trafficking disorders and diseases of nucleotide metabolism will invariably lead to a regression at different moments of late infancy, childhood and adolescence. However, they can previously have some kind of neurological abnormalities (cerebral palsy like symptoms) that could make deterioration difficult to appreciate. This is also the case for some metal, purine and pyrimidine disorders. Canavan disease and some mitochondrial disorders such as MELAS (mitochondrial encephalopathy and lactic acid acidosis) have also a notable regression. Finally, neurodevelopment and neurodegeneration can behave as opposites throughout disease evolution, but they may also run in parallel [10]. Additionally, the lack of natural history studies for long periods of life in most metabolic diseases, do not allow concise knowledge about possible regression in adulthood or in the elderly. Other neurological signs such as chronic/recurrent headache appear in just a few IEM: MELAS, Hyperammonaemias, α-Methylacyl-CoA racemase (AMACR) deficiency (7 Sect. 42.2.4), NFE2L2 mutations leading to NRF2 accumulation with hypohomocysteinaemia. Hemiplegic migraine has been described in GLUT1DS, and in the following mutated genes: CACNA1A, ATP1A2, SCN1A.

1.5.3

Onset in Adulthood (>15 years to >70 years)

(See 7 Chap. 2) z

Specific Neurosensorial, Neurophysiological and Neuroradiological Signs and Symptoms (at any Age)

Neuroimaging, neurophysiology and ophthalmological investigations are helpful for elucidating neurologic and psychiatric syndromes. The most significant findings are

1

- Mitochondrial disorders may have isolated mild cognitive delay prior to developing more evident signs

- Creatine synthesis and transport defect

Energy defects

- Cell trafficking defects Collectrin defect (Hartnup-like) BPAN (autophagy disorder): mimics Rett syndrome synaptic vesicle disorders may present with) D and autism and/or other behavioural abnormalities. May also mimic Rett syndrome ( Fig 1.1)

- Lipid disorders Smith-Lemli-Opitz syndrome (SLOS), attenuated forms CTX (may present with mild ID before detecting other typical signs) Trans-2,3-enoyl-CoA reductase (TER) deficiency Choline kinase β (CHKβ) deficiency: may mimic Angelman/Rett syndrome Lysophosphatidyl-inositol acyltransferase (LPIAT1)

Complex molecule disorders

MAO: exhibitionism, violent behaviour

Others

Homocystinurias, SSADH, disorders with basal ganglia involvement (circuitries involved in obssesive-compulsive disorder)

Obsessive-Compulsive disorder

Wilson, mitochondrial disorders, neurodegenerative and intoxication disorders in particular at advanced stages of the disease

Depression

Urea cycle disorders, homocystinurias (including cobalamin and folate disorders), Wilson disease, CTX, Niemann-Pick C, late onset lysosomal disorders, ATP1A3: Childhood onset schizophrenia

Psychosis

Untreated PKU, tyrosinemia II, serine deficiency, Lesch-Nyhan disease, Wilson, PTPS (BH4 deficiency), Transketolase deficiency, NBIA syndrome, Lowe syndrome, TRAPCC related disorders, Neuroacanthocytosis

Self-injurious behaviour

Most intoxication disorders have ADHD and executive dysfuntion traits even with normal IQ

ADHD

Untreated PKU, organic acidurias (propionic aciduria), pyridoxine dependency, BCAA defects (BCKDK, BCAA transport), Hartnup disease, SSADH, GABA and glutamate signaling defects, biotinidase deficiency, cerebral folate deficiency, histinidemia, creatine defects, trimethyllysine hydroxylase deficiency (carnitine synthesis ), mitochondrial disorders, SLOS, LPIAT1, BPAN

Autism

BEHAVIOURAL/NEUROPSYCHIATRIC ABNORMALITIES

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. Fig. 1.11 IEM with predominant intellectual disability +/– behavioural and psychiatric manifestations

- Untreated PKU - Homocystinurias including cobalamin disorders - Urea cycle defects/organic acidurias Late-onset forms may have isolated mild cognitive delay prior to more evident signs (decompensations) - BCAA defects: BCKDK/transport - Hartnup disease - Purine disorders: Adenylosuccinate lyase deficiency Lesch-Nyhan disease - Neurotransmitter defects: Succinic semialdehyde dehydrogenase deficiency (SSADH) Monoamino oxidase deficiency (MAO) Glutamate and GABA signalling defects - Metal disorders: Occipital horn syndrome

Small molecule disorders

IEM WITH ISOLATED or PROMINENT ID +/– BEHAVIOURAL ABNORMALITIES

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89 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

presented in . Tables 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, and 1.32. Some are sufficiently distinctive to make a clinical diagnosis.

1.5.4

Deafness

The hearing loss in metabolic disorders is mostly sensorineural, symmetrical and (at least initially) high frequency. Mutations in connexins GJB2 (CNX26) and GJB6 (CNX3) cause up to 50% of recessive nonsyndromic deafness. Mitochondrial syndromic and non syndromic defects are also amongst the most common causes. Many genetic syndromes can mimic a metabolic disease; some are listed in . Table 1.21.

at least 15 genes causing neurodegeneration with brain iron accumulation (NBIA) have been identified so far (7 Sect. 34.2.3). Specific signs as listed in the following tables: 5 Basal ganglia, brain stem hyperintensities: . Table 1.23 5 Brain deposits: . Table 1.24 5 White matter abnormalities . Table 1.25 5 Brain dysplasia/malformation: . Table 1.26 5 Posterior fossa abnormalities: . Table 1.27

1.5.7

z 1.5.5

Head Circumference, Cephalhematomas, Subdural Hematomas (. Table 1.22)

Macrocephaly: Congenital macrocephaly may be an isolated early marker of GA1 and a few other cerebral OA (7 Chap. 22). Microcephaly: There are many untreated IEM in which microcephaly results from a progressive nonspecific cerebral atrophy. A few disorders present with an antenatal (congenital) microcephaly, among them mild forms of serine synthesis defects may be treatable (7 Sect. 24.2). Mutations in MFSD2A, required for omega-3 fatty acid transport in brain, have been recently shown to cause a lethal microcephaly syndrome (7 Sect. 42.4.13). Mutations in PYCR2, encoding pyrroline5-carboxylate reductase 2, cause a unique syndrome of postnatal microcephaly with severe hypomyelination (7 Sect. 21.4). Many Golgipathies present with severe microcephaly (congenital and post natal onset) (7 Chap. 44).

Neuroimaging Signs

Morphological evaluation is best undertaken by MRI. Cranial computer tomography (CT scan) is still important when looking for calcifications or in an emergency. Proton MR spectroscopy is a tool for assessing brain metabolites but is diagnostic only in a few disorders, including cerebral creatine disorders (absence of creatine peak), Canavan disease (high peak of N-acetyl aspartate) and some complex lipids/fatty acid defects such as Sjogren-Larsson syndromes and ELOV4 in which there is an additional lipid peak (7 Sect. 42.4) Mutations in

Abnormal fundoscopy findings (. Table 1.28)

Retinal dystrophies encompass retinitis pigmentosa, Leber congenital amaurosis (LCA), early onset retinal dystrophy and Stargardt disease. There are over 400 known inherited diseases in which the retina, macula or choroids are substantially involved [82]. Most of metabolic causes involve complex molecules (mostly lipids) and energetic processes. LCA, which is associated with several gene mutations, is a severe retinal dystrophy with infantile onset and is one of the most frequent cause of congenital blindness. Mutations in NMNAT (coding for NAD synthetase) have been recently described identifying a new disease pathway for retinal degeneration [83] (7 Sect. 24.1.2). Hereditary optic atrophy is common in neurodegenerative diseases due to IEM, especially white matter diseases and energy deficiencies, and deserves an extensive metabolic work-up. Optic atrophy is a frequent early presenting sign of primary (Leber hereditary optic neuropathy, RCD, PDH deficiency, biotinidase deficiency, Costeff optic atrophy syndrome) or secondary (organic acidurias) mitochondrial dysfunction. z

1.5.6

Neuro-ophthalmological Signs (. Tables 1.28 and 1.29)

Ophthalmoplegia, abnormal eye movements (. Table 1.29)

Abnormalities of eye movements can be an important diagnostic clue in many IEM. In few defects they can be the presenting sign, as with progressive external ophthalmoplegia (PEO) in several mitochondrial DNA disorders or vertical gaze palsy as in Niemann-Pick disease type C. PEO associated with peripheral neuropathy is suggestive of mitochondrial nuclear genes mutations. Furthermore, oculogyric crisis is an important feature in disorders affecting dopamine synthesis or transport (7 Sect. 30.5.7). Nystagmus, oculomotor apraxia (failure of saccade initiation) and oculogyric crisis are the most common abnormal eye movements in IEM [84].

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. Table 1.21 Sensorineural deafness Detectable in neonatal to infancy

Acyl-CoA oxidase deficiency Acetyl-CoA transporter (SLC33A1 mutations) Adenylate kinase 2 (reticular dysgenesis) Alport syndrome (COL4A mutations) Aminoacyl-tRNA synthetase deficiencies (mito and cytoplasmic), KARS Bjornstad syndrome (with pili torti) (BCSIL mutations) Cockayne syndrome Connexin Cx26 (GJB2) mutations (with ichthyosis) Encephalopathy with hyperkinurininuria ELOVL1 mutation (with ichthyosis and spasticity) Forkhead transcription factor FOXI1 (with distal tubular acidosis) H+ -ATPase (V-ATPase) (with distal tubular acidosis) Galactose-4-epimerase deficiency Heimler syndrome (PEX 1 and 7 mutations) MEDNIK syndrome PRPPS (phosphoribosylpyrophosphate synthetase deficiency) Riboflavin transporters (2 and 3) defects Rhizomelic chondrodysplasia punctata Sphingosine-1-P lyase deficiency Zellweger and variants Several cell trafficking disorders such as Waarderburg syndrome (with hypopigmentation):WS4A Ribosome defect: Treacher-Collins syndrome (conductive hearing loss) WFS1 mutations: Neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts.

Detectable in early to mid childhood

Aminoacylase deficiency Biotinidase deficiency (biotin responsive) (untreated or treated late) Chanarin-Dorfman syndrome Infantile Refsum disease (pseudo-Usher syndrome) Kearns-Sayre syndrome MEDNIK syndrome MPS type I, II, III (may be presenting sign) and IV α-Mannosidosis Mucolipidosis type II (I cell disease) Megaloblastic anemia, diabetes and deafness (B1-responsive) PHARC syndrome Perrault syndrome PRPP synthetase overactivity Riboflavin transporter defects Sphingolipidoses Mitochondrial non syndromic deafness: mutations in MTTS1 and MTRNR1: Mitochondrial DNA mutations (syndromic deafness): NARP, Pearson, Wolfram, MELAS, MERFF, Kearns-Sayre, MIDD, OPA1, DDP Dystonia-Deafness: Mohr-Tanebjaerg (TIMM8A) KARS1 mutations Several cell trafficking disorder (7 Chap. 44) PIK3C2A mutations (with congenital cataracts, nephrocalcinosis)

Detectable in late childhood to adolescence

β-Mannosidosis Fabry disease Refsum disease (adult form) Usher syndrome type II MERFF and other mitochondrial DNA mutations, Kearns-Sayre syndrome FDXR mutations (mitochondrial Fe-sulfur synthesis defect) Riboflavin transporter defects PRPS1 mutations (X-linked nonsyndromic sensorineural hearing deafness)

91 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.22 Head circumference Macrocephaly

Microcephaly Congenital and not congenital but progressive after birth

1. Small molecule disorders Glutaric aciduria type 1 Canavan disease (acetylaspartaturia) L-2-hydroxyglutaric aciduria

Infant born to mother with untreated PKU BCKDK (branched chain dehydrogenase kinase defect): not constant Serine synthesis defects improved by serine and brain serine transporter including Neu Laxova syndrome Glutamine synthesis defects Asparagine synthesis defects PYCR2 (pyrroline-5-carboxylate reductase 2 deficiency) Sulfite oxidase deficiency Cerebral folate deficiency due to FOLR1 mutations and DHFR deficiency Amisch lethal microcephaly (mitochondrial TPP transporter) SepSec (selenium metabolism defect) MFSD2A mutationn (omega3 fatty acid transport defect) CYB5R3 mutations (congenital methemoglobinemia)

2. Energy metabolism defects Some mitochondrial disorders

ACO2 (aconitase deficiency) GOT2 deficiency GLUT1DS and PDH Mitochondrial encephalopathies (in particular, severe early onset mitochondrial DNA depletions), POLGpathies.

3. Complex molecule disorders GM2 gangliosidosis (Sandhoff, Tay-Sachs) Krabbe disease (infantile form) Some phosphatidylinositol defects: PIK3CA (hemimegalencephaly), PIK3R2 (with polymicrogyria), INPPL1 mutations Desmosterolosis (may also produce microcephaly)

PI4K2A (with cutis laxa) Desmosterolosis Congenital ceroid lipofuscinosis Aminoacyl-tRNA synthetases and tRNA processing metabolism disorders RPL10, UTBF1 (ribosomopathies) Many neurodegenerative disorders with progressive brain atrophy

4. Cell trafficking disorders Golgipathies (like RAB39B, HERC STRADA mutations) TBCK mutations RAC1 mutations (may also cause microcephaly)

Dolichol kinase deficiency, DPM 13 (dolichol recycling defects) Different CDG syndromes such as COG1,2,4- 8,SLC35,TMEM 165 mutations (with post-natal microcephaly) Golgipathies related to RAB GTPases and their molecular partners (7 Chap. 44) Adaptinopathies (AP4 …), TRAPPCopathies Cytoskeleton disorders (tubulinopathies and others) IER3IP1: microcephaly, epilepsy and diabetes Vici syndrome WD-repeat proteins superfamily (WDR45B …)

Other genetic conditions: Alexander leukodystrophy Megalencephalic leukodystrophy with subcortical cysts Phacomatoses, PTEN (with autism, hamartomas). Overgrowth syndromes (mTOR1-AKT hyperactivation) NuRD complex mutations: CHD3, CHD4, and GATAD2B (neurodevelopmental disorders with macrocephaly and ID) Cephalhematomas: Glutaric aciduria type 1 Menkes disease

A large number of neurogenetic conditions that disrupt neurodevelopment. Rett syndrome due to MECP2 and Rett like mutations including CDKL5 and FOXG1 are amongst the most frequently described

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. Table 1.23 Basal ganglia & brainstem hyperintensities Leigh syndrome

Other types of hyperintensities

Hyperintensity of the Inferior olivary nucleus (brainstem)

SSDH (pallidum) L-2-hydroxyglutaric aciduria MMA (pallidum) NAXE and NAXD mutations MCT1 mutations (with thalami involvement) SLC19A3 mutations Wilson diseasea Cyt b5 reductase type II

Wilson disease Dihydropyrimidine dehydrogenase deficiency

Mitochondrial cytopathiesa PDH deficiencya

PDH POLG mutations Leber hereditary optic neuropathy

CTXa GM1 Gangliosidosisa (may produce T2 hypointensity) PDE10 deficiency AIMP1, AIMP2 (BG signal and hypomyelination)

Niemann Pick type C Salla disease Infantile neuroaxonal dystrophy Pontocerebellar hypoplasia (TSEN, EXOSC3 mutations)

MEDNIK

PMM2-CDG

KMT2B (histone methyltransferase): pallidum Acute thiamine depletion related to different causes (nutritional, alcoholism): Wernicke encephalopathya (thalami, brain stem)

Ataxia telangiectasia

1. Small molecule disorders ECHS1 mutations (enoyl CoA hydratase) Hydroxy-isobutyryl-CoA hydrolase 3-methylglutaconic aciduria 1 and 4 (7 Chap. 18, . Table 18.1). EPEMA syndrome (ETHE1 mutations) Sulfite oxidase deficiency Lipoylation defects including LIPT1 Vitamin related diseases (overlap with energy defects): Biotinidase deficiency Mutations in SLC19A3 (thiamine-biotin responsive basal ganglia disease) 2. Energy defects CoQ10 deficiency (including SQOR encoding sulfide: quinone oxidoreductase) Fumarase deficiency SUCLA2 (succinyl CoA synthetase) mutations Pyruvate carboxylase deficiency Pyruvate dehydrogenase deficiency KGD4 (coding for α-ketoglutarate dehydrogenase) >70 genes involved in oxidative phosphorylation, cofactors, and mitochondrial machinery including PTCD3 coding for one of the mitochondrial ribosomal proteins (7 Chaps. 14 and 37) 3. Complex molecule defects SERAC1 (MEGDEL syndrome: involvement of the putamen: ‘eye’ on the dorsal putamen) (also mitochondrial/energy dysfunction) (7 Sect. 35.3.7)

4. Cell trafficking disorders

Other genetic diseases:

Legend: aObserved in adulthood BG basal ganglia, PDE phosphodiesterase

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. Table 1.24 Basal ganglia & brain deposits Calcifications on CT scan

Metals

1. Small molecule defects: Carbonic anhydrase deficiency (CA2) (7 Sect. 19.4.2) Biopterin metabolism defects (DHPR) Folic acid metabolism defects: FOLR1, SLC46A1, MTHFR, DHFR NBIA syndromes (7 Sect. 34.2.3) 3-hydroxyisobutyric aciduria Congenital hypomagnesemia 2. Energy defects: Kearns-Sayre syndrome MELAS and other respiratory chain disorders Congenital lactic acidemias 3. Complex molecule defects: Krabbe disease GM2 Gangliosidosis KARS, FARSA, FARSB and SNORD118 (calcifications and cysts) (7 Sect. 39.2.3) Aicardi-Goutières related genes (7 Sect. 39.1.2) Cyt P450 hydroxylase (CYP2U1: SPG 56) (7 Sect. 35.4.6) Other genes with diverse functions: Primary familial brain calcifications (previously known as Fahr’s disease) (SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, JAM2 genes)a CSFR1 (AR inheritance: paediatric forms) JAM3: haemorrhagic destruction of the brain, subependymal calcification, and cataracts Collagen IV related disorders: COL4A1, COL4A2 Cockayne and other DNA repair defects Hypoparathyroidism

Copper: Wilson diseasea MEDNIK Manganese: Hypermanganesemia with cirrhosis Iron: Neurodegeneration with brain iron accumulation (NBIA) (7 Sect. 34.2.3): FTL Neuroferritinopathya (pallidum, putamen, caudate) low ferritin PANK2a (PKAN defect, HARP syndrome) tiger eye, RP COASY (CoA synthetase) similar to PKAN C2orf37/DCAF17 PLA2G6 mutations (pallidum>substantia nigra) cerebellar atrophy FA2H mutations (pallidum>substantia nigra) CPa aceruleoplasminaemiaa (diffuse hypointensity) low Cu and CER C19orf12 mutations (pallidum > substantia nigra) optic atrophy WDR45 (substantia nigra > pallidum) X linked dominant with MR ATP13A2 (caudate, putamen) GTPBP2

Legend: aObserved in adulthood RP retinitis pigmentosa, MR mental retardation, Cu copper, CER ceruloplasmin

. Table 1.25 White matter abnormalities With increased head circumference Glutaric aciduria type I (bitemporal atrophy) L-2-hydroxyglutaric aciduria Canavan disease (7 Sect. 22.10) Mucopolysaccharidosis (with vacuoles) Megalencephalic leukodystrophy with subcortical cysts (MLC1) Vacuolizing leukoencephalopathy Alexander disease (anterior) Hypomyelination

Periventricular

U fibres/other locations

Pyramidal tracts/ cavitating leukoencephalopathies

MRS lipid peak (continued)

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. Table 1.25 (continued) 1. Small molecule defects: Cerebral folate transport (FOLR1 mutations) and folate metabolism defects Untreated galactosemia Serine synthesis defects PYCR2 (pyrroline-5-carboxylate reductase 2 deficiency) S-Adenosylhomocysteine hydrolase (SAHH) Methionine S-adenosyltransferase deficiency Ribose-5-phosphate isomerasea (arabitol, ribitol peaks) SLC 25 A12 (aspartate glutamate carrier) (7 Sect. 11.11) Glutathione peroxidase 4 defect CYB5R3 mutations (congenital methemoglobinemia) 2. Energy defects: Mitochondrial HSP 60 chaperonopathy 3. Complex molecule defects: Fucosidosis Sialidosis 4H syndrome (hypomyelination, hypogonadotropic hypogonadism, hypodontia; POLR3A, B genes) tRNA synthetases: KARS RARS1 (with thin corpus callosum), DARS1 (with supratentorial, brainstem, cerebellum, and spinal cord lesions), EPRS1, AARS1 AIMP1, AIMP2 (+brain atrophy) 4. Cell trafficking defects: GJA12 /GJA13 connexins (PelizaeusMerzbacher like) Oculodentodigital dysplasia (GJA1) HABC (hypomyelination with cerebellum atrophy and atrophy of the basal ganglia, TUBB4A gene) Other cell trafficking defects: VPS11; SLC33A; FIG4 Other genetic defects Pelizaeus-Merzbacher disease (myelination arrest, PLP1) TMEM106B (Pelizaeus-Merzbacherlike disease) TMEM63A (mechanosensitive ion channel) SPTAN1 (beta spectrin) Trichothiodystrophy with photosensitivity (ERCC2, 3, GTF2H5, MPLK1P genes) Cockayne syndrome (ERCC6,8) Clinically, hypomyelination presents as nystagmus, spasticity/mixed movement disorder, ataxia and ID. Low choline is a marker in MRS

1. Small molecule defects Homocysteine remethylation defectsa Glutaric aciduria type Ia PKU (untreated, reversible)a Menkes disease 3-Methylglutaryl-CoA lyase defecta Thymidylate kinase deficiency (TYMK) a novel vanishing white matter disease NFE2L2 mutations (supratentorial multiple hyperintense lesions mimicking MS (7 Chap. 35) 2. Energy defects Mitochondrial cytopathy Kearns-Sayre syndrome MNGIE (with supratentorial cortical atrophy) 3. Complex molecules: CTXa Cockayne (with calcifications) Metachromatic leucodystrophya PBDa, PEX-7 Polyglucosan body diseasea Aicardi Goutières syndrome (with calcifications) Other genes: CACH (vanishing white matter disease) Cockayne (with calcifications) Hypomyelination with congenital cataracts (FAM126A)

U fibres: 1. Small molecules MCT1 homozygous mutations L-2-hydroxyglutaric Glutaric aciduria Ia Homocysteine remethylation defectsa 3-methylglutarylCoA lyase deficiencya 2. Energy defects: Mitochondrial cytopathies 3. Complex molecule defects: Polyglucosan body diseasea Other locations: Occipital WM: GM3 synthase heficiency X-ALD (posterior) Peroxisomal disorders Frontal WM: Alexander disease Metachromatic leukodystrophy Neuroaxonal leukodystrophy with axonal spheroids

With pyramidal tract involvement: 1. Small molecule defects Lipoilation defects (especially NDUFS1, NDUFA2: tigroid-like cavitation) 2. Energy defects Mitochondrial cytopathiesa COX deficiency due to mutations in APOPT1 Pyruvate metabolism defects (PDH, pyruvate carboxylase deficiency) Mitochondrial A83446 mutation 3. Complex molecule defects: Cerebrotendinous xanthomatosisa Adrenomyeloneuropathya Krabbe diseasea Cavitating leukoencephalopathies: Cystic leukoencephalopathy without megalencephaly (RNASET2-deficient leukoencephalopathy) Vanishing white matter disease (EIF2B2) With cystic leukomalacia (WM cysts): SOX (not only periventricular) Glutaric aciduria (in adults) GOT2 mutations PC, PDH With focal and asymmetric WM lesions (vasculopathies): RNASET2-related leukodystrophy NGLY1 related congenital disorder of deglycosylation Cathepsin A-related arteriopathy with strokes and leukodystrophy

DDHD2, (SPG54 with thin corpus callosum) FALDH DDHD2, (SPG54 with thin corpus callosum) FALDH (Sjogren Larsson syndrome) CPT 2 and several other FAO defects X-ALD and several other peroxisomal defects Chanarin Dorfmann and several other complex lipid synthesis defects Gaucher and NP C disease CTX and Smith Lemli Opitz syndrome

Legend: aObserved in adulthood CPT carnitine palmitoyl transfease, FAO fatty acid oxidation defects, CTX cerebrotendinous xanthomatosis, ALD adrenoleucodystrophy, MS multiple sclerosis, PBD peroxisome biogenesis defect

95 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.26 Brain dysplasia and malformations Gyration abnormalities

Corpus callosum hypoplasia/agenesis

1. Small molecule defects: Glutamine Synthetase deficiency Serine synthesis defects Asparagine synthesis defects Serine hydroxymethyltransferase type 2 MFSD2A defect (omega3 fatty acid transport defect) SLC35A2 (encoding an UDP-galactose transporter) 2. Energy metabolism defects: CPTII, MAD (multiple acyl-CoA dehydrogenase) Fumarase deficiency 3. Complex molecule defects: Peroxisomal disorders (Zellweger and others) CK syndrome (cholesterol metabolism defect): polymicrogyria or pachygyria Squalene synthase deficiency Perisylvian polymicrogyria: PIK3R2 (phosphoinositide 3 kinase) mutations 4. Cell trafficking disorders: O-glycosylation disorders: Muscle eye brain disease (POMGnT) Walker Warburg syndrome (POMT1) Fukuyama syndrome (fukutin) Congenital muscular dystrophy: DMC1C (fukutin related protein) DMC1D (protein large) CEDNIK syndrome (snare protein mutation) FIG4 (Temporo-occipital polymicrogyria) Most golgipathies with microcephaly NDE1 (dynamin): microhydranencephaly, lissencephaly Tubulin defects (TUBA1A, TUBB2B, TUBB3) Reelin gene (RELN) encoding an extracellular matrix associated glycoprotein Other genes: Different lissencephaly genes (L1S1, DCX, ARX, VLDLR) Periventricular nodular heterotopia (bilateral due to FLN1 mutations) FOXG1 defects

With gyration abnormalities 1. Small molecule defects: Non ketotic hyperglycinemia MCT1 (homozygous mutations) MOCS2 (molybdenum cofactor; 1 case corpus callosum agenesis) 3-hydroxyisobutyric aciduria Brain serine transporter defect Asparagine synthetase deficiency Serine hydroxymethyltransferase type 2 Glutathionuria (cc agenesis) 2. Energy metabolism defects: Complex II mitochondrial cytopathies (with leukodystrophy) PDH defect (with basal ganglia abnormalities) Fumarase deficiency (cc agenesis) 3. Complex molecule disorders Aicardi Goutières syndrome (with calcifications) EARS2 mutations Phospholipids synthesis /remodelling defects associated with spastic paraplegia: SPG 28 (DDHD1), SPG 49 (CYP2U1),SPG 54 (DDHD2), SPG 35 (FA2H), SPG 46 (GPA2), Desmosterolosis, lathosterolosis Hemizygous EBP deficiency in males 4. Cell trafficking disorders: EPG5 mutations (Vici syndrome) (cc agenesis) Most golgipathies with microcephaly Tubulinopathies with hypomyelination Others: ATP6AP2 CDK5RAP2, (cc agenesis) Genes that disrupt mid-brain development ACTH deficiency In general, all amino acid synthesis defects may present corpus callosum hypoplasia Any disease with hypomyelination/white matter disturbances may have cc hypoplasia

1.5.8

Neurophysiological Signs

Neurophysiologic studies are important for diagnosis and follow-up in IEM, especially if epilepsy or neuropathy are part of the clinical picture. The diagnosis of peripheral neuropathies has been already addressed in 7 Sect. 1.5.2 and in the . Fig. 1.10 algorithm of peripheral neuropathies. Electroencephalographic abnormalities (see also . Tables 1.17 and 1.18 and section epilepsy). Burst suppression pattern is frequently observed in several IEM in the neonatal period (see above 7 Sect. 1.3.2). In the neonatal manifestation of maple

syrup urine disease, EEG displays comb-like rhythms. In infantile neuronal ceroid lipofuscinosis (NCL), the first abnormality in the electroencephalogram (EEG) is the disappearance of eye opening/closing reaction, followed by a loss of sleep spindles. Subsequently the EEG becomes rapidly flat. In CLN2 disease, an occipital photosensitive response to photic stimulation at 1–2 Hz with eyes open is present. In patients with homocystinuria, centrotemporal spikes are often present resembling the epileptiform potentials in benign epilepsy with centrotemporal spikes. In Alpers disease, the EEG is very valuable in the early stage of the disease and displays, albeit not in all patients, rhythmic high-amplitude delta with

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. Table 1.27 Posterior fossa (and olivo-ponto-cerebellar) Hypoplasia

Progressive atrophy

Dentate nuclei/ cerebellar cortex hyperintensities

Global cerebellar hypoplasia: NKH, mitochondrial disorders, PDH, Zellweger, mucopolysaccharidoses (type I and II) Ribosomopathies: POLR1C, POLR3A, POLR3B CDG syndrome Joubert syndrome Dystroglycanopathies PCH (pontocerebellar hypoplasias): Asparagine mynthetase deficiency SEPSECS COASY (soenzyme A synthetase) Aminoacyl-tRNA synthetases and tRNA processing metabolism disorders AMPD2 EXOSC3, EXOSC8, EXOSC9, VPS53, 51, TBC1D23, PCLO (with optic atrophy) Dandy-Walker malformation: Hemizygous EBP deficiency in males (sterol metabolism) AP1S2, KIAA1109: trafficking defects Other cerebellar dysplasia: PACS2

1. Small molecule defects: L-2-hydroxyglutaric aciduria Mevalonic aciduria Adenylosuccinase deficiency SepSec (selenium metabolism) Glutamine synthetase (GS) deficiency SSDH deficiency 3-Methylglutaconic aciduria type 1 and CLPB mutations 2. Energy metabolism defects Mitochondrial cytopathiesa Leigh syndrome 3. Complex molecule defects X-linked adrenoleukodystrophya GM2 gangliosidosisa Niemann-Pick disease type Ca Cerebrotendinous xanthomatosisa Sialidosis type 1a Ceroid lipofuscinosisa DEGS1 mutations (with hypomyelination) FA2H mutations (with leukodystrophy) Neuroaxonal dystrophy (infantile) and other phospholipid synthesis defects Schindler disease Smith-Lemli-Opitz Nucleotide, tRNA and ribosome metabolism defects: QARS1, AIMP1, AIMP2, UBTF1, 4. Cell trafficking disorders: ZNHIT3 (PEHO-Like syndrome), AP4E1, SLC9A6 Others: Galloway-Mowat, cerebellar atrophy: YRDC, GON7, LAGE3, OSGEP, TP53RK, TPRKB, WDR4: SCA in generala Dentatorubralpallidoluysian atrophya Progressive myoclonus epilepsiesa Spinal and bulbar muscular atrophya

Dentate nuclei hyperintensities: L-2-hydroxyglutaric aciduria Semialdehyde succinate dehydrogenase deficiencya Wilson diseasea NBIA (some late onset cases together with hypointensities)a Mitochondrial encephalopathya Cerebrotendinous xanthomatosisa Polyglucosan body diseasea Cerebellar atrophy and cerebellar cortex T2-hyperintensity: Some mitochondrial disorders Coenzyme Q10 deficiency Infantile neuroaxonal dystrophy PMM CDG Late infantile NCL pontocerebellar hypoplasia type 7 Marinesco-Sjörgen syndrome Christianson syndrome

Stroke-like episodes: MELAS, POLG1, complex1, mt DNA mutations, CoQ10 defects, KSS, Twinkle, TK2, CABC1; SCA spinocerebellar atrophy Cerebrovascular strokes: homocystinurias, CDGs, hyperammonaemias, ITPA mutations (venous thrombosis) aObserved in adulthood

superimposed (poly)spikes (RHADS), usually over the posterior regions. Somatosensory evoked potentials (SSEP) are helpful in delineating posterior column involvement, e.g. in Friedreich ataxia or cobalamin deficiency. Giant SSEP are found in some of the progressive myoclonic epilepsies including late infantile neuronal ceroid lipofuscinosis. Visual evoked potentials help to detect early involvement of the optic nerve, e.g. in mitochondrial disorders,

infantile neuroaxonal dystrophy, Alpers disease and in hypomyelinating disorders. The electroretinogram (ERG) is important in detecting retinal involvement which is of use in the differential diagnosis of neurodegenerative disorders. Retinal involvement is part of the neuronal ceroid lipofuscinoses, but also of panthotenate-associated neurodegeneration (PKAN), mitochondrial disorders and many others (see also . Table 1.28 Abnormal Fundoscopy).

97 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.28 Retinal manifestations Cherry red spot

Retinitis pigmentosa and others

Optic atrophy

Cytochrome C oxidase deficiency Niemann-Pick diseases type A, B Galactosialidosis (neuraminidase deficiency) Gangliosidosis GM1 (landing) Gangliosidosis GM2 (Sandhoff, Tay Sachs) Nephrosialidosis Sialidosis type I Farber disease

Retinitis pigmentosa: Methylene tetrahydrofolate dehydrogenase defect (MTHFD1) CblCa Respiratory chain disorders (Kearns Sayre, NARP, mtDNA deletions)a ACO2 (aconitase deficiency) Abetalipoproteinemia Vitamin E malabsorption (tocopherol carrier) LCHAD deficiency CDG Peroxisomal defectsa Refsum diseasea Mucopolysaccharidoses Ceroid lipofuscinosis Panthothenate kinase deficiency (Harp syndrome) HARS mutations Dehydrodolichol diphosphate synthase deficiency Fatty acid 2-hydroxylase (FA2H) deficiency Ceramide kinase-like (CERKL) mutation PHARC syndrome (ABHD12) VAC14 mutations VPS13B: Cohen syndrome, ID, obesity, neutropenia and retinopathy ACBD5: retinal dystrophy with leukodystrophy Inosine-5′-monophosphate dehydrogenase1 Taurine tranporter deficiency (SLC6A6)

MMA and PA Sulfite oxidase (infantile) ATAD3A mutations Biotinidase deficiency CblCa Ribose-5-phosphate isomerasea Canavan disease (early sign) LHON (Leber due to mitochondrial DNA deletionsa) DOA autosomal-dominant optic atrophy (OPA1) Leigh syndrome (all causes) Mitochondrial cytopathiesa ACO2 (aconitase deficiency) Iron sulfur cluster disorders Ceroid lipofuscinosis (CLN3a, CLN4a) Krabbe disease (infantile) Metachromatic leukodystrophy Infantile Neuroaxonal dystrophy (PLA2G6) Schindler disease Fatty acid 2-hydroxylase (FA2H) deficiency Pelizaeus-Merzbacher disease (presenting sign early in infancy) Peroxisomal biogenesis defectsa Pyruvate dehydrogenase deficiencya SOPH syndrome (NBAS mutation) X-ALDa 3-Methylglutaconic aciduria type 3 (Costeff due to OPA mutations) Dolichol synthesis/recycling defects: SRD5A3-CDG (Ig) (with nystagmus colobomas, cataracts, glaucoma, micro-ophthalmia DPM1-CDG, MPDU1-CDG SLC25A46 mutations CDC42 (cell trafficking disorder): Takenouchi-Kosaki syndrome

Gyrate atrophy with OAT deficiency Aceruloplasminemiaa Mucolipidosis type IV Heterozygous ELOVL4 mutations (AD juvenile form of macular degeneration Stargardt type 3) Sjögren-Larsson syndrome (FALDH) macular dystrophy with very suggestive retinal crystalline inclusions Extinguished ERG with normal fundoscopy: NAD synthase deficiency (NMNAT1) Leber congenital amaurosis Other findings: thin retina and reduced vascularization in GLUT1DS with normal ERG aObserved

in adulthood. LHON, Leber congenital optic atrophy; SOPH syndrome: Short stature, optic atrophy, Pelger-Huet anomaly

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. Table 1.29 Ophthalmoplegia, ptosis, eye movements, strabismus Supranuclear gaze palsy

Niemann-Pick C (vertical), Gaucher (horizontal) ATP13A2, GBA PANK2 (horizontal and vertical supranuclear gaze palsy)

Oculogyric crisis

Neurotransmitter defects, Pyridox(am) ine-5-phosphate oxidase deficiency GLUT1DS, Wilson, PKAN, diverse causes of dystonia-parkinsonism syndromes, GRIN1 mutations. Other genetic conditions: channelopathies, Rett syndrome, H-ABC, ataxia-telangiectasia

Nystagmus

Vit E deficiency, SLC19A3 (biotinthiamine responsive BBGG disease), DNAJC12, L-2-hydroxyglutaric aciduria Abetalipoproteinemia (with progressive gaze disturbances and a characteristic pattern of dissociated nystagmus) Leigh syndrome, SACS, MECR, FA2H, ECHS1, HIBCH PHARC, CYB5R3 (porphyria), NLC, GBA (Gaucher) SPTBN2 (cell trafficking). Chanarin-Dorfman syndrome (CGI58), ELOVL1 mutations Paelizaeus-Merzbacher disease (PLP1) Disorders with ataxia, cerebellar dysfunction and hypomyelination may have nystagmus.

Oculomotor apraxia

PIK3R5, Gaucher types 2 and 3, Vitamin E deficiency, PDH, CDG, Lesch-Nyhan, Dopamine transporter deficiency. Ataxia telangiectasia, ataxia with oculomotor apraxia (AOA,2, 3,4) Diseases with cerebellar involvement may have oculomotor apraxia

External ohphtalmoplegia

Mitochondrial disorders: mitochondrial deletions and point mutations including spastin SPG7, Christianson syndrome

Others

Ocular flutter: PC, GLUT1DS, DGUOK, some tRNA synthetase defects, CDG, Dopamine transporter deficiency, MSUD Eyelid myoclonus: DHPR Palpebral ptosis: neurotransmitter defects, mitochondrial disorders, diseases with muscle involvement Abnormal saccade pursuits: common in diseases with cerebellar involvement (i.e.Niemann-Pick C, cerebrotendinous xanthomatosis)

1.5.9

Recommended Laboratory Tests in Neurological Syndromes

. Table 1.30

Specific Organ Signs and Symptoms

1.6

In the following sections medical specialities are listed by alphabetical order. Where possible, disorders are classified in tables according to pathophysiological groups. The following diagnostic checklist is primarily based upon the authors’ personal experience and information from the chapters of this book. It is, of course not exhaustive and should be progressively updated according to the personal experiences of all readers. 1.6.1

Cardiology

All pertinent information on cardiac failure, cardiomyopathies and heart rythym disorders is presented in 7 Sects. 1.3.7 and 1.4.8 and . Tables 1.11 and 1.12. Orthostatic hypotension is a presenting symptom in dopamine β-Hydroxylase deficiency and other extremely uncommon monoamine defects such as cytochrome b561 deficiency and norepinephrine transporter deficiency (7 Sect. 30.5). It is also frequent in occipital horn syndrome (7 Sect. 34.1.2). Cardiac valve disease with thickening of valves leading to dysfunction (insufficiency and/or stenosis) is most common in MPS with accumulation of dermatan sulfate (MPS I, II, VI and VII), this being the most abundant GAG in heart valves (7 Chap. 41).

1.6.2

Dermatology

z

Hair Abnormalities (. Table 1.31)

z

Hyperkeratosis/Ichthyosis (. Table 1.32)

Most are linked to complex molecules or trafficking disorders and not or poorly treatable. The classification of erythroderma and inherited ichthyosis is clinically based and distinguishes between syndromic and non-syndromic ichthyosis forms [85] although this can be difficult to determine at birth and even in infancy. Bullous ichthyosis/epidermolytic

1

99 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.30 Main neurological syndromes from childhood to adolescence and recommended laboratory tests (focused on treatable disorders) Predominant neurological syndrome

Laboratory tests (rational approach based on associated clinical signs and treatable disorders)

Treatable disorders

Isolated developmental delay/ intellectual disability (ID)

Basic laboratory testsa: blood glucose, acid-base status, blood counts, liver function, creatine kinase, uric acid, thyroid function, alkaline phosphatase Plasma: lactate, ammonium, amino acids, total homocysteine, folate, biotinidase activity, copper, ceruloplasmin Urine: creatine metabolites, organic acids (including 4-hydroxybutyric acid), amino acids, glycosaminoglycanes (GAGs) and oligosaccharides purines, pyrimidines, Consider maternal phenylalanine

Phenylketonuria (PKU), homocystinurias, urea cycle defects, amino acid synthesis defects, thyroid defects, biotinidase deficiency, Hartnup disease, occipital horn syndrome

With dysmorphic features

Consider also: plasma sterols, peroxisomal studies (very long-chain fatty acids, phytanic acid, plasmalogens), transferrin isoelectric focusing for glycosylation studies (CDG), oligosaccharides and GAGs in urine For the study of ID +/− dysmorphic features, genetic tests (cytogenetic studies, microarrays, NGS, and targeted studies) have the highest diagnostic yield.

Peroxisomal diseases (only partially by some supplements), SLO

Behavioural and psychiatric manifestations including autistic signs

Basic laboratory testsa Plasma: ammonium, amino acids, homocysteine, total homocysteine, folate, sterols (including oxysterols), copper, ceruloplasmin Urine: GAGs and oligosaccharides, organic acids (4-hydroxybutyric acid), amino acids, purines, creatine, creatinine and guanidinoacetate Depending on additional clinical signs and brain MRI pattern: peroxisomal studies, lysosomal studies, consider CSF for BCAA studyin spite of normal plasma BCAA (transport defect)

PKU, urea cycle disorders, homocystinurias, folate metabolism defects, Wilson disease, BCKDH kinase deficiency, BCAA transport defect, CTD, mild forms of SLO, Niemann-Pick disease type C, X-ALD (at some stages), Hartnup disease

Epilepsy

Basic laboratory testsa adding calcium, magnesium, phosphate, manganese, peripheral erythrocyte morphology Plasma: lactate, ammonium, amino acids, total homocysteine, folate, biotinidase activity, copper and ceruloplasmin, VLCFA Urine: organic acids, creatine, creatinine and guanidinoacetate, sulphite test, purines and pyrimidines, pipecolic acid and 5-AASA CSF: glucose, lactate, amino acids, 5-methyltetrahydrofolate (5-MTHF), pterins, biogenic amines, citrate, GABA Consider lysosomal studies and targeted tests if PME Consider genetic tests for GPI-anchor biosynthesis pathway defects and other defects of complex lipid synthesis (FA2H, ELOVL4, GM3 synthetase)

GLUT1DS, homocystinurias, IEM of folate metabolism, organic acidurias, biotinidase deficiency, sodium dependent multivitamin transporter, creatine synthesis defects, serine biosynthesis defects, BCKDK defects, MoCo deficiency, CAD deficiency, Menkes disease (only partially treatable), late onset forms of pyridoxine dependent epilepsy, pterin defects (DHPR), AADC deficiency, consider SLC35-A2-CDG SLC13A5 mutations may respond to acetazolamide KCNQ2 mutations may respond to carbamazepine (continued)

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. Table 1.30 (continued) Predominant neurological syndrome

Laboratory tests (rational approach based on associated clinical signs and treatable disorders)

Treatable disorders

Ataxia

Basic laboratory testsa adding albumin (for AOA1 and AOA4), cholesterol, triglycerides, and alphafoetoprotein (for AT, AOA2, AOA4), blood smear for acanthocytes Plasma: lactate, pyruvate, ammonium, amino acids, biotinidase activity, vitamin E, sterols (including oxysterols), ceruloplasmin, peroxisomal studies (including phytanic acid), coenzyme Q10, transferrin electrophoresis Urine: organic acids (including 4-hydroxybutyric and mevalonic acids), amino acids, purines CSF: glucose, lactate, pyruvate Consider lysosomal/mitochondrial/NBIA studies depending on the clinical and brain MRI signs Consider lipidome studies (plasma, CSF) Consider genetic panels of inherited ataxias and other NGS techniques

PDH deficiency (thiamine-responsive; ketogenic diet), biotinidase deficiency, GLUT-1, abetalipoproteinemia, CTX, Refsum disease, coenzyme Q10 deficiencies, Hartnup disease, CAD deficiency, Niemann-Pick disease type C Consider channelopathies, PRRT2 and ATP1A3 mutations (may respond to acetazolamide, carbamazepine)

Dystonia-Parkinsonism

Basic laboratory testsa Plasma: lactate, pyruvate, ammonium, amino acids, total homocysteine, biotinidase activity, sterols (including oxysterols), copper, ceruloplasmin, uric acid, manganese Urine: organic acids, uric acid, creatine, creatinine and guanidinoacetate, purines, GAGs, oligosaccharides CSF: glucose, lactate, pyruvate, amino acids, 5-methyltetrahydrofolate, pterines, biogenic amines, GABA Consider lysosomal/mitochondrial/NBIA studies depending on the clinical and brain MRI signs Consider genetic panels of inherited dystonias, parkinsonism, and other NGS techniques

Neurotransmitter defects, GLUT-1 deficiency, thiamine transport defects (TBBGD), PDH defects, organic acidurias, homocystinurias, IEM of folate metabolism, defects of creatine biosynthesis, Wilson disease, biotinidase deficiency, Niemann-Pick disease type C, CTX, manganese defects Consider Dopa responsive conditions (sometimes only transitory response): POLG, SYNJ1, DNAJC6, CLCT, VPS35, PLA2G6, tWARS

Chorea

Basic laboratory testsa Plasma: lactate, pyruvate, ammonium, amino acids, total homocysteine, folate, biotinidase activity, sterols (including oxysterols), copper, ceruloplasmin, uric acid, galactose -1-P, transferrin electrophoresis Urine: organic acids, uric acid, creatine, creatinine and guanidinoacetate, purines, galactitol, sulphite test CSF: glucose, lactate, pyruvate, amino acids, 5-methyltetrahydrofolate, pterins, biogenic amines, GABA Consider NCL studies and GPI-anchor synthesis defect genetic tests Consider genetic panels of inherited choreas, and other NGS techniques

GA1 and other classic organic acidurias (MMA, PA), GAMT, GLUT1DS, homocystinurias, pterin and neurotransmitter defects, Niemann-Pick disease type C, Wilson disease, galactosaemia, cerebral folate deficiency due to FOLR mutations, MoCo deficiency, NKH (attenuated, late-onset forms can be partially treatable)

101 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.30 (continued) Predominant neurological syndrome

Laboratory tests (rational approach based on associated clinical signs and treatable disorders)

Treatable disorders

Spasticity

Basic laboratory testsa Plasma: lactate, pyruvate, ammonium, amino acids, total homocystinuria, folate, biotinidase activity, vitamin E, triglycerides, cholesterol, sterols, peroxisomal studies, Urine: organic acids, amino acids, GAGs, oligosaccharides, sialic acid CSF: glucose, biogenic amines, pterins and 5-MTHF Consider lysosomal/mitochondrial/ NBIA studies depending on clinical and MRI findings Consider genes related to HSP and plasma, CSF lipidome

HHH, arginase deficiency, ornithine amino transferase deficiency, homocysteine remethylation defects, biotinidase deficiency, cerebral folate deficiencies, GLUT1D, dopamine synthesis defects (atypical TH), CTX, vitamin E deficiency

Peripheral neuropathy

Basic laboratory testsa Plasma: lactate, pyruvate, ammonium, amino acids, folate, vitamin E, triglycerides, cholesterol, acylcarnitines, sterols, peroxisomal studies, transferrin electrophoresis, sorbitol levels Urine: amino acids, GAGs, oligosaccharides, thymidine, porphyrins Consider lysosomal/mitochondrial/ NBIA studies depending on clinical and MRI findings

Refsum disease, X-ALD (treatable at some stages), homocysteine remethylation defects, CTX, abetalipoproteinemia, LCHAD, trifunctional protein, PDH, vitamin E malabsorption, ornithine amino transferase, serine deficiency, porphyrias, sorbitol dehydrogenase deficiency

AADC amino acid decarboxylase, AOA ataxia with oculomotor apraxia, AT ataxia telangiectasia, 5-AASA 5-aminoadipic semialdehyde, BCKDH branched chain ketoacid dehydrogenase, CTX cerebrotendinous xanthomatosis, DHPR dihydropteridine reductase, HHH hyperammonaemia, hyperornithinaemia, homocitrullinuria, FOLR folate receptor, GA1 glutaric aciduria type 1, GAG glycosamineglycan, GAMT guanidinoacetate methyltransferase, GTPCH GTP cyclohydrolase I, LCHAD long-chain 3-hydroxyacyl-CoA dehydrogenase, HSP hereditary spastic paraparesis, MMA methylmalonic aciduria, MoCo molybdenum cofactor deficiency, NGS next generation sequencing, NKH nonketotic hyperglycinaemia, PA propionic acidaemia, PDH pyruvate dehydrogenase deficiency, PME progressive myoclonus epilepsy, X-ALD X-linked adrenoleukodystrophy, TH tyrosine hydroxylase aThese basic laboratory tests should be considered as a routine screening in every neurological syndrome

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. Table 1.31 Hair abnormalities: mostly onset in neonatal period and infancy Alopecia, absent eyebrows and sparse eyelashes

Brittle Hair

Pili Torti, Hirsutism

Trichorrhesis Nodosa

Argininosuccinic aciduria Citrullinemia Menkes syndrome

Pili torti: Menkes disease

Argininemia Argininosuccinic aciduria Lysinuric protein intolerance Menkes disease

Pili Torti: Netherton syndrome Bjornstad syndrome

Netherton syndrome

Small molecule metabolism defects Acrodermatitis enteropathica (zinc) Biotin-responsive MCD (fatty acids) Calciferol metabolism defects (vit D) Essential fatty acid deficiency Menkes disease (Copper) Methylmalonic and propionic acidurias OAT deficiency (peculiar fine, sparse, straight hair) Ornithine decarboxylase defect (7 Sect. 21.8) Porphyrias (congenital erythropoietic, Hepatoerythropoietic Cutanea tarda (in adults) Zinc deficiency

Complex molecule defects and miscellaneous RFT1-CDG Conradi-Hunermann syndrome Ehlers-Danlos type IV IFAP syndrome (7 Sect. 37.11) Netherton syndrome (SPINK5) Steinert disease (adult) Woodhouse-Sakati syndrome (adult) Many trafficking disorders involving vesicular and organelles trafficking, cytoskeleton and autophagy (7 Chap. 44)

Pollitt’s syndrome Trichothiodystrophy Mucopolysaccharidosis Bjornstad syndrome

Hirsutism: MPS III (and to a lesser extent several other MPSs) Oliver-McFarlane syndrome

Many defects are linked to small molecules disorders and are treatable IFAP ichthyosis follicularis, atrichia, and photophobia, OAT ornithine amino transferase deficiency

hyperkeratosis has been redefined as keratinopathic ichthyosis. Collodion babies present with a tight shiny cast that cracks after some time, resulting in irregularly branched fissures [86]. AR congenital ichthyosis (ARCI) refers to harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma. About 40 inherited disorders of complex lipids (7 Chaps. 35 and 40), cholesterol (7 Chap. 37) and complex fatty acids synthesis, remodel-

ling, catabolism, and transport (7 Chap. 42) presenting with ichthyosis have been described. The vast majority present as neuro-cutaneous syndromes, chondrodysplasia punctata or multiple congenital anomalies, as do CDG or serine synthesis defects (including Neu Laxova syndrome) (7 Sect. 24.2). Among the neurocutaneous syndromes comprising spastic paraparesis, Sjögren-Larsson syndrome presents at birth with a very severe pruriginous ichthyosis that responds dramatically

103 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.32 Hyperkeratosis, ichthyosis Hyperkeratosis CEDNIK (neuro-cutaneous syndrome: keratosis on palms and soles) (7 Sect. 44.3.2) MEDNIK syndrome: keratodermia (see below) (7 Sect. 34.1.4) Ichthyosis (see below) Tyrosinemia type II (keratosis on palms and soles) (7 Sect. 17.3) SAM syndrome (DSG1) (keratosis on palms and soles and ichthyosiform erythrodermia) Erythropoietic protoporphyria (seasonal palmar keratoderma) Angiokeratosis Aspartylglucosaminuria Beta-mannosidosis, fucosidosis Fabry disease (presenting sign) Galactosialidosis Schindler disease (adult form) (7 Sect. 41.3.1) Kawasaki disease Ichthyosis (with Congenital Erythrodermia) Lysosomal diseases

X-linked steroid sulfatase (non pruritic) Austin disease: multiple sulfatase deficiency Gaucher disease type II (collodion baby)

Complex lipids synthesis and remodelling Phospholipids (7 Chap. 35) Sphingolipids (7 Chap. 40) Non mitochondrial fatty acid metabolism including peroxisomal defects (7 Chap. 42)

Early ARCI: phospholipase A1 deficiency (PNPLA1) ABHD12 (harlequin ichthyosis) Ceramide synthesis defects KDSR, CERS3, CYP4F22 Late ARCI: epidermal lipase N deficiency (LIPN) Chanarin Dorfmann syndrome (ABDH5) Sjogren Larsson syndrome (FADH) (pruritic) Elongase 4 and 1 deficiency (ELOVL4, ELOVL1) Serine synthesis defects Sphingosine-1-phosphate Lyase deficiency (7 Sect. 40.3.4) SLC27A4 (Ichthyosis prematurity syndrome) (7 Sect. 42.4.2) Adult Refsum disease Chondrodysplasia punctata (CDP I, II, III)

Cholesterol synthesis defect (7 Chap. 37)

Conradi Hunermann syndrome (X-linked) (transient) CHILD syndrome (unilateral) Sterol-C4 methyl oxidase deficiency (spares palms and soles) IFAP syndrome

Dolichol synthesis and recycling defects (7 Chap. 43)

MPDU1-CDG: Mannose-P-dolichol utilization defect 1 SRD5A3-CDG: with eye findings DK1- CDG: with loss of hair eyebrows and eyelashes

Trafficking disorders

CEDNIK syndrome (7 Sect. 44.3.2) MEDNIK syndrome (AP1S1 mutations) (7 Sect. 34.1.4) Other vesicular trafficking (SNAP29, SUMF1, VIPAS39)

Organic acidurias

Holocarboxylase synthetase deficiency, biotinidase deficiency, MMA

Primary immuno deficiencies

Omenn, Wiskott Aldrich, graft versus host disease

Others

Netherton syndrome: debilitating pruritis with bamboo hair Connexin Cx26 (GJB2) with deafness Disorders of pre-rRNA processing (dyskeratosis congenita) (7 Chap. 39)

IFAP ichthyosis follicularis, atrichia, and photophobia, SAM syndrome, severe dermatitis, multiple allergies and metabolic wasting linked to mutations in Desmoglein 1

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to Zileuton (7 Sect. 42.4.5). Sterol methyl-C4 oxidase, a sterol metabolism disorder, is another treatable ichthyosis with a spectacular improvement on statin and cholesterol supplement (7 Sect. 37.7.1) Ichthyosis and keratodermia are also cardinal signs of CEDNIK (7 Sect. 44.3.2) and MEDNIK syndromes (7 Sect. 34.1.4). z

Vesiculobullous Lesions/Skin rashes/Photosensitivity (. Table 1.33)

The majority are linked to small molecule disorders leading either to an accumulation of a toxic compounds (such as in porphyrias and organic acidemias) or deficiency of an essential small molecules (as in Hartnup, LPI or Zinc deficiency). z

Cutis laxa/Nodules/Xanthomas/Miscellaneous (. Table 1.34)

Most are linked to primary complex molecules synthesis or trafficking disorders. Ehlers-Danlos syndromes (EDS) are collagenopathies that comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders. Its principal clinical features reflect varying degrees of connective tissue fragility, affecting mainly the skin, ligaments, blood vessels, and internal organs. There are 16 EDS variants described so far, which include defects in noncollagenous proteins including genes involved in glycosaminoglycans (GAG) synthesis. Deficiency of galactosyltransferase I and II affects the initial steps in the formation of the GAG chains [87] (7 Sect. 41.1). Cutis laxa syndrome forms a group of diseases, mostly elastinopathies characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibres and other proteins of the extracellular matrix. Syndromic forms of cutis laxa are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins [88]. A number of metabolic disorders are associated with inherited cutis laxa among them copper metabolism defects such as Menkes disease (7 Sect. 39.1.2), GLUT10 (7 Sect. 8.6), combined disorder of N- and O- linked glycosylation (mutations in ATP6V0A2, COG7-CDG and other CDG defects 7 Chap. 43), proline synthesis defects (7 Sect. 21.3), and PI4K2A mutations (7 Chap. 35, 7 Table 35.1). All are also neurologic disorders.

1.6.3

Endocrinology (. Table 1.35)

IEM may be associated with endocrine dysfunction, the most frequent being disorders of carbohydrate metabolism (diabetes and hyperinsulinism) (7 Chap. 6). Diabetes may occur with iron overload, mitochondriopathies, and thiamine sensitive disorders. The clinical spectrum of some forms of IEM changes from

. Table 1.33 Vesiculous bullous lesions, photosensitivity Photosensitivity & skin rashes

Vesiculo bullous lesions

Acrocyanosis

Infantile Porphyrias: (7 Chap. 33) Congenital erythropoietic porphyria Erythrohepatic porphyria Erythropoietic protoporphyria Adult Porphyrias: Hereditary coproporphyria Porphyria variegata Porphyria cutanea tarda 5ALA dehydratase Biotinidase deficiency (7 Chap. 27) ETHE1 mutations (7 Sect. 20.9) Hartnup disease (7 Sect. 25.4) CLTRN2 (7 Sect. 25.5) Mevalonic aciduria (with fever) (7 Sect. 37.1) SECISPB2 mutations (7 Sect. 34.5) Zinc deficiency (7 Sect. 34.6) Respiratory chain disorders NAXE and NADP (7 Sect. 11.14) Glutamine synthetase deficiency (7 Sect. 24.1.1) Prominent Mongolian blue spots and a characteristic papular rash are prominent in severe MPS II (7 Sect. 41.2)

Acrodermatitis enteropathica (7 Sect. 34.6.1) Biotin responsive disorders (7 Chap. 27) Congenital erythropoietic porphyria (sun exposed skin) LPI (lupus like skin lesions) (7 Sect. 25.3) MMA, PA (isoleucine deficiency) (7 Sect. 18.1) Lipin 2 deficiency (Majeed syndrome) (7 Sect. 35.1.4) NAXE and NADP deficiency Zinc deficiency

(ETHE1 mutations) (orthostatic) 7 Sect. 20.9 Aicardi Goutières syndrome (Chilblains) (7 Sect. 39.1.2)

LPI lysinuric protein intolerance, ALA aminolevulinic acid

hypoglycaemia in childhood to diabetes in adulthood. Mitochondriopathies can be associated with all types of endocrine disorders, the most frequent being diabetes and dysthyroidism. Hypothyroidism is encountered in mitochondriopathies, cystinosis, primary hyperoxaluria and the Allan-Herndon-Dudley syndrome (7 Sect. 8.9). Long term consequences of IEM on fertility, reproduction and bone metabolism are still poorly understood and should be prospectively investigated.

105 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.34 Cutis laxa and laxity, nodules, xanthoma, and miscellaneous Cutis laxa, skin laxity

Xanthoma

Nodules, lipodystrophy and lipomatosis

Miscellaneous

Copper defects (7 Sect. 34.1) Menkes disease, occipital horn syndrome Proline synthesis defects (de Barsy syndrome): P5C-synthetase (cutis laxa type III), (7 Sect. 21.3) P5-phosphate reductase CDG syndromes (7 Chap. 43) ATP6V0A2, GALNT1-CDG Phospholipids synthesis defects PTDSS1 (7 Sect. 35.3.3) PI4K2A (7 Table 35.1) GLUT 10 (7 Sect. 8.6) TALDO (transient) (7 Sect. 7.10)

Hyper lipoproteinemias (7 Chap. 36): Apo CII defect (eruptive) Apolipoprotein A1 defect (planar) Autosomal dominant hypercholesterolaemia Autosomal recessive hypercholesterolaemia Dysbetalipoproteinemia (hyperlipoproteinaemia type III) Hepatic lipase Lipoprotein lipase (eruptive) Sitosterolaemia (childhood) Cerebrotendinous xanthomatosis (7 Sect. 38.3) Niemann Pick A (7 Sect. 40.2.2)

Nodules PMM2-CDG syndrome (7 Chap. 43) Farber disease (7 Sect. 40.2.8) PSMB8 (mutations in Proteasome) Gain-of-function of glutamine synthetase (erythematic subcutaneous nodules)

Telangiectasias, purpuras, petechiae Ethylmalonic aciduria (ETHE1 mutations) (7 Sect. 20.9) Prolidase deficiency (7 Sect. 31.4.1)

Lipodystrophy and lipomatosis Triglycerides synthesis defects (7 Sect. 35.2): Perilipin deficiency AGPAT II and SEIPIN mutations Phospholipids synthesis defects (7 Sect. 35.3): PCYT1A mutations (with SMD) PIK3CA-related overgrowth spectrum Mitochondrial defect: MERFF syndrome: multiple lipomas (7 Chap. 10) POLR3A variants (WiedemannRautenstrauch syndrome)

Hyper and hypo-pigmented skin maculae (salt and pepper syndrome) GM3 synthetase deficiency (7 Sect. 40.1.6)

Laxity, dysmorphic scarring, easy bruising Ehlers-Danlos syndrome (16 types) of which B4GALT7B3GALT6 and CHST14

Pachydermia with seborrhoea and hyperhydrosis Hypertrophic osteoarthropathy: SLC2A1 and 15PGDH deficiencies (7 Sect. 42.5.2)

Ulceration (skin ulcers) Prolidase deficiency (7 Sect. 31.4.1) HSAN type 1 (7 Sect. 40.1.1) Inflammatory dermatosis Sweet syndrome, Majeed syndrome (7 Sect. 35.1.4) Aplasia cutis congenita: EOGT-CDG Progressive reticular dys pigmentation: POGLUT1CDG Salt and pepper syndrome: ST3GAL5-CDG H syndrome (SLC29A3a mutations) Mastocytosis: in encephalopathy due to GNB1 mutations (G protein signalling pathway defect)

H syndrome: hyperpigmentation, hypertrichosis, and induration: SLC29A3 encodes the human equilibrative nucleoside transporter 3 SMD spondylometaphyseal dysplasia, HSAN Hereditary sensory and autonomic neuropathy

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. Table 1.35 Endocrine abnormalities Pancreas

Thyroid/parathyroid and growth hormone

Adrenal/sex glands

Diabetes (and pseudodiabetes) Abnormal proinsulin cleavage Aceruleoplasminemia (7 Sect. 34.2.3.1) Diabetes, deafness and TRMA syndrome (7 Sect. 29.1.1) Diabetes type II: FAO? Kir 6.2, glucokinase (GCK) mutations (7 Chap. 6) Hemochromatosis (adult) MCT1 mutations MMA, PA, IVA, ketolytic defects) (7 Chap. 18) Respiratory chain defects (7 Table 10.1) Untreated cystinosis Wolfram syndrome (7 Table 10.2) Woodhouse-Sakati syndrome (C2orf37) (7 Sect. 34.2.3.9)

Hyperthyroidism GlutarylCoA oxidase deficiency? Allan-Herndon-Dudley syndrome (peripheral thyrotoxicosis with high T3) (7 Sect. 8.9)

Hypogonadism, sterility PMM2-CDG Galactosemia PLA2G6 mutation spectrum (7 Sect. 35.4.2) Kalman syndrome Perrault syndrome (several mitochondrial genes: C10orf2, CLPP, HARS2, LARS2, HSD17B4) (7 Table 10.2) D-bifunctional protein deficiency (7 Sect. 42.2.2) X-linked ALD (7 Sect. 42.2.1) Fabry disease Cystinosis (males) Alstrom disease Hemochromatosis (7 Sect. 34.2.1) Endosomal ferrireductase defect Selenoprotein defect 4H syndrome (7 Sect. 39.3.2) Several syndromes caused by vesicular trafficking defects (7 Table 44.2) Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) Non-lysosomal β-glucosidase (GBA2) deficiency (testicular hypotrophy) (7 Sect. 40.3.1)

Hypothyroidism Allan-Herndon-Dudley syndrome (low brain T3) (7 Sect. 8.9) Respiratory chain defect (7 Table 10.1) Cystinosis (7 Chap. 26) Fabry disease (7 Sect. 40.2.7) Selenoprotein defect (7 Sect. 34.5) Sphingosine-1-phosphate lyase insufficiency syndrome (7 Sect. 40.3.4) Hypoparathyroidism LCHAD deficiency (7 Sect. 12.1) Respiratory chain defect Trifunctional enzyme deficiency Kenny-Caffey syndrome (with primary bone dysplasia syndrome linked to autosomal dominant or recessive mutations in FAM111A or TBCE respectively) STX16 Pseudohypoparathyroidism Growth hormone deficiency Respiratory chain defects

Hyperinsulinism (7 Chap. 6) SUR1 and KIR6.2 mutations Glucokinase overactivity GDH overactivity SCHAD deficiency MCT1 overactivity

Sexual ambiguity Congenital adrenal hyper- and hypoplasia Disorders of adrenal steroid metabolism Salt-losing syndrome Disorders of adrenal steroid metabolism FAO (CPT II) (7 Sect. 12.1.1) Respiratory chain (mt DNA deletions)

GDH glutamodehydrogenase

Hypogonadism is almost constant in women with classic galactosaemia, frequent in CDG syndromes, cystinosis, and iron overload and in some complex lipids disorders such as in PNPLA 6 mutations spectrum (7 Sect. 35.4.4). Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS) is a multisystem disorder responsible for several endocrinopathies (7 Sect. 40.3.4). Many IEM may interfere with growth. Several involve various overlapping mechanisms, many of them involving the mechanistic target of rapamycin (mTOR) signalling pathway [89]. They can lead either

to congenital short stature or severe failure to thrive that can be presenting sign. In almost all IEM short stature is associated with other signs such as visceral failure, metabolic disturbances (hypoglycaemia, acidosis, hyperlactataemia, hyperammonaemia, liver disturbances …), dysmorphic features, abnormal head circumference, immunohaematological findings or neurological involvement. There are many monogenic causes of isolated short stature that are beyond the scope of this chapter [90].

107 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

1.6.4

Gastroenterology and Nutritional Findings

Persistent anorexia, feeding difficulties, chronic vomiting, failure to thrive, frequent infections, osteopenia, and generalized hypotonia isolated or in association with chronic diarrhoea may be the presenting features in a number of IEM in infancy. They are easily misdiagnosed as cow’s milk protein intolerance, celiac disease, chronic ear, nose & throat infections, late-onset chronic pyloric stenosis etc. Congenital immunodeficiencies are also frequently considered, although only a few presents early in infancy with this clinical picture [91]. There are two groups of IEM presenting with chronic diarrhoea and failure to thrive: 5 Disorders of the intestinal mucosa or the exocrine function of the pancreas with almost exclusive intestinal effects, for example congenital chloride diarrhoea, glucose-galactose malabsorption, lactase and sucrase-isomaltase deficiencies, abetalipoproteinemia type II (Anderson disease), enterokinase deficiency, acrodermatitis enteropathica and selective intestinal malabsorption of folate and vitamin B12, the latter also causing systemic disease. A new congenital diarrhoea disorder linked to mutations in DGAT1 involved in triglycerides synthesis has been recently described (7 Sect. 35.2.1). 5 Systemic disorders which also give rise to GI and nutritional abnormalities. In clinical practice, these groups are sometimes very difficult to distinguish, because a number of specific intestinal disorders can give rise to various systemic clinical abnormalities and vice versa. There are also several metabolic phenocopies linked to chronic deficient intake in a specific essential nutrient (mostly vitamins), as summarized in . Table 1.36. z

Abdominal Pain (Recurrent)

z

Acute Pancreatitis

See acute symptoms section 7 Sect. 1.4.7 and . Table 1.10. 5 Hyperlipoproteinemia type I and IV, familial lipoprotein lipase deficiency (7 Table 36.2) 5 Lysinuric protein intolerance (7 Sect. 25.3) 5 Organic acidurias (MMA, PA, IVA, MSUD) (7 Sect. 18.1) 5 Respiratory chain disorders (Pearson, MELAS) (7 Table 10.2) 5 Citrin deficiency (7 Sect. 19.3.2)

z z

Chronic Diarrhoea, Failure to Thrive, Osteoporosis Hypocholesterolaemia

5 5 5 5 5 5 5

Abetalipoproteinemia type I and II (7 Table 36.2) Chylomicron retention disorder (7 Table 36.2) PMM2-CDG (7 Sect. 43.2.1) Infantile Refsum disease (7 Sect. 42.2.9) Mevalonic aciduria (7 Sect. 37.1) Smith-Lemli-Opitz syndrome (7 Sect. 37.10) Tangier disease (alpha-lipoprotein deficiency) (7 Sect. 36.3)

z

HELLP Syndrome (Mothers Whose Babies have…)

z

Intestinal Obstruction

z

Inflammatory Bowel Disease

5 Carnitine palmityl transferase I deficiency (7 Sect. 12.1) 5 LCHAD deficiency and other fatty acid β-oxidation disorders, (7 Sect. 12.2.3) 5 Respiratory chain defects (7 Chap. 10). 5 MNGIE syndrome is a mitochondrial cytopathy due to mutations in thymidine phosphorylase and other mitochondrial genes (7 Table 10.2) 5 Intestinal ulcerations 5 Cytosolic PLA2G4A mutations (7 Sect. 42.5.1) 5 5 5 5

Glycogenosis type Ib (7 Sect. 5.1.2) Mevalonate kinase (7 Sect. 37.1) Chronic granulomatosis (X-linked) SCID: ADA, RIPK1 (receptor-interacting serine/ threonine kinase 1) … (7 Sect. 32.3)

Recurrent inguinal and umbilical hernia are a frequent finding in MPS I, II and VI (7 Sect. 41.2)

1.6.5 z

Haematology

Red Blood Cell Disturbances

Many IEM can cause anaemia (. Table 1.37). Over 95% of macrocytic anaemias are secondary to acquired deficiencies of folate or vitamin B 12, but many IEM of vitamin B 12 and folate metabolism also present with macrocytic anaemia (with the notable exception of MTHFR deficiency) (7 Chap. 28) and one thiamine transporter deficiency (7 Chap. 29). Haemolytic anaemias are due to deficiencies of glycolytic, glutathione oxidoreduction and pentose phosphate shuttle enzymes (some of which are

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. Table 1.36 Chronic diarrhoea, poor feeding, vomiting, failure to thrive Leading symptoms

Other signs

Age of onset

Diagnosis (disorder/enzyme deficiency)

Severe watery diarrhoea, attacks of dehydration

Nonacidic diarrhoea, hypochloraemic alkalosis

Congenital to infancy

Congenital chloride diarrhoea

Acidic diarrhoea, reducing substances in stools

Neonatal

Glucose galactose malabsorption (7 Sect. 8.1) Lactase deficiency

Acidic diarrhoea, reducing substances in stools after weaning

Neonatal to infancy

Sucrase isomaltase deficiency

Skin lesions, alopecia

Neonatal or post weaning

Acrodermatitis enteropathica (7 Sect. 34.6.1)

Non bloody, watery diarrhoea

Neonatal

DGAT mutations (7 Sect. 35.2.1) Plasmalemma vesicle associated protein (PVAP)

Cholangitis crisis

Infancy

MPI-CDG (Ib), ALG8- CDG (Ih), ALG6-CDG (Ic) (7 Sect. 43.2)

Protein losing enteropathy

Hypoglycaemia Fat-soluble vitamins malabsorption, severe hypocholesterolaemia Osteopenia, steatorrhea

Cholestatic jaundice

PMM2-CDG (1a) Neonatal to infancy

Bile acid synthesis defects (7 Chap. 38) Infantile Refsum (7 Sect. 42.2.9)

Ichthyosis, keratodermia, deafness, MR

MEDNIK (7 Sect. 34.1.4)

Hepatomegaly, hypotonia, retinitis pigmentosa, deafness

Infancy

Infantile Refsum

Abdominal distension, ataxia, acanthocytosis, peripheral neuropathy, retinitis pigmentosa

Infancy

Abetalipoproteinemia I and II (no acanthocytes, no neurological sign in type II) (7 Table 36.2)

Pancreatic insufficiency, neutropenia, pancytopenia

Early in infancy

Pearson syndrome (7 Table 10.2)

PMM2-CDG (1a)

Schwachman Diamond syndrome (SBDS, DNAJC21, EFL1, SRP54) (Ribosomopathies: 7 Chap. 39, 7 Table 39.1)

109 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.36 (continued) Leading symptoms

Other signs

Age of onset

Diagnosis (disorder/enzyme deficiency)

Severe failure to thrive, anorexia, poor feeding, with predominant hepatosplenomegaly

Severe hypoglycaemia, inflammatory bowel disease, neutropenia,

Neonatal to early infancy

Glycogenosis type Ib (no splenomegaly) (7 Sect. 5.1.2)

Hypotonia, vacuolated lymphocytes, adrenal gland calcifications

Neonatal

Wolman disease (7 Sect. 36.3)

Cardiomyopathy, retinopathy, micronystagmus

Infancy

Chylomicron retention disorder (no splenomegaly)

Recurrent infections, inflammatory bowel disease,

Infancy

Chronic granulomatosis (X-linked)

Megaloblastic anaemia, neuropathy, homocystinuria, MMA

1–5 years

Intrinsic factor deficiency (7 Sect. 28.1.1)

Leuconeutropenia, osteopenia, hyperammonaemia, interstitial pneumonia,

Infancy

Lysinuric protein intolerance (7 Sect. 25.3)

Recurrent fever, inflammatory bowel syndrome, hyper-IgD

Infancy

Mevalonate kinase (7 Sect. 37.1)

Recurrent infections Lymphopenia

Inflammatory bowel syndrome, intractable diarrhoea

Early infancy

SCID (adenosine deaminase, RIPK1 mutations) (7 Sect. 32.3)

Severe failure to thrive, anorexia, poor feeding, with megaloblastic anaemia

Oral lesion, neuropathy, infections, pancytopenia, homocystinuria, MMA

1–2 years

TC II deficiency (7 Sect. 28.1.4)

Stomatitis, peripheral neuropathy, infections, intracranial calcifications

Infancy

Congenital folate malabsorption (7 Sect. 28.3.1)

Severe pancytopenia, abnormal marrow precursors, lactic acidosis

Neonatal

Pearson syndrome (7 Table 10.2)

Severe hypoproteinaemia, putrefaction diarrhoea

Infancy

Enterokinase deficiency

Diarrhoea after weaning, cutaneous lesion (periorificial), low plasma zinc

Infancy

Acrodermatitis enteropathica

Ketoacidotic attacks, vomiting

Infancy

Organic acidurias (MMA, PA) (7 Sect. 18.1)

Severe failure to thrive, anorexia, poor feeding, no significant hepato-splenomegaly, no megaloblastic anaemia

Intrinsic factor deficiency

Mitochondrial DNA deletions (7 Sect. 10.4.1) Vomiting, lethargy, hypotonia, hyperammonaemia

Infancy

Urea cycle defects (7 Chap. 19) (mainly OTC)

Frequent infections, lymphopenia

Infancy

Adenosine deaminase defect (7 Sect. 32.3)

Developmental delay, relapsing petechiae, orthostatic acrocyanosis

Infancy

Ethe1 mutations (7 Sect. 20.9)

Skin laxity, pili torti, hypothermia, hypotonia, seizures, facial dysmorphism

Menkes disease (7 Sect. 34.1.2) Occipital horn syndrome

Bold face: treatable disorders MMA methylmalonic acidaemia, PA propionic acidaemia, CDG congenital disorder of glycosylation, OTC ornithine transcarbamylase, MR mental retardation

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. Table 1.37 Red blood cells disturbances Acanthocytosis polycythemia

Anaemias: macrocytic

Anaemias: non macrocytic, haemolytic, congenital dyserythropoietic or due to combined mechanisms

Acanthocytosis Abetalipoproteinemia (7 Table 36.2) Panthothenate kinase deficiency (7 Sect. 34.2.3) Inborn errors of cobalamin (Cbl C) (7 Sect. 28.2.1.3) Wolman disease (7 Sect. 36.1) Polycythemia Inherited manganism (7 Sect. 34.4.1)

Cobalamin metabolism defects (7 Sects. 28.1 and 28.2) Imerslund-Gräsbeck disease Intrinsic factor deficiency TC II deficiency Cbl C, Cbl D, Cbl E, Cbl F, Cbl G deficiencies Methionine synthase (CblG)deficiency Folate metabolism defects (7 Sect. 28.3) Dihydrofolate reductase deficiency Glutamate formimino transferase deficiency Congenital folate malabsorption MTHDF1-deficiency Others Hereditary orotic aciduria (7 Sect. 32.3.6) Mevalonic aciduria (7 Sect. 37.1) Pearson syndrome (7 Table 10.2) (dyserythropoiesis) Respiratory chain disorders Thiamine responsive megaloblastic anaemia (7 Sect. 29.1.1) Blackfan diamond anaemia (7 Sect. 39.3.4) Congenital methaemoglobinemia (7 Sect. 1.5.1, . Table 1.14)

Abetalipoproteinemia (7 Table 36.2) Adenylate kinase deficiency (7 Sect. 32.3.4) Adenosine triphosphatase deficiency Carnitine transport defect Congenital erythropoietic porphyria (7 Sect. 33.2.3) Erythropoietic protoporphyria (7 Sect. 33.9) SLC11A2 mutations (7 Sect. 34.2.2) Endosomal ferri reductase (STEAP 3) (7 Sect. 34.2.2) Galactosaemia (7 Chap. 14) GLUT1DS (haemolysis triggered by exercise) (7 Sect. 8.3) Glycolytic and PPP deficiencies (7 Chap. 7) Hemochromatosis (7 Sect. 34.2.1) IRIDA (7 Sect. 34.2.2) Lecithin cholesterol acyltransferase deficiency (7 Table 36.1) Majeed syndrome (dyserythropoietic) (7 Sect. 35.1.4) Mevalonic aciduria (7 Sect. 37.1) MLASA syndrome (7 Table 10.2) PNPO and PLP deficiency (7 Sect. 29.2) Porphyrias (diverse types) (7 Chap. 33) Glutathione synthetase deficiency (7 Sect. 31.3.2) Pyrimidine 5-nucleotidase deficiency (7 Sect. 32.3.7) SEC23B-CDG (congenital dyserythropoietic anaemia II) (7 Chap. 43) Severe liver failure (all causes) Sitosterolaemia (with stomatocytes) (7 Table 36.2) Transaldolase deficiency (7 Sect. 7.10) Wilson disease (7 Sect. 34.1.1) Wolman disease (7 Table 36.2) Sideroblastic anaemia Isolated (see also 7 Sect. 33.2) X-linked sideroblastic anaemia (B6 responsive) (7 Sect. 33.1) GLRX5 (iron sulfur cluster) (adults) Syndromic: Mitochondrial disorders Pseudouridine synthase 1 (PUS1) and mitochondrial tyrosyl-tRNA synthase (YARS2): MLSA syndrome (7 Table 10.2) Pearson syndrome (7 Table 10.2) MLSA plus syndrome: MT-ATP6, NDUFB11 mutations SLC25A38 mutations (7 Chap. 10) TRNT1 mutations (7 Chap. 39)

111 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

associated with neurological signs) (7 Chaps. 7 and 31), abnormal erythrocyte nucleotide metabolism (7 Chap. 32) porphyrias (7 Chap. 33), and disorders of lipid metabolism or hypersplenism. Sideroblastic anaemias are observed in mitochondrial disorders such as Pearson syndrome or mitochondrial tyrosyl- tRNA synthetase deficiency presenting with MLASA: myopathy, lactic acidosis, and sideroblastic anaemia syndrome (7 Chaps. 10 and 39). The pyridoxine-responsive anaemia (or X-linked sideroblastic anaemia) presents in the second decade of life; 90% of patients are B 6 responsive (7 Sect. 33.1). Microcytic anaemia is a prominent sign in five disorders with iron deficiency (7 Sect. 34.2.2). Blackfan Diamond anaemias (many of them with congenital

anomalies) belong to the newly classified group of ribosomopathies (7 Sect. 39.3.5). z

White Blood Cells Disturbances (. Table 1.38)

Isolated neutropenia involve specific mechanisms as in Glycogenosis type B in a context of hypoglycaemia, frequent infections and colitis (7 Sect. 5.1.2), in Dursun syndrome (G6PC3 deficiency) in a context of pulmonary arterial hypertension and cardiac abnormalities or in Barth syndrome in a context of cardiomyopathy (7 Sect. 35.3.8). Pancytopenia in IEM may result from many mechanisms some of them complex and not fully understood. Discounting ‘peripheral’ pancytopenia (or bicytopenia) linked to an exaggerated destruction of blood cells in

. Table 1.38 White blood cells Pancytopenia - thrombocytopenia - leucopenia

Vacuolated lymphocytes

Miscellaneous

Peripheral causes: All conditions with major hepato/ splenomegaly causing hypersplenism (7 Sects. 1.6.6 and 1.3.5): Gaucher disease type I and III (mostly anemia and thrombopenia), Niemann Pick disease type A and B, − MPS, MLP Oligosaccharidoses, Wolman disease

LSD Multiple sulfatase deficiency (7 Sect. 41.2) Ceroid lipofuscinosis (7 Sect. 40.5) I-cell disease (7 Sect. 41.3) GM1-gangliosidosis (7 Sect. 40.2.3) Niemann-Pick Ia (7 Sect. 40.2.2) MPS (7 Sect. 41.2) Pompe disease (7 Sect. 5.2.3) Sialidosis (7 Sect. 41.3) Wolman disease (7 Sect. 36.1) Neutral lipid storage (Jordan anomaly) (7 Sect. 35.2.3)

Hyperleucocytosis (>100.000): Leucocyte adhesion deficiency syndrome (SLC35C1-CDG (IIc): GDP fucose transporter 1) (7 Table 43.2)

Isolated neutropenia Barth syndrome (myocardiopathy) (7 Sect. 35.3.8) Glycogenosis type Ib (7 Sect. 5.1.2) Dursun syndrome (G6PC3) (7 Sect. 5.1.2) Pancytopenia, Bicytopenia Cobalamin metabolism defects (7 Sects. 28.1 and 28.2) Folate metabolism defects (7 Sect. 28.3) Lysinuric protein intolerance (7 Sect. 25.3) Organic acidurias (MMA, PA, IVA) in acute attacks) (7 Sect. 18.1) Pearson syndrome (7 Table 10.2) Respiratory chain disorders Transaldolase deficiency (7 Sect. 7.10) Adenylate kinase 2 deficiency (with deafness) (7 Sect. 32.3.4) SCID: ADA, RIPK1 (lymphopenia) (7 Sect. 32.3.1) Hemophagocytic lymphohistiocytosis (see right column) Ribosomopathies: Schwachman Diamond syndrome (SBDS, DNAJC21, EFL1, SRP54) (7 Chap. 39) Trafficking disorders: Congenital neutropenia (JAGN1, VPS45, WAS), Cohen syndrome DNM2 mutations (neutropenia with CMT) (7 Chap. 44) CDG: SLC35A-CDG (IIf) (7 Table 43.2)

Pelger-Huet anomaly (7 Sect. 37.6) Lamilin mutations Mother of foetus with Greenberg lethal dwarfism (7 Sect. 37.6) SOPH syndrome (7 Sect. 44.3.2) NBAS mutations (7 Sect. 44.3.2)

Hemophagocytic lymphohistiocytosis: Cobalamin C Gaucher disease Lysinuric protein intolerance Niemann-Pick disease Propionic acidaemia Methylmalonic aciduria Trafficking disorders (7 Table 44.2)

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the spleen as in Gaucher disease, four groups of mechanisms leading to metabolic ‘central pancytopenia’ may be identified 1. Failure to make stem cells that turn into blood cells because of lack of appropriate availability of indispensable compounds to make nucleic acids such as B vitamins (B1, B12, Folate, B6), purine/pyrimidines (several defects of which responsible for SCID), essential amino acids (BCAA, or Lysine in LPI), or defective energy supply (as in Pearson syndrome) 2. Fibrosis or scarring of bone marrow cells due to myelofibrosis, osteopetrosis, or aplastic anaemias like in ribosomopathies (such as Blackfan Diamond and Schwachman Diamond syndrome) (7 Sect. 39.3) or CDG and trafficking disorders leading to severe congenital neutropenia or Cohen syndrome (7 Sect. 44.3.2). 3. Immune system destroying healthy bone marrow cells as in hemophagocytic lymphohistiocytosis (HLH) where there is marked inappropriate and ineffective T cell activation that leads to an increased hemophagocytic activity. The T cell activated macrophages engulf erythrocytes, leukocytes, platelets, as well as their progenitor cells (7 Sect. 44.3.2). Several mechanisms may lead to HLH. 4. Suppression of bone marrow function due to illness or toxic coumponds like in acute episodes of organic acidurias where bone marrow suppression is an important concern and, diagnostic sign and is rapidly reversible on acute treatment (7 Sect. 18.1.1).

1.6.6

Hepatology

z

Cholestatic Jaundice and Cirrhosis (. Table 1.39)

z

Liver Failure (Ascites, Edema) See 7 Sects. 1.3.5) and 1.4.9), and . Tables 1.6 and 1.13)

Acute liver failure is defined as the rapid development of severe impairment of hepatic synthetic function including hypoalbuminaemia (responsible for ascites and oedema) and the development of coagulopathy (prolonged blood prothrombin time and/or a prolonged blood activated partial thromboplastin time). When acute neurologic symptoms are present it may mimic a Reye like episodes (7 Sect. 1.4.5). Less severe liver dysfunction includes abnormal biochemical markers of liver function (mostly alanine ALT and aspartate AST aminotranferases) but without clinical symptoms (no ascites, no haemorrhagic syndrome). In TMEM 199 mutations the adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, hypercholesterolemia, low serum ceruloplasmin and abnormal N- and mucin-type O-glycosylation (7 Chap. 43, 7 Table 43.2).

z

Hepatomegaly and Hepatosplenomegaly Without Prominent Hepatic Dysfunction (7 Sect. 1.3.5)

There are four mechanisms by which IEM can lead to hepatomegaly in paediatrics: 5 Storage (glycogen, neutral lipids, complex lipids) 5 Cholestasis, (bile retention) 5 Fibrosis/cirrhosis, and 5 Inflammatory and immune processes A few clinical criteria allow an initial diagnostic approach: 5 Consistency of the liver (rock hard: cirrhosis; firm to hard: fibrosis and cholestasis; soft to normal: storage with or without splenomegaly), 5 Ultrasound findings (nodules, hyperechoic liver suggesting steatosis, others), 5 Clinical context: coarse facies and dysostosis, neurological deterioration, failure to thrive and gastrointestinal signs, inflammatory, immunologic or hematologic signs, and hypoglycaemia. A firm or rock-hard consistency may indicate tyrosinemia type I, galactosaemia, GSD type IV, severe neonatal hemochromatosis (7 Sect. 34.2.1.5), α1-antitrypsin deficiency, Wilson disease (7 Sect. 34.1.1), cystic fibrosis, Niemann-Pick and Gaucher disease (7 Sect. 40.2). When the liver consistency is normal or soft and there is associated splenomegaly (HSM), a LSD should be considered; coarse facies, bone changes, joint stiffness, ocular symptoms, vacuolated lymphocytes, and neurologic deterioration are strongly suggestive of the mucolipidoses (mannosidosis, ISSD, sialuria, sialidosis) and MPSs I, II, VI and VII (7 Chap. 41). Failure to thrive, anorexia, poor feeding, severe diarrhoea, hypotonia, hypothermia, and frequent infections are presenting signs in Niemann-Pick type A, Farber, Gaucher type II (7 Sect. 40.2), and Wolman diseases (7 Sect. 36.1), and also in chronic granulomatous disease, intrinsic factor deficiency (7 Sect. 28.1.1), GSD type Ib, lysinuric protein intolerance (7 Sect. 25.3) and familial histiocytosis [92] (7 Chap. 39). HSM can be the only presenting sign in Gaucher disease type I and in Niemann-Pick disease type B (with asymptomatic interstitial pneumonia in the latter) and is observed in several lipoprotein disorders like apolipoprotein C-II, Apo AV, α & β LCAT deficiencies), or cholesteryl ester storage disorder (7 Chap. 36). HSM with liver failure in early infancy is the presenting sign of PMP deficiency due to ABCD3 mutations (7 Sect. 42.2.6). Familial lipoprotein lipase presents with HSM, abdominal pain, xanthomas, acute pancreatitis and massive hypertriglyceridemia (7 Chap. 36, 7 Table 36.2). In late infancy or childhood, HSM associated with myoclonic jerks, ophthalmoplegia, and neurologic deterioration strongly suggest the late-onset forms of Niemann-Pick type C (7 Sect. 40.4) or subacute neu-

113 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

. Table 1.39 Cholestatic jaundice and cirrhosis Cholestatic Jaundice

Cirrhosis

Small molecule accumulation disorders causing intoxication (with metabolic marker) Arginase deficiency (7 Sect. 19.2) Galactosemia (7 Sect. 14.1) Tyrosinemia type I (7 Sect. 17.1)

Arginase deficiency Argininosuccinate lyase deficiency (7 Sect. 19.2) Galactosaemia HFI (7 Sect. 15.2) Hypermanganesemia with dystonia (7 Chap. 34). Hemochromatosis (7 Sect. 34.2.1) SAH hydrolase deficiency (7 Sect. 20.4) Tyrosinemia type I Wilson disease (7 Sect. 34.1.1)

Complex molecule catabolism, synthesis, or trafficking disorders (most with metabolic marker) α-1-antitrypsin deficiency Bile acid metabolism disorders (7 Chap. 38) Byler disease Cystic fibrosis CDG including COG 6 and 7-CDG (7 Table 43.2) N-Glycanase deficiency (7 Sect. 43.5.1) Cerebrotendinous xanthomatosis (7 Sect. 38.3) Cholesterol synthesis defects (Smith-Lemli-Opitz syndrome) (7 Sect. 37.10) Mevalonic aciduria (7 Sect. 37.1) MEDNIK syndrome (7 Sect. 34.1.4) MEGDHEL syndrome (filipin test) (7 Sect. 35.3.7) Niemann-Pick type C disease (filipin test) (7 Sect. 40.4) Peroxisomal disorders including ACOX2 and PMP 70 deficiency and methylacyl-CoA racemase deficiency (7 Sect. 42.2.4) SCYL1 variants (Calfan syndrome with low gamma GT) (7 Sect. 44.3.2 and 7 Table 44.2)

α-1-antitrypsin deficiency CDG syndromes several types including MPI-CDG (Ib) (7 Sect. 43.2.2) Cholesterol ester storage disease (7 Sect. 36.3) Cystic fibrosis FARSB (7 Sect. 39.2.3 and 7 Table 39.1) Gaucher disease (7 Sect. 40.2.1) Glycogenosis type IV (7 Sect. 5.1.4) GPDH1 mutation (7 Sect. 35.1.1) Niemann-Pick disease (7 Sects. 40.2.2 and 40.4) Peroxisomal disorders (7 Chap. 42) SCYL1 variant (Calfan syndrome) (7 Sect. 44.3.2) Wolman disease (7 Sect. 36.1)

Energy deficiency and other mechanisms CPT1 deficiency (late infantile to adult) (7 Sect.12.2.2) LCHAD deficiency (early infancy) (7 Sect. 12.2.3) Transaldolase deficiency (neonatal) (7 Sect. 7.10)

LCHAD deficiency Transaldolase deficiency Alpers progressive infantile poliodystrophy (7 Table 10.2)

ronopathic Gaucher type III diseases (7 Sect. 40.2.1). CCDC 115 mutations may present with a storagedisease-like phenotype involving hepatosplenomegaly which regresses with age like several other trafficking disorders that involve vesicular, organelle and interorganelle trafficking including the trichohepatoenteric syndrome (7 Chap. 44, 7 Table 44.2). When hepatomegaly is not associated with splenomegaly, three clinical circumstances should be considered. Situations with fasting hypoglycaemia suggest GSD type I or type III (in which the liver can extend down to the iliac crest) or Fanconi-Bickel syndrome (in which glycogenosis is associated with tubulopathy) (7 Sect. 8.5); these patients have a doll-like appearance and short stature. FBPase deficiency is considered when

hypoglycaemia is associated with recurrent attacks of lactic acidosis triggered by fasting or by intercurrent infections (7 Sect. 15.3). In argininosuccinic aciduria there can be hepatomegaly and failure to thrive that can mimic hepatic GSD (7 Sect. 19.2). Isolated hepatomegaly with a protuberant abdomen is a presenting sign of GSD type VI and IX but may be also the only presenting sign in GSD type III. It is also observed in the rare entities, cholesteryl ester storage disease, Tangier disease, (7 Chap. 36) and neutral lipid storage disorders (7 Sect. 35.2.3. Cytoplasmic glycerol 3 phosphate dehydrogenase 1 deficiency, presenting with isolated soft asymptomatic hepatomegaly and transient hypertriglyceridemia in infancy, has been recently described (7 Sect. 35.1.1).

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Paediatric Fatty Liver Disease [Non-alcoholic Fatty Liver Disease (NAFLD)]

Steatosis is defined by the presence of fat in hepatocytes when examined under light microscopy and can be classed as microvesicular or macrovesicular. It is highly suspected based on a hyperechoic liver ultrasound. The known causes of steatosis in children may be classified according to their typical clinical presentation [93]: (i) acute liver failure (7 Sects. 1.4.9 and 1.4.5); (ii) neonatal or infantile jaundice; (7 Sect. 1.3.5) (iii) hepatomegaly, splenomegaly or hepatosplenomegaly; (above) (iv) developmental delay/psychomotor retardation (7 Sect. 1.5) and perhaps most commonly v) the asymptomatic child with incidental discovery of abnormal liver enzymes (below). z

Isolated Elevated Transaminases

A careful clinical and echographic (hyperehoic liver suggesting steatosis) evaluation is required. Always rule out a myopathy, haemolysis and a macrotransaminemia. Look at gamma-glutamyl transpeptidase. Search first for Wilson disease (after 3 years), alpha-1-antitrypsine deficiency, cystic fibrosis, glycogenosis, Wolman disease and hereditary fructose intolerance. Other causes are listed below in alphabetical order 5 Acute Intermittent Porphyria 5 Bile acid synthesis defects (cholestasis with normal GGT) Including ACO2 5 Bile acid conjugation defects 5 CDG syndromes (including congenital disorder of N-linked deglycosylation 5 Chanarin-Dorfman syndrome 5 Cellular trafficking disorders (NBAS, RINT1 SCYL1….) 5 Fatty acid oxidation defects 5 Glycerol-3-phosphate deshydrogenase deficiecy 5 Glycogenosis (mostly types VI and IX) 5 Hemochromatosis 5 Hereditary fructose intolerance and fructose biphosphatase deficiency 5 Lipoprotein metabolism defects 5 Lysosomal storage: Wolman, Gaucher, Niemann Pick disease type C and B 5 Methionine demethylation defects 5 Mevalonate kinase deficiencg 5 Mitochondrial aminoacyl t-RNA synthetases defects (LARS, MARS, HARS) 5 Mitochondrial respiratory chain defects (mostly TRMU, ribonucleotide reductase, mt-DNA depletion 5 Transaldolase deficiency 5 Urea cycle defects, citrin and HHH syndrome 5 Wilson disease

1.6.7

Immunology (See Also Neutropenia . Table 1.38)

The main immunologic manifestations of IEM are (i) Combined immunodeficiencies (CID, SCID) involving T and B cells (ii) phagocytes deficiencies involving polymorphonuclear, monocytes or mastocytes (iii) diseases of immune dysregulation and (iv) auto-inflammatory disorders. Some disorders are restricted to the immune system while some other are associated with extraimmune manifestations like deafness, anaemia, dermatologic, osseous, or neurologic signs that may be preponderant. z

Inflammatory Syndrome, Recurrent Fever

z

Macrophage Activating Syndrome, Haemophagocytosis

5 5 5 5 5 5

Gaucher disease Lysinuric protein intolerance Niemann-Pick disease type A and B Propionic acidemia Familial histiocytosis TRMU mutation (with transient infantile liver failure)

z

Severe Combined Immune Deficiency (SCID)

5 Hyper-IgD syndrome and mevalonate kinase deficiency (7 Sect. 37.1) 5 Aicardi Goutières syndrome (altered cytokine expression) (7 Sect. 39.1.2) 5 Majeed syndrome (LPIN2 mutations) (7 Sect. 35.1.4) 5 Fabry disease: bouts of fever (7 Sect. 40.2.7) 5 PSMB8 mutations in proteasome: nodular erythema, muscular weakness and lipodystrophy 5 HOIL1/LUBAC mutations: autoinflammation, immunodeficiency, and amylopectinosis 5 RBCK1 (E3 ubiquitin ligase) autoinflammation with recurrent episodes of sepsis, 5 COG7-CDG (malignant hyperthermia) 5 Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) 5 Cryopyrin-associated periodic syndromes (CAPS) 5 Histiocytosis-lymphadenopathy plus syndrome (SLC29A3 mutations) (7 Chap. 39)

As a predominant presenting sign (7 Chap. 32) 5 Adenosine deaminase 1 deficiency (with costochondral abnormalities) 5 Purine nucleoside phosphorylase (with hypouricemia and developmental delay)

115 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

5 Adenylate kinase 2 (reticular dysgenesis with deafness) 5 Cytidine deaminase deficiency (autosomal recessive type II hyper-IgM syndrome) 5 Transferrin receptor 1 deficiency 5 RIPK1 mutation (with early-onset inflammatory bowel disease, and progressive polyarthritis), lymphopenia and altered production of various cytokines. As an associated finding: 5 α-Mannosidosis 5 Hereditary orotic aciduria (with megaloblastic anemia) (7 Chap. 32) 5 VICI syndrome (7 Chap. 44) 5 NRF2 superactivity 5 Folate and B12 disorders(7 Chap. 28): – Hereditary folate malabsorption – Transcobalamin II deficiency – Methylene tetrahydrofolate dehydrogenase deficiency (MTHFD1) Deletions of the PLCG2 encoding phospholipase Cγ(2), an enzyme expressed in B cells, natural killer cells, and mast cells present with cold urticaria, immunodeficiency and autoimmunity (7 Chap. 35)

1.6.8

Myology

Many IEM can present with severe hypotonia, muscular weakness, and poor muscle mass. These include most of the late-onset forms of UCD and many OA. Severe neonatal hypotonia and progressive myopathy with or without nonobstructive idiopathic cardiomyopathy, can be the specific presenting findings in a number of inherited energy deficiencies; the most frequent conditions are mitochondrial RCD and other congenital hyperlactataemias, FAO defects, PBD, muscular GSD, alpha-glucosidase deficiency, and some other LSD (7 Sects. 1.3.3 and 1.3.7). Hypotonia, generalized weakness, reduced muscle mass and developmental delay are also the presenting features of the Allan-HerndonDudley syndrome (7 Sect. 8.9). Several defects of cytoplasmic triglycerides and phospholipids synthesis present with congenital progressive myopathy including choline kinase deficiency (7 Sect. 35.3.1). Severe neonatal hypotonia with elevated CK and brain dysfunction are major findings in most of the dolichol synthesis and recycling defects (7 Chap. 43). A congenital myasthenic syndrome pyridostigmine responsive can be a presenting sign in ALG2, ALG14, DPAGT1, GFPT1, and

GMPPB-CDGs that bridges myasthenic disorders with dystroglycanopathies (7 Chap. 43). ISPD mutations (coding for isoprenoid synthase containing domain) are a common cause of congenital and limb girdle muscular dystrophy [94]. z

Exercise Intolerance, Myoglobinuria, Cramps, Muscle Pain, Elevated CK

See acute symptoms 7 Sect. 1.4.6. z

Myopathy (Progressive)

There are many metabolic myopathies but only a few have an effective treatment. Disorders are listed in alphabetical order: 5 Allan-Herndon-Dudley syndrome (monocarboxylate transporter 8 deficiency) (7 Sect. 8.9) 5 Adenylate deaminase deficiency (7 Sect. 32.4.1) 5 Carnitine transport defect and fatty acid oxidation disorders 5 Creatine synthesis defect linked to AGAT deficiency 5 Choline kinase deficiency (7 Sect. 35.3.1) 5 CDG syndromes: DPAGT1- CDG, ALG14 –CDG and ALG 2-CDG (myasthenic syndrome), 5 Dolichol synthesis defects (7 Chap. 43, 7 Table 43.4) 5 ETF, ETF dehydrogenase, FAD synthase and mitochondrial FAD transporter deficiencies (7 Chap. 12) 5 Glycogenosis type II (alpha glucosidase deficiency), Danon disease (LAMP-2) (7 Chap. 5) 5 Glycogenosis type III, IV, 0b (muscle type), AMPK mutations 5 Glycogenosis type V (dominant PYGM mutation in adult) 5 ISPD mutations (isoprenoid synthase containing domain): limb girdle muscular dystrophy 5 Neutral Lipid Storage Diseases: ATGL and CGI-58 Deficiencies (7 Sect. 35.2.3) 5 Phosphoglucomutase deficiency (7 Sect. 43.4.6) 5 RBCK1 mutations (E3 ubiquitin ligase) 5 Respiratory chain disorders (Kearns-Sayre, MLASA syndrome and others) (. Table 14.2) 5 Vici syndrome (. Table 44.2)

1.6.9

Nephrology (. Table 1.40)

Nephrolithiasis/nephrocalcinosis, polycystic kidneys, tubulopathy, abnormal urine colour/odour) are the main renal manifestations of IEM. Atypical Haemolytic Uremic Syndrome (HUS), nephrotic syndrome and tubulointerstitial nephropathy may also be presenting signs. DGKE mutations responsible for HUS with

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. Table 1.40 Nephrology Nephrolithiasis (stone composition) See also 7 Sect. 36.2, Nephrocalcinosis

Tubulopathy

Urines (colour, odour)

Miscellaneous

APRT deficiency (2–8 dihydroxy adenine) (7 Sect. 32.2.3) Cystinuria (cystine) (7 Sect. 25.1) Hereditary hyperparathyroidism (calcium) Hereditary renal hypouricemia (uric acid) Hyperoxaluria type I and II (oxalic acid) Lesh-Nyhan (uric acid) (7 Sect. 32.1.6) Molybdenum cofactor deficiency (xanthine) (7 Sect. 20.10) PRPP synthase superactivity (uric acid) RTA type I XO (xanthine) (7 Sect. 32.2.2) Familial juvenile hyperuricemic nephropathy (uromodulin) (7 Sect. 32.2.4) 5 Oxoprolinuria (7 Sect. 31.3.2)

RTA type I / II PC deficiency SURF1 (with Leigh) MMA GSDI CPT I deficiency Dent disease CA II (proximal) Forkhead transcription factor FOXI1 and H+ -ATPase (V-ATPase) (both with dRTA and early deafness)

Abnormal odour DMGHDH (fish) 3-MCG (cat) GAII (sweaty feet) IVA (sweaty feet) MSUD (maple syrup) PKU (musty odor) TMAU (fish) (7 Sect. 31.1) Tyr I (boiled cabbage) MAT I/III deficiency (7 Sect. 20.1) MTO defect (extraoral halitosis) (7 Sect. 20.2)

Nephrotic syndrome: Respiratory chain disorders (coenzyme Q synthesis defects) DGKE (7 Sect. 35.1.5) SPLIS (steroid resistant) Sphingosine-1-phosphate lyase deficiency (7 Sect 40.3.4) Disorders of pre-rRNA processing (dyskerin and NOP10 defects) (7 Sect. 39.3.3)

Hypochloraemic alkalosis Bartter and Gitelman syndromes Congenital chloride diarrhea Hupra syndrome (7 Table 10.2)

Abnormal colour Alkaptonuria (black) Indicanuria (blue) Myoglobinuria (red) Porphyria (red) Beets lovers (red)

Nephropathy (tubulointerstitial) : GSD1 MMA RCD (pseudo Senior-Loken syndrome) X-prolyl aminopeptidase 3 (nephronophtisis like) Ciliopathies (TMEM67…)

.

Polycystic kidneys: CDG syndromes PMM2 promotor mutations (HIPKD syndrome) CPT II deficiency GAII Zellweger syndrome

CPT carnitine palmitoyl transferase, DMGDH dimethylglycine dehydrogenase, GSD glycogenosis, GAII glutaric aciduria type 2, HUS hemolytic uremic syndrome, HFI hereditary fructose intolerance, HIPKD hyperinsulinism polycystic renal disease, MAT methionine S-adenosyltransferase, MCG methylcrotonylglycinuria, MMA methylmalonic aciduria, MTO methane thiol oxidase, dRTA distal tub ular acidosis, PC pyruvate carboxylase, RCD respiratory chain disorder, RTA renal tubular acidosis, SPLIS sphingosine-1-phosphate lyase insufficiency syndrome (7 Chap. 40), TMAU trimethylaminuria, XO xanthine oxidase

nephrotic syndrome provides an interesting new mechanism of atypical HUS (7 Sect. 35.1.5). z

Oxalurias and Oxalosis: Glyoxylate Detoxification Disorders

Primary hyperoxaluria type 1 (PH1) is a disorder of glyoxylate metabolism characterized by the accumulation of oxalate due to a deficiency of the peroxisomal hepatic enzyme L-alanine: glyoxylate aminotransferase (AGT) . The defect in AGT, which normally converts glyoxylate to glycine, results in an increase of the glyoxylate pool, which is converted to oxalate (poorly soluble) and glycolate (without associated pathology). Differential diagnosis includes primary hyperoxaluria type 2 (PH2), primary hyperoxaluria type 3 (PH3), Dent disease, and familial hypercalciuria-hypomagnesemia-nephrocalcinosis (7

Sect. 34.3) as well as secondary forms of hyperoxaluria (enteric hyperoxaluria, dietary hyperoxaluria), and idiopathic calcium oxalate urolithiasis. PH2 is due to mutations in GRHPR coding for a cytosolic enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase catalytic activities. The enzyme has widespread tissue expression. PH3 is caused by mutations in HOGA1 which codes for the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase 1. Clinical presentation of PH1 is variable, ranging from occasional symptomatic nephrolithiasis to nephrocalcinosis and end-stage renal disease with systemic involvement. PH3 has a less severe course than PH1 or PH2 and may be silent. Diagnosis of PH1-3 is suspected on clinical features along with pure calcium oxalate monohydrate stone composition and confirmed by urine

117 Clinical Approach to Inborn Errors of Metabolism in Paediatrics

oxalate: creatinine ratio, L-glycerate excretion, molecular genetic testing and infrequently by enzyme catalytic activity from liver biopsy. In a proportion of patients with primary hyperoxaluria type 1, treatment with pyridoxine (vitamin B6) may decrease oxalate excretion and prevent kidney stone formation [95].

1.6.10

Neurology and Psychiatry

See 7 Sects. 1.3.1, 1.3.2, and 1.4.3.

1.6.11

Ophthalmologic Signs

See also neuro-ophthalmologic signs, 7 Sect. 1.5.7. z

Cataracts

Congenital cataracts may occur as isolated defects or may be associated with other anterior chamber developmental anomalies such as microphthalmia or aniridia. Both the structure and stability of the lens crystallins and maintenance of strong cellular homeostatic systems are necessary to maintain normal lens function. Recent evidence suggests that newly synthesized proteins might be present in the lens nucleus, and that central nuclear fibre cells, largely restricted to glycolysis as an intrinsic energy source, receive metabolic support from the anterior epithelium through circulation of fluid. As lens crystallins make up over 90% of soluble lens proteins, their short-range ordered packing in a homogeneous phase is important for the maintenance of lens transparency [96]. Most cataracts caused by IEM are syndromic although some of them may appear as presenting sign or even remained isolated. The pathophysiology, involving intoxication mechanism (as in galactosaemias), lipid membrane disturbances or energy process required for maintenance of lens crystallins transparency, is still poorly understood. The recent description of SLC7A8 mutations in congenital cataracts highlights the role of transporters required to import all amino acids involved in lens cell metabolism and in particular also those required for the synthesis of the tripeptide glutathione (GSH), which is a vital antioxidant known to be important for the preservation of lens transparency [97] (7 Chap. 25). Metabolic causes of cataracts according to age of onset (. Table 1.41). z

Corneal Clouding (. Table 1.42)

z

Ectopia Lentis (Dislocation of the Lens)

5 Classical homocystinuria (7 Sect. 20.6) 5 Sulfite oxidase deficiency (7 Sect. 20.11)

5 Marfan syndrome 5 Marchesani syndrome z

Keratitis with Corneal Opacities

These are presenting signs of two treatable disorders: 5 Tyrosinemia type II 5 Fabry disease (X-linked) 5 IFAP syndrome (AD or X-linked both with photophobia) (see . Tables 1.29, 1.30 and 7 Sect. 37.11) z

Miscellaneous

5 Alacrimia: N-glycanase 1 deficiency (7 Chap. 43) 5 Conjunctivitis, blepharitis: Acrodermatitis enteropathica, cystinosis, tyrosinemia type II, PA, MCD 5 Colobome: Familial hypomagnesemia (7 Chap. 39), trafficking disorders (ACTB, TBC1D23, PACS1) (7 Table 44.2) 5 Microcornea: Ehlers Danlos type IV 5 Macular telangiectasia type 2: Serine Palmitoyltransferase (subunit 1 or 2) (7 Sect. 40.1.1)

1.6.12

Orthopaedic Signs (. Table 1.43)

The updated nosology of genetic skeletal disorders comprises 461 disorders classified within 42 different groups [98]. Of these, many are caused by IEM. 5 Multiplex dysostosis is a characteristic hallmark of a number of LSD (MPS, oligosaccharidosis and mucolipidosis) (7 Chap. 41). Conversely glycosaminoglycans (GAG) synthesis defects (many of them classified in O-glycosylation disorders) (7 Chap. 43) display major clinical features that include short long bones, joint dislocations or laxity and scoliosis and additional suggestive features such as skin laxity with or without atrophy and blue sclerae [99] (7 Chap. 41). 5 Severe osteopenia is a major feature in many treated or untreated IEM. 5 Bone dysplasia (primary or syndromic) is a preponderant sign in complex lipid synthesis and remodelling defects. These comprise plasmalogen and peroxisomal defects (mostly presenting with rhizomelic chondrodysplasia punctata) (7 Sect. 42.1), most cholesterol synthesis defects with polymalformative syndromes, (7 Chap. 37), and phospholipid (PL) metabolism disorders (7 Chap. 35). PL disorders may present as (1) hyperostotic dwarfism as in Lenz Majewski syndrome, (2) Pure spondylometaphyseal dysplasia (SMD), as in opsismodysplasia or syndromic SMD associated with cone rod dystrophy, (PCYT1A, PLCB3, PISD mutations: Liberfarb syndrome), or sphingomyelin synthase 2 deficiency (7 Sect. 40.1.9). Many trafficking disorders including

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. Table 1.41 Cataracts Categories of disorders

Detectable at birth ( Leu

Fed state

AIle +++, Ala ↓

U: ↑

MSUD and mild variant (PP2Cm) [1]

AIle± ↑, Ala ↑, Gln ↑

UOA: Lac ↑, 2KG ↑

E3 deficiency

↑

AIle -

UOA: Alphaketoacids ↓/N

BCAT2 deficiency

↓

All normal

CSF ↓

BCKAD kinase deficiency

Met ↑, Tyr ↑, Pipecolic ac ↑

UOA: Phenolic acids↑

Hepatic failure

Cit ↑, Cys2 ↑, 3Mhis ↑ Citrulline

Cystine

Renal failure

↑

See Gln

U: ASA ↑/N

UCDs: ASSD, ASLDCitrin deficiency, PC, TMEM70

↓

See Gln

U: Orotic ↑/N/↓

NAGS, CPS, OTC

↓

All normal

U: Orotic N

Short bowel syndrome Intestinal failure

↓

Gln ± ↑, Pro ↓, Arg ↓, Orn ± ↓

↓

All normal

↑

Cys2 ↑, 3MHis ↑, BCAA ↓ Alone ± ↑

↓+++

SulfoCys ↑

↑

Cit ↑, BCAA ↓, 3MHis ↑

N

All normal

P5CS deficiency UOA: Lac ↑, Krebs cycle metabolites

ATP synthase deficiency (NARP), other mitochondrial disorders Renal failure Heterozygote ASS

U: SulfoCys ↑, tau ↑

Sulfite oxidase deficiency Renal failure

U: Cys ↑, Lys ↑, Orn ↑, Arg ↑

Cystinuria (continued)

150

3

G. Touati et al.

. Table 3.1

(continued)

Plasma Amino Acid

Variation

Other Plasma Amino Acids

Investigations in other fluids

Diagnoses

Glutamine

↑

Cit ↓, Orn ↓, Arg ↓

UOA: Orotic ↑ (OTC, OAT)

Mitochondrial UCD, neonatal OAT deficiency

Cit ↓ or N, Ala ↑, Pro ↑

P: Lac ↑ UOA: Orotic N, 3-OHP ↑, PG ↑, MC ↑, 3-MCG ↑

CA-VA deficiency

Cit ↑+++

U: Cit ↑+++, Orotic acid ↑

ASSD

Cit ↑, ASA ↑

U: Cit ↑, ASA ↑, orotic acid ↑

ASLD

Cit N, Arg ↑

U: Arg N or ↑ Orotic acid ↑

ARGD

Cit ↓, Orn ↑, Homocit ↑

U: Orn N or ↑, Homocit ↑, Orotic acid ↑

HHH

Cit ± ↑, Orn ↓, Lys ↓, Arg ↓

U: Cit ↑, Orn ↑, Lys ↑, Arg↑, Orotic acid ↑

LPI

↑++

All normal

Glutaminase deficiency (tandem repeat expansion)

N or ↓

Cit ± ↑, Ala ↑, Lys ↑ ± Ser↓

PC deficiency MAS deficiency

Cit ↑, Thr ↑, Orn ↑, Lys ↑, Arg ↑

Citrin deficiency

Cit N, Gly↑, Ala↑, Lys↑

U: Abnormal organic acids

Organic acidurias

CSF: ↓ +++

Glutamine synthesis deficiency

Alone

CSF: ↑, U ↑

NKH Neonatal disseminated herpes virus infection. (Gycine is extremely elevated) (7 Chap. 23)

Ala ↑

CSF: N, U ↑

Valproate

Ala ↑±, 2-aminoadipate

CSF: ↑, U ↑ P: Lac ↑ UOA: Lac ↑, 2KG ↑, 2KA ↑

Lipoic acid synthesis deficiency (LIAS, BOLA3, GLRX5, NFU1)

Gln N, Ala ↑, Lys ↑

CSF: N, U ↑, UOA

Organic acidurias

Thr ↑ ±

CSF: Gly ↑ ±, Thr ↑ ±

PNPO and PLPBP deficiency

↓ +++ Glycine

↑

Glycine

N/↓

Ser ↓ +/++

CSF: Gly ↓

Serine deficiency

Histidine

↑

Alone

U: ± ↑

Histidase deficiency

Homocystine

±↑

All normal

Secondary to B12, folate deficiency. MTHFR polymorphism

↑

See methionine

MTHFR deficiency, cobalamin disorders

↓

P: Creatine ↓

NRF2 [2]

3

151 Diagnostic Procedures

. Table 3.1

(continued)

Plasma Amino Acid

Variation

Other Plasma Amino Acids

Investigations in other fluids

Diagnoses

Lysine

↑ ++

Orn ↓

U: Lys, Pipecolic/Sacca↑ Orn ↓

Hyperlysinemia type I/II

↑

Gln ↑, NH3 ↑

Urea cycle disorders

Gln ↓, NH3 ↑, Ala ↑, Cit ↑±

PC deficiency

↑

Methionine

Mutations NADK2 [3]

↓

Gln ↑, Cit ± ↑, Orn ↓, Arg ↓

U: Cit ↑, Orn ↑, Lys ↑, Arg ↑ UOA: Orotic ↑

LPI

↓

HCy2 ↑

U: HCy2 ↑ alone

MTHFR deficiency

UOA: MMA ↑

Cobalamin metabolism

↑

Ornithine

↑ Lys in urine/CSF ↑ Lactate, ↑pipecolic

↑

↓

Alone

MATD, SAHHD, ADKD, GNMTD

HCy2 ↑, Cys2 ↓, Disulfide

U: HCy2 ↑

CBS deficiency

Tyr ↑, BCAA ↓, Pipecolic ac ↑

U: Phenolic acid derivatives

Hepatic failure

Alone

U: ± ↑

OAT deficiency

Gln ↑, Cit ↓, HomoCit ± ↑

U: Orn ± ↑, HomoCit ↑ UOA: Orotic acid↑

HHH syndrome

Gln ± ↑, Pro ↓, Cit ↓, Arg ↓

P5CS deficiency

Arg ↓, Lys ↓

U: Cit ↑, Orn ↑, Lys ↑, Arg ↑ UOA: Orotic ↑

LPI

Gln↑, Cit ↓, Arg ↓

UOA: Orotic ↑ (OTC, OAT)

Mitochondrial UCD, neonatal OAT deficiency

UOA phenolic acids

PKU

Phenylalanine

↑ +++

Tyr ↓

↑±

Tyr ± ↓

Pipecolic

↑

All normal

CSF: Pip ± ↑, P: VLCFA CSF: Pip ± ↑, P and U: αAASA

Peroxisomal diseases αAASADH deficiency

Met↑, Tyr ↑, BCAA ↓

UOA: Phenolic acids

Hepatic failure

Alone

U: N or ↑. Aminoaciduria

Hyperprolinemia I

Alone

U: N or ↑, P5C ↑

Hyperprolinemia II

Proline

↑

Biopterin synthesis disorders and DNAJC12 [4]

Arginine, ornithine N/↑

SLC25A22 deficiency

Ala ↑

Hyperlactatemia. Mitochondrial disorders

↓

Cit ↓, Orn ↓, Arg ↓

P5CS deficiency

Serine

↓

All others N Citrulline ↑ ±

CSF: ↓

Serine synthesis deficiency MAS deficiency

Sulfocysteine

↑

Cys2 low Cys2 very low

U: Sulfocys 0, all AA normal U: Sulfocys ↑, tau ↑

Anticoagulant Sulfite oxidase and molybdenum cofactor deficiencies

Taurine (see 7 Chap. 25.8)

↓+++

U:↑ 8-oxo-7,8-dihydroguanosine

Taurine transporter deficiency

Threonine

↑

See glycine

PNPO deficiency (continued)

152

3

G. Touati et al.

. Table 3.1

(continued)

Plasma Amino Acid

Variation

Other Plasma Amino Acids

Investigations in other fluids

Diagnoses

Tyrosine

↑ +++

Alone

U: ↑ alone, phenolic acids

Tyrosinemia type II, III

↑

Met ↑, BCAA ↓

UOA: Succinylacetone 0, phenolic acids

Hepatic failure

UOA: Succinylacetone +, phenolic acids

Tyrosinemia type I

Investigations in other fluids

Diagnoses

Urine amino acid

Variation

Plasma amino acids

Iminopeptiduria

↑

N

Prolidase deficiency

Neutral amino acids

↑

N

Hartnup and collectrin deficiency [5]

± slightly modified, 2-aminoAd 2-aminoadipate, 2KA, 2 ketoadipate, 2KG 2-ketoglutarate, 3-MCG 3-methylcrotonylglycine, 3MHis 3-methylhistidine, 3-OHP 3-hydroxy-propionic, AA amino acids, ADKD adenosine kinase deficiency, AIle alloisoleucine, Ala alanine, Arg arginine, ARGD arginase deficiency, ASA argininosuccinic acid, ASLD argininosuccinic lyase deficiency, Asn asparagine, ASSD argininosuccinic synthetase deficiency, BCAA branched chain amino acids (valine, isoleucine, alloisoleucine, leucine), BCKAD branched-chain ketoacid dehydrogenase, BCKDD branched-chain ketoacid dehydrogenase kinase deficiency, CA-VA carbonic anhydrase, CA-VA carbonic anhydrase VA, CBS cystathionine-β-synthase, Cit citrulline, Cys2 cystine, Disulfide disulfide cysteine-homocysteine, FBP fructose biphosphatase, Gln glutamine, Gly glycine, GNMTD glycine N-methyltransferase deficiency, Hcy2 homocystine, HHH triple H syndrome (Hyperammonemia, Hyperornithinemia, Homocitrullinuria), HomoCit homocitrulline, Lac lactate, LIAS lipoic acid synthetase, LPI lysinuric protein intolerance, Lys lysine, MATD methionine s-adenosyltransferase deficiency, MC methylcitrate, Met methionine, MMA methylmalonic acid, MSUD maple syrup urine disease, MTHFR methylene tetrahydrofolate reductase, NARP neuropathy, ataxia, and retinitis pigmentosa, NH3 ammonia, NKH non ketotic hyperglycinemia, NRF2 NF-E2-related factor 2, OAT ornithine aminotransferase, OAT ornithine aminotransferase, Orn ornithine, P5C Δ1-pyrroline-5-carboxylate, P5CS Δ1-pyrroline-5-carboxylate synthase, PEPCKC Phosphoenol pyruvate carboxykinase cytoplasmic, PC pyruvate carboxylase, PG propionylglycine, Pip pipecolic, PKU phenylketonuria, PNPO pyridox(am)ine 5੝-phosphate oxidase, PNPO pyridox(am)ine-5-phosphate oxidase, Pro proline, SAHHD S-adenosylhomocysteine hydrolase deficiency, SLC25A22 potential transporter of P5C, glutamate-γ-semialdehyde or glutamate, SulfoCys sulfocysteine, Tau taurine, Thr threonin, Tyr tyrosine, UCD urea cycle disorder, Def deficiency, UOA urine organic acids, VLCFA very long chain fatty acids, αAASA alpha-amino adipic semi aldehyde, αAASADH alpha-aminoadipic semialdehyde dehydrogenase

. Table 3.2

Interpretation of urine organic acids analysis

Principal OA

Other OAs

Causes of variation

Adipic

Very high isolated

Non metabolic (plastifier?)

Other investigations

See 3-OH- butyric and EMA lines

Dicarboxylic acids (DCA)

If Adipic > Sebacic

Ketosis, beta oxidation disorder

If Adipic < Sebacic

MCT supplementation

Acylcarnitines

See Adipic, 3-OH-n-butyric and EMA lines

Branched chain dicarboxylic acids

Squalene synthase deficiency

Dimethylsulfoxide and Dimethylsulfone,

Methanethiol

Methanethiol oxidase deficiency

3,6-Epoxyoctanedioic

Other epoxy (C10, C12, C14), 2-OH-sebacic, DCA with ad>sub

Peroxisomal diseases

Idem but ad < sub

MCT supplementation

Sterols

3

153 Diagnostic Procedures

. Table 3.2

(continued)

Principal OA

Other OAs

Causes of variation

Other investigations

Ethylmalonic

>20 μmol/mmol C alone

SCAD deficiency

>20 μmol/mmolC ± IBG, 2MBG, IVG

Valproate, RC, GAII, ETHE1

Acylcarnitines

>100 μmol/mmolC + IBG, nBG, 2MBG, IVG, HG, SG, 2OHG, DCA, glut

Glutaric aciduria type II

>100 μmol/mmolC + nBG

SCAD deficiency

20–100

Ethylmalonic encephalopathy (ETHE1)

High ± succinate, malate

Fumarase deficiency, PEPCKC

± high with other KC derivatives + lactate

Respiratory chain disorders, PEPCKC

3-OH-glutaric

Glutaric aciduria type I

EMA, 2-CH3succinic, IBG, nBG, 2MBG, IVG, HG, SG, DCA, 2-OHG

Glutaric aciduria type II/III

Glyceric

Glycerate kinase deficiency

L isomer

D-glycerate dehydrogenase or glyoxylate reductase def (hyperoxaluria type II)

Glycerol

No

Glycerol kinase deficiency Chromosome Xp21 deletion syndrome

Glycolic

Oxalic

Type I oxalosis

4HB

SSADH deficiency

Lactic, ethyleneglycol

Ethyleneglycol intoxication

High ± and SG ±

Mild or asymptomatic MCAD deficiency

High + SG + DCA

MCAD deficiency

High + SG + DCA + EMA + glut + IBG + EMBG + IVG + nBG

Glutaric aciduria type II

Homogentisic

Alone

Alkaptonuria

3-Hydroxy-n-butyric

High ++, AcAc, DCA

Ketosis (starvation, diabetes) Ketolysis defects

AACp

High ±, DCA, 3HDC

Hepatic failure

AACp

Low, DCA, 3HDC, ± acylglycines

Fatty acid oxidation defects

Redox + acylcarnitines

Alone

Drug addiction

4,5 diOH-hexanoic lactone and acid, 3,4-diOH-butyric, 2,4-diOH-butyric, glycolic

Succinic semialdehyde dehydrogenase deficiency

Fumaric

Glutaric

Glyceric

Hexanoylglycine

4-Hydroxy-butyric

3-Hydroxydicarboxylic acids (3HDC)

See 3-Hydroxy-n-butyric line

2-Hydroxy-glutaric

Very high. 2KG (D-glutaric ac,)

D or L-2-OH glutaric aciduria

High ± acylglycines

Glutaric aciduria type II

Moderately high

Respiratory chain disorders

Glutaric normal or high

Glutaric aciduria type I

3-OH-butyric elevated

Ketosis

3-Hydroxy-glutaric

Acylcarnitines

Acylcarnitines

Acylcarnitines

(continued)

154

G. Touati et al.

. Table 3.2

3

(continued)

Principal OA

Other OAs

Causes of variation

3-Hydroxy-isobutyric

2-Ethylhydracrylic

3-OH-isobutyric dehydrogenase def

2-Hydroxy-isovaleric

2-OH-3-CH3Val, 2-OH-isocaproic, 2-oxo-isovaleric, 2-oxo-3-CH3Val, 2-oxo-isocaproic, AcLeu, AcIle

Maple syrup urine disease

3-Hydroxy-isovaleric

Slightly elevated Elevated

Valproate treatment Biotinidase deficiency

Other investigations

AACp

See: 3-Hydroxy-propionic Isovalerylglycine 3-methyl-crotonylglycine 3-Methyglutaconic 3-Methyl-3-OH-glutaric 3-Hydroxy-propionic

Isovalerylglycine

2-Ketoglutaric

Lactic

Alone

Bacterial infections

AACu

PG, TG, MC, (2M3KB, 2M3HB, 3HIV)

Propionic acidemia

PG, TG, MC, 3MCG, (2M3KB, 2M3HB, 3HIV)

Biotinidase or holocarboxylase synthetase deficiency

Lactic, PG, MC, 3MCG

CA-VA deficiency

Ammonia plasma AACp Redox

MMA, PG, TG, MC, (2M3KB, 2M3HB, 3HIV)

Methylmalonic aciduria (different causes)

AACp+u

3-OH-isovaleric

Isovaleric acidaemia

Acylcarnitines

Other acylglycines, glutaric, EMA

Glutaric aciduria type II, ETHE1 mutations

Alone

2-KGD deficiency TPK1 deficiency SLC25A19 transporter deficiency E3 deficiency DOOR syndrome

Redox

Lactic, BCKA, BCHA

E3 deficiency

Redox AACp

Lactic, KC der

Respiratory chain disorders

Redox

Lactic, glut, TG, 2OHG,3OHG, 2-oxoAD, 2OHAd

Lipoic acid synthesis deficiency

AACp Redox

Alone

Bacterial infections Mitochondrial disorders

AACp+u

2HIB, 2HB, Pyr, KC derivatives

Respiratory chain disorders

Redox AACp

KC derivates +3MG

Pearson, respiratory chain disorders

CAAp+u

High KB, low or very low KC derivatives

PC deficiency

AACp Redox

3-OHProp, PG, MC, 3MCG, 3HIV

CA-VA deficiency

Ammonia plasma AACp Redox

Glut, TG, 2OHG,3OHG, TG, 2-oxoAD, 2-OH-adipic, 2KG

Lipoic acid synthesis deficiency

AACp Redox

Other specific organic acids

Organic acidurias

3

155 Diagnostic Procedures

. Table 3.2

(continued)

Principal OA

Other OAs

Causes of variation

Malonic

Alone

Malonyl-CoA decarboxylase deficiency

+ Methylmalonic

ACSF3 def

Methanethiol

Dimethylsulfide, Dimethylsulfoxide and dimethylsulfone

Methanethiol oxidase deficiency

3-methylcrotonylglycine

3-OH-isovaleric

3-CH3-crotonyl-CoA carboxylase deficiency

3-methyl-glutaconic

Very high +3-CH3-glutaric

3-CH3-glutaconyl-CoA hydratase deficiency

3-CH3-glutaric ±

Costeff syndrome CLPB mutations MEGDEL (SERAC mutations) POLG mutations Barth syndrome ATP synthase (TMEM70 mutations) ATAD3 mutations

3-CH3-glutaric, lactate, KC derivatives

Respiratory chain disorders, Pearson

3-CH3-glutaric, 3-OH-3-CH3-glutaric, 3HIV

HMG-CoA lyase deficiency

2-Methyl-2,3dihydroxybutyric 2-Methyl-3-hydroxybutyric

Short-chain enoyl-CoA hydratase (ECHS1) and 3-hydroxyisobutyryl-CoA hydrolase (HIBCHD) 3-OHProp, PG, TG, MC

Propionate metabolism defects

3-OH-nBut, AcAc, 2-CH3–3-oxo-but, TG

β-Ketothiolase deficiency

Tiglylglycine

MHBD deficiency (HSD10)

3-Hydroxy-3-methylglutaric

3HIV, 3MG, 3-CH3-glutaric

HMG-CoA lyase deficiency

Methylmalonic

15 to 250 μmol/mmol crea, isolated

SUCLA2/SUCLG1 Methylmalonyl-CoA racemase deficiency

15 to 250 μmol/mmol crea + 3HIB, 3-OHProp

Methylmalonic semialdehyde dehydrogenase deficiency

High (>250) with same OA as propionic acidemia (not always)

Methylmalonic acidurias: methylmalonyl-CoA mutase deficiency CblA, CblB IF, IGS, TCII, CblC, D, F, J CblX (HCFC1 deficiency) Nutritional B12 deficiency

Mevalonolactone

Mevalonic

Mevalonate kinase deficiency

N-acetylaspartate

Alone

Canavan disease or aspartoacylase deficiency

Orotic

Urea cycle disorders

Other investigations

Acylcarnitines

Acylcarnitines

AACp (met↓, Hcy+)

AACp

UMP synthase deficiency (hereditary orotic aciduria) Phenolic compounds: (Phenyllactic)

Phenylacetic, mandelic, phenylpyruvic, 4-OH-phenylacetic, 4-OH-phenyllactic, 4-OH-phenylpyruvic

Phenylketonuria

AACp

Phenylpyruvic, 4-OH-phenylacetic, 4-OH-phenyllactic, 4-OH-phenylpyruvic, N-AcTyr

Hepatic insufficiency

AACp

(continued)

156

G. Touati et al.

. Table 3.2

3

(continued)

Principal OA

Other OAs

Causes of variation

Pyroglutamic (Oxoproline)

Alone, very high

Glutathione synthetase or oxoprolinase deficiency

± High

Secondary: Amino acid infusion, UCD, paracetamol intoxication

Other investigations

Suberylglycine

See Hexanoylglycine

Succinylacetone

Several peaks, Succinylacetoacetic, 4-OH-phenyllactic, 4-OH-phenylpyruvic, N-AcTyr

Fumarylacetoacetate lyase def (Tyrosinemia type I) Maleylacetoacetate isomerase deficiency (screening, asymptomatic)

AACp: Not specific

Uracil

Pyroglu, Orotate

Urea cycle disorders

AACp

Thymine

Dihydropyrimidine dehydrogenase def

Vanilpyruvic

Transitory in newborns

Vanillactic

Dopa treatment Aromatic amino acids decarboxylase deficiency Pyridoxine-related disorders Xanthurenic acid

Neurotransmitters in CSF

Coeliac disease, chronic dialysis, malabsorption

2HB 2-hydroxy-n-butyric, 2HIB 2-hydroxy-isobutyric, 2KG 2-ketoglutaric, 2KGD 2-ketoglutarate dehydrogenase, 2M3HB 2-metyl3-hydroxy-butyric, 2M3KB 2-methyl-3-ketobutyric, 2MBG 2-methylbutyrylglycine, 2-OH-3CH3Val 2-hydroxy-3-methylvaleric, 2-OHAd 2-hydroxy-adipic, 2OHG 2-hydroxyglutaric, 2-OH-isocaproic 2-hydroxy-isocaproic, 2-oxoAd 2-oxo-adipic, 3HDC 3-hydroxydicarboxylic acids (3-OH-adipic, 3-OH-suberic, 3-OH-sebacic, 3-OH-dodecanedioic, 3-OH-tetradecanedioic), 3HIB 3-hydroxy-isobutyric, 3HIV 3-hydroxy-isovaleric, 3MCG 3-methyl-crotonylglycine, 3MG 3-methylglutaconic, 3OHG 3-hydroxyglutaric, 3-OH-n-But 3-hydroxy-n-butyric, 3-OHProp 3-hydroxy-propionic, 4HB 4-hydroxy-butyric, AAC amino acid chromatography (p plasma, AcAc acetoacetic, AcIle acetylisoleucine, AcLeu acetylleucine, Ad adipic, BCHA branched-chain 2-hydroxy acids, BCKA branched-chain keto acids, CA carbonic anhydrase, Cb cobalamin variant, CSF cerebrospinal fluid, DCA dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, tetradecanedioic), def deficiency, DOOR syndrome deafness, onychodystrophy, osteodystrophy, mental redardation, E3 common protein of 2-ketoacid dehydrogenase complexes, EMA ethylmalonic acid, ETHE1 ethylmalonic encephalopathy, GA glutaric aciduria, Glut glutaric, HG hexanoylglycine, HMG 3-hydroxy-3-methyl-glutaric, IBG isobutyrylglycine, IF intrinsic factor, IGS Imerslund-Gräsbeck syndrome (cubilin/amnionless deficiency), IVG isovalerylglycine, KB ketone bodies (3-hydroxy-n-butyrate + acetoacetate), KC der Krebs cycle derivatives, MAS malate aspartate shuttle, MC methylcitrate, MCAD medium-chain acyl-CoA dehydrogenase, MCT medium chain triglycerides, MDH malate dehydrogenase, MHBD 2-Methyl-3hydroxybutyryl-CoA dehydrogenase, MMA methylmalonic acid, MMSA methylmalonic semialdehyde, MSUD maple syrup urine disease, N-AcTyr N-acetyltyrosine, nBG n-butyrylglycine, PC pyruvate carboxylase, PG propionylglycine, Pyr pyruvate, PyroGlu pyroglutamic (or oxoproline), RC respiratory chain, Redox simultaneous measurement of plasma lactate, pyruvate, 3-OH-butyrate and aceto-acetate, SCAD short-chain acyl-CoA dehydrogenase, Seb sebacic, SG suberylglycine, SLC25A19 transporter (thiamine carrier) (Amisch lethal microcephaly), SSADH succinic semialdehyde dehydrogenase, SUCLA succinyl-CoA synthetase, SUCLG succinylCoA ligase, TC II transcobalamin II, TG tiglylglycine, TPK1 thiamine pyrophosphate kinase 1, u urine, UCD urea cycle deficiency, UMP uridyl-monophosphate, β-AIB β-aminoisobutyric, β-Ala β-alanine, β-ox def fatty acids β-oxidation defects

3

157 Diagnostic Procedures

. Table 3.3 Assessment of intermediary metabolism over the course of the day. The protocol of investigation is adapted to the clinical situation for each patient Parameters in blood

Breakfast Before

Lunch 1 h after

Glucose1

X

X

Acid-base

X

X

Lactate2

X

Pyruvate2

Before

Night

Dinner 1 h after

Before

1 h after

04 h

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Free fatty acids

X

X

X

X

X

X

X

Ketone bodies

X

X

X

X

X

X

X

Ammonia

X

X

X

X

X

X

X

Amino acids

X

Carnitine

X

Acylcarnitines

X

Hormones3

X

X

X

X

X

X

X

Urine 24 h

collection4

Amino acids, organic acids, ketone bodies, urea, creatinine

1Glucose

should be determined immediately. deproteinization (with perchloric acid) at the bedside is the only way of ensuring that the results for calculating redox potential ratios can be accurately interpreted. 3Hormones (insulinemia, cortisol, growth hormone) are useful in the investigation of hypoglycaemia 4Urine samples are collected both overnight and during the day and should be frozen immediately 2Immediate

sampling is undertaken, for example local or general anoxia may influence the results for lactate, lactate/pyruvate ratio and ammonia measurements. Continuous glucose monitoring over a period of 2–3 days during normal activities, using a highly portable subcutaneous probe and recording device, is commonly used in the assessment of individuals with known glycogen storage disease, but is also useful in the investigation of patients who have symptoms at home that may or may not be related to hypoglycaemia [6]. kInterpretation

This investigation may show abnormalities in the metabolic and endocrine profiles throughout the day or specifically only during either the fasting or fed states. The data must be compared to age related reference values [7, 8]. All physiological (food refusal) or pathological conditions (malnutrition, cardiac, renal or liver failure)

that may influence the results need to be taken in account. 1. In glycogenosis (GSD) type I and in disorders of gluconeogenesis, blood glucose and lactate move in opposite directions, with hypoglycaemia and hyperlactataemia more pronounced in the fasted than in the fed state. In GSD type III, VI and IX, glucose and lactate change in parallel, with a moderate increase of glucose and lactate in the post-prandial state. Fasting hypoglycaemia and ketosis with postprandial hyperlactataemia and postprandial hyperglycaemia is usual in glycogen synthase deficiency (7 Chap. 5). Repeated assays are required for glucose and insulin in primary hyperinsulinism, as hyperinsulinemia is frequently erratic and difficult to prove. An insulin level >3 μU/ml with a glucose concentration lower than 2.8 mmol/l should be considered abnormal (7 Chap. 6).

158

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2. In patients with pyruvate dehydrogenase (PDH) deficiency, plasma lactate, in association with pyruvate, may be persistently raised, but usually decreases during fasting (7 Chap. 11). Lactate may be normal, moderately raised or very high in mitochondrial respiratory chain (RC) disorders [7] (7 Chap. 10). It may be difficult to distinguish a moderate elevation of lactate from a falsely raised level due to difficult sampling. However, the presence of a lactaturia with an elevation of alanine in blood is very suggestive of a true hyperlactatemia (the upper threshold for lactate reabsorption is at approx 4  mmol/l). Lactate measurement in cerebrospinal fluid (CSF) may also be of help in patients with neurological disorders. 3. Measurements of ketone bodies are useful for the diagnosis of hyperketotic states, i.e. ketolysis defects or some RC disorders. The simultaneous measurement of blood glucose, free fatty acids and ketone bodies is necessary for the diagnostic and therapeutic evaluation of hypoketotic states, i.e. disorders of fatty acid oxidation (FAO) or ketogenesis (7 Chaps. 12 and 13); data must be interpreted with regard to age and length of fasting (Fasting Test [below] and also 7 Fig. 1.3). See also 7 Sect. 1.4.12. 4. The lactate/pyruvate ratio (L/P), normally around 10:1, and the 3-hydroxy-butyrate/acetoacetate ratio (3OHB/AcAc), normally >1 after an overnight fast and G mutation—implications for diagnosis and management. J Neurol Neurosurg Psychiatr 84(8):936–938 DiMauro S, Hirano M (1993) MERRF. In: Adam MP, Ardinger HH, Pagon RA et  al (eds) GeneReviews((R)). University of Washington, Seattle Thorburn DR, Rahman J, Rahman S (1993) Mitochondrial DNA-Associated Leigh Syndrome and NARP.  In: Adam MP, Ardinger HH, Pagon RA et  al (eds) GeneReviews((R)). University of Washington, Seattle) Pitceathly RD, Murphy SM, Cottenie E et  al (2012) Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology 79(11):1145–1154 Yu-Wai-Man P, Chinnery PF (1993) Leber Hereditary Optic Neuropathy. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews((R)). University of Washington, Seattle Halter JP, Michael W, Schupbach M et  al (2015) Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Brain 138(Pt 10):2847–2858 Murphy R, Turnbull DM, Walker M, Hattersley AT (2008) Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med 25(4):383–399 Stumpf JD, Saneto RP, Copeland WC (2013) Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 5(4):a011395 Whittaker RG, Devine HE, Gorman GS et al (2015) Epilepsy in adults with mitochondrial disease: a cohort study. Ann Neurol 78(6):949–957 Stuppia G, Rizzo F, Riboldi G et al (2015) MFN2-related neuropathies: clinical features, molecular pathogenesis and therapeutic perspectives. J Neurol Sci 356(1–2):7–18 Ognjenovic J, Simonovic M (2018) Human aminoacyl-tRNA synthetases in diseases of the nervous system. RNA Biol 15(4– 5):623–634 Hatefi Y (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54:1015–1069 Smits P, Smeitink J, van den Heuvel L (2010) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010:737385 Mayr JA (2015) Lipid metabolism in mitochondrial membranes. J Inherit Metab Dis 38(1):137–144 Ferdinandusse S, Waterham HR, Heales SJ et al (2013) HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 8:188 Tiranti V, Viscomi C, Hildebrandt T et  al (2009) Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 15(2):200–205 Calvo SE, Clauser KR, Mootha VK (2016) MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res 44(D1):D1251–D1257

10

268

45.

46.

47.

48.

49.

50.

51.

52.

10

53.

54.

55.

56.

57.

58.

59.

60.

S. Rahman and J. A. Mayr

Sacconi S, Salviati L, Nishigaki Y et al (2008) A functionally dominant mitochondrial DNA mutation. Hum Mol Genet 17(12):1814–1820 Bitner-Glindzicz M, Pembrey M, Duncan A et  al (2009) Prevalence of mitochondrial 1555A-->G mutation in European children. N Engl J Med 360(6):640–642 Kim HL, Schuster SC (2013) Poor Man’s 1000 genome project: recent human population expansion confounds the detection of disease alleles in 7,098 complete mitochondrial genomes. Front Genet 4:13 Hikmat O, Naess K, Engvall M et  al (2020) Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis 43(4):726–736 Wedatilake Y, Brown RM, McFarland R et  al (2013) SURF1 deficiency: a multi-centre natural history study. Orphanet J Rare Dis 8:96 Calvo SE, Compton AG, Hershman SG et al (2012) Molecular diagnosis of infantile mitochondrial disease with targeted nextgeneration sequencing. Sci Transl Med 4(118):118ra110 Riley LG, Cowley MJ, Gayevskiy V et al (2020) The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease. Genet Med 22(7):1254–1261 Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W (2014) Lipoic acid biosynthesis defects. J Inherit Metab Dis 37(4): 553–563 Atkuri KR, Cowan TM, Kwan T et al (2009) Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia. Proc Natl Acad Sci U S A 106(10):3941–3945 Harel T, Yoon WH, Garone C et al (2016) Recurrent De Novo and Biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, Results in Distinct Neurological Syndromes. Am J Hum Genet 99(4):831–845 Kanabus M, Shahni R, Saldanha JW et  al (2015) Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation. J Inherit Metab Dis 38(2):211–219 Mandel H, Saita S, Edvardson S et  al (2016) Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria. J Med Genet 53(10):690–696 Ganetzky R, Stojinski C (1993) Mitochondrial short-chain Enoyl-CoA Hydratase 1 deficiency. In: Adam MP, Ardinger HH, Pagon RA et  al (eds) GeneReviews((R)). University of Washington, Seattle Larson AA, Balasubramaniam S, Christodoulou J et al (2019) Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6. Mitochondrion 44:58–64 Rahman S, Clarke CF, Hirano M (2012) 176th ENMC International Workshop: diagnosis and treatment of coenzyme Q(1)(0) deficiency. Neuromuscul Disord 22(1):76–86 Suomalainen A, Elo JM, Pietilainen KH et al (2011) FGF-21 as a biomarker for muscle-manifesting mitochondrial respi-

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269

Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle Michèle Brivet, Pauline Gaignard, and Manuel Schiff Contents 11.1

Pyruvate Carboxylase (PC) Deficiency – 273

11.1.1 11.1.2 11.1.3 11.1.4 11.1.5

Clinical Presentation – 273 Metabolic Derangement – 273 Genetics – 274 Diagnostic Tests – 274 Treatment and Prognosis – 275

11.2

Phosphoenolpyruvate Carboxykinase (PEPCK) Deficiency – 275

11.3

Pyruvate Dehydrogenase Complex (PDHC) Deficiency – 276

11.3.1 11.3.2 11.3.3 11.3.4 11.3.5

Clinical Presentation – 276 Metabolic Derangement – 277 Genetics – 277 Diagnostic Tests – 278 Treatment and Prognosis – 278

11.4

Dihydrolipoamide Dehydrogenase (DLD) Deficiency – 279

11.4.1 11.4.2 11.4.3 11.4.4 11.4.5

Clinical Presentation – 279 Metabolic Derangement – 279 Genetics – 279 Diagnostic Tests – 279 Treatment and Prognosis – 279

11.5

2-Ketoglutarate Dehydrogenase Complex (KDHC) Deficiency – 279

11.5.1 11.5.2 11.5.3 11.5.4 11.5.5

Clinical Presentation – 279 Metabolic Derangement – 280 Genetics – 280 Diagnostic Tests – 280 Treatment and Prognosis – 280

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_11

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11.6

Succinyl-CoA Ligase (SUCL) Deficiency – 280

11.7

Succinate Dehydrogenase (SDH) Deficiency – 280

11.8

Fumarase (FH) Deficiency – 281

11.9

Mitochondrial Aconitase (ACO) deficiency – 281

11.10

Mitochondrial Isocitrate Dehydrogenase (IDH) deficiency – 282

11.11

Malate-Aspartate Shuttle (MAS) defects – 282

11.12

Mitochondrial Citrate Carrier Deficiency – 282

11.13

Mitochondrial Pyruvate Carrier (MPC) deficiency – 282

11.14

NAD(P)HX System Repair Defects – 283

11.15

Protein-Bound Lipoic Acid Defects and Defects in Cofactors – 283 References – 283

271 Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle

Pyruvate Metabolism and the Tricarboxylic Acid Cycle Pyruvate is formed by glycolysis from glucose and other monosaccharides, from lactate and from alanine, a neoglucogenic amino acid (. Fig.  11.1). The final stage of glycolysis converts glyceraldehyde-3phosphate (GAP) into pyruvate generating cytosolic reduced adenine nucleotide (NADH) via GAP dehydrogenase (GAPDH). NADH is shuttled into the mitochondrion for re-oxidation, via the malate-aspartate shuttle (MAS) or via the glycerol-3-phosphate (G3P) shuttle. Two enzymes and two carriers are required for the function of the MAS: the two enzymes, glutamate oxaloacetate transaminase (GOT) and malate dehydrogenase (MDH) are present both in the cytoplasm (GOT1 and MDH1) and in the mitochondrial matrix (GOT2 and MDH2). The two carriers are located in the inner mitochondrial membrane (AGCs and OGC). AGC1 (or Aralar) is highly expressed in central nervous system and in skeletal muscle whereas AGC2 (or citrin) is mainly present in intestine and liver. The calcium sensibility of AGC1 plays a major role in the calcic regulation of substrate supply for the oxidative phosphorylation (OXPHOS) to the mitochondria. In neurons AGC1 is also crucial to supply cytosolic aspartate for N-Acetyl-aspartate formation (7 Chap. 22). In the presence of high levels of glycolytically produced NADH, the cytosolic MDH1 reduces oxaloacetate into malate. Malate is exported from the cytosol into the mitochondrial matrix by OGC in exchange for 2-ketoglutarate. In the mitochondria, the oxidation of malate into oxaloacetate regenerates NADH, which can be used to pass electrons to the respiratory chain for ATP synthesis. Oxaloacetate and glutamate are then transformed into aspartate and 2-ketoglutarate by GOT2. AGC1 exports aspartate from the matrix to the cytosol in exchange for glutamate plus a proton and aspartate is then converted into oxaloacetate by GOT1 achieving the cycle. The G3P shuttle acts in a way similar to the MAS to re-oxidize the cytosolic pool of NADH but it is mainly involved in lipid biosynthesis (7 Chap.  35). Dihydroxyacetone phosphate from glycolysis is reduced to G3P by the cytosolic NAD-dependent G3PDH.  The mitochondrial G3PDH re-oxidizes G3P to DHAP and transfers two electrons from FAD to the electron transport chain. The mitochondrial pyruvate carrier allows the uptake of pyruvate into mitochondria. Pyruvate can be then converted into acetyl-coenzymeA (acetyl-coA) by the pyruvate dehydrogenase complex (PDHC) for further oxidation in the TCA cycle. Pyruvate can also enter the gluconeogenic pathway by sequential conversion into oxaloacetate by pyruvate carboxylase (PC), followed

by conversion to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase (PEPCK). Acetyl-coA is also formed by fatty acid oxidation. One of the primary functions of the TCA cycle is to generate reducing equivalents in the form of NADH and reduced flavin adenine dinucleotide (FADH2), which are utilized to produce energy under the form of ATP in the electron transport chain by the OXPHOS.  The MAS senses cytosolic calcium (Ca2+) with respect to its Ca2+ sensitive component AGC1 and plays an essential role in the control of substrate supply for OXPHOS. Another important role of the TCA cycle comes from the fact that succinyl-CoA is at the crossroad of several pathways (ketolysis, catabolism of isoleucine,valine, threonine, methionine, odd chain fatty acids and cholesterol) and that succinyl-CoA ligase (SUCL) can yield directly GTP and ATP in the absence of oxygen (a mechanism known as substrate level phosphorylation) and participates to mtDNA maintenance.

kIntroduction

Owing to the role of pyruvate and the tricarboxylic acid (TCA) cycle in energy metabolism, as well as in gluconeogenesis, lipogenesis and amino acid synthesis, defects in pyruvate metabolism and in the TCA cycle almost invariably affect the central nervous system. The severity and the different clinical phenotypes vary widely among patients and are not always specific, the range of manifestations extending from overwhelming neonatal lactic acidosis with early death to relatively normal adult life and variable effects on systemic functions. Similar clinical manifestations may be caused by other defects of energy metabolism, especially defects of the mitochondrial respiratory chain (7 Chap. 10). Diagnosis relies primarily on biochemical analysis of accumulated metabolites in body fluids, DNA analysis and, in some instances, confirmation by definitive enzymatic assays in cells or tissues. Prenatal diagnosis is now achieved preferentially by DNA analysis. Pyruvate carboxylase (PC) deficiency constitutes a defect both in the TCA cycle and in gluconeogenesis, but generally presents with severe neurological dysfunction and lactic acidosis rather than with fasting hypoglycaemia. Deficiency of phosphoenolcarboxykinase (PEPCK) is limited to its cytosolic form and affects gluconeogenesis. Deficiency of pyruvate dehydrogenase complex (PDHC) impedes glucose oxidation and aerobic energy production, and ingestion of carbohydrate aggravates lactic acidosis. The defects of mitochondrial pyruvate carrier have the same presentation as PDHC deficiencies. Treatment of disorders of pyruvate metabolism comprises avoidance of fasting (PC

11

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CYTOSOL

ACLY

Serine Glucose

Fructose-1,6-bisphosphate Acetyl-coA Dihydroxyacetone phosphate

Glyceraldehyde-3-phosphate GAPDH

NAD NADH

Malate

NADH

NAD

Fatty Acids cPEPCK

cG3PDH NAD

NADH

Glycerol-3-phosphate

P-enolpyruvate

Oxaloacetate MDH1 GOT1

NADH NAD

2-ketoglutarate Glutamate Aspartate

Lactate Alanine

Pyruvate

Fatty acids

LDH OGC

AGCs

mG3PDH

MPC

IMM

FADH2 FAD

Pyruvate P-enolpyruvate CO2

mPEPCK

11

FAD

PDHC CO2

NAD

FADH2 NAD

NADH

2-ketoglutarate Glutamate Aspartate

Acetyl-CoA

PC

CIC

NADH

GOT2 Oxaloacetate

Citrate CS

NADH

ACO

MDH2

NAD

Aconitate

Malate FH

ACO

Fumarate FADH2

Isocitrate NAD

SDH

IDH

FAD Ketolysis

NADH

2-ketoglutarate

Succinate

Acetoacetyl-CoA

SCOT

ATP (GTP)

SUCL

KDHC

ADP (GDP) Pi

NADH

Succinyl-CoA

Aceto acetate

NAD

Ketolysis

Glutamate

CO2

Methylmalonyl-CoA Propionyl-CoA

MITOCHONDRION

Met, thr, ile, val, odd-chain fatty acids, cholesterol

. Fig. 11.1 Overview of glucose, pyruvate/lactate, fatty acid and amino acid oxidation by the tricarboxylic acid cycle. ACLY ATP, citrate lyase; ACO, aconitase; AGCs, aspartate glutamate carriers 1 et 2; ATP, adenosine triphosphate; CIC, citrate carrier; CS, citrate synthase; FH, fumarase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GOT1, GOT2, glutamate oxaloacetate transaminases 1 and 2; cG3PDH, mG3PDH, cytosolic and mitochondrial glycerol-3-phosphate dehydrogenases; GTP, guanosine triphosphate;

IDH, isocitrate dehydrogenase; IMM, inner mitochondrial membrane; KDHC, 2-ketoglutarate dehydrogenase complex; LDH, lactate dehydrogenase; MDH1, MDH2, malate dehydrogenases 1 and 2; MPC, mitochondrial pyruvate carrier; OGC, oxoglutarate carrier; PDHC, pyruvate dehydrogenase complex; PC, pyruvate carboxylase; cPEPCK, mPEPCK, cytosolic and mitochondrial phosphoenolpyruvate carboxykinases; SCOT, succinyl-CoA 3-oxoacid CoA transferase; SDH, succinate dehydrogenase; SUCL, succinyl-CoA ligase

273 Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle

deficiency) or minimising dietary carbohydrate intake (PDHC deficiency) and enhancing anaplerosis (restoration of pools of intermediate metabolites). Dihydrolipoamide dehydrogenase (E3) deficiency affects PDHC and also the 2-ketoglutarate dehydrogenase complex (KDHC) and the branched-chain 2-ketoacid dehydrogenase (BCKD) complex (7 Chap. 18), with biochemical manifestations of all three disorders. The deficiencies of the TCA cycle enzymes interrupt the cycle but do not always result in accumulation of the corresponding substrates. Succinyl-CoA ligase deficiency causes a mild methylmalonic accumulation. Succinate dehydrogenase deficiency represents a unique disorder affecting both the TCA cycle and the respiratory chain. The defects of the malate-aspartate shuttle (MAS) impede the import of reduced nicotinamide adenine dinucleotide (NADH) from the cytosol to the mitochondrion and the subsequent pyruvate oxidation. NAXE and NAXD deficiencies disrupt the cellular NAD(P)HX repair system and cause lethal neurometabolic disorders of early childhood.

11.1

Pyruvate Carboxylase (PC) Deficiency

11.1.1Clinical Presentation

PC deficiency is an autosomal recessive disorder with an incidence of around 1 in 250,000. Several dozen patients have been described in detail, allowing the definition of three overlapping phenotypes that probably constitute a continuum from the most severe (type B) to the less severe form (type C). For a review see [1]. 1. Patients with the French phenotype (type B) become acutely ill 3–48 h after birth with hypothermia, hypotonia, lethargy and vomiting [1, 2, 3]. These children exhibit a severe neurological neonatal deterioration with initially a preserved level of consciousness but then rapid deterioration with rigidity, hypokinesia and tremor (resembling infantile parkinsonism) and abnormal ocular movements [2]. Hepatomegaly, seizures and failure to thrive may occur. Most die in the neonatal period in the setting of severe lactic acidosis with intractable tubulopathy and multiorgan (liver) failure. Some survive, but they remain unresponsive and severely hypotonic and finally succumb from respiratory infection before the age of 5 months. 2. Patients with the North American phenotype (type A) become severely ill between 2 and 5  months of age. They develop progressive hypotonia and are unable to smile. Frequent episodes of acute vomiting, dehydration, tachypnoea, facial pallor, cold cyanotic extremities and lactic acidosis, characteristically precipitated by metabolic or infectious stress, occur. Clinical examination reveals pyramidal tract signs, ataxia and nystagmus. All patients are severely men-

tally retarded and most of them have seizures. Hepatomegaly and renal dysfunction (tubular acidosis) may also be present. Neuroradiological findings (also found in type B) include subdural effusions, severe antenatal ischaemia-like brain lesions and periventricular haemorrhagic cysts, followed by progressive cerebral atrophy and delayed myelination. Leigh syndrome has also been reported but its frequency remains uncertain. The course of the disease is generally progressive, with death in infancy. 3. The Type C phenotype is more benign and has only been reported in a few patients without clear ethnic predilection [1]. The clinical course is dominated by the occurrence of acute episodes of lactic acidosis and ketoacidosis, usually responding rapidly to hydration and bicarbonate therapy. Despite the important enzyme deficiency, the patients have a near-normal cognitive and neuromotor development. However, dystonia, episodic ataxia, dysarthria, transitory hemiparesis, seizures and subcortical leukodystrophy have been described in some cases. Prenatal features have been reported on a limited number of cases. Ultrasound examination and MRI had revealed frontal horn impairment associated with subependymal and paraventricular cysts in few cases which could be suggestive of a PC deficiency in unknown families [4].

11.1.2Metabolic Derangement

PC is a biotinylated mitochondrial matrix enzyme that converts pyruvate and CO2 to oxaloacetate. It plays an important role in gluconeogenesis, anaplerosis and lipogenesis. For gluconeogenesis, pyruvate must first be carboxylated into oxaloacetate, because the last step of glycolysis, conversion of phosphoenolpyruvate to pyruvate is irreversible. Oxaloacetate, which cannot diffuse freely out of the mitochondrion, is translocated into the cytoplasm via the MAS.  Once in the cytoplasm, oxaloacetate is converted into phosphoenolpyruvate by PEPCK, which catalyses the first committed step of gluconeogenesis. The anaplerotic role of PC, i.e. the generation of TCA cycle intermediates from oxaloacetate, is even more important. In severe PC deficiency, the lack of TCA cycle intermediates lowers reducing equivalents in the mitochondrial matrix. This drives the redox equilibrium between 3-OH-butyrate and acetoacetate in the direction of acetoacetate thereby lowering the 3-OHbutyrate/acetoacetate ratio. Aspartate, formed in the mitochondrial matrix from oxaloacetate by transamination, also decreases. As a consequence, the translocation of reducing equivalents between cytoplasm and mitochondrial matrix by the MAS is impaired. This drives

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the cytoplasmic redox equilibrium between lactate and pyruvate in the direction of lactate, and the lactate/pyruvate (L/P) ratio increases. Reduced TCA cycle activity also plays a role in the increase of lactate and pyruvate. Since aspartate is required for the urea cycle, plasma ammonia and citrulline can increase. The low 2-ketoglutarate production explains the low plasma level of glutamate. The energy deprivation induced by PC deficiency has been postulated to impair astrocytic buffering capacity against excitotoxic insults and to compromise microvascular morphogenesis and autoregulation, leading to white matter degeneration [1]. The key-role of PC in lipogenesis derives from the condensation of oxaloacetate with intramitochondrially produced acetyl-CoA into citrate. Deficient lipogenesis explains the widespread demyelination of the cerebral and cerebellar white matter and symmetrical periventricular cavities around the frontal and temporal horns of the lateral ventricles, reported in the few detailed neuropathological descriptions of PC deficiency. PC is present in oligodendrocytes, where it plays an anaplerotic role [5]. PC deficiency in the oligodendrocytes should result in insufficient fatty acid synthesis and myelin malformation, whereas the impairment of oxidative metabolism in microglial cells is associated with an inflammatory response possibly contributing to neurodegeneration [6]. In a patient with the type B phenotype, muscle biopsy disclosed nemaline rods that probably occurred due to defective energy metabolism. Mitochondrial accumulation in type 1 fibers raises the possibility that the thin filaments may become the target structures of mitochondrial dysfunction [7]. PC requires biotin as a cofactor. Secondary PC deficiency is thus also observed in biotin-responsive multiple carboxylase (7 Chap. 27) and in carbonic anhydrase VA deficiency (7 Chap. 19).

11.1.3Genetics

PC deficiency is an autosomal recessive disorder. PC is a tetramer formed by 4 identical subunits organized in two conformational states over the course of its two steps enzymatic reaction. In the fatal form, the presence of at least one truncating mutation in the PC gene tends to lead to type B presentation while biallelic missense mutations tend to lead to type A, with some exceptions. Structure-function studies showed that missense mutations disturbing the ligands fixation or the balance between the two conformational states seem to be associated to type A presentation. Missense mutations associated to type C

presentation destabilize the monomers but do not lead to a misbalance between the conformers [8]. The p. Ala610Thr mutation, frequent in Indo-American patients, is associated with type A. Mosaicism was reported in a few cases and found to be correlated with prolonged patient survival [9].

11.1.4Diagnostic Tests

The most severely affected patients typically exhibit an elevated L/P ratio, low hydroxybutyrate/acetoacetate (H/A) ratio with paradoxical postprandial ketosis, hypercitrullinemia and hyperammonemia, with low glutamine, parameters that often remain unaltered in types A and C. Hence, the possibility of PC deficiency should be considered in any child presenting with lactic acidosis and neurological abnormalities, especially if associated with hypoglycaemia, hyperammonaemia or ketosis. In neonates, a high L/P ratio associated with a low H/A ratio is nearly pathognomonic [2]. Discovery of cystic periventricular leukomalacia at birth associated with lactic acidosis is also highly suggestive. Typically, blood lactate increases in the fasting state and decreases after ingestion of carbohydrate. In patients with type B, blood lactate concentrations reach 10–20  mM (normal T p.(Arg147Trp). In northern Europe, 6% of the general population have one of these variants on both alleles [18]. SCAD deficiency can be associated with these variants or with rare mutations. LCHAD & MTP deficiency. Most Caucasian patients are homozygous for the c.1528G>C p.(Glu510Gln) mutation in the LCHAD domain of the α-subunit; this gives rise to isolated LCHAD deficiency. Patients with complete or partial deficiencies of all 3 enzyme activities are said to have generalised MTP deficiency. This can result from mutations affecting either subunit [13] and includes most compound heterozygotes for c.1528G>C and a second α-subunit mutation.

The relationship between genotype and phenotype varies in different FAODs. In CPT II and VLCAD deficiencies, homozygous nonsense mutations are generally associated with severe early onset disease, whereas late onset rhabdomyolysis is associated with conservative missense mutations (such as the c.439C>T) CPT2 mutation and the c.848T>C p.(Val283Ala) ACADVL mutation) [32, 33]. The latter is the commonest mutation in Caucasians with VLCAD deficiency and has only been found in mildly affected or asymptomatic patients. For patients with rare mutations, it is easier to predict the clinical course from the residual enzyme activity or fatty acid oxidation flux. The genotype correlates less closely with phenotype in MCAD and carnitine transporter deficiencies. MCAD deficient patients with the same genotype may die or remain asymptomatic, depending on their exposure to fasting stress. Some ACADM mutations are, however, less likely to cause clinical problems. In particular, the c.199T>C p.(Tyr42His) mutation is associated with significant residual activity and is relatively benign: it accounts for >6% mutant alleles in most screened populations but there have only been a few reports of clinical problems [34].

tines. If the results suggest a specific diagnosis, this is confirmed by enzyme assays or mutation analysis. If the metabolite results are non-specifically abnormal or if they are normal despite strong clinical suspicion, it may be helpful to measure acylcarnitine production in vitro or flux through the pathway or to sequence a panel of FAOD genes (or the whole exome). 12.1.4.1Abnormal Metabolites z Acylcarnitines

In most FAODs, acyl-CoA intermediates accumulate proximal to the defect and are transesterified to carnitine. The acylcarnitine abnormalities are best analysed by tandem mass spectrometry (TMS). The usual samples are plasma or dried blood spots on filter paper. . Table 12.2 lists the typical abnormalities in different FAODs. The diagnostic specificity can be increased by measuring the ratios of different acylcarnitines. For example, C8 acylcarnitine is raised in patients with MCAD and MAD deficiencies and in MCAD deficiency carriers at times of stress; the presence of a raised C8/C10 acylcarnitine ratio increases the specificity for MCAD deficiency, which is particularly useful in newborn screening programs. Severe CPT II and CACT deficiencies, however, cause identical acylcarnitine abnormalities, as do LCHAD and MTP deficiencies; distinction requires genetic or enzyme analysis. The clinical circumstances have a major effect on the acylcarnitine profile. Abnormalities are usually more marked in stressed patients but, if the plasma free carnitine concentration is very low, abnormal acylcarnitines may be hard to detect. Abnormalities may be reduced or masked completely by intravenous glucose or dietary treatment, such as the use of medium-chain triglycerides (MCT) in long-chain FAODs. Interpretation is especially difficult for samples obtained terminally or postmortem: these often show multiple raised acylcarnitine species, resembling MAD deficiency. Acylcarnitine analysis can be completely normal in patients with high residual enzyme activity, such as mild VLCAD or MTP deficiencies; abnormalities are sometimes detectable after overnight fasting, exercise or loading with carnitine. Myopathic CPT II deficiency is particularly hard to diagnose; the sum of the C16:0 and C18:1 acylcarnitine concentrations may be raised relative to acetylcarnitine but this is not reliable. There are no abnormal acylcarnitine species in patients with deficiencies of the carnitine transporter or CPT I but free carnitine concentrations are usually abnormal.

12.1.4Diagnostic Tests z

The investigation of a suspected FAOD starts by looking for abnormal metabolites, particularly acylcarni-

Free and Total Carnitine Concentrations

Plasma free and total carnitine concentrations are best measured by an enzymatic radioisotope tech-

295 Disorders of Mitochondrial Fatty Acid Oxidation & Riboflavin Metabolism

. Table 12.2

Abnormal metabolites seen in fatty acid oxidation disorders Urinary acylglycines

Urinary organic acidsa

Deficiency

Plasma acylcarnitines

CT

Low free carnitine

±(DCA)

CPT IA

Virtually absent long- & medium-chain acylcarnitines, high free carnitine

(Variable DCA)

CACT and CPT II severe

C18:1, C18:2, C16, C16-DC, C18:2-DC, C18:1-DC

Variable DCA

CPT II mild

↑(C16 + C18:1)/C2b

VLCAD

C16:1, C14:2, C14:1, C18:1b

MCAD

C10:1, C8, C6

Hexanoyl-, suberyl-, phenylpropionyl-

DCA [suberic > adipic], (KB)

SCAD

C4

Butyryl-

Ethylmalonic, methylsuccinic, KB

LCHAD / MTP

C18:1-OH, C18-OH, C16:1-OH, C16-OHb

3-Hydroxydicarboxylic acids, DCA

HADH

±C4-OH

±(3-hydroxybutyric, 3-hydroxyglutaric)

NADK2

±C10:2

±Lactic, ethylmalonic, glutaric, fumaric

MAD: severe

C4, C5, C5-DC, C6, C8, C10, C12, C14:1, C16, C18:1

Isobutyryl-, isovaleryl-, hexanoyl-, suberyl-,

Ethylmalonic, glutaric, 2-hydroxyglutaric, DCA

MAD: mild

C6, C8, C10, C12

Isobutyryl-, isovaleryl-, hexanoyl-, suberyl-

Ethylmalonic, adipic, DCA, KB

Variable DCA

aThese

are typical organic acids during acute illness; those in parentheses are mildly elevated. Organic acids are often normal during anabolism. DCA, C6-C10 saturated straight-chain dicarboxylic acids; Variable DCA, C6-C12 saturated and unsaturated straight-chain dicarboxylic acids bAcylcarnitines can be normal during anabolism (e.g. mild VLCAD and MTP deficiencies) or even during catabolism (e.g. mild CPT II deficiency) ‘For VLCAD & MCAD deficiencies, the main abnormal acylcarnitines are in bold’ KB ketone bodies, other abbreviations in . Fig. 12.1

nique. Carnitine can be formed from acetyl- and acylcarnitines during derivatisation for TMS. Nevertheless, with careful sample preparation, TMS can provide a reasonable estimate of the plasma free carnitine concentration. Measurement in dried blood spots is less reliable. Plasma free and total carnitine concentrations are usually A p.(Arg41Gln), [7]. The genotype correlates poorly with phenotype, which depends on exposure mental stress [7].

z

Prenatal Diagnosis

Molecular techniques are used in families where the mutations are known. For HMG-CoA lyase deficiency, enzyme assays can be performed on chorionic villi or cultured amniocytes.

13.1.4Diagnostic Tests

13.1.5Treatment and Prognosis

A general approach to hypoketotic hypoglycaemia is given in 7 Chap. 1 (7 Fig. 1.2 and 1.4). Samples collected during an episode of hypoglycaemia can be very valuable in disorders of KB metabolism. If the plasma free fatty acid concentration is raised with an inappropriately small rise in total KB (FFA/ total KB >2.5) it implies a defect of ketogenesis or fatty acid oxidation [2]. These can be distinguished by analysing metabolites or measuring fatty acid oxidation flux in vitro.

Patients should avoid fasting and maintain a high carbohydrate intake during any metabolic stress, such as infections. An intravenous infusion of glucose is required if drinks containing glucose or glucose polymers are refused or vomited. Intravenous sodium bicarbonate may be needed if there is severe acidosis in HMGCoA lyase deficiency. Sodium DL-3-hydroxybutyrate has been given to an adolescent with HMG-CoA lyase deficiency during acute decompensation and appeared to contribute to his recovery [9]. A moderate protein or leucine restriction is recommended in HMG-CoA lyase deficiency because of its role in leucine catabolism [2, 7]. There is less agreement about the need for a low fat diet [7]. Indeed, some patients have developed normally without any dietary restriction [6]. Carnitine supplements are usually given in HMG-CoA lyase deficiency, though their value is unproven. HMG-CoA synthase deficiency has a good prognosis after the presenting illness: most patients have no further episodes of encephalopathy. Neurological problems are commoner in HMG-CoA lyase deficiency, particularly in neonatal-onset cases. These patients are also more likely to have recurrent episodes of encephalopathy as older children or adults. Pregnancy carries a high risk in HMG-CoA lyase deficiency: the eight reported pregnancies included one termination, one intrauterine death and one maternal death during decompensation at 9 weeks gestation [10]. Pregnant women with either defect should be given intravenous glucose during labour and during illnesses with vomiting.

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c.109G>A respectively the clinical to environ-

HMG-CoA Synthase Deficiency

During decompensation, urine contains saturated, unsaturated and 3-hydroxy-dicarboxylic acids, 5-hydroxyhexanoic acid and other metabolites, of which 4-hydroxy-6-methyl2-pyrone is the most specific [4]. Blood acylcarnitine analysis is normal when patients are well but acetylcarnitine may be raised during illness. The diagnosis is confirmed by mutation analysis. Enzyme assays require a liver biopsy and are complicated by a cytoplasmic isoenzyme, involved in cholesterol synthesis. z

HMG-CoA Lyase Deficiency

Even when healthy, patients excrete increased quantities of 3-hydroxy-3-methylglutaric, 3-hydroxyisovaleric, 3-methylglutaconic and 3-methylglutaric acids (. Fig.  13.1); 3-methylcrotonylglycine may also be present. Blood acylcarnitine analysis shows raised 3-hydroxyisovalerylcarnitine concentrations. The diagnosis is confirmed by mutation analysis or measuring HMG-CoA lyase activity in leukocytes or cultured fibroblasts. HMG-CoA lyase deficiency is included in the newborn screening programs for several countries, including the USA. Cases need to be distinguished from other causes of increased C5-hydroxyacylcarnitines (3-hydroxyisovalerylcarnitine or 2-methyl-3-hydroxybutyrylcarnitine, which have the same mass): 3-methylcrotonyl-CoA carboxylase deficiency (in the infant or mother), T2 deficiency, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, multiple carboxylase deficiency (2 disorders) and various disorders associated with 3-methylglutaconic aciduria (7 Chaps. 10, 18 and 35). Confirmatory tests include urine organic acid analysis (for the infant and mother), plasma acylcarnitine analysis and serum biotinidase assay.

13.2

Defects of Ketone Body Utilisation or Transport

Defects of ketone body utilisation or transport include succinyl-CoA:3-oxoacid CoA transferase (SCOT), mitochondrial acetoacetyl-CoA thiolase (T2) and monocarboxylate transporter 1 (MCT1) deficiencies. 13.2.1Clinical Presentation

Typically, patients present with episodes of severe ketoacidosis in early childhood and are healthy between

307 Disorders of Ketogenesis and Ketolysis

episodes, with a normal blood pH. Decompensation is generally triggered by fasting or an infection with poor feeding and vomiting. Tachypnoea, due to acidosis, is accompanied by dehydration, caused by vomiting and an osmotic diuresis; consciousness may be reduced if the acidosis is severe and a few patients have seizures. Blood glucose, lactate and ammonia concentrations are normal in most cases but there may be hypo- or hyperglycaemia or mild hyperammonaemia [11, 12]. Approaching 50% patients with SCOT deficiency become acidotic within a few days of birth, the others presenting within the first two years [2]. In T2 deficiency, neonatal onset is very rare and the initial episode of acidosis is usually between 6 and 24 months of age; a few patients are never acidotic [10]. Only six patients with homozygous MCT1 deficiency have been reported [13– 15]. Their acute presentations were indistinguishable from ketolysis defects and occurred by two years of age. Most patients with SCOT or T2 deficiencies make a full recovery following episodes of acidosis but a few die or are left with mental retardation, ataxia or dystonia [11, 12]. Neuroimaging shows abnormalities in the basal ganglia in a number of patients with T2 deficiency. Some of these patients have presented with hypotonia, dystonia or chorea without any preceding episodes of acidosis [11, 16]. All the patients with homozygous MCT1 deficiency had developmental delay and several had epilepsy; cranial MRI showed abnormal signal involving the subcortical U-fibres and in the basal ganglia and thalami; two siblings had agenesis of the corpus callosum [15].

13.2.2Metabolic Derangement

KB utilisation occurs in extrahepatic mitochondria, starting with the transfer of coenzyme A from succinylCoA to acetoacetate, catalysed by SCOT.  This forms acetoacetyl-CoA, which is converted to acetyl-CoA by T2. The second reaction can also be catalysed to some extent by medium-chain 3-ketoacyl-CoA thiolase (T1), which may explain why T2 deficient patients do not have permanent ketosis (unlike those with severe SCOT deficiency). SCOT is not expressed in liver and has no role other than ketolysis. In contrast, T2 is expressed in liver, where it participates in ketogenesis. Patients with T2 deficiency present with ketoacidosis, suggesting that T1 is a more effective substitute in ketogenesis than in ketolysis. T2 also cleaves 2-methylacetoacetyl-CoA in the isoleucine degradation pathway and T2 deficiency causes the accumulation of isoleucine-derived acyl-CoA esters: these may be responsible for the basal ganglia lesions found in some T2 deficient patients [16].

The episodes of ketoacidosis in patients with MCT1 deficiency indicate the need for these transporters to facilitate the rapid entry of KB into target cells at times of stress. MCT1 and other monocarboxylate transporters are also important for lactate transport, including lactate shuttling from glia to neurons. The learning difficulties in MCT1 deficient patients may reflect this rather than the episodes of ketoacidosis.

13.2.3Genetics

SCOT, T2 and MCT1 deficiencies are inherited as autosomal recessive traits with biallelic mutations in the OXCT1, ACAT1 and SLC16A1 genes, respectively. Single heterozygous mutations in OXCT1 or SLC16A1 have also been found in a number of patients investigated for ketoacidosis, suggesting that carriers have an increased risk of acidosis if exposed to sufficient stress [13, 17, 18]. The episodes of ketoacidosis tend to be less severe in SLC16A1 heterozygotes than in homozygotes and start later in childhood; cyclical vomiting is initially suspected in some heterozygotes. Heterozygous SLC16A1 mutations have also been associated with muscle injury [19] and with exerciseinduced hyperinsulinism [20]. The latter is caused by promoter mutations that prevent the normal silencing of MCT1 expression in pancreatic β-cells (7 Chap. 6). Apart from this, the genotype shows little correlation with the clinical phenotype in these disorders, though it is related to the severity of the biochemical abnormalities (see below). The frequency of ketoacidosis depends primarily on exposure to environmental stress [2, 11].

13.2.4Diagnostic Tests

A general approach to ketoacidotic states is presented in 7 Chap. 1 (7 Fig. 1.3). z

SCOT & MCT1 Deficiencies

These conditions need to be considered in a number of patients because ketoacidosis is relatively common. A plasma free fatty acid: total KB ratio   T) is common among patients with African ancestry. Though genotype-phenotype matching is complicated by allelic heterogeneity, it appears that GALT genotypes associated with even trace residual GALT activity, including S135L and others, are associated with milder clinical outcomes [22, 23]. Many alleles of GALT associated with substantial residual activity have been reported. The Duarte variant galactosemia (D2) allele is the best known; it includes an N314D (c.940A > G) polymorphism that exists, in cis, with 3 intronic changes and a small deletion in the promoter region of the gene (c.-119_-116delGTCA) that is believed to be causal [24]. Patients who inherit a Duarte allele in trans with a ‘classic’ GALT mutation, such as Q188R, have what is called Duarte variant galactosemia (D/G). Of note, the D2 allele, and therefore D/G galactosemia, are found predominantly in individuals of European ancestry [25]. D/G is associated with approximately 25% residual GALT activity and does not require diet therapy [12–14]. D/G is identified by newborn screening in some populations at up to 10 times the prevalence of classic galactosaemia [24].

14.1.4Diagnostic Tests

Newborn screening (NBS) for galactosaemia is undertaken in many countries by measurement of GALT enzyme activity, with or without blood total galactose measurement, using dried blood spots usually collected within 48  hours after birth [19]. Because the GALT activity assay (Beutler test) is coupled, infants with G6PDH deficiency may show apparently diminished activity. Some programmes quantify Gal-1P in addition to total galactose. Depending on the screening approach and cut-offs used, false positive and even some false negative results can occur [2]. If the NBS turn-around

319 Disorders of Galactose Metabolism

time is long, infants with classic galactosemia may already be ill before the NBS result is received. The diagnosis of GALT deficiency galactosaemia is confirmed or refuted by a quantitative assay of GALT activity in freshly drawn erythrocytes. The use of an LC-MS/MS-based erythrocyte GALT enzyme assay may better inform the clinician as to whether the patient has classic galactosemia vs. clinical variant galactosemia [26]. All assays of erythrocyte GALT activity can give a false-negative result if the patient received a blood transfusion within 2–3 months prior to the blood draw. In this situation, more informative tests will include assay of urinary galactitol, erythrocyte Gal-1P, or mutation analysis in GALT. Cultured skin fibroblasts can also be used for study. If taken post-mortem, liver or kidney cortex may provide diagnostic enzyme information, but these specimens must be adequately collected and stored. Infants with D/G or another partial GALT deficiency are detected at high rates by some but not all NBS programs [19]. Follow-up assessment of an infant with suspected partial GALT deficiency involves quantitation of urine galactitol and/or erythrocyte Gal-1P, repeat quantitative investigation of GALT enzyme activity, and GALT sequencing, if available. Galactose tolerance tests present a potential risk to the child should they have profound GALT deficiency, or some other significant cause of milk intolerance, and should not be used to evaluate the need for treatment of partial GALT deficiency. z

Prenatal Diagnosis

GALT deficiency is inherited as an autosomal recessive trait. If familial GALT mutations are known, informative prenatal diagnosis can be performed by genotyping DNA from a chorionic villous (CVS) biopsy or amniotic fluid cells. Full GALT sequencing may be informative even in the absence of known familial mutations. Historically, prenatal testing has also been achieved by measuring GALT activity in primary or cultured CVS cells, or in cultured amniotic fluid cells, or by measuring galactitol in amniotic fluid; however, genetic testing of a fetal DNA source may be preferable [2].

14.1.5Treatment and Prognosis z

Prenatal and Newborn Considerations

Due to family history some infants are diagnosed with classic galactosemia prenatally. Though some of these mothers have been advised to restrict their own dietary lactose or galactose intake during pregnancy, this does not seem to prevent the accumulation of Gal-1P and galactitol in the fetus or amniotic fluid, presumably due to endogenous synthesis. Furthermore, the outcomes for infants whose mothers restricted milk intake in pregnancy were no better than for those whose mothers did not [27].

Newborns suspected of classic galactosemia must be treated immediately by exclusion of all lactose from the diet, including both breast milk and milk-based formula. Most newborns suspected of having classic galactosemia are switched to a soya-based formula with no apparent adverse effects [28], although an elemental formula may be used if soya presents a problem [29]. In the presence of significant liver disease, a medium-chain triglyceride containing casein hydrolysate preparation may be preferable. Infants who are seriously ill at diagnosis may require considerable supportive care, including the management of a coagulopathy and septicaemia. When a lactose-free diet is instituted early enough, signs disappear promptly, jaundice resolves within days, cataracts may clear, liver and kidney functions return to normal, and liver cirrhosis may be prevented [2]. A guideline for the treatment of galactosemia was published in 2017 [11]. z

Infants and Young Children

Dietary restriction of high lactose or galactose foods becomes more complex as the infant with classic galactosemia transitions to solid foods; calcium (+ vitamin D) supplementation may also become advisable. Parents may require assistance in learning to scrutinize food labels to look for hidden sources of galactose or lactose from milk powder or solids, hydrolysed whey (a sweetener), drugs in tablet form, toothpaste, baking additives, fillers, sausages, etc. Further, not all dairy products are problematic; for example, some hard cheeses contain very little, if any, galactose because milk sugars were cleared by the fermenting microorganisms [30]. Galactose is present at high levels in dairy milk but also at low levels in a great number of vegetables, fruits, legumes (beans, peas, lentils etc.) and other foods [30]. When compared with endogenous production, however, it is unlikely that absorption of galactose from these cryptic dietary sources has a significant impact on the expanded whole-body pool. Further, an observational study of 231 adults and children with classic galactosemia, some of whom consumed diets that restricted both dairy and many non-dairy sources of galactose, and others whose diets restricted only dairy, showed no significant association between markers of long-term outcome and rigor of non-dairy galactose restriction in childhood or later life [31]. z

Older Children and Adults

Current recommendations are that patients with classic galactosemia should continue dietary restriction of galactose for life; however, it remains unclear how rigorous that restriction should be for older children and adults. Anecdotal reports suggest that children and/ or adults may experience elevated red blood cell Gal1P and develop cataracts after ingesting high levels of

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lactose ([32], G.T.  Berry, unpublished observations). However, at least two cases of classic galactosaemia have been reported in which stopping dietary restriction of galactose after early childhood resulted in outcomes that were no worse than those of patients who continued treatment [2]. Several small studies have also demonstrated that defined quantities of galactose appear to be well tolerated by children and adults with classic galactosaemia [33, 34], although individual differences among patients may render some more sensitive to exposure than others. Finally, the failure to understand long-term disease mechanisms, the lack of true disease-related biomarkers, and the marked variability in clinical outcomes among patients has led to a continued diversity in degrees of dietary galactose restriction, especially among older children and adults [31, 35]. z

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Biochemical Monitoring

Erythrocyte Gal-1P concentration is the most common biochemical marker used to monitor treatment. The level can be very high at diagnosis if the infant is drinking dairy milk, and then falls gradually over weeks to months after the initiation of dietary galactose restriction. Even with good dietary compliance, the Gal-1P concentration may plateau above normal. The usefulness of monitoring Gal-1P is open to question, however, as most, but not all, studies addressing the question have shown no correlation between erythrocyte Gal-1P and long-term outcome in patients with classic galactosemia [1, 2]. Other metabolites, including erythrocyte or plasma galactose, erythrocyte, plasma, or urine galactitol, and erythrocyte or urine galactonate, are also consistently increased in patients and have been suggested as alternative or additional markers [2]. Untargeted metabolomic studies have also revealed numerous other perturbed pathways and markers in treated patients as compared with controls [36]. Abnormal glycans may also be informative, at least in infants [2]. However, there are currently no data available to demonstrate the superiority of any of these other markers over Gal-1-P for biochemical monitoring. z

Long-Term Outcome and Complications

Despite the rapid clinical response to lactose exclusion in newborns with classic galactosaemia, long-term complications are common, and appear to be largely independent of the severity of initial illness or the strictness of dietary compliance [1, 2, 20, 27, 31]. Decreased bone density is common and early identification by DXA scan may allow intervention to help reduce the risk of osteoporosis later in life [2, 37]. Mild growth retardation, delayed speech development, verbal dyspraxia, difficulties in spatial orientation and visual perception, and

intellectual deficits have been variably described as complications of treated galactosaemia [1, 2, 38]. Reduced leptin levels [39] tremor, ataxia, dystonia and choreic movements [20, 40, 41], increased frequency of gastrointestinal problems [42], and introverted personality and/or anxiety/depression [20, 41] have also been reported. The quality of life in treated patients has been unfavourable compared with that of patients with PKU [43]. Patients with classic galactosemia may require intense professional help and/or oversight in many spheres [44, 45]. By mid-childhood or later, patients vary markedly in terms of the number of long-term sequelae present and the severity of those sequelae. Contrary to some early reports, IQ is no longer thought to decrease with age [1, 2]. A minority of patients also develop severe neurological disease with cerebellar dysfunction, and brain MRI and FDG-PET scans may reveal abnormalities, though results have been highly variable [20, 46]. z

Fertility and Pregnancy

Hypergonadotropic hypogonadism or primary ovarian insufficiency (POI) occurs in almost all women with classic galactosaemia [22, 47], but not in Duarte variant galactosemia [48] nor has it been reported in females homozygous for the S135L mutation [1, 2]. Galactosemiaassociated POI presents clinically with delayed puberty and menarche, primary or secondary amenorrhoea, or oligomenorrhoea [2, 22]. About 2/3 of girls with classic galactosemia achieve spontaneous menarche, although most of those who do, cease having regular spontaneous menses within 5  years [22]. Male gonadal function appears largely unaffected [2, 49].The cause of ovarian dysfunction in classic galactosemia remains unclear, but is often signalled early in infancy or childhood by hypergonadotropism with a perturbation in granulosa cell function, as evidenced by reduced circulating levels of anti-Müllerian hormone (AMH) [2, 22, 47]. Indeed, by AMH levels, a vast majority of girls with classic galactosemia show evidence of severely diminished numbers of normally-developing ovarian follicles by 2–6 months of age [47], suggesting the initial damage may have occurred very early in development, perhaps in utero. Of note, histological studies of ovarian tissue from a small number of girls below the age of 5 with classic galactosemia suggest that despite low levels of detected circulating AMH, a substantial pool of primordial follicles may nonetheless exist [50]. The hormonal intervention required to help some girls achieve or complete puberty, and women avoid the negative general health consequences of early menopause, can be complicated by the fact that seemingly all oral hormone drug tablets contain lactose as an »inactive« filler. However, some women with classic galacto-

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semia have received these pills for many years with no obvious negative side effects (G.T. Berry, personal observation). It is important to stress that the hormonal treatments that enable girls and women with classic galactosemia to achieve or complete puberty and maintain good bone health, etc., are not known to have any impact on fertility [22, 50]. A minority of women with classic galactosaemia, including those with no detectable residual GALT activity in blood, have experienced one or more successful pregnancies and deliveries. Some of these women subsequently developed secondary amenorrhoea. In a recent study, over 40% of a small number of women with galactosemia who actually tried to become pregnant were successful [51]. Whether these women are representative of the larger population remains unclear. Galactose metabolite concentrations in blood do not appear to increase significantly during pregnancy, or following 1  week postpartum even in those who choose to breast feed [52]. Infants born to mothers with classic galactosaemia appear normal and healthy. z

Management of Partial GALT Deficiency Attributable to Duarte Galactosemia (D/G)

Duarte (D2) galactosaemia (D/G) does not require diet therapy. Yet, at present there is still no uniform standard of care for infants with Duarte (D2) galactosaemia (D/G), though this is expected to change (McCandless, Pediatrics) [12, 14, 48]. Historically, some centres advised lactose restriction in infancy or until erythrocyte Gal-1P levels normalised and remained normal following a lactose challenge or a normal lactose-containing diet, often tested at 1 year of age. Other centres advised no follow-up testing or intervention. However, the recent publications of a well-powered study demonstrating no detectable difference in developmental outcomes in subjects 6-12 years of age with D/G, whether or not they drank milk in infancy [12], and another showing no increased risk for acute complications or adverse effects on early childhood developmental in those younger than 6 years of age [13], has encouraged many healthcare providers who used to recommend dietary intervention for infants with D/G to reconsider their approach [14]. z

14.2

Uridine Diphosphate Galactose 4′-Epimerase (GALE) Deficiency

14.2.1Clinical Presentation

GALE deficiency ranges from an apparently benign ‘peripheral’ condition associated with GALE deficiency restricted to circulating red and white blood cells to a severe ‘generalized’ disorder resulting from widespread GALE impairment that presents with life-threatening illness in the newborn period [3]. Of note, unlike GALT deficiency, even the most severely affected patients with GALE deficiency exhibit some residual GALE activity, at least in some tissues. The lack of infants detected with complete absence of GALE deficiency, although true null alleles of GALE have been identified in the compound heterozygous state, is presumed to reflect ascertainment bias; namely, that complete loss of GALE may be incompatible with survival of a fetus to term [3]. The severe or generalized form of GALE deficiency is extremely rare, with a total of 6 patients from three families reported. However, a new enigmatic phenotype with features of a congenital defect of glycosylation has recently surfaced associated with the presence of homozygosity for the severe mutation [4]. The original affected infants exposed to milk showed clinical presentation similar to classic galactosemia; they were rapidly switched to low-galactose formula. One child died from unexplained liver failure at 4 months of age. Despite continued dietary restriction, some, but not all, affected children showed learning difficulties, sensorineural hearing loss, and other long-term complications; however, POI has not been reported. Patients with an intermediate form of GALE deficiency have also been described, with clinical findings ranging from transient illness with seizures, to vomiting and hypoglycaemia that resolved upon dietary restriction of galactose, to juvenile cataracts and developmental delay [3]. Six members of an extended family homozygous for a novel missense variant of GALE (p.R51W) [5] have recently been reported with thrombocytopenia and a further patient homozygous for a different variant, (p.Thr150Met), reported with chronic thrombocytopenia, dysmegakaryopoiesis, macrocytosis, and lymphopenia [54].

Heterozygotes for Classic Galactosaemia

Heterozygotes for GALT deficiency are predicted to occur at a frequency of about 1/112 individuals in populations where classic galactosemia impacts about 1/50,000 birth. Heterozygotes, or carriers, have not been shown to be at increased risk of premature menopause, presenile cataracts, or other disease manifestations associated with classic galactosemia [53].

14.2.2Metabolic Derangement

Patients with GALE deficiency exposed to milk accumulate galactose, galactitol, Gal-1P, and UDPgal in blood (7 Fig. 6.1). As in GALT deficiency, patients with severe GALE deficiency exposed to high levels of dietary lactose may also show abnormal glycosylation of

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proteins in blood]; this may be a secondary biochemical complication not primarily related to the genetic defect. Of note, erythrocyte GALE activity does not correlate well with that seen in other tissues, such as lymphoblasts, and is poor at differentiating between peripheral and generalised forms of the disease.

14.2.3Genetics

GALE deficiency is inherited as an autosomal recessive trait; the recurrence risk for couples with an affected child is therefore 1:4. Due to incomplete ascertainment, the true population incidence is not known, and may vary significantly between groups [3]. A number of mutations have been identified and characterised. The c.280G  >  A (V94M) mutation has been found in the homozygous state in the majority of patients with the severe phenotype, whereas other mutations are associated with the intermediate or asymptomatic phenotypes. Of note, some mutations identified in the compound heterozygous state in mildly affected patients appear to be profoundly impaired when expressed in model systems, suggesting that these naturally-occurring mutations could also result in severe disease if inherited together with another severe allele. 14.2.4Diagnostic Tests

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Infants with GALE deficiency may be detected by NBS on the basis of elevated total galactose or Gal-1P but normal GALT [3]. However, many newborn screening programs only measure total blood galactose in follow-up to an abnormal GALT activity result; by definition, these programs will not detect cases of GALE deficiency [19]. Diagnosis of GALE deficiency is confirmed by quantitative assay of GALE in freshly drawn erythrocytes or other cells. Further studies of GALE activity in transformed lymphoblasts, and erythrocyte Gal-1P or urinary galactitol measured while on and off dietary galactose, may help characterise the disorder further. If the familial GALE mutations are known, DNA analysis may be the fastest method of determining whether or not an infant is affected. 14.2.5Treatment and Prognosis

Newborns at risk for generalized GALE deficiency should be maintained on low galactose formula until the diagnosis can be confirmed or excluded. Once confirmed, patients with generalized GALE deficiency should be treated and followed much like patients with classic galactosemia, though less stringent dietary galac-

tose restriction may be advisable to ensure sufficient exogenous galactose for synthesis of galactoproteins and galactolipids. As with GALT deficiency, erythrocyte Gal-1P levels tend to remain slightly elevated in treated patients. The oldest patients reported with generalized GALE deficiency are now in their third decade; they have not shown evidence of progressive disease (JH Walter, personal communication). True peripheral GALE deficiency does not require galactose restriction. However, since intermediate forms are now recognised, measurement of erythrocyte Gal-1P and urine galactitol while the patient is on a normal galactose intake, and monitoring of psychomotor progress, may be advisable.

14.3

Galactokinase (GALK) Deficiency

14.3.1Clinical Presentation

Historically, untreated galactokinase deficiency has been considered largely benign except for diet-dependent cataracts and in rare cases pseudotumour cerebri [7]. However, a recent report detailing the outcomes of 18 patients with profound galactokinase deficiency identified by newborn screening in Germany [8] raised concern as many experienced long-term complications. The large majority of these patients were homozygous for the Romani founder mutation c.82C > A (p P28T). Most were clinically well as infants regardless of diet; however, complications were reported in close to 30%. These included hypoglycaemia, failure to thrive, microcephaly, intellectual disability, and hypercholesterolemia, with most symptoms seemingly more prevalent in those with poor dietary compliance. Complications did not appear to correlate with known consanguinity. It remains unclear whether GALK deficiency was causal.

14.3.2Metabolic Derangement

Patients with profound GALK deficiency lack the ability to phosphorylate galactose (. Fig. 14.1) and consequently accumulate galactose and galactitol, but not Gal-1P. As in classic galactosemia, these patients accumulate galactitol in the lens when consuming a high galactose diet, causing osmotic swelling, denaturation of proteins, and cataracts. 14.3.3Genetics

GALK deficiency is inherited as an autosomal recessive disorder. Historically, GALK deficiency was considered extremely rare (  A) was identified as the founder mutation in most Roma patients and in German patients who immigrated from Bosnia [6].

14.3.4Diagnostic Tests

Newborns with profound GALK deficiency may be discovered by NBS due to elevated total blood galactose following exposure to high levels of dietary galactose. These infants will be missed if they have not been exposed to milk, or if the NBS protocol does not test total blood galactose, or only tests samples secondary to low GALT activity [19]. Older children and adults with nuclear cataracts should be tested for possible GALK deficiency by enzyme assay of freshly drawn erythrocyte or another cell type. Elevated galactose and galactitol may also be detected in urine if the patient is on a high galactose diet.

14.3.5Treatment and Prognosis

Initial treatment of GALK deficiency involves elimination of milk and other high galactose foods from the diet. Cryptic sources of dietary galactose, such as fruits

and vegetables, are generally allowed. Once a patient is on a galactose-restricted diet urinary levels of galactitol should normalize. When diagnosis and intervention occur within the first few weeks of life, cataracts may be prevented or may resolve over time. However, when treatment is late and cataracts are already dense, they may require surgical removal. Patients who have had their lenses surgically removed remain at risk for recurrent cataracts originating from remnants of the posterior lens capsule. Recurrence can be avoided by continuing the galactose-restricted diet. As for carriers of GALT mutations, the speculation that heterozygosity for GALK deficiency predisposes to the formation of presenile cataracts remains unproven [55, 56].

14.4

Galactose Mutarotase (GALM) Deficiency

Eight infants from a Japanese cohort who presented with elevated total galactose while consuming milk, but who proved negative for all other anticipated possible causes of galactosemia, were determined to be homozygous for pathogenic mutations in GALM encoding galactose mutarotase (GALM). Two of the patients were reported to have congenital cataracts and two others transient cholestasis but were otherwise well [9]. GALM catalyzes the epimerization of β-D-galactose, which is released by cleavage of lactose, to α-D-galactose, a substrate for GALK.  While this epimerization can occur spontaneously in aqueous solution, GALM speeds the process in vivo, enabling efficient metabolism of large quantities of dietary galactose. Patients with GALM deficiency should be treated with dietary galactose restriction to prevent the buildup of galactose metabolites and the occurrence of cataracts, and perhaps other outcomes. Functional and prevalence studies of GALM variants suggest that GALM deficiency may be very rare worldwide but present in about 1/10,000 individuals of African ancestry, and about 1/80,000 individuals of Japanese ancestry [57].

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14.5

Fanconi-Bickel Syndrome

Fanconi-Bickel Syndrome is a rare, recessively inherited disorder of glucose and galactose transport resulting from deficiency of glucose transporter 2 (GLUT2). A few cases have been discovered during newborn screening for galactose in blood. The clinical features of the disorder are those of glycogen storage disease and renal tubular dysfunction. The diagnosis is confirmed by mutation analysis. For further details, see 7 Chap. 8.

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14.6

Portosystemic Venous Shunting and Hepatic Arteriovenous Malformations

Portosystemic bypass of splanchnic blood via ductus venosus or intrahepatic shunts causes alimentary hypergalactosaemia, which may be discovered during metabolic NBS [10].

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Genet Med 21(6):1286–1294. https://doi.org/10.1038/s41436018-0340-x Kim MJ, Ko JS, Seo JK et al (2012) Clinical features of congenital portosystemic shunt in children. Eur J Pediatr 171: 395–400 Welling L, Bernstein LE, Berry GT et  al (2017) International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. J Inherit Metab Dis 40(2):171–176. https://doi.org/10.1007/s10545-016-9990-5 Carlock G, Fischer ST, Lynch ME, Potter NL, Coles CD, Epstein MP, Mulle JG, Kable JA, Barrett C, Edwards SM, Wilson E, Fridovich-Keil JL (2019) Developmental outcomes in Duarte galactosemia. Pediatrics 143(1):e20182516 Fridovich-Keil JL, Carlock G, Patel S, Potter NL, Coles CD (2021) Acute and early developmental outcomes of children with duarte galactosemia. JIMD reports 63(1):101–106. https:// doi.org/10.1002/jmd2.12267 McCandless SE (2019) Answering a question older than most pediatricians: what to do about Duarte Variant Galactosemia. Pediatrics 143(1):e20183292. https://doi.org/10.1542/ peds.2018-3292. PMID: 30593448 Berry GT, Nissim I, Lin Z et al (1995) Endogenous synthesis of galactose in normal men and patients with hereditary galactosaemia. Lancet 346:1073–1074 Berry GT, Moate PJ, Reynolds RA et al (2004) The rate of de novo galactose synthesis in patients with galactose-1-phosphate uridyltransferase deficiency. Mol Genet Metab 81:22–30 Schadewaldt P, Kamalanathan L, Hammen HW, Wendel U (2004) Age dependence of endogenous galactose formation in Q188R homozygous galactosemic patients. Mol Genet Metab 81:31–44 Tran TT, Liu Y, Zwick ME et  al (2015) A De Novo variant in galactose-1-P uridylyltransferase (GALT) leading to classic galactosemia. JIMD Rep 19:1–6 Pyhtila BM, Shaw KA, Neumann SE, Fridovich-Keil JL (2015) Newborn screening for galactosemia in the United States: looking back, looking around, and looking ahead. JIMD Rep 15:79–93 Coss KP, Doran PP, Owoeye C et al (2013) Classical galactosaemia in ireland: incidence, complications and outcomes of treatment. J Inherit Metab Dis 36(1):21–27. https://doi. org/10.1007/s10545-012-9507-9 Calderon FRO, Phansalkar AR, Crockett DK, Miller M, Mao R (2007) Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene. Hum Mutat 28(10):939–943 Frederick AB, Zinsli AM, Carlock G, Conneely K, FridovichKeil JL (2018) Presentation, progression, and predictors of ovarian insufficiency in classic galactosemia. J Inherit Metab Dis 41(5):785–790 Ryan EL, Lynch ME, Taddeo E, Gleason TJ, Epstein MP, Fridovich-Keil JL (2013) Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia. J Inherit Metab Dis 36(6):1049– 1061. https://doi.org/10.1007/s10545-012-9575-x Fridovich-Keil JL, Gambello MJ, Singh RH et al (1993–2020) Duarte variant galactosemia. 2014 Dec 4 [Updated 2020 Jun 25]. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews® [Internet] Carney AE, Sanders RD, Garza KR, McGaha LA, Bean JLH, Coffee BW, Thomas JW, Cutler DJ, Kurtkaya N, Fridovich-Keil JL (2009) Origins, distribution, and expression of the Duarte-2 (D2) allele of galactose-1-P uridylyltransferase (GALT). Hum Mol Genet 18(9):1624–1632

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Demirbas D, Huang X, Daesety V et  al (2019) The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency. Mol Genet Metab 126(4):368–376. https://doi.org/10.1016/j. ymgme.2019.01.016 Hughes J, Ryan S, Lambert D et al (2009) Outcomes of siblings with classical galactosemia. J Pediatr 154:721–726 Vandenplas Y, Castrellon PG, Rivas R et  al (2014) Safety of soya-based infant formulas in children. Br J Nutr 111: 1340–1360 Sabatino JA, Starin D, Tuchman S, Ferreira C, Regier DS (2019) Elevated urine oxalate and renal calculi in a classic galactosemia patient on soy-based formula. JIMD Rep 49(1):7–10. Published 2019 Jun 21. https://doi.org/10.1002/jmd2.12056 Van Calcar SC, Bernstein LE, Rohr FJ et al (2014) A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab 112:191–197 Frederick A, Cutler DJ, Fridovich-Keil JL (2017) Rigor of non-dairy galactose restriction in early childhood, measured by retrospective survey, does not associate with severity of five long-term outcomes quantified in 231 children and adults with classic galactosemia. J Inherit Metab Dis 40(6): 813–821 Beigi B, O’Keefe M, Bowell R, Naughten E, Badawi N, Lanigan B (1993) Ophthalmic findings in classical galactosaemiaprospective study. Br J Ophthalmol 77:162–164 Bosch AM, Bakker HD, Wenniger-Prick LJ, Wanders RJ, Wijburg FA (2004) High tolerance for oral galactose in classical galactosaemia: dietary implications. Arch Dis Child 89: 1034–1036 Knerr I, Coss KP, Kratzsch J et  al (2015) Effects of temporary low-dose galactose supplements in children aged 5–12 y with classical galactosemia: a pilot study. Pediatr Res 78: 272–279 Adam S, Akroyd R, Bernabei S, Bollhalder S et al (2015) How strict is galactose restriction in adults with galactosaemia? Mol Genet Metab 115:23–26 Fischer T, Frederick AB, Tran V, Li S, Jones DP, and Fridovich-Keil JL (2019) Metabolic perturbations in classic galactosemia beyond the Leloir pathway: Insights from an untargeted metabolomic study. Journal of Inherited Metabolic Disease, 42(2):254–263. https://doi.org/10.1002/jimd.12007 van Erven B, Welling L, van Calcar SC et al (2017) Bone health in classic galactosemia: systematic review and meta-analysis. JIMD Rep 35:87–96. https://doi.org/10.1007/8904_2016_28 Welling L, Waisbren SE, Antshel KM et al (2017) Systematic review and meta-analysis of intelligence quotient in earlytreated individuals with classical galactosemia. JIMD Rep 37:115–123. https://doi.org/10.1007/8904_2017_22 Knerr I, Coss KP, Doran PP et al (2013) Leptin levels in children and adults with classic galactosaemia. JIMD Rep 9:125–131 Kuiper A, Grünewald S, Murphy E et  al (2019) Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia. J Inherit Metab Dis 42(3):451–458. https://doi.org/10.1002/jimd.12054 Waisbren SE, Potter NL, Gordon CM et  al (2012) The adult galactosemic phenotype. J Inherit Metab Dis 35:279–286 Shaw KA, Mulle JG, Epstein MP, Fridovich-Keil JL (2017) Gastrointestinal health in classic galactosemia. JIMD Rep 33:27–32

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Disorders of Fructose Metabolism Beat Steinmann and René Santer Contents 15.1

Essential Fructosuria – 329

15.1.1 15.1.2 15.1.3 15.1.4 15.1.5 15.1.6

Clinical Presentation – 329 Metabolic Derangement – 329 Genetics – 329 Diagnosis – 329 Differential Diagnosis – 329 Treatment and Prognosis – 330

15.2

Hereditary Fructose Intolerance – 330

15.2.1 15.2.2 15.2.3 15.2.4 15.2.5 15.2.6

Clinical Presentation – 330 Metabolic Derangement – 330 Genetics – 330 Diagnosis – 331 Differential Diagnosis – 331 Treatment and Prognosis – 332

15.3

Fructose-1,6-Bisphosphatase Deficiency – 332

15.3.1 15.3.2 15.3.3 15.3.4 15.3.5 15.3.6

Clinical Presentation – 332 Metabolic Derangement – 333 Genetics – 333 Diagnosis – 334 Differential Diagnosis – 334 Treatment and Prognosis – 334

15.4

Sorbitol Dehydrogenase Deficiency – 334

15.4.1 15.4.2 15.4.3 15.4.4 15.4.5

Clinical Presentation – 335 Metabolic Derangement – 335 Genetics – 335 Diagnosis – 335 Treatment and Prognosis – 335

References – 335

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_15

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consumption of fructose, particularly from sweetened beverages using industrially produced high-fructose corn syrup (HFCS), has been associated with an increased prevalence of obesity, metabolic syndrome, non-alcoholic fatty liver disease, type-2 diabetes, and gout [1] which underscores the importance of understanding the metabolic consequences of fructose consumption.

Fructose Metabolism Fructose is one of the main sweetening agents in the human diet. It is found in its free form in honey, fruits and many vegetables, and is associated with glucose in the disaccharide sucrose in numerous foods and beverages. Sorbitol, also widely distributed in fruits and vegetables, is converted into fructose in the liver by sorbitol dehydrogenase (. Fig.15.1). In recent years, increased

Glycogen

Pi Glycogen Phosphorylase a

G-1-P Pi

G-6-Phosphatase

Glucose

G-6-P ATP Gluco-/Hexokinase

NADPH/H+ Aldehyde Reductase NADP+

G-6-P Isomerase

Sorbitol NAD+

ATP

Sorbitol Dehydrogenase NADH/H+

F-6-P ATP

Pi

Phosphofructokinase

F-1,6-Bisphosphatase ATP ADP

Fructose

15

F-1-P

F-1,6-P2

Fructokinase Aldolase A

Aldolase B DHA-P ATP

Glycerol

GAH

Triokinase

GAH-3-P Pi

NAD+

NADH/H+

Triglycerides

Glyceraldehyde-3-Phosphate Dehydrogenase

GA-1,3-P2

Lactate

Pyruvate

Alanine

NAD+

Krebs Cycle

. Fig. 15.1 Fructose metabolism. The four enzyme defects related to fructose metabolism are boxed and depicted by solid red bars across the arrows; the diminished activity of aldolase B toward

fructose-1,6-bisphosphate is depicted by a broken bar. DHA-P dihydroxyacetone phosphate, F fructose, G glucose, GA glycerate, GAH glyceraldehyde, P phosphate, Pi inorganic phosphate

329 Disorders of Fructose Metabolism

Fructose is transported by the facilitative glucose transporter-5 (GLUT5) across the intestinal apical membrane into the cytosol and may enter portal circulation by basolateral GLUT2 [2]. Fructose can then be taken up by GLUT2  in the liver and the renal cortex and is metabolised in a pathway composed of fructokinase, aldolase B and triokinase. While for years the liver has been considered the most important organ in fructose metabolism, this notion has recently been challenged by isotope tracing studies in rodents demonstrating that low doses of fructose are almost completely converted to glucose by the intestine while higher doses are only partially metabolised, and fructose and organic acids produced by colonic bacteria from unabsorbed sugars, appear in the portal vein [3]. kIntroduction

Four inborn errors related to the pathway of fructose metabolism are depicted in . Fig. 15.1. Essential fructosuria is a harmless anomaly characterised by the appearance of fructose in the urine after the intake of fructose-containing food. In hereditary fructose intolerance (HFI), fructose may provoke prompt gastrointestinal discomfort and hypoglycaemia upon ingestion, symptoms that can vary from patient to patient and depend on the ingested dose. Fructose may cause liver and kidney failure when taken persistently and its intake becomes life-threatening when given intravenously. Sorbitol dehydrogenase deficiency has recently been reported to cause a slowly progressive neuropathy. The pathomechanism is unclear but may be related to accumulation of intracellular sorbitol. Fructose-1,6bisphosphatase (FBPase) deficiency is also usually considered an inborn error of fructose metabolism although, strictly speaking, it is a defect of gluconeogenesis. The disorder is manifested by the appearance of hypoglycaemia and lactic acidosis (neonatally, or later during prolonged fasting or induced by fructose) and may be life-threatening.

15.1

Essential Fructosuria

15.1.1Clinical Presentation

Essential fructosuria is a rare non-disease; it is detected by routine screening of urine for reducing sugars. It is caused by a deficiency of fructokinase, also known as ketohexokinase (KHK), the first enzyme of the main fructose pathway (. Fig.15.1).

15.1.2Metabolic Derangement

In essential fructosuria, ingested fructose is partly (10– 20%) excreted as such in the urine, the rest is slowly metabolised by an alternative pathway, namely conversion into fructose-6-phosphate by hexokinase in adipose tissue and muscle (. Fig.15.1).

15.1.3Genetics

The mode of inheritance is autosomal recessive and the frequency has been estimated at 1:130,000. However, since the condition is asymptomatic and harmless and since laboratories are abandoning tests for reducing substances in urine in favour of specific glucose tests, it may be more prevalent than reported. Tissue-specific alternative splicing of KHK results in two isoforms, ketohexokinase A, widely distributed in most foetal and adult organs but with no clear physiological role, and ketohexokinase C, expressed in adult liver, kidney and small intestine, which is affected in essential fructosuria [4]. Numerous variants have been reported to databases from exome or genome studies but only two pathogenic variants of KHK, p.G40R and p.A43T have been detected in affected individuals, i.e., a family with three compound heterozygotes [5]. The effect of these variants on protein function has been characterised based on the crystallographic structure [6].

15.1.4Diagnosis

Fructose gives a positive test for reducing sugars and a negative reaction with glucose oxidase. It can be identified by various techniques, such as thin-layer chromatography, and quantified enzymatically. Fructosuria depends on the time and amount of fructose, sorbitol and sucrose intake and, thus, is inconstant. Fructosetolerance tests neither provoke an increase in blood glucose as in normal subjects, hypoglycaemia or other changes as occur in HFI and FBPase deficiency, nor are metabolic changes in liver detectable by 31P-magnetic resonance spectroscopy (MRS) [7].

15.1.5Differential Diagnosis

Acute liver diseases such as e.g. tyrosinaemia or galactosaemia may lead to fructosuria.

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15.1.6Treatment and Prognosis

Dietary treatment is not indicated, and the prognosis is excellent. Judged from animal studies this condition may be protective against the metabolic syndrome [8].

15.2

with HFI are free of caries, the diagnosis has also been suspected by dentists. Although several hundred patients with HFI have been identified since its recognition as an inborn error of metabolism in the 1950s [9, 10], these observations indicate that affected subjects may remain undiagnosed and still have a normal life span.

Hereditary Fructose Intolerance 15.2.2Metabolic Derangement

15.2.1Clinical Presentation

15

Individuals with hereditary fructose intolerance (HFI) are perfectly healthy as long as they do not ingest food containing fructose, sucrose and/or sorbitol. Consequently, no metabolic derangement occurs during breast-feeding. The younger the child and the higher the dietary fructose load, the more severe the reaction. In the acute presentation of HFI, an affected newborn infant who is not breast-fed but receives a cow’s milk formula sweetened and enriched with fructose or sucrose – formulas which should be obsolete today – is in danger of severe liver and kidney failure and death. At weaning from breast-feeding or from a fructose/ sucrose-free infant formula, the first symptoms appear with the intake of fruits and vegetables [9, 10]. They are generally those of gastrointestinal discomfort, nausea, vomiting, restlessness, pallor, sweating, trembling, lethargy and, eventually, apathy, coma, jerks and convulsions. At this stage, laboratory signs may be those of acute liver failure and generalised dysfunction of the renal proximal tubules. If the condition is unrecognised and fructose not excluded from the diet, the disease may take a chronic, fluctuating course with failure to thrive, liver disease manifested by hepatomegaly, jaundice, bleeding tendency, oedema, ascites, and signs of proximal renal tubular dysfunction. Laboratory findings are those of liver failure, proximal renal tubular dysfunction and derangements of intermediary metabolism. Note that hypoglycaemia after fructose ingestion is shortlived and can be easily missed or masked by concomitant glucose intake. HFI can be suspected in an asymptomatic infant, if the parents have excluded certain foods from the diet, having become aware that they are not tolerated. In older children, a distinct aversion towards foods containing fructose may develop; these feeding habits protect them but are sometimes considered as neurotic behaviour. At school age, HFI is occasionally recognised when hepatomegaly or growth delay is found [11]. Some adults were diagnosed after developing life-threatening reactions with infusions containing fructose, sorbitol or invert sugar (a mixture of glucose and fructose obtained by hydrolysis of sucrose) when these IV solutions were still in use [12]. Because approximately half of all adults

HFI is caused by deficiency of the second enzyme of the fructose pathway, aldolase B (. Fig. 15.1), which splits fructose-1-phosphate (F-1-P) into dihydroxyacetone phosphate and glyceraldehyde. As a consequence of the high activity of fructokinase, intake of fructose results in accumulation of F-1-P and trapping of phosphate. This has two major effects [13]: (i) inhibition of glucose production by blockage of gluconeogenesis (by inhibition of aldolase A, . Fig. 15.1) and of glycogenolysis (by inhibition of glycogen phosphorylase a) which induces a rapid drop in blood glucose, and (ii) overutilisation and diminished regeneration of ATP; this depletion of ATP results in an increased production of uric acid, a release of magnesium, and a series of other disturbances, including impaired protein synthesis and ultrastructural lesions which are responsible for hepatic and renal dysfunction. The accumulation of F-1-P has also been shown to result in deficient glycosylation of proteins, e.g., serum transferrin, by inhibiting phosphomannose isomerase [14] (7 Chap. 43). Residual activity measurable with fructose-1,6bisphosphate as substrate (see below) is mainly due to the isozyme aldolase A. Thus, glycolysis and gluconeogenesis are not impaired in the fasted state in HFI patients and thus they tolerate long fasting periods. It should be noted that the IV administration of fructose to normal subjects also induces the metabolic derangements described above (including the drop in ATP and Pi, and rise in urate and Mg++) to an equivalent extent, although they are more transient than in patients with HFI, as demonstrated by 31P-MRS [7]. In normal subjects, IV fructose results in increased glycaemia because of its rapid conversion into glucose. However, the equally rapid conversion of fructose into lactate may provoke metabolic acidosis. For these reasons, the use of fructose, sorbitol and invert sugar has been strongly discouraged for parenteral nutrition in general [15].

15.2.3Genetics

HFI is an autosomal-recessive disorder. Three different genes coding for aldolases have been identified. While

331 Disorders of Fructose Metabolism

isozymes A and C are mainly expressed in muscle and brain, respectively, aldolase B is the major fructaldolase of liver, renal cortex, and small intestine. At present, according to different databases approximately 70 causative variants of the aldolase B gene (ALDOB) have been reported. Among them, three amino acid substitutions, p.A150P,1 p.A175D, and p.N335K are relatively common among patients of European descent [16]. Since the three most common pathogenic variants are responsible for more than 90% of HFI cases in some European regions and still more than 50% of cases from the more heterogeneous population in North America, a non-invasive diagnostic approach using molecular genetic methods has been advocated [17, 18]. Among these methods, multiplex ligation-dependent probe amplification (MLPA) assays can also detect copy number variations present on approximately 6% of mutant alleles not detectable by standard sequencing techniques [Santer, unpublished]. From molecular genetic neonatal screening studies in England and Germany, the prevalence of HFI has been calculated as 1:18,000 [1] and 1:29,600, respectively [17].

15.2.4Diagnosis

Whenever HFI is suspected, fructose should be eliminated from the diet immediately. The beneficial clinical and chemical effects of withdrawal, usually seen within days, provide a first diagnostic clue. Laboratory findings will subsequently show a fall in the elevated serum transaminases and bilirubin, improved levels of blood clotting factors, and amelioration of proximal tubular dysfunction (proteinuria, glucosuria, generalised hyperaminoaciduria, hyperphosphaturia, hypophosphataemia, hyperuricuria, metabolic acidosis). A cornerstone in the diagnosis of HFI is a careful nutritional history, with special emphasis on the time of weaning when fruits and vegetables were introduced [1, 19]. If the nutritional history is suggestive or other aspects are indicative of HFI (e.g., a positive family history), the disorder should be confirmed by molecular diagnosis (above) on DNA from peripheral leukocytes. This is a non-invasive approach and has the advantage over enzymatic measurement in liver tissue in that it eliminates the complication of secondarily lowered aldolase B activity in a damaged liver. If no pathogenic variants can be found despite a strong clinical and nutritional history suggestive of

1

Note that the initiation codon ATG for methionine in the ALDOB cDNA was ignored in previous designations and that, e.g., ‘p.A150P’ was originally named ‘p.A149P’

HFI, an enzymatic determination or a functional test should be undertaken after a few weeks of fructose exclusion. In liver biopsies from HFI patients, the capacity of aldolase to split F-1-P is reduced, usually to a few percent of normal (mean 5%, range 0–15%) [19], although residual activities as high as 30% of normal have been reported [12]. There is also a distinct (but less marked) reduction in the activity of aldolase B toward fructose-1,6-bisphosphate (mean 17%, range 5–30%). As a consequence, the ratio of Vmax towards fructose1,6-bisphosphate versus the Vmax towards F-1-P, which is approximately 1 in control liver, is increased to 2 to ∞ in HFI patients [19]. Aldolase activity is normal in blood cells, muscle, and skin fibroblasts, which contain a different isozyme, aldolase A.  The enzymatic determination of aldolase B in small intestinal mucosa is not recommended because of inconsistent results. For postmortem diagnosis, molecular studies and measurements of enzyme activity in liver and kidney cortex should be done. It should be noted that the level of residual activity has never been shown to correlate with the degree of tolerance to fructose. However, if the clinical history is suggestive for HFI in the absence of pathogenic variants within ALDOB, an IV fructose tolerance test is recommended, in which fructose (200 mg/kg b.w.) is injected as a 20% solution intravenously within 2 minutes. Blood samples are taken at 0 (2), 5, 10, 15, 30, 45, 60 and 90 minutes for determination of glucose and phosphate. In normal subjects, blood glucose increases by 0–40%, with no or minimal changes in phosphate [19]. In HFI patients, glucose and phosphate decrease within 10–20 minutes. As a rule, the decrease of phosphate precedes and occurs more rapidly than that of glucose. The test should only be undertaken in an experienced metabolic centre, with careful monitoring of glucose and an indwelling catheter for the (exceptional) case of symptomatic hypoglycaemia and its treatment by IV glucose administration. Oral fructose tolerance tests are not recommended, because they provoke more ill effects and are less reliable [19].

15.2.5Differential Diagnosis

A high degree of diagnostic awareness is often needed in HFI because the spectrum of symptoms and signs is wide and nonspecific; HFI has been misdiagnosed as pyloric stenosis, gastro-oesophageal reflux, galactosaemia, tyrosinaemia, non-IgE-mediated gastrointestinal food hypersensitivity, intrauterine infection, glycogen and other storage disorders, ornithine transcarbamylase deficiency, and later in life as Wilson disease, leukaemia, and growth retardation. Fructosuria may be secondary to liver damage, e.g., in tyrosinaemia.

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HFI is frequently confused with fructose malabsorption [20], a condition caused by defective fructose transport in the small intestine whose metabolic basis, however, is not well understood. The ingestion of fructose, and to a considerably lesser extent of sucrose, leads to abdominal pain and diarrhoea. Since this condition is diagnosed by breath hydrogen analysis after an oral load of fructose, HFI has to be excluded before such a tolerance test is performed, otherwise deleterious effects may occur [21]. In sucrase-isomaltase deficiency, the ingestion of sucrose results in bloating, abdominal cramps and fermentative osmotic diarrhoea; free fructose, however, is well tolerated.

15.2.6Treatment and Prognosis

15

In acute intoxication, intensive care may be required and supportive measures such as fresh frozen plasma may be needed. The main therapeutic step in HFI, however, is the immediate elimination of all sources of fructose from the diet. This involves the avoidance of all types of food in which fructose, sucrose and/or sorbitol occur naturally or have been added during processing. Fructose and sorbitol may be present in medications (e.g., syrups, immunoglobulin solutions, rinsing fluids, enema solutions, amiodarone infusion containing polysorbate 80 [22]) and infant formulas (without adequate declaration of the carbohydrate composition). In this respect, it is deplorable that European Union regulations allow infant formulae to contain up to 20% of their total carbohydrate content as sucrose [23]. Sucrose should be replaced by glucose, maltose and/ or starch to prevent the fructose-free diet from containing too much fat. Despite the availability of books and online information on food composition, a dietician should be consulted and practical aspects of the diet (e.g., the considerable variability of the fructose content of different food types, and the influence of storage temperature or method of preparation and manner of cooking on bioavailability) be discussed. Substitution of vitamins, especially ascorbic acid and folates, in the form of a multivitamin preparation should be prescribed to make up for their diminished intake from fruits and vegetables. After institution of a fructose-free diet most abnormalities disappear rapidly, except for hepatomegaly, which may persist for months or even years [24]. It has recently been shown by H+-MRS studies that patients with HFI have an increased intrahepatic triglyceride content [25], a fact which has been explained in animals by the endogenous synthesis of fructose by the polyol pathway [26] (7 Chap. 7). In AldoB knock-out mice

F-1-P leads to increased concentration of intrahepatic triglycerides, but by blocking fructokinase with osthole, the triglyceride accumulation could be prevented [27]. Hence, osthole, a coumarinic derivative obtained from plants may be a future therapeutic approach in HFI patients. Different thresholds of fructose intake for the development of certain symptoms have appeared in the literature, ranging from 40–250 mg/kg b.w./day as compared with an average intake of 1–2 g/kg/day in Western societies [1]. Insufficient restriction of fructose has been reported to cause isolated growth retardation, as evidenced by catch-up growth on a stricter diet [11]. Recommendations for maximum doses have not been validated in different genotypes and sensitivity is known to be different in individual patients with identical ALDOB variants. Thus, it should be suggested to parents that they keep fructose intake as low as possible and that, at least in childhood, it should not be determined by subjective tolerance. For dietary control, the regular taking of the nutritional history is still best, as there are no good sensitive chemical parameters except, perhaps, transaminases. Quantification of carbohydrate-deficient proteins, e.g., transferrin, has been suggested for dietary monitoring [14]; however, the sensitivity of this procedure has not been validated. Patients (and their parents) must be made aware that infusions containing fructose, sorbitol or invert sugar are life-threatening. There are numerous reports in the literature of fructose ingestion by mistake and that is why HFI, if present, should be reported on any hospital admission by an emergency card. The prognosis of HFI on diet is excellent with normal growth, intelligence and life span.

15.3

Fructose-1,6-Bisphosphatase Deficiency

15.3.1Clinical Presentation

In about half of all cases, fructose-1,6-bisphosphatase (FBPase) deficiency presents in the first 1 to 4 days of life with severe hyperventilation caused by profound lactic acidosis and marked hypoglycaemia. Later on, episodes of irritability, somnolescence or coma, apnoeic spells, dyspnea and tachycardia, muscular hypotonia, and moderate hepatomegaly may occur. Most affected children experience a number of acute attacks before the diagnosis is made. As reported in the first patient described [28], episodes are typically triggered by a febrile episode accompanied by refusal to feed and vomiting. Attacks may also follow ingestion of large amounts

333 Disorders of Fructose Metabolism

of fructose (~1 g/kg b.w. in one dose) especially after a period of fasting. FBPase deficiency may be lifethreatening and, as in HFI, administration of IV fructose is contraindicated and may lead to death. In between attacks, patients are usually well, although mild, intermittent or chronic acidosis may exist. The frequency of the attacks decreases with age, and the majority of survivors display normal somatic and psychomotor development [29]. In contrast to HFI, chronic ingestion of fructose does not lead to gastrointestinal symptoms – hence there is no aversion to sweet foods – or failure to thrive, and only exceptionally is there disturbed liver function. Analysis of plasma during acute episodes reveals lactate accumulation (up to 15–25  mM) accompanied by a decreased pH and an increased lactate/pyruvate ratio (up to 40), hyperalaninaemia, an increase in glycerol which may mimic hypertriglyceridaemia [30], and glucagon-resistant hypoglycaemia. Hyperketonaemia may be found, but in several patients ketosis has been reported to be moderate or absent (below and [31]). Increased levels of free fatty acids and uric acid may also be found. Urinary analysis reveals increased lactate, alanine, glycerol, and, in most cases, ketones and glycerol3-phosphate. Clinicians should be aware that detection of the strongly hydrophilic compounds glycerol and glycerol-3-phosphate is best when the urease pretreatment non-extraction method [32], hydrophilic interaction chromatography (HILIC) or ion-pairing reverse phase chromatography is used.

with FBPase deficiency [31]. This may be explained by pyruvate accumulation resulting in an increase of oxaloacetate and, hence, in the diversion of acetyl-CoA away from ketone-body formation into citrate synthesis. This, in turn, results in increased synthesis of malonyl-CoA in the cytosol. Elevated malonyl-CoA, by inhibiting carnitine-palmitoyl transferase I, prevents the entry of long-chain acyl-CoA into the mitochondria and, thereby, further reduces ketogenesis. It also promotes accumulation of fatty acids in liver and plasma, as documented in some patients. Children with FBPase deficiency generally tolerate sweet foods, up to 2  g fructose/kg b.w. per day, when given regularly distributed over the day and, in contrast to subjects with HFI, they thrive on such a diet [34]. Nevertheless, loading tests with IV fructose do induce hypoglycaemia, as in HFI. This is caused by the inhibitory effect of the rapidly formed but slowly metabolised F-1-P on liver glycogen phosphorylase a. That higher doses of fructose are required for hypoglycaemia to occur is explained by the fact that, in contrast to the aldolase B defect in HFI, FBPase deficiency still allows F-1-P to be converted into lactate. 31P-MRS of the liver following IV administration of fructose (200  mg/kg b.w.) has documented a slower decrease in the fructoseinduced accumulation of F-1-P and a delayed recovery of the ensuing depletion of Pi and ATP (both of which are signs of fructose toxicity) in patients with FBPase deficiency as compared with healthy controls [7].

15.3.3Genetics 15.3.2Metabolic Derangement

Deficiency of hepatic FBPase, a key enzyme in gluconeogenesis, impairs the formation of glucose from all gluconeogenic precursors, including dietary fructose (. Fig.15.1). Consequently, maintenance of normoglycaemia in patients with the defect is exclusively dependent on glucose (and galactose) intake and degradation of hepatic glycogen and, to a minor degree, on glucose production by the muscle [33]. Thus, hypoglycaemia is likely to occur when glycogen reserves are limited (as in newborns) or exhausted (as when fasting). The defect provokes accumulation of the gluconeogenic substrates lactate, pyruvate, alanine, and glycerol. The lactate/ pyruvate ratio is usually increased which is explained by secondary impairment of conversion of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate; this results in accumulation of NADH/H+ which shifts the equilibrium of pyruvate and lactate (. Fig.15.1). Hyperketonaemia and ketonuria, which usually accompany hypoglycaemia, may be absent in some patients

FBPase deficiency is a rare autosomal-recessive disorder. In addition to European and North American patients, many cases have been diagnosed in Japan. The high proportion of Turkish patients in our own series might simply be the result of the high rate of parental consanguinity. There is evidence for the existence of more than one isozyme with FBPase activity in humans. The muscle isoform has different kinetic characteristics to the liver isoform and is not affected in FBPase deficiency. Only the liver-type isoform gene (FBP1) has been cloned and characterised. To date, more than 50 different mutations in all regions of the gene have been published. Among them, a gross deletion including the entire exon 2 (c.-2426_170+5192del) is common in patients of Turkish and Armenian descent [35]. The c.959dupG mutation has been reported to be responsible for 46% of mutated alleles in Japan [36] but only 14% in Central Europe [38]; c.841G>A has repeatedly been detected in Pakistani patients [30].

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There are several patients in whom no mutation of the coding region of FBP1 could be found. Therefore, we have supposed that these patients carry mutations within the promoter region of FBP1 or, more hypothetically, in the gene for the bifunctional enzyme which controls the concentration of fructose2,6-bisphosphate, the main physiological regulator of FBPase [37]. 15.3.4Diagnosis

15

Whenever possible, the diagnosis of FBPase deficiency should be made by molecular analysis on DNA from peripheral leukocytes. If no mutation is found despite highly suggestive clinical and laboratory findings, the determination of enzymatic activity in a liver biopsy should be undertaken; the residual activity may vary from zero to 30% of normal, indicating genetic heterogeneity of the disorder. Obligate heterozygotes have intermediate activity. Diagnosis is not possible in mixed leukocytes but seems to be reliable in isolated and stimulated monocytes [29]; however, cultured skin fibroblasts, amniotic fluid cells and chorionic villi do not express FBPase. Loading tests with fructose (or with glycerol or alanine) or fasting tests should not be part of the initial investigations as they provide only a tentative diagnosis. However, such functional tests may be useful, and may point to a disturbance in the regulation of the fructose6-phosphate – fructose-1,6-bisphosphate substrate cycle if mutation analysis and enzyme activity are normal despite a strong clinical and chemical suspicion of FBPase deficiency. 15.3.5Differential Diagnosis

Since FBP has only recently been shown to be inhibited by metformin [38], it is not surprising that diminished glucose production and a propensity to lactic acidosis is seen under this medication. Congenital disorders with primary or secondary affection of gluconeogenesis and pyruvate metabolism have to be considered, e.g., (i) glycogenosis type Ia and Ib presenting with the same metabolic profile (fasting hypoglycaemia and lactic acidosis) and hepatonephromegaly, hyperlipidaemia, and hyperuricaemia; (ii) pyruvate carboxylase deficiency when in context with neurological symptoms; (iii) fatty acid oxidation defects; and (iv) some rare liver-specific presentations of respiratory chain disorders with fasting hypoketotic hypoglycaemia and hyperlactataemia due to deficient energy production required for gluconeogenesis in the liver may also mimick FBP (7 Chap. 1).

15.3.6Treatment and Prognosis

Whenever FBPase deficiency is suspected, adequate amounts of IV or oral glucose should be given. The acute, life-threatening episodes should be treated with an IV bolus (1  ml/kg b.w. of 20% glucose as a rule of thumb) followed by a continuous infusion of glucose at high rates (e.g., 10–12  mg/kg b.w./ min for newborns) and bicarbonate to control hypoglycaemia and acidosis. If correction of acidosis is not really needed, recovery from it in response to glucose is a good (positive) indicator for the diagnosis of FBPase deficiency. Furthermore, the infusion of glycerol (that may even contain additional fructose), as frequently practiced in patients with brain oedema and hypoglycaemia in Japan, is extremely dangerous unless FBPase deficiency is excluded [34, 39]. Maintenance therapy should be aimed at avoiding fasting, particularly during febrile episodes. This involves frequent feeding, the use of slowly absorbed carbohydrates (such as uncooked starch), and a gastric drip, if necessary. In small children, restriction of fructose, sucrose and sorbitol is also recommended, as are restrictions of fat (to 20–25%) and protein (to 10% of energy requirements). In the absence of any triggering effects leading to metabolic decompensation, individuals with FBPase deficiency are healthy and no carbohydrate supplements are needed. Once FBPase deficiency has been diagnosed and adequate management introduced, its course is usually benign. Growth, psychomotor and intellectual development are unimpaired, and tolerance to fasting improves with age with the effect that the disorder in general does not present a problem in later life [30]. Pregnancies were reported to be uncomplicated [29, 40]. Many patients, however, become obese because their concerned parents overfeed them and they continue these eating habits when older. Under carefully observed conditions, a hypocaloric fructose-free diet (800–900  kcal/m2/day) can lead to a considerable weight loss in obese patients without the development of lactic acidosis and hypoglycaemia [Steinmann, personal observation]. Note added in proof: A large retrospective series of 18 patients with FBPase deficiency has been recently published; most displayed a consistent metabolic phenotype with fasting hypoglycaemia and lactic acidosis, liver abnormalities and developed adult steatosis. [M Gorce et al. JIMD 2022, 45:215–222].

15.4

Sorbitol Dehydrogenase Deficiency

For years, the sorbitol dehydrogenase pathway was a matter of interest to explain complications of diabetes mellitus. In diabetes large amounts of glucose may enter

335 Disorders of Fructose Metabolism

cells with low activity of sorbitol dehydrogenase, such as the retina, lens or nerve cells. Glucose is there converted by aldehyde reductase, the first step of the polyol pathway, to sorbitol (. Fig. 15.1) which accumulates and is supposed to cause osmotic effects and shortage of NADPH with the result of retinopathy, cataract formation, or peripheral neuropathy.

15.4.1Clinical Presentation

Only recently, a congenital defect of sorbitol dehydrogenase (SORD) has been described in patients who presented with a slowly progressive neuropathy clinically classified as the axonal type of Charcot-Marie-Tooth disease (CMT2) or as distal hereditary motor neuropathy (dHMN) [41]. Hallmark of the disorder is a mild to moderate limb weakness, typically affecting the distal muscle groups of the lower extremities and often accompanied by foot deformities. Cataracts have not been observed. Age of onset typically is late childhood or early adulthood. Delayed milestones are uncommon but onset as early as 2 years has been reported.

15.4.2Metabolic Derangement

Reported patients showed a complete loss of the SORD protein and a diminished enzymatic activity in fibroblasts, with the effect of an increased intracellular sorbitol concentration. Serum fasting sorbitol concentration was markedly increased. Although the exact pathomechanisms for progressive synaptic degeneration and motor impairment are not known, similar mechanisms as in diabetic complications are suggested.

15.4.3Genetics

SORD deficiency is an autosomal-recessive disorder, nonetheless almost 70% of the cases are sporadic and a history of consanguinity is uncommon. This is due to a common variant, c.757delG in exon 7 of SORD, that most probably occurs because of recurrent gene conversion events from a highly homologous non-functioning pseudogene most likely arisen from gene duplication on chromosome 15. SORD has long been unrecognised even in the era of whole exome sequencing probably because of the existence of this pseudogene and despite its relatively high frequency. Homozygosity for the common variation alone causes a frequency of 1:100,000 which means that sorbitol dehydrogenase deficiency is a frequent form of hereditary neuropathies.

15.4.4Diagnosis

Since detailed nerve conduction studies in SORDdeficient patients invariably showed a motor axonal neuropathy, this patient group should systematically be screened for elevated serum sorbitol concentration (7 Chap. 1). An approximately 10% detection rate in undiagnosed CMT2 and dHMN has been reported. Targeted genetic diagnosis is possible using Sanger based sequencing techniques or neuropathy panels if attention is payed to the existence of the pseudogene.

15.4.5Treatment and Prognosis

SORD deficiency is a potentially treatable disorder. Substrate reduction therapy by aldose reductase inhibitors has been shown to normalise intracellular sorbitol concentration in patient-derived fibroblasts, and also significantly ameliorated the motor phenotype in an animal model [41]. Likewise, clinical trials with aldose reductase inhibitors in diabetic patients show a good safety profile and an improvement of nerve conduction [42]. Hence these substances may be a therapeutic option in the future.

References 1. Cox TM (2002) The genetic consequences of our sweet tooth. Nat Rev Genet 3:481–487 2. Ferraris RP, Choe JY, Patel CR (2018) Intestinal absorption of fructose. Ann Rev Nutr 38:41–67 3. Jang C, Hui S, Lu W et  al (2018) The small intestine converts dietary fructose into glucose and organic acids. Cell Metab 27:351–361 4. Asipu A, Hayward BE, O’Reilly J, Bonthron DT (2003) Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria. Diabetes 52:2426–2432 5. Bonthron DT, Brady N, Donaldson IA, Steinmann B (1994) Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet 3:1627–1631 6. Trinh CH, Asipu A, Bonthron DT, Phillips SE (2009) Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr 65:201–211 7. Boesiger P, Buchli R, Meier D, Steinmann B, Gitzelmann R (1994) Changes of liver metabolite concentrations in adults with disorders of fructose metabolism after intravenous fructose by 31P magnetic resonance spectroscopy. Pediatr Res 36:436–440 8. Miller CO, Yang X, Lu K et al (2018) Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects. Am J Physiol Endocrinol Metab 315:E386–E393 9. Chambers RA, Pratt RT (1956) Idiosyncrasy to fructose. Lancet 271:340

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10. Froesch ER, Prader A, Labhart A, Stuber HW, Wolf HP (1957) Die hereditäre Fructoseintoleranz, eine bisher nicht bekannte kongenitale Stoffwechselstörung. Schweiz Med Wochenschr 87:1168–1171 11. Mock DM, Perman JA, Thaler MM, Morris RC Jr (1983) Chronic fructose intoxication after infancy in children with hereditary fructose intolerance. A cause of growth retardation. N Engl J Med 309:764–770 12. Lameire N, Mussche M, Baele G, Kint J, Ringoir S (1978) Hereditary fructose intolerance: a difficult diagnosis in the adult. Am J Med 65:416–423 13. Van den Berghe G (1978) Metabolic effects of fructose in the liver. Curr Top Cell Regul 13:97–135 14. Jaeken J, Pirard M, Adamowicz M, Pronicka E, Van Schaftingen E (1996) Inhibition of phosphomannose isomerase by fructose1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance. Pediatr Res 40:764–766 15. Woods HF, Alberti KGMM (1972) Dangers of intravenous fructose. Lancet II:1354–1357 16. Cross NCP, de Franchis R, Sebastio G et  al (1990) Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet 335:306–309 17. Santer R, Rischewski J, von Weihe M et al (2005) The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat 25:594 18. Davit-Spraul A, Costa C, Zater M et al (2008) Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France – identification of eight new mutations. Mol Genet Metab 94:443–447 19. Steinmann B, Gitzelmann R (1981) The diagnosis of hereditary fructose intolerance. Helv Paediatr Acta 36:297–316 20. Gibson PR, Newnham E, Barrett JS, Shepherd SJ, Muir JG (2007) Fructose malabsorption and the bigger picture. Aliment Pharmacol Ther 25:349–363 21. Müller P, Meier C, Böhme HJ, Richter T (2003) Fructose breath hydrogen test – is it really a harmless diagnostic procedure? Dig Dis 21:276–278 22. Curran BC, Havill JH (2002) Hepatic and renal failure associated with amiodarone infusion in a patient with hereditary fructose intolerance. Crit Care Resusc 4:112–115 23. Commission Delegated Regulation (EU) 2016/127 of 25 September 2015 supplementing Regulation (EU) No 609/2013 of the European Parliament and of the Council as regards the specific compositional and information requirements for infant formula and follow-on formula and as regards requirements on information relating to infant and young child feeding. L25/1 (2016). Off J Eur Union 59:1–29 24. Odièvre M, Gentil C, Gautier M, Alagille D (1978) Hereditary fructose intolerance in childhood. Diagnosis, management and course in 55 patients. Am J Dis Child 132:605–608 25. Simons N, Debray FG, Schaper NC et  al (2019) Patients with aldolase B deficiency are characterized by increased intrahepatic triglyceride content. J Clin Endocrinol Metab 104:5056–5064 26. Patel C, Sugimoto K, Douard V et  al (2015) Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK−/− and GLUT5 −/− mice. Am J Physiol Gastrointest Liver Physiol 309:G779–G790

27. Lanaspa MA, Andres-Hernando A, Orlicky DJ et  al (2018) Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest 128:2226–2238 28. Baker L, Winegrad AI (1970) Fasting hypoglycemia and metabolic acidosis associated with deficiency of hepatic fructose1,6-bisphosphatase activity. Lancet II:13–16 29. Åsberg C, Hjalmarson O, Alm J et al (2010) Fructose 1,6-bisphosphatase deficiency: enzyme and mutation analysis performed on calcitriol-stimulated monocytes with a note on long-term prognosis. J Inherit Metab Dis 33:178 30. Afroze B, Yunus Z, Steinmann B, Santer R (2013) Transient pseudo-hypertriglyceridemia: a useful biochemical marker of fructose-1,6-bisphosphatase deficiency. Eur J Pediatr 172: 1249–1253 31. Morris AA, Deshphande S, Ward-Platt MP et  al (1995) Impaired ketogenesis in fructose-1,6-bisphosphatase deficiency: a pitfall in the investigation of hypoglycemia. J Inherit Metab Dis 18:28–32 32. Kato S, Nakajima Y, Awaya R et al (2015) Pitfall in the diagnosis of fructose-1,6-bisphosphatase deficiency: difficulty in detecting glycerol-3-phosphate with solvent extraction in urinary GC/MS analysis. Tohoku J Exp Med 237:235–239 33. Huidekoper HH, Visser G, Ackermans MT, Sauerwein HP, Wijburg FA (2010) A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis 33:25–31 34. Baerlocher K, Gitzelmann R, Nüssli R, Dumermuth G (1971) Infantile lactic acidosis due to hereditary fructose 1,6-diphosphatase deficiency. Helv Paediatr Acta 26:489–506 35. Santer R, du Moulin M, Shahinyan T et al (2016) A summary of molecular genetic findings in fructose-1,6-bisphosphatase deficiency with focus on a common long-range deletion and the role of MLPA analysis. Orphanet J Rare Dis 11:44–50 36. Kikawa Y, Inuzuka M, Jin BY et  al (1997) Identification of genetic mutations in Japanese patients with fructose-1,6bisphosphatase deficiency. Am J Hum Genet 61:852–861 37. Hers HG, Van Schaftingen E (1982) Fructose 2,6-bisphosphate two years after its discovery. Biochem J 206:1–12 38. Hunter RW, Hughey CC, Lantier L et  al (2018) Metformin reduces liver glucose production by inhibition of fructose1-6-bisphosphatase. Nat Med 24:1395–1406 39. Hasegawa Y, Kikawa Y, Miyamaoto J et al (2003) Intravenous glycerol therapy should not be used in patients with unrecognized fructose-1,6-bisphosphatase deficiency. Pediatr Int 45:5–9 40. Sugita G, Tsuyoshi H, Nishijima K, Yoshida Y (2014) Fructose1,6-bisphosphatase deficiency: a case of a successful pregnancy by closely monitoring metabolic control. JIMD Rep 14:115–118 41. Cortese A, Zhu Y, Rebelo AP et al (2020) Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet 52:473–481 42. Sekiguchi K, Kohara N, Baba M et al (2019) Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: a randomized double-blind placebo-controlled study in Japan. J Diabetes Investig 10: 466–474

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Hyperphenylalaninaemia Peter Burgard, Robin H. Lachmann, and John H. Walter Contents 16.1

Phenylalanine Hydroxylase Deficiency – 339

16.1.1 16.1.2 16.1.3 16.1.4 16.1.5

Clinical Presentation – 339 Metabolic Derangement – 339 Genetics – 339 Diagnostic Tests – 340 Treatment and Prognosis – 340

16.2

DNAJC12 Deficiency – 346

16.2.1 16.2.2 16.2.3 16.2.4 16.2.5

Clinical Presentation – 346 Metabolic Derangement – 346 Genetics – 346 Diagnostic and Confirmatory Tests – 346 Treatment and Prognosis – 346

16.3

Maternal PKU – 346

16.3.1 16.3.2 16.3.3

Clinical Presentation – 346 Metabolic Derangement – 347 Treatment and Prognosis – 347

16.4

HPA and Disorders of Biopterin Metabolism – 348

16.4.1 16.4.2 16.4.3 16.4.4 16.4.5

Clinical Presentation – 348 Metabolic Derangement – 348 Genetics – 348 Diagnostic and Confirmatory Tests – 348 Treatment and Prognosis – 349

References – 351

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_16

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ylases 1 & 2, (and thus necessary for the production of dopamine, catecholamines, melanin and serotonin), and for alkylglycerol monooxygenase (AGMO) and 3 isoforms of nitric oxide synthase [1]. The physiological role of AGMO, which is involved in ether lipid metabolism, is not yet fully characterised. Defects in either PAH, the production or recycling of BH4 or DNAJC12 may result in hyperphenylalaninaemia (HPA), as well as in deficiency of TYR, L-dopa, dopamine, melanin, catecholamines and 5-hydroxytryptophan (5HT). When hydroxylation to TYR is impeded, PHE may be transaminated to phenylpyruvic acid (a ketone excreted in increased amounts in the urine, whence the term phenylketonuria or PKU), and further reduced and decarboxylated.

Phenylalanine Metabolism Phenylalanine (PHE), an essential aromatic amino acid, is mainly metabolised in the liver by the PHE hydroxylase (PAH) system (. Fig. 16.1). The first step in the irreversible catabolism of PHE is hydroxylation to tyrosine (TYR) by PAH. This enzyme requires the active pterin, tetrahydrobiopterin (BH4), which is formed in three steps from guanosine triphosphate (GTP), and DNAJC12 which functions as a co-chaperone with HSP70 for correct folding and stability of the aromatic amino acid hydroxylases. During the hydroxylation reaction BH4 is converted to the inactive pterin-4a-carbinolamine. Two enzymes regenerate BH4 via quinoid-dihydrobiopterin (qBH2). BH4 is also an obligate co-factor for tyrosine hydroxylase and tryptophan hydrox-

GTP GTPCH Dihydroneopterin-3-P PTPS 6-Pyruvoyltetrahydrobiopterin Sepiapterin

SR

n.e.

qBH2

SR DHPR 7,8-BH2

DHFR

PCD

BH4

Pterin-4a-carbinolamine DNAJC12 PAH

Phenylalanine

Tyrosine

–

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Tyrosine

– Tryptophan Arginine Phenylpyruvate Phenylacetate Phenyllactate

Alkylglycerol

TyrH TrpH NOS

AGMO

L-dopa

Dopamine

Catecholamines Melanin

5-OH tryptophan

Serotonin

5-HIAA

Citrulline + NO Glycerol + Aldehyde

. Fig. 16.1 The phenylalanine hydroxylation system, including the synthesis and regeneration of pterins and other pterinrequiring enzymes. AGMO, alkylglycerol monooxygenase; BH2, dihydrobiopterin (quinone); BH4, tetrahydrobiopterin; DHFR, dihydrofolate reductase; DHPR, dihydropteridine reductase; DNAJC12, heat shock protein of the HSP40 family; GTP, guanosine triphosphate; GTPCH, guanosine triphosphate cyclo-

hydrolase; 5HIAA, 5-hydroxyindoleacetic acid; NO, nitric oxide; n.e., non-enzymatic; NOS, nitric oxide synthase; P, phosphate; PAH, PHE hydroxylase; PCD, pterin-4a-carbinolamine dehydratase; PTPS, pyruvoyl-tetrahydrobiopterin synthase; SR, sepiapterin reductase; TrpH, tryptophan hydroxylase; TyrH, tyrosine hydroxylase. Encircled minus sign indicates inhibition. The enzyme defects are depicted by bars across the arrows

339 Hyperphenylalaninaemia

kIntroduction

Mutations within the gene for the hepatic enzyme phenylalanine hydroxylase (PAH) and those involving production or recycling of tetrahydrobiopterin metabolism or DNAJC12 are associated with hyperphenylalaninaemia (HPA). Severe PAH deficiency, which results in a blood phenylalanine (PHE) greater than 1200  μmol/L when individuals are on a normal protein intake, is referred to as classic phenylketonuria or just PKU. Milder defects associated with concentrations between 600 μmol/L and 1200 μmol/L are termed HPA, and those with concentrations less than 600  μmol/L but above 120  μmol/L, mild HPA (MHP). Disorders of biopterin metabolism have in the past been called malignant PKU or malignant HPA. However, such disorders are now best named according to the underlying enzyme deficiency. A comprehensive nomenclature is provided in [2]. Deficiency of DNAJC12, a heat-shock protein (HSP40) which functions as a co-chaperone with HSP70, necessary for correct folding and stability of the PAH protein, also leads to HPA in individuals without mutant PAH genes [3]. PKU if left untreated leads to permanent central nervous system damage. Dietary restriction of PHE along with amino acid, vitamin and mineral supplements, started in the first weeks of life and continued through childhood, is an effective treatment and allows for normal cognitive development. Pharmacologic treatment with BH4 can reduce blood PHE concentrations in individuals with residual PAH activity. Therapy with PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), a non-human enzyme, can also reduce blood PHE concentration. Lifelong treatment is now generally recommended for all patients with PKU, although, as yet, there is insufficient data to know how necessary this is. Less severe forms of PAH deficiency may or may not require treatment, depending on the degree of HPA; however, there is no evidence-based concentration for a raised blood PHE below which treatment is not required. PHE is a potent teratogen and high blood concentrations during pregnancy lead to the maternal PKU syndrome [4]. This can be prevented by strict dietary control of maternal blood PHE throughout pregnancy. Disorders of pterin metabolism lead to both HPA and disturbances in central nervous system amines. Generally, they require treatment with oral BH4 and neurotransmitters.

16.1

Phenylalanine Hydroxylase Deficiency

16.1.1Clinical Presentation

The natural history of untreated PKU is progressive, irreversible neurological impairment during infancy with the subsequent development of mental, behav-

ioural, neurological and physical impairments. The most common outcome is moderate to profound intellectual developmental disorder (IQ ≤ 50), often associated with a mousey odour (resulting from the excretion of phenylacetic acid), eczema (20–40%), reduced hair, skin and iris pigmentation (a consequence of impaired melanin synthesis), reduced growth and microcephaly, and neurological impairments (25% epilepsy, 30% tremor, 5% spasticity of the limbs, 80% EEG abnormalities). The brains of patients with PKU untreated in childhood have reduced arborisation of dendrites, impaired synaptogenesis and disturbed myelination. Other neurological features include pyramidal signs with increased muscle tone, hyperreflexia, Parkinsonian signs and abnormalities of gait and tics. Almost all untreated patients show behavioural problems, which include autistic spectrum disorders, hyperactivity, stereotypy, aggressiveness, anxiety and social withdrawal. The clinical phenotype correlates with PHE blood concentrations, reflecting the degree of PAH deficiency.

16.1.2Metabolic Derangement

Although the pathogenesis of brain damage in PKU is not fully understood, it is causally related to the increased concentrations of blood PHE.  Tyrosine (TYR) becomes a semi-essential amino acid, with reduced blood concentrations leading to impaired synthesis of other biogenic amines, including melanin, dopamine and norepinephrine. Increased blood PHE concentrations cause an imbalance of other large neutral amino acids (LNAA) within the brain, resulting in decreased brain concentrations of methionine, TYR and serotonin. The ratio of PHE concentrations in blood/brain is about 4:1 [5]. In addition to the effects on amino acid transport into the brain, elevated PHE inhibits TYR hydroxylation to dopamine and tryptophan decarboxylation to serotonin. The phenylketones phenylpyruvate, phenylacetate, phenylacetylglutamine and phenyllactate are not abnormal metabolites, but appear in increased concentration and are excreted in the urine.

16.1.3Genetics

PAH deficiency is autosomal-recessively transmitted. At the time of writing >1200 different PAH mutations have been described (7 http://www.biopku.org/home/pah. asp). Most patients are compound heterozygous. Although there is no single prevalent mutation, certain ones are more common in different ethnic populations: the R408W mutation accounts for approximately 30% of alleles in Europeans with PKU; in East Asians and

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South East Asians the R243Q mutation is the most prevalent (13% of alleles). The prevalence of PAH deficiency varies between different populations (e.g. 1  in 1,000,000 in Finland and 1 in 4,200 in Turkey). Overall global prevalence in screened populations is approximately 1 in 12,000, giving an estimated carrier frequency of 1 in 55. Genotypes correlate well with biochemical phenotypes, pre-treatment PHE concentrations and PHE tolerance [6], which are determined by the milder mutation in compound heterozygotes. However, owing to the many other factors that affect clinical phenotype, correlations between mutations and neurological, intellectual and behavioural outcome are weak. Genetic analysis is of limited practical use in clinical management, but may be of value in determining genotypes associated with BH4 responsiveness (7 http://www.biopku.org/ BioPKU_DatabasesBIOPKU.asp) [6] and is essential to diagnose DNAJC12 deficiency [3].

5 Non-PKU-HPA or mild hyperphenylalaninaemia (MHP) (PHE  ≤  600  μmol/L; >5% residual PAH activity), 5 BH4-Responsive PKU/HPA (blood PHE concentrations decrease substantially after oral administration of BH4, thus increasing dietary PHE tolerance. Although the spectrum of severity is continuous, such a classification has some use in terms of indicating the necessity for and type of treatment. Prenatal diagnosis, rarely requested, is possible by means of PAH analysis on chorion villus biopsy (CVB) or amniocentesis where the index case has mutations identified previously.

16.1.5Treatment and Prognosis 16.1.5.1Principles of Treatment z

16.1.4Diagnostic Tests

16

Blood PHE is normal at birth but rises rapidly within the first days of life. In most Western nations PKU is detected by newborn population screening (NBS). There is variation between different countries and centres in the age at which screening is undertaken (day 1 to day 5), in the methodology used (Guthrie microbiological inhibition test, enzymatic techniques, HPLC, or tandem mass spectrometry) and the concentration of blood PHE that is taken as a positive result requiring further investigation (120–240 μmol/L, but with some laboratories also using a PHE/TYR ratio >3). Co-factor defects must be excluded by investigation of pterins in blood or urine and dihydropteridine reductase (DHPR) in blood and DNAJC12 deficiency by mutation analysis (7 Sect. 16.2). HPA may be found in preterm and sick babies, particularly after parenteral feeding with amino acids and in those with liver disease (where blood concentrations of methionine, TYR, leucine/isoleucine and PHE are usually also raised), and in treatment with chemotherapeutic drugs or trimethoprim. PAH deficiency may be classified according to the blood PHE concentration when patients are on a normal protein-containing diet, after a standardised protein challenge, or after standardised loading with BH4 [2]. 5 Classic PKU (PHE  ≥1200  μmol/L; less than 1% residual PAH activity), 5 Hyperphenylalaninaemia (HPA) or mild PKU (PHE >600 μmol/L and 600  μmol/L [7], France, USA, Australasia >360  μmol/L [8–10], and 2016 European Society for PKU (ESPKU) guidelines >360  μmol/L [11]. To stay below these, patients with classic PKU have to reduce nutritional PHE intake to 200–400 mg/day or 4–8 g natural protein per day. In all but the USA recommendations, treatment target blood PHE concentrations are age related but show substantial variation. . Table 16.1 shows recommendations for Germany, the USA, France, the Netherlands, Switzerland, Australasia, and the 2016 ESPKU guidelines. With the exception of blood PHE concentrations for the first decade of life and during pregnancy, reported evidence levels are most often low (quasi-experimental designs, non-analytic studies or expert opinion) or not specified and most recommendations are classified as weak. Blood PHE target ranges differ particularly for age groups older than ten years, without clinical evidence that these differences matter. French guidelines accept 900 μmol/L for adults without

16

341 Hyperphenylalaninaemia

. Table 16.1 countries

Daily phenylalanine (PHE) tolerances and target blood ranges, showing different targets aimed for in various

Germany [7]

Netherlands [26]

Switzerland [100]

USA [10]

Australasia [7, 71]

Europe [11]

France [8]

Blood PHE concentration indicating treatment (μmol/l)

>600

Not specified

>400

>360

>360

>360

>360

Patient age (years)

PHE tolerance mg/day

Target blood PHE range (lower- upper boundary; μmol/L)

0

130–400

40–240

120–360

120–360

120–360

1

200–400

2

200–400

3–4

200–400

5–9

200–400

10–11

350–800

12–14

350–800

120–600

120–600

15

350–800

120–360 (>360b)

16–17

450–1000

>17

450–1000

Pregnancy

120–400a

120–240

100–300

120–360

60/120– 360

100–400

120–480 40–900

100–600

120–600 40–1200

120–600 (900c) 120-360

Not specified

100–300

120–360

70–250

120–360

120–360

atolerance

will usually increase in later stages of pregnancy after informed decision cacceptable in individuals without clinical signs bacceptable

clinical signs and Australasian guidelines recommend accepting patients’ informed decisions for concentration above 360 μmol/L after childhood. Since PHE is an essential amino acid, excessive restriction is also harmful and, particularly in infancy, will result in impaired growth and cognitive development. In order to prevent PHE deficiency a lower limit for blood PHE is also defined. The lower limit is formulated ambiguously in the US guideline recommending 120  μmol/L but stating that concentrations 60–120 μmol/L should not be regarded as too low. The degree of protein restriction required means that in order to provide a nutritionally adequate supply a semi-synthetic diet is necessary. This is composed of the following: 5 Unrestricted natural foods with a very low PHE content (16  years. The enzyme converts PHE independently from PAH and BH4 to a harmless compound, transcinnamic acid, and ammonia metabolised in the liver to urea. Covalent attachment of polyethylene glycol polymer chains (PEGylation) ‘mask’ the agent from the host’s immune system, reducing immunogenicity and antigenicity. However, during early treatment (≤6  months) but also later (at year 1) all patients develop antibodies against PEG and PAL and more than 90% experience adverse events like hypersensitivity, arthralgia/arthritis, injection site/generalized skin reactions or lymphadenopathy, and about 9% anaphylaxis episodes [25]. Treatment is initiated by a titration phase when subcutaneous injections must be accompanied by a trained observer (able to recognise signs of acute systemic hypersensitivity/anaphylaxis, to administer an epinephrine autoinjector, and call emergency services if necessary) for at least one hour following each injection. Patients must always carry the epinephrine autoinjector and be able to master its application. Daily subcutaneous injection of 20–60  mg of the enzyme per maintenance dose is effective in reducing PHE concentrations below 120  μmol/L and often allows a normal diet. In clinical trials up to 40% of

343 Hyperphenylalaninaemia

patients showed episodes of hypophenylalaninaemia (70% of adult patients from accessing treatment [35] and two thirds have PHE concentrations above the recommended range [36]. Dietary treatment of PKU is almost impossible without the support of a specialised team, which should include a dietitian, a metabolic paediatrician or physician for adult patients, a biochemist running a metabolic laboratory and a psychologist skilled in the behavioural management of a life-long diet. All professionals, and the families themselves, must fully understand the principles and practice of the diet. The therapeutic team should be trained to work in an interdisciplinary way in a treatment centre, training camps can improve long-term knowledge about the condition and its treatment [2, 11, 37].

16.1.5.3Alternative Therapies/Experimental

Trials Although dietary treatment is highly successful, it is difficult and compliance is often poor, particularly as individuals reach adolescence. Hence there is a need to develop more acceptable therapies. 5 The large neutral amino acids (LNAA; phenylalanine, tyrosine, tryptophan, leucine, isoleucine and valine) compete for the same transport mechanism (the L-type amino acid carrier) to cross the bloodbrain barrier as well as for the absorption by the intestinal mucosa [28]. Studies in the PAHenu2/2 mouse and in patients have shown a reduction in brain PHE concentrations and some positive effect on neuropsychological functions when LNAAs (apart from PHE) have been given enterally [29]. The greatest benefit may be to patients who are unable to comply with conventional dietary management, but it is likely to be of limited efficacy. 5 Gene therapy. A number of different PAH gene transfer vehicles have been tried in the PAHenu2/2 mouse. Vectors based on recombinant adenoassociated viruses (rAAVs) expressed in either liver or muscle are currently the favoured vector system. An rAAV vector with genes for PAH and BH4 synthesis injected into skeletal muscle or infused into the intraportal vein or naked DNA injected in the tail vein of PAHenu2/2 mice, showing a classical PKU phenotype, resulted in correction of PHE for more than 1  year [30]. A phase 1/2 trial of liver delivery with an AAV vector is now underway in adults with PKU (7 ClinicalTrials.gov Identifier: NCT04480567). 5 Liver transplantation fully corrects PAH deficiency [31], but the risks of transplantation surgery and

16.1.5.5Outcome

The outcome for PKU mainly depends upon the age at start of treatment, blood PHE concentrations in different age periods, duration of periods of blood PHE deficiency and the individual gradient for PHE transport across the blood-brain barrier. The most important single factor is the blood PHE concentration in infancy and childhood. Dietary treatment started within the first 3 weeks of life with average blood PHE concentrations ≤  400  μmol/L in infancy and early childhood result in near-normal intellectual development. However, for each 300 μmol/L increase in blood PHE during the first 6 years of life, IQ is reduced by 0.5 of a standard deviation (SD), and during age 5–10  years the reduction is 0.25 SD. Furthermore, IQ at the age of 4 years is reduced by 0.25 SD for each 4 weeks of delay in the start of treatment and for each 5 months of insufficient PHE intake. After the age of 10 years all large studies show stable IQ performance, at least until mid-adulthood irrespective of PHE concentrations [38–41], and a normal school career if compliance during the first 10 years has been accord-

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ing to treatment recommendations [42–44]. A Bayesian meta-analysis covering the age range from 2 to 35 years distinguished long-term and concurrent blood PHE concentrations in a critical (120

↑

↑

–

↓a

N

PAH

GTPCH

50–1200

↓↓

↓↓

–

↓

N

GTCH1

PTPS

240–2500

↓↓

↑↑

–

↓

N

PTS

DHPR

180–2500

↓↓

N or ↑

–

↓

↓

QDPR

PCD

180–1200

↓

↑

↑↑

N

N

PCBD1

DNAJC12

>120

N

N

–

↓

N

DNAJC12

CSF, cerebrospinal fluid; DHPR, dihydropterin reductase; GTPCH, guanosine triphosphate cyclohydrolase I; 5-HIAA, 5-hydroxyindole acetic acids; HVA, homovanillic acid; N, normal; PAH, phenylalanine hydroxylase; PCD, pterin-4a-carbinolamine dehydratase; PHE, phenylalanine; PTPS, 6-pyruvoyl-tetrahydropterin synthase aIn PAH deficiency, as long as PHE concentrations remain elevated, there is a secondary inhibition of tyrosine and tryptophan hydroxylases causing depletion in CSF amines

loading test is reported to identify BH4-responsive PAH deficiency and discriminate between co-factor synthesis or regeneration defects and is useful if pterin analysis is not available [91, 92]. 16.4.4.3CSF Neurotransmitters

The measurement of HVA and 5-HIAA is an essential part of the diagnostic investigation and is also subsequently required to monitor amine replacement therapy with L-dopa and 5HT.  CSF must be frozen in liquid nitrogen immediately after collection and stored at –70 °C prior to analysis. If blood stained, the sample should be centrifuged immediately and the supernatant then frozen. The reference ranges for HVA and 5-HIAA are age related [93] (see also 7 Chap. 30). 16.4.4.4Confirmatory Tests

Apart from DHPR measurement in erythrocytes, measurement of enzyme activity is not necessary for the initial diagnosis. Molecular analysis is available for all conditions and is now likely to be the method of choice for confirmation of the diagnosis. Where results can be obtained in an acceptable time frame gene panels or next generation sequencing may be used as an alternative to pterin analysis as a first line investigation in infants with HPA on NBS. Where necessary, for further confirmation DHPR activity can be measured in fibroblasts, PTPS activity in erythrocytes and fibroblasts and GTPCH activity in liver, cytokine-stimulated fibroblasts and stimulated lymphocytes. If PAH deficiency and disorders of biopterin metabolism cannot be confirmed as a cause of HPA, molecular analysis should be undertaken for DNAJC12 mutations [3].

16.4.4.5Prenatal Diagnosis

If the mutation of the index case is already known prenatal diagnosis can be undertaken in the first trimester by mutation analysis following chorionic villus biopsy. Analysis of amniotic fluid neopterin and biopterin in the second trimester is available for all conditions. Enzyme analysis can be undertaken in foetal erythrocytes or in amniocytes in both DHPR deficiency and PTPS deficiency. GTPCH is only expressed in foetal liver tissue.

16.4.5Treatment and Prognosis

For GTPCH deficiency, PTPS deficiency and DHPR deficiency the aim of treatment is to control the HPA and to correct CNS amine deficiency. In DHPR deficiency treatment with folinic acid is necessary to prevent CNS folate deficiency [58], and it may also be required in GTPCH and PTPS deficiency, where a reduction in CSF folate can be a consequence of long-term treatment with L-dopa. PCD deficiency does not usually require treatment, although BH4 may be used initially if the child is symptomatic. In PTPS and GPCH deficiency, blood PHE responds to treatment with oral BH4 (available as sapropterin dihydrochloride). In DHPR deficiency, BH4 may also be effective in reducing blood PHE, but higher doses may be required than in GTPCH and PTPS deficiency. This, in theory, might lead to an accumulation of BH2 and inhibition of BH4 dependent enzymes [94]. Consequently, it has been recommended that in DHPR deficiency HPA should be corrected by dietary means and BH4 should

P. Burgard et al.

350

not be given. However, a number of patients with DHPR deficiency have been successfully treated with BH4 and in a single case report, BH4 up to a dose of 40  mg/kg/day did not cause a further increase in CSF BH2 [95]. CNS amine replacement therapy is given as oral L-dopa with carbidopa (usually in 1:10 ratio, but also available in 1:4 ratio) and 5HT. Carbidopa is a dopadecarboxylase inhibitor that reduces the peripheral conversion of L-dopa to dopamine, thus limiting side effects and allowing a reduced dose of L-dopa to be effective. Side effects (nausea, vomiting, diarrhoea, irritability) may also be seen at the start of treatment. For this reason L-dopa and 5HT should initially each be started in a low dose (. Table 16.3), which is increased gradually to the recommended maintenance dose. Further dose adjustment depends on the results of CSF HVA and 5-HIAA concentrations. Additional medications, developed primarily for treatment of Parkinson’s disease, have been used as an adjunct to therapy, with the aim of reducing the dose and frequency of amine replacement medication and improving residual symptoms and preventing diurnal variation. These include selegiline (L-deprenyl), a

. Table 16.3

16

monoamine oxidase-B inhibitor [96], entacapone, a catechol-O-methyltransferase (COMT) inhibitor and pramipexole, a dopamine agonist. Pramipexole, in higher doses, has been reported to cause adverse psychiatric effects [97]. For further discussion on the use of medication see [87]. 16.4.5.1Monitoring of Treatment

CSF amine concentrations should be monitored 3-monthly in the 1st year, 6-monthly in early childhood and yearly thereafter. Where possible, CSF should be collected before a dose of medication is given. CSF folate should also be measured. Hyperprolactinaemia occurs as a consequence of dopamine deficiency and measurement of serum prolactin can be used as a method to monitor treatment, with normal values indicating adequate L-dopa replacement. It has been suggested that 3 blood prolactin measurements over a 6 hour period may be a more sensitive and less invasive marker than the CSF HVA concentration in deciding on dose adjustment [98]. Blood PHE must also be monitored, but this only needs to be undertaken frequently in DHPR deficiency where a low-PHE diet is used.

Medication used in the treatment of disorders of biopterin metabolism

Drug

Dose (oral)

Frequency

GTPCH

PTPS

PCD

DHPR

BH4

2–5 mg/kg/day, increasing to 5–10 mg/day according to blood PHE response

Once daily

+

+

±

±a

5HT

1–2 mg/kg/day, increasing by 1–2 mg/kg/day every 4–5 days up to maintenance dose of 8–10 mg/ kg/day

Give in four divided doses; final maintenance dose dependent on results of CNS neurotransmitters

+

+

–

+

L-Dopa (as combined preparation with carbidopa)

1–2 mg/kg/day, increasing by 1–2 mg/kg/day every 4–5 days up to maintenance dose of 10–12 mg/ kg/day

Give in four divided doses; final maintenance dose dependent on results of CNS neurotransmitters

+

+

–

+

Selegiline (L-deprenyl)

0.1–0.25 mg/day

In three or four divided doses (as adjunct to 5HT and L-dopa; see text)

±

±

–

±

Entacapone

15 mg/kg/day

In two or three divided doses

±

±

–

±

Pramipexole

0.006 mg/kg/day increasing to 0.010 mg/kg/dayb

In two to three divided doses

±

±

–

±

Calcium folinate (folinic acid)

15 mg/day

Once daily

±

±

–

+

BH4, tetrahydrobiopterin; CNS, central nervous system; DHPR, dihydropterin reductase; GTPCH, guanosine triphosphate cyclohydrolase I; 5HT, 5-hydroxytrytophan; PCD, pterin-4a-carbinolamine dehydratase; PTPS, 6-pyruvoyl-tetrahydropterin synthase aSee text bHigher doses (0.030–0.033 mg/kg/day) have been used but may cause psychiatric adverse effects [97]

351 Hyperphenylalaninaemia

16.4.5.2Outcome

Without treatment the natural history of GTPCH, PTPS and DHPR deficiency is poor, with progressive neurological disease and early death. The outcome with treatment depends upon the age at diagnosis and initiation of therapy and the phenotypic severity [88]. Most children with GTPCH deficiency have some degree of learning difficulties despite adequate control. Patients with PTPS deficiency may have a satisfactory cognitive outcome if detected early. Those with DHPR deficiency, if started on diet, amine replacement therapy and folinic acid within the first months of life, can show normal development and growth. Late diagnosis in all these conditions is associated with a much poorer outcome. The outcome of pregnancies in women with biopterin synthesis disorders on treatment appears to be good without worsening of symptoms or other disease specific complications. Foetal outcome was also satisfactory [99].

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Disorders of Tyrosine Metabolism Anupam Chakrapani, Paul Gissen, and Patrick McKiernan Contents 17.1

Hereditary Tyrosinaemia Type I (Hepatorenal Tyrosinaemia): Fumarylacetoacetate Hydrolase Deficiency – 357

17.1.1 17.1.2 17.1.3 17.1.4 17.1.5

Clinical Presentation – 357 Metabolic Derangement – 358 Genetics – 359 Diagnostic Tests – 359 Treatment and Prognosis – 360

17.2

Maleylacetoacetate Isomerase Deficiency (Mild Hypersuccinylacetonaemia, MHSA) – 361

17.2.1 17.2.2 17.2.3 17.2.4

Clinical Presentation – 361 Metabolic Derangement and Genetics – 361 Diagnostic Tests – 362 Treatment and Prognosis – 362

17.3

Hereditary Tyrosinaemia Type II (Oculocutaneous Tyrosinaemia, Richner-Hanhart Syndrome): Hepatic Cytosolic Tyrosine Aminotransferase Deficiency – 362

17.3.1 17.3.2 17.3.3 17.3.4 17.3.5

Clinical Presentation – 362 Metabolic Derangement – 362 Genetics – 363 Diagnostic Tests – 363 Treatment and Prognosis – 363

17.4

Hereditary Tyrosinaemia Type III: 4-hydroxyphenylpyruvate Dioxygenase Deficiency – 363

17.4.1 17.4.2 17.4.3 17.4.4 17.4.5

Clinical Presentation – 363 Metabolic Derangement – 363 Genetics – 363 Diagnostic Tests – 364 Treatment and Prognosis – 364

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_17

17

17.5

Transient Tyrosinaemia – 364

17.6

Alkaptonuria: Homogentisate Dioxygenase Deficiency – 364

17.6.1 17.6.2 17.6.3 17.6.4 17.6.5

Clinical Presentation – 364 Metabolic Derangement – 365 Genetics – 365 Diagnostic Tests – 365 Treatment and Prognosis – 365

17.7

Hawkinsinuria – 365

17.7.1 17.7.2 17.7.3 17.7.4 17.7.5

Clinical Presentation – 365 Metabolic Derangement – 365 Genetics – 366 Diagnostic Tests – 366 Treatment and Prognosis – 366

References – 366

357 Disorders of Tyrosine Metabolism

Tyrosine Metabolism Tyrosine is a non-essential amino acid that is derived from two sources, diet and hydroxylation of phenylalanine (. Fig. 17.1). Besides forming an integral part of proteins, it is a precursor of DOPA, thyroxine and melanin. Post- translational modifications of tyrosine residues in proteins by phosphorylation and sulfation have important roles in signal transduction and modulation of interaction between proteins. Tyrosine is both glucogenic and ketogenic, since its catabolism, which proceeds predominantly in the liver cytosol, results in the formation of fumarate and acetoacetate. The first step of tyrosine catabolism is conversion into 4-hydroxyphenylpyruvate by cytosolic tyrosine aminotransferase. Transamination of tyrosine can also be accomplished in the liver and in other tissues by mitochondrial aspartate aminotransferase, but this enzyme plays only a minor role under normal conditions. The penultimate intermediates of tyrosine catabolism, maleylacetoacetate and fumarylacetoacetate, are reduced to succinylacetoacetate, followled by decarboxylation to succinylacetone. The latter is the most potent known inhibitor of the heme biosynthetic enzyme, 5-aminolevulinic acid dehydratase (porphobilinogen synthase; 7 Fig. 39.1).

kIntroduction

Six inherited disorders of tyrosine metabolism are known (7 Tyrosine Metabolism). Hereditary tyrosinaemia type I is characterised by progressive liver disease and renal tubular dysfunction with rickets. Hereditary tyrosinaemia type II (Richner-Hanhart syndrome) presents with keratitis and blistering lesions of the palms and soles and neurological complications. Tyrosinaemia type III may be asymptomatic or associated with mental retardation. Hawkinsinuria may be asymptomatic or present with failure to thrive and metabolic acidosis in infancy. In alkaptonuria, symptoms of osteoarthritis usually appear in adulthood. Maleylacetoacetate isomerase deficiency is associated with asymptomatic mild hypersuccinylacetonaemia. Other inborn errors of tyrosine metabolism include oculocutaneous albinism caused by a deficiency of melanocyte-specific tyrosinase, converting tyrosine into DOPA-quinone; deficiency of tyrosine hydroxylase, the first enzyme in the synthesis of dopamine from tyrosine; and deficiency of aromatic L-amino acid decarboxylase, which also affects tryptophan metabolism. The latter two disorders are covered in 7 Chap. 30.

Phenylalanine Mitochondria Tyrosine

Tyrosine 6

1 4-Hydroxyphenylpyruvate

4-hydroxyphenylpyruvate

2 Homogentisate

4-Hydroxyphenyllactate

3 Maleylacetoacetate Succinylacetoacetate

4 Fumarylacetoacetate

CO2

5 Succinylacetone Fumarate

Acetoacetate

– Porphobilinogen

5-Aminolevulinic acid 7

. Fig. 17.1 The tyrosine catabolic pathway. 1, Tyrosine aminotransferase (deficient in tyrosinaemia type II); 2, 4-hydroxyphenylpyruvate dioxygenase (deficient in tyrosinaemia type III, hawkinsinuria, site of inhibition by NTBC); 3, homogentisate dioxygenase (deficient in alkaptonuria); 4, Maleylacetoacetate isomerase (deficient in maleylacetoacetate isomerase deficiency; 5, fumarylacetoacetase (deficient in tyrosinaemia type I); 6, aspartate aminotransferase; 7, 5-aminolevulinic acid dehydratase (porphobilinogen synthase). Enzyme defects are depicted by solid red bars across the arrows

17.1

Hereditary Tyrosinaemia Type I (Hepatorenal Tyrosinaemia): Fumarylacetoacetate Hydrolase Deficiency

17.1.1Clinical Presentation

The clinical manifestations of tyrosinaemia type I are very variable, and an affected individual can present at any time from the neonatal period to adulthood. There is considerable variability of presentation even between members of the same family. Clinically, tyrosinaemia type I may be classified based on the age at onset of symptoms, which broadly

17

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correlates with disease severity: an acute form that manifests before 6  months of age (but rarely in the first 2 weeks of life) with acute liver failure; a subacute form presenting between 6  months and 1  year of age with liver disease, failure to thrive, coagulopathy, hepatosplenomegaly, rickets and hypotonia; and a more chronic form that presents after the first year with chronic liver disease, renal disease, rickets, cardiomyopathy and/or a porphyria-like syndrome. Treatment of tyrosinaemia type I with nitisinone in the last 25 years (7 Sect. 17.1.5) has dramatically altered its natural history. z

17

Hepatic Disease

The liver is the major organ affected in tyrosinaemia type I, and its involvement is a major cause of morbidity and mortality. Liver disease can manifest as acute hepatic failure, cirrhosis or hepatocellular carcinoma; all three conditions may occur in the same patient. The more severe forms of tyrosinaemia type I present in infancy with vomiting, diarrhoea, bleeding diathesis, hepatomegaly, mild jaundice, hypoglycaemia, oedema and ascites. Typically, liver synthetic function is most affected and, in particular, coagulation is markedly abnormal compared with other tests of liver function. Sepsis is common, and early hypophosphataemic bone disease may be present secondary to renal tubular dysfunction. Acute liver failure may be the presenting feature or may occur subsequently, precipitated by intercurrent illnesses, as hepatic crises which are associated with hepatomegaly and coagulopathy. Mortality is high in untreated patients [1]. Chronic liver disease leading to cirrhosis eventually occurs in most individuals with tyrosinaemia type I  – both as a late complication in survivors of early-onset disease and as a presenting feature of the later-onset forms. The cirrhosis is usually a mixed micro and macronodular type with a variable degree of steatosis. Hepatocyte dysplasia is common, with a high risk of malignant transformation [1, 2]. Unfortunately, the heterogeneity of the nodules make it difficult to detect malignant changes at an early stage (7 Sect. 17.1.5). z

Renal Disease

A variable degree of renal dysfunction is detectable in most patients at presentation, ranging from mild tubular dysfunction to renal failure. Proximal tubular disease is very common and may deteriorate during hepatic crises. Hypophosphataemic rickets is the most common manifestation of proximal tubulopathy, but generalised aminoaciduria, renal tubular acidosis and glycosuria may also be present [3]. Prior to the nitisinone era 40% developed nephrocalcinosis [4]. Rare renal manifestations include distal renal tubular disease and renal impairment.

z

Neurological Crises

Acute neurological porphyria like crises can occur at any age. Typically, the crises follow a minor infection associated with anorexia and vomiting, and occur in two phases: an active period lasting 1–7 days characterised by progressive ascending polyneuropathy, painful paresthesias and autonomic signs that may progress to paralysis, followed by a recovery phase over several days to months [5]. Complications include seizures, extreme hyperextension, self-mutilation, respiratory paralysis and death. These neurological crises are generally seen after discontinuation of Nitisinone treatment. z

Neurodevelopmental

It has recently been recognized that many patients with tyrosinaemia type I have a spectrum of significant learning difficulties; these include lowered IQ and school performance, limited attention span and impaired executive function [6, 7]. The aetiology of these cognitive deficits is uncertain; whether they are related to nitisinone treatment, high tyrosine levels, low phenylalanine levels, a complication of liver failure, or are an intrinsic feature of tyrosinaemia type I per se, is currently unknown. z

Other Manifestations

Cardiomyopathy is an occasional incidental finding but may be clinically significant [8]. Pancreatic cell hypertrophy may result in clinically significant hyperinsulinism [9].

17.1.2Metabolic Derangement

Tyrosinaemia type 1 is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), (. Fig. 17.1, enzyme 5) which is mainly expressed in the liver and kidney. The compounds immediately upstream from the FAH reaction, maleylacetoacetate (MAA) and fumarylacetoacetate (FAA), and their derivatives, succinylacetone (SA) and succinylacetoacetate (SAA) accumulate and have important pathogenic effects. The effects of FAA and MAA occur only in the cells of the organs in which they are produced; these compounds are not found in body fluids of patients. On the other hand, their derivatives, SA and SAA are readily detectable in plasma and urine and have widespread effects. FAA, MAA and SA disrupt sulfhydryl metabolism by forming glutathione adducts, thereby rendering cells susceptible to free radical damage [10]. Disruption of sulfhydryl metabolism is also believed to cause secondary deficiency of two other hepatic enzymes, 4-hydroxyphenylpyruvate dioxygenase and methionine adenosyltransferase, resulting in hypertyrosinemia and hypermethioninemia. Additionally, FAA and MAA are

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alkylating agents and can disrupt the metabolism of thiols, amines, DNA and other important intracellular molecules including inhibition of base excision repair by FAA, suggesting a mechanism for carcinogenesis in tyrosinaema type I [11]. As a result of these widespread effects on intracellular metabolism, hepatic and renal cells exposed to high levels of these compounds undergo either apoptotic cell death or a significant alteration of gene expression [12, 13]. In patients who have developed cirrhosis, self-induced correction of the genetic defect and the enzyme abnormality occurs within some nodules. The clinical expression of hepatic disease may correlate inversely with the extent of mutation reversion in regenerating nodules [14]. SA is a potent inhibitor of the enzyme 5-aminolevulinic acid (5-ALA) dehydratase (block 7, . Fig. 17.1). 5-ALA, a neurotoxic compound, accumulates and is excreted at high levels in patients with tyrosinemia type I and is believed to cause the acute neurological crises seen during decompensation [5]. SA is also known to disrupt renal tubular function, heme synthesis and immune function [15–17]. z

Newborn Screening

There is strong clinical evidence to support newborn screening for tyrosinemia type I, as the detection and treatment of patients in early life results in a dramatically better outcome than when treatment is initiated late [18, 19]. Screening using tyrosine levels alone has been used in the past and has resulted in very high falsepositive and false-negative rates [20]. SA is a highly sensitive and specific marker for tyrosinaemia type I, and assays based on the inhibitory effects of SA on 5-ALA dehydratase, either alone or in combination with tyrosine levels, have greatly improved diagnostic accuracy [20]. Screening methods based on the direct measurement of SA in dried blood spots by tandem mass spectrometry have also demonstrated excellent test accuracy; several laboratory-based methods have been described and commercial kit-based assays are available, facilitating the routine inclusion of tyrosinaemia type I in many newborn screening programmes [21]. Maleylacetoacetate isomerase deficiency (7 Sect. 17.2) can cause mild hypersuccinylacetonaemia and may be detected on newborn screening using SA as the primary biomarker, depending on the limits of detection used in individual screening laboratories. This condition is believed to be asymptomatic and SA levels are orders of magnitude lower than those seen in Tyrosinemia type 1. z

Prenatal Diagnosis

The description of the geographical and ethnic distribution of causative mutations in many populations worldwide has enabled improved carrier detection, prenatal

diagnosis and pre-implantation diagnosis [22]. Antenatal diagnosis is best performed by mutation analysis on chorionic villus sampling (CVS) or amniocytes. Alternative methods include FAH assay on CVS or amniocytes and determination of SA levels in amniotic fluid. However, FAH is expressed at low levels in chorionic tissue and interpretation of results may be difficult. Assay for elevated SA levels in amniotic fluid is very reliable and can be performed as early as 12  weeks; however, in occasional affected pregnancies normal SA amniotic fluid levels have been reported [23]. When mutation analysis is not available for prenatal diagnosis, we recommend a strategy combining initial screening for the common pseudodeficiency mutation and FAH assay on CVS at 10  weeks; in the case of low FAH activity revealed by CVS, amniocentesis for amniotic fluid SA levels is subsequently performed at 11–12 weeks for confirmation.

17.1.3Genetics

Tyrosinaemia type I is inherited as an autosomal recessive trait. Almost 100 mutations have been reported in FAH [24]. The most common mutation, I c.1062 + 5G > A, is found in about 25% of the alleles worldwide and is the predominant mutation in the French-Canadian population, in which it accounts for >90% of alleles. Another mutation, c.554-1G > T, is found in around 60% of alleles in patients from the Mediterranean area. Other FAH mutations are common within certain ethnic groups: W262X in Finns, D233V in Turks, and Q64H in Pakistanis. There is no clear genotype-phenotype correlation; spontaneous correction of the mutation within regenerative nodules may influence the clinical phenotype [14]. A novel mutation c.103G > A was found in a patient with a mild phenotype who did not excrete succinylacetone and was successfully treated with diet alone [25]. A pseudodeficiency mutation, R341W, has been reported in healthy individuals who have in  vitro FAH activity indistinguishable from that in patients with tyrosinaemia type I [26]. The frequency of this mutation in various populations is unknown, but it has been found in many different ethnic groups.

17.1.4Diagnostic Tests

In symptomatic patients, biochemical tests of liver function are usually abnormal. In particular, liver synthetic function is severely affected  – coagulopathy and/or hypoalbuminaemia are often present even if other tests of liver function are normal. In most acutely ill patients, α-fetoprotein levels are greatly elevated. A Fanconi-type

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tubulopathy is often present with aminoaciduria, phosphaturia and glycosuria, and radiological evidence of rickets may be present. Significantly elevated levels of succinylacetone in dried blood spots, plasma or urine are pathognomonic of tyrosinaemia type I. Mildly elevated levels (50  μmol/l or a whole blood concentration of 20–40 μmol/l. Dietary restriction of phenylalanine and tyrosine is necessary to prevent the known adverse effects of hypertyrosinaemia (7 Sect. 17.2). We currently aim to maintain tyrosine levels between 200 and 400 μmol/l with a phenylalanine level of >30 μmol/l using a combination of a protein-restricted diet and phenylalanine- and tyrosine free amino acid mixtures. Occasionally specific phenylalanine supplementation is necessary. A small proportion of acutely presenting patients (7 years

26

7–31

9 (35%)

HCC hepatocellular carcinoma, n/a not applicable, NTBC 2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione, or nitisinone

z

Liver Transplantation

Liver transplantation provides a functional cure of tyrosinaemia type I and allows a normal unrestricted diet [31]. However, even in optimal circumstances, it is associated with approximately 5-10% mortality and necessitates lifelong immunosuppressive therapy. Therefore, at present liver transplantation in tyrosinaemia type I is restricted to patients with acute liver failure who fail to respond to nitisinone therapy, patients with proven or suspected HCC or where nitisinone is unavailable. The long-term impact of liver transplantation on renal disease in patients with tyrosinaemia type I relates to the era in which they were treated. Prior to nitisinone, all patients had tubular dysfunction and some had glomerular dysfunction before receiving transplants. In this group tubular function improved in most patients but they had higher rates of glomerular dysfunction owing to nephrotoxic immunotherapy [31, 32]. Patients pretreated with nitisinone usually have normal renal function at transplant, and this combined with the modern immunosuppression regimens ensures they have a much improved renal prognosis [33]. After transplantation, when nitisinone is discontinued, renal production results in significantly elevated plasma and urinary SA levels. The functional significance of these findings is unclear, but does not seem to be associated with renal dysfunction or malignancy. At present nitisinone treatment, which would probably necessitate reintroduction of dietary restriction, is not indicated. z

Supportive Treatment

In the acutely ill patient supportive treatment is essential. Clotting factors, albumin, electrolytes and acid/ base balance should be closely monitored and corrected as necessary. Tyrosine and phenylalanine intake should be kept to a minimum during acute decompensation.

Vitamin D is necessary to treat rickets. Infections should be treated aggressively. z

Pregnancy

A few pregnancies in patients on nitisinone treatment have been reported with encouraging outcomes and where pregnancy occurs Nitisinone should be continued [34, 35]. Pregnancy is a realistic expectation for the majority of women who have had liver transplantation for any indication. Although close monitoring is required the outcome is excellent for both mother and infant. In our experience, a number of women have had successful pregnancies after liver transplant for tyrosinaemia type I.

17.2

Maleylacetoacetate Isomerase Deficiency (Mild Hypersuccinylacetonaemia, MHSA)

17.2.1Clinical Presentation

All six cases of MHSA described to date [27] have been asymptomatic up to 13 years of age. All were detected incidentally during the course of newborn screening for Tyrosinemia type 1 in Quebec using succinylacetone as the primary biomarker. No abnormalities in coagulation, liver function, AFP, and plasma amino acids were detected on follow up.

17.2.2Metabolic Derangement and Genetics

Mildly elevated succinylacetone levels are caused by deficiency of the enzyme maleylacetoacetate isomerase (. Fig. 17.1, enzyme 4). Five of the six reported patients

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have been found to have pathogenic biallelic mutations in GSZT1 which encodes for the enzyme. One patient, with the lowest SA levels at diagnosis, was found to have only one sequence variant, and it is speculated that certain single deleterious mutations may also cause MHSA; alternatively, the biochemical phenotype may be determined by alternative pathways of maleylacetoacetate metabolism [27].

17.2.3Diagnostic Tests

In the Quebec MHSA cohort diagnosed on newborn screening, plasma SA levels were elevated to around tenfold the upper limit of normal. Coagulation studies (INR and Prothrombin time), AFP, and plasma tyrosine levels were normal. In contrast, all cases of Tyrosinemia type 1 were associated with SA levels 1000-fold the upper limit of normal, along with abnormal coagulation studies, AFP, and plasma tyrosine levels at presentation. SA levels in maleylacetoacetate isomerase deficiency were found to decrease over time, but remained above the reference range. The enzyme deficiency has been demonstrated in bacterial mutation expression assays, and direct liver enzyme assay has not yet been reported.

17.2.4Treatment and Prognosis

17

Theoretically, treatment with Nitisinone plus dietary restriction would be expected to be effective. The parents of the six reported patients were offered this option, but all instead chose non-treatment alongside a surveillance programme with regular monitoring of liver and kidney function through clinical, biochemical, and imaging techniques [27]. All parameters remained normal without any treatment for up to 13 years, with a progressive decline in plasma and urine SA levels to just above the normal range.

17.3

Hereditary Tyrosinaemia Type II (Oculocutaneous Tyrosinaemia, Richner-Hanhart Syndrome): Hepatic Cytosolic Tyrosine Aminotransferase Deficiency

17.3.1Clinical Presentation

The disorder is characterised by ocular lesions (about 75% of the cases), skin lesions (80%), or neurological complications (60%), or by any combination of these

[36]. The disorder usually presents in infancy but can become manifest at any age. Eye symptoms are often the presenting problem and may start in the first months of life with photophobia, lacrimation and intense burning pain. The conjunctivae are inflamed and on slit-lamp examination herpetic-like corneal ulcerations are found. The lesions stain poorly with fluorescein. In contrast with herpetic ulcers, which are usually unilateral, the lesions in tyrosinaemia type II are bilateral. Neovascularisation may be prominent. Untreated, serious damage may occur with corneal scarring, visual impairment, nystagmus and glaucoma. Skin lesions specifically affect pressure areas and most commonly occur on the palms and soles. They begin as blisters or erosions with crusts and progress to painful, nonpruritic hyperkeratotic plaques with an erythematous rim, typically ranging in diameter from 2 mm to 3 cm. Clinically, tyrosinemia II has to be differentiated from other severe forms of palmoplantar keratoderma such as Olmsted syndrome [37]. Neurological complications are highly variable: some patients are developmentally normal, whilst others have variable degrees of developmental retardation. More severe neurological problems, including microcephaly, seizures, self-mutilation and behavioural difficulties, have also been described [38]. It should be noted that the diagnosis of tyrosinaemia type II has only been confirmed by enzymatic and/or molecular genetic analysis in a minority of the early described cases and it is possible that some of these patients have actually had tyrosinaemia type III. 17.3.2Metabolic Derangement

Tyrosinaemia type II is due to a defect of hepatic cytosolic tyrosine aminotransferase (. Fig.  17.1, enzyme 1). As a result of the metabolic block, tyrosine concentrations in serum and cerebrospinal fluid are markedly elevated. The accompanying increased production of the phenolic acids 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenylacetate (not shown in . Fig. 17.1) may be a consequence of direct deamination of tyrosine in the kidneys, or of tyrosine catabolism by mitochondrial aminotransferase (. Fig. 17.1). Corneal damage is thought to be related to crystallisation of tyrosine in the corneal epithelial cells, which results in disruption of cell function and induces an inflammatory response. Tyrosine crystals have not been observed in the skin lesions. It has been suggested that excessive intracellular tyrosine enhances cross-links between aggregated tonofilaments and modulates the number and stability of microtubules [39]. As the skin lesions occur on pressure areas, it is likely that mechanical factors also play a role. Studies on a

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rat model of Tyrosinemia type II have suggested that hypertyrosinemia-induced disruption of energy metabolism and oxidative stress may underlie the neurological complications [40].

17.3.3Genetics

Tyrosinaemia type II is inherited as an autosomal recessive trait due to mutations in TAT. Several different mutations have so far been reported [24]. Prenatal diagnosis using mutation analysis on chorionic villus sampling has been reported.

17.3.4Diagnostic Tests

Plasma tyrosine concentrations are usually above 1200 μmol/l. When the tyrosinaemia is less pronounced a diagnosis of tyrosinaemia type III should be considered (7 Sect. 17.4). Urinary excretion of the phenolic acids 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenylacetate is highly elevated, and N-acetyltyrosine and 4-tyramine are also increased. The diagnosis can be confirmed by mutation analysis. Patients diagnosed using tyrosine levels as part of expanded neonatal screening programmes have been reported. In a neonatally diagnosed patient early detection by screening facilitated presymptomatic treatment and identification of an affected 8-year old sibling who suffered with plantar hyperkeratosis [41].

pregnancies have been followed by normal fetal outcome [42, 43], although these have only been associated with mild hypertyrosinaemia. In view of the uncertainty regarding possible fetal effects of maternal hypertyrosinaemia, dietary control of maternal tyrosine levels during pregnancy is recommended. In one pregnancy [44] treated with a low-protein diet to maintain plasma tyrosine levels of 100–200 μmol/l and phenylalanine levels of 200–400  μmol/l, a normal fetal and maternal outcome was reported.

17.4

Hereditary Tyrosinaemia Type III: 4-hydroxyphenylpyruvate Dioxygenase Deficiency

17.4.1Clinical Presentation

Only a few cases of tyrosinaemia type III have been described, and the full clinical spectrum of this disorder is not completely known [45]. Many of the patients have presented with neurological symptoms, including intellectual impairment, ataxia, increased tendon reflexes, tremors, microcephaly and seizures; some have been detected by the finding of a high tyrosine concentration on neonatal screening. The most common long-term complication has been intellectual impairment, found in 75% of the reported cases. None have developed signs of liver disease. Eye and skin lesions have not been reported so far, but as oculocutaneous symptoms are known to occur in association with hypertyrosinaemia it is reasonable to be aware of this possibility.

17.3.5Treatment and Prognosis

Treatment consists in a phenylalanine- and tyrosinerestricted diet, and the skin and eye symptoms resolve within weeks of treatment [42]. Generally, skin and eye symptoms do not occur at tyrosine levels 500 micromol/L, but the long term clinical efficacy of this approach is not yet known [56]. One patient has been treated with low dose nitisinone (0.2–0.5 mg/day) in conjunction with a low protein diet through pregnancy, without any adverse fetal effects [56].

17.7

Hawkinsinuria

17.6.3Genetics 17.7.1Clinical Presentation

Alkaptonuria is an autosomal recessive disorder. Over 200 mutations have been identified in the gene for homogentisate dioxygenase (HGD) most of them private missense mutations [50]. There is no apparent correlation between the genotype, biochemical findings, and clinical manifestations [24, 50]. The estimated incidence is between 1:250,000 and 1:1,000,000 live births.

This rare condition, which has only been described in a few families [57], is characterised by failure to thrive and metabolic acidosis in infancy. After the first year of life the condition appears to be asymptomatic. Early weaning from breastfeeding seems to precipitate the disease; the condition may be asymptomatic in breastfed infants.

17.6.4Diagnostic Tests

17.7.2Metabolic Derangement

Alkalinisation of the urine from alkaptonuric patients results in immediate dark brown colouration of the urine. Excessive urinary homogentisate also results in a positive test for reducing substances. Gas chromatography-mass spectrometry (GC-MS)-based organic acid screening methods can specifically identify and quantify homogentisic acid. Homogentisate may also be quantified by HPLC and by specific enzymatic methods. Genetic testing is confirmatory and widely available.

The abnormal metabolites produced in hawkinsinuria (hawkinsin (2-cysteinyl-1,4-dihydroxycyclohexenylacetate) and 4-hydroxycycloxylacetate) are thought to derive from incomplete conversion of 4-hydroxyphenylpyruvate to homogentisate caused by a defect in 4-hydroxyphenylpyruvate dioxygenase (HPD; . Fig. 17.1, enzyme 2). Hawkinsin is thought to be the product of a reaction of an epoxide intermediate with glutathione, which may be depleted. The metabolic

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acidosis is believed to be due to pyroglutamic acid accumulation secondary to glutathione depletion.

5.

17.7.3Genetics

7.

Hawkinsinuria is a condition allelic to tyrosinaemia type III, and a single dominant mutation HPD, c.772A > G (Asn241Ser) has been reported in affected patients [57]. Using bioinformatic analysis of protein structure the authors concluded that hawkinsinuria is caused by mutations associated with the retention of partial HPD function and which leads to the production of hawkinsin and 4-hydroxycyclohexylacetate.

17.7.4Diagnostic Tests

Identification of urinary hawkinsin or 4-hydroxycyclohexylacetate by GC-MS is diagnostic [57]. Hawkinsin is a ninhydrin-positive compound, which appears between urea and threonine in ion-exchange chromatography of urine amino acids. Increased excretion of 4-hydroxycyclohexylacetate is detected on urine organic acids analysis. In addition to hawkinsinuria there may be moderate tyrosinaemia, increased urinary 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, metabolic acidosis and 5-oxoprolinuria during infancy. Mutation analysis of HPD is confirmatory.

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8.

9. 10.

11.

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15.

16.

17.7.5Treatment and Prognosis

17.

Symptoms in infancy respond to a return to breastfeeding or a diet restricted in tyrosine and phenylalanine along with vitamin C supplementation. N-Acetylcysteine has also been reported to be effective [58]. The condition is asymptomatic after the first year of life, and affected infants are reported to have developed normally.

18.

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Meissner T, Betz RC, Pasternack SM et  al (2008) RichnerHanhart syndrome detected by expanded newborn screening. Pediatr Dermatol 25:378 Barr DG, Kirk JM, Laing SC (1991) Outcome in tyrosinaemia type II. Arch Dis Child 66:1249–1250 Cerone R, Fantasia AR, Castellano E et  al (2002) Pregnancy and tyrosinaemia type II. J Inherit Metab Dis 25:317–318 Francis DE, Kirby DM, Thompson GN (1992) Maternal Tyrosinaemia II: management and successful outcome. Eur J Pediatr 151(3):191–196 Barroso F, Correia J, Bandeira A et al (2020) Tyrosinemia type III: a case report of siblings and literature review. Rev Paul Pediatr 38:e2018158 Rice DN, Houston IB, Lyon IC et al (1998) Transient neonatal tyrosinaemia. J Inherit Metab Dis 12:13–22 Mamunes P, Prince PE, Thornton NH et al (1976) Intellectual deficits after transient tyrosinemia in the term neonate. Pediatrics 57:675–680 Phornphutkul C, Introne WJ, Perry MB et  al (2002) Natural history of alkaptonuria. N Engl J Med 347:2111–2121 Wu K, Bauer E, Myung G, Fang MA (2019) Musculoskeletal features of alkaptonuria: a case report and literature review. Eur J Rheumatol 6(2):98–101 Zatkova A, Ranganath L, Kadasi L (2020) Alkaptonuria: current perspectives. Appl Clin Genet 13:37–47 Braconi D, Milucci L, Bernadini G, Santucci A (2015) Oxidative stress and mechanisms of ochronosis in alkaptonuria. Free Radic Biol Med 88(Pt A):70–80 Brunetti G, Tummolo A, D’Amato G et al (2018) Mechanisms of enhanced osteoclastogenesis in alkaptonuria. Am J Pathol 188(4):1059–1068 Introne WJ, Perry MB, Troendle J (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 103(4):307–314 Ranganath LR, Khedr M, Milan AM et  al (2018) Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: evaluation of the effect of nitisinone in the United Kingdom national Alkaptonuria Centre. Mol Genet Metab 125(1-2):127–134 Davison AS, Harrold JA, Hughes G et  al (2018) Clinical and biochemical assessment of depressive symptoms in patients with alkaptonuria before and after two years of treatment with nitisinone. Mol Genet Metab 125(1-2):135–143 Sloboda N, Wiemann A, Merten M et al (2019) Efficacy of low dose nitisinone in the management of alkaptonuria. Mol Genet Metab 127(3):184–190 Item CB, Mihalek I, Lichtarge O, Jalan A et  al (2007) Manifestation of hawkinsinuria in a patient compound heterozygous for hawkinsinuria and tyrosinemia III.  Mol Genet Metab 91:379–383 Gomez-Ospina N, Scott AI, Oh GJ (2016) Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine. J Inherit Metab Dis 39(6):821–829

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Branched-Chain Organic Acidurias/Acidaemias Manuel Schiff, Anaïs Brassier, and Carlo Dionisi-Vici Contents 18.1

Maple Syrup Urine Disease, Isovaleric Aciduria, Propionic Aciduria, Methylmalonic Aciduria – 371

18.1.1 18.1.2 18.1.3 18.1.4 18.1.5

Clinical Presentation – 371 Metabolic Derangement – 374 Genetics – 375 Diagnostic Tests – 376 Treatment and Prognosis – 376

18.2

3-Methylcrotonyl Glycinuria – 382

18.2.1 18.2.2 18.2.3 18.2.4 18.2.5

Clinical Presentation – 382 Metabolic Derangement – 382 Genetics – 382 Diagnostic Tests – 382 Treatment and Prognosis – 382

18.3

3-Methylglutaconic Aciduria – 383

18.4

Short/Branched Chain Acyl-CoA Dehydrogenase Deficiency – 384

18.5

2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency – 384

18.6

Isobutyryl-CoA Dehydrogenase Deficiency – 384

18.7

3-Hydroxyisobutyric Aciduria – 384

18.8

Malonyl-CoA Decarboxylase Deficiency – 385

18.9

ACSF3 Deficiency – 385

18.10

Short-Chain Enoyl-CoA Hydratase 1 (ECHS1) Deficiency – 385 References – 386

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_18

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Catabolism of Branched-Chain Amino Acids The three essential branched-chain amino acids (BCAAs), leucine, isoleucine and valine, are initially catabolised by a common pathway (. Fig.  18.1). The first reaction, which occurs primarily in muscle, involves reversible transamination to 2-oxo- (or keto) acids and is followed by oxidative decarboxylation to coenzyme A (CoA) derivatives by branched-chain oxo- (or keto) acid dehydrogenase (BCKD). The latter enzyme is similar in structure to pyruvate dehydrogenase (7 Chap. 11, 7 Fig.

11.2). Subsequently, the degradative pathways of BCAAs diverge. Leucine is catabolised to acetoacetate and acetyl-CoA, which enters the Krebs cycle. The final step in the catabolism of isoleucine involves cleavage into acetylCoA and propionyl-CoA, which also enters the Krebs cycle via conversion into succinyl-CoA.  Valine is also ultimately metabolised to propionyl-CoA.  Methionine, threonine, fatty acids with an odd number of carbons, the side chain of cholesterol, and bacterial gut activity also contribute to the formation of propionyl-CoA.

Valine

Isoleucine

Leucine

2-Oxo-3-methyl -N-valeric acid 1

2-Oxoisocaproic acid 1

2-Oxoisovaleric acid 1 Isobutyryl-CoA

2-Methylbutyryl-CoA

Isovaleryl-CoA

9

6

2

Methylacrylyl-CoA

Tiglyl-CoA

3-Methylcrotonyl-CoA

10

3

3-OH-Isobutyryl-CoA 11

2-Methyl-3-OH -butyryl-CoA

3-Methylglutaconyl-CoA 4

3-OH-Isobutyric acid

7

12 2-Methylacetoacetyl-CoA

3-OH-3-Methylglutaryl-CoA

Methylmalonic semialdehyde

5 8 Acetoacetate

Acetyl-CoA 14 Malonyl-CoA 16 Acetyl-CoA

18

. Fig. 18.1 Pathways of branched-chain amino acid catabolism. 1, Branched-chain 2-ketoacid dehydrogenase complex; 2, isovaleryl-coenzyme A (CoA) dehydrogenase; 3, 3-methylcrotonyl-CoA carboxylase; 4, 3-methylglutaconyl-CoA hydratase; 5, 3-hydroxy3-methylglutaryl-CoA lyase; 6, short/branched chain acyl-CoA dehydrogenase deficiency; 7, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase, MHBD (HSD10) ; 8, 2-methylacetoacetyl-CoA thiolase; 9, isobutyryl-CoA dehydrogenase; 10, enoyl-CoA hydra-

kIntroduction

Branched-chain organic acidurias or organic acidaemias are a group of disorders that result from an abnormality of specific enzymes involving the catabolism of

13 Propionyl-CoA 15 Methylmalonyl-CoA 17 Succinyl-CoA

tase, ECHS1; 11, 3-hydroxyisobutyryl-CoA deacylase or hydrolase, HIBCH; 12, 3-hydroxyisobutyric acid dehydrogenase; 13, methylmalonic semialdehyde dehydrogenase; 14, acetyl-CoA carboxylase (cytosolic); 15, propionyl-CoA carboxylase; 16, methylmalonyl-CoA epimerase; 17, malonyl-CoA decarboxylase; 18, methylmalonyl-CoA mutase. Enzyme defects are indicated by solid bars

branched-chain amino acids (BCAAs; Catabolism of Branched-chain Amino Acids). Collectively, the most commonly encountered are maple syrup urine disease (MSUD), isovaleric aciduria (IVA), propionic aciduria

371 Branched-Chain Organic Acidurias/Acidaemias

(PA) and methylmalonic aciduria (MMA). They can present clinically as a severe neonatal-onset form of metabolic distress, an acute and intermittent late-onset form, or a chronic progressive form presenting as hypotonia, failure to thrive, and developmental delay. Other rare disorders involving leucine, isoleucine, and valine catabolism are 3-methylcrotonylglycinuria, 3-methylglutaconic aciduria, short−/branched-chain acyl-CoA dehydrogenase deficiency, 2-methyl-3hydroxybutyryl-CoA dehydrogenase deficiency, isobutyryl-CoA dehydrogenase deficiency, enoyl-CoA hydratase (ECHS1) deficiency, 3-hydroxyisobutyric aciduria (3-hydroxy-isobutyryl-CoA hydrolase or deacylase, HIBCH, deficiency), malonic aciduria (malonylCoA decarboxylase deficiency) and combined methylmalonic and malonic aciduria (ACSF3 deficiency). Most of these disorders can be diagnosed by identifying specific acylcarnitines and organic acid profiles in plasma and urine by tandem MS or by gas chromatography-mass spectrometry (GC-MS) and all can be detected by newborn screening using tandem MS. In MSUD, diagnostic confirmation relies on plasma aminoacids determination.

18.1

Maple Syrup Urine Disease, Isovaleric Aciduria, Propionic Aciduria, Methylmalonic Aciduria

18.1.1Clinical Presentation

Children with maple syrup urine disease (MSUD), isovaleric aciduria (IVA), propionic aciduria (PA), or methylmalonic aciduria (MMA) have many clinical and biochemical features in common. There are three main clinical presentations: 1. A severe neonatal-onset form with acute metabolic decompensation and neurological distress. 2. An acute, intermittent, late-onset form also with recurrent episodes of metabolic decompensation. 3. A chronic, progressive form presenting as hypotonia, failure to thrive, and developmental delay. In addition, prospective data gathered by newborn screening programmes, mainly using tandem MS and the systematic screening of siblings of affected subjects, have demonstrated the existence of milder or asymptomatic forms, especially for IVA. 18.1.1.1Severe Neonatal-Onset Form z General Presentation

The general presentation is that of a toxic encephalopathy with either ketosis or ketoacidosis (type I or II in the classification of neonatal inborn errors of metabolism

in 7 Chap. 1) in IVA, PA, MMA and in beta ketothiolase deficiency or without abnormalities in routine laboratory tests in MSUD.  An extremely evocative clinical setting is that of a full-term infant born after a normal pregnancy and delivery who, after an initial symptomfree period, undergoes relentless deterioration with no apparent cause and is unresponsive to symptomatic therapy. The interval between birth and clinical symptoms may range from hours to weeks, depending on the severity of the defect, and may be related to the timing of the sequential catabolism of carbohydrates, proteins, and fats. Typically, the first signs are poor feeding and drowsiness, followed by unexplained progressive coma. There may be cerebral oedema with a bulging fontanelle, arousing suspicion of a central nervous system (CNS) infection. At a more advanced stage, neurovegetative dysregulation with polypnea/respiratory distress, hiccups, apnoeas, bradycardia, and hypothermia may appear. In this comatose state, most patients have characteristic changes in muscle tone and exhibit involuntary movements. Generalised hypertonic episodes with opisthotonus, boxing or pedalling movements (typical of MSUD), and slow limb elevations, spontaneously or upon stimulation, are frequently observed. Another pattern is that of axial hypotonia and limb hypertonia with large-amplitude tremors and myoclonic jerks, which are often mistaken for convulsions and are more frequently seen in MMA and PA. In contrast, true seizures occur late and inconsistently. The electroencephalogram may show a burst-suppression pattern. In addition to neurological signs, patients may present with dehydration and mild hepatomegaly. z

Specific Signs

Maple syrup urine disease Concomitantly with the onset of the symptoms, the patient emits an intense (sweet, malty, caramel-like) maple-syrup-like odour. In general, neonatal (classic) MSUD does not lead to pronounced abnormalities seen on routine laboratory tests. Patients are not severely dehydrated, often present with elevated uric acid [1] have no metabolic acidosis, no hyperammonaemia or only a slight elevation (1100 μmol/l) and/or rapid onset of neurological symptoms. Maternal MSUD In pregnant women with MSUD, maintaining the plasma leucine level between 100 and 300  μmol/l and plasma valine and isoleucine in the upper normal ranges resulted in the delivery of healthy infants. Leucine tolerance increased progressively from the 22nd week of gestation from 350 to 2100 mg/day. The risk of metabolic decompensation in the mother during the catabolic postpartum period can be minimised by careful monitoring after delivery in a metabolic referral centre [50]. Liver transplantation Liver replacement results in a clear increase in wholebody BCKD activity to at least the level seen in the very mild MSUD variant; liver transplantation allows removal of dietary restrictions, protection from acute decompensations during illness, arrest although not reversion of neurocognitive impairment progression, prevention of life-threatening cerebral edema, metabolic and clinical stability. Explanted livers of MSUD patients have been successfully used in domino transplantation [51, 52]. Prognosis Treated patients with classic neonatal MSUD generally survive; they are usually healthy between episodes of metabolic imbalance, and some attend regular schools and have normal IQ scores. However, the average intellectual performance is clearly below that of normal subjects [48]. Recently, abnormal neurocognitive profile with higher verbal than performance abilities was reported in a cohort of 21 MSUD school-age patients [53]. The intellectual outcome is inversely related to how long after birth plasma leucine levels remained above 1 mmol/l and is dependent on the quality of long-term metabolic control [48]. This suggests that inclusion of

379 Branched-Chain Organic Acidurias/Acidaemias

MSUD in neonatal screening programmes by tandem MS may improve the prognosis. Normal development and normal intellectual outcome and performance can be achieved at least in prospectively treated patients [3] and if average long-term plasma leucine levels are not more than 1.5–2 times normal. However, some patients may present mental health problems despite good metabolic control. Children may have inattention and hyperactivity, and older patients may show generalised anxiety, panic or depression, resulting in poor educational and social achievement [48, 54]. In addition, timely evaluation and intensive treatment of minor illnesses at any age is essential, as late death attributed to recurrence of metabolic crises with infections has occurred [3]. z

Isovaleric Aciduria

Acute phase management in the newborn Intensive treatment with nonspecific measures (glucose infusion with appropriate electrolytes to provide calories and reduce endogenous protein catabolism,) including exogenous toxin (and ammonia) removal may be needed in newborns. Such infants are often in a poor clinical condition precluding the effective use of alternate pathways to enhance the removal of isovalerylCoA.  In these circumstances, the administration of intravenous L-carnitine (100–400  mg/kg/day) and oral L-glycine (250–400  mg/kg/day) are effective means of treatment. Carbamylglutamate (oral loading dose of 50–100  mg/kg followed by 200  mg/kg/d in 4 divided doses) has been successfully used to treat hyperammonaemia in acutely ill patients with IVA [55]. Dietary therapy The aim of treatment is to reduce the isovaleric acid burden to a minimum. Such a therapy consists of a lowprotein diet with supplemental glycine and carnitine and should be started as soon as possible after birth. In most patients the amount of protein tolerated meets the official protein requirements; a special amino acid mixture free of leucine is sometimes needed. Excessive protein intake should be avoided. Carnitine and glycine therapy For supplemental therapy either oral L-carnitine (50–100 mg/kg/day) or oral L-glycine (150–300 mg/kg/ day) can be used. Under stable conditions, the need for both supplementations is still controversial, but it can be useful during metabolic stress when toxic isovalerylCoA accumulation increases the need for detoxifying agents [56]. Supplementation with large doses of carnitine gives rise to an unpleasant odour in many IVA patients. Prognosis Prognosis is better than for the other organic acidurias. Even when a patient is compliant with treatment, metabolic crises can occur during catabolic stress, making a short hospitalisation for intravenous fluid (glucose/

electrolytes/buffer) necessary. With puberty, metabolic crises rarely occur. Growth is normal; intellectual prognosis depends on early diagnosis and treatment and, subsequently, on long-term compliance [57]. According to this, inclusion of IVA into neonatal screening programmes by tandem MS should improve the prognosis. So far there is no evidence that uncomplicated maternal IVA has any adverse effect on the unborn child [58]. In asymptomatic individuals identified by newborn screening and showing a mild biochemical phenotype it is crucial to follow the course of the inherited metabolic disturbance prospectively, as far as possible without any therapeutic regimen in order to better define the natural history. z

Propionic Aciduria and Methylmalonic Aciduria

Recommendations and treatment guidelines have been published by the EIMD consortium [18, 43]. Acute phase management in the newborn The urinary excretion of propionic acid is negligible, and no alternate urinary pathway is sufficient to effectively detoxify newborns with PA.  However, this does not mean that exogenous toxin removal procedures are inevitably required. Extracorporal detoxification such as haemo(dia)filtration and haemodialysis (peritoneal dialysis is far less efficient), together with measures to promote anabolism, should be considered when neonatal illness is accompanied by severe hyperammonaemia (>400 μmol/l). In contrast to PA, the efficient removal of toxin in MMA takes place via urinary excretion, because of the high renal clearance of methylmalonic acid (22 ± 9 ml/min per 1.73 m2), which allows excretion of as much as 4–6  mmol MMA/day. Thus, in some cases not complicated by very high ammonia levels, emergency treatment may be limited to rehydration and promotion of anabolism [59]. When conservative measures with high energy supply are sufficient, hyperammonaemia (especially in PA) may be controlled by the use of sodium benzoate and/or carbamylglutamate [60]. The use of sodium phenylbutyrate is not recommended because in MMA and PA hyperammonemia is usually associated with decreased levels of glutamine [18, 42]. Metabolic decompensation in MMA and PA may be complicated by severe lactic acidosis due to thiamine deficiency, requiring vitamin supplementation [61]. Long-term management The goal of treatment is to reduce the production of methylmalonic or propionic acid by means of 5 5 5 5

Natural protein restriction Maintaining an optimal calorie intake Carnitine supplementation (100 mg/kg/day) Reduction of intestinal production of propionate by metronidazole

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Dietary management The aim of dietary treatment is to reduce the production of propionate by both the restriction of precursor amino acids using a low-protein diet and avoidance of prolonged fasting to limit oxidation of odd-chain fatty acids, which are liberated from triglyceride stores during lipolysis. The low-protein diet must provide at least the minimum amount of protein, nitrogen and essential amino acids to meet requirements for normal growth. Figures for estimates of safe levels of protein intake for infants, children and adolescents are available [44], which can be used as a guide for low-protein diets. In early childhood this is often 1–1.5 g/kg/day. To improve the quality of this diet it may be supplemented with a relatively small amount of synthetic amino acids free from the precursor amino acids. However, the long-term value of these supplements remains uncertain, and metabolic balance can often be achieved without them [44, 46]. Some studies have shown that the addition of a special amino acid mixture to a severely restricted diet has no effect on growth or metabolic status and that these amino acids are mostly broken down and excreted as urea [46]. Long fasts should be avoided. In order to prevent fasting at night nocturnal tube feeding may be required in the early years of management. In children with severe forms of PA and MMA, anorexia and feeding problems are almost invariably present, and in order to maintain a good nutritional status, feeds have to be given via nasogastric tube or gastrostomy at some stage. This is essential to provide adequate dietary intake, to prevent metabolic decompensation and to help parents cope with a child who may be difficult to feed [44, 46]. Most patients with a late-onset form are easier to manage. Individual protein tolerance can be quite high. Even though this allows a less rigid protein restriction and leads to a lower risk of malnutrition, these patients must be taught to reduce their protein intake immediately during intercurrent illness to prevent metabolic imbalance. Vitamin therapy Every patient with MMA should be tested for responsiveness to vitamin B12. Some late-onset forms (and, more rarely, neonatal-onset forms) are responsive to vitamin B12; thus, parenteral vitamin therapy, starting with hydroxocobalamin 1000–2000  μg/day for about 10  days, must be carefully tried during a stable metabolic condition. During this period 24-h urine samples are collected for an organic acid analysis. Vitamin B12 responsiveness leads to a prompt and sustained decrease of propionyl-CoA by-products, mainly MMA. However, as biochemical results may be difficult to assess, B12 responsiveness must later be confirmed by molecular

studies. Most B12 responsive patients need only mild protein restriction or none at all. Vitamin B12 is either given orally once a day or administered once a week (1000–2000 μg i.m.). In some cases, i.m. hydroxocobalamin therapy can be kept in backup for intercurrent infections. Carnitine therapy Chronic oral administration of L-carnitine (100 mg/ kg/day) appears to be effective not only in preventing carnitine depletion but also in allowing urinary propionylcarnitine excretion and with subsequent reduction of propionate toxicity [18]. Metronidazole therapy Microbial propionate production can be suppressed by antibiotics. Metronidazole, an antibiotic that inhibits anaerobic colonic flora, has been found to be specifically effective in reducing urinary excretion of propionate metabolites by 20–40% in MMA and PA patients. Longterm metronidazole therapy (at a dose of 10–20 mg/kg once daily for 10 consecutive days each month) may be of significant clinical benefit [18]. Regardless, metronidazole therapy remains questionable. Of note, reversible axonal peripheral neuropathy ascribed to metronidazole has been reported in 2 PA sibs [62]. Growth hormone Growth hormone (GH) induces protein anabolism. It is contraindicated in the acutely ill patient but potentially useful in the long term for those in whom growth is poor. There is a place for recombinant human GH treatment as an adjuvant therapy in some patients with MMA and PA, mainly in those with reduced linear growth, but controlled long-term studies are needed [18]. Biochemical monitoring During the course of decompensation, plasma ammonia, blood gases, electrolytes, calcium, phosphate, lactate, glucose, uric acid, lipase and ketones in urine (or blood) should be monitored. Some groups prefer also to measure urea and urea to MMA molar ratio in urine [46]. Regular amino acid analysis (all essential amino acids, and in particular isoleucine) is important. Furthermore, MMA in plasma or urine should be controlled in order to define the lowest possible level in each individual patient on treatment. There may be little practical use for the measurement of acylcarnitines and of odd-chain fatty acids in terms of directing clinical management. Regarding propionic acid metabolites in urines, there is no consensus on which specific metabolites would be more specific. Determination of plasma methylcitric acid and FGF21 could be of help in predicting disease burden, long-term complications and the impact of transplantation in PA and MMA [63]. Therefore, intra-individual variations in a given patients associated with clinical and laboratory parameters are to be considered altogether.

381 Branched-Chain Organic Acidurias/Acidaemias

Prognosis Around 15% of patients with MMA are vitamin B12 responsive and have mild disease and a good long-term outcome [12, 64]. Conversely, both vitamin B12unresponsive patients with MMA and those with PA have severe disease and many encephalopathic episodes, mainly due to intercurrent infections [65]. Among all patients with all forms of MMA, mut0 patients have the poorest prognosis, and vitamin B12-responsive cblA and mut− patients, the best [12, 18, 66]. Owing to earlier diagnosis and better treatment, outcomes for PA and MMA patients have improved [46, 64, 65]. Survival rates into early and mid-childhood can now exceed 70%. However, morbidity, in terms of cognitive development, remains high, with a majority of patients having DQ/IQ in the mildly to moderately retarded range [67, 68]. With improved management, the frequency of growth retardation has decreased, and now most patients with PA and MMA have growth curves within the normal range [46]. Abnormal neurological signs (mainly movement disorders, chorea, dystonia) continue to increase with age [12, 65]. Chronic progressive impairment of renal function is a frequent and serious complication that manifests in patients with high MMA excretion [12, 69]. Including PA and MMA into newborn screening programmes by tandem MS may make it possible to identify the non-neonatal forms of the diseases in the newborn period and contribute to a further improvement in the outcomes in this group. Decreased early mortality, less severe symptoms at diagnosis and more favourable short-term neurodevelopmental outcomes were recorded in patients identified through expanded newborn screening. However, the short duration of follow-up so far does not allow drawing final conclusions about the effects of newborn screening on long-term outcome [65]. There are only a few reports of female patients with MMA who have carried a pregnancy to term [70]. The outcome was favourable despite high MMA levels in blood and urine However, the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. Among 17 reported pregnancies, only one was associated with mild metabolic decompensation in the mother [70]. Liver/kidney transplantation In MMA, liver transplantation or combined liverkidney transplantation eradicates episodes of hyperammonaemia and has resulted in excellent long-term survival in some patients suggesting stabilization of neurocognitive development [71]. However, some patients have developed acute decompensation and basal ganglia necrosis years after liver transplantation and while on a normal diet. Today, it is recommended that such patients

be maintained on a mild protein restricted diet and with continued carnitine supplementation. Long-term follow-up will be mandatory to evaluate whether patients who undergo early liver transplant [72] need kidney transplantation later in life. Such an early liver transplant appears a reasonable choice for treating severe MMA in an attempt to prevent renal failure and the need of kidney transplant [73]. In the setting of kidney failure, the best option is probably a combined liverkidney transplantation [74]. Though initially viewed as a successful option in MMA patients in end-stage renal failure, with significant improvement in their metabolic control [69], isolated kidney transplantation should rather be reserved for adult cblA patients with end-stage renal failure. For PA, cardiomyopathy, when present, may be partially reversible following liver transplantation [20, 22]. Liver transplantation experience in PA is still limited. Some studies reported clinical improvement and improved dietary protein tolerance [75, 76]. However, others have reported a high mortality risk as well as high morbidity especially worsening of preexisting renal failure [77]. Management of intercurrent decompensations Acute intercurrent episodes are prevented or minimised by awareness of the situations that may induce protein catabolism. These include intercurrent infections, trauma, anaesthesia and surgery, and dietary indiscretion. In all cases, the main response comprises a reduction in protein intake. All patients should have detailed instructions (sick day protocol), including information on a semi-emergency diet, in which natural protein intake is reduced by half, and an emergency diet, in which it is stopped. In both, energy supply is augmented using carbohydrates and lipids, such as solutions based on protein-free formula base powder or a mixture of glucose polymer and lipids diluted in an oral rehydration solution. For children treated with specific amino acid mixtures the usual supplements can be added, though one should be aware that they increase osmolarity and that their taste renders nasogastric tube feeding often unavoidable. Their use is contraindicated in MMA and PA in cases of severe hyperammonaemia. At home, the solution is given in small, frequent drinks during day and night or by nasogastric tube [44]. After 24–48  h, if the child is doing well the usual diet is resumed within 2 or 3 days. In cases of clinical deterioration with anorexia and/ or gastric intolerance or if the child is obviously unwell, the patient must be hospitalised to evaluate the clinical status, to search for and treat intercurrent disease and to halt protein catabolism. Emergency therapy depends on the presence of dehydration, acidosis, ketosis and hyperammonaemia. Most often, intravenous rehydration for

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12–24  h results in sufficient clinical improvement to allow for progressive renutrition with continuous enteral feeding. During this renutrition step enough natural protein to at least cover the minimal dietary requirements should be introduced into the feeds. The energy intakes are supplied with carbohydrates and lipids. During this stage of management, close metabolic evaluation is recommended, as the condition is labile and may deteriorate, requiring adjustment of the therapy. Conversely, if the patient’s condition improves quickly the usual diet should be initiated without delay. During periods when enteral feeding is contraindicated or poorly tolerated, as can occur with severe or prolonged decompensation, the use of total parenteral nutrition may be an effective mean for improving metabolic control and preventing further deterioration [18, 43].

18.2

3-Methylcrotonyl Glycinuria

18.2.1Clinical Presentation

The clinical phenotype described in 3-methylcrotonylCoA carboxylase (3-MCC) deficiency (MCCD) has been highly variable ranging from neonatal onset with severe neurological involvement and even death to a complete lack of symptoms in adults [78]. In the past 15  years family studies and newborn screening have identified a number of totally asymptomatic newborn infants, siblings and mothers with MCCD who have very low carnitine concentrations in blood. Many symptoms and signs in consanguineous families, initially attributed to MCCD, are most likely due to rare homozygous disease causing mutations in other disease genes [79]. However, in a small number of affected individuals, MCCD does appear to cause metabolic decompensation with hypoglycaemia, ketonaemia and severe metabolic acidosis.

tonase on 3-methylcrotonyl-CoA and the subsequent hydrolysis of the CoA-ester.

18.2.3Genetics

3-MCC is a heteromeric enzyme consisting of α(biotin-containing) and β-subunits. MCCD results from loss of function mutations in MCCC1 and MCCC2 respectively encoding these subunits. More than 50 mutations have been identified in both genes [78, 80]. They are associated with an almost total lack of enzyme activity in fibroblasts. The apparent biochemical severity of all the MCC mutations contrasts with the variety of the clinical phenotypes. The introduction of tandem MS into newborn screening has revealed an unexpectedly high prevalence of this disorder, which in certain areas appears to be the most frequent organic aciduria found [81].

18.2.4Diagnostic Tests

The diagnosis relies on a characteristic urinary profile of organic acids, with huge excretion of 3-HIVA and 3-methycrotonylglycine and without the lactate, methylcitrate, and tiglylglycine found in multiple carboxlase deficiency (MCD) (7 Chap. 27). Supplementation with pharmacological doses of biotin does not alter this pattern. Total and free carnitine concentrations in plasma are extremely low. The presence of 3-hydroxyisovaleryl carnitine (C5OH) in plasma and in dried blood spots is characteristic for MCCD. However, diagnostic approach based solely on detection of C5OH may lead to overdiagnosis. In view of it’s generally benign nature, it is debatable whether or not MCCD should be included in newborn screening programmes [82].

18.2.5Treatment and Prognosis

18

18.2.2Metabolic Derangement

3-MCC is one of the four biotin-containing carboxylases known in humans (. Fig. 18.1, enzyme 3). Its deficiency leads to accumulation of 3-methylcrotonyl-CoA and 3-methylcrotonic acid. Most of the 3-methylcrotonyl-CoA is conjugated with glycine to form 3-methylcrotonylglycine (MCG) whereas acylation with carnitine leading to the formation of 3-hydroxyisovaleryl carnitine appears to be only a minor pathway. 3-Hydroxyisovalerate (3-HIVA), another major metabolite, is derived through the action of a cro-

Asymptomatic individuals most probably do not require treatment. In those with metabolic crisis glycine and carnitine therapies directed at increasing the excretion of glycine and carnitine conjugates are complementary rather than competitive means of detoxification. Glycine supplementation (175  mg/kg/day) increases the excretion of 3-MCG. Carnitine supplementation (100 mg/kg/ day) corrects the very low plasma carnitine levels and increases the excretion of 3-HIVA. Long-term treatment of symptomatic infants based on a mildly proteinrestricted diet is debatable.

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18.3

3-Methylglutaconic Aciduria

Primary 3-methylglutaconic aciduria caused by 3-methylglutaconyl-CoA hydratase deficiency (AUH mutations) has only been identified in very few individuals, who presented with a wide spectrum of clinical signs of a neurometabolic disease ranging from no symptoms (at 2  years of age) to mild neurological impairment, severe encephalopathy with basal-ganglia involvement, quadriplegia, athetoid movement disorder, severe psychomotor retardation and leukoencephalopathy in a 61-year-old woman. 3-Methylglutaconyl (MGC)-CoA is metabolised to 3-hydroxy-3-methylglutaryl-CoA by 3-MGC-CoA hydratase (. Fig.  18.1, enzyme 4). Defective activity is characterised by urinary excretion of 3-MGC and 3-methylglutaric acids. Both metabolites derive from accumulated 3-methylglutaconyl-CoA, through hydrolysis and dehydrogenation, respectively. The combined urinary excretion of 3-MGC and 3-methylglutaric acids range from 500 to 1000 mmol/mol creatinine, of which 3-methylglutaric acid represents about 1%. The metabolic pattern also includes 3-HIVA, which differentiates it from the other secondary causes (below). 3-MGC-CoA hydratase activity can be mea-

. Table 18.1

sured in fibroblasts. The role of the human 3-MGC-CoA hydratase in leucine metabolism has been elucidated, and different mutations in AUH have been identified. No clear therapeutic regimen has been described. Carnitine supplementation may have beneficial effects. Secondary 3-MGC acidurias are a relatively common finding in a number of metabolic disorders, particularly mitochondrial disease. In most the excretion of 3-MGC acid is only slightly increased and accompanied by other disease specific metabolites. However, there are some disorders where 3-MGC aciduria is a more significant and consistent finding with urinary excretion >40  μmol/mmol creatinine. Previously, 3-MGC acidurias had been classified into types I to V 3-MGC aciduria, but they are now reclassified and named according to their pathological mechanism and defective protein or historical name (. Table  18.1) [83]. There remain, however, disorders for which the underlying pathological mechanism is still unclear [84]. For example, mutations in CLPB were found in individuals with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-MGC aciduria without any obvious mitochondrial respiratory chain dysfunction [85].

Classification of disorders with significant 3-methylglutaconic aciduria

Defect

Name

Gene

Previous classification

Reference

Primary

Leucine catabolism

3 HMG CoA hydratase deficiency

AUH

Type I

This chapter

Secondary

Phospholipidpar remodelling

TAZ defect or Barth syndrome

TAZ

Type II

SERAC1 defect or MEGDEL syndrome

SERAC1

Type IV

7 Chapter 35

Sengers syndrome

AGK

Type IV

OPA3 defect or Costeff syndrome

OPA3

Type III

DNAJC19 defect or DCMA syndrome

DNAJC19

Type V

TMEM70 defect

TMEM70

Type IV

Component of the MICOS complex

QIL1 deficiency

QIL/ MIC13

Mitochondrial DNA deletion

Pearson/Kearns-Sayre

Subunit of mitochondrial import machinery

TIMM50 deficiency

TIMM50

Unknown

CLPB defect

CLPB

NOS 3-MGCAciduria

Unknown

Mitochondrial membrane associated disorder

NOS, not otherwise specified

Type IV

7 Chapter 10

This chapter

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18.4

M. Schiff et al.

Short/Branched Chain Acyl-CoA Dehydrogenase Deficiency

Isolated 2-methylbutyrylglycinuria, caused by 2-methylbutyryl-CoA dehydrogenase deficiency (MBD) and encoded by ACDSB (. Fig. 18.1, enzyme 6), is an autosomal recessive disorder of isoleucine metabolism [86]. A few patients have been diagnosed following various clinical symptoms, and a set of asymptomatic subjects of Hmong descent were identified through newborn screening with elevated C5-acylcarnitine concentrations in blood spots. Detection of MBD deficiency in newborn screening is not limited to this population, and an increasing number of asymptomatic patients have been extensively investigated. Clinical relevance of this disorder remains in doubt and requires careful long-term follow-up of affected individuals. Theoretically, valproic acid should be avoided, as valproyl-CoA could be a substrate of MBD.

18.5

18

2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency

Only a few patients with 2-methyl-3-hydroxybutyrylCoA dehydrogenase (MHBD) deficiency (HSD10 disease) have been described. All male patients had an unusual neurodegenerative and progressive disease, and some affected females had psychomotor retardation and speech delay. Related women (mothers and grandmothers of patients) have shown mild to moderate developmental delay. In early childhood the severe neurodegenerative symptoms included rigidity, dystonic posturing, spastic diplegia, dysarthria, choreoathetoid movements, restlessness, cortical blindness, myoclonic seizures, brain atrophy, periventricular white matter and basal ganglia abnormalities. The majority of patients identified so far have had a severe progressive neurological phenotype rather than ketoacidotic attacks, in contrast to patients with a defect in the next step of isoleucine degradation attributable to 2-methylacetoacetyl-CoA thiolase deficiency. Nevertheless, one 6-year old boy has been diagnosed with MHBD deficiency in the course of a severe ketoacidotic crisis in the absence of any neurological symptoms thus mimicking 2-methylacetoacetylCoA thiolase deficiency [87]. MHBD deficiency (. Fig. 18.1, enzyme 7) is a defect in the degradation of isoleucine but also in neurosteroid metabolism. MHBD is a multifunctional protein with an additional non-enzymatic role required for mitochondrial integrity and cell survival [87–89]. Laboratory findings include marked elevations of urinary 2-methyl3-hydroxybutyrate and tiglylglycine without elevation of 2-methylacetoacetate. The organic acid excretion is

more pronounced after a 100-mg/kg oral isoleucine challenge. Enzyme studies have shown markedly decreased activity of MHBD in fibroblasts and lymphocytes. MHBD deficiency is caused by mutations in HADH2 on the X-chromosome. A short-term stabilisation of neurological symptoms and a biochemical response to an isoleucine-restricted diet have been observed in some patients [88, 89]. The deficiency of 2-methyl-acetoacetyl-CoA thiolase (. Fig.  18.1, enzyme 8), also known as 3-ketothiolase or T2, is discussed in 7 Chap. 13.

18.6

Isobutyryl-CoA Dehydrogenase Deficiency

The mitochondrial enzyme isobutyryl-CoA dehydrogenase (IBD) catalyses the third step in the degradation of valine (. Fig. 18.1, enzyme 9). It is encoded by ACAD8 [90]. Fewer than 20 patients with IBD deficiency have been described. Only the first patient, a 2-year-old, was diagnosed following the investigation of anaemia and dilated cardiomyopathy. Other patients have been identified following the expansion of newborn screening [90, 91]. This disorder can be detected on the basis of elevated butyrylcarnitine/isobutyrylcarnitine (C4carnitine) concentrations in newborns’ blood spots analysed by tandem MS. The presence of this metabolite, which is also present in short-chain acyl-CoA dehydrogenase deficiency, requires further investigation for precise diagnosis [91]. The possible clinical implication of this enzyme defect is not known, and to date most of the identified patients have remained asymptomatic. However, a few patients have moderate speech delay and careful follow-up is necessary.

18.7

3-Hydroxyisobutyric Aciduria

A few patients with increased excretion of 3-hydroxyisobutyric acid (3-HIBA), an intermediate of the catabolic pathways of valine and thymidine, have been identified. This condition may be linked to various enzymatic defects. Unfortunately, in most cases described, the enzymatic diagnosis has been speculative. Clinical presentation is heterogeneous. Some patients present in infancy, with acute metabolic episodes with ketoacidosis, hypoglycaemia or hyperlactataemia. Muscle involvement and hypertrophic cardiomyopathy have been reported. CNS involvement is highly variable, ranging from normal development to brain dysgenesis observed in neonates. Several enzyme defects may underlie 3-hydroxyisobutyric aciduria. However, only combined

385 Branched-Chain Organic Acidurias/Acidaemias

deficiency of malonic, methylmalonic and ethylmalonic semialdehyde dehydrogenase (MMSDH) (. Fig.  18.1, enzyme 13) [92] and 3-hydroxyisobutyryl-CoA deacylase also called hydrolase deficiency (. Fig. 18.1, enzyme 11) have been identified [93]. Mutations in ALDH6A1 encoding MMSDH were found in two unrelated developmentally delayed patients with 3-hydroxyisobutyric aciduria [94]. 3-hydroxy-isobutyryl-CoA hydrolase or deacylase, HIBCH (. Fig. 18.1, enzyme 11), deficiency was reported in patients presenting Leigh-like disease with elevated hydroxy-C4-carnitine and multiple mitochondrial respiratory chain defects and mutations in HIBCH [95] (7 Chap. 10).

18.8

Malonyl-CoA Decarboxylase Deficiency

Malonyl-CoA decarboxylase (MLYCD) deficiency is a rare condition, with fewer than 30 cases reported, in which there is excessive excretion of malonic acid. MLYCD is usually expressed in fibroblasts or leukocytes, and various mutations have been reported in MLYCD [96]. A neonatal form has been described presenting with progressive lethargy, hypotonia, hepatomegaly, metabolic acidosis, and mild hyperammonaemia, variously associated with hypoglycaemia and/or hyperlactacidaemia. Cardiac failure due to cardiomyopathy was present in some patients at birth. In the late-onset forms, most have presented with acute metabolic episodes secondary to intercurrent infections. Some patients were previously known to be affected with a mild and nonspecific psychomotor retardation. Other children have been diagnosed following systematic screening for mental retardation and hypotonia. Cardiomyopathy was present in about 40%. The physiological role of MLYCD, a cytosolic enzyme, could be in the regulation of cytoplasmic malonyl-CoA abundance and, thus, of mitochondrial fatty acid uptake and oxidation (. Fig.  18.1, enzyme 16). Patients with MLYCD deficiency display a number of phenotypes that are reminiscent of mitochondrial fatty acid oxidation disorders [96]. However, in contrast to these, dicarboxylic aciduria together with ketonuria is found during catabolic episodes and the patients exhibit normal ketogenesis on acute fat-loading tests. The disorder is autosomal recessive. More than 20 mutations in MLYCD have been reported. No hotspot mutations have been identified. No genotype-phenotype relationship was detected, and siblings may have different presentations [96]. Total and free carnitine concentrations in plasma are low. Documented accumulation of malonylcarnitine would allow tandem MS screening of newborn blood spots. MLYCD activity has been found to be

reduced in cultured fibroblasts and/or leukocytes of most defective cell lines, with residual activity of less than 10% of control [96]. No rules for treatment and prognosis have been established. Carnitine supplementation corrects the carnitine deficiency and may improve the cardiomyopathy and muscle weakness. Conversely, some patients have worsened despite carnitine supplementation and have recovered with a long-chain triglyceride-restricted/ medium-chain triglyceride-supplemented diet [97]. Long-term prognosis is unknown. Except for the two patients who developed extrapyramidal signs following an acute crisis, most patients have residual mild developmental delay. There are subjects identified by newborn screening who remained asymptomatic at least during preschool age.

18.9

ACSF3 Deficiency

ACSF3 deficiency is a rare disorder presenting with combined malonic and methylmalonic aciduria (CMAMMA) due to mutations in ACSF3, which encodes a putative methylmalonyl-CoA and malonylCoA synthetase, a member of the acyl-CoA synthetase family [98]. Diagnosis relies on a characteristic profile of urinary organic acids, in which malonic and methylmalonic acids are constant findings. Abnormal succinic aciduria has been found in about half the cases, as have various dicarboxylic and glutaric acidurias. The disorder has been detected in a number of asymptomatic infants in the Quebec newborn urine screening programme and appears to be benign [98].

18.10

Short-Chain Enoyl-CoA Hydratase 1 (ECHS1) Deficiency

Short-chain enoyl-CoA hydratase (ECHS1) (. Fig.  18.1, enzyme 10), a mitochondrial matrix enzyme, active in valine catabolism and short-chain fatty acid β-oxidation, is immediately upstream of HIBCH in the valine pathway (. Fig. 18.1, enzyme 11). A recent literature review of 45 cases of ECHS1 deficiency caused by mutations in ECHS1, identified 4 main phenotypes: a severe rapidly fatal neonatal form with white matter abnormalities; a severe infantile form with developmental delay, pyramidal and extrapyramidal signs, optic atrophy, feeding difficulties, and degeneration of the deep gray nuclei; a similar but less severe infantile form with slower progression, and lastly a disorder characterised by paroxysmal exercise-induced dystonic attacks and isolated pallidal degeneration on MRI. Urine metabolite testing can distinguish between ECHS1 and HIBCH deficiencies. Blood acylcarnitine profile has been found normal in ECHS1 deficiency [99].

18

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De Baulny HO, Benoist JF, Rigal O et al (2005) Methylmalonic and propionic acidemias: management and outcome. J Inherit Metab Dis 28:415–423 Dionisi Vici C, Deodato F, Roschinger W et  al (2006) “Classical” organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 29:383–389 Hörster F, Tuncel AT, Gleich F et  al (2020) Delineating the clinical spectrum of Isolated Methylmalonic Acidurias: cblA and mut [published online ahead of print, 2020 Aug 5]. J Inherit Metab Dis. https://doi.org/10.1002/jimd.12297 Grünert SC, Mullerleile S, De Silva L et  al (2013) Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis 8:6 Nizon M, Ottolenghi C, Valayannopoulos V et al (2013) Longterm neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis 8:148 Brassier A, Boyer O, Valayannopoulos V et  al (2013) Renal transplantation in 4 patients with methylmalonic aciduria: a cell therapy for metabolic disease. Mol Genet Metab 110: 106–110 Raval DB, Merideth M, Sloan JL et al (2015) Methylmalonic acidemia (MMA) in pregnancy: a case series and literature review. J Inherit Metab Dis 38:839–846 Niemi AK, Kim IK, Krueger CE et  al (2015) Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. J Pediatr 166:1455–1461 Spada M, Calvo PL, Brunati A et al (2015) Liver transplantation in severe methylmalonic acidemia: the sooner, the better. J Pediatr S0022–3476(15):00878–00871 Spada M, Calvo PL, Brunati A et al (2015) Early liver transplantation for neonatal-onset methylmalonic acidemia. Pediatrics 136:e252–e256 Brassier A, Krug P, Lacaille F et  al (2020) Long-term outcome of methylmalonic aciduria after kidney, liver, or combined liver-kidney transplantation: the French experience. J Inherit Metab Dis 43(2):234–243. https://doi.org/10.1002/jimd. 12174 Kasahara M, Sakamoto S, Kanazawa H et  al (2012) Livingdonor liver transplantation for propionic acidemia. Pediatr Transplant 16:230–234 Barshes NR, Vanatta, Patel AJ et  al (2006) Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Pediatr Transplant 10:773–778 Charbit-Henrion F, Lacaille F, McKiernan P et al (2015) Early and late complications after liver transplantation for propionic acidemia in children: a two centers study. Am J Transplant 15:786–791 Grünert SC, Stucki M, Morscher RJ et al (2012) 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. Orphanet J Rare Dis 7:31 Shepard PJ, Barshop BA, Baumgartner MR et  al (2015) Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD.  Genet Med 17:660–667 Stucki M, Suormala T, Fowler B, Valle D, Baumgartner MR (2009) Cryptic exon activation by disruption exon splice enhancer: novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. J Biol Chem 284:28953–28957

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Grünert SC, Stucki M, Morscher RJ, Suormala T, Bürer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kölker S, Möslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR (2012) 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. Orphanet J Rare Dis 7:31. https://doi.org/10.1186/1750-1172-7-31. PMID: 22642865; PMCID: PMC3495011 Wilcken B (2016) 3-Methylcrotonyl-CoA carboxylase deficiency: to screen or not to screen? JIMD 39:171–172 Wortmann SB, Kluijtmans LA, Rodenburg RJ et  al (2013) 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. J Inherit Metab Dis 36:913–921 Jones DE, Perez L, Ryan RO (2020) 3-Methylglutaric acid in energy metabolism. Clin Chim Acta 502:233–239. https://doi. org/10.1016/j.cca.2019.11.006 Wortmann SB, Ziętkiewicz S, Kousi M et al (2015) CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet 96:245–257 Porta F, Chiesa N, Martinelli D, Spada M (2019) Clinical, biochemical, and molecular spectrum of short/branchedchain acyl-CoA dehydrogenase deficiency: two new cases and review of literature. J Pediatr Endocrinol Metab 32(2):101–108. https://doi.org/10.1515/jpem-2018-0311. PMID: 30730842. Fukao T, Akiba K, Goto M et al (2014) The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation. J Hum Genet 59:609–614 Garcia-Villoria J, Navarro-Sastre A, Fons C et al (2009) Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis. Clin Biochem 42:27–33 Yang SY, He XY, Miller D (2007) HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids. Mol Genet Metab 92:36–42 Pedersen CB, Bischoff C, Christensen E et al (2006) Variations in IBD (ACAD8) in children with elevated C4-acylcarnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 60:315–320 Oglesbee D, He M, Majumber N et al (2007) Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency. Genet Med 9:108–116 Chambliss KL, Gray RG, Rylance G et  al (2000) Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 23:497–504 Brown GK, Huint SM, Scholem R et  al (1982) Hydroxyisobutyryl-coenzyme A deacylase deficiency: a defect in valine metabolism associated with physical malformations. Pediatrics 70:532–538 Sass JO, Walter M, Shield JP et al (2012) 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase. J Inherit Metab Dis 35:437–442 Ferdinandusse S, Waterham HR, Heales SJ et al (2013) HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 8:188 Salomons GS, Jakobs C, Landegge Pope L et al (2007) Clinical, enzymatic and molecular characterization of nine new patients with malonyl- coenzyme A decarboxylase deficiency. J Inherit Metab Dis 30:23–28

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42(1):107–116. https://doi.org/10.1002/jimd.12032. PMID: 30740739. Masnada S, Parazzini C, Bini P, Barbarini M, Alberti L, Valente M, Chiapparini L, De Silvestri A, Doneda C, Iascone M, Saielli LA, Cereda C, Veggiotti P, Corbetta C, Tonduti D (2020) Phenotypic spectrum of short-chain enoyl-Coa hydratase-1 (ECHS1) deficiency. Eur J Paediatr Neurol. S10903798(20)30151-3. https://doi.org/10.1016/j.ejpn.2020.07.007. Epub ahead of print. PMID: 32800686

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Disorders of the Urea Cycle and Related Enzymes Johannes Häberle and Vicente Rubio Contents 19.1

Mitochondrial Urea Cycle Disorders – 392

19.2

Cytosolic Urea Cycle Disorders – 397

19.3

Urea Cycle Mitochondrial Transporter Defects – 400

19.3.1

Hyperornithinemia, Hyperammonaemia and Homocitrullinuria (HHH) Syndrome – 400 Citrin Deficiency – 400

19.3.2

19.4

Urea Cycle Defects Due to Deficiencies of Ancillary Enzymes – 402

19.4.1 19.4.2

Δ1-Pyrroline-5-Carboxylate Synthetase (P5CS) Deficiency – 402 Carbonic Anhydrase Va (CAVA) Deficiency – 402

19.5

Transient Hyperammonaemia of the Newborn (THAN) – 403 References – 403

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_19

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Urea Cycle and Related Enzymes The urea cycle is the main route for ammonia detoxification (. Fig. 19.1). Its defects generally cause hyperammonaemia. The complete cycle is found only in periportal hepatocytes and involves two mitochondrial and three cytosolic enzymes as well as the mitochondrial ornithine/citrulline antiporter and the activating mitochondrial enzyme N-acetylglutamate synthase, which can turn the cycle on or off. In addition, liver mitochondrial carbonic anhydrase Va, the hepatic aspartate/glutamate mitochondrial antiporter citrin, and the intestinal enzyme Δ1-pyrroline-5-carboxylate synthetase supply the cycle with, respectively, bicarbonate, aspartate, and, if needed, with ornithine made de novo. In extrahepatic tissues urea cycle enzymes make arginine from citrulline produced from ornithine or made from arginine by nitric oxide synthase. Thus, UCDs can also impact on arginine-derived functions including those of the nitric oxide system.

kIntroduction

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Urea cycle disorders (UCDs) are genetic defects causing loss of function of any of the urea cycle (UC) enzymes carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase (ARG1), the mitochondrial ornithine/citrulline antiporter (ORC1) and the CPS1-activating enzyme N-acetylglutamate synthase (NAGS). Their frequency is about 1:35,000 births, with at least 25% presenting in newborns [1]. Deficiencies of the mitochondrial enzymes NAGS, CPS1 and OTC primarily cause hyperammonaemia. Those of the extramitochondrial enzymes ASS, ASL and ARG1, and of the ORC1 antiporter also produce specific alterations in the levels of some amino acids that may be important in disease pathogenesis and are valuable for diagnosis. Deficiencies of the hepatic mitochondrial carbonic anhydrase Va (CAVA) and citrin aspartate/glutamate antiporter, as well as those of the bifunctional enzyme Δ1-pyrroline-5-carboxylate synthetase (P5CS) can also cause hyperammonaemia by restricting the supply to the UC of bicarbonate, aspartate and de novo made ornithine, respectively. Inheritance of UCDs is autosomal recessive except P5CS deficiency, which can be dominant or recessive, and OTC deficiency, which is X-linked. Acute hyperammonaemia, a clinical emergency caused by most UCDs, usually first manifests soon after birth with irritability, food refusal, vomiting, vegetative instability, muscular hypotonia, convulsions, somnolence, lethargy, coma and death or neurological sequelae

if untreated. Partial UC enzyme deficiencies can result in a later onset of hyperammonaemia and/or poor appetite, vomiting, failure to thrive, developmental delay, cognitive impairment, abnormal behaviour or frank neurologic and/or psychiatric manifestations, as well as hepatomegaly and increased liver enzymes in plasma, or even acute liver failure. ARG1 deficiency rarely causes acute hyperammonaemia. Instead, it produces developmental delay, seizures and spastic diplegia. Increased plasma ammonia and glutamine and low citrulline characterise NAGS, CPS1 and OTC deficiencies. Amongst these, a high urinary excretion of orotic acid is only observed in OTC deficiency. ASS, ASL and ARG1 deficiencies present with a high plasma citrulline and characteristic plasma and urinary amino acid profiles. Treatment of UCDs aims at rapidly lowering ammonia by minimizing ammonia production by using protein restriction and prevention of catabolism; and by maximizing ammonia removal by attempting to enhance residual UC function with arginine or citrulline where appropriate, by nitrogen scavenging using alternate pathway therapy with benzoate and/or phenylacetate or phenylbutyrate and by employing dialytic measures. Liver transplantation is curative or nearly so for most of these disorders but probably not for ASL deficiency. Administration of N-carbamylglutamate can replace the missing N-acetylglutamate in NAGS deficiency, virtually curing this deficiency. Citrin deficiency dramatically differs from other UCDs in that carbohydrates should be limited and high amounts of protein given.

19.1

Mitochondrial Urea Cycle Disorders

These comprise CPS1, OTC and NAGS deficiencies. Since the exclusive role of NAGS is to produce the essential activator of CPS1, N-acetyl-L-glutamate (NAG), NAGS deficiency is clinically indistinguishable from CPS1 deficiency. OTC deficiency is the most frequent urea cycle error (generally about 60% of UCD patients) whereas CPS1 and NAGS deficiency are very rare (respectively, 1:1,300,000 and  C was found in several independent families, causing the change p.Trp484Arg and possibly in addition a splicing defect, with resultant severe NAGS deficiency [16]. In CPS1 and OTC deficiencies >260 mutations and  >500 mutations have been found in the corresponding CPS1 and OTC genes, with 5  kg body weight). Until then, aggressive conservative measures must be employed aimed to preserve mental function [3]. Conservative treatment requires a low-protein diet in most patients, although trying to approach the FAO/ WHO recommendations for daily protein intake [26, 28], thus making necessary the individual titration of protein tolerance. To avoid dietary deficiencies, essential amino acids, vitamins, and trace elements should be monitored regularly and supplemented as needed. In addition, most patients will require nitrogen scavenging drugs. Oral sodium benzoate (an unlicensed medication, although it is used in low amounts in the food industry and as a pharmaceutical excipient) and/or oral sodium phenylbutyrate or oral glycerol phenylbutyrate (a more palatable alternative to standard preparations of sodium phenylbutyrate; there is a sugar-encapsulated sodium phenylbutyrate preparation that is taste-neutral), are recommended, each given in an amount of 200–250 mg/ kg/d divided in 3 doses (in the case of glycerol phenylbutyrate 5–12.4 g/m2/d divided in 3 doses) [3, 29]. To maximize the residual urea cycle function, L-arginine and/or L-citrulline (both chemicals or food supplements and not licensed drugs) are given in a daily oral dose of 100– 200 mg/kg, divided in 3 doses [3]. Outcome Patients with mitochondrial UCDs manifested during the newborn period have a significant risk of death [30] or, if they survive, of learning difficulties [31]. Both survival and neurocognitive outcome largely depend on the duration and the extent of the hyperammonaemia. Several strategies have been proposed to improve outcome, including education of health care professionals for increasing awareness, establishment of metabolic centres, and automatic ‘red flags’ in the emergency departments for certain situations [32], in addition to ensuring the availability of routine and rapid determination of ammonia in an emergency set-

ting [3]. Liver transplantation, although preventing further hyperammonaemia, will not restore mental function if lost [33, 34]. Pregnancy and Postpartum Period Most female OTC patients go through pregnancy without any problems but their increasing extra protein needs (first trimester 1 g/day; second trimester 10 g/day; third trimester 31 g/day) should be met. The postpartum period also requires special attention for all UCDs, as several case reports on fatal crises highlight the particular risk during this period of severe protein catabolism [35, 36].

19.2

Cytosolic Urea Cycle Disorders

This group of disorders is the second most frequent among the UCDs and includes ASS and ASL deficiencies, each representing about 15% of the UCD patients, and ARG1 deficiency, representing 3% [1]. z

Clinical Presentation

Newborns Newborn presentations of ASS and ASL deficiencies closely resemble those of mitochondrial UCDs (7 Sect. 19.1), with hyperammonaemic encephalopathy of similar severity, although peak plasma ammonia may not be as high and the onset delayed to day 6–7 of life or even later [3]. At the other end of the clinical spectrum are patients who may have been detected by newborn screening but who are asymptomatic [37, 38]. ARG1 deficiency only rarely presents in the newborn period, either with neonatal hyperammonaemia and/or cholestasis [reviewed in 39]. Children, adolescents and adults Outside the newborn period, the symptoms in patients with ASS and ASL deficiencies are similar to those of mitochondrial UCDs (7 Sect. 19.1). ASS deficiency has been reported presenting with acute liver failure [40], treated in some patients with liver transplantation, although other patients recovered with conservative management. ASS deficient patients are at particular risk of developing acute hyperammonaemia in the post-partum period [36] and in other severe catabolic circumstances. In contrast, ASL deficient patients are less prone to recurrent hyperammonaemic decompensation but can still develop intellectual disability, seizures and chronic hepatopathy [30]. Marked hepatomegaly can be a presenting sign mimicking hepatic glycogenosis. Arterial hypertension is also sometimes found in adolescents and adults with ASL deficiency [41]. Brittle hair due to trichorrhexis nodosa is almost pathognomonic for ASL deficiency, resulting

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from arginine deficiency and responding well to arginine administration. The clinical picture of patients with ARG1 deficiency is entirely different, being characterised primarily by developmental delay with neurological and intellectual impairment, growth retardation and spastic tetra- or diplegia [42]. This last manifestation starts in late infancy and is progressive if plasma arginine levels remain elevated. Many patients with ARG1 deficiency have seizures and may even develop status epilepticus. z

19

Metabolic Derangements

The impairment of the UC at the level of ASS, ASL and ARG1 explains the characteristically elevated plasma and urinary levels of citrulline, argininosuccinate and arginine in the corresponding deficiency of each of these enzymes, and the decreased level of arginine in ASS and ASL deficiency (prior to treatment with L-arginine). Inhibition of ASS by argininosuccinate or by arginine [43] accounts for the increased citrulline levels in ASL and ARG1 deficiencies, although the increase is generally lower than in ASS deficiency. The normal or increased citrulline levels differentiate extramitochondrial from mitochondrial UCDs. The high renal clearance of argininosuccinate explains the lower relative increase in the plasma levels of this amino acid in ASL deficiency than the increase of citrulline in ASS deficiency (typically 1000-fold increase). In ARG1 deficiency, the presence in extrahepatic tissues of a second arginase (ARG2) may explain the relatively modest increase (about 15-fold) of plasma arginine, the normal or near-normal plasma ornithine, and the presence of urea, which, nevertheless, is generally decreased [42]. Citrulline and argininosuccinate include in their molecular structure one molecule of ornithine and, respectively, one and two atoms of waste nitrogen. Consequently, the abundant urinary excretion of these intermediates in ASS and ASL deficiencies effectively removes waste nitrogen, although with simultaneous loss of two (ASS deficiency) or one (ASL deficiency) ornithine molecules per urea equivalent. This renders the supply of ornithine an essential determinant of how much waste nitrogen is excreted in ASS and ASL deficiencies, justifying the administration of arginine (converted to ornithine upon cleavage by arginase) [44]. In line with the poorer waste nitrogen-carrying capacity of citrulline than that of argininosuccinate, hyperammonaemic crises are more frequent in ASS deficiency than in ASL deficiency and appear to be due to a secondary impairment of OTC because of the poor availability of ornithine, which is reflected in the frequent observation of increased orotic acid excretion during these crises. Interestingly, orotic acid excretion is also

frequently elevated in ARG1 deficiency [42], possibly reflecting increased CP production because of overactivation of the NAGS-CPS1 axis (arginine is a NAGS activator [45]), compounded with decreased ornithine availability for the OTC reaction in the liver. ASS and ASL have a paramount role in the recycling to arginine of the citrulline produced when nitric oxide (NO) is made by NO synthase. ASL also belongs to an intracellular membrane-bound protein complex that channels exogenous arginine to NO synthase, and its mutations can prevent such channelling [46]. Inadequate NO synthesis and other toxic factors, perhaps argininosuccinate or its derivative guanidino compounds such as guanidinosuccinate, may be involved in the pathogenesis of ASL deficiency and explain the more important neurocognitive alterations than in other UCDs [47]. Animal studies and preliminary data in humans suggest that drugs that supply NO might be beneficial in ASL deficiency [48]. In ARG1 deficiency, the mild and sporadic hyperammonaemia does not account for the spastic diplegia and the seizures, suggesting that central nervous system toxicity of increased arginine or its metabolites (polyamines, guanidino compounds, NO, agmatine) is a crucial pathogenic factor. Spastic paraplegia is a common feature of ARG1 deficiency, of P5CS deficiency (7 Sect. 21.3) and of the HHH syndrome (7 Sect. 21.2), all 3 processes in which ornithine delivery to the mitochondria or arginine/ornithine balance is impaired [49]. Seizures could be due to either accumulation of guanidinoacetate, a known proepileptogenic compound [50], and/or to the secondary imbalance between glutamate and γ-amino-butyric acid (GABA), given the important interconnections between ornithine and glutamate metabolism [51] (7 Chap. 30). z

Genetics

DNA is generally used for genetic analysis of these disorders. The existence of pseudogenes restricts cDNA studies of ASS1 to fibroblasts and the liver. One common mutation has been described in classical ASS deficiency (c.1168G>A, p.Gly390Arg) in patients from all ethnic backgrounds [52]. Common mutations in mild ASS deficiency (most frequent, c.535T>C, p.Trp179Arg and c.1085G>T, p.Gly362Val) have mainly been found in Turkish patients [52]. There are few recurrent ASL mutations associated with a severe phenotype (c.857A>G, p.Gln286Arg is the most frequent) or with milder clinical course (e.g. c.532G>A, p.Val178Met) [53]. Intragenic complementation [54] complicates determination of disease-causality of individual mutations. Mutations in ARG1 (>60 reported) are mainly private, with few being recurrent [55]. See 7 http://grenada. lumc.nl/LSDB_list/lsdbs for listing of mutations.

399 Disorders of the Urea Cycle and Related Enzymes

z

Diagnostic Tests

Biochemical assays The mainstay of biochemical diagnosis of cytosolic UCDs is the plasma amino acid profile. Markedly elevated citrulline levels are highly suggestive of ASS deficiency, with few alternatives to consider in the differential diagnosis, namely the deficiencies of ASL, citrin, pyruvate carboxylase, and dihydrolipoamide dehydrogenase (see also 7 Chap. 3, 7 Table 3.2). Plasma citrulline levels >500 μmol/l are pathognomonic for ASS deficiency. Similarly, the presence of argininosuccinate (and/or its two anhydrides) in plasma and urine is pathognomonic for ASL deficiency. In ARG1 deficiency elevation of arginine in plasma is characteristic. Levels are often not very high in newborns but they increase during infancy and often reach >500 μmol/l in untreated patients. Enzyme studies In ASS deficiency, ASS activity is rarely assayed. In ASL and ARG1 deficiencies, red blood cells are an easily accessible source for direct enzyme assays but conflicting results for ASL have been reported [56]. Overall, enzyme studies are currently not standard for confirmation of the diagnosis of a cytosolic UCD but are a valuable tool if mutation analysis fails. Mutation analysis Mutation analysis is now used to confirm the diagnosis and to offer future prenatal testing. In ASS deficiency, it is performed with a high success rate by sequencing the 14 coding ASS1 exons and flanking intronic regions. To improve the detection rate, RNA from fibroblasts (but not from blood cells due to the expression of pseudogenes) can be used. The same approach with a similar excellent detection rate can be applied in ASL deficiency and in ARG1 deficiency, where RNA studies using lymphocytes further improve the diagnostic yield. Newborn screening Newborn screening for ASS and ASL deficiencies can be incorporated in the amino acid profile determined routinely by tandem-MS/MS. Elevation of citrulline and the presence of argininosuccinate respectively suggest ASS and ASL deficiency; elevations of arginine are suggestive for ARG1 deficiency but not present in all patients. Based on the experience in some newborn screening programs, there are concerns that patients with mild or asymptomatic disease might be subjected to unnecessary treatment [37, 56], rendering further studies essential.

z

Treatment and Prognosis

Emergency management follows the same principles as for mitochondrial UCDs, with identical dosages of infusions and medications (7 Sect. 19.1), except for ASL deficiency, for which a short infusion of L-arginine is given at up to 400 mg/kg over 90–120 min, followed by maintenance infusion of up to 400 mg/kg/day, since the response of some patients is very rapid and renders additional drugs unnecessary. Maintenance treatment for ASS and ASL deficiencies is as for CPS1 and OTC deficiencies, although, particularly in patients with ASL deficiency, there is a lower risk of recurrent metabolic crises. Nevertheless, a low-protein diet is required in most patients including its supplementation with essential amino acids, vitamins, and trace elements. Nitrogen scavenging drugs are usually needed for metabolic stability: 200–250  mg/kg/day sodium benzoate and/or sodium phenylbutyrate or glycerol phenylbutyrate), distributed in 3 equal doses. To enhance partial urea cycle function, L-arginine (but not L-citrulline) should be given at a dose of 100–300 mg/ kg/day in 3 dosages. To minimize potential argininosuccinate toxicity in ASL deficiency a reduced dose (in comparison to earlier literature) of arginine is recommended (100–300 mg/kg/day) [3]. Liver transplantation prevents hyperammonaemia but it does not reverse neurological damage. It should be considered for patients with poor metabolic control despite compliance with conservative therapy, or those with liver failure. In ARG1 deficiency L-arginine and L-citrulline must not be given, and the aim is to lower plasma arginine to A and c.851-854del in Japan (70% of the disease alleles) or c.851-854del, c.615+5G>A, IVS16ins3kb (c.1750+72_1751-4dup17ins), and c.1638_1660dup23 among Chinese (>80% of the alleles in a large patient cohort). A number of alleles are shared

by different Far East populations, while the p.Arg360* mutation appears to be widespread [59]. A frequency of 1/17,000 homozygotes or compound heterozygotes for disease-causing alleles has been estimated for Japan, similar to the NICCD frequency in that country, indicating full penetrance for this clinical form, but much more frequent than CTLN2 (1/100,000– 1/230,000  in Japan) [58]. A lower penetrance among females than among males can account for the lower frequency of CTLN2 in women than in men. z

Diagnosis

Biochemical assays In newborns with intrahepatic cholestasis the finding of increased plasma citrulline without significant hyperammonaemia, with normal or elevated levels of arginine and without urinary orotic acid, particularly with a high plasma level of alpha-fetoprotein and/or increased galactose in blood and urine, is strongly suggestive of NICCD [59]. In patients identified by neonatal screening with increased blood citrulline, it is important to first exclude ASS deficiency. Plasma ammonia and glutamine and urinary orotic acid are high in severe ASS deficiency but not in NICCD, and the reverse is true for arginine. Alpha-fetoprotein is increased in NICCD only. If tyrosine and alpha-fetoprotein are elevated, succinylacetone should be assayed to exclude tyrosinaemia type 1. A specific diagnosis of FTTDCD is difficult to make unless NICCD had been diagnosed previously. The presence of dyslipidemia is the paramount chemical indicator of FTTDCD, although increased citrulline levels and high lactate/pyruvate ratios can also be suggestive biomarkers. Nevertheless, blood citrulline levels can be increased by other factors such as by eating watermelon [65] or in renal failure [66]. CTLN2 can be differentiated from classical ASS deficiency by the lack of increase in the level of plasma glutamine (. Fig. 19.2) and the normal or somewhat increased arginine level in citrin deficiency, these levels being respectively high and low in ASS deficiency, and by the absence of urinary orotic acid in CTLN2. Protein studies Western blots of lymphocytes or cultured fibroblasts using antibodies that recognize the N-terminal moiety of citrin generally detect little or no cross-reactive immune material in most patients with citrin deficiency (but see [67]). Mutation analysis Mutation detection in both copies of SLC25A13 is the gold standard for diagnosis. In populations with prevalent mutations, the affected alleles can be searched first. RNA analysis is possible in cultured fibroblasts and peripheral blood lymphocytes [68].

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Newborn screening NICCD can be suspected in newborns presenting in the screening with elevated citrulline or galactosaemia, hypermethionaemia, tyrosinaemia or hyperphenylalaninaemia, particularly in regions with a high carrier ratio (Far East countries) [58]. Recently, a pilot study done in China on 237,630 newborns combined metabolic screening for citrulline levels with genetic screening for 28 SLC25A13 mutations in those newborns with normalhigh or high citrulline levels (about 30,000 newborns). They used a high-throughput iPLEX genotyping assay, identifying five NICCD patients [69]. z

19

Treatment and Prognosis

Emergency management of hyperammonaemic episodes in CTLN2 should avoid carbohydrate or glycerol infusions, because they worsen the hyperammonaemia [58, 61]. Mannitol infusion to combat brain oedema appears safe. Measures to rapidly decrease ammonia such as haemodialysis can be used, as well as administration of intravenous sodium benzoate and sodium phenylacetate. Arginine appears beneficial and should be administered. Energy should be provided while restricting the carbohydrate supply by using MCTs and amino acids. In NICCD the initial treatment may require packed red blood cells [59] and albumin for anaemia and hypoproteinaemia, respectively, and supportive measures for coagulopathy and liver insufficiency when present and severe. It is also essential to provide a lactose-free formula particularly if galactosaemia is observed, with some reduction in the fraction of calories provided by sugars in favour of MCTs and protein. Levels of fatsoluble vitamins and Zn should be monitored and supplemented when needed. Maintenance treatment of NICCD involves the use of lactose-free and MCT-enriched formula, relaxing this use with clinical improvement or at the end of the first year. When introduced, other foods should be protein-rich and fat-rich, such as eggs or fish. In CTLN2, the diet should follow the patient preferences for high protein/fat and low carbohydrate. Arginine (5–15  g/day reported) and sodium pyruvate (3–6  g in three 2 g-dosages reported) can be given [58], although presently the mainstay for maintenance therapy is MCTs administration providing about 20% of the daily caloric needs. Alcohol must be prohibited. Vigilance for hepatocellular carcinoma is necessary. If steatohepatitis and neuropsychiatric manifestations do not improve, liver transplantation provides a permanent cure. For FTTDCD a protein and MCT-rich and carbohydrate-poor diet with no lactose is recommended. Sodium pyruvate may improve growth. It is a chemical, although calcium pyruvate is sold as a food supplement.

Outcome of NICCD is generally good with little intervention. The prognosis for CTLN2 has been poor without liver transplantation. Presently the awareness of avoiding glucose or glycerol infusions and the introduction of MCTs and possibly also of arginine and pyruvate appear to have improved the outcome of conservative treatment.

19.4

Urea Cycle Defects Due to Deficiencies of Ancillary Enzymes

19.4.1Δ1-Pyrroline-5-Carboxylate

Synthetase (P5CS) Deficiency P5CS, encoded by ALDH18A1, catalyses the first common step of de novo ornithine and proline synthesis. Its deficiency has been reported to cause a fasting hyperammonaemia and cutis laxa syndrome with global developmental delay (De Barsy syndrome), and/or spastic paraplegia, with the peculiarity of having dominant or recessive inheritance and frequent de novo mutations (reviewed in [51]). This deficiency is described in 7 Chap. 21. 19.4.2Carbonic Anhydrase Va (CAVA)

Deficiency There is little experience on this disease as only 20 patients have been reported thus far [70–75]. However, the disorder may be more frequent than appreciated, since it was found in 10 out of 96 patients with earlyonset hyperammonaemia in whom genetic diagnosis of other UCDs had failed [71]. z

Clinical Presentation

Most patients have developed neonatal symptoms identical to those with neonatal onset UCDs, presenting with hyperammonaemic encephalopathy within the first days after birth. In contrast to other neonatally presenting UCDs, all but one patient survived without sequelae, including those patients requiring haemodialysis. Surprisingly, the patient who died [73] presented brain oedema with increased intracranial pressure and brain herniation when the blood biochemical parameters had normalized, casting doubts on the reasons for the brain oedema, as arterial hypertension was reported in this 18-month infant. The majority of patients have had only a single hyperammonaemic crisis; those who had a second one had a milder episode [70, 71]. No symptoms have yet been described in children, adolescents or adults.

403 Disorders of the Urea Cycle and Related Enzymes

z

Metabolic Derangement

Bicarbonate cannot cross the mitochondrial membrane, and the spontaneous conversion of CO2 to bicarbonate can be too slow for the needs of urea synthesis. CAVA accelerates this conversion within liver mitochondria, supplying the bicarbonate used intramitochondrially by CPS1, pyruvate carboxylase, propionyl CoA carboxylase and 3-methylcrotonyl CoA carboxylase. Therefore, CAVA deficiency impairs the urea cycle, gluconeogenesis and branched-chain amino acid metabolism, yielding an unusual combination of biochemical findings [76]. These include hyperammonaemia, decreased plasma citrulline and absence of urinary orotic acid, hypoglycaemia, metabolic acidosis, high plasma lactate and urinary ketone bodies, and a urinary profile of organic acids containing carboxylase-related metabolites (7 Chap. 27). The apparently successful empirical use of carbamylglutamate could be justified if the affinity of CPS1 for bicarbonate were increased when the enzyme is saturated by its essential allosteric activator, acetylglutamate (of which carbamylglutamate is an analogue). z

Genetics

CAVA is caused by mutations in CA5A. A deletion of exon 6 (c.619-3421_774+502del) may be prevalent in patients from the Indian subcontinent [71, 76]. A locus specific homepage can be found at: 7 http://databases. lovd.nl/shared/genes/CA5A. z

Diagnostic Tests

Biochemical assays should include plasma ammonia, blood lactate and urine ketone bodies, in addition to blood glucose and plasma amino acid profiles. Organic acids in the urine should be analysed to search for carboxylase metabolites. Blood acylcarnitine profiles are normal in this disorder [76]. Enzyme studies would require analysis of liver tissue and thus mutation analysis is used to confirm CAVA deficiency. Mutation analysis. The first mutations were reported in 2014 [70]. CA5A is small (only seven coding exons) but requires careful design of oligonucleotide primers because of highly homologous sequences of pseudogenes. As the gene is mainly expressed in the liver, use of RNA for analysis would require invasive sampling and therefore has not been reported.

Otherwise, management is standard, including sufficient fluid and energy substitution, balance of acid-base status and of glucose homeostasis, and protein restriction during hyperammonaemia. Maintenance treatment was not required in the patients reported in the literature as all interventions could be reduced soon after recovery from the metabolic crisis. Nevertheless, an emergency plan should be provided along with appropriate family counselling. Outcome in CAVA deficiency generally appears excellent but observations in more patients are needed.

19.5

The term THAN refers to a condition mostly described in premature infants (but sometimes also in term newborns), which was often found together with respiratory distress syndrome. The cause of THAN is not clear but some authors suggest shunting of blood via the open ductus venosus (transporting high levels of ammonia up to 300 μmol/l) and thus escaping clearance by the hepatic UC [77, 78]. In this condition ammonia may be greatly increased (>3000 μmol/l), whilst glutamine is usually in the reference range resulting in a plasma ratio of glutamine/ammonia A) mutation, a founder mutation in Scandinavia originating from Faroe Islands, show a unique clinical character with onset between 2 months and 8 years, and a slow and in some patients only partial clinical response to biotin treatment [33, 49]. To date, the prognosis for most surviving, welltreated patients with HCS deficiency seems to be good,

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with the exception of those who show only a partial or no response to biotin [5, 40, 41, 46, 49]. Careful followup studies are needed to judge the long-term outcome. Irreversible neurological auditory-visual deficits, as described for biotinidase deficiency, have not been reported. Prenatal biotin treatment (10  mg/day) has been reported in a few pregnancies [46]. It is unclear whether prenatal treatment is essential; treatment of atrisk children immediately after birth may be sufficient.

27.5.2Biotinidase Deficiency

The introduction of neonatal screening programmes has resulted in the detection of asymptomatic patients with residual biotinidase activity [48]. Based on measurement of serum biotinidase activity, the patients are classified into those with profound biotinidase deficiency, with less than 10% of mean normal biotinidase activity, and those with partial biotinidase deficiency, with 10–30% residual activity. z

Profound Biotinidase Deficiency

In early-diagnosed children with complete biotinidase deficiency, 5–10  mg of oral biotin per day promptly reverses or prevents all clinical and biochemical abnormalities. For chronic treatment, the same dose is recommended. Under careful clinical and biochemical control, it may be possible to reduce the daily dose of biotin to 2.5 mg. However, biotin has to be given throughout life and regularly each day, since biotin depletion develops rapidly [11]. Some patients with profound deficiency have been reported to develop symptoms, e.g. hair loss, during puberty and adulthood that could be resolved when biotin dosage was increased to 15 or 20 mg [12]. Neonatal screening for biotinidase deficiency [50] allows early diagnosis and effective treatment. In such patients, the diagnosis must be confirmed by quantitative measurement of biotinidase activity. Treatment should be instituted without delay, since patients may become biotin deficient within a few days after birth [11]. In patients who are diagnosed late, irreversible brain damage may have occurred before the commencement of treatment. In particular, auditory and visual deficits often persist in spite of biotin therapy [13, 20–22], and intellectual impairment and ataxia have been observed as long-term complications [13, 18, 20, 21]. Patients with residual activity up to 10%, usually detected by neonatal screening or family studies, may remain asymptomatic for several years or even until adulthood [16, 42]. According to our experience with 61 such patients (52 families), however, they show a very high risk of becoming biotin deficient and should be treated [12, 42, 50].

z

Partial Biotinidase Deficiency

Patients with partial biotinidase deficiency (10–30% residual activity) are mostly detected by neonatal screening or in family studies and usually remain asymptomatic. However, over 20 children with partial deficiency who were identified by newborn screening but were not treated with biotin eventually did develop symptoms typical of profound biotinidase deficiency, such as hypotonia, skin rashes and loss of hair, particularly when they were stressed by an infectious disease or moderate gastroenteritis. In the vast majority all symptoms were readily reversed upon biotin treatment [47, 48]. Thus, because some untreated children will develop symptoms and conclusive evidence is lacking, it seems prudent to supplement patients with 10–30% of residual activity with biotin, e.g. 2.5–5 mg/day [47, 48].

27.5.3SLC5A6 Deficiency

One patient was treated with large doses of biotin (10 mg/ day, then 30 mg/ day), pantothenic acid (250 mg/day, then 500 mg/day), and lipoic acid (150 mg/day, then 300 mg/ day) and exhibited limited improved motor and verbal skill development, but normalized height and weight, and improved head growth [23]. Another patient made some recovery on biotin alone (5  mg/day) however, escalation of biotin (to 10  mg/ 2× day) and introduction of pantothenic acid (250 mg/day), was required for improved appetite and growth, and resolution of diarrhoea. Nevertheless, delayed gross motor development remained [24]. The final treated patient was given weekly biotin (10  mg, intramuscular), dexpanthenol (250  mg, intramuscular) and α-lipoic acid (300 mg, intravenous) at the age of 7 years of age. The patients overall condition improved, including attenuation of cyclical vomiting, good seizure control, improved attention and recovery of a limited vocabulary and ability to walk with a frame [25].

References 1.

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3. 4.

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Zempleni J et al (2014) Novel roles of holocarboxylase synthetase in gene regulation and intermediary metabolism. Nutr Rev. 72:369–376 Leon-Del-Rio A et  al (2017) Holocarboxylase synthetase: a moonlighting transcriptional coregulator of gene expression and a cytosolic regulator of biotin utilization. Annu Rev Nutr 37:207–223 Leon-Del-Rio A (2019) Biotin in metabolism, gene expression, and human disease. J Inherit Metab Dis 42:647–654 Zeng WQ, Al-Yamani E, Acierno JS Jr et  al (2005) Biotinresponsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77:16–26 Baumgartner ER, Suormala T (1997) Multiple carboxylase deficiency: inherited and acquired disorders of biotin metabolism. Int J Vitam Nutr Res 67:377–384

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Larson AA et al (2019) Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6. Mitochondrion 44:58–64 Yang X, Aoki Y, Li X et al (2001) Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency. Hum Genet 109:526–534 Suormala T, Fowler B, Duran M et al (1997) Five patients with a biotin-responsive defect in holocarboxylase formation: evaluation of responsiveness to biotin therapy in vivo and comparative studies in vitro. Pediatr Res 41:666–673 Sherwood WG, Saunders M, Robinson BH et al (1982) Lactic acidosis in biotin-responsive multiple carboxylase deficiency caused by holocarboxylase synthetase deficiency of early and late onset. J Pediatr 101:546–550 Watabe D et al (2018) Psoriasis-like dermatitis in adulthood: a skin manifestation of holocarboxylase synthetase deficiency. Acta Dermato Venereologica 98(8):805–806 Baumgartner ER, Suormala TM, Wick H, Bausch J, Bonjour JP (1985) Biotinidase deficiency associated with renal loss of biocytin and biotin. Ann N Y Acad Sci 447:272–286 Wolf B (2012) Biotinidase deficiency: “if you have to have an inherited metabolic disease, this is the one to have”. Genet Med 14:565–575 Wastell HJ, Bartlett K, Dale G, Shein A (1988) Biotinidase deficiency: a survey of 10 cases. Arch Dis Child 63:1244–1249 Bottin L, Prud’hon S, Guey S et  al (2015) Biotinidase deficiency mimicking neuromyelitis optica: initially exhibiting symptoms in adulthood. Mult Scler J 12:1604–1607 McSweeney N, Grunewald S, Bhate S et al (2010) Two unusual clinical and radiological presentations of biotinidase deficiency. Eur J Paediatr Neurol 14:535–538 Moeslinger D, Stockler-Ipsiroglu S, Scheibenreiter S et  al (2001) Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr 160:277–282 Baumgartner ER, Suormala TM, Wick H et  al (1989) Biotinidase deficiency: a cause of substance necrotizing encephalomyalopathy (Leigh syndrome). Report of a case with lethal outcome. Pediatr Res 26:260–266 Grunewald S, Champion MP, Leonard JV, Schaper J, Morris AA (2004) Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 35:211–216 Ramaekers VTH, Suormala TM, Brab M et  al (1992) A biotinidase Km variant causing late onset bilateral optic neuropathy. Arch Dis Child 67:115–119 Weber P, Scholl S, Baumgartner ER (2004) Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol 46:481–484 Wolf B, Spencer R, Gleason T (2002) Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. J Pediatr 140:242–246 Duran M, Baumgartner ER, Suormala TM et  al (1993) Cerebrospinal fluid organic acids in biotinidase deficiency. J Inherit Metab Dis 16:513–516 Subramanian VS, Constantinescu AR, Benke PJ, Said HM (2017) Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child. Hum Genet 136(2):253–261. https://doi.org/10.1007/s00439-016-1751-x Schwantje M, de Sain-van der Velden M, Jans J et  al (2019) Genetic defect of the sodium-dependent multivitamin transporter: a treatable disease, mimicking biotinidase deficiency. JIMD Rep 48(1):11–14. Published 2019 May 28. https://doi. org/10.1002/jmd2.12040 Byrne AB, Arts P, Polyak SW et al (2019) Identification and targeted management of a neurodegenerative disorder caused by

biallelic mutations in SLC5A6. NPJ Genom Med 4:28. Published 2019 Nov 14. https://doi.org/10.1038/s41525-019-0103-x 26. Mardach R, Zempleni J, Wolf B et  al (2002) Biotin dependency due to a defect in biotin transport. J Clin Invest 109:1617–1623 27. Sweetman L, Surh L, Baker H, Peterson RM, Nyhan WL (1981) Clinical and metabolic abnormalities in a boy with dietary deficiency of biotin. Pediatrics 68:553–558 28. Burri BJ, Sweetman L, Nyhan WL (1985) Heterogeneity in holocarboxylase synthetase in patients with biotin-responsive multiple carboxylase deficiency. Am J Hum Genet 37:326– 337 29. Sakamoto O, Suzuki Y, Li X et al (1999) Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in holocarboxylase synthetase deficiency. Pediatr Res 46:671–676 30. Suormala TM, Baumgartner ER, Bausch J et  al (1988) Quantitative determination of biocytin in urine of patients with biotinidase deficiency using high-performance liquid chromatography (HPLC). Clin Chim Acta 177:253–270 31. Blom W, de Muinck Keizer SM, Scholte HR (1981) AcetylCoA carboxylase deficiency: an inborn error of de novo fatty acid synthesis. N Engl J Med 305:465–466 32. Tarailo-Graovac M et al (2016) Exome sequencing and the management of neurometabolic disorders. N Engl J Med 374:2246–55 33. Lund AM, Joensen F, Hougaard DM (2007) Carnitine transporter and holocarboxylase synthetase deficiencies in The Faroe Islands. J Inherit Metab Dis 30:341–349 34. Strovel ET et al (2017) Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med 19:1079 35. The Human Gene Mutation Database (2015). http://www. hgmd.cf.ac.uk/ac/index.php 36. Aoki Y, Suzuki Y, Li X et al (1997) Characterization of mutant holocarboxylase synthetase (HCS): a Km for biotin was not elevated in a patient with HCS deficiency. Pediatr Res 42:849– 854 37. Dupuis L, Campeau E, Leclerc D, Gravel RA (1999) Mechanisms of biotin responsiveness in biotin-responsive multiple carboxylase deficiency. Mol Genet Metab 66:80–90 38. van JL H, Josefsberg S, Freehauf C et al (2008) Management of a patient with holocarboxylase synthetase deficiency. Mol Genet Metab 95:201–205 39. Soloranza-Vargas RS, Pacheco-Alvarez D, Leon-del-Rio A (2002) Holocarboxylase synthetase is an obligate participant in biotin-mediated regulation of its own expression and of biotindependent carboxylases mRNA levels in human cells. PNAS 99:5325–5330 40. Wilson CJ, Myer M, Darlow BA et  al (2005) Severe holocarboxylase synthetase deficiency with incomplete biotin responsiveness resulting in antenatal insult in samoan neonates. J Pediatr 147:115–118 41. Slavin TP, Zaidi SJ, Neal C, Nishikawa B, Seaver LH (2014) Clinical presentation and positive outcome of two siblings with holocarboxylase synthetase deficiency caused by a homozygous L216R mutation. JIMD Rep 12:109–114 42. Suormala TM, Baumgartner ER, Wick H et  al (1990) Comparison of patients with complete and partial biotinidase deficiency: biochemical studies. J Inherit Metab Dis 13:76–92 43. Baur B, Suormala T, Bernoulli C, Baumgartner ER (1998) Biotin determination by three different methods: specificity and application to urine and plasma ultrafiltrates of patients with and without disorders in biotin metabolism. Int J Vitam Nutr Res 68:300–308

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Suzuki Y, Aoki Y, Sakamoto O et al (1996) Enzymatic diagnosis of holocarboxylase synthetase deficiency using apo-carboxyl carrier protein as a substrate. Clin Chim Acta 251:41–52 Suormala T, Fowler B, Jakobs C et al (1998) Late-onset holocarboxylase synthetase-deficiency: pre- and post-natal diagnosis and evaluation of effectiveness of antenatal biotin therapy. Eur J Pediatr 157:570–575 Aoki Y, Suzuki Y, Sakamoto O et al (1995) Molecular analysis of holocarboxylase synthetase deficiency: a missense mutation and a single base deletion are predominant in Japanese patients. Biochim Biophys Acta 1272:168–174 Jay AM, Conway RL, Feldman GL et al (2015) Outcomes of individuals with profound and partial biotinidase deficiency

48. 49.

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ascertained by newborn screening in Michigan over 25 years. Genet Med 17:205–209 Wolf (2015) Why screen newborns for profound and partial biotinidase deficiency? Mol Genet Metab 114:382–387 Santer R, Muhle H, Suormala T et al (2003) Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects. Mol Genet Metab 79:160–166 Wolf B (1991) Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis 14:923–92725

511

Disorders of Cobalamin and Folate Transport and Metabolism Brian Fowler, D. Sean Froese, and David Watkins Contents 28.1

Disorders of Absorption and Transport of Cobalamin – 513

28.1.1 28.1.2 28.1.3 28.1.4 28.1.5

Hereditary Intrinsic Factor Deficiency – 513 Defective Transport of Cobalamin by Enterocytes (ImerslundGräsbeck Syndrome) – 513 Haptocorrin (R Binder) Deficiency – 514 Transcobalamin Deficiency – 514 Transcobalamin Receptor Deficiency – 515

28.2

Disorders of Intracellular Utilisation of Cobalamin – 516

28.2.1 28.2.2 28.2.3

Combined Deficiencies of Adenosylcobalamin and Methylcobalamin – 516 Adenosylcobalamin Deficiency: CblA (MMAA) & CblB (MMAB) – 519 Methylcobalamin Deficiency: CblE (MTRR) & CblG (MTR) – 520

28.3

Disorders of Absorption and Metabolism of Folate – 522

28.3.1

Hereditary Folate Malabsorption (Proton-Coupled Folate Transporter Deficiency, SLC46A1) – 522 28.3.2 Cerebral Folate Deficiency (Folate Receptor α Deficiency, FOLR1) – 522 28.3.3 Reduced Folate Carrier Deficiency (SLC19A1) – 523 28.3.4 Methylenetetrahydrofolate Dehydrogenase Deficiency (MTHFD1) – 523 28.3.5 Dihydrofolate Reductase Deficiency (DHFR) – 523 28.3.6 Glutamate Formiminotransferase Deficiency (FTCD) – 524 28.3.7 Methylenetetrahydrofolate Reductase Deficiency (MTHFR) – 524 28.3.8 Methenyltetrahydrofolate Synthetase Deficiency (MTHFS) – 525 28.3.9 10-Formyltetrahydrofolate Dehydrogenase Deficiency (ALDH1L2) – 526 28.3.10 Serine Hydroxymethyltransferase 2 Deficiency (SHMT2) – 526

References – 526

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_28

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Extracellular Cytoplasm

cblG Homocysteine

Methionine Methionine Synthase MeCbl

28

PRDX1 (epi-cblC) HCFC1 (cblX) THAP11 ZNF143

Lyso

cblJ

TC R-Cbl

R-Cbl TCblR

cblC R-Cbl

cblE cblD-v1 Cbl cblD

Cbl

cblF cblD-v2 Cbl cblB

Mitochondrion

AdoCbl cblA AdoCbl Methylmalonyl-CoA mutase L-Methylmalonyl-CoA

Succinyl-CoA mut

. Fig. 28.1 Cobalamin (Cbl) endocytosis and intracellular metabolism. The cytoplasmic, lysosomal, and mitochondrial compartments are indicated: AdoCbl adenosylcobalamin, CoA coenzyme A, MeCbl methylcobalamin, OHCbl hydroxocobalamin, TC transcobalamin (previously TCII), V1 variant 1, V2 variant 2, cblA-cblG,

Cobalamin Transport and Metabolism Cobalamin (Cbl or vitamin B12) is a cobalt-containing water-soluble vitamin that is synthesised by lower organisms but not by higher plants and animals (. Fig. 28.1). The only source of Cbl in the human diet is animal products. Cbl is needed for only two reactions in man, but its metabolism involves complex absorption and transport systems and multiple intracellular conversions. As methylcobalamin (MeCbl), it is a cofactor of the cytoplasmic enzyme methionine synthase, which converts homocysteine to methionine. As adenosylcobalamin (AdoCbl), it is a cofactor of the mitochondrial enzyme methylmalonyl-coenzyme A mutase, which is

and cbIJ, refer to the sites of blocks. PRDX1 (epi-cblC), HCFC1 (cblX), THAP11 and ZNF143 refer to disorders affecting expression of the cblC protein (MMACHC). Inborn errors are indicated by solid bars

involved in the catabolism of valine, threonine and oddchain fatty acids into succinyl-CoA, an intermediate of the Krebs cycle: Absorption of dietary Cbl first involves binding to a glycoprotein (haptocorrin, R binder) in the saliva. In the intestine, haptocorrin is digested by proteases, allowing the Cbl to bind to intrinsic factor (IF), which is produced in the stomach by parietal cells. Using the specific receptor cubam, the IF-Cbl complex enters the enterocyte. Following release from this complex Cbl enters the portal circulation bound to transcobalamin (TC), the physiologically important circulating Cbl-binding protein. Inherited defects of several of these steps are known.

513 Disorders of Cobalamin and Folate Transport and Metabolism

28.1

Disorders of Absorption and Transport z Metabolic Derangement IF is either absent or immunologically detectable but of Cobalamin

The serum cobalamin (Cbl) level is usually low in patients with disorders affecting absorption and transport of Cbl, with the exception of transcobalamin (TC) deficiency. Patients with disorders of intracellular Cbl metabolism typically have serum Cbl levels within the reference range, although levels may be reduced in the cblF and cblJ disorders. Homocystinuria (Hcy) and hyperhomocysteinaemia, as well as megaloblastic anaemia and neurological disorders, are major clinical findings in patients with disorders of Cbl absorption and transport, as well as those with defects of cellular metabolism that affect synthesis of MeCbl. Methylmalonic aciduria and acidaemia (MMA), resulting in metabolic acidosis, are seen in disorders that result in decreased synthesis of AdoCbl. Increased urine MMA and plasma Hcy are also found in nutritional vitamin B12 deficiency. Severe vitamin B12 deficiency in newborn infants, which may occur in breast fed infants born to vegan mothers or those with subclinical pernicious anaemia, can result in a disorder that ranges from an elevation in serum concentration of propionylcarnitine detected by newborn screening, to one presenting with severe neonatal encephalopathy. The mother does not necessarily have a very low serum concentration of vitamin B12. IM vitamin B12 replacement therapy to normalize the vitamin B12 serum concentration reverses the metabolic abnormality [1]. Inherited disorders of Cbl metabolism are divided into those involving absorption and transport and those involving intracellular utilisation [2–4]. New disorders continue to be discovered and the spectrum of clinical abnormalities widens. Developing guidelines [5] lead to harmonised treatment strategies, although doses given need to be individually tested.

28.1.1 z

Hereditary Intrinsic Factor Deficiency

non-functional. There have been reports of IF with reduced affinity for Cbl or cubam, or with increased susceptibility to proteolysis. z

z

Diagnostic Tests

The haematological abnormalities in the defects of Cbl absorption and transport should be detected by measurement of red blood cell indices, complete blood count and bone marrow examination. Low serum Cbl levels are present. In contrast to acquired forms of pernicious anaemia, there is normal gastric acidity and cytology, and anti-IF antibodies are absent. Cbl absorption, as measured by the Schilling test, is abnormal and normalised by exogenous IF.  Because the Schilling test is rarely available, and because differentiation between hereditary IF deficiency and ImerslundGräsbeck syndrome on the basis of other clinical findings has proven difficult in some cases, sequencing of CBLIF, AMN and CUBN may represent an appropriate first-line means of correctly diagnosing these disorders [7]. z

Treatment and Prognosis

IF deficiency can be treated initially with hydroxocobalamin (OHCbl), 1 mg/day i.m., to replenish body stores until biochemical and haematological values become normal. The subsequent dose of OHCbl required to maintain values within or above the reference range may be as low as 0.25 mg every 3 months.

28.1.2

Clinical Presentation

Presentation is usually from 1 to 5  years of age, but in cases of partial deficiency can be delayed until adolescence or adulthood. Patients present with megaloblastic anaemia as the main finding, together with failure to thrive, often with vomiting, alternating diarrhoea and constipation, anorexia and irritability. Hepatosplenomegaly, neutropenia/thrombocytopenia, stomatitis or atrophic glossitis, developmental delay and myelopathy or peripheral neuropathy may also be found [6].

Genetics

Approximately 100 patients of both sexes have been reported. Inheritance is autosomal recessive. Mutations in the gene for IF (CBLIF) have been identified in several patients with IF deficiency [7, 8].

z

Defective Transport of Cobalamin by Enterocytes (Imerslund-Gräsbeck Syndrome)

Clinical Presentation

Defective transport of Cbl by enterocytes, also known as Imerslund-Gräsbeck syndrome or megaloblastic anaemia 1 (MGA1), is characterised by prominent megaloblastic anaemia with pallor, fatigue and failure to thrive manifesting once foetal hepatic Cbl stores have been depleted. The disease usually appears between the ages of 1  year and 5 years, but onset may be even later [9]. Many patients have

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proteinuria that is not of the classic glomerular or tubular types, does not respond to therapy with Cbl and is not progressive [10]. A benign form of albuminuria has been associated with reduced cubilin function [11]. Neurological abnormalities, such as spasticity, truncal ataxia and cerebral atrophy, may be present as a consequence of the Cbl deficiency. A loss of interaction between cubilin and the vitamin D binding protein in the kidney may lead to hypovitaminosis D due to excess vitamin D excretion in patients with null mutations of cubulin [12, 13]. z

Metabolic Derangement

This disorder is caused by defects of the IF-Cbl receptor, cubam, which comprises two components. Cubilin was first purified as the IF-Cbl receptor from the proximal renal tubule. A second component, amnionless, colocalises with cubilin in the endocytic apparatus of polarised epithelial cells, forming a tightly bound complex that is essential for endocytosis of IF-Cbl and other molecules, including vitamin D-binding protein, albumin, transferrin and apolipoprotein A [2, 14]. Thus, defective function of either protein may cause this disorder. z

Genetics

Around 300 cases have been reported. Inheritance is autosomal recessive, with environmental factors affecting expression [15]. Most patients are found in Finland, Norway, Saudi Arabia and Turkey, and among Sephardic Jews. A p.Pro1297Leu mutation in the cubilin gene (CUBN) was the most common causal variant in Finnish families, while mutations in the amnionless gene (AMN) were identified in Norwegian patients. Mutations of both CUBN and AMN have been identified in patients of Eastern Mediterranean origin [8]. z

Diagnostic Tests

The diagnosis is aided by finding low serum Cbl levels, megaloblastic anaemia and proteinuria. Most of the reports in the literature do not comment on the levels of homocysteine and methylmalonic acid. Gastric morphology and pancreatic function are normal; there are no IF autoantibodies and IF levels are normal. As previously noted, in the absence of the Schilling test, molecular analysis of CBLIF, CUBN and AMN may be the best means of differentiating between hereditary IF deficiency and Imerslund-Gräsbeck syndrome [7].

28.1.3Haptocorrin (R Binder) Deficiency z

Clinical Presentation

Very few cases have been described, and it is not clear whether this entity has a distinct phenotype. Haematological findings are absent and neurological findings such as subacute combined degeneration of the spinal cord in one man in the fifth decade of life and optic atrophy, ataxia, long-tract signs and dementia in another may be coincidental. It has been suggested that a deficiency of haptocorrin may be responsible for a number of patients with unexplained low serum Cbl levels. Haptocorrin deficiency has also been identified in individuals with serum Cbl levels within the reference range [16, 17]. z

Metabolic Derangement

The role of haptocorrin is uncertain, but it could be involved in the scavenging of toxic Cbl analogues or in protecting circulating MeCbl from photolysis. Deficiency of haptocorrin has been described in isolation and in association with deficiency of other specific granule proteins such as lactoferrin [18]. z

Genetics

A patient with severe deficiency of haptocorrin was shown to be compound heterozygous for two nonsense mutations (c.270delG and c.315C > T) in TCN1, which encodes haptocorrin. Members of this patient’s family with moderate haptocorrin deficiency, as well as unrelated individuals with moderate deficiency, were found to be heterozygous for one of the mutations [17]. z

Diagnostic Tests

Serum Cbl levels are low because most circulating Cbl is bound to haptocorrin. TC-Cbl levels are normal, and there are no haematological findings of Cbl deficiency. A deficiency or absence of haptocorrin is found in plasma, saliva and leukocytes. z

Treatment and Prognosis

It is likely that no treatment is needed because of the lack of a clearly defined phenotype.

28.1.4Transcobalamin Deficiency z

Treatment and Prognosis

Treatment with parenteral OHCbl corrects the anaemia and the neurological findings, but not the proteinuria. As with hereditary IF deficiency, once Cbl stores are replete, low doses of parenteral OHCbl may be sufficient to maintain normal haematological and biochemical values.

z

Clinical Presentation

In transcobalamin (TC) deficiency, symptoms usually develop much earlier than in other disorders of Cbl absorption, typically within the first few months of life. Even though the only TC in cord blood is of foetal ori-

515 Disorders of Cobalamin and Folate Transport and Metabolism

gin, patients are not sick at birth. Presenting findings include pallor, failure to thrive, mouth ulcerations, weakness and diarrhoea. Although the anaemia is usually megaloblastic, patients with pancytopenia or isolated erythroid hypoplasia have been described [19]. Leukaemia may be mistakenly diagnosed because of the presence of immature white cell precursors in an otherwise hypocellular marrow [20]. Neurological disease is not an initial finding but may develop with delayed treatment, with administration of folate in the absence of Cbl, or with inadequate Cbl treatment. Neurological features include developmental delay, weakness, ataxia, hypotonia, neuropathy, myelopathy and encephalopathy and, rarely, retinal degeneration. Immunologic abnormalities including agammaglobulinaemia, low IgG and low T and B cell counts may be present; some patients have had recurrent infections. z

Metabolic Derangement

The majority of patients have no immunologically detectable TC, although others have some detectable TC that is able to bind Cbl but cannot support cellular Cbl uptake. z

Genetics

Inheritance is autosomal recessive. There have been at least 50 cases, including both twins and siblings. Diseasecausing deletions, nonsense mutations and activation of an intra exonic cryptic splice site have been described in TCN2, which encodes transcobalamin [19]. z

Diagnostic Tests

Serum Cbl levels are not usually low, because the majority of serum Cbl is bound to haptocorrin and not to TC.  Cbl bound to TC, as reflected by the unsaturated vitamin B12-binding capacity, is low provided that the test is performed before Cbl treatment is started. Reports of levels of Cbl-related metabolites are inconsistent. Patients with plasma total homocysteine within the reference range and moderately increased urine methylmalonic acid have been reported, as well as patients with methylmalonic aciduria and homocystinuria. DNA testing is possible for both diagnosis and heterozygote detection in families in which the molecular defect has been identified. Assays using antibodies generated against recombinant human TC allow reliable measurement of serum TC even in patients who have been treated with Cbl [21]. In atypical cases, study of TC synthesis in cultured fibroblasts or amniocytes allows both pre- and postnatal diagnosis in patients [22]. z

Treatment and Prognosis

Adequate treatment requires administration of oral or parenteral OHCbl or cyanocobalamin (CNCbl) at a

dose of 0.5–1  mg, initially daily then twice weekly, to maintain serum Cbl levels in the range of 1000– 10,000  pg/ml. Intravenous Cbl is not recommended because of its rapid loss in the urine. Folic acid or folinic acid can reverse the megaloblastic anaemia and has been used in doses up to 15 mg p.o. four times daily. However, folates must never be given as the only therapy in TC deficiency, because of the danger of neurological deterioration. Treatment with Cbl, particularly when instituted during the first months of life, has been associated with favourable patient outcomes. A review of TCdeficient patients found a single patient, among 19 older than 6 years old at the latest follow-up, with significant intellectual deficits, possibly due to sub-optimal therapy. A second patient had neurological findings that responded to treatment optimization [19].

28.1.5Transcobalamin Receptor Deficiency z

Clinical Presentation

Several subjects with a defect affecting the cell surface receptor that recognises the TC-Cbl complex and modulates its uptake by carrier-mediated endocytosis have been identified on newborn screening. They had moderate elevations of serum methylmalonic acid and, in most cases, also of homocysteine, but most did not show clinical signs of Cbl deficiency [23]. Attributing bilateral central artery occlusions to hyperhomocysteinemia [24] in a single patient is questionable. z

Metabolic Derangement

Cellular uptake of Cbl bound to TC is markedly decreased in patient fibroblasts [23], apparently without prejudicing synthesis of MeCbl and AdoCbl. z

Genetics

Inheritance is autosomal recessive. Eight individuals homozygous for a 3-bp deletion (c.262_264delGAG) in CD320 that encodes the TC receptor, have been described, in addition to one patient heterozygous for this variant together with c.297delA [25]. The c.262_264delGAG variant has been shown to cause diminished Cbl uptake in an in vitro system [23]. It was present at a frequency of 3% in an Irish control population [26]. z

Treatment and Prognosis

Since most of the affected individuals lack clinical signs of Cbl deficiency, it is likely that treatment is not necessary. Mild or moderate elevations of homocysteine or methylmalonic acid experienced by these individuals appear to be responsive to oral supplementation with cobalamin.

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28.2

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Disorders of Intracellular Utilisation of Cobalamin

Disorders of intracellular Cbl metabolism have been classified as cbl mutants (A-G, J), based on the biochemical phenotype and on somatic cell analysis (. Fig. 28.1). They encompass disruption of proteins required for transport or metabolism of Cbl to its cofactor forms. Recently, a new group of disorders that disrupt transcription of one of these enzymes, MMACHC, has been described. These include variants of HCFC1 (cblX), THAP11, ZNF143 and PRDX1. Precise diagnosis of the inborn errors of Cbl metabolism requires either identification of causal mutations or tests in cultured fibroblasts, including complementation analysis.

28.2.1Combined Deficiencies

of Adenosylcobalamin and Methylcobalamin Five distinct disorders are associated with functional defects in both methylmalonyl-CoA mutase and methionine synthase. They are characterised by both methylmalonic aciduria and homocystinuria. 28.2.1.1CblF (LMBRD1) z Clinical Presentation

Most patients with cblF disease have presented in the first year of life. Frequent findings have included intrauterine growth retardation (2 patients), feeding difficulties (4), failure to thrive (8), developmental delay (8) and persistent stomatitis (5). Other findings are haematological features (6), congenital cardiac anomalies (6), and small for gestational age (6) [27]. A complete blood count and bone marrow examination may reveal megaloblastic anaemia, neutropenia and thrombocytopenia. Two patients have had minor facial anomalies including pegged teeth and bifid incisors; four have had structural heart defects. One patient died suddenly at home in the first year of life; two others died after cardiac surgery [28]. z

Metabolic Derangement

The defect in cblF appears to be a failure of Cbl transport across the lysosomal membrane following its release from TC in the lysosome. As a result, Cbl accumulates in lysosomes and cannot be converted to either AdoCbl or MeCbl. The inability of cblF patients to absorb oral Cbl suggests that IF-Cbl also has to pass through a lysosomal stage in the enterocyte before Cbl is released into the portal circulation.

z

Genetics

Sixteen patients with the cblF disorder have been reported. Mutations in LMBRD1 have been identified in all reported patients [28–30], inherited in an autosomal recessive manner. This gene encodes a lysosomal membrane protein. A deletion mutation (c.1056delG), which is found on a common haplotype [31], occurs in patients from different ethnic groups and represents two-thirds of disease-causing alleles that have been identified. z

Diagnostic Tests

The serum Cbl level may be low, and the Schilling test has been abnormal when tested. Usually, increased plasma total homocysteine, methylmalonic acid and C3 acylcarnitine, low to normal plasma methionine, homocystinuria and methylmalonic aciduria are found, although urine and plasma elevations of homocysteine were not reported in the original patient. In fibroblasts from cblF patients, total incorporation of labelled CNCbl is elevated, but CNCbl is not converted to either AdoCbl or MeCbl. Most of the label is found as free CNCbl in lysosomes. There is decreased function of both Cbl-dependent enzymes. z

Treatment and Prognosis

Treatment with parenteral OHCbl (first daily and then biweekly, or even less frequently) at a dose of 1 mg/day seems to be effective in correcting the metabolic and clinical findings. The original patient responded to oral Cbl before being switched to parenteral Cbl, despite the fact that the Schilling test performed on two occasions showed an inability to absorb Cbl with or without IF. 28.2.1.2CblJ (ABCD4) z Clinical Presentation

Six patients have been reported with the cblJ disorder. The first two patients presented in the newborn period. One had feeding difficulties, hypotonia, lethargy and bone marrow suppression; the second had feeding difficulties, macrocytic anaemia and congenital heart defects [32]. Subsequently, three patients of Chinese descent were reported with later onset (4 to 6  years of age), hyperpigmentation and prematurely grey hair; one additionally reported dizziness and headaches [33–35]. Macrocytic anaemia, methylmalonic aciduria and hyperhomocysteinemia were present in all cases. z

Metabolic Derangement

As in the cblF disorder, there is decreased ability to transfer Cbl across the lysosomal membrane into the cytoplasm, resulting in accumulation of free Cbl in lyso-

517 Disorders of Cobalamin and Folate Transport and Metabolism

somes. Although the exact role of the two proteins involved in lysosomal transport of Cbl remains to be elucidated, current evidence suggests that LMBRD1 (responsible for cblF) may be involved in lysosomal targeting and subsequent protection of ABCD4 (responsible for cblJ), which mediates Cbl transport across the lysosomal membrane. z

Genetics

Mutations in ABCD4, which encodes an ATP-binding cassette transporter, have been identified in all six cases. Inheritance is autosomal recessive. Three patients, from Taiwan (2) and China (1), were homozygous for c.423C > G (p.Asn141Lys). z

z Diagnostic Tests

Patients have had elevated urine methylmalonic acid and hyperhomocysteinemia. Serum Cbl was low in several patients; intestinal absorption has not been investigated. Results of studies of cultured fibroblasts in the earlyonset patients were identical to those of cblF fibroblasts; studies of the first Taiwanese patient showed a milder cellular phenotype, with moderately reduced MeCbl synthesis and apparently normal AdoCbl synthesis. z

structural heart defects and dysmorphic features may be present [40]. A small number of cblC patients were not diagnosed until after the first year of life and some as late as the end of the fourth decade of life. The patients in this group who were diagnosed earlier had findings overlapping those found in the younger onset group. Major clinical findings in the late-onset cblC group included confusion, disorientation and gait abnormalities and incontinence. Macrocytic anaemia was seen in only about a third of the oldest patients [38, 39]. Therefore, it is important to search for the cblC disorder by determination of metabolite levels in the presence of neurological findings alone.

Treatment and Prognosis

As for cblF, biochemical abnormalities respond dramatically to parenteral B12. 28.2.1.3CblC (MMACHC) z Clinical Presentation

This is the most frequent inborn error of Cbl metabolism, and over 750 patients are known [36–38]. Many were acutely ill in the first month of life, and most were diagnosed within the first year. This early-onset group shows feeding difficulties and lethargy, followed by progressive neurological deterioration. This may include hypotonia, hypertonia or both, abnormal movements or seizures and coma. Severe pancytopenia or a non-regenerative anaemia, which is not always associated with macrocytosis and hypersegmented neutrophils, but which is megaloblastic on bone marrow examination, may be present. Patients may develop multisystem pathology, such as renal failure, hepatic dysfunction, cardiomyopathy, interstitial pneumonia or the haemolytic uraemic syndrome characterised by widespread microangiopathy. Additional features include an unusual retinopathy consisting of perimacular hypopigmentation surrounded by a hyperpigmented ring and a more peripheral salt-and-pepper retinopathy sometimes accompanied by nystagmus, microcephaly and hydrocephalus [38, 39]. Congenital

Metabolic Derangement

In the cblC disorder, there is disruption of a protein (MMACHC) that plays a role in the early steps of cellular Cbl metabolism [2]. MMACHC binds Cbl and catalyses removal of upper axial ligands from alkylcobalamins (including the methyl group from MeCbl and the adenosyl group from AdoCbl) and from CNCbl. z

Genetics

In most cases, the cblC disorder is caused by biallelic mutations in MMACHC. A common mutation, c.271dupA, accounts for 40% or more of all disease alleles in patient populations of European origin [37]. In the homozygous state, or in combination with other truncating variants, this mutation is generally associated with early, severe disease [36, 38]. Alternatively, c.394C > T has been associated with a later, milder presentation. A different mutation, c.609G  >  A (p. Trp203*), represents over 50% of disease-causing alleles in Chinese cblC patients [41, 42], and is predominantly associated with early onset disease, although there is considerable phenotypic variability. Mutation of PRDX1, an overlapping proximal gene of MMACHC, results in epigenetic silencing of MMACHC transcription (called: epi-cblC). Mutation of PRDX1 leading to silencing of MMACHC has been described in the heterozygous state combined with genetic mutation of MMACHC in three patients with cblC disease [43]. z

Diagnostic Tests

Increased plasma total homocysteine, low to normal plasma methionine, homocystinuria and methylmalonic acidaemia and aciduria are the biochemical hallmarks of this disease. In general, the methylmalonic acid levels seen are lower than those found in patients with methylmalonyl-CoA mutase deficiency but higher than those seen in the Cbl transport defects. A complete

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blood count and bone marrow examination allow detection of the haematological abnormalities. Fibroblast studies show decreased accumulation of CNCbl, decreased synthesis of both AdoCbl and MeCbl, and decreased function of both methylmalonylCoA mutase and methionine synthase. Cells fail to complement those of other cblC patients and patients with mutations in HCFC1. Differentiation between cblC and cblX-like disorders (next section) requires DNA sequencing. Prenatal diagnosis can be performed by mutation analysis, by in vitro studies in cultured chorionic villus cells (interpreted with caution, chorionic villus biopsies should not be used) and amniocytes, and by measuring methylmalonic acid and total homocysteine levels in amniotic fluid. Except for mutation analysis, these techniques cannot detect heterozygotes. z

Treatment and Prognosis

Treatment is usually with 1 mg/day OHCbl (parenteral) in combination with oral betaine. Elevated metabolite levels improve but are not usually completely normalised. Oral OHCbl has been found to be insufficient, and neither folinic acid nor carnitine was effective. Doses as high as 20 mg OHCbl a day have been used, emphasizing the need to titrate doses in individual patients, while blood vitamin B12 levels has been proposed as a prognostic marker [44]. Both in vitro studies and studies of patients indicate that CNCbl is ineffective in treatment of this disease, possibly reflecting the role of the MMACHC protein in decyanation of CNCbl. 12–30% of early-onset cblC patients have previously been reported to have died, and most survivors have had moderate or severe neurological impairment despite treatment [38, 45]. However, a more recently studied cohort indicated that prognosis is likely improving [46]. Patients with later onset tend to have better outcomes. Treatment starting early in life, before neurologic impairment becomes established, is important for optimal patient response, but long-term outcome remains uncertain. Thus, newborn screening plays an increasing role in early detection and treatment [47]. 28.2.1.4Disorders of MMACHC Transcription:

CblX (HCFC1) and Related Disorders (HAP11; ZNF143) z

Clinical Presentation

Exome sequencing of a male patient with a diagnosis of cblC disease based on complementation analysis, in whom no MMACHC mutations could be detected, identified a hemizygous mutation in HCFC1 on the X chromosome. Subsequently, HCFC1 mutations were identified in an additional 14 male patients [48, 49]. Patients have presented in the first months of life with a similar clinical presentation to cblC patients, although the metabolic abnormalities are milder and the neuro-

logic presentation is more severe, with choreoathetosis, intractable epilepsy and severe developmental delay and sometimes with manifestations before birth (such as microcephaly and cortical malformations). z

Metabolic Derangement

The cblX disorder is caused by mutations at HCFC1, which functions as a transcriptional co-regulator in association with other transcription factors, including THAP11 and ZNF143. This trio affects expression of a number of genes, including MMACHC. The metabolic consequences relating to cobalamin metabolism stem from decreased MMACHC expression leading to decreased synthesis of both AdoCbl and MeCbl. This is also a vesicular trafficking disorder (between the nucleus and the endoplasmic reticulum) (7 Chap. 43). z

Genetics

HCFC1 is X-linked. All cblX patients have been male, with hemizygous HCFC1 mutations affecting the kelch domain near the N-terminus of the protein [48]. The most common mutation is c.344C  >  T (p.Ala115Val). Mutation of ZNF143 [50] and THAP11 [51] have each been identified in single patients with autosomal recessive inheritance. z

Diagnostic Tests

Patients have moderately elevated serum and urine levels of methylmalonic acid that are usually lower than those seen in other inborn errors of Cbl metabolism. Serum total homocysteine has been elevated in some patients, but others had values within the reference range. Fibroblasts studies place these patients within the cblC complementation group and diagnosis therefore depends on identification of mutations. z

Treatment and Prognosis

Since MMACHC deficiency alone appears not to be responsible for all clinical abnormalities, correction of methylmalonic acid and homocysteine levels with OHCbl is unlikely to prevent all manifestations of this disorder. 28.2.1.5CblD (MMADHC) z Clinical Presentation

This defect was first described in two brothers with combined methylmalonic aciduria and homocystinuria. The elder sibling had behavioural problems and mild mental retardation at the age of 14 years, and also ataxia and nystagmus. Heterogeneity of the cblD defect was established by discovery of one patient with isolated methylmalonic aciduria who presented prematurely with respiratory distress, cranial haemorrhage, necrotising enterocolitis and convulsions but without anaemia, and

519 Disorders of Cobalamin and Folate Transport and Metabolism

two unrelated patients with isolated homocystinuria, megaloblastic anaemia and neurological changes but without metabolic decompensation [52]. Following the discovery of MMADHC, the gene responsible for cblD [53, 54], further patients were described whose clinical presentation broadly resembled that of the cblC, cblA/B and cblE/G defects, respectively. z

Metabolic Derangement

The cblD defect is caused by mutations in MMADHC and can cause deficient synthesis of both AdoCbl and MeCbl together, or of either in isolation. This suggests that the product of MMADHC plays a role in directing Cbl from the MMACHC protein to the two Cbldependent enzymes. z

Genetics

Biallelic MMADHC mutations have been found in all patients belonging to the cblD complementation group regardless of the phenotype. The nature and location of mutations within the gene seem to determine the phenotype. Thus the combined-defect patients have crippling mutations towards the C-terminus; isolated homocystinuria patients have missense mutations towards the C-terminus; and isolated methylmalonic aciduria patients have mutations leading to a stop codon toward the N-terminus, in which case re-initiation of translation occurs at one of two downstream start codons. z

Diagnostic Tests

Methylmalonic aciduria with or without increased plasma total homocysteine and homocystinuria, or isolated homocystinuria may be found. In fibroblast studies, findings can be similar to those of the cblC, cblA/B or cblE/G defects, although differences in the severity and responsiveness to addition of OHCbl to the culture medium may be seen. This heterogeneity emphasises the necessity of complementation or genetic analysis to make a specific diagnosis. z

Treatment and Prognosis

This depends on the sub-type and is similar to that described for the cblC, cblA/B and cblE/G defects, respectively. Too few patients have so far been identified to allow clear conclusions on outcome to be made.

28.2.2Adenosylcobalamin Deficiency: CblA

(MMAA) & CblB (MMAB) z

The phenotype resembles methylmalonyl-CoA mutase deficiency (7 Chap. 19), although often less severe. z

Metabolic Derangement

The defect in cblB is deficiency of Cbl adenosyltransferase, which catalyses the final step in intramitochondrial synthesis of AdoCbl, the cofactor for methylmalonylCoA mutase [55]. The defect in cblA results from mutations in MMAA [56]. Enzymatic studies of the MMAA gene product suggest that this protein is involved in transfer of AdoCbl from adenosyltransferase to methylmalonyl-CoA mutase and in maintaining mutasebound AdoCbl in its active form. z

Genetics

MMAA encodes a polypeptide belonging to the G3E family of GTP-binding proteins. Over 60 mutations in MMAA have now been described among approximately 200 cblA patients [56–58]. The most common of these is a c.433C  >  T (p.Arg145*) nonsense mutation. Inheritance is autosomal recessive. MMAB encodes cobalamin adenosyltransferase. Over 30 mutations in MMAB have been identified in cblB patients [55, 59]. Virtually all of these mutations are clustered in the regions of the protein identified as the active site of adenosyltransferase. Inheritance is autosomal recessive. z

Diagnostic Tests

Total serum Cbl is usually normal. Urinary methylmalonic acid levels are elevated above reference values (typically  C, which may represent up to 25% of mutant alleles. Mutations in the methionine synthase gene, MTR, have been found in cblG patients [65]. The most common of these mutations is c.3518C > T (p.Pro1173Leu). z

Diagnostic Tests

Homocystinuria and hyperhomocysteinaemia are almost always found in the absence of methylmalonic acidaemia, although one cblE patient had transient unexplained methylmalonic aciduria. Hypomethioninaemia and cystathioninaemia may be present, and there may be increased serine in the urine. Methionine synthase function is decreased in cultured fibroblasts from both cblE and cblG patients. Uptake of CNCbl is normal but synthesis of MeCbl is decreased in both disorders. Complementation analysis and gene sequencing distinguish cblE from cblG and cblD-HC patients. z

Treatment and Prognosis

Both disorders are treated with OHCbl or MeCbl, 1 mg i.m., first daily and then once or twice weekly. Although the metabolic abnormalities are nearly always corrected, existing neurological findings and eye abnormalities such as nystagmus and impaired visual acuity tend to persist. Treatment with betaine (250  mg/kg/day) has been used, and one cblG patient was treated with L-methionine (40 mg/kg/day) and showed neurological improvement. In one family with cblE, a boy developed normally to the age of 14 years following maternal treatment with OHCbl during the second trimester and from birth, in contrast to his older brother treated with delay who showed significant developmental delay at 18 years. Some patients may benefit from high-dose folic or folinic acid treatment.

521 Disorders of Cobalamin and Folate Transport and Metabolism

tic value and is usually unavailable in the clinical setting. Differentiation of folate derivatives present in clinical samples requires mass spectrometric analysis and is not available in most clinical laboratories. Several proteins have been shown to play a role in transport of folates across cellular membranes [66, 67]. The reduced folate carrier (RFC) supports a low-affinity high-capacity system for uptake of reduced folates at micromolar concentrations. It appears to play an important role in folate uptake by many types of cells, including haematopoietic cells. The folate receptors (FRα and FRβ) are a family of folate-binding proteins that are attached to the cell surface by a glycosylphosphatidylinositol anchor; they support a high-affinity low-capacity uptake system for 5-methyltetrahydrofolate and folic acid that is active at nanomolar concentrations of folate. The protein-coupled folate transporter (PCFT) supports uptake of reduced and oxidised folates at acid pH [68]. Uptake of folate in the intestine appears to depend on function of the PCFT and not RFC whereas transport of folate across the blood-brain barrier at the choroid plexus requires both PCFT and FRα [69].

Folate Metabolism Folic acid  (pteroylglutamic acid) is plentiful in foods such as liver, leafy vegetables, legumes and some fruits. Its metabolism involves reduction to dihydrofolate  (DHF) and tetrahydrofolate  (THF), followed by addition of a single-carbon unit, which is provided by serine, glycine or histidine; this carbon unit occurs in various redox states (methyl, methylene, methenyl or formyl). Transfer of this single-carbon unit is essential for the endogenous formation of methionine, thymidylate  (dTMP) and formylglycineamide ribotide  (FGAR) and formylaminoimidazolecarboxamide ribotide (FAICAR), two intermediates of purine synthesis (. Fig. 28.2). These reactions also allow regeneration of DHF and THF. The predominant folate derivative in blood and in cerebrospinal fluid is 5-methyltetrahydrofolate  (the product of the methylenetetrahydrofolate reductase reaction). Folate can be measured by folate binding protein assay in serum, red blood cells, or cerebrospinal fluid.  Serum folate level is the most common test; red cell folate is thought to reflect body stores more accurately than serum folate, but on the whole adds little diagnos-

Folic acid DHF 6

10 10-Formyl THF

THF FIGLU

Histidine

7 Serine

5-Formimino THF

Glycine 2 5-Methyl THF

3 5, 10-Methylene THF

Homocysteine

NH3

5-Formyl THF (folinic acid) 9

8

5, 10-Methenyl THF

4

5 10-Formyl THF

dUMP

GAR

AICAR

dTMP

FGAR

FAICAR

Formate

1 Serine Methionine

Cystathionine

. Fig. 28.2 Folic acid metabolism (genes in italics): 1, methionine synthase; 2, methylenetetrahydrofolate reductase (MTHFR); 3, methylenetetrahydrofolate dehydrogenase (MTHFD1); 4, methenyltetrahydrofolate cyclohydrolase (MTHFD1) 5, formyltetrahydrofolate synthetase (MTHFD1); 6, dihydrofolate reductase (DHFR); 7, glutamate formiminotransferase (FTCD); 8, formiminotetrahydrofolate cyclodeaminase (FTCD); 9, methenyltetrahydrofolate synthe-

tase (MTHFS); 10, formyltetrahydrofolate dehydrogenase (ALDH1L2); AICAR aminoimidazole carboxamide ribotide, DHF dihydrofolate, dTMP, deoxythymidine monophosphate, dUMP deoxyuridine monophosphate, FAICAR formylaminoimidazole carboxamide ribotide, FGAR formylglycinamide ribotide, FIGLU formiminoglutamate, GAR glycinamide ribotide, THF tetrahydrofolate. Enzyme defects are indicated by solid bars

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28.3

Disorders of Absorption and Metabolism of Folate

28.3.1Hereditary Folate Malabsorption

(Proton-Coupled Folate Transporter Deficiency, SLC46A1)

28

z

Clinical Presentation

This rare condition presents in the first months of life with severe megaloblastic anaemia, diarrhoea, stomatitis, failure to thrive and usually progressive neurological deterioration with seizures and sometimes with intracranial calcifications. Peripheral neuropathy has been seen, as have partial defects in humoral and cellular immunity [70, 71]. z

Metabolic Derangement

All patients have severely decreased intestinal absorption of oral folic acid or reduced folates, such as 5-formyltetrahydrofolic acid (formyl-THF, folinic acid) or 5-methyl-THF. There is also decreased transport of folate across the blood-brain barrier. Transport of folates across other cell membranes is not affected in this disorder. The disorder is the result of decreased function of the proton-coupled folate transporter (PCFT) [68]. Folate metabolism in cultured fibroblasts is normal. z

Genetics

Approximately 30 patients with this disorder have been reported. It is caused by mutations affecting SLC46A1, which encodes the PCFT.  It is an autosomal recessive trait. z

Diagnostic Tests

Measurement of serum, red blood cell and CSF folate levels and a complete blood count and bone marrow analysis should be performed. The most important diagnostic features are the severe megaloblastic anaemia in the first few months of life, together with low serum folate levels. Measurements of related metabolite levels have been sporadically reported and inconsistently found abnormalities include increased excretion of formiminoglutamate, orotic aciduria, increased plasma sarcosine and cystathionine and low plasma methionine. Folate levels in CSF remain low even when blood levels are high enough to correct the megaloblastic anaemia [70]. Folate absorption can be investigated by measuring serum folate levels following an oral dose of between 5 and 100 mg of folic acid. z

and in raising the level of folate in the CSF. Folinic acid (5-formyl-THF) [71] is more effective in raising CSF levels and has been given in combination with high-dose oral folic acid. The clinical response to folates has varied with worsening seizures in some cases. It is important to maintain both blood and CSF folate in the normal range using parenteral or even intrathecal routes if necessary, although the optimal dose of folate is unknown. In some cases high oral doses of folinic acid (up to 400 mg orally daily) may eliminate the need for parenteral therapy. 28.3.2Cerebral Folate Deficiency (Folate

Receptor α Deficiency, FOLR1) z

z

High-dose oral folic acid (up to 60  mg daily) or lower parenteral doses in the physiological range correct the haematological and gastrointestinal abnormalities but are less effective in correcting the neurological findings

Metabolic Derangement

There is a decreased level of 5-methyl-THF, the major circulating form of folate in the CSF, with normal blood levels of the vitamin. This is the result of decreased FRα (folate receptor α) function at the choroid plexus. z

Genetics

Mutations in FOLR1, which encodes FRα, have been identified in a small number of families with cerebral folate deficiency [74]. The disorder segregates as an autosomal recessive trait in these families. Cerebral folate deficiency without FOLR1 mutations has been attributed to antibodies directed against FRα. z

Diagnostic Tests

Patients are characterised by decreased CSF levels of folate in the presence of normal serum folate levels. z

Treatment and Prognosis

Clinical Presentation

This disorder usually presents in the first year of life, with psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia and refractory myoclonic epilepsy, associated with normal blood folate levels and low folate levels only in the cerebrospinal fluid (CSF) [72]. Several affected children have developed autistic features. It is important to distinguish between the primary defect and secondary causes such as acquired (perinatal asphyxia, CNS infection) and genetic (Rett syndrome, Kearn Sayre disease, MTHFR deficiency, white matter disease) disorders which also have decreased cerebral folate levels (although, in general, these secondary defects show less depleted levels than folate receptor deficiency) [73].

Treatment and Prognosis

The cerebral folate deficiency syndrome responds exclusively to folinic acid (10–20  mg/day) and not to folic acid. Folinic acid therapy can restore CSF folate concentrations, reverse white matter choline and inositol depletion and improve clinical symptoms [74, 75].

523 Disorders of Cobalamin and Folate Transport and Metabolism

28.3.3Reduced Folate Carrier Deficiency

(SLC19A1) z

Clinical Presentation

A single patient in his teens has been reported with a homozygous mutation in the gene encoding the reduced folate carrier and recurrent severe megaloblastic anaemia, in the context of dietary insufficiency [76]. Diagnosis was complicated by the presence of low serum vitamin B12 levels, but his haematological symptoms did not respond to therapy with cyanocobalamin. z

Metabolic Derangement

There is decreased uptake of folate by haematopoietic cell precursors due to decreased function of the reduced folate carrier. z

Genetics

The patient was homozygous for a 3-bp deletion in SLC19A1, the gene encoding the reduced folate carrier, resulting in deletion of a highly conserved phenylalanine residue. In vitro analyses demonstrated that this sequence variant adversely affected reduced folate carrier function. z

Diagnostic Tests

The patient had serum folate levels within the reference interval but decreased red blood cell folate. Levels of homocysteine and AICAR were elevated. z

Treatment and Prognosis

four patients [80]. Studies in fibroblasts from the first identified patient showed adequate function of 10-formyl-THF-dependent purine biosynthesis with impairment of methylene-THF-dependent thymidylate synthesis and methyl-THF-dependent conversion of homocysteine to methionine [81]. Synthesis of MeCbl from exogenous CNCbl was somewhat reduced due to deficiency of methyl-THF [80]. z

Genetics

Mutations in MTHFD1 have been identified in affected individuals in all three families, consistent with autosomal recessive inheritance [77–79]. z

Diagnostic Tests

Patients have normal serum folate levels and decreased cerebral folate levels. Serum total homocysteine is elevated, with normal or low-normal methionine levels. Diagnosis in all cases has depended on identification of mutations in MTHFD1. z

Treatment and Prognosis

Treatment with oral folinic acid has been associated with reduction of total homocysteine to within the reference range and correction of megaloblastic marrow morphology, and with improved neurological function, although seizures in the initial patient were not corrected and maculopathy with retinal atrophy in a second patient was resistant to therapy. Two patients that had been treated long-term with folinic acid had normal neurological development at 8 and 22 years.

The patient responded to therapy with folic acid. 28.3.5Dihydrofolate Reductase Deficiency

(DHFR)

28.3.4Methylenetetrahydrofolate

Dehydrogenase Deficiency (MTHFD1) z

Clinical Presentation

Nine individuals from seven families have been reported. Affected individuals have had megaloblastic anaemia, severe combined immunodeficiency and atypical haemolytic uraemic syndrome [77–79]. Seizures, developmental delay and neuroimaging abnormalities have also been reported [72]. Two untreated patients died at 9 weeks of age. z

Metabolic Derangement

Serum folate levels are within the reference range, while cerebrospinal fluid folate levels are reduced. The product of MTHFD1 is a trifunctional cytoplasmic enzyme that catalyzes synthesis of 10-formyl-THF from THF and formate and its conversion to 5,10-methylene-THF. Biochemical studies demonstrated deficient 5,10-methyleneTHF dehydrogenase specific activity in fibroblasts from

z

Clinical Presentation

Three families with apparent dihydrofolate reductase deficiency have been described [82, 83]. Findings included megaloblastic anaemia, cerebral folate deficiency and seizures, and in severe cases, pancytopenia, cerebral atrophy and severe developmental delay, z

Metabolic Derangement

Plasma and red cell folate levels are within the normal range. However, there are relatively high levels of the oxidised forms of folates (dihydrofolate and folic acid), reflecting the deficiency in dihydrofolate reductase, which catalyses reduction of dihydrofolate to tetrahydrofolate, and (at a slower rate) folic acid to dihydrofolate. z

Genetics

Homozygous mutations in DHFR have been identified in affected individuals in all three families, consistent with autosomal recessive inheritance. The mutations

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affect well-conserved amino acid residues, and decreased dihydrofolate reductase function has been shown in affected individuals. z

28

Diagnostic Tests

Patients have decreased cerebral folate levels. Serum and red cell folate levels are normal, but the proportion of tetrahydrofolate derivatives is decreased. This disorder can be differentiated from cerebral folate deficiency due to mutations in FOLR1 by the presence of megaloblastic anaemia. z

28.3.6Glutamate Formiminotransferase

Deficiency (FTCD) Clinical Presentation

Patients have been identified on the basis of elevated blood levels of formiminoglutamate. Approximately 50 patients have been described but the clinical significance of this disorder has been unclear. Identification of multiple patients by newborn screening has led to the conclusion that the disorder is generally asymptomatic [84, 85]. z

Metabolic Derangement

Histidine catabolism is associated with a formimino group transfer to THF, with the subsequent release of ammonia and the formation of 5,10-methenyl-THF. A single octameric enzyme catalyses two different activities: glutamate formiminotransferase and formiminotetrahydrofolate cyclodeaminase. These activities are found only in the liver and kidney, and defects in either of them will result in formiminoglutamate excretion. z

Treatment and Prognosis

28.3.7Methylenetetrahydrofolate Reductase

Deficiency (MTHFR) This section is restricted to the severe form of this deficiency. The role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR) with respect to the risk for common disease, such as neural tube defects or cardiovascular disease, is beyond the scope of this chapter [86]. z

Clinical Presentation

Over 200 patients with severe MTHFR deficiency have been described [87–90]. Most were diagnosed in infancy, and more than half presented in the first year of life. The most common early manifestation was progressive encephalopathy with apnoea, seizures, microcephaly, hypotonia, feeding problems and failure to thrive. However, patients became symptomatic at any time from infancy to adulthood, and in the older patients ataxic gait, psychiatric disorders (schizophrenia) and symptoms related to cerebrovascular events have been reported. At least one adult with severe enzyme deficiency was completely asymptomatic. Autopsy findings have included dilated cerebral vessels, microgyria, hydrocephalus, perivascular changes, demyelination, gliosis, astrocytosis and macrophage infiltration. In some patients, thrombosis of both cerebral arteries and veins was the major cause of death. There have been reports of patients with findings similar to those seen in subacute degeneration of the spinal cord due to Cbl deficiency. It is important to note that MTHFR deficiency is not associated with megaloblastic anaemia.

Genetics

The condition is caused by mutations in FTCD and is inherited as an autosomal recessive trait [84, 85]. When tested, expressed enzyme activity was 60% of controls. z

z

Formiminoglutamate excretion has responded in some cases to folate therapy. Since most cases have been asymptomatic, clinical benefit of treatment of this condition is unclear.

Treatment and Prognosis

Treatment with oral folinic acid has been associated with normalisation of red cell volume and of megaloblastic marrow morphology, and with improved neurological function. There may be transient improvement of seizures, but ultimately folinic acid therapy has not proved effective in seizure control. In severely affected individuals, neurological dysfunction and developmental delay persist despite therapy.

z

used traditionally to help to establish the diagnosis. Normal to high serum folate levels are found. Hyperhistidinaemia and histidinuria have been reported. Formiminoglutamate overlaps with C4 acylcarnitine on tandem mass spectrometry, which has allowed its detection on newborn screening.

Diagnostic Tests

Elevated formiminoglutamate and hydantoin propionate excretion and elevated levels of formiminoglutamate in the blood following a histidine load have been

z

Metabolic Derangement

Methyl-THF is the methyl donor for the conversion of homocysteine to methionine, and in MTHFR deficiency its lack results in an elevation of total plasma homocysteine levels and decreased levels of methionine. Total CSF folate levels are also severely reduced. The block in the conversion of methylene-THF to methyl-THF does not result in the trapping of folates as methyl-THF and

525 Disorders of Cobalamin and Folate Transport and Metabolism

does not interfere with the availability of reduced folates for purine and pyrimidine synthesis in contrast to disorders at the level of methionine synthase. This explains why patients do not have megaloblastic anaemia. It is not clear whether the neuropathology in this disease results from the elevated homocysteine levels, from decreased methionine and resulting interference with methylation reactions or from some other metabolic effect. It has been reported that individuals with a severe deficiency in MTHFR may be at increased risk following exposure to nitrous oxide anaesthesia [91]. z

Genetics

MTHFR deficiency is inherited as an autosomal recessive disorder. Over 100 mutations causing severe deficiency have been described in MTHFR, in addition to polymorphisms that result in intermediate enzyme activity and that may contribute to disease in the general population [46, 88]. Most of these mutations are restricted to one or two families. Exceptions are a c.1542G  >  A mutation that results in a splicing mutation, that was seen in 21 of 152 mutant alleles in a large study [88]; and a c.1141C > T mutation that is present at high frequency in the Old Order Amish [92]. A recent review has summarized all known mutations [89]; mutations in this publication are listed using the original as well as the HGVS numbering system. z

Diagnostic Tests

Because methyl-THF is the major circulating form of folate, serum folate levels may sometimes be low. There is a severe increase of plasma total homocysteine (60– 320  μmol/l, with controls less than 14  μmol/l), together with low plasma methionine levels ranging from zero to 18 μmol/l (mean: 12 μmol/l, range of control means from different laboratories: 23–35  μmol/l). Although neurotransmitter levels have been measured in only a few patients, they are usually low. Direct measurement of MTHFR specific activity can be performed in liver, leukocytes, lymphocytes and cultured fibroblasts. Severe MTHFR deficiency has been associated with complete lack of enzyme activity, and with mutations causing reduced affinity for NADPH, decreased FAD responsiveness, abnormal inhibition of enzyme activity by S-adenosylmethionine and reduced affinity for methyleneTHF [88]. The level of residual enzymatic activity is associated with disease severity, whereby those with strongly reduced or completely absent activity are more likely to present with earlier, more severe disease [89]. z

Treatment and Prognosis

It is important to diagnose MTHFR deficiency early because, in the infantile forms, the only patients who have done well are those who were treated from birth.

This underpins the need for effective newborn screening that currently needs to be based on a critical selection of the window for low methionine supported by second tier testing for total homocysteine [5]. Early treatment with betaine following prenatal diagnosis has resulted in the best outcome [93]. Suggested doses have been in the range of 2–3  g/day (divided twice daily) in young infants and 6–9  g/day in children and adults, good results were claimed with a dosage of 100/mg/kg/day [94]. Betaine is a substrate for betaine-homocysteine S-methyltransferase (BHMT), which converts homocysteine to methionine but is mainly active in the liver. Therefore, betaine may be expected to have the doubly beneficial effect of lowering homocysteine levels and raising methionine levels. Because BHMT is not present in the brain, the central nervous system effects must be mediated through the effects of the circulating levels of metabolites. The dose of betaine should be modified according to plasma levels of homocysteine and methionine. Other therapeutic agents with unproven efficacy but possibly helpful in isolated cases include folic acid or reduced folates, methionine, pyridoxine, Cbl and carnitine. In 3 patients with severe MTHFR deficiency measurable 5-methyltetrahydrofolate in cerebrospinal fluid was only achieved with mefolinate (5-methyltetrahydrofolate) supplements and not with either folic acid or folinic acid [95]. Most of the treatment protocols omitting betaine have not been effective. Dramatic improvement was reported in a patient with severe enzyme deficiency following early introduction of methionine supplements.

28.3.8Methenyltetrahydrofolate Synthetase

Deficiency (MTHFS) z

Clinical Presentation

Three patients have been reported with deficiency in 5,10-methenyltetrahydrofolate synthetase (MTHFS) [96, 97]. They have presented with global developmental delay, microcephaly, hypotonia, seizures, spasticity and cerebral hypomyelination. Cerebral 5-methyltetrahydrofolate levels were low or low normal. One patient had macrocytic anaemia; another had unexplained episodes of hyperthermia. z

Metabolic Derangement

MTHFS catalyzes the ATP-dependent conversion of 5-formyltetrahydrofolate (folinic acid) to methenyltetrahydrofolate. Folinic acid plays no known role in folatedependent one-carbon metabolism; it is generated from methenyltetrahydrofolate in a secondary reaction catalyzed by serine hydroxymethyltransferase. It has been suggested the folinic acid functions as a storage form of

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tetrahydrofolate. Deficiency of MTHFS results in trapping of folinic acid generated by the activity of serine hydroxymethyltransferase and accumulation of folinic acid in cells.

z

Treatment and Prognosis

Not known.

28.3.10Serine Hydroxymethyltransferase 2 z

28

Genetics

This is an autosomal recessive disorder caused by mutations in MTHFS. z

Diagnostic Tests

Patients have been characterized by low or low normal cerebral folate levels that did not respond to therapy with folinic acid. z

Treatment and Prognosis

Treatment with 5-methyltetrahydrofolate resulted in increase of cerebral folate levels and increased alertness and vocalizations in one patient; no change in EEG or MRI findings were detected. Long-term response to this therapy is not known.

Deficiency (SHMT2) z

Five patients from four families have been recently described with SHMT2 deficiency [99]. Each presented with a similar phenotype, characterized by congenital microcephaly, dysmorphic features, intellectual disability, and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Also, four out of five patients showed hypertrophic cardiomyopathy or atrial-septal defects, which tended to progress over time. MRI revealed corpus callosum abnormalities in all patients and perisylvian polymicrogyria-like pattern in four patients. z

28.3.910-Formyltetrahydrofolate

Dehydrogenase Deficiency (ALDH1L2) z

Clinical Presentation

A single patient with ichthyosis, significant developmental delay and hypotonia has been reported [98]. There was increasing hyperactivity and attention deficit in his teens. Diagnosis was complicated by previous identification of a deleterious RPS6KA3 mutation, which causes Coffin-Lowry syndrome, but did not explain all clinical features. z

Metabolic Derangement

The patient had deficiency of the mitochondrial form of 10-formyl-THF dehydrogenase, which catalyses breakdown of 10-formyl-THF to CO2 and THF with generation of NADPH from NADP+. This results in increased cellular levels of 10-formyl-THF and possibly decreased NADPH levels. z

Genetics

The disorder is apparently the result of compound heterozygous mutations in ALDH1L2, which encodes the mitochondrial form of formyl-THF dehydrogenase [98].

Clinical presentation

Metabolic Derangement

In plasma all metabolites were in the normal range whereas in fibroblasts affected individuals showed a significant decrease in glycine/serine ratios compared to controls. Folate metabolism was also impaired in that 5-methyltetrahydrofolate levels were increased in relation to total folate. The substrate of SHMT2, tetrahydrofolate (THF), was undetectable in mitochondria-enriched control fibroblast samples, but low levels were measurable in patient fibroblasts. ATP and ROS production were also impaired in fibroblasts. z

Genetics

Biallelic SHMT2 variants were identified in all individuals. They were missense/in-frame deletion and homozygous in one family. z

Diagnostic Tests

Consistent clinical manifestations in all individuals, albeit of variable severity, seem to constitute a welldefined and recognizable clinical syndrome. Studies of folate forms and amino acids in fibroblasts, together with genetic analysis confirm the diagnosis. z

Treatment and Prognosis

Not known.

References z

Diagnostic Tests

Abnormalities on MRI and MR (1H-MRS) spectroscopy were observed and metabolic changes were reported in cultured fibroblasts.

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Lubout CMA, Goorden SMI, van den Hurk K et  al (2020) Successful treatment of hereditary folate malabsorption with intramuscular folinic acid. Pediatr Neurol 102:62–66 Pope S, Artuch R, Heales S, Rahman S (2019) Cerebral folate deficiency: analytical tests and differential diagnosis. J Inherit Metab Dis 42:655–672 Masingue M, Benoist JF, Roze E et  al (2018) Cerebral folate deficiency in adults: a heterogeneous potentially treatable condition. J Neurol Sci 396:112–118. https://doi.org/10.1016/j. jns.2018.11.014. Epub 2018 Nov 10 Steinfeld R, Grapp M, Kraetzner R et al (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85:354–363 Delmelle F, Thöny B, Clapuyt P et  al (2016) Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation. Eur J Paediatr Neurol 20(5):709–713. https://doi. org/10.1016/j.ejpn.2016.05.021. Epub 2016 Jun 13 Svaton M, Kramarzova KS, Kanderova V et al (2020) A homozygous deletion in the SLC19A1 gene as a cause of folatedependent recurrent megaloblastic anemia. Blood 135(26):2427–2431. https://doi.org/10.1182/blood.2019003178. PMID: 32276275; PMCID: PMC7330012 Keller MD, Ganesh J, Heltzer M et al (2013) Severe combined immunodeficiency resulting from mutations in MTHFD1. Pediatrics 131:e629–e634 Burda P, Kuster A, Hjalmarson O et al (2015) Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment. J Inherit Metab Dis 38:863–872 Ramakrishnan KA, Pengelly RJ, Gao Y et  al (2016) Precision molecular diagnosis defines specific therapy in combined immunodeficiency with megaloblastic anemia secondary to MTHFD1 deficiency. J Allergy Clin Immunol Pract 4:1160–1166 Bidla G, Watkins S, Chéry C et al (2020) Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency. Mol Genet Metab 130:179–182 Field MS, Kamynina E, Watkins D, Rosenblatt DS, Stover PJ (2015) Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proc Natl Acad Sci U S A 112:400–405 Banka S, Blom HJ, Walter J et  al (2011) Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet 88:216–225 Cario H, Smith DEC, Blom H et al (2011) Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet 88:226–231 Majumdar R, Yori A, Rush PW et al (2017) Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria. Mol Genet Genomic Med 5:795–799 Ahrens-Nicklas RC, Ganetzky RD, Rush PW, Conway RL, Ficicioglu C (2019) Characteristics and outcomes in patients

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94.

95.

96.

97.

98.

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with formiminoglutamic aciduria detected through newborn screening. J Inher Metab Dis 42:140–146 Liew S-C, Gupta ED (2015) Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet 58:1–10 Thomas MA, Rosenblatt DS (2005) Severe methylenetetrahydrofolate reductase deficiency. In: Ueland PM, Rozen R (eds) MTHFR polymorphisms and disease. Landes Bioscience, Georgetown, pp 41–53 Burda P, Schäfer A, Suormala T et al (2015) Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. Hum Mutat 36:611–621 Froese DS, Huemer M, Suormala T et  al (2016) Mutation update and review of severe methylenetetrahydrofolate reductase deficiency. Hum Mutat 37:427–438 Huemer M, Mulder-Bleile R, Burda P et al (2016) Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency. J Inherit Metab Dis 39:115–124 Selzer RR, Rosenblatt DS, Laxova R, Hogan K (2003) Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45–50 Strauss KA, Morton DH, Puffenberger EG et  al (2007) Prevention of brain disease from severe methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175 Schiff M, Benoist JF, Tilea B et  al (2010) Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34:137–145 Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM (2014) Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurol 71(2):188–194. https://doi.org/10.1001/jamaneurol.2013.491 Knowles L, Morris AAM, Walter JH (2016) Treatment with Mefolinate (5-Methyltetrahydrofolate), but not folic acid or Folinic acid, leads to measurable 5-Methyltetrahydrofolate in cerebrospinal fluid in methylenetetrahydrofolate reductase deficiency. JIMD Rep 29:103–107. https://doi. org/10.1007/8904_2016_529 Rodan LH, Qi W, Ducker GS et al (2018) 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab 125:118–126 Romero JA, Abdelmoumen I, Hasbani D, Khurana DS, Schneider MC (2019) A case of 5.10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia. Mol Gen Metab Rep 21:100545 Sarret C, Ashkavand Z, Paules E et al (2019) Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome. NPJ Genomic Med 4:17 García-Cazorla À, Verdura E, Juliá-Palacios N, et  al. (2020) Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome. Acta Neuropathol. https://doi.org/10.1007/s00401020-02223-w. Epub ahead of print.

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Disorders of Thiamine and Pyridoxine Metabolism Garry Brown and Barbara Plecko Contents 29.1

Disorders of Thiamine (vitamin B1) Metabolism – 532

29.1.1

29.1.5 29.1.6 29.1.7

Thiamine Metabolism Dysfunction Syndrome 1 (SLC19A2, THTR1 Deficiency) – 533 Thiamine Metabolism Dysfunction Syndrome 2 (SLC19A3, THTR2 Deficiency) – 534 Thiamine Metabolism Dysfunction Syndrome 3 (Microcephaly, Amish Type) and Thiamine Metabolism Dysfunction Syndrome 4 (Bilateral Striatal Degeneration and Progressive Polyneuropathy Type): Mitochondrial TPP Transporter deficiency (SLC25A19) – 535 Thiamine Metabolism Dysfunction Syndrome 5 (Episodic Encephalopathy Type, TPK1 Deficiency) – 535 Thiamine-Responsive α-ketoacid Dehydrogenase Deficiencies – 536 Thiamine-Responsive Pyruvate Dehydrogenase Deficiency – 536 Thiamine-Responsive Maple Syrup Urine Disease – 536

29.2

Disorders of Pyridoxine Metabolism – 537

29.2.1 29.2.2 29.2.3 29.2.4

Antiquitin Deficiency (ALDH7A1) – 539 Hyperprolinemia Type II – 541 Pyridox(am)ine 5’-phosphate Oxidase (PNPO) Deficiency – 541 Congenital Hypophosphatasia (Tissue Non Specific Alkaline Phosphatase) – 542 Hyperphosphatasia-Mental Retardation Syndrome (HPMRS) – 542 PLP Binding protein (PLPBP, Formerly PROSC) Deficiency – 542 Other B6 Responsive Disorders – 543

29.1.2 29.1.3

29.1.4

29.2.5 29.2.6 29.2.7

References – 543

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_29

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T

THTR 1,2 T

TPP TPK MTPPT TPP

29

Transketolase PDH BCAKDK KGDH 2-Hydroxyacyl CoA lyase

2-Hydroxyacyl CoA lyase

. Fig. 29.1 Thiamine transport. THTR1 and THTR2 thiamine transporter 1 and 2, TPP thiamine pyrophosphate, MTPPT mitochondrial, TPP transporter, TPK thiamine pyrophosphate

Thiamine Metabolism Thiamine is transported across cell membranes by two closely related transporters, THTR1 and THTR2, encoded by SLC19A2 and SLC19A3, respectively (. Fig. 29.1). Both transporters are widely expressed in the body, but they differ in kinetic properties and in the level of expression in different tissues. In the upper small intestine, where dietary thiamine is absorbed, THTR2 is the major transporter at the luminal surface whereas THTR1 predominates at the basal surface. The active cofactor of thiamine, thiamine pyrophosphate (TPP), is formed in the cytoplasm by the enzyme thiamine pyrophosphokinase (TPK). There the cofactor is attached directly to the transketolase and 2-hydroxyacyl CoA lyase apoproteins, while a TPP transporter (MTPPT) in the inner mitochondrial membrane delivers the cofactor to the α-ketoacid dehydrogenases in the mitochondrial matrix.

kIntroduction

Thiamine (vitamin B1) is a water-soluble vitamin transported across cell membranes by two closely related transporters, THTR1 and THTR2. The active cofactor

kinase, PDH pyruvate dehydrogenase, BCAKDK branched chain aminoacid dehydrogenase kinase, KGDH ketoglutarate dehydrogenase

of thiamine, thiamine pyrophosphate (TPP), is formed in the cytoplasm by the enzyme thiamine pyrophosphokinase. TPP enters mitochondria with a specific TPP transporter. Pyridoxine (vitamin B6) is a water-soluble vitamin with broad availability from various food sources, including dairy products, meat, cereals and vegetables. The three vitamers, pyridoxal, pyridoxamine and pyridoxine and their phosphorylated esters are absorbed in the small intestine. Within the cells vitamers are re-phosphorylated by kinases and further oxidised to the active cofactor pyridoxal 5´-phosphate (PLP) by pyridox(am)ine 5´- phosphate oxidase (PNPO). Within the cell PLP homeostasis is regulated by the PLP-binding protein (PLPBP, formerly called PROSC). 29.1

Disorders of Thiamine (vitamin B1) Metabolism

Thiamine (vitamin B1) has long been recognised as an essential dietary component. The minimal daily requirement is about 0.5  mg/1000 Kcal and this is normally provided by a well-balanced diet. Requirements do vary,

533 Disorders of Thiamine and Pyridoxine Metabolism

however, and are increased in parallel with carbohydrate intake, during pregnancy and lactation, in hypermetabolic states and in infants. The active form of the vitamin is thiamine pyrophosphate (TPP) and this is a coenzyme for a number of important metabolic enzymes: pyruvate dehydrogenase, branched chain α-ketoacid dehydrogenase, α-ketoglutarate dehydrogenase, transketolase and the peroxisomal enzyme, 2-hydroxyacyl CoA lyase. As an essential component of these highly regulated enzymatic reactions, thiamine plays a crucial role in carbohydrate metabolism and the metabolic switch from the fed to the fasting state. Acute thiamine deficiency states (such as total parenteral nutrition without thiamine supplement) are life threatening emergencies and present as cardiac failure, Gayet Wernicke encephalopathy, or lactic acidosis [1, 2]. Metabolic markers are hyperlactatemia with hyperpyruvic acidaemia, a normal lactate to pyruvate ratio, slight elevation of branched chain amino acids in plasma, presence of α-ketoglutarate, pyruvate and branched chain α- ketoacids in urine, with a positive DNPH reaction, and low transketolase activity in red blood cells. However, these markers are rarely available under emergency conditions and diagnosis relies on primary care physicians in the emergency room and the life-saving therapeutic test of administration of thiamine intravenously at a dose of 5  mg/kg/day. This dose may be given without risk of adverse effects. Thiamine-dependent inborn errors of metabolism are rare and can arise from defects in thiamine transport or the biosynthesis and intracellular transport of thiamine pyrophosphate. They can also be due to intrinsic structural defects in thiamine-dependent enzymes which alter the affinity of the enzyme for the cofactor (. Table 29.1). Patients with these different conditions present with a wide range of clinical and biochemical manifestations, reflecting different patterns and degrees of involvement of the thiamine-dependent enzymes. Many details remain to be elucidated about the natural history and response to treatment of these conditions. In many cases, patients only respond to high doses of thiamine, however, these are readily tolerated and can be used safely.

29.1.1Thiamine Metabolism Dysfunction

Syndrome 1 (SLC19A2, THTR1 Deficiency) z

Clinical Presentation

THTR1 deficiency results in thiamine-responsive megaloblastic anaemia [3, 4]. The hallmarks of this condition are megaloblastic anaemia, diabetes mellitus and sensorineural deafness. The anaemia is often the first manifes-

tation and develops during infancy or early childhood. Although the anaemia is megaloblastic in character, ringed sideroblasts may be present in the marrow and some patients develop thrombocytopaenia. Diabetes usually develops later in childhood, although patients have been reported with neonatal diabetes. Other manifestations of the condition include cardiac abnormalities, short stature, retinal abnormalities, optic atrophy and stroke-like episodes. Cardiac involvement includes arrhythmias, congenital malformations and cardiomyopathy [5]. z

Metabolic Derangement

There have been few biochemical studies in patients with THTR1 deficiency. It is likely that the megaloblastic erythropoiesis is related to deficiency of transketolase in the pentose phosphate shunt, with impaired synthesis of ribose-5-phosphate. The blood thiamine and TMP concentrations have been reduced in some patients, but are often normal. This is consistent with experimental evidence that intestinal absorption of thiamine does not depend on this transporter. Apart from the anaemia, many of the features of THTR1 deficiency are shared with various mitochondrial diseases, however, biochemical defects in energy metabolism have not been widely documented. The blood and cerebrospinal fluid lactate concentrations are usually normal. The diabetes is non-autoimmune and insulin secretion is not impaired, at least initially. Diabetic ketoacidosis has developed in a small number of patients. z

Genetics

Many mutations in SLC19A2 have now been described, with small deletions, duplications, frameshift and nonsense mutations more common than missense mutations. Many are clustered in exon 2 of the gene. Most have been found in single individuals and there is no clear genotype/phenotype correlations [6]. z

Treatment and Prognosis

Patients with THTR1 deficiency generally respond well to thiamine supplementation, but not all clinical manifestations respond to the same extent. Treatment with doses of thiamine between 25-50  mg/day usually produces a good response in the anaemia, diabetes and cardiac arrhythmias. Deafness and other neurological features do not usually respond as well, however this may be improved with early diagnosis and treatment. With long term treatment, thiamine-responsiveness may decrease and previously well-controlled patients may become transfusion- and insulin-dependent [4].

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. Table 29.1

29

Disorders of Thiamine Metabolism

Defect (mechanism)

Disorder

Diagnostic tests

Effective dose of thiamine

Defective intake

Total parenteral nutrition without B1 supplementation Breast-fed babies of B1 deficient mothers Berri-Berri, Wernicke encephalopathy

Raised blood lactate Excretion of α-ketoacids in urine Low erythrocyte transketolase

2-4 mg/day (20 mg in emergency)

Defective transport

Thiamine metabolism dysfunction syndrome 1: Thiamine transporter 1 (THTR1, SLC19A2) deficiency: Thiamine-responsive megaloblastic anaemia with diabetes and deafness

Megaloblastic anaemia Hyperglycemia No specific abnormalities relating to thiamine or TPP DNA testing

25-50 mg/day

Defective transport

Thiamine metabolism dysfunction syndrome 2: Thiamine transporter 2 (THTR2, SLC19A3) deficiency: Biotin/thiamine-responsive basal ganglia disease

Reduced free thiamine in CSF Raised blood and cerebrospinal fluid lactate (only in some patients) DNA testing

50–100 mg/day (Biotin 2–10 mg/day)

Defective mitochondrial TPP transport

Thiamine metabolism dysfunction syndrome 3: microcephaly, Amish type Thiamine metabolism dysfunction syndrome 4: bilateral striatal degeneration and progressive polyneuropathy type Mitochondrial TPP transporter (SLC25A19) deficiency

Raised blood and CSF lactate Urinary excretion of α-ketoglutarate (in Amish microcephaly type) DNA testing

400-600 mg/day Some effect in patients with striatal degeneration and polyneuropathy if diagnosed early

Defective cofactor biosynthesis

Thiamine metabolism dysfunction syndrome 5: Episodic encephalopathy type: TPK1 deficiency

Low blood TPP Raised blood and CSF lactate Urinary excretion of α-ketoglutarate DNA testing

100-500 mg/day (more effective with early diagnosis)

Defective binding of TPP to apoenzyme

Thiamine-responsive pyruvate dehydrogenase complex deficiency

Raised blood lactate Normal L/P ratio DNA testing

50-1000 mg/day

Defective binding of TPP to apoenzyme

Thiamine-responsive maple syrup urine disease

Raised plasma leucine, isoleucine, valine and alloisoleucine DNA testing

50-1000 mg/day

29.1.2Thiamine Metabolism Dysfunction

Syndrome 2 (SLC19A3, THTR2 Deficiency) z

Clinical Presentation

Deficiency of this transporter most commonly results in biotin-responsive basal ganglia disease [7]. Onset is usually during childhood when patients develop a subacute encephalopathy characterised by speech and swallowing difficulty, confusion, dystonia and rigidity. This is associated with symmetric lesions in the caudate nucleus and putamen. However, patients with different clinical presentations have also been identified and the clinical spectrum continues to evolve.

The earliest, and most severe presentation of this condition is infantile Leigh syndrome. Patients present soon after birth with seizures, feeding difficulty and respiratory distress. Typical MRI findings in the brain are progressive cerebral atrophy and bilateral lesions in the thalami and basal ganglia [7]. Later presentations, in adolescence or adulthood, include Leigh-like [8], or Wernicke-like encephalopathy [9] and generalised dystonia and seizures [10]. z

Metabolic Derangement

The most significant biochemical finding is a marked reduction in the concentration of free thiamine in CSF [11]. Blood and CSF lactate concentration is elevated in

535 Disorders of Thiamine and Pyridoxine Metabolism

only minority of patients, and there is increased, but variable urinary excretion of organic acids. z

Genetics

In the original cohort of patients from Saudi Arabia, there was a high degree of parental consanguinity and a common missense mutation, p.Thr422Ala, in SLC19A3 [12]. In the remaining patients, different missense, nonsense, splicing and frameshift mutations have been identified. There is no clear genotype-phenotype correlation in relation to course, outcome or response to treatment. z

Treatment and Prognosis

The first patients to be described all had a rapid response to 5-10 mg/day biotin and remained symptom-free provided the diagnosis was established promptly and treatment was continued. Other patients have been treated effectively with a combination of biotin and thiamine (2-10 mg/day of biotin and 50-100 mg/day of thiamine), or thiamine alone. The failure of some patients to respond to biotin alone, and the effectiveness of thiamine supplementation means that this is now the usually recommended treatment. In a controlled study of combined biotin and thiamine versus thiamine alone, all patients diagnosed and treated early had a favourable outcome. There was no long term difference between the two treatments in terms of sequelae, but recovery from acute episodes was slightly faster in patients treated with both biotin and thiamine [13]. Patients with severe infantile Leigh syndrome do not respond as well to thiamine treatment and generally have a much poorer prognosis.

episodes of flaccid paralysis and encephalopathy, with motor and sensory neuropathy, precipitated by intercurrent illness. Age at presentation ranged from early childhood to teenage and patients developed a progressive axonal neuropathy, dystonia and dysarthia [15]. MRI changes were present in the caudate nucleus and putamen, but not the globus pallidus. z

z

z

Clinical Presentation

Deficiency of the mitochondrial TPP carrier (SLC25A19) was first described in patients with Amish lethal microcephaly. These patients have a distinctive facial appearance and a characteristic pattern of brain abnormalities [14]. Death usually occurs within the first six months. A different presentation of TPP transporter deficiency has been identified in five families from outside of the Amish community. These patients experienced acute

Genetics

Patients from the Amish community with lethal microcephaly have a common missense mutation, p.Gly177Ala in SLC25A19 [16]. Different missense mutations have been identified in the reported patients from outside the Amish community. z

Treatment and Prognosis

Most patents with Amish type microcephaly die during infancy. Some of the patients with striatal degeneration and polyneuropathy with early diagnosis have improved with thiamine treatment, although one patient with chronic symptoms, diagnosed at age 18, did not respond.

29.1.4Thiamine Metabolism Dysfunction

Syndrome 5 (Episodic Encephalopathy Type, TPK1 Deficiency)

29.1.3Thiamine Metabolism Dysfunction

Syndrome 3 (Microcephaly, Amish Type) and Thiamine Metabolism Dysfunction Syndrome 4 (Bilateral Striatal Degeneration and Progressive Polyneuropathy Type): Mitochondrial TPP Transporter deficiency (SLC25A19)

Metabolic Derangement

In patients with Amish lethal microcephaly, increased urinary excretion of α-ketoglutarate is a consistent finding, however this was absent in the patients from the unrelated families described subsequently. In these patients, the lactate concentration in cerebrospinal fluid was raised during acute episodes.

z

Clinical Presentation

This is a rare condition, with only twenty patients reported to date (reviewed in [17]). Patients usually present during early childhood with episodic encephalopathy, ataxia, psychomotor retardation, dystonia and dysarthria and seizures. In one family, two siblings developed generalised dystonia without any episodes of encephalopathy or ataxia. Brain MRI changes include global atrophy and abnormal signal in the cerebellum, dentate nuclei, basal ganglia, brain stem and spinal cord. z

Metabolic Derangement

Elevated blood and CSF lactate concentrations during episodes of ataxia, and enhanced urinary excretion of α-ketoglutarate are consistent findings. Blood and muscle TPP concentrations are significantly reduced and

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measurement of the blood concentration is an effective screening test. The major biochemical consequence of the enzyme defect appears to be deficiency of pyruvate and α- ketoglutarate dehydrogenases, however the activity of these enzymes in vitro is normal in the presence of TPP. z

29

Genetics

A variety of mainly missense mutations in TPK1 have been identified, with no common mutation in unrelated families. z

Treatment and Prognosis

Of the twenty reported patients, five died in childhood. Fourteen of the patients received thiamine supplementation (range (100-500 mg/day). Eight improved significantly, while the remainder (in whom neurological abnormalities were already established at diagnosis), showed no improvement. 29.1.5Thiamine-Responsive α-ketoacid

Dehydrogenase Deficiencies In some individuals, the normal dietary thiamine intake is not sufficient to sustain function of some TPP-dependent enzymes. This is the case in a small number of patients with pyruvate dehydrogenase deficiency and maple syrup urine disease, in whom high doses of thiamine have been reported to improve the clinical and/or biochemical features. The impaired enzyme activity in these patients is proposed to result from a structural defect which reduces the affinity of the enzyme for the cofactor, but which can be overcome if the cofactor concentration is increased by pharmacological doses of the vitamin precursor.

cognition, but they may develop problems due to peripheral neuropathy. The rare adult patient with unusual presentation of pyruvate dehydrogenase deficiency may also respond to thiamine supplementation. z

Biochemical Derangement

Blood and cerebrospinal fluid lactate concentrations are often normal or elevated only during acute episodes. In a number of patients, in  vitro studies with cultured fibroblasts have been performed to correlate the clinical response with correction of the enzyme defect in the presence of excess TPP, however, these do not always yield unequivocal results. z

Genetics

z

Treatment and Prognosis

The TPP binding site is shared between the α and β subunits of the E1 component of the pyruvate dehydrogenase complex, however all thiamine-responsive patients identified to date have had mutations in PDHA1, the gene for the E1α subunit. The mutations are missense changes, mostly involving amino acid residues adjacent to the TPP binding site.

It is difficult to establish definitively if any of the reported cases of thiamine-responsive pyruvate dehydrogenase deficiency are truly responsive. Almost all patients have received other treatments, as thiamine alone has not controlled symptoms. Doses of thiamine have varied widely from 50–1200  mg/day, and while this has led to clinical improvement in some cases, more often only the biochemical abnormalities have normalised and the clinical course has remained unaltered. Reports of initial improvement are rarely followed up with documentation of later outcome, and only a small number of patients have survived to adolescence with normal cognitive development.

29.1.6Thiamine-Responsive Pyruvate

Dehydrogenase Deficiency z

29.1.7Thiamine-Responsive Maple Syrup

Urine Disease

Clinical Presentation

Over 20 patients with pyruvate dehydrogenase deficiency have been claimed to be thiamine- responsive [18]. They usually present later, and are less severely affected, than is usual with this condition. Most common features are delayed development and hypotonia from late infancy, sometimes with episodes of ataxia in association with intercurrent illness. The great majority have lesions in the brain characteristic of Leigh Syndrome. A small number of these patients have normal development and

z

Clinical Presentation

This has been described in over 10 patients [19]. Presentation is usually similar to the intermediate form of maple syrup urine disease, with episodes of ketoacidosis or ataxia in late infancy, and delayed development. z

Metabolic Derangement

These patients have elevated branched chain amino acid and α-ketoacid concentrations in blood and

537 Disorders of Thiamine and Pyridoxine Metabolism

urine at diagnosis which reduce, but do not necessarily normalise, with thiamine supplementation. Episodes of acute decompensation with severe ketoacidosis are less common than in classic maple syrup urine disease and are usually suppressed with thiamine treatment. z

Genetics

Almost all thiamine-responsive maple syrup urine disease patients have mutations in DBT the gene for the E2 component of the complex [20] and this may reflect the fact that binding of the E1 enzyme to the E2 core of the complex influences its affinity for TPP. A single thiamineresponsive patient with a mutation in BCKDHB, encoding the E1β subunit, has been reported. z

Treatment and Prognosis

It is again difficult to assess the status of thiamineresponsiveness in patients with maple syrup urine disease. Patients have been given a wide range of thiamine dosage, up to 1000  mg/day, and most have also received dietary branched chain amino acid restriction. There are few long term follow up studies, although several patients remain healthy as adults, with normal cognitive function and no episodes of metabolic decompensation.

Diet

Pyridoxal-P

Vitamin B6 Metabolism Pyridoxine (vitamin B6) is a water-soluble vitamin with broad availability from various food sources, including dairy products, meat, cereals and vegetables. The three vitamers, pyridoxal, pyridoxamine and pyridoxine and their phosphorylated esters are absorbed in the small intestine. For cellular uptake and transport across the blood-brain barrier, phosphorylated forms undergo dephosphorylation by intestinal phosphatases and tissue non-specific alkaline phosphatase (TNSAP) respectively. The transport mechanism of B6 vitamers across cell membranes has not yet been fully elucidated, but it is assumed, that there are two different transporters, one across the endothelium and one across the mitochondrial membrane [21]. Within the cells vitamers are rephosphorylated by kinases and further oxidised to the active cofactor pyridoxal 5’-phosphate (PLP) by pyridox(am)ine 5’-phosphate oxidase (PNPO). As free PLP is highly reactive by its aldehyde group, its intracellular concentration is tightly regulated by negative feedback mechanisms as well as by the action of PLPBP (. Fig. 29.2).

Pyridoxamine-P

IP

Absorption

Disorders of Pyridoxine Metabolism

29.2

Pyridoxine-glucoside

IP

Pyridoxal

Pyridoxamine

PK

PK

Pyridoxine PK

Liver

Blood Cell membrane

Pyridoxine-P

Pyridoxamine

Pyridoxine

PNPO

PLP TNSALP PIGV anchor

Pyridoxal Cell

Pyridoxamine-P

PK

PK

Pyridoxamine-P

PK

Pyridoxine-P

PNPO

PLP PLPBP . Fig. 29.2 Pyridoxine metabolism. IP intestinal phosphatases, PK pyridoxine kinase, PNPO pyridox(am)ine 5´-phosphate oxidase, TNSAP tissue non-specific alkaline phosphatase, PLPBP pyridoxal 5´-phosphate binding protein

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kIntroduction

29

While the liver seems to be the most important organ of pyridoxal 5’-phosphate (PLP) formation, pyridox(am) ine 5’-phosphate oxidase (PNPO) is expressed in various cell types including neurons. PLP is one of the most abundant cofactors and, in humans participates in about 70 reactions mainly in amino acid and neurotransmitter metabolism. The daily requirement is 0.1 to 0.3 mg/day in infants and 1.2-1.4 mg/day in adults. Systemic vitamin B6 deficiency causes seizures, failure to thrive and anemia in a variety of species, and

. Table 29.2

also human infants fed a formula with low vitamin B6 content due to overheating during sterilisation. Nutritional vitamin B6 deficiency is rarely seen nowadays and usually occurs together with other vitamin deficiencies in malnutrition or in association with severe chronic disease. There are several mechanisms that lead to an increased requirement for pyridoxine and/or PLP [21] (. Table 29.2): (i) inborn errors affecting the pathways of B6 vitamer metabolism: PNPO deficiency, alkaline phosphatase defects and congenital hyperphosphatasia;

Disorders of Pyridoxine Metabolism

PLP related mechanism

Biochemical abnormalities Urine

Coeliac disease Chronic dialysis Malabsorption, depletion

↑ xanthurenic acid

Drug interaction (eg. hydrazines, D- penicillamine, enzyme inducing anticonvulsants) PNPO Deficiency Reduced PLP formation

Vanillactatea

Plasma

CSF

Response to vitamin B6

↑ threonine, glycine and serine

To very low doses of pyridoxine

↑ homocysteine

Preventive B6 supplementation

↑ PM and PM/ PA

↓ to normal PLP° sec. AA and NT changes NTchanges

Mainly to PLP, in certain mutations also pyridoxine

Congenital Hypophosphatasia Reduced PLP uptake

↓ AP, ↓Ph, ↑ Ca ↑PLP

To pyridoxine (or PLP)

Congenital Hyperphosphatasia Reduced PLP uptake

↑ AP

unknown

PLPBP Deficiency (formerly PROSC)

↓ PLP, secondary AA and NT changes°

To pyridoxine or PLP

↑ AASA, ↑6-oxo PIP ↓ PLP° secondary AA and NT changes

To pyridoxine (or PLP)

Antiquitin Deficiency (PDE) PLP inactivation

AASA, P6C ↑6-oxo PIP

↑ Pipecolic acida ↑6-oxo PIP

Hyperprolinemia II PLP inactivation

↑ Prolin, P5C

↑ Prolin, P5C

To pyridoxine (or PLP)

Classical Homocystinuria Chaperone

↑ homocyst(e) ine

↑↑ homocysteine, methionine

To pyridoxine in about 50% of patients

Gyrate atrophy, OAT Chaperone

↑ ornithine

To pyridoxine in some patients

X-linked sideroblastic anaemia

Enzyme assay in RBC and DNA

To pyridoxine in about 90% of patients

AA aminoacid, AP alkaline phosphatase, AASA alpha aminoadipic acid, Ca calcium, PA pyridoxic acid, 6-oxo PIP 6-oxo pipecolate, PDE pyridoxine dependent epilepsy, P6C piperideine-6-carboxylate, P5C pyrrolin-5-carboxylate, Ph phosphate, PLP pyridoxal 5’-phosphate, PM pyridoxamine, PLPBPD pyridoxal 5´-phosphate binding protein deficiency, PNPO pyridox(am)ine 5’-phosphate oxidase, NT neurotransmitter, OAT ornithine delta-aminotransferase aInconsistent findings, °before specific treatment with vitamin B 6

539 Disorders of Thiamine and Pyridoxine Metabolism

(ii) inborn errors that lead to accumulation of small molecules that react with PLP and inactivate it: hyperprolinemia type II and antiquitin deficiency (pyridoxine dependent epilepsy); (iii) inborn errors affecting intracellular PLP homeostasis: PLP-binding protein (PLPBP) deficiency (formerly named PROSC deficiency) and (iv) specific PLP dependent enzymes: X-linked sideroblastic anemia, classical homocystinuria, gyrate atrophy of the choroid; (v) drugs as D-penicillamine or isozianid that affect the metabolism of B6 vitamers or react with PLP; (vi) coeliac disease, which is thought to lead to malabsorption of B6 vitamers or renal dialysis, which leads to increased losses of B6 vitamers from the circulation; There are currently six known inborn errors of metabolism, all of autosomal recessive inheritance, that lead to vitamin B6 dependent epilepsy, either by inactivation, reduced formation, reduced cellular uptake of PLP or disturbed intracellular PLP homeostasis, that can be recognized by respective biomarkers, except for PLPBPD (. Table 29.2). In each of these entities, seizures are a hallmark of the disease, with no or incomplete response to common anticonvulsants, but a good response to pyridoxine or PLP. As PLP is an abundant cofactor in several metabolic pathways, secondary metabolic changes as hypoglycaemia, hyperglycinaemia and elevated lactate are frequent confounders and may mislead the clinician towards other (untreatable) IEM.  In the group of vitamin B6 dependent epilepsies, seizures typically recur upon withdrawal of vitamin B6 and illustrate B6 dependency in contrast to mere responsiveness, as seen in nutritional deficiencies and also as a nonspecific phenomenon due to GABA-ergic effects of vitamin B6 supplementation. As biomarkers and/or genetic analysis are both available to test for IEM associated with vitamin B6 responsive seizures (. Table  29.2), withdrawal in responders is no longer relevant.

rarely, burst suppression patterns. Seizures are typically resistant to common anticonvulsants aside from a possible partial or transient response to phenobarbitone. Imaging is non-diagnostic, but may show thinning of the corpus callosum, cysts of the posterior fossa, white matter anomalies or cortical dysplasia [24, 25]. z

Metabolic Derangement

z

Genetics

Antiquitin (ALDH7A1) encodes for α-aminoadipic semialdehyde dehydrogenase, an enzyme involved in lysine degradation (. Fig.  29.3). The accumulating compound, α-aminoadipic acid semialdehyde (AASA), is in equilibrium with L-Δ1-piperideine-6-carboxylate (PC6) δ, which inactivates PLP by a so called Knoevenagel condensation [26]. The Knoevenagel product has not been shown in  vivo to date. AASA (and P6C) in urine (plasma or CSF) can be determined semiquantitatively by LC-MS-MS and serve as reliable biomarkers, even when patients are on treatment with pyridoxine. Simultaneous determination of sulfocysteine is crucial to exclude molybdenum cofactor and sulfite oxidase deficiency causing secondary inhibition of antiquitin [27] (7 Sect. 20.11). Pipecolic acid in plasma, the first described biomarker of PDE, is less specific as it can also be found in peroxisomal disease and has been found normal in older patients while on pyridoxine [28, 29]. (see also 7 Fig. 30.1) Recently 6-oxo pipecolate (PIP) has been described as a novel biomarker of ALDH7A1 deficiency, which is stable at room temperature and would be a suitable biomarker for newborn screening [30]. A number of secondary phenomena have been described in CSF of affected patients: low GABA, homovanillic acid (HVA) and hydroxyindole acetic acid (HIAA) concentrations. PLP levels in CSF, if measured pre-treatment, are markedly decreased, while PLP in plasma is low-normal. Enzymatic testing of antiquitin activity in fibroblasts, though feasible, has not been established as a routine investigation.

29.2.1Antiquitin Deficiency (ALDH7A1) z

Clinical Presentation

Antiquitin deficiency is the most common form of pyridoxine dependent epilepsy (PDE). Typically, patients present in the neonatal period with myoclonic and tonic seizures or status epilepticus, but later onset from childhood to even adolescence has been observed [22, 23, 24]. About one third of affected neonates have a history of asphyxia and some may also present with encephalopathy (inconsolable crying, sleeplessness) or systemic features including hypoglycemia, lactic acidosis or acute abdomen. The EEG changes can range from nonspecific slowing and discontinuity to focal discharges, or

Diagnosis is confirmed by Sanger sequencing of ALDH7A1. Over 165 different mutations have been described to date with no clear genotype to phenotype correlation. The carrier frequency is estimated to be as high as 1:127 with an estimated incidence of antiquitin deficiency of about 1:64.300 pregnancies [31]. The E427Q mutation, which results in complete enzyme deficiency, accounts for about 30% of all mutant alleles within Europe. Deletions of ALDH7A1 have been reported and can only be detected by MLPA techniques [32]. In 2009 it was shown, that antiquitin deficiency is allelic to folinic acid responsive seizures [33].

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L-lysine H2N

COOH NH2

H2N

COOH

2-keto 6-aminocaproic acid

O

29

Piperideine-2-carboxylate

N

HOOC

COOH

Saccharopine

N

COOH

O Piperideine-6-carboxylate

NH2

H HOOC

Pipecolic acid

COOH

N

N

COOH

COOH NH2 Alpha aminoadipic semialdehyde

Inactivation of pyridoxal 5’-phosphate (PLP) by a Knoevenagel condensation

HOOC

COOH NH2 Alpha aminoadipic acid

. Fig. 29.3

z

Adapted Lysine degradation and antiquitin deficiency (blue bar)

Treatment and Prognosis

In most cases the administration of pyridoxine, 100 mg iv. or po., leads to prompt cessation of seizures. In about 14% the response to pyridoxine has been ambiguous and may be missed by a single dose administration [34]. Therefore, the administration of 30 mg/kg in 2 to 3 SD over three consecutive days has been recommended to identify patients with delayed response [22]. As first administration of pyridoxine may lead to severe apnea, resuscitation equipment should be at hand.

About 90% of patients have complete seizure control on pyridoxine monotherapy. To prevent side effects of pyridoxine, such as peripheral neuropathy, dosages should not exceed 300  mg/day. In those with breakthrough seizures during febrile illness, doubling of the pyridoxine dose over a few days is effective. Despite complete seizure control only 25% of PDE patients show normal development, irrespective of treatment delay. This may be due to the accumulation of potentially toxic metabolites within the L-lysine pathway that

541 Disorders of Thiamine and Pyridoxine Metabolism

do not normalise upon pyridoxine treatment. Therefore add-on therapies, such as a lysine restricted diet (LRD) and arginine supplementation for competitive inhibition of cellular lysine uptake have been applied in a still limited number of patients [35, 36, 37]. Patients with early initiation of add-on LRD with or without additional arginine supplementation have shown a variable decrease of intermediary lysine metabolites, in some cases associated with cognitive improvement as well as better seizure control. Prenatal treatment with 100 mg of pyridoxine starting from 3 months in pregnancies at risk may lead to better outcome [38], but warrants rapid confirmation testing after birth, as an unaffected offspring had proconvulsive effects on high dose pyridoxine therapy [39]. As some patients with antiquitin deficiency have been shown to have additional benefit from folinic acid, mainly during the neonatal period or infancy, folinic acid (3–5 mg/kg/day) is recommended for patients who fail to respond to pyridoxine alone. The role of folinic acid is not completely understood, but might be due to partially overlapping cofactor function and a ‘B6 sparing effect’ (P. Clayton, personal communication, 2014).

29.2.2Hyperprolinemia Type II

Among the six IEM with vitamin B6 dependent seizures, this has probably the most attenuated phenotype [40]. It is in this IEM that the inactivating mechanism of PLP by a Knoevenagel condensation was first described [41]. The accumulated inactivating compound is Δ1-pyrroline5-carboxylate (P5C) due to deficiency of Δ1-pyrroline-5carboxylate dehydrogenase. The diagnosis can be made by marked elevation of plasma proline concentration and the presence of P5C in urine. The disorder is described in 7 Chap. 21, 7 Sect. 21.7. 29.2.3Pyridox(am)ine 5’-phosphate Oxidase

(PNPO) Deficiency z

Clinical Presentation

The clinical presentation of PNPO deficiency is indistinguishable from antiquitin deficiency except for a higher rate of prematurity which is found in 61% of all published cases [42]. The disease was first described in Taiwan, where PLP is the first line drug to test for vitamin B6 responsiveness [43]. Seizures recurred when patients were switched to pyridoxine and they showed a neurotransmitter profile that mimicked aromatic L-amino acid decarboxylase deficiency [44]. In contrast to antiquitin deficiency, patients with PNPO deficiency show signs of systemic PLP deficiency beyond the neo-

natal period, as failure to thrive and anaemia. In the neonatal period, the EEG is usually severely abnormal and a burst suppression pattern has been described in two thirds of published cases. Brain MRI imaging can be normal, but shows white matter changes and atrophy if diagnosis and specific treatment are significantly delayed. The function of PNPO might in fact be much broader than previously thought as some mutations were shown to be associated with infertility and miscarriage [45]. z

Metabolic Derangement

PNPO deficiency leads to severe (systemic) PLP deficiency and impaired function of PLP dependent enzymes [46]. A plasma profile of vitamin B6 vitamers reveals a high pyridoxamine/pyridoxic acid ratio and is indicative of PNPO deficiency even when on vitamin B6 supplementation [47]. PNPO activity can now be measured in dried blood spots and allows a quick and accurate diagnosis [48]. Vanillactate in urine reflects the buildup of dopamine metabolites, but is an inconstant and unspecific finding. While the original patients with PNPO deficiency were found to have decreased urinary HVA and HIAA, there are now two reports of elevated levels of these metabolites prior to treatment, an observation which remains unexplained. PLP concentrations in CSF prior to treatment have been found to be low but this may also be an inconsistent finding [48]. z

Genetics

In 2005 PLP dependent seizures were shown to be caused by PNPO deficiency [46]. To date a total of 27 different mutations in PNPO have been reported [21]. The R116Q variant is of special interest, as it shows a high carrier frequency in the general population but incomplete penetrance of epilepsy in the homozygous state. In 2014, two reports documented a significant proportion of patients with novel pyridoxine-responsive PNPO mutations, with residual enzyme activity of 8% or above [45, 49]. R225H seems to be a prevalent pyridoxine-responsive founder mutation in Kosovo and neighbouring countries [52]. z

Treatment and Outcome

Patients with PNPO deficiency have a short time window for specific treatment in order to prevent irreversible brain damage. Outside of Asia, PLP is an unlicensed chemical and can be purchased from naturopathic stores with uncertainty about the exact PLP content [50]. Effective dosages vary from 30 to 60 mg/kg/day. Patients often require frequent dosing of 4–6 single dosages/day. To avoid oxidation PLP should be dissolved immediately before oral administration. According to recent

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reports on liver toxicity and cirrhosis, transaminases should be monitored and the lowest effective dose used [51, 52]. PNPO patients who are seizure free on pyridoxine monotherapy should not necessarily be switched to PLP, as in addition to the risk of liver toxicity of PLP, status epilepticus has been observed in single patients when switched to PLP quickly [52].

29.2.4Congenital Hypophosphatasia (Tissue

29

Non Specific Alkaline Phosphatase) z

Clinical Presentation

Only patients affected by the severe form of perinatal or infantile congenital hypophosphatasia (CHP) present with neonatal seizures, sometimes before the skeletal manifestation of osteomalacia due to poor bone mineralisation becomes apparent [53]. The EEG is usually severely abnormal and can show a burst suppression pattern. Prior to the availability of enzyme replacement therapy, this condition was fatal as a result of respiratory insufficiency.

29.2.5Hyperphosphatasia-Mental

Retardation Syndrome (HPMRS) HPMRS or Mabry syndrome, is a clinically recognizable syndrome with facial dysmorphism, brachytelephalangy and seizures of neonatal or childhood onset. The majority of cases are caused by mutations in PIGV, or less frequently in PIGO or PGAP2, that encode the synthesis of phosphatidylinositol (GPI) –anchors of various membrane-bound proteins such as TNSAP [58] (7 Chap. 35). Mildly to moderately elevated AP in serum is a hallmark of the disease. To date it remains unclear, if seizures of these patients respond to pyridoxine.

29.2.6PLP Binding protein (PLPBP, Formerly

PROSC) Deficiency

CHP is caused by a deficiency of Tissue Non Specific Alkaline Phosphatase (TNSAP). This enzyme has three substrates, namely inorganic pyrophosphate, phosphoethanolamine and PLP for cellular uptake. Cerebral PLP deficiency is supported by secondary changes of neurotransmitters reported in single patients [54], but expected phenomena of ubiquitous intracellular PLP deficiency, such as severe anemia, are absent. The diagnosis of CHP is straight forward with markedly reduced levels of alkaline phosphatase (AP) in routine clinical chemistry, elevated serum calcium and reduced serum phosphate, and elevated phosphoethanolamine upon amino acid analysis. PLP in plasma prior to treatment is markedly elevated.

In 2016 Darin et al. reported seven patients with a new genetic background of vitamin B6 dependent epilepsy - at that time called PROSC deficiency [59]. Since then a total of 31 patients have been described, most of them presenting with neonatal onset of therapy-resistant, clonic, tonic clonic or myoclonic seizures [60–64]. Seizure onset beyond the neonatal period may occur and one patient has been identified with an isolated dystonic movement disorder presenting from age 3 months [63]. Primary or acquired microcephaly and intellectual disability are frequently observed and may correlate with the underlying genotype rather than with therapeutic delay. Cranial MRI may be normal or show structural anomalies as a simplified gyral pattern, anterior cysts or swelling of white matter as well as hyperdensities of dentate nuclei. MRI changes and the presence of lactic acidosis in 50% of cases reported so far may mislead towards primary mitochondrial disorders and prevent a therapeutic trial with pyridoxine. EEG changes vary from normal to diffuse slowing or burst suppression patterns.

z

z

z

Metabolic Derangement

Genetics

CHP is caused by mutations in ALPL and there is some genotype-phenotype correlation and an increased frequency of specific mutations in some ethnic populations. z

Treatment and Prognosis

There is a variable and inconsistent response to treatment with pyridoxine and worsening of seizures upon pyridoxine has been observed [55]. It is questionable if the availability of enzyme replacement therapy will alter the CNS manifestation of infantile CHP, as enzyme replacement therapy cannot cross the blood brain barrier [56, 57].

Metabolic Derangement

PLPBP is a cytosolic as well as mitochondrial protein involved in intracellular PLP homeostasis and suggested to act as a carrier of PLP towards PLP-dependent enzymes [21, 64]. There is no specific biomarker to indicate PLPBP deficiency. Pre-treatment concentration of PLP in CSF and plasma is markedly reduced. Dysfunction of PLP-dependent enzymes may be indicated by elevated lactate (about 50% of cases), glycine, methionine, threonine or vanillactate in urine. z

Genetics

PLPBP deficiency is a panethnic condition. Functional and structural studies have been performed in a limited number of missense mutations [65] and have shown a

543 Disorders of Thiamine and Pyridoxine Metabolism

dimeric protein structure as well as an additonal role of PLPBP in the regulation of cell division and proper muscle function [66]. z

Treatment and Prognosis

A considerable proportion of patients with PLPBP deficiency shows a favorable response to pyridoxine monotherapy, 100–200  mg/day [60–64], while some patients needed a switch from pyridoxine to PLP [59, 63] or even addition of folinic acid to become seizure free [63]. Emerging genotype phenotype correlation suggests that loss of function mutations cause a more severe phenotype associated with intellectual disability, whereas missense variants that do not affect the PLP binding site seem to be associated with a better outcome [63].

5.

6.

7.

8.

9.

10.

29.2.7Other B6 Responsive Disorders

Some IEM caused by defects of PLP dependent enzymes benefit from cofactor supplementation [21]. This is true for about 50% of all cases with classical homocystinuria and warrants a pyridoxine challenge prior to the initiation of a methionine restricted diet and/or medication (7 Chap. 20). Pyridoxine responsiveness is also seen in some cases of gyrate atrophy, caused by deficiency of ornithine aminotransferase (7 Chap. 21). The pyridoxine-responsive anaemia (or X-linked sideroblastic anaemia) is caused by a defect in the erythroid-specific form of 5-aminolevulinate synthase (7 Chap. 33). In all these B6 responsive disorders vitamin B6 vitamers may act as a chaperone on the mutated protein [67]. In aromatic acid decarboxylase (AADC) deficiency a trial with pyridoxine is recommended, as PLP can optimize residual AADC activity with positive response reported in some patients (7 Chap. 30). A stepwise increase of pyridoxine is advised to identify the lowest effective dose. For the risk of (reversible) neuropathy pyridoxine doses should be kept below 300 mg/day wherever possible.

11.

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66.

67.

Tremiño L, Forcada-Nadal A, Rubio V (2018) Insight into vitamin B(6) -dependent epilepsy due to PLPBP (previously PROSC) missense mutations. Hum Mutat 39:1002–1013 Fux A, Sieber SA (2020) Biochemical and proteomic studies of human pyridoxal 5´-phosphate binding protein (PLPBP). ACS Chem Biol 17:254–261 Cellini B, Montioli R, Oppici E, Astegno A, Voltattorni CB (2014) The chaperone role of the pyridoxal 5’-phosphate and its implications for rare diseases involving B6-dependent enzymes. Clin Biochem 47:158–165

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Disorders of Neurotransmission Ángeles García-Cazorla, Rafael Artuch, and Phillip L. Pearl Contents 30.1

Gamma Amino Butyric Acid (GABA) Neurotransmitter Disorders – 549

30.1.1 30.1.2 30.1.3 30.1.4 30.1.5

Gamma Amino Butyric Acid Transaminase Deficiency – 549 Succinic Semialdehyde Dehydrogenase Deficiency – 549 Glutamic Acid Decarboxylase (GAD) Deficiency – 550 GABA Receptor Mutations – 551 GABA Transporter Deficiency – 551

30.2

Glutamate Neurotransmitter Disorders – 551

30.2.1 30.2.2

Glutamate Receptor Mutations – 551 Mitochondrial Glutamate Transporter Defect – 553

30.3

Glycine Neurotransmitter Disorders – 553

30.4

Choline Neurotransmitter Disorders – 555

30.5

Monoamine Neurotransmitter Disorders – 556

30.5.1 30.5.2 30.5.3 30.5.4 30.5.5 30.5.6 30.5.7 30.5.8 30.5.9

Tyrosine Hydroxylase Deficiency – 558 Aromatic L-Amino Acid Decarboxylase Deficiency – 558 Dopamine β-Hydroxylase Deficiency – 560 Monoamine Oxidase-A Deficiency – 560 Guanosine Triphosphate Cyclohydrolase I-Deficiency – 561 Sepiapterin Reductase Deficiency – 562 Dopamine Transporter Defect – 562 Brain Dopamine-Serotonin Vesicular Transport Defect – 562 Other Defects – 562

30.6

Synaptic Vesicle Disorders (see also 7 Chap. 44) – 563

30.6.1 30.6.2

Disorders of SV Exocytosis – 563 Disorders of SV Endocytosis – 567

References – 567

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_30

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Neurotransmitters

30

Chemical transmission in the nervous system is characterized by amazing complexity. Classical neurotransmitter systems involve inhibitory aminoacidergic [γ-aminobutyric acid (GABA) and glycine], excitatory aminoacidergic (aspartate and glutamate), cholinergic (acetylcholine), monoaminergic (mainly adrenaline, noradrenaline, dopamine, and serotonin), and purinergic (adenosine and adenosine mono-, di-, and triphosphate). New approaches based on synaptic physiology include synaptic vesicle defects as a new category of inborn errors of neurotransmission and cell trafficking disorders. Defects of neuropeptides, channels (as neurotransmitter modulators), other signalling molecules and cellular processes will be gradually integrated in the complexity of neurotransmission diseases in the future. GABA is formed from glutamic acid by glutamic acid decarboxylase (. Fig. 30.1). It is catabolized into succinic acid through the sequential action of two mitochondrial enzymes, GABA transaminase and succinic semialdehyde dehydrogenase. Glutamic acid decarboxylase and GABA transaminase require pyridoxal phosphate as a coenzyme. Pyridoxal phosphate also participates in the synthesis of dopamine and serotonin, and in many other pathways including the glycine cleavage system. A major inhibitory neurotransmitter, GABA is present in high concentration in the central nervous system, predominantly in the grey matter. GABA modulates brain activity by binding to sodium-independent, high-affinity, mostly GABAA receptors (. Fig.  30.2). Glutamate is the major excitatory neurotransmitter in the brain. Its function requires rapid uptake to replenish intracellular neuronal pools following extracellular release. Glutamatergic receptors (. Fig. 30.2) mediate neuronal plasticity, learning and behaviour. Glycine, a non-essential amino acid, is an intermediate in many metabolic processes but also one of the major inhibitory neurotransmitters in the central nervous system. The inhibitory glycine receptors and transporters (. Fig.  30.3) are mostly found in the brain stem and spinal cord. Choline is the major neurotransmitter at the neuromuscular junction (. Fig. 30.4).

kIntroduction

This Chapter deals with inborn errors of neurotransmitter biosynthesis, catabolism, and defects of their transporters, receptors and synaptic vesicle trafficking disorders at the pre-synaptic terminal. Defects of GABA

Glutamine Homocarnosine

Glutamate

B6 L-Histidine

Guanidinobutyrate

1

GABA

B6

2

D-2-HG

SSA α-KG 3

CH3 CH CH CH2 CH2 COOH Gamma-hydroxybutyrate (GHB) OH OH Succinate (DHHA) TCA cycle

. Fig. 30.1 Brain metabolism of γ-aminobutyric acid (GABA). B6 pyridoxal phosphate, 1 glutamic acid decarboxylase, 2 GABA transaminase, 3 succinic semialdehyde dehydrogenase, D-2-HG D-2hydroxybutyrate, α-KG alpha ketoglutarate, TCA tricarboxylic c-ycle, DHHA 4,5-dihydroxyhexanoic acid, SSA succinic semialdehyde. Enzyme defects are depicted by solid bars. The block at conversion of homocarnosine to GABA remains to be clarified

catabolism include GABA transaminase deficiency and succinic semialdehyde dehydrogenase (SSADH) deficiency. Glutamic acid decarboxylase (GAD) deficiency is a new defect of GABA synthesis that presents as neonatal seizures. Mutations in GABA receptors and GABA transporter cause dominantly inherited epilepsies while mutations in glutamate receptors associate with complex neurodevelopmental and psychiatric disorders. Mitochondrial glutamate transporter is a cause of severe epileptic encephalopathy. Hyperekplexia is usually due to a dominantly inherited defect of the α1 subunit of the glycine receptor which causes excessive startle responses and is treatable with clonazepam. Defects of choline synthesis, transporter and their receptors lead to congenital myasthenia. Monoamine metabolism synthesis defects are: Tyrosine hydroxylase (TH) deficiency, which impairs synthesis of L-dopa and causes a neurological disease with prominent extrapyramidal signs, and a variable response to L-dopa; Aromatic L-amino acid decarboxylase (AADC) located upstream of the neurotransmitter amines with a challenging treatment; Dopamine β-hydroxylase deficiency which presents with severe orthostatic hypotension and sympathetic failure. Monoamine-oxidase A (MAO-A) is a catabolism deficiency, located downstream that causes behavioral disturbances with no effective treatment. Monoamine

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“transportopathies” produce early parkinsonismdystonia and include dopamine transporter defect and vesicular monoamine transporter type 2 defect. Guanosine triphosphate cyclohydrolase-I (GTPCH-I) and sepiapterin reductase (SR) deficiencies are pterin disorders upstream of L-dopa and 5-hydroxytryptophan (5-HTP) with normal baseline phenylalaninaemia and effective treatment (especially GTPCH-I deficiency). Synaptic vesicle trafficking defects at the pre-synaptic terminal include 14 disorders of exocytosis, which frequently cause severe neurodevelopmental encephalopathies, and 20 endocytosis defects, that mostly present as early-onset parkinsonism, but also as classical Parkinson disease.

30.1

Gamma Amino Butyric Acid (GABA) Neurotransmitter Disorders

30.1.1Gamma Amino Butyric Acid

Transaminase Deficiency GABA-Transaminase deficiency is an extremely rare autosomal recessive (AR) disease, with reports published thus far for only 17 individuals from 11 families. The oldest identified patient is currently 32 years old [1, 2]. z

Clinical Presentation

Clinical findings in the index family were neonatal seizures, lethargy, hypotonia, hyperreflexia, poor feeding, severe developmental impairment, and a high-pitched cry [3]. Linear growth was accelerated, attributable to a pro-growth hormone secreting effect by GABA. In this Flemish sibship, there was early mortality and spongiform leukodystrophy. Patients have uniformly presented with neonatal or early infantile encephalopathy, often accompanied by hypotonia, lethargy, seizures, and extrapyramidal manifestations. Choreoathetosis, subcortical myoclonus, and accelerated growth are common clinical manifestations. EEGs show burst suppression, modified hypsarrhythmia, multifocal spikes, generalized spikewave, or diffuse background slowing. MRIs show delayed myelination and progressive cerebral atrophy, specifically at the thalami, and thin corpus callosum and brainstem. Milder phenotypes related to higher residual enzymatic activity are emerging with survival into adulthood [2, 4]. z

Metabolic Derangement

Cerebrospinal fluid (CSF) GABA conjugates and β-alanine are increased. CSF free GABA was elevated up to 60-fold for all patients where CSF was studied (reference T) [61]. z

Treatment and Prognosis

Therapy with L-dihydroxyphenylserine (L-Dops) is available. This compound can be directly converted by AADC into noradrenaline, thereby by-passing the defective enzyme. Administration of 100– 500 mg L-Dops orally twice or three times daily increases blood pressure and restores plasma norepinephrine levels, however plasma epinephrine concentration still remains below a detectable level [62]. Droxidopa, an orally available synthetic amino acid precursor of norepinephrine is a new alternative. Long-term, open-label treatment with droxidopa was well tolerated and provided sustained improvement in neurogenic orthostatic hypotension. However, kidney function, anemia, and hypomagnesaemia only partially improved (56 Wassenberg) [63]. Several clinical trials with this drug are completed or ongoing (7 www.clinicaltrials.gov). The prognosis on therapy is satisfactory to good.

30.5.4Monoamine Oxidase-A Deficiency z

Clinical Presentation

Monoamine oxidase-A (MAO-A) deficiency has been identified in five generations of one Dutch family [64]. Only males were affected. They showed borderline ID with aggressive and violent behaviour, arson, attempted rape, and exhibitionism. Additionally, a functional polymorphism of the MAO-A gene promoter region may act as a genetic modifier of the severity of autism in males [65]. Other MAO-A polymorphisms have been related to abnormal limbic circuitry for emotion regulation and cognitive control, explaining impulsive aggression and serious delinquency [66]. MAO exists as two X-linked

561 Disorders of Neurotransmission

isoenzymes (A and B). Patients with a contiguous gene syndrome affecting both the MAO-A and -B genes, and also the gene responsible for Norrie disease, have been described with severe intellectual deficiency and blindness [67]. Patients with only the MAO-B and Norrie genes affected had no intellectual impairment or abnormalities in urine catecholamine metabolites. z

Metabolic Derangement and Genetics

MAO-A deficiency is a X-linked inherited defect in the catabolism of both serotonin and the catecholamines. Patients have marked elevations of serotonin, normetanephrine, 3-methoxytyramine, and tyramine reported in urine. The concentrations of the metabolites downstream of the metabolic block, VMA, HVA, 5-HIAA, and MHPG, were markedly reduced. A point mutation in the eighth exon of MAO-A, causing a premature truncation of the protein, has been reported [64]. z

Diagnostic Tests, Treatment and Prognosis

Elevated urinary serotonin, normetanephrine, metanephrine, and 3-methoxytyramine is the characteristic pattern in random urine samples (. Table  30.3). The ratios in urine of normetanephrine to VMA, normetanephrine to MHPG or HVA/VMA are altered [68]. The discovery of this disorder suggests that it might be worthwhile performing systematic urinary monoamine analysis when investigating unexplained, significant, behaviour disturbances, particularly when these occur in several male family members. In CSF, nearly absent HVA and 5-HIAA are observed, with no accumulation of 3-OMD and 5-HTP (differential diagnosis with AADC deficiency) and normal pterin profile. No effective treatment is known at present. ID and behaviour abnormalities seem to be stable over time.

30.5.5Guanosine Triphosphate

Cyclohydrolase I-Deficiency z

Clinical Presentation

This is the most common dopamine-responsive dystonia [69, 70]. Onset is typically about age 6 years, although reported as early as the first week of life or in adulthood, including ages over 50 years [71]. Lower limb dystonia is generally the initial and most prominent symptom, becoming generalized unless treated with L-dopa. Diurnal fluctuation with improvement after sleep is typical. Other clinical features include HRS, OGC, generalized hypotonia, proximal weakness, paroxysmal exercise-induced dystonia, sleep disturbances and impaired cognition [71]. The disease is

classified into two types, postural dystonia and action dystonia forms. The dystonia may have a relapsingremitting course, and be associated with OGC, depression, and migraine. Adult onset patients can start with parkinsonism features and may have mild cognitive impairment and impulsivity [72]. GTPCH can be also inherited as an AR disease and clinical manifestations and very similar to those of sepiapterin reductase deficiency. AR GTPCH-1 deficiency also causes hyperphenylalaninaemia (7 Chap. 16). z

Metabolic Derangement and Genetics

GTPCH-I is the initial and rate-limiting step in BH4 biosynthesis, the essential cofactor of various aromatic amino acid hydroxylases (. Fig.  30.4) with highest affinity for TH. The deficiency is characterized by defective biosynthesis of serotonin and catecholamines. GTPCH-I deficiency can be inherited as both AD and AR trait. The incidence of autosomal dominant GTPCH-I is generally reported to be 2.5–4 fold greater among females than males [71]. A dominant negative mechanism has been proposed [71]. This effect might also account for the phenotypic heterogeneity of DRD, as the degree of enzyme inactivation depends on the specific genetic abnormality. Point mutations and large rearrangements have been reported [71]. z

Diagnostic Tests

Patients with AD GTPCH-1 deficiency have normal Phe levels in body fluids. The following tests may be helpful in diagnosis (. Table 30.3): (1) Measurement of pterins especially in CSF (biopterin and neopterin are decreased from 20% to 50% of normal levels and are the biochemical hallmarks of the disease). (2) Measurement of CSF HVA and 5-HIAA. A normal or slightly low CSF HVA in combination with low 5-HIAA is observed, with no accumulation of biogenic amine precursors (3-OMD and 5-HTP). (3) An oral Phe-loading test. In general, it reveals a 2–6  hour increase in Phe levels and Phe/Tyr ratio. (4) Mutation analysis. (5) Measurement of enzyme activity in fibroblasts. Biochemical alterations of the AR form are described in . Table 30.3. z

Treatment and Prognosis

Patients have been treated with a combination of low dose L-dopa (4–5 mg/kg/day) and a dopa-decarboxylase inhibitor. There is normally a complete or near-complete response of motor problems soon after therapy initiation. Even when therapy is started after a delay of several years, results are satisfactory. However, for action dystonia and adult onset cases, levodopa does not always show complete effects [71].

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30.5.6Sepiapterin Reductase Deficiency

30.5.7Dopamine Transporter Defect

z

Dopamine transporter (DAT) deficiency syndrome due to SLC6A3 mutations is an AR disorder presenting as early infantile progressive parkinsonism dystonia with a wide variety of neurological signs [77]. Atypical presentations appear later in childhood including juvenile onset with a milder course [78]. Overall, the clinical picture shows progressive parkinsonism-dystonia that is medically refractory. Other signs are masked facies, eye movement disorders, and some gastrointestinal symptoms. CSF HVA is elevated. SLC6A3 mutations reduce levels of DAT and the binding affinity of dopamine. Genotype-phenotype analysis suggests that higher residual DAT activity contributes to later presentations. SLC6A3 missense mutations have been linked to adult parkinsonism and ADHD (attention deficit hyperactivity disorder) [79].

Clinical Presentation

Sepiapterin reductase deficiency (SRD) is implicated in the final step of BH4 synthesis. Friedman et  al. [73] reported the largest SRD series to date highlighting significant delay in diagnosis, with frequent misdiagnoses of cerebral palsy. Clinical features of SRD are axial hypotonia, motor and language delay, oculogyric crises, weakness, dystonia with diurnal fluctuation, parkinsonism, sleep disturbances, behavioral and psychiatric abnormalities [73]. Tremor of the limbs and head at rest, inhibited by skin contact and spontaneous movement, has been reported as presenting symptoms during infancy [74]. z

Metabolic Derangement, Genetics and Diagnostic tests

Central nervous system BH4 depletion contributes to deficient dopamine and serotonin biosynthesis, though with normal availability in peripheral tissues due to alternative metabolic pathways that bypass SR and therefore lack of hyperphenylalaninemia on newborn screening [73]. SRD is AR; different SPR pathogenic variants have been reported [73]. CSF shows elevated biopterin and sepiapterin (the hallmark of the disease) with normal neopterin levels, and very low HVA and 5-HIAA (. Table 30.3). Urine pterins are normal. The phenylalanine loading test is frequently positive. Fibroblast enzyme activity is reduced. Accumulation of sepiapterin in urine may be a potential biomarker. Consensus guidelines for the diagnosis and treatment of tetrahydrobiopterin deficiencies (GTPCH-I and SRD) have been recently published [75]. z

30.5.8Brain Dopamine-Serotonin Vesicular

Transport Defect Mutations in SLC18A2, encoding vesicular monoamine transporter-2 (VMAT2), have been described as an AR cause of severe infantile parkinsonism, autonomic instability, and developmental delay. VMAT2 transports dopamine and serotonin into synaptic vesicles. CSF neurotransmitter metabolites were normal, while depletion of platelet serotonin suggests that these blood cells can be model cells for some pathways relevant for neurological diseases [80]. Treatment with L-dopa caused worsening, whereas dopamine agonists (pramipexole) led to symptomatic improvement [81].

Treatment and Prognosis

For SRD, therapeutic approaches involve dopamine and serotonin precursor supplementation; most patients respond well to L-dopa and 5-hydroxytryptophan combination. Improvement in motor and sleep symptoms have been reported with the combination of L-dopa and carbidopa. Since dyskinesias may appear after treatment, a very low starting dose of L-dopa (around 0.5  mg/kg daily) with slow increment is advised. Regarding 5-HTP treatment (a precursor of serotonin), improvement in sleep, motor, and cognitive aspects have been reported (doses ranging from 1 to 6 mg/kg daily) [75]. Urinary sulphatoxymelatonin has been proposed as a biomarker of serotonin status in biogenic aminedeficient patients, including SRD [76].

30.5.9Other Defects

Other extremely uncommon monoamine defects are cytochrome b561 deficiency and norepinephrine transporter deficiency, both associated with orthostatic hypotension. AR b561 deficiency is associated with hypoglycemia and neurological and genitourinary dysfunction. Disrupted ascorbate recycling was suggested to cause functional DBH deficiency and defective norepinephrine synthesis from dopamine [82]. Norepinephrine transporter deficiency seems to be caused by heterozygous SLC6A2 gene mutations, with orthostatic hypotension and tachycardia [83].

563 Disorders of Neurotransmission

30.6

Synaptic Vesicle Disorders (see also 7 Chap. 44)

Synapses are equipped with a highly specialized protein machinery to ensure proper neuronal communication. At the presynaptic neuron, neurotransmitter molecules are packed into synaptic vesicles (SVs), ≈40 nm diameter lipid bi-layered organelles containing numerous proteins [84]. SVs are synthesized at the neuronal soma as SV precursors, and travel along the axon to generate mature SVs at synapses. At the synapse, mature SVs translocate to the active zone plasma membrane, where they dock via the interaction of the SV protein synaptobrevin 2 and the plasma membrane proteins SNAP25 and syntaxin 1, that form the SNARE (soluble N-ethylmaleimide–sensitive fusion factor [NSF] attachment protein receptor) complex (. Fig. 30.6). When an action potential travelling along the axon invades the presynaptic compartment, membrane depolarization occurs, and massive Ca2+ influx evokes an ultrafast SV fusion with the plasma membrane. The vesicular synaptic proteins, as well as the SV membrane, are then retrieved in an endocytotic process that can be clathrin-independent or -dependent [85]. Although mutations in genes that regulate biogenesis and axonal transport of the SVs may affect neurotransmission, disorders of the SV that have been reported to impair neuronal transmission are those involved in exocytosis and endocytosis (. Fig.  30.7). There are ~80 genetic defects linked to the SV [86]. We discuss disorders of the pre-synatic terminal (34), all of which impair SV transport, dynamics, and recycling, and therefore considered disorders of cellular trafficking (7 Chap. 44).

30.6.1Disorders of SV Exocytosis

Exocytosis of the SV is mediated by SNARE proteins and their key regulators that drive synaptic transmission as an integrated membrane fusion-machine. Syntaxin 1, SNAP25 and synaptobrevin/VAMP2 are the core of this molecular complex. Additional proteins such as MUNC18, MUNC13, synaptotagmins, and complexins regulate the SNARE proteins and therefore participate in the neurotransmission process (. Fig. 30.6). Together they constitute an assembly of proteins that interact as a single structure regulated by neuronal activity. The participation of lipids is also important to modulate membrane dynamics and protein interactions. z

Clinical Presentation

Mutations in syntaxin 1A (STX1A) and 1B (STX1B), SNAP25, VAMP2, synaptotagmin 1 (SYT1), MUNC18– 1 (also called STXBP1), UNC13A, RIMS1 and CPLX1 are considered SNAREopathies [87]. They present clinically as neurodevelopmental encephalopathies starting the first year of life, with a constellation of symptoms including global developmental delay, epilepsy (some as severe epileptic encephalopathies), movement disorders (typically hyperkinetic, e.g. dyskinesias, stereotypies), and neuropsychiatric signs including autism spectrum. These symptoms may overlap and present as a combination resulting in a spectrum of “synaptopathies”. Other less common signs are neuromuscular dysfunction, ataxia, and ocular abnormalities such as cone-rod dystrophy in RIMS1 mutations (. Table  30.4). The most prevalent are MUNC18-1/STXBP1 with 250+ cases reported [88]

Synaptic Vesicle Neurotransmitters SYNTAXIN NFS

MUNC18

SYNAPTOTAGMIN Synaptobrevin

MUNC13

Ca2+

SNAP-25

CPLX 1/2 RIMS 1/2

. Fig. 30.6 Synaptic Vesicle exocytosis. SNARE proteins establish interactions between them addressed to synaptic vesicle priming, docking and neurotransmitter release. Syntaxin-1, synaptobrevin and SNAP-25 form the membrane fusion complex. Syntaxin-1,

Munc18–1, and 13, NSF, SNAP-25, RIMS and CPLX contribute to exocytosis through membrane fusion. Synaptotagmin-1 acts as a calcium sensor trigging fast neurotransmitter release

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Uncoating: clathrin, auxilin (DNAJC6), Hsc-70

Transmitter loading: transporters (VMAT2), proton pumps

Budding: dynamin1 clathrin, endodynamin, amphiphysin, endophilin, synaptojanin 1, WASP

RAB Reserve pool: synapsins, actin

VPS PARK2

Mobilisation: CaMKII, synapsins

30

PINK1

SLC

18A

2

DJ1 Docking: GTPbinding proteins (Rab), SNARES

Tethering/Priming: SNAREs, NSF, SNAPS, Complexin 1, 2, Tomosyn, CAPS, SV2A, Syntaphilin, Rab3a, Doc2. STXBP1, UNC13A, RIMS1,2, SCNA, VAMP2, SNAP25, SYN1, SYN2, STX1B, NAPB

Ca2+

Fusion, Calcium sensor: Synaptotagmin: SYT1

Coating: clathrin, GAK, AP2, AP-180, Synaptotagmins, TPI1 Synaptobrevin, Epsin, Eps-15, Endophilin, NSF, SNAPS, Syntaphilin.

. Fig. 30.7 Synaptic Vesicle cycle disorders at the pre-synaptic terminal. Synaptic Vesicles (SV) are filled with neurotransmitters and recruited to sites within the active zone in a process called docking. These SV are primed for release. The rise in cytosolic calcium that occurs after an action potential triggers the opening of a fusion pore between the SVs and plasma membrane. Neurotransmitters are then released. The empty vesicle can be recovered by different ways: (1) a direct reclosing of the fusion pore and reformation of the vesicle

(“kiss and run”); (2) complete fusion followed by clathrin-dependent endocytosis, removal of the clathrin coat, and return of the vesicle to the releasable pool; (3) fast, non-clathrin mediated endocytosis: the endocytosed vesicle fuses with an endosome and mature vesicles are formed by budding from the endosome. Proteins marked in bold letters cause SV disorders and are related to their specific action in the different biological processes of the SV cycle including mitophagy and autophagy

and STX1B ~50 patients described [89]. There are other genes involved in exocytosis that may alter neurotransmitter homeostasis by interacting with SNARE proteins or through other mechanisms incompletely understood (. Table 30.4). This is the case of NAPB, PRRT2, SV2A, SYN1, SYN2, GS27 or GOSR22, SYT14, and SNCA. PRRT2 mutations are a major cause of paroxysmal movement disorders and migraine. SNCA mutations lead to late-onset Parkinson disease and dementia [90].

brane fusion and a higher number of excitatory postsynaptic currents leading to a hypertransmission state. Little has been reported about biomarkers in these diseases, including studies of CSF neurotransmitter levels. In a personal observation (García-Cazorla), 5-HIAA and GABA levels tended to be high in some STXBP1 patients, although normal in others; functional studies were not performed. Other -omic approaches may contribute to reveal biomarkers in the future.

z

Metabolic Derangement and Genetics

In general, these diseases are caused by heterozygous missense loss of function mutations, although gain of function has been described in the only reported case of UNC13A and some STXBP1 cases [87]. Accordingly, these patients have an increased probability of mem-

z

Diagnostic tests, treatment and prognosis

Clinical diagnosis is based on the neurological features and confirmation requires DNA sequencing. Treatment is symptomatic. Regarding prognosis, STXBP1 patients may progress towards parkinsonism over time. Syntaxin-binding protein 1 is a chaperone of alpha-

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. Table 30.4

Synaptic vesicle disorders and neurological manifestations

Genetic defect and encoded protein [Inheritance] MIM number

Biological function

Other additional Neurological and extraNeurological signs

NEURODEVELOPMENTAL ENCEPHALOPATHIES WITH EPILEPSY AS PREDOMINANT NEUROLOGICAL MANIFESTATION. Genes responsible of ID/ASD as prominent neurological manifestation are also very likely to produce epilepsy (SYN1, SYN2) NAPB (N-ethylmaleimide-sensitive factor attachment protein, beta) [AR]

SNARE complex dissociation and recycling: synaptic vesicle docking. EXOCYTOSIS and ENDOCYTOSIS

Early epileptic encephalopathy (multifocal seizures), progressive microcephaly, profound global developmental delay, hypotonia, limb tremulousness and stereotypies

PRRT2 (proline-rich transmembrane protein 2) [AD]

SNARE protein interaction. Regulates EXOCYTOSIS, possibly via interaction with SNAP25.

Benign familial infantile epilepsy, infantile convulsions and choreoathetosis and paroxysmal kinesigenic dyskinesia, migraine, hemiplegic migraine, non-syndromic ID.

SNAP25 (synaptosomal-associated protein, 25-Kd) [AD]

SNARE protein. EXOCYTOSIS

Early epilepsy and developmental delay, hypotonia, ID. Polymorphisms have been related to neuropsychiatric disorders

STXBP1 (syntaxin-binding protein-1, Munc18-1) [AD]

SNARE protein. EXOCYTOSIS

Multiple forms of epilepsy, non-syndromic ID without epilepsy, movement disorders (tremor, ataxia, hyperkinetic movements). Autistic features.

STX1B (syntaxin1B) [AR]

SNARE protein. EXOCYTOSIS

Febrile seizures with or without epilepsy, myoclonic astatic epilepsy.

SV2A (synaptic vesicle glycoprotein 2A) [AD]

SV protein. Regulates EXOCYTOSIS and vesicle fusion by maintaining the SV readily releasable pool

Refractory tonic and myoclonic seizures, microcephaly, growth retardation, optic atrophy, severe hypotonia. Increased T2 signal white matter, thin corpus callosum.

DNM1 (dynamin1) [AD]

SV cycle, Clathrin-mediated ENDOCYTOSIS.

Early onset epileptic encephalopathy, LennoxGastaut, West syndrome, ID, hypotonia. Earlyonset parkinsonism

TPI1 (triosephosphate isomerase 1) [AR]

SV cycle. ENDOCYTOSIS.

Hemolytic anemia, episodic seizures, periodic dystonia, axonal neuropathy and psychomotor delay (7 Chap. 7)

CPLX1(complexin 1) [AR]

SNARE protein. EXOCYTOSIS

Myoclonic epilepsy, often migrating, severe hypotonia and encephalopathy

DISEASES WITH INTELLECTUAL DISABILITY and AUTISM as the predominant neurological manifestation (see also VAMP2 and RIMS1) SYN1(synapsin1) [XLD, XLR] and SYN2 (synapsin 2) [AD]

Regulation of Neurotransmitter release. EXOCYTOSIS

ASD and epilepsy

UNC13A or MUNC13–1 (Protein unc-13 homolog A) [AD]

SV docking/priming. EXOCYTOSIS

Dyskinetic movement disorder, developmental delay, and autism.

DISEASES WITH MOVEMENT DISORDERS as the predominant neurological manifestation PARKINSONISM (Dystonia-Parkinsonism) RAB39B (Ras-related protein Rab-39B) [XLR]

Small GTPases. ENDOCYTOSIS

Waisman Syndrome: delayed psychomotor development, intellectual disability, and early-onset Parkinson’s disease (PD). Probable neurodegeneration.

LRRK2 (Leucine-rich repeat serine/ threonine-protein kinase 2) [AD]

ENDOCYTOSIS and recycling.

Late onset Parkinson Disease (sporadic and dominant) (PARK8).

SCNA (synuclein alpha) [AD]

SV tethering. EXOCYTOSIS Synaptic protein distribution and SV release.

Late onset Parkinson Disease, Dementia (continued)

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. Table 30.4

(continued)

Genetic defect and encoded protein [Inheritance] MIM number

Biological function

Other additional Neurological and extraNeurological signs

SYNJ1 (synaptojanin 1) [AR]

SV cycle, ENDOCYTOSIS and recycling. Phosphoinositide phosphatase protein involved in SV recycling through lipid metabolism.

Pediatric and Juvenile Parkinsonism, dystonia, and cognitive deterioration. May response transiently to L-dopa. Severe early onset epileptic encephalopathy is other form of presentation. Low CSF HVA levels have been described.

DNM1L (dynamin-like protein 1) [AR]

SV cycle ENDOCYTOSIS. Required for formation of endocytic vesicles.

Severe infantile parkinsonism with tremor in the neonatal period Low HVA in CSF, and findings consistent with lactic encephalopathy might be found. Severe early onset epileptic encephalopathy is other form of presentation

VPS35 (vacuolar protein sorting 35) [AD] #614203; VPS13C. [AR]

SV cycle. endosome-trans-golgi trafficking and membrane-protein recycling. ENDOCYTOSIS

VPS35: Tremor-predominant, L-dopa-responsive parkinsonism. VPS13C. Early-onset parkinsonism

PINK1 (Serine/threonine-protein kinase PINK1, mitochondria) [AR]

SV recycling. Mitochondrial protein. SV mobilization and autophaghy.

Early-onset Parkinson’s disease.

DJ1 or PARK7 (Protein/nucleic acid deglycase DJ-1) [AR]

SV recycling. Interacts with lipid phosphatase to inhibit PINK1

Autosomal recessive early onset Parkinson’s disease.

PRKN or PARK2 (parkin) [AR]

SV recycling, ENDOCYTOSIS. Interacts with RAB, VPS. Mitophagy

Juvenile Parkinson’s disease.

ATP13A2 (Cation-transporting ATPase 13A2) and ATP6AP2 (cation transportin ATPase 6, accessory protein 2). [XLR]

SV endosomal pathway. Cation pump of cell membranes. ENDOCYTOSIS

ATP13A2: Kufor-Rakeb syndrome: autosomal recessive hereditary parkinsonism with dementia, and juvenile onset. Some forms of spastic paraplegia. ATP6AP2: X-linked ID, epilepsy, and parkinsonism.

GAK (cyclin G-associated kinase) susceptibility gene

SV endosomal pathway. ENDOCYTOSIS

Increases the risk of Parkinson’s disease.

DNAJC12 (Heat shock cognate 71 kDa protein) [AR]. DNAJC13 (DnaJ homolog subfamily C member 13) [AD]. DNAJC6 (auxilin) [AR]. DNAJC26, DNAJC10 (both risk factors), DNAJC5 o CSPalpha [AD]

SV cycle, ENDOCYTOSIS and recycling.Co-chaperone family member. DNAJC13 is involved in autophagy

DNAJC12: HVA and 5-HIAA depletion with hyperphenylalaninemia.Non progressive DNAJC13: Late-onset Parkinsonism associated with Lewy body pathology. DNAJC6: parkinsonism-dystonia starting from 7 years onwards. Partial response to L-Dopa. Low HVA levels in CSF. DNAJC26: early-onset parkinsonism. DNAJC26 and DNAJC10: sporadic Parkinson Disease; DNAJC5: adult cerebral lipofuscinosis

CLTC (Clathrin). [AD]

SV cycle, ENDOCYTOSIS

ID, hypotonia and early parkinsonism

30

OTHER ABNORMAL MOVEMENTS (Neurodevelopmental encephalopathies with epilepsy, and ID/ASD have also hyperkinetic movements) GS27 or GOSR2 (Golgi SNAP receptor complex 2) [AR]

SV cycle, SNARE protein Indirectly regulates EXOCYTOSIS

Early-onset ataxia in patients with progressive myoclonic epilepsy. Mild cerebral atrophy. Very mild cognitive impairment. Epilepsy

SYT14 (synaptotagmin 14) [AR]

SV cycle: EXOCYTOSIS

Childhood onset psychomotor delay and progressive spinocerebellar ataxia

VAMP2 (Vesicle-associated membrane protein 2) [AD]

SV cycle: SNARE protein EXOCYTOSIS

Neurodevelopmental encephalopathy with hypotonia, ID, autistic features and hyperkinetic movements.

OTHER symptoms: RIMS1(SNAREopathy, AD, EXOCYTOSIS): cone-rod dystrophy, one family reported with high intellectual quotient and ASD ID intellectual disability, AD autosomal dominant, AR autosomal recessive, ASD autism spectrum disorder, XL X-linked, XLR X-linked recessive, XLD X-linked dominant

567 Disorders of Neurotransmission

synuclein and could contribute to its misfolding and aggregation [91].

30.6.2Disorders of SV Endocytosis

The membranes of SVs after neurotransmitter release are retrieved via recycling mechanisms and are regenerated as SVs after refilling with neurotransmitters (. Fig.  30.7). Ultrafast endocytosis is clathrinindependent and mediates direct recycling of SVs very rapidly. Clathrin mediated endocytosis is thought to be one of the major mechanisms of endocytosis. Clathrin covers vesicles by polymerization of multiple clathrin molecules. Several proteins and phosphoinositides participate in this endocytic process.

z

References 1.

z

Clinical Presentation

Mutations in LRRK2, ATP13A2, ATP6AP2, diverse DNAJC genes (. Table 30.4), SYNJ1 (synaptojanin-1), Vps13c, Vps35, Rab39B, GAK, CLTCL1 (clathrin), DNM1L, DJ1 or PARK7, PRK2 or PARK2 (Parkin), PINK1 and TPI1 are endocytic-related SV diseases. Parkinsonism is the most common clinical manifestation. Some genes are linked to pediatric and juvenile parkinsonism: CLTCL1, RAB39B, SYNJ1, DNM1L [92], Vps13c, PINK1, DJ1, PRK2, ATP13A2, ATP6AP2, DNAJC12 and 6 [86, 90, 93]. Early-onset parkinsonism is often associated with developmental delay, ID, and other movement disorders. Other genes produce classical late-onset Parkinson disease: LRRK2, Vps35, DNAJC subtypes 10, 13, 26. DNAJC5 (CSP-alpha) mutations cause adult-onset cerebral lipofuscinosis and may present with parkinsonism (7 Chap. 44). Clathrin (CLTC) mutations may cause intellectual disability as a single sign and associate with early hypotonia and refractory epilepsy. SYNJ1 can also present as severe early epileptic encephalopathy. TPI1 (triosephosphate isomerase 1) deficiency causes hemolytic anemia (7 Chap. 7) [86, 93] (. Table 30.4). z

2.

3.

4.

5.

6.

7.

8.

Metabolic Derangement and Genetics

These disorders affect diverse steps of the trafficking processes involved in clathrin-dependent endocytosis (. Fig. 30.7), including clathrin removal of coated vesicles (such as in auxilin/DNAJC6 mutations), endosometrans-golgi trafficking (vacuolar protein sorting), membrane-protein recycling, and autophagy (parkin). Synaptojanin 1 (SYNJ1) is a phosphoinositide phosphatase protein involved in SV recycling through lipid metabolism. ATP13A2 and ATP6AP2 genes encode flippases involved in calcium pump (see also traffic Chapter). Inheritance is diverse: AD, AR and X-linked (SYN1, Rab39B).

Diagnostic tests, treatment, and prognosis

Clinical diagnosis is based on the neurological features and confirmation requires DNA sequencing. Some disorders have been described to have low levels of HVA in the CSF: DNAJC6 [94], CLCT [95, 96], SYNJ1, and may respond, at least partially or transiently, to L-dopa treatment, mimicking dopamine biosynthesis defects. VPS35 also responds to L-dopa. The great majority of these disorders have a neurodegenerative course. However, in most of them only few patients have been described and the long-term outcome is unknown.

9.

10.

11.

12.

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571

Disorders of Peptide and Amine Metabolism Ron A. Wevers, Ertan Mayatepek, and Valerie Walker Contents 31.1

Disorders of Trimethylamine Metabolism – 572

31.1.1

Trimethylaminuria (Fish Malodour Syndrome) – 572

31.2

Disorders of Choline Metabolism – 575

31.2.1 31.2.2

Dimethylglycine Dehydrogenase Deficiency – 575 Sarcosine Dehydrogenase Deficiency – 576

31.3

Disorders of Glutathione Metabolism – 578

31.3.1

γ-Glutamylcysteine Synthetase Deficiency (Synonym: Glutamate-Cysteine Ligase Deficiency) – 578 Glutathione Synthetase Deficiency – 578 γ-Glutamyl Transpeptidase Deficiency (Synonym: Glutathionuria) – 579 Dipeptidase Deficiency (Synonym: Cysteinylglycinuria) – 580 5-Oxoprolinase Deficiency – 580 Glutathione Reductase Deficiency – 581 Glutathione Peroxidase 4 Deficiency (Synonym: Spondylometaphyseal Dysplasia, Sedaghatian Type) – 581 NRF2 Superactivity (Synonym: Immunodeficiency, Developmental Delay, and Hyperhomocysteinaemia) – 581

31.3.2 31.3.3 31.3.4 31.3.5 31.3.6 31.3.7 31.3.8

31.4

Other Disorders of Peptide Metabolism – 582

31.4.1 31.4.2

Prolidase Deficiency – 582 X-Prolyl Aminopeptidase 3 Deficiency (Synonym: Nephronophthisislike Nephropathy Type 1) – 582 Serum Carnosinase Deficiency (Synonym: Carnosinemia) – 583 Homocarnosinosis – 583

31.4.3 31.4.4

References – 583

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_31

31

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R. A. Wevers et al.

Intestine

Liver

Lecithin

Choline Bacteria

1 FMO3

TMA

31

Bacteria

TMA

TMA-N-Oxide

Urine

2

TMA-N-Oxide (fish)

. Fig. 31.1 Metabolism of trimethylamine. FMO3 flavin-containing monooxygenase 3, TMA trimethylamine, bacterial choline TMAlyase, bacterial TMA-N-oxide reductase. The enzyme defect in trimethylaminuria is indicated by a solid blue bar

Trimethylamine Metabolism Trimethylamine (TMA) is a tertiary amine, a strong base (pKa 9.8), and in its non-protonated free form is volatile and malodorous at ambient temperatures. It is a bacterial metabolite produced in the colon by the action of a wide range of resident micro-organisms on dietary components: free and lecithin-bound choline, trimethylamine-N-oxide (TMAO) in salt water fish, carnitine and betaine. The generated TMA is readily absorbed from the colon and transported to the liver where more than 90% is oxygenated by microsomal flavin-containing monooxygenase 3 (FMO3) which requires FAD as a prosthetic group. The product is TMAO which is water soluble, non-odorous and is excreted in urine (. Fig.  31.1). FMO3 also catalyses oxygenation of a broad range of drugs [1]. The abundance of liver FMO3 varies with ethnicity and between individuals. Production of FMO3 commences within days of birth but is low throughout childhood. Expression is reduced peri-menstrually, and activity is inhibited by sulfur-containing glucosinolates present in brassica vegetables and by nitric oxide mediated S-nitrosylation. (Reviewed [1–6]).

kIntroduction

Trimethylamine (TMA) is a volatile tertiary amine which smells of decaying fish. It is a bacterial metabolite which is produced by anaerobes resident in the

human colon from choline (free and lecithin-bound), trimethylamine-N-oxide (TMAO) in salt water fish, carnitine and betaine. Catabolism of choline occurs within the mitochondria and involves the sequential removal of two methyl groups by dimethylglycine dehydrogenase (DMGDH) and sarcosine dehydrogenase (SDH). Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine and glycine. It is ubiquitous in the eukaryotic organism and plays a role in many fundamental cellular processes. The chapter describes metabolic disorders in trimethylamine metabolism, choline metabolism, the glutathione cycle and peptide metabolism.

31.1

Disorders of Trimethylamine Metabolism

31.1.1Trimethylaminuria (Fish Malodour

Syndrome) z

Clinical Presentation

Trimethylaminuria (TMAU) is a metabolic disorder in which TMA accumulates in the body and is excreted in the breath, sweat, urine and vaginal secretions. This causes an unpleasant, pervasive body odour of decaying fish, detectable by most of the population at very low TMA concentrations. Inherited TMAU is pan-ethnic,

573 Disorders of Peptide and Amine Metabolism

with autosomal recessive inheritance. TMAU does not cause physical problems, but frequently impacts seriously on the life of the individual. Affected children may be ridiculed or bullied, become isolated, depressed and have poor educational achievement. Older individuals have low self- esteem, obsessional behavior, become socially isolated and have problems in forming relationships [2–6]. Four forms of TMAU can be recognized [1, 4]: (i) A severe form presents with persisting malodour, generally from infancy or early childhood, sometimes later, which is exacerbated by sweating and menstruation. An estimated incidence is 1  in 40,000  in the UK, but it is probably under-diagnosed [7]. (ii) Mild/moderate TMAU is more common. The incidence is unknown. It presents with episodic malodour starting at any age, often at puberty or peri-menstrually. (iii) Transient TMAU has occurred in preterm neonates when fed on choline-supplemented milk formulae. This resolved with withdrawal of the supplement and was attributed to the normal neonatal FMO3 deficiency coupled with a heavy TMA substrate load. Although transient TMAU has been reported in infants and young children, this resulted from low physiological expression of FMO3 coupled with polymorphisms of the gene [7, 8], and there may be a life-long risk for recurrence. (iv) Increased excretion of TMA as an occasional consequence of underlying disease. This may contribute to malodour in severe chronic liver disease and rarely viral hepatitis, advanced renal failure with bacterial overgrowth in the small intestine, urine infection with TMAO degrading bacteria, anatomical abnormalities of the intestine such as blind loops with abnormal bacterial colonisation, vaginitis and gingivitis [3, 4]. z

Metabolic Derangement

TMAU occurs when the quantity of TMA absorbed from the diet exceeds the enzyme capacity of hepatic FMO3. The quantity of TMA depends on the amount and form of TMA precursors ingested and the relative abundance of TMA-producing bacterial species. Enzyme capacity is reduced by mutations of FMO3, physiologically decreased expression, or by chemical inactivation of FMO3. In severe TMAU genetic deficiency of FMO3 is the over-riding factor. In mild/moderate TMAU the aetiology is multifactorial, with variable contributions from decreased FMO3 production (genetic or physiological) and/or activity, and/or substrate overload (excess dietary precursors or an abnormal gut microflora). Malodour develops intermittently when an increase in one or more of the risk factors disrupts the finely balanced detoxification system [1–4, 6]. Many of the drugs oxygenated by FMO3 in vitro are also extensively metabolised by the hepatic cytochrome

P450 system or detoxified by other routes such as glucuronidation. Exceptions include benzydamine, itopride, ranitidine, cimetidine, ethionamide and sulindac sulfide, the active sulindac metabolite. Genetic variants of FMO3 decreased oxygenation of benzydamine, sulindac sulfide & methimazole in vivo [1]. There is an on-going controversy about whether raised circulating TMAO increases the risk for cardiovascular disease and other life-style illnesses. There is no evidence that a low TMAO in TMAU is protective [1]. z

Genetics

The FMO3 gene is highly polymorphic. Up to August 2020, 231 transcript variants were recorded on a shared data base (7 https://databases.lovd.nl/shared/genes/ FMO3; accessed 25.03.2022). Whole exome sequencing (WES) has extended the list [9]. More than 40 variants cause severe TMAU. Most of these are mis-sense, others being nonsense or small deletions causing a frame-shift mutation [1, 4, 7, 9, 10]. Most of the other variants are single nucleotide polymorphisms (SNPs). A few of these are common (frequency >1%), but most are rare. Of the few which have been investigated, most have little or no effect on FMO3 activity [1, 9]. Two SNPs (p.Glu158Lys) and (p.Glu308Gly) present in cis on the same allele reduce FMO3 activity in vitro. This allele is common, with homozygosity estimated at 2–5% and 4% in German & Irish populations, respectively. Whilst this is seldom manifest, mild TMAU may occur in individuals who are homozygous for the allele, or compound heterozygous for the variant and an allele with a severe mutation, when TMA absorption is excessive [8, 10]. WES has raised the possibility that polymorphisms in genes other than FMO3 may disturb TMA metabolism. Variants with predicted pathogenicity were identified in genes in oxido-reductase pathways in individuals with biochemically substantiated TMAU but no detectable FMO3 mutations [11]. z

Diagnostic Tests

Poor body and oral hygiene, gingivitis, vaginosis and urine infection are excluded and the possibility of another malodorous inborn error considered. Urine analysis is the front-line diagnostic approach. This should not be undertaken at the onset of, or during, menstruation. Urine is collected into containers containing 2  ml 6M HCl (urine pH  2.0) to convert free TMA to non-volatile salt and frozen until analysis by proton NMR spectroscopy or mass spectrometric procedures for TMA, TMAO and total TMA [4, 11]. A random urine sample is collected if the odour is obvious. If not, samples should be collected for 2–12  h or for a

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timed 6–8  h save, after eating 300  g marine fish or a choline-rich meal (2 eggs +400 g baked (haricot) or soya beans), or after drinking 5 g choline in orange juice. The test should be repeated if the results are negative or border-line. Malodour may be detectable at TMA concentration >10  μmol/L; 18–20  μmol/mmol creatinine [2]. To estimate FMO3 capacity, free TMA excreted as a percentage of total TMA excreted is calculated from the ratio of TMA to TMA + TMAO. Ratio 0–9% not affected; 10–39% mild/ moderate TMAU (mild 10–19%, moderate 20–39%); ≥40% severe TMAU [6, 10]. Genetic testing (sequencing the entire coding region and intron/exon boundaries of FMO3) has been advised if the ratio is ≥10% [7]. Although its additive value in severe cases has been questioned [4], it provides firm evidence of the diagnosis which may accelerate decisions about schooling and psychological support, and enables early testing of asymptomatic siblings. Prenatal diagnosis is possible if the family mutation is known, but is not indicated. In those with mild or intermittent symptoms, knowing the genetic contribution may help understanding and management in some cases [4, 10]. z

Treatment

Careful explanation, with genetic counselling if indicated, provides insight. Severely disturbed patients may need psychiatric help. Patients should be warned about increased risk for malodour peri-menstrually, with systemic infections and sweating, and advised about hygiene: low pH soaps (pH  5.5–6.5) to reduce TMA volatility, antiperspirants, light clothing and good ventilation in warm environments, regular laundering of clothes, not to take non-prescribed food supplements such as fish oil capsules, carnitine and health foods with high lecithin & choline and to report possible adverse reactions to prescribed medications promptly. Dietary management aims to reduce the TMA load: avoidance of marine fish and other sea foods, foods rich in choline(egg yolks, liver, kidneys) and lecithin (brassicas [brussels sprouts, broccoli, cabbage, cauliflower], soy beans and other legumes, rapeseed and sunflower oils). Brassicas are also contra-indicated because they inhibit FMO3 [2]. Choline restriction increases folate requirement, and supplements should be given. Moderate restriction is tolerable and often effective in mild/moderate TMAU.  There are published recommendations for more choline- restrictive diets, but these must be supervised by a dietitian because of the risks to the brain and liver [6]. Choline should not be restricted in pregnancy, when breast feeding or in infancy. Riboflavin to activate FMO3 may reduce and even normalise urine TMA

excretion of those with residual FMO3 function. For special occasions, TMA production by the gut microflora may be reduced by short courses of antibiotics (neomycin or metronidazole), or lactulose to reduce intestinal transit time, but these should not be taken continuously [4, 6]. Probiotics are not of proven benefit [3]. Ingestion of large amounts of white button mushrooms (Agaricus bisporus) and of chlorophyllin decreases TMAO reducing Firmicutes. Activated charcoal and chlorophyllin reduced urine TMA and malodour in one study. None of the above supplements have been systematically evaluated. A novel approach to reducing odour may be to promote diffusion of nonprotonated TMA into the acidic core of synthetic vesicles applied as a skin gel [12]. Catabolism of Choline The catabolism of choline (. Fig. 31.2) occurs within the mitochondria and involves the sequential removal of two methyl groups by dimethylglycine dehydrogenase (DMGDH) and sarcosine dehydrogenase. These are related flavin enzymes with covalently linked FAD which use folate as co-factor. The methyl groups from dimethylglycine and sarcosine are transferred to tetrahydrofolate (THF), forming 5,10-methylene THF. The electrons are transferred from FAD to electron transfer flavoprotein (ETF) and thence to the mitochondrial respiratory chain.

Phosphocholine

Choline

Acetylcholine

Betaine aldehyde

Homocysteine

Methionine

Respiratory chain

FAD ETF ETF-QO

Betaine N,N-Dimethylglycine Dimethylglycine dehydrogenase FAD Sarcosine Folate Sarcosine dehydrogenase Glycine

. Fig. 31.2 Catabolism of choline. ETF, electron transfer flavoprotein; ETF-QO, ETF-ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide. The enzyme defect in dimethylglycine dehydrogenase deficiency is indicated by a solid bar. Sarcosine dehydrogenase converts sarcosine to glycine

575 Disorders of Peptide and Amine Metabolism

31.2

Disorders of Choline Metabolism

31.2.1Dimethylglycine Dehydrogenase

Deficiency z

Clinical Presentation

An adult patient with dimethylglycine dehydrogenase deficiency was investigated for an abnormal body odour resembling fish, which was present from 5 years of age, was increased by stress and effort and caused him major social, psychological and professional problems [13]. The patient had chronic muscle fatigue with persistent elevation of creatine kinase (CK) to around four times normal. Intelligence was normal. Since this first description one further patient with this defect has been reported [14]. This concerns an 11  months old male child with DMGDH mutations hospitalised with an upper respiratory tract infection. There was no malodour and CK was 10 times the upper reference range limit. High CK persisted after recovery from the infection. The diagnosis was accomplished using Whole Exome Sequencing. More patients are required to fully understand the clinical presentation and phenotype as well as the clinical significance of DMGDH defects [15]. z

Metabolic Derangement

Dimethylglycine dehydrogenase (DMGDH) is involved in choline- and in 1-carbon metabolism (. Fig. 31.2). It catalyzes the oxidation of the tertiary amine N,Ndimethylglycine and the formation of 5,10-methylene tetrahydrofolate. The crystal structure of the enzyme has been published [16]. Dimethylglycine accumulated in body fluids of the adult patient (around 100-fold in plasma and 20-fold in urine) explaining the malodour [13]. Interestingly, data from Magnusson et al. are consistent with a possible causal role of dimethylglycine deficiency in diabetes development [17]. z

Genetics

The DMGDH gene is on chromosome 5q12.2-12.3 [18]. Sequence analysis suggests that the genes for DMGDH and SARDH (sarcosine dehydrogenase) have diverged from a common ancestor. The affected patient is homozygous for an inactivating point mutation (326 A>G leading to H109R at the protein level) of the DMGDH gene. From expression studies, this mutated gene codes for a stable protein lacking enzyme activity [19]. The mutated enzyme has a reduced affinity for FAD, a 27-fold decrease in specific activity and a 65-fold increase in Km. This explains the effect on

the pathway and the pathogenicity of the mutation [20]. The second patient had a homozygous mutation in a highly conserved nucleotide (c.101+2 T>C) [14]. The paper does not mention body fluid metabolite levels. DMGDH deficiency is inherited as an autosomal recessive trait. z

Diagnostic Tests

The diagnosis can be made by exome sequencing (as in the second patient) and at the metabolite level. Against the background of the seemingly mild clinical features of DMGDH deficiency, most future cases will be discovered through whole exome- or genome sequencing. Functional confirmation of the defect can be accomplished by finding raised levels of dimethylglycine in plasma and urine. To this end proton NMR spectroscopy can be used; NMR has the advantage that it can also diagnose trimethylaminuria, another inherited cause of a fishy odour [13; see under 31.1]. Targeted techniques to measure dimethylglycine have been described (GC [21], LC-MS/MS [22], LC-colorimetry [23]) and an untargeted metabolomics strategy may also qualify. Dimethylglycine is currently not detected in routine screening methods for inborn errors of metabolism. Reference values for dimethylglycine are: 5 Plasma: healthy adults: 1–5 μmol/L 5 Urine: 5 infants (birth to 2 months): A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function. Hum Mutat 40(3):299–309. https://doi.org/10.1002/humu.23693 Peter VG, Quinodoz M, Pinto-Basto J et al (2019) The Liberfarb syndrome, a multisystem disorder affecting eye, ear, bone, and brain development, is caused by a founder pathogenic variant in thePISD gene. Genet Med 21(12):2734–2743. https://doi.org/10.1038/s41436-019-0595-x Horibata Y, Ando H, Sugimoto H (2020) Locations and contributions of the phosphotransferases EPT1 and CEPT1 to the biosynthesis of ethanolamine phospholipids. J Lipid Res. https://doi.org/10.1194/jlr.RA120000898 Steenbergen R, Nanowski TS, Beigneux A et  al (2005) Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J Biol Chem 280(48):40032–40040. https://doi.org/10.1074/jbc. M506510200 Sengers RC, Trijbels JM, Willems JL et al (1975) Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated with lactic acidosis after exercise. J Pediatr 86(6):873–880. https://doi.org/10.1016/s0022-3476(75)80217-4 Mayr JA, Haack TB, Graf E et al (2012) Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet 90(2):314–320. https://doi.org/10.1016/j. ajhg.2011.12.005 Haghighi A, Haack TB, Atiq M et  al (2014) Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients. Orphanet J Rare Dis 9:119. https://doi.org/10.1186/ s13023-014-0119-3 Beck DB, Cusmano-Ozog K, Andescavage N et  al (2018) Extending the phenotypic spectrum of Sengers syndrome: congenital lactic acidosis with synthetic liver dysfunction. Transl Sci Rare Dis 3(1):45–48. https://doi.org/10.3233/TRD180020 Aldahmesh MA, Khan AO, Mohamed JY et al (2012) Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus. Hum Mutat 33(6):960–962. https://doi.org/10.1002/humu. 22071 Sarig O, Goldsher D, Nousbeck J et al (2013) Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1. Am J Med Genet A 161A(9):2204–2215. https://doi.org/10.1002/ajmg.a.36059 Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S et al (2017) Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases. Ann Neurol 82(6):1004–1015. https://doi. org/10.1002/ana.25110

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dynamics. Biochimie 125:250–258. https://doi.org/10.1016/j. biochi.2015.09.005 Sasaki T, Takasuga S, Sasaki J et  al (2009) Mammalian phosphoinositide kinases and phosphatases. Prog Lipid Res 48(6):307–343. https://doi.org/10.1016/j.plipres.2009.06.001 Shears SB, Ganapathi SB, Gokhale NA et al (2012) Defining signal transduction by inositol phosphates. Subcell Biochem 59:389–412. https://doi.org/10.1007/978-94-007-3015-1_13 Staiano L, De Leo MG, Persico M et  al (2015) Mendelian disorders of PI metabolizing enzymes. Biochim Biophys Acta 1851(6):867–881. https://doi.org/10.1016/j.bbalip.2014.12.001 Volpatti JR, Al-Maawali A, Smith L et al (2019) The expanding spectrum of neurological disorders of phosphoinositide metabolism. Dis Model Mech 12(8). https://doi.org/10.1242/ dmm.038174 Thompson K, Bianchi L, Rastelli F et al (2022) Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease. HGG Adv 3(2):100097. https://doi.org/10.1016/j.xhgg.2022.100097. eCollection 2022 Apr 14 Lee RG, Balasubramaniam S, Stentenbach M et al (2022) Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease. Hum Mol Genet Feb 11:ddac040. https://doi. org/10.1093/hmg/ddac040

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Inborn Errors of Lipoprotein Metabolism Presenting in Childhood Uma Ramaswami and Steve E. Humphries Contents 36.1

Disorders of Low Density Lipoprotein Metabolism – 679

36.2

Disorders of Triglyceride (TG) Metabolism – 688

36.3

Disorders of High Density Lipoprotein Metabolism – 689

36.4

Disorders of Sterol Storage – 690

36.5

Conclusion – 690 References – 690

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_36

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Bile Acid Cholesterol Liver

LDLR

LDLR

LDL

Enterohepatic circulation

LDLR SR-B1 LRP1

Peripheral Tissues Free Cholesterol

Dietary Fat

HTGL

IDL

CM CMR

Reverse Cholesterol Transport

VLDL LCAT LPL

Blood vessel

LPL

Blood vessel

LCAT

CETP HDL LCAT CETP Cholesteryl Ester Transfer Protein HTGL Hepatic triglyceride lipase LCAT lecithin cholesterol acyltransferase LPL lipoprotein lipase

36

HDL High density lipoprotein LDL low density lipoprotein IDL Intermediate density lipoprotein VLDL very low density lipoprotein

. Fig. 36.1 Schematic diagram of lipid and lipoprotein metabolism. This figure demonstrates five major lipoprotein classes. These are chylomicrons, very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low-density lipoprotein (LDL) and highdensity lipoprotein (HDL). Chylomicrons are triglyceride-rich particles produced by the intestine. They are the largest of the lipoproteins. Their primary function is to transport dietary triglyceride and choles-

Lipid and Lipoprotein Metabolism (. Fig. 36.1) Very low-density lipoprotein (VLDL) particles are relatively large particles, which are produced in the liver. The function of VLDL is to transport endogenously synthesized triglycerides (TG) and cholesterol to the peripheral tissue. Intermediate density lipoproteins (IDL) are created with the metabolism of VLDL by lipoprotein lipase. IDL particles may be removed by the liver or are converted to low-density lipoprotein (LDL) particles by hepatic triglyceride lipase. LDL particles contain ~45% cholesterol and they are the major carrier of cholesterol to peripheral tissues. LDL particles are heterogeneous. Small dense LDL particles have been associated with increased risk for cardiovascular disease. Increased concentrations of small dense LDL particles are associated with male gender and diabetes, particularly in adults. LDL particles are recog-

CM Chylomicrons CMR Chylomicron remnants

LDLR LDl receptor SRBP Scavenger receptor B1 LRP1 LDLR-related protein 1

terol from the intestinal lumen to sites of storage or metabolism. Chylomicrons are rapidly cleared and are usually absent after fasting. The clearance of chylomicrons occurs through the action of lipoprotein lipase (LPL), which creates chylomicron remnants. These chylomicron remnants are cleared from the circulation by the liver. These remnants are thought to be atherogenic by damaging the endothelium. (Adapted from Daniels SR. Pediatric Cardiology 2003)

nized by specific LDL receptors that are highly expressed in the liver. Once LDL particles bind to the receptor they are internalized into the cell. This pathway removes approximately 75% of LDL particles. The remaining LDL particles are removed by macrophages. High density lipoproteins are produced by the liver and the gastrointestinal tract, as well as by peripheral catabolism of chylomicrons and VLDL particles. HDL particles are also heterogeneous. HDL2 is the subfraction that is associated with protection against atherosclerosis. HDL3 is a smaller particle and increased in alcohol consumption, obesity, diabetes, cigarette smoking, uraemia and hypertriglyceridemia. HDL particles are involved in reverse transport of free cholesterol from peripheral tissues to the liver providing an explanation for the protective effect of HDL particles against atherosclerosis.

679 Inborn Errors of Lipoprotein Metabolism Presenting in Childhood

Lipoprotein (a) or Lp(a) has also been found to be associated with the atherosclerotic process. The structure of Lp(a) is similar to LDL, but with the addition of a large ‘little a’ protein bound to apoB via a single cysteine-mediated disulphide bond. Its plasma levels are regulated independently from LDL, and risk of coronary heart disease is greatly increased if both LDL and Lp(a) are elevated. One way Lp(a) may be related to atherosclerosis is because the (a) protein has structural similarities to plasminogen, and it may inhibit the thrombolytic activity of plasminogen.

kIntroduction

Lipids are highly diverse molecules that are traditionally best known for their role in the formation of biological membranes and cellular systems and as a way to store energy. In the last decade, lipids have taken a more centre stage in apoptosis, cell signaling, inflammation, immunity and inborn errors of metabolism (IEMs). Inborn errors of lipoprotein metabolism are a group of genetic disorders exemplified by changes in plasma lipids due to defects in the protein lipid-carriers (lipoproteins), lipoprotein receptors, or enzymes responsible for the hydrolysis and clearance of lipoprotein-lipid complexes [1]. The proteins responsible for the maintenance of normal plasma and tissue lipids, which are primarily triglycerides and free and esterified cholesterol, include the apolipoproteins A-I, A-II, A-IV, A-V, B, C-I, C-II, C-III, and E with key enzymes including lipoprotein lipase (LPL), hepatic triglyceride lipase (LIPC), lecithin cholesterol acyltransferase (LCAT), and cholesterol ester transfer protein (CETP); and key receptors being the low-density lipoprotein receptor (LDL-R) for LDLcholesterol (LDL-c), and the ATP-binding cassette transporter 1 (ABC1A) for HDL-cholesterol (HDL-c) levels [2, 3]. A number of genetic abnormalities of lipoprotein metabolism have been described in childhood (Lipid and lipoprotein metabolism; . Fig.  36.1, . Table 36.1). z

Plasma Lipid and Lipoprotein Metabolism

The major classes of lipids circulating in plasma are cholesterol, cholesteryl ester, triglycerides and phospholipids. Lipids are important components of many of the body’s tissues. They serve as building blocks for hormones and are a vital component of cell membranes (7 Chap. 35). However, lipids are insoluble in water. Thus, to be transported in the blood stream, they must be packaged into large, complex water-soluble molecules called lipoproteins. The structure of a lipoprotein is made up of a core consisting of cholesteryl ester and triglyceride covered by a polar surface

layer consisting of phospholipids, free cholesterol and protein moieties called apolipoproteins. These lipoprotein particles have differing densities, which are determined by the relative content of protein and lipid. The apolipoproteins perform functions related to transport and uptake into cells. z

Lipoprotein Disorders Presenting in Childhood

A number of genetic abnormalities that results in dyslipidemia in childhood have been described, of which heterozygous familial hypercholesterolaemia is the most common inherited lipid disorder with a prevalence of roughly 1 in 250 [5]. The responsible genes, inheritance and the observed plasma lipoprotein patterns for lipoprotein disorders manifesting in childhood are listed in . Table 36.1.

36.1

Disorders of Low Density Lipoprotein Metabolism

In the majority of these disorders, the atherosclerotic process begins in childhood, and the extent and rate of progression has a direct relationship with increases in lipid levels. Secondary causes of hyperlipidemia, including obesity, hypothyroidism, metabolic syndromes are not discussed in this chapter but form an important differential diagnosis in disorders of lipoprotein metabolism presenting in children. Whilst healthy lifestyles and a lower saturated fat intake is the cornerstone of treatment of lipid disorders in children, lipid-lowering therapies are becoming increasingly more important, with minimal adverse effects and no short-term effect on growth and development. There are many established therapies and emerging therapies for lipoprotein disorders and these are detailed in . Tables 36.2 and 36.3. There are five known genetic disorders causing elevated LDL-C that are expressed in children and that cause early atherosclerosis and premature coronary artery disease (CAD). These include familial hypercholesterolaemia (FH), familial ligand defective apo-B (FLDB), autosomal recessive hypercholesterolaemia, sitosterolemia, and mutations in proprotein convertase subtilisinlike kexin type 9 (PCSK9). These disorders arise from either gene mutations that affect LDL receptor activity or abnormalities in the LDL receptor itself. The presence of these disorders indicates a significantly elevated risk for premature atherosclerosis and CAD in adulthood. Of these genetic disorders affecting LDL receptor activity, FH is the most common disorder diagnosed in childhood, and usually identified by cascade screening. Identifying children and adolescents at enhanced risk for atherosclerosis is important for long-term car-

36

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. Table 36.1

Monogenic lipoprotein associated disorders presenting in childhood

Disorder

Inheritance

Protein & gene responsible

Observed plasma lipoprotein pattern

Frequency; ethnicity

Key references

Disorders affecting low density lipoprotein metabolism

36

AD familial hypercholesterolemia

ADa

LDL receptor – LDLR (heterozygous mutations) May have additional polygenic component

↑ LDL

1 in 250

[4–6]

AR familial hypercholesterolemia

AR

LDL receptor – LDLR (homozygous/compound heterozygous mutations)

↑ LDL

1 in 106

[4, 5]

AD familial hypercholesterolemia

ADa

Proprotein convertase subtilisin/kexin 9 – PCSK9

↑ LDL

In the UK – 2% of mutation positive FH

[4, 5, 7]

Familial liganddefective apo-B, FLBD

ADa

Apo-B – APOB May have polygenic component

↑ LDL

Two four common mutations: p. (R3527Q) in Caucasians. In the UK: ~5% of mutation positive FH patients; common allele p.R3527W in East Asians Identical phenotype to LDLR mutation FH

[4, 5, 8, 9]

AD familial hypercholesterolemia

AD

Apolipoprotein E APOE. One variant only described, p.(Leu167del)

↑ LDL

Unkown

[10]

AR familial hypercholesterolemia

ARa

LDL-receptor adaptor protein 1 – LDLRAP1 Commonly truncation mutations

↑ LDL

Rare except in Sardinia

[6, 11]

AR familial hypercholesterolemia

ARa

Homozygosity for pathogenic lysosomal acid lipase variants– LIPAb

↑ LDL

Familial Hypobetalipoproteinemia (FHBL)

ADa

Apo-B – APOB subjects generally have truncatng mutations. May have polygenic component.

↓ Apo-B lipoproteins (chylomicrons, VLDL, LDL)

Rare

[14–16]

Abetalipoproteinemia

ARa

Large sub-unit of microsomal triglyceride transfer protein – MTTP

↓ Apo-B lipoproteins, no chylomicrons, ↓ HDL

3 mmol/l

yes

Check at 8 and 10 yrs & thereafter annually

no

Definite FH

no

Not FH If LDL-C * >5 mmol/l

no

yes no

LDL-C * >3.5 mmol/l

Highly probable FH

yes

LDL-C >4.0 mmol/l and parent has premature CHD or high LDL-C yes

Clinical management

* Exclude secondary causes

. Fig. 36.2

Identification of childhood heterozygous FH

hepatosplenomegaly and life threatening pancreatitis. Severe elevation in TG (>500  mg/dL) is rare in childhood and is usually associated with genetically based recessive metabolic defects, including defects in lipoprotein lipase (LPL) and apoCII (the activator of LPL). With LPL and apoCII deficiency, massive increases in chylomicrons and VLDL-C can occur, producing TG >1000 mg/dL and as high as 5000 to10,000 mg/dL. Such profound increases in TG can produce pancreatitis and eruptive xanthomas, but are not associated with premature atherosclerosis because the TG-enriched particles are too large to enter the vascular wall. These children require a very low-fat diet (  T (p.

39

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C. R. Ferreira et al.

A307S) transversion in TSEN54, a likely founder mutation. PCH2, 4 and 5 are allelic disorders and represent a continuum of clinical phenotypes [19–21].

of primary CoQ10 biosynthetic defect. Diagnosis is based on molecular grounds.

z

39.2.3

Treatment

No treatments are available so far.

39.2.2

Disorders of tRNA Modification – Prototype: Non-syndromic Intellectual disability

Transfer RNA undergoes several modifications needed for proper function (. Fig.  39.2). Many disorders of tRNA modification are associated with non-syndromic intellectual disability, including TRMT1, FTSJ1, NSUN2, ADAT3, and PUS3 deficiencies. Other defects of cytosolic tRNA modification lead to GallowayMowat syndrome, with intellectual disability, cerebellar atrophy, and early-onset steroid-resistant nephrotic syndrome; the latter findings elicit a differential diagnosis

Mutations in the tRNA synthetase genes fall into two categories. The first are those involved in cytoplasmic protein synthesis [24]. These enzymes synthesize the amino acid-tRNA conjugates in the cytoplasm. The second group of tRNA synthetases are transported to mitochondria, where they synthesize the amino acidtRNAs used for mitochondrial protein synthesis [25]. With the exception of GARS and KARS, mitochondrial and cytoplasmic aaRSs are encoded by distinct nuclear genes. Each compartment has unique tRNA synthetases that cannot substitute for each other if one has a mutation. z

THG1L G

39

A Acceptor stem C C

m1G: TRMT10A D-loop

TΨC-loop

9

49 50 48

26

46 Variable loop

m22G: TRMT1 m C: DALRD3 Cm, Gm: FTSJ1 A-to-I editing: ADAT3 3

m5C: NSUN2 mcm5U, mcm5s2U, ncm5U, ncm5Um: ELP1, ELP2

39

m5C: NSUN2 m7G: WDR4

Ψ: PUS3

32 37 34

t6A: KEOPS complex

Anticodon loop

. Fig. 39.2 Secondary cloverleaf structure of tRNA showing position and type of modification, as well as protein/complex responsible for such modification. Only modifications of cytosolic tRNA (not mitochondrial tRNA) are shown. Cm 2’-O-methylcytidine, Gm 2’-O-methylguanosine, m1G 1-methylguanosine, m22G N2,N2dimethylguanosine, m3C 3-methylcytosine m5C, 5-methylcytosine, m7G 7-methylguanosine, mcm5U 5-methoxycarbonylmethyluridine, mcm5s2U 5-methoxycarbonylmethyl-2-thiouridine, ncm5U 5-carbamoylmethyluridine, ncm5Um 5-carbamoylmethyl-2’-O-methyluridine, Ψ pseudouridine, t6A N6-threonylcarbamoyladenosine

Disorders of tRNA Aminoacylation: Neurodegenerative and Systemic Disorders

Clinical Manifestation

The phenotype of each group of tRNA synthetases is variable, and the symptoms for each tRNA synthetase defect are different. However, each specific defect tends to have a more consistent phenotype. The cytoplasmic defects (typically denoted as XARS1, where X is the amino acid attached by the enzyme to its respective tRNA) can present as neurodegenerative disorders like Charcot-Marie-Tooth disease with progressive weakness and muscle atrophy, Perrault syndrome with sensorineural hearing loss and ovarian dysgenesis, Usher syndrome with congenital deafness and retinitis pigmentosa, infantile leukodystrophy, or visceral presentations like interstitial lung and liver disease. Inheritance is autosomal dominant or recessive. Specific findings with each defect are listed in . Table 39.1. All mitochondrial tRNA synthetases are nuclear encoded and inherited as autosomal recessive conditions designated as XARS2. The most common phenotype is that of a combined, usually severe, disorder of oxidative phosphorylation (see also 7 Chap. 10). However, other phenotypes overlap those seen in defects of cytoplasmic tRNA synthesis including Perrault syndrome, interstitial lung disease with pulmonary hypertension, and leukodystrophy with microcephaly. Renal disease with hyperuricemia and primary metabolic alkalosis is seen in SARS2 deficiency [26]. Specific findings with each defect are listed in . Table 39.1. z

Diagnostic Tests

Diagnosis should be facilitated by aminoacylation assays as shown recently for patients with LARS2 and

731 Disorders of Nucleic Acid Metabolism, tRNA Metabolism and Ribosomal Biogenesis

KARS deficiencies [27]. For the most part, however, diagnosis is based on symptoms and most often a rapid move to broad molecular testing as there are no diseasespecific biochemical markers. z

Treatment

Therapies are limited and usually symptomatic. Infusion of high levels of leucine and/or total protein in patients with LARS1 deficiency has been reported to improve acute liver dysfunction [28]. However, similar treatment with specific amino acids has either not been reported or has not been successful in the other disorders.

39.3

Ribosomal Biogenesis

See . Fig. 39.1, insert A, red pathway. Mitochondrial ribosomal proteins are nuclear encoded, but the mitochondrial ribosomal RNA genes are part of the mitochondrial chromosome. Thus, all told, there is the potential for hundreds of disorders related to ribosomal structure and function. This chapter will only deal with non-mitochondrial ribosomal disorders.

39.3.1

Disorders of Pre-rRNA Transcription: Craniofacial Anomalies

Disorders of pre-rRNA transcription lead to defects of neural crest cell development. Since neural crest cells give rise to craniofacial mesenchyme (including bones and cartilage), these disorders lead to craniofacial anomalies [29]. Acrofacial dysostosis is thus seen in Treacher Collins syndrome and acrofacial dysostosis, Cincinnati type; the latter, caused by mutations in the POLR1A gene, can be accompanied by limb anomalies such as bowed femurs. Diagnosis is suspected on clinical grounds, although the specific molecular defect can only be ascertained by sequencing.

39.3.2

z

Disorders of 5S rRNA and tRNA Transcription: Neurodegeneration, Leukodystrophy and Systemic Disorders

Clinical Presentation

Biallelic loss-of-function variants of RNA polymerases (POLR3A and its interactors POLR3B and POLR1C) are known to cause a series of related but still different entities. POLR3A variants can cause 4H leukodystrophy, Wiedemann-Rautenstrauch syndrome (WRS), and progressive spastic ataxia [30–32]. Variants in POLR1C can

cause hypomyelinating leukodystrophy type 11, and variants in POLR3B have been found in individuals with cerebellar hypoplasia-endosteal sclerosis (CHES), that shows overlap with both 4H leukodystrophy and WRS [30, 31]. The exact pathogenesis explaining the various signs and symptoms associated with decreased POLR3A activity, such as myelination, dental, bone and fat tissue abnormalities, remains unclear [30, 32]. POLR3-related leukodystrophy is a well-recognizable clinical entity if all features are present. It is a hypomyelinating leukodystrophy with different combinations of four major clinical findings: (1) neurologic dysfunction; (2) abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth); (3) endocrine abnormalities (hypogonadotropic hypogonadism manifesting as delayed or absent puberty or short stature); and (4) ocular abnormality (progressive myopia). POLR3-related leukodystrophyy and 4H leukodystrophy are the terms for five previously described overlapping clinical phenotypes, described before the molecular basis was delineated, including: hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); ataxia, delayed dentition, and hypomyelination; tremor-ataxia with central hypomyelination; leukodystrophy with oligodontia; and hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum. A large cohort of POL3A and POL3B mutation-proven cases of 4H syndrome is characterized by a progressive disorder with motor dysfunction due to increasing ataxia, and sometimes with episodes of faster deterioration triggered by minor infections [33]. The main neurological manifestation is developmental delay usually noted between the age of 1–2 years (50%). Most of the patients present with signs of cerebellar dysfunction (tremor, dysmetria and gait ataxia), and some patients are never able to walk independently. Other features include dystonia and oculomotor disorders (abnormal smooth pursuit, nystagmus, vertical gaze limitation). Pyramidal signs are usually absent in children and develop slowly in older patients. Cognition vary widely, from normal cognitive abilities to intellectual disability in most. Among non-neurologic manifestations, dental abnormalities are present in most patients (delayed dentition and hypodontia), as well as delayed puberty or primary amenorrhea, and progressive myopia [31, 33]. WRS is a neonatal progeroid condition characterized by prenatal and early postnatal growth retardation, sparse scalp hair, generalized lipodystrophy with characteristic fatty tissue accumulations, and an unusual face characterized by a triangular shape, apparently low-set eyeballs partly covered by the lower eyelids, small mouth, pointed chin and natal teeth [30]. More recently, hypomorphic biallelic variants in POLR3A have been reported as a cause of autosomal recessive adolescent-onset progressive spastic ataxia. The

39

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732

phenotype additionally includes tremor and involvement of the central sensory tracts, leading to the diagnosis of complicated hereditary spastic paraplegia. Some patients present ataxia with extrapyramidal features and dental problems (hypodontia, periodontal disease) [32, 34]. Neuroimaging abnormalities are a key feature in POLR3-related leukodystrophy, with brain MRI showing hypomyelination in combination with relative preservation of myelination of specific brain structures. T2 hypointensity of the dentate nuclei, ventrolateral thalamus, pyramidal tracts within the posterior limb of the internal capsule, globus pallidus and optic radiations is present. Moreover, cerebellar atrophy can be present. Supratentorial atrophy and thin corpus callosum is present in adult patients, reflecting progressive cerebral white matter volume loss [33, 35]. MRI findings differ in progressive spastic ataxia, and the most consistent finding on FLAIR images is bilateral hyperintensities along the superior cerebellar peduncles, combined with a hypointense correlate in T1-weighted images, indicating secondary myelin degradation. In addition, most cases show cervical cord atrophy and slight hypoplasia of the corpus callosum [32, 34]. z

39

Metabolic Derangement and Genetics

RNA polymerase (pol) I synthesizes the large rRNA, pol II synthesizes mRNA, and pol III synthesizes tRNA and 5S rRNA. The nuclear RNA polymerases are complex enzymes, made up of 12 or more subunits. Reduction of POLR3A leads to reduction of the total pool of tRNAs and a deregulated transcription of certain types of noncoding RNAs [36, 37]. Treatment is still symptomatic and individualized, including a multidisciplinary team. Seizures, spasticity or dystonia are managed in a routine manner [31, 33].

39.3.3

Disorders of Pre-rRNA Processing: Skeletal Dysplasia and Systemic Disorders

Mutation of specific proteins that participate in telomere maintenance and pre-rRNA modification are associated with dyskeratosis congenita, while defects in dyskerin and NOP10 affecting the catalytic pseudouridylation site cause cataracts, enterocolitis, sensorineural hearing loss, and steroid-resistant nephrotic syndrome [38]. Defects in pre-rRNA cleavage lead to skeletal dysplasias, such as cartilage-hair hypoplasia (RMRP), POP1, and NEPRO deficiencies. The diagnosis can be suspected on clinical and radiographic grounds.

39.3.4

Disorders of Maturation of 40S and 60S Ribosomal Subunits – Prototype: Diamond-Blackfan Syndrome

Diamond-Blackfan syndrome(s) is the most common phenotype related to ribosomal dysfunction [39]. It is caused by mutations in at least 20 genes, the most common of which is RPS19. Originally recognized as a genetic form of normochromic, macrocytic anemia, congenital anomalies are present in 30–50% of patients, including craniofacial. Malformations, congenital heart defects, and genitourinary abnormalities. Upper extremity (especially thumb) abnormalities are particularly characteristic. Other blood cell lines may be diminished. Low birthweight and infantile failure to thrive are common. Malignancies may develop including acute myelogenous leukemia, myelodysplastic syndrome, and some solid tumors, especially osteosarcoma. The diagnosis is usually first suspected on the basis of hematologic abnormalities or congenital anomalies, Hemoglobin F and red blood cell adenosine deaminase may be elevated. Confirmation is by DNA sequencing [40]. Mutations in RPS19 account for ~25% of patients with the rest of patients having scattered mutations across the other >20 genes. Therapy is symptomatic and may include RBC transfusions or bone marrow transplant [41].

39.3.5

Disorders of Active 80S Ribosome Assembly: Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, hematologic abnormalities, and metaphyseal changes [42]. The pancreatic involvement leads to malabsorption, growth failure, fatsoluble vitamin deficiency, low serum concentrations of isoamylase and cationic trypsinogen, and fatty infiltration with a hyperechoic pancreas. The most common hematologic abnormality is neutropenia (intermittent or persistent), but other frequent findings include anemia, thrombocytopenia, myelodysplasia and leukemia [43]. Severe skeletal changes in infancy can lead to short ribs mimicking asphyxiating thoracic dystrophy. SDS is caused by an inability to remove the eukaryotic initiation factor 6 (EIF6) from the pre-60S ribosome subunit, a process needed for the assembly of the active 80S ribosome [44]. The diagnosis is typically suspected on clinical grounds, and is confirmed molecularly.

733 Disorders of Nucleic Acid Metabolism, tRNA Metabolism and Ribosomal Biogenesis

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lysophosphatidylcholine and interferon signature on newborn screening blood spots. Mol Genet Metab 122:134–139. https:// doi.org/10.1016/j.ymgme.2017.07.006 Rice GI, Meyzer C, Bouazza N et al (2018) Reverse-transcriptase inhibitors in the Aicardi–Goutières syndrome. N Engl J Med 379:2275–2277. https://doi.org/10.1056/NEJMc1810983 Phizicky EM, Hopper AK (2010) tRNA biology charges to the front. Genes Dev 24:1832–1860. https://doi.org/10.1101/ gad.1956510 Budde BS, Namavar Y, Barth PG et  al (2008) tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet 40:1113–1118. https://doi.org/10.1038/ng.204 van Dijk T, Baas F, Barth PG, Poll-The BT (2018) What’s new in pontocerebellar hypoplasia? An update on genes and subtypes. Orphanet J Rare Dis 13:92. https://doi.org/10.1186/ s13023-018-0826-2 Namavar Y, Barth PG, Kasher PR et al (2011) Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 134:143–156. https://doi.org/10.1093/brain/awq287 Steinlin M, Klein A, Haas-Lude K et al (2007) Pontocerebellar hypoplasia type 2: variability in clinical and imaging findings. Eur J Paediatr Neurol 11:146–152. https://doi.org/10.1016/j. ejpn.2006.11.012 Sánchez-Albisua I, Frölich S, Barth PG et  al (2014) Natural course of pontocerebellar hypoplasia type 2A. Orphanet J Rare Dis 9:70. https://doi.org/10.1186/1750-1172-9-70 Cusack S (1997) Aminoacyl-tRNA synthetases. Curr Opin Struct Biol 7:881–889. https://doi.org/10.1016/s0959440x(97)80161-3 Duchêne A-M, Pujol C, Maréchal-Drouard L (2009) Import of tRNAs and aminoacyl-tRNA synthetases into mitochondria. Curr Genet 55:1–18. https://doi.org/10.1007/s00294-008-0223-9 Belostotsky R, Ben-Shalom E, Rinat C et al (2011) Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 88:193–200. https://doi.org/10.1016/j.ajhg.2010.12.010 van der Knaap MS, Bugiani M, Mendes MI et al (2019) Biallelic variants in LARS2 and KARS cause deafness and (ovario) leukodystrophy. Neurology 92:e1225. https://doi.org/10.1212/ WNL.0000000000007098 Casey JP, McGettigan P, Lynam-Lennon N et al (2012) Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Mol Genet Metab 106:351–358. https://doi. org/10.1016/j.ymgme.2012.04.017 Trainor PA, Merrill AE (2014) Ribosome biogenesis in skeletal development and the pathogenesis of skeletal disorders. Biochim Biophys Acta 1842:769–778. https://doi.org/10.1016/j. bbadis.2013.11.010 Paolacci S, Li Y, Agolini E et al (2018) Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. J Med Genet 55:837–846. https://doi.org/10.1136/ jmedgenet-2018-105528 Bernard G, Vanderver A (1993) POLR3-related leukodystrophy. In: Adam MP, Ardinger HH, Pagon RA et  al (eds) GeneReviews®. University of Washington, Seattle Minnerop M, Kurzwelly D, Wagner H et  al (2017) Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain 140:1561–1578. https:// doi.org/10.1093/brain/awx095 Wolf NI, Vanderver A, van Spaendonk RML et al (2014) Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology 83:1898–1905. https://doi. org/10.1212/WNL.0000000000001002 Rydning SL, Koht J, Sheng Y et  al (2019) Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and

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Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses Marie T. Vanier, Catherine Caillaud, and Thierry Levade Contents 40.1

Disorders of Sphingolipid Synthesis – 737

40.1.1

Serine Palmitoyltransferase (Subunit 1 or 2) Deficiency and HSAN1 – 739 40.1.2 Ketosphinganine Reductase Deficiency and Hyperkeratosis – 740 40.1.3 Defects in Ceramide Synthases 1 and 2 and Myoclonic Epilepsy – 740 40.1.4 Dihydroceramide Δ4-Desaturase Deficiency and Leukodystrophy – 740 40.1.5 Fatty Acid 2-Hydroxylase Deficiency (SPG35/FAHN) – 740 40.1.6 GM3 Synthase Deficiency and Amish Epilepsy Syndrome – 741 40.1.7 GM2/GD2 Synthase Deficiency (SPG26) – 741 40.1.8 Defects in Skin Ceramide Synthesis: Autosomal Recessive Congenital Ichthyoses (ARCI) – 741 40.1.9 Sphingomyelin Synthase 2 Mutations and Osteoporosis – 742 40.1.10 Mutations in Ceramide Kinase-Like (CERKL) Gene and Retinal Dystrophy – 742

40.2

Disorders of Lysosomal Sphingolipid Degradation: Sphingolipidoses – 742

40.2.1 40.2.2

Gaucher Disease – 743 Acid Sphingomyelinase-Deficient Niemann-Pick Disease (Type A, Type B and Intermediate Forms) – 745 GM1 Gangliosidosis – 746 GM2 Gangliosidoses – 747 Krabbe Disease – 749 Metachromatic Leukodystrophy – 750

40.2.3 40.2.4 40.2.5 40.2.6

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_40

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40.2.7 40.2.8 40.2.9

Fabry Disease – 751 Farber Disease/Acid Ceramidase Deficiency – 753 Prosaposin Deficiency – 753

40.3

Disorders of Non-Lysosomal Sphingolipid Degradation – 754

40.3.1

Non-lysosomal β-Glucosidase (GBA2) Deficiency: SPG46 and Ataxia – 754 Neutral Sphingomyelinase-3 Deficiency – 754 Alkaline Ceramidase 3 (ACER3) Deficiency: Infantile Leukodystrophy – 754 Sphingosine-1-phosphate Lyase (SGPL1) Deficiency: A Multisystemic Disorder – 754

40.3.2 40.3.3 40.3.4

40.4

Niemann-Pick Disease Type C – 755

40.5

Neuronal Ceroid Lipofuscinoses – 757 References – 761

737 Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal…

Sphingolipid Structure and Metabolism Sphingolipids are ubiquitous lipids found in all mammalian cell membranes and in plasma lipoproteins. Many exhibit dual functions, as key structural elements, but also as modulators of numerous biological/ physiological functions. Their backbone is a long chain sphingoid base (sphingosine being the prototype) that can be N-acylated by a variety of fatty acids, forming ceramides (Cer) (. Fig. 40.1). Depending on the type of hydrophilic head group linked to the 1-OH group of the sphingoid base, two main classes of sphingolipids are distinguished. Phosphosphingolipids contain phosphorylcholine (sphingomyelin), phosphorylethanolamine, or a phosphate group. Glycosphingolipids contain one (glucose or galactose) or several sugar residues and can be overly complex. Sialic acid (N-acetyl-neuraminic acid in humans) containing glycosphingolipids are named gangliosides. Depending on the precise structure (sugar and linkage) of the oligosaccharide moiety, several glycosphingolipid lineages (ganglio-, globo-, etc) have been defined. “Cerebroside” usually refers to the major myelin lipid galactosylceramide; “sulfatide” to its sulfated derivative. Lysosphingolipids (e.g., psychosine) lack the fatty acid of ceramide. The main sphingolipids are depicted in . Figs.  40.1. and 40.2. Sphingolipids are synthesised and degraded in different subcellular compartments. A further aspect of sphingolipid homeostasis not discussed here is the recycling or salvage pathway. Biosynthesis (. Fig. 40.1). The de novo synthesis of ceramide occurs in the endoplasmic reticulum (ER) and starts by the condensation of serine and palmitoylCoA, a reaction catalysed by serine palmitoyltransferase. The resulting 3-ketosphinganine is reduced to sphinganine prior to N-acylation by ceramide synthases. Distinct fatty acids, including 2-hydroxylated long chain fatty acids and ω-hydroxylated ultra-long chain fatty acids, can be incorporated (7 Chap. 42). Then, dihydroceramide is desaturated to produce ceramide. The sphingosine that is released by the action of ceramidases on the ceramide derived from the degradation of complex sphingolipids can also be N-acylated by ceramide synthases. Subsequent steps of sphingolipid synthesis (except galactosylceramide) occur in the Golgi apparatus, where ceramide is transformed to sphingomyelin or to glucosylceramide; stepwise addition of further monosaccharides, catalysed by specific glycosyltransferases, leads to the formation of more complex neutral glycosphingolipids and gangliosides. Sphingolipids are then transported and inserted into various membranes. Degradation (. Fig. 40.2). After transport by the endolysosomal pathway to the lysosome, sphingolipid degradation proceeds by stepwise hydrolysis by specific

acid sphingohydrolases, some of which may need cofactors called sphingolipid activator proteins (also lysosomal) for their in  vivo action. Specific nonlysosomal degradation reactions also operate at the plasma membrane, Golgi/ER interface, or ER level (. Fig. 40.1).

kIntroduction

This chapter first discusses inherited diseases involving the metabolism of sphingolipids. Sphingolipidoses, i.e., diseases resulting from defects in the lysosomal degradation of sphingolipids, constitute one of the major historical groups among lysosomal storage disorders (LSDs). Defects of sphingolipid biosynthesis or of nonlysosomal sphingolipid degradation, more recently identified, are also briefly described. Niemann-Pick C disease, now reclassified as a disorder of lysosomal trafficking of cholesterol also involving sphingolipids, constitutes a separate category. The chapter finally describes neuronal ceroid lipofuscinoses, now recognised as another important group among LSDs.

40.1

Disorders of Sphingolipid Synthesis

Most of the genes encoding the enzymes, transporters and activators operating in the sphingolipid synthesis pathway have been characterised, and an increasing number of monogenic defects affecting some steps of the biosynthesis of sphingolipids have been delineated in recent years (. Table 40.1). A majority of disorders were first described as a component of a genetically heterogeneous clinical syndrome – e.g., hereditary sensory and autonomic neuropathies (HSAN), autosomal recessive hereditary spastic paraplegias,– before the function of the protein encoded by the mutated gene was recognised. Mechanisms underlying the pathophysiology of most sphingolipid synthesis disorders are still enigmatic. Except for HSAN1, the reported mutations result in a loss of function of the corresponding enzyme. Alterations in the sphingolipid profile of the diseased tissues have not been described in all conditions. In general, it is still unknown whether tissue dysfunction and symptoms are due to the lack (or insufficient production) of one or more sphingolipid species, and/or accumulation of a precursor molecule or a potentially toxic metabolite. Regarding genetic transmission, except for HSAN1 due to a defect in serine palmitoyltransferase 1 or 2, and possibly the defects in ceramide synthase 2 and sphingomyelin synthase 2, enzymatic deficiencies of sphingolipid synthesis are inherited as autosomal recessive traits. So far, their diagnosis relies on DNA analysis

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O

C 22:0 (Fatty acid)

Ganglio-series a

series b

β

β

HN OH

Sphingosine (Sphingoid base)

OH

β

β

Typical Ceramide (Cer)

β

-Cer

β

β

β

Gal

β

Globo-series

GalNAc

β

Neu5Ac

α

β

α

Sphingomyelin Pcholine-Cer

SGPL1

β

-Cer

β

β

-Cer

β

β

β

-Cer

GD2

GM2

-Cer

B4GALNT1

β

-Cer ST3GAL5

UDP-Gal

UDP-Glc

β

-Cer

β

-Cer

GD3

Glycosphingolipids

β

-Cer

Dihydroceramide

β

CMP-Neu5Ac

Sulfatide

β

β

GM3

PAPS

GalCer

UDP-Gal

-Cer

SO4

2-OHAcyl-CoA

FA2H

-Cer

GD1b

β

β

LacCer

GlcCer

DEGS1

2-OH-FA

β

[SPG26]

GBA2

CERS1-6

Golgi apparatus

CERS1-6

[SPG35] Acyl-CoA

ω-OHULCFA-CoA

FATP4

Sphinganine

CYP4F22 ω-OHULCFA

ULCFA

Endoplasmic reticulum

KDSR

40

β

β

Cer

So

β

-Cer

[SPG46]

ACER3

β

β

SGMS2 SMPD4

FA

-Cer

Gb3

Hexadecenal

β

β

GM1a

Gb4

So1P

β

-Cer

GT1b

GD1a

Glc

β

Ketosphinganine SPTLC1/2

GD3, GD2, GD1a, GD1b: disialogangliosides GT1b: trisialoganglioside

[HSAN1]

Palmitoyl-CoA + Serine

GM1, GM2, GM3: monosialogangliosides

+Ala or Gly

Deoxysphinganine Deoxymethylsphinganine

N-acetylneuraminic acid: sialic acid found in normal human cells

. Fig. 40.1 Schematic representation of the structure of the main sphingolipids, depicting pathways of their biosynthesis, and of their non-lysosomal degradation. Red arrows denote the defective pathways that are discussed in this chapter. Solid black bars indicate metabolic blocks. Mutated genes are indicated within grey (biosynthesis) or green (non-lysosomal degradation) boxes. Cer ceramide, FA fatty acid, Gal galactose, GalCer galactosylceramide, GalNAc

N-acetyl-galactosamine, Gb3 globotriaosylceramide, Gb4 globotetraosylceramide (globoside), Glc glucose, GlcCer glucosylceramide, LacCer lactosylceramide, Neu5Ac N-acetyl-neuraminic acid, 2-OHFA 2-hydroxy-fatty acid, ω-OH-ULCFA ω-hydroxy ultra-long chain fatty acid, PAPS 3ƍ-phosphoadenosine-5ƍ-phosphosulfate, Pcholine phosphorylcholine, So sphingosine, So1P sphingosine-1-phosphate, ULCFA ultra-long chain fatty acid

although biochemical testing in plasma is possible for detection of HSAN1. There is currently no effective specific therapy for this type of IEM.  Most of these conditions remain extremely rare. Their clinical spectrum is broadening with description of new cases and

the field is likely to quickly evolve in the near future. For these reasons, and since comprehensive reviews on the subject with exhaustive referencing have been published quite recently [1, 2], only a brief outline of each disorder will be given in this chapter.

739 Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal…

. Table 40.1

Sphingolipid biosynthesis disorders

Enzyme

Gene

Metabolic disturbance

Main clinical features

Disorders with primarily nervous system involvement Serine palmitoyltransferase, subunit 1 or 2

SPTLC1 or SPTLC2

Accumulation of 1-deoxysphingolipids (in plasma)

[HSAN1] – Peripheral sensory neuropathy, distal sensory loss, ulcerative mutilations Macular telangiectasia type 2

Ceramide synthase 1

CERS1

Possibly decreased C18-ceramide levels (in cultured cells)

Progressive myoclonic epilepsy and cognitive decline

Ceramide synthase 2

CERS2

Possibly decreased very-long chain ceramide levels (in cultured cells)

Progressive myoclonic epilepsy

Dihydroceramide delta4-desaturase

DEGS1

Increased dihydroceramides/ceramides ratio (in cultured fibroblasts) and dihydrosphingolipids in plasma

Hypomyelinating leukodystrophy

Fatty acid 2-hydroxylase

FA2H

Possibly decreased hydroxylated sphingomyelin levels (in cultured cells)

Spastic paraplegia [SPG35], dystonia, dysarthria, ataxia

GM3 synthase

ST3GAL5 (SIAT9)

Lack of GM3, GD3 and higher gangliosides, and increased lactosylceramide and Gb4 levels (in plasma and cultured cells)

[Amish infantile epilepsy] Epilepsy, intellectual disability, ‘salt-andpepper’ syndrome

GM2/GD2 synthase

B4GALNT1

Decreased GM2 and increased GM3 levels (in cultured cells)

Spastic paraplegia [SPG26], ataxia

Disorders with primarily skin involvement 3-Ketosphinganine reductase

KDSR

Reduced ceramide content in skin

Symmetric erythrokeratoderma

Ceramide synthase 3

CERS3

Lack of ceramides with very-long chain fatty acids (in cultured cells)

Ichthyosis [ARCI9]

(Ultra-long chain) fatty acid ω-hydroxylase

CYP4F22

Decreased ultra-long acylceramide levels (in skin and cultured cells)

Ichthyosis [ARCI5]

Patatin-like phospholipase domain-containing 1

PNPLA1

Loss of ω-O-acylceramides in skin

Ichthyosis [ARCI10]

Increased capacity of sphingomyelin synthesis (in cultured cells)

Osteoporosis and skeletal dysplasia

Disorders with primarily bone involvement Sphingomyelin synthase 2

SGMS2

40.1.1Serine Palmitoyltransferase (Subunit

1 or 2) Deficiency and HSAN1 A defect in the very first step of sphingolipid biosynthesis is the major cause underlying the dominant hereditary sensory and autonomic neuropathy (HSAN1). Other (unrelated) genes that have been linked to HSAN1 are ATL1, RAB7A and DNMT1 [1]. This peripheral neuropathy is characterised by a late onset (between the second and fourth decade), a slow disease progression, and primarily sensory deficits (loss of pain and temperature sensation spreading from the distal limbs). Painless ulcerations in the lower limbs are quite frequent, as well

as spontaneous lancinating pain attacks. Hypohidrosis is also seen. Some patients exhibit a more severe phenotype, starting in early childhood, with motor involvement, global hypotrophy, and developmental retardation [1]. Macular telangiectasia type 2 is also associated with the same gene defects [3]. Current evidence related to the metabolic derangement points to the accumulation of abnormal sphingoid bases (and their derivatives) as the main pathogenic mechanism. Specific mutations of SPTLC1 or SPTLC2 encoding subunits 1 or 2 of serine palmitoyltransferase, the first and rate-limiting step in the de novo synthesis of sphingolipids, alter its substrate specificity. Instead

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of using L-serine as a substrate (. Fig.  40.1), the mutant enzyme preferentially uses L-alanine or L-glycine. The resulting 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine, and 1-deoxy-ceramides (or some other derivatives), which cannot be converted to complex sphingolipids, appear to account for the observed neurotoxicity. Of note is the fact that only several missense mutations in the SPTLC1 or SPTLC2 gene cause the autosomal dominant disorder HSAN1. Substitution of Ser331 in the subunit 1 of serine palmitoyltransferase seems to result in an early-onset and more severe phenotype. When a hereditary sensory neuropathy (or macular telangiectasia type 2) is suspected, elevated plasma levels of 1-deoxy-sphinganine and 1-deoxymethylsphinganine, as determined by liquid chromatography coupled to mass spectrometry, provide a strong biochemical argument in favour of a SPTLC1/2 defect. Moreover, plasma 1-deoxy-sphingolipid levels seem to correlate with disease severity. There is currently no effective specific therapy. However, a 10-week pilot study on patients affected with HSAN1 showed that, as in a mouse model for this disease, L-serine supplementation (200 or 400  mg/kg/ day) could reduce the plasma levels of 1-deoxysphingolipids [4, 5]. Whether such a supplementation can ameliorate the sensory deficits still requires further investigation. A recent study has identified novel, dominantly acting SPTLC1 variants that cause a childhood-onset form of amyotrophic lateral sclerosis. In contrast to the situation of HSAN1, these variants result in unregulated activity of serine palmitoyltransferase and elevated levels of its canonical sphingolipid products [6].

40

40.1.2Ketosphinganine Reductase Deficiency

and Hyperkeratosis A skin disorder with well-demarcated symmetric scaling, erythema, and keratoderma mostly affecting the face, palms and soles has been described in four probands [7]. Four additional patients with hyperkeratosis or a harlequin ichthyosis-like phenotype were reported, in whom thrombocytopenia was also observed [8]. All carried biallelic mutations in KDSR, which encodes the second enzyme of sphingolipid biosynthesis. Deficient activity of 3-ketosphinganine reductase led to a reduction of total ceramide content in the affected skin. Systemic therapy by isotretinoin markedly improved the scaling and erythema in two patients.

40.1.3Defects in Ceramide Synthases 1 and 2

and Myoclonic Epilepsy Six human ceramide synthases, encoded by CERS genes, have been characterised. They display distinct tissuespecificities as well as acyl-CoA substrate specificities, which can explain the neurological (CERS1 and 2) or dermatologic (CERS3, see 7 Sect. 40.1.8) expression in case of a defect in one of them. Very recently, a homozygous missense mutation in CERS1 has been identified in 4 siblings of an Algerian family showing progressive myoclonic epilepsy and cognitive decline/dementia. The mutation was associated with decreased C18-ceramides levels in cultured fibroblasts. It has also been proposed that progressive myoclonic epilepsy since age 10 in an adult patient (associated with ataxia, dysarthria and photosensitivity) was due to a heterozygous deletion of CERS2 together with decreased very-long chain ceramides in fibroblasts [1]. 40.1.4Dihydroceramide Δ4-Desaturase

Deficiency and Leukodystrophy This autosomal recessive condition has been described in 20 patients, presenting with a progressive tetraspasticity, developmental delay and failure to thrive [9, 10]. Variable disease severity has been observed, including isolated spastic paraparesis. The most severely affected patient died at 18 months of age. Abnormal eye movements were frequently seen before 6  months of age. Seizures were also frequently reported. EMG showed reduced nerve conduction velocities. Brain MRI revealed a general hypomyelination, a thinning of corpus callosum, and progressive cerebellar and supra- and infratentorial atrophy. Pathogenic mutations in DEGS1 result in reduced activity of the desaturase that catalyses the last step of ceramide biosynthesis, i.e., the introduction of a 4,5-double bond in the sphingoid base backbone. This leads to increased levels of dihydrosphingolipids (dihydro-ceramides, sphingomyelins and monohexosylceramides), and increased dihydroceramide/ceramide ratio in patients’ blood, muscle, and fibroblasts.

40.1.5Fatty Acid 2-Hydroxylase Deficiency

(SPG35/FAHN) Mutations in FA2H encoding fatty acid 2-hydroxylase result in a complex hereditary spastic paraplegia, SPG35, also called fatty acid hydroxylase-associated

741 Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal…

neurodegeneration (FAHN). To date, about 70 patients have been reported, with varied ethnicity. Most patients present in childhood and develop slowly progressive lower and then upper limb spasticity, dysarthria, and mild cognitive decline. Dystonia is another common neurologic feature, and a rigid-hypokinetic syndrome may appear over time. MRI shows signs of leukodystrophy and diffuse cortical and pontocerebellar atrophy. Neurodegeneration with brain iron accumulation (NBIA), mostly located in globus pallidus (T2 hypodensity, but no “eye of the tiger” sign), can occur, although not in all patients. The clinical spectrum of SPG35 is widening, with later onset patients and more clinical variability [11]. The underlying abnormality is likely the insufficient production of 2-hydroxy-galactosphingolipids. Indeed, 2-hydroxylated long chain and very-long chain fatty acids are essentially found in galactosylceramides and sulfatides from myelin, and their proportion relative to non-hydroxylated fatty acids is known to increase with brain development and myelin maturation. Not unexpectedly, in Fa2h-deficient mice, brain galactosylceramides were found to contain almost exclusively non-hydroxylated fatty acids.

40.1.6GM3 Synthase Deficiency and Amish

Epilepsy Syndrome The deficiency of GM3 synthase resulting from ST3GAL5 (SIAT9) mutations causes an autosomal recessive infantile-onset symptomatic epilepsy, also called Amish epilepsy syndrome. During the first 3 months of life, affected children show irritability and failure to thrive. Then, within the first year of life, generalized tonic-clonic seizures as well as other seizure types develop, along with a profound developmental stagnation and regression. In some patients, brain MRI shows occipital white matter abnormalities and atrophy in the visual cortex. The severity of the disease varies significantly, some patients suffering from visual loss and deafness. Most patients exhibit hyperpigmented macules on the dorsal part of hands and feet, but also in other locations. Some patients also show patches of skin depigmentation. These skin changes are not associated with the severity of the neurologic disease. The combination of hyper and hypo-pigmented skin maculae, facial dysmorphism, scoliosis, intellectual disability, seizures, choreoathetosis, and spasticity has been described under the term “salt-and-pepper” syndrome. Associated biochemical features in plasma and cultured cells are the lack of GM3, GD3 and

higher gangliosides, and increased lactosylceramide and Gb4 levels.

40.1.7GM2/GD2 Synthase Deficiency

(SPG26) Mutations of B4GALNT1 resulting in a defect of GM2/GD2 synthase are associated with SPG26, a slowly progressive complex hereditary spastic paraplegia with mild to moderate cognitive impairment. A dozen of multiplex families from various ethnic origins have so far been described. The clinical picture is a progressive weakness, with spastic gait and lower limb spasticity. EMG shows an axonal sensorimotor neuropathy in many patients. The disease can be accompanied by cerebellar symptoms, dysarthria, and dysphagia [12], as well as fever-induced ataxia with myokymia. Studies in cultured fibroblasts of patients have shown decreased GM2 levels with an increase of its precursor, GM3.

40.1.8Defects in Skin Ceramide Synthesis:

Autosomal Recessive Congenital Ichthyoses (ARCI) Autosomal recessive congenital ichthyoses (ARCI) represent a heterogeneous group of disorders of epidermal cornification, in which at least 9 causative genes have been identified. Three of those, CERS3, CYP4F22 and PNPLA1, encode proteins involved in ceramide synthesis (. Fig.  40.1). Specific ceramides are particularly abundant in the stratum corneum of the skin, where they play a crucial role in maintaining skin barrier homeostasis, preventing water loss, and protecting against microbial infections. These ceramides may in particular contain α- or ω-hydroxylated fatty acids and ultra-long chain fatty acids (ULCFAs; C26 or longer) (7 Chap. 42). Acylceramides are unique, very hydrophobic ceramide species present in the epidermis, which contain C28-C36 ω-hydroxylated ULCFAs and are further esterified with linoleic acid. CYP4F22 encodes the fatty acid ω–hydroxylase required for acylceramide synthesis, using ULCFAs as substrates [13]. Ceramide synthase 3 (CERS3), which is markedly expressed in the skin, generates epidermisspecific ceramides by N-acylating sphinganine with ULCFA-CoAs (and likely ω-hydroxylated ULCFACoAs). Indeed, functional analysis of a skin sample and in vitro differentiated keratinocytes from a patient with a CERS3 missense mutation severely affecting

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enzyme activity demonstrated an impairment in the synthesis of ceramides with non-hydroxylated and ω-hydroxylated ULCFA moieties, disturbing epidermal differentiation and leading to premature keratinisation. On the other hand, PNPLA1 encodes a protein (patatinlike phospholipase domain containing 1) with transacylase activity, that transfers linoleic acid from triacylglycerols to the ω-hydroxy fatty acid in ceramide [14]. Once these acylceramides are glucosylated at the C1 position, the corresponding glucosylceramides are transported to the so-called lamellar bodies, possibly by ABCA12, the mutations of which cause harlequin ichthyosis (ARCI4). Acylceramides in the stratum corneum have been shown to play a key role in the formation and stabilisation of cornified envelopes through covalent binding to corneocyte proteins, and ultimately in skin permeability barrier. It is therefore logical that defective synthesis of these lipids will manifest as severe skin disorders. For the above defects, the ARCI clinical phenotype has been quite variable in different patients, often including lamellar ichthyosis and palmo-plantar hyperlinearity, but also in some cases collodion membrane at birth (that may be self-improving) and more or less severe congenital ichthyosiform erythroderma. For ichthyotic manifestations due to these defects, topical application of some specific ceramides could be envisioned.

40.1.9Sphingomyelin Synthase 2 Mutations

and Osteoporosis

40

Heterozygous pathogenic variants in SGMS2 have been reported in 6 families affected by early-onset osteoporosis [15]. Whereas patients carrying the p.R50* variant had a normal development, low-bone mineral density, a history of multiple vertebral and peripheral fractures, and transient peripheral nerve palsies, patients with a missense variant presented with a more severe phenotype, including short stature, more severe cranial sclerosis and spondylometaphyseal dysplasia. The mechanisms that underlie the consequences of mutations in the sphingomyelin synthase 2 isoform on skeletal homeostasis and bone mineralization still require investigation.

40.1.10Mutations in Ceramide Kinase-Like

(CERKL) Gene and Retinal Dystrophy Mutations in CERKL have been associated with a group of inherited retinal dystrophies presenting as retinitis pigmentosa or cone rod dystrophy. The name

ceramide kinase-like was given because of 29% identity and 50% similarity with the human ceramide kinase that converts ceramide into ceramide 1-phosphate, but neither the substrate nor the function of the CERKL protein are yet known. At the current stage of knowledge, this disorder thus does not belong to sphingolipid synthesis disorders. It has been listed here by default due to its name, as it cannot yet be classified from a metabolic viewpoint (see [1] for more details).

40.2

Disorders of Lysosomal Sphingolipid Degradation: Sphingolipidoses

Sphingolipidoses are a subgroup of lysosomal storage disorders in which sphingolipids accumulate in one or several organs as the result of a primary deficiency in enzymes or activator proteins involved in their degradative pathway. Except for Fabry disease (X-linked recessive), the mode of inheritance is autosomal recessive. The clinical presentation and course of the classic forms are often typical. Late-onset forms, often less typical, have been overlooked in the past. No global biochemical screening procedure is available to date, but multiplex assay of lyso-sphingolipids can be of help. In nearly all sphingolipidoses (but not activator deficiencies) the diagnosis, oriented by clinical findings and anamnesis, is easily made by demonstration of the enzymatic defect, generally expressed in most cells and tissues (leukocytes represent the most widely used enzyme source, followed by dried blood spots). All efforts should then be made to identify the causal mutations in every patient. Conversely, whenever possible, diagnoses made in a proband by first-line gene analysis should be completed by a functional assay. Some specific therapies are well established (e.g., nonneuronopathic Gaucher and Fabry diseases), and more have been approved or are in late stage of clinical trials. However, despite recent advances, progress towards therapy of the neurological forms remains limited. Lysosomal Degradation of Sphingolipids and Sphingolipidoses Only the main sphingolipids implicated in sphingolipidoses are depicted in . Fig.  40.2. The scheme illustrates their degradation by stepwise hydrolysis, and shows enzymatic blocks leading to a disease. It also indicates which sphingohydrolase or sphingolipid activator protein (7 Sects. 40.2.4, 40.2.5, 40.2.6, and 40.2.9) is implicated, as well as the name commonly used to designate the various disorders.

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More complex gangliosides β β

GM1

β

β

β

-Cer

α

β

β

-Cer

Sandhoff α

β

β

β-Hexosaminidase A, B

GM1-β-Galactosidase

GM1-gangliosidosis GM2

Gb4

β

β

-Cer

Gb3

β

-Cer

Fabry β-Hexosaminidase A GM2-activator protein

Tay-Sachs, Sandhoff β

GM3

α-Galactosidase A sap-B

β

-Cer Sialidase sap-B

Glc Gal

β

GalNAc

LacCer

β

GALC, GM1-β-gal sap-A, sap-C

Neu5Ac

Lysosome

-Cer GlcCer

β

-Cer

MLD

Sulfatide β

Krabbe

GalCer β

-Cer

-Cer

SO4

ARSA sap-B

Cer GALC sap-A, sap-C

Farber Fabry α

β

-Cer

α-Galactosidase A sap-B

Gaucher

Glucocerebrosidase Sphingomyelin sap-C

Pcholine-Cer Sphingomyelinase

Niemann-Pick A/B Ceramidase sap-D

Sphingoid base (mostly sphingosine) + LCFA / VLCFA

Gb2

. Fig. 40.2 Lysosomal degradation of sphingolipids. ARSA arylsulfatase A, GALC galactocerebrosidase, GalCer galactosylceramide (or galactocerebroside), GalNAc N-acetylgalactosamine, Gb2 galactobiosylceramide, Gb3 globotriaosylceramide, Gb4 globotetraosylceramide (globoside), GlcCer glucosylceramide (or glucocerebroside), GM1 GM1 ganglioside,

GM2 GM2 ganglioside, GM3 GM3 ganglioside, LacCer lactosylceramide, LCFA long chain fatty acids, MLD metachromatic leukodystrophy, Neu5Ac N-acetyl-neuraminic acid (sialic acid), Pcholine, phosphorylcholine, sap saposin, VLCFA, very long chain fatty acids. Enzyme defects are indicated by solid bars across the arrows

40.2.1Gaucher Disease

erally associated with hepatomegaly. The degree of visceromegaly is highly variable, in both children and adults. Hypersplenism may lead to anaemia, thrombocytopenia and, thus, a bleeding tendency. Leukopenia is less frequent. Children may show delayed growth and menarche. Subcapsular splenic infarctions may cause attacks of acute abdominal pain and medullary infarction of long bones, excruciating pain referred to as bone crises. Essentially in adult patients, bone involvement represents a major cause of morbidity. Aseptic necrosis of the femoral head and spontaneous fractures due to osteopenia are other common complications. Lung involvement with diffuse infiltration may occur. In adults, pulmonary hypertension has been described in rare, usually splenectomised, patients. Co-morbidities with close association to GD have been identified, particularly non-Hodgkin’s B-cell lymphoma and multiple myeloma, and Parkinson’s disease [17–19]. Peripheral polyneuropathy was also reported more frequently than in a control population.

z

Clinical Presentation

Historically, three clinical phenotypes of Gaucher disease (GD) are recognised, but the full disease spectrum is a continuum. All types are panethnic, but type 1 has a particularly high prevalence in the Ashkenazi Jewish population (carrier frequency 1:13). The overall incidence is about 1:40,000–1:50,000 live births. For a comprehensive review, see [16]. Type 1 It is defined by the lack of neurological symptoms, and accounts for about 90% of all cases in the Western world. It can present at any age, but manifests in childhood in more than half of patients. There is a wide variability in the pattern and severity of the symptoms, from extremely handicapping to asymptomatic forms, with most symptomatic patients having visceral, haematological and (more frequently in adults) skeletal disease. Children often show severe splenomegaly, gen-

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Type 2 (acute neuronopathic GD) Classically, patients

present early in infancy with brain stem dysfunction and pyramidal signs. Retroflexion of the neck, opisthotonos, feeding difficulties and squint are major early signs, apnoeas appear later, and trismus and stridor are less frequent. Splenomegaly is constant but may not be present initially. The downhill clinical course is rapid, with pronounced spasticity, failure to thrive and cachexia, and few of these patients survive beyond the age of 2 years. Some other patients show strabismus, paucity of facial movements, less sign or none at all of pyramidal involvement, irritability or cognitive impairment and a slower course (some survive up to 5 years) [16, 20]. The perinatal lethal form is associated with hepatosplenomegaly, pancytopenia, and skin changes. Many of these cases are associated with hydrops fetalis, and some have been described as “collodion babies”. Arthrogryposis is seen in 40% of cases [20]. This type is heterogeneous. It is the predominant form in FarEast countries, India, Pakistan, and Egypt. The mean age at onset is 5 years (between 5 months and 46 years), with a mean age of neurological onset around 8  years. The most common form consists in severe systemic involvement and supranuclear saccadic horizontal gaze palsy, with or without developmental delay, hearing impairment and other brain stem deficits. The second most common phenotype shows a relatively mild systemic disease but progressive myoclonic encephalopathy, with seizures, dementia, and death. There are also patients with severe systemic involvement and supranuclear gaze palsy who develop a progressive myoclonic encephalopathy [16, 21]. Brain stem auditory evoked response (BAER) testing may reveal abnormal wave forms (III and IV). A particular presentation with cardiac involvement (heart valve and aortic calcification), supranuclear gaze palsy, mild hepatosplenomegaly, and bone disease, has been associated with homozygosity for the D409H mutation. In neurological GD, extrapyramidal involvement has also been observed. In view of future clinical trials, consensus criteria for inclusion of a patient within neuronopathic GD (especially gaze palsy) have been defined [22]. Type 3 (subacute or chronic neuronopathic GD)

40

z

Metabolic Derangement

The primary metabolic defect resides in a block of the lysosomal degradation of (β-)glucosylceramide (glucocerebroside, glucosylceramide, GlcCer, Gb1) and glucosylsphingosine. In the vast majority of cases this is due to the deficient activity of acid β-glucosidase (glucocerebrosidase, glucosylceramidase) (. Fig.  40.2). Exceedingly rare cases, presenting as type 3 or 1 (reviewed in [23]) are due to a deficiency of the saposin sap-C (7 Sect. 40.2.9). GlcCer accumulates in macrophages, inducing their transformation into Gaucher cells. GlcCer storage is massive in liver and spleen of patients in all types. Although

elevated in cerebral grey matter of type 2 and type 3 patients, its concentration in brain remains low. Glucosylsphingosine (or lysoGb1) also accumulates (in much smaller amounts) in tissues (but not in brain of GD type 1 patients), and in plasma for all types. This compound, formed by slow deacylation of GlcCer, also plays a role in pathophysiology of the disease, directly (immunogenicity [24], promotion of aggregation of α-synuclein, disruption of cellular Ca2  + homeostasis) or indirectly, through an alternate pathway involving the neutral glucosylceramidase GBA2 (. Fig. 40.1) [16]. The pathophysiology of the disease remains poorly understood, including the link between mutated GBA1 protein and Parkinson disease, and the relationship between Gaucher cells in tissues developed from M2 macrophages and blood monocytes with an inflammatory M1 phenotype [16]. z

Genetics

The disease (except for sap-C deficiency) is caused by mutations in GBA1 (>500 known). The most common variant in Ashkenazim, c.1226A>G (p.Asn409Ser) (former N370S), is also very frequent in Caucasian populations. The finding of one single such allele in a patient is predictive of a non-neuronopathic phenotype. The severity can vary widely in Gaucher patients with the same genotype, including N370S homozygotes [25]. The second most frequent mutation, c.1448  T>C (p. Leu483Pro) (former L444P), first described in Norbottnian type 3, is usually associated with types 3 or 2 when homozygous. Complex alleles due to genetic rearrangements are more frequently observed in severe forms, including perinatal lethal forms. A number of genotype-phenotype correlations have been made [26]. z

Diagnostic Tests

Bone marrow examination (not mandatory) may have revealed Gaucher cells. Several plasma biomarkers, e.g. chitotriosidase, the chemokine CCL18/PARK, and lysoGb1 are typically very elevated, but they are above all used to monitor treated patients (below). The assay of glucocerebrosidase activity in peripheral blood lymphocytes/ leukocytes or dried blood spots (DBS) (using fluorogenic or short-chain glucosylceramide substrates) constitutes the primary diagnostic test. DNA testing, complicated by the existence of a highly homologous pseudogene, is required for carrier detection, and improves diagnostic accuracy for patients with high residual enzyme activity. In sap-C deficiency, glucocerebrosidase activity is normal; the findings of Gaucher cells and elevated levels of lysoGb1 (or, less specific, chitotriosidase), should lead to PSAP sequencing. z

Treatment and Prognosis

Two approaches are currently available for the specific treatment of GD type 1 (and visceral manifestations of type 3 [27]: enzyme replacement therapy (ERT) and sub-

745 Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal…

strate reduction therapy (SRT). Splenectomy enhances the risk of progression of the disease at other sites, especially bone and lung, and should be avoided. Pregnancy is not contraindicated in untreated patients, but bleeding may become critical before and after birth; there is a good experience of ERT throughout pregnancy [28]. Conducted with slow infusions of a recombinant enzyme exposing mannose groups (optimal uptake by macrophages), ERT has largely proved safe and effective. Imiglucerase has been used worldwide for over 25 years; velaglucerase alfa [29] was approved 10 years ago, taliglucerase alfa 8 years ago [30]. The natural history of GD type1 can be dramatically improved. ERT prevents progressive manifestations and ameliorates GD-associated anaemia, thrombocytopenia, organomegaly, bone pain, fatigue, and bone crises. However, the enzyme does not cross the blood-brain barrier, and this treatment has no effect on the neurological manifestations of types 2/3. While ERT aims at restoring the degradation rate of the accumulated substrate, SRT tends to reduce the cell burden by slowing down the rate of synthesis of the substrate to a level where it can be slowly cleared by a deficient enzyme with some residual activity. This may be achieved by small molecules that can be administered orally. Two inhibitors of GlcCer synthase are currently approved for treatment of GD type 1: miglustat [31], and eliglustat [32]. Thus far, no specific treatment is approved for neuronopathic forms. A trial is planned with venglustat (another substrate inhibitor able to cross the blood brain barrier), in combination with imiglucerase. 40.2.2Acid Sphingomyelinase-Deficient

Niemann-Pick Disease (Type A, Type B and Intermediate Forms) Since the early 1980s, the heterogeneous group of “Niemann-Pick disease” has been divided in two separate entities: “acid sphingomyelinase-deficient NiemannPick disease” or “acid sphingomyelinase deficiency” (ASMD) [33], and Niemann-Pick disease type C (below). z

Clinical Presentation

ASMD has historically been categorised into a severe, acute neuronopathic form, or type A, and a nonneuronopathic form, or type B, but there appears to be a continuum ranging from mild to severe type B, and then from late-onset neurological forms toward severe classic type A. Type A has its highest prevalence in Ashkenazim and is rare in other ethnic groups. Type B does not have an Ashkenazi Jewish predilection, and appears more frequent in southern Europe, North Africa, Turkey, the Arabian Peninsula, and in Chile than in northern Europe. Classic Niemann-Pick Disease Type A The neonatal

period is usually normal, with vomiting or diarrhoea, or

both, appearing in the first weeks of life. Failure to thrive often motivates the first consultation, leading to the discovery of a prominent and progressive hepatosplenomegaly and lymphadenopathy, in most cases before 3-4 months of age and sometimes earlier. Hypotrophy is observed in 70% of the cases [34, 35]. Neurological examination is essentially normal until the age of 5-10 months, when the child shows hypotonia, progressive loss of acquired motor skills, lack of interest in the surroundings and reduction of spontaneous movements. Psychomotor retardation may at first be overlooked owing to the poor general condition. Initial axial hypotonia is later combined with bilateral pyramidal signs. A decrease of nerve conduction velocities is generally present. A cherry-red spot in the retina is a typical feature but is often not present until an advanced stage. Loss of motor function and intellectual deterioration continue to the point where patients become spastic and rigid. Seizures are rare. Brownish-yellow discoloration and xanthomas may be detected in the skin. Death usually occurs between 1.5 and 3  years. Cases with a milder systemic involvement, slightly protracted onset of neurological symptoms and slower course are also seen [34]. Niemann-Pick Disease Type B Type B is a chronic, non-

neuronopathic disease, with a highly variable degree of systemic involvement. Most typically, the presenting sign is splenomegaly or hepatosplenomegaly in late infancy or childhood [35, 36], but discovery may occur at any age from birth until late adulthood. Bruising and epistaxis are frequent. Hypersplenism occurs in a small proportion of patients. Splenectomy, seldom necessary, should be avoided. The most constant associated signs are radiographic abnormalities of the lung (diffuse, reticulonodular infiltrations) and interstitial lung disease with variable impairment of pulmonary function (low DLCO) [37]. In adults with a long follow-up, pulmonary involvement is often the main complaint, ranging from dyspnoea on exertion (frequent) to oxygen dependency. In children, retarded body growth is a common finding between the ages of 6 and 16  years. Skeletal age and puberty are often delayed [36]. Alterations of liver function are in general mild, but possibly underestimated; a few cases have been described with liver cirrhosis and liver failure. Hypercholesterolaemia with markedly decreased HDL-cholesterol is common even in children. Other features associated with the disease are joint/limb pain, bruising, headache, abdominal pain, and diarrhoea. True type B patients do not have neurological involvement and are intellectually intact, but ophthalmoscopic examination may reveal a retinal macular halo or cherry red maculae [36]. Although there are severe forms, a common phenotype is that of a moderately serious disorder compatible with an essentially normal lifespan [38]. In a longitudinal study the disease was characterised by hepatosplenomegaly, worsening athero-

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genic lipid profile, gradual deterioration in pulmonary function and stable liver dysfunction. Intermediate Forms of ASMD This is a heterogeneous

category. Some patients are closer to type A with a late infantile, juvenile, or adult neurological onset and a slowly progressive disease that may include cerebellar ataxia, extrapyramidal involvement, or psychiatric disorders [39, 40]. Some others are closer to type B, with minimal nervous system involvement (often peripheral neuropathy) and/or mild mental retardation [41]. z

Metabolic Derangement

A primary deficiency of the lysosomal (or acid) sphingomyelinase (ASM) (. Fig. 40.2) resulting from mutations in SMPD1 leads to the progressive accumulation of sphingomyelin in systemic organs in all types of the disease, and in brain in the neuronopathic forms [33]. Sphingomyelin storage is massive in liver and spleen in type A, slightly less so in type B. A significant increase of unesterified cholesterol occurs secondarily [42]. By in  vitro measurements, a marked ASM deficiency is observed in all patients, but hydrolysis of sphingomyelin in live cells demonstrates a significant level of residual activity in typical type B patients, suggesting this could be enough to protect the brain. Sphingosylphosphocholine (lysosphingomyelin) (increased in systemic organs of all types and in type A brain) likely participates in the pathogenic cascade. z

40

Genetics

More than 250 disease-causing mutations of SMPD1 are known [43]. In Ashkenazi Jewish type A patients, 3 variants collectively account for >90% of alleles. In type B, the globally most common (albeit with large regional differences) mutation, p.Arg610del (R608del), has always been correlated with a non-neuronopathic phenotype even in heteroallelic status. SMPD1 appears paternally imprinted. z

Diagnostic Tests

Bone marrow usually reveals the presence of (nonspecific) foamy and/or sea-blue histiocytes. Among plasma biomarkers, only a striking elevation of lysosphingomyelin is specific of ASMD, since abnormal levels of the oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol, and of “lysosphingomyelin-509” (now more properly renamed N-palmitoyl-O-phosphocholine-serine or PPCS), are also elevated in Niemann-Pick C (7 Sect. 40.4), and for oxysterols, in acid lipase deficiencies and some other conditions (reviewed in [44]). Chitotriosidase is moderately elevated. The diagnosis is made by demonstration of a deficiency in ASM activity in leukocytes/ lymphocytes, DBS, or cultured cells (much higher level of activity) [45]. The choice of a specific substrate is

critical. Radioactively labelled native sphingomyelin or a short-chain analogue with LC-MS/MS measurement are best. The fluorogenic substrate should be used with caution. The in vitro assay does not reliably distinguish A from B phenotypes. z

Treatment and Prognosis

Recommendations for clinical monitoring of ASMD patients have been published [46]. In type A patients, bone marrow transplantation (BMT) has not improved symptoms. In type B, splenectomy may have a deleterious effect on the lung disease. Pregnancy is not contraindicated, although monitoring for bleeding is advisable. Morbidity/mortality of types B and intermediate has been studied [47]. No specific therapy is yet approved, but interim results at 30  months of an ERT phase 1b trial in 5 type B adults treated with olipudase alfa have shown safety and efficacy [48], and a multicentric phase 2–3 trial is underway in adults and children.

40.2.3GM1 Gangliosidosis z

Clinical Presentation

Three main clinical phenotypes are described, based on age at first symptom and severity of disease progression. In the typical early infantile form (or type 1) [49, 50] infants are often hypotonic in the first days or weeks of life, with poor head control. The arrest in neurological development is observed at 3–6  months of age. Feeding difficulties and failure to thrive are common. Many patients show facial and peripheral oedema. Dysmorphic features (87% of cases), with coarse facies, moderate macroglossia, hypertrophic gums, depressed nasal bridge) are present very early or develop with time. Cardiomyopathy is seen in 1/3 of cases. Hepatomegaly and later splenomegaly are almost always present. Dorsolumbar kyphoscoliosis is common. The few patients showing no dysmorphic expression and possibly no hepatosplenomegaly overlap with type 2a (below). After a few months, signs of visual failure appear, often with a pendular nystagmus. A macular cherry-red spot is found in about 50% of cases, but seldom before 6  months of age. As time passes, hypotonia gives way to spasticity. Rapid neurological regression is usual after the first year of life. Seizures occur in10% of cases. Most patients die before age 3. Radiological signs in the long bones and spine are constant in typical patients but can be minimal in cases with only psychomotor deterioration. Subperiosteal bone formation can be present at birth. Widening of the diaphyses and tapering of the extremities appear later. At the age of 6 months, striking Hurler-like bone changes are seen, with vertebral beaking in the thoracolumbar zone, broadening of the shafts of the long

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bones with distal tapering and widening of the metacarpal shafts with proximal pinching of the four lateral metacarpals. Prenatal symptoms have also been described, and GM1 gangliosidosis is a cause of nonimmune foetal hydrops. Type 2 is characterized by more variability of neurological signs, the frequent absence of dysmorphia and hepatosplenomegaly, less severe skeletal changes, and a progression slower than type 1. Type 2 is now subdivided into a late infantile variant (type 2a), with onset between 7 months and 2-3 years of age, and a juvenile variant (type 2b) with onset between 3 and 10 years of age [50, 51] . First signs can be unsteadiness in sitting or standing, muscle hypotonia, often gait abnormalities, but also pyramidal signs or dysphagia (late infantile form), ataxia, dysarthria, dystonia. Seizures are frequent. Cognitive decline is not always present in the juvenile form. Vision is generally normal. Radiography of the spine reveals moderate but constant changes, with mild anterosuperior hypoplasia of the vertebral bodies at the thoracolumbar junction. The adult form or chronic late-onset variant (or type 3) has a less severe phenotype, with onset in late childhood, adolescence or adulthood, Dysarthria, dysphagia, and extrapyramidal signs, especially dystonia, are the most common signs. Cognitive impairment is absent to moderate, and there are no ocular abnormalities. Bone changes are inconstant. The course of the disease is very slow [52–54]. z

Metabolic Derangement

GM1 gangliosidosis is due to a deficient activity of lysosomal acid β-galactosidase (. Fig. 40.2), which cleaves glycoconjugates containing a terminal β-galactosidic linkage and is necessary for the degradation of GM1 ganglioside, other galactose-containing glycosphingolipids or oligosaccharides, and keratan sulfates (7 Chap. 41). Consequently, the most severe forms of the disease combine features of a neuronal lipidosis, a mucopolysaccharidosis and an oligosaccharidosis. Acid β-galactosidase functions in a multienzyme lysosomal complex with neuraminidase, the protective protein/ cathepsin A (PPCA) and N-acetyl-galactosamine-6sulfate sulfatase. This explains the quite similar clinical phenotype of galactosialidosis, a distinct condition due to the deficiency of PPCA, which causes a combined secondary deficiency of acid β-galactosidase and acid sialidase (neuraminidase) (7 Chap. 41). Finally, β-galactosidase deficiency can be associated with two clinically different diseases, GM1 gangliosidosis, with prominent features of a sphingolipidosis, and Morquio B disease (mucopolysaccharidosis type IVB), in which abnormalities of mucopolysaccharide metabolism prevail. In tissues from patients with GM1 gangliosidosis, three main groups of accumulated compounds

have been identified: the sphingolipid GM1 ganglioside, glycoprotein-derived oligosaccharides and keratan sulfate. Massive storage of GM1 occurs in brain tissue. Increased levels of its lysocompound, potentially of pathogenetic significance, have been reported. Galactose-containing oligosaccharides have been found in liver and urine. Keratan sulfate and other mucopolysaccharides accumulate in liver and spleen. Keratan sulfate excretion in urine is lesser in GM1 gangliosidosis than in Morquio B disease. z

Genetics

More than 160 disease-causing mutations of GLB1 have been described. Neither the type nor location of the mutation correlates well with a specific phenotype. z

Diagnostic Tests

Vacuolated lymphocytes may be found in peripheral blood, and foamy histiocytes in the bone marrow. Radiographic bone examination showing Hurler-like abnormalities (above) may suggest the diagnosis. In the infantile form, brain computerised tomography (CT) and magnetic resonance imaging (MRI) usually give nonspecific results, with diffuse atrophy of the central nervous system (CNS) and features of myelin loss in the cerebral white matter. Lesions in the basal ganglia may be present in the adult form. Analysis of urinary oligosaccharides is a good orientation test. In the classic early infantile form, excretion is massive, with a pathognomonic profile. Excretion can be much lower in forms with predominant neurodegenerative disease. Mucopolysaccharide analysis in urine usually shows increased levels of keratan sulfate. The diagnosis is established by demonstration of a deficient activity of acid β-galactosidase, which can be measured on leukocytes or DBS using an artificial fluorogenic substrate. A subsequent study of neuraminidase should be performed to exclude galactosialidosis. z

Treatment and Prognosis

There is currently no approved specific treatment. A combined miglustat/ketogenic diet (Syner-G) is in trial in infantile forms [49]. Two gene therapy phase 1-2 trials are ongoing or planned. 40.2.4GM2 Gangliosidoses

GM2 gangliosidoses are divided into three genetic and biochemical subtypes: Tay-Sachs disease (B or B1 variant) (TSD), Sandhoff disease (0 variant) (SD), and GM2 activator deficiency (AB variant). All are characterised by impaired lysosomal catabolism of GM2 ganglioside (. Fig.  40.2), which requires three gene products: the β-hexosaminidase α- and β-subunits and

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the GM2 activator protein. TSD corresponds to a deficiency of the α-subunit and thus of β-hexosaminidase A (αβ-heterodimer), SD, to a deficiency of the β-subunit and thus of both β-hexosaminidases A and B (ββ-homodimer). Classic TSD has a remarkably high carrier rate (estimated to ~1:27) in the Ashkenazi Jewish population, and in subjects of French-Canadian descent. Infantile forms are most common, but juvenile and adult forms are also recognised. A particular enzymatic/ molecular variant of TSD (B1 variant) has a high incidence in Northern Portugal and is globally more frequent in southern Europe. Variant AB is exceedingly rare, albeit probably underdiagnosed. z

40

Clinical Presentation

The infantile forms of the three subtypes have a remarkably similar presentation and evolution [49, 55, 56]. Around 4-6 months of age, motor weakness and hypotonia are the usual earliest signs, almost constantly associated with a typical startle response to sounds with extension of the arms (hyperacusis). Hypotonia progresses, with loss of acquired milestones. Loss of visual attentiveness is also seen early, and ophthalmoscopic examination almost invariably reveals a typical macular cherry-red spot in the retina. Blindness follows, and spasticity, swallowing disorder, and seizures develop. Macrocephaly begins by 18 months of age. By year 3 the child is demented and decerebrate. Death often occurs, due to aspiration pneumonia. In SD, despite an additional accumulation of glycolipids and oligosaccharides in visceral organs, organomegaly and bony abnormalities are rarely observed. Late infantile and juvenile forms [55, 57] are mostly due to a deficiency of β-hexosaminidase A (often B1 variant). The onset of symptoms is usually between 2 and 10  years of age, with ataxia, incoordination, and dysarthria, followed by progressive psychomotor deterioration, spasticity, and seizures. Myoclonus can be prominent. Cherry red-spots are inconstant. Chronic or adult forms [58–60] can show 4 typical presentations: lower motor neuron disorder, cerebellar ataxia, psychosis often with mood disorder (30–50% of adult-onset patients, particularly TSD), or a complex phenotype mixing these manifestations, e.g. a syndrome of lower motor neuron and spinocerebellar dysfunction with supranuclear ophthalmoplegia. Some patients show autonomic dysfunction. z

Metabolic Derangement

The catabolism of GM2 ganglioside requires the GM2 activator protein to extract GM2 from the plasma membrane before presenting it to hexosaminidase A (αβ-heterodimer). Hexosaminidase B (ββ-homodimer) hydrolyses other substrates with a terminal hexosamine (glycoproteins and glycolipids), but not GM2 ganglio-

side. In TSD (affecting the α-subunit), hexosaminidase A only is deficient. In SD (affecting the β-subunit) both hexosaminidases are inactive. In GM2 activator deficiency, the substrate is not made available to the otherwise normally functioning enzyme. All types are characterised by storage of GM2 ganglioside in neurons. This results in meganeurites, with aberrant neurite formation that may play a role in the pathophysiological mechanisms. GM2 storage is very pronounced in infantile forms, less so in juvenile forms, and even less in adult forms. Increased levels of lysoGM2 have also been reported in brain tissue of infantile forms. In SD, asialo-GM2 also accumulates in brain, while other compounds - such as globoside and oligosaccharides  - accumulate in liver and other visceral organs. z

Genetics

More than 130 mutations of HEXA have been identified. Three of them account for >95% of the Ashkenazi Jewish alleles. A carrier screening programme initiated in the 1970s was successful to decrease incidence of the disease in this population. A 7.6 kb deletion is common in French Canadian patients. Mutations at codon 178 result in the enzymatic B1 variant. Relatively good genotype-phenotype correlations have been reported. More than 40 mutations (including a common 16  kb deletion) in HEXB, and 6 in the GM2-activator GM2A gene have been described. z

Diagnostic Tests

The clinical diagnosis can easily be confirmed by enzyme testing on leukocytes, serum, DBS, or cultured fibroblasts. The assay for total hexosaminidases (A + B) using a synthetic fluorogenic substrate is straightforward and allows the diagnosis of SD. For hexosaminidase A (deficient in TSD), the sulfated synthetic substrate specific for the α-subunit is the method of choice (B and B1 variant); a high residual activity is found in SD, owing to excess of hexosaminidase S (αα-dimer). In GM2 activator deficiency, hexosaminidase A activity measured in vitro is normal; electron microscopic examination of a skin or conjunctival biopsy may provide strong evidence in favour of the diagnosis by demonstrating concentric lamellated bodies in nerve endings. The CSF shows increased levels of GM2. The definitive diagnosis requires GM2A sequencing. z

Treatment and Prognosis

Seizures are generally responsive to standard treatment. No effective curative treatment is currently available. Neither miglustat nor chaperone therapy (pyrimethamine) trials led to measurable clinical improvement. A combined miglustat/ketogenic diet (Syner-G) is still in trial in infantile forms [49]. Trials using venglustat (SRT,

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see 7 Sect. 40.2.1) in late-onset forms, and N-acetyl-Lleucine, are recruiting.

40.2.5Krabbe Disease z

Clinical Presentation

Krabbe disease (or globoid cell leukodystrophy) leads to demyelination of the central and peripheral nervous system. Its estimated overall incidence is between 0.75 and 1 in 100,000 live births. It is more frequent in Scandinavia (but not in Finland). The classic early infantile form accounts for about 65% of diagnosed cases. The incidence of late onset cases (more common in Japan, Italy, Sicily) has been underestimated. Infantile forms Clinical presentation is quite uniform,

usually very suggestive of the diagnosis. In the early infantile form, the onset is from birth to 6 months of age (often 3–4 months) [61]. Initial symptoms include increasing irritability, crying, vomiting and other feeding problems, hyperesthesia, tonic spasms on light or noise stimulation, and signs of peripheral neuropathy. Bouts of unexplained fever are also common. This stage with hypertonic episodes is followed by permanent opisthotonic posturing with characteristic flexed upper extremities and extended lower extremities. Seizures may appear. Hyperpyrexia and hypersalivation are frequent. As the disease progresses blindness occurs, followed by loss of bulbar functions and hypotonia. Death occurs from hyperpyrexia, respiratory complications, or aspiration, classically before the age of 2 years but in current practice not so rarely later. In the late infantile phenotype (onset between 7 and 12 months, about 10% of cases), patients typically present with a loss of developmental milestones and poor feeding, crying and irritability being later signs [62]. Later onset forms Clinical recognition of these forms is

more difficult. The juvenile form [63] starts between the ages of 13 months and 10 years (mostly T (historical 502C>T); [64, 68, 69]. Some common polymorphisms influence enzyme activity and may be responsible for a pseudodeficiency state, particularly when in compound heterozygosity with a diseasecausing allele [68]. Four infantile cases were assigned to mutations in the sap-A domain of PSAP. z

Diagnostic Tests

MRI shows areas of hyperintensity on T2-weighted images (7 Sect. 1.5.6) that correlate well with areas of demyelination and globoid cell accumulation [70]. In lateonset cases, T2-weighted images may show more localised areas of hyperintensity with less involvement of cerebellum and deep grey matter [71]. In adult-onset cases, typical T2 hyperintensities along the pyramidal tracts involving optic radiations and corticospinal tracts are nearly constant [64, 72]. In typical infantile cases, CT shows diffuse cerebral atrophy with hypodensity of the white matter. Calcifications may be observed in the thala-

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mus, basal ganglia, and periventricular white matter. Motor nerve conduction velocities are consistently low in infantile and most late infantile cases, but only about 60% of juvenile or adult patients display signs of peripheral neuropathy. Brain stem evoked potentials have also been studied [73]. Protein in CSF is usually elevated in infantile cases, but inconstantly in late-onset cases. The ultimate diagnosis is made by studying GALC activity in leukocytes, DBS, or cultured fibroblasts. This assay is subject to pitfalls of either technical (substrate) or biological (pseudodeficiency) nature. Use of a natural radiolabelled substrate (historical gold standard) is currently challenged by LC-MS/MS techniques using short-chain analogues [74, 75]. The less sensitive fluorogenic substrate should be used with caution. In Krabbe disease, like in metachromatic leukodystrophy (7 Sect. 40.2.6), a pseudodeficiency state is relatively common and can lead to misinterpretation of correct data. Genotyping is essential as prenatal diagnosis is currently done using molecular genetics. In sap-A deficiency, GALC activity was found deficient in leukocytes but not in cultured fibroblasts (sap-A may stabilise GALC). A recent observation is the usefulness of psychosine measurement (in plasma, DBS, or red blood cells) for screening and diagnosis, and differentiation of patients with an infantile vs late onset form [76]. z

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Treatment and Prognosis

Detailed management guidelines have been published [77]. In advanced disease, supportive analgesic treatment of the often-severe pain that can result from radiculopathy is important, as is treatment of spasticity. Allogenic BMT or cord blood transplantation may be effective in preventing onset or halting progression of the disease in late-onset cases. In symptomatic infantile cases HSCT has given poor results, but umbilical cord blood transplantation to asymptomatic 12- to 44-dayold babies appeared promising [78], leading to newborn screening in several states in the USA [79]. However, long-term follow-up indicated that over time most children developed slowly progressive motor and language deterioration along with somatic growth failure and persistent cognitive deficits [80]. A recent study in mouse models indicates that HSCT likely exerts its therapeutic benefit by restoring phagocyte function rather than cross-correcting myelin cells of GALC [81]. Promising preclinical attempts to gene therapy have been published.

40.2.6Metachromatic Leukodystrophy z

Clinical Presentation

Metachromatic leukodystrophy (MLD) is panethnic, with reported incidences ranging between 1:40,000 and 1:170,000, with higher frequencies in specific ethnic groups.

The late infantile form [82] is the most common. First symptoms appear before 30 months of age (usually between 1 and 2 years, with a median onset of 18 months): walking delay, progressive difficulty in  locomotion around 14-16  months (weaker lower limbs and falls); 15% of children never walk independently. Examination usually shows hypotonia, reduced or absent deep tendon reflexes and extensor plantar responses. Walking and then standing soon become impossible. The child develops spastic quadriplegia, speech deterioration, gradual mental regression and optic atrophy leading to blindness, followed by a vegetative state and death. Gallbladder abnormalities are quite frequent [83]. The early-juvenile form, with age of onset between 30 months and 4–6 years. Has usually a similar, but less rapid evolution. In the late-juvenile form the onset ranges between 6 and 14 years. Failure in school, behavioural problems or disturbance of cognitive function may precede motor abnormalities. Progressive difficulties in walking, with pyramidal signs and peripheral neuropathy, together with cerebellar ataxia constitute the most common presentation, but various other symptoms can occur, such as hemiplegia, dystonia and choreoathetosis. Spasticity may become prominent, and seizures may also develop [82]. A severity scoring based on a gross motor function classification (“GMFM”) has been developed for late infantile and juvenile forms [84]. Age of entry into the different stages and dynamics of decline of gross motor function [85], natural course of language and cognition [86] have been reported. Two distinct types of adult MLD have been identified. In the first group, patients have predominant motor disease, with pyramidal and cerebellar signs, dystonia and peripheral neuropathy, or isolated peripheral neuropathy. In the more frequent second group, behavioural and psychiatric problems (often confused with schizophrenia) are the presenting symptoms, followed by dementia and spastic paresis [87]. z

Metabolic Derangement

The primary metabolic defect is a block in lysosomal degradation of sulfatide (or galactosylceramide-sulfate) and other sulfated glycolipids (. Fig. 40.2). In vivo, sulfatide is presented to the enzyme arylsulfatase A (ARSA) as a 1:1 complex with sap-B (7 Sect. 40.2.9). A deficiency of either ARSA or sap-B can cause MLD. A few cases with sap-B deficiency have been documented, most with a late infantile form. Sulfatide is a prominent lipid component of the myelin sheath. Its ratio to galactocerebroside plays a role in the stability and physiological properties of this membrane. Progressive accumulation of sulfatides (and of lysosulfatide) in the central and peripheral nervous system will soon lead to disruption of the newly formed myelin and intense demyelination. In MLD, sulfatides also accumulate in the kidney

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(reflected by abnormal excretion in urine sediment), and the gallbladder. z

Genetics

About 200 different ARSA mutations are known [88]. There is a relatively good genotype-phenotype correlation [82]. Two very frequent ARSA polymorphisms (leading to the loss of an N-glycosylation site or of a polyadenylation signal) result in reduction of the amount of enzyme and constitute the molecular basis of ARSA pseudodeficiency [88]. They often occur jointly but can also be found independently. In some countries, as many as 15% of the general population carry one pseudodeficiency (pd) allele [82]. MLD due to sap-B deficiency is panethnic, but seems more frequent in Saudi Arabia, Turkey, and North Africa. These patients have mutations in PSAP. z

Diagnostic Tests

MRI shows similar fairly characteristic symmetrical changes of the central white matter in all forms. A sheet-like area of abnormal T2 signal hyperintensity initially envelops the frontal and parietal periventricular and central white matter regions, faint in mild disease and denser in moderate to severe disease. As severe disease develops, the sheet of white matter signal intensity abnormality also involves the inner half of the subcortical white matter, and a tigroid pattern emerges [89, 90]. The late infantile form also involves cerebral atrophy. Abnormalities are also described by diffusion tensor imaging (DTI) [91] and proton magnetic resonance spectroscopy (MRS). In most patients, motor nerve conduction velocities of peripheral nerves are decreased, and sensory nerve action potentials have a diminished amplitude with a prolonged peak latency. Decreased nerve conduction is not always present in adult MLD.  The CSF protein content is usually elevated in late infantile patients (although not at an early stage), inconstantly in the juvenile form and rarely in the adult form. Determination of ARSA activity in leukocytes (or cultured fibroblasts) using a p-nitrocatechol-sulfate substrate constitutes the first biochemical test. Development of LC-MS/MS methods is in progress [92]. Pseudodeficiency is a major pitfall [82]. Individuals homozygous for a pd. allele (1–2% of the European population), or subjects compound heterozygotes for a disease-causing mld and a pd. allele, have about 5–15% of normal ARSA activity but no detectable clinical abnormality or pathology. Deficient ARSA activity is therefore not enough to conclude to the diagnosis of MLD.  The study of sulfatides in the urinary sediment circumvents the problem. MLD (but also multiple sulfatase deficiency, see below) patients excrete massive (late infantile and juvenile patients) or significant (adultonset type) amounts of sulfatides, while subjects with an

ARSA pseudodeficiency have levels within or slightly above the normal range. ARSA pseudodeficiency also poses problems in genetic counselling. In a newly diagnosed family, it is important to measure enzyme activity in both parents. Full genotyping of the index case and study of parental DNA are highly recommended. Prenatal testing of MLD by DNA analysis is the preferred strategy. Another cause of erroneous interpretation of an ARSA deficiency is multiple sulfatase deficiency (MSD), due to a deficiency in the formylglycine-generating enzyme encoded by SUMF1. Whenever a deficiency of one sulfatase is found, it is mandatory to systematically measure the activity of another one (here, arylsulfatase B or iduronate-2-sulfatase) to exclude MSD, as the clinical picture can be misleading, and urinary excretion of sulfatides (but also of glycosaminoglycans) is abnormal. In MLD patients with sap-B deficiency, the in vitro ARSA assay will not show a deficiency. Studies of sulfatides and globotriaosylceramide (Gb3) excretion in urine are essential. Both lipids are elevated (combined MLD and Fabry pattern). The definitive diagnosis requires PSAP sequencing. z

Treatment and Prognosis

Symptomatic treatment of spasticity and of pain resulting from radiculopathy is important. Allogenic HSCT has been performed in a number of cases. It is generally considered that adult-onset and juvenile-onset patients benefit, with slowing of the disease progression and improvement of cognitive functions, but challenging reports have appeared [82, 93]. Whether HSCT is indicated in the late infantile form remains controversial [82]. Symptomatic patients are not candidates; presymptomatic affected siblings who received HSCT showed significant difference in survival and CNS involvement compared with untransplanted siblings, with no effect on the peripheral neuropathy. A recent study indicates that donor macrophages can digest accumulated sulfatides and indirectly enable remyelination, albeit without evidence of cross-correction of oligo-and astro-glia [94]. Nevertheless, preliminary evidence of safety and therapeutic benefit has been reported in a phase I/II trial with lentiviral haematopoietic stem cell gene therapy in presymptomatic or very-early symptomatic late infantile/ early-juvenile patients [95]. A phase 1-2 trial with intrathecal delivery of recombinant ARSA is also ongoing.

40.2.7Fabry Disease z

Clinical Presentation

Fabry disease, the only X-linked sphingolipidosis, is associated with severe multiorgan dysfunction [96–98]. From data from a recent newborn screening study [99] and after correction for non-pathogenic variants, an incidence of

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1:8500 males is obtained, much higher than historical estimations. This suggests a considerable underdiagnosis of atypical phenotypes. Of note, many heterozygous females are symptomatic. Patients are typically divided into a classic form and non-classic (variant or late-onset) forms, which correlate with residual enzyme activity and mutations [100]. Hemizygous males with the classic form have a disease onset during the first decade, typically with crises of severe pain in the extremities (acroparaesthesias) provoked by exertion or temperature changes, that may last hours to days. Unexplained bouts of fever and hypohidrosis, heat, cold and exercise intolerance, gastrointestinal problems, and corneal dystrophy (cornea verticillata) not affecting vision, are other manifestations. At this stage, renal function, urinary protein excretion and cardiac function and structure are generally still normal. Characteristic skin lesions, angiokeratomas, appear on the lower part of the abdomen, buttocks, and scrotum in 80% of patients. Progressive renal involvement, which may result in end-stage renal disease and require dialysis or transplantation, occurs in adulthood. Cardiac manifestations include left ventricular hypertrophy, valvular disease (mitral insufficiency), ascending aortic dilatation, coronary artery disease and conduction abnormalities leading to congestive heart failure, arrhythmias, and myocardial infarction. Cerebrovascular manifestations include early stroke, transient ischaemic attacks, white matter lesions, hemiparesis, vertigo or dizziness, and complications of vascular disease, in particular hearing loss. Depressive symptoms are also frequent. Acroparaesthesias, neuropathic pain, gastrointestinal problems can occur even in early childhood (before 5  years of age) [98]. Patients belonging to the second group show atypical cardiac, renal, or cerebrovascular manifestations with a milder, later onset phenotype, or a single organ involvement. Clinical manifestations in heterozygous females range from asymptomatic to fullblown disease, as severe as in affected males but with globally a later onset and slower progression. z

Metabolic Derangement

The primary defect is a deficient activity of the lysosomal enzyme α-galactosidase A, which releases galactose from ceramide trihexoside (globotriaosylceramide, Gb3) and related glycosphingolipids (especially galabiosylceramide, Gb2), due to mutations of GLA (. Fig. 40.2). This results in progressive accumulation of Gb3  in many tissues. The striking elevation of lysoGb3 observed in plasma of patients and tissues of Fabry mice suggests that this compound is also an important player in pathological events of the disease [101]. In vascular endothelial cells, perithelial and smooth muscle cells, this leads to ischaemia and infarction especially in the kidney, heart, and brain. Early and substantial deposition of Gb3 occurs in podocytes, leading to proteinuria, and with age, in cardiomyocytes,

causing cardiac hypertrophy and conduction abnormalities. Small-fibre polyneuropathy is the cause of pain and anhidrosis. Lysosomal storage and cellular dysfunction are believed to trigger a cascade of events resulting in tissue ischaemia and development of irreversible cardiac and renal tissue fibrosis [97]. z

Genetics

Fabry disease has an X-linked recessive transmission. Adequate genetic counselling in the family, including female carrier detection, is therefore essential. Nearly 1000 variants of GLA are known, and defining their pathogenicity remains a crucial problem, especially in screening programmes [102]. For key mutations associated with the classic or non-classic phenotypes, see [103]. De novo mutations are rare. In females, the X-chromosome inactivation pattern seems more contributive to disease expression than the mutation itself [104]. z

Diagnostic Tests

In affected males with the classic phenotype, the disease is readily diagnosed by showing a profoundly deficient α-galactosidase A activity in leukocytes. DBS are better suited to large-scale screening, but subsequent confirmation in leukocytes is essential. In hemizygous patients with a variant form, interpretation may sometimes be difficult due to a high residual activity. In heterozygous females, the enzyme assay is not reliable since it shows normal to low levels of activity. Measuring lysoGb3 in plasma or DBS has proved a valuable complementary tool for the diagnosis of patients with variant forms and female heterozygotes [102, 105]; this biomarker correlates with the disease phenotype, and it can also be used for monitoring of therapy [106]. In urinary sediment, Gb3 and Gb2 are excreted in large amounts by untreated hemizygous males (except those with a renal graft or with a cardiac variant), and in smaller amounts by 90% of heterozygote females, symptomatic or not. The diagnosis must in all cases be confirmed by GLA analysis. Knowing the pathogenic mutation conditions further family screening. Results of GLA sequencing alone can often be difficult to interpret in cases of suspected Fabry disease [107], and definite diagnosis should therefore combine several biological and clinical criteria. In atypical  – particularly cardiac  – variants, electron microscopic study of the target organ may be necessary [107]. z

Treatment and Prognosis

The disease results in a significant reduction in life expectancy due to renal disease and cardio- or cerebrovascular complications [97]. There is also the psychosocial burden of a rare, chronic, and progressive disease. Management and treatment recommendations have been published for adult patients [103] and children [108]. Alleviation of pain and treatment of the renal and cardiac disease are important issues. Dialysis or renal

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transplantation may be necessary for patients with endstage renal failure. There is a more than 15  yearexperience of ERT with recombinant α-galactosidase A products (agalsidase alpha or agalsidase beta). Longterm studies have shown a small but significant effect on cardiovascular and renal complication rates, above all loss of renal function, provided treatment is started early enough. It does not prevent strokes, nor progression of the disease. Several factors may influence effectiveness [106, 109]. The efficacy of ERT in adult female patients has been reviewed [110]. The oral pharmacological chaperone migalastat has also been approved for treatment of patients aged 16  years or older with an amenable mutation [111, 112]. Treatments under evaluation are second-generation ERT (pegunigalsidase-alfa, with a much longer plasma half-life; moss-alphaGal), and recent SRT compounds (venglustat and lucerastat), as well as gene-based therapy; (see [106] for review).

40.2.8Farber Disease/Acid Ceramidase

Deficiency z

Clinical Presentation

The very rare “Farber lipogranulomatosis“is clinically heterogeneous. It often presents during infancy causing death within the first year, but later onset cases (up to an adult age) have been described, as well as foetal forms [113]. The most frequent signs are painful joint swelling, deformation and contractures, periarticular subcutaneous nodules, and hoarseness due to laryngeal involvement. The presentation of some patients mimics juvenile idiopathic arthritis [114]. Hepatomegaly and a macular cherry-red spot may be present. Neurological manifestations are of variable severity (from mild to psychomotor deterioration and epilepsy); juvenile-onset patients may show neurological involvement only. A distinct form of acid ceramidase deficiency showing spinal muscular atrophy and progressive myoclonic epilepsy (SMA-PME) has been delineated [115], with more cases being recently described [116]. z

Metabolic Derangement and Genetics

The deficiency of acid ceramidase activity leads to the storage of ceramides in various organs [117]. More than 60 mutations of ASAH1 have already been described [118], including a large deletion. z

Diagnostic Tests

Electron microscopy of an excised nodule or of a skin biopsy may reveal inclusions with typical curvilinear bodies in histiocytes, and “banana bodies” in Schwann cells. In vitro measurement of ceramidase activity requires a specific substrate available in only few laboratories [119]; so are ceramide precursors loading tests in living fibroblasts or ceramide levels determinations. It is

therefore often easier and quicker to directly sequence ASAH1. z

Treatment and Prognosis

Currently there is no specific therapy. Good results of BMT have been reported only in patients without CNS involvement [120]. Development of ERT and gene therapy is being facilitated by the availability of a suitable mouse model.

40.2.9Prosaposin Deficiency z

Clinical Presentation

The nine published cases have shown almost the same course, with severe neurovisceral storage disease manifesting immediately after birth with rapidly fatal course and death between 4 and 30 weeks of age. The patients have hepatosplenomegaly, hypotonia, massive myoclonic bursts, abnormal ocular movements, dystonia, and seizures [121]. z

Metabolic Derangement and Genetics

Sphingolipid activator proteins are small glycoproteins that are required as cofactors for the lysosomal degradation of sphingoglycolipids with short hydrophilic head groups and ceramide. They act either by solubilising the substrate or by mediating enzyme binding to the membrane or modifying the enzyme conformation. PSAP encodes the prosaposin protein, which is transported to the lysosome where it is processed to four homologous proteins. Sap-A is a cofactor for degradation of galactosyl- and lactosylceramide; its deficiency causes a Krabbe disease variant (4 cases known); sap-B is involved in the in vivo degradation of sulfatides and Gb3, and its deficiency causes an MLD variant (>25 cases known); sap-C is necessary for hydrolysis of glucosylceramide, and its deficiency causes a Gaucher disease variant (5 cases known). Although no patient has been described with sap-D deficiency, this factor is implicated in ceramide degradation. Prosaposin deficiency is due to the combined lack of all four sap- factors, explaining tissue storage of all the lipids cited above. Lipid studies in liver tissue revealed a combined increase of glucosylceramide, lactosylceramide and ceramide. The disorder is autosomal recessive. Mutations identified in patients explain abolished production of the prosaposin precursor and thus of all four factors. z

Diagnostic Tests

Gaucher-like cells are found in bone marrow. Study of glycolipids in urine sediment shows a pattern close  to that described for sap-B deficiency. Galactocerebrosidase activity has been reported to be deficient in leukocytes and fibroblasts. Loading tests

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in living fibroblasts have shown a severe block in ceramide hydrolysis. In practice, the finding of a concomitant elevation of lysoGb3 and lysoGb1 in plasma [121], or of sulfatides and Gb3 in urine, should lead to complete PSAP sequencing.

40.3

Disorders of Non-Lysosomal Sphingolipid Degradation

40.3.1Non-lysosomal β-Glucosidase (GBA2)

Deficiency: SPG46 and Ataxia

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GBA2 is a membrane-associated protein localised at the endoplasmic reticulum (ER) and Golgi, most likely facing the cytosol. This enzyme can hydrolyse glucosylceramide to ceramide and glucose. While acting on the same substrate but in a different subcellular location, GBA2 is distinct from the lysosomal acid β-glucosidase GBA1 deficient in Gaucher disease (7 Sect. 40.2.1). The formed ceramide re-enters the biosynthetic pathway (. Fig. 40.1) or could play a role as a bioactive lipid in case of excessive formation. Since 2013, several studies have shown that mutations in GBA2 should be added to the heterogeneous group of ARCAs (autosomal recessive cerebellar ataxias), and also underlie the hereditary (complex) spastic paraplegia locus SPG46. Most patients with GBA2 deficiency develop in childhood a marked spasticity in lower extremities with progressive gait disturbances and later, ataxia and other cerebellar signs. Variable additional symptoms have been reported, such as hearing loss or cognitive impairment, or Marinesco-Sjögren syndrome. Some patients presented testicular hypotrophy associated with spermatozoid head abnormalities [1]. Besides DNA sequencing, diagnosis can be achieved by determination of enzyme activity using a specific method. Potential interactions between GBA1 and GBA2 may play a role in Gaucher disease. The paradoxical clinical amelioration reported in mouse models of Gaucher and Niemann-Pick C (7 Sects. 40.2 and 40.4) diseases after GBA2 inhibition remains an intriguing observation [122, 123].

40.3.2Neutral Sphingomyelinase-3

Deficiency Affected children from 12 unrelated families have just been described to harbour biallelic variants in SMPD4, which encodes a putative neutral sphingomyelinase, neutral sphingomyelinase-3, a type of enzyme able to hydrolyse sphingomyelin at neutral pH.  Sixteen different SMPD4 variants were identified, all likely resulting

in loss of function of the corresponding protein [124]. Most patients shared a severe neonatal presentation including intra-uterine growth retardation, microcephaly, neonatal respiratory distress, congenital arthrogryposis, abnormal muscular tone, and seizures. One third of children died before 1 year of age. MRI showed microcephaly with a simplified gyral pattern, cerebellar hypoplasia and hypomyelination. Whether this phenotype and the ER stress and disturbed autophagy observed in fibroblasts from affected children is linked to abnormal sphingomyelin degradation requires further investigation.

40.3.3Alkaline Ceramidase 3 (ACER3)

Deficiency: Infantile Leukodystrophy Whether the deficiency of ACER3, which is not a lysosomal storage disease, represents a true sphingolipid degradation or a remodelling defect remains to be determined. A homozygous missense mutation in ACER3, coding for alkaline ceramidase 3, localised to both the Golgi complex and the ER, has recently been described in two siblings with leukodystrophy. They presented with neurological regression at 6–13  months of age, truncal hypotonia, appendicular spasticity, dystonia, optic disc pallor, peripheral neuropathy, and neurogenic bladder. The ACER3 mutation was associated with undetectable ACER3 catalytic activity towards natural and synthetic ACER3-specific substrates, and an accumulation in plasma of ACER3 substrates, C18:1- and C20:1-ceramides and dihydroceramides, as well as some complex sphingolipids, including monohexosylceramides and lactosylceramides [125].

40.3.4Sphingosine-1-phosphate Lyase

(SGPL1) Deficiency: A Multisystemic Disorder Loss of function of sphingosine 1-phosphate (S1P) lyase, the last enzyme which irreversibly cleaves S1P and releases a fatty aldehyde, thus connecting sphingolipid and glycerophospholipid metabolisms, results in various clinical phenotypes. The most severe, early-onset forms include foetal hydrops with congenital brain malformations, congenital steroid-resistant nephrotic syndrome, primary adrenal insufficiency, adrenal calcifications, ichthyosis, primary hypothyroidism, neurological defects, and lymphopenia [126–129]. A juvenile form characterised by an axonal peripheral neuropathy has also been reported [130]. The plasma levels of S1P as well as the sphingosine/ sphinganine ratio were increased in the patients.

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40.4 z

Niemann-Pick Disease Type C

Clinical Presentation

Niemann-Pick disease type C (NP-C) is panethnic, with an estimated incidence at birth around 1 in 100,000 [131, 132]. The clinical course is extremely heterogeneous and age at presentation varies from the perinatal period to late adulthood. Visceral involvement (liver, spleen, and lung) and neurological or psychiatric manifestations arise at different times, and they follow an independent course. Systemic disease, when present, always precedes the onset of neurological symptoms; the systemic component may decrease with time, be minimal, or absent. Apart from a small subset of patients who die in the perinatal period and exceptional adult cases, all patients ultimately develop a progressive and fatal neurological disease. For periods other than perinatal, some patients may show only systemic signs, while others start to show neurological symptoms. A classification by neurological form (rather than by age at disease onset) is justified, because a correlation between age at neurological onset and following course of disease and lifespan has been established [131]. Perinatal Presentations

z

Foetal period

Foetal hydrops or foetal ascites (often with splenomegaly) can occur. z

of adults (aged up to 60 years) have been described with systemic disease only [131].

Neonatal period

In early life, liver involvement is often present. About one third of NP-C patients show a prolonged neonatal cholestatic icterus with hepatosplenomegaly. In most patients, the cholestasis resolves spontaneously and only hepatosplenomegaly remains. Such patients will later develop neurological symptoms, although rarely with an adult onset [131, 133]. In a few infants, the liver disease worsens, and they die from hepatic failure before 6 months of age, defining a neonatal, cholestatic rapidly fatal form. Affected siblings may present differently and develop a neurological (often early infantile) form. A few neonates (more often with NPC2 mutations) develop a severe respiratory insufficiency with pulmonary alveolar proteinosis and die in their first months, or after onset of neurological symptoms in their first years. Isolated (hepato)splenomegaly can also start at the neonatal period [131]. Isolated splenomegaly or hepatosplenomegaly can be the first sign of NP-C and be detected at any age (differential diagnosis with NP-B and Gaucher type 1), with a highly variable delay before onset of neurological symptoms. A handful

Period with Isolated Systemic Symptoms

Neurological Forms z

Early infantile form

In the severe early infantile neurological onset form, infants with a pre-existing hepatosplenomegaly (often with a history of neonatal cholestatic jaundice) show hypotonia and an early delay in motor milestones that becomes evident between the ages of 9 months and 2 years. Most never learn to walk. The mental status is less severely affected. A loss of acquired motor skills is followed by spasticity with pyramidal tract involvement and mental regression. Signs of white matter involvement are present. Survival rarely exceeds 6 years [131, 134]. z

Late-infantile- and juvenile-onset neurological forms (classic NP-C, 50–60% of incident cases)

In the late infantile form, hepatosplenomegaly has generally been present for a varying period, but may be absent. Language delay is frequent. At the age of 3–5  years, the first obvious neurological signs are gait problems and clumsiness, due to ataxia. The motor problems worsen, cognitive dysfunction appears. In the juvenile form, onset of neurological disease is between 5–6 and 12  years, with more insidious and variable symptoms. Splenomegaly is variable. School problems, with difficulty in writing and impaired attention, are common and may lead to misdiagnosis. The child becomes clumsier with increasing learning disabilities, and obvious ataxia. In both forms, vertical supranuclear saccades palsy, with an increased latency of initiation of vertical saccades, is almost constant when correctly assessed, and an early sign. Vertical supranuclear gaze palsy develops later. Gelastic cataplexy occurs in about 20% of patients and can be the presenting symptom. As ataxia progresses, dysphagia, dysarthria and dementia develop. Action dystonia is also frequent. About half of the patients develop seizures, which may become difficult to treat. In a later stage, the patients develop pyramidal signs and spasticity and severe swallowing problems. Most require gastrostomy. Death usually occurs between 7 and 12–14 years of age in late-infantile-onset patients, and is very variable in the juvenile form, some patients being still alive by age 30 or more [131, 133]. z

Adolescent/adult onset form

Age at diagnosis varies between 15 and 60 years or more. In adult-onset patients, presentation is even more insidious, and diagnosis seldom made at an early stage. Atypical signs may in retrospect have been present since adolescence. Major signs are ataxia, dystonia and dysarthria, movement disorders, with variable cognitive dys-

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function; psychiatric symptoms and dementia are dominant in certain patients [133, 135]. In recent cohorts, supranuclear vertical saccades palsy was a nearly constant sign. Epilepsy is rare in adult NP-C. Splenomegaly is inconstant. z

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Metabolic Derangement

The disease is due to a defect of NPC1 (in most cases) or NPC2. NPC1 is a large late endosomal/lysosomal protein with 13 transmembrane helices [of which 5 form a sterol-sensing domain (SSD)], and 3 luminal loops. NPC2 is a small, single-domain luminal lysosomal protein. Although the full function of NPC1 may be more complex, it is established that the two proteins work in sequence, in a “hand-off ” model, to regulate the export of endocytosed cholesterol from the late endosomal/ lysosomal (LE/Ly) compartment. (see also 7 Chap. 44) Loss of function of either protein thus results in accumulation and sequestration of unesterified cholesterol in LE/Ly (hence a delay in subsequent homeostatic reactions). The transport mechanism is in large part elucidated. Facilitated by lysobisphosphatidic acid (LBPA), NPC2 binds cholesterol from intraluminal vesicles, docks into NPC1 middle loop and transfers the sterol to the N-terminal NPC1 loop. The latter rotates to form a tunnel pathway between the other loops, allowing cholesterol to pass through the glycocalyx and reach the SSD [136, 137]. Final steps of egress are still unknown. The defect of NPC1 or NPC2 results in a similar complex lipid storage profile. In liver and spleen, besides unesterified cholesterol, sphingomyelin, several glycolipids, sphingosine and LBPA, accumulate, with no prevailing compound. In brain, despite clearly abnormal filipin staining in neurons, there is no global increase of cholesterol (nor of sphingomyelin) in grey matter, and storage of GM2 and GM3 gangliosides is the dominant abnormality [42]. Sphingolipid accumulation appears to be secondary to cholesterol storage [42, 138]. Main pathologic changes in brain, besides neuronal storage, are a prominent loss of Purkinje cells, neuroaxonal dystrophy, neurofibrillary tangles, meganeurite formation and ectopic dendritogenesis. Signs of myelination delay and severe myelin loss are only prominent in the early infantile neurological form [42]. Other described abnormalities such as Impairment in Ca2+ release from acidic compartments and defects in autophagy likely play a significant role in the pathogenic cascade. z

Genetics

Approximately 95% of patients harbour mutations in NPC1, the remainder in NPC2. More than 500 diseasecausing NPC1 mutations are known. The most frequent ones in patients of western European descent are p. Ile1061Thr, followed by p.Pro1007Ala, albeit with marked geographical differences. Some 60 families are known with NPC2 mutations. Studies in multiplex fami-

lies indicate that mutations correlate with the global neurological form rather than with the systemic manifestations. Certain mutations (e.g., p.Pro1007Ala) are associated with a milder block in cholesterol trafficking (‘variant’ filipin test, see below) [131, 132]. z

Diagnostic Tests

Neuroimaging is generally not contributive to the diagnosis. Foamy and sea-blue histiocytes may (not always) be found in bone marrow aspirates. Until recently, the “filipin test” (i.e. demonstration in cultured cells of an accumulation of unesterified cholesterol in perinuclear vesicles, visualised by fluorescence microscopy after staining with filipin) was considered as the firstline diagnostic assay, followed by genetic testing [139]. This incurred a skin biopsy and fibroblast culture, and expert interpretation in the 15% of cases with milder accumulation (“variant profile”) [44]. Several plasma metabolites have emerged as sensitive NP-C biomarkers [44], and their measurement (in plasma, or DBS for some of them), has now replaced the filipin test as the recommended first-line assay [132]. The oxysterols cholestane-3β, 5α, 6β-triol and 7-ketocholesterol, the bile acid 3β,5α,6β-trihydroxy-cholanoyl-glycine, and N-palmitoyl-O-phosphocholine-serine [PPCS] (correct structure and name of “lysosphingomyelin-509”), are elevated in nearly all patients with NP-C, but also in acid sphingomyelinase deficiency (ASMD) (and for oxysterols, in some other diseases) (7 Sect. 40.2.2) [44]. Distinction can be made by the concomitant study of lysosphingomyelin, strikingly elevated only in ASMD.  Elevated values for one or several biomarkers are a strong argument, but the tests have limitations, and the definitive diagnosis of NP-C requires molecular analysis of NPC1 and NPC2. In the not so rare cases in which genetic testing remains inconclusive, the filipin test regains ground as the best functional approach. Only molecular genetics testing is now used for prenatal diagnosis [131, 139]. z

Treatment and Prognosis

Clinical management guidelines have been published [132, 139]. Cataplectic attacks can be treated by clomipramine or CNS stimulants. Management of epilepsy, when present, is essential. With progression, most patients will require tube feeding or gastrostomy. To date, miglustat is the only treatment specifically approved for neurological manifestations of NP-C, in the EU and other countries (not in the USA). Indications, clinical utility, and monitoring have been discussed [139], and studies prior to 2018 reviewed [140]. Initial data indicating effect on swallowing impairment, stabilisation of patients for 1 year or more and a slower rate of progression of the disease after treatment have been confirmed. Patients with later onset forms appear as better responders [141, 142]. Effect on survival has also been studied.

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Encouraging results were obtained in a phase 1-2 trial with intrathecal administration of 2-hydroxypropyl-βcyclodextrin (HPBCD) [143], but data from the phase 2b-3 trial have not been published. Promising results have been reported for a phase 2/3 trial with oral administration of arimoclomol, a heat shock (hsp70 and hsp40) proteins enhancer [144]. Other trials with IV administration of HPBCD, or oral administration of N-acetyl-Lleucine are ongoing. At variance with NP-C1, there is a rationale for HSCT in NP-C2 patients, but neurological follow-up at 9 years of age in the only patient known to survive the procedure is rather poor [134].

40.5

Neuronal Ceroid Lipofuscinoses

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive neurodegenerative diseases, among the most frequent in childhood. The term NCL is widely used in Europe, but the generic name “Batten disease” is common in the USA. The past 25 years have seen major advances in the field and the clinical diversity has now been linked to a wide genetic heterogeneity, with 13 different genes identified to date. Five of them encode soluble proteins, the others encode transmembrane or cytosolic proteins whose function still remain incompletely understood. NCLs have been linked to lysosomal storage diseases, due to the lysosomal accumulation of lipopigments, and localisation of several NCL proteins to the lysosome, even though other NCL proteins are localised to non-lysosomal cellular compartments. z

Clinical Presentation

NCLs are usually characterised by progressive psychomotor retardation, seizures, visual loss, and early death. Four main clinical forms have been described according to the age of onset and the order of appearance of clinical signs: infantile, late infantile (the most common in South Europe), juvenile (common in Anglo-Saxon countries), and adult (rare) [145]. However, numerous other clinical variants have been reported. This clinical heterogeneity is related to the diversity of the genes involved and to the variable severity of mutations. Therefore, the first classification based on the clinical forms has now been replaced by a new one using the genetic loci and including various forms with different ages of onset although one form is usually predominant for each gene [146] (. Table 40.2). Classic Infantile Neuronal Ceroid Lipofuscinosis (Santavuori-Haltia Disease) Linked to PPT1 (CLN1 Disease) Its inci-

dence is high in Finland (1  in 20,000). Children with infantile NCL are normal at birth. Symptoms usually begin between 6 and 24  months. They include delayed development, hypotonia, deceleration of head growth,

seizures, and jerks. Sleep disturbances are seen in most children. Rapid visual impairment occurs due to optic atrophy and macular degeneration. Stereotyped hand movements may be present. Death takes place in the first decade of life. Whereas mutations in PPT1 are mainly responsible for this classic infantile NCL, later-onset forms (juvenile, adult) have also been described, probably due to less severe mutations. z

Variants due to another gene

Mutations have occasionally been found in KCTD7 (CLN14 disease) in patients with infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, and premature death. KCTD7 mutations have also been involved in non NCLphenotypes such as opsoclonus myoclonus ataxia syndrome associating acute onset of myoclonus and ataxia with abnormal opsoclonus-like eye movements [147, 148]. Classic Late Infantile Neuronal Ceroid Lipofuscinosis (Jansky-Bielschowsky Disease) Linked to TPP1 (CLN2 Disease) Children may be initially referred for delayed

speech. Seizures, which may be of any type (partial, generalised tonic-clonic, absences) occur between 2 and 4  years of age. Ataxia, myoclonus, and developmental regression become apparent, followed by a gradual decline of visual ability culminating in blindness by 5 or 6 years. Death happens in middle childhood after a bedridden stage. Besides this classic late-infantile NCL, mutations in TPP1 have also been involved in atypical phenotypes with delayed onset and slower progression. Moreover, mutations in TPP1 have been reported in autosomal recessive spinocerebellar ataxia 7 (SCAR7). Patients showed ataxia, but neither visual abnormalities nor epilepsy, and the disease is slowly progressive until old age. z

Variants due to other genes

Variants with similar or later onset, or delayed evolution compared to the classic late infantile form have been described. The Northern epilepsy or progressive epilepsy with mental retardation (EPMR) linked to CLN8 is characterised by tonic-clonic seizures occurring between 5 and 10 years. Mental deterioration is observed 2–5  years after the onset of epilepsy. Vision problems are rare. Some patients are surviving well over 40 years. Mutations in CLN8 have also been reported in a subset of late-infantile patients from Turkish consanguineous families. Variants in CLN5 have been identified in Finland as well as other countries, such as Italy [149]. This form usually begins around 4.5–6 years of age by clumsiness and difficulties in concentration. Visual impairment, ataxia and epilepsy appear a few years later. Life expectancy is between 13 and 35 years. Two additional genes are commonly involved in late-infantile variants

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. Table 40.2 Classification of NCLs. The different loci are organized according to the age of onset of the main clinical form (indicated in bold in the right column). The non-NCL phenotypes associated to the same genes are given in italics. ATP13A2 and KCTD7 have rarely been linked with NCL phenotypes

40

Gene (disease name)

Protein name (abbreviation)

Protein location and type

Clinical forms

CTSD (CLN10 disease)

Cathepsin D

Lysosomal enzyme

Congenital Late infantile, juvenile, adult

PPT1 (CLN1 disease)

Palmitoyl protein thioesterase 1 (PPT1)

Lysosomal enzyme

Classic infantile Late infantile, juvenile, adult

KCTD7 (CLN14 disease)

Potassium channel tetramerization domain-containing protein 7 (KCTD7)

Cytosolic protein, associated with plasma membrane

Infantile, late infantile (rare) Progressive myoclonic epilepsy Opsoclonus-myoclonus ataxia-like syndrome

TPPI (CLN2 disease)

Tripeptidyl peptidase 1 (TPP1)

Lysosomal enzyme

Classic late infantile Juvenile, protracted, spinocerebellar ataxia recessive type 7 (SCAR7)

CLN5 (CLN5 disease)

CLN5 protein

Soluble lysosomal protein

Late infantile Juvenile, adult

CLN6 (CLN6 disease)

CLN6 protein

Endoplasmic reticulum membrane protein

Late infantile Adult type A Kufs Juvenile cerebellar ataxia

MFSD8 (CLN7 disease)

MFSD8 Major facilitator domaincontaining protein 8

Lysosomal membrane protein

Late infantile Juvenile, protracted Adult macular or cone-rod dystrophy

CLN8 (CLN8 disease)

CLN8 protein

Endoplasmic reticulum membrane protein

Late infantile Protracted Northern epilepsy (EPMR)

CLN3 (CLN3 disease)

CLN3 protein

Lysosomal membrane protein

Classic juvenile Protracted Autophagic vacuolar myopathy, retinitis pigmentosa, adult cone-rod dystrophy

ATP13A2 (CLN12 disease)

ATP13A2

Lysosomal membrane protein

Juvenile (rare) Kufor-Rakeb syndrome, hereditary spastic paraplegia (SPG78), juvenile onset amyotrophic lateral sclerosis-like

DNAJC5 (CLN4 disease)

Cysteine-string protein alpha (CSPα)

Cytosolic protein, associated with vesicular membranes

Adult type A Kufs (dominant)

CTSF (CLN13 disease)

Cathepsin F

Lysosomal enzyme

Adult type B Kufs

GRN (CLN11 disease)

Progranulin

Soluble lysosomal protein

Adult Frontotemporal lobar dementia (heterozygous)

presenting a clinical pattern close to the CLN2 disease. Mutations in CLN6 are mainly seen in patients originating from South Europe, the Indian subcontinent, and South America. CLN7 (MFSD8) has been initially involved in Turkish patients with late-infantile NCL, but abnormalities in this gene have now been reported in patients from different countries [147].

Classic Juvenile Neuronal Ceroid Lipofuscinosis (Batten or Spielmeyer-Vogt Disease) Linked to CLN3 (CLN3 Disease) The onset is between 4 and 10 years of age. Visual

failure is usually the first clinical sign and it results in total blindness in 2–3  years. Seizures appear between 5 and 18 years. They are tonic-clonic at onset, but multifocal motor seizures become more frequent with age.

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Speech becomes dysarthric and echolalia is frequent. Many patients develop signs of parkinsonism. Mental capacity is progressively altered, and dementia becomes evident in several years. Behavioural problems with aggressiveness may occur. Most patients live until the late teens or early/late 20s. Cardiac signs have been reported in adolescent and adult CLN3 patients, such as left ventricular hypertrophy and bradycardia leading to a risk of death [150]. A protracted atypical phenotype has recently been reported in patients showing a rapid visual failure followed 20 years later by seizures, hypertrophic cardiomyopathy, the presence of autophagic vacuoles in muscle biopsy and only mild cognitive impairment after 40 years of evolution. z

Variant due to another gene

Mutations in ATP13A2 (now CLN12 disease) have rarely been associated with a juvenile NCL variant showing learning difficulties around 8 years, followed by unsteady gait, myoclonus, mood disturbance, and extrapyramidal signs such as akinesia, rigidity and dysarthric speech. ATP13A2 is mainly involved in non-NCL disorders such as Kufor-Rakeb syndrome (rare parkinsonian syndrome with juvenile onset), but also autosomal recessive spastic paraplegia (SPG78) and juvenile-onset amyotrophic lateral sclerosis-like [148]. Adult Neuronal Ceroid Lipofuscinosis (Kufs Disease)

Symptoms usually start around age 30  years, but onset during adolescence or late adulthood has been reported. Kufs disease is usually inherited as an autosomal recessive trait, but a rare dominant form (called Parry disease) also exists. Classically, two major forms of Kufs disease have been delineated. Type A is characterised by PME while type B is marked by dementia and a diversity of motor signs. Retinal vision is generally preserved. Previously the genes involved in these forms had remained uncharacterised although PPT1 mutations had been found in some patients. CLN6 is now considered as a major gene in recessive type A Kufs disease and the dominant form (called CLN4 disease) has been linked to DNAJC5 (CLN4) encoding cysteine-string protein alpha (CSPα). Causal abnormalities have also been found in CTSF (CLN13) encoding cathepsin F in patients with type B Kufs disease. Moreover, mutations have been reported in GRN (CLN11) encoding progranulin in siblings with rapidly progressive visual failure around 20  years, myoclonic seizures, cerebellar ataxia, and early cognitive deterioration. Unexpectedly, these patients were homozygous for a GRN mutation, while heterozygous mutations in the same gene are a major cause of frontotemporal lobar dementia. These two diseases significantly differ by their age of onset and neuropathology [147].

z

Congenital form

This rare form presents with microcephaly and seizures at birth, resulting in death within the first days of life. Mutations in CTSD (or CLN10) have been found in some patients, but other causative genes probably remain to be identified [147]. z

Metabolic Derangement

Ceroid lipofuscinoses are characterised by the accumulation of autofluorescent ceroid lipopigments, mainly in neural tissues. They show different ultrastructural patterns, such as granular, curvilinear or fingerprint profiles [151]. The main components of this storage material are either saposins A and D in infantile forms, or subunit c of mitochondrial ATP synthase in late infantile and juvenile forms. They are probably not disease-specific substrates, but secondary markers. NCL proteins are mainly localised in the lysosome (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12, CLN13), but also in the ER (CLN6, CLN8) or in the cytosol in association with vesicular membranes (CLN4, CLN14). Some of them are soluble proteins: palmitoyl protein thioesterase 1 (CLN1), tripeptidyl peptidase 1 (CLN2), cathepsin D (CTSD), cathepsin F (CTSF) and CLN5. Others are transmembrane proteins (CLN3, CLN7, CLN12), the function of which is still incompletely understood; for a review, see [148]. Briefly, CLN1 is involved in the degradation of S-fatty acylated proteins (depalmitoylation) and in the maintenance of the synaptic pool by regulating exo- and endocytosis and synaptic vesicle recycling. (see also 7 Chap. 44) It is linked to CSPα (CLN4) which is likely its substrate. CLN2 is a serine protease which removes tripeptides from proteins facilitating their degradation in lysosomes, but its substrates are not yet clearly defined. It is possibly involved in macroautophagy and TNFα-induced apoptosis. Cathepsin D is an aspartyl protease important for apoptosis and autophagy; it is probably implicated in the biogenesis and synaptic transmission in GABAergic neurons. Cathepsin F is a lysosomal cysteine protease. It is involved in endosomal and lysosomal trafficking regulation via its newly discovered role in the cleavage of LIMP-2 (a mannose6-phosphate independent receptor). The function of CLN5 is still debated, but it has been reported to interact with different other NCL proteins, especially CLN8 and CLN3. Progranulin (CLN11) plays important roles in inflammation, tumorigenesis, and lysosomal function (lipid homeostasis). CLN3 function has not been elucidated, but this protein was shown to impact ionic balance, endolysosomal trafficking and autophagy. CLN6 and CLN8 localize to the ER. It has recently been demonstrated that they form a complex recruiting lysosomal enzymes at the ER to promote their transfer to the Golgi

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[152]. MFSD8 (CLN7) belongs to the major facilitator superfamily and has been reported to be an endolysosomal chloride channel. Loss of CLN7 leads to alterations in mTORC1 signalling, as well as lysosomal size and exocytosis. ATP13A2 (CLN12) is a lysosomal P5-type ATPase with a neuroprotective activity during oxidative stress, metal exposure or α-synuclein toxicity. KCTD7 (CLN14) has been implicated in the regulation of neural signalling and transmission (K+ conductance) and of autophagy-lysosomal pathways. CSPα, altered in the rare dominant CLN4 adult form, is a chaperone protein abundant in neurons essential for short and longterm synaptic maintenance. z

40

Genetics

NCLs are usually inherited in an autosomal recessive manner (except the CLN4 adult form which is dominantly transmitted). They result from mutations in the 13 known genes encoding the various NCL proteins [147] (. Table  40.2). Numerous PPT1 (CLN1) mutations have been reported, but p.Arg122Trp and p. Arg151* are common in Finnish and non-Finnish patients, respectively. Two mutations are common in TPPI (CLN2): c.509-1G > C and p.Arg208*, but around 150 variants, mainly private, have now been described [153]. For CLN3, a 1  kb deletion (c.461280_677 + 382del966) is particularly frequent (80–90% of alleles). Concerning CLN5, p.Tyr392* is frequent in the Finnish population, but different mutations have been found in other countries. Northern epilepsy is mainly due to the p.Arg24Gly variant, but other CLN8 abnormalities have been described in patients presenting with late infantile forms. Numerous variants have been reported in the other NCL genes characterised to date; details are given in the NCL Mutation Database (7 http://www. ucl. ac. uk/ncl- disease/mutation- andpatient-database). z

Diagnostic Tests

Electrophysiological studies are helpful to establish the diagnosis of NCLs. Electroretinogram (ERG) is generally diminished at presentation and it becomes rapidly extinguished. In infantile NCL, the first abnormality in the electroencephalogram (EEG) is the disappearance of eye opening/closing reaction, followed by a loss of sleep spindles. Then, EEG becomes rapidly flat. In CLN2 disease, an occipital photosensitive response to photic stimulation at 1–2  Hz with eyes open is present. MRI shows progressive brain atrophy, particularly severe in CLN1 disease, sometimes beginning on cerebellum in other forms. Vacuolated lymphocytes are a common feature of CLN3 disease. Electron microscopy (EM) on skin biopsies shows the presence of pathological inclusions. Granular osmiophilic deposits (GROD) are mainly found in early-

onset forms (CLN1 and CLN10). Curvilinear (CV) profiles are present in the classic CLN2 disease and in the variant CLN7, while fingerprints (FP) are common in CLN3. Mixed inclusions diversely associating GROD, CV and FP are found in other clinical forms. EM remains useful to confirm the diagnosis of atypical forms of NCL [151]. For the CLN1 and CLN2 diseases, diagnosis is rapidly established by measuring the activity of palmitoyl protein thioesterase 1 and of tripeptidyl peptidase 1, respectively. These enzymatic tests can be performed on leukocytes, DBS, or cultured fibroblasts. For CLN3 disease, diagnostic testing can be firstly targeted to the common 1  kb deletion. For all the NCL genes, complete sequencing is performed either using Sanger sequencing or more frequently next generation sequencing (NGS) based on gene panels focused on lysosomal storage disorders or other conditions (myoclonic epilepsies, retinitis pigmentosa, ...) sharing clinical features with NCLs. Prenatal diagnosis is available for NCL families using the specific enzymatic test and/or detection of the previously characterised mutations. Preimplantation diagnosis can also be offered to parents in some countries. z

Treatment and Prognosis

Among symptomatic treatments, antiepileptic drugs need to be selected with caution (lamotrigine is usually efficient, but carbamazepine and phenytoin can worsen the symptoms). Diazepines should be useful on seizures, anxiety, and sleep disturbances. Gastrostomy is used to maintain nutritional status in the late stages of the disease. Specific therapies are in development for NCL and some of them have already entered the clinic [154]. In CLN2, enzyme replacement therapy (ERT) based on intracerebroventricular infusion of recombinant TPP1 (Cerliponase alfa) has demonstrated its capacity to slow or stabilise the disease progression [155]. It has now been approved for the treatment of CLN2 disease. Other ERTs might be suitable for NCLs involving soluble lysosomal proteins. Gene transfer approaches have been largely investigated in different animal models and clinical trials are now ongoing or planned, using either direct intracerebral (CLN2) or intrathecal (CLN6, CLN3) administration of AAV vectors (serotype 9 or 10). Gene therapy will probably be used for other NCLs in the future. In addition, different pharmacological therapies focused on potential targets to modulate disease have been explored. In CLN1, a treatment combining cysteamine bitartrate and N-acetylcysteine did not significantly change the course of the disease. A non-steroidal immunosuppressant, mycophenolate mofetil, was tested on CLN3 patients with no clear clinical benefit. Other candidate drugs will likely be found based on further advances

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on the molecular pathways involved in NCLs [156]. Neural stem cell transplantation is another option tested in patients, but without meaningful benefits to date.

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Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects, Mucopolysaccharidoses, Oligosaccharidoses and Sialic Acid Disorders Simon Jones and Frits A. Wijburg Contents 41.1

Glycosaminoglycans Synthesis Defects – 767

41.2

Mucopolysaccharidoses – 767

41.2.1 41.2.2 41.2.3 41.2.4 41.2.5

Clinical Presentation – 767 Metabolic Derangement – 774 Genetics – 774 Diagnostic Tests – 774 Treatment and Prognosis – 774

41.3

Oligosaccharidoses and Mucolipidoses – 777

41.3.1 41.3.2 41.3.3 41.3.4 41.3.5

Clinical Presentation – 777 Metabolic Derangements – 779 Genetics – 779 Diagnostic Tests – 779 Treatment and Prognosis – 780

References – 780

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_41

41

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S. Jones and F. A. Wijburg

Dermatan sulfate O COOH

6

H2COH S O O O

O S

2

O

7

O

etc

NAc

NAc-galacto- Glucuronate NAc-galactosamine samine sulfate

Heparan sulfate O COOH O

H2COH O

O

NAc

1

Iduronate sulfate

COOH O

O S

3b

H2COH O

COOH O

O

1

2

N S

H2CO S O O

O S

O

etc

NAc

3a

Iduronate NAc-galacto- Glucuronate NAc-galactosamine sulfate samine sulfate sulfate 6-sulfate

Keratan sulfate 4a H2CO S O

O

H2CO S O

4b Galactose 6-sulfate

NAc-glucosa- Galactose mine 6-sulfate

Glycosaminoglyans Glycosaminoglycans, (GAGs, mucopolysaccharides) are essential constituents of connective tissue, including cartilage and vessel walls. They are composed of long sugar chains, containing highly sulfated, alternating uronic acid and hexosamine residues, assembled into repeating units. The polysaccharide chains are bound to specific core proteins within complex macromolecules called proteoglycans (PG). GAGs are grouped in two families: sulfated GAGs, mainly represented by chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparan sulfate (HS) and heparin (. Fig. 41.1) and nonsulfated GAGs including mainly hyaluronan (HA). PG biosynthesis involves several enzymes and transporters in four main steps: core protein synthesis, GAG synthesis (including the linker tetrasaccharide and subsequent chain elongation), GAG sulfation and PG secretion. Core protein synthesis occurs in the rough endoplasmic reticulum where some early modifications, such as N-glycosylation,

H2CO O

S O

O

etc

NAc

NAc

. Fig. 41.1 Main repeating units in mucopolysaccharides and location of the enzyme defects in the mucopolysaccharidoses. NAc N-acetyl, S sulfate, 1, α-iduronidase (MPS I: Hurler and Scheie disease), 2, iduronate sulfatase (MPS II: Hunter disease); 3a, heparan N-sulfatase (MPS IIIA: Sanfilippo A disease); 3b,

41

O

H2COH O

NAc-galactosamine 6-sulfate

α-N-actylglucosamindase (MPS IIIB: Sanfilippo B disease); 4a, N-acetyl-galactosamine-6-sulfatase (MPS IVA: Morquio A disease); 4b, β-galactosidase (MPS IVB: Morquio B disease); 6, NAcgalactosamine-4 sulfatase (MPS VI: Maroteaux-Lamy disease); 7, β-glucuronidase (MPS VII: Sly disease)

take place. The core protein then moves to the Golgi apparatus for GAG biosynthesis (see also 7 Chaps. 43 and 44). Degradation of GAGs takes place inside the lysosomes and requires several acid hydrolases. Deficiencies of specific degradative enzymes are the cause of a variety of eponymous disorders, collectively termed mucopolysaccharidoses (MPSs).

kIntroduction

Genetic defects in enzymes that are involved in the lysosomal degradation of the GAGs, collectively termed mucopolysaccharidoses (MPSs), (. Fig.  41.1) and the oligosaccharide chains of glycoproteins (. Fig.  41.6), collectively termed oligosaccharidosis lead to chronic and invariably progressive disorders. Although these disorders share many clinical features, the presentation can be highly variable and the spectrum of phenotypic severity is extremely broad. Signs and symptoms include bone

767 Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects…

dysplasia (dysostosis multiplex), hepatosplenomegaly, neurological abnormalities, cardiac disease and, in some of the disorders, developmental regression. Life expectancy is generally reduced at the severe end of the clinical spectrum. MPSs and oligosaccharidoses are transmitted in an autosomal recessive manner, except for the X-linked MPS II (Hunter syndrome). Diagnosis of these disorders is usually by detecting increased concentrations of (partially degraded) GAGs or oligosaccharides in urine, confirmed by specific enzyme assays in serum, leukocytes or skin fibroblasts followed by mutational analysis. Over recent years important advances have been made in the disease modifying treatment of a number of the MPSs, including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) and many more treatment options, including gene therapy, are currently under study. While current treatments may result in improvement of a number of clinically relevant symptoms there is generally significant residual disease, especially involving the skeletal tissue, growth, the heart and the cervical spine. Prenatal diagnosis is possible for all the MPSs and oligosaccharidoses. Disorders of GAGs and oligosaccharides synthesis may not present primarily with neurological symptoms but rather should be suspected in patients with a combination of characteristic clinical features in more than one connective tissue compartment: bone and cartilage, ligaments, and subepithelial (skin, sclerae). Some produce distinct clinical syndromes mostly presenting with bone dysplasias (7 Sect. 1.6.12). Disorders involving synthesis of N-Glycans and O-Glycans are generally classified as congenital disorders of glycosylation (CDGs) (7 Chap. 43). GAG synthesis defects can also affect protein homoeostasis, intracellular trafficking, assembly of matrix proteins and cell signalling. (7 Chap. 44).

41.1

Glycosaminoglycans Synthesis Defects

A number of genetic disorders of bone and connective tissue caused by mutations in genes encoding for glycosyltransferases, sulfotransferases and transporters that are responsible for the synthesis of sulfated GAGs have been described [1]. Twenty-eight defects that are currently known are summarized in . Table 41.1 after the recent review by Paganini et al. [2]. 41.2

typic severity has led to separation of MPS I in different subtypes (Hurler, Hurler/Scheie and Scheie phenotypes; MPS IH, IH-S and IS respectively) and in MPS II in the neuronopathic and non-neuronopathic phenotypes. Furthermore, MPS III is subdivided into 4 types (A to D), depending on the deficient enzyme and MPS IV into 2 subtypes (A and B), also depending on the specific enzyme deficiency. Both MPS III, IV and VI may result in a severe (often called ‘classical’) phenotype as well as a (much) more attenuated phenotype. In MPS III this is also referred to as rapid progressing (RP) and slow progressing (SP) phenotypes. All MPSs are rare and information about their birth prevalence is relatively limited. Although there are differences between regions, MPS I and MPS III are the most prevalent disorders, except for the United Arab Emirates and Turkey where MPS VI is most frequent. MPS are all chronic, progressive and multisystem disorders. Although patients generally appear normal at birth, accumulation of GAGs already starts before birth and may lead to very early symptoms such as hydrops fetalis and intrauterine death (MPS VII) or the presence of skeletal deformities such as thoracolumbar kyphosis at birth (MPS IH). In general, MPSs present with one or more of the following characteristic symptoms: 1. Dysmorphic features from an early age in combination with growth failure, umbilical and/or inguinal hernia, protruding abdomen and musculoskeletal disease; all frequent in MPS IH and MPS IH-S, MPS II, MPS VI and MPS VII. 2. Primarily skeletal disease (skeletal dysplasia) with growth failure and relatively minor dysmorphic features (MPS IV). 3. Slowing of cognitive development (especially of language development) and behavioural problems followed by cognitive decline in combination with (mild) coarse facial features (MPS III).

Mucopolysaccharidoses

41.2.1Clinical Presentation

Seven separate types of MPSs are distinguished: Mucopolysaccharidosis (MPS) I, II, III, IV, VI, VII, IX and X (. Table 41.2). In addition, differences in pheno-

It is important to note that the wide phenotypic spectrum observed in all MPS subtypes can lead to an atypical, pauci-symptomatic, presentation which may easily lead to misdiagnosis, for instance, of a skeletal dysplasia e.g. in MPS IVA and MPS VI, or a stable cognitive impairment in MPS III, with an increasing number of MPS diagnoses being made in adults. Important signs and symptoms in MPS include: 5 Dysostosis multiplex is a term used to describe the skeletal disease associated with MPS and consists of a collection of radiographic abnormalities resulting from defective endochondral and membranous growth throughout the body. Typically, the growth of the long bones is stunted, vertebral bodies are hypoplastic and abnormally shaped, which may result in kyphosis with or without scoliosis (. Fig. 41.2), and the knees are in the valgus position. Hip abnor-

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. Table 41.1 Causative gene

Glycosaminoglycans (GAGs) synthesis defects (after [2]) Clinical entities

Skeletal phenotype

Defects in the synthesis of the linker region ‘linkeropathies’. Chondroitin sulfate, DS, HS and heparin are attached to serine residues of the core protein through a tetrasaccharide linkage region, composed of one xylose (Xyl), two gal and one GlcUA (see 7 Chap. 43) XYLT1

Desbuquois dysplasia type 2

Disproportionate short stature, microretrognathia, congenital dislocations

XYLT2

Spondyloocular syndrome

Short trunk,osteopenia with bone fragility, eye defects, hearing impairment, cardiac septal defects

FAM20B

Neonatal short limb dysplasia

Midface hypoplasia, thoracic hypoplasia, Very short stature, multiple dislocations

B4GALT7

Ehlers–Danlos syndrome (EDS) Spondylodysplastic type 1 including Larsen

DD, short stature,osteopenia, radioulnar synostosis, hypermobile joints, loose but elastic skin

B3GALT6

EDS spondylodysplastic type 2 syndrome,

Severe kyphoscoliosis, epimetaphyseal dysplasia, craniofacial disproportion, osteopenia, joint laxity, defective wound healing, loose skin,hypotonia.

B3GAT3

Larsen-like syndrome

DD, multiple dislocations, bone fragility, heart valves anomalies, cutis laxa

Defects in GAG chain elongation including substrate synthesis. After the synthesis of the linkage region, GAG chain elongation continues with the polymerization of specific repeated disaccharide units

41

CSGALNACT1

Joint dislocations and skeletal Dysplasia, Desbuquois-like

Nonproportioned stature, hyperlordosis, Mild facial dysmorphism and joint laxity

CHSY1

Temtamy preaxial brachydactyly syndrome

DD, growth retardation, joint dislocations, abnormal bone patterns in hand and feet, deafness

EXTL3

Immunoskeletal dysplasia with neurodevelopmental abnormalities

Skeletal dysplasia with short stature, Craniosynostosis, vertebral anomalies, kyphosis, brachydactyly, DD and immunodeficiency

EXT1/EXT2

Hereditary multiple exostosis Type 1 and 2 (multiple osteochondromas)

Cartilaginous/bony tumours in long bones, ribs and other skeletal elements.

SLC35D1

Schneckenbecken dysplasia

Neonatal lethal chondrodysplasia, oval vertebral bodies, extremely short long bones and small ilia

SLC35A3

Multiple congenital Malformation syndrome

Limb deformities, knee and hip dislocation, scoliosis, hand and foot anomalies

SLC10A7

Skeletal dysplasia, osteoporosis, multiple Dislocations and amelogenesis imperfecta syndrome

Severe disproportionate short stature, microretrognathia, congenital dislocations, advanced ossification, amelogenesis imperfecta

769 Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects…

. Table 41.1

(continued)

Causative gene

Clinical entities

Skeletal phenotype

CANT1

Desbuquois dysplasia type 1

Joint dislocations, facial dysmorphism, advanced bone age,extra ossification Centre, phalangeal dislocation

TGDS

Catel–Manzke syndrome

Cleft palate, glossoptosis, micrognathia, Bilateral hyperphalangy

DSE

Ehlers–Danlos syndrome Musculocontractural type 2

Joint dislocations, skin hyperextensibility, Bruisability and fragility, muscle hypoplasia

GORAB

Gerodermia osteodysplastica

Lax and wrinkled skin, osteoporosis, reduced bone mass, susceptibility to fracture

Defects in GAG chain sulfation. Sulfation is an important step in PG biosynthesis; in the Golgi apparatus GAGs are sulfated by specific sulfotransferases that catalyse the transfer of sulfate groups from 30-phosphoadenosine 50-phosphosulfate (PAPS), the universal sulfate donor, to the sugar moiety of GAG chains. The intracellular sulfate pool rely mainly on extracellular uptake by the SLC26A2 transporter and only a small amount may come from the catabolism of sulfur-containing amino acids (7 Chap. 20) Achondrogenesis type 1B

Foetal or perinatal lethality, micromelia, Short extremities and trunk

Atelosteogenesis type 2

Perinatal lethality, shortened limbs, cervical kyphosis, flattened vertebrae with coronal clefts, cleft palate,‘hitchhiker’ thumb

Diastrophic dysplasia

Joint dysplasia, joint pain and contractures, scoliosis, cleft palate,‘hitchhiker’ thumb, cystic swelling of the external ear

Recessive multiple epiphyseal dysplasia

Scoliosis, clubfoot and double-layered patella

Spondyloepimetaphyseal dysplasia, Pakistani-type

Short stature, short and bowed lower limbs, enlarged knee joints, kyphoscoliosis, mild brachydactyly, osteoarthritis

Brachyolmia type 1

Short trunk, platyspondyly with irregular and narrow intervertebral spaces, scoliosis, corneal opacities in some cases

CHST3

Recessive Larsen syndrome

Short stature, knee dislocation, hip dislocation, clubfoot, kyphoscoliosis, intervertebral disc degeneration, rarely cardiac involvement

CHST14

Ehlers–Danlos syndrome Musculocontractural type 1

Contractures of thumbs and fingers, clubfoot, kyphoscoliosis, hypotonia, hyperextensible thin skin, easy bruisability, joint hypermobility, atrial septal defect, ocular involvement

IMPAD1

Chondrodysplasia with joint dislocations, gPAPP type

Short stature, brachydactyly, joint dislocations, micrognatia, cleft palate, facial dysmorphism

SLC26A2

PAPSS2

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. Fig. 41.2 Lateral X-ray of the spinal column of a 12  year old MPS I Hurler patient who had a successful hematopoietic stem cell transplantation at the age of 1 year. Abnormally shaped dysplastic vertebral bodies with thoracolumbar kyphosis. In addition, broad oar shaped ribs can be observed

41

. Fig. 41.3 Femoral and acetabular pathology due to dysostosis multiplex in a 15 year old boy with MPS IVA

malities, due to failure of ossification of the lateral acetabular roof, medial proximal epiphyseal growth failure of the femur and coxa valga, lead to a form of hip dysplasia often accompanied by deformation leading to subluxation or dislocation of the femoral head (. Fig. 41.3).

Other radiologic findings include bullet-shaped metacarpals and phalanges, an enlarged and thickened skull, broad clavicles and broad oar-shaped ribs (. Fig. 41.2). The pathophysiology of the dysostosis multiplex is complex and not fully understood. Intra- and extracellular deposition of GAGs and GAG fragments leads to impaired cell-to-cell signalling, altered biomechanical properties and upregulated inflammatory pathways, all of which are believed to affect the growth plate, osteoclasts and osteoblasts, thus contributing to the skeletal dysplasia. Dysostosis multiplex can be observed in all MPSs, but is most pronounced in MPS I, II, IVA, VI and VII (. Table 41.2). Facial dysmorphism, with progressive coarsening of facial features with flat face, depressed nasal bridge, bulging forehead, thickening of the tongue and lips, thick and often abundant hair (hirsutism), is a feature in MPS I, VI and VII and to a lesser extent in MPS II, III and IVA (. Figs. 41.4 and 41.5). 5 The cause of the dysmorphism is the combination of dysostosis multiplex in facial and cranial bones and subcutaneous storage of GAGs. 5 Corneal clouding, probably as a result of accumulation of GAGs in keratocytes is a common feature in MPS I, VI and VII but can also be detected in patients with III and IVA.  In addition, glaucoma, retinopathy and optic nerve disease are common in MPS [3]. 5 Cardiac valve disease with thickening of valves leading to dysfunction (insufficiency and/or stenosis) is most common in MPS with accumulation of dermatan sulfate (MPS I, II, VI and VII), which is the most abundant GAG in heart valves [4]. A generally milder valvular disease also occurs in MPS IVA.  In addition, cardiomyopathy and coronary artery stenosis has been reported in a number of MPS. 5 Hepatosplenomegaly, which is often and erroneously, considered as a clinical hallmark of lysosomal storage disorders, is a common symptom in MPS I, II, VI and VII but can be minimal or absent in the more attenuated, slowly progressive phenotypes. In addition, hepatosplenomegaly is usually absent in MPS IVA (and probably IX) and often less prominent in MPS III. 5 Central nervous system (CNS) disease with progressive cognitive impairment occurs in the severe, rapid progressive, phenotypes of MPS I and II and in MPS VII, and is a key feature of MPS III; all MPS in which heparan sulfate is one of the accumulating GAGs. Other disorders of the CNS include compression of the spinal cord due to stenosis of the spinal canal (MPS I, II, VI and VII), atlanto-occipital instability (MPS IVA) and communicating hydrocephalus (MPS I, II and VI). Compression of the

++ ++

Hurler-Scheie

Scheie

Hunter, neuronopathic phenotype

Hunter, attenuated phenotype

MPS IH-S

MPS IS

MPS II

?

Sanfilippo D

Morquio A

Morquio B

Maroteaux-Lamy

Sly

−

MPS IIID

MPS IVA

MPS IVB

MPS VI

MPS VII

MPS IX

++

Multiple sulfatase deficiency

+

++

?

++

+++

+

+

?

+/−

+/−

+/−

++

++

++

++

+++

Valvular heart disease

N-acetyl-glucosamine-6sulfatase

− +++ +++ +++

+++ − − −

+++

?

?

+++

?

Formylglycine-generating enzyme

Arylsulfatase K (ARSK)

−

SUMF1

ARSK

HYALI

GUSB

Β-glucuronidase Hyaluronidase

ARSB

GLB1

GALNS

GNS

HGSNAT

NAGLU

SGSH

IDS

IDUA

Gene

N-acetylgalactosamine-4sulfatase

Β-galactosidase

?

+

Acetyl CoA glucosamine N-acetyltransferase

−

+++

N-acetylgalactosamine-6sulfatase

N-acetyl glucosamindase

−

+++

+++

Heparan-N-sulfatase

++

−/+

Iduronate-2-sulfatase

Alpha-L-iduronidase

Enzyme deficiency

−

++

++

− +++

++

++

Spinal cord compression

++

+++

Progressive cognitive impairment

HS, DS

+/− DS

HA

DS, HS, CS

DS

KS

KS, CS

HS

HS, DS

HS, DS

Main GAG accumulating (urine screening)

WBC

Cultured cells

WBC

WBC

WBC

WBC

WBC

WBC

Plasma

WBC

Plasma

WBC

Diagnostic enzyme assay

Accumulating GAGs: HS heparan sulfate, DS dermatan sulfate, KS keratan sulfate, CS chondroitin sulfate, HA hyaluronic acid Presence of signs and symptoms: − never reported, +/− vary rare, + can be present, ++ often present, +++ almost always present,? not known (only very few patients reported)

++

+++

+++

+++

?

+

MPS X

Austin

+++

Sanfilippo C

MPS IIIC

+

Sanfilippo B

MPS IIIB

+

Sanfilippo A

MPS IIIA

++

++

+++

Hurler

MPS IH

Dysostosis multiplex

Disease name

The 7 different MPS, with the most important clinical signs and symptoms

MPS type

. Table 41.2

Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects… 771

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spinal cord in MPS I, II and VI is caused by dural thickening (pachymeningitis cervicalis) and thickening of the transverse ligaments at the level of the the craniocervical junction. This often presents insidiously with loss of endurance before more obvious signs of ascending paralysis become apparent. 5 Recurrent inguinal and umbilical hernia are a frequent finding in MPS I, II and VI and are probably related to abnormalities in connective tissue due to accumulation of dermatan sulfate in combination with increased intra-abdominal pressure as a result of hepatosplenomegaly. z

. Fig. 41.4

Facial features of Hurler syndrome (MPS IH)

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. Fig. 41.5 Classical facial features in a 10 year old boy with Sanfilippo syndrome

MPS I: Hurler Syndrome (MPS IH), Hurler-Scheie Syndrome (MPS IH-S) and Scheie Syndrome (MPS IS)

Patients with MPS I have deficiency of the enzyme α-liduronidase (. Fig.  41.2) and accumulate the GAGs dermatan and heparan sulfate (DS, HS). Infants with severe disease (MPS 1H, Hurler syndrome) are usually diagnosed in the first year of life [5]. Upper airway obstruction and frequent ear, nose and throat infections dominate the clinical picture at an early stage. The full clinical picture of short stature, hepatosplenomegaly, increasing facial dysmorphism (. Fig.  41.4), cardiac disease, progressive learning difficulties and corneal clouding generally evolves over the second and third years of life but may also be present early in the first year of life. Signs and symptoms of dysostosis multiplex, leading to severe spinal and hip disease, are particularly pronounced in MPS IH.  If left untreated, patients with severe MPS I usually die before the age of 10  years as a result of cardiorespiratory disease. The severe MPS IH phenotype appears to be much more prevalent than the more attenuated forms of the disease although under- or misdiagnosis may be involved. At the other end of this clinical spectrum patients with Scheie syndrome (MPS IS) are intellectually normal, often reach an almost normal height and can live a normal life span, although many patients become disabled as a result of progressive joint disease, corneal opacity and cardiac valve lesions. The symptoms of patients between these two extremes can be extremely variable (Hurler-Scheie syndrome, MPS I H-S) and can include short stature, coarse facies, corneal clouding, joint stiffness, deafness and valvular heart disease. The onset of symptoms in MPS IH-S is observed between ages 3 and 8  years, and there is usually variable intellectual dysfunction. Untreated, the condition usually leads to death from cardiac or respiratory disease during the second or third decade of life. As separating the MPS I H-S phenotype from the MPS IH and IS phenotypes can be difficult or sometimes not possible, classification of MPS I in a neuronopathic phenotype (including MPS IH and the more severe MPS I H-S patients) and a nonneuronopathic phenotype (including the more attenu-

773 Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects…

ated MPS I H-S and the MPS IS patients) seems to be a more realistic approach. z

Hunter Syndrome (MPS II)

MPS II (Hunter syndrome) differs from other MPS in that its inheritance is X-linked recessive and manifesting female heterozygotes are exceptionally rare. Like MPS I, this disorder is a spectrum with severely affected patients sharing many of the clinical signs and symptoms of patients with the severe form of MPS I, with the exception that the cornea remains clear in MPS II [6]. Differentiating MPS II from MPS I on clinical signs and symptoms is thus often difficult or not feasible. Severe patients (neuronopathic phenotype) appear to be more prevalent than attenuated, non-neuronopathic patients. More recently, an intermediate phenotype group has been reported for MPS II.  These patients may have a stable cognitive impairment of many decades [7]. Prominent Mongolian blue spots and a characteristic papular rash are other features that are prominent in severe MPS II. Patients with the more attenuated form of MPS II can live well into adult life, and a number have gone on to have their own families. z

Sanfilippo Syndrome (MPS III)

There is a defect in the degradation of heparan sulfate in all of the four subtypes of MPS III (A, B, C and D, Sanfilippo syndrome). This results in a disorder which primarily affects the central nervous system, whereas somatic abnormalities are relatively mild [8], often leading to a considerable delay in diagnosis. The condition has three phases. After a symptom free interval of one to two years, the first phase, usually before diagnosis, consists of slowing of cognitive development, often primarily affecting speech. Some patients have ear disease and will fail hearing tests, which is the usual reason given, initially, for the speech delay. In the second phase (age 3–10  years), cognitive development stops and the illness is dominated by a severe behavioural disturbance, characterized by hyperactivity, challenging behaviour, and profound sleep disturbances, gradually followed by a decline in cognition. Abundant and thick scalp hair and hirsutism and progressive coarse facial features are frequently noted (. Fig. 41.5). The third phase of the illness (usually starting at the end of the first decade) is associated with continuing loss of skills and motor functions, epilepsy and slow deterioration into a vegetative state, death usually occurring early in the third decade. There are no absolute differences in clinical signs and symptoms between the MPS III subtypes. As in all the other MPSs there is considerable heterogeneity, and not all patients will follow the same rapid progression of neurocognitive deterioration and patients with attenuated phenotypes have been reported [9–11]. Somatic

manifestations in MPS III include mild dysostosis multiplex, ENT problems and, sometimes, hepatomegaly. z

Morquio Disease (MPS IV)

MPS IV (Morquio disease) is caused by a defect in the degradation of keratan sulfate. In classic Morquio type A (MPS IVA, galactose-6-sulfatase deficiency) the patients are affected by a very severe skeletal dysplasia characterised by vertebral platyspondyly, hip dysplasia (. Fig. 41.3) and genu valgum [12]. Intellectual impairment does not occur in MPS IVA, but the height prognosis is very poor, with affected adults ranging from 95 to 105  cm when fully grown. Odontoid hypoplasia is often associated with a high risk for atlanto-occipital subluxation which renders the patients vulnerable to acute or chronic cervical cord compression. However, patients with a more attenuated phenotype may show only moderate to (almost) no growth retardation with, during childhood years, only few skeletal manifestations easily misdiagnosed as for instance bilateral Perthes disease. In Morquio B (MPS IVB, β-galactosidase deficiency) the skeletal involvement is similar, but often not as pronounced, but patients may have central nervous system disease and a slowly progressive neurodegenerative course (β-galactosidase deficiency also causes GM1gangliosidosis see 7 Sect. 40.2.3). z

Maroteaux-Lamy Syndrome (MPS VI)

Patients with MPS VI (Maroteaux-Lamy syndrome) have somatic features resembling MPS I, but without neurological impairment [13]. As in all MPSs, MPS VI shows a wide phenotypic spectrum of symptoms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. In addition, patients may have cardiac valve disease, hearing loss, obstructive sleep apnoea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Cervical cord compression, communicating hydrocephalus, optic nerve atrophy and blindness may occur, often closely resembling MPS I. z

Sly Syndrome (MPS VII)

MPS VII (β-glucuronidase deficiency, Sly syndrome) is a very rare and variable disorder, which probably has nonimmune hydrops fetalis as its most common presentation. Patients who survive pregnancy have a clinical disease similar to MPS I, including the same degree of clinical heterogeneity. In patients who survive the prenatal and neonatal presentation with hydrops, the hydrops may resolve followed by the typical MPS I like presentation. However, as in all other MPS disorders, patients with a much more attenuated phenotype are now increasingly reported. In these patients clinical signs and symptoms may resemble those of MPS I, II and VI [14].

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MPS IX

MPS IX (hyaluronidase deficiency) appears to be extremely rare. This disorder was first reported by Natowicz et  al. [15] and has only been reported in 4 patients from 2 families and is clinically characterized by short stature and periarticular soft masses and symptoms resembling familial juvenal idiopathic arthritis. z

Multiple Sulfatase Deficiency (Austin Disease)

Multiple sulfatase deficiency is caused by mutations in the sulfatase modifying factor 1 gene (SUMF1), leading to a deficiency of the FGE (formylglycine-generating enzyme) protein. As FGE is involved in the posttranslational activation of all sulfatases in the endoplasmatic reticulum, its deficiency leads to a deficiency of 17 different sulfatases, including all lysosomal sulfatases. Multiple sulfatase deficiency is very rare and clinical signs and symptoms are variable, with progressive psychomotor retardation invariably present [16]. However, the course of the disease varies from rapid progressive to a slower evolution [17]. Urinary GAG concentrations can be in the normal range, necessitating direct enzymatic assay of multiple sulfatases in the diagnostic workup or SUMF1 mutation analysis.

41.2.2Metabolic Derangement

41

MPS comprise a group of lysosomal storage disorders caused by a deficiency in one (or more in the case of multiple sulfatase deficiency) of the lysosomal enzymes (hydrolases) involved in the degradation of GAGs (. Table 41.1). GAGs are linear polysaccharides ubiquitously distributed in extracellular matrices and on cell surfaces throughout the body and have many structural and complex biological functions. The classification of these polysaccharides is based on the repeating structural units in the molecule (. Fig. 41.1). GAGs display a very high degree of heterogeneity with regards to molecular mass, disaccharide construction, and the degree of sulfation, all important for their biological functions. The GAGs dermatan sulfate, heparan sulfate, chondroitin sulfate and keratan sulfate (DS, HS, CS and KS) are long polysaccharides, generally covalently attached to specific core proteins that form proteoglycans. The GAG hyaluronan (HA) is not sulfated or protein linked. There are important differences in the abundance of the different GAGs between different tissues, which appear to be partially related to the signs and symptoms of the different MPSs.

41.2.3Genetics

All MPSs are inherited as autosomal recessive traits except for MPS II, which is X-linked. All genes have been located and sequenced and genetic testing is available for all disorders for confirmation and for carrier detection, allowing genetic counselling and family planning. Genotype  - phenotype correlation is generally poor. However, several mutations, including two nonsense mutations, can predict the severe Hurler phenotype in MPS I [18]. With the exception of only a few predictive mutations in MPS II, IIIA, IV and VI, there is only poor predictive value of genotyping in the other MPSs.

41.2.4Diagnostic Tests

Diagnosis of MPS used to rely on quantification of urinary GAGs by a dimethylmethylene blue dye binding assay (DMB) [18], followed by two-dimensional electrophoresis for qualification of the type of excreted GAGs. However, MS/MS based methods proved to have a superior sensitivity and are now considered gold standard for urinary GAG screening [19–21]. A positive screening is followed by analysis of the relevant enzyme activity in leucocytes or cultured skin fibroblasts. Enzymatic studies in leucocytes and/or plasma will establish a final diagnosis. Subsequent mutational analysis will identify the mutations, which can sometimes be predictive of the phenotype in some MPSs, and can be used for genetic counselling of involved families. In case of a sulfatase deficiency, it is necessary to measure at least one other sulfatase, in order to exclude multiple sulfatase deficiency as the cause of the disease. As early initiation of treatment may lead to improved outcomes, several countries or regions have introduced newborn screening (NBS) for a number of mucopolysaccharidoses, predominantly MPS I, in their national screening program, including the US, Taiwan and Northern Italy [22–26]. High-throughput enzyme assays by either MS/MS or fluorimetric analysis allow for sensitive multiplexed screening of MPS I, II and VI.

41.2.5Treatment and Prognosis

Multi-disciplinary symptomatic care remains the most important aspect of the management of patients with MPS. As MPSs are all multi-systemic disorders, multidisciplinary teams preferably should involve at least

775 Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects…

orthopaedic surgeons, neurologists, neurosurgeons, ear, nose and throat surgeons, cardiologists, physical therapists, rehabilitation specialists and ophthalmologists. Metabolic paediatricians, internists and clinical geneticists are often essential in such teams to guarantee the necessary holistic approach. Expert opinion based guidelines for the management of MPS I, II, IVA and VI have been published [27–31]. In addition, guidelines on the management of several clinical symptoms and procedures, including spinal cord compression in MPS IVA [30] and MPS VI [31, 32]; orthopaedic management of extremities in MPS IVA [33]; thoracolumbar kyphosis in MPS I [34, 35]; hip dysplasia in MSP I [36] and MPS VI [37]; anaesthesia and airway management, including OSAS, in MPSs [38, 39]; cardiac disease [4] and eye disorders [3, 40, 41] may help to optimize treatment. Pain is a very common symptom in MPS [42] and this should be addressed directly and separately. Severe behavioural problems and sleep disturbances, generally present in patients with MPS III, often require a tailored psychological and pharmacological treatment plan. It is important to note that anaesthesia in patients with MPS needs special attention as it carries a high risk due to the upper airway obstruction resulting from anatomical changes due to the dysostosis multiplex and GAG deposition in soft tissues, restrictive pulmonary disease, cardiovascular disease and potential instability of the atlanto-occipital joint [34]. Therefore, anaesthesia should be performed experienced team and after full information about the clinical signs and symptoms of the individual patient has been acquired. In addition, patients with MPSs may have an increased risk for peri- or post-surgical development of spinal cord lesions, remote from the site of surgery, leading to paraplegia [43–45]. This may be caused by a combination of low mean arterial pressure in conjunction with potentially compromised arterial spinal circulation, the duration of the surgery and the position on the operating table. Stringent preoperative evaluation, careful positioning on the operation table, perioperative monitoring of motor-evoked potentials and somatosensory-evoked potentials and prevention of low blood pressure during the operation are probably essential to prevent these complications. As a result of the complexity of the disorders, necessitating the presence for a dedicated multi-disciplinary team, patients with MPS are best managed at specialized treatment centres. Disease modifying treatment options are available for several of the MPS and consist of hematopoietic stem cell transplantation (HSCT) and intravenous enzyme replacement therapy (ERT). Clinical studies on the effectiveness of intra-cerebroventricular enzyme therapy, intrathecal enzyme therapy and gene therapy are currently ongoing, and may lead to a significant improvement of the clinical outcome of MPS over the next years.

z

Hematopoietic Stem Cell Transplantation

HSCT for an MPS was first performed in the UK over 30  years ago in a patient with MPS I Hurler phenotype and this procedure is now the preferred treatment strategy for these patients, if diagnosed before the age of approximately 2.5  years [46] (. Table  41.3). The success of HSCT has dramatically improved over the last decades, with a marked decrease in morbidity and mortality and an improved rate of engraftment, due to changes in chemotherapeutic conditioning, supportive care and stem cell source [62]. A recent large multi-centre study showed that the long-term outcome of Hurler patients after HSCT improves after early referral for HSCT, using noncarrier donors and regimens designed to achieve full-donor chimerism [62]. However, there is still considerable residual disease burden in many patients, often related to the musculoskeletal system which apparently responds less well to HSCT.  Early diagnosis of MPS I Hurler patients through NBS may lead to early transplantation, thus improving the outcome of HSCT. Indeed, early HSCT leads to improved cognition in MPS I [63]. Long-term effectiveness of early HSCT in MPS I on important late complications such as cardiac valve disease and skeletal disease still remains to be established. Nevertheless, older age at HSCT is associated with a poorer physical quality of life during long-term follow-up of these children, early transplantation will also improve the somatic outcome [64]. HSCT is also performed in patients with the severe neuropathic phenotype of MPS II [48] and in patients with MPS IV [50], MPS VI [51] and MPS VII [52], and beneficial effects have been reported. However, as only small patient series have been studied, the exact place of HSCT in the treatment of these MPS needs to be further delineated (. Table 41.3). HSCT has been shown to be largely ineffective in MPS III [49]. z

Enzyme Replacement Therapy

Intravenous ERT for MPSs was first approved for clinical use in MPS I [65, 66] and later for MPS II [67], IVA [68], VI [69] and VII [70]. These pivotal trials, in combination with long-term follow up studies, have demonstrated that ERT can effectively treat a number of symptoms resulting in improvement on the 6  minute walk test, improved joint mobility and pulmonary function, a reduction of liver and spleen size and improved growth, all of which may lead to improved survival [70– 72]. However, all studies show that there is generally still significant residual disease burden despite long-term ERT. Studies comparing the effects of ERT in sibships, which include older siblings treated with ERT after the development of significant clinical symptoms, and younger siblings treated before the onset of significant symptomatology, have demonstrated that an early start

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. Table 41.3

41

HSCT indication in Mucopolysaccharidoses and Oligosaccharidosis

Disease

Numbers reported

Indication

Other therapeutic options

Key refs

MPSI

>200

Standard of care in neuronopathic phenotype

–

[47]

MPSII

>25

In young, neuronopathic cases with a good donor

ERT

[48]

MPSIII

>10

Not indicated (not effective)

–

[49]

MPSIVA

>5

Experimental

ERT

[50]

MPSVI

>45

Usually offered in cases where ERT not available

ERT

[51]

MPSVII

1

Experimental

ERT

[52]

Alpha mannosidosis

20–30

In young, neuronopathic cases with a good donor

ERT

[53, 54]

Beta mannosidosis

G seems to be associated with a mild phenotype (ectodermal signs, mild developmental disability, no liver disease, no glycosylation deficiency). On the other hand, the loss-of-function mutations c.511C>T and c.1238_1239insA are associated with a severe phenotype including lethality between 1 and 15  months. Since the COG complex is most probably not only involved in glycosylation but also in other cellular functions, defects in this protein complex might be more appropriately called ‘CDG-plus’ [41].

43.4.4COG6 Deficiency (COG6-CDG)

43.4.5Autosomal Recessive Cutis Laxa Type

The conserved oligomeric Golgi (COG) complex consists of eight subunits, divided in two lobes. Lobe A comprises subunits 1–4, and lobe B subunits 5–8. These lobes are bridged by subunits 1 and 8. The COG complex plays an important role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been reported in CDG patients. At least 28 patients have been described with COG6-CDG.  Predominant clinical features are liver involvement, microcephaly, developmental/intellectual disability, recurrent infections, early lethality, and ectodermal symptoms (hypohydrosis predisposing to hyperthermia, and hyperkeratosis). Most of these symptoms are present in other COG-CDG.  The clos-

Patients with this disorder, also called ‘wrinkly skin syndrome,’ already have generalized cutis laxa at birth, but this becomes less obvious later on and may disappear with age. Furthermore, they show congenital or postnatal microcephaly, increased joint laxity, ophthalmological abnormalities (strabismus, myopia, amblyopia, etc.) and, rarely, cardiac defects. Mental development is mostly normal. There is a combined defect in N- and O-glycosylation demonstrated by a type 2 serum transferrin IEF pattern and an abnormal serum apolipoprotein C-III IEF pattern. Skin biopsy shows an abnormal elastic fibre structure and a decrease of elastin.

43.4.3Steroid 5-α-Reductase Deficiency

(SRD5A3-CDG)

2 (ATP6V0A2-CDG)

ENDOPLASMIC RETICULUM

CYTOSOL

N-linked  glycosylation

Acetyl-CoA

Dolichol-PP

Protein prenylation DHDDS Geranylgeranyl-PP

Farnesyl-PP

Polyprenol-PP NgBR

SRD5A3 Polyprenol

Dolichol

DK1

DK1 Dolichol-P

DPM1/2/3 Dolichol-P-mannose MPDU1

Ubiquinon

Cholesterol

. Fig. 43.2

Schematic representation of the dolichol synthesis and utilization/recycling

O-linked mannosylation GPI-anchor synthesis (C-linked mannosylation)

43

830

J. Jaeken and E. Morava

Two major (and closely related) functions of the V-ATPase V0 domain are (i) maintenance of the pH gradient along the secretory pathway by proton transport and (ii) regulation of protein transport through the facilitation of vesicle fusion. However, the exact mechanism by which mutations in the V-ATPase a2 subunit affect glycosylation remains to be elucidated. At least 35 variants have been reported. This seems to be another ‘CDG-plus’ [42].

43.4.6Phosphoglucomutase 1 Deficiency

(PGM1-CDG) PGM1 is a key enzyme in glycogenesis and it is important for effective glycolysis during fasting. The disease has two major phenotypes: one is a myopathic glycogenosis (type XIV), and the other a multisystem presentation including growth deficiency, hypoglycemia, malformations (such as cleft uvula, cleft palate), and liver, cardiac and endocrine involvement. Contrary to most other CDG, PGM1 deficiency shows no or only minor neurological involvement. It is the only primary CDG that shows a defect in the assembly as well as in the processing of N-glycans (CDG-I/II). Serum transferrin IEF shows a type 2 pattern (in fact a combined type1/type 2 pattern), and mass spectrometry of serum transferrin a decreased galactosylation. Galactose supplementation improves glycosylation of patients’ fibroblasts, and patients on oral galactose treatment show improved glycosylation and also clinical improvement. It has been shown by isotope studies that galactose therapy is effective through the replenishment of galactose-1-P and the nucleotide sugars UDP-glucose and UDP-galactose [43].

43.4.7Golgi Homeostasis Disorders:

TMEM199 and CCDC115 Deficiencies

43

Two new disorders with abnormal Golgi N- and O-glycosylation have recently been described. The affected proteins are involved in Golgi homeostasis. Both disorders show a type 2 pattern on serum transferrin IEF. The seven reported patients with TMEM199 deficiency showed only a chronic, non-progressive (over decades) liver disease with mild hepatic steatosis, elevated serum aminotransferases and alkaline phosphatase, hypercholesterolemia, and low serum ceruloplasmin [44]. In CCDC115 deficiency, the 11 reported individuals displayed a storage disease-like phenotype with hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol,

in combination with abnormal copper metabolism and neurological symptoms. Two patients died of liver failure, and one was successfully treated by liver transplantation [45].

43.4.8Manganese and Zinc Transporter

Defect: SLC39A8 Deficiency SLC39A8 (also known as ZIP8) is a divalent cationic membrane transporter important for the uptake of manganese (Mn) into cells. Compound heterozygous and homozygous mutations in SLC39A8 have recently been described in patients with phenotypes ranging from cranial synostosis, hypsarrythmia, and disproportionate dwarfism to cerebellar atrophy, hypotonia, global developmental delay and recurrent infections. Serum Mn levels were reduced and transferrin IEF showed a type 2 pattern, due to dysfunction of the Mn-dependent enzyme ß-1,4-galactosyltransferase. Oral galactose supplements (up to 3.75 g/kg/d) corrected the glycosylation defect. Oral Mn therapy in two patients was associated with biochemical normalization and considerable neurological improvement. Close monitoring is important to avoid Mn toxicity [46]. See also 7 Chap. 34.

43.5

Congenital Disorders of Deglycosylation (CDDG)

43.5.1N-glycanase 1 (NGLY1) Deficiency

N-glycanase catalyzes deglycosylation of misfolded N-linked glycoproteins by cleaving the glycan chain before the proteins are degraded by the proteasome. It is a cytoplasmic component of the endoplasmic reticulumassociated degradation (ERAD) pathway. At least 22 patients have been reported [47]. All patients showed developmental disability, movement disorders and hypotonia. Common features comprised intrauterine growth restriction, alacrimia/hypolacrimia, chalazion, microcephaly, seizures, peripheral neuropathy, hyporeflexia, and liver involvement (increased serum transaminases and alpha-foetoprotein, cytoplasmic storage). Two patients died at 9 months and 5 years of age. Serum transferrin IEF is normal in this CDDG. Six of the 22 patients were homozygous for the c.1201A>T/p.R401X variant, that was associated with severe disease.

43.5.2Lysosomal Storage Disorders

Besides the cytoplasmic protein deglycosylation disorder, NGLY1 deficiency, there are also lysosomal protein

831 Congenital Disorders of Glycosylation, Dolichol and Glycosylphosphatidylinositol Metabolism

deglycosylation disorders namely the lysosomal storage diseases due to enzymatic defects (sphingolipidoses such as GM1-gangliosidosis a.o., mucolipidoses such as MPS I a.o., oligosaccharidoses such as fucosidosis a.o.; see 7 Chaps. 40 and 41).

19.

20.

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2. 3.

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Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P et al (1980) Familial psychomotor retardation with markedly fluctuating serum proteins, FSH and GH levels, partial TBG-deficiency, increased serum arylsulphatase A and increased CSF protein: a new syndrome? Pediatr Res 14:179 Jaeken J, Hennet T, Matthijs G, Freeze HH (2009) CDG nomenclature: time for a change! Biochim Biophys Acta 1792:825–826 Jaeken J, van Eijk HG, van der Heul C et al (1984) Sialic aciddeficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta 144:245–247 Wopereis S, Grünewald S, Morava E et al (2003) Apolipoprotein C-III isofocusing in the diagnosis of genetic defects in Oglycan biosynthesis. Clin Chem 49:1839–1845 Abu Bakar N, Lefeber DJ, van Scherpenzeel M (2018) Clinical glycomics for the diagnosis of congenital disorders of glycosylation. J Inherit Metab Dis 41:499–513 Brasil S, Pascoal C, Francisco R et  al (2018) CDG therapies: from bench to bedside. Int J Mol Sci 19:1304. https://doi. org/10.3390/ijms19051304 Bruneel A, Cholet S, Tran-Maignan T, Thaï Mai D, Fenaille F (1864) CDG biochemical screening: where do we stand? Biochim Biophys Acta Gen Subj 2020:129652. https://doi. org/10.1016/j.bbagen.2020.129652 Chang IJ, He M, Lam CT (2018) Congenital disorders of glycosylation. Ann Transl Med 6:477. https://doi.org/10.2103/ atm.2018.10.45 Ferreira C, Altassan R, Marques-Da-Silva D, Francisco R, Jaeken J, Morava E (2018) Recognizable phenotypes in CDG. J Inherit Metab Dis 41:541–553 Francisco R, Marques-da-Silva D, Brasil S et  al (2019) The challenge of CDG diagnosis. Mol Genet Metab 126:1–5 Jaeken J, Péanne R (2017) What is new in CDG? J Inherit Metab Dis 40:569–586 Makhamreh MM, Cottingham N, Ferreira CR, Berger S, Al-Kouatly HB (2020) Nonimmune hydrops fetalis and congenital disorders of glycosylation: a systematic literature review. J Inherit Metab Dis 43:223–233 Ng BG, Freeze HH (2018) Perspectives on glycosylation and its congenital disorders. Trends Genet 34:466–476 Péanne R, de Lonlay P, Foulquier F et  al (2018) Congenital disorders of glycosylation (CDG): quo vadis? Eur J Med Genet 61:643–663 van Tol W, Wessels H, Lefeber DJ (2019) O-glycosylation disorders pave the road for understanding the complex human O-glycosylation machinery. Curr Opin Struct Biol 56:107–118 Altassan R, Witters P, Saifudeen Z et al (2018) Renal involvement in PMM2-CDG, a mini-review. Mol Genet Metab 123:292–296 Francisco R, Pascoal C, Marques-da-Silva D et  al (2019) Keeping an eye on congenital disorders of O-glycosylation: a systematic literature review. J Inherit Metab Dis 42:29–48 Marques-da-Silva D, Dos Reis Ferreira V, Monticelli M et  al (2017) Liver involvement in congenital disorders of glycosyl-

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833

Disorders of Cellular Trafficking Ángeles García-Cazorla, Carlo Dionisi-Vici, and Jean-Marie Saudubray Contents 44.1

Cellular Mechanisms of Trafficking – 834

44.1.1 44.1.2 44.1.3

Membrane Trafficking – 834 Membrane Contact Sites – 837 Other Types of Cellular Trafficking – 838

44.2

Cellular Trafficking in the Nervous System: Polarization and Compartmentalization – 850

44.2.1

Trafficking Defects in the Neuronal Soma (ER-Golgi-PM-Endosome-Lysosome-Autophagosome) – 850 Axonal and Other Cytoskeleton Related Trafficking Defects – 852 Synaptic Vesicle Cycle Disorders – 852 Dendrites and Post-synaptic Neuron Compartment Traffic Defects – 852 Glia Trafficking Disorders – 852

44.2.2 44.2.3 44.2.4 44.2.5

44.3

Main Clinical Presentations of Cellular Trafficking Disorders – 853

44.3.1 44.3.2

Neurological Manifestations – 853 Extra-Neurological Manifestations – 855

References – 856

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_44

44

834

Á. Garcia-Cazorla et al.

kIntroduction

44

Cellular trafficking is essential to maintain critical biological functions. The machinery of proteins and the mechanisms that regulate membrane trafficking is immense and tend to be cell and tissue specific. Mutations in more than 300 genes are known to be associated with disorders of cellular trafficking and include those that affect: (i) membrane trafficking, that mediate the most important pathway to move cargo using membrane bound transport vesicles; (ii) membrane contact sites (MCS) or areas of close apposition between the membranes of organelles; (iii) Other mechanisms such as cytoskeleton mediated cargo/organelle transport, transcytosis, regulation of membrane phospholipids, and gap junctions. Vesicle trafficking proteins coordinate vesicle formation, transport, tethering and fusion with the target membrane. Coat, Adaptors, Calveolins, GTPases, Rab, TBC, TRAPP, VPS and SNAREs are families of proteins that regulate these functions and are vulnerable to mutations. Diseases of cellular trafficking affect all tissues and organs. The great majority of mutations cause a loss of function of transport machinery. Depending on the function and location of the affected protein, we have tentatively defined the following pathophysiological categories: vesicular trafficking disorders; organelle-related trafficking disorders (including MCS); cytoskeleton-related trafficking disorders; and autophagy disorders. Other membrane and vesicular trafficking such as glial and neuronal receptor trafficking disorders are brain specific. The nervous system is especially vulnerable to these diseases since neurons are highly polarized and compartmentalized. In fact, neurons need sophisticated transport mechanisms to release cargos at the exact place at the exact moment. Early neurodevelopmental encephalopathies with congenital and post-natal microcephaly, often associated with brain malformations and epilepsy, are predominantly related to Golgi and cytoskeleton trafficking diseases. Motor disorders and dementias tend to have a late onset and are mostly related to dysfunctions in the endocytic pathway. They include spastic paraparesis, ataxia, Parkinson’s disease, peripheral neuropathy (in particular Charcot-MarieTooth) and other neurodegenerative disorders such as amyotrophic lateral sclerosis. Other tissues are also involved and often include well-defined syndromes with multisystem manifestations, such as familial hemophagocytic lymphohistiocytosis, Chediak-Higashi, Hermansky-Pudlak, ARC, Lowe, Cohen, CEDNIK and Vici syndromes. Certain biomarker analyses may be of help for the diagnosis and include copper and ceruloplasmin profiles (for Wilson and Menkes disease, MEDNIK syndrome, and SLC33A1 defect), serum transferrin isoforms (for CDG syndromes), and lysosomal-related testing in plasma and urine (for Mucolipidosis type II, Multiple sulpha-

tase deficiency, and Yunis-Varon syndrome). Mutation analysis, via targeted Sanger or exome analysis, represents the most reliable method to diagnose disorders of intracellular trafficking. Mutation analysis via targeted Sanger or exome analysis is the only reliable method of diagnosis of an autophagy-related disorder. Thus far, there are very few treatments for this group of emerging disorders.

44.1

Cellular Mechanisms of Trafficking

Cellular trafficking is the exchange of signals and metabolites between cellular compartments. This exchange was first thought to occur by two broad mechanisms: diffusion or active transport through the cytoplasm and vesicular trafficking. A third mechanism that has been recently described is the exchange of signals and metabolites at regions where organelles form functional contacts [1]. Historically, and from De Duve to current times, different methods of study have been used to describe the ultrastructural cell anatomy. Today, cutting-edge structural methods, biochemical, cell-based and computational approaches, associated with the discovery of an increasing number of genes involved in these processes, pushes the understanding of trafficking and related diseases to unprecedent levels of detail and complexity [2].

44.1.1Membrane Trafficking

Membrane trafficking encompasses the full range of processes that go into the movement of cargo using membrane bound transport vesicles (vesicular trafficking). This transport can take place within different organelles in the same cell, or across the cell membrane to and from the extracellular environment [3]. The underlying molecular machinery is estimated to comprise more than 2000 proteins [4]. Membrane trafficking can be divided into two pathways: exocytosis and endocytosis (. Fig. 44.1). Exocytosis refers to the movement of cargo to the plasma membrane (PM) or out of the cell. Newly synthesized molecules (proteins, lipids or carbohydrates) move from the endoplasmic reticulum (ER) via the Golgi to the cell membrane or extracellular space. ERderived cargo enters the Golgi in its cis cisterna (CGN) and moves through the medial and trans cisternae (TGN). In the trans Golgi, proteins destined for secretion are packed into secretory vesicles that subsequently fuse with the PM. In the Golgi, cargo is sorted not only to the PM but also to endosomes and lysosomes, or back to the ER [3, 5, 6] (. Fig. 44.1). Endocytosis is the opposite movement: the cargo moves into the cell from the plasma membrane and can

44

835 Disorders of Cellular Trafficking

Caveolin

AP2 Clathrin Early endosome RAB5 Sec24

COPI

AP1

COPII

Recycling endosome

RAB11 AP3

Nucleus Golgicomplex AP4

Late endosome

Lysosome

CLIC/CEEG

ERGIC AP5 Endoplasmic reticulum

CGN

TGN

Secretory granules

Dynamin

Endophylin

Flotilin

SNARE proteins

. Fig. 44.1 Basic mechanisms of cell trafficking. Black arrows indicate the exocytic pathway. Red arrows indicate the endocytic pathway. AP1,2,3,4,5 subtypes of Adaptor Proteins; They mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. COPI Coat Protein I (vesicles are surrounded by COPI) COPII Coat Protein II (COPII vesicles bud off from the ER in the secretory or exocytic pathway towards the Golgi). CGN Cis Golgi Network; CLATHRIN Clathrin-coated vesicles mediate endocytosis from the plasma membrane to endosomal compartments and the Golgi; CLIC/CEEG The CLIC/GEEC (CG) pathway is a clathrinindependent endocytic pathway mediated by uncoated tubulovesicular primary carriers called clathrin-independent carriers (CLICs) which arise from the plasma membrane and later mature into early

endocytic compartments called Glycosylphosphotidylinositolanchored protein (GPI-AP) enriched compartments (GEECs). Dynamin the detachment of budded vesicles from the plasma membrane may be facilitated by the GTPase Dynamin, via membrane scission. ERGIC Endoplasmic Reticulum-Golgi Intermediate Compartment or tubule vesicular transporter. RAB5, RAB11 subtypes of RAB proteins (GTPase family). Sec24 Component of the coat protein complex II (COPII). It has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex. SNARE dock the transport vesicle at the correct membrane location. TGN Trans Golgi Network. Endophylin, Flotilin, Caveolin mediate endocytosis in an independent clathrin manner

be used for the uptake of nutrients or to direct cargo for recycling or degradation via autophagy. Cargo can be internalized at the PM via clathrin-coated vesicles, caveolar or raft-dependent routes [5]. These three internalization routes depend on the GTPase dynamin for fission of the forming PM vesicle. However, fluid-phase cargo can also enter the cell via a dynamin-independent process. In the endocytic pathway, proteins and membranes are internalized via a set of endosomes (early and late) to the lysosome, which is a major degradation site for internalized and cellular proteins [5, 6]. Cellular proteins can get to lysosomes either from the PM via the endocytic pathway or from the cytoplasm via the autophagy and the cytoplasm-to-vacuole targeting (CVT) pathways. The main families of vesicle trafficking proteins include those that coordinate vesicle formation, GTPases of the Rab family, transport and tethering factors, and SNARE proteins that mediate vesicle fusion with the target membrane [7, 8] (see also . Fig. 44.2).

5 COAT and ADAPTOR proteins self-assemble on the membrane, helping to collect and concentrate the vesicle cargo. There are three well-characterised coat proteins: 1-Clathrin-coated vesicles mediate endocytosis from the PM to endosomal compartments and the Golgi. 2- Coat protein I (COPI) surrounds vesicles that mediate retrograde transport within the Golgi and towards the ER. 3- COPII vesicles bud off in the opposite direction, from the ER in the secretory or exocytic pathway towards the Golgi [3, 6, 9]. Central to the appropriate sorting of cargo, specific coat subunits (known as cargo adaptors) contain binding surfaces that recognize specific cargo proteins and are responsible for capture of specific cargo into the forming vesicles. Adaptor proteins are: (i) Sec24: cargo adaptor that contains multiple cargo binding sites to capture diverse set of proteins; (ii) AP1, AP2, AP3, AP4 and AP5 that binds to different membranes (. Fig. 44.1).

44

. Fig. 44.2

Lipid droplet related BSCL2, REEP1, ATL-1, SPAST, ABCD1, VPS13A, VPS13C

Interorganelle and membrane contact sites CERT, EMC1, ACBD5, BCAP31, VAPB, TDP-43, ADRA1A, VAP9, PSEN1, REEP1, VPS13A, MFN2, SNCA, VPS13C, PACS2, VDAC1, SigR1

Lysosome related defects - Biogenesis of lysosomal related organelles complex (BLOC) - Lysosomal trafficking regulators - MYO5A; -RAB27A

Golgi-related defects (“golgipahies”) - TRAPPC: TRAPPC6B, 6A, C12, C9 , TRAPC11 - VPS: VPS13B, VPS53, VPS51, VPS15 - RAB: RAB3GAP1, RAB3GAP2, RAB18 - OTHER proteins that interact with RAB are codified by the genes: RUSC2, COL4A3BP, BIG2, COSR2, CDC42, TBC1D20, TBC1D23. CDGs (COG complex, SLC35A and TMEM165): see Chapter X (CDG); - Other golgipathies: WDR62, CDK5RAP2, SLC9A6, DENND5A, HERC1, STRADA, RAC1, GD1, PACS1, BICD1, KIF1C, TANGO2, GOSR2, FAM134B, OSBPL2

ORGANELLE AND INTERORGANELLE TRAFFICKING

OTHERS

Microtubule network defects Tubulinopathies: TUBA1A, TUBA8, TUBB, TUBB2, TUBB2B, TUBB3, TUBB4A, TUBB4B, TUBB6, TUBG1 Related to other cytoskeleton proteins: MTMR14, DNM2

Retrograde transport (dynein defects) DYNC1H1, DCTN1, BICD2, LIS1, NDE1

Anterograde transport (kinesin defects) KIF5A, KIF5C, KIF1A, KIF1C, KIF14, KIF16A, KIF4A, KIF7, KIF12A, KIF11, KIF10, KIF6, KIF15, KIF2A, KIF1BP/KBP

CYTOSKELETON RELATED

Genes are in italics

Membrane phospholipid regulators defects: Flippases defects (ATP8A2, ATP8B1, ATP11C, ATP13A2, ATP1A3); Brain barriers transcytosis defects: FOLR1; Glial trafficking defects: GJB1, GJC2, Panx1; Neuronal receptors and cell adhesion molecules (CAM) trafficking defects: Neuroligins, SLITRK1, JAKMIP1, CNTNAP2

DCTN1, MTMR14, DNM2

Cytoskeleton proteins involved in autophagy

EPG5, WDR45 ,SNX14, SPG11, ZFYVE26, A P5Z1, TECPR2, RAB7, ATG5, PARK2 , PINK, SQSTM1 SPG52, 47, 50, 51, ALSJ, ALS17, FIG4, CHMP2B, MTMR13

AUTOPHAGY

Main families of proteins and genes involved in cell traffic diseases according to pathophysilogical categories

Other proteins involved in vesicular trafficking are codified by the following genes: OCRL1, UNC45A, PRF1 , ARFGEF2 , TRIP11, NBEAL2 , MBL, MCFD2, DYM, SH2D1A, XIAP, ITK, CD27, MAGT1, SKIV2L, TTC37, ACTN1, RUNX1, FLY1, PAX3, MITF,TYR, EIF2AK3, SAR1B, SUMF1, MCFD2, SPATA16, GORAB, FGD1, INPP5E, MORMS; MYO5B, BIN1, MTMR14, HCFC1, CHMP2B, 4B, ELMO2, EPS15L1, GPNMB, IQCF, CNPY3, KIAA1109, ERGIC1, CLTRN, DYSF, DKC1, NFE2L2, WFS1, NUP107, HYOU1, ALMS1, ARCN1, ATF6, DCN, FYCO1, IGF2R, IL17RD, LMAN2L, LRBA, OPTN, OSBPL2 , PLEKHM1, SORT1, STX16, GET4

Families of proteins involved in membrane trafficking diseases: - COAT protein complex related - TRAFFICKING PROTEIN PARTICLE COMPLEX (TRAPPCpathies) - VACUOLAR PROTEIN SORTING (VPS) - SNARE related proteins - ADAPTOR RELATED PROTEIN COMPLEX defects, “adaptinopathies”: - CAVEOLIN proteins - TBC proteins - RAB proteins - SLC (solute carrier family) proteins - ATP (ATPases) proteins

VESICULAR TRAFFICKING

836 Á. Garcia-Cazorla et al.

837 Disorders of Cellular Trafficking

5 CALVEOLIN proteins, a family of small proteins (18–24 kDa), are the principal components of caveolae membranes, forming caveolae by polymerization [10]. They are a structural component of transport vesicles derived from the trans-Golgi network. They function in signal transduction, endocytosis, transcytosis, cholesterol transport, and lipid homeostasis [11] by mediating clathrin non-dependent endocytosis (. Fig. 44.1). 5 RAB proteins: the small soluble Ras-related proteins in the brain (Rab) comprise the largest family of small GTP binding proteins within the Ras superfamily with over 60 members. In membrane traffic they assist in a variety of steps: budding, movement docking, tethering and fusion of transport carriers operating between the endomembrane compartments of the cell [12]. They allow transport vesicles to recognise a specific target. Rab proteins can be expressed on both transport vesicles and target membranes, providing a further level of regulation. They are also important regulators of autophagy [13]. 5 TBC domain-containing proteins contain a conserved protein motif present in many eukaryotic proteins. They function as GTPase activating proteins (GAPs) for the small GTPase Rab, which can promote the hydrolysis of Rab-GTP to Rab-GDP [14]. 5 TRAFFICKING PROTEIN PARTICLE (TRAPP) participate in events upstream of vesicle fusion (secretory pathway), and in some aspects of vesicle transport to their correct intracellular target membrane. In humans, the TRAPP complex is formed by the core proteins TRAPPC1, 2, 3, 4, 5, 6, and 2L that self-assemble to form a stable core [15]. This TRAPP core interacts with a number of accessory proteins to form TRAPP II and III. Both of them participate in the secretory pathway and TRAPP III is also involved in autophagy [16]. 5 VACUOLAR PROTEIN SORTING (VPS) is a protein complex composed of VPS 26, 29, 35, 16 and 41 with an important role in trafficking transmembrane receptors toward the endosome compartment (from endosomes to the TGN) [17]. VPS16 and VPS41 are key components of the HOPS complex. The HOPS complex mediates autophagosome-lysosome and endosome-lysosome fusion through several different interactions with SNARE proteins, including catalysing the formation of the SNARE complex and protection of the trans-SNARE complex from disassembly once formed [18]. 5 SNARE proteins (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) mediate membrane fusion by the formation of the SNARE complex assembly. SNAREs are divided in three families depending on the subcellular localization. Synaptosomal-associated proteins (SNAP) and syntaxins

(STX) belong to the target SNARE (t-SNAREs) family and are located at target membranes. Synaptobrevin (SYB) (VAMP, from vesicle-associated membrane protein) are vesicle SNAREs (v.SNARE) enriched in vesicle membranes. The formation of the SNARE complex brings into close apposition the target and vesicle membranes during an exothermic process that overcomes the energy barrier required for membrane fusion [19] (see also 7 Chap. 30, disorders of neurotransmission). 5 CYTOSKELETON assist in bidirectional transport (anterograde and retrograde) between the compartments of the secretory pathway or the endocytic pathway [20]. Most vesicle traffic along microtubules using kinesin or dynein motors, although they can also use myosin II and myosin V motors to move along the actin network (7 Sect. 44.2). In this Chapter, we have schematically defined main groups of pathophysiogical categories (. Fig.  44.2) based on the function of the specific proteins known to be involved in human disease.

44.1.2Membrane Contact Sites

Organelle communication at membrane contact sites (MCS) is gaining wide acceptance in multiple areas of cell biology [1]. Membrane contact sites are classically defined as areas of close apposition between the membranes of two organelles and can be homotypic (between identical organelles) and heterotypic (between two different organelles or two different membrane types) [21]. Well-studied heterotypic contacts involve the Endoplasmic Reticulum (ER) such as the ER-mitochondrial, ER-PM (plasma membrane), ER-Golgi, ER-peroxisomes and ER-lipid droplets (LDs). In the last years, organelle contacts that do not involve the ER have been discovered: LDs-peroxisomes, and membrane contact sites with mitochondria and other organelles (endosomes, lysosomes, PM, LDs, peroxisomes and mitochondrial inner and other membranes). Recently, a consensus on the definition of MCS has been published [21]. The authors propose a set of unifying characteristics that they consider essential features: 5 Tethering: a contact site is defined by the presence of tethering forces that arise from protein-protein or protein-lipid interactions and not by the distance between two organelles. The most common distance is from 10 to 80 nm distance although some contact sites have the capacity to be much larger (over 300 nm) [22]. 5 Lack of fusion: fusion is a characteristic of vesicular trafficking (such as SNARE proteins mediated fusion) but not of membrane contact sites.

44

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ER-Golgi (TGN): - Amyotrophyc lateral sclerosis: VAPB - Intellectual disability: CERT1

Golgi

ER-Endosome: - Parkinson disease: VPS13C

ER

Endosome-lysosomelipid droplet: VPS13A and VPS13C bind to the ER, tethering it to mitochondria (VPS13A), to late endosome/lysosomes (VPS13C) and to lipid droplets (both VPS13A and VPS13C) Chorea-acanthocytosis: VPS13A Parkinson’s disease: VPS13C

44

ER-Lipid droplet: - Spastic paraparesis BSCL2 (Seipin) (*), REEP1 and ATL1 (Atlastin-1)

Lysosome

Endosome

Peroxisome Lipid droplet

Lipid droplet-peroxisomes: - Spastic paraparesis: Spastin (SPAST), ABCD1 (ATP-binding cassette sub-family D member 1)

ER-Mitochondria - Amyotrophyc lateral sclerosis: TARDBP, alpha1 receptor, VAPB, SigR1 - Alzheimer’s disease: Presenilin, alpha-synuclein - Spastic paraparesis: REEP1, SigR1 - Chorea-acanthocytosis: VPS13A - CMT: MFN2, alpha-synuclein - GM1 gangliosidosis - Parkinson disease: VDAC1 - Epileptic encephalopathy: PACS2

. Fig. 44.3 Membrane contact sites and related diseases. Genes are written in italics followed by the correspondent protein. ABCD1 ATP-binding cassette sub-family D member 1, CERT1 ceramide transfer protein, MFN2 mitofusin 2, PACS2 phosphofurin acidic cluster sorting protein 2, REEP receptor expression-enhancing protein 1, SigR1 RNA polymerase sigma factor, TARDBP DNA-bind-

ing protein 43, VAPB vesicle-associated membrane protein-associated protein B/C, VDAC voltage-dependent anion-selective channel protein 1, VPS vacuolar protein sorting-associated protein. (*) Seipin related disorders include not only spastic paraparesis but a spectrum of clinical manifestations (lipodystrophy with neurodegeneration, epileptic encephalopathy) (7 Chap. 35)

5 Specific function: to date, three types of functions have been suggested: (i) the specific bidirectional transport of molecules such as ions, calcium, lipids, amino acids and metals; (ii) the transmission of signaling information important for remodeling activities such as organelle biogenesis, dynamics, positioning, fission and autophagy [23]; (iii): the positioning in trans, of enzymes so as to regulate their activity. 5 Defined proteome/lipidome: contacts need a functional protein and/or membrane composition required for all the above functions and the maintenance of their architecture.

associate and interact composing multi-protein complexes with specific functions. Extracellular vesicles or neuronal exosomes is a type of vesicular membrane trafficking that mediates intercellular communication (i.e communication between neurons and other cells). They are released from multivesicular bodies to the extracellular space. There are no monogenic disorders of extracellular vesicles described so far. However, they have been highlighted for their diagnostic potential of neurodegenerative diseases such as Alzheimer disease, since they can be studied to asses -omic information in the CSF of patients [24]. Transcytosis is a phenomenon that is present in many different cells, from neurons to intestinal cells. Steps along this pathway include endocytosis (adsorptive or receptor-mediated internalization), intracellular vesicular trafficking, and exocytosis [25]. Several receptors capable of inducing receptor-mediated transcytosis are present in the BBB (blood brain barrier) (insulin, transferrin, lipoprotein receptors) and in the BCSFB (blood cerebrospinal fluid barrier) (folate receptor FOLR1) [26]. FOLR1 mutations cause an early-onset neurodegenerative disease (7 Sect. 28.3.3, . Fig. 44.2, . Table 44.1).

Metabolic pathways at MCS are tightly regulated. Mutations in proteins involved in these pathways may cause human diseases and are depicted in . Fig. 44.3. 44.1.3Other Types of Cellular Trafficking

Transport across the cytoskeleton is an important mechanism of molecular and organelle trafficking. This is ruled by microtubules, motor and adaptor proteins that

NEONATAL SEIZURES Are rare in these group of disorders, however epilepsy beyond the neonal period is common

MACROCEPHALY Is rare in these group of disorders

SOME CAUSE WELL-DEFINED GENETIC SYNDROMES: SLC9A6: mimics Angelman Synd. TAU neuronal inclusions; AP1S2: Pettigrew Syndrome, EE and ID, Dandy-Walker, BBGG abnormality; DYM: Dyggve-Melchior-Clausen syndrome (ID, dwarfism); RAB proteins (RAB3GAP1, 2, RAB18) and TBC1D20: Warburg-Micro Syndrome, Marsof Syndrome, ID, progressive spasticity, axonal neuropathy, microphthalmia, cataracts; VPS13B: Cohen Syndrome, ID, obesity, neutropenia and retinopathy;AP1S1: MEDNIK Syndrome, high copper excretion; (7 Chap. 39) CDC42: TakenouchiKosaki Syndrome, ID, EE, optic atrophy, macrothrombocytopenia, lymphedema

SPECIFIC CLINICAL FEATURES

KIF5A (Kinesin, Anterograde Transport): INTRACTABLE NEONATAL MYOCLONUS

CYTOSKELETON disorders

(continued)

CNPNY3 (ER/cochaperone): NEONATAL-First months of life SEIZURES-EE. Progressive brain atrophy. Hippocampal malformation. (ER, Lysosome, Autophagosome, Dendrites /endo-lysosomal): NEONATAL SEIZURES, EE, post-natal MICROCEPHALY, SPASTICITY, ID, Parkinsonism. Brain atrophy, thin CC. HCFC1 (ER, Nucleus): NEONATAL SEIZURES (some cases), EE, microcephaly, choreoathetosis, ID. Cortical malformations (some cases). High Homocisteine and MMA (CblC mimicking). ATAD1: AMPA receptor trafficking defect. NN Hypertonia +/−seizures

TBCK (RABGTPase binding): MACROCEPHALY or normocephaly, hypotonia, dysmorphy, brain atrophy

RAB39B (is also a SV protein): with ID, EE and autism; HERC1: with ID, EE, hypotonia, ataxia RAC1 that may produce MICROCEPHALY can also cause MACROCEPHALY

GENES + Other clinical signs

VESICULAR TRANSPORT

GENES + Other signs

VESICULAR TRANSPORT

GENES + Other signs

GOLGIPATHIES

GENES + Other signs

IER3IP1: microcephaly, epilepsy and diabetes;

OFTEN ASSOCIATE CORTICAL DYSPLASIA + HYPOMYELINATION +/−OTHER BRAIN MALFORMATIONS KIF14: Meckel syndrome; KIF16A: plus blindness; KIF7: Acrocallosal and Joubert syndrome; KIF15: with thrombocytopenia; KIF1BP/KBP: Golderg-Shprintzen syndrome; KIF5A: Neonatal seizures, SP. NDE1: Microhydranencephaly, Lissencephaly TUBA1A: Lissencephaly; TUBB3: complex cortical dysplasia with other brain malformations

SPECIFIC CLINICAL FEATURES

VESICULAR TRANSPORT

Kinesin (Anterograde Transport) deficiencies and NDE1 deficiency (Dynein Retrograde Transport): (NudE neurodevelopmental protein 1): KIF5C, KIF10, KIF2A, KIF14, KIF16A, KIF7, KIF15, Kinesin-binding protein KIF1BP/KBP, KIF5A, NDE1 Tubulins (microtubule network): TUBA1A, TUBA8, TUBB, TUBB2A, TUBB2B, TUBB3, TBCD, TUBG1

GENES INVOLVED

CYTOSKELETON disorders

COPB2, COPD, CDK5RAP2, ZNHIT3, AP4E1, WDR62, SLC9A6, AP1S2, DENNDA, RAC1, DYM, RAB proteins (RAB3GAP1, 2, RAB18), TRAPPCpathies (TRAPPC9,11,12,6A, 6B, 4), COL4A3BP, AP1S1 ARFGEF2, CDC42, VPS13B,VPS53, VPS51, VPS1, TBC1D23, TBC1D20

GENES INVOLVED

GOLGIPATHIES

EARLY ONSET ENCEPHALOPATHIES: clinical signs may appear during the first year of life

MICROCEPHALY as prominent sign In general, these diseases associate prominent BRAIN STRUCTURE/ BRAIN IMAGE alterations and are GLOBAL developmental encephalopathies with multiple NRL symptoms, in particular EPILEPSY/ EPILEPTIC ENCEPHALOPATHY. They may have EXTRA-NRL signs (skeletal, multisystem, well-defined genetic syndromes)

. Table 44.1

Disorders of Cellular Trafficking 839

44

WITH DIVERSE ORGAN INVOLVEMENT: VPS15 (ID, renal failure, retinitis pigmentosa, dysmorphy), FLNA (ID, EE, PV heterotopia, frontometaphyseal dysplasia, connective tissue abnormalites (Ehlers-Danlos like)); ATP7 (TGN): MENKES Syndrome (mild variants: occipital Horn Syndrome, Peripheral Neuropathy); AP3B1: Hermansky-Pudlak syndrome 2 (albinism, infections)

WITH RHABDOMYOLISIS (and Epilepsy and microcephaly): TRAPPC11 and TANGO2 (may present with metabolic crises, mild hyperammonaemia and hypoglycemia, long QT, but also other late NRL forms such as ID, spastic paraparesis and myastheniform symptoms)

WITH RHABDOMYOLISIS (and Epilepsy and microcephaly): TRAPPC2L (ER-Golgi transport): may have also late-onset presentation

WITH DIVERSE ORGAN INVOLVEMENT: SUMF1 (Multiple sulfatase deficiency), SNAP29 (CEDNIK syndrome; is a SV), OCRL: Lowe syndrome, Dent disease 2 and 1 (CLCN5); TBCD: Hypoparathyroidismretardation-dysmorphism syndrome; TBCE: Encephalopathy, progressive, with amyotrophy and optic atrophy

WITH ARTHROGRYPOSIS: SLC35A3 (is a CDG), ERGIC1, KIAA1109 (Alkuraya-Kucinskas syndrome (arthrogryposis, Dandy-Walker))

PACS2: ER-Mitochondria MCS defect. Seizures difficult to treat during the first year. Dysmorphism+cerebellar dysgenesis

GENES + Other signs

AUTOPHAGY

GENES + Other signs

EPG5: VICI Syndrome: agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency. ID, seizures

WITH RETINAL DISTROPHY: Interorganelle trafficking and Membrane Contact Sites: -EMC1: cerebellar atrophy, visual impairment and psychomotor retardation; -ACBD5: retinal dystrophy with leukodystrophy

WITH DIVERSE ORGAN INVOLVEMENT: Seipinopathies (7 Sect. 35.2.2): include not only SP but EE, lipodystrophy and Celia’s disease (neurodegeneration); VPS33A: MPS plus, Lysosome related

WITH ARTHROGRYPOSIS: VPS33B and VIPAS39 (lysosome-interorganelle): ARC1 and ARC2

ORGANELLE AND INTERORGANELLE TRAFFICKING

GENES + Other signs

GOLGIPATHIES

GENES + Other signs

VESICULAR TRANSPORT

INTERORGANELLEMCS

BRAIN IMAGE FEATURES OF EARLY ONSET Encephalopathies

COMPLEX encephalopathy with MULTISYSTEM INVOLVEMENT

(continued)

44

. Table 44.1

840 Á. Garcia-Cazorla et al.

Most Golgipathies with MICROCEPHALY Tubulinopathies NDE1 (Dynamin): Microhydranencephaly, Lissencephaly

THIN CC: Most Golgipathies with MICROCEPHALY Tubulinopathies with hypomyelination Others: ATP6AP2 CC AGENESIS: CDK5RAP2

ATP6AP2, AP4E1, TBCD, VPS1, TBCK, TRAPPCpathies

ATAXIA Most of them are SCA with onset in adolescence and adulthood May associate SP, epilepsy

SCYL1 (SCA21), GORS2 (progressive myoclonic epilepsy with ataxia); ATG5: SCA SNX14, ATG5 (both SCA) SPTBN2 (SCA5 and 14), KIF1C (spastic ataxia)

GOLGIPATHIES AUTOPHAGY CYTOSKELETON disorders

(continued)

VPS13D (SCA4), RUBCN (SCA15), SIL1 (Marinesco-Sjoegren Syndrome: SCA with Congenital Cataract and ID; AMP1 (Synaptic Vesicle disorder)): spastic ataxia, also causes a congenital myasthenic syndrome

JAKMIP1 (disorder of GABA receptor trafficking)—synaptopathy spectrum; CNTNAP2: autism

POST-SYNAPTIC RECEPTOR TRAFFICKING

VESICULAR TRAFFICKING

CAM: Neuroligins: NLGN1, NLGN3, NLGN4: autism spectrum disorders; NORMALLY LATE-ONSET: adolescence, adulthood: SLITRK1: obsessive compulsive disorder, SLITRK4: schizophrenia

ASTROCYTIC TRAFFICKING

PREDOMINANT MOTOR DISORDERS

WDR45: Autistic traits, Rett-like phenotype, evolution towards NBIA

AP1S2, AP1S1

BBGG

AUTOPHAGY

HYPOMYELINATION: Tubulinopathies VPS11; FOLR1, SLC33A: CCHLND. Low serum ceruloplasmin and copper GJB1, GJA12: Pelizaeus-Merzbacherlike DEMYELINATION: Pannexin (Panx1): Demyelination, ACBD5

LEUKODYSTROPHY

PAX3, MITF, TYR: Waardenburg syndrome (different types); NPC1, NPC2: Niemann-Pick disease, type C1/ C2; EIF2AK3: Wolcott-Rallison syndrome; FGD1: Aarskog-Scott syndrome; INPP5E: Mental retardation, truncal obesity, retinal dystrophy, and micropenis MORMS; GET4 (VT): 1 case, EE, thin CC, brain atrophy (ER to Golgi RT, Syntaxin 5, TA protein); Psychiatric: CLTN (collectrin): Hartnup-like; GD1l: X-linked ID; PACS1: Schuurs-Hoeijmakers syndrome (SHMS): ID; SCARB2: epilepsy with or without renal failure; CERT: ID (also ER-TCN MCS dysfunction)

Cerebellar Atrophy: ZNHIT3 (PEHO-Like Syndrome), AP4E1, SLC9A6 PCH: VPS53, 51, TBC1D23, PCLO (with optic atrophy) Joubert malformation: AP4E1 Dandy-Walker: AP1S2, KIAA1109 Other cerebellar dysplasia: PACS2

POSTERIOR FOSSA

VESICULAR TRAFFICKING

OTHER NEUROPEDIATRIC DISEASES that may appear or are mostly detectable beyond the first year of life

CORTICAL MALFORMATIONS

THIN CC CC AGENESIS

BRAIN ATROPHY

Disorders of Cellular Trafficking 841

44

AMIOTROPHYC LATERAL SCLEROSIS (ALS)

PARKINSONISM and other MOVEMENT DISORDERS Most of them pediatric or juvenile parkinsonism and other early-onset movement disorders

SPASTIC PARAPARESIS (SPG) Most of them complex and late-onset

(continued)

44

. Table 44.1

AP4B1, AP4E1(Complex Spastic Paraparesis), WASHC5 (SPG8), NIPA1 (magnesium transporter): SPG6; MAST syndrome: SPG21; SPART: Troyer Syndrome, SPG20. Infantile onset: AP4E1, AP4M1, AP4S1. APSZ1: progressive SP; TGFBR1:onset in the first decade; VPS37A: early onset SP with pectus carinatum and hypertrichosis; ARL6IP1, UBAP1 BCSL2 (Seipin), REEP1, Atlastin-1 (ATL-1) (Organelle interplay Lipid Droplet, FA incorporation in LD): complex spastic paraparesis Connexin47 (C47), GJA12: SP, Leukodystrophy FIG4: Yunis-Varon syndrome; type 2 (SDCO): Striatonigral degeneration, childhood-onset; PRKN: PARKIN deficiency (Parkinson Disease 2); PINK1: Parkinson Disease 6: NADGP: Neurodegeneration with ataxia, dystonia and gaze palsy VPS13C: Early-onset PARKINSONISM (may also cause Leigh-like features); ATP6AP2: Early-onset PARKINSONISM; VPS13A: chorea-achantocytosis; VPS16, VPS4: early-onset dystonia. These are also lysosome-related disorders; GAK. LRRK2: diversity of clinical phenotypes; RME-8; SYNJ1: pediatric-juvenile onset PD; VPS16: adolescence-onset dystonia; VPS26A: atypical PD, no L-Dopa response. VPS35: parkinsonism. ATP8A2: cerebellar ataxia and atrophy, ID, chorea, severe hypotonia, optic atrophy; ATP1A3: Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), Alternating hemiplegia, Dystonia 12 (all AD); Rapid-onset parkinsonism Kufor-Rakeb Synd/ SP: ATP13A2 alpha-Synuclein, VDAC1, SigR1 (Parkinson Disease); BCAP31(deafness, dystonia and cerebellar hypomyelination), TUBB4A: Torsion dystonia 4 (DYT4), Hypomyelinating leukodystrophy; TUBB6: congenital facial palsy with ptosis and velopharyngeal dysfunction; ACTB: dystonia, juvenile onset RAB39B: Early-onset parkinsonism CHMP2B: ALS type 17; Spatacsin (ALS type5 (SPG11 Type3)); ALSJ (ALS2); FIG: FIG4 deficiency: type 1 (BTOP): Polymicrogyria bilateral temporo-occipital; type 2 (ASL11): ASL type 11; type 3 (CMT4J): CMT type 4

VESICULAR TRAFFICKING

ORGANELLE AND INTERORGANELLE GLIAL TRAFFICKING AUTOPHAGY

VESICULAR TRAFFICKING

FLIPPASES

INTERORGANELLEMCS CYTOSKELETON disorders GOLGIPATHY AUTOPHAGY

VESICULAR TRAFFICKING: OPTN

TANGO2, SLC33A1(SPG42), AP related genes are also Golgipathies, ATL1 (atlastin)

GOLGIPATHIES

CYTOSKELETON disorders: KIF5A

REEP1 (SPG31), KIF1C (spastic ataxia 2, SPG 58); KIF5A (various phenotypes all AD: SPG10, CMT2, ALS); KIF1A (SPG30)

CYTOSKELETON disorders

INTERORGANELLE/MCS: VAP9, VAPB, SigR1: ALS and SMA

SPAST and ABCD1: FA trafficking from LDs into peroxisomes (different types of SP: SPG4, 52, 47, 50, 51) SPG11 (spatacsin): Type1 SP type 11; Other phenotypes: CMT2; ALS type5. Spastizin (ZFYVE26): SP type 15 or Kjellin syndrome TECPR2: SP type 49; AP5Z1: SP type 48

AUTOPHAGY

842 Á. Garcia-Cazorla et al.

TBK1 deficiency (TANK binding kinase 1): susceptibility to encephalopathy infection-induced; FTD; type 2 (FTD3): Frontotemporal dementia; C9orf72: frontotemporal dementia. Also involved in endosomal trafficking CHMP2B, 4B: Frontotemporal dementia, cataracts; TREM2: Nasu-Hakola disease (early-onset fronto-temporal dementia and recurrent bone fractures); BIN1: progressive dementia and amyloid deposition

AUTOPHAGY VESICULAR TRAFFICKING

Glial trafficking defects: Connexin32 (C32) (GJB1): Multiple Sclerosis; Connexin47 (C47) (GJC12): Leukodystrophy, Multiple Sclerosis; Pannexin (PANX1): Demyelination. Deafness related defects: WFS1, UNCA5A, AP1S1, VPS33B, VPAS39, RFTL, MYH9,PAA3,MTF,TYR,SUMF1,MYC58,RAB23,MYO5B, BCAP31

Presenilin, amyloid precursor protein: Alzheimer disease; TMEM106B: FTD and a hypomyelination disorder

INTERORGANELLEMCS

AD autosomal dominant, AR autosomal recessive, ARPHM periventricular heterotopia with microcephaly, ARC arthrogryposis, cholestasis and renal dysfunction type 1, AT anterograde transport, BBGG basal ganglia, CAM cellular adhesion molecules, CC corpus callosum, CCHLND congenital cataracts, hearing loss, and neurodegeneration, EE epileptic encephalopathy (patients may exhibit different degrees of epilepsy severity), Enc encephalopathy, DMC Dyggve-Melchior-Clausen syndrome, ID intellectual disability, HMSNO hereditary motor and sensory neuropathy, INH inheritance, MRXSCH mental retardation X-linked syndrome Christianson, MRD48 mental retardation autosomal dominant type 48, MIC microcephaly congenital or postnatal, MACRO macrocephaly, MCS membrane contact site, MEDNIK mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, mma methylmalonic acid, NRL neurological, PM primary, congenital microcephaly, POM post-natal onset microcephaly, PEHO-Like syndrome progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy infantile cerebellar optic atrophy-like (PEHO Like syndrome), PCH pontocerebellar hypoplasia, PD Parkinson disease, PM primary, congenital microcephaly, POM post-natal microcephaly, MIC PM or POM microcephaly, SCA spinocerebellar ataxia, SP spastic paraparesis, RT retrograde trafficking, SP spastic paraparesis, Synd syndrome, TGN trans Golgi network, TKS Takenouchi-Kosaki syndrome, V vesicle, SV synaptic vesicle, XL X-linked, ER endoplasmic reticulum, VT vesicular trafficking

OTHER DISORDERS

DEMENTIA

FAM134B: neuropathy hereditary sensory and autonomic type IIB; RAB18, 39B, RAB7, RAB3GAP1: CMT.

GOLGIPATHIES

GLIAL TRAFFICKING: Connexin32 (C32): CMT

KIF1A: Hereditary sensory neuropathy type IIC (AR), spastic paraparesis 30 (AR); DCTN1 (Dynactin1/P150): Distal hereditary motor neuropathy Perry syndrome (AD); KIF5A: SPG10; CMT2 ALS; DNM2: CMT with neutropenia

CYTOSKELETON disorders

VESICULAR TRAFF: ATP7; TGF (HMSNO), LITAF, MTMR2, 5, SH3TC2

DCTN1 deficiency type 1: Neuropathy, distal hereditary motor, type VIIB; FIG, SPG11, RAB7: CMT2; TMR13

AUTOPHAGY

VESICULAR TRAFFICKING: ATP7

PERIPHERAL NEUROPATHY Most of them are Charcot-Marie-Tooth (CMT) subtypes

INTERORGANELLE: VAPB

CYTOSKELETON disorders: BICAUDAL; DYNC1H1

SPINAL MUSCLE ATROPHY (SMA)

Disorders of Cellular Trafficking 843

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Regulation of membrane phospholipids by phospholipid flippases (P4-ATPases contribute to membrane transport (see also 7 Chap. 35)). Flippases translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes [27]. Several of these flippases are involved in neurological and hematological disorders (. Fig. 44.2, . Table 44.2). . Table 44.2

Gap junctions-hemichannels constitute a type of membrane trafficking between astrocytes and oligodendrocytes. Connexins and Pannxenins are proteins, hemichannels, involved in this kind of transport. Mutations in genes encoding for some subtypes of these proteins can cause neurological disorders [28] (. Fig.  44.2, . Table 44.1), as described in 7 Sect. 44.2.5.

Extraneurological manifestations of trafficking disorders Pathophysiological category

Genes

Vesicular Trafficking

DKC1, FLI1, HYOU1, JAGN1, MAGT1, NBAS, PACS1, PRF1, RAB27A, STXBP2, TMEM173, TTC37, UNC13D, VIPAS39, VPS13B,

OIT

COG1, COG4, COG6, MYO5A, SLC35A1, SLC35C1

VOIT

AP3B1, AP3D1, BLOC156, COPA, LAMTOR2, LRBA, LYST, STX11, VPS33B, VPS45

Autophagy

EPG5, TBK1

Cytoskeleton

WAS

Others

ITK, MBL2, NFE2L2, SH2D1A, SKIV2L, XIAP

HLH Chediak-Higashi syndrome (LYST) Familial HLH (PRF1, STX11, STXBP2, UNC13D) Griscelli syndrome (MYO5A, RAB27A) Lymphoproliferative syndrome (CD27, ITK, SH2DA1, XIAP) STING-associated vasculopathy (TMEM173)

Vesicular trafficking

AP3B1, CD27, ITK, LYST, NBAS, PRF1, RAB27A, STX11, STXBP2, TMEM173, UNC13D

OIT

MYO5A

Others

SH2D1A, XIAP

Specific Erythrocyte Abnormalities Congenital dyserythropoietic anemia type II (SEC23B) SLC35C1-CDG, lack of erythrocyte H-antigen (SLC35C1) Rabenosyn-5 deficiency, macrocytosis, megaloblastoid erythropoiesis (RBSN)

Vesicular trafficking

RBSN, SEC23B

OIT

SLC35C1

Cytoskeleton

TBCE

Specific Platelet Abnormalities Hermansky-Pudlak syndrome (AP3B1, DTNBP1, BLOC1S3, BLOC1S6) Macrothrombocytopenia (MYH9) Platelet-type bleeding disorder (ACTN1, FLI1) Wiskott-Aldrich syndrome (WAS)

Vesicular trafficking

DTNBP1, FLI1, NBEAL2,

VOIT

BLOC1S3, BLOC1S6, LRBA, TMEM165

Vesicular trafficking and cytoskeleton

CDC42

Autophagy

AP3B1

Cytoskeleton

ACTN1, MYH9, WAS

Others

RUNX1

Vesicular trafficking

JAGN1, NBAS, VPS13B

OIT

SLC35C1

VOIT

LYST, VPS45

Cytoskeleton

WAS

Autophagy and cytoskeleton

DNM2

Immunohaematological Immune Dysfunction Chediak-Higashi syndrome (LYST) Griscelli syndrome (MYO5A, RAB27A) Takenouchi-Kosaki syndrome (CDC42) Vici syndrome (EPG5) Wiskott-Aldrich syndrome (WAS)

44

Specific White Blood Cell Abnormalities Charcot-Marie-Tooth disease 2M: Neutropenia (DNM2) Chediak-Higashi syndrome (LYST) NBAS deficiency (NBAS): Pelger-Huet anomaly Severe congenital neutropenia (JAGN1, VPS45, WAS)

44

845 Disorders of Cellular Trafficking

. Table 44.2

(continued) Pathophysiological category

Genes

Vescicular trafficking

DTNBP1, GPNMB, RAB27A, TYR

VOIT

AP3B1, AP3D1, ATP7A, BLOC1S3, BLOC1S6, LYST,

Autophagy

EPG5

Cytoskeleton

MLPH

OIT and cytoskeleton

MYO5A

Others

MITF, PAX3

Hyperpigmentation Alstrom syndrome (ALMS1) Craniolenticulosutural dysplasia (SEC23A)

Vescicular trafficking

GPNMB, SEC23A

Cytoskeleton

ALMS1, KIF1B,

Ichthyosis ARC syndrome (VIPAS39, VPS33B) CEDNIK syndrome (SNAP29) MEDNIK syndrome (AP1S1) Multiple sulfatase deficiency (SUMF1)

Vesicular trafficking

SNAP29, SUMF1, VIPAS39

VOIT

AP1S1, VPS33B

Nodular/papular lesions Lowe syndrome (OCRL) Lymphoproliferative syndrome X-linked (XIAP)

OIT

AP1S3, OCRL

Others

XIAP

Eruptions Dyskeratosis congenita X-linked (DKC1) MEDNIK syndrome (AP1S1) Palmoplantar punctate keratoderma (AAGAB) Wiskott-Aldrich syndrome (WAS)

Vescicular trafficking

AAGAB, DKC1, FLI1, GPNMB, PRF1, RAC1, TMEM173

OIT

AP1S1, ATP2C1, COG6

Cytoskeleton

WAS

Laxity Geroderma osteodysplasticum (GORAB) Menkes disease (ATP7A) Wrinkly skin syndrome (ATP6V0A2)

Vesicular trafficking

ATP6V0A2, NBAS

OIT

COG7, GORAB, SLC39A13

VOIT

ATP7A

Increased skin thickness – lipodystrophy CDG syndromes (COG4, COG6, COG7, SLC35C1, TMEM165) Lipoid proteinosis (ECM1) MPS-plus syndrome (VPS33A) Mucolipidosis II (GNPTAB)

Vesicular trafficking

KIAA1109

OIT

SLC35C1

VOIT

GNPTAB, TMEM165

Cytoskeleton

ECM1, KIF11

VOIT and autophagy

VPS33A

Vascular skin abnormalities Craniolenticulosutural dysplasia (SEC23A)

Vesicular trafficking

SEC23A

Hair abnormalities Menkes disease (ATP7A) Trichohepatoenteric syndrome (SKIV2L, TTC37) Warburg micro syndrome (RAB3GAP1, RAB18, TBC1D20) Yunis-Varon syndrome (FIG4, VAC14)

Vesicular trafficking

DTNBP1, RAB18, RAB3BAP1, SEC23A, TTC37, TYR

OIT

COG4, COG7, CTNS

VOIT

AP1S1, ATP7A, BLOC1S3, CAV1, TBC1D20

OIT and cytoskeleton

MYO5A

Autophagy

EPG5, FIG4, VAC14

Cytoskeleton

ALMS1, KIFBP, MLPH

Others

MITF, PAX3, SKIV2L

Skin & hair Hypopigmentation Griscelli syndrome (MYO5A, RAB27A, MLPH) Hermansky-Pudlak syndrome (AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1) Menkes disease (ATP7A) Vici syndrome (EPG5) Waardenburg syndrome (MITF, PAX3)

(continued)

846

Á. Garcia-Cazorla et al.

. Table 44.2

(continued) Pathophysiological category

Genes

Vesicular trafficking

DYSF, LPIN1, PIK3R4, RFT1, SIL1, SLC33A1, STRADA, TMEM173, VIPAS39

OIT

ACBD5, COG8, CTNS, SLC35A1, SLC35C1

VOIT

ARCN1, CAV3, ERGIC1, LAMP2, LYST, TANGO2, TMEM165, TRAPPC11, TRAPPC2L, VPS33B

Autophagy

EPG5, MTMR14, SQSTM10, TBCD, VPS13D

Cytoskeleton

ACTB, BIN1, KIF5C, TUBB3

Autophagy and cytoskeleton

DNM2

Vesicular trafficking

ATPV06A2, CDC42, EIF2AK3, HYOU1, PIK3R4, RAB18, RAB3GAP1, RAB3GAP2, RFT1, SEC23A, SUMF1, TRAPPC2, VPS13B

OIT

COG1, COG6, COG7, DYM, PACS1, RAB33B, SLC35A2, VPS33A

VOIT

AP3D1, ARCN1, ATP7A, GNPTAB, TBC1D20, TMEM165, TRIP11

Autophagy

FIG4, VAC14

Cytoskeleton

ACTB, DYNC2H1, KIFBP

Other skeletal signs Paget disease (SQSTM1) Primary intraosseous vascular malformation (ELMO2) STING-associated vasculopathy (TMEM173)

Vesicular trafficking

ELMO2, TMEM173

VOIT

COPA, LRBA

VT and AUTOPHAGY

SQSTM1

Structural bone abnormalities Hypoparathyroidism-retardation-dysmorphism syndrome (TBCE) Osteopetrosis type 1, 3 (PLEKHM1, TCIRG1) Waardenburg syndrome (PAX3)

Vesicular trafficking

AP2S1, HERC1, NBAS, UNC45A

OIT

COG1, CTNS, GORAB

VOIT

IL17RD, OCRL, STX16

Autophagy

TBCE

VOIT and autophagy

PLEKHM1

OIT and autophagy

SQSTM1, TCIRG1

Cytoskeleton

ALMS1

Others

PAX3

Vesicular trafficking

KIAA1109, VIPAS39

OIT

SLC35A3

VOIT

ERGIC1, VPS33B

Cytoskeleton

BICD2, KIF5C, TBCD

Vesicular trafficking

ATP6V0A2, RAB3GAP1

OIT

SLC35A1

VOIT

ATP7A, SLC10A7

Musculoskeletal Muscular abnormalities Acute recurrent myoglobinuria (LPIN1) Centronuclear myopathy (MTMR14) Danon disease (LAMP2) Marinesco-Sjogren syndrome (SIL1) MECRCN (TANGO2) Vici syndrome (EPG5)

Skeletal dysplastic changes Dyggve-Melchior-Clausen disease (DYM) Multiple sulfatase deficiency (SUMF1) Spondyloepiphyseal dysplasia tarda (TRAPPC2) Yunis-Varon syndrome (FIG4, VAC14)

44

Arthrogryposis ARC syndrome (VPS33B, VIPAS39) Neurogenic multiplex arthrogryposis (ERGIC1) Progressive encephalopathy brain atrophy and thin corpus callosum (TBCD) Joint laxity SLC35A1-CDG (SLC35A1) Cutis laxa type IIA (ATP6V0A2) SSASKS syndrome (SLC10A7) Warburg micro syndrome (RAB3GAP1)

44

847 Disorders of Cellular Trafficking

. Table 44.2

(continued) Pathophysiological category

Genes

Vesicular trafficking

DCK1, NGLY1, RFT1, TMEM199, TTC37, UNC45A, VIPAS39

OIT

COG2, COG4, COG5, COG6, COG7, COG8

VOIT

AP1S1, CAV1, IGF2R, NPC1, NPC2, PEX13, TMEM165, TRAPPC11, VPS33A, VPS33B

Cytoskeleton

ALMS1, DYNC2H1

Others

ITK, SKIV2L

Vesicular trafficking

ATP7B, BCAP31, HYOU1, NBAS, PRF1, UNC13D

OIT

COG4, STX11

VOIT

SCYL1,

Others

SH2D1A, STXBP2, XIAP

Vescicular trafficking

EIF2AK3, PRF1, RFT1, SUMF1

OIT

COG4

VOIT

AP3B1, AP3D1, CAV1, GNPTAB, LYST, NPC1, NPC2, TRAPPC11, VPS33A, VPS45

VOIT and autophagy

PLEKHM1, TCIRG1

VT and cytoskeleton

CD27

Others

ITK, SKIV2L

Vesicular trafficking

HYOI1, TTC37, UNC45A,

VOIT

AP1S1, ARCN1, LRBA, SAR1B, TMEM165

OIT

COG4, COG6, COG8, SLC35A2

Autophagy

FIG4, VAC14

Cytoskeleton

KIFBP, MYO5B, WAS

Others

SKIV2L, SLC2A10, XIAP

Vesicular trafficking

RAB23, STRADA, VPS13B

OIT

COG1, PACS1, SLC35A1

VOIT

ARCN1

Cytoskeleton

DYNC2H1, FLNA

Cardiomyopathy Danon disease (LAMP2) Familial hypertrophic cardiomyopathy (CAV3) Martsolf syndrome (RAB3GAP2) Vici syndrome (EPG5) Wolfram syndrome (WFS1)

Vesicular trafficking

RAB3GAP2, WFS1

VOIT

CAV3, GNPTAB, TANGO2, LAMP2

Cytoskeleton

MYO5B

Others

NFE2L2

Arrhythmia Long QT syndrome type 9 & 11 (CAV3, AKAP9) MECRCN (TANGO2)

VOIT

CAV3, TANGO2

OIT

AKAP9

Digestive Chronic liver disease ARC syndrome (VPS33B, VIPAS39) CDG type II (COG2, COG4, COG5, COG6, COG7, COG8, RFT1, TMEM165, TMEM199) MEDNIK syndrome (AP1S1) Trichohepatoenteric syndrome (SKIV2L, TTC37)

Acute liver failure and hepatitis-like attaks Familial HLH (PRF1, UNC13D, STX11, STXBP2) RALF (recurrent acute liver failure) (NBAS, SCYL1) Wilson disease (ATP7B) Hepato(spleno)megaly Mucolipidosis II (GNPTAB) Multiple sulfatase deficiency (SUMF1) Niemann-pick disease type C (NPC1, NPC2) Trichohepatoenteric syndrome (SKIV2L, TTC37)

Gastrointestinal signs Chylomicron retention disease (SAR1B) Goldberg-Shprintzen megacolon syndrome (KIFBP) MEDNIK syndrome (AP1S1) Microvillus inclusion disease (MYO5B)

Cardiological Congenital heart disease Carpenter syndrome (RAB23) Saladino Noonan syndrome (DYNC2H1) Schuurs-Hoeijmakers syndrome (PACS1)

(continued)

848

Á. Garcia-Cazorla et al.

. Table 44.2

(continued) Pathophysiological category

Genes

Cytoskeleton

MYH9

Vesicular trafficking

DKC1, KIAA1109, RAB18, RAB23, RAB3GAP1, RAB3GAP2, RNF13, SEC23A, SIL1, SLC33A1, SUMF1, WFS1

VOIT

AP1S1, ARCN1, FYCO1, GNPTAB, INPP5E, ORCL, PEX13, TBC1D20, TRAPPC11

Autophagy

EPG5, FIG4, VAC14

VOIT and autophagy

CHMP4B

Cytoskeleton

ACTB, ALMS1, KIF11, KIF1B, TUBG1

Vesicular trafficking

ATXN2, CHM, KIAA1109, PIK3R4, SUMF1, TYR, VPS13B, WFS1

OIT

SLC35A2

VOIT

AP3B2, BLOC1S3

Autophagy

AP5Z1, FIG4, VAC14

VOIT and autophagy

SPG11

Cytoskeleton

ALMS1, KIF11, TUBB, TUBB4B

Cytoskeleton and autophagy

ZFYVE26

VOIT and cytoskeleton

INPP5E

Corneal abnormalities Carpenter syndrome (RAB23) Congenital stromal corneal dystrophy (DCN) Cystinosis nephropathic (CTNS) Multiple sulfatase deficiency (SUMF1)

Vesicular trafficking

DCN, RAB23, SUMF1, TRAPPC2

OIT

CTNS

VOIT

GNPTAB, TBC1D20

Hypopigmentation Chediak-Higashi syndrome (LYST) Hermansky-Pudlak syndrome (AP3B1, AP3D1, DTNBP1) Waardenburg syndrome (MITF)

Vesicular trafficking

DTNBP1

VOIT

AP3B1, AP3D1, LYST

Others

MITF, PAX3

Coloboma Baraitser-Winter syndrome (ACTB) Pontocerebellar hypoplasia type 11 () Schuurs-Hoeijmakers syndrome (PACS1)

VOIT

TBC1D23

OIT

PACS1

Cytoskeleton

ACTB

Other ocular abnormalities Achromatopsia-7 (ATF6) Glaucoma open angle (OPTN) Goldberg-Shprintzen megacolon syndrome (KIFBP)

Vesicular trafficking

NGLY1, RAB18, RAB3GAP1, SFB2WFS1

OIT

ATF6, COG5, SLC39A13

VOIT

LAMP2, OCRL, OPTN, TMEM165

Cytoskeleton

KIF14, KIF1B, KIFBP, TUBG1

Other cardiac abnormalities MATINS (macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss) (MYH9) Ocular Cataract Lowe syndrome (OCRL) Multiple sulfatase deficiency (SUMF1) Vici syndrome (EPG5) Warburg micro syndrome (RAB3GAP1, RAB18, TBC1D20) Yunis-Varon syndrome (FIG4, VAC14)

Retinopathy Alkuraya-Kucinskas syndrome (KIAA1109) Choroideremia (CHM) Cohen syndrome (VPS13B) Leber amaurosis with deafness (TUBB4B) Wolfram syndrome (WFS1)

44

849 Disorders of Cellular Trafficking

. Table 44.2

(continued) Pathophysiological category

Genes

Vesicular trafficking

VIPAS39, VPS33B

OIT

SLC35A1

VOIT

OCRL

Autophagy

EPG5

Vesicular trafficking

EIF2AK3, LPIN1, STRADA

OIT

CTNS, SCARB2, SLC35A1, SLC35A2

VOIT

OCRL, VPS33A

Cytoskeleton

KIF14, WAS

Others

NUP107

Vesicular trafficking

KIAA1109, RAB23, TTC37, WFS1

OIT

PACS1

VOIT

PEX13, VPS33A

Cytoskeleton

DYNC2H1

Endocrinological abnormalities Cohen syndrome (VPS13B) (short stature,truncal obesity) Kenny-Caffey syndrome (TBCE) (hypoparathyroidism) Osteopetrosis type 1 & 3 (TCIRG1, PLEKHM1) Pseudohypoparathyroidism IB (STX16) Wolfram syndrome (WFS1) (diabetes)

Vesicular trafficking

STRADA, VPS13B, WFS1

VOIT

LRBA, PLEKHM1, STX16, TANGO2

VOIT and AUTOPHAGY

TCIRG1

Cytoskeleton

TBCE

Genital/reproductive abnormalities Carpenter syndrome (RAB23) Globozoospermia 6 (SPATA16) Marinesco-Sjogren syndrome (SIL1) Martsolf syndrome (RAB3GAP2) Warburg micro syndrome (RAB3GAP1 RAB18, TBC1D20)

Vesicular trafficking

PANX1, RAB18, RAB23, RAB3GAP1, RAB3GAP2, RAC1, SIL1, WFS1

VOIT

TBC1D20

Autophagy

PRKN, VAC14

Cytoskeleton

TBCE

Others

SPATA16

Vesicular trafficking

CD27, DKC1, ITK, MAGT1

OIT

COG1, COG4, COG6, SLC35A1, SLC35C1

VOIT

IGF2R

Autophagy

PRKN

Cytoskeleton

KIF1B

Others

RUNX1, SH2D1A, XIAP

Renal Tubulopathy ARC syndrome (VIPAS39, VPS33B) SLC35A1-CDG (SLC35A1) Dent disease type 2 (OCRL) Lowe syndrome (OCRL) Chronic kidney disease CDG type II (COG1, COG6, COG7, SLC35A1, SLC35A2) Cystinosis nephropathic (CTNS) Lowe syndrome (OCRL) Wolcott-Rallison syndrome (EIF2AK3)

Renal dysplasia/malformation Alkuraya-Kucinskas syndrome (KIAA1109) Saladino-Noonan syndrome (DYNC2H1) Trichohepatoenteric syndrome (TTC37) Zellweger syndrome (PEX13) Endocrine, reproductive, neoplasia

Neoplasia Adenocarcinoma of lung (PRKN) Hepatocellular carcinoma somatic (IGF2R) Lymphoproliferative syndrome 1 & 2 (ITK, CD27) Pheochromocytoma (KIF1B)

OIT organelle/interorganelle trafficking, VOIT vesicular and organelle/interorganelle trafficking, HLH hemophagocytic lymphohistiocytosis, CDG congenital disorder of glycosylation

44

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44.2

Cellular Trafficking in the Nervous System: Polarization and Compartmentalization

Neurons are the largest known cells, with complex and highly polarized morphologies. As such, neuronal signaling is highly compartmentalized, requiring sophisticated transfer mechanisms to convey and integrate information within and between sub-neuronal compartments [29]. Organelles, proteins and RNAs are actively transported to synaptic terminals for the remodelling of pre-existing neuronal connections and formation of new ones [30]. Mechanisms of intraneuronal communication are tightly regulated and disclose a high susceptibility to genetic mutations that produce both early-onset neurodevelopmental and late-onset neurodegenerative diseases [29]. The specialized domains of neurons are located in the cytosol, axons, axon growth cones, axon initial segment, nodes of Ranvier, dendrites (proximal and distal), and synapses (pre-synaptic and postsynaptic specializations). Each domain contains specific sets of proteins and plays distinct functions that rely on regulated trafficking from biosynthetic and endosomal compartments. These mechanisms may vary depending on different cell types and brain regions. Abnormalities in trafficking mechanisms in glial cells have also been described to cause neurological disorders.

44.2.1Trafficking Defects in the Neuronal

Soma (ER-Golgi-PM-EndosomeLysosome-Autophagosome) z

44

Exocytic Pathway Defects

As already mentioned, the exocytic pathway moves cargo from the ER through the Golgi to the PM. There are two major steps in the exocytic pathway mediated by vesicles: ER-to-Cis Golgi and Trans Golgi-to-PM. The great length of neuronal projections and the need for precise spatiotemporal control over membrane and secreted protein localization make neurons particularly vulnerable to defects in each of the ER-Golgi compartment export and trafficking. Here we describe only some of the most representative diseases according to the main affected proteins and subcellular compartments (. Figs. 44.2 and 44.3 . Table 44.1). 1-ER-to-Cis Golgi defects include mutations in genes affecting the COPII machinery. They are linked to diverse neurological diseases (. Figs.  44.2 and 44.3, . Table 44.1): I. Most are early-onset neurodevelopmental disorders with congenital or post-natal microcephaly (+/− cortical and other brain malformations), intellectual

disability, and white matter disorders. They are related to diverse type of proteins such as COP, SEC, TRAPPC, TBC, VPS and RAB (RAB GTPases, RAB-effectors, RAB-regulating proteins) [7, 8]. TANGO2 defects belong also to this localization but may associate rhabdomyolysis episodes and other clinical manifestations mimicking fatty acid oxidation disorders [31–33] (7 Sect. 1.4.6). II. Late-onset presentations can appear in late childhood, adolescence and adulthood related with motor dysfunctions such spastic paraparesis (i.e. TECPR2, TANGO2, SLC33A1 defects) [34], and Charcot-Marie-Tooth (CMT) disease (i.e TFG, CNPNY3 defects) [35]. TREM2 is a trafficking defect between the ER and ERGIC, linked to a syndrome characterized by early-onset fronto-temporal dementia and recurrent bone fractures (i.e. NasuHakola disease, also known as polycystic lipomembranous osteodyplasia with sclerosing leukoencephalopathy) [36]. 2-Trans Golgi-to-Plasma Membrane defects involve complex severe encephalopathies such as diverse adaptinopathies: MEDNIK syndrome (AP1S1 adaptor protein defect) (full description in 7 Sect. 34.1.4), AP1S2 (Pettigrew Syndrome) [37], ARFGEF2 (microcephaly, periventricular heterotopia), and ATP7 mutations (Menkes Syndrome), and complex spastic paraparesis (AP4B1, AP4E1) [38]. Several glycosylation defects (COG1, 7, 8) are related to trafficking alterations between the ER and the Golgi complex. z

Endocytic Pathway Defects

In the endocytic pathway, cargo can be internalized at the PM by a number of routes: membrane receptors are mainly internalized via clathrin-coated vesicles whereas other proteins are internalized by caveolar or raft dependent routes [5]. Early and late-endosomes to lysosomes belong to the clathrin-coated endocytic pathway (. Figs. 44.1 and 44.4). kGolgi to Endosomes Trafficking Defects

Diseases in this subcellular compartment often present as complex early-onset encephalopathies that often associate multisystem involvement. This is the case of Rabenosyn-5 deficiency and SLC9A6, DENND5A, and ARFGEF2 mutations [39, 40]. kLate Endosome to Lysosome and Trafficking Defects

Endosomes and lysosomes are acidic organelles that degrade plasma membrane components, extracellular and intracellular macromolecules and cellular fragments. The endolysosomal vesicle and autophagosomes communicate to each other. Therefore, some proteins involved

ER

GM130 COG5

VPS13B

RAB6

TBC1D20, RAB18, RAB3GAP2/1 SEC31A, 24B

TREM2

TBC1D20

RAB1

TRAPPC9

DYME

TGN SE

AP1S1

RAB6

RE

EE

LE

A

α-tubulin β-tubulin

RAB4,11

L

RAB7, ATP6AP2, SNAP29

RBSN, SLC9A6, DENND5A, ARFGEF2

VPS53

RAB2 RAB33A/B

CGN

Golgi complex

RAB6

VPS13B

Autophagy related

– Microtubule

TUBA8 TUBA1A

+

Dynactin

Spastin

+

TUBB5 TUBB2B TUBB3

TBCE

DYNC1H1, DCTN1, BICD2, LIS1, NDE1

Microtubule network

2

Microtubule

Lis 1

Dynein: retrograde

–

Dynein

Cargo

–

–

+

KIF21A

+

TUBA1A, TUBA8, TUBB, TUBB2, TUBB2B, TUBB3, TUBB4A, TUBB4B, TUBB6, TUBG1

Tubulinopathies

Microtubule

KIF5A

Microtubule

KIF1B

Mitochondrion

Synaptic vesicle cycle disorders: See Chapter 30

Synaptic vesicles

3

KIF5A, KIF5C, KIF1A, KIF1C, KIF14, KIF16A, KIF4A, KIF7, KIF12A, KIF11, KIF10, KIF6, KIF15, KIF2A, KBP

Kinesin: anterograde

. Fig. 44.4 Disorders of neuronal trafficking. There are three neuronal compartments with specialized traffic mechanisms: 1-Cytoplasm; 2-Axon; 3-Presynaptic terminal. Here we include only some of the most representative genes responsible of neurological diseases and their predominant cellular localization (in the green squares). Highlighted in blue are RAB proteins that behave in different cellular exocytic and endocytic processes. A autophagosome, CGN cis Golgi network, EE early endosome, L lysosome, LE early endosome, RE recycling, endosome, SE secretory endosome, TGN trans Golgi network

Nucleus

1

EPG5, WDR45 ,SNX14, SPG11, ZFYVE26, AP5Z1, RAB7, ATG5, SQSTM1

Disorders of Cellular Trafficking 851

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in this pathway can also have roles in autophagy. Clinical presentations include neonatal seizures (ATP6AP2) [41], complex multisystem syndromes such as CEDNIK syndrome (SNAP29 mutations) see below (7 Sect. 1.6.2) and ARC syndrome (VPS33B and VIPAS39 defects) [42] and peripheral neuropathy (CMT) as in RAB7 defects (late endosome to lysosome: pathway) [43]. Lysosome biogenesis defects (type 7 and 8 Hermansky-Pudlak syndrome; see later) and several phosphoinositide-phosphatase-producing myopathies (7 Sect. 35.5), Lowe syndrome and CMT types 4B1 and 4B2, also belong to this category. k3-Autophagy Defects

The autophagy pathway allows to engulf areas of the cytoplasm, including membrane-bounded organelles and deliver the material for degradation in the lysosome to generate nutrients (. Fig. 44.3). Disorders present as early complex encephalopathies with multisystem involvement such as VICI syndrome (EPG5 mutations) see below [44], neurodevelopmental disorders with brain iron accumulation (WDR45 defect; full description 7 Sect. 34.2.2), spastic paraparesis (spastin, ABCD1, spastacsin, spastizin, TECPR2 and AP5Z1 mutations), amyotrophic lateral sclerosis (CHMP2B, FIG4 mutations), peripheral neuropathy (CMT disease) due to DCTN1, FIG4, spactacsin and RAB7 mutations, parkinsonism and other movement disorders (FIG4, PRKN, PINK1, RAB39B mutations), and dementia (TBK1, FTD3) [45].

els in the opposite direction and is dependent on dynein. It is essential for autophagy-lysosomal degradation and neurotrophic factor signalling. In addition to motor proteins and microtubules, motor adaptor proteins compose intricate protein kinase signalling pathways (. Fig.  44.4). Dynactin, BICD2, Hook, LIS1 and NDEL1 are dynein-related adaptor proteins. Most of the kinesin adaptors including HAP1, JIP1 and TRAK1 are also adaptors for dynein [46]. Mutations in genes encoding components of the axonal transport machinery have been implicated in the pathogenesis of neurological diseases (. Figs. 44.2 and 44.4, . Table 44.1). Most of them are late-onset motor diseases (. Table  44.1) (motor neuropathies, CMT, spastic paraparesis, ALS, SMA, CFEOM: congenital fibrosis of extraocular movements) and early-onset encephalopathies associated with cortical migration abnormalities (. Table 44.1).

44.2.3Synaptic Vesicle Cycle Disorders

Synaptic vesicle disorders are a group of neurological diseases of cellular traffic located at the presynaptic terminal with involvement in neurotransmission. They include both exocytic and endocytic defects and are described in 7 Chap. 30 [48]. 44.2.4Dendrites and Post-synaptic Neuron

Compartment Traffic Defects 44.2.2Axonal and Other Cytoskeleton

Related Trafficking Defects

44

The cytoskeleton is responsible for moving vesicles throughout the cell and is composed by the following main elements: 5 Microtubules are crucial for long-range intracellular transport and are dynamic structures consisting of heterodimers of alpha-tubulin and beta-tubulin [46]. 5 Motor proteins, including the myosin, dynein, and kinesin families of proteins, are responsible for the anterograde and retrograde transport of cargo. In general, myosins are actin-dependent motors, whereas dyneins and kinesins are microtubuledependent motors [47].

Neuronal dendrites are highly branched and specialized compartments with distinct structures and secretory organelles (e.g., spines, Golgi outposts), and a unique cytoskeletal organization that includes microtubules of mixed polarity [49]. Post-synaptic diseases linked to mutations in neurotransmitter receptors have been described in 7 Chap. 30. Dendritic membrane traffic includes specific proteins such as septins and cytoskeleton-based mechanisms with specific functions of great complexity that are fundamental for processes such as learning and cognition. The details of these unique mechanisms, mostly based on the spatial control related to the highly arborized morphology of dendrites, are beyond the scope of this Chapter.

44.2.5Glia Trafficking Disorders

Neurons shuttle diverse substances along axon microtubules through a bidirectional, ATP-dependent process known as axonal transport. Anterograde transport, from the cell body to the axon tip, is driven by kinesins and deliver substances such as RNAs, proteins and organelles towards synapses. Retrograde transport trav-

Commonly, glial cells communicate with each other and with neurons via gliotransmitters but can also communicate using hemichannels. Oligodendrocytes form extensive functional interactions among them and with astrocytes through special structures called gap junc-

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Neuron ATP Panx1 CH

Cx47 GJC

Cx47/Cx43 GJC

Cx43 GJC Cx30 GJC

Oligodendrocyte Cx32/Cx30 GJC Cx32 GJC Oligodendrocytes

Astrocytes

. Fig. 44.5 Disorders of glial trafficking. Connexins (Cx) and Pannexins (Panx) in glial cells. GJC: Gap Junction. The opening of Panx1 CH (Panx1 channels) may lead to ATP release from the oligodendrocytes. Mutations in genes that codify for Cx32,Cx47 and

Panx1 produce neurological diseases. Cx32 is codified by GJB1 (Multiple Sclerosis). Cx47 is codified by GJC2 (Leukodystrophy, Multiple Sclerosis). Panx1 is codified by PANX1 (Demyelination)

tions. Gap junctions, composed of one or more of the 21-member connexin (Cx) family, function as intercellular channels and have the ability to pass small signalling molecules, metabolites, and electrical stimuli directly between contacting cells (51-Vejar, 2019). Connexins are integral membrane proteins that oligomerize into homomeric or heteromeric hexamers, also called connexons, in the ER or Golgi apparatus. Upon microtubule-dependent transport to the cell surface, connexons may function as hemichannels. Pannexons channels are similar than connexins but localized in the oligodendrocytes (. Fig. 44.5). Mutations in genes coding these trafficking proteins cause white matter disorders such as multiple sclerosis (Connexin32 (Cx32), GJB1 gene, and Cx47, GJA12 gene), hypomyelinating leukodystrophies (Cx32, Cx47, which causes Pelizaeus-Merzbacher-like disease), demyelinating leukodystrophies (Cx47 and Pannexin 1, Panx1 gene), spastic paraparesis (Cx47) and peripheral neuropathy (Cx32, CMT disease) [28] (7 Sect. 1.5).

reporting the exhaustive details of every genetic defect. See also . Table 44.1. Cross reference is indicated each time a specific defect is described elsewhere in the book.

44.3

Main Clinical Presentations of Cellular Trafficking Disorders

There are more than 300 different genes involved in human cellular trafficking diseases [50]. Due to the dimension and complexity of the topic, we will describe the general traits of clinical manifestations rather than

44.3.1Neurological Manifestations

Most disorders of cellular trafficking exhibit neurological manifestations that may present as isolated nervous system diseases but also associated with symptoms involving other organs. They can appear at any age from the neonatal period to adulthood. Whereas early presentations tend to have a global involvement affecting multiple functions of the brain and sometimes the peripheral nervous system (7 Chap. 1), late-onset diseases, starting beyond adolescence, are more likely to have predominant motor symptoms such as spastic paraparesis, motor neuron disorders and peripheral neuropathies (7 Chap. 2). In general, they have a progressive character and there are almost no effective treatments. z

Early-Onset Encephalopathies

These disorders are developmental encephalopathies that appear during the first year of life including the neonatal period. Frequent features include microcephaly, brain structural abnormalities, and the coexistence of multiple neurological signs, particularly epilepsy, sometimes refractory to antiepileptic treatment. They

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may have multisystem involvement and some constitute well-defined genetic syndromes (see also 7 Chap. 1). kNeonatal Manifestations

Neonatal seizures are rare in trafficking disorders. Five genes have been involved, most are vesicular transport defects and tend to associate congenital or post-natal microcephaly and brain malformations. Some examples include mutations in CNPY3 (hipoccampal malformation) [51], ATP6AP2 (post-natal microcephaly and brain atrophy), HCFC1 (cortical malformation) and PACS2 (ER-mitochondrial membrane contact site defect, that associates cerebellar dysgenesis) [52]. KIF5A mutations cause intractable neonatal myoclonus and is a cytoskeleton disorder [53]. kMicrocephaly

Both congenital and post-natal Microcephaly (POM), is a major manifestation of these diseases and the most frequent sign in developmental brain disorders [7]. Congenital microcephaly is related to disturbed mechanisms in cortical progenitor division and their subsequent survival and differentiation, whereas POM involves defective neuronal maturation, synaptic pruning, myelination and neurodegeneration [7, 54]. The Golgi apparatus and the cytoskeleton strongly regulates these processes. Around 30 genetic defects classified as “golgipathies” and 20 genes involved in cytoskeleton functions are responsible for disease (. Table  44.1). RAB, TRAPP and VPS proteins are amongst the most common involved in Golgi defects [55, 56], whereas kinesins and tubulins are the proteins involved in cytoskeleton disorders [57]. These diseases often associate cortical and other brain malformations and are global, severe, developmental encephalopathies with multiple neurological and extra-neurological sings. Well-defined genetic syndromes are depicted in . Table 44.1. kMacrocephaly

44

It is rare in these disorders. Only four genes have been involved. In general, macrocephaly is associated to intellectual disability, autistic signs and epilepsy in different combinations. They include golgipathies such as mutations in RAB39B (that codifies for a synaptic vesicle protein, see 7 Chap. 30), HERC1 [58], RAC1 (which may also produce microcephaly) [59], and the vesicular transport protein TBCK (which may also cause brain atrophy with normocephaly). kComplex Encephalopathies with Multisystem Involvement

They include around 30 defects. Arthrogryposis is a prominent sign in vesicular transport defects such as mutations in SLC35A3 [60], ERGIC1 [61] and KIAA1109 (Alkuraya-Kucinskas syndrome) [62], and interorgan-

elle trafficking defects such as mutations in VPS33B and VIPAS39 that cause ARC1 and ARC2 syndromes respectively (ARC: Arthrogryposis, Renal involvement and Cholestasis) [63]. Rhabdomyolysis is often found in TANGO2 mutations. Patients may have metabolic crises with rhabdomyolysis, mild hyperammonaemia, hypoglycaemia and long QT interval (abnormal cardiac rhythm) [31–33]. TANGO2 is associated with a wide spectrum of neurological manifestations such as intellectual disability, spastic paraparesis, epilepsy and myasthenic symptoms, that are not always associated with metabolic crises [33]. Mutations in TRAPPC11 may also cause myopathy in patients with intellectual disability, epilepsy and microcephaly [64]. Other important examples are Menkes disease (MD), caused by ATP7A mutations, and Vici syndrome (EPG5). MD is a disorder of copper metabolism but also a Golgipathy since ATP7A is a Golgi transport protein (7 Sect. 34.1.3). Vici syndrome, caused by EPG5 mutations [44], is a disorder of autophagy that includes early-onset severe neurological symptoms, agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency (see also below). kOther Disorders with Intellectual Disability and/or Neuropsychiatric Symptoms as Main Neurological Signs

That exhibit symptoms usually beyond the first year of life, include around 25 genes that belong to diverse pathophysiological categories (. Table  44.1). Here we highlight WDR45 mutations, a disorder of autophagy that cause beta-propeller protein-associated neurodegeneration (BPAN). The most common form of presentation is intellectual disability and autism with hand stereotypies mimicking Rett syndrome with subsequent parkinsonism-dystonia in adolescence. NBIA (neuronal brain iron accumulation) with evident brain image characteristic abnormalities appears over time (7 Sect. 34.2.3). kSeveral Disorders Have Biomarkers

5 SLC9A6 mutations (Golgipathy): mimics Angelman syndrome and has TAU neuronal inclusions [65]. 5 CDC42 mutations (Golgipathy): Takenouchi-Kosaki Syndrome (ID, epileptic encephalopathy, optic atrophy, and lymphedema) associates also macrothrombocytopenia [66]. 5 KIF15 mutations (cytoskeleton disorder): congenital microcephaly with thrombocytopenia. 5 HCFC1 mutations (vesicular transport defect): epileptic encephalopathy, microcephaly, choreoathetosis, cortical malformations and high homocysteine and MMA (CblX. See 7 Sect. 28.2.1).

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5 ER3IP1 mutations (vesicular transport defect): microcephaly, epilepsy and diabetes. 5 FOLR1 mutations (transcytosis defect): low folate levels in the CSF in patients with encephalopathy (7 Sect. 28.3.2), myoclonic epilepsy and a progressive character; 5 Menkes disease (ATP7A mutations), MEDNIK syndrome and CCHLND (congenital cataracts, hearing loss, and neurodegeneration) due to SLC33A1 mutations, exhibit low serum ceruloplasmin and copper (7 Sect. 34.1.4) 5 Abnormalities on brain imaging are excellent biomarkers for several early-onset encephalopathies (. Table 44.1). z

Motor Disorders

These tend to have a late-onset particularly if isolated as a clinical manifestation. Early-onset presentations are less common and appear in association with other signs such as intellectual disability, and epilepsy. Additionally, mutations in the same gene may cause different clinical phenotypes. Overall, they are neurodegenerative disorders (see also 7 Chaps. 1 and 2). kSpastic Paraparesis

That tends to be complex (associated to other neurological and non-neurological signs). Around 30 genetic defects have been described. Autophagy and vesicular transport are the most common pathophysiological categories involved. The endocytic pathway is frequently affected. Genes associated with infantile onset SP include AP4E1, AP4M1, AP4S1 [67]. Spastic paraparesis that develops during the first decade of life is caused by mutations in TGFBR1 and VPS37A (with pectus carinatum and hypertrichosis) [68]. kAtaxia

It presents frequently as spinocerebellar ataxia (SCA) with onset in adolescence and adulthood. It may be associated with other symptoms such as spastic paraparesis, epilepsy and intellectual disability. There are about 11 genes involved [50]. kParkinsonism and Other Movement Disorders

There are about 20 genes responsible for parkinsonism. Endocytic defects [69] including autophagy are quite common. GAK, SYNJ1, VPS35 and RME8 mutations are some examples. The secretory pathway may also be affected and in this case other neurological signs are often associated. This is the case of RAB39B (early-onset parkinsonism, intellectual disability) [70]. ATP13A2 mutations cause a rapid-onset Parkinsonism (Kufor-Rakeb Syndrome). Hyperkinetic disorders include early-onset dystonia caused by VPS16 and

VPS41 which have been recently reported [18] and chorea-acanthocytosis caused by mutations in VPS13A. kMotor Neuron Disorders

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that results in progressive degeneration of motor neurons. Dysregulation of endocytic transport that in turn affects lysosome function and autophagy is commonly involved as main mechanism of disease. An infantile-onset motor neuron disease, Spinal Muscle Atrophy (SMA) may be caused by mutations in BICD1, DYNC1H1, VAPB and ATP7 [71]. kPeripheral Neuropathy

It presents in most cases as Charcot-Marie-Tooth (CMT) disease. Mutations in genes that involve the endocytic pathway (such as SH3TC2), cytoskeleton disorders (such as FIG4 mutations) and Golgipathies are common in these group of disorders [50]. DNM2 mutations causes CMT with neutropenia. FAM134B mutations produce hereditary sensory and autonomic neuropathy type IIB [72]. kDementia and Others

Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are the most common forms of cognitive deterioration in cellular trafficking disorders. Mutations in Presenilin and BIN1 are associated with AD. CHMP2B and 4B mutations cause FTD with cataracts. TREM2 mutations [73] produce early-onset FTD and recurrent bone fractures (Nasu-Hakola disease).

44.3.2Extra-Neurological Manifestations

The non-neurological manifestations, which may affect immuno-haematological, musculoskeletal, digestive, cardiological, renal, endocrine, reproductive, ocular, skeletal, renal, ocular, skin and hair systems are rarely isolated but more often part of a multisystem disease or a well-defined syndromic phenotype (. Table  44.2). Only a few characteristic syndromes are described below. The most relevant manifestations of the immunohaematological system are immune dysfunctions/deficiencies, familial hemophagocytic lymphohistiocytosis, and specific abnormalities of circulating blood cells. Vici syndrome, caused by autosomal recessive mutations in EPG5, was initially described as a new syndrome characterised by agenesis of the corpus callosum, skin and hair hypopigmentation, cataracts, cleft lip and palate, cardio/ myopathy and immunodeficiency. It causes a complex immunological dysfunction, with selective involvement of memory B cells, affecting both innate and adaptive immunity [74].

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Chediak-Higashi syndrome [75] is a rare autosomal recessive disorder caused by LYST (lysosomal trafficking regulator gene) mutations characterized by partial oculocutaneous albinism, severe immunodeficiency, mild bleeding, neurological dysfunction and lymphoproliferative disorder linked to defective natural killer lymphocytes and lethal in the absence of bone marrow transplantation. Differential diagnoses include oculocutaneous albinism, Hermansky Pudlak syndrome (see later) and Griscelli disease. Skin and hair abnormalities are frequent and include a wide spectrum of clinical manifestations such as hypopigmentation/albinism, ichthyosis, eruptions, nodular and papular lesions, skin laxity, and lipodystrophy, and structural hair abnormalities with or without pigmentary changes. Hermansky-Pudlak syndrome (HPS) is an AR multisytemic disorder characterized by an oculocutaneous albinism (abnormally light coloring of the skin, hair and eyes causing photophobia and nystagmus) and a bleeding tendency [76]. Other symptoms may include immune problems, pulmonary fibrosis, colitis and increased risk for skin cancer. There are ten types of HPS each caused by a different dysfunctional gene. CEDNIK syndrome (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and palmoplantar Keratoderma) is an AR disorder linked to mutations of SNAP29 which encodes a SNARE protein involved in vesicle fusion [77]. Musculoskeletal signs comprise myopathies with structural muscle abnormalities, recurrent myoglobinuria, skeletal dysplasia and structural bone abnormalities, arthrogryposis, and joint laxity. Dyggve-Melchior-Clausen disease caused by mutations of DYM is a rare, genetic spondylo-epi-metaphyseal dysplasia characterized by progressive short-trunked dwarfism, protruding sternum, microcephaly, intellectual disability and pathognomonic radiological findings (generalized platyspondyly, irregularly ossified femoral heads, a hypoplastic odontoid, and a lace-like appearance of iliac crests) [78]. Symptoms related to digestive system include acute and chronic liver disease and secretory diarrhea and inflammatory bowel disease. Recurrent acute liver failure (RALF) triggered by febrile infections is a common presenting sign in NBAS and SCYL1 mutations. Mutations in NBAS (involved in retrograde transport) cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype including SOPH syndrome. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of RALF episodes [79]. SCYL1 mutations underlie a syndrome characterized by RALF, peripheral neuropathy, cerebellar atrophy, and ataxia (. Table 44.1) [80].

Characteristic signs of cardiac involvement include congenital heart disease (such as Schuurs-Hoeijmakers syndrome due to PACS1 mutations, cardiomyopathy (dilated and hypertrophic; i.e. Vici syndrome: EPG5 mutations; Danon disease: LAMP2), and arrhythmia. CAV3, AKAP9 and TANGO2 mutations cause long QT syndrome. The visual apparatus is frequently affected in disorders of cellular trafficking. Cataract, retinopathy, corneal abnormalities, pigmentary changes (see above Hermansky-Pudlak and Chediak-Higashi syndrome) and coloboma represent the major presenting clinical manifestations. Kidney disease may manifest as tubular dysfunction with or without renal failure, as chronic kidney disease, or with renal dysplastic changes. Oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multisystem disorder due to OCRL mutations, leading to phosphatidylinositol-4,5- bisphosphate accumulation. It is characterized by congenital cataracts, glaucoma, intellectual disabilities, seizures, postnatal growth retardation and renal tubular dysfunction of the Fanconi type (proximal tubular acidosis; phosphate wasting leading to renal rickets, osteomalacia and pathological fractures) with chronic renal failure [81] (7 Sect. 35.5). The endocrine and reproductive systems may also be involved. Finally, some disorders of cellular trafficking are associated with specific type of cancer or with increased risk of neoplasia (. Table 44.2).

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66. Martinelli S, Krumbach OHF, Pantaleoni F et al (2018) Functional dysregulation of CDC42 causesdiverse developmental phenotypes. Am J Hum Genet 102:309–320 67. Tessa A, Battini R, Rubegni A et  al (2016) Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families. Eur J Neurol 23(10):1580–1587 68. Zivony-Elboum Y, Westbroek W, Kfir N (2012) A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. J Med Genet 49(7):462–472 69. Bandres-Ciga S, Saez-Atienzar S, Bonet-Ponce L (2019) The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson’s disease. Mov Disord 34(4):460–468 70. Giannandrea M, Bianchi V, Mignogna ML et  al (2010) Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet 86:185–195 71. Peeters K, Litvinenko I, Asselbergh B et  al (2013) Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. Am J Hum Genet 92(6):955–964 72. Kurth I, Pamminger T, Hennings JC et  al (2009) Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy. Nat Genet 41:1179–1181 73. Guerreiro R, Wojtas A, Bras J et al (2013) TREM2 variants in Alzheimer’s disease. N Eng J Med 368:117–127 74. Piano Mortari E, Folgiero V, Marcellini V (2018) The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy 14(1):22–37 75. Ajitkumar A, Yarrarapu SNS, Ramphul K (2020) Chediak Higashi Syndrome. 2020 Aug 13. In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL). PMID: 29939658 76. De Jesus RW, Young LR (2020) Hermansky-Pudlak syndrome. Semin Respir Crit Care Med 41(2):238–246 77. Fuchs-Telem D, Stewart H, Rapaport D et al (2011) CEDNIK syndrome results from loss-of-function mutations in SNAP29. Br J Dermatol 164:610–616 78. Cohn DH, Ehtesham N, Krakow D et al (2003) Mental retardation and abnormal skeletal development (Dyggve-MelchiorClausen dysplasia) due to mutations in a novel, evolutionarily conserved gene. Am J Hum Genet 72:419–428 79. Staufner C, Peters B, Wagner M et  al (2020) Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients. Genet Med 22(3):610–621 80. Schmidt WM, Kraus C, Hoger H et  al (2007) Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Rep 8:691–697 81. Lewis RA, Nussbaum RL, Brewer ED (2001) Lowe syndrome. Jul 24 [updated 2019 Apr 18]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, Amemiya A (eds) GeneReviews® [Internet]. University of Washington, Seattle; 1993–2020, Seattle

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Appendices Contents Chapter 45 Medications Used in the Treatment of Inborn Errors – 861 Andrew A. M. Morris and Simon Jones

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Medications Used in the Treatment of Inborn Errors of Metabolism Andrew A. M. Morris and Simon Jones

© Springer-Verlag GmbH Germany, part of Springer Nature 2022 J.-M. Saudubray et al. (eds.), Inborn Metabolic Diseases, https://doi.org/10.1007/978-3-662-63123-2_45

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The following table lists medication used in the treatment of IEM (. Table 45.1). The list is not exhaustive. Drugs are listed alphabetically by the main name (e.g. L-arginine is listed under Arginine). Readers should be aware that many of these drugs are unlicensed and the evidence base for their use is limited; there have very seldom been controlled trials due to the rarity of the disorders. When using this table, readers are advised to consult the specific chapters indicated. While every

45

effort has been made to ensure the accuracy of the information, before prescribing it is essential that the indications and dosage are checked against any local or national guidelines or formularies. The recommended doses related to body weight are generally those for paediatric patients, using these in adult patients may not be appropriate. For explanation of other abbreviations, see relevant chapters.

ERT

ERT

ERT

Increases LDL receptors by inhibiting PCSK9

Xanthine-oxidase inhibitor

Replenishes arginine

Agalsidase alfa

Agalsidase beta

Aglucosidase alfa

Alirocumab

Allopurinol

L–Arginine hydrochloride or free base

Remethylates homocysteine to methionine

Co-factor for carboxylases Treatment of presumed transporter defect

Betaine

Biotin

Substrate of nitrous oxide

Mode of action

Biotinidase deficiency; holocarboxylase synthetase deficiency; thiamine transporter 2 deficiency (biotin-responsive basal ganglia disease)

Classic homocystinuria Remethylation defects

5–20 mg/d

100–200 mg/kg/d in two to three divided doses, max 6–9 g/d

MELAS: 300–500 mg/kg/d

Citrin deficiency: 5–15 g/d in adults.

Citrin deficiency MELAS (unproven benefit)

UCDs 20 kg: 2.5–6 g/m2/d, max 6 g/d

Initial dosage 10–20 mg/kg per day in children and 2–10 mg/kg per day in adults

75 mg alt weeks (if necessary 150 mg) or 300 mg every 4 weeks

20 mg/kg alt weeks

1.0 mg/kg alt weeks

0.2 mg/kg alt weeks

Recommended paediatric dose (unless otherwise stated)

Urea cycle disorders (except arginase deficiency)

Disorders leading to hyperuricaemia (including PRPP synthetase superactivity, HGPRT deficiency and APRT deficiency)

Familial hypercholesterolaemia (heterozygotes and some homozygotes).

Pompe disease

Fabry disease

Fabry disease

Disorders

Medication used in the treatment of IEM

Medication

. Table 45.1

Oral or IV

Oral

Oral

Oral

Oral

Oral

SC

IV

IV

IV

Route

Holocarboxylase synthetase deficiency may require higher doses. Biotin-responsive basal ganglia disease should be treated with thiamine, with or without biotin

Acutely in MELAS: 500 mg/ kg IV over 90 mins, repeated after 2 hrs

IV loading dose: 250 mg/kg (200–400 mg/kg in ASL deficiency) over 90–120 min; IV maintenance: 250 mg/ kg/d (200–400 mg/kg in ASL deficiency)

Adjust dose to minimum required to maintain normal plasma uric acid concentration

If inadequate response to first line treatment and response to trial

Higher doses are frequently used

Remarks

(continued)

7 27, 29

7 20, 28

7 10

7 19

7 32

7 36

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7 40

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Chapter(s)

Medications Used in the Treatment of Inborn Errors of Metabolism 863

45

NAGS deficiency; CPS deficiency; hyperammonaemia associated with organic acidaemias

Synthetic analogue of N-acetylglutamate; stimulates CPS

Replenishes body stores; removes toxic acyl-CoA intermediates from within the mitochondria

ERT

Inhibits cholesterol 7α-hydroxylase (ratelimiting enzyme in bile acid biosynthesis)

Replenishes cholesterol

Bile acid sequestrant

NCarbamoylglutamate (Carglumic acid, Carbaglu)

L-Carnitine

Cerliponase alfa

Chenodeoxycholic acid

Cholesterol

Cholestyramine

5 mg/kg/d (children) 750 mg/d (adults) 25 mg/kg/d

Cerebrotendinous xanthomatosis (CTX) Oxysterol 7α-hydroxylase deficiency

Used as an alternative to arginine in CPS and OCT deficiencies; LPI

L-Citrulline

CPS & OCT deficiency: 100–200 mg/kg/d, max 6 g/d in divided doses LPI: 50–100 mg/kg/d in 3–5 doses

6–8 mg/kg/d, initial doses may be higher

Δ4–3-Oxosteroid 5β-reductase deficiency (3-ORD); 3β-Dehydrogenase deficiency

Cholic acid

Replenishes citrulline and arginine

Age ≥12 yrs: 12–24 g/d Age 6–11 yrs: 4 g up to 3 times daily Homozygous FH aged 0.5 × 109/L

Corrects abnormal glycosylation

Higher doses (up to 400 mg/d orally) have been used in hereditary folate malabsorption. Monthly IV doses of 20–25 mg/kg have been used in FOLR1 deficiency. Use 5-Methyl tetrahydrofolate in MTHFR deficiency

Combination with statin increases the risk of rhabdomyolysis, esp. if renal impairment. Bezafibrate may reduce rhabdomyolysis in partial CPT II & VLCAD deficiencies

If inadequate response to first line treatment and response to trial

Remarks

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7 43

7 41

7 16, 28

7 12, 36

7 36

7 36

7 16

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Chapter(s)

866 A. A. M. Morris and S. Jones

Acute porphyrias

Inhibits 5-aminolevulinic acid synthase

Co-factor for methylmalonyl CoA mutase and methionine synthase

Alternative fuel source, allowing reduced carbohydrate intake in GSD III, replaces deficient endogenous ketone body production in MADD

Neurotransmitter replacement

ERT

ERT

Promotes anabolism; inhibits catabolism

N-Methyl-d-aspartate (NDMA) channel antagonist

Haem arginate, (haematin, haemin)

Hydroxocobalamin (vitamin B12)

D- or D,L-3Hydroxybutyrate

5-Hydroxytryptophan

Idursulfase

Imiglucerase

Insulin

Ketamine

NKH

Acute decompensation in organic acidaemias, urea cycle disorders, MSUD, FAO disorders

Gaucher disease

MPS II (Hunter)

Disorders of neurotransmitter synthesis

GSD III; MADD; other FAO disorders; Ketogenesis defects

Disorders of cobalamin metabolism

Bile acid amidation defects 1 and 2

3-phosphoglycerate dehydrogenase def; phosphoserine aminotransferase deficiency

Replenishes glycine

Glycocholic acid

Isovaleric acidaemia

Forms isovalerylglycine with high renal clearance

Glycine

Urea cycle disorders

Converted to phenylacetate, which combines with glutamine to form phenylglutamine which has high renal clearance

Glycerol phenylbutyrate

15 mg/kg/d in neonates, 9 mg/ kg/d in infants (range 1–30 mg/ kg/d) in four divided doses

0.05–0.2 IU/kg/h

30–60 U/kg alt weeks

0.5 mg/kg weekly

1–2 mg/kg, increasing gradually to 8–10 mg/kg in four divided doses

300–2000 mg/kg/d in 3–6 divided doses

IM 1–2 mg daily or 5 mg weekly (up to 10 mg daily sometimes given); oral 10 mg once or twice daily

3–4 mg/kg once daily for 4 days

15 mg/kg/d

200–300 mg/kg/d

150 mg/kg/d in three divided doses

5–12.4 g/m2/d in 3 divided doses

Oral or IV

IV

IV

IV

Oral

Oral

IM or oral

IV

Oral

Oral

Oral

Always give with IV solutions containing glucose & with frequent blood glucose monitoring

Lower doses are also used

Monitor CSF 5HIAA levels

Possibly protects against cardiomyopathy in GSD III. May improve cardiomyopathy and leukodystrophy in MADD

IM dose may be reduced to once or twice weekly according to response

Adjunct to treatment with serine

Up to 600 mg/kg/d during decompensation

1 ml contains 1.1 g glycerol phenylbutyrate

(continued)

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74

7 40

7 41

7 16, 30

7 5, 12,13

7 18, 28

7 33

7 38

7 24

7 18

7 19

Medications Used in the Treatment of Inborn Errors of Metabolism 867

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Mode of action

ERT

Ex vivo stem cell Lentiviral gene therapy

Microsomal transfer protein inhibitor, reduces lipoprotein secretion

Increase plasma lysine; increase ornithine excretion (OAT deficiency)

Replenishes Mg

Improves glycosylation

Chelating agent

Achieves measurable levels of CSF levels of 5-methyltetrahydrofolate

Reduces propionate production by gut bacteria

Pharmacological chaperone for mutant alpha-galactosidase A

Inhibitor of glucosylceramide synthase, the first enzyme in glycosphingolipid synthesis

Medication

Laronidase

Libmeldy

Lomitapide

L-Lysine-HCl

Magnesium

Mannose

Mercaptopropionylglycine (Tiopronin)

5-Methyl tetrahydrofolate

Metronidazole

Migalastat

Miglustat

(continued)

45

. Table 45.1

Gaucher disease; neurological manifestations of Niemann Pick C

Fabry disease with amenable mutations

Propionic and methylmalonic acidaemia

5,10-Methylenetetrahydrofolate reductase deficiency

Cystinuria

Mannose phosphate isomerase deficiency (MPI-CDG)

Primary hypomagnesaemia with secondary hypocalcaemia

Lysinuric protein intolerance; OAT deficiency

Homozygous familial hypercholesterolaemia

Presymptomatic late infantile and early juvenile metachromatic leukodystrophy(MLD); early symptomatic early juvenile MLD

MPS1 (Hurler/Scheie or pre-HSCT in Hurler disease)

Disorders

Up to 300 mg/d (Gaucher) or 600 mg/d (NPC) in 3 divided doses

123 mg alt daily (adult)

10–20 mg/kg once daily

15–60 mg/d

10–20 mg/kg/d, up to max 1 g/d in three divided doses

1 g/kg/d in four to six divided doses

0.5–1.5 ml/kg/d MgSO4 10% solution IV; oral maintenance 0.4–3.9 mmol/kg/d elemental Mg in three to five divided doses

LPI: 20–30 mg/kg/d in three divided doses; OAT deficiency (adults): 10–15 g/d in 5 divided doses

Adults: initially 5 mg daily, increased at 4 week intervals, max 60 mg/d

Gene corrected CD34 + ve autologous stem cells

100 U/kg (0.58 mg/kg) weekly

Recommended paediatric dose (unless otherwise stated)

Oral

Oral

Oral

Oral

Oral

Oral

IV or Oral

Oral

Oral

IV

Route

Only recommended for patients with mild to moderate Gaucher disease who are unsuitable for enzyme replacement therapy.

For a limited period (e.g. 10 days) each month

Available as calcium mefolinate

Adjunct to other drugs ± lipoprotein apheresis. Often causes gastrointestinal & liver function disturbances.

Generally only available via approved centres

Remarks

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7 28

7 25

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868 A. A. M. Morris and S. Jones

Replenishes deficiency state

Inhibits free fatty acid release from adipose tissue, reducing synthesis of various lipids; increases HDL-cholesterol

Inhibits 4-hydroxyphenylpyruvate dioxygenase

Somatostatin analogue

Competitive inhibitor of AGAT – reduces guanidinoacetate production

Chelating agent

Dopamine agonist

Active co-factor

Nicotinamide

Nicotinic acid (niacin)

Nitisinone (NTBC)

Octreotide

L-Ornithine

Penicillamine

Pramipexole

Pyridoxal-phosphate

Pyridox(am)ine 5੝-phosphate oxidase deficiency

Adjunct to therapy in disorders of BH4 synthesis

Wilson disease; cystinuria

Guanidinoacetate methyltransferase deficiency

30–60 mg/kg/d in 4–6 divided doses

6–35 μg /kg/d in two divided doses

Wilson disease: up to 20 mg/ kg/d in divided doses (maintenance dose in adults 750–1500 mg/d); cystinuria: 30 mg/kg/d up to 3–4 g in 3–4 divided doses

400–800 mg/kg/d

5–10 μg/d increasing up to 30–50 μg/d as required – given in 3–4 divided doses or by continuous pump (IV or SC)

1–4 mg/d

Alkaptonuria

Persistent hyperinsulinism

1 mg/kg/d (2 mg/kg/d in liver failure) in one to two divided doses

Adult dose: 100–200 mg 3 times daily, gradually increased over 2–4 weeks to 1–2 g three times daily

50–300 mg/d

Tyrosinaemia type I

Hyperlipidaemia

Hartnup disease

Oral

Oral

Oral or IV

Oral

IV or SC

Oral

Oral

Oral

Oral

Monitor liver transaminases and use lowest effective dose possible

Allows reduction in L-dopa therapy

Give 1 hour before food. In Wilson disease give with pyridoxine 25 mg/d

Given in combination with creatine monohydrate

Recommended in adults only, along with mild protein restriction. Avoid in pregnancy

Combine with low-TYR, low-PHE diet to maintain plasma TYR 200– 400 μmol/l. Aim to maintain nitisinone levels >50 μmol/l in plasma or 20–40 μmol/l in whole blood

Seldom used due to flushing and other side effects

(continued)

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7 16

7 25, 34

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7 17

7 36

7 25

Medications Used in the Treatment of Inborn Errors of Metabolism 869

45

Mode of action

Co-factor

Coenzyme

ERT

Monoamine-oxidase-B inhibitor

Replenishes serine

Medication

Pyridoxine

Riboflavin

Sebelipase alfa

Selegiline (L-deprenyl)

L-Serine

(continued)

45

. Table 45.1

3-Phosphoglycerate dehydrogenase, phosphoserine aminotransferase, 3-phosphoserine phosphatase deficiencies GOT2 deficiency

As adjunct to therapy with 5HT & L-dopa in BH4 defects

Lysosomal acid lipase deficiency (Wolman or CESD phenotypes)

up to 500–700 mg/d in six divided doses

0.1–0.25 mg/kg/d in three to four divided doses

1–5 mg/kg weekly for Infantile onset, 1mg/kg alternate weekly for later onset cases

100–400 mg/d in two to three divided doses; up to 80 mg/ kg/d has been used in RFVT2/3 deficiencies (Brown-Vialetto-van Laere syndrome)

Trial of 100 mg IV with EEG monitoring or 30 mg/kg/d for 3 days; maintenance 5–30 mg/ kg/d (max 500 mg/d; infants 30 mg/kg/d, max 300 mg)

Pyridoxine dependent epilepsy

Mild variants of ETF/ETFQO deficiencies; ACAD9 deficiency; riboflavin transporter deficiencies RFVT1–3; FAD transporter defect & FAD synthase deficiency; dihydrolipoamide dehydrogenase deficiency; glutaric aciduria type I; L-2 hydroxyglutaric aciduria; trimethylaminuria

50–500 mg/d. CBS deficiency: up to 10 mg/ kg/d (max 500 mg/d).

Recommended paediatric dose (unless otherwise stated)

Pyridoxine-responsive forms of cystathionine β-synthase (CBS), γ-cystathionase & ornithine aminotransferase deficiencies; X-linked sideroblastic anaemia; primary hyperoxaluria type 1, GOT2 deficiency, AADC deficiency

Disorders

Oral

Oral

IV

Oral

Oral

Oral

Route

190 mg/kg/d given to a pregnant mother whose fetus had 3-phosphoglycerate dehydrogenase deficiency

To prevent breakthrough seizures, dose may be doubled for the first 3 days of intercurrent infection

Peripheral neuropathy can occur with high doses (>900 mg daily in adults)

Remarks

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Thiamine responsive variants of PDH deficiency, MSUD & complex 1 deficiency Thiamine transporter 2 deficiency (biotin-responsive basal ganglia disease); mitochondrial TPP transporter def

HMG-CoA reductase inhibitors

ERT

To overcome lack of transporter

Replacement of BH4

Chelating agent

Co-factor

To overcome lack of transporter

Statins

Taliglucerase alfa

Taurine

Tetrahydrobiopterin (BH4)

Tetrathiomolybdate

Thiamine

Wilson disease

Disorders of BH4 synthesis or recycling; BH4 responsive forms of PAH deficiency

SLC6A6 taurine transporter deficiency

Gaucher Disease type 1

Hyperlipidaemias; simvastatin has been used in SLO syndrome and in lathosterolosis

Adult Citrin deficiency

Restores hepatic cytosolic NADH/NAD+ ratio

Sodium pyruvate

Guanidinoacetate methyltransferase deficiency

Reduces glycine availability for guanidinoacetate synthesis Urea cycle disorders

NKH

Reduces blood glycine levels

Converted to phenylacetate, which combines with glutamine to form phenylglutamine which has high renal clearance

Hyperammonaemia

Combines with glycine to form hippuric acid, which has high renal clearance – removes N2 and reduces blood ammonia

Sodium phenylbutyrate

Sodium benzoate

100–400 mg/d

50–1200 mg/d; 500–2000 mg/d in PDH deficiency

Bis-choline tetrathiomolybdate 15–60 mg/d for adults in divided doses

1–3 mg/kg/d in BH4 defects; 5–20 mg/kg/d in PAH deficiency

100 mg/kg/d

60u/kg alt weeks

Doses depend on specific statin, age & response

3–6 g/d in 3 divided doses

Up to 250 mg/kg/d (20 kg); max 12 g/d

100 mg/kg/d in divided doses

250–750 mg/kg/d in 3–6 divided doses

250 mg/kg/d in divided doses (20 kg); max 12 g/d

Oral

Oral

Oral

Oral

Oral

IV

Oral

Oral

Oral

Oral

Oral

Oral

Not commercially available

May be contraindicated in DHPR deficiency

Not licensed in EU

No benefit has been confirmed in SLO syndrome

IV dose: 250 mg/kg over 90–120 min, followed by 250–500 mg/kg/d (20 kg)

IV dose: 250 mg/kg over 90–120 min, followed by 250–500 mg/kg/d (20 kg)

(continued)

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7 11, 18,

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7 20

7 40

7 36, 37

7 19

7 19

7 15

7 23

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Medications Used in the Treatment of Inborn Errors of Metabolism 871

45

Chelating agent

Anaplerotic substrate

Replacement therapy

Replenishes UMP

ERT

ERT

ERT

Co-factor; antioxidant

Replenishes vitamin E stores; free radical scavenger

Increases Zn; impairs Cu absorption

Triethylene tetramine (trientine)

Triheptanoin

Ubiquinone (coenzyme Q10)

Uridine

Velaglucerase

Velmanase alfa

Vestronidase alfa

Vitamin C

Vitamin E (alpha tocopherol)

Zinc

Alt alternate, max maximum

Mode of action

Medication

(continued)

45

. Table 45.1

Acrodermatitis enteropathica (AE); Wilson disease

Abetalipoproteinaemia, Glutathione synthetase deficiency

Hawkinsinuria; tyrosinaemia type III (4 hydroxyphenylpyruvate dioxygenase deficiency); Transient tyrosinaemia of the newborn; Glutathione synthase deficiency

MPSVII

Alpha-Mannosidosis

Gaucher Disease Type 1

UMP Synthase deficiency (hereditary orotic aciduria); CAD deficiency

Inborn errors of CoQ10 synthesis

Long-chain FAODs; PC deficiency

Wilson disease

Disorders

Elemental zinc doses: AE: 1–2 mg/kg/d in infancy, thereafter 30–100 mg/d; Wilson disease: 50 mg/d (