Magnetic Resonance of Myelination and Myelin Disorders 3540222863, 9783540222866

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M.S. van der Knaap, J. Valk

Magnetic Resonance of Myelination and Myelin Disorders Third Edition

Marjo S. van der Knaap Jaap Valk

Magnetic Resonance of Myelination and Myelin Disorders Third Edition With 647 Figures in 3873 parts

With contributions by: F. Barkhof V. Gieselmann G.J. Lycklama à Nijeholt E. Morava P.J.W. Pouwels J.A.M. Smeitink

123

R. van den Berg J.M.C. van Dijk R.J. Vermeulen R.J.A. Wanders R.A. Wevers

Marjo S. van der Knaap, MD, PhD Department of Child Neurology VU University Medical Center De Boelelaan 1117 1081 HV Amsterdam The Netherlands Jaap Valk, MD, PhD Department of Radiology VU University Medical Center De Boelelaan 1117 1081 HV Amsterdam The Netherlands

Third Edition ISBN-10 3-540-22286-3 Springer Berlin Heidelberg New York ISBN-13 978-3-540-22286-6 Springer Berlin Heidelberg New York Second Edition ISBN 3-540-59277-6 Springer Berlin Heidelberg New York Library of Congress Control Number: 2004117334 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provision of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable to prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springeronline.com © Springer-Verlag Berlin Heidelberg, 1989, 1995, 2005 Printed in Germany The use of designations, trademarks, 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. Product liability: The publisher can not guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Dr. Ute Heilmann, Heidelberg, Germany Desk editor: Dörthe Mennecke-Bühler, Heidelberg, Germany Production: PRO EDIT GmbH, Heidelberg, Germany Cover-Design: Frido Steinen-Broo, Pau, Spain Typesetting and Reproduction: AM-productions GmbH, Wiesloch, Germany Printing and Binding: Stürtz GmbH, Würzburg, Germany Printed on acid-free paper

21/3151Di - 5 4 3 2 1 0

Preface

Preface to the Third Edition Reading through the prefaces of the two previous editions, we can say that much of what was said there still holds. At the same time, however, much has changed. There has been immense progress in the technical possibilities of magnetic resonance and in the knowledge of genetic defects, biochemical abnormalities, and cellular processes underlying myelin disorders. This immense progress has prompted us to embark upon the enormous task of rewriting the previous edition and adding 40 chapters. In doing so we have tried to cover most white matter disorders, hereditary and acquired, and to present a collection of images to illustrate the field to the fullest possible extent. This edition will therefore be more complete than the previous ones. The number of illustrations has increased considerably. This was necessary to reflect not only the typical patterns of a disease, but to show also the variability that exists in some disorders. The best example of this is found in Alexander disease. Genetic verification now makes it possible to recognize very different patterns of imaging abnormalities, all related to a defect in the same gene. Today’s increased insight into disease classification based on increased knowledge of related genes and proteins is best reflected in the chapter on congenital muscular dystrophies. This is the first time that we have invited a number of experts in special fields to write or co-write a chapter, in order to assure the highest level of scientific accuracy. To assemble the knowledge presented in this work we have also harvested the literature, profiting from the work and discoveries of many others.

Our thanks go to our colleagues at the VU University Medical Center and to those in other hospitals who referred their patients to us. We are indebted to all colleagues who allowed us to use their MR images, published or unpublished, making it possible for us to present illustrations of nearly all known white matter disorders. Two colleagues were particularly helpful and provided us with essential and unpublished figures: our friends Susan Blaser, from the Hospital for Sick Children in Toronto, and Zoltán Patay, from the King Faisal Hospital in Riyadh. Many people at the VU University Medical Center have been of great technical help to us in producing high quality images and in providing secretarial assistance. The contributions of these people are mentioned separately in the acknowledgements. Our special thanks go to patients with white matter disorders and their families. They came to see us and were willing to work with us and to go through the procedure of diagnostic testing, including MR examinations. Many patients and families were also willing to participate in our research projects to advance the understanding of white matter disorders. Patients with white matter disorders are the focus of our work. They are our most important collaborators. Often they are children. To show our gratitude to them, we have decided that all profits of this book will go to the Foundation for Children with White Matter Disorders. Amsterdam, May 2005 M.S. van der Knaap J. Valk

VI

Preface

Preface to the Second Edition The first edition of this book was well received by readers and reviewers and we are very grateful for the positive reactions. We were convinced then, and even more now, that MRI and MRS have much to offer in diagnosis, therapy monitoring and research of hereditary and acquired myelin disorders. In the last few years, a great deal of new information has become available concerning the genetic basis of inborn errors of metabolism and neurodegenerative disorders, the role of subcellular structures, the enzyme biochemistry, the pathophysiological mechanisms of posthypoxic-ischemic cerebral damage, and the inflammatory processes in infectious and inflammatory disorders. MR images of many rare disorders have become available, either in our own experience or published by other groups. MR spectroscopy could confirm its role in certain clinical applications. Because of these developments, it was necessary for us to rewrite the book almost completely. In some fields developments are so fast that we have not have caught all the latest developments. The pattern of the new approaches has, however, been established, making the assimilation of newly available information easy. We are extremely grateful for the help of colleagues to make this book as complete as possible. The positive reactions of those from whom we requested MR pictures or other forms of support were of enormous encouragement to us during our efforts to complete this project. We hope this work will be as warmly welcomed by our colleagues as the first edition. Amsterdam, January 1995 M.S. van der Knaap J. Valk

Preface to the First Edition Magnetic resonance imaging (MRI) is now considered to be the imaging modality of choice for the majority of disorders affecting the central nervous system. This is particularly true for gray and white matter disorders, thanks to the superb soft tissue contrast in MRI which allows gray matter, unmyelinated, and myelinated white matter to be distinguished and their respective disorders identified. The present book is devoted to the disorders of myelin and myelination. A growing amount of detailed in vivo information about myelin, myelination, and myelin disorders has

been derived both from MRI and from MR spectroscopy (MRS). This prompted us to review the clinical, laboratory, biochemical, and pathological data on this subject in order to integrate all available information and to provide improved insights into normal and disordered myelin and myelination. We will show how the synthesis of all available information contributes to the interpretation of MR images. Following a brief historical review of the increasing knowledge on myelin and myelin disorders, we propose a new classification of myelin disorders based on the subcellular localization of the enzymatic defects as far as the inborn errors of metabolism are concerned. This classification serves as a guide throughout the book. All items of the classification will be discussed and, whenever relevant and possible, illustrated by MR images. We are aware of the fact that in a number of myelin disorders MRI is not a part of the usual diagnostic work up because a definite diagnosis is reached by other means, such as biochemical investigations of blood and urine, enzyme assessment or detection of specific antibodies. However, in many disorders MRI may facilitate a rapid diagnosis and early instigation of treatment, thus preventing structural cerebral damage. In other cases the role of MRI is to visualize the extent of brain damage and give an indication of the prognosis. In disorders which present in a nonspecific way, for instance with behavioral problems or learning difficulties, MRI can be one of the first-line investigations. It is important to be acquainted with the various MRI patterns of the myelin disorders, as an early diagnosis may be of major importance in young families with a view to the provision of adequate genetic counseling. MRS has been of limited clinical importance until now, and its application in patients only has a short history. We do, however, expect it to be a promising technique in the field of myelin and myelin disorders in clinical as well as in basic, experimental research and have, therefore, devoted a separate chapter to this subject. This volume was written by a neuroradiologist and a neurologist/child neurologist. It is the product of close cooperation, animated discussions, strong arguments, restructuring, rewriting, and editing, in which they had an equal share. If the reader finds value in this monograph, it is because of this dual effort. Amsterdam and Utrecht, March 1989 J. Valk M.S. van der Knaap

Acknowledgements

The preparation of this book was a project of several years and could not have been concluded successfully without the support and collaboration of many people. Thanks to all. Special thanks go to our colleagues: Jeroen Vermeulen and Leo Smit, pediatric neurologists, and Frederik Barkhof and Jonas Castelijns, neuroradiologists, at the VU University Medical Center (VUMC) in Amsterdam; Martin Heitbrink and Bart Wiarda, radiologists at the Medical Center Alkmaar; and Erik Veldhuizen, radiologist at the MRI center, Amsterdam, for their continuous support during this endeavor. We are grateful to the MRI technicians at the VUMC, who guaranteed the quality of the MR examinations and had the patience and empathy to deal with very sick children and their parents. We want to mention especially the help of Karin Barbiers and Erwin Kist, who headed this team and carried out the retrieval of older examinations to the Image Management System. We received great support from the audiovisual center at the VUMC. We are especially indebted to Daan van Eijndhoven, Rene den Engelsman, and

Annuska Houtappels, who digitized older films and helped us improve the quality of the images. Excellent secretarial help was provided by Sigrid Bruinsma, who single-handedly took care of the reference section. Staff members of the VUMC Library Els van Deventer, Linda Glas, Margreet Bosshardt, and Cisca Frederiks were very helpful in providing us with the necessary literature. Technical support and guidance with computer programs and settings were provided by the Department of Informatics of the VUMC. We are grateful for their kind and prompt assistance. Special thanks go to Michiel Sprenger, Guido Zonneveld, and Peter Theijsmeijer. We acknowledge the continuous friendly and encouraging support of the editorial staff of SpringerVerlag, Dr. Ute Heilmann and Mrs Dörthe MenneckeBühler. Amsterdam, May 2005 M.S. van der Knaap J. Valk

Contents

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

25 26 27 28 29 30 31 32

Myelin and White Matter . . . . . . . . . Classification of Myelin Disorders . . . . Selective Vulnerability . . . . . . . . . . Myelination and Retarded Myelination Lysosomes and Lysosomal Disorders . . Metachromatic Leukodystrophy. . . . . Multiple Sulfatase Deficiency . . . . . . Globoid Cell Leukodystrophy (Krabbe Disease) . . . . . . . . . . . . . . GM1 Gangliosidosis . . . . . . . . . . . . GM2 Gangliosidosis . . . . . . . . . . . . Fabry Disease . . . . . . . . . . . . . . . . Fucosidosis . . . . . . . . . . . . . . . . . Mucopolysaccharidoses . . . . . . . . . Free Sialic Acid Storage Disorder . . . . Neuronal Ceroid Lipofuscinoses . . . . Adult Polyglucosan Body Disease . . . . Peroxisomes and Peroxisomal Disorders . . . . . . . . Peroxisome Biogenesis Defects . . . . . Peroxisomal D-Bifunctional Protein Deficiency . . . . . . . . . . . . . Peroxisomal Acyl-CoA Oxidase Deficiency. . . . . . . . . . . . . X-linked Adrenoleukodystrophy . . . . Refsum Disease . . . . . . . . . . . . . . . Mitochondria and Mitochondrial Disorders. . . . . . . Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes . . . . . . . . . Leber Hereditary Optic Neuropathy . . Kearns–Sayre Syndrome . . . . . . . . . Mitochondrial Neurogastrointestinal Encephalomyopathy. . . . . . . . . . . . Leigh Syndrome and Mitochondrial Leukoencephalopathies . . . . . . . . . Pyruvate Carboxylase Deficiency . . . . Multiple Carboxylase Deficiency . . . . Cerebrotendinous Xanthomatosis . . . Cockayne Syndrome . . . . . . . . . . . .

1 20 25 37 66 74 82 87 96 103 112 119 123 133 137 147 151 154 167 172 176 191 195

204 212 215 221 224 245 248 252 259

33 34

35 36 37 38 39 40 41 42 43 44 45 46 47

48

49 50 51 52 53 54 55 56 57 58 59 60 61 62 63

Trichothiodystrophy with Photosensitivity . . . . . . . . . Pelizaeus–Merzbacher Disease and X-linked Spastic Paraplegia Type 2 . . . . . . . . . . . 18q– Syndrome . . . . . . . . . . . . . Phenylketonuria . . . . . . . . . . . . Glutaric Aciduria Type 1 . . . . . . . . Propionic Acidemia . . . . . . . . . . Nonketotic Hyperglycinemia . . . . Maple Syrup Urine Disease . . . . . . 3-Hydroxy 3-Methylglutaryl-CoA Lyase Deficiency . . . . . . . . . . . . Canavan Disease . . . . . . . . . . . . L-2-Hydroxyglutaric Aciduria . . . . D-2-Hydroxyglutaric Aciduria . . . . Hyperhomocysteinemias . . . . . . . Urea Cycle Defects . . . . . . . . . . . Serine Synthesis Defect Caused by 3-Phosphoglycerate Dehydrogenase Deficiency . . . . . . Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase Deficiency. . . . . . . . . . . Galactosemia . . . . . . . . . . . . . . Sjögren–Larsson Syndrome . . . . . Lowe Syndrome . . . . . . . . . . . . Wilson Disease . . . . . . . . . . . . . Menkes Disease . . . . . . . . . . . . Fragile X Premutation . . . . . . . . . Hypomelanosis of Ito . . . . . . . . . Incontinentia Pigmenti . . . . . . . . Alexander Disease . . . . . . . . . . . Giant Axonal Neuropathy . . . . . . . Megalencephalic Leukoencephalopathy with Subcortical Cysts . . . . . Congenital Muscular Dystrophies . . Myotonic Dystrophy Type I . . . . . . Myotonic Dystrophy Type 2 . . . . . X-linked Charcot–Marie–Tooth Disease . . . . . . . . . . . . . . . . .

. . 268

. . . . . . .

. . . . . . .

272 281 284 294 300 306 311

. . . . . .

. . . . . .

321 326 334 338 342 360

. . 369

. . . . . . . . . . .

. . . . . . . . . . .

372 377 383 387 392 400 406 409 412 416 436

. . . .

. . . .

442 451 469 473

. . 476

X

Contents

64 65 66 67 68

69 70 71 72 73

74

75

76 77 78 79 80

81 82 83 84 85

Oculodentodigital Dysplasia . . . . . . Leukoencephalopathy with Vanishing White Matter . . . . . . . Aicardi–Goutières Syndrome . . . . . . Leukoencephalopathy with Calcifications and Cysts . . . . . . . Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated White Matter Lactate . . . Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum . . Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids . . . Dentatorubropallidoluysian Atrophy . Cerebral Amyloid Angiopathy . . . . . . Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy . . . . . . . . Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy . . . . . . . . Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (Nasu-Hakola Disease). . . . . . . . . . . Pigmentary Orthochromatic Leukodystrophy . . . . . . . . . . . . . . Adult-Onset Autosomal Dominant Leukoencephalopathies . . . . . . . . . Inflammatory and Infectious Disorders . . . . . . . . . Multiple Sclerosis . . . . . . . . . . . . . Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Encephalomyelitis . . . . . . . . . . . . . Acquired Immunodeficiency Syndrome . . . . . . . . . . . . . . . . . . Progressive Multifocal Leukoencephalopathy . . . . . . . . . . Brucellosis . . . . . . . . . . . . . . . . . Subacute Sclerosing Panencephalitis . Congenital and Perinatal Cytomegalovirus Infection . . . . . . . .

479 481 496 505

510 519 526 530 535

541

549

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102

552 557

103 104 105

559 561 566

106 107 108

604 616 628 635 640 645

109

Whipple Disease . . . . . . . . . . . . Toxic Encephalopathies . . . . . . . . Iatrogenic Toxic Encephalopathies . Central Pontine and Extrapontine Myelinolysis . . . . . . . . . . . . . . Hypernatremia . . . . . . . . . . . . . Marchiafava–Bignami Syndrome . . Posterior Reversible Encephalopathy Syndrome . . . . . Langerhans Cell Histiocytosis . . . . Post-Hypoxic–Ischemic Damage . . Post-Hypoxic–Ischemic Leukoencephalopathy of Neonates . Neonatal Hypoglycemia . . . . . . . Delayed Posthypoxic Leukoencephalopathy . . . . . . . . White Matter Lesions of the Elderly . Subcortical Arteriosclerotic Encephalopathy . . . . . . . . . . . . Vasculitis . . . . . . . . . . . . . . . . Leukoencephalopathy and Dural Venous Fistula . . . . . . . Leukoencephalopathy after Chemotherapy and/or Radiotherapy . . . . Gliomatosis Cerebri . . . . . . . . . . Diffuse Axonal Injury . . . . . . . . . Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration . . . . . . . . . . . . . . Diffusion-Weighted Imaging . . . . Magnetization Transfer Imaging . . Magnetic Resonance Spectroscopy: Basic Principles, and Application in White Matter Disorders. . . . . . . Pattern Recognition in White Matter Disorders. . . . . . .

. . 658 . . 664 . . 679 . . 684 . . 690 . . 695 . . 699 . . 709 . . 714 . . 718 . . 749 . . 755 . . 759 . . 767 . . 773 . . 801 . . 808 . . 818 . . 823

. . 832 . . 839 . . 854

. . 859 . . 881

References . . . . . . . . . . . . . . . . . . . . . 905 Subject Index . . . . . . . . . . . . . . . . . . 1075

Contributors

F. Barkhof, MD PhD Department of Radiology and MR Center for MS Research VU University Medical Center Amsterdam, The Netherlands V. Geiselmann, PhD Institut fur Physiologische Chemie Rheinische Friedrich-Wilhelms-Universität Bonn, Germany G.J. Lycklama à Nijeholt, MD PhD Department of Radiology VU University Medical Center Amsterdam, The Netherlands

R. van den Berg, MD PhD

Department of Radiology VU University Medical Center, Amsterdam and Department of Radiology Leiden University Medical Center Leiden, The Netherlands M.S. van der Knaap, MD PhD

Department of Child Neurology VU University Medical Center Amsterdam, The Netherlands J.M.C. van Dijk, MD PhD

Department of Neurosurgery Leiden University Medical Center Leiden, The Netherlands

E. Morava, MD

Nijmegen Center for Mitochondrial Disorders and Department of Pediatrics University Medical Center Nijmegen Nijmegen, The Netherlands

R.J. Vermeulen, MD PhD

P.J.W. Pouwels, PhD

R.J.A. Wanders, PhD Department of Clinical Chemistry and Department of Pediatrics Academic Medical Center Amsterdam, The Netherlands

Department of Clinical Physics and Informatics VU University Medical Center Amsterdam, The Netherlands

Department of Child Neurology VU University Medical Center Amsterdam, The Netherlands

J.A.M. Smeitink, MD PhD

Nijmegen Center for Mitochondrial Disorders and Department of Pediatrics University Medical Center Nijmegen Nijmegen, The Netherlands J. Valk, MD PhD

Department of Radiology VU University Medical Center Amsterdam, The Netherlands

R.A. Wevers, PhD

Laboratory of Pediatrics and Neurology University Medical Center Nijmegen St Radboud Nijmegen, The Netherlands

List of Abbreviations

ACE ACTH AD ADC ADEM ADP AD PEO AHEM AIDS ALD ALDP ALL AMN ANCAs ANCL AP4 APLA APBD apoE APP aPTT ASLD ASSD ATP BAEP BCNU BDNF bFGF BIDS BMAA BOMAA BPD CAA CACH CACT CADASIL cANCA CARASIL

angiotensin converting enzyme adrenocorticotropic hormone Alexander disease apparent diffusion coefficient acute disseminated encephalomyelitis adenosine diphosphate autosomal dominant progressive external ophthalmoplegia acute hemorrhagic encephalomyelitis acquired immunodeficiency syndrome adrenoleukodystrophy ALD protein acute lymphocytic leukemia adrenomyeloneuropathy anti-neutrophil cytoplasm antibodies adult neuronal ceroid lipofuscinosis (or Kufs disease) 2-amino-4-phosphonobutyrate anti-phospholipid antibodies adult polyglucosan body disease apolipoprotein E amyloid precursor protein activated partial thromboplastin time argininosuccinate lyase deficiency argininosuccinate synthetase deficiency adenosine triphosphate brain stem auditory evoked potential bis-chloroethyl-nitrosourea brain-derived neurotrophic factor basic fibroblast growth factor brittle hair, impaired intelligence, decreased fertility, short stature (syndrome) β-N-methylamino-L-alanine β-N-oxalylmethylamino-L-alanine D-bifunctional protein deficiency cerebral amyloid angiopathy childhood ataxia with central nervous system hypomyelination mitochondrial carnitine/acylcarnitine transporter cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy cytoplasmic form of ANCA cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

CAMFAK CD Cho CIPO CIS CK CMD CMT CMTX CMV CNP CNS COFS COX CPEO CPM CPSD CPT Cr CREST CS CSF CSI CT CTX DAB DAGC DAI DAVF DHAPAT DM 1 DM 2 DNA DNC dNTP DOA DOPA DPHL DRPLA

cataracts–microcephaly–failure to thrive–kyphoscoliosis (syndrome) Canavan disease; cluster determinant choline chronic intestinal pseudo-obstruction clinically isolated symptom creatine kinase congenital muscular dystrophy Charcot–Marie–Tooth disease X-linked form of CMT cytomegalovirus 2’3’-cyclic nucleotide 3’-phosphodiesterase central nervous system cerebro-oculofacioskeletal (syndrome) cytochrome-c oxidase chronic progressive external ophthalmoplegia central pontine myelinolysis carbamyl phosphate synthetase deficiency carnitine palmitoyl transferase creatine calcinosis, Raynaud syndrome, esophageal problems, sclerodactylia, and telangiectasia (syndrome) Cockayne syndrome; concentric sclerosis (or Baló disease) cerebrospinal fluid chemical shift imaging computed tomography/tomogram cerebrotendinous xanthomatosis diaminobenzidine dystrophin-associated glycoprotein complex diffuse axonal injury cranial dural arteriovenous fistula dihydroxyacetonephosphate acyltransferase myotonic dystrophy type 1 myotonic dystrophy type 2 deoxyribonucleic acid deoxynucleotide carrier deoxyribonucleoside triphosphate dominant optic atrophy dihydroxyphenylalanine delayed posthypoxic leukoencephalopathy dentatorubropallidoluysian atrophy

XIV

List of Abbreviations

DS DSA DTI DWI EAA EAE ECD ECG EDSS EEG EGF eIF ELISA EMG EPI EPM EPMR ERG FA FAD FADH2 FCMD FD FISH FLAIR FSE FSH 5-FU FvLINCL GA GABA GAMT GAN GDP GE GEF GFAP GIP GLD Glx GOM GRACILE GROD GTE GTO GTP GVHD HAART HABC

diffuse sclerosis (or Schilder disease) digital subtraction angiography diffusion tensor imaging diffusion-weighted imaging excitatory amino acid experimental allergic encephalomyelitis ethyl cysteinate dimer electrocardiography/electrocardiogram Expanded Disability Status Scale electroencephalogram epidermal growth factor eukaryotic initiation factor enzyme-linked immunosorbent assay electromyogram echo planar imaging extrapontine myelinolysis progressive epilepsy with mental retardation electroretinography/electroretinogram fractional anisotropy flavin adenine dinucleotide flavin adenine dinucleotide, reduced Fukuyama congenital muscular dystrophy Fabry disease fluorescent in situ hybridization fluid-attenuated inversion recovery fast spin echo follicle-stimulating hormone 5-fluorouracil Finnish variant of late-infantile neuronal ceroid lipofuscinosis gestational age γ-aminobutyric acid guanidinoacetate methyltransferase giant axonal neuropathy guanosine diphosphate gradient echo guanine-nucleotide exchange factor glial fibrillary acidic protein general insertion protein globoid cell leukodystrophy glutamine, glutamate, GABA granular osmiophilic material growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death (syndrome) granular osmiophilic deposits glyceryl trierucate glyceryl trioleate guanosine triphosphate graft-versus-host disease highly active/aggressive anti-retroviral treatment hypomyelination with atrophy of the basal ganglia and cerebellum

HCHWA-D Dutch type of hereditary cerebral hemorrhage with amyloidosis HDL high-density lipoproteins HDLS hereditary diffuse leukoencephalopathy with spheroids 5HIAA 5-hydroxyindoleacetic acid HIV-1 human immunodeficiency virus type 1 HLA human leukocyte antigen HMG-CoA 3-hydroxy-3-methylglutarylcoenzyme A HMI hypomelanosis of Ito HMPAO hexamethylpropyleneamine oxime HSP hereditary spastic paraplegia; heat shock protein HTLV human T-cell lymphotropic virus HUS hemolytic–uremic syndrome HVA homovanillic acid IBIDS ichthyosis, brittle hair, impaired intelligence, decreased fertility, short stature (syndrome) IFN interferon Ig immunoglobulin IGF insulin-like growth factor INCL infantile neuronal ceroid lipofuscinosis (or Santavuori disease) IP incontinentia pigmenti IQ intelligence quotient IR inversion recovery IRD infantile Refsum disease ISIS image-selective in vivo spectroscopy ISSD severe infantile sialic acid storage disease IVL intravascular lymphomatosis JNCL juvenile neuronal ceroid lipofuscinosis (or Spielmeyer–Vogt disease, or Batten disease) KA kainate kDa kiloDalton KSS Kearns–Sayre syndrome LAMP lysosome-associated membrane protein LBSL leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate LCC leukoencephalopathy with calcifications and cysts LCH Langerhans cell histiocytosis LDL low-density lipoproteins LGMD limb girdle muscular dystrophy LH luteinizing hormone LHON Leber hereditary optic neuropathy LINCL late-infantile neuronal ceroid lipofuscinosis (or Jansky– Bielschowsky disease) MAG myelin-associated glycoprotein MAP microtubule-associated protein MBS Marchiafava–Bignami syndrome MBP myelin basic protein

List of Abbreviations

MCE MD MDC1A MEB MELAS MEPOP

MERRF MHC MHPG MICS MIL mIns MLC MLD MNGIE MOBP MOG MOM MOSP MPP MPS MPTP MR MRA MRI mRNA MRS MS MSD MSUD MT mtDNA MTI MTR NAA NAAG NAD NADH NALD NARP NAWM NBCA

multicystic encephalopathy Menkes disease; myotonic dystrophy merosin-deficient congenital muscular dystrophy muscle–eye–brain disease mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes mitochondrial encephalomyopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudoobstruction myoclonic epilepsy with ragged red fibers major histocompatibility complex 3-methoxy-4-hydroxyphenylglycol microcephaly–intracranial calcifications syndrome multifocal inflammatory leukoencephalopathy myo-inositol megalencephalic leukoencephalopathy with subcortical cysts metachromatic leukodystrophy mitochondrial neurogastrointestinal encephalomyopathy myelin-associated oligodendrocytic basic protein myelin oligodendrocyte glycoprotein mitochondrial outer membrane myelin-/oligodendrocyte-specific protein mitochondrial processing peptidase mucopolysaccharidoses; mucopolysaccharidoses methylphenyltetrahydropyridine magnetic resonance magnetic resonance angiography magnetic resonance imaging messenger RNA magnetic resonance spectroscopy multiple sclerosis multiple sulfatase deficiency maple syrup urine disease magnetization transfer mitochondrial DNA magnetization transfer imaging magnetization transfer ratio N-acetylaspartate N-acetylaspartyl glutamate nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide, reduced neonatal adrenoleukodystrophy neurogenic muscle weakness, ataxia, and retinitis pigmentosa normal-appearing white matter n-butyl cyanoacrylate

NCL nDNA NKH NMDA NMO NRTI NT OCRL ODDD OGIMD OHS OMgp ONMR OSP OTCD PACNS PAF PAN pANCA PAS PCD PCr PCR PDE PDGF PDHc PEP PET Pi PIBIDS PIP2 PKU PLOSL PLP PMD PME PML PMP PNS POLD POLIP PPAR ppm

neuronal ceroid lipofuscinosis nuclear DNA nonketotic hyperglycinemia N-methyl-D-aspartate neuromyelitis optica (or Devic disease) nucleoside analogue reverse transcriptase inhibitor neurotrophin oculocerebrorenal syndrome of Lowe oculodentodigital dysplasia oculogastrointestinal muscular dystrophy occipital horn syndrome oligodendrocyte myelin glycoprotein onychotrichodysplasia, neutropenia, mental retardation (syndrome) oligodendrocyte-specific protein ornithine transcarbamylase deficiency primary angiitis of the CNS platelet activating factor polyarteritis nodosa perinuclear form of ANCA periodic acid–Schiff pyruvate carboxylase deficiency phosphocreatine polymerase chain reaction phosphodiesters platelet-derived growth factor pyruvate dehydrogenase complex processing enhancing protein positron emission tomography inorganic phosphate photosensitivity, ichthyosis, brittle hair, impaired intelligence, decreased fertility, short stature (syndrome) phosphatidylinositol 4,5-biphosphate phenylketonuria polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy proteolipid protein Pelizaeus–Merzbacher disease; proximal myotonic dystrophy phosphomonoesters progressive multifocal leukoencephalopathy peroxisomal membrane protein peripheral nervous system pigmentary orthochromatic leukodystrophy polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction peroxisome proliferator activating receptor parts per million

XV

XVI

List of Abbreviations

PPRE PPT1 PRES PRESS PROMM PTS PVA PVL QA RCDP RD RF RNA RPLS RPR RR rRNA RXR SAE SAP SCA SCL SD SE SIBIDS SLE SLS SP SPECT SPG2 SSEP SSPE STEAM STIR

peroxisome proliferator response element palmitoyl protein thioesterase 1 posterior reversible encephalopathy syndrome point-resolved spectroscopy proximal myotonic myopathy peroxisome targeting signals polyvinyl alcohol periventricular leukomalacia quisqualate rhizomelic chondrodysplasia punctata Refsum disease radiofrequency ribonucleic acid reversible posterior leukoencephalopathy syndrome rapid plasma reagin (test) relapsing remitting ribosomal RNA retinoic acid receptor subcortical arteriosclerotic encephalopathy sphingolipid activator protein spinocerebellar ataxia subcortical leukomalacia Salla disease spine echo osteosclerosis, ichthyosis, brittle hair, impaired intelligence, decreased fertility, short stature (syndrome) systemic lupus erythematosus Sjögren–Larsson syndrome secondary progressive single photon emission computed tomography spastic paraparesis type 2 somatosensory evoked potential subacute sclerosing panencephalitis stimulated-echo acquisition mode short tau inversion recovery

T TE TI TNF-α TORCH TPP1 TR tRNA TSD TSE TTD TTP TvLINCL TYROBP UDP US UV V-CAM VDAC VDRL VEGF VEP VLA-4 VLCFA vLINCL VMA VWM WD WM WWS XALD XP ZS

Tesla toxic encephalopathy; echo time inversion time tumor necrosis factor-alpha toxoplasmosis, rubella, cytomegalovirus, herpes simplex tripeptidyl peptidase 1 repetition time transfer RNA Tay–Sachs disease turbo spin echo trichothiodystrophy with photosensitivity thrombotic thrombocytopenic purpura Turkish variant of late-infantile neuronal ceroid lipofuscinosis TYRO protein tyrosine kinase binding protein uridine diphosphate ultrasound/ultrasonography ultraviolet cellular adhesion molecules voltage-dependent, anion-selective channel Venereal Disease Research Laboratory (test) vascular endothelial growth factor visual evoked potential very late antigen 4 very-long-chain fatty acids variant late-infantile neuronal ceroid lipofuscinosis vanillyl mandelic acid vanishing white matter Wilson disease white matter Walker–Warburg syndrome X-linked adrenoleukodystrophy xeroderma pigmentosum Zellweger syndrome

Chapter 1

Myelin and White Matter

1.1

Introduction

Myelin makes up most of the substance of the white matter in the central nervous system (CNS). It is also present in large quantities in the peripheral nervous system (PNS). In both the CNS and the PNS, myelin is essential for normal functioning of the nerve fibers. The white matter in the CNS is composed of a vast number of axons, which are ensheathed with myelin, which is responsible for the white color. Besides myelinated axons, white matter contains many cells of the neuroglia type, but no cell bodies of neurons. The axons it contains originate from neuronal cell bodies in gray matter structures. There are two main types of macroglia in the white matter: astrocytes and oligodendrocytes. Among the many putative functions of glial cells, it is proposed that they contribute to the structural and nutritive support of neurons, regulate the extracellular environment of ions and transmitters, guide migrating neurons during development, and play an important part in repair and regeneration. The best known function of glial cells is the ensheathment of axons with myelin by oligodendrocytes. Gray matter contains the nerve cell bodies with their extensive dendritic arborization. The myelin content of gray matter structures is much lower, but

Fig. 1.1. T2-weighted MR image compared with a postmortem section prepared with a myelin stain, illustrating the capability of MRI to reflect histology

some myelin is present around intracortical and intranuclear fibers. The myelin content of the thalamus and the globus pallidus is relatively high.

1.2

Morphology of Myelin

Myelin is a spiral membranous structure that is tightly wrapped around axons. It has a very high lipid content and is soluble in fat solvents. Hence, when ordinary paraffin sections of the brain are prepared for light microscopic examination, most of the myelin dissolves away. After staining, the sites where myelin was present appear as round spaces that are empty except that each has a little round dot in the center, which represents a cross section of the axon. By means of fixatives that make myelin insoluble, it is possible to demonstrate it in paraffin sections. Osmic acid fixes myelin so that it does not dissolve in paraffin sections. Osmic acid itself stains myelin black. When examined under very low power, the white matter appears black (Fig. 1.1). If the white matter is examined under high power the myelin will be seen to be arranged in small rings around each nerve fiber. There are several myelin stains that can be used once the tissue has been fixed by some other means. Commonly used stains include hematoxylin, Luxol fast blue, and Oil-Red-O.

2

Chapter 1

Myelin and White Matter

Fig. 1.3. A micelle

Fig. 1.4. A lipid bilayer

Fig. 1.2. Electron micrograph of white matter with myelin sheaths

The information derived from light microscopic investigations is limited and is inadequate when more detailed information about myelin structure is required. Analysis of the structure of myelin began in the 1930s, stimulated by polarization-microscope studies and X-ray diffraction work, which led to the suggestion that the myelin sheath was made up of layers or lamellae. The lamellar structure was confirmed by electron microscopic studies. In electron micrographs myelin is seen as a series of alternating dark and less dark lines separated by unstained zones. These lines are wrapped spirally around the axon (Fig. 1.2). The evidence available from studies using polarized light, X-ray diffraction and electron microscopy led to the current view of myelin as a system of condensed plasma membranes with alternating protein-lipid-protein-lipid-protein lamellae as the repeating subunit. Plasma membranes are composed predominantly of lipids and proteins, and also contain carbohydrate components. The lipid elements of the membranes are phospholipids, glycolipids, and cholesterol. A common property of these lipids is that they are amphipathic. This means that the lipid molecules contain both hydrophobic and hydrophilic regions, corresponding to the nonpolar tails and the polar head groups, respectively. Hydrophobic substances are in-

soluble in water, but soluble in oil. Conversely, hydrophilic substances are insoluble in oil, but soluble in water. In an aqueous environment, the amphipathic character of the lipids favors aggregation into micelles or a molecular bilayer. In a micelle (Fig. 1.3), the hydrophobic regions of the amphipathic molecules are shielded from water, while the hydrophilic polar groups are in direct contact with water. The stability of this structure lies in the fact that significant free energy is required to transfer a nonpolar molecule from a nonpolar medium to water. Likewise, a great deal of energy is required to transfer a polar moiety from water to a nonpolar medium. Thus, the micelle provides a minimal energy configuration and is accordingly thermodynamically stable. The molecular bilayer, the basic structure of plasma cell membranes, also satisfies the thermodynamic requirements of amphipathic molecules in an aqueous environment. A bilayer exists as a sheet in which the hydrophobic regions of the lipids are protected from the water while the hydrophilic regions are immersed in water (Fig. 1.4).As the structure of the bilayer is an inherent part of the amphipathic character of the lipid molecules, the formation of lipid bilayers is essentially a self-assembly process. In comparison with other molecular bilayers, the myelin bilayer is unique in having a very high lipid

1.2

Morphology of Myelin

Fig. 1.5. Membrane split open to demonstrate the layers.The lipid bilayer is interrupted by proteins embedded in this layer. Glycoprotein chains rise from the surface of the membrane

content and containing chiefly saturated fatty acids with an extraordinarily long chain length. This fatty acid composition leads to a closely packed, highly stable membrane structure. The presence of unsaturated fatty acids in a bimolecular leaflet leads to a more loosely packed, less stable structure, as unsaturated fatty acid chains have a kinked, hook-like configuration. Lipids containing such unsaturated fatty acids cannot approach neighboring molecules as closely as saturated lipids can, since the latter are rod-like structures. There will be much less total interaction between the tails of an unsaturated lipid and a neighboring molecule than between the tails of two saturated lipids, and the resulting binding forces will be much smaller. Lipids containing long-chain fatty acids are more tightly held in a membrane structure than those containing shorter chain fatty acids, since with increasing length of the hydrocarbon chain the binding interactions between the lipid molecules become stronger. It has also been suggested that verylong-chain fatty acids can form complexes by interdigitation of the hydrocarbon tail on one side with the hydrocarbon tail of a lipid on the opposite side of the bimolecular leaflet. Such complexes would contribute to the stability of the myelin membrane. If this lipid composition is changed, as is the case in a number of demyelinating disorders, it is clear that the stability of the myelin membrane may be diminished. The bimolecular lipid structure allows for interaction of amphipathic proteins with the membrane. These proteins form an integral part of the membrane, with hydrophilic regions protruding from the inner and outer faces of the membrane and connected by a hydrophobic region traversing the hydrophobic core of the bilayer. In addition, there are peripheral proteins, which do not interact directly with the lipids in the bilayer, but are bound to the hydrophilic regions of specific integral proteins. Thus, the cell membrane is a bimolecular lipid leaflet coated with proteins on both sides (Fig. 1.5). There is inside-outside asymmetry of the lipids. In addition, integral and peripheral proteins

are asymmetrically distributed across the membrane bilayer and the protein composition on the inside is different from that on the outside of the bilayer. On electron microscopic examination, a plasma membrane is shown as a three-layered structure and consists of two dark lines separated by a lighter interval. It is also revealed that the plasma membrane is not symmetrical in form: the dark line adjacent to the cytoplasm is denser than the leaflet on the outside. From both X-ray diffraction and electron microscope data it can be seen that the smallest radial subunit that can be called myelin is a five-layered structure of protein-lipid-protein-lipid-protein (Fig. 1.6). The repeat distance is 160–180 Å. The dark lines seen in electron microscopic studies represent the protein layers and the unstained zones, the lipids. The uneven staining of the protein layers results from the way the myelin sheath is generated from the plasma membrane. The less dark lines (so-called intraperiod lines) represent the closely apposed outer protein coats of the original cell membrane. The dark lines (so-called major dense lines) are the fused inner protein coats of the cell membrane. High-magnification electron micrographs show that the intraperiod line is double in nature (Fig. 1.6). The myelin sheath is not continuous along the entire length of axons, but axons are covered by segments of myelin, which are separated by small regions of uncovered axon, the nodes of Ranvier. The myelin lamellae terminate as they approach the node. The region where the lamellae terminate is known as the paranode. Electron micrographs of longitudinal sections of paranodal regions show that the major dense lines open up and loop back upon themselves, enclosing cytoplasm within the loop (Fig. 1.7). In that part of the paranode most distant from the node, the innermost lamellae of the myelin terminate first, and succeeding turns of the spiral of lamellae then overlap and project beyond the ones lying beneath. Thus, the outermost lamella overlaps all the others and terminates nearest the node, so that the myelin sheath

3

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Myelin and White Matter

Fig. 1.6. The electron microscopic picture of a myelin sheath (upper left) reveals the five-layered structure of myelin with major dense lines and intraperiod lines. A higher magnification of two myelin lamellae (lower left) shows the periodicity of myelin even more clearly. On the right, a schematic representation of an electron microscopic picture of a myelin sheath surrounding an axon (A) demonstrates major dense lines (md) and intraperiod lines (ip)

Fig. 1.7. Node of Ranvier, where the nerve fiber between two myelinated segments is bare.The outer myelin layers envelope the inner layer and cover these at the nodal junctions

gradually becomes thinner with increasing proximity to the node. Schmidt-Lantermann clefts such as are described in the PNS are rare in the CNS. These are funnelshaped clefts within myelin sheaths. They contain cytoplasm and extend from the soma of the myelinforming cell to the inner end of the myelin sheath. In a transverse section of a myelin sheath they appear as islands of cytoplasm between openings of the major dense lines. There is considerable variation in the number of myelin lamellae in the sheaths surrounding different axons. Generally, the larger the diameter of the axon the thicker its myelin sheath. In addition to this direct relationship between axon size and myelin thickness, the lengths of internodal segments also vary with the size of the axon: the larger the nerve fiber, the greater the internodal length.

1.3

and myelin sheaths can be observed. In the gray matter they aggregate closely around neuronal cell bodies, where they are called satellite oligodendrocytes. PNS myelin is formed by Schwann cells. The CNS myelin membranes originate from and are part of the oligodendroglial cell membrane. The oligodendrocytes form flat cell processes, which are wrapped around the nerve axon in a spiral fashion (Fig. 1.8).

Oligodendrocytes

Oligodendrocytes are the key cells in myelination of the CNS. They are cells of moderate size with a small number of short, branched processes. They are the predominant type of neuroglia in white matter and are frequently found interposed between myelinated axons. Actual connections between oligodendrocytes

Fig. 1.8. Diagram showing the axon being rolled in the myelin sheath

1.4

Astrocytes

Fig. 1.9. Impression of the threedimensional structure of oligodendrocytes with their plasma membrane extensions as myelin sheaths covering the axons that cross their region

With the exception of the outer and lateral loops of the flat cell processes, the cellular cytoplasm disappears from these processes and the remaining cell membranes condense into a compact structure in which each membrane is closely apposed to the adjacent one. If myelin were unrolled from the axon it would be a flat, spade-shaped sheet surrounded by a tube containing cytoplasm. Although the myelin sheath is an extension of the oligodendroglial cell membrane, the chemical composition of myelin is quite different from that of the oligodendroglial cell membrane. The oligodendroglial cell membrane is transformed into myelin in processes of modification and differentiation. On the same axon, adjacent myelin segments belong to different oligodendrocytes. A single oligodendrocyte provides the myelin for many internodal segments of different axons simultaneously. One oligodendrocyte can be responsible for the production and maintenance of up to 40 nerve fibers (Fig. 1.9). This has implications for disease conditions and reparative processes, as the destruction of even only a few oligodendrocytes can have an extensive demyelinating effect. Together with the Schwann cells of the PNS, oligodendrocytes are unique in their ability to produce vast amounts of a characteristic unit membrane. The ratio between cell body surface membrane and myelin membrane is estimated at 1:620 in the case of oligodendrocytes. The deposition and maintenance of such large expanses of membrane require optimal coordination of the synthesis of its various lipid and protein components and their interaction to ensure production of a stable membrane on the one hand and a well-regulated and controlled breakdown and replacement of spent components needed to support the myelin membrane on the other.

1.4

Astrocytes

Astrocyte functions have long been a subject of debate. Their major role has long been thought to be a sort of skeletal function, providing packing for other CNS components. It is becoming increasingly clear that astrocytes are of fundamental importance in maintaining the structural and functional integrity of neural tissue. A well-known function of astrocytes is concerned with repair. When damage is sustained, astrocytes proliferate, become larger, and accumulate glycogen and filaments. This state of gliosis can be total, in which case all other elements are lost, leaving a glial scar, or occur against a background of regenerating or normal CNS parenchyma. Following demyelination, astrocytes synthesize growth factors thought to be involved in myelin repair.Astrocytes may also phagocytose debris in some conditions. Astrocytes are involved in transport and in maintaining the blood–brain and CSF–brain barriers. End-feet of astrocytes form part of these barriers in perivascular and subpial regions. Endothelial tight junctions form the primary seal of the blood–brain barrier. The role of astrocytes in the blood–brain barrier is less well defined. They are physically separated from endothelial cells by the basal lamina and do not contribute directly to the physical barrier. Perivascular astroglial end-feet contain many transport proteins, including transporters of monocarboxylates, glucose, and glutamate, as well as water. Aquaporin-4 is the only known water channel in the brain and has a localization in the astroglial end-feet. Astrocytes play a part in the process of myelin deposition. They promote the adhesion of oligodendrocyte processes to axons and stimulate myelin formation by local secretion of different growth factors. As-

5

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Chapter 1

Myelin and White Matter

trocytes and neurons are the sources of platelet-derived growth factor (PDGF), which promotes oligodendrocyte progenitors to proliferate, migrate, and differentiate. Astrocytes release basic fibroblast growth factor (bFGF), which promotes oligodendroglial differentiation. Extension of oligodendrocyte processes, a critical early step in myelin formation, is facilitated by astrocytic bFGF. Insulin-like growth factor I (IGF-I), which plays a crucial role in oligodendrocyte development and myelin formation, is produced by various cells, including astrocytes. It acts as an oligodendrocyte mitogen and a differentiation and survival factor and is one of the main regulators of the amount of myelin production.Astrocytes express neurotrophin-3 (NT-3), which promotes proliferation of oligodendroglial precursors and oligodendrocyte survival. There is evidence that NT-3 in combination with brain-derived neurotrophic factor (BDNF) can induce proliferation of endogenous oligodendrocyte progenitors and the subsequent myelination of regenerating axons. Astrocytes and oligodendrocytes communicate via gap junction-mediated contacts. Astrocytes have a role in the conduction of nerve impulses. Astrocytes and axons have an intimate relationship at the node of Ranvier. Perinodal astrocytes and nodal parts of the axon have a high concentration of sodium channels, indicating specialization of astrocyte function at these sites. Synthesis of the neurotransmitters glutamate and GABA (gamma aminobutyric acid) can originate either from glutamine or from α-ketoglutarate or another tricarboxylic acid cycle intermediate plus an amino acid as a donor of the amino group. Neurons lack the enzymes glutamine synthetase and pyruvate carboxylase, which are present exclusively in astrocytes. Astrocyte processes in perisynaptic regions take up the excitatory neurotransmitter glutamate from the synapse and recycle it to its precursor glutamine. Therefore, astrocytes are important in the synthesis and recycling of some neurotransmitters and protect neurons from excitotoxicity.

1.5

Biochemical Composition of Mature Myelin and White Matter

The most conspicuous feature of the composition of myelin as opposed to other membranes is the high ratio of lipid to protein. It is one of the most lipid-rich membranes, lipids making up 70–80% lipid by dry weight. In comparison with other membranes, the protein concentration of 20–30% is low. For example, the concentration of protein in liver cell membranes is 60%. Myelin is a relatively dehydrated structure, containing only 40% water.

CNS white matter is half myelin and half nonmyelin on a dry weight basis. Owing to the high myelin content, white matter has a relatively low water content and a high lipid content. The water content of white matter is 72% and that of gray matter 82%. The nonmyelin portion of white matter contains about 80% water. Myelin is mainly responsible for the gross chemical differences between white and gray matter. Myelin is rich in all lipid classes, although nonpolar lipids and glycolipids (galactolipids) are particularly well represented. The lipids of CNS myelin are composed of 25–28% cholesterol, 27–30% galactolipid, and 40– 45% phospholipid when expressed as percentages of total lipid weight. When lipid data are expressed as molar ratios, CNS myelin preparations contain cholesterol, phospholipid and galactolipid in a ratio varying between 4:3:2 and 4:4:2. The biochemical composition of mature gray and white matter is shown in Table 1.1. With respect to white matter, separate figures are given for the myelin and nonmyelin portions, CNS white matter being half myelin and half nonmyelin on a dry weight basis. In Table 1.1 the lipid figures are expressed as percentages of total lipid weight. Since the water content and the dry weight lipid content of gray matter and white matter, myelin and nonmyelin, differ widely, the figures expressed in this way give no direct information about lipid concentration in either dry or wet tissue. However, from the data presented, these concentrations can be calculated. When the lipid compositions of gray and white matter are compared, the most conspicuous difference to emerge is that white matter is relatively rich in galactolipids and relatively poor in phospholipids. Galactolipids (galactocerebroside and sulfatide) constitute 25–30% of the lipids in white matter, whereas they account for only 5–10% of those in gray matter. Phospholipids account for two-thirds of the total lipids in gray matter, but less than half those in white matter. There are, strictly speaking, no myelin-specific lipids that are not found elsewhere in the brain. However, the most specific distinguishing feature of myelin lipids is the high cerebroside content, and cerebroside can be considered the most typical myelin lipid. During development, the concentration of cerebroside in brain is directly proportional to the amount of myelin present. Ethanolamine phosphoglyceride in plasmalogen form (plasmenylethanolamine) is the major myelin phospholipid. Approximately 80% of the ethanolamine phosphoglycerides of myelin and white matter are present in plasmalogen form, and only a small proportion are formed by phosphatidylethanolamine. Conversely, the plasmalogens, which comprise nearly one-third of the total phospholipids, are mainly of the ethanolamine type with lesser amounts of

1.5

Biochemical Composition of Mature Myelin and White Matter

Table 1.1. Composition of human CNS gray matter, white matter, myelin portion and nonmyelin portion of whole white matter. From Norton and Cammer (1984)

Watera Total proteinb Total lipidb Cholesterol Glycolipids Cerebroside Sulfatide Phospholipids Ethanolamine PG Choline PG Serine PG Inositol PG Sphingomyelin Plasmalogensc

Gray matter

White matter

Myelin

Nonmyelind

82 55.3 32.7 22.0 7.3

72 39.0 54.9 27.5 26.4 19.8 5.4 45.9 14.9 12.8 7.9 0.9 7.7 11.2

44 30.0 70.0 27.7 27.5

82 62.2 41.2 14.6 28.2 19.9 7.7 51.9 6.8 16.5 20.4 1.0 5.6 9.2

5.4 1.7 69.5 22.7 26.7 8.7 2.7 6.9 8.8

22.7 3.8 43.1 15.6 11.2 4.8 0.6 7.9 12.3

a

Percentage of total brain weight Figures for total protein and total lipid are percentages of dry weight; all others are percentages of total lipid weight Plasmalogens are primarily ethanolamine phosphoglycerides d Figures for bovine brain, which are thought to be in close agreement with those for human brain (Norton and Autilio 1966) PG phosphoglycerides b c

plasmenylserine. Phosphatidylcholine is the major choline phosphoglyceride; only traces of choline phosphoglyceride have the plasmalogen form. Gangliosides are minor myelin lipids and make up only 0.3–0.7% of total myelin lipids. They are localized mainly in neuronal membranes, and gray matter is 10 times as rich in gangliosides as in white matter. Gangliosides are complex sialic acids containing glycosphingolipids. GM1, a monosialoganglioside, is the major myelin ganglioside accounting for about 70 mol % of the total myelin ganglioside content. Within the CNS, the ganglioside GM4 (sialogalactosylceramide) is probably specific for myelin and oligodendroglia. It is a derivative of cerebroside. Myelin lipids contain somewhat different fatty acid constituents than other membranes. Characteristic of myelin are α-hydroxy fatty acids in cerebrosides and sulfatides and high amounts of long-chain fatty acids in the different lipid classes. There are monounsaturated fatty acids, but only low amounts of polyunsaturated fatty acids. Table 1.2 shows the chemical structures of the main lipid constituents of myelin. The protein composition of myelin is simpler than that of other membranes. Proteolipid protein and myelin basic protein encompass approximately 60– 80% of the total protein. Most myelin proteins are unique to myelin. Proteolipid protein (PLP) and its isoform DM 20 make up about 50% of the total protein in CNS myelin. Their concentration in white matter is about 5

times that in gray matter. The proteins are encoded by the same gene and are formed by alternative splicing of the primary gene transcript. The proteins differ by a hydrophilic peptide 35 amino acids in length, whose presence generates PLP. DM 20 is predominant in early development, whereas PLP is the major protein in mature myelin. The proteins are very hydrophobic. There are multiple isoforms of myelin basic protein (MBP), arising from different patterns of splicing of the primary gene transcript. The heterogeneity is increased further by various posttranslational modifications. Myelin basic proteins account for 30–35% of the total myelin protein. MBP contains no extensive regions of hydrophobic residues and is hydrophilic. MBP is the antigen which, when injected into an animal, elicits a cellular immune response, producing the CNS autoimmune disease called experimental allergic encephalomyelitis. There are several CNS myelin glycoproteins: myelin-associated glycoprotein (MAG), myelin/oligodendrocyte glycoprotein (MOG), and oligodendrocyte-myelin glycoprotein (OMgp). These are highmolecular-weight proteins. They are quantitatively minor myelin components: MAG accounts for about 1% of total protein and MOG, for 0.05%. Other minor myelin proteins are oligodendrocytespecific protein (OSP), which is a tight junction protein, myelin-associated oligodendrocytic basic protein (MOBP), a small basic protein distributed throughout compact myelin, and myelin/oligodendrocyte-specific protein (MOSP), which is located on

7

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Table 1.2. Structure of the important myelin lipids Cerebroside

sphingosine

galactose

fatty acid Sulfatide

sphingosine

galactose

sulfate

fatty acid Phosphatidylethanolamine

fatty acid glycerol

fatty acid phosphate

Phosphatidylcholine = lecithin

fatty acid glycerol

fatty acid phosphate

Phosphatidylserine

fatty acid phosphate

Phosphatidylinositol

serine

fatty acid glycerol

fatty acid phosphate

Ethanolamine plasmalogens

inositol

*fatty acid glycerol

fatty acid phosphate

GM3 ganglioside

choline

fatty acid glycerol

Sphingomyelin

ethanolamine

sphingosine

fatty acid

phosphate

choline

ethanolamine

N-acylsphingosine glucose galactose

GM2 ganglioside

N-acetylneuraminic acid

N-acylsphingosine glucose galactose

N-acetylneuraminic acid

N-acetylgalactosamine GM1 ganglioside

N-acylsphingosine glucose galactose

N-acetylneuraminic acid

N-acetylgalactosamine galactose Sphingolipids of myelin are formed from sphingosine. N-acylsphingosine is termed ceramide. A phosphorylcholine group attached to ceramide forms sphingomyelin; glucose or galactose in glycosidic linkage forms cerebroside (most often: galactosylceramide). When the glucose or galactose is esterified with sulfate, sulfatide is formed. Phosphoglycerides contain two fatty acids in ester linkage at the α and β position of glycerol and at the α’ position a phosphate group to which the moiety definitive of the class is linked. For example, a choline group defines phosphatidylcholine. The plasmalogens are similarly formed, except that at the α position of the glycerol there is a 1:2 unsaturated ether structure (*). Gangliosides are synthesized from N-acylsphingosine by stepwise addition of sugars and N-acetylneuraminic acid.

1.6

the extracellular surface of oligodendrocytes and myelin. Highly purified myelin contains a number of enzymes. Two of these enzymes, 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNP) and a cholesterol ester hydrolase, are found at much higher specific activities in myelin than in brain homogenates. It appears that these enzymes are fairly myelin specific, and are probably also present in oligodendroglial membranes. Many other enzymes are found that are not specific to myelin but also present in other brain fractions. The exact function of the two enzymes is not known. In particular, their contribution to the metabolism of myelin constituents is not known. CNP catalyzes the hydrolysis of several 2’,3’-cyclic nucleotide monophosphates, all of which are converted to the corresponding 2’-isomer. The substrates of the enzyme are not present in nervous tissue. CNP is one of the proteins formerly called Wolfgram proteins, a heterogeneous group of high-molecular-weight myelin proteins named after the investigator who first suggested that myelin contained proteins other than proteolipid protein and myelin basic protein.

1.6

Molecular Architecture of Myelin

The currently accepted view of the myelin structure is that of a double lipid bilayer, each coated on both sides with protein. The resulting repeating subunit consists of radial protein-lipid-protein-lipid-protein lamellae. Some proteins are fully or partially embedded in the bilayer, and others are attached to the surface by weaker linkages. Both proteins and lipids have an asymmetrical distribution. Galactolipids, cholesterol, phosphatidylcholine, and sphingomyelin are preferentially located in the former extracellular half of the bilayer (intraperiod line). Ethanolamine plasmalogen and myelin basic protein are preferentially located in the former cytoplasmic half of the bilayer. Membranes are fluid structures. Lipid molecules diffuse rapidly in the plane of the membrane, as do proteins, unless anchored by specific interactions. The spontaneous rotation of lipids from one side of the membrane to the other is a very slow process. The transition of a molecule from one membrane surface to the other is called transverse diffusion, or flip-flop. In view of the asymmetry of lipids in the bilayer, the transverse mobility must be limited. The diffusion within the plane of the membrane is referred to as lateral diffusion. Proteolipid protein consists of alternating hydrophilic and hydrophobic sequences with four stretches of hydrophobic residues that are of sufficient length to span the lipid bilayer. It is an integral membrane protein that passes through the bilayer four times

Molecular Architecture of Myelin

(four transmembrane domains). The hydrophobic transmembrane segments are linked by hydrophilic portions on both sides of the membrane. This means that the protein has domains in both the intraperiod and the major dense lines. Probably both isoforms, PLP and DM 20, are involved in stabilizing the intraperiod line. Their role is described as that of ‘adhesive struts’ or ‘spacers,’ maintaining a set distance between apposed lamellae. DM 20 is the major proteolipid protein in early development, whereas PLP is the major product in mature myelin. It is believed that DM 20 has a still unidentified regulatory role in early oligodendrocyte progenitor development and differentiation, and that PLP plays a part later on in oligodendrocyte function, in the proper formation of the intraperiod line of myelin during its final elaboration and compaction. Myelin basic protein is an extrinsic protein located on the cytoplasmic face of the myelin membranes at the major dense lines. It probably stabilizes the major dense lines by keeping the cytoplasmic faces of the myelin lamellae in close apposition. Myelin-associated oligodendrocytic basic protein is another small basic protein distributed throughout compact myelin at the major dense lines. There is evidence that MOBP reinforces the apposition of the cytoplasmic faces of the myelin sheath. Gangliosides are located almost entirely on the external surface of membranes. They may have an important role in cell surface recognition and signal transduction processes such as those that occur during myelination. Myelin glycoproteins are transmembrane proteins with the polypeptide extending through the lipid bilayer and the glycosylated portion of the molecule exposed on the outer surface of the bilayer. They are all implicated in recognition and cell–cell interactions. MAG is one of these proteins. Its external region contains immunoglobulin-like domains. Thus, MAG is a member of the immunoglobulin superfamily. It is concentrated in the inner periaxonal membrane of the myelin sheath and absent from the compact multilamellar myelin sheath. The exposed, periaxonal position is compatible with its postulated involvement in oligodendrocyte–axon interaction, including maintenance of the structural integrity of the glia– axon adhesion in mature myelin. The observation that the protein can be detected at the very earliest stages of myelination has led to the hypothesis that the protein may also play a role in mediating the oligodendrocyte-axon recognition events that precede myelination and specify the initial path of myelin deposition. MOG is another of the myelin glycoproteins. It also belongs to the immunoglobulin superfamily. The protein is located at the outermost layer of the myelin sheath and the oligodendrocyte plasma membrane.

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The function of this glycoprotein is unknown. It may be involved in the adhesion between neighboring myelinated fibers and function as glue in the maintenance of axon bundles in the CNS. MOG may also be a cell surface receptor that transduces signals from the external milieu to the inside of the oligodendrocyte or myelin sheath. The enzyme CNP is found in myelin and oligodendrocytes. Within the myelin sheath it is localized on the cytoplasmic side of noncompact regions, e.g., periaxonally and in the paranodal loops. CNP is essential for axonal survival but not for myelin assembly.

1.7

Myelinogenesis

The time-course of the appearance of newly synthesized lipids and proteins in myelin indicates that myelin is not laid down as a unit. Different components are synthesized and processed in different cellular compartments, are transported to the sites of myelin formation by different mechanisms, and show different rates of entry into the myelin sheath. For example, MBP enters the myelin sheath with almost no lag after synthesis, whereas proteolipid protein enters myelin with a lag-time of 30–40 min following synthesis. Once protein synthesis is stopped with cycloheximide, the entry of MBP is halted immediately, but proteolipid protein continues to be incorporated into myelin for 30 min. These data indicate that MBP and PLP are assembled by different mechanisms, with PLP taking a longer and more circuitous route through the cytoplasm. Lipids also continue to be incorporated into myelin for 4 h after protein synthesis has stopped. MBP is synthesized on free polyribosomes near the plasma membrane or the adjacent myelin sheath. The myelin membrane is surrounded by and infiltrated with cytoplasmic channels, called the outer loops and longitudinal incisures of Schmidt-Lantermann, respectively. Myelin basic protein mRNA is translocated from the nucleus to the myelin membrane via these cytoplasmic channels. MBP synthesized here is rapidly sequestered into the myelin sheath and appears in the cytoplasmic leaflet of compact myelin (major dense lines). mRNAs for several other myelin proteins follow similar trafficking pathways. Proteolipid protein and DM 20 are synthesized on polyribosomes bound to the endoplasmic reticulum. The nascent protein is inserted into the endoplasmic reticulum and passes through the Golgi apparatus to the plasma membrane and myelin sheath via vesicular transport. Inclusion in the plasma membrane occurs by fusion of the vesicles with the plasma membrane. The inside of the vesicle after fusion becomes the outside of the plasma membrane. As a conse-

quence, substances transported to the plasma membrane via vesicles end up in the extracellular leaflet of the myelin sheath. MAG resembles proteolipid protein as far as the site of synthesis and transport to the plasma membrane are concerned. The same two mechanisms of synthesis and transport can be distinguished for myelin lipids, i.e., the routes of PLP and MBP, respectively. The endoplasmic reticulum is the site of synthesis of phosphatidylcholine and cholesterol. The Golgi apparatus is the site of synthesis of cerebroside, sulfatide, sphingomyelin, and gangliosides. The lipids are transported from the Golgi apparatus to the plasma membrane by a vesicle-mediated process. Expression on the cell surface occurs by fusion of the vesicles with the plasma membrane. The lipids are located predominantly in the extracellular leaflet of the myelin lamellae. In contrast, the myelin phospholipids that predominantly reside on the inner leaflet, including phosphatidylserine and ethanolamine plasmalogens, are synthesized in the superficial cytoplasmic channels of the myelin sheath and rapidly enter compact myelin, possibly with phospholipid transfer proteins as carriers. Several other phospholipids are also synthesized in the superficial cytoplasmic channels. After reaching the outermost myelin layers, substances penetrate to the deepest layers over a period of a few days. This movement of substances from outer to inner layers occurs at rates consistent with lateral diffusion along the spirally wound bilayer.

1.8

Regulation of Myelinogenesis

Elaboration of the myelin sheath involves a precisely ordered sequence of events beginning with the initial ensheathment of the axon, proceeding to formation of multiple loose wrappings and eventually compaction to form the mature multilamellar myelin sheath. These processes imply a temporally regulated program of gene expression in the oligodendrocyte to ensure that the appropriate biochemical components are synthesized in the appropriate proportions at each stage of myelinogenesis. Just before the onset of rapid myelin membrane synthesis the expression of genes of myelin proteins is sharply up-regulated. There is evidence of a coordinated mechanism for synchronous activation of the myelin protein genes. This period of sharp up-regulation of expression of myelin genes is the most vulnerable part of the myelination process and is called the critical period. Apparently, there are both tissue-specific and stage-specific mechanisms controlling myelin genes. Myelin genes are only expressed in oligodendrocytes and Schwann cells. The expression of the genes is de-

1.8

velopmentally regulated and is probably intimately associated with the stage of differentiation of these cells. Control mechanisms are active at the transcriptional level. Regulatory regions, including the promoter regions, have been identified for myelin protein genes. Key sites for tissue-specific expression of myelin proteins are clustered near the promoter regions, and within these clusters are several motifs that may be involved in coordinating the regulation of myelin-specific genes. The alternative splicing patterns produced from the primary myelin protein transcripts are also developmentally regulated. The splicing patterns for the different proteins have been shown to change in the course of development. In both the CNS and the PNS, glial cells are influenced to produce myelin by both neuronal targets that they ensheathe and by a range of hormones and growth factors produced by neurons and astrocytes. There is a continuous oligodendrocyte-neuron-astrocyte interaction in the process of myelination and myelin maintenance. Proliferation of oligodendrocyte precursor cells depends on electrical activity of neurons. Oligodendrocyte number is also dependent on number of axons. Differentiation of oligodendroglia has been shown to depend heavily on the presence and the integrity of axons. Gene expression for myelin constituents is modulated by the presence of axons. Within oligodendrocytes, proteins are produced that are thought to be involved in the induction of myelination (e.g., glia-specific surface receptors for differentiation signals), in the initial deposition of the myelin sheath (e.g., axon-glial adhesion molecules), and in its wrapping and compaction around the nerve axon (e.g., structural proteins of compact myelin). A minimal axonal diameter is important for the initiation of myelination. Final myelin sheath thickness is also related to axonal size. This match is reached by local control mechanisms. Therefore, a single oligodendrocyte can be associated with several axons of different sizes, the myelin sheaths being thicker for larger axons. Larger axons also have longer internodes. Astrocytes are essential in the process of myelination and myelin maintenance. They produce trophic factors, including PDGF, bFGF, IGF-I, and NT-3. These factors promote proliferation, migration and differentiation of oligodendrocyte progenitors, extension of oligodendrocyte processes, adhesion of oligodendrocyte processes to axons, myelin formation and myelin maintenance. Hormones have a dramatic effect on myelinogenesis. A deficiency of growth hormone during the critical period leads to hypomyelination. Most of the effects of growth hormone are mediated by IGF-I. Administration of this substance in early development leads to an increase in all brain constituents, but par-

Regulation of Myelinogenesis

ticularly and disproportionately in the amount of myelin produced per oligodendrocyte. Thyroid hormone also has an effect on myelinogenesis. Hypothyroidism during early development leads to hypomyelination, whereas hyperthyroidism accelerates myelination. Steroids have a complex influence. None of the myelin protein genes is transcriptionally regulated by steroids, but steroids probably act at the posttranslational level, stimulating the translation of MBP and PLP mRNAs and inhibiting the translation of CNP mRNA. The importance of iron in myelination has been examined. Iron and the iron mobilization protein transferrin are localized in oligodendrocytes, and may participate in the formation and/or maintenance of myelin by complexing with enzymes involved in the synthesis of myelin components. Myelination is vulnerable to undernourishment. If there is undernourishment during the critical period just prior to the onset of rapid myelin synthesis, myelination is more severely reduced than total brain weight, whereas the number of oligodendrocytes is unaltered. The hypomyelination is permanent. Severe undernutrition during the critical period leads to decreased levels of IGFs and a failure in up-regulation of myelin genes. Successful myelination is also dependent on function. It is known that myelination is diminished by preventing the conduction of impulses in a nerve. Impulse conduction is a stimulus to myelination. Premature activity accelerates myelination. Hypermyelination has incidentally been noticed in cerebral anomalies, supposedly via the stimulus of epilepsy. It has been shown that oligodendrocyte progenitor cells express adenosine receptors, which are activated in response to action potential firing. Action potential firing leads to the nonsynaptic release of several substances from axons, including ATP and adenosine. Adenosine acts as a potent neuroglial transmitter to inhibit oligodendrocyte progenitor cell proliferation, stimulate differentiation, and promote the formation of myelin. After formation the myelin sheath and the axon remain mutually dependent. The myelin sheath needs an intact axon, as demonstrated by the studies on wallerian degeneration. On the other hand, for maintenance of the normal structure and function the axon requires an intact myelin sheath. Normal astrocytes are essential for an intact myelin-axon unit. Since myelin, once deposited, is a relatively stable substance metabolically, it is relatively invulnerable to adverse external factors. Generalized vulnerability of myelin to noxious agents and adverse influences is likely to be confined to the period just before and during active myelination.

11

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Chapter 1

1.9

Myelin and White Matter

Myelination of the Nervous System

Myelination of each of the multiple connecting fiber systems of the CNS takes place at a different time in early development. Some fiber systems start to myelinate halfway through gestation or later and rapidly attain their maximal degree of myelination, whereas other systems attain their maximal degree of myelination only slowly. It is, therefore, not correct to refer to myelination as a singular process. There is a marked, temporal diversity in topographic patterns of myelination throughout the last half of gestation and during the first 2 postnatal years. Thus, at any time in the early development of the human brain there are multiple separate or intermixed regions of unmyelinated, partly myelinated, or completely myelinated tracts. Myelination of the nervous system follows a fixed pattern consisting of ordered sequences of myelinating systems apparently governed by some rules: 1. The first rule, probably governing all other rules, is that tracts in the nervous system become myelinated at the time they become functional. 2. Most tracts become myelinated in the direction of the impulse conduction. 3. Myelination starts in the PNS before it starts in the CNS. 4. Myelination in central sensory areas tends to precede myelination in central motor areas. 5. Myelination in the brain occurs earlier in areas of primary function than in association areas. 6. Roughly speaking, myelination progresses from caudal (spinal cord) to rostral parts (brain) and spreads from central (diencephalon, pre- and postcentral gyri) to peripheral parts of the brain. However, there are many exceptions to this rule. It is important to note that the times mentioned below for myelination of the different tracts and structures of the brain are only generalizations and approximations. In the first place, there is a considerable degree of normal variation. Secondly, the onset of myelination is difficult to define. It can be defined as the first myelin tube found on light microscopic examination, as the appearance of the first myelin lamella on ultrastructural examination, or as the first evidence of the presence of myelin constituents in immunological investigations. In the 4th month of gestation myelin is first seen in the anterior motor roots and soon appears in the posterior roots. In the 5th month of gestation myelination starts in the dorsal columns of the spinal cord and the anterior and lateral spinothalamic tracts for conduction of somatesthetic stimuli.

In the 6th month of gestation myelination proceeds rapidly cephalad in the medial lemniscus and spinothalamic tracts in the brain stem tegmentum. Myelin begins to appear in the statoacoustic tectum and tegmentum and the lateral lemniscus for the conduction of acoustic stimuli. Myelin is seen in the inner, vestibulocerebellar part of the inferior cerebellar peduncle. In the 7th month of gestation myelination is still largely confined to structures outside the diencephalon and cerebral hemispheres. Progress of myelination is seen in the optic nerve, optic chiasm and tracts, inferior cerebellar peduncle, the parasagittal part of the cerebellum, the descending trigeminal tract, superior cerebellar peduncle, capsule of the red nucleus, capsule of the inferior olivary nucleus, vestibulospinal, reticulospinal and tectospinal descending tracts to the spinal cord and posterior limb of the internal capsule. In the eighth month of gestation, myelination starts in the corpus striatum (in particular globus pallidus), anterior limb of the internal capsule, subcortical white matter of the post- and precentral gyri, rostral part of the optic radiation as well as corticospinal tracts in midbrain and pons, transpontine fibers, middle cerebellar peduncles and cerebellar hemispheres. In the ninth month of gestation, myelination continues in the thalamus (in particular ventrolateral nucleus), putamen, central part of the corona radiata, distal part of the optic radiation, acoustic radiation, anterior commissure, midportion of the corpus callosum and fornix. However, in a child born at term, most of the structures and tracts mentioned are not fully myelinated and, in fact, in some myelination has just started. Apart from some myelin in the central tracts of the corona radiata connected with the pre- and postcentral gyri, and the primary optic and acoustic radiations, the cerebral hemispheres are still largely unmyelinated. During the first postnatal year, myelin spreads throughout the entire brain. By the postnatal age of 12 weeks myelination is well advanced in the corona radiata, the optic radiation and the corpus callosum, but the frontal and temporal white matter are still largely unmyelinated. By the age of about 8 months, the adult state is foreshadowed in that none of the fiber systems is still completely devoid of myelin sheaths. Myelin sheaths are still sparse in the temporal and frontal areas. It is not until the end of the second postnatal year that an advanced state of myelination is seen in all subcortical areas. Histologically, myelination reaches completion in early adulthood.

1.10

1.10

Compositional Changes in the Developing Brain

The DNA content of brain is considered to be a reliable indicator of cell number. The period of cellular proliferation can, therefore, be followed by measuring the amount of DNA per brain volume. In human brain two major periods of cell proliferation have been detected by measuring DNA levels. The first period begins at 15–20 weeks of gestation and corresponds to neuroblast proliferation. The second period begins at 25 weeks of gestation and continues into the 2nd year of postnatal life. This latter period corresponds to multiplication of glial cells and includes a second wave of neuronogenesis, producing mainly cerebellar neurons. The ratio of protein to DNA indicates cell size. This ratio increases after neuronal division ends, reflecting in part the arborization of neuronal processes. The maximum ratio of protein to DNA is reached at 2 years of age. The outgrowth of neuronal axons and dendrites results in a rapid increase in total ganglioside content in the brain. Increasing lipid content indicates membrane formation with, in particular, an increase in quantity of axonal, dendritic, and myelin membranes. The increasing lipid content is associated with a concomitant decrease in water content. The most rapid increase in lipid content of the brain begins after the period of greatest increase of DNA and protein and is closely related to the onset of myelination. At birth, cerebral hemispheric white matter contains very little myelin and the white matter composition of neonates is very different from the composition of mature myelinated white matter. There is an important overall decrease in water content of the brain after birth and the change in water content is larger for white matter than for gray matter. The water content of neonatal gray matter is about 89% and of neonatal unmyelinated white matter about 87%, whereas the water content of adult gray matter is estimated to be 82% and of adult myelinated white matter 72%. The lipid composition of cerebral white mat-

Compositional Changes in the Developing Brain

ter at different ages is shown in Table 1.3. A major change is an increase in total lipid content, with a relative increase in glycolipids. One of these, cerebroside, is usually considered to be a marker for myelin as it is deposited at the same rate in the brain as myelin. However, cerebroside is not restricted to myelin and as much as 30% of it may be present in membranes other than myelin. There is a relative decrease (but absolute increase) in phospholipids in the white matter, which were relatively high in concentration in unmyelinated white matter and are relatively low in concentration in myelin. The relative contribution of cholesterol to total lipids remains constant, but the absolute cholesterol content of white matter increases with deposition of myelin. The changes in gray matter composition are much less important. Myelin deposition in gray matter is minor. The changes in white matter composition are not caused only by glial cell proliferation, growth of axons and dendrites, and myelin deposition, but also by some changes in myelin composition. The composition of the myelin first deposited is somewhat different from that in adults. The most important changes are an increase in cholesterol and glycolipids as a proportion of total lipid and a decrease in phospholipids. In the immature brain significant amounts of glucose are present in the glycolipids, whereas in a mature brain glycolipids are present mainly as galactolipids. In contrast to the modest decrease in total phospholipids, more marked variations in the relative contribution of individual phospholipids are found. Sphingomyelin and ethanolamine phosphoglycerides increase, whereas choline phosphoglycerides decline. The molar ratio of galactolipids and choline phosphoglycerides appears to be a sensitive marker of myelin maturation. In human unmyelinated white matter much of the cholesterol present is esterified. The same is true for cholesterol in newly formed myelin. During myelin maturation there is a decrease in the amount of cholesterol esters, and in adult white matter cholesterol is present almost entirely in the free form. The ratio of cholesterol to phospholipids in myelin increases after

Table 1.3. Lipid composition of human brain during development. From Svennerholm (1963) Lipid composition of (frontal) cerebral cortex

Lipid composition of (frontal) cerebral white matter

Age

2 months

1 year

5 years

2 months

1 year

5 years

Total lipidsa

28.4

31.3

29.5

29.5

49.6

58.2

Cholesterolb

21.5

19.8

19.3

26.4

25.0

24.4

76.8

7.6

75.6

66.1

53.4

49.8

1.8

2.6

4.1

7.5

21.6

25.8

Phospholipids Glycolipidsb a b

b

Expressed as percentage of dry weight Expressed as percentage of total lipid weight

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Chapter 1

Myelin and White Matter

birth and reaches the adult value at about 5 years of age. The ratio of galactolipids to phospholipids reaches the adult value at about the same time. During development the ganglioside composition of myelin becomes simplified. The polysialogangliosides decline and the monosialoganglioside GM1 content approaches about 90% of the total gangliosides with increasing age. The total ganglioside content remains constant. Maturation of myelin is accompanied by an increase in hydroxy fatty acids and saturated and monounsaturated fatty acids. Maturation of myelin is also accompanied by changes in the proteins. As the brain matures there is a change in occurrence of the major isoforms of the major myelin proteins. For example, initially, early in myelination, DM 20 is the principal isoform, whereas in adult brain DM 20 is present at much lower levels than the isoform PLP. With advancing development the contribution of PLP and MBP to myelin proteins shows a relative increase, whereas the high-molecular-weight proteins decrease. On the whole, the differences in chemical composition of immature myelin and adult myelin are not striking, which suggests that only subtle remodeling of myelin occurs in humans once myelination has started. The major difference between white matter early in life and in adult life seems to be the quantity of myelin rather than its quality.

1.11

1.12

Aging of Myelin

With increasing age, human brain weight decreases and water content increases. Levels of DNA and numbers of neurons in the cerebral cortex decrease significantly with aging. Little change is found in some regions, including the brain stem. Multiple morphological changes take place with increasing age. The most prominent neuronal changes are the appearance of senile plaques (areas of degenerating neuronal processes, reactive nonneuronal cells, and amyloid), increasing deposits of lipofuscin, and areas of neurofibrillary tangles. Synapses and dendrites are lost with aging. Neurotransmitter systems are also affected by aging. Acetylcholinesterase, choline acyltransferase, tyrosine hydroxylase, DOPA decarboxylase, and glutamic acid decarboxylase, enzymes involved in cholinergic, and dopaminergic and GABA-ergic transmission, respectively, show appreciable decreases. The total myelin content of white matter is reduced in old age. Low myelin concentrations of white matter most probably reflect the continuous loss of neurons with degeneration of axons and of the myelin sheaths. The lipid composition of myelin is quite constant during aging, with the possible exception of galactolipids, which tend to decline. Some differences are seen in the fatty acid composition of myelin phosphoglycerides and cerebrosides during aging. Myelin proteins do not undergo distinct quantitative changes in their relative proportions during old age.

Myelin Turnover

The principal features of myelin metabolism are its high rate of synthesis during the active stages of myelination, when each oligodendroglial cell makes more than three times its own weight of myelin per day, and its relative metabolic stability after the completion of myelination. Individual components turn over at quite different rates. There are conflicting data about the precise half-lives of the various myelin lipids and proteins. This is understandable, since there are several variables in the experimental design that have considerable influence on the observed, real or apparent, half-lives. However, some general conclusions can be formulated. The concept of relative long-term metabolic stability of most myelin components has been confirmed. Some components do turn over much faster than others, and all components show both a slow- and a fast-turnover component. The data indicate that newly formed myelin is catabolized faster than old myelin. Hence, myelin that has been deposited early in life appears to have a higher metabolic stability than newly synthesized myelin.

1.13

Function of Myelin

Nerve fibers transmit information to other nerve fibers and to receptors of effector organs. The information is transmitted via an electric impulse called the action potential, which is conducted in an all-ornone way, i.e., the impulse is propagated or not. More detailed information is provided by temporal and spatial summation of many action potentials within one nerve. Myelin plays an important role in the impulse propagation. It is an insulator, but more important is its function to facilitate conduction in axons. In a resting nerve fiber, polarization of the membrane exists: the inside is charged negatively compared with the outside. In an excited area the situation is reversed: the inside is charged positively compared with the outside. This is called membrane depolarization. There is a difference in potential between excited and adjacent resting fiber sections owing to the inversion of polarization in the excited area. In an effort to compensate this difference in potential, local circuits of currents flow into the active region of the axonal membrane through the axon and out through the adjacent, polarized sections of the

1.14

Myelin Disorders: Definitions

Fig. 1.10. Because of the myelin sheath, the conduction in a myelinated nerve fiber is saltatory, jumping from node to node

membrane. These local circuits depolarize the adjacent section of the membrane. As soon as this depolarization reaches the threshold of excitation, an action potential arises. These local circuits depolarize the adjacent section of membrane in continuous sequential fashion. Of course, the local circuits do not only flow in the direction of the impulse conduction. However, they cause no renewed excitation in the membrane that has just been excited because a temporary state of inexcitability, called the refractory period exists, which ensures that the fiber conducts the action potential in one direction and does not remain permanently excited. In unmyelinated fibers impulses are propagated in this way, and the entire membrane surface needs to be successively excited when an action potential travels along it. In myelinated fibers, the excitable axonal membrane is only exposed to the extracellular space at the nodes of Ranvier. In the area of the node of Ranvier, the axon is rich in sodium channels. The remainder of the axolemma is covered by the myelin sheath, which has a much higher resistance and much lower capacitance than the axonal membrane. When the membrane at the node is excited, the local circuit generated cannot flow through the high-resistance sheath, and therefore flows out through the next node of Ranvier and depolarizes the membrane there (Fig. 1.10). In this so-called saltatory conduction, the impulse jumps from node to node, whereby the conduction velocity is considerably increased. Saltatory nerve conduction is not only faster, but it also saves energy because only parts of the membrane need to depolarize and repolarize for impulse conduction. For conduction velocities in unmyelinated fibers equivalent to those in the fastest conducting myelinating fibers, impossibly large unmyelinated fibers and energy expenditures several orders of magnitude greater would be required. There are several factors that influence conduction velocity. Conduction velocity increases with increasing fiber diameter as a consequence of the smaller internal resistance, leading to an increased flow of current and thus shortening the time necessary for the excitation of the adjacent membrane section or the next node of Ranvier. Increase in myelin thickness, which accompanies increase in fiber diameter, also increases conduction velocity, mainly as the result of a change in myelin sheath capacitance. The internodal distance influences conduction velocity. With shorter internodal distances, the fibers behave more

and more like unmyelinated fibers while with longer internodal distances the current density at the next node of Ranvier becomes smaller. Consequently, there is an optimal ratio of internode distance to axon diameter. With increasing temperature conduction velocity increases, reaching a maximum at about 42 °C and decreasing thereafter.

1.14

Myelin Disorders: Definitions

‘Demyelination’ means, literally: loss of myelin and the literal interpretation of ‘demyelinating disorders’ is: disorders characterized by loss of myelin. The term demyelination is commonly used to indicate the process of losing myelin, which is caused by primary involvement of oligodendroglia or myelin membranes. Myelin loss that is secondary to axonal loss and simultaneous loss of axons and myelin sheaths is not usually included under the heading of demyelination. However, there is considerable confusion about the meaning of the terms demyelination and demyelinating disorders. Sometimes demyelination is used to mean all conditions in which loss of myelin occurs, irrespective of whether the myelin membrane was primarily affected or was broken down secondary to or at the same time as axonal loss. This is probably partly because it is not always clear whether the loss of myelin is primary or secondary in nature. The mutual dependence of axons and myelin sheaths is an important factor in this respect. Demyelination will eventually lead to axonal loss, and in the end axonal degeneration will lead to loss of myelin. Hence, using histological examination it may be very difficult to differentiate between primary and secondary myelin loss. Another confusing factor is that some disorders show evidence of simultaneous primary neuronal degeneration and primary demyelination. The random use of related terms, such as dysmyelination, myelinoclastic disorders, white matter disorders, leukoencephalopathies and leukodystrophies add to the confusion. Poser (1957) introduced the concept of ‘dysmyelination.’ He proposed dividing the disorders characterized by primary myelin loss into ‘myelinoclastic disorders’ and ‘dysmyelinating disorders’ (1961, 1978). He considered the myelinoclastic disorders to be the true demyelinating disorders, in which the myelin sheath is destroyed after having been normal-

15

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Chapter 1

Myelin and White Matter

ly constituted. Examples are multiple sclerosis and acute disseminated encephalomyelitis. The dysmyelinating disorders comprise those disorders in which “myelin is not formed properly, or in which myelin formation is delayed or arrested, or in which the maintenance of already formed myelin is disturbed.” Examples are metachromatic leukodystrophy and adrenoleukodystrophy. The idea behind the concept of dysmyelinating and myelinoclastic disorders is to distinguish between inherited disorders, especially inborn errors of metabolism, leading to disturbed myelination and myelin loss, and acquired disorders characterized by primary myelin loss. However, the definition of dysmyelinating disorders, as formulated by Poser, does not exclude all acquired disorders. There are many conditions characterized by a disturbance of myelination, and most of these are caused by external factors. Moreover, myelin may have been constituted normally in inherited disorders, only to be lost after many years. There are several definitions of the term ‘leukodystrophy.’ Seitelberger (1984) defines leukodystrophies as degenerative demyelinating processes caused by metabolic disorders. Morell and Wiesmann (1984) state that leukodystrophies are disorders affecting primarily oligodendroglial cells or myelin. The disorders have to be of endogenous origin with a pattern compatible with genetic transfer of a metabolic defect. The clinical criterion is a steadily progressive deterioration of function. Menkes (1990) defines leukodystrophies as a group of genetically transmitted diseases in which abnormal metabolism of myelin constituents leads to progressive demyelination. Common concepts in these definitions are demyelination and inborn errors of metabolism. Heritability is implied. As such, the leukodystrophies are identical with inherited demyelinating disorders. The terms ‘white matter disorders’ and ‘leukoencephalopathies’ comprise all disorders that selectively or predominantly involve the white matter of the CNS, irrespective of the underlying pathophysiologic mechanism and histopathologic basis. ‘White matter disorders’ is a literal translation of leukoencephalopathies. Sometimes these terms are used as if they are interchangeable with ‘demyelinating disorders,’ but usually they are used in the context of a wider range of disorders, characterized by either primary myelin loss or nonselective damage to myelin, axons and supportive tissue of the white matter. For instance, when the terms white matter disorder and leukoencephalopathy are applied in elderly people, ischemic white matter lesions are also implied, which do not involve or do not only involve a selective loss of myelin. In this book the following definitions are used: – ‘Demyelination’ is reserved for the process of myelin loss caused by primary and selective abnormality of either oligodendroglia or of the

–

–

–

– –

–

myelin membrane itself. ‘Demyelinating disorders’ are conditions characterized by demyelination. Examples: metachromatic leukodystrophy, multiple sclerosis. ‘Hypomyelination’ is reserved for conditions with a significant permanent deficit in myelin deposited. The most extreme variant of hypomyelination is amyelination. Example: Pelizaeus-Merzbacher disease. ‘Dysmyelination’, as the literal translation of the name implies, is reserved for conditions in which the process of myelination is disturbed, leading to abnormal, patchy, irregular myelination, sometimes but not necessarily combined with myelin loss. Examples: some amino acidopathies, damaged structure of unmyelinated white matter after perinatal hypoxia or encephalitis. ‘Retarded myelination’ is reserved for disorders in which the deposition of myelin is delayed, but progressing. Examples: inborn errors of metabolism with early onset, malnutrition, hydrocephalus. ‘Myelin disorders’ comprise all the above-mentioned conditions. ‘White matter disorders’ and ‘leukoencephalopathies’ can be defined as all conditions in which predominantly or exclusively white matter is affected. Either myelin or a combination of myelin and other white matter components is involved. Hence, white matter disorders comprise all myelin disorders, but also, for instance, white matter infections and infarctions, which may affect various white matter components nonselectively. ‘Gray matter disorders’ comprise all disorders in which neurons and axons are predominantly or exclusively affected.

1.15

Levels of Myelin Involvement

Both inherited and acquired myelin disorders can arise at the level of the myelin membranes or the oligodendroglial cells. As a consequence, the processes of myelin build-up, maintenance, and turnover may be disturbed. The processes of myelin build-up and deposition are highly complex and require the expression of many genes, the presence of many substances, the activity of many enzymes, optimal coordination of processes within the oligodendrocytes, and optimal cooperation with the environment. Complex and dynamic processes are particularly vulnerable, and the process of active myelination is easily disturbed. Some inborn errors of metabolism lead to a shortage of myelin components, and as a consequence to a disturbance of the process of myelination. An example is found in Pelizaeus-Merzbacher disease. Acquired dis-

1.16

orders, such as hormonal imbalances and severe malnutrition, can also lead to disturbed myelin build-up. A disturbance of myelin maintenance and turnover can lead to demyelination. In some inborn errors of metabolism, the basic enzymatic defect involves the breakdown of one of the myelin components. This component is trapped in the myelin sheath, and its concentration increases gradually. Finally, the myelin composition is altered to such a degree that the stability is lost, leading to demyelination. Examples are metachromatic leukodystrophy and globoid cell leukodystrophy. Of the acquired demyelinating disorders, toxic disorders in particular can lead to a disturbance of myelin maintenance and turnover. Myelin is rich in lipids and has a long half-life. Consequently, lipophilic substances easily accumulate in myelin, disturbing the stability of the myelin membrane and leading to demyelination. The myelin membrane may be intact and normal in appearance, biochemical composition, and function until it is attacked from the outside. This appears to be the case in several acquired demyelinating disorders, including inflammatory processes (e.g., multiple sclerosis, acute disseminated encephalomyelitis), metabolic disturbances (e.g., central pontine myelinolysis, Marchiafava-Bignami syndrome) and hypoxia (delayed posthypoxic demyelination). Demyelinating disorders can also arise at the level of the oligodendrocytes. Damage to oligodendrocytes can lead to disturbances of myelin build-up, maintenance, and turnover. In some inborn errors of metabolism storage of unwanted material occurs, ultimately leading to dysfunction and death of oligodendrocytes. In globoid cell leukodystrophy the toxic substance psychosine is thought to lead to oligodendroglial cell death and myelin loss. In acquired demyelinating disorders, selective oligodendroglial cell death can also occur. This is the case, for instance, in progressive multifocal leukoencephalitis, in which viral infection of oligodendrocytes is present. Of course, in many disorders more than one mechanism of myelin affection is involved. In disturbances of myelin build-up the myelin that is laid down may have an abnormal composition and configuration. Delayed myelination, dysmyelination, and early demyelination can occur at the same time. In other disorders, oligodendroglial cell death and myelin breakdown independent of oligodendroglial cell death occur simultaneously.

1.16

Biochemical Changes Related to Demyelination

Demyelinating disorders can be subdivided into two large categories: inherited disorders due to an inborn error of metabolism and acquired disorders sec-

Biochemical Changes Related to Demyelination

ondary to adverse factors in the internal or external environment. Biochemical analysis of myelin and white matter demonstrates an abnormal composition of the same type in many demyelinating disorders of diverse etiology. The concept of the nonspecific process of myelin breakdown suggests that when maintenance of normal myelin is no longer possible it follows a stereotyped route to complete destruction, largely irrespective of the initiating causes. The etiological factors can be wallerian degeneration, infections such as subacute sclerosing panencephalitis, or intoxications with such agents as triethyltin, but also inherited metabolic diseases, e.g., X-linked adrenoleukodystrophy, Canavan disease, and many other demyelinating diseases. In inherited diseases affecting myelin metabolism, biochemical analysis often reveals certain abnormalities superimposed on the nonspecific compositional abnormalities. These abnormalities are specific for a particular disorder or type of disorders. For instance, an elevation of the very long-chain fatty acids of the cholesterol esters is specific for a subgroup of peroxisomal disorders, including Xlinked adrenoleukodystrophy. An elevation of sulfatide is found in the white matter of patients with metachromatic leukodystrophy. The specific biochemical abnormalities of myelin in the various disorders are discussed in separate chapters. Here we will limit our discussion to the nonspecific myelin abnormalities. It should, however, be kept in mind that the degree of abnormality varies considerably among different diseases and among different cases of the same disease depending on the stage of disease. In degenerating myelin, the proportion of total protein to total lipid is not usually dramatically altered, but the proportions of individual lipids are abnormal. The amount of galactolipids is decreased, and cerebroside is usually much more severely affected than sulfatide. Moderate decreases of ethanolamine phosphoglycerides (mostly plasmalogen) are common. The amount of unesterified cholesterol is increased, often strikingly so, constituting almost half or even more than half the total lipid content, in contrast to approximately 27% in normal myelin. No esterified cholesterol is found in the degenerating myelin sheath. Such abnormal myelin is an intermediate form between normal myelin and completely catabolized myelin. The abnormalities are a result of partial degradation. The compositional changes in white matter as a whole depend primarily on the extent of myelin loss and only secondarily on changes in myelin composition. Typical white matter changes are increased water content and reduced lipid-to-protein ratios, with specific decreases in such major myelin constituents as cholesterol, cerebroside, sulfatide, and ethanolamine phosphoglycerides. In addition, there

17

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Chapter 1

Myelin and White Matter

is an increase in cholesterol esters in whole white matter in a number of diseases, but not in all. The fatty acid composition of these esters is different from that of the small amount of esters normally present in white matter, but closely resembles the fatty acids linked to the 2-position in phosphatidylcholine. It is assumed that these esters come from myelin cholesterol and phosphoglyceride fatty acids. The presence of cholesterol esters is taken as evidence of an active phagocytosis of myelin and, as such, as an indicator of active demyelination, but the absence of cholesterol esters does not mean that there is no active demyelination. The presence of cholesterol esters is reflected in sudanophilia on histological examination. It is probable that the mechanism of breakdown is slightly different in sudanophilic myelin destruction and nonsudanophilic breakdown.

1.17

Demyelination: Loss of Function

In normal myelinated nerve fibers, conduction is saltatory and internodal conduction time is fairly regular. The conduction in demyelinated axons differs dramatically from that in normal fibers. The impulse conduction may be either saltatory or continuous. If the impulse conduction remains saltatory, the internodal conduction time varies widely from internode to internode. The internodal conduction time is prolonged by increased leakage of current between the nodes and by depression of excitability of the nodal membrane. There is, therefore, a decreased current generation capacity and an increased threshold for excitation. In demyelinated fibers, a very slow continuous conduction (about 5% of the conduction velocity of normal fibers) may be seen over short stretches. A so-called safety factor for impulse conduction can be calculated. If the required minimum is not reached, impulse propagation is blocked. Furthermore, the refractory period of demyelinated fibers is increased, which leads to failure to transmit high-frequency trains of impulses. It is clear that demyelination, depending on its extent and severity, can lead to serious loss of function. However, damage to neurons, although not as prominent as destruction of myelin, may also play a part in the functional deficit. Especially in inborn errors of metabolism, substances may also accumulate in the membranes of axons, and in this way axonal dysfunction may arise, contributing to the functional loss.

1.18

Remyelination

Remyelination in the CNS is possible. Remyelinated fibers can be recognized because the internodes are too short and the myelin sheath is too thin for the size

of the axon. Even with time, there is no restitution of the normal axon-to-myelin ratio. The new myelin sheath in itself is normal with normal lamellar periodicity. Remyelination also occurs when the demyelinated lesion was depleted of oligodendrocytes. The necessary supply of oligodendrocytes is provided by proliferation of remaining, mature oligodendrocytes and possibly also by proliferation of progenitor cells followed by differentiation into myelinating oligodendrocytes. It is often found that axons tend to be remyelinated in clusters, suggesting that a single oligodendrocyte myelinates many axons in the vicinity. Remyelination among the demyelinating disorders is variable. The most successful examples of remyelination are found in those conditions in which demyelination has occurred rapidly, irrespective of whether the condition is acute and monophasic or relapsing and remitting. Remyelination is much more limited in demyelinating disorders with a protracted, chronic course. The presence of additional axonal damage has an adverse effect on potential remyelination. Some local factors, when present, may stimulate remyelination. There is evidence that epidermal growth factor, interleukin-2, immunoglobulins, platelet-derived growth factor and insulin growth factors may stimulate survival and proliferation of oligodendrocytes and remyelination. In contrast, the presence of T-CD4+ immune cells interferes with remyelination.

1.19

Retarded Myelination

The process of myelination is both complex and protracted. This means that the process is vulnerable to adverse factors over a long period of time, namely from the second half of gestation up to the end of the 1st or 2nd year of life. Many stress factors that act on the incompletely myelinated brain and interfere with the process of myelination do not have such a profoundly adverse effect on the mature brain. For instance, in the mature brain in which myelination is complete, stress factors such as malnutrition or hormonal imbalances will not appreciably reduce the amount of myelin. Well-known factors potentially leading to retardation of myelination include malnutrition, hormonal imbalances (growth hormone deficiency, hypothyroidism, hypocortisolism, hypercortisolism), prenatal exposure to toxins (alcohol, anticonvulsants), chromosomal abnormalities, pre- and postnatal asphyxia, cerebral infections, hydrocephalus, and inborn errors of metabolism with early onset. It is important to realize that myelination is dependent on normal function and interaction of oligodendrocytes, neurons, and astrocytes and that retarda-

1.19

tion of myelination can be related to dysfunction of oligodendroglia and myelin, dysfunction of astrocytes, or neuronal dysfunction. Cerebral infections and perinatal asphyxia may lead to disturbance of myelination through white matter damage or through neuronal damage. In addition, inborn errors of metabolism may disturb the process of myelination either directly, at the level of the oligodendrocyte or myelin sheath, or indirectly, at the level of the astrocyte or neuron. It is important to realize that a disturbance of myelination may also be seen in neuronal disorders with early onset. For instance, in Menkes

Retarded Myelination

disease, Alpers disease, infantile neuronal ceroid lipofuscinosis, infantile GM1 gangliosidosis, and infantile GM2 gangliosidosis, all of which are neuronal disorders, myelination is severely retarded and the white matter looks severely abnormal on MRI, whereas in the later onset variants of neuronal ceroid lipofuscinosis, GM1 gangliosidosis and GM2 gangliosidosis these white matter abnormalities do not occur. It has been demonstrated that myelination is an expression of the functional maturity of the brain. Retarded myelination is an expression of immaturity or dysfunction.

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Chapter 2

Classification of Myelin Disorders

The history of classifications of myelin disorders shows how each classification reflects the state of scientific development of its time. A revised classification based on the most recent scientific insights is proposed at the end of this chapter. Interest in CNS myelin dates back to the nineteenth century. In 1854, Virchow was the first to suggest the name ‘myelin’ when he described the sheaths around axons in the CNS. It is not certain when Schwann (1810–1882) first described the cells since named after him, which supply the myelin sheaths around the peripheral nerve fibers. In 1878, Ranvier described the nodes that have since been given his name in his “Leçons sur l’histologie du système nerveux.” He believed that the nodes prevented the essentially liquid myelin from flowing to the bottom of the nerve fiber (axon). But despite this conviction, he showed considerable insight into the functional role of the myelin sheath, both as an insulator and as a facilitatory agent in CNS functions. It was not until 1960–1961 that the role of the oligodendrocyte in the formation of myelin in the CNS became clear, and this was due to the work of Bunge. During the nineteenth century and early twentieth century, important progress was made in the clinical and histological description of several demyelinating disorders. Multiple sclerosis was recognized as a clinical disease entity, and the characteristic histological abnormalities, in the form of multiple demyelinated, sclerotic plaques within otherwise normal white matter, were described. Prominent names in this development are Carswell (1838), Cruveilhier (1835–1842) and Charcot (1868). In 1897, Heubner described a rare neurological disease in children, using the name diffuse sclerosis as opposed to multiple sclerosis. The disease was histologically characterized by diffuse demyelination of the cerebral white matter and eventual striking hardening of the white matter. Since that time, the term ‘diffuse sclerosis’ has commonly been used to describe cerebral diseases with diffuse demyelination and sclerotic hardening of the cerebral white matter. Pelizaeus in 1899 and Merzbacher in 1910 reported on a chronic progressive familial type of diffuse sclerosis. In 1912, Schilder described a nonfamilial case of more acute diffuse cerebral demyelination in a child, and he suggested the name encephalitis periaxialis diffusa rather than diffuse sclerosis. In this case, more prominent signs of inflammation and a less symmet-

rical distribution were observed than in the familial cases described up to that time. Schilder considered that this disease was a nosological and histological entity related to multiple sclerosis and thought there were acute and chronic variants of diffuse sclerosis just as there were acute and chronic types of multiple sclerosis. Since Schilder’s time a number of familial neurological disorders have been recognized, which were histologically characterized by diffuse demyelination and again presented under the heading of diffuse sclerosis. In 1916, Krabbe described a familial infantile form of diffuse sclerosis.Another familial variant, with a later onset and a less rapid progression, was reported in 1925 by Scholz and in 1928 by Bielschowsky and Henneberg. Scholz noted that in this case the myelin breakdown products did not show the usual (orthochromatic) staining properties, but stained metachromatically. In 1921, Neubürger drew attention to the fact that the term diffuse sclerosis was being applied to several very different disease entities, and he proposed a distinction between inflammatory and degenerative forms. In 1928, Bielschowsky and Henneberg suggested the name ‘hereditary progressive leukodystrophies’ for the degenerative forms of diffuse sclerosis and devised the following classification, based on the time of onset of the disease and its clinical course: 1. Infantile type of Krabbe 2. Subacute juvenile type of Scholz 3. Chronic type of Pelizaeus-Merzbacher Hallervorden (1940) recognized that there were endogenous and exogenous factors causing diffuse demyelination and that a distinction was possible between disorders in which demyelination is invariably present and forms a specific part of the disease and disorders in which demyelination occurs occasionally and is nonspecific. He proposed a more extended classification based on these subdivisions: I. Endogenous central demyelination A. Specific demyelinating diseases a. Diffuse sclerosis of Krabbe and Scholz b. Pelizaeus-Merzbacher disease B. Nonspecific occasional demyelination e.g. Tay-Sachs disease II. Exogenous central demyelination A. Specific demyelinating diseases

Classification of Myelin Disorders

a. Inflammatory types: – Disseminated sclerosis (= multiple sclerosis) – Diffuse sclerosis (Schilder) – Concentric sclerosis (Balò) – Neuromyelitis optica (Devic) – Encephalomyelitis disseminata – Infectious encephalitis b. Toxic-metabolic types: – Funicular myelosis (= vitamin B12 deficiency) – Marchiafava-Bignami disease B. Nonspecific occasional demyelination a. Disturbances of blood flow, e.g. subcortical atherosclerosis (= Binswanger disease) b. Edema c. Toxic processes (carbon monoxide) d. Tumors Until that time, distinctions between different diseases had been based on neuropathological and clinical aspects of different demyelinating disorders. From about this time onwards, histochemical methods and chemical analyses became increasingly important. The classification proposed by Blackwood in 1957 is a reflection of this development. It is based not only on morphological but also on histochemical differences between various subgroups of diffuse sclerosis: I Disseminated sclerosis (= multiple sclerosis) II Diffuse demyelinating cerebral sclerosis 1. With replacement of myelin by sudanophilic lipid a. With large bilateral cerebral plaques b. With concentric demyelination (Balò type) 2. a. With replacement of myelin by metachromatic PAS-positive lipid (Norman type or Scholz type) b. With associated degeneration of interfascicular oligodendroglia (Greenfield type) 3. With replacement of myelin by nonmetachromatic PAS-positive lipid (globoid cell or Krabbe type) Meanwhile, insight into normal biochemistry and into mechanisms of biochemical derangement was growing. The concept of hereditary inborn errors of metabolism caused by an enzyme defect leading to dysfunction and breakdown of myelin started to emerge. Fölling (1934) reported 10 patients in the same family with mental retardation and phenylpyruvic acid in their urine. Jervis discovered in 1947 that the underlying metabolic defect in phenylketonuria is a deficiency of phenylalanine hydroxylase. In 1955, Diezel found that the lipids stored in the globoid cells in Krabbe disease have very similar properties to those of cerebroside. In 1970, Suzuki

and Suzuki were the first to propose a deficiency of galactocerebrosidase as the underlying biochemical cause of this disease. Advances in histochemistry also made it possible to discover the basis of metachromatic leukodystrophy. Metachromasia had already been found by Alzheimer in 1910, by Scholz in 1925, and later by Von Hirsch and Peiffer (1955 and 1957). Edgar (1955) pointed out that this condition was characterized by a remarkable elevation of white matter hexosamine. In 1964, Austin et al. demonstrated a decrease in arylsulfatase A activity in metachromatic leukodystrophy. The enzyme defects of an increasing number of hereditary diseases were detected, whereas in other cases the precise enzyme defect could not yet be discovered but typical biochemical abnormalities characteristic for the diseases could be demonstrated. The increased insight into hereditary metabolic disorders and the ongoing ability to distinguish different hereditary and acquired demyelinating disorders on the basis of a combination of clinical, histological and biochemical data, were reflected in the classification proposed by Raine (1984). Raine distinguished five main categories: I Acquired inflammatory and infectious diseases of myelin 1. Multiple sclerosis 2. Multiple sclerosis variants (Schilder, Balò, Devic) 3. Acute disseminated encephalomyelitis 4. Acute hemorrhagic leukoencephalopathy 5. Progressive multifocal leukoencephalopathy II Hereditary metabolic disorders of myelin 1. Metachromatic leukodystrophy 2. Globoid cell leukodystrophy (Krabbe) 3. Adrenoleukodystrophy 4. Refsum disease 5. Pelizaeus-Merzbacher disease 6. Dysmyelinogenetic leukodystrophy (Alexander) 7. Spongy degeneration (Canavan) 8. Phenylketonuria III Acquired toxic-metabolic diseases of myelin 1. Hexachlorophene neuropathy 2. Hypoxic encephalopathy IV Nutritional diseases of myelin 1. Vitamin B12 deficiency 2. Central pontine myelinolysis 3. Marchiafava-Bignami disease V Traumatic diseases of myelin 1. Edema 2. Compression 3. Barbotage 4. Pressure release In this classification, four of the five categories involve acquired demyelinating disorders, and only one

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Chapter 2

Classification of Myelin Disorders

involves hereditary demyelinating disorders. The logical continuation of this development is a refinement of the classification of hereditary demyelinating disorders. For instance, in some diseases the inborn error affects the metabolism of amino acids, and in other diseases it affects the lipid metabolism. A further subdivision can be made among the disorders of lipid metabolism according to the type of lipids involved. In 1987, Poser proposed a classification of hereditary myelin disorders based on the biochemical group of compounds whose metabolism is disturbed. He distinguished six categories: 1. Disorders of glycosphingolipid metabolism a. Ganglioside: GM1 and GM2 gangliosidoses, hematoside sphingolipodystrophy b. Sulfatide: metachromatic leukodystrophy c. Galactocerebroside: globoid cell leukodystrophy 2. Disorders of phosphosphingolipid metabolism a. Sphingomyelin: Niemann-Pick disease 3. Disorders of fatty acid metabolism a. Adrenoleukodystrophy 4. Disorders of amino acid metabolism a. Phenylalanine: phenylketonuria b. Branched-chain amino acids: maple syrup urine disease c. Many other amino acidopathies 5. Multiple abnormalities a. Mucosulfatidosis 6. Unknown abnormalities a. Idiopathic spongy sclerosis (Canavan) b. Fibrinoid leukodystrophy (Alexander) c. Pelizaeus-Merzbacher disease d. Idiopathic sudanophilic leukodystrophy An important development during the last few decades concerns the knowledge of subcellular structures, their role in normal metabolism and the consequences of their dysfunction. Major subcellular structures are the nucleus, lysosomes, mitochondria, peroxisomes, cytoplasm matrix, smooth and rough endoplasmic reticulum, Golgi apparatus, ribosomes, and microtubules. Demyelinating disorders have been described as resulting from nuclear, lysosomal, mitochondrial, peroxisomal, and cytoplasmic enzyme dysfunctions. Classification of hereditary demyelinating disorders according to the subcellular localization of the underlying metabolic defect stresses the clinical, biochemical, and neuropathological similarities within one category and the differences between the different categories. For the same reason, it is preferable to classify the acquired demyelinating disorders according to their underlying causes into noninfectious–inflammatory, infectious–inflammatory, toxic–metabolic, hypoxic–ischemic and traumatic. A number of

disorders remain for which the primary defect is largely or completely unknown. An important point is that with increasing scientific insight the difference between ‘primary demyelinating disorders’ or ‘myelin disorders’ and ‘primary neuronal or axonal degenerative disorders’ is becoming less clear. It is evident now that in a classic ‘primary demyelinating disorder’ such as multiple sclerosis, early and important axonal damage and loss occurs. Some disorders, such as vanishing white matter, are characterized by serious loss of both axons and myelin sheaths, and it may be that neither of them is really ‘primary.’ Several ‘primary neuronal disorders’ with infantile onset are accompanied by prominent white matter abnormalities, which are not seen in the later onset forms of the same disorders. This is the case, for instance, in infantile GM2 gangliosidosis, infantile GM1 gangliosidosis, and infantile neuronal ceroid lipofuscinosis. We agree with Hallervorden and Poser that these disorders must have a place in a classification of myelin disorders, just as they also belong in a classification of neuronal disorders. Because of the difficulties in distinguishing ‘primary neuronal/axonal disorders’ from ‘primary myelin disorders,’ we use the neutral word ‘leukoencephalopathies’ to comprise all disorders that predominantly affect the white matter of the CNS, irrespective of whether or not the white matter abnormalities are the result of a primary abnormality of myelin. We propose the following classification of leukoencephalopathies: I Hereditary disorders 1. Lysosomal storage disorders a. Metachromatic leukodystrophy b. Multiple sulfatase deficiency c. Globoid cell leukodystrophy (Krabbe disease) d. GM1 gangliosidosis e. GM2 gangliosidosis f. Fabry disease g. Fucosidosis h. Mucopolysaccharidoses i. Sialic acid storage disorders j. Neuronal ceroid lipofuscinoses k. Polyglucosan body disease 2. Peroxisomal disorders a. Peroxisome biogenesis defects b. Bifunctional protein deficiency c. Acyl-CoA oxidase deficiency d. X-linked adrenoleukodystrophy and adrenomyeloneuropathy e. Refsum disease 3. Mitochondrial dysfunction with leukoencephalopathy a. Mitochondrial myopathy encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

Classification of Myelin Disorders

4. 5. 6.

7.

b. Leber hereditary optic neuropathy c. Kearns-Sayre syndrome d. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) e. Leigh syndrome and mitochondrial leukoencephalopathies f. Pyruvate carboxylase deficiency g. Multiple carboxylase deficiency h. Cerebrotendinous xanthomatosis Nuclear DNA repair defects a. Cockayne syndrome b. Trichothiodystrophy with photosensitivity Defects in genes encoding myelin proteins a. Pelizaeus-Merzbacher disease b. 18q– syndrome Disorders of amino acid and organic acid metabolism a. Phenylketonuria b. Glutaric aciduria type 1 c. Propionic acidemia d. Nonketotic hyperglycinemia e. Maple syrup urine disease f. 3-Hydroxy 3-methylglutaryl-CoA lyase deficiency g. Canavan disease h. L-2-Hydroxyglutaric aciduria i. D-2-Hydroxyglutaric aciduria j. Hyperhomocysteinemias k. Urea cycle defects l. Serine synthesis defects Miscellaneous a. Sulfite oxidase deficiency and molybdenum cofactor deficiency b. Galactosemia c. Sjögren-Larsson syndrome d. Lowe syndrome e. Wilson disease f. Menkes disease g. Premutation fragile X h. Hypomelanosis of Ito i. Incontinentia pigmenti j. Alexander disease k. Giant axonal neuropathy l. Megalencephalic leukoencephalopathy with subcortical cysts m. Congenital muscular dystrophies n. Myotonic dystrophy type I o. Proximal myotonic dystrophy p. X-linked Charcot-Marie-Tooth disease q. Oculodigitodental dysplasia r. Vanishing white matter s. Aicardi-Goutières syndrome and variants t. Leukoencephalopathy with calcifications and cysts u. Leukoencephalopathy with involvement of brain stem and spinal cord and elevated white matter lactate

v. Hypomyelination with atrophy of the basal ganglia and cerebellum w. Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids x. Dentatorubropallidoluysian atrophy y. Amyloid angiopathy z. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) aa. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) bb. Nasu-Hakola disease cc. Pigmentary orthochromatic leukodystrophy dd. Adult autosomal dominant leukoencephalopathies II Acquired myelin disorders 1. Noninfectious-inflammatory disorders a. Multiple sclerosis and variants b. Acute disseminated encephalomyelitis and acute hemorrhagic encephalomyelitis 2. Infectious-inflammatory disorders a. Subacute HIV encephalitis b. Progressive multifocal leukoencephalitis c. Brucellosis d. Subacute sclerosing panencephalitis e. Congenital cytomegalovirus infection f. Whipple disease g. Other infections 3. Toxic-metabolic disorders a. Toxic leukoencephalopathies (endogenous and exogenous toxins) b. Central pontine and extrapontine myelinolysis c. Salt intoxication d. Marchiafava-Bignami syndrome e. Vitamin B12 deficiency, folate deficiency f. Malnutrition g. Paraneoplastic syndromes h. Posterior reversible encephalopathy syndrome 4. Hypoxic–ischemic disorders a. Posthypoxic–ischemic leukoencephalopathy of neonates b. Delayed posthypoxic–ischemic leukoencephalopathy c. Subcortical arteriosclerotic encephalopathy (Binswanger disease) d. Vasculitis e. Vasculopathy of other origin 5. Traumatic disorders a. Diffuse axonal injury The category of so-called cytoplasmic enzyme deficiencies is not listed in this classification. The rationale is that such a disease category would represent a

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Chapter 2

Classification of Myelin Disorders

very heterogeneous group of disorders as the cytoplasm contains enzymes of many different biochemical pathways. This is why it is preferable in this case to make a subdivision according to the specific metabolic pathway involved. However, the group of amino acidopathies and organic acidopathies is heterogeneous, as some of the enzymes concerned are in fact mitochondrial or peroxisomal. In view of the relative homogeneity in clinical presentation, diagnostic tests, and treatment strategies, we prefer to place them in one category, which is also in keeping with general practice.

Over the years, this classification has been modified repeatedly. The basic defects of a steadily increasing number of hereditary myelin disorders have been elucidated, and the number of ‘unknown’ disorders is decreasing. Even the present classification of leukoencephalopathies is provisional and will have to be adapted in the future to take account of expanding scientific insights. The structure of the proposed classification allows easy integration of further information.

Chapter 3

Selective Vulnerability

Within the context of this book, attention is paid to the concept of selective vulnerability, for two reasons. In the first place, the recognition of patterns of selective vulnerability contributes to the understanding of pathogenetic mechanisms of cerebral damage in the different disorders. In the second place, the recognition of patterns of selective vulnerability is of practical value and contributes to the diagnostic specificity of MRI interpretation. The concept of MRI pattern recognition is based on the concept of selective vulnerability. Spielmeyer (1925), Meyer (1936), Vogt and Vogt (1937) and Scholz (1953) introduced the concept that, apart from the distribution of infarctions in vascular territories and border zones, specific brain regions may be more vulnerable to ischemic injury than others. Spielmeyer tried to find an explanation for this difference by suggesting that variations in the local vascular supply facilitated vascular insufficiency in such areas as the hippocampus. As we now know, structures of the CNS have different degrees of sensitivity to oxygen deprivation. Of the cellular elements of the CNS, the neurons are the most vulnerable, followed by oligodendroglia, astroglia and, finally, endothelial cells. Within the group of neurons, some neuronal cell types are more vulnerable to hypoxic–ischemic damage than others. Structures more liable to damage by hypoxia–ischemia are the hippocampus, the Purkinje cells of the cerebellum, the striatum, and the neocortex. Within these structures there is a further order of sensitivity among the different cell types, as indicated in Table 3.1. Vogt and

Fig. 3.1. Carbon monoxide intoxication in a 42-year-old male patient.The T2-weighted images show the hyperintense lesion in the globus pallidus

Table 3.1. Hierarchy of selective vulnerability to hypoxic–ischemic conditions for different CNS structures Structure

Hierarchy of vulnerability

Hippocampus Cerebellum

CA1 > CA4 > CA3 > granule cells Purkinje cells > stellate or basket cells > granule cells > Golgi cells Small to medium-sized neurons > large neurons Layers 3, 5, 6> layers 2, 4

Striatum Neocortex

Vogt (1937) suggested the physicochemical properties of specific neurons as the reason for the unequal vulnerability to disease and introduced the term ‘topistic areas.’ The ‘pathoclisis’ of a region is determined by specific chemical and physical properties, which are also the essence of the specific function of that region. Meyer (1936) stated that it was too simple to assume that only the physicochemical or local vascular factors were involved, and that other factors should also be taken into consideration. Such factors, according to him, are the nature of the noxious agent, the ‘porte d’entrée,’ the path of distribution, and developmental factors. Meyer initiated a discussion about the pathophysiology of the selective involvement of the basal ganglia in some disorders. He drew attention to the selective involvement of the globus pallidus in carbon monoxide intoxication (Fig. 3.1), which is more constant than the involvement of other structures, such as the pars compacta of the substantia nigra, cornu ammonis, Purkinje cell layer of the cerebellum, and

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Chapter 3

Selective Vulnerability

Fig. 3.2. Pyruvate dehydrogenase complex deficiency in an 8-year-old boy.The images depict selective involvement of the globus pallidus and the substantia nigra, the latter probably due to transsynaptic degeneration

Fig. 3.3. Kernicterus in a 1-week-old neonate.The upper row shows a proton density and a T2-weighted image at the level of the basal ganglia. The lower row shows a FLAIR and a T1-weighted image at the same level.The images show the typical involvement of the globus pallidus and the pulvinar.The globus pallidus lesions are hardly seen on the T2weighted image, but the T2-weighted image shows the abnormal signal of the pulvinar more clearly than the other images. It is not completely clear why the globus pallidus has a high signal on the T1-weighted image

cerebral white matter. However, the globus pallidus may also be selectively involved in respiratory failure, mitochondrial defects (Fig. 3.2), kernicterus (Fig. 3.3), and intoxications with ether, potassium cyanide, and dinitrobenzol (leading to methemoglobinemia). Meyer, who was well aware of the differences of these conditions, suggested the common factor responsible for the involvement of the globus pallidus was interference with oxygen transport by either severe hypoxia or anemia or ‘inhibition of the respiratory en-

zymes,’ showing that awareness of something like the mitochondrial system already existed. This discussion was renewed recently by Johnston and Hoon (1999), who compared three conditions in children: pyruvate dehydrogenase complex deficiency with a Leigh-like presentation and lesions in the basal ganglia (Fig. 3.2); kernicterus with abnormalities prominently involving the globus pallidus but also involving the nucleus subthalamicus (Fig. 3.3); and posthypoxic-ischemic encephalopathy caused by

Selective Vulnerability

Fig. 3.4. T2-weighted series depicting the late pattern of acute profound ischemia in a term neonate.There is a triangular gliosis in the perirolandic white matter, with focal ulegyria of the cortex. In addition, there are lesions in the dorsal part of the putamen, the ventrolateral part of the thalamus, and the dentate nucleus

acute profound asphyxia in a term neonate with basal ganglia abnormalities typically located in the dorsal part of the putamen and the ventrolateral part of the thalamus (Fig. 3.4). The authors try to explain the difference in location of the lesion by arguing that the neuronal circuit involved in asphyxia is different from that involved in mitochondrial disorders and kernicterus. They suggest that bilirubin toxicity is affecting mitochondria in the globus pallidus, in this way providing a link with mitochondrial respiratory chain disorders. They reason that, on the other hand, glutamate toxicity in particular affects the putamen, thalamus, and cerebral cortex in hypoxic–ischemic conditions. In an earlier edition of this book (1995) we made the same observation as Johnston and Hoon in 1999: carbon monoxide intoxication affects the globus pallidus preferentially and most consistently, whereas hypoxia in cases of near-drowning or strangulation preferentially involves the putamen and caudate nucleus (Figs. 3.5, 3.6), layers 3, 5 and 6 of the cerebral cortex, and Purkinje cells in the cerebellar cortex. In carbon monoxide intoxication we assumed a mitochondrially mediated effect on the globus pallidus. However, our hypotheses are apparently too simple, and important details of the pathophysiology of the development of brain lesions elude our understand-

ing. It is a fact, for instance, that in inherited mitochondrial encephalopathies with cellular energy failure the putamen and caudate nucleus are usually preferentially affected and not the globus pallidus (Fig. 3.7). With this observation, it is questionable whether the preferential involvement of the globus pallidus in carbon monoxide intoxications can be blamed on mitochondrial dysfunction. It is clear that hypoxia–ischemia, some toxic substances, some metabolites increased to toxic levels in inborn errors of metabolism, hypoglycemia, and some nutritional deficiencies (e.g. thiamine deficiency) all interfere with mitochondrial function. In more general terms, regardless of its cause, energy depletion will lead to failure of mitochondrial oxidative phosphorylation,ATP depletion, accumulation of glutamate and other excitatory amino acids, opening of ion channels, accumulation of Ca2+ in the cell, activation of polyunsaturated fatty acid cascades and, finally, cell death. It would be logical if all forms of cerebral energy failure, either caused by hypoxia–ischemia, hypoglycemia, primary mitochondrial dysfunction or deficiencies, intoxications and inborn errors of metabolism mediated through mitochondrial dysfunction, would lead to selective involvement of the same brain structures. This, however, is not true. It is correct that sometimes the pattern of abnormalities

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Chapter 3

Selective Vulnerability

Fig. 3.5. A 3-year-old boy suffered near-drowning and prolonged attempts at resuscitation. Not only the striatum is involved, but also the globus pallidus, the thalamus, the hippocampus, and tracts in the brain stem. In addition, cortical laminar necrosis is seen in the higher slices

Fig. 3.6. A young woman has been anoxic for at least 3 min during resuscitation.The FLAIR images show that the lesions are confined to the striatum

Fig. 3.7. Leigh syndrome in an 8-month-old boy, caused by the Leigh/NARP mutation with a high percentage of heteroplasmy.There are lesions in the putamen and caudate nucleus

Selective Vulnerability

Fig. 3.8. Leigh syndrome related to a complex I deficiency in a 3-year-old boy.The MR pattern shows symmetrical lesions in the wall of the third ventricle, the dorsal part of the midbrain, and the dentate nucleus.The mamillary bodies are not affected

Fig. 3.9. Pattern of thiamine deficiency, which is very similar to that of Leigh syndrome (cf. Fig. 3.8). An important difference is that in thiamine deficiency the mamillary bodies are involved in most cases, whereas in Leigh syndrome they are not

in Leigh syndrome (Fig. 3.8) and the pattern of thiamine deficiency (Fig. 3.9) are very similar, although the lesions in the mamillary bodies, typical for thiamine deficiency, are consistently lacking in Leigh syndrome, but most different causes of energy failure lead to very different patterns of abnormalities (Figs. 3.1, 3.2, 3.4–3.13). The biochemical explanation for the differences in selectively involved structures is unclear, and apparently our present models are too simplistic.

Apart from mitochondrially mediated disorders, other conditions may involve the basal ganglia predominantly or selectively. This is the case in many inborn errors of metabolism other than mitochondriopathies, in hepatic failure (Fig. 3.14), and in classic Creutzfeldt-Jakob disease (Fig. 3.15). The explanations must be different from those so far proposed. In glutaric aciduria type I there is typically involvement of the putamen and caudate nucleus, but not of the cortical layers and Purkinje cells. The neo-

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Chapter 3

Selective Vulnerability

Fig. 3.10. Typical involvement of the parieto-occipital region in a neonate with hypoglycemia; in the worst cases this leads to multicystic encephalopathy restricted to this region. Selective vulnerability of this region for hypoglycemia disappears with age, indicating the influence of morphologic and biochemical maturation of the brain on the pattern of resulting damage

Fig. 3.11. Series of T2-weighted images showing the classic triad of late sequelae of recurrent or prolonged partial hypoxia–ischemia in a preterm neonate: periventricular leukomalacia.There is a periventricular rim of signal abnormality; the ventricles have an irregular border, especially in the trigonum and occipital horns; and there is loss of white matter volume, the sulci in the parieto-occipital region abutting the ventricular walls

striatal dysfunction and degeneration in glutaric aciduria type I was demonstrated to be at least partly related to N-methyl-D-aspartate receptor-mediated neurotoxicity of the endogenously accumulating 3-hydroxyglutarate (Kolker et al. 2002). In methylmalonic academia, as in carbon monoxide intoxication, there is preferential involvement of the globus pallidus. In this disease the selective lesion is due to accumulation of methylmalonate and alter-

native metabolites. Methylmalonate has been implicated in inhibition of respiratory chain complex II, and it also inhibits the tricarboxylic cycle (Okun et al, 2002). Preference for the (neo)striatum in CreutzfeldtJakob disease is partly due to the local severe loss of parvalbumin-positive GABA-ergic inhibitory neurons. As in patients with liver failure and hepatocerebral syndromes, the striatum has a high signal

Selective Vulnerability

Fig. 3.12. In Kearns-Sayre syndrome, the subcortical white matter and the globus pallidus are preferentially affected

Fig. 3.13. In mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) the lesions have an infarct-like appearance on MR images, as shown on these transverse FLAIR images in a 9-year-old girl, but do not, as a rule, respect vascular territories. (Courtesy of Dr. M. Heitbrink and Dr. B. Wiarda, Department of Radiology, Medical Center Alkmaar, The Netherlands)

Fig. 3.14. IR images of a 3-year-old boy with hepatic failure, showing the effects of T1 shortening of the basal ganglia. Because of the T1 shortening, the basal ganglia can no longer be distinguished from the surrounding white matter

intensity on both T1- and T2-weighted images. In Creutzfeldt-Jakob disease this could be related to a higher concentration of manganese (Guentchev et al. 1999). In intoxications with methylene dioxymethamphetamine (MDMA, or ‘ecstasy’) the lesions in the globus pallidus are due to severe brain dopaminergic neurotoxicity combined with less severe serotonergic neurotoxicity (Reneman 2001; Ricaurte et al. 2002).

Scholz (1953, 1963) stated that under specific pathophysiological conditions focal ischemic brain injury could be attributed to peculiarities of the vascular anatomy, while in other conditions the pattern of brain damage could only be explained by the unique properties of the cells themselves. One of the most important observations he made was the influence of the nature of the insult on the resulting damage to the CNS. In acute obstruction of cerebral ves-

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Fig. 3.15. Involvement of the basal ganglia is seen in sporadic ’classic’ Creutzfeldt-Jakob disease.The putamen and caudate nucleus have a high signal on the T2-weighted image, whereas the globus pallidus has a high signal on the T1-weighted image

Fig. 3.16. In progressive multifocal leukoencephalopathy the white matter is predominantly involved, to a much greater extent than the gray matter.This results in a sharp demarcation of white from gray matter when the lesion abuts the cortex, as shown in these images

sels, he found experimentally that “the cerebral and cerebellar cortical layers, especially the Purkinje cells, were destroyed, whereas the shorter the duration of ischemia the greater the possibility for selection to take place and for the innate characteristics of the structures to be expressed in a special pattern of morphological alterations.” This, in fact, also seems to be true for other conditions, such as toxic encephalopathies and inherited metabolic disorders. We could add that the “innate characteristics” mentioned by Scholz should not be seen as a static concept, but rather as a condition that is the product of genetic endowment, stage of development, interaction with other structures in neuronal functional circuits, and dependence on their functional activity and the local condition at the time of the insult. There are several pathophysiological mechanisms that help to explain selective vulnerability of certain brain areas relative to others: 1. Level of activity is an important factor in selective vulnerability. Energy depletion by hypoxia–ischemia, toxic influences, and metabolic derangements will have the greatest effect on structures with the highest oxygen demand and chemical turnover. Gray matter in adults has a higher level

of activity than white matter and will as a rule be damaged first and most severely. In infants, actively myelinating zones have a high activity and are, therefore, liable to damage. In term neonates with acute profound asphyxia, lesions can be seen in primary myelinating zones in the cerebral cortex, subcortical tracts, and basal ganglia (Fig. 3.4). 2. Specific chemical affinity contributes to selective vulnerability. It has been known for a long time that certain areas in the brain are especially liable to damage by certain toxic agents. Hexachlorophene intoxication involves myelin sheaths exclusively. Hexachlorophene encephalopathy, induced in preterm neonates by washing them for antiseptic reasons with hexachlorophene-containing solutions, causes a myelinopathy with splitting of the myelin lamellae and intramyelinic vacuole formation. Vacuolating myelinopathy in the neonate always has a special distribution, irrespective of its cause, related to the distribution of myelinated versus unmyelinated areas. A clear example is found in maple syrup urine disease. Intoxication with triethyltin, cuprizone, toxic heroin, or poisoned cocaine also leads to myelin splitting and vacuolation. Furthermore, lipophilic substances

Selective Vulnerability

generally accumulate preferentially in myelin. Organic solvents such as are used by painters lead to irregular, patchy demyelination and can cause socalled house-painter’s dementia or an organic psychiatric syndrome. Demyelination, loss of gray–white matter distinction, and signal changes in the basal ganglia have been described in toluene sniffers. Heavy metal poisoning also shows selective affinity for certain brain regions, as seen for example in Wilson disease (neostriatum, mesencephalon, dentatorubral tracts, nucleus dentatus), lead encephalopathy (cerebellar white matter in adults, cortical neurons in infants and children), and mercury poisoning in Minamata disease (occipital and parietal cortex). 3. Accumulation and/or deficiency of substances have different effects on different areas of the brain. In inborn errors of metabolism, the selection of primary targets and the pattern of spread of the lesions may be influenced by these factors. Differences in selective vulnerability may be explained by differences in residual activity of enzymes in the various cells, in importance of the enzyme function missing, in effects of the accumulation of abnormal breakdown compounds (psychosine in Krabbe disease), in sensitivity to lack of substances that are not formed, and presence of other factors within the cell with synergistic or antagonistic effects. It is often very difficult, if not impossible, to define the factors responsible for well-known patterns of selective involvement in inborn errors of metabolism. Shortage of dietary nutrients may also lead to selective damage. Malnutrition of infants in the 1st year of life leads to delayed myelination. Cobalamin deficiency in subacute combined tract degeneration leads to involvement of specific areas in the brain and spinal cord. 4. Patterns of selective vulnerability may be related to distribution of neurotransmitter systems. In some inborn errors of metabolism, some neurodegenerative disorders and some toxic–metabolic encephalopathies, selective vulnerability may result from interference with a neurotransmitter system. For instance, inborn errors of GABA metabolism have been described that lead to dysfunction of structures in which GABAergic neurotransmission is important. In Segawa syndrome, hereditary progressive dystonia with marked diurnal variation, disturbances of dopaminergic neurotransmission cause nigrostriatal dysfunction. In hyperammonemia, impairment of the neurotransmission by glutamate occurs. 5. The density of synapses for excitatory amino acids determines the sensitivity to adverse effects of these substances. Excitotoxicity due to overstimu-

lation by excess excitatory amino acids (glutamate and aspartate) has recently been recognized as a final common pathway for inflicting injury upon the CNS. Many conditions can lead to an abnormal accumulation of excitatory amino acids. The preferential distribution of lesions by this mechanism will basically be in areas with the highest density of related receptors. 6. The density of mitochondria and varying percentages of mutated mitochondrial DNA have been suggested as explanations for the selective involvement of CNS structures in mitochondrial encephalopathies. Some reports have linked the percentage of mutated mitochondrial DNA in the basal ganglia in MELAS to local levels of lactate in MRS (Dubeau et al. 2000). 7. Antigen–antibody reactions may be at the root of selective CNS lesions. This is the case in a number of the paraneoplastic and parainfectious lesions of the brain. Antibodies against tumor antigens may, for example, cross-react with similar antibodies on Purkinje cells. Paraneoplastic CNS disorders such as limbic encephalitis and brain stem encephalitis may be caused by this mechanism. In parainfectious disorders, for example those related to Mycoplasma pneumoniae infections, the same mechanism may play a part and lead to myelin damage in patients with acute disseminated encephalomyelitis. 8. Bacterial, viral, or fungal infection may involve specific structures in the brain. For example, progressive multifocal leukencephalitis is an infection of the oligodendrocyte, and thus predominantly involves white matter (Fig. 3.16). In other disorders the porte d’entrée may be responsible for the localization of the lesion, e.g., in herpes simplex encephalitis (Fig. 3.17). 9. Hyper- or hypo-osmolar conditions may cause white matter lesions in specific brain areas. In sodium intoxication in infants, unmyelinated areas appear to be most severely involved, probably because of the lower ‘resistance’ to the shifts of water. In central pontine myelinolysis the central part of the pons is mainly involved, for unknown reasons. 10. Another important factor is the nature (severity, duration, recurrence) of the noxious event. This can be seen in neonates with perinatal asphyxia. The pattern of brain damage in chronic or recurrent partial hypoxia-ischemia is very different from the pattern observed in acute profound hypoxia-ischemia. Whereas the first leads to periventricular leukomalacia (Fig. 3.11), the second leads mainly to lesions in the basal ganglia, thalamus, and perirolandic cortex (Fig. 3.4). 11. Trans-synaptic degeneration illustrates that the function of the brain depends on functional cir-

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Fig. 3.17. Predominant but not exclusive involvement of temporal lobes is seen in herpes simplex infections, shown here in a FLAIR and a T1-weighted image with contrast (upper row) and two trace diffusionweighted images (b=1000) (lower row).The ADC values in the affected areas are low (–40 % relative to normal appearing tissue)

cuits, so that damage to one part of the circuit influences function, and possibly the structure of other parts of the circuit. This was established long time ago by Guillain and Mollaret for hypertrophic olivary degeneration. The Guillain-Mollaret triangle consists of the connections of three nuclei: nucleus ruber, nucleus dentatus, and nucleus olivary inferior. Disruption of this circuit by trauma, tumor, or surgery leads to lesions in the inferior olivary nucleus. It is important to recognize this as a product of trans-synaptic degeneration, and not, in tumor cases, as recurrent or multifocal tumor. Another example is substantia nigra degeneration secondary to lesions in the globus pallidus or secondary lesions in the limbic system when one part is affected (Fig. 3.2). 12. In neonates and infants the developmental stage is also of great importance in determination of which areas will be affected by a noxious agent. The patterns of hypoxic–ischemic lesions in preterm and term neonates are well described and show the changes in vulnerability, which depend on developmental factors. Another example is found in several neuronal storage disorders, such as GM1 gangliosidosis, GM2 gangliosidis and neuronal ceroid lipofuscinosis. It is only in the early-infantile onset variants that the cerebral

white matter is involved, probably due to a combination of hypomyelination and white matter degeneration. These diseases primarily involve neurons and axons, and later onset variants lead to degeneration of gray matter structures only. However, if the disease has its onset before completion of myelination, the white matter of the CNS is also severely affected. It may be that the complex process of myelin deposition, which requires joint activity and cross-talk of oligodendrocytes, axons, and astrocytes, is disturbed because of axonal abnormalities. We found evidence for apoptosis of oligodendrocytes in infantile GM1 gangliosidosis, and this may be the primary problem, but it may also be that this is the consequence of the failed collaboration and subsequently in itself a cause for further myelin loss. Understanding mechanisms of selective vulnerability contributes to the understanding of patterns of cerebral involvement as shown by MRI. On the other hand, MRI gives us insight into patterns of selective vulnerability and into what we understand about them and what we do not. In disorders of quite different origins, some final common pathways may explain similarities in image abnormalities. On the

Selective Vulnerability

Fig. 3.18. Urea cycle disorder and encephalopathy related to a metabolic decompensation with hyperammonemia in a 6-year-old boy. Images show asymmetrical infarct-like lesions involving the frontal lobes, predominantly affecting the left hemisphere.The distribution of the lesions does not correspond to a vascular territory, and the lesions differ in some aspects from those seen in infarctions, especially with respect to the cortical involvement

other hand, even in disorders that have rather obvious similarities as far as pathogenesis is concerned, striking differences in image abnormalities are sometimes observed, indicating the inadequacy of our present understanding of pathogenetic and pathoplastic mechanisms. An illustration of this inadequacy is provided by the involvement of cerebral structures in hyperammonemia. Impaired function of the urea cycle enzymes leads to hyperammonemia and raised concentrations of glutamine in the brain. Hyperammonemia can also be caused by hepatic failure of quite different origins (acquired, other inborn errors of metabolism) and still leads to an encephalopathy. MRS has revealed high concentrations of glutamine in the brain in hyperammonemia, irrespective of its origin. On the basis of similarities in the pathogenesis of encephalopathy in these disorders, a similar clinical picture and similar MR images might be expected. However, the expressions of these disorders, clinically and on MRI, are very different. In urea cycle disorders, large cerebral lesions involving cortex and white matter are seen, with asymmetrical distribution and asymmetrical neurological signs and symptoms (Fig. 3.18). In encephalopathy due to hepatic failure related to an acquired disease, brain involvement and neurological symptomatology are symmetrical. MRI shows a symmetrical T1 shortening of the basal ganglia, including globus pallidus, putamen, caudate nucleus and other central gray matter structures (Fig. 3.14). This means that other factors in addition to hyperammonemia must be involved. Selective vulnerability, and thus MRI pattern recognition, is not a static concept; it also refers to dynamic changes. It has become clearer with MRI than it ever was with neuropathology that among the white matter disorders there are great differences in early involvement of brain structures and spread in the course of time. In the lysosomal storage disorders involving the white matter, especially the sphingolipidoses, the temporal progression is remarkably con-

stant: the central white matter is involved first, including periventricular white matter and corpus callosum, and the demyelination proceeds centrifugally from there. The arcuate fibers are the last to be involved. An explanation proposed for this feature is that in these disorders abnormal substances accumulate in membranes, leading to a progressively altered myelin composition and progressively unstable myelin membrane that is liable to breakdown. As the arcuate fibers are the last to myelinate they contain the youngest myelin, which is altered least. However, some amino acidopathies and organic acidopathies primarily involve the arcuate fibers and the demyelination progresses in a centripetal way. It is obvious that the biochemical abnormalities and interactions are completely different in the latter disorders than in lysosomal disorders: interference with energy metabolism, lack of normal myelin components, and presence of toxic metabolites are important in amino acidopathies and organic acidopathies. However, it is still difficult to explain why the arcuate fibers are first affected. MRI shows an involvement of the periventricular white matter in the occipital lobe and the splenium of the corpus callosum in the early phases of most patients with the cerebral form of X-linked adrenoleukodystrophy. The disease spreads in a frontal direction. The reason for this occipital preference is unclear. It is noteworthy that in about 10% of patients with cerebral X-linked adrenoleukodystrophy the pattern is reversed, starting in the frontal lobes and the genu of the corpus callosum and progressing towards the dorsal parts of the brain. The reason for the frontal predominance in these patients is even less clear. The cerebral involvement in Xlinked adrenoleukodystrophy tends to be symmetrical, as in the lysosomal disorders, but there are exceptions in which one side of the brain is far more severely involved than the other. It would be worth knowing whether the areas primarily involved are more vulnerable to the disease (and if so, why?) or whether the

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areas that are primarily spared are more resistant to the process (and if so, why?). Symmetry of cerebral involvement can be expected to be a general rule in inborn errors of metabolism, toxic encephalopathies, and neurodegenerative disorders, as toxic influences, genetic factors, and deficiencies of essential substances are thought to be similar for the left and right sides of the brain. In a number of disorders, however, asymmetrical involvement is the rule. An example is found once more in urea cycle disorders. In all urea cycle disorders, metabolic derangement is characterized by the accumulation of urea precursors, notably ammonium, and by increased glutamine in the brain. During episodes of metabolic derangement focal brain lesions occur, which are seen on MRI to be strikingly asymmetrical (Fig. 3.18). The large lesions can involve an entire hemisphere or a large part of it. Such an MRI pattern may be misinterpreted as an infarction, because the distribution of the lesion may suggest the involvement of one or more vascular territories. The MRI characteristics of the lesion, however, are different from those of infarctions, even though both show low signal intensities on T1-weighted images and high signal intensities on T2-weighted images. These differences can be described by the way in which gray and white matter are simultaneously involved, the way in which the whole affected area is swollen and demarcated from the rest of the brain, the slightly inhomogeneous change in signal intensity, and the often ‘unusual’ vascular territory that is occupied by the

lesion. The lesions in urea cycle disorders are not mediated by vascular changes, but are probably the result of a direct toxic effect in the involved area, mediated by the presence of elevated levels of glutamine. The asymmetrical and focal nature of the lesions is however unexplained, however. Another well-known example of asymmetry is found in MELAS, a mitochondrial disorder. The lesion usually has a cortical predominance and is restricted to one part of the brain, again simulating an infarction (Fig. 3.13). However, the lesion is not located in a vascular territory or a border zone area. Here too, there is no explanation for the asymmetry. The basis of this book is the recognition of MR patterns that allow differentiation between disease categories and between disease entities. Knowledge of which structures are selectively damaged by a specific disease lies at the basis of this approach. MRI has an edge on histopathology, because it gives us the privilege of seeing patterns in an early stage of disease and allows us to follow their development. This has not only helped in pattern recognition of classified disorders, but also helped us to recognize unfamiliar patterns and to define new entities. In all the chapters concerning specific disorders, one section is devoted to the description of MRI patterns of that specific disorder; another section is devoted to the description of pathogenetic mechanisms. As far as possible, these two will be linked. A separate chapter will deal with the principles of MRI pattern recognition.

Chapter 4

Myelination and Retarded Myelination

4.1

Myelination

It was Flechsig (1920) who originally put forward the view that the degree of myelination of the CNS might be correlated with functional capacity. In his theory he stated that myelination started in projection pathways before association pathways, in peripheral nerves before central pathways, and in sensory areas before motor ones. Although he modified his theory slightly in response to his critics, he continued to maintain that fibers always myelinated in the same order: first the afferent (sensory), then the efferent (motor), then the association fibers. The histological study of fetal development has confirmed that myelination proceeds systematically and, in nerve pathways with several neurons, in the order of conduction of the impulse. The first signs of myelination appear in the column of Burdach at the gestational age (GA) of 16 weeks, becoming stronger from the 24th week onward. The column of Goll starts to myelinate at 23 weeks of gestation. Cerebellar tracts start to myelinate at about 20 weeks of gestation, and the amount of myelin at birth is considerable. Pyramidal tracts start to myelinate at 36 weeks at the level of the pons, but at birth the amount of myelin is still small. In other tracts, for example, the rubrospinal tracts, the pattern of the pyramidal tract is followed. In a term neonate at a GA of 40 weeks myelin stains reveal myelin in the medulla oblongata, in the central parts of the cerebellar white matter, in the cerebellar peduncles and the vermis, in the medial lemniscus and fasciculus medialis longitudinalis in the pons and mesencephalon, in the posterior limb of the internal capsule, spreading into the globus pallidus and thalamus and, in the thalamocortical connections in the centrum semiovale, upwards to the parasagittal parts of the postcentral gyrus and backwards into the optic radiation. Paul Flechsig’s lithographs (1920) demonstrate this myelination pattern beautifully (Fig. 4.1). Several authors, including Keene and Hewer (1931) and Yakovlev and Lecours (1967), have published diagrams of the progress of myelination (Fig. 4.2). MRI is unique in making it possible to visualize the progress of myelination in vivo in astonishing detail. It is now possible to describe the state of myelination in preterm and term neonates in detail and to follow this process through up to full maturation. In the preterm child with a GA of less than 30 weeks the following structures show myelination:

cerebellar vermis, inferior cerebellar peduncles, vestibular nuclei, superior cerebellar peduncles and their decussation, dentate nucleus, medial longitudinal fasciculus, medial geniculate bodies, subthalamic nuclei, inferior olivary nuclei and ventrolateral nuclei of thalamus. Myelin can also be seen in the fasciculus gracilis and cuneatus and in their nuclei (Counsell et al. 2002; Sie et al. 1997). In the period between 30 and 36 weeks of gestation the quantity of myelin in the aforementioned structures increases, but from weeks 30–36 of gestation no myelin is seen in any new sites on MRI. This is not in agreement with histological descriptions of the myelin process. Reasons for this are the lower sensitivity of MRI to small quantities of myelin, also the reason for a time-lag in myelination timetables between histology and MRI, and the higher spatial resolution of histological methods. At a GA of 36 weeks evidence of the presence of myelin appears on T1weighted images in the posterior limb of the internal capsules (with higher intensity in the area of the corticospinal tracts) and in the tracts from and to the precentral and postcentral gyri in the corona radiata. In the period between 37 and 42 weeks of gestation myelination of these tracts also becomes visible on T2-weighted images. At this time myelination is visible in the tegmentum pontis but not in the basis pontis. Myelin now also appears in the lateral geniculate bodies and in the optic tracts, chiasm, and nerves. The myelin density in the basal ganglia and corticospinal tracts increases, and myelin shows up in the optic radiation. During the 1st month after birth, myelination progresses rapidly. It becomes more prominent in the areas mentioned above. The pattern of myelin presence in the cerebellum changes (see below). On T1-weighted MR images myelin becomes visible in the rest of the striatum and caudate nucleus. Myelin in the optic pathways becomes more prominent, and myelin is also present in cortical layers of the primary motor and sensory cortex and in the hippocampus and parahippocampal gyrus. With increasing myelination in the occipital and parietal lobes, the splenium of the corpus callosum starts to myelinate. From the 3rd or 4th month onward myelination proceeds in the frontal direction, and from the 4th to 5th month onward, also in the temporal direction. The anterior limb of the internal capsule shows myelination from the 3rd to 4th month onward, proceeding in the 5th month to-

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Fig. 4.1. Lithograph in left upper row is reproduced from work of Paul Flechsig (1920), who used refined histological techniques to depict ongoing myelination in the brain. Progress of myelination of a young infant is presented here. Note that myelin (dark in the image) is already circling around the temporal horn to reach the hippocampus and parahippocampal gyrus. Also note myelination of the auditory pathway in the superior temporal gyrus.The two T2-weighted coronal MR images show the same features in vivo. Myelination in this case is somewhat further advanced than on the lithograph, already spreading towards the parietal U fibers

wards the genu of the corpus callosum. At 6 months myelination starts to spread in the frontal lobes, and on the T1-weighted images the pattern of myelination is seen to be more or less complete at about 8 months. The corpus callosum reflects the myelination of the parts it connects. T1-weighted images show myelin in the splenium at 3 months and in the genu at about 6 months of age; T2-weighted images show this 4–6 weeks later. It should be clear that we are describing ’apparent’ myelination, i.e. myelination as it appears on T1- or T2-weighted images, which is dependent on pulse sequences and field strength. The apparent progress in myelination on T2-weighted images lags behind that seen on T1-weighted images. Because of this, myelina-

tion can be followed for much longer on T2-weighted than on T1-weighted images. On T2-weighted images myelination does not reach the arcuate fibers in the frontal and temporal areas before the 12th–14th and 14th–18th months, respectively. Myelination is not an all-or-none process. Myelinated white matter gradually replaces the unmyelinated white matter. In T2-weighted series unmyelinated white matter has higher signal intensity than gray matter. With ongoing myelination, white matter becomes darker, and eventually it can no longer be differentiated from gray matter. This transition or ’cross-over’ period is reached in the parietal and occipital areas between 8 and 10 months after birth. After this period myelinated white matter has lower

4.2

MRI Pulse Sequences

Fig. 4.2. Classic diagram of progression of myelination as conceived by Yakovlev and Lecours. Most of the structures mentioned can also be made visible on MRI. Appearance of myelination on MR images is 1 or 2 weeks behind this schedule with conventional MR techniques. From Yakovlev and Lecours (1967), with permission

signal intensity than gray matter on T2-weighted images in this region. The frontal and temporal lobes show this cross-over at 12–14 and 14–18 months, respectively. T1-weighted images show the same reversal in signal as the T2-weighted images, but in the reverse direction. Unmyelinated white matter has a lower signal than gray matter, whereas myelinated white matter has a higher signal. Because of the preferential T1-shortening effect of myelin, which exceeds the T2-shortening effect, the signal reversal on T1weighted images occurs weeks to months before it occurs on the T2-weighted images. This implies that there is a phase, for the cerebral hemispheric white matter mainly in the second half of the 1st year of life, in which white matter structures have a higher signal than gray matter on both T1- and T2-weighted images.

4.2

MRI Pulse Sequences

T1-weighted spin echo (SE) or inversion recovery (IR) and T2-weighted SE sequences are complementary. In the first 6 months of life, T1-weighted images show to better advantage which areas contain myelin, while T2-weighted SE images, with the proper pulse sequence, differentiate partially myelinated from nonmyelinated and completely myelinated white matter more adequately. In MRI, pulse sequences should be chosen so that the contrast/noise ratio is as high as possible and the differences between tissues are maximal. It is, therefore, useful to consider the T1 and T2 values of gray matter and of unmyelinated and myelinated white matter in order to make an adequate choice. Holland et al. (1987) found that at a field strength of 0.35 T, T1 of white matter is 1615±120 ms

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(mean±standard deviation) at birth, 1150±60 ms at 6 months and 580±50 ms at 1 year; T2 of white matter is 91±6 ms at birth, 64±6 ms at 6 months, 57±5 ms at 1 year and 53±3 ms at 3 years. For gray matter the corresponding T1 measurements are 1590±60 ms at birth, 1300±70 ms at 6 months and 890±75 ms at 1 year, and the corresponding T2 measurements 88±8 ms at birth, 67±7 ms at 6 months, 69±3 ms at 1 year and 62±3 ms at 3 years. The changes observed with increasing age can be explained by a decreasing water content and increasing myelin content. Protons in the myelin membrane are less mobile, water content is lower, and T1 and T2 are, therefore, shorter in myelinated areas. A long TR, long TE sequence is advantageous to allow full benefit of the T2 differences between gray matter, unmyelinated white matter and myelinated white matter and to minimize T1 effects, which counteract the T2 effects. We use a 3000/120 SE series, which shows unmyelinated white matter with high signal intensity, gray matter and partially myelinated white matter with intermediate signal intensity, and myelinated areas with low signal intensity. In our SE 3000/120 series, the transition or ’isointense’ pattern between gray and white matter is reached in the parietal and occipital lobes in normal children by the age of 6–9 months.With a different pulse sequence, for instance SE 2000/80, this transition phase may be 7–12 months. Because of the heavier T2-weighting in our series, the T2-decay trajectories traverse each other at a somewhat steeper angle and the transition period is, therefore, more clearly marked and of shorter duration. Fast or turbo spin echo (FSE or TSE) sequences are time-saving procedures and are frequently used in imaging of neonates and infants, but they have important disadvantages. Instead of one ’projection’ or line in the k-space (the virtual spatial frequency space from where the image is reconstructed by Fourier transformation), FSE sequences generate multiple spin echoes from a single RF excitation, which are close enough together (echo spacing in the order of 15 ms) to provide multiple ’projections’ or lines in the k-space. Imaging time is shortened by a factor of the number of echoes collected in the train. SEs are, therefore, acquired at slightly different TEs, which will affect the resulting image. The repetition of refocusing 180° pulses improves local magnetic homogeneity, thus diminishing magnetic susceptibility effects. On FSE and TSE images hemorrhages and calcifications will consequently be less conspicuous. Because of the short time interval between refocusing pulses, the apparent T2 of adipose tissue becomes longer and the fat signal will be less suppressed than on conventional T2-weighted SE images. Fat will, therefore, appear bright on heavily T2-weighted FSE images. Other factors influence FSE images. The mag-

netization transfer component present in multislice conventional SE images is increased in FSE and influenced by the number of slices. From this it will be clear that MR images made with FSE sequences cannot be compared with conventional SE images. The influence of the FSE techniques on the estimation of the progress of myelination is probably negligible, but the influence on the depiction of disease conditions should be considered, especially when the abnormalities are subtle. In examination of neonates it is impossible to be sure in advance whether abnormalities will be found. T1-weighted SE or IR series are of great importance for following the spurt of myelination during the first 6°months after birth. They demonstrate the progression of myelination beautifully, but they are less reliable than T2-weighted images for assessing the quantity of myelin deposited. The difference in T1 between gray matter and unmyelinated white matter at birth gives the unmyelinated white matter a darker appearance than the cortex. With ongoing myelination the white matter will become brighter than the cortex. Between these structures, again, a cross-over or contrast inversion takes place. In T1-weighted images, however, this is a less striking event than in T2weighted images. In premature neonates the unmyelinated white matter appears much darker than the rim of cortical gray matter. Even at 40°weeks of GA this difference is still present, although less marked. After that, the unmyelinated white matter rapidly changes its signal and becomes almost isointense with gray matter. The white matter structures in which myelin is advancing stand out as very bright and attract most attention in the assessment of myelination age. A comparison of T1- and T2-weighted images makes it clear that the T1-weighted images are more sensitive indicators of the presence of myelin, even when it is present only in small amounts. Partially myelinated structures, which are isointense or even still mildly hyperintense relative to gray matter on T2-weighted images, are already white on T1-weighted images. The reason for the higher myelin sensitivity of T1- than of T2-weighted images can be found in a number of factors at the molecular level. The special structure of the myelin membrane with a lipid : protein ratio of 70 : 30 (dry weight) and a cholesterol content of 30% is important. The construction of lipid layers separated by a 40-molecule thick layer of water, into which the hydrophilic phosphate polar groups of lipids and the cholesterol hydroxyls project, creates a unique lipid–water interfacial interaction seven times as intense as that at a typical protein–lipid interface. There is a field-dependent cross-relaxation between protons of myelin water and protons of myelin lipid, a phenomenon known as magnetization transfer. The apparent effect of these conditions is a shortening of T1 induced by myelin, which is more pronounced than

4.3

would be expected to result from deposition of membranous structures alone. Fluid-attenuated inversion recovery (FLAIR) images use a combination of an IR pulse with an inversion time chosen to suppress the water signal, followed by a heavily T2-weighted FSE. Because the water signal is suppressed, abnormalities will stand out clearly. FLAIR pulses are not very useful in the estimation of progress of myelination. The difference between gray, unmyelinated and myelinated white matter is much less on FLAIR images than on conventional T1- and T2-weighted images. It is probably the suppression of the water signal in the water-rich environment of the neonatal brain that is responsible for this diminished contrast, since the disappearance of ’free’ water in the brain of neonates and its replacement by myelinated structures play a major part in the maturation process.

4.3

Diffusion-weighted Imaging and Diffusion Tensor Imaging

Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) use the microscopic movement of water molecules and the relative loss of phase of protons caused by this movement in different brain structures as a means of image contrast. Parameters that are frequently used are the apparent diffusion coefficient (ADC) of tissues and the relative anisotropy of brain structures, usually expressed as fractional anisotropy (FA). The relative anisotropy is practically zero in gray matter in term-born neonates and in adults: diffusion in gray matter is isotropic. However, at a GA of 26 weeks cortical anisotropy is not zero, because at that time the cortical cyto-architecture is dominated by radial glial fibers and radially oriented apical dendrites of the pyramidal cells. This structure is disrupted in time by the addition of basal dendrites and thalamocortical efferents. White matter ADC and FA depend on stage of maturation. During the early development of the brain ADC values are high, and they subsequently fall. This is because of the initial high water content and the subsequent overall decrease in water content together with the development of more densely packed structures with a high density of membranes that hinder free water movement. FA is initially low and increases rapidly. The increase in FA can be observed even in the premyelination state. The increase in FA during early development is not only the result of the progressing myelination; other contributing factors are the number of microtubule-associated proteins in axons, axon caliber changes, and a significant increase in the number of glia. More densely packed structures have higher FA. Both ADC and FA can be displayed in

Diffusion-weighted Imaging and Diffusion Tensor Imaging

Table 4.1. Apparent diffusion coefficient (ADC) (×10–3 mm 2/s) and fractional anisotropy (FA) (103) in term neonates Region

ADC

FA

Frontal white matter

1.62–1.73

190–210

Posterior limb internal capsule

1.06–1.01

410–500

Occipital cortex

1.15–1.20

150–180

Occipital white matter

1.58–1.69

330–370

Corpus callosum Genu Splenium

1.22–1.37 1.17–1.32

Thalamus

1.23–1.08

Mesencephalon (tegmentum)

0.99–1.09

Pons, anterior

1.13–1.27

Pons, posterior

0.94–1.06

420–480

images. In contrast with ADC maps, FA images show excellent gray–white matter contrast. In clinical practice, estimation of ADC and FA of different brain structures makes it possible to quantitate the progress of brain maturation, including myelination, and to visualize the formation of white matter tracts. In addition, DWI offers anisotropic diffusion maps that can be displayed separately for each diffusion gradient direction or as an averaged ADC map, the so-called trace map. Measurements of ADC are available for different ages from the fetal period to adult age. ADC values decrease in between these points in time and development, from 1.50–1.95 × 10–3 mm2/s for white matter in the fetal brain to about 0.87–0.95 × 10–3 mm2/s in the mature brain. Maturity in this respect is reached at the age of approximately 2 years. For the basal ganglia the corresponding data are, respectively, 1.56 × 10–3 mm2/s and 0.79 × 10-3 mm2/s. More detailed data are available for term neonates (see Table 4.1). ADC and FA values are different for different brain structures, depending on their structure and stage of development. ADC values decrease with ongoing maturation and FA values rise. This process is exponential. The decrease in ADC and increase in FA are fast in the first 3–6 months, followed by a slower further decrease and increase, respectively. White matter anisotropy increases over the next 6 months, leveling in the 2nd year of life. The numbers in Table 4.1 are only guidelines.ADC and FA values reported from different centers can differ substantially. Data given here are in the same order of magnitude as those reported by Neill et al. (1998). Detailed measurements of diffusion tensor characteristics related to brain maturation have been taken and have shown regional differences running parallel to the progress of myelination as seen on conventional MR images (Mukherjee et al. 2002). Unfortunately,

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Table 4.2. Magnetization transfer ratio (%) during development Projection fibers (pyramidal tracts) At 1 month 23–25 % At 3 months 25–27 % At 6 months 31–33 % At 20 months 34–37 % Association fibers

Commissural fibers

At 1 month 19–21 % At 3 months 22–25 % At 6 months 28–30 % At 20 months 29–33 % At 1 month 23–24 % At 3 months 24–25 % At 6 months 29–33 % At 20 months 34–37 %

the reported values refer to ’eigenvalues’ of the diffusion tensor and are not directly comparable to ADC and FA values.

4.4

Magnetization Transfer

With magnetization transfer (MT) quantitative information about the condition of brain tissue can be obtained by estimating MT ratios (MTRs), either voxel based and displayed as maps, or measured globally and displayed as MTR histograms. It has been shown that MTR changes in infants correlate with changes in the degree of myelination (Van Buchem et al. 2001). MTR can be used to quantitate the progress of myelination and monitor the regional development. MTR values (%) show an increase over time (Rademacher et al. 1999) (Table 4.2). Gray matter structures also show an increase in MTR over time; these changes, however, are much less impressive (Rademacher et al. 1999). It is possible to use MTR whole-brain histograms to monitor the progress of brain maturation. This will possibly develop into a method that will allow easy estimation of retarded maturation and be a good tool for individual follow-up studies (Van Buchem et al. 2001).

4.5

Myelination: Timetables

In daily practice it is useful to have a timetable of normal progress of myelination at hand. Even with a considerable variation, it is evidently possible to provide a time scale for normal development and to assess reliably significant delay in myelination. There are several approaches to making a timetable and each one has its own advantages and disadvantages. The methods can be subdivided in nonquantitative (visual inspection), semi-quantitative (ratios) and quantitative (absolute values).

Table 4.3. Signal intensity of central white matter relative to white matter on long TR SE images Stage

Age

Short TE MWM

Long TE MWM

I

1st month

↑

=/↓

II

2nd months

=/↓

↓/↓↓

III

3rd–6th months

↓

↓↓

IV

7th–9th month

↓

↓↓

V

>9th month

↓

↓↓

↑↑ hyperintense, ↑ slightly hyperintense, = isointense, ↓ slightly hypointense, ↓↓ hypointense, SE spin echo, MWM myelinated white matter, TE echo time

Timetables can be based upon the visual inspection of changes on T1- and T2-weighted images. T1-weighted images are very useful in the first 6 months of life, as discussed above, whereas T2- weighted images provide more useful information after 6 months. Combination of T1 and T2 data has distinct advantages, especially in cases with delayed or distorted myelination. At term birth, T1-weighted images show evidence of myelination in the medulla spinalis, cerebellar white matter, dorsal part of the pons, mesencephalon, posterior limb of the internal capsula (in particular the area of the corticospinal tracts), and the postcentral parasagittal areas, as a continuation of the long ascending spinocortical tracts. The optic radiation becomes myelinated soon after birth. The splenium of the corpus callosum is myelinated in the 3rd month, the truncus in the 4th and 5th month, and the genu in the 5th and 6th months. In the 3rd and 4th months myelination spreads to the anterior limb of the internal capsule. From the parietal parasagittal area, myelination starts to spread in anterior and posterior directions. After this stage further distinction on T1weighted images becomes difficult. Additional T2-weighted images can be used to refine the assessment of myelination. Myelination of the central parts of the brain can be distinguished from the hemispheric white matter, making it possible to compose a timetable based on signal intensities with five steps of progression (see Tables 4.3, 4.4). Some markers are useful in daily practice. On long TR, long TE SE images, the splenium of the corpus callosum has a low signal by 6 months of age, the genu at 8 months of age. The cross-over in the occipital lobe, when gray and white matter have a uniform and indistinguishable intermediate signal intensity (are isointense), occurs at about 7–9 months. At about 9 months the ‘adult’ contrast between gray and white matter starts to emerge in the occipital lobes. The anterior limb of the internal capsule is myelinated on the heavily T2-weighted sequence at 8–11 months. At 12 months the frontal white matter starts to myeli-

4.5

Myelination: Timetables

Table 4.4. Signal intensities of peripheral white matter relative to white matter on long TR SE images Short TE stage

age

UWM

Long TE MWM

UWM

MWM =

I

1st month

↓

↑

↑

II

2nd month

=

=

↑↑

=

III

3rd-6th month

↑

=

↑↑

=

IV

7th-9th month

=

=

V

>9th month

↓

↓↓

↑↑ hyperintense; ↑ slightly hyperintense; = isointense; ↓ slightly hypointense; ↓↓ hypointense; MWM myelinated white matter; UWM unmyelinated white matter; TE echo time

nate; it should be nearly complete at 14 months of age. The temporal lobe is the last to myelinate; this occurs between 14 and 18 months of age. The U-fibers of the cerebral hemispheric white matter become fully myelinated between 18 and 24 months. Use of marker sites can be helpful, especially for research purposes, to provide the necessary detail and quantitation. An approach defining specific targets for myelination, and scoring in a large population the time of onset and completion of myelination of such targets, leads to normal values with definition of normal variation. In a semi-quantitative way the progress of myelination can be assessed by calculating a ratio between the averaged signal intensity of a chosen region of interest and dividing that by the averaged signal intensity of a fully myelinated structure. For this purpose the posterior limb of the internal capsule is often chosen, because myelination is complete at that structure at a GA of 44 weeks. A ratio so obtained is independent of type of equipment and field strength. In myelin disorders that also affect the posterior limb of the internal capsule, of course, this does not apply. The head of the caudate nucleus has also been used as a reference. Some groups have used this more refined method of marker sites in combination with estimation of time of contrast cross-over between structures and used this approach to look at the detailed progress of myelination in the cerebellum and brain stem in the first months of life. Martin et al. (1990) took as target areas the cerebellar hemispheres, dentate nucleus, nucleus ruber, middle cerebellar peduncle, corpus medullare cerebelli, pontine tegmentum, basis pontis, medial lemniscus, and corticospinal tracts. They defined five stages of progress of cerebellar myelination, depending on the relative signal intensities of these regions. Landmarks of these studies used for time estimates were again the gradually darker appearance of myelinated areas on T2-weighted images, the further extension of myelination towards the subcortical structures, and inversion of contrast between structures. An example of the first marker is the gradual

darkening of the rim around the dentate nucleus in the first weeks of life; of the second marker, the extension of myelin into the cerebellar folia; and of the third marker, the cross-over in signal intensities between the corticospinal tracts and the substantia nigra. When automatic scaling is used, which is usually the case on MR systems, it proves difficult to identify the five stages as described by these authors. Usually, however, three stages of maturation can be distinguished in the posterior fossa. The structures involved in the recognition of these three stages on T2weighted transverse images are: the basis pontis, the tegmentum pontis, the middle cerebellar peduncle, the dentate nucleus, the peridentate white matter, the corpus medullare cerebelli, and the white matter extending into the cerebellar folia (Fig. 4.3). In stage 1 (1 months, 3–4 months), tegmentum and basis pontis are now approximately as dark as each other; the dentate nucleus and the cerebellar white matter appear completely dark and isointense with the middle cerebellar peduncle. After completion of these stages, myelination starts to extend towards the cerebellar folia, gradually shaping the ’arbor vitae’ of the cerebellum. We could make the assessment more detailed and add more structures: pyramidal tracts, medial lemniscus, and medial longitudinal fasciculus, structures that can be distinguished in good-quality images of the brain stem and cerebellum. A similar diagram could be produced for the mesencephalic structures, where the signal intensity, of the red nucleus, the substantia nigra, the corticospinal tracts, medial lemniscus, and inferior calicles changes with time, depending on the pulse sequence used.

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Fig. 4.3. Myelination of the posterior fossa (nd nucleus dentatus; mcp middle cerebellar peduncle; V vermis cerebelli; 1 peridentate white matter; 2 corpus medullare; 3 peripheral white matter; IV fourth ventricle)

Fig. 4.4. Myelination and gyration are both part of the maturation process of the brain. These axial T2-weighted images obtained in infants with gestational ages (GAs) of 23, 27, and 35 weeks demonstrate brain maturation in that period. At 23 weeks of gestation the germinal matrix is visible at the trigonum, frontal horns and caudothalamic notch. The brain surface is still smooth. The sylvian fissure is hardly visible. At

27 weeks there are still remains of the germinal matrix, but it is less conspicuous. At 35 weeks of gestation myelination has started in the posterior limb of the internal capsule. (The dark dot represents the corticospinal motor tract.) The gyral development over this period is beautifully shown in these images. From Childs and Ramenghi et al. (2001), with permission

4.6

Gyration

Quantitative measurements can be used to assess myelination of the brain in general, and in different structures in particular. Examples are measurements of T1, T2, ADC, FA, and MTR. It is clear that myelination is not the only concern as far as development of the CNS is concerned. Progression of gyration should be included in an inventory of brain maturation. For premature children such a maturation index has been proposed (Childs et al. 2001), which provides a standardized method of assessing cerebral maturation. Four parameters are assessed in this scale: cortical folding, myelination, germinal matrix distribution, and glial cell migration (see also Fig. 4.4).

4.6

Gyration

The brain of premature children and neonates is immature, not only in myelination but also in development in gyri (gyration). Histopathological, intrauterine ultrasound and MR studies have yielded insight into the development of some major fissures, which provide landmarks of gyral development: the interhemispheric fissure (before 15 weeks of GA), the parieto-occipital fissure, the calcarine fissure, the central rolandic sulcus (visible at a GA of 23–25 weeks), and the development of the insula, visible at a GA of 18 weeks, with overriding frontal, temporal and parietal opercula at 28–29 weeks’ gestation (Chi et al. 1977). For MRI, insight into gyral development from the age of 26–28 weeks gestation is most important, as preterm infants often come for MRI. In premature infants the cerebral cortex is still entirely or relatively smooth and lacking in sulci, depending on the postconceptional age of the infant. Over time, shallow sulci develop in an ordered sequence. The sulci increase in number and become deeper. The gyri become increasingly branched. Most of the process of a conversion of a smooth, lissencephalic brain into a nearly fully developed cortical gyral pattern occurs between 26 and 44 weeks of gestation. The mature pattern of gyri and sulci is normally reached at the age of 3 months after term. In our study of gyral development in preterm and term neonates (Van der Knaap et al. 1996) gyral development was graded for differ-

Fig. 4.5. A–D. Patterns of sulcus configuration for gyral development score 2 (A or B), score 3 (C), and score 4 (D). From Van der Knaap et al. (1996), with permission

ent brain areas using a five-point scoring system (Fig. 4.5): (1) The surface is smooth without gyri and sulci or there is, at most, some undulation of the cortical surface area. (2) Width of the gyri is greater than the depth of the sulci. (3) Width of the gyri is equal to the depth of the sulci. (4) Width of the gyri is less than the depth of the sulci. (5) Gyri and sulci are branched. Seven cortical areas were studied separately: (1) the frontal lobe minus the area of the central sulcus, (2) the area of the central sulcus, (3) the parietal lobe minus the area of the central sulcus, (4) the occipital lobe minus the medial area, (5) the medial occipital area, (6) the posterior part of the temporal lobe, and (7) the anterior part of the temporal lobe. The five stages of gyration distinguished are shown in Figs. 4.6–4.10. The ages of the children ranged from 30 to 42 weeks. At all ages the development of the rolandic area and the medial part of the occipital lobe (areas 2 and 5) was most advanced. In the parietal area, occipital area and posterior temporal area (areas 3, 4, and 6), an intermediate rate of gyral development was found. Gyral development was slowest and latest in the frontal and anterior temporal areas (areas 1 and 7).

45

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Myelination and Retarded Myelination

Fig. 4.6. Sagittal T1-weighted, and coronal and transverse T2-weighted images in a preterm infant at a GA of 30 weeks, showing stage 1 gyration. The depth of the central, parietooccipital and calcarine sulci is about equal to the width of the

bordering gyrus. The frontal and temporal cortical surface is smooth; the cortex is slightly undulating in the posterior area. From Van der Knaap et al. (1996), with permission

4.6

Fig. 4.7. Preterm infant at a GA of 32 weeks. Sagittal T1- and coronal and transverse T2-weighted images show gyration stage 2. The central and calcarine sulci are now deeper than

Gyration

the bordering gyri. Compared with stage 1 sulci are better defined and increased in number in the remaining areas. From Van der Knaap et al. (1996), with permission

47

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Chapter 4

Myelination and Retarded Myelination

Fig. 4.8. Gyration at a GA of 36 weeks. Sagittal and coronal T1- and transverse T2-weighted images demonstrate stage 3 gyration. The central sulcus and sulci of the medial occipital area are now becoming branched. Sulci are becoming better

defined and more numerous.The depth of the sulci is equal or greater than the width of the gyri in most areas. From Van der Knaap et al. (1996), with permission

4.6

Fig. 4.9. Gyration at a GA of 39 weeks. Sagittal and coronal T1- and transverse T2-weighted images depict stage 4 gyration.The central and sulci of the medial occipital area are now branched. The number of sulci and gyri has increased again.

Gyration

The sulci have a closed form in most areas. The depth of the majority of sulci is greater than that of the bordering gyri.From Van der Knaap et al. (1996), with permission

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Fig. 4.10. Gyration at a GA of 42 weeks, depicted on sagittal T1-weighted, and coronal and transverse T2-weighted images, showing stage 5 gyration. Branching of sulci is now seen in all areas. From Van der Knaap et al. (1996), with permission

4.8

4.7

Delayed Myelination, Irregular Myelination, Hypomyelination, and Arrest of Myelination

Once MRI criteria for normal progress of myelination have been established, it is possible to diagnose delays in this process. If it is true that myelination expresses functional maturity a correlation between delay in myelination and delayed development of psychomotor functions can be expected. Roughly speaking, this appears to be the case. We have been able to confirm it in a group of children with hydrocephalus, in whom MRI and neuropsychological data were obtained before and twice after shunting. There was a strong correlation between (a) the progress of myelination as compared with the normal myelination standard and (b) the progress of mental development as compared with the normal developmental standard. It is important to follow up the progress of myelination in any child in whom a delay is suspected, to see whether, and if so when, the child catches up with normal myelination. It might be assumed that a longer delay in the restoration of the normal pattern would coincide with a poorer prognosis. There are many possible causes for a delay in myelination: hypoxia–ischemia, congenital infections, congenital malformations, chromosomal abnormalities, congenital heart failure, postnatal infections, hydrocephalus, hypothyroidism, hypercortisolism, hypocortisolism, fetal intoxications, malnutrition, and inborn errors of metabolism. The delay is usually bilateral and symmetrical, but unilateral delay is seen in cases with hemimegalencephaly, unilateral porencephalic cysts, cerebral hemiatrophy, or unilateral periventricular leukomalacia. The critical period in myelin development was initially thought to coincide with the proliferation of myelin-forming cells, rather than with the period of membrane accumulation. The mechanism of ’stunting’ of oligodendroglial proliferation as a cause of hypomyelination has been under discussion, because in animal research no major deficits of oligodendrocytes could ever be established, except in severely starved animals. Therefore the induction of myelin membrane formation, rather than cell proliferation, seems to be the actual critical event. Damage in critical periods is often limited to areas in which myelination is beginning at that time. This knowledge is helpful in establishing the time of insult in infants and children.

Iconography of Myelination and Gyration

Irregular myelination with local or generalized hypermyelination, or myelination not following the normal routes of progress, is rare, but is seen occasionally. Hypermyelination, or advanced myelination, has been observed in patients with Sturge-Weber syndrome. It has been suggested that epileptic seizures may stimulate myelination. However, advanced myelination or hypermyelination is not seen in most patients with infantile forms of epilepsy. Local hypermyelination in the basal ganglia is manifest histologically as the so-called status marmoratus, a late sequela of perinatal hypoxia. In this case the myelination does not involve the proper targets and does not occur around axons but around astrocytic extensions. Because of the low signal intensity of the basal ganglia on T2-weighted images and the dark appearance of myelin in this sequence, MRI has so far not succeeded in identifying this condition. Hypomyelination or arrest of myelination occurs in Pelizaeus-Merzbacher disease, a disorder of proteolipid protein synthesis, one of the major myelin proteins. In this disorder no myelin, or only very little, is produced. In Salla disease, a lysosomal storage disorder, and DNA repair disorders such as Cockayne syndrome and trichothiodystrophy with sun hypersensitivity hypomyelination is also present. To establish a secure diagnosis of retarded or arrested myelination, at least two observations sufficiently far apart are necessary.

4.8

Iconography of Myelination and Gyration

Illustrations in this chapter show the progress of gyration (Figs. 4.4–4.10) and myelination in normal neonates and infants (Figs. 4.11–4.23). Many examples of disturbances of myelination are found in the other chapters in this book. In Table 4.4 the myelination of some important structures on MRI is indicated. In some cases a more detailed look at structures in relation to their surroundings is useful, in order to see how contrast changes over time. The structures in the posterior fossa are a good example (Fig. 4.3). We also include an example of diffusion-weighted imaging in estimating the progress of myelination (Fig. 4.24).

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Myelination and Retarded Myelination

Fig. 4.11. Myelination at a GA of 32 weeks. The sagittal T1weighted series (upper row) shows the features of the premature brain nicely: lack of gyration in the frontal areas, with some gyration in the parietal and occipital lobes.The midsagittal image shows myelin present in the medulla oblongata, the

dorsal part of the pons, the mesencephalon, and the corpus medullare of the cerebellum. The transverse T1-weighted series shows the same features and gives a good impression of the high water content of the unmyelinated white matter

4.8

Fig. 4.12. Myelination at a GA of 39 weeks. A sagittal T1weighted SE series is shown from right to left.In the brain stem, the basis pontis is still not myelinated (arrow). The corpus cal-

Iconography of Myelination and Gyration

losum is still thin and also unmyelinated. From the basal ganglia, myelinated white matter tracts can be followed towards the post-rolandic gyrus (arrows)

53

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Chapter 4

Myelination and Retarded Myelination

Fig. 4.13. Myelination 2 weeks after birth at term, as seen on a T1-weighted transverse inversion recovery (IR) series. Myelination is seen in the medulla oblongata, middle cerebellar peduncle, tegmentum pontis (especially medial lemniscus, arrows), colliculus inferior, decussation of the superior cerebel-

lar peduncles, optic tracts, posterior limb of the internal capsule, white matter tracts in the basal ganglia and ascending tracts towards the post-rolandic gyrus. Note in the upper images that cortical gray matter is also myelinated

4.8

Fig. 4.14. T2-weighted transverse series of myelination 2 weeks after birth at term for comparison.Cerebellar myelination is still in stage 1: the hilus of the dentate nucleus is bright; the dentate nucleus is surrounded by a dark band (arrow), again followed by bright cerebellar white matter. Contrast inversion of these structures during the progress of myelination

Iconography of Myelination and Gyration

will give clues to the age of myelination. On T2-weighted images the tegmentum pontis (arrow) and mesencephalon are darker than the ventral pons. Myelin can also be seen in the superior vermis, posterior limb of the internal capsule, basal ganglia and ascending tracts into the post-rolandic gyrus (arrows)

55

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Chapter 4

Myelination and Retarded Myelination

Fig. 4.15. In the posterior fossa T2-weighted images show that cerebellar myelination has progressed to stage 2 in this 2-month-old infant.The bright ring around the dentate nucleus has disappeared, but the peripheral white matter of the cerebellum is still bright.There is still a difference between the

basis pontis and tegmentum pontis, although much less pronounced than before. In the mesencephalon, the pyramidal tracts and decussation of the superior cerebellar peduncles can be identified

4.8

Fig. 4.16. IR images at 3 months. The myelinated structures can easily be identified. Note the beginning of myelination in the pyramidal tracts in the mesencephalon (large white arrow) and the strongly myelinated decussation of the superior cerebellar peduncles (small black arrow). The colliculus inferior (black arrow) and the auditory tracts are also clearly myelinat-

Iconography of Myelination and Gyration

ed. The optic tract is myelinated, as is the optic radiation. The posterior limb of the internal capsule is fully myelinated at the postnatal age of 2 weeks. Myelin has now spread to the precentral gyrus and will advance dorsally and ventrally to myelinate the occipital, the frontal and, finally, the temporal lobes

57

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Chapter 4

Myelination and Retarded Myelination

Fig. 4.17. At the age of 5 months the genu of the corpus callosum starts to myelinate. On IR images myelination will soon appear to be complete.T2-weighted images will then be more useful in providing information about maturation of the brain

4.8

Fig. 4.18. T2-weighted series at 4 months of age. In the pons, basis and tegmentum have a low signal; the medial lemniscus has an even lower signal (arrow), as do the middle cerebellar peduncles. The corpus medullare of the cerebellum is myelinated, but myelination is not yet extending towards the cortex. At the level of the mesencephalon, the decussation of the

Iconography of Myelination and Gyration

superior cerebellar peducles, the colliculus inferior (arrow), the pyramidal tracts,the corpus mamillare and the optic tract have a low signal. The posterior limb of the internal capsule is also dark (arrows). A difference is visible between the unmyelinated white matter in the frontal and temporal regions and the occipital and parietal region where myelination has started

59

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Myelination and Retarded Myelination

Fig. 4.19. T2-weighted coronal images at the age of 4 months, showing the difference between still unmyelinated white matter in the frontal and temporal lobe and the more advanced myelination posteriorly

4.8

Fig. 4.20. Myelination at 7–8 months of age. On the T2weighted images the central parts are now myelinated,including the genu of the corpus callosum. The crossover between

Iconography of Myelination and Gyration

gray and white matter in the occipital and parietal areas has started; there is little contrast between gray and white matter. In the frontal and temporal regions this is not yet the case

61

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Myelination and Retarded Myelination

Fig. 4.21. Myelination at 12–13 months. The adult contrast is now emerging in all lobes except the temporal lobe, the latest to myelinate.The T2-weighted series shows that the spread of myelin into the arcuate fibers is still not complete

4.8

Iconography of Myelination and Gyration

Fig. 4.22. Adult pattern of myelination on T2-weighted images in a 5-year-old child.The temporal lobes now also show the adult gray–white matter contrast

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Myelination and Retarded Myelination

Fig. 4.23. Adult pattern of myelination on T1-weighted (IR) images.These images were taken from a 5-year-old boy

Fig. 4.24. Diffusion-weightedimaging (DWI) and diffusion tensor imaging (DTI) allow further refinement and quantitation of the progress of myelination.These images depict single-shot EPI with single diffusion gradient in slice, read or phase direction at b=1000, showing anisotropy of myelinated fibers depending on the gradient direction in a baby boy 3 months of age

4.8

Iconography of Myelination and Gyration

Fig. 4.25. Images demonstrating evolution of FA over time, measured with 12+1 diffusion gradient settings

Table 4.5. Myelination on MRI: chronological table (WM white matter). From:Yakovlev and Lecours (1967), with permission Regions of CNS Cerebellar peduncles Tegmentum pontis Basis pontis Medial lemniscus Pyramidal tracts Optic nerve Optic radiation Internal capsule, posterior limb Internal capsule, anterior limb Corpus callosum splenium Corpus callosum genu Parieto-occipital WM Frontal WM Temporal WM

Fetal age (weeks)

Postnatal age (weeks)

24 28 32 + + +

4 8 +++ +++ ++ ++ + + ++ + + ++ ++ + +

36 40 ++ +++ + +

+ +

+

++ +++

20 +++ +++ +++ +++ + +++ +++

6 +++ +++ +++ +++ ++ +++ +++

9 +++ +++ +++ +++ ++ +++ +++

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

+++

+++ +++

+++ ++ + +++

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

+

12 +++ +++ + ++ + +++ ++

+

+ +

++

++

16 +++ +++ ++ +++ + +++ +++

Postnatal age (months)

+ ++

++ ++ + +++ +++

12 >12 +++ Further re+++ finement of +++ myelination in subcortical +++ arcuate fibers +++ continues for +++ several years +++

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

65

Chapter 5

Lysosomes and Lysosomal Disorders R.A. Wevers, V. Gieselmann

5.1

Lysosomal Biogenesis and Biochemical Functions

Lysosomes are hydrolase-rich organelles surrounded by membranes and with an acidic interior milieu. They are present in almost all types of body cells. Their number varies greatly, depending on cell type and function. They display considerable structural heterogeneity and appear in all shapes, sizes, and densities. They have been given their name because they are small bodies (soma = body) containing various enzymes that are hydrolytic (lysis = dissolution). These hydrolases catalyze reactions in which macromolecules and macromolecular structures are degraded into smaller components. Among the more than 50 different lysosomal enzymes so far identified are proteases, nucleases, glycosidases, lipases, phospholipases, sulfatases, and phosphatases. The variety of enzymes enables the lysosome to digest almost all types of biological macromolecules, such as proteins, polysaccharides, lipids, and nucleic acids. The lowmolecular components released are transported to the cytoplasm to be reused. For this purpose the lysosomal membrane contains various transporters to translocate amino acids, sugars, and possibly nucleotides into the cytoplasm. The lysosomal membrane separates the hydrolytic enzymes from the cytoplasm to prevent uncontrolled lysis of cytoplasmic components. The acidic interior of lysosomes provides a favorable environment for the digestive activities of the enzymes: oligomeric proteins dissociate into monomers, proteins dissociate away from the protecting membrane, and stabilizing complexes become split. The low pH is generated by a complex multisubunit ATP-dependent proton pump. Several subunits of this proton pump are found on the cytosolic side of the lysosomal membrane, and others are integral lysosomal membrane proteins. Furthermore, the lysosomal membrane harbors various proteins, with highly glycosylated intralysosomal domains (e.g. LAMP1 and 2). The high carbohydrate content is thought to protect the lysosomal membrane from hydrolytic attack by the enzymes. Lysosomal enzymes, along with secretory proteins and plasma membrane proteins, are synthesized on membrane-bound polyribosomes on the rough endoplasmic reticulum. An important question is how proteins, which are destined for specific intracellular compartments, are targeted at their destination from

their site of synthesis. The signal that specifies the destination of each nascent protein resides in its sequence or spatial structure. The cellular transport machinery recognizing these signals distributes the proteins to the diverse cellular compartments. Some signal peptides direct proteins specifically into the nucleus, mitochondria, or peroxisomes. Membrane, secretory, or lysosomal proteins are also sorted initially via signal peptides into the lumen of the endoplasmic reticulum. Here the lysosomal enzyme proteins undergo glycosylation, as do most of the secretory and plasma membrane proteins. The glycosylation step involves the transfer of a large oligosaccharide with high mannose content to selected asparagine residues of the nascent protein. Subsequently, the signal peptide is cleaved, the protein folds, and the processing of the asparagine-linked oligosaccharide begins. From the endoplasmic reticulum the proteins travel via vesicular transport to the Golgi apparatus. In the cis compartment of the Golgi complex, oligosaccharide side chains of lysosomal enzymes are phosphorylated and thus acquire mannose-6-phosphate moieties. In contrast, oligosaccharide side chains of secretory and membrane proteins are trimmed and remodeled further to yield complextype side chains. The synthesis of the mannose-6phosphate residues is initiated by a phosphotransferase, which specifically recognizes lysosomal enzymes. Recognition does not occur by way of a signal peptide but is mediated by a spatial signal depending on the three-dimensional structure of the enzymes. Given the structural diversity of lysosomal enzymes the precise nature of the signal shared by all enzymes is still a mystery. So far, only surface-located lysine residues seem to be an essential common component of this topogenic signal. Phosphorylated lysosomal enzymes then proceed through the remainder of the Golgi complex (from cis- through medial to trans-Golgi). In the trans-Golgi network (TGN) they bind to mannose-6-phosphate receptors, which segregate the enzymes into distinct transport vesicles away from secretory and cell surface proteins. There are two mannose-6-phosphate receptors, which bind different but overlapping sets of enzymes. Once lysosomal enzymes are bound, the mannose-6-phosphate receptor–enzyme complexes are collected in clathrin-coated pits, which bud off to form coated vesicles. Most of these transport vesicles deliver the complexes to acidic early endosomes, but

5.1

complexes do also arrive at late endosomes. The low pH in the endosomes causes lysosomal hydrolases and receptors to dissociate. After dissociation, mannose-6-phosphate receptors are retrieved from this compartment and returned to the TGN, whereas lysosomal enzymes are delivered to mature lysosomes. Thus, receptors do not occur in lysosomes. Their absence is an important histochemical feature of lysosomes and differentiates them from late endosomes. Mannose-6-phosphate receptors also cycle between the endosomal compartment and the plasma membrane. One of the receptors can bind lysosomal enzymes at the plasma membrane and mediate their endocytosis and subsequent delivery to lysosomes. This is probably a recapture mechanism, since depending on cell type, 5–40% of newly synthesized lysosomal enzymes escape receptor binding in the TGN and are secreted. A proportion of these enzymes bind to the mannose-6-phosphate receptors on the plasma membrane and are recaptured, internalized, and delivered to lysosomes. Sorting signals within the cytoplasmic tails of the receptors are crucial for their correct intracellular trafficking. Although the mannose-6-phosphate recognition pathway is a major route for targeting soluble lysosomal enzymes, there is evidence for an alternative mechanism, independent of mannose-6-phosphate, and localizing soluble acid hydrolases to lysosomes. Although it seems likely that this pathway is also receptor mediated, attempts to demonstrate this receptor have so far been unsuccessful. Only in cases of activator proteins – see below – has the multiligand receptor sortilin been shown to be involved in lysosomal trafficking independent of mannose-6-phosphate. Lysosomal membrane glycoproteins travel the same route as soluble enzymes from the rough endoplasmic reticulum via the Golgi apparatus and endosomes to lysosomes. However, the transport of lysosomal membrane glycoproteins to lysosomes is independent of the mannose-6-phosphate receptor system, depending rather on signals in their cytoplasmic portion. An example is the classic lysosomal marker enzyme acid phosphatase. It is synthesized as a transmembrane precursor protein with a large luminal domain and a short cytoplasmic tail. After reaching the TGN the enzyme precursor is repeatedly recycled between the cell surface and the endosomal compartment before reaching the lysosome. After its delivery to the lysosome, acid phosphatase undergoes proteolytic processing of the membrane-anchoring domain, resulting in conversion to a soluble form. Sorting signals for this mannose-6-phosphate receptor-independent pathway reside in the short cytoplasmic tail of the acid phosphatase precursor. In addition to oligosaccharide processing, lysosomal hydrolases are synthesized as pre-proenzymes,

Lysosomal Biogenesis and Biochemical Functions

and almost all undergo proteolytic processing. The pre-piece is the signal sequence, which is cleaved immediately after transport into the endoplasmic reticulum. With the exception of aspartylglucosaminidase, which is already processed in the endoplasmic reticulum, the pro-piece is cleaved later in endosomal compartments. Cleavage is completed after arrival of the enzymes in the lysosomes. For lysosomal proteases, cleavage of proenzymes is accompanied by activation of the enzymes. Prior to arrival in the lysosomes the pro-piece keeps the proteases in an inactive state. In lysosomal enzymes other than proteases, however, the biological significance of this proteolytic processing is poorly understood. Some enzymes involved in the degradation of sphingolipids need the assistance of enzymatically inactive activator proteins for hydrolysis of their substrates. So far, five different activator proteins encoded by two different genes have been identified. One gene codes for the GM2 ganglioside activator protein only, whereas the other encodes a precursor protein that harbors four different but homologous sphingolipid activator proteins (SAPs). The mature SAPs A, B, C, and D – also called saposins – are generated from this precursor via proteolytic processing. They act on different enzymes and facilitate the degradation of various sphingolipids. They also differ in their mode of action. GM2-activator protein and SAP-B bind the lipid substrates and present them to the respective enzymes, whereas SAP-C activates the enzyme directly. Lysosomes are the final destination of endocytic, autophagic and phagocytic routes. The endosomal membranous network connects the lysosomes to the Golgi apparatus and the plasma membrane. Early endosomes start to accumulate internal membranes, and as this accumulation proceeds they mature into late endosomes. Since late endosomes are rich in luminal membranes they are also referred to as multivesicular bodies (MVBs) or multivesicular endosomes. Lipid and protein composition of these luminal membranes differs from that of early endosomes, suggesting a specific partitioning event during their generation. Thus, for some proteins it has been shown that tagging with ubiquitin directs them through this luminal compartment for lysosomal degradation, whereas other proteins seem to be quite stable in these membranes. This endocytotic lysosomal route can also be used to terminate growth factor receptor signaling, a process that is crucial for cellular regulation. Thus, ligand activation of epidermal growth factor receptor does not only activate downstream signaling pathways, but also induces endocytosis. Endocytosed receptors may be cycled back to the plasma membrane for continuous signaling or can be delivered to the lysosome for degradation, resulting in signal termination. Thus, the balance between recycling

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and lysosomal delivery has a key role in regulation of the signal intensity of at least some tyrosine kinase receptors. The MVBs/late endosomes can fuse homotypically, but they also fuse with lysosomes, forming a hybrid organelle. The dense lysosomes can be regarded as storage granules of hydrolytic enzymes, which fuse with late endosomes to perform their hydrolytic task on the late endosome contents. During this process continuous condensation occurs to recover lysosomes from this hybrid organelle. Autophagy is the process by which the cell sequesters parts of its own cytoplasm, often containing entire organelles. In the first step, called autophagic sequestration, a cytoplasmic membrane, which is probably derived from the endoplasmic reticulum, envelops a region of cytoplasm in a closed vacuole called an autophagosome. Through fusion, the sequestered material is transferred to lysosomes. The lysosomal membrane protein LAMP2 seems to be essential for the maturation of autophagosomes. In normal cells this process is important because of its participation in cell renewal and turnover of wornout cell constituents. In secretory cells there is a special kind of autophagy, called crinophagy. It occurs by way of direct fusion between secretory granules and lysosomes and results in the destruction of excess secretory material. Alternatively, in chaperone-mediated autophagy proteins can be unfolded in the cytoplasm and transported directly through the lysosomal membrane. Finally, phagocytosis is the process by which cells internalize large particles, such as bacteria. Thus, phagocytosis is particularly active in neutrophils and macrophages. After internalization the interior of a phagosome initially resembles the extracellular milieu. However, phagosomes may fuse with endosomes and slowly acquire the characteristics of late endosomes and lysosomes. In this context it is important to note that lysosomes also generate peptides via hydrolysis of phagocytosed material to load MHCII molecules. Thus, lysosomes have an essential role in the immune system, maintaining the health of cells and the body’s defense against foreign invaders. Apart from the catabolic functions, lysosomes have also been shown to play an essential part in the repair of plasma membrane defects. In wounded cells lysosomes can fuse with the defective plasma membrane via a calcium-triggered exocytotic process. Lysosomes can thus serve as a reservoir allowing for rapid provision of membrane lipids in the case of extended defects that cannot be compensated by lipid biosynthesis within an appropriate time period. This clearly demonstrates that lysosomes also have anabolic functions.

5.2

The Pathobiochemistry of Lysosomal Disease in Humans

More than 45 different lysosomal diseases are currently known in man (Table 5.1). They can be caused by defects in the genes of individual lysosomal hydrolases, activator proteins, transporters, lysosomal membrane proteins, or enzymes modifying lysosomal hydrolases. In general a profound deficiency with residual activity of the respective protein 95 mmHg), male gender, atrial fibrillation, coronary artery infarcts, diabetes mellitus, smoking, alcohol abuse, drug abuse, hyperhomocysteinemia, antiphospholipid antibodies, several coagulation disorders, the presence of the apolipoprotein E e4 allele, and probably other genetic factors. A study involving psychiatric patients showed periventricular and deep white matter abnormalities in a high percentage of patients with major depression. Important as these

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Fig. 98.1. a FLAIR (upper two rows) and T2-weighted (lower two rows) images of a 64-year-old woman with “benign senescent memory impairment.” The images show hyperintense changes in the deep and periventricular white matter and basal ganglia. The FLAIR images show the abnormalities with greater conspicuity. Clinical and MRI follow-up over the course of 4 years did not show any progression (nondecliner)

98.3

Fig. 98.1. a

Pathogenetic Considerations

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Fig. 98.1. b The gradient echo images of the same 64-year-old woman show hemosiderin deposits, residues of microhemorrhages, in the basal ganglia, more prominent on the left side, and around the anterior commissure. CT scan showed no calcifications

studies are to establish rules for population-based prevention, in individual cases they offer only guidelines. The overall impression one may develop is that leukoaraiosis is too general a concept, so that examined populations and selected cases do not form a homogeneous entity. Certainly some general rules for prevention have been drawn from the research results obtained so far, but future research should aim at the definition of more homogeneous subgroups to obtain better insight in the pathophysiological mechanisms underlying the final common visual product leukoaraiosis.

98.4

Therapy

The development of leukoaraiosis is strongly related to age, and secondarily to risk factors. As they get older, nearly 100% of people will have white matter lesions. At the moment of detection of white matter lesions, whether related to neurological or neuropsychological complaints or as an incidental finding, risk factors should be searched for, where possible treated, and habits such as smoking, excessive drinking, and lack of exercise should be changed. The most important way to take action is by promoting preventive measures that would improve the lifestyle and health of the general population.

98.5

Magnetic Resonance Imaging

With the introduction of CT it became clear that there were age-related changes of the brain, amongst them more or less extensive periventricular areas of hypodensity. MRI showed these changes to better advantage as hyperintense changes on T2-weighted images, and later even better on FLAIR images. Many scales were developed to grade these signal abnormalities and to relate them to neurofunctional deficits, when

present. The lesions seen on MRI in older individuals can be graded as follows: ∑ Frontal and occipital caps: white matter hyperintensity around the frontal horns and the triangular area of the ventricles ∑ A periventricular 1- to 3-mm-thick rim of high signal intensity, best seen on proton density or FLAIR images (These two findings are considered to be without clinical significance and represent areas of looser tissue and widened Virchow–Robin spaces) ∑ Patchy deep white matter lesions, partly isolated, partly confluent ∑ Confluent deep white matter hyperintensity, continuous with periventricular white matter changes ∑ One or a few lacunar infarctions within the affected deep white matter MR has been used extensively to study the process of aging of brain structures in vivo. Pathological studies of the brain depict the terminal phases of disease only and are limited by the relatively small number of samples that can be examined per patient, as a rule in the order of 350–450 at most. In contrast, MR data about normal aging are abundant and can be used as reference data for MR studies in older patients, for example to provide normal values per age group of ventricular and sulcal width, hippocampal and temporal lobe volume, magnetization transfer ratios and histograms, fractional anisotropy, apparent diffusion coefficients, T1 and T2 relaxation times, regional cerebral blood volume, and metabolite concentrations. General experience is that over the age of 50 years one may expect to see white matter abnormalities in patients and controls, increasing exponentially with age (Figs. 98.1 and 98.2). Population-based studies have linked these white matter abnormalities to various risk factors, and also tried to find predictive factors that would indicate risks for future strokes and cognitive decline. The problem with these studies,

98.5

Magnetic Resonance Imaging

Fig. 98.2. FLAIR images of a 71-year-old man presenting with mild apraxia of the left arm and no cognitive impairment. In the periventricular white matter hyperintensities a few lacunar

infarctions are noted.The Trace diffusion-weighted image and ADC map (third row, middle and right) show a small recent infarction with low ADC values in the right periventricular area

especially those that include large populations, is that only basic MR techniques have been used – T1and T2-weighted images – without employment of techniques that allow a better definition of tissue characteristics. The inclusion, for example, of gradient echo refocusing pulse sequences would have shown the members of these populations with micro-

hemorrhages (Fig. 98.1) and thus have identified a group with possibly a different pathogenesis, other risk factors, and different prognosis. Other MR sequences would possibly have led to further differentiation, for example, on the basis of the estimation of tissue integrity with magnetization transfer ratios, or on the basis of the change of brain metabolites in

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Fig. 98.3.

White Matter Lesions of the Elderly

98.5

Magnetic Resonance Imaging

Fig. 98.3. (continued). A 62-year-old man without cognitive complaints, presenting with left-sided hemianopia. The FLAIR images (upper two rows) show hyperintensities consistent with normal aging, except for the left parietal lesion, involving cortex and subcortical white matter. The gradient echo images (third row) show a few low-intensity spots in the left parietal

area, and a single spot in the right parietal area.The fourth row shows Trace diffusion-weighted images with b = 1000; the fifth row shows ADC maps. The left parietal lesion is bright on the Trace images and has ADC values as low as 0.52 ¥ 10–3 mm2/s, confirming the presence of a fresh infarction

MRS, including the presence of lactate in the lesions. Probably the most important MR technique to relate the white matter abnormalities to clinical findings is perfusion imaging. This allows not only the estimation of the degree of hypoperfusion in the involved areas, but also the reserve capacity of the tissue, giving a quantitative measure of the severity of the white matter damage. In daily routine one will be confronted mainly with patients referred for memory disorders and cognitive decline. Apart from ruling out rare causes such as brain tumors, chronic subdural hematomas, and so on, a protocol should be used that will enable assessment of most of the factors responsible for cognitive decline according to present knowledge. This means an inventory of cerebral and cerebellar cortical and deep gray matter structures, including the hippocampus and temporal lobe structures, of white matter abnormalities, and of the presence of microhemorrhages (Fig. 98.1). In patients with rapidly progressive cognitive decline diffusion-weighted imaging with ADC maps should be added to the program (Figs. 98.2 and 98.3). In centers dedicated to the research of mild cognitive impairment, or where vascular factors seem to be important, MR angiography should be included. MRS and chemical shift imaging may give additional

information about neuronal and axonal loss, and about the presence of lactate, indicating anaerobic glycolysis. In many patients follow-up studies will be required. Postprocessing of data is then also very important, to obtain adequate comparable information. This will give a clue with respect to the rate of progression, and information about the efficacy of therapeutic measures and changes in lifestyle (Fig. 98.4). Differential diagnosis is important, because many other disorders may present with deep white matter abnormalities. Disorders with multifocal and partially confluent white matter abnormalities, often accompanied by cognitive impairment, are amyloid angiopathy, CADASIL, multiple sclerosis, cerebral vasculitis, systemic lupus erythematosus, chronic exposure to organic solvents (housepainter’s dementia), and several infections including HIV encephalopathy and progressive multifocal leukoencephalopathy. In Alzheimer disease, in particular in the late-onset forms, white matter abnormalities are common. Disproportional hippocampal atrophy suggests Alzheimer disease. It is important to realize that more and more “mixed” dementias are being recognized, caused by a combination of vascular and neurodegenerative factors.

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Fig. 98.4. FLAIR images of a 67-year-old woman with mild cognitive impairment (first row).There are white matter hyperintensities in the deep and periventricular white matter and corpus callosum, and scattered small lesions in the basal ganglia. Images of the same patient 4 years later (second row) show progression of the abnormalities, with lacunar infarctions in both hemispheres and the brain stem (not shown).

Also clinically there was clear progression of the cognitive disorder. ADC values in this patient in the centrum semiovale had gone up from 0.85–0.95 ¥ 10–3 mm2/s to 1.20–1.25 ¥ 10–3 mm2/s; fractional anisotropy values changed from 0.450 to 0.224, indicating loss of structural integrity. MRS showed lactate in the lesions in the last examination. All evidence is that this patient is a decliner

Chapter 99

Subcortical Arteriosclerotic Encephalopathy

99.1

Clinical Features and Laboratory Investigations

This disease was first described by Binswanger in 1894 as encephalitis subcorticalis chronica progressiva, later renamed by Olzewski (1962) as subcortical arteriosclerotic encephalopathy (SAE). It was believed for a long time that the disease was very rare. Only a few documented cases appeared in the literature before the advent of CT and MRI. CT and, even more, MRI have made it clear that white matter abnormalities are frequent in the brains of older patients. This has opened a discussion that is still going on about the diagnostic criteria for the disease. These criteria comprise: ∑ A vascular risk factor or evidence of systemic vascular disease ∑ Evidence of focal cerebral disease ∑ Evidence of subcortical dysfunction ∑ Bilateral deep white matter abnormalities on CT or MRI ∑ Absence of multiple or bilateral cortical lesions on CT or MRI ∑ Absence of severe dementia (mini mental scale >10) The age of onset is between 40 and 60 years and most patients have a history of chronic hypertension, often poorly controlled, and often one or more vascular incidents. The patients usually present with a slowly developing subcortical frontal dysfunction with loss of interest, lack of drive, alternations in mood and personality, loss of appropriate social conduct and lack of judgment, parkinsonian gait disturbances, urinary incontinence, and pseudobulbar palsy. Minor strokes may occur with a variable degree of improvement of the neurological deficits. Gradually the dementia progresses and more neurological symptoms become manifest, including dysarthria, clumsiness, disturbances of gait, ataxia and apraxia, and finally profound global dementia. It may be difficult to distinguish SAE on clinical grounds from Alzheimer disease and other vascular dementias. There are no specific laboratory markers for the disease. Discussion has been going on for a long time whether or not SAE is a disease entity, but after the reviews of Fisher (1989) and Caplan (1995) there seem to be sufficient arguments to do so.

99.2

Pathology

Externally the brain in patients with SAE appears normal. The brain weight is average. In most cases the arteries at the base of the brain show moderate to severe arteriosclerosis. The lateral ventricles are moderately to highly enlarged. In advanced cases the cerebral hemispheric white matter appears wrinkled, firm, rubbery, and discolored gray or yellow, especially in the periventricular, frontal, and parietal regions. Histopathologically, the white matter lesions consist of partial loss of myelin sheaths, oligodendroglial cells, and axons, producing a decrease of the meshwork density of white matter tissue, along with mild reactive fibrillary gliosis and sparse macrophages.Arteriosclerosis is invariably present in these areas of incomplete infarction, and there is severe stenosis of the smallest vessels by fibrohyalinose material. The U fibers are usually spared. The temporal lobes, too, in contrast to the findings in CADASIL, are uninvolved. État criblé, widening of the Virchow–Robin spaces, is an almost constant feature. État criblé results from spiraled elongation of penetrating arteries and arterioles in white matter and central gray matter nuclei. Blood vessels in areas of état criblé are thickened, ectatic, and have sclerotic walls. The perivascular tissue shows reactive astrocytosis and isomorphic gliosis with glial fibers extending along degenerated axons. There is perivascular leakage of serum proteins. Multiple lacunar infarctions, état lacunaire, are also a frequent finding. Lacunes are small cavitary lesions that result from ischemic strokes due to occlusion of penetrating cerebral arterioles. Lacunes predominate in the basal ganglia, internal capsule, pons, and centrum semiovale. Fresh lacunes show necrosis and liquefaction, followed by absorption of necrotic material by fatty macrophages. In the chronic stage an irregular cavity remains, whose walls show dense fibrillary connective tissue and gliosis. Reabsorption of minute hemorrhages may also result in lacunes leaving hemosiderin-filled macrophages in the walls and in the vicinity of the lesions.

99.3

Pathogenetic Considerations

The main characteristic of SAE is arteriosclerosis with narrowing and occlusion of the deep perforating cerebral arteries and their branches. These arteries

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and arterioles are end vessels without collateral circulation. They form an arterial end and border zone in the periventricular region. The cortex and subcortical white matter are within the territory of supply of the cortical vessels and their leptomeningeal anastomoses. SAE is characterized by microinfarctions, focal or diffuse demyelination, and gliosis of the periventricular and deep white matter, in combination with lacunar infarctions in the basal ganglia and brain stem. It is commonly accepted that SAE type encephalopathy is caused by ischemia in the distal watershed territories described above. The ischemia is the combined effect of arteriosclerosis and decreased brain perfusion from hypotension or low cardiac output. Elongation of the medullary arteries with dilatation of the perivascular spaces leads to an état criblé. There are numerous risk factors underlying these changes, such as age, hypertension, hypotension, smoking, inadequate diet, and diabetes mellitus. A number of genetic factors may also play a role. Hyperhomocysteinemia and hyperlipidemia have been identified as important risk factors. Effects of sustained daytime hypertension, hypertensive crises, and the absence of a normal nocturnal dip in blood pressure are considered to be particularly damaging. Another factor that may play a role in the development and progression of SAE is coagulation activation, leading to a hypercoagulable state. In a selected group of SAE patients, fibrinogen, thrombin–antithrombin complex, prothrombin fragment1+2, and cross-linked D-dimer were found to be significantly increased. Obstructive sleep apnea, which produces increased platelet activation, higher epinephrine levels with vasoconstrictive effect, and higher blood pressure, also plays a role. There is little doubt that the changes caused by these factors are responsible for the abnormalities seen on MRI. That these MRI changes do not necessarily have the same histopathological background is illustrated by the observation that some patients with severe periventricular abnormalities on MRI have a mild clinical presentation, whereas other patients with much less severe MRI abnormalities have advanced clinical symptoms.

99.4

Therapy

There is no cure for SAE. Whenever hypertension is present, treating it may slow down the progress of disease. Other risk factors such as hyperlipidemia and hyperhomocysteinemia should be treated, and bad habits such as smoking and excessive drinking should be given up. There is some evidence that in an early stage the disease can still be influenced by these measures. Some success has been booked with med-

ication. The robust evidence for the effectiveness of cholinergic treatments in Alzheimer disease, and the frequent occurrence of mixed dementias, has led to the testing of galantamine (Reminyl) in a group of patients with SAE. Galantamine has a dual cholinergic mode of action, and reduces behavioral symptoms in Alzheimer disease. This is the result of its potential to modulate systems involving other neurotransmitters such as serotonin and dopamine, which affect mood and emotional balance.Application of galantamine in SAE patients led to significant cognitive improvement over 6 months, long-term maintenance of cognition for at least 12 months, and improvement of both behavioral and functional symptoms. These data suggest a result that is, so far, unsurpassed by other drugs or treatment regimens.

99.5

Magnetic Resonance Imaging

In patients with presenile dementia and a history of hypertension the diagnosis SAE depends on two parameters: the clinical establishment of a subcortical type of dementia and the establishment of diffuse damage to periventricular and deep white matter by means of an imaging modality, CT or MRI. In uncomplicated cases of SAE, CT and MRI identify a relatively well preserved cortex, moderately to more seriously enlarged ventricles, and a broad area of reduced density around the ventricles on CT or, on MRI, a zone of high signal intensity on T2-weighted and FLAIR images, involving the periventricular and deep white matter (Figs. 99.1–99.3). The more central lesions, closest to the ventricles, are usually confluent; farther away from the center there are often many isolated lesions of different size (Figs. 99.1 and 99.3). Within the confluent areas there may be spots with still higher signal intensity on T2-weighted images, possibly representing infarctions. In some cases small cavities are present with low signal intensity on FLAIR images, often with a bright rim, as residues of lacunar infarctions (Fig. 99.3). In the early phases of the disease the U fibers are usually spared (Fig. 99.1). In cases of longer standing white matter disorder the subcortical fibers may also be partially involved (Figs. 99.2 and 99.3). In some cases cortical infarctions are also seen. Apart from the periventricular and deep white matter lesions there are often isolated hyperintense lesions scattered throughout the basal ganglia, the pons, and midbrain, representing small infarctions (Figs. 99.1 and 99.2). Widened Virchow– Robin spaces and lacunar infarctions are best seen on FLAIR images (Fig. 99.3). The corpus callosum is usually less affected than in multiple sclerosis, but this is a rule with many exceptions. Sagittal FLAIR images will often show involvement of the under layer and thinning of the corpus callosum (Fig. 99.3).

99.5

Magnetic Resonance Imaging

Fig. 99.1. FLAIR images of a 56-year-old woman. The patient had the antecedents of SAE with longstanding hypertension and multiple transient ischemic attacks. Her images show some of the characteristics seen in CADASIL, with the involve-

ment of the external capsule and the dark appearance of the globus pallidus, but the temporal lobes are not affected. Family history and tests for CADASIL were negative

Standard MRI series are fully capable of displaying most of the cerebral abnormalities. Fast imaging sequences can often be used to advantage. FLAIR is very useful to show older lacunar infarctions and enlarged perivascular spaces within the affected white matter and the basal ganglia as spots with low signal intensity, and to show the demarcation of the ventricles from the periventricular abnormalities. FLAIR is also useful when estimation of lesion load is required in research programs. Gradient refocused images should be standard in a MR protocol for dementing illnesses in the older age group, because they will show spots with high magnetic susceptibility, representing hemosiderin deposits in microhemorrhages. They are found in a high percentage of patients with SAE and in many other vascular disorders. Diffusion-weighted imaging may be helpful in identifying fresh infarctions, which will otherwise be lost in the brightness of the lesions that probably represent old infarctions, myelin loss, and gliosis. MRS usually shows decrease

in N-acetylaspartate and, in some cases, presence of some lactate. The differential diagnosis includes in the first place periventricular and deep white matter changes which occur in normal elderly people with varying severity. The differentiation from normal pressure hydrocephalus may be difficult when the ventricles are greatly enlarged. Additionally, the combination of SAE and normal pressure hydrocephalus seems very possible. Stiffening of the walls of the ventricles in SAE may even play a role in the pathogenesis of normal pressure hydrocephalus. Other vascular diseases such as amyloid angiopathy and CADASIL have to be considered. Unlike CADASIL, patients with SAE do not have prominent abnormalities in the external and extreme capsules and the anterior temporal lobes, although the images may show some similarities (Fig. 99.1). Rarer are vasculitides, Fabry disease, Lyme disease, HIV infection, leukoencephalopathy after chemotherapy or radiotherapy, and toxic encephalo-

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Fig. 99.2. A 58-year-old man with progressive subcortical dementia and transient ischemic attacks. The T2-weighted series shows a periventricular leukoencephalopathy extending into the centrum semiovale, in some areas also involving the U

fibers. Small lesions are seen in the left cerebellar hemisphere. Diffuse hyperintensities are present in the pons. There are small, punctate lesions in the basal ganglia and in the corpus callosum

Fig. 99.3. A 64-year-old man with more advanced dementia and a history of hypertension and transient ischemic attacks. The axial FLAIR images (first and second rows) show ventriculomegaly, periventricular leukoencephalopathy, and prominent white matter atrophy. État criblé of the basal ganglia is

visualized. The sagittal FLAIR images (third and fourth rows) show more clearly the involvement of the corpus callosum and the fornix, both thinned and partly hyperintense.The état criblé of the basal ganglia is beautifully seen

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99.5

Fig. 99.3.

Magnetic Resonance Imaging

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pathies. In general, vascular diseases share a pattern of irregularly confluent periventricular white matter abnormalities with often multiple isolated lesions at the periphery, multifocal lesions in the basal ganglia,

and often also brain stem lesions. The presence of small lacunes adds to the suspicion of a vascular disorder.

Chapter 100

Vasculitis

100.1 Introduction The term “vasculitis” refers to inflammation of the vessel walls. There are many causes of vasculitis, but they result in only a few histological patterns of vascular inflammation, of which necrotizing vasculitis and granulomatous reaction are the most prominent. Because vessels of any type in any organ can be affected, there are a wide variety of clinical manifestations. This, combined with etiological nonspecificity of the histological lesions, complicates the diagnosis of vasculitis. The past few decades have seen important progress in this field, enabling a laboratory diagnosis in some cases. A good example is the discovery in 1982 of the anti-neutrophil cytoplasm antibodies (ANCAs), subdivided into a perinuclear form (pANCA), related to Churg–Strauss syndrome and microscopic polyarteritis, and a cytoplasmic form (cANCA), related to Wegener disease. The blood tests for these antibodies are now widely available, but they need careful application and interpretation. Other findings, such as the detection of anti-neuronal antibodies, anti-centromere antibodies, and anti-phospholipid antibodies (APLA), have shed some light on the pathophysiology of a number of disorders and have demonstrated a link between systemic lupus erythematosus (SLE) and Sneddon disease. Many more autoantibodies have been identified and they may help in better understanding the complex pathology underlying these disorders. Despite these discoveries the diagnosis of vasculitis remains often difficult, in particular in the primary vasculitides of the CNS.

Fig. 100.1. Different vasculitic disorders may preferentially attack blood vessels of a particular size. AS, arteriosclerosis; cAA, cerebral amyloid angiopathy; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; PACNS, primary angiitis of the CNS; PAN, polyarteritis nodosa; MPAN, micropolyarteritis nodosa; SLE, systemic lupus erythematosus

To organize the discussion we suggest the following classification: A subclassification that may be helpful in reaching a diagnosis is division according to the size of vessels affected by the disorder, even though there is a considerable overlap. Takayasu disease and giant cell arteritis affect large vessels; primary angiitis of the CNS and polyarteritis nodosa affect medium-sized vessels; Wegener granulomatosis, Churg–Strauss syndrome, rheumatoid disorders, SLE, microscopic polyarteritis, scleroderma, and many other vasculitic disorders involve small vessels: arterioles, capillaries, and venules. Behçet disease involves all types and sizes of vessels, arterial or venous (Fig. 100.1).

100.2 Clinical Presentation and Laboratory Findings As in all relapsing multifocal disorders that may affect both gray and white matter, the clinical manifestations of the disease depend on the localization of the abnormalities, progression over time, and the nature of the disease. Symptoms may be neurological or psychiatric or both, and cognitive deterioration may be the leading feature. When the cerebral manifestations are part of a systemic disorder the diagnosis may be easier, unless the cerebral symptoms are the first or only manifestation. Clinically there are many factors to consider: age, gender, presence of skin lesions, involvement of other organs (in particular kidneys, lungs, and paranasal sinuses), medication, drug abuse, and neurological

774 Chapter 100 Vasculitis Table 100.1. Classification of CNS vasculitis (including nonvasculitic disorders that may present with similar pathology to some of the vasculitides) Primary vasculitis of the CNS Granulomatous angiitis of the CNS (primary angiitis of the CNS) Giant cell arteritis (arteritis temporalis) (Benign primary angiitis of the CNS) Secondary vasculitis of the CNS Systemic vessel wall disease Takayasu arteritis Polyarteritis nodosa Moyamoya syndrome Autoimmune-mediated disorders Rheumatoid arteritis Systemic lupus erythematosusa (SLE) Sneddon diseasea Anti-phospholipid antibody (APLA) syndrome Sjögren disease Scleroderma Neurosarcoidosis Wegener granulomatosisb Churg–Strauss syndromeb Microscopic polyarteritisb Behçet disease Infectious vasculitis Borreliosis (Lyme disease) Lues Tuberculosis Varicella-zoster Herpes zoster ophthalmicus (delayed hemiplegia) Drug-related vasculitis Aminopenicillins Ergot alkaloids Allopurinol Interleukin-2 Retinoids Methylphenidate Quinolones Penicillin Cocaine, heroin, amphetamines, ecstasy Disorders primarily obstructing the vascular lumenc Disorders of coagulation Intravascular lymphomatosis Sickle cell disease a b c

APLA-related disorder. ANCA-related disorder. Disorders that may present with similar pathology to some of the vasculitides, but have an endoluminal cause and often require different treatment.

signs, including cognitive deterioration, focal cortical symptoms, stroke-like episodes, etc. Relevant laboratory tests include erythrocyte sedimentation rate, complement activation, immune status and antibodies in blood and CSF, protein and cell content of the CSF, and assessment of coagulation factors. All these items may be unrevealing, even in histologically confirmed cases of vasculitis. MRI may play an important role, even though the abnormalities found on MRI are usually not diagnostic. It is rare, however, that cerebral vasculitis exists with a negative MRI. A normal MRI should even lead to reconsideration of the diagnosis. MRA may be helpful in showing the vascular abnormalities, but special contrast-enhanced techniques should be used. Intra-arterial DSA may be helpful in some cas-

Fig. 100.2. Intra-arterial DSA of the right internal carotid artery in a 37-year-old woman with biopsy-proven granulomatous angiitis of the CNS, showing the irregular size of the lumen of the posterior temporal artery. Other vessels also show irregular borders

es, for example, in moyamoya syndrome, Takayasu disease, and infectious vasculitis. In quite a number of cases a leptomeningeal or brain biopsy will still be required, especially in primary angiitis of the CNS, to ascertain the diagnosis. However, this is not full proof either. The most important features and data of the different forms of vasculitis will be briefly reviewed. 100.2.1 Primary Vasculitis of the CNS Granulomatous angiitis (also primary angiitis of the CNS, PACNS) is the most important representative of primary vasculitides of the CNS. The presenting clinical signs of granulomatous angiitis are nonspecific, often suggesting global dysfunction of the CNS.Acute or subacute onset confusion, headache, change of personality, paresis, cranial neuropathy, or loss of consciousness are often presenting signs but as such nonspecific. The most frequent presenting symptoms of granulomatous angiitis are headache (68%), paresis (56%), and confusion (55%). In almost 25% of the patients fever and elevated blood pressure are noted. Dermatological abnormalities are rare. Funduscopy reveals vascular changes in 25% of patients. The erythrocyte sedimentation rate is in most cases elevated. CSF pressure is usually increased, and CSF is nearly always abnormal with increased total protein, lymphocytic pleocytosis, and in 30% of the patients decreased glucose levels.

100.2

Clinical Presentation and Laboratory Findings

Fig. 100.3. T1-weighted images with contrast (first row) of a 46-year-old woman with granulomatous angiitis of the CNS, showing an enhancing infarction in the right parietal lobe. MRA (second row) shows rapid and irregular tapering of the more distal branches of the middle and posterior cerebral arteries

Postmortem examination of brain tissue and examination of brain biopsy material show an inflammatory process of small arteries and arterioles, preferentially involving deep white matter and leptomeningeal vessels. Intima proliferation and fibrosis are frequent, with multinuclear giant cells of the Langhans type and foreign body type. In comparison with the other vessel layers, the media is relatively spared. Granulomata with macrophages and lymphocytes are present. The cause of the disease is unknown. MRI and angiography are helpful in revealing the CNS lesions, consisting of multiple white and gray matter lesions and changes of caliber in the cerebral vessels (Figs. 100.2 and 100.3). MRA is usually not informative, but may show vascular irregularities (Fig. 100.3). The MRI pattern is not specific, but may suggest a vasculitis by a combination of multiple white and gray matter lesions and infarctions of different sizes (Fig. 100.4). Diffusion-weighted imaging may show lesions with high signal intensity and low ADC values, representative of infarctions. Without treatment the disease is usually fatal. However, granulomatous angiitis responds to highdose steroids and cytotoxic agents such as cyclophosphamide and azathioprine.

Giant cell arteritis or arteritis temporalis usually occurs in patients, male and female, who are over the age of 55 years. It often involves the superficial temporal arteries, which become swollen, tortuous, tender, and nodular. Pulsations are usually diminished. Eventually the vessels become hardened and shrink. Clinical problems most often consist of acute visual failure of one eye. Signs of CNS dysfunction are relatively rare. However, all larger and medium-sized vessels of the head and neck may become involved. Of particular interest are the carotid, vertebral, and ophthalmic arteries, including the ciliary arteries and the central artery of the retina. The cervical portions of the carotid and vertebral arteries are usually involved, the intracranial arteries to a lesser extent, and the spinal arteries least of all. The erythrocyte sedimentation rate is in most cases elevated. Histologically segmental, multifocal panarteritis is found. The intima of the vessels is thickened by subendothelial fibrosis, narrowing or occluding the lumen. The internal elastic lamina is severely but irregularly fragmented. The media is infiltrated by small and large mononuclear cells, some of the epithelioid type. Giant cells of either Langhans or foreign body type are almost invariably present, either in the media close to the damaged internal elastic lami-

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Fig. 100.4. A 57-year-old woman with multiple stroke-like episodes over the years. FLAIR images show a large temporoparieto-occipital infarct on the right side and several lesions in the left hemisphere, with some focal cortical atrophy. Note that the distribution of the infarction does not reflect a single

vascular territory, similar to what is seen in MELAS. A mitochondrial disorder was ruled out and the diagnosis granulomatous angiitis of the CNS was established. Courtesy of Dr. M. Heitbrink and Dr. B. Wiarda, Department of Radiology, Medical Center Alkmaar, The Netherlands

na or in the adjacent intima. With healing there is scarring and occasionally aneurysm formation. In some cases the vessels are occluded by organizing thrombus. MRI will show intracerebral lesions, but there is no specific pattern. MRA usually lacks resolution to visualize the abnormal vessels. Intra-arterial DSA may be more helpful in showing the diseased vessels. Diagnosis, however, is usually established by biopsy of the temporal vessels. A negative biopsy does not exclude the diagnosis. Therapy includes the use of corticosteroids and immunosuppressives. Benign primary angiitis of the CNS is best characterized as a self-limiting form of granulomatous angiitis of the CNS. This, of course, is a diagnosis a posteriori, because there are no criteria by which to distinguish progressive forms from nonprogressive.

100.2.2 Secondary Vasculitis of the CNS 100.2.2.1 Systemic Vessel Wall Disease Takayasu arteritis affects the aortic arch and its branches, in particular in young women of Asiatic origin. The smaller intracranial vessels are usually not involved. The neurological symptoms are variable because they depend on the extent of the blood vessel abnormalities, in particular the involvement of the carotid and vertebral arteries. Visual problems are relatively frequent, most often as one-sided amaurosis fugax. Many other neurological symptoms are possible, including hemiparesis, aphasia, cranial nerve palsies, coordination problems, and vertigo. Laboratory investigations are unrevealing. Histologically there are lesions in the media and adventitia of the vessels, but they are predominant in the adventitia. The lesions demonstrate collagenous proliferation and perivascular lymphocyte infiltration. The media shows an inflammatory granulomatous re-

100.2

Clinical Presentation and Laboratory Findings

Fig. 100.5. Two intra-arterial DSA images (left) of Takayasu disease. On the left-hand image the narrowing of the neck vessels is clearly visible. The selective injection of the subclavian

artery (middle) shows irregular narrowing of the arteries. The MRA image on the right shows narrowing and wall irregularities of the subclavian arteries and the neck arteries

action, narrowing the lumen. The cerebral lesions are secondary to either diminished perfusion or emboli. MRA, especially contrast-enhanced MRA of the aortic arch and branches, is now fully capable of making an inventory of all involved vessels (Fig. 100.5). Treatment consists of corticosteroids, immunosuppressives, and, where necessary, interventional radiology or vascular surgery for bypasses, stent placement, and transposition of vessels. In polyarteritis nodosa CNS manifestations usually develop in patients who have had systemic disease for several years, in particular with involvement of the kidneys and the lungs. Clinically two main groups of CNS involvement can be distinguished: one with general signs of CNS involvement, including changes of consciousness and epileptic seizures; the other with focal or multifocal signs, including ataxia, aphasia, hemiparesis, sensory disorders, ophthalmoplegia, and visual disorders. The most common neurological presentation is polyneuropathy. The erythrocyte sedimentation rate is often but not always increased. CSF is usually normal. Histologically the small arteries and arterioles are most often affected, especially in the leptomeninges, the deep white and gray matter, and the choroid plexus. The affected vessels show fibrinoid or hyaline necrosis of the media and destruction of the internal elastic lamina. Inflammatory granuloma affects the entire thickness of the vessel wall, with secondary intima lesions, eventually obstructing the vessel lumen. Segmental vessel wall necrosis may lead to the formation of

small aneurysms. The parenchymal lesions are small infarctions, multiple and disseminated, sometimes hemorrhagic. Part of the periarteritis nodosa group is abuse-associated vasculitis, best described in intravenous methamphetamine users, and hepatitis B virus-associated vasculitis. In these cases, too, the disorder is systemic. MRI shows the cerebral involvement as multiple white and gray matter lesions, both lacunar and territorial infarctions. High-resolution MRA may also show vascular abnormalities. Moyamoya syndrome, (moyamoya meaning “puff of smoke,”) was long considered an ethnic disease limited to patients of Japanese ancestry. Today, however, it is clear that the disease occurs in Europe and America as well. The disease is a progressive arteritis of the supraclinoid portion of the carotid arteries, eventually leading to complete occlusion. The disease usually starts at a young age, rarely under the age of 10 years. The fact that the disease is limited to the carotid arteries has led to the suggestion that the disease is related to a defect in embryogenesis, which is different for the carotid arteries from what it is for the vertebrobasilar system. In the later phases an extensive collateral circulation characteristically develops, partly via external carotid arteries, partly via the posterior cerebral artery circulation. Laboratory investigations are unrevealing in moyamoya syndrome. Histopathological examination in moyamoya syndrome reveals that the principal alterations are stenosis and occlusion of the distal portions of the internal carotid arteries and the proximal

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Fig. 100.6. FLAIR images of a 9-year-old boy with moyamoya syndrome and multiple cortical infarctions (first two rows).The image pattern is similar to what is seen in MELAS, but the images through the basal ganglia suggest the presence of many abnormal vessels. The third row shows the source images of the MRA, revealing the abundance of small and very small vessels all through the brain, reflecting the collateral circulation,

most intensive in the basal ganglia. The intra-arterial DSA of the left internal carotid artery (fourth row, next page) shows the typical changes of moyamoya syndrome with a “puff” of abnormal vessels in the center. The later phase (fifth row) shows the remaining circulation via the posterior cerebral artery, with the collateral “puff of smoke” in the basal ganglia, and the leptomeningeal collaterals in the parietal lobe

parts of the anterior and middle cerebral arteries. This is combined with numerous dilated, thin-walled collateral arteries branching from the posterior parts of the circle of Willis. In the stenotic arteries the

intima shows massive fibrous thickening, without atheromatous features. The internal elastic lamina is usually preserved but extremely wavy and often duplicated or triplicated. The media is atrophic. There is

100.2

Clinical Presentation and Laboratory Findings

Fig. 100.6. (continued).

no inflammatory infiltration, but thrombosis, recanalization, and aneurysm formation may occur. The diagnosis can be established with radiological techniques. The anastomoses via lenticulostriate arteries in the basal ganglia give rise to the typical appearance of a cloud (“puff of smoke”) on intra-arterial DSA (Fig. 100.6), whereas on MRI the usual appearance is of multiple infarctions, both territorial and hypoperfusion-related border zone infarctions. Either the cortex or the cerebral white matter is principally affected (Figs. 100.6 and 100.7). On high-resolution images multiple dilated small vessels may be visible in the basal ganglia (Figs. 100.6 and 100.7). In advanced cases there may be dilated small vessels scattered throughout the brain.

There is no real cure for the disease, but microvascular surgery may help to restore some of the perfusion by vascular anastomoses 100.2.2.2 Autoimmune-Related Disorders The rheumatological syndromes associated with CNS disease due to vasculitis include a broad spectrum of autoimmune diseases. At one end of this spectrum one finds organ-specific diseases with organ-specific antibodies, for example Hashimoto disease of the thyroid. In the middle of the spectrum the lesions tend to be localized in one organ but the antibodies are not organ-specific. A typical example is primary biliary cirrhosis, where the small bile ductules are the main target of inflammatory cell infiltration but the serum

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Fig. 100.7.

100.2 䊴

Fig. 100.7. A series of T2-weighted images (first and second rows) of a 9-year-old boy with moyamoya syndrome.There are extensive white matter abnormalities in the deep white matter of the cerebral hemispheres suggesting a leukodystrophy. Note that within the abnormal white matter many punctate lesions are present, with high signal intensity in parts and low signal intensity in others. The blown-up image of the basal ganglia shows this to better advantage (third row, left).The axial and sagittal T1-weighted images (third row, middle and right) show that there is an abundance of small abnormal vessels in the brain parenchyma. The source images of the MRA and the MRA itself (fourth row) confirm this. The MRA demonstrates that the large cerebral arteries are occluded. Note the contribution of external vessels to perfusion of the cerebral parenchyma on the left side of the image. The intra-arterial DSA confirmed the diagnosis of moyamoya syndrome

Clinical Presentation and Laboratory Findings

antibodies, mainly antimitochondrial, are not organspecific.At the other end of the spectrum the disorder is not organ-specific; lesions and antibodies are not confined to a single organ. In SLE, and many other autoimmune disorders, lesions are seen in the skin, renal glomeruli, joints, serous membranes, and blood vessels. Rheumatoid disease with CNS vasculitis is a relatively rare occurrence. In all patients joint disease is apparent. Patients may have had demonstrable rheumatoid arthritis for between 1 and 30 years prior to the onset of their neurological problems. CNS disease manifests itself nonspecifically by a multitude of possible neurological signs and symptoms, including seizures, dementia, hemiparesis, cranial nerve palsies, blindness, cerebellar ataxia, and dysphasia.

Fig. 100.8. The transverse and coronal FLAIR images of a 9-year-old boy presenting with progressive dementia show multiple, mainly cortical infarctions. The MRI would be com-

patible with a diagnosis of MELAS. In this case the clinical and laboratory diagnosis was SLE

Fig. 100.9. The FLAIR images of a 25-year-old woman with a multiple sclerosis-like presentation show an MRI pattern compatible with this diagnosis. Shortly after the MRI she was diag-

nosed with SLE. Courtesy of Dr. M. Driessen-Kletter, Department of Neurology, Twenteborg Hospital, Almelo, The Netherlands

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Fig. 100.10.

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Clinical Presentation and Laboratory Findings

Fig. 100.10. (continued). Images of a 50-year-old female patient with SLE.The upper row of T1-weighted images show high signal intensity in the basal ganglia, the pulvinar, and the dentate nucleus. The T2-weighted images (second and third rows) demonstrate a broad rim of hyperintensity around the lateral ventricles. The basal ganglia, pulvinar, dentate nucleus, and multiple areas of the cortico-subcortical junction appear

very dark, suggesting calcium deposits. Gradient echo images (fourth row) show hypointensity in the same areas. The CT images (fifth row) confirm that there are massive calcifications in these areas. Note that the corpus medullare of the cerebellum is also calcified. Courtesy of Dr. E. Gut, Department of Neuroradiology, Kliniken Schmieder, Allensbach, Germany

Serum rheumatoid factors are present and the erythrocyte sedimentation rate is elevated. Histological examination reveals in a number of cases amyloid deposits together with signs of vasculitis. MRI is nonspecific and in most cases shows scattered white matter lesions, sometimes mimicking multiple sclerosis. The presence of systemic abnormalities will in most cases suggest the diagnosis. Therapy of rheumatoid disorders is often complex and may include antiphlogistic medication, corticosteroids, immunosuppressives, cytokines and many supportive measures. Systemic lupus erythematosus (SLE) is a chronic, relapsing-remitting disease, with variable involvement of different organ systems. The disease occurs preferentially in adolescent and young adult women. Frequent findings include malar rash (butterfly rash), nonerosive arthritis involving multiple joints leading to tenderness, swelling, and effusion, serositis of pleura or pericardium, renal abnormalities, Raynaud phenomenon, lymphadenopathy, and gastrointestinal complaints. Cerebral involvement often presents with neuropsychiatric symptoms. Neurological disease is the second or third leading cause of death after renal disease. Neurological manifestations usually follow systemic manifestations by more than a year. The symptomatology is related to the site of CNS involvement.Also, there may be spinal cord involvement with transverse myelitis. There are criteria for the diagnosis of SLE (American College of Rheumatology), which contain both clinical symptoms and more or less specific laboratory findings, such as hemolytic anemia with reticulo-

sis, lymphopenia, elevated anti-DNA antibodies, false positive test to syphilis (VDRL), complement activation, and an abnormal titer of autoantibodies, such as lupus anticoagulant, anti-cardiolipin and other APLA. Immune complexes and diminished levels or altered metabolism of the fourth component of the complement cascade have been found in the CSF of patients with CNS disease. Antibodies to neuronal antigens, often cross-reacting with lymphocytic antigens, are preferentially seen in the serum and CSF of patients with neurological manifestations. The principal diagnostic test for the disease is the presence of antinuclear antibodies; antibodies against doublestranded native DNA are specific for SLE. Histological true vasculitis of the CNS is rare, but vasculopathic changes are common. Microscopic changes are most marked in small vessels and consist of acute fibrinoid necrosis and marked thickening of the vessel wall with minimal inflammatory cell infiltration. Some vessels are occluded by thrombi with corresponding microinfarcts. Autoimmune factors that play a role in the cerebral vascular changes in SLE have been identified as lupus anticoagulant, APLA, and anti-cardiolipin antibodies. They link SLE with the pure anti-phospholipid syndrome and with Sneddon disease, which is probably a variation of the antiphospholipid syndrome. Many different MRI patterns can be encountered in SLE. Sometimes the MRI pattern mimics MELAS, showing mainly cortical infarctions (Fig. 100.8). Sometimes it mimics multiple sclerosis (Fig. 100.9). In other cases there are more widespread white matter lesions (Figs. 100.10 and 100.11). In some patients se-

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Fig. 100.11. A 56-year-old woman with a long history of complicated SLE.There is symmetrical involvement of the cerebral hemispheric white matter, the anterior and posterior limbs of the internal capsule, the external capsule, the thalamus (especially the pulvinar), the midbrain, pons, middle cerebellar pe-

duncles, the hilus of the dentate nucleus, and the peridentate white matter. Courtesy of Dr. R. Schiffmann, Developmental and Metabolic Neurology Branch,National Institutes of Health, Bethesda, Maryland, USA

vere involvement of the basal ganglia is seen, a pattern that has to be differentiated from central venous thrombosis. In still other patients there is extensive calcification of the basal ganglia, dentate nucleus, centrum semiovale, and cortico-subcortical junction (Fig. 100.10). Enhancement may occur in active lesions. In some cases, despite neuropsychiatric symptoms, conventional MRI is normal. In those cases estimation of magnetization transfer histograms may detect abnormalities, without otherwise visible lesions. Therapy is usually with corticosteroids and immunosuppressives. Sneddon syndrome is characterized by a combination of generalized livedo racemosa (or reticularis), a cutaneous condition featured by a reddish-purple reticulated pattern predominantly present on trunk and extremities, and diffuse intravascular coagulation leading to cerebrovascular manifestations. The skin abnormality is not specific, but may be also be associated with polyarteritis nodosa, SLE, rheuma-

toid arthritis, thrombocytopenic purpura, and polycythemia. At an early age the patients develop cerebrovascular manifestations, including larger and smaller arterial territorial infarctions, with severe neurological consequences and often cognitive deterioration. Sneddon syndrome is linked with the presence of anti-cardiolipin antibodies (one of the APLA), and therefore Sneddon syndrome may be regarded as belonging to the APLA-related disorders. However, the presence of APLA is highly variable in Sneddon disease (41% positive). In APLA-positive patients, audible mitral regurgitation is observed more frequently. There is a close relationship between Sneddon syndrome, SLE, and “pure” APLA syndrome. It has been suggested that Sneddon syndrome might cover a continuum of various clinical and biological entities, ranging from APLA-related SLE patients, to primary APLA-positive patients, and Sneddon syndrome in the middle.

100.2

Clinical Presentation and Laboratory Findings

Fig. 100.12. Gradient echo images of two patients with Sneddon syndrome. The upper two images are of a 53-yearold woman who has suffered multiple infarctions in the past. She is now wheelchair-bound and suffering from progressive cognitive impairment.The lower two images are of a 42- year-old woman who has also suffered multiple transient ischemic attacks and permanent infarctions. She also has impairment of cognitive functions. In both women there is ventriculomegaly.The gradient echo images show the preferential occurrence of the hemorrhages at the surface of the brain and the ependymal lining.This is not often seen in other vasculitides. The superficial hemorrhages result in focal superficial hemosiderosis.The black rim around the brain stem in the upper images is also caused by hemosiderin. In the lower images punctate black dots are seen nearly everywhere in the brain, reflecting microhemorrhages

Nonspecific laboratory findings include an elevated erythrocyte sedimentation rate. The finding of APLA in addition to typical skin abnormalities confirms the diagnosis. Histopathologically Sneddon syndrome particularly attacks small cortical arteries. Infarctions are, therefore, most often located in cortical areas. They are often hemorrhagic, and hemosiderin deposits are also found in the leptomeninges. MRI shows a variable number of smaller and larger infarctions, in which cortical involvement is most prominent. With gradient echo techniques multiple hemosiderin deposits with extensive superficial hemosiderosis is the most common finding. In our experience this finding is more constant in Sneddon syndrome than in other vasculitides (Fig. 100.12). Treatment according to the guidelines for SLE and APLA syndrome is the rule. Anti-phospholipid antibody syndrome. Anti-phospholipid antibodies (APLA) are antibodies against phospholipids and are found in a variety of clinical disorders. The discovery of APLA followed the observation that in a patient with SLE the activated partial thromboplastin time (aPTT) was prolonged (lupus anticoagulant). Despite this, patients with high levels of APLA do not develop hemorrhagic complications

unless they also have thrombocytopenia. On the contrary, patients present with a hypercoagulative state which leads to thrombotic complications, stroke, myocardial infarctions, dementia, and fetal loss. APLA syndrome is found in up to 30–50% of patients with SLE. Patients without SLE or other systemic disease can also develop APLA syndrome, referred to either secondary or primary or pure APLA syndrome. Children may develop secondary APLA syndrome during viral infections. Up to 30% of patients with HIV-infection develop secondary APLA syndrome.“Pure” APLA syndrome occurs in patients without any of these antecedents. Venous thrombosis is a relatively frequent occurrence in APLA syndrome. About 30% of patients with APLA syndrome acquire deep venous thrombosis. In patients with APLA syndrome and SLE the figure is even 40%. In drug-induced or parainfectious APLA syndrome it is less than 5%. Patients with APLA syndrome may prove difficult to treat for venous thrombosis and they have a high rate of recurrence. In young adults with APLA syndrome there is an increased risk of arterial disease, leading to myocardial infarctions, stroke, and a higher incidence of peripheral vascular occlusions. In addition to brain damage by territorial infarctions, patients often present with

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early-onset dementia, the average age at onset being 52 years. In these patients there is usually no history of major strokes. Associated findings include livedo racemosa, Raynaud phenomenon, superficial thrombophlebitis, cardiac valve vegetations, and mitral regurgitation. Laboratory testing for APLA syndrome is complex and several subtests are involved. There is no simple screening test for the condition. Testing should be done when one or more of the major clinical manifestations occur: arterial or venous thrombosis, thrombocytopenia, or frequent miscarriages. Primary APLA syndrome patients are more often male, and have a low titer of anti-nuclear antibodies. MRI can, with the appropriate techniques, demonstrate the involvement of the CNS. MRI shows white matter abnormalities, suggestive of small vessel disease. Apart from the white matter involvement, lesions usually extend into the cortical layers. In fresh infarctions diffusion-weighted imaging is helpful. Gradient echo sequences will show microhemorrhages when present. Therapeutically one has to be aware that, although APLA syndrome is considered to be an autoimmune disease, immunosuppressive therapy does not prevent recurrent thrombosis, fetal loss, or neurological syndromes and should therefore not be considered. A possible exception to this rule is the treatment of catastrophic cases, in which also plasmapheresis may be attempted. In thrombotic forms anticoagulant therapy is usually the treatment of choice. In Sjögren syndrome, an autoimmune disorder, neurological complications are not uncommon, most often affecting the PNS. CNS involvement is reported in 25–30% of the patients, presenting as trigeminal neuropathy, recurrent aseptic meningoencephalitis, or unifocal or multifocal cerebral parenchymatous lesions.Also lesions of the spinal cord may occur resulting from a necrotizing vasculitis and leading to transverse myelitis, chronic progressive myelitis, a Brown– Séquard syndrome, or a neurogenic bladder. Patients may also present with neuropsychiatric symptoms. The involvement of the salivary and lacrimal glands (the “sicca” manifestations) is usually manifest before CNS or PNS symptoms, but may also appear later. More general constitutional symptoms may also be present, such as fatigue, malaise, low-grade fever, Raynaud syndrome, lymphadenopathy, arthralgia, myalgia, as well as involvement of lungs, kidneys, muscles, and joints. Lymphoproliferative disorders are potential complications. This disease has much in common with rheumatoid arthritis and SLE. Pathological studies of peripheral nerves and muscle show acute or chronic vasculitis or perivascular inflammation. In a few cases in which biopsy of the CNS was performed, either an unambiguous vasculitis was found or, more typically, a mononuclear vas-

culopathy with a perivascular mononuclear reaction infiltrating in the cerebral parenchyma, usually involving the white matter. On MRI more or less extensive white and gray matter lesions have been reported, including partial territorial infarctions. Microbleeds, present in histopathological studies, can be seen on gradient echo sequences. Lesions in the posterior fossa are rare. The MRI pattern is not specific and the differential diagnosis includes multiple sclerosis, SLE, Behçet disease, and microscopic polyarteritis nodosa. Scleroderma (scleros=hard, derma=skin) is a progressive disease that leads to hardening of the skin and connective tissue and is part of the group of arthritic conditions called connective tissue diseases. There are two main forms of scleroderma, a localized and a systemic form. The localized form is subdivided into two forms, morphea and linear scleroderma. Morphea is a cutaneous lesion with indurated, slightly depressed plaques of thickened dermal fibrous tissue, white or yellowish, with pinkish-purplish halo. The linear form of scleroderma is a line of thickened tissue, which affects the skin, but can also affect the muscles and bone underneath, limiting movements of limbs when affected. The underlying cortex can also be affected when the abnormality occurs on the forehead. Linear scleroderma is usually present on arms, legs, or on the forehead. It may appear as a long streak resembling a deep saber wound, often referred to as “en coup de sabre.” The systemic form of scleroderma can affect any part of the body, skin, blood vessels, and internal organs. The systemic form is also referred to as diffuse scleroderma or CREST (calcinosis, Raynaud syndrome, esophageal problems, sclerodactylia, and telangiectasia) syndrome. The presence of two of the five symptoms mentioned is enough to make the diagnosis CREST. When CREST is present together with other symptoms of scleroderma, it is referred to as “limited scleroderma plus CREST.” In scleroderma many organs and organ systems may be involved, including skin; blood vessels; respiratory system; musculoskeletal system; cardiovascular system; genitourinary system; ears, nose, and throat (sicca syndrome); renal system; endocrine system; PNS; and CNS. Focusing on neurological involvement: peripheral nerve manifestations may lead to pain and paresthesias from nerve entrapment, for instance trigeminal neuralgia and carpal tunnel syndrome. Involvement of the CNS may lead to (partial) territorial strokes, epileptic seizures, with as pathological substrate focal narrowing of middle-sized arteries, and more or less extensive intracerebral calcifications, probably related to an underlying cerebrovascular pathology. Some patients present with recurrent loss of consciousness and multiple spontaneous intracerebral hemorrhages.

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Anti-centromere antibodies have been found in patients with scleroderma and Raynaud syndrome and in CREST patients and may facilitate the diagnosis. Extractable nuclear antibodies and other autoantibodies may also be found. When peripheral skin lesions are present, the diagnosis can be confirmed by skin biopsy. The skin is thickened as a result of overproduction of collagenous tissue, overgrowing hair follicles and sweat glands. Histologically there are two major findings: fibrotic changes, resulting from endothelial damage of small vessels and subsequent collagen deposition, and vasculopathy, consisting of fibrinoid necrosis of arterioles, lymphoid hyperplasia, and thickening of the basement membrane. The cause of scleroderma is unknown. Recently it has been suggested that cellular microchimerism with a lifelong status could form an immunological basis for amplification of autoimmune reactions leading to clinical manifestations of systemic sclerosis. Microchimerism has been defined by the presence of a small number of circulating cells transferred from another individual. This transfer may occur during pregnancy between mother and fetus or, in multigestational pregnancies, between fetuses. Other causes are blood transfusion, bone marrow transplantation, and organ transplants. Microchimerism has been implicated not only in systemic sclerosis, but in the pathogenesis of autoimmune diseases more generally. An increased number of microchimeric cells has been found in peripheral blood and tissues of patients with systemic sclerosis, and they have been proven to be specifically activated and capable of recognizing human leukocyte antigens (HLA) from patients. At this moment there is no specific treatment for scleroderma. Attempts are under way to build upon the remarkably successful use of TNF-a neutralizing treatments for rheumatoid arthritis, which may have paved the way for similar approaches in rheumatoidlike disorders MRI is nonspecific and presentations vary widely. Infarctions may occur in middle-sized artery territories. In addition, macro- and microhemorrhages and extensive calcifications may be present. In other cases lesions mimic patterns found in multiple sclerosis. Where frontal linear scleroderma is present one may expect underlying cortical abnormalities, calcifications, and atrophy. Neurosarcoidosis occurs in approximately 5% of patients with systemic sarcoidosis, also called Besnier– Boeck–Schaumann disease. Sarcoidosis is a systemic granulomatosis of unknown cause, especially affecting the lungs with lung fibrosis, but also found in hilar lymph nodes, skin, liver, spleen, eyes, phalangeal bones, parotid glands, and the CNS. In the CNS facial nerve paralysis is the most common manifestation,

Clinical Presentation and Laboratory Findings

but findings may also mimic tuberculosis, multiple sclerosis, lymphomas, and fungal infections of the brain. Extra-axial manifestations may show features comparable to convexity meningiomas. Spread along the perivascular spaces, leptomeningeal involvement, involvement of the optic nerve, the pituitary gland, the floor of the third ventricle, and the hypothalamus have all been reported. Spinal manifestations are not rare. Although the cause of sarcoidosis still is unknown, it is generally accepted that sarcoidosis results from exposure of genetically predisposed individuals to specific environmental agents. The finding of associations between the human leukocyte antigens of the major histocompatibility complex and sarcoidosis supports this hypothesis. So does the difference in prevalence rates between ethnic groups.Another possible association is between sarcoidosis and bacterial DNA, especially DNA of Propionibacterium acnes or granulosum. Further studies will have to confirm the value of these findings. Laboratory tests are not very helpful in establishing the diagnosis. A positive angiotensin converting enzyme (ACE) test in the CSF may support the diagnosis, but the test may also be negative or neutral. The results of this test should therefore be interpreted with care. The cell count in the CSF is usually slightly elevated, as is the protein content. Histologically the manifestations can be divided into those with proliferation of granulomatous tissue, leading to more solid lesions in the suprasellar region, the brain, and spinal cord, and those with leptomeningeal and perivascular involvement with features of an inflammatory vasculitis. MRI can portray the major manifestations: the suprasellar–leptomeningeal involvement (Fig. 100.13) and the spread along the perivascular spaces (Fig. 100.14), in both cases with enhancement after contrast injection. In other cases the lesions mimic multiple sclerosis patterns. In several patients an extra-axial process very similar to a meningioma has been described. Intramedullary lesions are also easily demonstrated on spinal MR. Therapeutically corticosteroids may be beneficial. In more chronic cases cyclophosphamide and methotrexate are treatment options. Wegener granulomatosis (Wegener disease) may lead to cerebral lesions, either as lesions primarily located in the nasal cavities and sinuses and extending intracranially, or as necrotizing cerebral vasculitis, nearly always in the presence of active sinusitis, otitis, or lung disease. A limited form of Wegener disease, without upper and lower respiratory tract disease, has been repeatedly described and has a better prognosis. The clinical features are protean, but ocular manifestations are common.

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Fig. 100.13. Sagittal T1-weighted, contrast-enhanced, fat-suppressed images of a patient with neurosarcoidosis, showing the characteristic images of involvement of the hypothala-

mus, pituitary stalk, the leptomeninges around the brain stem and cerebellum, in the sulcus cinguli, and in the foramen of Magendie

Fig. 100.14. In this patient with neurosarcoidosis, the involvement concerns the perivascular spaces. The two FLAIR images (left column) show multiple infarct-like lesions involving in

both cortex and white matter. After contrast injection (middle and right columns) enhancement occurs, in part with a stripelike pattern following the course of the perivascular spaces

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The diagnosis may be sustained by the presence of cytoplasmic anti-neutrophil antibodies (ANCAs). The optimal evaluation of serum ANCA levels requires assessment of the presence of two principal ANCA targets: myeloperoxidase and proteinase 3. The cytoplasmic (c-ANCA) staining pattern of neutrophils stems largely from antibodies to proteinase 3; the perinuclear (p-ANCA) staining pattern is derived from antibodies to myeloperoxidase and several other antigens, including lactoferrin, cathepsin G, and elastase. ANCAs are detected in patients with different disorders, such as infections, inflammatory bowel disease, autoimmune hepatitis, and malignancies. With the presence of c-ANCAs, high titers of proteinase 3, and the absence of antinuclear antibodies, the diagnosis of Wegener disease becomes more definitive. Histologically Wegener disease is characterized by necrotizing panarteritis of the middle great vessels. Multiple foci of arteritis develop in the nasal sinuses, the respiratory tract, the eye, and the kidneys. There is much similarity between Wegener disease and involvement of the CNS by other granulomatous and arteritic diseases, including Churg–Strauss syndrome and microscopic polyarteritis nodosa. There is a close relationship between Wegener disease, Churg–Strauss syndrome, and microscopic polyarteritis (as distinct from polyarteritis nodosa). The latter involves predominantly if not exclusively arteries, whereas the other disorders virtually always affect vessels smaller than arteries. In limited Wegener disease the histopathological characteristics are similar to those of the typical disease, but without the upper and lower respiratory tract and kidney involvement. The ANCA test is less likely to be positive. In limited Wegener disease 50–60% of the patients have sinusitis, and 6% have hearing loss due to formation of granulomatous tissue between eustachian tube and tympanum. Destruction of the petrous part of the temporal bone and inflammatory masses at the base of the skull may also be present. Erosion of the lamina papyracea of the orbital walls may occur. Involvement of single or multiple cranial nerves may occur, especially of the eighth, ninth, tenth, and twelfth cranial nerves. The cranial neuropathies are caused either by necrotizing small vessel vasculitis or by a granulomatous process in the meninges. Leptomeningeal enhancement on contrast-enhanced MRI has been described in Wegener granulomatosis. Isolated intracranial or spinal lesions may also be seen (Fig. 100.15). The lesions will enhance after contrast injection (Fig. 100.15). MR and CT examinations of the nasal sinuses and mastoids are important in the evaluation of cerebral involvement by continuous extension.

Clinical Presentation and Laboratory Findings

Churg–Strauss syndrome belongs to the group of necrotizing vasculitides. It is characterized by an eosinophil-rich and granulomatous inflammation and necrotizing vasculitis involving the small- to medium-sized vessels, affecting particularly the respiratory tract. The disease is associated with asthma and peripheral eosinophilia, often combined with necrotizing glomerulonephritis. Cerebral manifestations occur in about 10% of the patients. About 60% of patients are p-ANCA-positive. MRI findings are variable and the cerebral lesions are similar to those seen in many other vasculitides. They consist of macro- or microinfarctions and micro- or macrohemorrhages. Microscopic polyarteritis (polyangiopathy) is also characterized by necrotizing vasculitis of the small vessels, arteriolae, capillaries, or veins, without granulomas. The disease is nearly always associated with necrotizing glomerulonephritis and often with pulmonary capillaritis and hemorrhage. Peripheral neuropathy occurs less frequently than in polyarteritis nodosa. Sinusitis, which is rare in polyarteritis nodosa, occurs in 9% of patients with microscopic polyarteritis. CNS involvement is rare, but when present will be caused by necrotizing vasculitis. The p-ANCA reaction is found in 50–80% of the patients with microscopic polyarteritis and in less than 20% of patients with polyarteritis nodosa. Histologically there is necrotizing vasculitis of small vessels, with microinfarctions and microhemorrhages. MRI may show any degree of small vessel disease, with involvement of both white and gray matter. Additionally, MRI may show small and larger infarctions. MRA is usually negative. Behçet disease is a multisystem recurrent vasculitis of supposedly autoimmune origin, involving many organs. The original clinical triad of symptoms includes oral ulcers, genital ulcers, and anterior or posterior uveitis. The disease is frequently encountered in a specific geographic distribution extending from Japan to the eastern Mediterranean countries, passing through China and Iran: the area that was supposedly the ancient silk route. The disease mainly affects young adults. The female:male ratio is 11:1 in Turkey, less pronounced in other countries. In Turkey the prevalence is 80–300 per million inhabitants, whereas the prevalence is 1 per 100,000 in the USA. Behçet disease is known to cause a variety of other manifestations, such as arthritis, arterial and venous thrombosis, pulmonary angiitis, cardiac disorders, cutaneous lesions, rectocolitis, and lesions of the CNS. CNS involvement is estimated to occur in 5–50% of the cases. Neurological manifestations occur in a wide variety of forms, due to the involvement of either the leptomeninges, the brain parenchyma, or the blood vessels. All sizes of blood vessels are involved, and arteries as well as veins. Clinically the CNS involvement becomes apparent as meningoen-

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790 Chapter 100 Vasculitis Fig. 100.15. A 9-year-old boy with Wegener disease.The FLAIR images through the brain show subcortical and cortical spots with hyperintensity. In the thoracic spinal cord there is an intramedullary lesion with ring enhancement and lower signal intensity in the core of the lesion. In the lungs there are multiple granulomas

cephalitis, cranial nerve palsies, cerebellar ataxia, spastic para- or tetraparesis, raised intracranial pressure, and dementia. Parenchymal CNS involvement occurs in the majority of the patients, predominantly in the basal ganglia and brain stem and spinal cord. CSF showed pleocytosis and elevated protein or an elevated CSF pressure. The cause of Behçet disease is unknown. Viral and bacterial infections have been suggested, until now without sufficient evidence. It is widely assumed that Behçet disease is an autoimmune disorder, even though not all the facts agree with that view. Arguments against the autoimmune hypothesis are the male predominance, the lack of any specific antigen or antibody, and the lack of a relationship with HLA class II antigens. Genetic susceptibility, however, exists in some populations. In Turkey 84% of patients with Behçet disease are positive for HLA B51, which is not found in other populations. Histologically the vasculitis in the CNS is characterized by perivascular cell infiltration, infarctions with small necrotic areas surrounding the blood vessels, microhemorrhages, loss of myelin, and gliosis. Behçet disease is unparalleled among the vasculitides

in its ability to attack blood vessels of any kind and any size, veins as well as arteries, with preference for certain organs. In the brain Behçet disease involves predominantly the white matter of the cerebral hemispheres, the basal ganglia, and the brain stem. Obstruction of arteries may lead to territorial infarcts; involvement of smaller vessels leads to small vessel disease and lacunar infarctions; thrombosis of venous structures may lead to venous infarctions or raised intracranial pressure. MRI plays an important role in the diagnosis and follow-up of neuro-Behçet, and should aim at depicting the various forms of CNS involvement: ∑ White matter abnormalities often involve the cerebral hemispheres, with isolated and confluent lesions in the centrum semiovale and somewhat less prominent involvement of periventricular areas than in multiple sclerosis. However, they are often difficult to distinguish from multiple sclerosis. ∑ Lesions are often present in the basal ganglia, midbrain, and pons; the brain stem lesions are more frequent, larger, and more extensive than in multiple sclerosis (Figs. 100.16 and 100.17).

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Clinical Presentation and Laboratory Findings

Fig. 100.16. Behçet disease may cause lesions anywhere in the brain, but most often involves the brain stem and basal ganglia in an asymmetrical fashion.The FLAIR images (first and second rows) of a 53-year-old woman depict the lesions in the midbrain, pons and around the fourth ventricle. Note the

enhancement of the lesions on the T1-weighted images after contrast (third row). Courtesy of Dr. G. Akman-Demir, Department of Neurology, Medical Faculty, Istanbul University, Istanbul, Turkey

∑ Small, and occasionally large, infarctions may be present; diffusion-weighted images may be added to the usual protocol, which includes proton density, T2-weighted, and FLAIR images, in order to catch fresh infarctions.

∑ Leptomeningeal involvement is especially to be expected in patients presenting with cranial nerve palsies and in those with meningoencephalitis; contrast administration and T1-weighted images with fat suppression are required for adequate depiction.

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Fig. 100.17. A 28-year-old man with Behçet disease. Note the involvement of the internal capsule on the right, the midbrain and the medulla. Courtesy of Dr. G. Akman-Demir, Department

of Neurology, Medical Faculty, Istanbul University, Istanbul, Turkey

∑ Visualization of microhemorrhages, as often seen in pathological specimens, demands a gradient echo technique on MRI. ∑ In patients with raised intracranial pressure, thrombosis of the large venous sinuses has to be ruled out; on a T1-weighted sagittal image this may already be obvious when the superior sagittal sinus is involved. Thrombosis of other intracranial veins can be made visible with MR phlebography. ∑ In patients presenting with large territorial infarctions MRA may show the occluded vessels. ∑ Spinal cord lesions will be visible on proton density and T2-weighted images, and the spinal lesions will usually enhance after contrast injection, as will many of the intracranial lesions in Behçet disease (Fig. 100.16).

100.2.2.3 Infectious Vasculitis A number of infectious disorders may give rise to vasculitis and related cerebral lesions. Lyme disease (neuroborreliosis) is an infectious disease caused by Borrelia burgdorferi, which may affect many organs, such as skin (90% of all patients), joints, heart, CNS, and PNS. The first manifestation is often a skin lesion, known as erythema (chronicum) migrans. This may be followed by bacterial dissemination, presenting initially as a flu-like disorder, with fever, malaise, and diffuse pain. About 15% of patients subsequently develop one or more features of CNS involvement: lymphocytic meningitis (in the USA) or meningoencephalitis (in Europe), uni- or bilateral facial paresis (to be differentiated from neurosarcoidosis and Guillain–Barré syndrome), and polyradiculitis (which may mimic Guillain–Barré syndrome). In a minority of patients focal encephalomyelitis will develop with prominent white matter involvement on MRI. In untreated or unsuccessfully treated patients, late neurological symptoms may develop, which include chronic encephalomyelitis, with focal neurological

Therapy in Behçet disease may be topical when oral aphthae and genital ulcers are concerned. More extensive systemic involvement usually requires corticosteroid and immunosuppressive therapy.

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Clinical Presentation and Laboratory Findings

Fig. 100.18. Images of a 10-year-old girl with neuroborreliosis. The T2-weighted images show multiple lesions of different sizes, asymmetrically spread through the centra semiovalia of both hemispheres. The T1-weighted, contrast-enhanced images in the coronal and sagittal planes show that several

lesions enhance. These images do not allow differentiation from acute disseminated encephalomyelitis (ADEM) or multiple sclerosis. From Demaerel et al. (1995), with permission and by courtesy of Dr. P. Demaerel, Department of Radiology, University Hospitals Gasthuisberg, Leuven, Belgium

abnormalities and also focal abnormalities on MRI. A chronic infection may lead to confusional states, with memory loss and cognitive impairment. Due to limitations in diagnostic technology, Lyme disease is still primarily a clinical diagnosis, usually accepted only when the antecedents of the patient include a tick-

bite, erythema migrans, and one or more of the manifestations within the scope of Lyme disease. The cause of Lyme disease is an infection by a member of a group of spirochetes, originally named Borrelia burgdorferi, now referred to as Borrelia burgdorferi sensu lato, subdivided into at least three

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Fig. 100.19. A 10-year-old boy with Lyme disease presented with low back pain radiating to his legs. The T1-weighted, contrast-enhanced sagittal images (first row) of the lower thoracic and lumbar spine show the enhancing and thickened caudal roots. In the coronal plane (second row, left and middle) and

transverse plane (second row, right) the enhancement and thickening of nerve roots is confirmed. From Demaerel et al. (1998), with permission and by courtesy of Dr. P. Demaerel, Department of Radiology, University Hospitals Gasthuisberg, Leuven, Belgium

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species: Borrelia burgdorferi sensu stricto, Borrelia burgdorferi garinii, and Borrelia burgdorferi afzelii. The first group is responsible for the North American Lyme infections, the latter two for the European forms, which have some differences in clinical features. The disease is a zoonosis, with humans as inadvertent host. The disease is transmitted to humans by a bite from the hard-shelled ixodid ticks. These ticks are especially abundant in areas where the ecological circumstances, climate, food, and the different vectors for their procreation are present. The life cycle of the ticks runs a three-phase course over a 2-year cycle. Even in areas with a high proportion of infected ticks only 1–2% of humans with a tick bite will become infected. Diagnosis of Lyme disease is not straightforward. Serological tests take a long time and may be unreliable because of crossover reactions, which can lead to false positives. CSF examination may be positive for inflammatory markers, pleocytosis, slight rise in protein, and usually normal glucose. A test can be performed to show anti-Borrelia antibodies with a Lymespecific ELISA. PCR may be applied to detect bacterial DNA. There is no specific MR pattern of Lyme disease. There may be many small lesions dispersed through the hemispheres, sometimes very similar to the pattern of multiple sclerosis (Fig. 100.18). Lesions in the corpus callosum are less common. After injection of contrast, active lesions may enhance (Fig. 100.18). Special techniques should be used to image the cranial nerves when involved; in the active phase these will also enhance. Leptomeningeal enhancement may occur in patients with meningoencephalitis, but in our experience this is rare in the chronic form. Lesions in the spinal cord and involvement of nerve roots may also occur (Fig. 100.19). Antibiotic therapy is effective when given appropriately and cures up to 90–95% of patients. In patients with chronic disease the percentage is lower, 80–85%. Tuberculosis is caused by Mycobacterium tuberculosis. Involvement of the brain is usually due to hematogenous spread from a primary focus, in most cases the lungs. Intracranial manifestations include extension of a subpial or subependymal focus, resulting in involvement of the basal leptomeninges, which causes basal leptomeningitis. Occlusion of the CSF pathways leads to hydrocephalus. The infection may also induce vasculitis of the smaller and middle-sized cerebral arteries, often the lenticulostriate arteries or the posterior cerebral artery branches, the thalamoperforate arteries, leading to small infarctions in the basal ganglia and deep white matter. Multiple miliary abscesses may also occur, as well as tuberculous intraparenchymal granulomas (tuberculomas), cerebritis, larger abscesses, and pachymeningitis. Spinal cord

Clinical Presentation and Laboratory Findings

infection is less common, but arachnoiditis and focal intramedullary tuberculomas may occur. Tuberculous spondylitis may lead to secondary involvement of spinal cord and roots. Because of migration of individuals from regions in the world where tuberculosis is still endemic and the higher incidence of cases in immunocompromised individuals, one should be aware of the possibility of a tuberculous infection. The demonstration of Mycobacterium tuberculosis or bacterial DNA in the body fluids or biopsy material makes a certain diagnosis. Brain involvement is often secondary to a pulmonary infection. Indirect markers are pleocytosis in the CSF, high protein and low glucose levels and presence of indicators of inflammation in the plasma. Often CSF has transformed into a thick, yellowish fluid, which may be the cause of a communicating hydrocephalus. Histologically, the different forms of tuberculosis of the brain and meninges have different aspects. Tuberculomas occur in the brain parenchyma and in the leptomeninges and choroid plexus. The larger tuberculomas have a granulomatous border, often with Langhans giant cells, encompassing a central caseating necrosis. They are usually small and multiple, but incidentally may become larger and have mass effect. Leptomeningeal tuberculosis can consist of isolated tuberculomas of varying size, often associated with tuberculomas in the brain tissue. A second form appears as generalized meningitis, presenting as a grayish, gelatinous, thick exudate, predominantly at the base of the brain. The exudate consists of polymorphonuclear cell infiltrations, fibrin exudation, endarteritis, hemorrhages and caseous necrosis. Perivascular intraparenchymal inflammatory extensions are frequent and hemorrhagic infarctions may ensue. MR images, standard morphological and T1weighted images with and without contrast, where available with fat suppression, depict the described manifestations and secondary effects (Fig. 110.20). MRA demonstrates the affected vessels. Diffusionweighted imaging will show infarction or abscesses. Therapy consists of tuberculostatic medication and necessary supplements. Syphilitic angiitis is caused by a spirochete, Treponema pallidum, and presents clinically as a multisystem infection. Neurosyphilis is one of its manifestations. Neurosyphilis can be classified into distinct syndromes that span all stages of dissemination of the disease. In the first phase the local genital infection and skin abnormalities prevail, but a meningeal syphilitic infection at the onset may lead to cranial nerve palsies and ocular changes. Four to 7 years after the primary infection, a meningovascular syphilis may develop, with focal nervous system ischemia, secondary to thrombosis. Parenchymatous manifestations of neurosyphilis occur 10–30 years after the primary infec-

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Fig. 100.20. Tuberculous meningoencephalitis. The first row shows one T1-weighted and two T2-weighted images; the second row shows T1-weighted images with contrast. The images in the first row show ventriculomegaly and periventricular

leukomalacia. Focal lesions are seen in the basal ganglia and mesencephalon.The contrast-enhanced images show the typical basal leptomeningitis

tion with general paresis or tabes dorsalis. In this late phase other parenchymatous lesions, gummata, or cranial nerve involvement, hearing loss, or optic neuritis may occur. In this late phase cognitive decline, delusions, and paresis are part of the clinical picture, although nowadays, because of proper treatment, rarely observed. In combination with HIV infection, the neurological manifestations of neurosyphilis occur at an earlier date, accelerate faster, and are more severe. The gold standard for the diagnosis is the demonstration of spirochetes by dark-field examination, which is easy when skin or genital lesions are present. In neurosyphilis this is more difficult and the diagnosis is suggested by clinical findings, medical history, and CSF analysis. Serological studies can confirm the diagnosis. Treponema tests include the fluorescent treponemal antibody absorption double staining hemagglutination test, and the Treponema immobilization test. Nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) test and the

rapid plasma reagin (RPR) test, are more sensitive than specific. False positive results can be obtained in SLE, herpes simplex infections, pregnancy, and Lyme disease. Pathophysiologically the infection leads to an obliterative endarteritis of terminal arterioles, resulting in inflammatory and necrotic lesions. MRI is not specific in cases of neurosyphilis. Contrast-enhanced T1-weighted images show the leptomeningitis, infarctions, and gummata when present. In HIV-positive patients the diagnosis may be even more difficult. When treated in time the infection can be cured. Various regimes of antibiotics are now available. In patients with HIV, however, treatment failure is frequent. Varicella-zoster complications stem from infection with the varicella-zoster virus, a virus that occurs exclusively in humans and causes chickenpox (varicella). It then becomes latent in cranial nerve and dorsal root ganglia, and frequently reactivates decades later

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Clinical Presentation and Laboratory Findings

Fig. 100.21. Left-sided infarction of the brain following left-sided herpes zoster ophthalmicus

to produce shingles (herpes zoster) and postherpetic neuralgia. Latency depends on age of the virus and immune status of the patient. The reactivated virus may cause symptoms in elderly immunocompetent individuals or in immunocompromised patients and may produce disease of the brain and spinal cord. Recently varicella-zoster virus has been detected in blood vessels and other tissues by PCR, and this has widened the clinical spectrum of acute and chronic disorders ascribed to varicella-zoster virus, including large vessel granulomatous arteritis, myelitis, and small vessel encephalitis, all of which may occur without the rash typical of varicella-zoster. Varicella-zoster becomes latent in ganglia along the entire neuraxis. Unlike herpes virus, it cannot be cultivated from human ganglia. With special techniques, such as in situ hybridization, Southern blot, and PCR analysis, viral DNA has been found in trigeminal and thoracic ganglia. Early reactivation of the virus after chickenpox with an interval of only several months, associated with granulomatous arteritis of the medium-sized vessels, may be seen in children presenting with an infarction. These infarctions may be located in the posterior fossa, with basilar artery arteritis, or, more often, in the carotid artery territories, causing either larger territorial infarctions or infarctions in the territories of the lenticulostriate arteries. Myelitis in immunocompetent individuals is usually less severe than in immunocompromised patients. In the latter group small vessel encephalitis may develop, with poor prognosis. MRI is not specific in varicella-zoster vasculitis, but may show resulting infarctions. MRA may indicate the affected middle-sized vessels. There is no curative therapy for the vasculitis, which is in most cases self-limiting. Supportive measures depending on the neurological symptoms are indicated. Delayed contralateral hemiplegia following herpes zoster ophthalmicus tends to occur in middle age

(mean age 55 years, range 7–96 years). The hemiplegia occurs one week to 2 years after the onset of the herpes zoster ophthalmicus. Delayed hemiplegia following herpes zoster ophthalmicus has often been considered to be the equivalent of granulomatous angiitis. Sufficient clinical differences, however, exist to justify the assumption of two distinct entities. Symptoms tend to be milder in this disorder than in primary granulomatous angiitis of the nervous system. Most patients with this disorder survive, even without steroids. Microscopic tissue examination reveals the same histological abnormalities in both disorders. MRA is nonspecific, but will show the unilateral involvement of the brain (Fig. 100.21). 100.2.2.4 Drug-Related Vasculitis There is a long list of drugs that may cause drug-induced vasculitis, including therapeutic and diagnostic pharmaceuticals and substances used in drug abuse. To the first category belong, among many others, allopurinol, amphetamine, ergot alkaloids, ephedrine, ginseng, interleukin-2, methylphenidate, oxymethazoline, penicillin, and hepatitis B vaccine. To the second category belong cocaine, heroin, methylphenidate, and methamphetamines. In many cases of the first group the vasculitis is restricted to the skin, but extension to other organs is very well possible. Extension to the brain is rare. Cocaine may lead to vasculitis, vasospasm, and increased platelet aggregation resulting in infarctions (strokes), leukoencephalopathy, and hemorrhages. Chronic cocaine dependency has also been linked to a moyamoya-like vasculopathy, with obstructed vessels and extensive collateral circulation, in particular the basal ganglia. The risk of myocardial infarction is increased in young individuals using cocaine. In heroin abuse strokes and hemorrhages are less frequent than in cocaine abuse. A spongiform leukoencephalopathy is far more frequent in heroin

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Fig. 100.22. A 43-year-old woman presenting with a series of transient ischemic attacks, all related to different brain localizations. T2-weighted images of the brain show multiple lesions of different sizes involving cortex and subcortical white

matter and deep white matter. This pattern can be seen in intravascular coagulation, for example in sepsis, but also in intravascular metastases.In this case the cause was intravascular lymphomatosis

abuse (see Chap. 87), but has occasionally been described in cocaine abuse. MRI patterns in drug-related vasculitides are inconsistent and depend on the vessels involved. Lesions will usually have the features of infarctions. Diffusion-weighted imaging, therefore, should be part of the MR protocol.

IVL have been described in the age range of 30–80 years. The clinical signs and symptoms of IVL may mimic those of vasculitis, and the cerebral form has a variable presentation. Often there are stroke-like episodes or repetitive transient ischemic attacks. Focal cortical symptoms, confusion, disorientation, dementia, and seizures may follow. Meningoencephalitis-like presentation has also been described. Proper diagnosis is important, because IVL is a treatable condition and early diagnosis may prevent irreparable damage. Manifestations in other organs – skin or lungs, for example – anemia, and high erythrocyte sedimentation rate may help to arrive at the correct diagnosis. Usually the diagnosis can be made by examination of blood or bone marrow samples, biopsies of skin lesions, or bronchial lavage in pulmonary manifestations. Cerebral manifestations as seen on MRI include infarct-like lesions dispersed throughout the brain (Fig. 100.22), venous occlusion of the large sinus or cortical veins with venous infarctions, and enhancement of leptomeninges after contrast injection. Diffusion-weighted imaging may help to indicate the nature of the cerebral lesions and identify them as infarctions. MRA may show abnormalities of arteries but is not diagnostic. In cases where there is venous involvement, MR phlebography is useful to show the obstructed veins. Treatment consists of polychemotherapy. The name of sickle cell disease stems from the abnormal form of the red blood cells, which look like crescents. It is an autosomal recessive disease which has its highest incidence in Africa. It is caused by a defect in the b-hemoglobin gene. Sickle cell anemia will develop in homozygously affected individuals. Het-

100.2.3 Disorders Primarily Obstructing the Vessel Lumen Hypercoagulative states. There are a number of inherited and acquired disorders that lead to a change in the complex process of coagulation, which may invoke hemorrhages when hemostasis is insufficiently controlled or thrombosis with obliteration of vessel lumina when coagulation surpasses its necessary biological function and causes unsolicited thrombosis. Such inherited factors are: elevated von Willebrand factor, factor V Leiden, fibrinogen polymorphisms, protein C and protein S deficiencies, and many others. In various conditions hypercoagulation may be induced by changes in the blood composition, as may happen in cancer patients, and in postoperative and post-traumatic conditions with extended immobilization. The resulting lesions will occur in unpredictable places and therefore neurological signs and MR findings are not specific. Intravascular lymphomatosis (IVL) is a very rare non-Hodgkin lymphoma characterized by proliferation of lymphoma cells in the vascular lumina, both arterial and venous, without involvement of adjacent parenchymal tissue. IVL with cerebral involvement is predominantly of B cell lineage. Patients with cerebral

100.3

erozygous carriers will have some abnormal erythrocytes, but symptoms will be only precipitated under conditions with low oxygen tension, such as in highlying geographical regions. Sickle cells are less prone to parasitic (malarial) infection than normal blood cells. It is hypothesized that in former centuries carriers of sickle cell disease were more likely to survive malaria and were responsible for the recurrence of sickle cell carriership in subsequent generations. Today the disease affects 1 in 500 newborns with AfroAmerican parents and 1 in 1000 newborns with Hispano-American parents in the USA. The disease is found everywhere in Africa, throughout Middle and South America and Cuba, and in Mediterranean countries such as Italy, Greece, and Turkey. The clinical picture is highly variable, as many different organs may suffer ischemic insults. The nature of the disease, however, is such that it often causes cerebrovascular accidents. Sickle cell disease is one of the many sources of watershed and arterial territorial infarctions in children and relatively young adults. Neurological symptoms depend on the location of the infarctions. At the molecular level sickle cell anemia is caused by a single base mutation leading to the substitution of valine for glutamic acid at position 6 of the b-hemoglobin molecule. Homozygously affected individuals have abnormal hemoglobin, hemoglobin S. Under circumstances with low oxygen tension and acidosis the abnormal hemoglobin molecules polymerize, resulting in increased cell rigidity and the characteristic sickle shape. This leads to sludging in smaller vessels and to hemolysis. The majority of strokes occur in younger patients. Many factors can precipitate stroke, such as dehydration, pregnancy, low hematocrit value, cardiomegaly, and abnormal liver functions. Sickled cells are less flexible, which slows their passage through the vessels. The red blood cells containing the abnormal hemoglobin S seem also to be abnormally adherent to the endothelium. Because of the stasis, platelets will also become more adherent, and fibrin deposition follows, with subsequent occlusion of the lumen. Ischemic infarctions account for 70% of cerebrovascular episodes, and these infarctions are most often caused by occlusion of large arteries at the base of the brain. Occlusion of smaller vessels most often involves smaller cortical branches. On MRI lesions may include small, disseminated infarctions, border zone or territorial infarctions, and in rare cases thrombosis of the large venous sinuses. MRA may show obstructed vessels. The anticancer drug hydroxyurea has given patients with sickle cell disease some hope. It was found that taking this drug caused an increase in the production of fetal hemoglobin, which is normally present only in newborns. The presence of sufficient fetal

Magnetic Resonance Imaging

hemoglobin causes the red blood cells to stop sickling. It has been proven effective in preventing crisis. The long-term side effects of this medication are, however, still unknown. Animal experiments with gene replacement of the defective gene have given new hope.

100.3 Magnetic Resonance Imaging Vasculitis can lead to a wide variety of MRI patterns. The lesions can be focal, asymmetrically distributed throughout the brain parenchyma, sometimes mimicking multiple sclerosis, or lesions can be more confluent. Infarctions may occur in vascular territories or border zones, or they may present as small lacunar infarctions. Involvement of the basal ganglia, thalamus, midbrain, pons, medulla oblongata, and leptomeninges is often seen. Lesions may become hemorrhagic and macro- and microhemorrhages may occur. With cortical and leptomeningeal localizations superficial hemosiderosis may follow. In later phases of the disease atrophy may become apparent. It is evident that the MRI pattern of vasculitis is not specific. Disorders which may share this gamut of MRI patterns include multiple sclerosis, acute disseminated encephalomyelitis, extrapontine myelinolysis, progressive multifocal leukoencephalopathy, radiation vasculopathy, subcortical arteriosclerotic encephalopathy (Binswanger disease), eclampsia, neoplasms and emboli. Clinical and laboratory data are helpful in further differentiation of these disorders. Some of the vasculitic disorders may present with a more characteristic MRI pattern. Vasculitis in SLE can lead to extensive calcifications, which may be prominent in the basal ganglia, the geniculate bodies, and the dentate nucleus. On T1-weighted images this may lead to high signal intensity in the involved areas, sometimes blotting out the basal ganglia. This phenomenon may also be seen in such disorders as hypoparathyroidism, pseudo-hypoparathyroidism, liver failure, and parenteral nutrition. The signal intensity on T2-weighted images is decreased. These calcifications are largely symmetrical, but there seem to be exceptions to this rule. An MRI protocol covering the features of vasculitis should include T1- and T2-weighted, FLAIR images, and diffusion-weighted imaging (Trace images and ADC maps). In addition gradient echo images are mandatory to note the hemosiderin deposits, which are ubiquitous in most cases of vasculitis. MRA can be helpful, but a contrast-enhanced high-resolution (512 ¥ 512) sequence should preferably be used. We prefer slow machine injection of 15–20 ml contrast, about 1 ml per second, followed by 20 ml of saline, during the MRA acquisition, with a presaturation slab

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blocking the larger venous sinuses. With this protocol, MR images will show the central cerebral vessels as well as their second and third ramifications. After this procedure a contrast-enhanced, fat-suppressed, T1-weighted image is obtained in at least one direction to identify enhancement of lesions, a frequent observation in vasculitis. When unusual MR patterns are present, vasculitis should be always be considered a possible cause, especially with clinical suspicion. The combination of MRI findings with the clinical and laboratory data

may lead to the correct diagnosis. It should be noted that in most of the vasculitic disorders, but in particular in SLE and Behçet disease, mild to extensive white matter disease can be found in absence of clinical neurological abnormalities. The reverse is also true: in SLE, despite evident neurological manifestation, the findings at MRI and autopsy may be disappointing. Quantitative estimation of CNS involvement may be reached by magnetization transfer ratio histogram analysis, diffusion tensor imaging, ADC mapping, and MRS.

Chapter 101

Leukoencephalopathy and Dural Arteriovenous Fistulas R. van den Berg, G.J. Lycklama à Nijeholt, and J.M.C. van Dijk

101.1 Clinical Features and Laboratory Investigations Cranial dural arteriovenous fistulas (DAVFs) represent 10–15% of all intracranial arteriovenous lesions. The exact etiology of cranial DAVFs is still unknown. Development of DAVFs has been described after surgery, head trauma, and in relation to dural sinus thrombosis. In adults, it is generally accepted that DAVFs are acquired conditions. Pediatric cases are rare; DAVFs have infrequently been demonstrated in utero and may be present in neonates, associated with a dural sinus malformation. Clinical symptoms of DAVFs are related to the fistula itself, e.g., pulsatile tinnitus, or to the venous hypertension in the involved venous territory. The clinical symptomatology and the risk of aggressive complications, such as intracranial hemorrhage, correlate directly with the venous drainage pattern of DAVFs. Depending on the venous drainage and the flow characteristics, DAVFs may cause orbital symptoms including exophthalmia and cranial nerve deficits. A focal area of cortical venous reflux – retrograde drainage in a cortical leptomeningeal vein – may cause focal neurological deficits, such as aphasia or motor weakness. DAVFs can also cause remote symptoms. Lesions located in the cavernous sinus, tentorium, and foramen magnum can cause venous congestion of the brain stem or spinal cord with related symptomatology. The retrograde transmission of the arterial pressure in a more extensive venous network, in combination with impaired venous outflow through the sinuses, may lead to venous hypertension, resulting in CSF absorption abnormalities and papilledema. These venous pressure disturbances may lead to symptoms of parkinsonism, such as rigidity, bradykinesia, and gait disturbances, and global cognitive dysfunction with dementia as the most severe presentation. The presence of cortical venous reflux in cranial DAVFs carries an annual mortality rate of 10.4%. The annual risk of hemorrhage is estimated to be 8.1% per year. The risk of nonhemorrhagic neurological deficit is 6.9% per year. The annual event rate for patients with aggressive DAVFs is therefore 15%.

101.2 Pathology Histopathologically, DAVFs are located within the wall of the sinus. The fistula itself has no intervening capillary bed or nidus and consists of small venules. Intimal hyperplasia of both dural arteries and veins is noticed. The arterioles show hypertrophied walls, mainly characterized by media hyperplasia. Organized thrombi have been demonstrated in the dural sinuses in up to 100% of cases. Immunohistochemically, DAVFs show strong staining for basic fibroblast growth factor (bFGF) in the subendothelial layer and hypertrophied media of the arteries in the sinus wall and in the fibrous connective tissues around the sinuses, sparing the endothelium. Vascular endothelial growth factor (VEGF) stains positively in the endothelium of the dural sinus, small arteries, and veins in the sinus walls. In addition, VEGF stains positively in the endothelium of many capillaries in the sinuses that are obstructed by an organized thrombus. No such findings are encountered in dural sinuses of control specimens. The factors stimulating bFGF and VEGF are not known, but it is postulated that tissue hypoxia and or intraluminal shear stress resulting from venous hypertension stimulates the expression of these angiogenic growth factors. The acute and chronic parenchymal abnormalities in the case of cortical venous reflux (aggressive type of fistulas) are related to venous hypertension. Acute changes include diffuse cerebral edema and petechial hemorrhages within the gray and white matter. Chronic changes include markedly dilated and thickened, hyalinized walls of the parenchymal veins. Gliosis may occur within the white matter.

101.3 Pathogenetic Considerations The association of DAVFs with venous thrombosis has been described frequently. Another important factor contributing to the development of DAVFs is venous or sinus hypertension. Sinus thrombosis does not always lead to the development of DAVFs, and it has been stated that venous hypertension is a prerequisite for formation of a DAVF, even in the absence of sinus thrombosis. DAVFs have also been reported to develop following intracranial surgery, trauma, surgery in remote areas of the body, and in the post-

802 Chapter 101 Leukoencephalopathy and Dural Arteriovenous Fistulas Table 101.1. Classification of cranial dural arteriovenous fistulas Borden classification

drainage. This causes chronic (venous) ischemia. In those cases where extensive reflux is seen in combination with impaired venous outflow through the sinuses, venous pressures can rise to very high levels.

1. Venous drainage directly into dural venous sinus or meningeal vein 2. Venous drainage into dural venous sinus with cortical venous reflux

101.4 Therapy

3. Venous drainage directly into subarachnoid veins (only cortical venous reflux)

The natural history of the disease is related to the venous drainage pattern of the DAVF. DAVFs with antegrade drainage only present with focal symptoms due to the fistula itself, and morbidity and mortality are limited. In these cases treatment should aim only at diminution of the focal symptomatology. DAVFs with cortical venous reflux, however, may lead to severe complications and require aggressive treatment. Disconnection of the cortical venous reflux is obligatory to protect the patient from sequelae such as intracranial hemorrhage and nonhemorrhagic neurological deficits. Partial treatment will not reduce the risk of occurrence of these complications. Both endovascular embolization and surgery are available to treat DAVFs. Surgical disconnection of the fistulous vein(s) used to be the gold standard for treatment, but with the introduction of liquid adhesive embolics, which have been shown to produce a durable result without recanalization, these techniques should be regarded as equal. The choice of treatment mode should be decided by the interventional neuroradiologist and the neurosurgeon. If endovascular treatment is chosen, the arterial route is used preferentially. The goal of arterial embolization, in which a liquid embolic agent such as nbutyl cyanoacrylate (NBCA) should be regarded as superior to polyvinyl alcohol (PVA) particles, is to penetrate the fistulous point and to occlude the proximal part of the refluxing vein. If this cannot be accomplished, occlusion of the fistulous vein through an alternative route is indicated. The least aggressive is selective disconnection of the refluxing vein(s). This will leave the DAVF itself untreated. If the fistulous zone is more extensive and the cortical venous reflux is found on multiple sites of the dural sinus, or if venous hypertension is the main problem, obliteration of the sinus may be the only treatment option left. However, first a thorough angiographic examination of the venous drainage of the normally draining veins, including the veins of the posterior fossa, is necessary. Sacrifice of the dural sinus can only be performed if adequate venous drainage of the brain is guaranteed. Only if the sinus is no longer used for the drainage of the brain parenchyma, and the veins of the posterior fossa do not enter the involved segment, the sinus can be sacrificed. Selective disconnection of the cortical venous reflux or sacrifice of (a part of) a dural sinus can also be performed by an open surgical approach or by a com-

Cognard classification I.

Venous drainage into dural venous sinus with antegrade flow

IIa.

Venous drainage into dural venous sinus with retrograde flow

IIa-b. Venous drainage into dural venous sinus with retrograde flow and cortical venous reflux IIb.

Venous drainage into dural venous sinus with antegrade flow and cortical venous reflux

III.

Venous drainage directly into subarachnoid veins (only cortical venous reflux)

IV.

Type III with venous ectasias of the draining subarachnoid veins

partum period. The wide variety of etiological factors should not be regarded as direct causes of DAVFs; rather, they represent environments that may be conducive to the development of a DAVF in particular patients. Two principal theories on the pathogenesis of DAVFs have been proposed. The first claims that DAVFs are caused by enlargement of preexisting microfistulas in the dura. These microfistulas enlarge because of increased venous pressure, associated either with sinus thrombosis or with sinus outflow obstruction. The second theory points to the development of angiogenic factors, such as the above mentioned bFGF and VEGF, either directly from the organization of a sinus thrombosis or indirectly from local tissue hypoxia due to an increased venous pressure. Many classifications have been proposed for DAVFs, of which the Borden classification and the Cognard classification are most commonly used. The common concept of both classifications is to differentiate between DAVFs with antegrade drainage in the dural sinus (benign type: Borden 1, Cognard types I and IIa), and DAVFs with cortical venous reflux (aggressive type: Borden 2 and 3, Cognard type IIb and higher) (Table 101.1). The importance of the venous drainage pattern lies in the correlation with clinical symptomatology and the risks of hemorrhage. The retrograde transmission of the arterial pressure in the venous network leads to venous hypertension and congestion and impairs parenchymal venous

101.5

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bination of endovascular and surgical approaches. In patients with occlusion of the affected sinus at both proximal and distal sites (isolated sinus), a direct approach to the diseased sinus can be obtained through a small burr hole that allows direct puncture of the dural sinus. Subsequently the fistulous zone of the DAVF can be closed using coils or other thrombogenic material.

101.5 Magnetic Resonance Imaging In the presence of a DAVF with cortical venous reflux, unenhanced CT images may show hypodensities, representing areas of gliosis, edema, or venous ischemia. Abnormally enlarged pial veins can be depicted due to their increased density compared to the brain parenchyma (Fig. 101.1). Contrast-enhanced CT will show extensive enhancement of the enlarged pial venous network. In the absence of cortical venous reflux, a DAVF might be occult on MRI. In such cases, the location of the DAVF within the dura and the lack of a mass effect on the brain parenchyma make it very difficult to see the nidus of the fistula on MRI. MRA is more sensitive in depicting the nidus, although the lack of flow information in time is one of the drawbacks. MRA after injection of a bolus of intravenous contrast may solve this limitation. In DAVFs with cortical venous reflux MRI shows prominent flow voids on the surface of the brain corresponding to dilated cortical vessels, or more subtle serpiginous or dot-like vascular structures (Fig. 101.2). These are highly suggestive of the correct diagnosis. Hydrocephalus secondary to the venous hypertension in the superior sagittal sinus can be present. The brain parenchyma, particularly the white matter, may show T2 hyperintensity (Fig. 101.2). This is related to venous hypertension and congestion of the brain in the earlier stages and gliosis in later stages. The cerebral involvement may be extensive (Fig. 101.2) or focal (Fig. 101.4). Dependent on the localization of the shunt, the cerebellum, deep gray nuclei, or brain stem may be affected. DAVFs have been described as the cause of bilateral thalamic hyperintensities on T2-weighted images. The differential diagnosis in bilateral thalamic T2 hyperintensities should include basilar artery infarction, tumor infiltration, and deep venous occlusion. The differential diagnosis of more diffuse T2 hyperintensities would include superior sagittal sinus thrombosis with venous congestion, diffuse glioma, and other leukoencephalopathies. However, the combination of an abundance of dilated pial vessels, contrast enhancement of these vessels, and deep white matter T2 hyperintensity is highly suggestive of a DAVF and mandates further angiographic analysis.

Fig. 101.1. A 57-year-old man presented with rapid cognitive decline related to a DAVF located in the torcular region. On the plain CT scan dilated pial veins are demonstrated in the right temporal region

Angiography is obligatory to confirm the diagnosis DAVF and for treatment planning. Selective contrast injections into the different branch arteries of the external carotid artery will reveal rapid arteriovenous shunting through the fistula into the cerebral venous system, thereby arterializing the venous system. Important concomitant findings are outflow obstruction due to venous sinus occlusion, which can result in extracranial drainage via collateral routes, including the orbital system, and which augments the risk of retrograde flow into the cortical and cerebellar veins. The transit time of contrast when injected selectively into the internal carotid artery is delayed, compatible with venous congestion. In the normal situation venous drainage is seen 4–6 s after the beginning of the arterial phase. In addition to the analysis of the venous reflux, the venous drainage of the brain should be examined with the same diligence, not only to detect focal areas of delayed venous drainage, but also to determine whether sacrifice of a dural sinus or a refluxing vein is a potential treatment option.

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Fig. 101.2.

101.5

Fig. 101.3. Angiography of the patient presented in Fig. 101.2. Selective injection of the external carotid artery (first row, left) shows hypertrophy of the superficial temporal artery and middle meningeal artery. Immediate enhancement of the superior sagittal sinus is seen, suggesting the presence of a DAVF. Selective internal carotid artery injection (first row, right; middle row, left) shows filling of the artery of the falx cerebri through a (hypertrophied) ophthalmic artery (first row, right).There is early enhancement of the superior sagittal sinus, consistent with a DAVF.There is slow passage of contrast through the brain parenchyma because of venous congestion, resulting in a late parenchymal and venous phase.This is also illustrated by the poor visibility of peripheral arteries in the early phase (middle row, left) and by the “pseudo-phlebitic” aspect of the brain parenchyma in a later phase of the angiogram (middle row, right). After treatment by both an endovascular approach (selective glue injections in external carotid branches feeding the arteriovenous fistula) and by direct placement of coils in the superior sagittal sinus (third row, left; middle row, right), there is a marked reduction in the size of external carotid artery branches.The internal carotid artery injection after treatment shows abnormal drainage of the brain due to occlusion of the superior sagittal sinus (third row, right).The brain is no longer using the superior sagittal sinus for its drainage. However the transit time of contrast is much shorter.The cognitive symptoms of the patient have disappeared almost completely

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Fig. 101.2. A 67-year-old woman had in her medical history an operation for an acoustic neurinoma on the right. She presented with a rapid cognitive decline.The T2-weighted images (first two rows) show a diffuse signal increase in the deep white matter of both cerebral hemispheres. Abnormal flow voids are visible on the cerebral surface and in the brain parenchyma, especially in the temporal lobes and in the posterior fossa.The T1-weighted images after contrast (third and fourth rows) show extensive enhancement of cortical and parenchymal veins

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Fig. 101.4. FLAIR images of a 51-year-old patient who had a single epileptic attack with visual signs.The images show an area of increased signal in the left occipital lobe (second row)

101.5

Fig. 101.5. Angiography of the patient presented in Fig. 101.4. Selective injection of the left vertebral artery shows no definite abnormalities (first row), except for nonenhancement of the left transverse and sigmoid sinus. Selective external carotid artery injection shows early filling of a dural tentorial sinus, located in the tentorium cerebelli, due to a DAVF located there.The fistula is fed by a transmastoid branch of the occipital artery (second row, right).There is reflux from the dural sinus into cortical veins in the area (third row), leading to local venous congestion

Magnetic Resonance Imaging

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Chapter 102

Leukoencephalopathy After Radiotherapy and Chemotherapy

102.1 Clinical Features and Laboratory Investigations In the treatment of malignancies three modalities play a major role: surgery, radiotherapy, and chemotherapy. Other treatment modalities such as hyperthermia and laser coagulation, often image-guided, are of some, but lesser importance. Radiotherapy and chemotherapy are not only applied in the treatment of primary brain tumors and metastases, but intrathecal and intravenous administration of chemotherapeutic drugs, together with cranial or total neuraxis irradiation, are also widely used in the prophylaxis of cerebral involvement in extracerebral malignancies. For many years the brain was considered to be relatively resistant to therapeutic doses of irradiation and chemotherapy, because neurons do not multiply and the turnover of glial cells is relatively slow. Also, the blood–brain barrier may prevent the penetration of chemotherapeutics into the brain. These concepts have to be modified, because it has become clear that adverse effects are not exceptional. In the classical description of the effects of radiotherapy three types of damage are distinguished according to their time of occurrence: acute reactions, which occur during the time of treatment and may change the treatment schedule; early delayed reactions, which are usually transient and appear from a few weeks to a few months after treatment; and late delayed reactions, with onset from several months to several years after treatment. Acute reactions are usually mild and of little consequence, but severe reactions may occur. Clinically they may present as mild signs of increased intracranial pressure. The patient may become confused, incoherent, and disoriented. In more severe cases the patient suffers from headaches, nausea, vomiting, and sometimes elevation of body temperature. Seizures occasionally occur, and the patient may lapse into coma. Discontinuation of the treatment and corticosteroid administration may be necessary and life-saving. Early delayed reactions are usually transient and disappear without treatment. Various clinical symptoms have been reported: somnolence, nausea, vomiting, dysarthria, dysphagia, cerebellar ataxia, and nystagmus.

Late delayed reactions are generally irreversible. The process begins insidiously with personality changes, gradually progressing over several months. Initially there is excessive drowsiness and loss of initiative and interest. In the course of time there is a decrease of cognitive functioning, confusion, irritability, and memory loss, eventually leading to global dementia. This classical description is used to describe timelinked reactions after radio- and chemotherapy. In addition, the “focal radiation injury” and “focal white matter injury” resulting from stereotactic radiosurgery, gamma knife surgery, or intensity-modulated radiotherapy may be seen as fitting within the classical concept. Clinically some of these injuries have important consequences. Focal radiation injury caused by irradiation of extracranial structures, e.g. of nasopharyngeal squamous cell tumors or pituitary tumors, may lead to damage of the brain – in these cases, damage to both temporal lobes, resulting in a complex behavioral change, the Klüver–Bucy syndrome. There are a number of irradiation- and chemotherapy-related patterns that need special consideration because of their consequences for the prognosis and sometimes the need for therapeutic management. This holds especially for multifocal inflammatory leukoencephalopathy (MIL), and the posterior reversible encephalopathy syndrome (PRES). MIL and PRES are addressed separately in Chaps. 88 and 92.

102.2 Pathology Neuropathological changes in acute reactions after radiotherapy are primarily characterized by cerebral edema, with flattening of gyri, obliteration of sulci, and signs of tentorial herniation. The lateral ventricles are narrowed. Vascular changes are present and consist of fibrinoid necrosis and thickening of the endothelium with extravasation of fibrinous material and perivascular lymphocytic infiltration. Because the early delayed reaction is usually transient and nonlethal in nature, the amount of information available on the histopathological features is limited. Foci of demyelination with central necrosis and petechial hemorrhages have been described. Lymphocytes and plasma cells are found in the perivascu-

102.3

lar spaces, and there is pronounced microglial and astrocytic proliferation in the affected areas. Vascular changes are not prominent in the affected areas, but occasionally the lesions are more marked and show fibrinoid necrosis, fibroproliferative vessel thickening, enlargement of endothelial cells, and capillary proliferation. The cytoarchitecture of the gray matter is usually intact. The neuropathological findings of the late delayed leukoencephalopathy are rather specific. The changes consist of demyelination, astrogliosis, multifocal coagulative necrosis, and cavitation. The periventricular white matter and the centrum semiovale are involved bilaterally, whereas the subcortical arcuate fibers, the cerebral cortex, and deep gray matter structures are usually spared. Within and around the necrotizing lesions conspicuous swelling of axons occurs. An inflammatory response is usually absent. There are marked vascular lesions, characterized by hyalinization, fibrosis, and necrosis of vessel walls and vascular thrombosis. Areas of endothelial proliferation and various degrees of adventitial fibroblast proliferation are found. Obliteration of the lumen may result. Deposition of iron salts and calcium in the vessel walls may occur. Calcifications may be extensive and be present in the subcortical areas, the basal ganglia, and, less commonly, in the pons. It is noteworthy that mineralizing angiopathy is more often seen in children than in adults. The installment of prophylactic irradiation and radiotherapy for acute lymphatic leukemia and the treatment of genetic disorders with bone marrow transplantation have focused attention on the side effects of these therapies. In most patients these reactions are transient and have the nature of temporary white matter edema, as has been confirmed by an occasional biopsy, and more recently by quantitative MR data. Multifocal white matter necrosis has the same neuropathological features as the radiation necrosis described above for late delayed post-irradiation reactions.

102.3 Pathogenetic Considerations Cranial irradiation and systemic, intracarotid, intravenous, and intrathecal chemotherapy, alone or in combination, may result in lesions of the CNS, of either the white matter, the gray matter, or both. In cases of combined therapy it is impossible to delineate the relative contributions of radiation and chemotherapy to the development of cerebral lesions. The total radiation dose and possible overdosage on specific targets, as well as the dose of systemic intravenously or intrathecally administered chemotherapeutics all influence the outcome. Some chemotherapeutic agents are radiosensitizers, for example bis-

Pathogenetic Considerations

chloroethyl-nitrosourea (BCNU), methotrexate, and cisplatin. They enhance the effect of radiation-induced changes. On the other hand, radiation may induce changes in the permeability of the blood–brain barrier and thus affect the delivery of potentially toxic agents. Other factors in the patient, such as nutritional status, type of primary malignancy, or pretransplant status, and the presence of a paraneoplastic syndrome, may well contribute to the development and severity of cerebral lesions. The acute post-therapy syndrome is thought to be due to vasogenic edema resulting from damage to the capillary endothelium. Early delayed reactions are believed to be due to demyelination and may be reversible to some degree. There are suggestions that they may be the result of an autoimmune reaction following sensitization for some myelin antigen that has become exposed by therapy-induced tissue necrosis. Antigens are released in the intracellular spaces by damaged myelin and glial cells, and may evoke hypersensitivity reactions. This hypothesis has never been proven, but the perivascular inflammatory reaction may be an argument. Another mechanism which may account for the marked demyelination in the absence of vascular changes in early delayed post-treatment leukoencephalopathy is primary damage to glial cells, in particular oligodendrocytes. Sometimes striking glial proliferations are noticed, associated with bizarre cells and giant multinuclear astrocytes, supporting this hypothesis. In the late delayed reactions vascular changes with secondary ischemic changes form the most likely explanation for the tissue damage. The endothelium of blood vessels is one of the most sensitive tissues of the brain. Damage to the endothelium leads to endothelial proliferation and changes in the vessel wall, with subsequent obliteration of the lumen and ischemia. Small vessels are usually most affected, but larger arteries may also suffer, and may be partially or totally occluded, possibly with formation of moyamoya-like collaterals. It is important to realize that the adverse consequences of irradiation of the brain, in particular in combination with chemotherapy, may be more severe in infants and children than in adults. The consequences for the immature brain may differ from those for the more mature brain. From the management of medulloblastomas in young children it has become clear that aggressive treatment approaches, especially craniospinal irradiation, can harm the developing brain. It is hard to predict what dose of radiotherapy will be harmful in each individual child. It is well known that very young children will have significant learning problems after full-dose radiotherapy, and that even older children may develop difficulties in school. However, a reduction in dosage may also re-

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duce efficacy on the tumor. Hence, approaches using reduced-dose craniospinal irradiation and chemotherapy, in order to reduce cognitive, endocrine, and psychological deficits, may decrease late effects, but carry with them the risk of having more treatment failures. The combination of radiotherapy and chemotherapy leads to synergistic inhibition of the synthesis of macromolecules and DNA repair, possibly further contributing to the damage. In a postmortem study of children with childhood leukemia treated with different modes of application of this combined therapy, comparing those who showed leukoencephalopathy and those who did not show leukoencephalopathy, it became clear that the development of white matter damage did not correlate with age, despite the different stages of myelination and neuronal differentiation in the pediatric age group. Nor was there a relationship with intercurrent infections, nutrition, or the presence of CNS leukemia. There was a clear relationship with the radiation dose the child had received in combination with intrathecal methotrexate. The total amount of intrathecally administered methotrexate seemed less important. The dose of methotrexate was important when given intravenously: the incidence of leukoencephalopathy increased with the total dose of intravenously administered methotrexate. To add substance to this discussion, the multicenter study of the German Late Effects (of acute lymphatic leukemia treatment) Working Group, summarizes findings in a large population treated with standard protocols (Hertzberg et al. 1997). In this study 118 former patients with acute lymphatic leukemia in first continuous remission underwent CT and/or MRI. The group was subdivided into: group A (39 patients), receiving intrathecal methotrexate and systemic medium–high dose methotrexate; group B (41 patients), receiving cranial irradiation (16.8 Gy) and intrathecal methotrexate or systemic methotrexate; and group C (38 patients), receiving irradiation (17.1 Gy) and intrathecal methotrexate. Abnormal MRI and CT scans were found in 61 of the 118 patients, consisting of white matter changes (diffuse or focal), brain atrophy, and calcifications. Of these 61 patients, 15 were from group A (38.5%), 23 from group B (56.1%), and 23 from group C (60.5%). Patients with definite CNS changes showed impaired neuropsychological function. It is clear from this report that methotrexate without irradiation can also lead to serious CNS changes, both of gray and white matter. This has been reported in more detail by Lövblad et al. (1998). They describe the cases of four children treated with high-dose intravenous and intrathecal methotrexate without irradiation. In all these cases the cure was prolonged, lasting for more than 1 year. These children developed serious CNS abnormalities with diffuse hyperintense white matter

changes on T2-weighted images and subcortical hyperdensities on CT, consistent with calcifications. The authors attribute these changes to a mineralizing angiopathy, commonly thought to be the result of cranial irradiation in combination with chemotherapy. From this and other reports it has become clear that chemotherapy without irradiation may also lead to leukoencephalopathy and mineralizing angiopathy.

102.4 Therapy In acute reactions corticosteroids are useful in alleviating cerebral vasogenic edema and may be life-saving in patients with imminent tentorial herniation. The importance of recognizing early delayed reactions is the fact that they are usually transient and do not necessarily require intervention or indicate a failure of therapy. In the late delayed reaction corticosteroids play a minor role. In cases with focal radiation necrosis, surgery is an option. In patients with neurological syndromes caused by toxic effects of cytostatic or immunosuppressive drugs that may be reversible, abortion of the therapy or a switch to other drugs may have a beneficial effect. Psychiatric syndromes, especially when caused by more permanent damage of both temporal lobes, as happens in the irradiation of nasopharyngeal and pituitary tumors, are difficult to treat and may require special measures.

102.5 Magnetic Resonance Imaging MRI is generally the first choice of imaging modalities in the follow-up of patients treated with cranial irradiation and/or chemotherapy, because its sensitivity is much better than that of CT. Only in the detection of microcalcifications, such as occur in mineralizing angiopathy, does CT have an advantage. All stages of radiation and chemotherapy injuries

䊳

Fig. 102.1. A 62-year-old woman treated with chemotherapy and irradiation for a right frontal glioma. The initial tumor is barely visible on the FLAIR images (first three rows) within a now much larger area of high signal involving the periventricular and deep frontal white matter, right more than left, and the corpus callosum.T1-weighted images after contrast (fourth row) show a rim of a few millimeters’ thickness along the wall of the left lateral ventricle as well as an enhancing dot in the right frontal area.The white matter changes can be attributed to the irradiation and chemotherapy.The enhancement,which did not change during further follow-up, probably represents either inactivated tumor tissue,or,more probably,radiation-induced changes

102.5

Fig. 102.1.

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Fig. 102.2. A 52-year-old male patient presented with a partial seizure. He had been treated previously for a right-sided nasopharyngeal squamous cell carcinoma with partial excision and radiotherapy.The right temporal lobe was included in

the irradiation field. Coronal T2-weighted images show the impact of the radiation on the right temporal lobe, involving both white and gray matter

have in common an increase in free tissue and, sometimes, intracellular water. The consequence of this is a higher signal intensity on T2-weighted and lower signal intensity on T1-weighted images. This signal behavior may, however, reflect many forms of underlying pathology, such as impairment of the blood–brain barrier due to endothelial damage and vasogenic edema, demyelination, gliosis, ischemia, and tissue necrosis. Newer techniques, such as diffusion-weighted imaging, perfusion imaging, and proton MRS, have been of considerable help in the determination of the structural tissue changes. Diffusion-weighted imaging, in combination with calculated ADC maps, or diffusion tensor imaging with the calculation of fractional anisotropy, have made it possible to differentiate between vasogenic edema and cytotoxic edema, and permits a better estimation of the prognosis of the abnormalities found. Contrast administration plays an important role, even though it does not dif-

ferentiate radiation necrosis from tumor recurrence. Perfusion imaging and MRS have a prominent role in distinguishing tumor recurrence from radiation necrosis. In necrotizing tissue perfusion is low, whereas in tumor recurrence it is usually high. MRS – if possible, chemical shift imaging to cover the whole area – shows in tumor recurrence high choline, lactate, and often the presence of some residual brain metabolites, for instance N-acetylaspartate in reduced concentration. In necrotic tissue N-acetylaspartate is usually absent, as is choline, whereas lactate is present. It is, however, not rare that both tissue necrosis and tumor recurrence are present at the same time. Microbleeds can be made visible on MR images with gradient echo or hybrid spin-echo–gradient-echo techniques. In the acute reaction MR findings are nonspecific. The images may be completely normal or subtly abnormal with poorly defined multifocal areas of hy-

102.5

Magnetic Resonance Imaging

Fig. 102.3. A 4-year-old boy was treated prophylactically with irradiation and intrathecal methotrexate because of acute lymphocytic leukemia. The T2-weighted images (upper row) show involvement of the basal ganglia, internal capsule, and

cerebral peduncles in the midbrain. The T1-weighted images (second row) reveal cysts in the basal ganglia, indicating that cystic necrosis has developed. With contrast, an enhancing recurrent tumor is seen in the third ventricle

perintensity on T2-weighted images, most often in both hemispheres. The abnormalities usually disappear spontaneously, given an uneventful clinical course. In early delayed reactions, occurring a few weeks to months after treatment, the white matter changes are also usually transient. Changes on MRI include high signal intensity on T2-weighted or FLAIR images in the basal ganglia, the cerebral peduncles, and the deep white matter. Diffusion-weighted imaging also shows high signal intensity in these areas, with also a high ADC value. The term “T2 shine-through” is sometimes used for this phenomenon, but seems not quite correct, because the combination of high signal on diffusion-weighted imaging and high diffusivity may reflect an underlying condition, most probably, but not only, vasogenic edema. It is in general an indication of a benign nature of the lesion. In some patients who develop a diffuse leukoencephalopathy a few weeks to a few months after treatment, the course is not benign and the white matter abnormalities are

not reversible. Enhancing lesions within the white matter correlate with tissue necrosis at autopsy. Transient white matter abnormalities are often found in patients treated for acute lymphocytic leukemia with prophylactic cranial irradiation, chemotherapy, and bone marrow transplantation. The lesions are located in the periventricular area and may be more or less extensive. There is no clear relationship between the severity of the lesions on MRI and the clinical condition and outcome. Diffusionweighted imaging and ADC maps may be helpful by showing the nature of the lesions. The lesions may remain visible for a long time after the clinical disappearance of symptoms. Late delayed reactions occur months to years after the initial treatment. Depending on the field of irradiation the lesions are more focal (Figs. 102.1–102.3) or more generalized (Figs. 102.4 and 102.5). So-called “diffuse radiation injury” can be caused by irradiation, by combined irradiation and chemotherapy, and by chemotherapy alone. The white matter lesions,

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Fig. 102.4. A 29-year-old woman with disseminated breast carcinoma. Metastases in the brain were treated with radiotherapy and systemic cytostatic treatment. The T2-weighted transverse series 6 months after radiotherapy (upper two rows) shows diffuse symmetrical deep white matter hyperintensity,

also involving the external capsule and the temporal lobes. In the cerebellum there are multiple, asymmetrical lesions and linear high-signal bands in the cerebellar foliae. T1-weighted images after contrast (third row) show multiple metastases and leptomeningeal carcinomatosis

when irradiation has covered the whole brain, are located in the white matter of both hemispheres and are symmetrical and confluent. Combinations of diffuse radiation injury and recurrent tumor may occur (Fig. 102.3). The lesions of late delayed reactions have a high signal intensity on proton density, T2-weight-

ed, and FLAIR images. ADC values are usually only slightly above those of normal cerebral tissue. Despite the sometimes extensive white matter lesions, patients may be asymptomatic. In more severe cases there may be slowing down of mental activity and cognitive impairment. The most severe form of late

102.5

Magnetic Resonance Imaging

Fig. 102.5. A 24-year-old man was treated for acute lymphocytic leukemia with chemotherapy and intrathecal methotrexate.Two months later he developed progressive encephalopathy. The T2-weighted images show extensive involvement of

arcuate fibers in parietal, frontal, and temporal lobes, as well as bilateral involvement of the posterior limb of the internal capsule, thalamus, corticospinal tracts in the midbrain, and both middle cerebellar peduncles

delayed reaction is necrotizing encephalopathy with areas of focal necrosis (Fig. 102.3). The borders of these lesions may enhance. To verify this diagnosis, perfusion studies may be performed, showing reduced perfusion, or MRS, showing loss of metabolites without a rise in choline concentration and with various amounts of lactate.

A disseminated necrotizing leukoencephalopathy with characteristic contrast enhancement of the white matter has been reported in patients with acute lymphoblastic leukemia after intense chemotherapy with methotrexate and prophylactic cranial irradiation, with either a fulminant or a less fulminant course. In these cases methotrexate was delivered both intra-

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Fig. 102.6.

102.5

Magnetic Resonance Imaging

Fig. 102.7. The T1-weighted images of the same patient as illustrated in Fig. 102.6, without (first row) and with contrast (second row), reveal multiple small punctate areas of contrast uptake, suggesting perivascular enhancement.These findings suggest an underlying angiitis or vasculopathy

venously and intrathecally. MRI initially shows extensive white matter abnormalities, with focal but symmetrical enhancement. On follow-up studies the

䊴

Fig. 102.6. An 18-year-old girl was treated 7 years ago with chemotherapy, irradiation, and autologous bone marrow transplantation for a non-Hodgkin lymphoma. She has been tumor-free since the treatment. However, since 1.5 years after the treatment she has developed slowly progressive encephalopathy with recently more rapid decline. The encephalopathy was characterized by concentration and memory problems, personality changes, subsequent global cognitive impairment, and finally increasing ataxia and spasticity. The T2-weighted images (first three rows) show extensive white matter changes,especially involving the arcuate fibers.There is some cerebral atrophy with ventriculomegaly, including the temporal horns, and widening of the subarachnoid spaces. There are bilateral lesions in the thalamus. Diffusion-weighted images (fourth row) at different b values and an ADC map show increased ADC values in the abnormal white matter areas (ADC values in the affected region 1.24–1.55). These values, unfortunately, only reflect the final phase of the process. Because of the insidious start and progress of the encephalopathy, initial ADC values are not available

enhancement disappears but atrophy sets in, leading to death within a few years. The MR pattern differs from that seen in autoimmune suppressive therapyrelated MIL. Severe late delayed reactions may also develop after treatment with a combination of irradiation, chemotherapy, and bone marrow transplantation. Years after treatment, and following an initially good response, a progressive encephalopathy may develop with loss of mental faculties and an array of neurological symptoms and ending in death. MRI shows white matter abnormalities predominantly involving the arcuate fibers and progressive atrophy (Figs. 102.6 and 102.7). Mineralizing angiopathy is more often seen in children than in adults. In children it is the most common abnormality seen on MRI and/or CT. Calcifications are found in the subcortical white matter and sometimes in the basal ganglia, in particular in the putamen. Lesions after gamma-knife therapy, stereotactic radiosurgery, and localized overdosage are not fundamentally different from the classic description. Here, too, the whole gamut of reactions is possible: from vasogenic transient edema, to severe white and/or gray matter lesions, to a cavitating (leuko)encephalopathy.

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Chapter 103

Gliomatosis Cerebri

103.1 Clinical Features and Laboratory Investigations Several synonyms are used for this condition: diffuse glioma of the brain, gliomatosis diffusa, gliomatous hypertrophy, blastomatous type of diffuse sclerosis, and central diffuse schwannosis. The clinical presentation is variable. Headache is present in most cases, and may be accompanied by focal seizures, changes in mental state, psychiatric syndromes, ataxia, dysphagia, dysphasia, and memory loss. The clinical picture suggests in most cases a multifocal progressive disorder. Initially, however, symptoms may be difficult to interpret, with only loss of concentration, behavioral problems, or psychiatric symptoms. Some patients present with diminished vision only, and papilledema is found at fundoscopy. The clinical symptoms are often discrepantly mild in view of the extensive abnormalities found on MRI, but they are progressive and lead to death. The median survival time is 14 months. Over the last 5–10 years there seems to have been an increase in the number of cases of gliomatosis cerebri, and younger patients are affected than in former years. The reason for this is unclear.

103.2 Pathology Macroscopically, there is swelling of the involved structures. Although all parts of the brain may be involved, including the brain stem and cerebellum, there is a preference for the central, periventricular areas and mesolimbic parts of the temporal lobe. The microscopic hallmark of gliomatosis cerebri is the presence of many moderately pleomorphic glial cells, infiltrating pre-existing structures, without significant destruction. Natural borders between structures are not respected. Usually, these cells are astrocytic in type and react positively with glial fibrillary acidic protein (GFAP). In other cases, the infiltrating cells have oligodendroglia-like elements and only a few cells are GFAP-positive astrocytes. Locally further dedifferentiation may take place, and some parts of the lesion may progress to anaplastic astrocytoma or glioblastoma multiforme. Finally, the entire neuraxis may be involved.

103.3 Pathogenetic Considerations No familial cases of gliomatosis cerebri have been reported. One study looking at the chromosomes of cells of gliomatosis cerebri revealed that the majority of the abnormal cells had the karyotype 44 XY, (del(6)(q25), del(14)(q21), del(15;21)(q10;q10), add(18)(q22), del(19)(p12), add(20)(p13), -21.A smaller proportion of cells had 88 chromosomes with a doubling of the normal karyotype.With the exception of the chromosome 6 deletion, these chromosomal changes do not resemble those found in astrocytomas, suggesting that gliomatosis cerebri is a separate entity (Hecht et al. 1995). Herrlinger et al. (2002) summarize the molecular genetic findings and find that genetic alterations in diffuse gliomatosis are not different from those found in infiltrating astrocytomas. They conclude on these grounds that gliomatosis cerebri should be considered a particularly invasive subform of glioma, rather than a distinct tumor entity that is entirely different from other cerebral gliomas. An extra argument for this is found in the dedifferentiation of gliomatosis cerebri into anaplastic astrocytomas and glioblastoma multiforme. In one report, gliomatosis cerebri was seen following radiation and chemotherapy for a extraneural metastasis of primary nongerminomatous germ cell tumor in the pineal region, providing evidence for exogenous induction of the tumor. 䊳

Fig. 103.1. Series of transverse T2-weighted images in a 56year-old woman (first two rows). She has a history of changes in personality over the past 2 years, leading to suspicion of frontotemporal dementia. The images show bilateral, nearly symmetrical signal abnormalities of the frontal lobes, connected via the genu of the corpus callosum and spreading toward the deep insular structures on both sides.The affected corpus callosum is markedly swollen.There is diminished gray–white matter distinction in the involved areas. The third and fourth rows contain diffusion-weighted images (Trace diffusion-weighted images with b = 1000 in the third row; ADC maps in the fourth row). The Trace diffusion-weighted images show a moderate increase in signal intensity in the involved area, whereas the ADC values are too high, indicating increased mobility of water. Note that this combination of moderately high signal increase on Trace diffusion-weighted images together with high ADC values in the affected area does not reflect vasogenic edema

103.3

Fig. 103.1.

Pathogenetic Considerations

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820 Chapter 103 Gliomatosis Cerebri

Fig. 103.2. Series of FLAIR images in a 25-year-old man with biopsy-proven gliomatosis cerebri.The biopsy was taken from the left frontal lobe. In this case the abnormalities are mildly asymmetrical and have a prominent mass effect.There is clear

involvement of the temporal lobes. In many places where the tumor touches upon the cortico-subcortical junction, the gray–white matter differentiation has disappeared

103.4 Therapy

103.5 Magnetic Resonance Imaging

Because neurosurgery is not an option in most cases, radiotherapy and chemotherapy are the only remaining therapies available. The results have been disappointing for many years, but with the drug temozolomide longer survival has been achieved.

Most useful for the diagnosis of gliomatosis cerebri are proton density, T2-weighted, and FLAIR sequences. They show increased signal intensity of the involved areas, with poor demarcation from noninvolved tissue, and with mass effect. When the cortico-subcorti-

103.5

Magnetic Resonance Imaging

Fig. 103.3. This 17-year-old girl presented with bilateral papilledema and no other neurological signs. The FLAIR images (upper two rows) reveal an asymmetrical presentation of gliomatosis cerebri with most prominent abnormalities on the right. The third row shows coronal T1-weighted images with contrast. The left-hand image was obtained directly after con-

trast administration, showing some contrast enhancement in the right frontal lobe. The two images on the right were obtained 1 h after the injection and show much more prominent contrast enhancement. The latter images make clear that the damage to the blood–brain barrier is far more extensive than the first postcontrast image would suggest

cal junction is involved, there may be a striking loss of demarcation of gray and white matter and the suggestion of some swelling (Figs. 103.1–103.3). When the periventricular structures are involved, the ventricle

will be locally narrowed, with distortion of its normal border (Figs. 103.2 and 103.3). In these centrally located cases, the corpus callosum is nearly always involved and may be severely swollen (Fig. 103.2).

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Fig. 103.4. Follow-up study of the same girl shown in Fig. 103.3, 6 months after radiotherapy and chemotherapy. It is clear that the process has advanced and the brain stem is seriously involved

There may be a striking symmetry of the abnormalities (Fig. 103.1), although this may disappear when the disease progresses. The disease may also be highly asymmetrical in the initial stage (Fig. 103.4). In some patients the spread of the disease clearly follows white matter tracts, with less severe involvement of gray matter structures. Focal calcification has been reported. In most cases, there is no or only partial enhancement of the involved structures after contrast injection. This, however, depends on the technique used. With triple-dose gadolinium one may see some enhancement; a delayed scan (e.g., 1 h delay) may show enhancement in an unexpectedly large area (Fig. 103.3). Leptomeningeal dissemination may be observed, the disseminated lesions showing contrast enhancement.

Diffusion-weighted imaging with ADC maps is useful, in combination with chemical shift imaging and perfusion imaging, to find the places with the highest malignancy to direct a brain biopsy, when considered necessary, or to direct a local boost or intensity-modulated radiotherapy. In the affected areas MRS shows decreased N-acetylaspartate, normal or increased choline, and, in some patients, strikingly increased myo-inositol. Myo-inositol is exclusively present in glial cells. The MR pattern of the disease is nearly always diagnostic. In cases with central location and symmetrical involvement of the thalamus, central venous thrombosis has to be excluded, for which purpose MRA can be used. Postictal changes may mimic the MR appearance of gliomatosis cerebri. In these cases the abnormalities disappear within 14 days.

Chapter 104

Diffuse Axonal Injury

104.1 Clinical Features and Laboratory Findings Head trauma, especially in motor vehicle accidents, can lead to a wide spectrum of cerebral and intracranial lesions, with usually different clinical presentations (epidural and subdural hematomas, subarachnoid and intracerebral hemorrhages, cerebral contusions, generalized cerebral edema, and secondary phenomena, such as hydrocephalus, raised intracranial pressure, and tentorial herniation), and different findings on CT and MRI. About 50% of patients with traumatic acceleration–deceleration injuries are diagnosed with diffuse axonal injury (DAI), also called shearing injury. Clinically, DAI is characterized by loss of consciousness following the accident, usually without a lucid interval, a very low score on the Glasgow Coma Scale, and discrepantly subtle abnormalities on CT scans. When lesions are seen on CT, they consist mainly of petechial hemorrhages at the cortico-subcortical junction, in the body or splenium of the corpus callosum, and/or in the basal ganglia and brain stem. Intracranial pressure measurements in patients with DAI are, at least in the beginning, normal, in contrast to the case with most of the other brain injuries. DAI may result in death. It is unclear how often death occurs in DAI, but one may assume that it occurs in a high percentage of the patients. When it comes to a correct estimation of the frequency of death, the problem is that numbers provided by different specialists – neurologists, traumatologists, and neuropathologists – are not consistent. In some reports (by neurologists) it is stated that DAI rarely results in death, whereas others (neuropathologists) claim that DAI is an important cause of death in acceleration–deceleration trauma. This difference is at least partly due to the different populations they encounter.About 90% of patients with a clinical diagnosis of DAI, however, will remain in a vegetative condition. In the first episode patients with DAI stay in the intensive care unit, in many cases artificially ventilated. During this period it would be important for the management of these patients to have a reliable prediction of outcome, most importantly to maintain the option to discontinue treatment that will not further improve the condition of the patient. Clinical and neurophysiological data are important in that re-

spect. EEG will reflect the seriousness of the functional disturbance of the brain, and will provide important information. MRI, in particular with more recent MR techniques, such as diffusion-weighted imaging, perfusion imaging, and MRS, may be helpful in predicting outcome.

104.2 Pathology Pathological findings depend heavily on the time between the initial accident and the postmortem analysis. Because of the many secondary reactions that occur after the initial trauma, histological findings may be different in different stages. Unfortunately, very often the time between the accident and death is not reported. In general, macroscopic findings may be normal or reveal focal atrophy, either cortical or in the rostral part of the brain stem. In early cases brain edema may be severe and tentorial herniation may be present. Microscopic examination may demonstrate that axons are torn completely, but more often the damage is incomplete. Focal alterations in the axoplasmic membrane may result in impairment of the axoplasmic transport. Swelling ensues and the axon is dissected. Early damage to the axons is shown by the presence of large numbers of eosinophilic and argyrophilic bulbs on nerve fibers, forming the so-called retraction balls, the pathological hallmark of shearing injury. Macroscopically, lesions in DAI are usually ovoid or elliptical, following the long axis of the injured axons. Their distribution is not uniform or symmetrical, but they occur particularly at the junction of gray and white matter, in the corpus callosum, septum, fornix, internal capsule, deep gray matter, tegmentum, and cerebellar foliae dorsal to the dentate nuclei. The lesions are often hemorrhagic; the hemorrhages occur in a linear pattern, following the distortion of layers. In later stages, atrophy dominates the picture. Of the basal ganglia, the lateral and ventral nuclei of the thalamus are most atrophic, usually with sparing of the anterior and dorsomedial nuclei, the pulvinar, the centromedian nuclei, and lateral geniculate bodies. Cholinergic neurons have been found to be more susceptible than neurons belonging to other categories of neurotransmitters. Immunocytochemical staining for b-amyloid precursor protein (b-APP) detects with great sensitivity axons that have im-

824 Chapter 104 Diffuse Axonal Injury

paired fast axonal transport. In normally functioning axons b-APP is transported with fast axonal transport and never builds up to a concentration that allows its detection in tissue samples. When this fast axonal transport system is damaged, b-APP rapidly accumulates in the disrupted segment. This accumulation occurs before morphological methods detect the axonal damage. It is not known whether axonal damage thus detected is potentially reversible. The b-APP staining technique has demonstrated that even in apparently minor head trauma damage may occur to axons. In animal experiments there is a good correlation between the amount of axonal damage and the clinical outcome.

104.3 Pathogenetic Considerations DAI is a shearing injury. It has been found experimentally that shearing injury is not induced by linear or translational forces but rather by rotational forces. A sudden acceleration–deceleration impact can produce rotational forces. Where the lesions occur depends on the distance to the rotational center, the arc of rotation, and the duration and intensity of the force. Because of the relative fixation of certain parts of the brain to the rigid skull, the deep and superficial portions may not move at the same rate and can even move in different directions. This will result in shear strain that manifests across the axons and results in axonal injury and rupture. Different brain parts have different consistencies depending on cell composition and cell density. Injuries to the brain will be most prominent at their junction, where differences in tissue densities are greatest. One such vulnerable site is the gray–white matter junction, involved in 60–70% of patients with DAI. Other vulnerable sites are the corpus callosum, corticospinal tracts, basal ganglia, and the brain stem. The initial damage to the brain is followed by secondary reactions related to hemorrhage, edema, changes in local perfusion, and triggering of biochemical cascades. Swelling of the brain may lead to tentorial herniation; swelling of the brain stem may lead to hydrocephalus. Disruption of neuronal and axonal connections leads to wallerian degeneration and atrophy. It is probably the extent of the lesions and the involvement of the rostral brain stem that leads to the vegetative state in many of the patients. It is thought that damage to the rostral part of the brain is the cause of a reduction in dopamine turnover. In the first few hours after the traumatic brain injury, catecholamines in the CSF are raised. Soon the catecholamine production is chronically decreased and the levels in the CSF drop. Plasma norepinephrine levels have been shown to correlate with the Glasgow Coma Score and may correlate with the outcome of

brain injury. Homovanillic acid, a breakdown product of the adrenergic neurotransmitter systems, is significantly decreased soon after brain injury, and the level correlates with the depth of coma.

104.4 Therapy Dopamine, one of the catecholamines, is an important neurotransmitter in the CNS. In DAI a reduction of dopamine turnover has been found. This observation has prompted the introduction of amantadine (Symmetrel) therapy in DAI. Amantadine is a drug known from treatment of Parkinson disease. Amantadine causes release of dopamine from central neurons, facilitates dopamine release by nerve impulses, and delays the uptake of dopamine by neural cells. It may also have a profound N-methyl-D-aspartate receptor antagonist effect, which may contribute to the neuroprotective effects after injury, by decreasing glutamate concentrations and thus excitotoxicity. In a randomized crossover design study in DAI patients, there was a consistent trend toward more rapid functional improvement with amantadine treatment, regardless of when during the first three months after injury the amantadine treatment was started (Meythaler et al. 2002). From these findings it is also clear that medication that results in dopaminergic blockade is contraindicated in the early stage of recovery from DAI.

104.5 Magnetic Resonance Imaging In emergency departments CT is usually the first imaging modality used in cases of head trauma. In most presentations of head trauma CT is capable of producing a correct diagnosis. CT has the advantage over MRI of more clearly showing skull fractures. In DAI there is usually a discrepancy between the depth of the coma as expressed in the Glasgow Coma Score and the lack of or subtle findings on CT (Fig. 104.1). White matter abnormalities develop over time (Fig. 104.1). MRI is the best imaging modality by which to confirm the diagnosis and to classify the lesions, usually employing the grading scale of Gennarelli. This scale divides the findings into three groups: lesions with and without hemorrhage at the gray–white matter junction, especially in the temporal and frontal areas (type 1), combined with lesions in and around the corpus callosum (type 2), and with lesions in the basal ganglia and the rostral brain stem (type 3). The scale roughly correlates with outcome. Conventional MRI with T1-weighted, T2-weighted, T2*-weighted, and FLAIR images is more sensitive in depicting tissue changes than is CT (Figs. 104.2–

104.5

Magnetic Resonance Imaging

Fig. 104.1. A 36-year-old man with severe head trauma. The first row of images, obtained on admission, shows evidence of white matter shearing in the frontal subcortical region, corpus callosum, basal ganglia, and thalami with presence of small hemorrhages. The second row of images, obtained 1 week later, shows the hemorrhages to be more pronounced.There is

a developing leukoencephalopathy in the frontal region. The third row shows the images obtained 6 weeks after the accident. The hemorrhages have now disappeared. The frontal cortex seems intact, whereas the frontal white matter is hypodense, related to wallerian degeneration

104.5). The role of T2*-weighted images in establishing the diagnosis is considerable. Even early on hemosiderin deposits depict the linear nature and multiplicity of lesions (Figs. 104.2 and 104.5). The role of MR is even more pronounced when newer tech-

niques, such as diffusion-weighted images with Trace and ADC maps, tensor diffusion imaging with fractional anisotropy and fiber tracking, perfusion imaging, and magnetization transfer ratio maps are added to the protocol. These techniques allow assessment of

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826 Chapter 104 Diffuse Axonal Injury

Fig. 104.2.

104.5

Magnetic Resonance Imaging

Fig. 104.3. A 14-year-old girl was the victim of a traffic accident. The FLAIR images on the left (first column) show some subdural blood in the left occipital region and a lesion in the left frontal lobe.There are lesions in the basal ganglia and thalami. Diffusion-weighted Trace images (second column) show

the lesions with greater conspicuity, especially those in the basal ganglia, thalami, and the medial parts of the occipital lobes. ADC values (third column) are low (Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the sinle N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity. Eur J Hum Genet 1999; 7: 125–130 Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M. Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. Hum Genet 2002; 110: 351–355 Reider-Grosswasser I, Bornstein N. CT and MRI in late-onset metachromatic leukodystrophy. Acta Neurol Scand 1987; 75: 64–69 Sangalli A, Taveggia C, Salviati A, Wrabetz L, Bordignon C, Severini GM. Transduced fibroblasts and metachromatic leukodystrophy lymphocytes transfer arylsulfatase A to myelinating Glia and deficient cells in vitro. Hum Gene Ther 1998; 9: 2111–2119 Schlote W, Harzer K, Christomanou H, Paton BC, Kustermann B, Schmid B, Seeger J, Beudt U, Schuster I, Langenbeck U. Sphingolipid activator protein 1 deficiency in metachromatic leucodystrophy with normal arylsulphatase A activity. A clinical, morphological, biochemical, and immunological study. Eur J Pediatr 1991; 150: 584–591 Scholz W. Klinische, pathologisch-anatomische und erbbiologische Untersuchungen.Z Neurol Psychiatrie 1925;99:651–717 Shapiro EG, Lockman LA, Knopman D, Krivit W. Characteristics of the dementia in late-onset metachromatic leukodystrophy. Neurology 1994; 44: 662–665 Solders G, Celsing G, Hagenfeldt L, Ljungman P, Isberg B, Ringdén O. Improved peripheral nerve conduction, EEG and verbal IQ after bone marrow transplantation for adult metachromatic leukodystrophy. Bone Marrow Transplant 1998; 22: 1119–1122 Stillman AE, Krivit W, Shapiro E, Lockman L, Latchaw RE. Serial MR after bone marrow transplantation in two patients with metachromatic leukodystrophy. AJNR Am J Neuroradiol 1994; 15: 1929–1932 Tylki-Szymañska A, Czartoryska B, Lugowska A. Practical suggestions in diagnosing metachromatic leukodystrophy in probands and in testing family members. Eur Neurol 1998; 40: 67–70 Van Bogaert L, Dewulf A. Diffuse progressive leukodystrophy in the adult with production of metachromatic degenerative products (Alzheimer-Baroncini). Arch Neurol Psychiatry 1939; 42: 1083–1097

Von Hirsch T,Pfeiffer J.Über histologische Methoden in der Differentialdiagnose von Leukodystrophien und Lipoidosen. Arch Psychiatrie Z Neurol 1955; 194: 88–104 Wrobe D, Henseler M. Huettler S, Pascual Pascual SI, Chabas A, Sandhoff K. A non-glycosylated and functionally deficient mutant (N215H) of the sphingolidpid activator protein B (SAP-B) in a novel case of metachromatic leukodystrophy (MLD). J Inherit Metab Dis 2000; 23: 63–76 Zafeiriou DI, Kontopoulos EE, Michelakakis HM, Anastasiou AL, Gombakis NP. Neurophysiology and MRI in late-infantile metachromatic leukodystrophy. Pediatr Neurol 1999; 21: 843–846 Zhang XL, Rafi MA, DeGala G, Wenger DA. Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency. Proc Natl Acad Sci 1990; 87: 1426–1430

7 Multiple Sulfatase Deficiency Al-Moutaery KR, Choudhury AR, Hassanen MO. Cervical cord compression and severe hydrocephalus in a child with Saudi variant of multiple sulfatase deficiency. Acta Neurochir (Wien) 1994; 131: 160–163 Aqeel AA, Ozand PT, Brismar J, Gascon GG, Brismar G, Nester M, Sakati N. Saudi variant of multiple sulfatase deficiency. J Child Neurol 1992; 7 (suppl): S12–S21 Austin JH. Studies in metachromatic leukodystrophy. Arch Neurol 1973; 28: 258–264 Basner R, von Figura K, Glössl J, Klein U, Kresse H, Mlekusch W. Multiple deficiency of mucopolysaccharide sulfatases in mucosulfatidosis. Pediatr Res 1979; 13: 1316–1318 Bateman BJ, Philippart M, Isenberg SJ. Ocular features of multiple sulfatase deficiency and a new variant of metachromatic leukodystrophy. J Pediatr Ophthalmol Strabismus 1984; 21: 133–139 Bharucha BA,Nalk G,Savliwala AS,Joshi RM,Kumta NB.Siblings with the Austin variant of metachromatic leukodystrophy multiple sulfatidosis. Indian J Pediatr 1984; 51: 477–480 Burch M, Fesnom AH, Jackson M, Pitts-Tucker T, Congdon PJ. Multiple sulphatase deficiency presenting at birth. Clin Genet 1986; 30: 409–415 Burk RD,Valle D,Thomas GH, Miller C, Moser A, Moser H, Rosenbaum KN. Early manifestations of multiple sulfatase deficiency. J Pediatr 1984; 104: 574–578 Conary JT, Hasilik A, von Figura K. Synthesis and stability of steroid sulfatase in fibroblasts from multiple sulfatase deficiency. Biol Chem Hoppe-Seyler 1988; 369: 297–302 Constantopoulos G. Multiple sulfatase deficiency with a novel biochemical presentation. Eur J Pediatr 1988; 147: 634–638 Cosmo MP, Pepe S, Annuziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes and essential and limiting factor for the activity of sulfatases. Cell 2003; 113: 445–456 Fedde K, Horwitz AL. Complementation of multiple sulfatase deficiency in somatic cell hybrids. Am J Hum Genet 1984; 36: 623–633 Guerra WF, Verity A, Fluharty AL, Nguyen HT, Philippart M. Multiple sulfatase deficiency: clinical, neuropathological, ultrastructural and biochemical studies.J Neuropathol Exp Neurol 1990; 49: 406–423 Harbord M, Buncic JR, Chuang SA, Skomorowski MA, Clarke JTR. Multiple sulfatase deficiency with early severe retinal degeneration. J Child Neurol 1991; 6: 229–235

References and Further Reading

Horwitz AL, Warshawsky L, King J, Burns G (1986) Rapid degradation of steroid sulfatase in multiple sulfatase deficiency. Biochem Biophys Res Commun 1986; 135: 389–396 Kepes JJ, Berry A, Zacharias DL. Multiple sulfatase deficiency: bridge between neuronal storage diseases and leukodystrophies. Pathology 1988; 20: 285–291 Landgrebe J, Dierks T, Schmidt B, von Figura K. The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family, which is conserved from pro- to eukaryotes. Gene 2003; 316: 47–56 Loffeld A, Gray RGF, Green SH, Roper HP, Moss C. Mild ichthyosis in a 4-year-old boy with multiple sulphatase deficiency. Br J Dermatol 2002; 147: 353–355 Macaulay RJB, Lowry NJ, Casey RE. Pathologic findings of multiple sulfatase deficiency reflect the pattern of enzyme deficiencies. Pediatr Neurol 1998; 19: 372–376 Mancini GMS, Diggelen van OP, Huijmans JG, Stroink H, Coo de RFM. Pitfalls in the diagnosis of multiple sulfatase deficiency. Neuropediatrics 2001; 32: 38–40 Nevsimalova S, Elleder M, Smid F, Zemankova M. Multiple sulphatase deficiency in homozygotic twins. J Inherit Metab Dis 1984; 7: 38–40 Perlmutter-Cremer N, Libert J,Vamos E, Sphel M, Kiebaers I. Unusual early manifestation of multiple sulfatase deficiency. Ann Radiol 1981; 24: 43–48 Raynaud EJ, Escourolle R, Baumann N, Turpin JC, Dubois G, Malpuech G, Lagarde R. Metachromatic leukodystrophy. Arch Neurol 1975; 32: 834–838 Rommerskirch W, von Figura K. Multiple sulfatase deficiency: catalytically inactive sulfatases are expressd from retrovirally introduced sulfatase cDNAs. Proc Natl Acad Sci 1992; 89: 2561–2565 Schmidt B, Selmer T, Ingendoh A, von Figura K. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency. Cell 1995; 82: 271–278 Soong BW, Casamassima AC, Fink JK, Constantopoulos G, Horwitz AL. Multiple sulfatase deficiency. Neurology 1988; 38: 1273–1275 Tanaka A, Hirabayashi M, Ishii M,Yamaoka S. Complementation studies with clinical and biochemical characterizations of a new variant of multiple sulphatase deficiency. J Inherit Metab Dis 1987; 10: 103–110 Vamos E, Lubairs I, Bousard N, Liberi J, Pirimutter N. Multiple sulphatase deficiency with early onset. J Inherit Metab 1981; 4: 103–104 Waheed A, Hasilik A, von Figura K. Enhanced breakdown of arylsulfatase A in multiple sulfatase deficiency. Eur J Biochem 1982; 123: 317–321

8 Globoid Cell Leukodystrophy Andrews JM, Cancilla PA, Grippo J, Menkes JH. Globoid cell leukodystrophy (Krabbe’s disease): morphological and biochemical studies. Neurology 1971; 21: 337–352 Arvidsson J, Hagberg B, Mansson J-E, Svennerholm L. Late onset globoid cell leukodystrophy (Krabbe’s disease) – a Swedish case with 15 years of follow-up. Acta Paediatr 1995; 84: 218–221 Austin J. Studies in globoid (Krabbe) leukodystrophy. Arch Neurol 1963; 9: 207–231 Austin J. Studies in globoid (Krabbe) leukodystrophy. J Neurochem 1963; 10: 921–930

Austin J, Suzuki K, Armstrong D, Brady R, Bachhawat BK, Schlenker J, Stumpf D. Studies in globoid (Krabbe) leukodystrophy (GLD). Arch Neurol 1970; 23: 502–512 Bajaj NPS, Waldman A, Orrell R, Wood NW, Bhatia KP. Familial adult onset of Krabbe’s disease resembling hereditary spastic paraplegia with normal neuroimaging. J Neurol Neurosurg Psychiatry 2002; 72: 635–638 Baker RH,Trautmann JC,Younge BR, Nelson KD, Zimmerman R. Late juvenile-onset Krabbe’s disease. Ophthalmology 1990; 97: 1176–1180 Baram TZ, Goldman AM, Percy AK. Krabbe disease: specific MRI and CT findings. Neurology 1986; 36: 111–115 Barone R, Brühl K, Stoeter P, Fiumara A, Pavone L, Beck M. Clinical and neuroradiological findings in classic infantile and late-onset globoid-cell leukodystrophy (Krabbe disease). Am J Med Genet 1996; 63: 209–217 Bernal OG, Lenn N. Multiple cranial nerve enhancement in early infantile Krabbe’s disease. Neurology 2000; 54: 2348– 2349 Bernardi B, Fonda C, Franzoni E, Marchiani V, Della Guistina E, Zimmerman RA. MRI and CT in Krabbe’s disease: case report. Neuroradiology 1994; 36: 477–479 Bernardi GL, Herrera DG, Carson D, DeGasperi R, Gama Sosa MA, Kolodny EH, Trifiletti R. Adult-onset Krabbe’s disease in siblings with novel mutations in the galactocerebrosidase gene. Ann Neurol 1997; 41: 111–114 Bischoff A, Ulrich J. Peripheral neuropathy in globoid cell leukodystrophy (Krabbe’s disease). Ultrastructural and histochemical findings. Brain 1969; 92: 861–870 Biswas S, Levine SM. Substrate-reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy. Pediatr Res 2002; 51: 40–47 Cavanagh N, Kendall B. High density on computed tomography in infantile Krabbe’s disease: a case report. Dev Med Child Neurol 1986; 28: 799–802 Choi S, Enzmann DR. Infantile Krabbe disease: complementary CT and MR findings. AJNR Am J Neuroradiol 1993; 14: 1164–1166 Demaerel Ph,Wilms G,Verdru P, Carton H, Baert AL.MR findings in globoid cell leukodystrophy. Neuroradiology 1990; 32: 520–522 De Stefano N, Dotti MT,Mortilla M, Pappagallo E,Luzi P,Rafi MA, Formichi P, Inzitari D, Wenger DA, Federico A. Evidence of diffuse brain pathology and unspecific genetic characterization in a patient with an atypical form of adult-onset Krabbe disease. J Neurol 2000; 247: 226–228 Ellis WG, Schneider EL, McCulloch JR, Suzuki K, Epstein CJ. Fetal globoid cell leukodystrophy (Krabbe disease). Pathological and biochemical examination. Arch Neurol 1973; 29: 253–257 Epstein MA, Zimmerman RA, Rorke LB, Sladky JT. Late-onset globoid cell leukodystrophy mimicking an infiltrating glioma. Pediatr Radiol 1991; 21: 131–132 Eto Y, Suzuki K. Brain spingoglycolipids in Krabbe’s globoid cell leucodystrophy. J Neurochem 1971; 18: 503–511 Eto Y, Suzuki K, Suzuki K. Globoid cell leukodystrophy (Krabbe’s disease): isolation of myelin with normal glycolipid composition. J Lipid Res 1970; 11: 473–479 Farina L, Bizzi A, Fiocchiaro G, Pareyson D, Shghirlanzoni A, Bertagnolio B, Savoiardo M, Naidu S, Wenger DA. MR imaging and proton MR spectroscopy in adult Krabbe disease. AJNR Am J Neuroradiol 2000; 21: 1478–1482 Farley TJ, Ketonen LM, Bodensteiner JB, Wang DD. Serial MRI and CT findings in infantile Krabbe disease. Pediatr Neurol 1992; 8: 455–458

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916 References and Further Reading Feanny SJ, Chuang SH, Becker LE, Clarke JTR. Intracerebral paraventricular hyperdensities: a new CT sign in Krabbe globoid cell leukodystrophy. J Inherit Metab Dis 1987; 10: 24–27 Finelli DA, Tarr RW, Sawyer RN, Horwitz SJ. Deceptively normal MR in early infantile Krabbe disease. AJNR Am J Neuroradiol 1994; 15: 167–171 Fu L, Inui K, Nishigaki T,Tatsumi N,Tsukamoto H, Kokubu C, Muramatsu T, Okada S. Molecular heterogeneity of Krabbe disease. J Inherit Metab Dis 1999; 22: 155–162 Giri S, Jatana M, Rattan R, Won J-S, Singh I, Sing AK. Galactosylsphingosine (psychosine) –induced expression of cytokine-mediated inducible nitric oxide synthases via AP-1 and C/EBP: implications for Krabbe disease. FASEB J 2002; 16: 661–672 Given CA 2nd, Santos CC, Durden DD. Intracranial and spinal MR imaging findings associated with Krabbe’s disease : case report. AJNR Am J Neuroradiol 2001; 22: 1782–1875 Goebel HH, Harzer K, Ernst JP, Bohl J, Klein H. Late-onset globoid cell leukodystrophy:unusual ultrastructural pathology and subtotal b-galactocerebrosidase deficiency. J Child Neurol 1990; 5: 299–307 Goebel HH, Kimura S, Harzer K, Klein H. Ultrastructural pathology of eccrine sweat gland epithelial cells in globoid cell leukodystrophy. J Child Neurol 1993; 8: 171–174 Grewal RP, Petronas N, Barton NW. Late onset globoid cell leukodystrophy. J Neurol Neurosurg Psychiatry 1991; 54: 1011–1012 Hagberg B. Krabbe’s disease: clinical presentation of neurological variants. Neuropediatrics 1984; 15: 11–15 Hagberg B, Kollberg H, Sourander P, Akesson HO. Infantile globoid cell leucodystrophy. Neuropediatrics 1969; 1: 74– 88 Harzer K, Knoblich R, Rolfs A, Bauer P, Eggers J. Residual galactosylsphingosine (psychosine) b-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta 2002; 317: 77–84 Henderson RD, MacMillan JC, Bradfield JM. Adult onset Krabbe disease may mimic motor neurone disease. J Clin Neurosci 2003; 10: 638–639 Hittmair K,Wimberger D,Wiesbauer P, Zehetmayer M, Budka H. Early infantile form of Krabbe disease with optic hypertrophy: serial MR examinations and autopsy correlation. AJNR Am J Neuroradiol 1994; 15: 1454–1458 Ida H, Rennert OM, Watabe K, Eto Y, Maekawa K. Pathological and biochemical studies of fetal Krabbe disease. Brain Dev 1994; 16: 480–4 Ieshima A, Eda I, Matsui A, Yoshino K, Takashima S, Takeshita K. Computed tomography in Krabbe’s disease: comparison with neuropathology. Neuroradiology 1983; 25: 323–327 Igisu H, Nakamura M. Inhibition of cytochrome C oxidase by psychosine (galactosylsphingosine). Biochem Biophys Res Commun1986; 137: 323–327 Itoh M, Hayashi M, Fujioka Y, Nagashima K, Morimatsu Y, Matsuyama H. Immunohistological study of globoid cell leukodystrophy. Brain Dev 2002; 24: 284–290 Jardim LB, Giugliani R, Fensom AH.Thalamic and basal ganglia hyperdensities – a CT marker for globoid cell leukodystrophy? Neuropediatrics 1992; 23: 30–31 Jardim LB, Giugliani R, Pires RF, Haussen S, Burin MG, .Rafi MA, Wenger DA.Protracted course of Krabbe disease in an adult patient bearing a novel mutation. Arch Neurol 1999; 56: 1014–1017 Jatana M, Giri S, Singh AK. Apoptotic positive cells in Krabbe brain and induction of apoptosis in rat C6 glial cells by psychosine. Neurosci Lett 2002; 330: 183–187

Jones BV, Barron TF, Towfighi J. Optic nerve enlargement in Krabbe’s disease. AJNR Am J Neuroradiol 1999 20: 1228– 1231 Kapoor R, McDonald WI, Crockard A, Moseley IF. Clinical onset and MRI features of Krabbe’s disease in adolescence. J Neurol Neurosurg Psychiatry 1992; 55: 331–332 Kobayashi T, Shinoda H, Goto I, Yamanaka T, Suzuki Y. Globoid cell leukodystrophy is a generalized galactosylsphingosine (psychosine) storage disease. Biochem Biophys Res Commun 1987; 144: 41–46 Kobayashi T,Goto I,Yamanaka T,Suzuki Y,Nakano T,Suzuki K.Infantile and fetal globoid cell leukodystrophy: analysis of galactosylceramide and galactosylsphingosine. Ann Neurol 1988; 24: 517–522 Kolodny EH, Raghavan S, Krivit W. Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases. Dev Neurosci 1991; 13: 232–239 Krabbe K. A new familial, infantile form of diffuse brain sclerosis. Brain 1916; 39: 74–114 Krivit W, Lockman LA, Watkins PA, Hirsch J, Shapiro EG. The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis 1995; 18: 398–412 Krivit W, Shapiro EG, Peters C, Wagner JE, Cornu G, Kurtzberg J, Wenger DA, Kolodny EH, Vanier MT, Loes DJ, Dusenbery K, Locman LA. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med 1998; 338: 1119–1126 Krivit W, Peters C, Shapiro EG. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria,Hurler,Maroteaux-Lamy,and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol 1999; 12: 167–176 Kurokawa T, Chen YJ, Nagata M. Late infantile Krabbe leukodystrophy: MRI and evoked potentials in a Japanese girl. Neuropediatrics 1987; 18: 182–183 Kwan E, Drace J, Enzmann D. Specific CT findings in Krabbe disease. AJNR Am J Neuroradiol 1984; 5: 453–458 LeVine SM, Pedchenko TV, Bronshteyn IG, Pinson DM. L-cycloserine slows the clinical and pathological course in mice with globoid cell leukodystrophy (twitcher mice). J Neurosci Res 2000; 60: 231–236 Liu HM. Ultrastructure of globoid leukodystrophy (Krabbe’s disease) with reference to the origin of globoid cells. J Neuropathol Exp Neurol 1970; 29: 441–462 Loes DJ, Peters C, Krivit W. Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method. AJNR Am J Neuroradiol 1999; 20: 316–323 Loonen MCB, van Diggelen OP, Janse HC, Kleijer WJ, Arts WFM. Late-onset globoid cell leucodystrophy (Krabbe’s disease): clinical and genetic delineation of two forms and their relation to the early-infantile form. Neuropediatrics 1985; 16: 137–142 Lyon G, Hagberg B, Evrard Ph, Allaire C, Pavone L, Vanier M. Symptomatology of late onset Krabbe’s leukodystrophy: the European experience. Dev Neurosci 1991; 13: 240–244 Malone MJ, Szöke MC, Looney GL. Globoid leukodystrophy: I. Clinical and enzymatic studies. Arch Neurol 1975; 32: 606–612 Marks HG, Scavina MT, Kolodny EH, Palmieri M, Childs J. Krabbe disease presenting as a pheripheral neuropathy. Muscle Nerve 1997; 20: 1024–1028

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Matsuda J, Vanier MT, Saito Y, Tohyama J, Suzuki K, Suzuki K. A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse. Hum Mol Genet 2001; 10: 1191–1199 Matsumoto R, Oka N, Nagahama Y, Akiguchi I, Kimura J. Peripheral neuropathy in late-onset Krabbe’s disease: histochemical and ultrastructural findings. Acta Neuropathol (Berl) 1996; 92: 635–639 McKelvie P, Vine P, Hopkins I, Poulos A. A case of Krabbe’s leukodystrophy without globoid cells. Pathology 1990; 22: 235–238 Menkes JH, Duncan C, Moossy J. Molecular composition of the major glycolipids in globoid cell leukodystrophy. Neurology 1966; 16: 381–393 Mitsuo K, Kobayashi T, Shinnoh N, Goto I. Biosynthesis of galactosylsphingosine (psychosine) in the Twitcher mouse. Neurochem Res 1989; 14: 899–903 Olsson Y, Sourander P, Svennerholm L. Experimental studies on the pathogenesis of leucodystrophies.I.The effect of intracerebrally injected sphingolipids in the rat’s brain. Acta Neuropathol (Berl) 1966; 6: 153–163 Percy AK, Odrezin GT, Knowles PD, Rouah E, Armstrong DD. Globoid cell leukodystrophy: comparison of neuropathology with magnetic resonance imaging. Acta Neuropathol (Berl) 1994; 88: 26–32 Phelps M, Aicardi J,Vanier MT. Late onset Krabbe’s leukodystrophy: a report of four cases. J Neurol Neurosurg Psychiatry 1991; 54: 293–296 Sabatelli M,Quaranta L,Madia F,Lippi G,Conte A,Lo Monaco M, Di Trapani G, Rafi MA, Wenger DA, Vaccaro AM, Tonali P. Peripheral neuropathy with hypomyelinating features in adult-onset Krabbe’s disease. Neuromusc Disord 2002; 12: 386–391 Sasaki M, Sakuragawa N,Takashima S, Hanaoka S, Arima M. MRI and CT findings in Krabbe disease. Pediatr Neurol 1991; 7: 283–288 Satoh J-I, Tokumoto H, Kurohara K,Yukitaka M, Matsui M, Kuroda Y, Yamamoto T, Ruruya H, Shinnoh N, Kobayashi T, Kukita Y,Haysashi K.Adult-onset Krabbe disease with the homozygous T1853C mutation in the galacotocerebosidase gene. Neurology 1997; 49: 1392–1399 Shen JS,Watabe K, Oshashi T, Eto Y. Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements. Gene Ther 2001; 8: 1081–1087 Sourander P,Hansson HA,Olsson Y,Svennerholm L.Experimental studies on the pathogenesis of leucodystrophies. II. The effect of sphingolipids on various cell types in cultures from the nervous system. Acta Neuropathol (Berl) 1966; 6: 231–242 Suzuki K. Twenty five years of the “psychosine” hypothesis: a personal perspective of its history and present status. Neurochem Res 1998; 23: 251–259 Suzuki K. Globoid cell leukodystrophy (Krabbe’s disease): update. J Child Neurol 2003; 18: 595–603 Suzuki K, Grover WD. Krabbe’s leukodystrophy (globoid cell leukodystrophy). Arch Neurol 1970; 22: 385–396 Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe’s disease): deficiency of galactocerebroside b-galactosidase. Proc Natl Acad Sci 1970; 66: 302–309 Suzuki Y, Suzuki K.The twitcher mouse: a model for Krabbe disease and for experimental therapies. Brain Pathol 1995; 5: 249–258

Svennerholm L,Vanier MT,Mansson JE.Krabbe disease:a galactosylsphingosine (psychosine) lipidosis. J Lipid Res 1980; 21: 53–64 Tada K,Taniike M,Tsukamoto H, Inui K, Okada S. Serial magnetic resonance imaging studies in a case of late onset globoid cell leukodystrophy. Neuropediatrics 1992; 23: 306–309 Taniike M, Mohri I, Eguchi N, Irikura D, Urade Y, Okada S, Suzuki K. An opoptotic depletion of oligodendrocytes in the twitcher, a murine model of globoid cell leukodystrophy. J Neuropathol Exp Neurol 1999; 58: 644–653 Tullu MS, Muranjan MN, Kondurkar PP, Bharucha BA. Krabbe disease – clinical profile. Indian Pediatr 2000; 37: 939–946 Turazzini M, Beltramello A, Bassi R, Del Colle R, Silvestri M. Adult onset Krabbe’s leukodystrophy: a report of 2 cases. Acta Neurol Scand 1997; 96: 413–415 Vanhanen L-L, Raininko R, Santavuori P. Early differential diagnosis of infantile neuronal ceroid lipofuscinosis, Rett Syndrome, and Krabbe disease by CT and MR. AJNR Am J Neuroradiol 1994; 15: 1443–1453 Vasconcelles E, Smith M. MRI nerve root enhancement in Krabbe disease. Pediatr Neurol 1998; 19: 151–152 Verdru P, Lammens M, Dom R, Van Elsen A. Globoid cell leukodystrophy: a family with both late-infantile and adult type. Neurology 1991; 41: 1382–1384 Wenger DA, Louie E. Pseudodeficiencies of arylsulfatase A and galactocerebrosidase activities. Dev Neurosci 1991; 13: 216–221 Wenger DA, Rafi MA, Luzi P. Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnosis and clinical implications. Hum Mutat 1997; 10: 268–279 Wenger DA, Rafi MA, Luzi P, Datto P, Constantino-Ceccarini E. Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab 2000; 70: 1–9 Zafeiriou DI, Michelakaki EM, Anastisiou AL, Gombakis NP, Kontopoulos EE. Serial MRI and neuropsychological studies in late-infantile Krabbe disease. Pediatr Neurol 1996; 15: 240–244 Zafeiriou DI, Anastasiou AL, Michelakaki EM, AugoustidouSavvopoulou PA, Katzos GS, Kontopoulos EE. Early infantile Krabbe disease: deceptively normal magnetic resonance imaging and serial neurophysiological studies. Brain Dev 1997; 19: 488–491 Zarifi MK,Tzika AA, Astrakas LG, Poussaint TY, Anthony DC, Darras BT. Magnetic resonance spectroscopy and magnetic resonance imaging findings in Krabbe’s disease. J Child Neurol 2001; 16: 522–526

9 GM1 Gangliosidosis Al-Essa M, Bakheet SM, Patay ZJ, Nounou RM, Ozand TP. Cerebral fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI, and clinical observations in a patient with infantile Gm1 gangliosidosis. Brain Dev 1999; 21: 559–562 Beratis NG, Varvarigou-Frimas A, Beratis S, Sklower SL. Angiokeratoma corporis diffusum in GM1 gangliosidosis, type 1. Clin Genet 1989; 36: 59–64 Cabral A, Portela R, Tasso T, Eusebio F, Moreira A, Marques dos Santos H, Soares J, Moura-Nunes JF. A case of GM1 gangliosidosis type I. Ophthalmic Paediatr Genet 1989; 10: 63–67

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918 References and Further Reading Callahan JW. Molecular basis of GM1 gangliosidosis and Morquio disease, type B. Structure-function studies of lysosomal b-galactosidase and the non-lysosomal b-galactosidase-like protein. Biochim Biophys Acta 1999; 1455; 85–103 Chen CY, Zimmerman RA, Lee CC, Chen FH, Yuh YS, Hsiao HS. Neuroimaging findings in late infantile GM1 gangliosidosis. AJNR Am J Neuroradiol 1998; 19: 1628–1630 Folkerth RD, Alroy J, Bhan I, Kaye EM. Infantile Gm1 gangliosidosis: complete morphology and histochemistry of two autopsied cases, with particular reference to delayed central nervous system myelination. Pediatr Dev Pathol 2000; 3: 73–86 Gascon GG, Ozand PT, Erwin RE. GM1 Gangliosidosis type 2 in two siblings. J Child Neurol 1992; 7: S41–S50 Goebel HH. Morphology of the gangliosidoses. Neuropediatrics 1984; 15: 97–106 Guazzi GC, D’Amore I, van Hoof F, Fruschelli C, Alessandrini C, Palmeri S, Federico A. Type 3 (chronic) GM1 gangliosidosis presenting as infanto-choreo-athetotic dementia, without epilepsy, in three sisters. Neurology 1988; 38: 1124–1127 Hinek A, Zhang S, Smith AC, Callahan JW. Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of b-galactosidase. Am J Hum Genet 2000; 67: 23–36 Inui K, Namba R, Ihara Y, Nobukuni K, Taniike M, Midorikawa M, Tsukamoto H. A case of chronic GM1 gangliosidosis presenting as dystonia: clinical and biochemical studies. J Neurol 1990; 237: 491–493 Kasama T, Taketomi T. Abnormalities of cerebral lipids in GM1gangliosidoses, infantile, juvenile, and chronic type. Jpn J Exp Med 1986; 56: 1–11 Kaye EM, Alroy J, Raghavan SS, Schwarting GA, Adelman LS, Runge V,Gelblum D,Johann G,Thalhammer DVM,Zuniga G. Dysmyelinogenesis in animal model of GM1 gangliosidosis. Pediatr Neurol 1992; 8: 255–261 Kobayashi T, Suzuki K. Chronic GM1 gangliosidosis presenting as dystonia: II. Biochemical studies. Ann Neurol 1981; 9: 476–483 Kobayashi O, Takashima S. Thalamic hyperdensity on CT in the infantile GM1-gangliosidosis. Brain Dev 1994; 16: 472–474 Kohlschütter A. Clinical course of GM1 gangliosidoses. Neuropediatrics 1984; 15: 71–73 Lin H-C, Tsai F-J, Shen C-H, Peng C-T. Infantile form Gm1 gangliosidosis with dilated cardiomyopathy: a case report. Acta Paediatr 2000; 89: 880–883 Morrone A, Bardelli T, Donati MA, Giorgi M, di Rocco M, Gatti R, Parini R, Ricci R, Tadeucchi G, D’Azzo A, Zammarchi E. b-Galactosidase gene mutations affecting the lysosomal enzyme and the elasin-binding protein in GM1-gangliosidosis patients with cardiac involvement. Hum Mutat 2000; 15: 354–366 Nardocci N, Bertagnolio B, Rumi V, Combi M, Bardelli P, Angelini L. Chronic GM1 gangliosidosis presenting as dystonia: clinical and biochemical studies in a new case. Neuropediatrics 1993; 24: 164–166 O’Brien JS, Storb R, Raff RF, Harding J, Appelbaum F, Morimoto S, Kishimoto Y, Graham T, Ahern-Rindell A, O’Brien SL. Bone marrow transplantation in canine GM1 gangliosidosis. Clin Genet 1990; 38: 274–280 Pampiglione G,Harden A.Neurophysiological investigations in GM1 and GM2 gangliosidoses. Neuropedatrics 1984; 15: 74–84 Sandhoff K, Conzelmann E.The biochemical basis of gangliosidoses. Neuropediatrics 1984; 15: 85–92

Shen W-C, Tsai FJ, Tsai C-H. Myelination arrest demonstrated using magnetic resonance imaging in a child with type GM1 gangliosidosis. J Formos Med Assoc 1998; 97: 296–299 Silva CMD, Severini MH, Sopelsa A, Coelho JC, Zaha A, d’Azzo A, Giugliani R. Six novel b-galactosidase gene mutations in Brazilian patients with GM1-gangliosidosis. Hum Mutat 1999; 13: 401–409 Suzuki K, Suzuki K, Chen GC. Morphological, histochemical and biochemical studies on a case of systemic late infantile lipidosis (generalized gangliosidosis). J Neuropathol Exp Neurol 1968; 27: 15–38 Suzuki K, Suzuki K, Kamoshita S. Chemical pathology of GM1 gangliosidosis (generalized gangliosidosis). J Neuropathol Exp Neurol 1969; 28: 25–73 Suzuki Y, Sakuraba H, Oshima A, Yoshida K, Shimmoto M, Takano T, Fukuhara Y. Clinical and molecular heterogeneity in hereditary b-galactosidase deficiency. Dev Neurosci 1991; 13: 299–303 Tanaka R, Momoi T,Yoshida A, Okumura M,Yamakura S,Takasaki Y, Kiyomasu T, Yamanaka C. Type 3 GM1 gangliosidosis: clinical and neurological findings in an 11-year-old girl. J Neurol 1995; 242: 299–303 Tominaga L, Ogawa Y,Taniguchi M, Ohno K, Matsuda J, Oshima A, Suzuki Y, Nanba E. Galactonojirimycin derivatives restore mutant human b-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse. Brain Dev 2001; 23: 284–287 Urban Z, Boyd CD. Elastic-fiber pathologies: primary defects in assembly – and secondary disorders in transport and delivery. Am J Hum Genet 2000; 67: 4–7 Uyama E,Terasaki T,Watanabe S,Naito M,Owada M,Araki S,Ando M.Type 3 GM1 gangliosidosis:characteristic MRI findings correlated with dystonia. Acta Neurol Scand 1992; 86: 609–615 van der Voorn JP, Kamphorst W, van der Knaap MS, Powers JM. The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction. Acta Neuropathol (Berl) 2004; 107: 539–545 Walkley SU, Baker HJ, Rattazzi MC, Haskins ME,Wu JY. Neuroaxonal dystrophy in neuronal storage disorders: evidence for major GABAergic neuron involvement. J Neurol Sci 1991; 104: 1–8 Wood PA, McBride MR, Baker HJ, Christian ST. Fluorescence polarization analysis, lipid composition, and Na+, K+-ATPase kinetics of synaptosomal membranes in feline GM1 and GM2 gangliosidosis. J Neurochem 1985; 44: 947–956 Yoshida K, Oshima A, Sakuraba H, Nakano T,Yanagisawa N, Inui K, Okada S, Uyama E, Namba R, Kondo K, Iwasaki S,Takamiya K, Suzuki Y. GM1 gangliosidosis in adults: clinical and molecular analysis of 16 Japanese patients. Ann Neurol 1992; 31: 328–332

10 GM2 Gangliosidosis Argov Z, Navon R. Clinical and genetic variations in the syndrome of adult GM2 gangliosidosis resulting from hexosaminidase A deficiency. Ann Neurol 1984; 16: 14–20 Bach G,Tomczak J, Risch N, Ekstein J.Tay-Sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure. Am J Med Genet 2001; 99: 70–75 Barnes D, Misra VP, Young EP, Thomas PK, Harding AE. An adult onset hexosaminidase A deficiency syndrome with sensory neuropathy and internuclear ophthalmoplegia. J Neurol Neurosurg Psychiatry 1991; 54: 1112–1113

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Barness LA, Henry K, Kling P, Laxova R, Kaback M, Gilbert-Barness E. A 7-year old white-male boy with progressive neurological deterioration. Am J Med Genet 1991; 40: 271–279 Beck M, Sieber N, Goebel HH. Progressive cerebellar ataxia in juvenile GM2-gangliosidosis type Sandhoff. Eur J Pediatr 1998; 157: 866–867 Brett EM, Ellis RB, Haas L, Ikonne JU, Lake BD, Patrick AD, Stephens R. Late onset GM2 gangliosidosis: clinical, pathological, and biochemical studies on 8 patients. Arch Dis Child 1973; 48: 775–785 Brismar J, Brismar G, Coates R, Gascon G, Ozand P. Increased density of the thalamus on CT scans in patients with GM2 gangliosidosis. Am J Neurol 1990; 11: 125–130 Çaliskan M, Özmen M, Beck M, Apak S.Thalamic hyperdensity – is it a diagnostic marker for Sandhoff disease? Brain Dev 1993; 15: 387–388 Chavany C, Jendoubi M. Biology and potential strategies for the treatment of GM2 gangliosidosis. Mol Med Today 1998; 4: 158–165 Chen B, Rigat B, Curry C, Mahuran DJ. Structure of the GM2A gene: identification of an exon 2 nonsense mutation and a naturally occurring transcript with an in-frame deletion. Am J Hum Genet 1999; 65: 77–87 Conzelmann E, Kytzia HJ, Navon R, Sandhoff K. Ganglioside GM2 N-acetyl-b-D-galactosaminidase activity in cultured fibroblasts of late-infantile and adult GM2 gangliosidosis patients and of healthy probands with low hexosaminidase level. Am J Hum Genet 1983; 35: 900–913 Cordeiro P,Hechtman P,Kaplan F.The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A. Genet Med 2000; 2: 319–327 Di Gregorio F, Ferrari G, Marini P, Siliprandi R, Gorio A.The influence of gangiosidosis on neurite growth regeneration. Neuropediatrics 1984; 15: 93–96 D’Souza G, McCann CL, Hedrick J, Fairley C, Nagel HL, Kushner JD, Kessel R. Tay-Sachs disease carrier screening: a 21-year experience. Genet Test 2000; 4: 257–263 Federico A, Palmeri S, Malandrini A, Fabrizi G, Mondelli M, Guazzi GC.The clinical aspects of adult hexosaminidase deficiencies. Dev Neurosci 1991; 13: 280–287 Fukumizu M,Yoshikawa H,Takashima N, Kurokawa T.Tay-Sachs disease: progression of changes on neuroimaging in four cases. Neuroradiology 1992; 34: 483–486 Goebel HH,Stolte G,Kustermann-Kuhn B,Harzer K.B1 Variant of GM2 gangliosidosis in a 12-year-old patient. Pediatr Res 1989; 25: 89–93 Gordon BA, Gordon KE, Hinton GG, Cadera W, Feleki V, Bayleran J, Hechtman P. Tay-Sachs disease: B1 variant. Pediatr Neurol 1988; 4: 54–57 Gray RGF, Green A, Rabb L, Broadhead DM, Besley GTN. A case of the B1 variant of GM2-gangiosidosis. J Inherit Metab Dis 1990; 13: 280–282 Grosso S, Farnetani MA, Berardi R, Margollicci M, Galluzzi P, Vivarelli R, Morgese G, Balestri P. GM2 gangliosidosis variant B1. Neuroradiologic features. J Neurol 2003; 250: 17–21 Guidotti JE, Mignon A, Haase G, Caillaud C, McDonnell N, Kahn A, Poenaru L. Adenoviral gene therapy of the Tay-Sachs disease in hexosaminedase A-deficient knock-out mice. Hum Mol Genet 1999; 8: 831–838 Hittmair K,Wimberger D, Bernert G, Mallek R, Schindler EG. MRI in a case of Sandhoff’s disease. Neuroradiology 1996; 38: S178-S180

Hund E, Grau A, Fogel W, Fosting M, Cantz M, KunstermannKuhn B, Harzer K, Navon R, Goebel HH, Meinck H-M.Progressive cerebellar ataxia, proximal neurogenic weakness and ocular motor disturbances: hexosaminidase A deficiency with late onset in four siblings.J Neurol Sci 1997; 145: 25–31 Jeyakumar M, Butters TD, Cortina-Borja M, Hunnam V, Proia RL, Pery VH,Dwek RA,Platt FM.Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc Natl Acad Sci 1999; 96: 6388–6393 Jeyakumar M, Norflus F, Tifft CJ, Cortina-Borja M, Butters TD, Proia RL, Perry VH, Dwek RA, Platt FM. Enhanced survival in Sandhoff disease mice receiving a combination of substrate deprivation therapy and bone marrow transplantation. Blood 2001; 97: 327–329 Johnson WG, Chutorian A, Miranda A. A new juvenile hexosaminidase deficiency disease presenting as cerebellar ataxia: clinical and biochemical studies. Neurology 1977; 27: 1012–1018 Karni A, Navon R, Sadeh M. Hexosaminidase A deficiency manifesting as spinal muscular atrophy of late onset. Ann Neurol 1988; 24: 451–453 Koelfen W, Freund M, Jaschke W, Koenig S, Schultze C. GM2 gangliosidosis (Sandhoff’s disease): two year follow-up by MRI. Neuroradiology 1994; 36: 152–154 Kotagal S,Wenger DA, Alcala H, Gomez C, Horenstein S. AB variant GM2 gangliosidosis: cerebrospinal fluid and neuropathologic characteristics. Neurology 1986; 36: 438–440 Kroll RA, Pagel MA, Roman-Goldstein S, Barkovich AJ, D’Agostino AN, Neuwelt EA. White matter changes associated with Feline GM2 gangliosidosis (Sandhoff disease): correlation of MR findings with pathologic and ultrastructural abnormalities. AJNR Am J Neuroradiol 1995; 16: 1912–1226 Lui Y, Wada R, Kawai H, Sango K, Deng C, Tai T, McDonald MP, Araujo K, Crawley JN, Bierfreund U, Sandhoff K, Suzuki K, Prioa RL. A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder. J Clin Invest 1999; 103: 497–505 Meek D, Wolfe LS, Andermann E, Andermann F. Juvenile progressive dystonia: a new phenotype of GM2 gangliosidosis. Ann Neurol 1984; 15: 348–352 Mugikura S, Takahashi S, Higano S, Kurihara N, Kon K, Sakamoto K. MR findings in Tay-Sachs disease. J Comput Assist Tomogr 1996; 20: 551–555 Nassogne MC, Commare MC, Lellouch-Tubiana A, Emond S, Zerah M, Caillaud C, Hertz-Pannier L, Saudubray JM. Unusual presentation of GM2 gangliosidosis mimicking a brain stem tumor in a 3-year-old girl. AJNR Am J Neuroradiol 2003; 24: 840–842 Navon R. Molecular and clinical heterogeneity of adult GM2 gangliosidosis. Dev Neurosci 1991; 13: 295–298 Navon R, Argov Z, Brand N, Sandbank U. Adult GM2 gangliosidosis in association with Tay-Sachs disease: a new phenotype. Neurology 1981; 31: 1397–1401 Navon R, Argov Z, Frisch A. Hexosaminidase A deficiency in adults. Am J Med Genet 1986; 24: 179–196 Neote K, Mahuran DJ, Gravel RA. Molecular genetics of b-hexosaminidase deficiencies. Adv Neurol 1991; 56: 189–207 Neufeld EF. Natural history and inherited disorders of a lysosomal enzyme a-hexosaminidase. J Biol Chem 1989; 264: 10927–10930 Norflus F, Tifft CJ, McDonald MP, Goldstein G, Crawley JN, Hoffmann A, Sandhoff K, Suzuki K, Proia RL. Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice. J Clin Invest 1998; 101: 1881–1888

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920 References and Further Reading Oya Y, Proia RL, Norflus F, Tifft CJ, Langaman C, Suzuki K. Distribution of enzyme-bearing cells in GM2 gangliosidosis mice: regionally specific pattern of cellular infiltration following bone marrow transplantation. Acta Neuropathol (Berl) 2000; 99: 161–168 Paw BH, Moskowitz SM, Uhrhammer N, Wright N, Kaback MM, Neufeld EF. Juvenile GM2 gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the a-subunit of b-hexosaminidase. J Biol Chem 1990; 265: 9452–9457 Platt FM, Butters TD. New therapeutic prospects for the glycosphingolipid lysosomal storage diseases. Biochem Pharmacol 1998; 56: 421–430 Platt FM, Neises GR, Reinkensmeier G, Towsend MJ, Perry VH, Proia RL, Winchester B, Dwek RA, Buters TD. Prevention of lysosomal storage in Tay-Sachs mice treated with Nbutyldeoxynojirimycin. Science 1997; 276: 428–431 Platt FM, Jeyakumar M, Andersson U, Priestman DA, Dewk RA, Butters TD.Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy. J Inherit Metab Dis 2001; 24: 275–290 Pullarkat RK, Reha H, Beratis NG. Accumulation of ganglioside GM2 in cerebrospinal fluid of a patient with the variant AB of infantile GM2 gangliosidosis. Pediatrics 1981; 68: 106–108 Rapin I, Suzuki K, Suzuki K, Valsamis MP. Adult (chronic) GM2 gangliosidosis: atypical spinocerebellar degeneration in a Jewish sibship. Arch Neurol 1976; 33: 120–130 Rattazzi MC, Dobrenis K.Treatment of GM2 gangliosidosis: past experiences, implications, and future prospects. Adv Genet 2001; 44: 317–339 Rubin M, Karpati G,Wolfe LS, Carpenter S, Klavins MH, Mahuran DJ. Adult onset motor neuropathy in the juvenile type of hexosaminidase A and B deficiency. J Neurol Sci 1988; 87: 103–119 Salaman MS, Clarcke JTR, Midroni G, Waxman MB. Peripheral and autonomic nervous system involvement in chronic GM2-gangliocidosis. J Inherit Metab Dis 2001; 24: 65–71 Sandhoff K, Harzer K, Wässle W, Jatzkewitz H. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem 1971; 8: 2469–2489 Schepers U, Glombitza G, Lemm T, Hoffmann A, Chabas A, Ozand P, Sandhoff K. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am J Hum Genet 1996; 59: 1048–105 Schnorf H, Gitzelmann R, Bosshard NU, Spycher M, Waespe W. Early and severe sensory loss in three adult siblings with hexosaminidase A and B deficiency (Sandhoff disease). J Neurol Neurosurg Psychiatry 1995; 59: 520–523 Specola N,Vanier MT, Goutières F, Mikol J, Aicardi J.The juvenile and chronic forms of GM2 gangliosidosis: clinical and enzymatic heterogeneity. Neurology 1990; 40: 145–150 Streifler JY, Gornish M, Hadar H, Gadoth N. Brain imaging in late-onset GM2 gangliosidosis. Neurology 1993; 43: 2055– 2058 Suzuki K,Vanier MT.Biochemical and molecular aspects of lateonset GM-2 gangiosidosis: B1 variant as a phenotype. Dev Neurosci 1991; 13: 288–294 Thomas PK, Young E, King RHM. Sandhoff disease mimicking adult-onset bulbospinal neuropathy. J Neurol Neurosurg Psychiatry 1989; 52: 1103–1106 Wada R, Tifft CJ, Proia RL. Microglial activation precedes acute neurodegenration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc Nat Acad Sci 2000; 97:10954–10959

Walkley SU, Siegel DA, Dobrenis K. GM2 Gangliosidosis and pyramidal neuron dendritogenesis. Neurochem Res 1995; 20: 1287–1299 Walkley SU, Siegel DA, Dobrenis K, Zervas M. GM2 gangliosidosis as a regulator of pyramidal neuron dendritogenesis.Ann NY Acad Sci 1998; 845: 188–199 Walkley SU, Zervas M, Wiseman S. Gangliosidosis as modulators of dendritogenesis in normal and storage diseaseaffected pyramidal neurons. Cereb Cortex 2000; 10: 1028– 1037 Ward CP, Fensom AH, Green PM. Biallelic discrimination assays for the three common Ashkenazi Jewish mutations and a common non-Jewish mutation, in Tay-Sachs disease, using fluorogenic taqman probes. Genet Test 2000; 4: 351–358 Willner JP, Grabowski GA, Gordon RE, Bender AN, Desnick RJ. Chronic GM2 gangliosidosis masquerading as atypical Friedreich ataxia: clinical, morphologic, and biochemical studies of nine cases. Neurology 1981; 31: 787–798 Yoshikawa H, Yamada K, Sakuragawa N. MRI in the early stage of Tay-Sachs disease. Neuroradiology 1992; 34: 394–395 Yüksel A,Yalçinkaya C, I0lak C, Gündüz E, Seven M. Neuroimaging findings in four patients with Sandhoff disease. Pediatr Neurol 1999; 21: 562–565

11 Fabry Disease Abe A, Gregory S, Lee L, Killen PD, Brady RO, Kulkarni A, Shayman JA. Reduction of globotriasylceramide in Fabry disease mice by substrate deprevation. J Clin Invest 2000; 105: 1563–1571 Altarescu G, Moore DF, Pursley R, Campia U, Goldstein S, Bryant M, Panza JA, Schiffmann R. Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke 2001; 32: 1559– 1562 Asano N, Ishii S, Kizu H, Ikeda H, Ikeda K, Kato A, Martin OR, Fan JQ. In vitro inhibition and intracellular enhancement of lysosomal a-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. Eur J Biochem 2000 267: 4179–4186 Ashley GA; Shabbeer J, Yasuda M, Eng CM, Desnick RJ. Fabry disease: twenty novel a-galactosidase A mutations causing the classical phenotype. J Hum Genet 2001; 46: 192–196 Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff CM, Beck M. Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study. J Inherit Metab Dis 2003; 26: 617–627 Brantom MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, Goldfarb L, Brady RO,Balow JE,Austin HA, Kopp JB.Natural history of Fabry renal disease.Medicine 2002; 81: 122–138 DeVeber GA,Schwarting GA,Kolodny EH,Kowall NW.Fabry disease: immunocytochemical characterization of neuronal involvement. Ann Neurol 1992; 31: 409–415 Dütsch M,Marthol H,Stemper B,Brys M,Haendl T,Hilz MJ.Small fiber dysfunction predominates in Fabry neuropathy. J Clin Neurophysiol 2002; 19: 575–586 Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ. Safety and efficacy of recombinant human a-galactosidase a replacement therapy in Fabry’s disease. N Engl J Med 2001; 345: 9–16 Feldt-Rasmussen U, Rasmussen AK, Mersebach H, Rosenberg KM, Hasholt L, Sorensen S. Fabry disease: a new challange in endocrinology and metabolism? Eur J Endocrinol 2002; 146: 741–742

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Filling-Katz MR, Merrick HF, Fink JK, Miles RB, Sokol J, Barton NW. Carbamazepine in Fabry’s disease: effective analgesia with dose-dependent exacerbation of autonomic dysfunction. Neurology 1989; 39: 598–600 Frustazi A, Chimenti C, Ricci R, Natale L, Russo MA, Pieroni M, Eng CM, Desnick RJ. Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 2001; 345: 25–32 Gahl WA. New therapies for Fabry’s disease. N Engl J Med 2001; 345: 55–57 Grewal RP. Stroke in Fabry’s disease. J Neurol 1994; 241: 153–156 Grewal RP, McLatchey SK. Cerebrovascular manifestations in a female carrier of Fabry’s disease. Acta Neurol Belg 1992; 92: 36–40 Hajioff D, Enever Y, Quiney R, Zuckerman J, Macdermot K, Mehta A. Hearing loss in Fabry patients: the effect of agalsidase alpha replacement therapy. J Inherit Metab Dis 2002; 26: 787–794 Kaye EM, Kolodny EH, Logigian EL, Ullman MD. Nervous system involvement in Fabry’s disease: clinicopathological and biochemical correlation. Ann Neurol 1988; 23: 505–509 Kleijer WJ, Hussaarts-Odijk LM, Sachs ES, Jahoda MGJ, Niermeijer MF. Prenatal diagnosis of Fabry’s disease by direct analysis of chorionic villi. Prenat Diagn 1987; 7: 283–287 Kornreich R, Bishop DF, Desnick RJ. a-galactosidase A gene rearrangements causing Fabry disease. J Biol Chem 1990; 265: 9319–9326 MacDermot KD,Holmes A,Miners AH.Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001; 38: 769–775 MacDermot KD. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001; 37: 750–760 Menzies DG, Campbell IW. Magnetic resonance in Fabry’s disease. J Neurol Neurosurg Psychiatry 1988; 51: 1240–1241 Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. Ann Neurol 1996; 40: 8–17 Moore DF, Scott LTC, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, Pease-Fye M, Ferri R, Brady RO, Herscovitch P, Schiffmann R. Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease. Reversal by enzyme replacement therapy. Circulation 2001; 104: 1506– 1512 Moore DF, Altarescu G, Ling GSF, Jeffries N, Frei KP, Weibel T, Charria-Ortiz G, Ferri R, Arai AE, Brady RO, Schiffmann R. Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke 2002; 33: 525–431 Moore DF, Altarescu G, Barker WC, Patronas NJ, Herscovitch P, Schiffmann R. White matter lesions in Fabry disease occur in ‘prior’ selectively hypometabolic and hyperperfused brain regions. Brain Res Bull 2003; 62: 231–240 Moore DF, Ye F, Schiffmann R, Butman JA. Increased signal intensity in teh pulvinar on T1-weighted images:a pathognomonic MR imaging sign of Fabry disease. AJNR Am J Neuroradiol 2003; 24: 1096–1101 Morgan SH, Rudge P, Smith SJM, Bronstein AM, Kendall BE, Holly E, Young EP, Crawfurd MA, Bannister R. The neurological complications of Anderson-Fabry disease (a-galactosidase A deficiency): investigation of symptomatic and presymptomatic patients. QJM [N Ser] 1990; 75: 491–504 Moumdjian R,Tampieri D, Melanson D, Ethier R. Anderson-Fabry disease: a case report with MR, CT and cerebral angiography. AJNR Am J Neuroradiol 1989; 10: S69-S70

Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H,Tanaka H. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 1995; 333: 288–293 Nelis GF,Jacobs GJA.Anorexia,weight loss,and diarrhea as presenting symptoms of angiokeratoma corporis diffusum (Fabry-Anderson’s disease). Dig Dis Sci 1989; 34: 1798–1800 Pastores GM,Thadhani R.Enzyme-replacement therapy for Anderson-Fabry disease. Lancet 2001; 358: 601–603 Rahman AN, Lindenberg R. The neuropathology of hereditary dystopic lipidosis. Arch Neurol 1963; 9: 373–385 Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF,Weibel T, Balow J, Brady RO. Enzyme replacement therapy in Fabry disease. A randomized controlled trail. JAMA 2001; 285: 2743–2749 Takanashi J, Barkocich JA, Dillon WP, Sherr EH, Hart KA, Packman S. T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease. AJNR Am J Neuroradiol 2003; 24: 916–921 Takenaka T, Murray GH, Qin G, Quirk JM, Oshima T, Qasba P, Clark K,Kulkarni AB,Brady RO,Medin JA.Long-term enzyme correction and lipid reduction in mulitple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. Proc Natl Acad Sci USA 2000; 97: 7515–7520 Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Brühl K, Gal A, Bunge S, Beck M. AndersonFabry disease: clinical manifestations of disease in female hetrozygotes. J Inherit Metab Dis 2001; 24: 715–724 Wiedemann F, Breuning F, Beer M, Sandstede J, Turschner O, Voelker W,Ertl G,Knoll A,Wanner C,Strotmann JM.Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease, a prospective strain rate imaging study. Circulation 2003; 108: 1299–1301

12 Fucosidosis Darby JK, Willems PJ, Nakashima P, Johnsen J, Ferrell RE, Wijsman EM, Gerhard DS, Dracopoli NC, Housman D, Henke J, Fowler ML, Shows TB, O’Brien JS, Cavalli-Sforza LL. Restriction analysis of the structural a-L-fucosidase gene and its linkage to fucosidosis. Am J Hum Genet 1988; 43: 749–755 Galluzzi P, Rufa A, Balestri P, Cerase A, Federico A. MR brain imaging of fucosidosis type I. AJNR Am J Neuroradiol 2001; 22: 777–780 Gordon BA, Gordon KE, Seo JC, Yang M, DiCioccio RA, O’Brien JS. Fucosidosis with dystonia. Neuropediatrics 1995; 26: 325–327 Inui K, Akagi M, Nishigaki T, Muramatsu T, Tsukamoto H, Okada S. A case of chronic infantile type of fucosidosis: clinical and magnetic resonance imaging. Brain Dev 2000; 22: 47–49 Ismail EAR, Rudwan M, Shafik MK. Fucosidosis: immunoloigal studies and chronological neuroradiological changes. Acta Paediatr 1999; 88: 224–227 Kretz KA, Cripe D, Carson GS, Fukushima H, O’Brien JS.Structure and sequence of the human a-L-fucosidase gene and pseudogene. Genomics 1992; 12: 276–280 Miano M, Lanino E, Gatti R, Morreale G, Fondelli P, Celle ME, Stroppiano M, Crescenzi F, Dini G. Four-year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation. Bone Marrow Transplant 2001; 27: 747–751

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922 References and Further Reading Michalski J-C, Klein A. Glycoprotein lysosomal storage disorders: a- and b-mannosidosis, fucosis and a-N-acetylgalactosaminidase deficiency. Biochim Biophys Acta 1999; 1455: 69–84 Ng Ying Kin NMK. Composition of the urinary glycoconjugates excreted by patient with type I and type II fucosidosis. Clin Chem 1987; 33: 44–47 Provenzale JM, Barboriak DP, Sims K. Neuroradiologic findings in fucosidosis, a rare lysosomal storage disease. AJNR Am J Neuroradiol 1995; 16: 809–813 Taylor RM, Farrow BRH, Stewart GJ, Healy PJ,Tiver K. Lysosomal enzyme replacement in neural tissue by allogeneic bone marrow transplantation following total lymphoid irradiation in canine fucosidosis. Transplant Proc 1987; 9: 2730– 2734 Taylor RM, Farrow BRH, Stewart GJ. Amelioration of clinical disease following bone marrow transplantation in fucosidasedeficient dogs. Am J Med Genet 1992; 42: 628–632 Terespolsky D, Clarke JTR, Blaser SI. Evolution of the neuroimaging changes in fucosidosis type II. J Inherit Metab Dis 1996; 19: 775–781 Tiberio G. Filocamo M, Gatti R, Durand P. Mutations in fucosidosis gene: a review. Acta Genet Med Gemellol 1995; 44: 223–232 Vellodi A, Cragg H, Winchester B, Young E, Downie CJC, Hoare RD, Stockes R, Banerjee GK. Allogenic bone marrow transplantation for fucosidosis. Bone Marrow Transplant 1995; 15: 153–158 Willems PJ, Gatti R, Darby JK, Romeo G, Durand P, Dumon JE, O’Brien JS. Fucosidosis revisited: a review of 77 patients. Am J Hum Genet 1991; 38: 111–131 Willems PJ, Seo H-C, Coucke P, Tonorenzi R, O’Brien JS. Spectrum of mutations in fucosidosis. Eur J Hum Genet 1999; 7: 60–67

13 Mucoplysaccharidoses General Albano LMJ, Sugayama SSMM, Bertola DR, Andrade CEF, Utagawa CY, Puppi F, Nader HB, Toma L, Coelho J, Leistner S, Burin M, Giugliani R, Kim CA. Clinical and laboratorial study of 19 cases of mucopolysaccharidoses. Rev Hosp Clin Fac Med S Paulo 2000; 55: 213–218 Barone R, Parano E,Trifiletti RR, Fiumara A, Pavone P.White matter changes mimicking a leukodystrophy in a patient with mucopolysaccharidosis: characterization by MRI. J Neurol Sci 2002; 195: 171–175 Dekaban AS, Constantopoulos G. Mucopolysaccharidosis types I, II, IIIA and V. Pathological and biochemical abnormalities in the neural and mesenchymal elements of the brain. Acta Neuropathol (Berl) 1977; 39: 1–7 Ero Y, Ohashi T. Gene therapy / cell therapy for lysosomal storage disease. J Inherit Metab Dis 2000; 23: 293–298 Fensom AH, Benson PF. Recent advances in the prenatal diagnosis of the mucopolysaccharidoses. Prenat Diagn 1994; 14: 1–12 Gieselmann V. Lysosomal storage diseases. Biochim Biophys Acta 1995; 1270: 103–136 Herrick IA, Rhine EJ. The mucopolysaccharidoses and anaesthesia: a report of clinical experience. Can J Anaesth 1988; 35: 67–73

Kachur E, del Maestro R. Mucopolysaccharidoses and spinal cord compression: case report and review of the literature with implications of bone marrow transplantation. Neurosurgery 2000; 47: 223–229 Kulkarni MV, Williams JC, Yeakley JW, Andrews JL, McArdle CB, Narayana PA, Howell RR, Jonas AJ. Magnetic resonance imaging in the diagnosis of the cranio-cervical manifestations of the mucopolysaccharidoses. Magn Reson Imaging 1987; 5: 317–323 Lee C, Dineen TE, Brack M, Kirsch JE, Runge VM. The mucopolysaccharidoses: characterization by cranial MR imaging. AJNR Am J Neuroradiol 1993; 14: 1285–1292 Levin TL, Berdon WE, Lachman RS, Anyane-Yeboa K. RuzalShapiro C, Roye DP. Lumbar gibbus in storage diseases and bone dysplasias. Pediatr Radiol 1997; 27: 289–294 Martin JJ, Ceuterick C. The contribution of pathology to the study of storage disorders. Pathol Res Pract 1988; 183: 375–385 Murata R, Nakajima S,Tanaka A, Miyagi N, Matsuoka O, Kogame S, Inoue Y. MR imaging of the brain in patients with mucopolysaccharidosis. AJNR Am J Neuroradiol 1989; 10: 1165–1170 Nelson J, Shields D, Mulholland HC. Cardiovascular studies in the mucopolysaccharidoses. J Med Genet 1990; 27: 94–100 Perretti A, Petrillo A, Pelosi L, Balbi P, Parenti G, Riemma A, Strisciuglio P. Detection of early abnormalities in the mucopolysaccharidoses by the use of visual and brainstem auditory evoked potentials. Neuropediatrics 1989; 21: 83–86 Purpura DP, Suzuki K. Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease. Brain Res 1976; 116: 1–21 Schiffmann R, Brady RO. New prospects for the treatment of lysosomal storage diseases. Drugs 2002; 62: 733–742 Scott HS, Bunge S, Gal A, Clarke LA, Morris CP, Hopwood JJ. Mutation update. Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 1995; 6: 288–302 Seto T, Kono K, Morimoto K, Inoue Y, Shintaku H, Hattori H, Matsuoka O, Yamano T, Tanaka A. Brain magnetic resonance imaging in 23 patients with mucopolysaccharidoses and the effect of bone marrow transplantation. Ann Neurol 2001; 50: 79–92 Shih S-L, Lee Y-J, Lin S-P, Sheu C-Y, Blickman JG. Airway changes in children with mucopolysaccharidoses. CT evaluation. Acta Radiol 2002; 43: 40–43 Sly WS, Vogler C. Brain-directed gene therapy for lysosomal storage disease: going well beyond the blood-brain barrier. Proc Natl Acad Sci 2002; 9: 5760–5762 Stone JE. Urine analysis in the diagnosis of mucopolysaccharide disorders. Ann Clin Biochem 1998; 35: 207–225 Wraith JE. The mucopolysaccharidoses: a clinical review and guide to management. Arch Dis Child 1995; 72: 263–267

Hurler Disease Afifi AK, Sato Y,Waziri MH, Bell WE. Computed tomography and magnetic resonance imaging of the brain in Hurler’s disease. J Child Neurol 1990; 5: 235–241 Barone R, Parano E,Trifiletti RR, Fiumara A, Pavone P.White matter changes mimicking a leukodystrophy in a patient with mucopolysaccharidosis: characterization by MRI. J Neurol Sci 2002; 195: 171–175

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Baxter MA, Wynn RF, Deakin JA, Bellantuono I, Edington KG, Cooper A, Besley GTN, Church HJ, Wraith JE, Carr TF, Fairbairn LJ. Retrovirally mediated correction of bone marrowderived mesenchymal stem cells from patients with mucopolysaccharidosis type I. Blood 2002; 99: 1857–1859 Beesley CE, Meaney CA, Greenland G, Adams V,Vellodi A,Young EP, Winchester BG. Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. Hum Genet 2001; 109: 503–511 Braunlin EA, Rose AG, Hopwood JJ, Candel RD, Krivit W. Coronary artery patency following long-term successful engraftment 14 years after bone marrow transplantation in the Hurler syndrome. Am J Cardiol 2001; 88: 1075–1077 Di Natale P, di Domenico C,Villani GRD, Lombardo A, Follenzi A, Naldini L. In vitro gene therapy of mucopolysaccharidosis type I by lentiviral vectors. Eur J Biochem 2002; 269: 2764–2771 Gabrielli O, Salvolini U, Maricotti M. Cerebral MRI in two brothers with mucopolysaccharidosis type I and different clinical phenotypes. Neuroradiology 1992; 34: 313–315 Grewal SS, Krivit W, Defor TE, Shapiro EG, Orchard PJ, Abel SL, Lockman LA, Ziegler RS, Dusenbery KE, Peters C. Hurler syndrome.Outcome of second hematopoietic cell transplantation in Hurler syndrome. Bone Marrow Transplant 2002; 29: 491–496 Hite SH, Peters C, Krivit W. Correction of odontoid dysplasia following bone-marrow transplantation and engraftment (in Hurler syndrome MPS 1H). Pediatr Radiol 2000; 30: 464–470 Johnson MA, Desai S, Hugh-Jones K, Starer F. Magnetic resonance imaging of the brain in Hurler syndrome. AJNR Am J Neuroradiol 1984; 5: 816–819 Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, Izykowski B, Phillips J, Doroshow R, Walot I, Hoft R, Neufeld EF. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001; 344: 182–188 Keeling KM, Brooks DA, Hopwood JJ, Li P, Thompson JN, Bedwell DM. Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of a-Liduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet 2001; 10: 291–299 Krivit W, Lockman LA, Watkins PA, Hirsch J, Shapiro EG. The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis 1995; 18: 398–412 Loeb H, Jonniaux G, Resibois A, Cremer N, Dodion J,Tondeur M, Gregoire PE, Richard J, Cieters P. Biochemical and ultrastructural studies in Hurler’s syndrome. J Pediatr 1968; 73: 860– 874 Rauch RA, Friloux LA III, Lott IT. MR Imaging of cavitary lesions in the brain with Hurler/Scheie. AJNR Am J Neuroradiol 1989; 10: S1–S3 Schmidt H, Ullrich K, von Lengerke H-J, Kleine M, Brämswig J. Radiological findings in patients with mucopolysaccharidosis I H/S (Hurler-Scheie syndrome). Pediatr Radiol 1987; 17: 409–414 Vellodi A,Young EP, Cooper A, Wraith JE, Winchester B, Meaney C, Ramaswami U, Will A. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child 1997; 76: 92–99 Walkley SU, Haskins ME, Shull RM. Alterations in neuron morphology in mucopolysaccharidosis type I*: a Golgi study. Acta Neuropathol (Berl) 1988; 75: 611–620

Watis RWE, Spellacy E, Adams JH. Neuropathological and clinical correlations in Hurler disease. J Inherit Metab Dis 1986; 9: 261–272 Winters PR, Harrod MJ, Molenich-Heetred SA, Kirkpatrick J, Rosenberg RN. a-L-Iduronidase deficiency and possible Hurler-Scheie genetic compound. Clinical, pathologic and biochemical findings. Neurology 1976; 26: 1003–1007 Wraith JE. Enzyme replacement therapy in mucopolysaccharidosis type I: progress and emerging difficulties. J Inherit Metab Dis 2001; 24: 245–250

Hunter Disease Adinolfi M. Hunter syndrome: cloning of the gene, mutations and carrier detection. Dev Med Child Neurol 1993; 35: 79–85 Bergstrom SK, Quinn JJ, Greenstein R, Ascensao J. Long-term follow-up of a patient transplanted for Hunter’s disease type IIB: a case report and literature review. Bone Marrow Transplant 1994; 14: 653–658 Clarke JTR, Willard HF, Teshima I, Chang PL, Skomorowski MA. Hunter disease (mucopolysaccharidosis type II) in a karyotypically normal girl. Clin Genet 1990; 37: 355–362 Clarke JTR, Greer WL, Strasberg PM, Pearce RD, Skomorowski MA, Ray PN.Hunter disease (mucopolysaccharidosis type II) associated with unbalanced inactivation of the X chromosomes in a karyotypically normal girl. Am J Hum Genet 1991; 49: 289–297 Davitt SM,Hatrick A,Sabharwal T,Pearce A,Gleeson M,Adam A. Tracheobronchial stent insertions in the management of major airway obstruction in a patient with Hunter syndrome (type II mucopolysaccharidosis). Eur Radiol 2002; 12: 458–462 Flomen RH, Green PM, Bentley DR, Giannelli F, Green EP. Detection of point mutations and a gross deletion in six Hunter syndrome patients. Genomics 1992; 13: 543–550 O’Brien DP, Cowie RA, Wraith JE. Cervical decompression in mild mucopolysaccharidosis type II (Hunter syndrome). Child Nerv Syst 1997; 13: 87–90 Parsons VJ, Hughes DG, Wraith JE. Magnetic resonance imaging of the brain, neck and cervical spine in mild Hunter’s syndrome (mucopolysaccharidoses type II). Clin Radiol 1996; 51: 719–723 Shimoda-Matsubayashi S, Kuru Y, Sumie H, Ito T, Hattori N, Okuma Y, Mizuno Y. MRI findings in the mild type of mucopolysaccharidosis II (Hunter’s syndrome). Neuroradiology 1990; 32: 328–330 Shinomiya N,Nagayama T,Fujioka Y,Aoki T.MRI in the mild type of mucopolysaccharidosis II (Hunter’s syndrome). Neuroradiology 1996; 38: 483–485 Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 1999; 22: 638–648 Vinchon M, Cotten A, Clarisse J, Chiki R, Christiaens J-L. Cervical myelopathy secondary to Hunter syndrome in an adult. AJNR Am J Neuroradiol 1995; 16: 1402–1403 Wehnert M, Hopwood JJ, Schröder W, Herrmann FH. Structural gene aberrations in mucopolysaccharidosis II (Hunter). Hum Genet 1992; 89: 430–432

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924 References and Further Reading Wilson PJ, Morris CP, Anson DS, Occhiodoro T, Bielicki J, Clements PR,Hopwood JJ.Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. (mucopolysaccharidosis type II / lysosomal storage disorder / X chromosome-linked mutations / sulfatase sequence homology) Proc Natl Acad Sci 1990; 87: 8531–8535 Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of Hunter’s syndrome. 2. Differences between the mild and severe forms. J Med Genet 1982; 19: 408–411 Zafeiriou DI, Augoustidou-Savvopoulou PA, Papadopoulou FA, Gombakis NP, Katzos GS, Kontopoulos EE, van Diggelen OP. Magnetic resonance imaging findings in mild mucopolysaccharidosis II (Hunter’s syndrome). Eur J Paediatr Neurol 1998; 2: 153–156

Sanfilippo Disease Andria G, di Natale P, del Giudice E, Strisciuglio P, Murino P. Sanfilippo B syndrome (MPS III B): mild and severe forms within the same sibship. Clin Genet 1979; 15: 500–504 Barone R, Nigro F, Triulzi F, Musumeci, S, Fiumara A, Pavone L. Clinical and neuroradiological follow-up in mucopolysaccharidosis type III (Sanfilippo syndrome). Neuropediatrics 1999; 30: 270–274 Fu H, Samulski RJ, McCown TJ, Picornell YJ, Fletcher D, Muenzer J. Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery. Mol Ther 2002; 5: 42–49 Gïngo˘ör N,Tunçbilek E. Sanfilippo disease type B. A case report and review of the literature on recent advances in bone marrow transplantation.Turk J Pediatr 1995; 37: 157–163 Haust MD, Gordon BA, Hong R, Choi JH, Langer LO, Spranger J, Opitz JM. Clinicopathological conference: an adolescent girl with severe mental impairment and mucopolysacchariduria. Am J Med Genet 1985; 22: 1–27 Jones MZ, Alroy J, Rutledge JC, Taylor JW, Alvord EC Jr, Toone J, Applegarth D, Hopwood JJ, Skutelsky E, Ianelli C, ThorleyLawson D, Mitchell-Herpolsheimer C, Arias A, Sharp P, Evans W, Sillence D, Cavanagh KT. Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics. J Neuropathol Exp Neurol 1997; 56: 1158–1167 Kurihara M, Kumagai K, Yagishita S. Case reports. Sanfilippo syndrome type C: a clinicopathological autopsy study of a long-term survivor. Pediatr Neurol 1996; 14: 317–321 Ozand PT,Thompson JN, Gascon GG, Sarvepalli SB, Rahbeeni Z, Nester MJ, Brismar J. Sanfilippo type D presenting with acquired language disorder but without features of mucopolysaccharidosis. J Child Neurol 1994; 9: 408–411 Petitti N, Holder CA, Williams DW III. Mucopolysaccharidosis III (Sanfilippo syndrome) type B. Cranial imaging in two cases. J Comput Assist Tomogr 1997; 21: 897–899 Vallani GRD, Follenzi A,Vanacore B, di Domenico C, Naldini L, di Natale P. Correction of mucopolysaccharidosis type IIIb fibroblasts by lentiviral vector-medicated gene transfer. Biochem J 2002; 364: 747–753 van de Kamp JJP, Niermeijer MF, von Figura K, Giesberts MAH. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B and C). Clin Genet 1981: 20: 152–160 van Schrojenstein-de Valk HMJ, van de Kamp JJP. Follow-up on seven adult patients with mild Sanfilippo B-disease. Am J Med Genet 1987; 28: 125–129

Zafeiriou DI, Savvopoulou-Augoustidou PA, Sewell A, Papadopoulou F, Badouraki M, Vargiami E, Gombakis NP, Katzos GS. Serial magnetic resonance imaging findings in mucopolysaccharidosis IIIB (Sanfilippo’s syndrome B). Brain Dev 2001; 23: 385–389

Morquio Disease Giugliani R, Jackson M, Skinner SJ, Vimal CM, Fensom AH, Fahmy N, Sjövall A, Benson PF. Progressive mental regression in siblings with Morquio disease type B (mucopolysaccharidosis IVB). Clin Genet 1987; 32: 313–325 Hughes DG, Chadderton RD, Cowie RA, Wraith JE, Jenkins JPR. MRI of the brain and craniocervical junction in Morquio’s disease. Neuroradiology 1997; 39: 381–385 Mikles M, Stanton RP. A review of Morquio syndrome. Am J Orthopod 1997; 26: 533–540 Nelson J, Grebbell FS. The value of computed tomography in patients with mucopolysaccharidosis. Neuroradiology 1987; 29: 544–549 Nelson J, Kinirons M. Clinical findings in 12 patients with MPS IVA (Morquio’s disease). Clin Genet 1988; 33: 121–125 Nelson J, Thomas PS. Clinical findings in 12 patients with MPS IVA (Morquio’s disease). Further evidence for heterogeneity. III. Odontoid dysplasia. Clin Genet 1988; 33: 126–130 Nelson J, Broadhead D, Mossman J. Clinical findings in 12 patients with MPS IVA (Morquio’s disease). Further evidence for heterogeneity. I. Clinical and biochemical findings. Clin Genet 1988; 33: 111–120 Northover H, Cowie RA,Wraith JE. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis 1996; 19: 357–365 Oshima A, Yoshida K, Shimmoto M, Fukuhara Y, Sakuraba H, Suzuki Y. Human b-glycosidase gene mutations in Morquio B disease. Am J Hum Genet 1991; 49: 1091–1093 Rigante D, Antuzzi R, Ricci R, Segni G. Cervical myelopathy in mucopolysaccharidosis type IV. Clin Neuropathol 1999; 18: 84–86 Stevens JM, Kendall BE, Crockard HA, Ransford A.The odontoid process in Morquio-Brailsford’s disease; the effects of occipitocervical fusion. J Bone Joint Surg [Br] 1991; 73: 851–858

Maroteaux-Lamy Disease Herskhovitz E,Young E, Rainer J, Hall CM, Lidchi V, Chong K,Vellodi A. Bone marrow transplantation for Maroteaux-Lamy syndrome (MPS VI):long-term follow-up.J Inherit Metab Dis 1999; 22: 50–62 Hite SH, Krivit W, Haines SJ, Whitley CB. Syringomyelia in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): imaging findings following bone marrow transplantation. Pediatr Radiol 1997; 27: 736–738 Tamaki N, Kojima N, Tanimoto M, Suyama T, Matsumoto S. Myelopathy due to diffuse thickening of the cervical dura mater in Maroteaux-Lamy syndrome: report of a case. Neurosurgery 1987; 21: 416–419 Uçakhan OO, Brodie SE, Desnick R, Willner J, Asbell PA. Longterm follow-up of corneal graft survival following bone marrow transplantation in the Maroteaux-Lamy syndrome. CLAO J 2001; 27: 234–237

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Vestermark S, Tønnesen T, Schultz Andersen M, Güttler F. Mental retardation in a patient with Maroteaux-Lamy. Clin Genet 1987; 31: 114–117 Vougioukas VI,Berlis A,Kopp MV,Korinthenberg R,Spreer J,van Velthoven V. Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature. Pediatr Neurosurg 2001; 35: 35–38 Wicker G, Prill V, Brooks D, Gibson G, Hopwood J, von Figura K, Peters C. Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Biol Chem 1991; 266: 21386–21391

Sly Disease Bernsen PLJA, Wevers RA, Gabreëls FJM, Lamers KJB, Sonnen AEH, Schuurmans Stekhoven JH. Phenotypic expression in mucopolysaccharidosis VII. J Neurol Neurosurg Psychiatry 1987; 50: 699–703 Fukuda S,Tomatsu S,Sukegawa K,Sasaki T,Yamada Y,Kuwahara T, Okamoto H, Ikedo Y, Yamaguchi S, Orii T. JSSIEM Meeting. Molecular analysis of mucopolysaccharidosis type VII. J Inherit Metab Dis 1991; 14: 800–804 Kyle JW, Birkenmeier EH, Gwynn B, Vogler C, Hoppe PC, Hoffmann JW, Sly WS. Correction of murine mucopolysaccharidosis VII by a human b-glucuronidase transgene. Proc Natl Acad Sci 1990; 87: 3914–3918 Ross CJD, Bastedo L, Maier SA, Sands MS, Chang PL. Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated recombinant cells. Hum Gene Ther 2000; 11: 2117–2127 Sewell AC, Gehler J, Mittermaier G, Meyer E. Mucopolysaccharidosis type VII (b-glucuronidase deficiency): a report of a new case and a survey of those in the literature. Clin Genet 1982; 21: 366–373 Tomatsu S, Fukuda S, Sukegawa K, Ikedo Y,Yamada S,Yamada Y, Sasaki T, Okamoto H, Kuwahara T, Yamaguchi S, Kiman T, Shintaku H, Isshiki G, Orii T. Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity. Am J Hum Genet 1991; 48: 89–96

14 Free Sialic Acid Storage Disorder Aula N, Salomäki P,Timonen R,Verheijen F, Mancini G, Månsson J-E, Aula P, Peltonen L. The spectrum of SLC17A5 gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. Am J Hum Genet 2000; 67: 832–840 Autio-Harmainen H, Oldfors A, Sourander P, Renlund M, Dammert K, Similiä S. Neuropathology of Salla disease. Acta Neuropathol (Berl) 1988; 75: 481–490 Baumkötter J, Cantz M, Mendla K, Baumann W, Friebolin H, Gehler J, Spranger J. N-Acetylneuraminic acid storage disease. Hum Genet 1985; 71: 155–159 Biancheri R,Verbeek E, Rossi A, Gaggero R, Roccatagliata L, Gatti R, van Diggelen OP,Verheijen FW, Mancini GMS. An Italian severe Salla disease variant associated with a SLC71A5 mutation earlier described in infantile sialic acid storage disease. Clin Genet 2002; 61: 443–447 Blom HJ, Andersson HC, Seppala R,Tietze F, Gahl WA. Defective glucuronic acid transport from lysosomes of infantile free sialic acid storage disease fibroblasts. Biochem J 1990; 268: 621–625

Chigorno V, Tettamanti G, Sonnino S. Metabolic processing of gangliocidosis by normal and Salla human fibroblasts in culture. J Biol Chem 1996; 36: 21738–21744 Daneman A, Stringer D, Reilly BJ. Neonatal ascitis due to lysosomal storage disease. Radiology 1983; 149: 463–467 Echenne B, Vidal M, Maire I, Michalski JC, Baldet P, Astruc J. Salla disease in one non-Finnish patient. Eur J Pediatr 1986; 145: 320–322 Fois A, Balestri P, Mancini GMS, Borgogni P, Margollicci MA, Molinelli M, Alessandri C, Gerli R. Free sialic acid storage disease. Eur J Pediatr 1987; 146: 195–198 Gillan JE, Lowden JA, Gaskin K, Cutz E. Congenital ascitis as a presenting sign of lysosomal storage disease. J Pediatr 1984; 104: 225 Grosso S, Berardi R, Farnetani MA, Margollicci M, Mancini GMS, Morgese G, Balestri P. Multiple neuroendocrine disorder in Salla disease. J Child Neurol 2001; 16: 775–777 Haataja L, Parkkola R, Sonninen P, Verhanen S-L, Scheutker J, Äärimaa T,Turpeinen U, Renland M, Aula P. Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder. Neuropediatrics 1994; 25: 238–244 Havelaar AC, Mancini GMS, Beerens CEMT, Souren RMA,Verheijen FW. Purification of the lysosomal sialic acid transporter. Functional characteristics of a monocarboxylate transporter. J Biol Chem 1998; 273: 34568–34574 Havelaar AC, Beerens CEMT, Mancini GMS,Verheijen FW.Transport of organic anions by the lysosomal sialic acid transporter: a functional approach towards the gene for sialic acid storage disease. FEBS Lett 1999; 446: 65–68 Jonas AJ. Studies of lysosomal sialic acid metabolism: retention of sialic acid by Salla disease lysosomes. Biochem Biophys Res Commun 1986; 137: 175–181 Kirchner L, Kircher S, Salzer-Muhar U, Paschke E, Birnbacher R, Stöckler-Ipsiroglu S. Infantile sialic acid storage disease and protein-losing gastroenteropathy. Pediatr Neurol 2003; 28: 313–317 Lemyre E, Russo P, Melançon SB, Gagné R, Potier M, Lambert M. Clinical spectrum of infantile free sialic acid storage disease. Am J Med Genet 1999; 82: 385–391 Linnankivi T, Lönnqvist T, Autti T. A case of Salla disease with involvement of the cerebellar white matter. Neuroradiology 2003; 45: 107–109 Mancini GMS, Verheijen FW, Glajaard H. Free N-acetylneuraminic acid (NANA) storage disorders: evidence for defective NANA transport across the lysosomal membrane. Hum Genet 1986; 73: 214–217 Mancini GMS, Verheijen FW, Beerens CEMT, Renlund M, Aula P. Sialic acid storage disorders: observations on clinical and biochemical variation. Dev Neurosci 1991; 13: 327–330 Mancini GMS, Beerens CEMT, Aula PP, Verheijen FW. Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides. J Clin Invest 1991; 87: 1329–1335 Mancini GMS, Hu P, Verheijen FW, van Diggelen OP, Janse HC, Kleijer WJ, Beemer FA, Jennekens FGI. Salla disease variant in a Dutch patient. Potential Value of polymorphonuclear leucocytes for hetrozygote detection. Eur J Pediatr 1992; 151: 590–595 Mancini GMS, Havelaar AC, Verheijen FW. Lysosomal transport disorders. J Inherit Metab Dis 2000; 23: 278–292 Nakano C, Hirabayashi Y, Ohno K,Yano K,Yano T, Mito T, Sakurai M. A Japanese case of infantile sialic acid storage disease. Brain Dev 1996; 18: 153–156

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926 References and Further Reading Parazzini C, Arena S, Marchetti L, Menni F, Filocamo M, Verheijen FW, Mancini GMS, Parini R. Infantile sialic acid storage disease: serial ultrasound and magnetic resonance imaging features. AJNR Am J Neuroradiol 2003; 24: 398–400 Paschke E, Höfler G, Roscher A. Infantile sialic acid storage disease: the fate of biosynthetically labelled N-acetyl-(3H)neuraminic acid in cultured human fibroblasts. Pediatr Res 1986; 8: 773–777 Paschke E,Trinkl G, Erwa W, Pavelka M, Mutz I, Roscher A. Infantile type of sialic acid storage disease with sialuria. Clin Genet 1986; 29: 417–424 Pueshel SM, O’Shea PA, Alroy J, Ambler MW, Dangond F, Daniel PF, Kolodny EH. Infantile sialic acid storage disease associated with renal disease. Pediatr Neurol 1988; 4: 207–212 Renlund M.Clinical and laboratory diagnosis of Salla disease in infancy and childhood. J Pediatr 1984; 104: 232–236 Renlund M, Aula P, Raivio KA, Autio S, Sainio K, Rapola J, Koskela S-L. Salla disease: a new lysosomal storage disorder with disturbed sialic acid metabolism. Neurology 1983; 33: 57–66 Renlund M,Chester MA,Lundblad A,Parkkinen J,Krusius T.Free N-acetylneuraminic acid in tissues in Salla disease and the enzymes involved in its metbolism. Eur J Biochem 1983; 130: 39–45 Renlund M, Kovanen PT, Raaivio K, Aula P, Gamhberg CG, Ehnholm C. Studies of the defect underlying the lysosomal storage of sialic acid in Salla disease. J Clin Invest 1986; 77: 568–574 Renlund M, Tietze F, Gahl WA. Defective sialic acid egress from isolated fibroblast lysosomes of patients with salla disease. Science 1986; 232: 579–763 Robinson RO, Fenson AH, Lake BD. Salla disease–rare or underdiagnosed? Dev Med Child Neurol 1997; 39: 153–157 Salomäki P, Aula N, Juvonen V, Renlund M, Aula P. Prenatal detection of free sialic acid storage disease: genetic and biochemical studies in nine families. Prenat Diagn 2001; 21: 354–358 Schleutker J, Leppänen P, Månson J-E, Erikson A, Weissenbach J, Peltonen L, Aula P.Lysosomal free sialic acid storage disorders with different phenotypc presentations – infantileform sialic acid storage disease and Salla disease – represent allelic disorders. Am J Hum Genet 1995; 57: 893–901 Schmid JA, Mach L, Paschke E, Glössl. Accumulation of sialic acid in endocytic compartments interferes with the formation of mature lysosomes. J Biol Chem 1999; 27: 19063– 19071 Seppala R,Renlund M,Bernardini I,Tietze F,Gahl WA.Renal handling of free sialic acid in normal humans and patients with Salla disease or renal disease. Lab Invest 1990; 63: 197–203 Sewell AC, Poets CF, Degen I, Stöß, Pontz BF. The spectrum of free neuraminic acid storage disease in childhood: clinical, morphological and biochemical observations in three nonFinnish patients. Am J Med Genet 1996; 63: 203–208 Sewell AC, Murphy HC, Illes R. Proton nuclear magnetic resonance spectroscopic detection of sialic acid storage disease. Clin Chem 2002; 48: 357–359 Sonninen P, Autti T, Varho T, Hämälläinen, Raininko R. Brain involvement in Salla disease.AJNR Am J Neuroradiol 1999;20: 433–443 Sperl W,Gruber W,Quatacker J,Monnens L,Thoenes W,Fink FM, Paschke E. Nephrosis in two siblings with infantile sialic acid storage disease. Eur J Pediatr 11991; 49: 447–482 Stevenson RE, Lubinsky M, Taylor HA, Wenger DA, Schoer RJ, Olmstead PM. Sialic acid storage disease with sialuria: clinical and biochemical features in the severe infantile type. Pediatr 1983; 72: 441–449

Thomas GH, Scocca J, Libert J, Vamos E, Miller CS, Reynolds LW. Alterations in cultured fibroblasts of sibs with an infantile form of free (unbound) sialic acid storage disorder. Pediatr Res 1983; 17: 307–312 Tietze F,Seppala R,Renlund M,Hopwood JJ,Harper GS,Thomas GH, Gahl WA. Defective lysosomal egress of free sialic acid (N-acetylneuraminic acid) in fibroblasts of patients with free sialic acid storage disease. J Biol Chem 1989; 26: 15316–15322 Tondeur M, Libert J, Vamos E, Van Hoof F, Thomas GH, Strecker G. Infantile form of sialic acid storage disorder: clinical, ultrastructural, and biochemical studies in two siblings. Eur J Pediatr 1982; 139: 142–147 Varho T, Komu M, Sonninen P, Holopainen I, Nyman S, Manner T, Sallinpää M, Aula P, Lundbom N. A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla disease. Neurology 1999; 52: 1668–1672 Varho T, Jääskeläinen S, Tolonen U, Sonninen P, Vainionpää L, Aula P, Sillanpää M. Central and peripheral nervous system dysfunction in the clinical variation of Salla disease. Neurology 2000; 55: 99–103 Varho TT, Alajoki LE, Posti KM, Korhonen TT, Renlund GG, Nyman SRG, Sillanpää, Aula PP. Phenotypic spectrum of Salla disease, a free sialic acid storage disorder. Pediatr Neurol 2002; 26: 267–273 Verheijen FW, Verbeel E, Aula N, Beerens CEMT, Havelaar AC, Joosse M, Peltonen L, Aula P, Galjaard H, van der Spek PJ, Mancini GMS. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet 1999; 23: 462–465 Wolburg-Buchholz K,Schlote W.Familial lysosomal storage disease with generalized vacuolisation and sialic aciduria. Sporadic Salla disease. Neuropediatrics 1985; 16: 67–75

15 Neuronal Ceroid Lipofuscinoses General Autti T, Raininko R, Vanhanen SL, Santavuori P. Magnetic resonance techniques in neuronal ceroid lipofuscinoses and some other lysosomal diseases affecting the brain. Curr Opin Neurol 1997; 10: 519–524 Autti R, Raininko R, Santavuori P, Vanhanen SL, Poutanen VP, Haltia M. MRI of neuronal ceroid lipofuscinosis. II. Postmortem MRI and histopathological study of the brain in 16 cases of neuronal ceroid lipofuscinosis of juvenile or late infantile type. Neuroradiology 1997; 29: 371–377 Boldrini R, Biselli R, Santorelli FM, Bosman C. Neuronal ceroid lipofuscinosis: an ultrastructural, genetic, and clinical study report. Ultrastruct Pathol 2001; 25: 51–58 Boustany RMN, Kolodny EH. Neurological progress. The neuronal ceroid lipofuscinoses: a review. Rev Neurol 1989; 145: 105–110 Brooks SS. Genetic counseling in the neuronal ceroid lipofuscinoses. Adv Genet 2001; 45: 141–158 Dawson G, Cho S. Batten’s disease: clues to neuronal protein metabolism in lysosomes. J Neurosci Res 2000; 60: 133–140 Dunn DW. CT in ceroid lipofuscinosis. Neurology 1987; 37: 1025–1026 Elleder M, Franc K, Kraus J, Nevsˇímalová S, Sixtová K, Zeman J. Neuronal ceroid lipofuscinosis in the Czech Republic: analysis of 57 cases. Report of the ‘Prague NLC group’. Eur J Paediatr Neurol 1997; 4: 109–114

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Gardiner RM. The molecular genetic basis of the neuronal ceroid lipofuscinoses. Neurol Sci 2000; 21: S15-S19 Goebel HH. Prenatal ultrastructural diagnosis in the neuronal ceroid lipofuscinoses. Pathol Res Pract 1994; 190: 728–733 Goebel HH. The neuronal ceroid-lipofuscinoses. J Child Neurol 1995; 10: 424–437 Goebel HH. Morphological diagnosis in neuronal ceroid lipofuscinosis. Neuropediatrics 1997; 28: 67–69 Goebel HH. The new nosography of the neuronal ceroid-lipofusinoses. Ann Pathol 2000; 20: 479–491 Goebel HH.Morphological aspects of the neuronal ceroid lipofuscinoses. Neurol Sci 2000; 21: S27-S33 Goebel HH, Mole SE, Lake BD, eds.The neuronal ceroid lipofuscinoses (Batten disease). Amsterdam: IOS Press, 1999 Goebel HH, Schochet SS, Jaynes M, Brück, W, Kohlschütter A, Hentati F. Progress in neuropathology of the neuronal ceroid lipofuscinoses. Mol Genet Metab 1999; 66: 367–372 Haltia M. The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 2003; 62: 1–13 Jolly RD. Dalefield RR, Palmer DN. Ceroid, lipofuscin and the ceroid-lipofuscinoses (Batten disease). J Inherit Metab Dis 1993; 16: 280–283 Junaid NA, Pullarkat RK. Biochemistry of neuronal ceroid lipofuscinoses. Adv Genet 2001; 45: 93–106 Kida E, Golabek AA, Wisniewski KE. Cellular pathology and pathogenic aspects of neuronal ceroid lipofuscinoses. Adv Genet 2001; 45: 35–68 Kleijer WJ, van Diggelen OP. Prenatal diagnosis of neuronal ceroid lipofuscinoses. Prenat Diagn 2000; 20: 819–821 Machen BC, Williams JP, Lum GB, Dyken P, Joslyn JN, Harpen MD, Dotson P. Magnetic resonance imaging in neuronal ceroid lipofuscinosis. J Comput Tomogr 1987; 11: 160–166 Mitchison GM, Mole SE. Neurodegenerative disease: the neuronal ceriod lipofuscinoses (Batten disease).Curr Opin Neurol 2001; 14: 795–803 Mole SE, Mitchison HM, Munroe PB. Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3 and CLN5. Hum Mutat 1999; 14: 199–215 Peltonen L, Savukoski M, Vesa J. Genetics of the neuronal ceroid lipofuscinoses. Curr Opin Genet Dev 2000; 10: 299– 305 Raininko R, Santavuori P, Heiskala H, Sainio K, Palo J. CT findings in neuronal ceroid lipofuscinoses. Neuropediatrics 1990; 21: 95–101 Santavuori P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev 1988; 10: 80–83 Santavuori P, Linnankivi T, Jaeken J, Vanhanen S-L, Telakivi T, Heiskala H. Psychological symptoms and sleep disturbances in neuronal ceroid-lipofuscinoses (NCL). J Inherit Metab Dis 1993; 16: 245–248 Santavuori P, Lauronen L, Kirveskari E, Åberg L, Sainio K, Autti T. Neuronal ceroid lipofuscinoses in childhood. Neurol Sci 2000; 21: S35–S41 Santavuori P,Vanhanen S-L, Autti T. Clinical and neuroradiological diagnostic aspects of neuronal ceroid lipofuscinoses disorders. Eur J Paediatr Neurol 2001; 5: 157–161 Wisniewski KE, Kida E, Patxot OF, Connell F. Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: review of date and observations. Am J Med Genet 1992; 42: 525–532 Wisniewski KE,Kida E,Connell F,Zhong N.Neuronal ceroid lipofuscinoses: research update. Neurol Sci 2000; 21: S49–S56 Wisniewski KE,Zhong N,Philippart M.Pheno-/genotypic correlations of neuronal ceroid lipofuscinoses. Neurology 2001; 57: 576–581

Wisniewski KE, Kida E, Golabek AA, Kaczmarski W, Connell F, Zhong N. Neuronal ceroid lipofuscinoses: classification and diagnosis. Adv Genet 2001; 45: 1–34 Zhong N. Neuronal ceroid lipofuscinoses and possible pathogenic mechanism. Mol Genet Metab 2000; 71: 195–206 Zhong N. Molecular genetic testing for neuronal ceroid lipofuscinoses. Adv Genet 2001; 45: 141–158

Neuronal Ceroid Lipofuscinosis: CLN1 Åberg K,Heiskala H,Vanhanen S-L,Himberg JJ,Hosking G,Yuen A, Santavori P. Lamotrigine therapy in infantile neuronal ceroid lipofuscinosis (INCL). Neuropediatrics 1997; 28: 77–79 Barohn RJ, Dowd DC, Kagen-Hallet KS. Congenital ceroid lipofuscinosis. Pediatr Neurol 1992; 8: 54–59 Bizzozero GA.The mechanisms and functional roles of protein palmitoyalation in the nervous system. Neuropediatrics 1997; 28: 23–26 Confort-Gouny S,Chabrol B,Vion-Dury J,Mancini J,Cozzone PJ. MRI and localized proton MRS in early infantile form of neuronal ceroid-lipofuscinosis. Pediatr Neurol 1993; 9: 57–60 Haltia M, Rapola J, Santavuori P, Keränen A. Infantile type of socalled neuronal ceroid-lipofuscinosis. 2. Morphological and biochemical studies. J Neurol Sci 1973; 18: 269–285 Haltia M, Rapola J, Santavuori P. Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathol (Berl) 1973; 26: 157– 170 Hofmann SL, Das AD, Lu JY, Wisniewski KE, Gupta P. Infantile neuronal ceroid lipofuscinosis: no longer just a ‘Finnish’ disease. Eur J Paediatr Neurol 2001; 5: 47–51 Jongen PJH, Gabreëls FJM, Schuurmans Stekhoven JH, Renier WO, Le Coultre R, Begeer JH. Early infantile form of neuronal ceroid lipofuscinosis. Clin Neurol Neurosurg 1987; 89: 161–167 Lake BD, Brett EM, Boyd SG. A form of juvenile Batten disease with granular osmiophilic deposits. Neuropediatrics 1996; 27: 265–269 Lönnqvist T, Vanhanen SL, Vettenranta K, Autti T, Rapola J, Santavuori P, Saarinen-Pihkala UM. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Neurology 2001; 57: 1411–1416 Lu J-Y, Verkruyse KA, Hofmann SL. The effects of lysomotropic agents on normal and INCL cells provide further evidence for the lysosomal nature of palmitoyl-protein thioesterase function. Biochim Biophys Acta 2002; 1583: 35–44 O’Rawe A, Mitchison HM, Williams R, Wheeler R, Andermann F, Andermann E, Hart YM, Martin JJ, Philippart M, Stephanson JBP, Gardiner RM, Mole SE. Genetic linkage analysis of a variant of juvenile onset neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Neuropediatrics 1997; 28: 21–22 Philippart M, Chugani HT, Bateman JB. New Spielmeyer-Vogt variant with granular inclusions and early brain atrophy. Am J Med Genet 1995; 57: 160–164 Salonen T, Heinonen-Kopra O, Vesa J, Jalanko A. Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations, which cause infantile neuronal ceroid lipofuscinosis. Mol Cell Neurosci 2001; 18: 131–140 Santauvori P, Haltia M, Rapola J. Infantile type of so-called neuronal ceroid-lipofuscinosis. Dev Med Child Neurol 1974; 16: 644–653

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928 References and Further Reading Santavuori P,Raininko R,Vanhanen SL,Launes J,Sainio K.MRI of the brain, EEG sleep spindles and SPECT in the early diagnosis of infantile neuronal ceroid lipofuscinosis. Dev Med Child Neurol 1992; 34: 61–79 Santavuori P, Vanhanen S-L, Sainio K, Nieminen M, Wallden T, Launes J, Raininko R. Infantile neuronal ceroid-lipofuscinosis (INCL):diagnostic criteria.J Inherit Metab Dis 1993; 16: 227–229 Svennerholm L, Fredman P, Jungbjer B, Mansson JE, Rynmark BM, Boström K, Hagberg B, Noren L, Santavuori P. Large alterations in ganglioside and neutral glycosphingolipid patterns in brains form cases with infantile neuronal ceroid lipofuscinosis/polyunsaturated fatty acid lipidosis. J Neurochem 1987; 49: 1772–1783 Tyynelä J, Palmer DN, Baumann M, Haltia M. Storage of saposins A and D in infantile neuronal ceroid-lipofuscinosis. FEBS Lett 1991; 330: 8–12 Van Diggelen OP, Thobois S, Tilikete C, Zabot M-T, Keulemans JLM, van Bunderen PA, Taschner PEM, Losekoot M, Voznyi YV. Adult neuronal ceroid lipofuscinosis with palmitoylprotein thioesterase deficiency:first adult-onset patients of a childhood disease. Ann Neurol 2001; 50: 269–272 Vanhanen S-L, Raininko R, Santavuori P. Early differential diagnosis of infantile neuronal ceroid lipofuscinosis, Rett syndrome, and Krabbe disease by CT and MR. AJNR Am J Neuroradiol 1994; 15: 1443–1543 Vanhanen S-L, Liewendahl K, Raininko R, Nikkinen P, Autti T, Sainio K, Santavuori P. Brain perfusion SPECT in infantile neuronal ceroid-lipofuscinosis (INCL) comparison with clinical manifestations and MRI findings. Neuropediatrics 1995; 27: 76–83 Vanhanen S-L, Raininko R, Santavuori O, Autti T, Haltia M. MRI Evaluation of the brain in infantile neuronal ceroid-lipofuscinosis. 1. Postmortem MRI with histopathological correlation. J Child Neurol 1995; 10: 438–443 Vanhanen S-L, Raininko R, Autti T, Santavuori P. MRI Evaluation of the brain in infantile neuronal ceroid-lipofuscinosis. 2. MRI findings in 21 patients. J Child Neurol 1995; 10: 444–450 Vanhanen S-L, Sainio J, Lappi M, Santavuori P. EEG and evoked potentials in infantile neuronal ceroid-lipofuscinosis. Dev Med Child Neurol 1997; 39: 456–463 Vanhanen SL, Puranen J, Autti T, Raininko R, Liewendahl K, Nikkinen P, Santavuori P, Suominen P,Vuari K, Häkkinen AM. Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics 2004; 35: 27–35 Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hofmann SL, Peltonen L. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 1995; 376: 584–587

Neuronal Ceroid Lipofuscinosis: CLN2 Carlesimo M,Giustini S,Rossodivita A,Cardona F,Calvieri S.Late infantile ceroid-lipofuscinoses. An ultrastructural study. Am J Dermatopathol 1993; 15: 456–460 D’Incerti L. MRI in neuronal ceroid lipofuscinosis. Neurol Sci 2000; 21: S71–S73 Ezaki J, Wolfe LS, Kominami E. Decreased lysosomal subunit cdegrading activity in fibroblasts from patients with late infantile neuronal ceroid lipofuscinosis. Neuropediatrics 1997; 28: 53–55

Ezaki J, Tadeka-Ezaki M, Kominami E. Tripeptidyl peptidase I, the late infantile neuronal ceroid lipofuscinosis gene product, initiates the lysosomal degeneration of subunit c of ATP synthase. J Biochem 2000; 128: 506–516 Fueki N, Linuma K, Kojima A, Yanai K, Haginoya K, Tada K, Ido T, Ito M. Reduced regional cerebral metabolic rate for glucose at the terminal stage in a case of late infantile neuronal ceroid lipofuscinosis. J Child Neurol 1990; 5: 98–100 Kurata K, Hayashi M, Satoh J, Kojima H, Nagata J, Tamagada K, Shinohara T, Morimatsu Y. Kominami E. Pathological study on sibling autopsy cases of the late infantile form of neuronal ceroid lipofuscinosis. Brain Dev 1999; 21: 63–67 Petersen B,Handwerker M, Huppertz H-I.Neurological findings in classical late onset infantile neuronal ceroid-lipofuscinosis. Pediatr Neurol 1996; 15: 344–347 Seitz D, Grodd W, Schwab A, Seeger U, Klose U, Nägele T. MR imaging and localized proton MR spectroscopy in late infantile neuronal ceroid lipofuscinosis. AJNR Am J Neuroradiol 1998: 19: 1373–1377 Sondhi D, Hackett NR, Alpblett RL, Kaminsky SM, Pergolizzi RG, Crystal RG. Feasibility of gene therapy for late neuronal ceroid lipofuscinosis. Arch Neurol 2001; 58: 1793–1798 Umehara F, Higuchi I,Tanaka HK, Niiyama T, Ezaki J, Kominani E, Osame M. Accumulation of mitochondrial ATP synthase subunit c in muscle in a patient with ceroid lipofuscinosis (late infantile form). Acta Neuropathol (Berl) 1997; 93: 628–632 Warburton MJ, Bernardini F.Tripeptildyl-peptidase I deficiency in classical late-infantile neuronal ceroid lipofuscinosis brain tissue. Evidence for defective peptidase rather than proteinase activity. J Inherit Metab Dis 2000; 23: 145–154

Neuronal Ceroid Lipofuscinosis: CLN 3 Autti T, Raininko R, Vanhanen SL, Santavuori P. MRI of neuronal ceroid lipofuscinosis. I. Cranial MRI of 30 patients with juvenile neuronal ceroid lipofuscinosis. Neuroradiology 1996; 38: 476–482 Bennett MJ, Gayton AR, Rittey CDR, Hosking GP. Juvenile neuronal ceroid-lipofuscinosis: developmental progress after supplementation with polyunsaturated fatty acids. Dev Med Child Neurol 1994; 36: 630–638 Boustany RMN, Filipek P. Seizures, depression and dementia in teenagers with Batten disease. J Inherit Metab Dis 1993; 16: 252–255 Brod RD, Packer AJ, Van Dyk HJL. Diagnosis of neuronal ceroid lipofuscinosis by ultrastructural examination of peripheral blood lymphocytes. Arch Ophthalmol 1987; 105: 1388– 1393 Bruun I, Reske-Nielsen E, Oster S. Juvenile ceroid-lipofuscinosis and calcifications of the CSF. Acta Neurol Scand 1991; 83: 1–8 Hofman IL. Observations in institutionalized neuronal ceroidlipofuscinosis patients, with special reference to involuntary movements. J Inherit Metab Dis 1993; 16: 249–251 Järvelä I, Autti T, Lamminranta S, Aberg L, Raininko R, Santavuori P. Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02-kb deletion). Ann Neurol 1997; 42: 799–802 Kimura S, Goebel HH. Light and electron microscopic study of juvenile neuronal cerroid-lipofuscinosis lymphocytes.Pediatr Neurol 1988; 4: 148–152

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Neuronal Ceroid Lipofuscinosis: CLN4 Augustine A, Fricchione G, Woznicki R, Broberg D, Holt J. Adult neuronal ceroid lipofuscinosis presenting with psychiatric symptoms (case report). Int J Psychiatry Med 1993; 19: 315–322 Berkovic S, Carpenter S, Andermann F, Andermann E, Wolfe LS. Kufs’ disease: a critical reappraisal. Brain 1988; 111: 27–62 Constantinidis J,Wisniewski KE,Wisniewski TM.The adult and a new late adult forms of neuronal ceroid lipofuscinosis. Acta Neuropathol (Berl) 1992; 83: 461–468 Donnet A, Habib M, Pellissier JF, Régis H, Farnarier G, Pelletier J, Gosset A, Roger J, Khalil R. Kufs’ disease presenting as progressive dementia with late-onset generalized seizures: a clinicopathological and electrophysiological study. Epilepsia 1992; 33: 65–74 Gelot A, Maurage CA, Rodriguez D. Perrier-Pallissib D, Larmande P, Ruchoux MM. In vivo diagnosis of Kufs’ disease by extracerebral biopsies. Acta Neuropathol (Berl) 1998; 96:102–108 Martin J-J. Adult type of neuronal ceroid-lipofuscinosis. Dev Neurosci 1991; 13: 331–338 Martin J-J.Adult type of neuronal ceroid-lipofuscinosis.J Inherit Metab Dis 1993; 16: 237–240 Tobo M, Misuyama Y, Ikari K, Itio K. familial occurrence of adulttype neuronal ceroid lipofuscinosis. Arch Neurol 1984; 41: 1091–1094

Neuronal Ceroid Lipofuscinosis: CLN 5 Autti T, Raininko R, Launes J, Nuutila A, Santavuori P, JanskiBielschowsky variant disease: CT, MRI, and SPECT findings. Pediatr Neurol 1992; 2: 121–126

Holmberg V, Lauronen K, Autti T, Santavuori P, Savukoski M, Uvebrand P, Hofman I, Peltonen L, Järvelä I. Phenotypegenotype correlation in eight patients with Finnish variant late infantile NCL (CLN5). Neurology 2000; 55: 579–581 Isosomppi J, Vesa J, Jalanko A, Peltonen L. Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5. Hum Mol Genet 2002; 11: 885–891 Lauronen L, Huttunen J, Kirveskari E,Wikström H, Sainio K, Autti T, Santavuori P. Enlarged Si and SII somatosensory evoked responses in the CLN5 form of neuronal ceroid lipofuscinosis. Clin Neurophysiol 2002; 113: 1491–1500 Rapola J, Lake BD. Lymphocyte inclusions in Finnish-variant late infantile neuronal ceroid lipofuscinosis (CLN5). Neuropediatrics 2000; 31: 33–34 Rapola J, Lähdetie J, Isosomppi J, Helminen P, Penttinen M, Järvelä I. Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCLfinnish; CLN5). Prenat Diagn 1999; 19: 685–688 Santavuori P, Rapola J, Nuutila A, Raininko R, Lappi M, Launes J, Herva R, Sainio K.The spectrum of Jansky-Bielschowsky disease. Neuropediatrics 1991; 22: 92–96 Santavuori P, Rapola J, Raininko R, Autti T, Lappi M, Nuutila A, Launes J, Sainio K. Early juvenile neuronal ceroid-lipofuscinosis or variant Jansky-Bielschowsky disease: diagnostic criteria and nomenclature. J Inherit Metab Dis 1993; 16: 230–232 Savukoski M, Klockars T, Holmberg V, Santavuori P, Lander ES, Peltonen L. CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. Nat Genet 1998; 19: 286–288 Tyynelä J, Suopanki J, Santavuori P, Baumann M, Haltia M. Variant late infantile neuronal ceroid-lipofuscinosis: pathology an biochemistry. J Neuropathol Exp Neurol 1997; 56: 369– 375 Uvebrant P, Hagberg B. Neuronal ceroid lipofuscinosis in Scandinavia. Epidemiology and clinical pictures. Neuropediatrics 1997; 28: 6–8 Varilo T, Savukoski M, Norio R, Santavuori P, Peltonen L, Järvelä J. The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population. Am J Hum Genet 1996; 58: 506–512 Vesa J, Chin MH, Oelgeschläger K, Isosomppi J, DellAngelica EC, Jalanko A, Peltonen L. Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Mol Biol Cell 2002; 13: 2410–2420 Williams R, Santavuori P, Peltonen L, Gardiner RM, Järvelá I. A variant form of late infantile neuronal ceroid lipofuscinosis (CLN5) is not an allelic form of Batten (Spielmeyer-VogtSjögren, CLN3) disease: exclusion of linkage to the CLN3 region of chromosome 16. Genomics 1994; 20: 289–290 Wisniewski KE, Kida E, Connell F, Elleder M, Eviatar L, Konkol RJ. New subform of the late infantile form of neuronal ceroid lipofuscinosis. Neuropediatrics 1993; 24: 155–163

Neuronal Ceroid Lipofuscinosis: CLN 6 Auger KJ, Ajene A, Lerner T. Progress toward the cloning of CLN6, the gene underlying a variant LINCL. Mol Genet Metab 1999; 66: 332–336 Gao H, Boustany R-MN, Espanola JA, Cotman SL, Srinidhi L, Antonellis KA, Gillis T, Qin X, Liu S, Donahue LR, Bronson RT, Faust JR, Stout D, Haines JL, Lerner TJ, MacDonald ME. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 2002; 70: 324–335

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930 References and Further Reading Heine C, Koch B, Storch S, Kohlschutter A, Palmer DN, Braulke T. Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A. J Biol Chem 2004; 279: 22347–22352 Pena HA, Cardozo JJ, Montiel CM, Molina OM, Boustany R-M. Serial MRI findings in the Costa Rican variant of neuronal ceroid-lipofuscinosis. Pediatr Neurol 2001; 25: 78–80 Sharp JD,Wheeler RB, Lake BD, Fox M, Gardiner RM,Williams RE. Genetic and physical mapping of the CLN6 gene on chromosome 15q21–23. Mol Genet Metab 1999; 66: 329–331 Wheeler RB, Sharp JD, Schultz RA, Joslin JM, Williams RE, Mole SE. The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet 2002; 70: 537–542

Neuronal Ceroid Lipofuscinosis: CLN 7 Mitchell WA,Wheeler RB, Sharp JD, Bate SL, Gardiner RM, Ranta US, Lonka L,Williams RE, Lehesjoki AE, Mole SE.Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8. Eur J Paediatr Neurol 2001; 5: 21–27 Topçu M, Tan H, Yalnizoglu D, Usubütün A, Saatçi I, Aynaci M, Anlar B, Topaloglu H, Turanli G, Köse G, Aysun S. Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies.Turk J Pediatr 2004; 46: 1–10 Wheeler RB, Sharp JD, Mitchell WA, Bate SL, Williams WA, Lake BD, Gardiner RM. A new locus for variant late infantile neuronal ceroid lipofuscinosis-CLN7. Mol Genet Metab 1999; 66: 337–378

Neuronal Ceroid Lipofuscinosis: CLN8 Hirvasniemi A, Lang H, Lehesjoki A-E, Leisti KJ. Northern epilepsy syndrome: an inherited childhood-onset epilepsy with associated mental deterioration. J Med Genet 1994; 31: 177–182 Lonka L, Kyttälä A, Ranta S, Jalanko A, Lehesjoki A-E. The neuronal ceroid lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum. Hum Mol Genet 2000; 9: 1691–1697 Ranta S, Lehesjoki A-E. Northern epilepsy, a new member of the NCL family. Neurol Sci 2000; 21: S43–S47 Ranta S, Lehesjoki A-E, Hirvasniemi A, Weissenbach J, Ross B, Leal SM, de la Chapelle A, Gilliam TC. Genetic and physical mapping of the progressive epilepsy with mental retardation (EPMR) locus on chromosome 8p. Genome Res 1996; 6: 351–360 Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, Kusumi K, Mole S. Liu W, Soares MB, de Fatima Bonaldo M, Hirvasniemi A, de la Chapelle A, Gilliam TC, Lehejoski A-E.The neuronal ceroid lipofuscinosis in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nat Genet 1999; 23: 233–236 Tahvanainen E,Ranta S,Hirvasniemi A.Karila E,Leisti J,Sistonen P, Weissenbach J, Lehesjoki E-E, de la Chapelle A. The gene for a recessively inherited human childhood progressive epilepsy with mental retardation maps to the distal short arm for chromosome 8. Proc Natl Acad Sci 1994; 91: 7267–7270

16 Adult Polyglucosan Body Disease Berkhoff M, Weis J, Schroth G, Sturzenegger M. Extensive white-matter changes in case of adult polyglucosan bodydisease. Neuroradiology 2001; 43: 234–236 Bigio EH,Weiner MF, Bonte FJ,White CL. Familial dementia due to adult polyglucosan bodydisease. Clin Neuropathol 1997; 16: 227–234 Boulan-Predseil P, Vital A, Brochet B, Darriet D, Henry P, Vital C. Dementia of frontal lobe due to adult polyglucosan bodydisease. J Neurol 1995; 242: 512–516 Bruno C, Servidei S, Shanske S, Karpati G, Carpenter S, McKee D, Barohn RJ,Hirano M,Rifai Z,DiMauro S.Glycogen branching enzyme deficiency in adult polyglucosan bodydisease.Ann Neurol 1993; 33: 88–93 Busard HLSM, Gabreëls-Festen AAWM, Reinier WO, Gabreëls FJM, Joosten EGM, van ‘t Hof MS, Rensing JBM. Adult polyglucosan bodydisease: the diagnostic value of axilla skin biopsy. Ann Neurol 1991; 29: 448–451 Cafferty MS, Lovelace RE, Hays AP, Servidei S, DiMauro S, Rowland LP. Polyglucosan body disease. Muscle Nerve 1991; 14: 102–107 Cavanagh JB. Corpora-amylacea and the family of polyglucosan diseases. Brain Res Rev 1999; 29: 265–295 Gray F, Gherardi R, Mashall A, Path MRC, Janota I, Poirier J. Adult polyglucosan body disease (APBD) J Neuropathol Exp Neurol 1988; 47: 259–474 Klein CM, Peter Bosch E, Dyck PJ. Probable adult polyglucosan bodydisease. Mayo Clinic Proc 2000; 75: 1327–1331 Lossos A, Baresh V, Soffer D, Argov Z, Gomori M, Ben-Nariah Z, Abramsky O, Steiner I. Hereditary branching enzyme dysfunction in adult polyglucosan bodydisease: a possible metabolic cause in two patients. Ann Neurol 1991; 30: 655–662 McDonald TD, Faust PL, Bruno C, DiMauro S, Goldman JE. Polyglucosan bodydisease simulating amyotrophic lateral sclerosis. Neurology 1993; 43: 785–790 Milde P, Guccion JG, Kelly J, Locatelli E, Jones RV. Adult polyglucosan bodydisease. Diagnosis by sural nerve and skin biopsy. Arch Pathol Lab Med 2001; 125: 519–522 Moses SW, Parvari R. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. Curr Mol Med 2002; 2: 177–188 Negishi C, Sze G. Spinal cord MRI in adult polyglucosan body disease. J Comput Assist Tomogr 1992; 16: 824–826 Okamoto K, Llena JF, Hirano A. A type of adult polyglucosan bodydisease. Acta Neuropathol (Berl) 1982; 58: 73–77 Rifai Z, Klitzke M,Tawil R, Kazee AM, Shanske S, DiMauro S, Griggs RC. Dementia of adult polyglucosan body disease. Evidence of cortical and subcortical dysfunction. Arch Neurol 1994; 51: 90–94 Robertson NP, Wharton S, Anderson J, Scolding NJ. Adult polyglucosan body disease associated with an extrapyramidal syndrome. J Neurol Neurosurg Psychiatry 1998; 65: 788–790 Robitaille Y, Carpenter S, Karpati G, DiMauro S. A distinct form of adult polyglucosan bodydisease with massive involvement of central and pheripheral neuronal processes and astrocytes. A report of four cases and a review of the occurence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing. Brain 1980; 103: 315– 336

References and Further Reading

Sindern E, Patzold T, Vorgerd M, Shin YS, Podskarbi T, Schröder JM, Malin JP. Adult polyglucosan body disease. Report of a case with predominant involvement of the central and peripheral nervous system and branching enzyme deficiency in leukocytes. Nervenarzt 1999; 70: 745–749 Sindern E, Ziemssen F, Ziemssen T, Podskarbi T, Shin Y, Brasch F, Müller KM, Schröder JM, Malin JP,Vorgerd M. Adult polyglucosan body disease. A postmortem correlation study. Neurology 2003; 61: 263–265 Vos AJM, Joosten EGM, Gabreëls-Festen AAWM. Adult polyglucosan body disease: clinical and nerve biopsy findings in two cases. Ann Neurol 1983; 13: 440–444 Wierzba-Bobrowicz T, Stroinska-Kús B. Adult polyglucosan body disease. Folia Neuropathol 1994; 32: 37–41 Ziemssen F, Sindern E, Michael Schröder J, Shin YS, Zange J, Kilimann MW, Malin J-P,Vorgerd M. Novel missence mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease. Ann Neurol 2000; 47: 536–540

17 Peroxisomes and Peroxisomal Disorders Aubourg P, Scotto J, Rocchiccioli F, Feldmann-Pautrat D, Robain O. Neonatal adrenoleukodystrophy. J Neurol Neurosurg Psychiatry 1986; 49: 77–86 Barth PG, Gootjes J, Bode H, Vreken P, Majoie CB, Wanders RJA. Late onset white matter disease in peroxisome biogenesis disorder. Neurology 2001; 57: 1949–1955 Barth PG, Majoie CB, Gootjes J,Wanders RJA,Waterham HR, van der Knaap MS, de Klerk JB, Smeitink J, Poll-The BT. Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 2004; 62: 439–444 Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, Chakraborty PK, Clarke JT, Boneh A, Moser A, Moser H, Valle D. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat 2002; 20: 284– 297 Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, Casey R, Zeiss C, Tyson H, Cutting GR, Raymond GV, Smith KD,Watkins PA, Moser AB, Moser HW, Steinberg SJ. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet 2002; 70: 1520–1531 Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Allen JT, Mclean BN, Brown AY, Vreken P, Waterham HR, Wanders RJA. Mutations in the gene encoding peroxisomal alphamethylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 2000; 24: 188–191 Gould SJ, Valle D. Peroxisome biogenesis disorders: genetics and cell biology.Trends Genet 2000; 16: 340–345 Gould SJ, Raymond GV, Valle D. The peroxisomal biogenesis disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: Mc Graw-Hill, 2001, pp 3181–3217 Kelley RI, Datta NS, Dobyns WB, Hajra AK, Moser AB, Noetzel MJ, Zackai EH, Moser HW. Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes. Am J Med Genet 1986; 23: 869–901 Mannaerts GP, van Veldhoven PP. Functions and organization of peroxisomal beta-oxidation. Ann NY Acad Sci 1996; 804: 99–115

Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. X-Linked Adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001, pp 3257–3301 Motley AM, Brites P, Gerez L, Hogenhout EM, Haasjes J, Benne R, Tabak HF,Wanders RJA,Waterham HR.Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet 2002; 70: 612–624 Poll-The BT, Saudubray JM, Ogier HA, Odievre M, Scotto JM, Monnens L, Govaerts LC, Roels F, Cornelis A, Schutgens RBH. Infantile Refsum disease: an inherited peroxisomal disorder. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy. Eur J Pediatr 1987; 146: 477–483 Setchell KD, Heubi JE, Bove KE, O’Connell NC, Brewsaugh T, Steinberg SJ, Moser A, Squires RH Jr.Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology 2003; 124: 217–232 Shimozawa N,Suzuki Y,Orii T,Moser A,Moser HW,Wanders RJA. Standardization of complementation grouping of peroxisome-deficient disorders and the second Zellweger patient with peroxisomal assembly factor-1 (PAF-1) defect. Am J Hum Genet 1993; 52: 843–844 Van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR,Wanders RJA. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet 2003; 72: 471–477. van der Knaap MS,Valk J.The MR spectrum of peroxisomal disorders. Neuroradiology 1991; 33: 30–37 Wanders RJA. Metabolic and molecular basis of peroxisomal disorders: a review. Am J Med Genet 2004; 126: 355–375 Wanders RJA,Heymans HSA,Schutgens RBH,Barth PG,van den Bosch H, Tager JM. Peroxisomal disorders in neurology. J Neurol Sci 1988; 88: 1–39 Wanders RJA, Barth PG, Heymans HSA. Single peroxisomal enzyme deficiencies. In: Scriver CR, Beaudet AL, Sly WS,Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001, pp 3219–3256. Wanders RJA, Jakobs C, Skjeldal OH. Refsum disease. In: Scriver CR, Beaudet AL, Sly WS,Valle D, eds.The metabolic and molecular bases of inherited disease.. New York: Mc Graw-Hill, 2001, pp 3303–3321 Wanders RJA,Vreken P, Ferdinandusse S, Jansen GA,Waterham HR, van Roermund CWT, van Grunsven EG. Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochem Soc Trans 2001; 29: 250–267

18 Peroxisome Biogenesis Defects Agamanolis DP, Patre S. Glycogen accumulation in the central nervous system in the cerebro-hepato-renal syndrome. J Neurol Sci 1979; 41: 325–334 Agamanolis DP, Robinson HB, Timmons GD. Cerebro-hepatorenal syndrome.Report of a case with histochemical and ultrastructural observations. J Neuropathol Exp Neurol 1976; 35: 226–246 Aikawa J, Chen WW, Kelley RI,Tada K, Moser HW, Chen GL. Lowdensity particles (W-particles) containing catalase in Zellweger syndrome and normal fibroblasts. Proc Natl Acad Sci USA 1991; 88: 10084–10088

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932 References and Further Reading Aubourg P, Robain O, Rocchiccioli F, Dancea S, Scotto J. The cerebro-hepato-renal (Zellweger) syndrome: lamellar lipid profiles in adrenocortical, hepatic mesenchymal, astrocyte cells and increased levels of very long chain fatty acids and phytanic acid in the plasma. J Neurol Sci 1985; 69: 9–25 Aubourg P,Scotto J,Rocchiccioli R,Feldmann-Pautrat D,Robain O. Neonatal adrenoleukodystrophy. J Neurol Neurosurg Psychiatry 1986; 49: 77–86 Bader PI, Dougherty S, Cangany N, Raymond G, Jackson CE. Infantile Refsum disease in four Amish sibs. Am J Med Genet 2000; 90: 110–114 Barkovich AJ, Peck WW. MR of Zellweger syndrome. AJNR Am J Neuroradiol 1997; 18: 1163–1170 Barth PG, Schutgens RBH, Bakkeren JAJM, Dingemans KP, Heymans HSA, Douwes AC, van der Klei-van Moorsel JM. A milder variant of Zellweger syndrome. Eur J Pediatr 1985; 144: 338–342 Barth PG, Wanders RJA, Schutgens RBH, Bleeker-Wagemakers EM, van Heemstra D. Peroximal b-oxidation defect with detectable peroxisomes: a case with neonatal onset and progressive course. Eur J Pediatr 1990; 149: 722–726 Barth PG, Gootjes J, Bode H, Vreken P, Majoie CBLM, Wanders RJA. Late onset white matter disease in peroxisome biogenesis disorder. Neurology 2001; 57: 1949–1955 Barth PG, Majoie CBLM, Gootjes J, Wanders RJA, Waterham HR, van der Knaap MS,de Klerk JBC,Smeitink J,Poll-The BT.Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 2004; 62: 439–444 Beard ME, Moser AB, Sapirstein V, Holtzman E. Peroxisomes in infantile phytanic acid storage disease: a cytochemical study of skin fibroblasts. J Inherit Metab Dis 1986; 9: 321– 334 Benke PJ, Reyes PF, Parker JC Jr. New form of adrenoleukodystrophy. Hum Genet 1981; 58: 204–208 Bizzozero OA, Ziñiga G, Lees MB. Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. J Neurochem 1991; 56: 872–878 Brosius U, Gärtner J. Cellular and molecular aspects of Zellweger syndrome and other peroxisome biogenesis disorders. Cell Mol Life Sci 2002; 59: 1058–1069 Budden SS, Kennaway NG, Buist NRM, Poulos A, Weleber RG. Dysmorphic syndrome with phytanic acid oxidase deficiency, abnormal very long chain fatty acids, and pipecolic acidemia:studies in four children.J Pediatr 1986; 108:33–39 Burdette DE, Kremser K, Fink JK, Pahan K, Stanley W, Sing I. Lateonset generalized disorder of peroxisomes. Neurology 1996; 46: 829–831 Chow CW, Poulos A, Fellenberg AJ, Christodoulou J, Danks DM. Autopsy findings in two siblings with infantile Refsum disease. Acta Neuropathol (Berl) 1992; 83: 190–195 De Leon GA, Grover WD, Huff DS, Moringo-Meure G, Punnett HH, Kistenmacher ML. Globoid cells, glial nodules, and peculiar fibrillary changes in the cerebro-hepato-renal syndrome of Zellweger. Ann Neurol 1977; 2: 473–484 Dimmick JE, Applegarth DA. Pathology of peroxisomal disorders. Perspect Pediatr Pathol 1993; 17: 45–98 Dodt G, Braverman N, Wong C, Moser A, Moser HW, Watkins P, Valle D, Gould SJ. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet 1995; 9: 115–125 Dubois J, Sebag G, Argyropoulou M, Brunelle F. MR findings in infantile Refsum disease: case report of two family members. AJNR Am J Neuroradiol 1991; 12: 1159–1160

Evrard P, Caviness VS, Prats-Vinas J, Lyon G. The mechanism of arrest of neuronal migration in the Zellweger malformation: an hypothesis based upon cytoarchitectonic analysis. Acta Neuropathol (Berl) 1978; 41: 109–117 Ferninandusse S, Denis S, Mooijer PAW, Zhang Z, Reddy JK, Spector AA, Wanders RJA. Identification of the peroxisomal b-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid. J Lipid Res 2001; 42: 1987–1995 Folz SJ, Trobe JD. The peroxisome and the eye. Surv Ophthalmol 1991; 35: 353–368 Ghaedi K, Honsho M, Shimozawa N, Suzuki Y, Kondo N, Fujiki Y. PEX3 is the casual gene responsible for peroxisome membrane assembly-defective Zellweger syndrome of complementation group G. Am J Hum Genet 2000; 67: 976–981 Goldfischer S, Powers JM, Johnson AB, Axe S, Brown FR, Moser HW. Striated adrenocortical cells in cerebro-hepato-renal (Zellweger) syndrome. Virchows Arch 1983; 401: 355–361 Gould SJ, Valle D. Peroxisome biogenesis disorders. Genetics and cell biology.Trends Genet 2000; 16: 340–345 Govaerts L, Sippell WG, Monnens L. Further analysis of the disturbed adrenocortical function in the cerebro-hepato-renal syndrome of Zellweger. J Inherit Metab Dis 1989; 12: 423–428 Groenendaal F, Bianchi MC, Battini R, Tosetti M, Boldrini A, de Vries LS, Cioni G. Proton magnetic resonance spectroscopy (1H-MRS) of the cerebrum in two young infants with Zellweger syndrome. Neuropadiatrics 2001; 32: 23–27 Heikoop JC, van den Berg M, Strijland A, Weijers PJ, Just WW, Meijer AJ,Tager JM.Turnover of peroxisomal vesicles by autophagic proteolysis in cultured fibroblasts from Zellweger patients. Eur J Cell Biol 1992; 59: 165–171 Heymans HSA, Schutgens RB, Tan R, van den Bosch H, Borst P. Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome). Nature 1983; 306: 69–70 Holmes RD, Wilson GN, Hajra A. Oral ether lipid therapy in patients with peroxisomal disorders. J Inherit Metab Dis 1987; 10: 239–241 Imamura A, Shimozawa N, Suzuki Y, Zhang Z,Tsukamoto T, Fujiki Y, Osumi T, Wanders RJA, Kondo N.Temperature-sensitive mutations of PEX6 in peroxisome biogenesis disorders in complementation group C (CG-C): comparative study of PEX6 and PEX1. Pediatr Res 2000; 48: 541–545 Jaffe R, Crumrine P, Hashida Y, Moser HW. Neonatal adrenoleukodystrophy. Clinical, pathologic, and biochemical delineation of a syndrome affecting both males and females. Am J Pathol 1982; 108: 100–111 Janssen A, Baes M, Gressens P, Mannaerts GP, Declerq P, van Veldhoven PP. Docosahexaemoic acid deficit is not a major pathogenic factor in peroxisome-deficient mice. Lab Invest 2000; 80: 31–35 Kelley RI,Datta NA,Dobyns WB,Hajra AK,Moser AB,Noetzel MJ, Zackal EH, Moser HW. Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes. Am J Med Genet 1986; 23: 869–901 Liu HM, Bangaru BS, Kiddd J, Boggs J. Neuropathological considerations in cerebro-hepato-renal syndrome (Zellweger’s syndrome) Acta Neuropathol (Berl) 1976; 34: 115–123 Manz HJ, Schuelein M, McCullough DC, Kishimoto Y, Eiben RM. New phenotypic variant of adrenoleukodystrophy. Pathologic, ultrastructural, and biochemical study in two brothers. J Neurol Sci 1980; 45: 245–260 Martinez M. Restoring the DHA levels in the brain of Zellweger patients. J Mol Neurosci 2001; 16: 309–316

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Martinez M, Vasques E. MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders. Neurology 1998; 51: 26–32 Matsumoto N, Tamura S, Moser A, Moser HW, Braverman N, Suzuki Y, Shimozawa N, Kondo N, Fujiki Y.The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6. J Hum Genet 2001; 46: 273–277 Matsumoto N, Tamura S, Furuki S, Miyata N, Moser A, Shimozawa N, Moser HW, Suzuki Y, Kondo N, Fujiki Y. Mutations in novel peroxin gene PEX26 that causes peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation. Am J Hum Genet 2003; 73: 233–246 Matsumoto N, Tamura S, Fujiki Y. The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase complexes to peroxisomes. Nat Cell Biol 2003; 5: 454–60 Maxwell MA, Allen T, Solly PB, Svingen T, Paton BC, Crane DI. Novel PEX1 mutations and genotype-phenotype correlations in Australian peroxisome biogenesis disorder patients. Hum Mutat 2002; 20: 342–351 Mito T,Takada K, Akaboshi S,Takashima S,Takeshita K, Origuchi Y. A pathological study of a peripheral nerve in a case of neonatal adrenoleukodystrophy. Acta Neuropathol (Berl) 1989; 77: 437–440 Muntau AC, Mayerhofer PU, Paton PC, Kammerer S, Roscher AA. Defective peroxisome membrane synthesis due to mutations in human PEX3 causes Zellweger syndrome, complementation group G. Am J Hum Genet 2000; 67: 967–975 Nakai A, Shigematsu Y, Nishida K, Kikawa Y, Konishi Y. MRI findings of Zellweger syndrome. Pediatr Neurol 1995; 13: 346–348 Okumoto K, Fujiki Y.PEX12 encodes an integral membrane protein of peroxisomes. Nat Genet 1997; 17: 265–266 Panjan DJ, Megliè NP, Neubauer D. A case of Zellweger syndrome with extensive MRI abnormalities and unusual EEG findings. Clin Electroencephalogr 2001; 32: 28–31 Passarge E, McAdams AJ. Cerebro-hepato-renal syndrome. J Pediatr 1967; 71: 691–702 Poll-The BT, Poulos A, Sharp P, Boue J, Ogier H, Odièvre M, Saudubray JM. Antenatal diagnosis of infantile Refsum’s disease. Clin Genet 1985; 27: 524–526 Poll-The BT,Gootjes J,Duran M,de Klerk JBC,Wenniger-Prick LJ, Admiraal RJC, Waterham HR, Wanders JA, Barth PG. Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet [A] 2004; 126: 333–338 Portsteffen H, Beyer A, Becker E, Epplen C, Pawlak A, Kunau WH, Dodt G. Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis disorders. Nat Genet 1997; 17: 449–452 Poulos A, Sharp P, Johnson D. Plasma polyenoic very-longchain fatty acids in peroxisomal disease: biochemical discrimination of Zellweger’s syndrome from other phenotypes. Neurology 1989; 39: 44–47 Powers JM. The pathology of peroxisomal disorders with pathogenetic considerations. J Neuropathol Exp Neurol 1995; 54: 710–719 Powers JM, Tummons RC, Caviness VS, Moser AB, Moser HW. Structural and chemical alterations in the cerebral maldevelopment of fetal cerebro-hepato-renal (Zellweger) syndrome. J Neuropathol Exp Neurol 1989; 48: 270–289 Powers JM, Moser HG. Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 1998; 8: 101–120

Preuss N, Brosius U, Biermanns M, Muntau AC, Conzelmann E, Gärtner J. PEX1 Mutations in complementation group 1 of Zellweger spectrum patients correlate with severity of disease. Pediatr Res 2002; 51: 706–714 Raafat F, Smith K, Halloran EA, Lacy D. Zellweger syndrome: a histochemical diagnosis of two cases. Pediatr Pathol 1991; 11: 413–420 Raas-Rothshild A, Wanders RJA, Mooijer PAW, Gootjes J, Waterham HR, Gutman A, Suzuki Y, Shimozawa N, Kondo N, Eshel G, Espeel M, Roels F, Korman SH. A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant,versus mild phenotype resembling Usher syndrome in the affected parents. Am J Hum Genet 2002; 70: 1062–1068 Raymond GV. Peroxisomal disorders. Curr Opin Neurol 2001; 14: 783–787 Reuber BE, Germain-Lee E, Collins CS, Morrell JC, Ameritunga R, Moser HW,Valle D, Gould SJ. Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders. Nat Genet 1997; 17: 445–448 Robertson EF, Poulos A, Sharp P, Manson J,Wise G, Jaunzems A, Carter R. Treatment of infantile phytanic acid storage disease: clinical, biochemical and ultrastructural findings in two children treated for 2 years. Eur J Pediatr 1988; 147: 133–142 Roels F, Espeel M, de Craemer D. Liver pathology and immunocytochemistry in congenital peroxisomal diseases: a review. J Inherit Metab Dis 1991; 14; 853–875 Roels F, Espeel M, Poggi F, Mandel H, van Maldergem L, Saudubray JM. Human liver pathology in peroxisomal diseases: a review including novel data. Biochimie 1993; 75: 281–292 Sarnat HB,Trevenen CL, Darwish HZ. Ependymal abnormalities in cerebro-hepato-renal disease of Zellweger. Brain Dev 1993; 15: 270–277 Schutgens RBH, Schrakamp G, Wanders RJA, Heymans HSA, Tager JM, van den Bosch H. Prenatal and perinatal diagnosis of peroxisomal disorders. J Inherit Metab Dis 1989; 12: 118–134 Scotto JM,Hadchouel M,Odievre M,Laudat MH,Saudubray JM, Dulac O, Beucler I, Beaune P. Infantile phytanic acid storage disease, a possible variant of Refsum’s disease: three cases, including ultrastructural studies of the liver. J Inherit Metab Dis 1982;5: 83–90 Sharp P, Johnson D, Poulos A. Molecular species of phosphatidylcholine containing very long chain fatty acids in human brain: enrichment in X-linked adrenoleukodystrophy brain and diseases of peroxisome biogenesis brain. J Neurochem 1991; 56: 30–37 Shimozawa N, Suzuki Y, Zhang Z, Imamura A, Ghaedi K, Fujiki Y, Kondo N. Identification of PEX3 as the gene mutated in a Zellweger syndrome patient lacking peroxisomal remnant structures. Hum Mol Genet 2000; 9: 1995–1999 Slawekci ML, Dodt G, Steinberg S, Moser AB, Moser HW, Gould SJ. Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders. J Cell Sci 1995; 108: 1817–1829 Torvik A,Torp S, Kase BF, Ek J, Skjeldal O, Stokke O. Infantile Refsum’s disease: a generalized peroxisomal disorder. Case report with postmortem examination. J Neurol Sci 1988; 85: 39–53 Ulrich J, Herschkowitz N, Heitz Ph, Sigrist Th, Baerlocher P. Adrenoleukodystrophy. Preliminary report of a connatal case. Light- and electron microscopical immunohistochemical and biochemical findings. Acta Neuropathol (Berl) 1978: 43: 77–83

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934 References and Further Reading Vamecq J, Draye JP, van Hoof F, Misson JP, Evrard P, Verellen G, Eyssen HJ, van Eldere J, Schutgens RH,Wanders RJA, Roels F, Goldfischer SL. Multiple peroxisomal enzymatic deficiency disorders. A comparative biochemical and morphologic study of Zellweger cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy. Am J Pathol 1986; 125: 524–535 Van Roermund CWT, Brul S, Tager JM, Schutgens RBH, Wanders RJA. Acyl-CoA oxidase, peroxisomal thiolase and dihydroxyacetone phosphate acyltransferase: aberrant subcellular localization in Zellweger syndrome. J Inherit Metab Dis 14: 152–164 Volpe JJ, Adams RD. Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration. Acta Neuropathol (Berl) 1972; 20: 175–198 Walter C, Gootjes J, Mooijer PA, Portsteffen H, Klein C, Waterham HR, Barth PG, Epplen JT, Kunau W-H, Wanders RJA, Dodt G. Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. Am J Hum Genet 2001; 69: 35–48 Wanders RJA, Boltshauser E, Steinmann B, Spycher MA, Schutgens RBH, Bosch van den H, Tager JM. Infantile phytanic acid storage disease, a disorder of peroxisome biogenesis: a case report. J Neurol Sci 1990; 98: 1–11 Wanders RJA, Schutgens RBH, van den Bosch H, Tager JM, Kleijer WJ. Prenatal diagnosis of inborn errors in peroxisomal b-oxidation. Prenat Diagn 1991; 11: 253–261 Wanders RJA, Schutgens RBH, Barth PG, Tager JM, van den Bosch H. Postnatal diagnosis of peroxisomal disorders: a biochemical approach. Biochimie 1993; 75: 269–279 Warren JS, Morrell JC, Moser HW, Valle D, Gould SJ. Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders.Am J Hum Genet 1998; 63: 347–359 Warren DS, Wolfe BD, Gould SJ. Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients. Hum Mutat 2000; 15: 509–521 Wei H, Kemp S, McGuiness MC, Moser AB, Smith KD. Pharmacological induction of peroxisomes in peroxisome biogenesis disorders. Ann Neurol 2000; 47: 286–296 Wilson GN, Holmes RD, Hajra AK. Peroxisomal disorders: clinical commentary and future prospects. Am J Med Genet 1988; 30: 771–792 Wolff J, Nyhan WL, Powell H, Takahashi D, Hutzler J, Hajra AK, Datta NS, Singh I, Moser HW. Myopathy in an infant with a fatal peroxisomal disorder. Pediatr Neurol 1986; 2: 141–146 Yahruas T,Braverman N,Dodt G,Kalish JE,Morrell JC,Moser HW, Valle D,Gould S.The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor. EMBO J 1996; 15: 2914–2923

19 Peroxisomal D-Bifunctional Protein Deficiency Akaboshi S, Tomita Y, Suzuki Y, Une M, Sohma O, Takashima S, Takeshita K. Peroxisomal bifunctional protein deficiency: serial neurophysiological examinations of a case. Brain Dev 1997; 19: 295–299 Clayton PT. Clinical consequences of defects in peroxisomal b-oxidation. Biochem Soc Trans 2001; 29: 298–305

Clayton PT, Lake BD, Hjelm M, Stephenson JBP, Besley GTN, Wanders RJA, Schram AW, Tager JM, Schutgens RBH, Lawson AM. Bile acid analysis in “pseudo-Zellweger”syndrome; clues to the defect in peroxisomal b-oxidation. J Inherit Metab Dis 1988; 11: 165–168 Espeel M, Roels F, van Maldergem L, de Craemer D, Dacremont G, Wanders RJA, Hashimoto T. Peroxisomal localization of the immunoreactive b-oxidation enzymes in a neonate with a b-oxidation defect. Pathological observations in liver, adrenal cortex and kidney. Virchows Arch [A] 1991; 419: 301–308 Ferdinandusse S, van Grunsven EG, Oostheim W, Denis S, Hogenhout EM, Ijlst L, van Roermund CWT, Waterham HR, Goldfischer S,Wanders RJA. Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of D-bifunctional protein. Am J Hum Genet 2002; 70: 1589–1593 Goldfischer S, Collins J, Rapin I, Neumann P, Neglia W, Spiro AJ, Ishii T, Roels F, Vamecq J, van Hoof F. Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities. J Pediatr 1986; 108: 25–32 Itoh M, Suzuki Y, Akaboshi S, Zhang Z, Miyabara S,Takashima S. Developmental and pathological expression of peroxisomal enzymes: their relationship of D-bifunctional protein deficiency and Zellweger syndrome. Brain Res 2000; 858: 40–47 Kaufman WE, Theda C, Naidu S, Watkins PA, Moser AB, Moser HW. Neuronal migration abnormality in peroxisomal bifunctional enzyme defect. Ann Neurol 1996; 39: 268–271 McGuinness MC, Moser AB, Poll-The BT, Watkins PA. Complementation analysis of patients with intact peroxisomes and impaired peroxisomal b-oxidation. Biochem Med Metab Biol 1993; 49: 228–242 Möller G, van Grunsven EG,Wanders RJA, Adamski J. Molecular basis of D-bifunctional protein deficiency. Mol Cell Endocrinol 2001; 171: 61–70 Naidu S, Hoefler G, Watkins PA, Chen WW, Moser AB, Hoefler S, Rance NE, Powers JM, Beard M, Green WR, Hashimoto T, Moser HW. Neonatal seizures and retardation in a girl with biochemical features of X-linked adrenoleukodystrophy: a possible new peroxisomal disease entity. Neurology 1988; 38: 1100–1107 Nakada Y, Hyakuna N, Suzuki Y, Shimozawa N,Takaesu E, Ikema R, Hirayama K. A case of pseudo-Zellweger syndrome with a possible bifunctional enzyme deficiency but detectable enzyme protein. Brain Dev 1993; 15: 453–456 Nakano K, Zhang Z, Shimozawa N, Kondo N, Ishii N, Funatsuka M, Shirakawa S, Itho M, Takashima S, Une M, Kana-aki RR, Mukai K, Osawa M, Suzuki Y. D-Bifunctional protein deficiency with fetal ascites, polyhydramnios, and contractures of hands and toes. J Pediatr 2001; 139: 865–867 Paton BC, Solly PB, Nelson PV, Pollard AN, Sharp PC, Fietz MJ. Molecular analysis of genomic DNA allows rapid, and accurate, prenatal diagnosis of peroxisomal D-bifunctional protein deficiency. Prenat Diagn 2002; 22: 38–41 Suzuki Y, Shimoxawa N, Yajima S, Tomatsu S, Kondo N, Nakada Y, Akaboshi S, Iai M, Tanabe Y, Hashimoto T, Wanders RJA, Schitgens RBH, Moser HW, Orii T.Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional protein enzyme deficiency with detectable enzyme protein: identification by means of complementation analysis. Am J Hum Genet 1994; 54: 35–43

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Suzuki Y, Jiang LL, Souri M, Miyazawa S, Fukuda S, Zhang Z, Une M, Shimozawa N, Kondo N, Orii T, Hashimoto T. D-3-Hydroxy-CoA dehydratase / D-3-hydroxyacul-CoA dehydrogenase bifunctional protein deficiency: a newly identified peroxisomal disorder. Am J Hum Genet 1997; 61: 1153– 1162 Suzuki Y, Zhang Z, Shimozawa N, Muro M, Shono H, Toda S, Miyahara S-I,Hashimoto T,Usuda N,Ito M,Takashima S,Kondo N. Prenatal diagnosis of peroxisomal D-3-hydroxyacylCoA dehydratase / D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency. J Hum Genet 1999; 44: 143–147 Van Grunsven EG, van Roermund CWT, Denis S, Wanders RJA. Complementation analysis of fibroblasts from peroxisomal fatty acid oxidation deficient patients shows high frequency of bifunctional protein enzyme deficiency plus intragenic complementation: unequivocal evidence for differential defects in the same enzyme protein. Biochem Biophys Res Commun 1997; 235: 176–179 Van Grunsven EG, van Berkel E, Ijlst L, Vreken P, De Klerk JBC, Adamski J, Lemonde H, Clayton PT, Cuebas DA, Wanders RJA. Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency. Proc Natl Acad Sci 1998; 95: 2128–2133 Van Grunsven EG, van Berkel E, Lemonde H, Clayton PT, Wanders RJA. Bifunctional protein deficiency: complementation within the same group suggesting differential enzyme defects and clues to the underlying basis. J Inherit Metab Dis 1998; 21: 298–301 Van Grunsven EG, van Berkel E, Mooijer PAW,Watkins PA, Moser HW, Suzuki Y, Jiang LL, Hashimoto T, Hoefler G, Adamski J, Wanders RJA. Peroxisomal bifunctional protein deficiency revisited:resolution of its true enzymatic and molecular basis. Am J Hum Genet 1999; 64: 99–107 Van Grunsven EG,Mooijer PAW,Aubourg P,Wanders RJA.EnoylCoA hydratase deficiency: identification of a new type of Dbifunctional protein deficiency. Hum Mol Genet 1999; 8: 1509–1516 Van Maldergem L, Espeel M, Wanders RJA, Roels F, Gerard P, Scalais E, Mannaerts GP, Casteels M, Gillerot Y. Neonatal seizures and severe hypotonia in a male infant suffering from a defect in peroxisomal b-oxidation. Neuromusc Disord 1992; 2: 217–234 Wanders RJA, van Roermund CWT, Schelen A, Schutgens RBH, Tager JM, Stephenson JBP, Clayton PT. A bifunctional protein with deficient enzymatic activity: identification of a new peroxisomal disorder using novel methods to measure the peroxisomal b-oxidation enzyme activities.J Inherit Metab Dis 1990; 13: 375–379 Wanders RJA,van Roermund CWT,Brul S,Schutgens RBH,Tager JM. Bifunctional protein deficiency: identification of a new type of peroxisomal b-oxidation of unknown aetiology by means of complementation analysis. J Inherit Metab Dis 1992; 15: 385–388 Watkins PA, Chen WW, Harris CJ, Hoefler G, Hoefler S, Blake DC Jr, Balfe A, Kelley RI, Moser AB, Beard ME, Moser HW. Peroxisomal bifunctional protein deficiency.J Clin Invest 1989; 83: 771–777 Watkins PA, McGuiness MC, Raymond GV, Hicks BA, Sisk JM, Moser AB, Mower HW. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol 1995; 38: 472–477

20 Acyl-CoA Oxidase Deficiency Clayton PT. Clinical consequences of defects in peroxisomal b-oxidation. Biochem Soc Trans 2001; 29: 298–305 Christensen E, Woldseth B, Hagve T-A, Poll-The BT, Wanders RJA, Sprecher H, Stokke O, Christophersen BO. Peroxisomal b-oxidation of polyunsaturated long chain fatty acids in human fibroblasts. The polyunsaturated and the saturated long chain fatty acids are retroconverted by the same acylCoA oxidase. Scand J Clin Lab Invest 1993; 53: 61–74 Kurian MA,Ryan S,Besley GTN,Wanders RJA,King MD.Straightchain acyl-CoA oxidase deficiency presenting with dysmorphia, neurodevelopmental autistic type regression and a selective pattern of leukodystrophy. J Inherit Metab Dis 2004; 27: 105–108 Mandel H, Berant M, Aizin A, Gershony R, Hemmli S, Schutgens RBH, Wanders RJA. Zellweger-like phenotype in two siblings: a defect in peroxisomal b-oxidation with elevated very long-chain fatty acids but normal bile acids. J Inherit Metab Dis 1992; 15: 381–384 Poll-The BT,Roels F,Ogier H,Scotto J,Vamecq J,Schutgens BBH, Wanders RJA, van Roermund CWT, van Wijland MJA, Schram AW, Tager JM, Saudubray J-M. A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J Hum Genet 1988; 42: 422–434 Su H-M, Moser AB, Moser HW,Watkins PA.Peroxisomal straightchain acyl-CoA oxidase and D-bifunctional protein are essential for the retroconversion step in docosahexaenoic acid synthesis. J Biol Chem 2001; 276: 38115–38120 Suzuki Y, Shimoxawa N, Yajima S, Tomatsu S, Kondo N, Nakada Y, Akaboshi S, Iai M, Tanabe Y, Hashimoto T, Wanders RJA, Schitgens RBH, Moser HW, Orii T.Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional protein enztme deficiency with detectable enzyme protein: identification by means of complementation analysis. Am J Hum Genet 1994; 54: 35–43 Suzuki Y, Iai M, Kamei A, Tanabe Y, Chida S,Yamaguchi S, Zhang Z, Takamoto Y, Shimozawa N, Kondo N. Peroxisomal acyl CoA oxidase deficiency. J Pediatr 2002; 140: 128–130 Watkins PA, McGuiness MC, Raymond GV, Hicks BA, Sisk JM, Moser AB, Mower HW. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol 1995; 38: 472–477

21 X-Linked Adrenoleukodystrophy Afifi AK,Menezes AH,Reed LA,Bell WE.Atypical presentation of X-linked childhood adrenoleukodystrophy with an unusual magnetic resonance imaging pattern. J Child Neurol 1996; 11: 497–499 Asano J-I, Suzuki Y, Yajima S, Iioue K, Shimozawa N, Kondo N, Murase M, Orii T. Effects of erucic acid therapy on Japanese patients with X-linked adrenoleukodystrophy. Brain Dev 1994; 16: 454–458 Aubourg P, Dubois-Dalcq M. X-linked adrenoleukodystrophy enigma: how does the ALD peroxisomal transporter mutation affect CNS glia? Glia 2000; 29: 186–190 Aubourg P, Blanche S, Jambaqué I, Rocchiccioli F, Kalifa G, Naud-Saudreau C, Rolland MO, Debré M, Chaussain JL, Griscelli C, Fischer A, Bougnères P-F. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 1990; 322: 1860–1866

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936 References and Further Reading Aubourg P, Adamsbaum C, Lavallard-Rousseau M-C, Rocchiccioli F, Cartier N, Jambaqué I, Jakobezak C, Lemaitre A, Boureau F, Wolf C, Bougnères P-F. A two-year trail of oleic and erucic acids (“Lorenzo’s oil”) as treatment for adrenomyeloneuropathy. N Engl J Med 1993; 329: 745–752 Aubourg P, Mandel JL. X-linked adrenoleukodystrophy. Ann NY Acad Sci 1996; 804: 461–476 Barkovich AJ, Ferriero DM, Bass N, Boyer R. Involvement of the pontomedullary corticospinal tracts: a useful finding in the diagnosis of X-linked adrenoleukodystrophy. AJNR Am J Neuroradiol 1997; 18: 95–100 Baumann M, Korenke GC, Widdige-Diedrichs A, Wilichowski E, Hunneman DH, Wilken B, Brockmann K, Klingebiel T, Niethammer D, Kühl J, Ebell W, Hanefeld F. Haematopoietic stem cell transplantation in 12 patients with cerebral Xlinked adrenoleukodystrophy. Eur J Pediatr 2003; 162: 6–14 Bekiesiñska-Figatowska M, Tylki-Szymañska A, Walekci J, Stradomska TJ. MRI findings in a asymptomatic boy with Xlinked adrenoleukodystrophy and his symptomatic mother. Neuroradiology 2001;43: 951–952 Bezman L, Moser AB, Raymond GV, Rinaldo P,Watkins PA, Smith KD, Kass NE, Moser HW. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol 2001; 49: 512–517 Borker A, Yu LC. Unrelated allogeneic bone marrow transplant in adrenoleukodystrophy using CD34+ stem cell selection. Metab Brain Dis 2002; 17: 139–142 Boutin B, Matsuguchi L, Lebon P, Ponsol G, Arthuis C. Immunohistochemical analysis of brain macrophages in adrenoleukodystrophy. Neuropediatrics 1989; 20: 202–206 Brown FR, Chen WW, Kirschner DA, Frayer KL, Powers JM, Moser AB, Moser HW. Myelin membrane from adrenoleukodystrophy brain white matter – biochemical properties. J Neurochem 1983; 41: 341–348 Cartier N, Guidoux S, Rocchiccioli F, Aubourg P. Simvastatin does not normalize very long chain fatty acids in adrenoleukodystrophy mice. FEBS Lett 2000; 478: 205–208 Confort-Gouny S, Vion-Dury J, Chabrol B, Nicoli F, Cozzone PJ. Localised proton magnetic resonance spectroscopy in Xlinked adrenoleukodystrophy. Neuroradiology 1995; 37: 568–575 Di Rocco M, Doria-Lamba L, Caruso U. Monozogotic twins with X-linked adrenoleukodystrophy and different phenotypes. Ann Neurol 2001; 50: 424 Dodd A, Rowland SA, Hawkes SLJ, Kennedy MA, Love DR. Mutations in the adrenoleukodystrophy gene. Hum Mutat 1997; 9: 500–511 Domagk J, Linke I, Argyrakis A, Spaar FW, Rahlf G, Schulte FJ. Adrenoleukodystrophy. Neuropediatrics 1975; 6: 41–64 Dubois-Dalcq M, Feigenbaum V, Aubourg P. The neurobiology of X-linked adrenoleukodystrophy, a demyelinating peroxisomal disorder.Trends Neurosci 1999; 22: 4–12 Dumic M, Gubarev n, Sikic N, Roscher A, Plavsic V, Filipovic-Grcic B. Sparse hair and multiple endocrine disorders in two women heterozygous for adrenoleukodystrophy. Am J Med Genet 1992; 43: 829–832 Dunne E, Hyman NM, Huson SM, Németh AH. A novel point mutation in X-linked adrenoleukodystrophy presenting as spinocerebellar degeneration. Ann Neurol 1999; 45: 652–655 Dziewas R, Stögbauer F, Oelerich M, Ritter M, Husstedt IW. A case of adrenomyeloneuropathy with unusual lesion pattern in magnetic resonance imaging. J Neurol 2001; 248: 341–342

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Izquierdo M, Adamsbaum C, Benosman A, Aubourg P, BittounJ. MR spectroscopic imaging of normal-appearing white matter in adrenoleukodystrophy. Pediatr Radiol 2000; 30: 621–629 Jorge P, Quelhas D, Oliveira P, Pinto R, Nogueira A. X-Linked adrenoleukodystrophy in patients with idiopathic Addison disease. Eur J Pediatr 1994; 153: 594–597 Kano S, Watanabe M, Kanai M, Koike R, Onodera O, Tsuji S, Okamoto K, Shoji M. A Japanese family with adrenoleukodystrophy with a codon 291 deletion: a clinical, biochemical, pathological, and genetic report. J Neurol Sci 1998; 158: 187–192 Kaplan PW, Tusa RJ, Shankroff J, Heller J, Moser HW. Visual evoked potentials in adrenoleukodystrophy: a trial with glycerol trioleate and Lorenzo oil. Ann Neurol 1993; 34: 169–174 Kemp S,Mooyer PAW,Bolhuis PA,van Geel BM,Mandel JL,Barth PG, Aubourg P,Wanders RJA. ALDP Expression in fibroblasts of patients with X-linked adrenoleukodystrophy. J Inherit Metab Dis 1996; 19: 667–674 Kemp S, Wei H-M, Lu J-F, Braiterman LT, McGuinness MC, Moser AB,Watkins PA,Smith KD.Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy. Nat Med 1998; 4: 1261–1268 Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJA, Moser HW. ABCD1 Mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat 2001; 18: 499–515 Koike R,Tsuji S, Ohno T, Suzuki Y, Orii T, Miyatake T. Physiological significance of fatty acid elongation system in adrenoleukodystrophy. J Neurol Sci 1991; 103: 188–194 Kok F, Neumann S, Sarde C-O, Zheng S,Wu K-H,Wei H-M, Bergin J, Watkins PA, Gould S, Sack G, Moser H, Mandel J-L, Smith KD. Mutational analysis of patients with X-linked adrenoleukodystrophy. Hum Mutat 1995; 6: 104–115 Korenke GC, Christen H-J, Kruse B, Hunneman DH, Hanefeld F. Progression of X-linked adrenoleukodystrophy under interferon-b therapy. J Inherit Metab Dis 1997; 20: 59–66 Kukowski B. Magnetic transcranial brain stimulation and multimodality evoked potentials in an adrenoleukodystrophy patient and members of his family.Electroencephalogr Clin Neurophysiol 1991; 78: 260–262 Kumar AJ, Rosenbaum AE, Naidu S, Wener L, Citrin CM, Lindenberg R, Kim WS, Zinreich SJ, Molliver ME, Mayberg HS, Moser HW. Adrenoleukodystrophy: correlating MR imaging with CT. Radiology 1987; 165: 497–504 Kumar AJ, Köhler W, Kruse B, Naidu S, Bergin A, Edwin D, Moser HW. MR findings in adult-onset adrenoleukodystrophy. AJNR Am J Neuroradiol 1995; 16: 1227–1237 Kurihara M, Kumagai K, Yagishita S, Imai M, Watanabe M, Suzuki Y, Orii T. Adrenoleukomyeloneuropathy presenting as cerebellar ataxia in a young child: a probable variant of adrenoleukodystrophy. Brain Dev 1993; 15: 377–380 Kurihara M, Kumagai K, Noda Y, Yagishita S. An autopsy case of atypical adrenoleukomyeloneuropathy in childhood. Brain Dev 2000; 22: 394–397 Kusaka H, Imai T. Ataxic variant of adrenoleukodystrophy: MRI and CT findings. J Neurol 1992; 239: 307–310 Loes DJ, Hite S, Moser H, Stillman AE, Shapiro E, Lockman L, Latchaw RE, Krivit W. Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 1994; 15: 1761–1766

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938 References and Further Reading Moser HW, Loes DJ, Melhem ER, Raymond GV, Bezman L, Cox CS, Lu S-e. X-linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics 2000; 31: 227–239 Moser HW, Brezman L, Lu SE, Raymond GV.Therapy of X-linked adrenoleukodystrophy: prognosis based upon age and MRI abnormality and plans for placebo-controlled trails. J Inherit Metab Dis 2000; 23: 273–277 Moser HW, Raymond GV, Koehler W, Sokolowski P, Hanefeld F, Korenke GC, Green A, Loes DJ, Hunneman DH, Jones RO, Lu SE,Uziel G,Giros ML,Roels F.Evaluation of the preventive effect of glyceryl trioleate-trierucate (“Lorenzo’s oil”) therapy in X-linked adrenoleukodystrophy: results of two concurrent trials. Adv Exp Med Biol 2003; 544: 369–387 Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993; 361: 726–730 Nishio H, Kodama S,Tsubota T,Takumi T,Takahashi T,Yokoyama S,Matsuo T.Adrenoleukodystrophy without adrenal insufficiency and its magnetic resonance imaging. J Neurol 1985; 232: 265–270 Nowaczyk MJM, Saunders EF, Tein I, Blaser SI, Clarke JTR. Immunoablation does not delay the neurologic progression of X-linked adrenoleukodystrophy. J Pediatr 1997; 131: 453–455 O’Neill BP, Marmion LC, Feringa ER.The adrenoleukomyeloneuropathy complex: expression in four generations. Neurology 1981; 31: 151–156 O’Neill BP,Moser HW,Saxena KM.Familial X-linked Addison disease as an expression of adrenoleukodystrophy (ALD): elevated C26 fatty acid in cultured skin fibroblasts. Neurology 1982; 32: 543–547 O’Neill GN, Aoki M, Brown RH Jr. ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN. Neurology 2001; 57: 1956–1962 Pai GS, Khan M, Barbosa E, Key L, Craver JR, Curé JK, Betros R, Singh I. Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients. Mol Genet Metab 2000; 69: 312–322 Paintlia AS, Gilg AG, Khan M, Singh AK, Barbosa E, Singh I. Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ALD: implications for potential therapies. Neurobiol Dis 2003; 14: 425–439 Pasco A, Kalifa G, Sarrazin JL, Adamsbaum C, Aubourg P. Contribution of MRI to the diagnosis of cerebral lesions of adrenoleukodystrophy. Pediatr Radiol 1991; 21: 161–163 Philips JP, Lockman LA, Shapiro EG, Blazar BR, Loes DJ, Moser HW, Krivit W. CSF findings in adrenoleukodystrophy: correlation between measures of cytokines, IgG production, and disease severity. Pediatr Neurol 1994; 10: 289–294 Poulos A, Gibson R, Sharp P, Beckman K, Grattan-Smith P. Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo’s oil. Ann Neurol 1994; 36: 741–746 Powell H, Tindall R, Schultz P, Paa D, O’Brien J, Lampert P. Adrenoleukodystrophy. Electron microscopic findings. Arch Neurol 1975; 32: 250–260 Powers JM, Moser HG. Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 1998; 8: 101–120

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22 Refsum Disease Baumgartner MR, Jansen GA, Verhoeven NM, Mooyer PAW, Jakobs C, Roels F, Espeel M, Fourmaintraux A, Bellet H, Wanders RJA, Saudubray JM. Atypical Refsum disease with pipecolic academia and abnormal catalase distribution. Ann Neurol 2000; 47: 109–113 Cammermeyer J. Neuropathological changes in hereditary neuropathies: manifestation of the syndrome heredopathia atactica polyneuritiformis in the presence of interstitial hypertrophic polyneuropathy. J Neuropathol Exp Neurol 1956; 15: 340–367 Casteels M, Croes K, van Veldhoven PP, Mannaerts GP. Peroxisomal localization of a-oxidation in human liver. J Inherit Metab Dis 1997; 20: 665–673

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940 References and Further Reading Chahal A, Khan H, Pai SG, Barbosa E, Singh I. Restoration of phytanic acid oxidation in Refsum disease fibroblasts from patients with mutations in the phytanoyl-CoA hydroxylase gene. FEBS Lett 1998; 429: 119–122 Dick JPR, Gibberd FB, Meeran K, Rose CF. Hypokalaemia in acute Refsum’s disease. J R Soc Med 1993; 86: 171–172 Dickson N,Mortimer JG,Faed JM,Pollard AC,Styles M,Peart DA. A child with Refsum’s disease: successful treatment with diet and plasma exchange. Dev Med Child Neurol 1989; 31: 81–97 Djupesland G, Flottorp G, Refsum S. Phytanic acid storage disease: hearing maintained after 15 years of dietary treatment. Neurology 1983; 33: 237–240 Dotti MT, Rossi A, Rizzuto N, Hayek G, Bardelli N, Bardelli AM, Federico A. Atypical phenotype of Refsum’s disease: Clinical, biochemical, neurophysiological and pathological study. Eur Neurol 1985; 24: 85–93 Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Allen JT, McLean BN, Brown AY, Vreken P, Waterham HR, Wanders RJA. Mutations in the gene encoding peroxisomal a-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 2000; 24: 188–191 Flament-Durand J, Noel P, Rutsaert J, Toussaint D, Malmendier C, Lyon G. A case of Refsum’s disease: clinical, pathological, ultrastructural and biochemical study. Pathol Eur 1971; 6: 172–191 Gibberd FB, Billimoria JD, Goldman JM, Clemens ME, Evans R, Whitelaw MN, Retsas S, Sherratt RM. Heredopathia atactica polyneuritiformis: Refsum’s disease. Acta Neurol Scand 1985; 72: 1–17 Gelot A, Vallat JM, Tabaraud F, Rocchiccioli F. Axonal neuropathy and late detection of Refsum’s disease. Muscle Nerve 1995; 18: 667–670 Gordon N, Hudson REB. Refsum’s syndrome heredopathia atactica polyneuritiformis.A report of three cases, including a study of the cardiac pathology. Brain 1959; 82: 41–55 Harari D, Gibberd FB, Dick JPR, Sidey MC. Plasma exchange in the treatment of Refsum’s disease (heredopathia atactica polyneuritiformis). J Neurol Neurosurg Psychiatry 1991; 54: 614–617 Hungerbühler JP, Meier C, Rousselle L, Quadri P, Bogousslavsky J.Refsum’s disease: management by diet and plasmapheresis. Eur Neurol 1985; 24: 153–159 Jansen GA, Ofman R, Ferdinandusse S, Ijlst L, Muijsers AO, Skjeldal OH, Stokke O, Jakobs C, Besley GTN, Wraith JE, Wanders RJA. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet 1997; 17:190–193 Jansen GA, Hogenhout EM, Ferdinandusse S,Waterham HR, Ofman R, Jakobs C, Skjeldal OH, Wanders RJA. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum’s disease. Hum Mol Genet 2000; 9: 1195–1200 Kuntzer T, Ochsner F, Schmid F, Regli F. Quantitative EMG analysis and longitudinal nerve conduction studies in a Refsum’s disease patient. Muscle Nerve 1993; 16: 857–863 Lemotte PK, Keidel S, Apfel CM. Phytanic acid is a retinoid X receptor ligand. Eur J Biochem 1996; 236; 328–333 Leppert D, Schanz U, Burger J, Gmür J, Blau N,Waespe W. Longterm plasma exchange in a case of Refsum’s disease. Eur Arch Psychiatry Clin Neurosci 1991; 241: 82–84 MacBrinn M, O’Brien JS. Lipid composition of the nervous system in Refsum’s disease. J Lipid Res 1968; 9; 552–561 Mihalik SJ, Morrell JC, Kim D, Sacksteder KA, Watkins PA, Gould SJ. Identification of PAHX, a Refsum disease gene. Nat Genet 1997; 17: 185–189

Millar JHD. Refsum disease – the effect of diet. Ulster Med J 1985; 54: 41–45 Nadal N, Rolland MO, Tranchant C, Reutenauer L, Gyapay G, Warter JM, Mandel JL, Koenig M. Localization of Refsum disease with increased pipecolic acidaemia to chromosome 10p by homozygosity mapping and carrier testing in a single nuclear family. Hum Mol Genet 1995; 4: 1963–1966 Oysu C, Aslan I, Basaran B, Baserer N.The site of the hearing loss in Refsum’s disease. Int J Pediatr Otorhinolaryngol 2001; 61: 129–134 Plant GR,Hansell DM,Gibberd FB,Sidey MC.Skeletal abnormalities in Refsum’s disease (heredopathia atactica polyneuritiformis). Br J Radiol 1990; 63: 537–541 Reese H, Bareta J. Heredopathia atactica polyneuritiformis. J Neuropathol Exp Neurol 1950; 9: 385–395 Singh I, Lazo O, Kalipada P, Singh AK. Phytanic acid a-oxidation in human cultured skin fibroblasts. Biochim Biophys Acta 1992; 1180: 221–224 Singh I, Pahan K, Dhaunsi GS, Lazo O, Ozand P. Phytanic acid a-oxidation. J Biol Chem 1993; 268: 9972–9979 Skjeldal OH, Nyberg-Hansen R, Stokke O. Neurological disorders and phytanic acid metabolism. Acta Neurol Scand 1988; 78: 324–328 Tranchant C, Aubourg P, Mohr M, Rocchicciolo F, Zaenker C, Warter JM. A new peroxisomal disease with impaired phytanic acid and pipecolic acid oxidation. Neurology 1993; 43: 2044–2048 Van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR,Wanders RJA. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet 2003; 72: 471–477 Verhoeven NM, Schor DSM, Roe CR, Wanders RJA, Jakobs C. Phytanic acid a-oxidation in peroxisomal disorders: studies in cultured human fibroblasts. Biochim Biophys Acta 1997; 1361: 281–286 Verhoeven NM, Schor DSM, ten Brink HJ, Wanders RJA, Jakobs C. Resolution of the phytanic acid a-oxidation pathway: identification of pristanal as product of the decarboxylation of 2-hydroxyphytanoyl-CoA. Biochem Biophys Res Commun 1997; 237: 33–36 Verhoeven NM, Wanders RJA, Poll-The BT, Saudubray J-M, Jakobs C. The metabolism of phytanic acid and pristanic acid in man: a review. J Inherit Metab Dis 1998; 21: 697–728 Wall WJH, Worthington BS. Skeletal changes in Refsum’s disease. Clin Radiol 1979; 30: 657–659 Wanders RJA, Heymans HSA, Schutgens RBH, Poll-Thé BT, Saudubray JM, Tager JM, Schrakamp G, van den Bosch H. Peroxisomal functions in classical Refsum’s disease: comparison with the infantile form of Refsum’s disease. J Neurol Sci 1988; 84: 147–155 Wanders RJA, Jansen GA, Skjeldal OH. Refsum disease, peroxisomes and phytanic acid oxidation: a review. J Neuropathol Exp Neurol 2001; 60: 1021–1031 Weinstein R. Phytanic acid storage disease: (Refsum’s disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. J Clin Apheresis 1999; 14: 181–184 Wierzbicki AS, Mitchell J, Lambert-Hammill M, Hancock M, Greenwood J, Sidney MC, de Belleroche J, Gibberd FB. Identification of genetic heterogeneity in Refsum’s disease. Eur J Hum Genet 2000; 8: 649–651 Wierzbicki AS, Sankaralingam A, Lumb PJ, Hardman TC, Sidey MC, Gibberd FB. Transport of phytanic acid on lipoproteins in Refsum disease. J Inherit Metab Dis 1999; 22: 29–36

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Wierzbicki AS, Lloyd MD, Schofield CJ, Feher MD, Gibberd FB. Refsum’s disease: a peroxisomal disorder affecting phytanic acid a-oxidation. J Neurochem 2002; 80: 727–735 Wills AJ, Manning NJ, Reilly MM. Refsum’s disease. Q J Med 2001; 94:403–406 Young SP, Johnson AW, Muller DPR. Effects of phytanic acid on the vitamin E status,lipid composition and physical properties of retinal cell membranes: implications for adult Refsum disease. Clin Sci 2001; 101: 697–705

23 Mitochondria and Mitochondrial Disorders Andreu AL, Bruno C, Dunne TC, Tanji K, Shanske S, Sue CM, Krishna S, Hadjigeorgiou GM, Shtilbans A, Bonilla E, DiMauro S. A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria. Ann Neurol 1999; 45: 127–130 Andreu AL, Tanji K, Bruno C, Hadjigeorgiou GM, Sue CM, Jay C, Ohnishi T, Shanske S, Bonilla E, DiMauro S. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999; 45: 820–823 Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69: 49–54 Benz R. Biophysical properties of porin pores from mitochondrial outer membrane of eukaryotic cells. Experientia 1990; 46: 131–137 Bosbach S, Kornblum C, Schroder R, Wagner M. Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. Brain 2003; 126: 1231–1240 Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995; 11: 144–149 Brown MD,Voljavec AS, Lott MT,Torroni A,Yang CC,Wallace DC. Mitochondrial DNA complex I and III mutations associated with Leber’s hereditary optic neuropathy. Genetics 1992; 130: 163–73 Bruno C, Martinuzzi A, Tang Y, Andreu AL, Pallotti F, Bonilla E, Shanske S, Fu J, Sue CM, Angelini C, DiMauro S, Manfredi G. A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the functional structure of complex IV. Am J Hum Genet 1999; 65: 611–620 Bruno C, Sacco O, Santorelli FM, Assereto S, Tonoli E, Bado M, Rossi GA, Minetti C. Mitochondrial myopathy and respiratory failure associated with a new mutation in the mitochondrial transfer ribonucleic acid glutamic acid gene. J Child Neurol 2003; 18: 300–303 Cheng MY,Hartl FU,Martin J,Pollock RA,Kalousek F,Neupert W, Hallberg EM, Hallberg RL, Horwich AL. Mitochondrial heatshock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. Nature 1989; 337: 620–625 Chol M, Lebon S, Benit P, Chretien D, de Lonlay P, Goldenberg A, Odent S, Hertz-Pannier L, Vincent-Delorme C, CormierDaire V, Rustin P, Rotig A, Munnich A. The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet 2003; 40: 188–191

Coates PM, Tanaka K. Molecular basis of mitochondrial fatty acid oxidation defects. J Lipid Res 1992; 33: 1099–1110 Cuezva JM, Flores AI, Liras A, Santaren JF, Alconada A. Molecular chaperones and the biogenesis of mitochondria and peroxisomes. Biol Cell 1993; 77: 47–62 De Lonlay P, Valnot I, Barrientos A, Gorbatyuk M, Tzagoloff A, Taanman JW,Benayoun E,Chretien D,Kadhom N,Lombes A, de Baulny HO, Niaudet P, Munnich A, Rustin P, Rotig A. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.Nat Genet 2001; 29: 57–60 DeVivo DC. The expanding clinical spectrum of mitochondrial disorders. Brain Dev 1993; 15: 1–22 De Vries DD, Ruitenbeek W, de Wijs IJ, Trijbels JM, van Oost BA. Enzymological versus DNA investigations in mitochondrial (encephalo-myopathies).J Inherit Metab Dis 1993;16:534–536 DiMauro S, Moraes CT. Mitochondrial encephalomyopathies. Arch Neurol 1993; 50: 1197–1208 DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348: 2656–2668 Glick B, Schatz G. Import of proteins into mitochondria. Annu Rev Genet 1991; 25: 21–44 Harding AE, Hammans SR. Deletions of the mitochondrial genome. J Inherit Metab Dis 1992; 15: 480–486 Heuvel L, Smeitink JAM. The oxidative phosphorylation (OXPHOS) system: nuclear genes and human genetic diseases. Bioessays 2001; 23: 518–525 Hsieh RH, Li JY, Pang CY, Wei YH. A novel mutation in the mitochondrial 16S rRNA gene in a patient with MELAS syndrome, diabetes mellitus, hyperthyroidism and cardiomyopathy. J Biomed Sci 2001; 8: 328–335 Loeffen JL, Smeitink JAM, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat 2000; 15: 123–134 Poulton J. Duplications of mitochondrial DNA: implications for pathogenesis. J Inherit Metab Dis 1992; 15: 487–498 Rahman S,Taanman JW, Cooper JM, Nelson I, Hargreaves I, Meunier B, Hanna MG, Garcia JJ, Capaldi RA, Lake BD, Leonard JV, Schapira AH. A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy. Am J Hum Genet 1999; 65: 1030–1039 Rosenberg MJ, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard MS, Koch T, Kalikin LM, Makalowska I, Morton DH, Petty EM, Weber JL, Palmieri F, Kelley RI, Schaffer AA, Biesecker LG. Mutant deoxynucleotide carrier is associated with congenital microcephaly.Nat Genet 2002; 32: 175–179 Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 2001; 29: 342–344 Scholte HR, Busch HF, Luyt-Houwen IE, Vaandrager-Verduin MH, Przyrembel H, Arts WF. Defects in oxidative phosphorylation. Biochemical investigations in skeletal muscle and expression of the lesion in other cells. J Inherit Metab Dis 1987; 10: 81–97 Shoubridge EA. Cytochrome c oxidase deficiency. Am J Med Genet 2001; 106: 46–52 Simon DK, Friedman J, Breakefield XO, Jankovic J, Brin MF, Provias J, Bressman SB, Charness ME, Tarsy D, Johns DR, Tarnopolsky MA. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Neurogenetics 2003; 4: 199–205 Smeitink JA. Mitochondrial disorders: clinical presentation and diagnostic dilemmas. J Inherit Metab Dis 2003; 26: 199–207 Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2001; 2: 342–352

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942 References and Further Reading Smeitink JAM, van den Heuvel LWPJ, Koopman WJH, Nijtmans LGJ, Ugalde C,Willems PHGM. Cell biological consequences of NADH: Ubiqunone oxidoreductase Deficiency. Curr Neurovasc Res 2004; 1:29–40 Stadhouders AM, Sengers RCA. Morphological observations in skeletal muscle from patients with a mitochondrial myopathy. J Inherit Metab Dis 1987; 10: 62–80 Suomalainen A, Kaukonen J. Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet 2001; 106: 53–61 Taylor RW, Morris AA, Hutchinson M, Turnbull DM. Leigh disease associated with a novel mitochondrial DNA ND5 mutation. Eur J Hum Genet 2002; 10: 141–144 Tiranti V, Corona P, Greco M,Taanman JW, Carrara F, Lamantea E, Nijtmans L, Uziel G, Zeviani M. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum Mol Genet 2000; 9: 2733–2742 Tulinius MH, Holme E, Kristiansson B, Larsson NG, Oldfors A. Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations. J Pediatr 1991; 119: 242–250 Tulinius MH, Holme E, Kristiansson B, Larsson NG, Oldfors A. Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes. J Pediatr 1991; 119: 251– 259 Tulinius M, Moslemi AR, Darin N, Westerberg B, Wiklund LM, Holme E, Oldfors A. Leigh Syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNATrp gene. Neuropediatrics 2003; 34: 87–91 Visapaa I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS,Makarow M,Van Coster R,Taylor RW,Turnbull DM, Suomalainen A, Peltonen L. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 2002; 71: 863–876 Vives-Bauza C, Del Toro M, Solano A, Montoya J, Andreu AL, Roig M. Genotype-phenotype correlation in the 5703G>A mutation in the tRNA (ASN) gene of mitochondrial DNA. J Inherit Metab Dis 2003;26:507–508 Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 1992; 256: 628–632 Wallace DC,Lott MT,Shoffner JM,Brown MD.Diseases resulting from mitochondrial DNA point mutations. J Inherit Metab Dis 1992; 15: 472–479 Zeviani M, DiDonato S. Neurological disorders due to mutations of the mitochondrial genome. Neuromusc Disord 1991; 1: 165–172 Zeviani M, Spinazzola A, Carelli V. Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 2003; 13: 262–270

24 Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes Abe K, Fujimura H, Nishikawa Y, Yorifuji S, Mezaki T, Hirono N, Nishitani N, Kameyama M. Marked reduction in CSF lactate and pyruvate levels after CoQ therapy in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Acta Neurol Scand 1991; 83: 356–359 Allard JC, Tilak S, Carter AP. CT and MR of MELAS syndrome. AJNR Am J Neuroradiol 1988; 9: 1234–1238

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Dubeau F, De Stefano N, Zifkin BG, Arnold DL, Shoubridge EA. Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree. Ann Neurol 2000; 47: 179–185 Fang W, Huang C-C, Lee C-C, Cheng S-Y, Pang C-Y,Wei Y-H. Ophthalmologic manifestations in MELAS syndrome. Arch Neurol 1993; 50: 977–980 Förster Ch, Hübner G, Müller-Höcker J, Pongratz D, Baierl P, Senger R, Ruitenbeek W. Mitochondrial angiopathy in a family with MELAS. Neuropediatrics 1992; 23: 165–168 Fujii T, Okuno T, Ito M, Motoh K, Hamazaki S, Okada S, Kusaka H, Mikawa H. CT, MRI, and autopsy findings in brain of a patient with MELAS. Pediatr Neurol 1990; 6: 253–256 Goto Y-I, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990; 348: 651–653 Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M, Nonaka I. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology 1992; 42: 545–550 Hamazaki S, Okada S, Kusaka H, Fujii T, Okuno T, Kashu I, Midorikawa O. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Acta Pathol Jpn 1989; 39: 599–606 Hammans SR, Sweeney MG, Hanna MG, Brockington M, Morgan-Hughes JA, Marding AE.The mitochondrial DNA transfer RNALeu(UUR) AÆG(3243) mutation. A clinical and genetic study. Brain 1995; 118: 721–734 Hanna MG, Nelson IP, Morgan-Hughes JA, Wood NW. MELAS: a new disease associated mitochondrial DNA mutation and evidence for further genetic heterogeneity.J Neurol Neurosurg Psychiatry 1998; 65: 512–517 Hirano M, Ricci E, Koenigsberger R, Defendini R, Pavlakis ST, DeVivo DC, DiMauro S, Rowland LP. MELAS: an original case and clinical criteria for diagnosis. Neuromusc Disord 1992; 2: 125–135 Hirano M, Pavlakis SG. Mitochrondial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol 1994; 9: 4–13 Ihara Y, Namba R, Kuroda S, Sato T, Shirabe T. Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone. J Neurol Sci 1989; 90: 263–271 Iizuka T, Sakai F, Suzuki N, Hata T,Tsukahara S, Fukuda M,Takiyama Y. Neuronal hyperexcitabilty in stroke-like episodes of MELAS syndrome. Neurology 2002; 59: 816–824 Iizuka T, Sakai F, Kan S, Suzuki N. Slowly progressive spread of the stroke-like lesion in MELAS. Neurology 2003; 61: 1238–1244 Inui K, Fukushima H, Tsukamoto H, Taniike M, Midorikawa M, Tanaka J, Nishigaki T, Okada S. Mitochondrial encephalomyopathies with the mutation of the mitochondrial tRNALeu(UUR) gene. J Pediatr 1992; 120: 62–66 Johns DR, Stein AG, Wityk R. MELAS syndrome masquerading as herpes simplex encephalitis. Neurology 1993; 43: 2471–2473 Joko T, Iwashige K, Hashimoto T, Ono Y, Kobayashi K, Sekiguchi N, Kuroki T, Yanasa R, Takayanagi R, Umeda F, Nawata H. A case of mitochondrial encephalopathy, lactic acidosis and stoke-like episodes associated with Diabetes Mellitus and hypothalamo-pituitary dysfunction. Endocr J 1997; 44: 805–809 Kärppä M, Syrjälä P,Tolonen U, Majamaa K. Peripheral neuropathy in patients with the 3243A>G mutation in mitochondrial DNA. J Neurol 2003; 250: 216–221

Kamada K, Takeuchi F, Houkin K, Kitagawa M, Kuriki S, Ogata A, Tashiro K, Koyanagi I, Mitsumori K, Iwasaki Y. Reversible brain dysfunction in MELAS: MEG and 1H MRS analysis. J Neurol Neurosurg Psychiatry 2001; 70: 675–678 Kato T, Murashita J, Shiori T, Terada M, Inubushi T, Kato N. Photic stimulation-induced alteration of brain energy metabolism measured by 31P-MR spectroscopy in patients with MELAS. J Neurol Sci 1998; 155: 182–185 Kim H-S, Kim D-I, Lee B-I, Lee B-I, Jeong E-K, Choi C, Lee JD,Yoon P-H, Kim E-J, Yoon YK. Diffusion-weighted image and MR spectroscopic analysis of a case of MELAS with repeated attacks.Yonsei Med J 2001; 42: 128–133 Kim I-O, Kim JY, Kim WS, Hwang WS, Yeon KM, Han MC. Mitochondrial myopathy-encephalopathy-lactic acidosis-and strokelike episodes (MELAS) syndrome: CT and MRI findings in seven children. AJR Am J Roentgenol 1996; 166: 641–645 Kimata KG, Goran L, Ajax ET, Davis PH, Grabowski T. A case of late-onset MELAS. Arch Neurol 1998; 55: 722–725 Kimura M, Hasegawa Y,Yasuda K, Sejima H, Inoue M,Yamaguchi S, Ando Y, Ohno S. Magnetic resonance imaging with fluidattenuated inversion recovery pulse sequences in MELAS syndrome. Pediatr Radiol 1997; 27: 153–154 Koga Y, Ishibashi M, Ueki I, Yatsuga S, Fukiyama R, Akita Y, Matsuishi T. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology 2002; 58: 827–828 Kolb SJ, Costello F, Lee AG, White M, Wong S, Schwartz ED, Messé SR, Ellenbogen J, Kasner SE, Galetta SL. Distinguishing ischemic stroke from the stroke-like lesions of MELAS using apparent diffusion coefficient mapping. J Neurol Sci 2003; 216: 11–15 Koo B, Becker LE, Chuang S, Merante F, Robinson BH, MacGregor D, Tein I, Ho VB, McGreal DA, Wherrett JR, Logan WJ. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations. Ann Neurol 1993; 34: 25–32 Kuriyama M, Umezaki H, Fukuda Y, Osame M, Koike K,Tateishi J, Igata A. Mitochondrial encephalomyopathy with lactatepyruvate elevation and brain infarctions. Neurology 1984; 34: 72–77 Kaufmann P, Koga Y, Shanske S, Hirano M, DiMauro S, King MP, Shon EA. Mitochondrial DNA and RNA processing in MELAS. Ann Neurol 1996; 40: 172–180 Lee M-L. Chaou W-T, Yang AD, Jong Y-J, Tsai J-L, Pang C-Y, Wei Y-H. Mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS); report of a sporadic case and review of the literature. Acta Paediatr Sin 1994; 35: 148–156 Lertrit P, Noer AS, Jean-Francois MJB, Kapsa R, Dennett X, Thyagarajan D, Lethlean K, Byrne E, Marzuki S. A new disease-related mutation for mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I. Am J Hum Genet 1992; 51: 457–468 Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol 2003; 53:128–132 Mariotti C, Saverese N, Soulalainen A, Rimoldi M, Comi G, Prelle A,Antozzi C,Servidei S,Jarre L,DiDonato S,Zeviani M.Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3224G mutation of mitochondrial DNA. J Neurol 1995; 242; 304–312

943

944 References and Further Reading Matsuzaki M, Izumi T, Shishikura K, Suzuki H, Hirayama Y. Hypothalamic growth hormone deficiency and supplementary GH therapy in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like-episodes. Neuropediatrics 2002; 33: 271–273 Matthews PM, Tampieri D, Berkovic SF, Andermann F, Silver K, Chityat D, Arnold DL. Magnetic resonance imaging shows specific abnormalities in the MELAS syndrome. Neurology 1991; 41: 1043–1046 Miyamoto A. Oki J, Takahashi S, Itoh J, Kusunoki Y, Cho K. Serial imaging in MELAS. Neuroradiology 1997; 39: 427–430 Möller HE, Wiedermann D, Kurlemann G, Hilbich T, Schuierer G. Application of NMR spectroscopy to monitoring MELAS treatment: a case report. Muscle Nerve 2002; 25: 593–600 Mongini T, Doriguzzi C, Chaiaò-Piat L, Silvestri G, Servidei S, Palmucchi L. MERFF/MELAS overlap syndrome in a family with A3243G mtDNA mutation. Clin Neuropathol 2002; 21: 72–76 Mori O, Yamazaki M, Ohaki Y, Arai Y, Oguro T, Shimizu H, Asano G. Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) with prominent degeneration of the intestinal wall and cactus-like cerebellar atrophy. Acta Neuropathol (Berl) 2000; 100: 712–717 Mosewich RK, Donat JR, DiMauro S, Ciafaloni E, Shanske S, Erasmus M, George D. The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke. Arch Neurol 1993; 50: 275–278 Nariai T, Ohno K, Ohta Y, Hirakawa K, Ishii K, Senda M. Discordance between cerebral oxygen and glucose metabolism, and hemodynamics in a mitochondrial encephalomyopathy, lactic acidosis, and strokelike episode patient. J Neuroimaging 2001; 11: 325–329 Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol (Berl) 1987; 74: 226–233 Ohshita T, Oka M, Imon Y, Wanatabe C, Katayama S, Yamaguchi S,Kajima T,Momori Y,Nakamura S.Neuroradiology 2000; 42: 651–656 Ooiwa Y, Uematsu Y, Terada T, Nakai K, Itakura T, Komai N, Moriwaki H.Cerebral blood flow in mitochondrial myopathy,encephalopathy, lactic acidosis, and strokelike episodes. Stroke 1993; 24: 304–309 Oppenheim C, Galanaud D, Samson Y, Sahel M, Dormont D, Wechsler B, Marsault C. Can diffusion weighted magnetic resonance imaging help differentiate stroke from strokelike events in MELAS? J Neurol Neurosurg Psychiatry 2000; 69: 248–250 Park H, Davidson E, King MP.The pathogenic A3243G mutation in human mitochondrial tRNALeu(UUR) decreases the efficiency of aminoacylation. Biochemistry 2003; 42: 958–964 Pavlakis SG, Phillips PC, DiMauro S, de Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984; 16: 481–488 Penn AMW,Lee JWK,Thuillier P,Wagner M,Maclure KM,Menard MR, Hall LD, Kennaway NG. MELAS syndrome with mitochondrial tRNA Leu(UUR) mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 1992; 42: 2147–2152 Pulkes T, Eunson L, Patterson V, Siddiqui A,Wood NW, Nelson IP, Morgan-Hughes JA, Hanna MG. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/ MELAS overlap syndrome and may be a frequent cause of MELAS. Ann Neurol 1999; 46: 916–919

Ravn K,Wibrand F,Hansen FJ,Horn N,Rosenberg T,Schwartz M. An mtDNA muation, 1445GA, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Eur J Hum Genet 2001; 9: 805–809 Rosen L, Philips S, Enzmann D. Magnetic resonance imaging in MELAS syndrome. Neuroradiology 1990; 32: 168–171 Sakuta R, Nonaka I. Vascular involvement in mitochondrial myopathy. Ann Neurol 1989; 25: 594–601 Sakuta R, Honzawa S, Murakami N, Goto Y, Nagai T. Atypical MELAS associated with mitochondrial tRNAlys gene A8296G mutation. Pediatr Neurol 2002; 27: 397–400 Satoh M, Ishikawa N, Yoshizawa T, Takeda T, Akisada M. N-Isopropyl-p-[123I]-iodoamphetamine SPECT in MELAS syndrome: comparison with CT and MR imaging. J Comput Assist Tomogr 1991; 15: 77–82 Serra G, Piccinnu R, Tondi M, Muntoni F, Zeviani M, Mastropaolo C.Clinical and EEG findings in eleven patients affected by mitochondrial encephalomyopathy with severe MERFF– MELAS overlap. Brain Dev 1996; 18: 185–191 Seyama K, Suzuki K, Mizuno Y, Yoshida M, Tanaka M, Ozawa T. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with special reference to the mechanism of cerebral manifestations. Acta Neurol Scand 1989; 80: 561–568 Shoji Y, Sato W, Hayasaka K,Takada G.Tissue distribution of mutant mitochondrial DNA in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). J Inherit Metab Dis 1993; 16: 27–30 Sparaco M, Simonati A, Cavellaro T, Bartelomei L, Grauso M, Piscioli F, Morelli L, Rizzuto N. MELAS: clinical phenotype and morphological brain abnormalities. Acta Neuropathol (Berl) 2003; 106: 202–121 Sue CM, Crimmins DS, Soo YS, Pamphlett R, Presgrave CM, Kotsimbos N, Jean-Fransois MJB, Morris JGL. Neuroradiological features of six kindreds with MELAS tRNALeu A3243G point mutation: implications for pathogenesis. J Neurol Neurosurg Psychiatry 1988; 65: 233–240 Suzuki T, Koizumi J, Shiraishi H, Ishikawa N, Ofuku K, Sasaki M, Hori T, Ohkoshi N, Anno I. Mitochondrial encephalomyopathy (MELAS) with mental disorder CT, MRI and SPECT findings. Neuroradiology 1990; 32: 74–76 Takahashi S, Tohgi H, Yonezawa H, Obara S, Nagane Y. Cerebral blood flow and oxygen metabolism before and after stroke-like episode in patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). J Neurol Sci 1998; 158: 58–64 Tanahashi C, Nakayama A, Yoshida M, Ito M, Mori M, Mori N, Hashizume Y. MELAS with mitochondial DNA 3243 point mutation: a neuropathological study. Acta Neuropathol (Berl) 2000; 99: 31–38 Tanji K, Gamez J, Cervera C, Mearin F, Ortega A, de la Torre J, Montoya J, Andreu AL, DiMauro S, Bonilla E. The A8344G mutation in mitochondrial DNA associated with stroke-like episodes and gastro-intestinal dysfunction. Acta Neuropathol (Berl) 2003; 105: 69–75 Taylor RW, Chinnery PF, Haldane F, Morris AAM, Bindoff FF, Wilson J,Turnbull DM. MELAS associated with a transfer RNA in the valine transfer RNA gene of mitochondrial DNA. Ann Neurol 1996; 40: 459–462 Terauchi A, Tamagawa K, Morimatsu Y, Kobayashi M, Sano T, Yoda S. An autopsy like case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) with a point mutation of mitochondrial DNA. Brain Dev 1996; 18: 224–229

References and Further Reading

Tokunaga M, Mita S, Murakami T, Kumamoto T, Uchino M, Nonaka I, Ando M. Single muscle fiber analysis of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Ann Neurol 1994; 35: 413–419 Tsuchiya K, Miyazaki H, Akebane H, Yamamoto M, Kondo H, Mizusawa H, Ideka K. MELAS with prominent white matter gliosis and atrophy of the cerebellar granular layer: a clinical, genetic, and pathological study. Acta Neuropathol (Berl) 1999; 97: 520–524 Valenne L, Peatau A, Soumalainen A, Ketonen L, Pihko H. Laminar cortical necrosis in MELAS syndrome: MR and neuropathological observations. Neuropediatrics 1996; 27: 154–160 Van Hellenberg Hubar JLM, Gabreëls FJM, Ruitenbeek W, Sengers RCA, Renier WO,Thijssen HOM, ter Laak HJ. MELAS syndrome. Report of two patients, and comparison with data of 24 patients derived from the literature. Neuropediatrics 1991; 22: 10–14 Wang XY, Noguchi K, Takashima S, Hayashi N, Ogawa S, Seto H. Serial diffusion-weighted imaging in a patient with MELAS and presumed cytotoxic oedema.Neuroradiology 2003; 45: 640–643 Yanagihara C, Oyama A,Tanaka M, Nakaji K, Nishimura Y. An autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with chronic renal failure. Intern Med 2001; 40: 662–665 Yoneda M, Maeda M, Kimura H, Fujii A, Katayama K, Kuriyama M. Vasogenic edema on MELAS: a serial study with diffusion-weighted MR imaging. Neurology 1999; 53: 2182– 2184 Yonemura K, Hasegawa Y, Kimura K, Minematsu K,Yamaguchi T. Diffusion-weighted MR imaging in a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. AJNR Am J Neuroradiol 2001; 22: 269–272

25 Leber Hereditary Optic Neuropathy Barbiroli B, Montagna P, Cortelli P, Lotti S, Lodi R, Barboni P, Monari L, Lugaresi E, Frassineti C, Zaniol P. Defective brain and muscle energy metabolism shown by in vivo 31P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation. Neurology 1995; 45: 1364–1369 Batiog˘lu F, Atilla H, Eryilmaz T. Chiasmal high signal on magnetic resonance imaging in the atrophic phase of Leber hereditary optic neuropathy. J Neuroophthalmol 2003; 23: 28–30 Bet L,Moggio M,Comi GP,Mariani C,Prelle A,Checcarelli N,Bordoni A,Bresolin,Scarpini E,Scarlato G.Multiple sclerosis and mitochondrial myopathy: an unusual combination of diseases. J Neurol 1994; 241: 511–516 Brown MD, Voljavec AS, Lott MT, MacDonald I, Wallace DC. Leber’s hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB J 1992; 6: 2791–2799 Brown MD, Allan JC, van Stavern GP, Newman NJ, Wallace DC. Clinical, genetic, and biochemical characterization of a Leber hereditairy optic neuropathy family containing both the 11778 and 11484 primary mutations. Am J Med Genet 2001; 104: 331–338 Bruyn GW,Vielvoye GJ,Went LN. Hereditairy spastic dystonia: a new mitochondrial encephalopathy? Putaminal necrosis as a diagnostic sign. J Neurol Sci 1991; 103: 195–202

Bu X, Rotter JI. X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: evidence from segregation analysis for dependence on X chromosome inactivation. Proc Natl Acad Sci USA 1991; 88: 8198–8202 Buhmann C, Ghadamosi J, Heesen C. Visual recovery in a man with the rare combination of mtDNA 11778m LHON mutation and a MS-like disease after mitoxantrone therapy. Acta Neurol Scand 2002; 106: 236–239 Chalmers RM, Harding AE. A case-control study of Leber’s hereditary optic neuropathy. Brain 1996; 119: 1481–1486 Cornelissen JC, Wanders RJA, Bolhuis PA, Bleeker-Wagemakers E, Oostra RJ, Wijburg FA. Respiratory chain function in Leber’s hereditary optic neuropathy: lack of correlation with clinical disease. J Inherit Metab Dis 1993; 16: 531–533 Cortelli P, Montagna P, Avoni P, Sangiorgi S, Bresolin N, Moggio M, Zaniol P, Mantovani V, Barboni P, Barbiroli B, Lugaresi E. Leber’s hereditary optic neuropathy: genetic, biochemical, and phosphorus magnetic resonance spectroscopy study in an Italian family. Neurology 1991; 41: 1211–1215 De Vries DD,Went LN, Bruyn GW, Scholte HR, Hofstra RMW, Bolhuis PA, van Oost BA. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet 1996; 58: 703–711 Dotti MT, Caputo N, Signorini E, Federico A. Magnetic resonance imaging findings in Leber’s hereditary optic neuropathy. Eur Neurol 1992; 32: 17–19 Fauser S, Leo-Kottler B, Besch D, Luberichs J. Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber’s hereditary optic neuropathy. Ophthalmic Genet 2002; 23: 191–197 Flanigan KM, Johns DR. Association of the 11778 mitochondrial DNA mutation an dymyelinating disease. Neurology 1993; 43: 2720–2722 Funakawa I, Kato H, Terao A Ichihashi K, Kawashima S, Hayashi T, Mitani K, Miyazaki S. Cerebellar ataxia in patients with Leber’s hereditary optic neuropathy. J Neurol 1995; 242: 75–77 Funalot B, Reynier P, Vighetto A, Ranoux D, Bonnefont J-P, Godinot C, Malthièry Y, Mas J-L. Leigh-like encephalopathy complicating Leber’s hereditary optic neuropathy. Ann Neurol 2002; 52: 374–377 Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol 2002; 52: 534–542 Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DAS. Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992; 115: 979–989 Horváth R, Abicht A, Shoubridge EA, Karcagi V, Rózsa C, Komoly S, Lochmüller H. Leber’s hereditary optic neuropathy presenting as multiple sclerosis-like disease of the CNS. J Neurol 2000; 247: 65–67 Huoponen K. Leber hereditary optic neuropathy: clinical and molecular genetic findings. Neurogenetics 2001; 3: 119– 125 Inglese M, Rovaris M, Bianchi S, La Mantia L, Mancardi GL, Ghezzi A, Montagna P, Salvi F, Filippi M. Magnetic resonance imaging, magnetisation transfer imaging, and diffusion weighted imaging correlates of optic nerve, brain, and cervical cord damage in Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 2001; 70: 444–449

945

946 References and Further Reading Jansen PHP, van der Knaap MS, de Coo IFM. Leber’s hereditary optic neuropathy with the 11778 mtDNA mutation and white matter disease resembling multiple sclerosis: clinical, MRI and MRS findings. J Neurol Sci 1996; 135: 176–180 Kellar-Wood H, Robertson N, Govan GG, Compston DAS, Harding AE. Leber’s hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol 1994; 36: 109–112 Kermode AG, Moseley IF, Kendall BE, Miller DH, MacManus DG, McDonald WI.Magnetic resonance imaging in Leber’s optic neuropathy. J Neurol Neurosurg Psychiatry 1989; 52: 671–674 Kim JY, Hwang J-M, Park SS. Mitochondrial DNA C4171A/ND1 is a novel primary mutation of Leber’s hereditary optic neuropathy with a good prognosis. Ann Neurol 2002; 51: 630–634 Larsson NG. Leber hereditary optic neuropathy: a nuclear solution of a mitochondrial problem. Ann Neurol 2002; 52: 529–530 Larsson NG, Andersen O, Holme E, Oldfors A, Wahlström J. Leber’s hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 1991; 30: 701–708 Leo-Kottler B, Luberichs J, Besch D, Christ-Adler M, Fauser S. Leber’s hereditary optic neuropathy: clinical and molecular genetic results in a patient with a point mutation at np T11253C (isoleucine to threotine) in the ND4 gene and spontaneous recovery. Graefes Arch Clin Exp Ophthalmol 2002; 240: 758–764 Leuzzi V, Bertini E, de Negri AM, Gallucci M, Garavaglia B. Bilateral striatal necrosis, dystonia and optic atrophy in two siblings. J Neurol Neurosurg Psychiatry 1992; 55: 16–19 Lev D, Yanoov-Sharav M, Watemberg N, Leshinksky-Silver E, Lerman-Sagie T. White matter abnormalities in Leber’s hereditary optic neuropathy due to the 3460 mitochondrial DNA mutation. Eur J Paediatr Neurol 2002; 6: 121–123 Lodi R, Carelli V, Cortelli P, Lotti S,Valentino ML, Barboni P, Pallotti F, Montagna P, Barbiroli B. Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 2002; 72: 805–807 Luberichs J, Leo-Kottler B, Besch D, Fauser S. A mutation hot spot in the mitochondrial ND6 gene in patients with Leber’s hereditary optic neuropathy. Graefes Arch Clin Exp Ophthalmol 2002; 240: 96–100 Man PYW, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet 2002; 39: 162–169 Man PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 2003; 72: 333–339 Marsden CD, Lang AE, Quinn NP, McDonald WI, Abdallat A, Nimri S. Familial dystonia and visual failure with stiatal CT lucencies. J Neurol Neurosurg Psychiatry 1986; 49: 500–509 Newman NJ. Leber’s hereditary optic neuropathy. Arch Neurol 1993; 50: 540–548 Newman NJ, Lott MT,Wallace DC.The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. J Ophthalmol 1991; 111: 750–762 Newman –Toker DE, Horton JC, Lessell S. Recurrent visual loss in Leber hereditary optic neuropathy. Arch Ophthalmol 2003; 121: 288–291

Nikoskelainen EK, Marttilla RJ, Huoponen K, Juvonen V, Lamminen T, Sonninen P. Savontaus M-L. Leber’s “plus”: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1995; 59: 160–164 Novotny EJ, Sing G, Wallace DC, Dorfman LJ, Louis A, Sogg RL, Steinman L. Leber’s disease and dystonia: a mitochondrial disease. Neurology 1986; 36:1053–1060 Parker WD Jr, Oley CA, Parks JK. A defect in mitochondrial electron-transport activity (NADH-coenzyme Q oxidoreductase) in Leber’s hereditary optic neuropathy. N Engl J Med 1989; 320: 1331–1333 Paulus W, Straube A, Bauer W, Harding AE. Central nervous system involvement in Leber’s optic neuropathy. J Neurol 1993; 240: 251–253 Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, da Costa J, Harding AE.The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995; 118: 319–337 Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros P, Sadun F, de Negri A-M, Andrade R, Schien S, Belfort R. A very large Brazilian pedigree with 11778 Leber’s hereditary optic neuropathy.Trans Am Ophthalmol Soc 2002; 100: 169–179 Shoffner JM, Brown MD, Stugard C, Jun AS, Pollock S, Haas RH, Kaufman A, Koontz D, Kim Y, Graham JR, Smith E, Dixon J, Wallace DC. Leber’s hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol 1995; 38: 163–169 Sudoyo H, Suryadi H, Lertrit P, Pramoonjage P, Lyrawati D, Marzuki S. Asian-specific mtDNA backgrounds associated with the primary G11778A mutation of Leber’s hereditary optic neuropathy. J Hum Genet 2002; 47: 594–604 Valentino ML, Avoni P, Barboni P, Pallotti F, Rengo Ch,Torroni A, Bellan M, Baruzzi A, Garrelli V. Mitochondrial DNA nucleotide changes C14482G and C14482A in the ND6 gene are pathogenic for Leber’s hereditary optic neuropathy. Ann Neurol 2002; 51: 774–778 Vanopdenbosch L, Dubois B, D’Hooge M-B, Meire F, Carton H. Mitochondrial mutations of Leber’s hereditary optic neuropathy: a risk factor for multiple sclerosis. J Neurol 2002; 247: 535–543 Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AMS, Elsas LJ, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242: 1427–1430 Weiner NC, Newman NJ, Lessell S, Johns DR, Lott MT, Wallace DC. Atypical Leber’s hereditary optic neuropathy with molecular confirmation. Arch Neurol 1993; 50: 470–473

26 Kearns Sayre syndrome Artuch R, Pavia C, Playán A, Vilaseca MA, Colomer J, Valls C, Rissech M, González MA, Pou A, Briones P,Montoya J, Pineda M. Multiple endocrine involvement in two pediatric patients with Kearns-Sayre syndrome. Horm Res 1998; 50: 99–104 Ashizawa T, Subramony SH. What is Kearns-Sayre syndrome after all? Arch Neurol 2001; 58: 1053–1054 Barthélémy C, Ogier de Baulny H, Diaz J, Cheval MA, Franchon P, Romero N, Goutières F, Fardeau M, Lombès A. Late-onset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation.Ann Neurol 2001; 49: 607–617

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Becher MW, Wills ML, Noll WW, Hurko O, Price DL. Kearns-Sayre syndrome with features of Pearson’s marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA deletion. Hum Pathol 1999; 30: 577–581 Boles RG, Roe T, Sanadheera D, Mahnovski V, Wong LJC. Mitochondrial DNA deletion with Kearns Sayre syndrome. Eur J Pediatr 1998; 157: 643–647 Brockington M, Alsanjari N, Sweeney MG, Morgan-Hughes JA, Scaravilli F, Harding AE. Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study. J Neurol Sci 1995; 131: 78–87 Chu BC, Terae S, Takahasi C, Kikuchi Y, Miyasaka K, Abe S, Minowa K, Sawamura T. MRI of the brain in the Kearns-Sayre syndrome: report of four cases and a review. Neuroradiology 1999; 41: 759–764 Coultier DL, Allen RJ. Abrupt neurological deterioration in children with Kearns-Sayre syndrome. Arch Neurol 1981; 38: 247–250 Curless RG, Flynn J, Bachynski B, Gregorios JB, Benke P, Cullen R. Fatal metabolic acidosis, hyperglycemia, and coma after steroid therapy for Kearns-Sayre syndrome. Neurology 1986; 36: 872–873 Daroff RB, Solitare GB, Pincus JH, Glaser GH. Spongiform encephalopathy with chronic progressive external ophthalmoplegia. Neurology 1966; 16: 161–169 Demange P, Pham Gia H, Kalifa G, Sellier N. MR of Kearns-Sayre syndrome. AJNR Am J Neuroradiol 1989; 10: S91 Flynn JT, Bachynski BR, Rodrigues MM, Curless RG, Joshi B. Hyperglycemic acidotic coma and death in Kearns-Sayre syndrome.Trans Am Ophthalmol Soc 1985; 83: 131–161 Gallastegui J, Hairiman RJ, Handler B, Lev M, Bharati S. Cardiac involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987; 60: 385–388 Herzberg NH, van Schooneveld MJ, Bleeker-Wagemakers EM, Zwart R, Cremers FPM, van der Knaap MS, Bolhuis PA, de Visser M. Kearns-Sayre syndrome with a phenocopy of choroideremia instead of pigmentary retinopathy. Neurology 1993; 43: 218–221 Ishikawa Y, Goto Y-I, Ishikawa Y, Minami R. Progression in a case of Kearns-Sayre syndrome.J Child Neurol 2000; 15: 750–755 Kamata Y, Mashima Y, Yokoyama M, Tanaka K, Goto Y-I, Oguchi Y.Patient with Kearns-Sayre syndrome exhibiting abnormal magnetic resonance image of the brain. J Neuroophthalmol 1998; 18: 284–288 Kleber FX, Park J-W, Hübner G, Johannes A, Pongratz D, König E. Congestive heart failure due to mitochondrial cardiomyopathy in Kearns-Sayre syndrome. Klin Wochenschr 1987; 65: 480–486 Klopstock T, Bishof F, Gerock K, Deuschl G, Seibel P, Ketelson UP, Reichmann H. 3.1-kb Deletion of mitochondrial DNA in a patient with Kearns-Sayre syndrome. Acta Neuropathol (Berl) 1995; 90: 26–129 Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulinius M. Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediatr Res 1990; 28: 131–136 Lertrit P, Imsumran A, Karnkirawattana P, Devahasdin V, Sangruchi T, Atchaneeyasakul L-o, Mungkornkarn C, Neungton N. A unique 3.5-kb deletion of the mitochondrial genome in Thai patients with Kearns-Sayre syndrome. Hum Genet 1999; 105: 127–131 Leung TF, Hui J, Shoubridge E, Li CK, Chik KW, Shing MMK,Wong GWK, Yeung WL, Yeun PMP. Aplastic anaemia in association with Kearns-Sayre syndrome. J Inherit Metab Dis 1999; 22: 86–87

Marin-Garcia J, Goldenthal MJ. Sarnat HB. Kearns-Sayre syndrome with a novel mitochondrial DNA deletion. J Child Neurol 2000; 15: 555–558 Marín-García J, Goldenthal MJ, Flores-Sarnat L, Sarnat HB. Severe mitochondrial cytopathy with complete A-V, PEO, and mtDNA deletions. Pediatr Neurol 2002; 27: 213–216 McShane MA,Hammans SR,Sweeney M,Holt IJ,Beattie TJ,Brett EM, Harding AE. Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet 1991; 48: 39–42 Mohri I, Taniike M, Fujimura H, Matsuoka T, Inui K, Nagai T, Okada S. A case of Kearns-Sayre syndrome showing a constant proportion of deleted mitochondrial DNA in blood cells during 6 years of follow-up. J Neurol Sci 1998; 158: 106–109 Muñoz A, Meteos F, Simón R, García-Silva MT, Cabello S, Arenas J.Mitochondrial diseases in children: neuroradiological and clinical features in 17 patients. Neuroradiology 1999; 41: 920–928 Nakagawa E, Hirano S, Yamanouchi H, Goto Y-I, Nonaka I, Takashima S. Progressive brainstem and white matter lesions in Kearns-Sayre syndrome: a case report. Brain Dev 1994; 16: 416–418 Nakagawa E,Osari S-i,Yamanouchi H,Matsuda H,Goto Y-I,Nonaka I. Long-term therapy with cytochrome c, flavin mononucleotide and thiamine diphosphate for a patient with Kearns-Sayre syndrome. Brain Dev 1996; 18: 68–70 Nakano T,Imanaka K,Uchida H,Isaka N,Takezawa H.Myocardial ultrastructure in Kearns-Sayre syndrome. Angiology 1987; 38: 28–35 Oldfors A, Fyhr I-M, Holme E, Larsson N-G, Tulinius M. Neuropathology in Kearns-Sayre syndrome. Acta Neuropathol (Berl) 1990; 80: 541–546 Poulton J, Morten KJ, Weber K, Brown GK, Bindoff L. Are duplications of mitochondrial DNA characteristic of KearnsSayre syndrome? Hum Mol Genet 1994; 3: 947–951 Provenzale JM,VanLandingham K.Cerebral infarction associated with Kearns-Sayre syndrome – related cardiomyopathy. Neurology 1996; 46: 826–828 Robertson Jr,WC,Viseskul C, Lee YE, Lloyd RV. Basal ganglia calcification in Kearns-Sayre syndrome. Arch Neurol 1979; 36: 711–713 Rötig A, Bourgeron T, Chretien D, Rustin P, Munnich A. Spectrum of mitochondrial DNA arrangements in the Pearson marrow-pancreas syndrome. Hum Mol Genet 1995; 4: 1327–1330 Schröder R, Vielhaber S, Wiedemann FR, Kornblum C, Papassotiropoulos A, Broich P, Zierz S, Elger CE, Reichmann H, Seibel P, Klockgether T, Kunz WS. New insights into the metabolic consequences of large-scale mtDNA deletions: a quantitative analysis of biochemical, morphological, and genetic findings in human skeletal muscle. J Neuropathol Exp Neurol 2000; 59: 353–360 Seneca S, Verhelst H, De Meirleir L, Meire F, Ceuterick-De Grootte C, Lissens W, Van Coster R. A new mitochondrial point mutation in the transfer RNAleu gene in a patient with clinical phenotype resembling Kearns-Sayre syndrome. Arch Neurol 2001; 58: 1113–1118 Simaan EM, Mikati MA, Touma EH, Rötig A. Unusual presentation of Kearns-Sayre syndrome in early childhood. Pediatr Neurol 1999; 21: 830–831 Valanne L, Ketonen L, Majander A, Soumalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 1998; 19: 369–377

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948 References and Further Reading Vásquez-Acevedo M, Vázquez-Memije ME, Mutchinick OM, Morales JJ, García-Ramos G, Gonzáles-Halphen D. A case of Kearns-Sayre syndrome with the 4,977-bp common deletion associated with a novel 7,704-bp deletion. Neurol Sci 2002; 23: 247–250 Wilichowski E,Korenke GC,Ruitenbeek W,De Meirleir L,Hagendorff A, Janssen AJM, Lissens W, Hanefeld F. Pyruvate dehydrogenase complex deficiency and altered respiratory chain function in a patient with Kearns-Sayre syndrome / MELAS overlap syndrome and A3243G mtDNA mutation. J Neurol Sci 1998; 157: 206–213 Wray SH,Provenzale JM,Johns DR,Thulborn KR.MR of the brain in mitochondrial myopathy AJNR Am J Neuroradiol 1995; 16: 1167–1173 Yoda S,Terauchi A, Kitahara F, Akabane T. Neurologic deterioration with progressive CT changes in a child with Kearns-Shy syndrome. Brain Dev 1984; 6: 322–327 Zanssen S, Molnar M, Buse G, Schröder JM. Mitochondrial cytochrome b gene deletion in Kearns-Sayre syndrome associated with a subclinical type of pheripheral neuropathy. Clin Neuropathol 1998; 17: 291–296 Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in KearnsSayre syndrome. Neurology 1988; 38: 1339–1346

27 Myo-, Neuro-, Gastrointestinal Encephalopathy Bardosi A, Creutzfeldt W, DiMauro S, Felgenhauer K, Friede RL, Goebel HH, Kohlschütter A, Mayer G, Rahlf G, Servidei S, van Lessen G, Wetterling T. Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder. Acta Neuropathol (Berl) 1987; 74: 248–258 Carrozzo R, Davidson MM, Walker WF, Hiranio M, Miranda AF. Cellular and molecular studies in the muscle and cultures from patients with multiple mitochondrial DNA deletions. J Neurol Sci 1999; 170: 24–31 Gamez J, Ferriero C, Accarino ML, Guarner L, Tadesse S, Marti RA, Andreu AL, Raguer N, Cervera C, Hirano M. Phenotypic variability in a Spanish family with MNGIE. Neurology 2002; 59: 455–457 Hirano M, Silvestri G, Blake DM, Lombes A, Minetti C, Bonilla E, Hays AP, Lovelace RE, Butler I, Bertorini TE,Threlkeld AB, Mitsumoto H, Salberg LM, Rowland LP, DiMauro S. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 1994; 44: 721–727 Hirano M, Garcia-de-Yebenes J, Jones AC, Nishino I, DiMauro S, Carlo JR, Bender AN, Hahn AF, Salberg LM, Weeks DE, Nygaard TG. Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter. Am J Hum Genet 1998; 63: 526–533 Hirano M, Nishigaki Y, Marti R. Mitochondrial neurogastrointestinal encephalopmyopathy (MNGIE): a disease of two genomes. Neurologist 2004; 10: 8–17 Ionasescu V. Oculogastrointestinal muscular dystrophy. Am J Hum Med Genet 1983; 15: 103–112 Kaidar-Person O, Golz A, Netzer A, Goldsher D, Joachims HZ, Goldenberg D. Rapidly progressive bilateral sensory neural hearing loss as a presentation of mitochondrial neurogastrointestinal encephalomyopathy. Am J Otolaryngol 2003; 24: 128–130

Kocaefe YC, Erdem S, Özgüç M, Tan E. Four novel thymidine phosphorylase gene mutations in mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) patients. Eur J Hum Genet 2003; 11: 102–104 Labauge P, Durant R, Castelnovo G, Dubois A. MNGIE: diarrhea and leukoencephalopathy. Neurology 2002; 25 :58 Marti R, Spinazzola A, Nishino I, Andreu AL, Naini A. Tadesse S, Oliver JA, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy and thymidine metabolism: results and hypothesis. Mitochondrion 2002; 2: 143–147 Martí R, Nishigaki Y, Hirano M. Elevated plasma deoxyuridine in patients with thymidine phosphorlyase deficiency. Biochem Biophys Res Commun 2003; 303: 14–18 Millar WS, Lignelli A, Hirano M. MRI of five patients with mitochondrial neurogastrointestinal encephalomyopathy. AJR Am J Roentgenol 2004; 182: 1537–1541 Nishino I, Spinazzola A, Hirano M. Thyamidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999; 283: 689–692 Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, Connolly AM, Verloes A, Guimarães J, Maillard I, Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL, Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I, Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 2000; 47: 792–800 Nishino I, Spinazzola A, Hirano M. MNGIE: from nuclear DNA to mitochondrial DNA. Neuromusc Disord 2001; 11: 7–10 Papadimitrou A, Comi GP, Hadjigeorgiou GM, Bordoni A, Sciacco M, Napoli L, Prelle A, Moggio M, Fagiolari G, Bresolin N, Salani S. Anastasopoulos I, Giassakis G, Divari R, Scarlao G. Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome. Neurology 1998; 51: 1086– 1092 Simon LT, Horoupian DS, Dorf LJ, Marks M, Herrick MK, Wasserstein P, Smith ME. Polyneuropathy, ophthalmoplegia, leukocenphalophathy and intestinal pseudo-obstruction: POLIP syndrome. Ann Neurol 1990; 28: 349–360 Soykan I, Cetinkaya H, Erdem S,Tan E, Aydin F, Bahar K, Özden A. Mitochondrial neurogastrointestinal encephalomyopathy. Diagnostic features in two patients. J Clin Gastroenterol 2002; 34: 446–448 Spinazzola A, Marti R, Nishino I, Andreu AL, Naini AL Tadesse S, Pela I, Zammarchi E, Donati MA, Oliver JA, Hirano M. Altered thymidine metabolism due to defects of thymidine phosphorylase. J Biol Chem 2002; 277: 4128–4133 Suomalainen A, Kaukomen J. Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet 2001; 106: 53–61 Teitelbaum JE, Berde CB, Nurko S, Buonomo C, Perez-Atayade AR, Vox VL. Diagnosis and management of MNGIE syndrome in children: case report and review of the literature. J Pediatr Gastroenterol Nutr 2002; 35: 377–383 Uncini A, Servidei S, Silvestri G, Manfredi G, Sabatelli M, Di Muzio A, Ricci E, Mirabella M, DiMauro S, Tonali P. Ophthalmoplegia, demyelinating neuropathy, leukoencephalopathy, myopathy, and gastrointestinal dysfunction with multiple deletions of mitochondrial DNA: a mitochondrial multisystem disorder in search of a name.Muscle Nerve 1994; 17: 667–674

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28 Leigh Syndrome and Mitochondrial Leukoencephalopathies General Absalon MJ, Harding CO, Fain DR, Li L, Mack KJ. Leigh syndrome in an infant resulting from mitochondrial DNA depletion. Pediatr Neurol 2001; 24: 60–63 Anzil AP, Weindl A, Struppler A. Ultrastructure of a cerebral white matter lesion in a 41-year-old man with Leigh’s encephalomyelopathy (LEM). Acta Neuropathol (Berl) 1981; Suppl VII: 233–238 Arri J,Tanabe Y. Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol 2000; 21: 1502–1509 Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 1993; 14: 1119–1137 Campos Y, Martin MA, Rubio JC, Solana LG, García-Benayas C, Terradas JL, Arenas J. Leigh syndrome associated with the T9176C mutation in the ATPase 6 gene of mitochondrial DNA. Neurology 1997; 49: 595–597 Coenen MJH, van den Heuvel LP, Smeitink JAM. Mitochondrial oxidative phosphorylation system assembly in man: recent achievements. Curr Opin Neurol 2001; 14: 777–781 Crompton MR. Spongiform subacute necrotising encephalomyelopathy. Acta Neuropathol (Berl) 1969; 13: 204–208 Davis PC, Hoffman JC, Braun IF, Ahmann P, Krawiecki N. MR of Leigh’s disease (subacute necrotizing encephalomyelopathy). AJNR Am J Neuroradiol 1987; 8: 71–75 De Lonlay-Debeney P, von Kleist-Retzow J-C, Hertz-Pannier L, Peudenier S, Cormier-Daire V, Berquin P, Chrétien D, Rötig A, Saudubray J-M,Baraton J,Brunelle F,Rustin P,van der Knaap M, Munnich A. Cerebral white matter disease in children may be caused by mitochondrial respiratoiry chain deficiency. J Pediatr 2000; 136: 209–214 Egger J, Wynne-Williams CJE, Erdohazi M. Mitochondrial cytopathy or Leigh’s syndrome? Mitochondrial abnormalities in spongiform encephalopathies.Neuropediatrics 1982; 13: 219–224 Egger J, Pincott JR, Wilson J, Erdohazi M. Cortical subacute necrotizing encephalomyelopathy. A study of two patients with mitochondrial dysfunction. Neuropediatrics 1984; 15: 150–158 Feigin I, Kim HS. Subacute necrotizing encephalomyopathy in a neonatal infant. J Neuropathol Exp Neurol 1977; 36: 364–372 Filiano JJ, Goldenthal MJ, Mamourian AC, Hall CCC, Marin-Garcia J. Mitochondrial DNA depletion in Leigh syndrome . Pediatr Neurol 2002; 26: 239–242 Goebel HH, Bardosi A, Friede RL, Kohlschütter A, Albani M, Siemes H. Sural nerve biopsy studies in Leigh’s subacute necrotizing encephalomyelopathy. Muscle Nerve 1986; 9:165–173 Greenberg SB, Faerber EN, Riviello JJ, de Leon G, Capitanio MA. Subacute necrotizing encephalomyelopathy (Leigh disease): CT and MRI appearances. Pediatr Radiol 1990; 21: 5–8 Howell N, Kubacka I, Smith R, Frerman F, Parks JK, Parker WD Jr. Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology 1996; 46: 219–222 Jiang Y-W,Qin J,Yuan U,Qi Y,Wu X-R.Neuropathologic and clinical features in eight Chinese patients with Leigh disease. J Child Neurol 2002; 17: 450–452

Kang PB, Hunter JV, Melvin JJ, Selak MA, Faerber EN, Kaye EM. Infantile leukoencepathopathy owing to mitochondrial enzyme dysfunction. J Child Neurol 2002; 17: 421–428 Kimura S, Kobayashi T, Amemiya F. Myelin splitting in the spongy lesion in Leigh encephalopathy. Pediatr Neurol 1991; 7: 56–58 Kirby DM, Kahler SG, Freckmann M-L, Reddihough D, Thornburn DR. Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated family. Ann Neurol 2000; 48: 102–104 Kissel JT, Kolkin S, Chakeres D, Boesel C, Weiss K. Magnetic resonance imaging in a case of autopsy-proved adult subacute necrotizing encephalomyelopathy (Leigh’s disease). Arch Neurol 1987; 44: 563–566 Kohlschütter A, Kraus-Ruppert R, Rohrer T, Herschkowitz NN. Myelin studies in a case of subacute necrotizing encephalomyelopathy (SNE). J Neuropathol Exp Neurol 1978; 37: 155–164 Krägeloh-Mann I, Grodd W, Nägele T. Proton spectroscopy in patients with Leigh’s disease and mitochondrial enzyme deficiency. Dev Med Child Neurol 1994; 36: 839–845 Majoie CB, Akkerman EM, Blank C, Barth PG, Poll-The BT, den Heeten GJ. Mitochondrial encephalomyopathy: comparison of conventional MR imaging with diffusion-weighted and diffusion tensor imaging: case report. Am J Neuroradiol 2002; 23: 813–816 Malandrini A, Palmeri S, Fabrizi GM, Villanova M, Berti G, Salvadori C, Gardini G, Motti L, Solimé F, Guazzi GC. Juvenile Leigh syndrome with protracted course presenting as chronic sensory motor neuropathy, ataxia, deafness and retinitis pigmentosa: a clinicopathological report.J Neurol Sci 1998; 155: 218–221 Masó E, Ferrer I, Herraiz J, Roquer J, Serrano S. Leigh’s syndrome in an adult. J Neurol 1984; 231: 253–257 Medina L, Chi TL, DeVivo DC, Hilal SK. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJNR Am J Neuradiol 1990; 11: 379–384 Montpetit VJA, Andermann F, Carpenter S, Fawcett JS, Zborowska-Sluis D, Giberson HR. Subacute necrotizing encephalomyelopathy. A review and a study of two families. Brain 1971; 94: 1–30 Moroni I, Bugiani M, Bizzi A, Castelli G, Lamantea E, Uziel G. Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics 2002; 33: 79–85 Morris AAM, Leopard JV.The treatment of congenital lactic acidoses. J Inherit Metab Dis 1996; 19: 573–580 Nakagawa M, Kaminishi Y, Isashiki Y, Yamada H, Higuchi I, Uchida Y, Osame M. Familial mitochondrial encephalomyopathy with deaf-mutism, ophthalmoplegia and leukodystrophy. Acta Neurol Scand 1995; 92: 102–108 Niers L, van den Heuvel L, Trijbels F, Sengers R, Smeitink J. Prerequisites and strategies for prenatal diagnosis of respiratory chain deficiency in chorionoc villi. J Inherit Metab Dis 2003; 26: 647–658 Rahman S. Blok RB, Dahl H-HM, Danks DM, Kirby DM, Chow CW, Christodoulou J,Thorburn DR. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996; 39: 343–351 Sandhu FS, Dillon WP. MR demonstration of leukoencephalopathy associated with mitochondrial encephalomyopathy (case report). AJNR Am J Neuroradiol 1991; 12: 375–379

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950 References and Further Reading Santorelli FM, Barmada MA, Pons R, Zhang LL, DiMauro S. Leigh-type neuropathology in Pearson syndrome associated with impaired ATP production and a novel mtDNA deletion. Neurology 1996; 47: 1320–1323 Santorelli FM, Tanji K, Shanske S, Krishna S, Schmidt RE, Greenwood RS, DiMauro S, De Vivo DC. The mitochondrial DNA A8344G mutation in Leigh syndrome revealed by analysis in paraffin-embedded sections: revisiting the past. Ann Neurol 1998; 44: 962–964 Seitz RJ, Langes K, Frenzel H, Kluitmann G,Wechsler W.Congenital Leigh’s disease: panencephalomyelopathy and peripheral neuropathy. Acta Neuropathol (Berl) 1984; 64: 167–171 Shtilbans A, Shanske S, Goodman S, Sue CM, Bruno C, Johnson TL, Lava NS, Waheed N, DiMauro S. G8363A mutation in the mitochondrial DNA transfer ribonucleic acidlys gene: another case of Leigh syndrome. J Child Neurol 2000; 15: 759–761 Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 1998; 19: 369–377 van der Knaap MS, Jakobs C, Valk J. Magnetic resonance imaging in lactic acidosis. J Inherit Metab Dis 1996; 19: 535–547 Walter GF, Brucher JM, Martin JJ, Ceuterick C, Pilz P, Freund M. Leigh’s disease – several nosological entities with an identical histopathological complex? Neuropathol Appl Neurobiol 1986; 12: 95–107 Weinstock A, Giglio P, Cohen ME, Bakshi R, Januario J, Balos L. Diffuse magnetic resonance imaging white-matter changes in a 15-year-old boy with mitochondrial encephalomyopathy. J Child Neurol 2002; 17: 47–49

Pyruvate Dehydrogenase Complex Deficiency Aleck KA, Kaplan AM, Sherwood WG, Robinson BH. In utero central nervous system damage in pyruvate dehydrogenase deficiency. Arch Neurol 1988; 45: 987–989 Bindhoff LA, Brich-Machin MA, Farnsworth L, Gardner-Medwin D, Lindsay JG, Turnbull DM. Familial intermittent ataxia due to defect of the E1 component of pyruvate dehydrogenase deficiency. J Neurol Sci 1989; 93: 311–318 Bonne G,Benelli C,de Meirleir L,Lissens W,Chaussain M,Diry M, Clot J-P, Ponsot G, Geoffroy V, Leroux J-P, Marsac C. E1 pyruvate dehydrogenase defiency in a child with motor neuropathy. Pediatr Res 1993; 33: 284–288 Brown GK. Pyruvate dehydrogenase E1a deficiency. J Inherit Metab Dis 1992; 15: 625–633 Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet 1994; 31: 875–879 Cederbaum SD, Blass JP, Minkoff N, Brown WJ, Cotton ME, Harris SH. Sensitivity to carbohydrate in a patient with familial intermittent lactic acidosis and pyruvate dehydrogenase deficiency. Pediatr Res 1976; 10: 713–720 Chabrol B, Mancini J, Benelli C, Gire C, Munnich A. Leigh syndrome: pyruvate dehydrogenase defect. A case with peripheral neuropathy. J Child Neurol 1994; 9: 52–55 Chow CW, Anderson RMcD, Kenney GCT. Neuropathology in cerebral lactic acidosis. Acta Neuropathol (Berl) 1987; 74: 393–396 Cross JH, Connelly A, Gadian DG, Kendall BE, Brown GK, Leonard JV. Clinical diversity of pyruvate dehydrogenase deficiency. Pediatr Neurol 1994; 10: 276–283 Dahl H-HM, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK. X-linked pyruvate dehydrogenase E1a subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis 1992; 15: 835–847

Dahl J-HM. Pyruvate dehydrogenase E1a deficiency: males and females differ yet again. Am J Hum Genet 1995; 56: 553–557 De Meirleir L, Lissens W, Denis R, Wayenberg J-L, Michotte A, Brucher J-M,Vamos E, Gerlo E, Liebaers I. Pyruvate dehydrogenase deficiency:clinical and biochemical diagnosis.Pediatr Neurol 1993; 9: 216–220 De Meirleir L, Specola N, Seneca S, Lissens W. Pyruvate dehydrogenase E1a deficiency in a family: different clinical presentation in two siblings. J Inherit Metab Dis 1998; 21: 224–226 De Meirleir L, Lissens W, Benelli C, Marsac C, de Klerk J, Scholte J, van Diggelen O, Kleijer W, Seneca S, Liebaers I. Pyruvate dehydrogenase complex deficiency and absence of subunit X. J Inherit Metab Dis 1998; 21: 9–16 Dey R, Mine M, Desguerre I, Slama A, van den Berghe L, Brivert M, Aral B, Marsac C. A new case of pyruvate dehydrogenase deficiency due to a novel mutation in the PDX1 gene. Ann Neurol 2003; 53: 273–277 Fujii T, van Coster RN, Old SE, Medori R, Winter S, Gubits RM, Matthews PM, Brown RM, Brown GK, Dahl H-HM, de Vivo DC. Pyruvated dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity. Ann Neurol 1994; 36: 83–89 Geoffroy V, Fouque F, Benelli C, Poggi F, Saudurbray JM, Lissens W, Meirleir LD, Marsac C, Lindsay JG, Sanderson SJ. Defect in the X-lipoyl-containing component of the pyruvated dehydrogenase complex in a patient with a neonatal lactic acidemia. Pediatrics 1996; 97: 267–272 Harada M,Tanouchi M, Arai K, Nishitani H, Miyoshi H, Hashimoto T.Therapeutic efficacy of a case of pyruvated dehydrogenase complex deficiency monitored by localized proton magnetic resonance spectroscopy. Magn Res Imaging 1996; 14: 129–133 Heckmann JM, Eastman R, Handler L, Wright M, Owen P. Leigh disease (subacute necrotizing encephalomyelopathy): MR documentation of the evolution of an acute attack. AJNR Am J Neuroradiol 1993; 14: 1157–1159 Kimura S, Osaka H, Saitou K, Ohtuki N, Kobayashi T, Nezu A. Improvement of lesions shown on MRI and CT scan by administration of dichloroacetate in patients with Leigh syndrome. J Neurol Sci 1995; 134: 103–107 Kimura S, Ohtuki N, Nezu A, Tanaka M, Takeshita S. Clinical and radiologic improvements in mitochondrial encephalomyelopathy following sodium dichloroacetate therapy. Brain Dev 1997; 19: 535–540 Kinosita H, Sakuragawa N, Tada H, Naito E, Kuroda Y, Nonaka I. Recurrent muscle weakness and ataxia in thiamine-responsive pyruvated dehydrogenase complex deficiency. J Child Neurol 1997; 12: 141–144 Kretzschmar HA, DeArmond SJ, Koch TK, Patel MS, Newth CJL, Schmidt KA, Packman S. Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease). Pediatrics 1987; 79: 370–373 Lie SO, Loken AChr, Strömme JH, Aagenaes O. Fatal congenital lactic acidosis in two siblings. Clinical and pathological findings. Acta Paeditr Scand 1971; 60: 129–137 Lissens W, de Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler IS, Patel MS, Robinson BH, Seyda A. Mutations in the X-linked pyruvate dehydrogenase (E1) asubunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 2000; 15: 209–219

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Marsac C, Stansbie D, Bonne G, Cousin J, Jehenson P, Benelli C, Leroux J-P, Lindsay G. Defect in the lipoyl-bearing protein X subunit of the pyruvated dehydrogenase complex in two patients with encephalomyelopathy. J Pediatr 1993; 123: 915–920 Matthews PM, Brown RM, Otero L, Marchington D, Leonard JV, Brown GK. Neurodevelopmental abnormalities and lactic acidosis in a girl with a 20-bp deletion in the X-linked pyruvate dehydrogenase E1a subunit gene. Neurology 1993; 43: 2025–2030 Matthews PM, Brown RM, Otero LJ, Marchingon DR, LeGris M, Howes R, Meadows LS, Shevell M, Scriver CR, Brown GK. Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients. Brain 1994; 117: 435–443 Michotte A, de Meirleir L, Lissens W, Denis R, Wayenberg JL, Liebears I, Brucher JM. Neuropathological findings of a patient with pyruvate dehydrogenase E1a deficiency presenting as a cerebral lactic acidosis.Acta Neuropathol (Berl) 1993; 85: 674–678 Morten KJ, Beattie P, Brown GK, Matthews PM. Dichloroacetate stabilizes the mutant E1a subunit in pyruvate dehydrogenase deficiency. Neurology 1999; 53: 612–616 Naito E, Ito M, Yokota I, Saijo T, Chen S, Maehara M, Kuroda Y. Concomitant administration of sodium dichloroacetate and thiamine in West syndrome caused by thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci 1999; 171: 56–59 Otero LJ, Brown GK, Silver K, Arnold SL, Matthews PM. Association of cerebral dysgenesis and lactic acidemia with Xlinked PHD E1a subunit mutations in females. Pediatr Neurol 1995; 13: 327-332 Robinson BH, MacMillan H, Petrova-Benedict R, Sherwood WG. Variable clinical presentation in patients with defective E1a component of pyruvate dehydrogenase complex. J Pediatr 1987; 111: 525–533 Robinson BH, MacKay N, Petrova-Benedict R, Ozalp I, Coskun T, Stacpoole PW. Defects in the E2 lipoyl containing component of the pyruvate dehydrogenase complex in patient with lactic acidemia. J Clin Invest 1990; 85: 1821–1824 Robinson BH, MacKay N, Chun K, Ling M. Disorders of pyruvate dehydrogenase carboxylase and the pyruvate dehydrogenase complex. J Inherit Metab Dis 1996; 19: 452–462 Rubio-Gozalbo ME, Heerschap A,Trijbels JMF, de Meirleir L,Thijssen HOM, Smeitink JAM. Proton MR spectroscopy in a child with pyruvate dehydrogenase complex deficiency. Magn Res Imaging 1999; 17: 939–944 Shany E, Saada A, Landau D, Shaag A, Hershkovitz E, Elpeleg ON. Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain. Biochem Biophys Res Commun 1999; 262: 163–166 Shevell MI,Matthews PM,Scriver CR,Brown RM,Otero LJ,Legris M, Brown GK, Arnold DL. Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol 1994: 11: 224–229 Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 1997; 77: 535–541 Takahashi S, Oki J,Tokumitsu A, Obata M, Ogawa K,Tokusashi Y, Saijo H, Okuno A. Autopsy findings in pyruvate dehydrogenase E1a deficiency: case report. J Child Neurol 1997; 12: 519–524 Wallace SJ. Deficiencies within the pyruvate dehydrogenase complex: clinical and pathological correlates. Dev Med Child Neurol 1985; 27: 249–260

Weber TA, Antognetti MR, Stacpoole PW. Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr 2001; 138: 390– 395 Wexler ID, Hemalatha SG, McConnell J, Buist NRM, Dahl H-HM, Berry SA, Cederbaum SD, Patel MS, Derr DS. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 1997; 49: 1655–1661 Wijburg FA, Barth PG, Bindoff LA, Birch-Machin MA, van der Blij JF, Ruitenbeek W, Turnbull DM, Schutgens RBH. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics 1992; 23: 147–152 Zand DJ, Simon EM, Pulitzer SB, Wang DJ, Wang ZJ, Rorke LB, Palmieri M, Berry GT. In vivo pyruvate detected by MR spectroscopy in neonatal dehydrogenase deficiency. AJNR Am J Neuroradiol 2003; 24: 1471–1474

Complex I Deficiency Andreu AL, Tanji K, Bruno C, Hadjigeorgiou GM, Sue CD, Jay C, Ohnishi T, Shanske S, Bonilla E, diMauro S. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999; 45: 820–823 Bénit P, Chretien D, Kadhom N, de Lonlay-Debeney P, CormierDaire V, Cabral A, Peudenier S, Rustin P, Munnich A, Rötig A. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex 1 deficiency. Am J Hum Genet 2001; 68: 1344–1352 Bentlage HACM, Wendel U, Schägger H, ter Lak HJ, Janssens AJM, Trijbels JMF. Lethal infantile mitochondrial disease with isolated complex 1 deficiency in fibroblasts but with combined complex 1 and IV deficiencies in muscle. Neurology 1996: 47: 243–248 Budde SMS, van den Heuvel LPWJ, Janssen AJ, Smeets RJP, Buskens CAF, deMeirleir L, van Coster R, Baethmann M, Voit T,Trijbels JMF,Smeitink JAM.Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene. Biochem Biophys Res Commun 2000; 275: 63–68 Chol M, Lebon S, Bénit P, Chretien D, de Lonlay P, Goldenberg A, Odent S, Hertz-Pennier L, Vincent-Delorme C, CormierDaire V, Rustin P, Rötig A, Munnich A. The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet 2003; 40: 188–191 Cooper JM, Mann VM, Krige D, Shapira AHV. Human mitochondrial complex I dysfunction. Biochim Biophys Acta 1992; 1101: 198–2003 Dionisi-Vici C, Ruitenbeek W, Fariello G, Bentlage H, Wanders RJA, Schägger H, Bosman C, Piontadosi C, Sabetta G, Bertini E. New familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency. Ann Neurol 1997; 42: 661–665 Fiellet F, Mousson Y, Grignon Y, Leonard JV, Vidailhet M. Necrotizing encephalopathy with mitochondrial complex I deficiency. Pediatr Neurol 1999; 20: 305–308 Houshmand M, Larsson N-G, Oldfors A,Tulinius M, Holme E. Fatal mitochondrial myopathy, lactic acidosis and complex I deficiency associated with a heteroplasmic AG mutation at position 3251 in the mitochondrial tRNALeu(UUR) gene. Hum Genet 1996; 97: 369–273

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952 References and Further Reading Kirby DM, Crawford M, Cleary MA, Dahl H-HM, Dennett X, Thornburn DR. Respiratiory chain complex I deficiency. An underdiagnosed energy generation disorder. Neurology 1999; 52: 1255–1264 Kirby DM, Boneh A, Chow CW, Ohtake A, Ryan MT, Thyagarajan D, Thorburn DR. Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh’s disease. Ann Neurol 2003; 54: 473–478 Loeffen J, Smeitink J,Triepels R, Smeets R, Schuelke M, Sengers R, Trijbels F, Hamel B, Mullaart R, van den Heuvel L. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 1998; 63: 1598–1608 Loeffen J, Smeets R, Smeitink J, Ruitenbeek W, Janssen A, Mariman E, Sengers R, Trijbels F, van den Heuvel L. The X-chromosomal NDUFA1 gene of complex I in mitochondrial encephalomyopathies:tissue expression and mutation detection. J Inherit Metab Dis 1998; 21: 210–215 Loeffen JLCM, Smeitink JAM,Trijbels JMF, Janssen AJM,Triepels RH, Sengers RCA, van den Heuvel LP. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat 2000; 15: 123–134 Loeffen J, Elpeleg O, Smeitink J, Smeets R, Stockler-Ipsiroglu S, Mandel H, Sengers R,Trijbels F, van den Heuvel L. Mutations in the complex I NCUFS2 gene of patients with cardiomyopathy and encephalomyopathy. Ann Neurol 2001; 49: 195–201 Morris AAM, Leonard JV, Brown GK, Bidouki SK, Bindhoff LA, Woodward CE, Harding AE, Lake BD, Harding BN, Farrell MA, Bell JE, Mirakhur M, Turnbull DM. Deficiency of respiratoiry chain complex I is a common cause of Leigh disease. Ann Neurol 1996; 40: 25–30 Ogle RF, Christodoulou J, Fagan E, Blok RB, Kirby DM, Seller KL, Dahl H-HM,Thorburn DR. Mitochondrial myopathy wiht tRNALeu(uur) mutation and complex I deficiency responsive to riboflavin. J Pediatr 1997; 130: 138–145 Pitkänen S, Feigenbaum A, Laframboise R, Robinson BH. NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings.J Inherit Metab Dis 1996; 19: 675–686 Dubio-Gozalbo ME, Ruitenbeek W, Wendel U, Sengers RCA, Trijbels JMF, Smeitink JAM. Systemic infantile complex I deficiency with fatal outcome in two brothers. Neuropediatrics 1998; 29: 43–45 Schuelke M, Smeitink J, Mariman E, Loeffen J, Plecko B, Trijbels F, Stockler-Ipsiroglu S, van den Heuvel L. Mutant NDUFV1subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 1999; 21: 260–261 Smeitink JAM, Loeffen JLCM, Triepels RH, Smeets RJP, Trijbels JMF, van den Heuvel LP. Nuclear genes of human complex I of the mitochondrial electron transport gene: state of the art. Hum Mol Genet 1998; 7: 1573–1579 Triepels RH, van den Heuvel LP, Loeffen JLCM, Buskens CAF, Smeets RJP, Rubio Gozalbo ME, Budde SMS, Mariman EC, Wijburg FA, Barth PG, Trijbels JMF, Smeitink JAM. Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I.Ann Neurol 1999; 45: 787–790 Triepels RH, van den Heuvel LP, Trijbels JM, Smeitink JA. Respiratoiry chain complex I deficiency. Am J Med Genet 2001; 106: 37–45 Trijbels JMF, Ruitenbeek W, Sengers RCA, Janssen AJM, van Oost BA. Benign mitochondrial encephalomyopathy in a patient with complex I deficiency. J Inherit Metab Dis 1996; 19: 149–152

Van den Heuvel L, Ruitenbeek W, Smeets R, Gelman-Kohan Z, Elpeleg O, Loeffen J, Trijbels F, Mariman E, de Bruijn D, Smeitink J. Demonstration of a new pathogenic mutation in the human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet 1998; 62: 262–268 Vogel R, Nijtmans L, Ugalde C, van den Heuvel L, Smeitink J. Complex I assembly: a puzzling problem. Curr Opin Neurol 2004; 17: 179–168 Wolf NI, Seitz A, Harting I, Smeitink JAM, Trijbels F, van den Heuvel LP, Schlemmer H, Ebinger F, Evert W, Rating D. New pattern of brain MRI lesions in isolated complex I deficiency. Neuropediatrics 2003; 34:156–159

Complex II Deficiency Birch-Machin MA, Taylor RW, Cochran B, Ackrell BAC, Turnbull DM. Late-Onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 2000; 48: 330–335 Bourgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J. Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome. Brain Dev 1992; 14: 404–408 Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Péquignot E, Munnich A, Rötig A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratoiry chain deficiency. Nat Genet 1995; 11: 144–148 Brockmann K, Bjornstad A, Dechent P, Korenke CG, Smeitink J, Trijbels JMF, Athanassopoulos S, Villagran R, Sjkeldal AH, Wilichowski E, Frahm J, Hanefeld F. Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency. Ann Neurol 2002: 52: 38–46 Taylor RW, Birch-Machin MA, Schaefer J, Taylor L, Shakir R, Ackrell BAC, Cochran B, Bindhoff LA, Jackson MJ, Griffiths P, Turnbull DM. Deficiency of complex II of the mitochondrial respiratoiry chain in late-onset optic atrophy and ataxia. Ann Neurol 1996; 39: 224–232

Complex IV Deficiency Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cariomyopathy. Am J Hum Genet 2003; 72: 104–114 Antonicka H, Leary SC, Guercin G-H, Agar JN, Horvath R, Kennaway NG, Harding CO, Jaksch M, Shoubridge EA. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet 2003; 12: 2693–2702 Bakker HD, van den Bogert C, Drewes JG, Barth PG, Scholte HR, Wanders RJA, Ruitenbeek W. Progressive generalized brain atrophy and infantile spasms associated with cytochrome c oxidase deficiency. J Inherit Metab Dis 1996; 19: 153–156 Bruno C, Martinuzzi A, Tang Y, Andreu AL, Pallotti F, Bonilla E, Shanske S, Fu J, Sue CM, Angelini C, DiMauro S, Manfredi G. A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the functional structure of complex IV. Am J Hum Genet 1999; 65: 611–620

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Campos Y, García-Redondo A, Férnandez-Moreno MA, Martínez-Pardo M, Goda G, Rubio JC, Martin MA, del Hoyo P, Cabello A, Bornstein B, Garesse R, Arenas J. Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome C oxidase II gene. Ann Neurol 2001; 50: 409–413 Clark KM, Taylor RW, Johnson MA, Chinnery PF, ChrzanowskaLightowlers ZMA, Andrews RM, Nelson IP, Wood NW, Lamont PJ, Hanna MG, Lightowlers RN,Turnbull DM. An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II results in lower levels of the protein and a mitochondrial encephalomyopathy. Am J Hum Genet 1999; 64: 1330–1339 Comi GP, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, Fortunato F, Zeviani M, Napoli L, Bresolin N, Moggio M, Ausenda CD, Taanman J-W, Scarlato G. Cytochrome c oxidase subunit I microdeletion in a patient wiht motor neuron disease. Ann Neurol 1998; 43: 110–116 DiMauro S, Nicholson JF, Hays AP, Eastwood AB, Papadimitriou A, Koenigsberger R, DeVivo DC. Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency. Ann Neurol 1983; 14: 226–234 DiMauro S, Servidei S, Zeviani M, DiRocco M, DeVivo DC, DiDonato S, Uziel G, Berry K, Hoganson G, Johnsen SD, Johnson PC. Cytochrome c oxidase defiency in Leigh syndrome. Ann Neurol 1987; 22: 498–506 Èaèiæ M, Wilichowski E, Mejasˇki-Bosˇnjak V. Cytochrome c oxidase partial deficiency-associated with Leigh disease presenting as an extrapyramidal syndrome. J Child Neurol 2001; 16: 616–619 Elia M Musumeci SA, Ferri R, Colamaria V, Azan G, Greco D, Stefanini MC. Leigh syndrome and partial deficit of cytochrome c oxidase associated with epilepsia partialis continua. Brain Dev 1996; 18: 207–211 Farina L, Chiapparini L, Uziel G, Bugiani M, Zeviani M, Savoiardo M. MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. AJNR Am J Neuroradiol 2002; 23: 1095– 1100 Goldenberg PC, Steiner RD, Merkens LS, Dunaway T, Egan RA, Zimmerman EA, Nesbit G, Robinson B, Kennaway NG. Remarkable improvement in adult Leigh syndrome with partial cytochome c oxidase deficiency. Neurology 2003; 60: 865–868 Hanna MG, Nelson IP, Rahman S, Lane RJM, Land J, Heales S, Cooper MJ, Shapira AHV, Morgan-Hughes JA,Wood NW. Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA. Am J Hum Genet 1998; 63: 29–36 Harpey J-P, Heron D, Prudent M, Charpentier C, Rustin P, Ponsot G, Cormier-Daire V.Diffuse leukodystrophy in an infant with cytochrome-c oxidase deficiency. J Inherit Metab Dis 1998; 21: 4748–752 Kaido M, Fujimura H,Taniike M,Yoshikawa H,Toyooka K,Yoirfuji S, Inui K, Okada S, Sparaco M, Yanagihara T. Focal cytochrome c oxidase deficiency in the brain and dorsal root ganglia in a case with mitochondrial encephalomyopathy (tRNAIle 4269 mutation): histochemical, immunohistochemical, and ultrastructural study. J Neurol Sci 1995; 131: 170–176 Mootha VK, Lepage P, Miller K, Bunkenborg J, Reigh M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A 2003; 100: 605–610

Morin C, Dubé J, Robinson BH, Lacroix J, Michaud J, De Braekeleer M, Geoffroy G, Lortie A, Blanchette C, Lambert MA, Mitchell GA. Stroke-like episodes in autosomal recessive cytochrome oxidase deficiency. Ann Neurol 1999; 45: 389–392 Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, Krishna S, Walker W, Glerum DM, van Coster R, Lyon G, Scalais E, Lebel R, Kaplan P, Shanske S, de Vivo DC, Bonilla E, Hirano M, DiMauro S, Schon EA. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 1999; 23: 333–337 Parfait B, Percheron A, Chretien D, Rustin P, Munnich A, Rötig A. No mitochondrial cytochrome oxidase (COX) gene mutations in 18 cases of COX deficiency. Hum Genet 1997; 101: 247–250 Péquignot MO, Dey R, Zeviani M, Tiranti V, Godinot C, Payau A, Sue C, Di Mauro S, Abitbol M, Marsac C. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome c oxidase deficiency. Hum Mutat 2001; 17: 374–381 Rahman S,Taanman J-W, Cooper JM, Nelson I, Hargreaves I, Meunier B, Hanna MG, García JJ, Capaldi RA, Lake BD, Leonard JV, Schapira AHV. A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy. Am J Hum Genet 1999; 65: 1030–1039 Rahman S,Brown RM,Chong WK,Wilson CJ,Brown GK.A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol 2001; 49: 797–800 Robinson BH. Human cytochrome oxidase deficiency. Pediatr Res 2000; 48: 581–585 Rossi A, Biancheri R, Bruno C, Di Rocco M, Calvi A, Pessagno A, Tortori-Donati P. Leigh syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings. AJNR Am J Neuroradiol 2003; 24: 1188–1191 Sacconi S, Salviati L, Sue CM, Shanske S, Davidson MM, Bonilla E, Niani AB, de Vivo DC, DiMauro S. Mutation screening in patients with isolated cytochrome c oxidase deficiency. Pediatr Res 2003; 53: 224–230 Salviati L, Sacconi S, Rasalan MM, Kronn DF, Braun A, Canoll P, Davidson M, Shanske S, Bonilla E, Hays AP, Schon EA, DiMauro S. Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease. Arch Neurol 2002; 59: 862–865 Santoro L, Carrozzo R, Malandrini A, Piemonte F, Patrono C, Villanova M, Tessa A, Palmeri S, Bertini E. Santorelli FM. A novel SURF1 mutation results in Leigh syndrome with peripheral neuropathy causes by cytochrome c oxidase deficiency. Neuromusc Disord 2000; 10: 450–453 Savasta S, Comi GP, Perini MP, Lupi A, Strazzer S, Rognoni F, Rossoni R. Leigh disease: clinical, neuroradiologic, and biochemical study of three new cases with cytochrome c oxidase deficiency. J Child Neurol 2001; 16: 608–613 Savoiardo M, Uziel G, Strada L,Visciani A, Grisoli M,Wang G. MRI findings in Leigh’s disease with cytochrome-c-oxidase deficiency. Neuroradiology 1991; 33: 507–508 Shoubridge EA. Cytochrome c oxidase deficiency. Am J Med Genet 2001; 106: 45–52 Silvestri G, Mongini T, Odoardi F, Modoni A, deRosa G, Doriguzzi C, Palmucci L, Tonali P, Servidei S. A new mtDNA mutation associated with a progressive encephalopathy and cytochrome c oxidase deficiency. Neurology 2000; 54: 1693– 1696

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954 References and Further Reading Sue CM, Karadimas C, Checcarelli N, Tanji K, Papadopuolou LC, Pallotti F, Guo FL, Shanske S, Hirano M, de Vivo DC, van Coster R, Kaplan P, Bonilla E, DiMauro S. Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2. Ann Neurol 2000; 47: 589–595 Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M, Zelante L. Gasparini P, Marzella R, Rocchi M, Bayona-Bafaluy MP, Enriquez J-A, Uziel G, Bertini E, DionisiVici C, Franco B, Meitinger T, Zeviani M. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998; 63: 1609–1621 Tiranti V, Jaksch M, Hofmann S, Galimberti C, Hoertnagel K, Lulli L, Freisinger P, Bindhoff L Gerbitz KD, Comi G-P, Uziel G, Zeviani M, Meitinger T. Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency. Ann Neurol 1999; 46: 161–166 Topçu M, Saatci I, Apak A, Söylemezoglu F, Akçören Z. Leigh syndrome in a 3-year-old boy with unusual brain MR imaging and pathologic findings. AJNR Am J Neuroradiol 2000; 21: 224–227 Tulinus M, Moslemi AR, Darin N, Westerberg B, Wiklund LM, Holme E, Oldfors A. Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNAtrp gene. Neuropediatrics 2003; 34: 87–91 Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J Cormier-Daire V, Munnich A, Bonnefont J-P, Rustin P, Rötig A. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 2000; 67: 1104–1109 Valnot I, von Kleist-Retzow J-C, Barrientos A, Gorbatyuk M, Taanman J-W, Mehanye B, Rustin P, Tzagoloff A, Munnich A, Rötig A. A mutation in the human heme A: farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet 2000; 9: 1245–1249 Van Coster R, Lombes A, De Vivo DC, Chi TL, Dodson WE, Rothman S, Orrechio EJ, Grover W, Berry GT, Schwartz JF, Habib A, DiMauro S. Cytochrome c oxidase-associated Leigh syndrome: phenotypic features and pathogenetic speculations. J Neurol Sci 1991; 104: 97–111 Varlamov DA, Kudin AP,Vielhaber S, Schröder R, Sassen R, Becker A, Kunz D, Haug K, Rebstock J, Heils A, Elger CE, Kunz WS. Metabolic consequences of a novel missense mutation of the mtDNA CO 1 gene.Hum Mol Genet 2002; 11:1997–1805 Von Kleist-Retzow J-C,Yao J,Taanman J-W, Chantrel K, Chretien D, Cormier-Daire V, Rötig A, Munnich A, Rustin P, Shoubridge EA. Mutations in SURF1 are not specifically associated with Leigh syndrome. J Med Genet 2001; 2001: 109–113 Willis TA, Davidson J, Gray RGF, Poultron K, Ramani P, Whitehouse W. Cytochrome oxidase deficiency presenting as birth asphyxia. Dev Med Child Neurol 2000; 42: 414–417 Zafeiriou DI, Koletzko B, Mueller-Felber W, Paetzke I, Kueffer G, Jensen M. Deficiency in complex IV (cytochrome c oxidase) of the respiratory chain, presenting as a leukodystrophy in two siblings with Leigh syndrome. Brain Dev 1995; 17: 117–121 Zeviani M, Corona P, Nijtmans L,Tiranti V. Nuclear gene defects in mitochondrial disorders. Ital J Nuerol Sci 1999; 20: 401– 408 Zhu Z, Yao J, Johns T, Fu K, de Bie I, Macmillan C, Cuthbert AP, Newbold RF, Wang J-C, Brown GK, Brown RM, Shoubridge AE. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998; 20: 337–343

ATPase 6 Gene Defect Baracca A, Bagori S, Carelli V, Lenaz G, Solaini G. Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial DNA T8993G mutation in the ATPase 6 gene encoding subunit a. J Biol Chem 2000; 275: 4177–4182 Carelli V, Baracca A, Bagogi S, Pallotti F,Valentino ML, Montagna P, Zevaini M, Pini A, Lenaz G, Baruzzi A, Solaini G. Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch Neurol 2002; 59: 264–270 Chowers I, Lerman-Sagie T, Elpeleg ON, Shaag A, Merin S. Cone and rod dysfunction in the NARP syndrome. Br J Ophthalmol 1999; 83: 190–193 Degoul F, François D, Diry M, Ponsot G, Desguerre I, Héron B, Marsac C, Moutard ML. A near homoplasmic T8993G mtDNA mutation in a patient with atypic Leigh syndrome not present in the mother’s tissues. J Inherit Metab Dis 1997; 20: 49–53 De Meirleir L, Senaca S, Lissens W, Schoentjes E, Desprechins B. Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatr Neurol 1995; 13: 242–246 De Vries DD, van Engelen BGM, Gabreëls FJM, Ruitenbeek W, van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome. Ann Neurol 1993; 34: 410–412 Dionisi-Vici C, Seneca S, Zeviani M, Fariello G, Rimoldi M, Bertini E, de Meirleir L. Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J Inherit Metab Dis 1998; 21: 2–8 Ferlin T, Landrieu P, Ramboud C, Fernandez H, Dumoulin R, Rustin R, Mousson B. Segregation of the G8993 mutant mitochondrial DNA trough generations and embryonic tissues in a family at risk of Leigh syndrome. J Pediatr 1997; 131: 447–449 Fryer A, Appleton R, Sweeney MG, Rosenbloom L, Harding AE. Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including ‘cerebral palsy’. Arch Dis Child 1994; 71: 419–422 Fujii T, Hattori H, Higuchi Y,Tsuji M, Mitsuyoshi I. Phenotypic differences between T C and T G mutations at nt 8993 of mitochondrial DNA in Leigh syndrome. Pediatr Neurol 1998; 18: 275–277 García JJ, Ogilvie I, Robinson BH, Capaldi RA. Structure, functioning, and assembly of the ATP synthase in cells from patients with the T8993G mitochondrial DNA mutation. J Biol Chem 2000; 275: 11075–11081 Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990; 46: 428–433 Leshinsky-Sliver E, Perach M, Basilevsky E, Hershkovitz E, Yanoov-Sharav M, Lerman-Sagie T, Leve D. Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA. Prenat Diagn 2003; 23: 31–33 Lodi R, Montagna P, Iotti S, Zaniol P, Barboni P, Puddo P, Barbiroli B. Brain and muscle energy metabolism studied in vivo by 31P-magnetic resonance spectroscopy in NARP syndrome. J Neurol Neurosurg Psychiatry 1994; 57: 1492–1496 Mak S-C, Chi C-S, Tsai C-R. Mitochondrial DNA 8993T >C Mutation presenting as juvenile Leigh syndrome with respiratory failure. J Child Neurol 1998; 13: 349–351

References and Further Reading

Mäkelä-Bengs P, Suomalainen A, Majander A, Rapola J, Kalimo H, Nuutila A, Pihko H. Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome.Pediatr Res 1995; 37: 634–639 Nagashima T, Mori M, Katayama K, Nunomura M, Nishihara H, Higara H, Tanaka S Goto Y-I, Nagashima K. Adult Leigh syndrome with mitochondrial DNA mutation at 8993. Acta Neuropathol (Berl) 1999; 97: 416–422 Pastores GM, Santorelli FM, Shanske S, Gelb BD, Fyfe B,Wolfe D, Willner JP.Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am J Med Genet 1994; 50: 265–271 Porto FBO, Mack G, Sterboul M-J, Lewin P, Flament J, Sahel J, Dofflus H. Isolated late-onset cone-rod dystrophy revealing a familial neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome with the T8993G mitochondrial mutation. Am J Ophthalmol 2001; 132: 935–937 Santorelli FM, Shanske S, Macaya A, DeVivo DC, DiMauro S.The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh’s syndrome. Ann Neurol 1993; 34: 827–834 Santorelli FM, Shanske S, Jain KD, Tick D, Schon EA, DiMauro S. A T C mutation at nt 8993 of mitochondrial DNA in a child with Leigh syndrome. Neurology 1994; 44: 972–974 Santorelli FM, Mak S-C, Vazquez-Memije ME, Shanske S, KranzEble P, Jain KD, Bleustone DL, de Vivo DC, DiMauro S. Clinical heterogeneity associated with the mitochondrial DNA T8993C point mutation. Pediatr Res 1996; 39: 914–917 Shoffner JM, Fernhoff PM, Krawiecki NS, Caplan DB, Holt PJ, Koontz DA,Takei Y, Newman NJ, Ortiz RG, Polak M, Ballinger SW, Lott MT, Wallace DC. Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology 1992; 42: 2168–2174 Suzuki Y,Wada T, Sakai T, Ishikawa Y, Minami R,Tachi N, Saitoh S. Phenotypic variability in a family with a mitochondrial DNA T8993C mutation. Pediatr Neurol 1998; 19: 283–286 Takahashi S, Oki J, Miyamoto A, Okuno A. Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome. Brain Dev 1999; 21: 200–204 Takanashi J-I, Sugita K, Tanabe Y, Maetomo T, Niimi H. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. J Neurol Sci 1997; 145: 83–86 Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JTR,Wherret J, Smith C, Rudd N, Petrova-Benedict R, Robinson BH. Heteroplasmic mtDNA mutation (TÆG) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992; 50: 852–858 Tsao C-Y, Mendell JR, Bartholomew D. High mitochondrial DNA T8993G mutation (>90 %) without typical features of Leigh’s and NARP syndromes. J Child Neurol 2001; 16: 533–535 Uziel G, Moroni I, Lemantea E, Fratta GM, Ciceri E, Carrara E, Zeviani M. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry 1997; 63: 16–22 Vászques-Memije ME, Shanske S, Santorelli FM, Franz-Elbe P, DeVivo DC, DiMauro S. Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations. J Inherit Metab Dis 1998; 21: 829–836 White SL, Shanske S, Biros I,Warwick L, Dahl HM,Thornburn DR, Di Mauro S. Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. Prenat Diagn 1999; 19: 1165–1168

Wilson CJ, Wood NW, Leonard JV, Surtees R, Rahman S. Mitochondrial DNA point mutation T9176C in Leigh syndrome. J Child Neurol 2000; 15: 830–833 Yamada T, Hayasaka S, Hongo K, Kubota H. Retinal dystrophy in a Japanese boy harboring the mitochondrial DNA T8993G mutation. Jpn J Ophthalmol 2002; 46: 460–462

29 Pyruvate Carboxylase Deficiency Ahmad A, Kahler SG, Kishnani PS, Artigas-Lopez M, Pappu AS, Steiner R, Millington DS, van Hove JLK. Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet 1999; 87: 331–338 Arnold GL, Griebel ML, Porterfield M, Brewster M. Pyruvate carboxylase deficiency. Clin Pediatr 2001; 40: 519–521 Atkin BM, Buist NRM, Utter MF, Leiter AB, Banker BQ. Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh’s disease. Pediatr Res 1979; 13: 109–116 Baal MG, Gabreëls FJM, Renier WO, Hommes FA, Gijsbers THJ, Lamers KJB, Kok JCN. A patient with pyruvate carboxylase deficiency in the liver: treatment with aspartic acid and thiamine. Dev Med Child Neurol 1981; 23: 521–530 Bartlett K, Ghneim HK, Stirk JH, Dale G, Alberti GMM. Pyruvate carboxylase deficiency. J Inherit Metab Dis 1984; 7: 74–78 Brun N, Robitaille Y, Grignon A, Robinson A, Robinson BH, Mitchell GA, Lambert M. Pyruvate carboxylase deficiency : prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am J Med Genet 1999; 84: 94–101 Carbone MA, MacKay N, Ling M, Cole DEC, Douglas C, Rigat B, Feigenbaum A, Clarke JTR, Haworth JC, Greenberg CR, Seargant L, Robinson BH. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet 1998; 62: 1312–1319 Carbone MA, Applegarth DA, Robinson BH. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat 2002; 20: 48–56 Greter J, Gustafsson J, Holme E. Pyruvate-carboxylase deficiency with urea cycle impairment. Acta Paediatr Scand 1985; 74: 982–986 Hamilton J, Rae MD, Logan RW, Robinson PH. A case of benign pyruvate carboxylase deficiency with normal development. J Inherit Metab Dis 1997; 20: 401–403 Higgins JJ, Glasgow AM, Lusk M, Kerr DS. MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol 1994; 9: 436–439 Higgins JJ, Ide SE, Oghalai JS, Polymeropoulos MH. Lack of mutations in the biotin-binding region of the pyruvate carboxylase (PC) gene in a family with partial PC deficiency. Clin Biochem 1997; 30: 79–81 Murphy JV, Isohashi F, Weinberg MB, Utter MF. Pyruvate carboxylase deficiency: an alleged biochemical cause of Leigh’s disease. Pediatrics 1981; 368: 401–404 Oizumi J, Shaw KNF, Giudici TA, Carter M, Donnell GN, Ng WG. Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cysturia. J Inherit Metab Dis 1983; 6: 89–94 Oizumi J, Donnell GN, Ng WG, Mulivor RA, Greene AE, Coriell LL. Congenital lactic acidosis associated with pyruvate carboxylase deficiency. Cytogenet Cell Genet 1984; 38: 81 Pineda M, Campistol J, Vilaseca MA, Briones P, Ribes A, Temudo T, Pons M, Cusi V, Rolland M-O. An atypical French form of pyruvate carboxylase deficiency. Brain Dev 1995;17: 276– 279

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956 References and Further Reading Robinson BH, Oei J, Sherwood WG, Applegarth D, Wong L, Haworth J, Goodyer P, Casey R, Zaleski LA.The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency. Am J Hum Genet 1984; 36: 283–294 Robinson BH, Toone JR, Benedict P, Dimmick JE, Oei J, Applegarth DA. Prenatal diagnosis of pyruvate carboxylase deficiency. Prenat Diagn 1985; 5: 67–71 Robinson BH, Oei J, Saudubray JM, Marsac C, Bartlett K, Quan F, Gravel R. The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by 3H-biotin incorporation, 35S-streptavidin labeling, and Northern blotting with a cloned cDNA probe. Am J Hum Genet 1987; 40: 50–59 Robinson BH, MacKay N, Chun K, Ling M. Disorders of pyruvate carboxylase and the pyruvate dehydrogenase comples. J Inherit Metab Dis 1996; 19: 452–462 Rutledge SL, Snead OC, Kelly DR, Kerr DS, Swann JW, Spink DL, Martin DL. Pyruvate carboxylase deficiency: acute exacerbation after ACTH treatment of infantile spasms. Pediatr Neurol 1989; 5: 249–252 Sander J, Packman S, Berg BO, Hutchison HT, Caswell N. Pyruvate carboxylase activity in subacute necrotizing encephalopathy (Leigh’s disease). Neurology 1984; 34: 515– 516 Saudubray JM, Marsac C, Charpentier C, Cathelineau L, Leaud MB, Leroux JP. Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings.Acta Paediatr Scand 1976; 65: 717–724 Stern HJ, Nayar R, Depalma L, Fifai N. Prolonged survival in pyruvate carboxylase deficiency : lack of correlation with enzyme activity in cultured fibroblasts. Clin Biochem 1995; 28: 85–89 Tada K, Takada G, Omura K, Itokawa Y. Congenital lactic acidosis due to pyruvate carboxylase deficiency: absence of an inhibitor of TPP-ATP phosphoryltransferase. Eur J Pediatr 1978; 127: 141–147 Tsuchiyama A, Oyanagi K, Hirano S, Tachi N, Sogawa H, Wagatsuma K, Nakao T,Tsugawa S, Kawamura Y.A case of pyruvate carboxylase deficiency with later prenatal diagnosis of an unaffected sibling. J Inherit Metab Dis 1983; 6: 85–88 Van Coster RN, Fernhoff PM, De Vivo DC. Pyruvate carboxylase deficiency: a benign variant with normal development. Pediatr Res 1991; 30: 1–4 Van Coster RN, Janssens S, Misson J-P, Verloes A, Leroy JG. Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples. Prenat Diagn 1998; 18: 1041–1044 Wallace JC, Jitrapakdee S, Chapman-Smith S. Pyruvate carboxylase. Biochem Cell Biol 1998; 30: 1–5 Wexler ID,Du Y,Lisgaris MV,Mandal SK,Freytag SO,Yang B-S,Liu T-C, Kwon M, Patel MS, Kerr DS. Primary amino acid sequence and structure of human pyruvate carboxylase. Biochim Biophys Acta 1994; 1227: 46–52 Wexler ID, Kerr DS, Du Y, Kaung MM, Stephenson W, Lusk MM, Wappner RS, Higgins JJ. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediatr Res 1998; 43: 579–584 Wong LTK, Davidson GF, Applegarth DE, Dimmick JE, Norman MG, Toone JR, Pirie G, Wong J. Biochemical and histologic pathology in an infant with cross-reacting material (negative) pyruvate carboxylase deficiency. Pediatr Res 1986; 20: 274–279

30 Multiple Carboxylase Deficiency Bakker HD, Westra M, Overweg-Plandsoen WCG, Waveren van G, Sillevis-Smitt JH, Abeling NGGM, Wanders RJA, Schutgens RBH, Gennip van AH. Normalisation of severe cranial CT scan abnormalities after biotin in a case of biotinidase deficiency. Eur J Pediatr 1994; 153: 861–866 Baumgartner ER, Suormala TM,Wick H, Probst A, Blauenstein U, Bachmann C,Vest M. Biotinidase deficiency: a cause of subacute necrotizing encephalomyelopathy (Leigh syndrome). Report of a case with lethal outcome. Pediatr Res 1989; 26: 260–266 Baumgartner ER, Suormala T. Multiple carboxylase deficiency: inherited and acquired disorders of biotin metabolism. Int J Vitam Nutr Res 1997; 67: 377–384 Bay CA, Berry GT, Glauser TA, Hayward JC, Wolf B, Sladky JT, Kaplan P. Reversible metabolic myopathy in biotinidase deficiency: its possible role in causing hypotonia. J Inherit Metab Dis 1995; 18: 701–704 Bousounis DP, Camfield PR, Wolf B. Reversal of brain atrophy with biotin treatment in biotinidase deficiency. Neuropediatrics 1993; 24: 214–217 Casado de Frías E, Campos-Castellü J, Careaga Maldonado J, Pérez Cerdá C. Biotinidase deficiency: result of treatment with biotin from age 12 years. Eur J Paediatr Neurol 1997; 1: 173–176 Cornejo Navarro P, Guerra A, Alvarez JG, Ortiz FJ. Cutaneous and neurologic manifestations of biotinidase deficiency.Int J Dermatol 2000; 39: 363–382 Fuchshuber A, Suormala T, Roth B, Duran M, Michalk D, Baumgartner ER. Holocarboxylase synthetase deficiency: early diagnosis and management of a new case. Eur J Pediatr 1993; 152: 446–449 Gibson KM, Bennett MJ, Nyhan WL, Mize CE. Late-onset holocarboxylase synthetase deficiency. J Inherit Metab Dis 1996; 19: 739–742 Ginat-Israeli T, Hurvitz H, Klar A, Blinder G, Branski D, Amir N. Deteriorating neurological and neuroradiological course in treated biotinidase deficiency. Neuropediatrics 1993; 24: 103–106 Haagerup A, Brandt Andersen J, Blichfeldt S, Fjord Christensen M. Biotinidase deficiency: two cases of very early presentation. Dev Med Child Neurol 1997; 39: 832–835 Honavar M, Janota I, Neville BGR, Chalmers RA. Neuropathology of biotinidase deficiency. Acta Neuropathol (Berl) 1992; 84: 461–464 Hymes J,Wolf B. Biotinidase and its roles in biotin metabolism. Clin Chim Acta 1996; 255: 1–11 Kalayci Ö, Coskun T,Tokatli A, Demir E, Erdem G, Güngör C,Yükselen A, Özalp I. Infantile spasms as the initial symptom of biotinidase deficiency. J Pediatr 1994; 124: 103–104 Kimura M, Fukui T, Tagami Y, Fujiwaki T, Yokoyama M, Ishioka C, Kumasaka K, Terada N, Yamaguchi S. Normalization of low biotinidase activity in a child with biotin deficiency after biotin supplementation. J Inherit Metab Dis 2003; 26: 715–719 Livne M, Gibson M, Amir N, Eshel G, Elpeleg ON. Holocarboxylase synthetase deficiency: a treatable metabolic disorder masquerading as cerebral palsy. J Child Neurol 1994; 9: 170–172 Mardach R, Zempleni J, Wolf B, Cannon MJ, Jennings ML, Cress S, Boylan J, Roth S, Cederbaum S, Mock DM. Biotin dependency due to a defect in biotin transport. J Clin Invest 2002; 109: 1617–1623

References and Further Reading

Mitchell G, Ogier H, Munnich A, Saudubray JM. Neurological deterioration and lactic acidemia in biotinidase deficiency – a treatable condition mimicking Leigh’s disease. Neuropediatrics 1986; 17: 129–131 Möslinger D,Stöckler-Ipsiroglu S,Scheibenreiter S,Tiefenthaler M, Mühl A, Seidl R, Strobl W, Plecko B, Suormala T, Regula Baumgartner ER. Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr 2001; 160: 277–282 Pomponio RJ, Hymes J, Reynolds TR, Meyers GA, Fleischhauer K, Buck GA, Wolf B. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children:molecular,biochemical,and clinical analysis. Pediatr Res 1997; 42: 840–848 Rahman S,Standing S,Dalton RN,Pike MG.Late presentation of biotinidase deficiency with acute visual loss and gait disturbance. Dev Med Child Neurol 1997; 39: 830–831 Ramaekers VT, Suormala TM, Brab M, Duran R, Heimann G, Baumgartner ER. A biotinidase Km variant causing late onset bilateral optic neuropathy. Arch Dis Child 1992; 67: 115–119 Ramaekers VT, Brab M, Rau G, Heimann G. Recovery from neurological deficits following biotin treatment in a biotinidase Km variant. Neuropediatrics 1993; 24: 98–102 Salbert BA, Astruc J, Wolf B. Ophthalmologic findings in biotinidase deficiency. Ophthalmologica 1993; 206: 177–181 Salbert BA, Pellock JM, Wolf B. Characterization of seizures associated with biotinidase deficiency. Neurology 1993; 43: 1351–1355 Sander JE, Malamud N, Cowan MJ, Packman S, Amman AJ,Wara DW. Intermittent ataxia and immunodeficiency with multiple carboxylase deficiencies: a biotin-responsive disorder. Ann Neurol 1980; 8: 544–547 Schürmann M, Engelbrecht V, Lohmeier K, Lenard HG, Wendel U, Gärtner J. Cerebral metabolic changes in biotinidase deficiency. J Inherit Metab Dis 1997; 20: 755–760 Schultz PE, Weiner SP, Belmont JW, Fishman MA. Basal ganglia calcifications in a case of biotinidase deficiency. Neurology 1988; 38: 1326–1328 Secor McVoy JR, Levy HL, Lawler M, Schmidt MA, Ebers DD, Hart PS, Dove Pettit D, Blitzer MG,Wolf B. Partial biotinidase deficiency: clinical and biochemical features. J Pediatr 1990; 116: 78–83 Suormala TM, Baumgartner ER, Wick H, Scheibenreiter S, Schweitzer S. Comparison of patients with complete and partial biotinidase deficiency: biochemical studies. J Inherit Metab Dis 1990; 13: 76–92 Suormala T, Ramaekers VTh, Schweitzer S, Fowler B, Laub MC, Schwermer C, Bachmann J, Baumgartner ER. Biotinidase Km-variants: detection and detailed biochemical investigations. J Inherit Metab Dis 1995; 18: 689–700 Suormala T, Fowler B, Jakobs C, Duran M, Lehnert W, Raab K, Wick H, Baumgartner ER. Late-onset holocarboxylase synthetase-deficiency: pre- and post-natal diagnosis and evaluation of effectiveness of antenatal biotin therapy. Eur J Pediatr 1998; 157: 570–575 Sweetman L, Nyhan WL. Inheritable biotin-treatable disorders and associated phenomena. Annu Rev Nutr 1986; 6: 317– 343 Tsao CY, Kien CL. Complete biotinidase deficiency presenting as reversible progressive ataxia and sensorineural deafness. J Child Neurol 2002; 17: 146 Wiznitzer M, Bangert BA. Biotinidase deficiency: clinical and MRI findings consistent with myelopathy. Pediatr Neurol 2003; 29: 56–58

Wolf B, Heard GS. Biotinidase deficiency. Adv Pediatr 1991; 38: 1–21 Wolf B, Hsia YE, Sweetman L, Feldman G, Boychuk RB, Bart RD, Crowell DH, Di Mauro RM, Nyhan WL. Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. Pediatrics 1981; 68: 113–118 Wolf B, Heard GS, Weissbecker KA, Secor McVoy JR, Grier RE, Leshner RT. Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol 1985; 18: 614–617 Wolf B, Norrgard K, Pomponio RJ, Mock DM, Secor McVoy JR, Fleischhauer K, Shapiro S, Blitzer MG, Hymes J. Profound biotinidase deficiency in two asymptomatic adults. Am J Med Genet 1997; 73: 5–9 Wolf B, Pomponio RJ, Norrgard KJ, Lott IT, Regula Baumgartner E, Suormala T, Ramaekers VTh, Coskun T, Tokatli A, Ozalp I, Hymes J. Delayed-onset profound biotinidase deficiency. J Pediatr 1998; 132: 362–365 Wolf B, Spencer R, Gleason T. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. J Pediatr 2002; 140: 242–246 Wolf B, Jensen K, Hüner G, Demirkol M, Baykal T, Divry P, Rolland MO, Perez-Cerdá C, Ugarte M, Straussberg R, Basel-Vanagaite L, Baumgartner ER, Suormala T, Scholl S, Das AM, Schweitzer S, Pronicka E, Sykut-Cegielska J. Seventeen novel mutations that cause profound biotinidase deficiency. Mol Gen Metab 2002; 77: 108–111

31 Cerebrotendinous Xanthomatosis Argov Z, Soffer D, Eisenberg S, Zimmerman Y. Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis. Ann Neurol 1986; 20: 89–91 Ballantyne CM, Vega GL, East C, Richards G, Grundy SM. Lowdensity lipoprotein metabolism in cerebrotendinous xanthomatosis. Metabolism 1987; 36: 270–276 Barkhof F, Verrips A, van der Knaap MS, van Engelen BGM, Gabreëls FJM, Keyser A, Wevers RA, Valk J. Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 2000; 217: 869–876 Bencze KS, van de Polder DR, Prockop LD. Magnetic resonance imaging of the brain and spinal cord in cerebrotendinous xanthomatosis. J Neurol Neurosurg Psychiatry 1990; 53: 166–167 Berginer VM, Berginer J, Salen G, Shefer S, Zimmerman RD. Computed tomography in cerebrotendinous xanthomatosis. Neurology 1981; 31: 1463–1465 Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 1984; 311: 1649–1652 Berginer VM, Salen G, Shefer S.Cerebrotendinous xanthomatosis. Neurol Clin 1989; 7: 55–74 Berginer VM, Berginer J, Korczyn AD, Tamor R. Magnetic resonance imaging in cerebrotendinous xanthomatosis: a prospective clinical and neuroradiological study. J Neurol Sci 1994; 122: 102–108 Canelas HM, Quintao ECR, Scaff M,Vasconcelos KS, Brotto MWI. Cerebrotendinous xanthomatosis: clinical and laboratory study of 2 cases. Acta Neurol Scand 1983; 67: 305–311 Chen W, Kubota S, Teramoto T, Ishida S, Ohsawa N, Katayama T, Takeda T, Kuroda K,Yahara O, Kasuhara T, Neshige R, Seyama Y. Genetic analysis enables definite and rapid diagnosis of cerebrotendinous xanthomatosis. Neurology 1998; 51: 865–867

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958 References and Further Reading Claydon PT, Verrips A, Sisterman E, Mann A, Mieli-Vergani G, Wevers R. Mutations in the sterol 27-hydrolase gene (CYP27A) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis. J Inherit Metab Dis 2002; 25: 501–513 De Stefano N, Dotti MT, Mortilla M, Frederico A. Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis. Brain 2001; 124: 121–131 Dotti MT, Frederico A. Cerebrotendinous xanthomatosis with predominant parkinsonian syndrome:further confirmation of the clinical heterogeneity. Mov Disord 2000; 15: 1017– 1019 Dotti MT, Salen G, Federico A. Cerebrotendinous xanthomatosis as a multisystem disease mimicking premature ageing. Dev Neurosci 1991; 13; 371–376 Dotti MT, Federico A, Signorini E, Caputo N, Venturi C, Filosomi G, Guazzi GC. Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings. AJNR Am J Neuroradiol 1994; 15: 1721–1726 Dotti MT, Mondillo S, Plewnia K, Agricola E, Frederico A. Cerebrotendinous xanthomatosis: evidence of lipomatous hypertrophy of the atrium septum. J Neurol 1998; 245: 723–726 Dotti MT, Rufa A, Frederico A. Cerebrotendinous xanthomatosis: heterogeneity of clinical phenotype with evidence of previously undescribed ophthalmological findings. J Inherit Metab Dis 2001; 24: 696–706 Elleder M, Michalec È, Jirásek A, Khun K, Havlová M, Ranny´ M. Membranocystic lesion in the brain in cerebrotendinous xanthomatosis. Histochemical and ultrastructural study with evidence of its ceroid nature. Virchows Arch [B] 1989; 57: 367–374 Frederico A, Dotti MT. Cerebrotendinous xanthomatosis. Neurology 2001; 57: 1743 Federico A,Dotti MT.Cerebrotendinous xanthomatosis:clinical manifestations, diagnostic criteria, pathogenesis and therapy. J Child Neurol 2003; 18: 633–638 Federico A, Dotti MT,Volpi N. Muscle mitochondrial changes in cerebrotendinous xanthomatosis. Ann Neurol 1991; 30: 734–735 Fiorelli M, Di Piero V, Bastianello S, Bozzao L, Federico A. Cerebrotendinous xanthomatosis: clinical and MRI study (case report). J Neurol Neurosurg Psychiatry 1990; 53: 76–78 Hokezu Y, Kuriyama M, Kubota R, Nakagawa M, Fujiyama J, Osame M. Cerebrotendinous xanthomatosis: cranial CT and MRI studies in eight patients. Neuroradiology 1992; 34: 308–312 Javitt NB. Biologic role(s) of the 25(R),26-hydroxycholesterol metabolic pathway. Biochim Biophys Acta 2000; 1529: 136–141 Kawabata M, Kuriyama M, Mori S, Sakashita I, Osame M. Pulmonary manifestations in cerebrotendinous xanthomatosis. Intern Med 1998; 37: 922–926 Kuriyama M, Fujiyama J,Yoshidome H,Takenage S, Matsumuro K, Kasama T, Fukuda K, Kuramoto T, Hoshita T, Seyama Y, Okatu Y, Osame M. Cerebrotendinous xanthomatosis: clinical and biochemical evaluation of eight patients and review of the literature. J Neurol Sci 1991; 102: 225–232 Lee M-H, Hazard S, Carpten DJ,Yi S, Cohen J, Gerhardt GT, Salen G, Patel SB. Fine-mapping, mutation analysis, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees. J Lipid Res 2001; 42: 159–169

Leitersdorf E, Reshef A, Meiner V, Levitzki R, Pressman Schwartz S, Dann EJ, Berkman N, Cali JJ, Klapholz L, Berginer VM. Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews of Moroccan origin. J Clin Invest 1993; 91: 2488–2496 Lui C-C, Chang W-N. MRI changes in cerebrotendinous xanthomatosis after treatment with chenodeoxycholic acid. Riv Neuroradiol 1998; 11: 10–11 Meiner V, Meiner Z, Reshef A, Björkem I, Leitersdorf E. Cerebrotendinous xanthomatosis: molecular diagnosis enables presymptomatic detection of a treatable disease. Neurology 1994; 44: 288–290 Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH. Cerebrotendinous xanthomatosis. A rare disease with diverse manifestations. Arch Neurol 2002; 59: 527–529 Mondelli M, Rossi A, Scarpini C, Dotti MT, Federico A. Evoked potentials in cerebrotendinous xanthomatosis and effect induce by chenodeoxycholic acid. Arch Neurol 1992; 49: 469–475 Mondelli M, Sicurelli F, Scarpini C, Dotti MT, Frederico A. Cerebrotendinous xanthomatosis: 11-year treatment with chenodeoxycholic acid in five patients. An electrophysiological study. J Neurol Sci 2001; 190: 29–33 Ohno T, Kobayashi S, Hayasi M, Suakurai M, Kanazawa I. Diphenylpyraline-responsive parkinsonism in cerebrotendinous xanthomatosis: long-term follow up of three patients. J Neurol Sci 2001; 182: 95–97 Pedley TA, Emerson RG, Warner CL, Rowland LP, Salen G. Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. Ann Neurol 1985; 18: 517–518 Peynet J, Laurent A, de Liege P, Lecoz P, Gambert P, Legrand A, Mikol J, Warnet A. Cerebrotendinous xanthomatosis: treatments with simvastatin, lovastatin, an chenodeoxycholic acid in 3 siblings. Neurology 1991; 41: 434–436 Restuccia D, Di Lazzaro V, Servidei S, Colosimo C, Tonali P. Somatosensory and motor evoked potentials in the assessment of cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid: a preliminary study. J Neurol Sci 1992; 112: 139–146 Salen G, Zaki G, Sabesin S, Boehme D, Sheper S, Mosbach EH. Intraphepatic pigment and crystal forms in patients with cerebrotendinous xanthomatosis (CTX). Gastroenterology 1978; 74: 82–89 Salen G, Shefer S, Berginer V. Biochemical abnormalities in cerebrotendinous xanthomatosis. Dev Neurosci 1991; 13: 363–370 Schimschock JR, Alvord EC, Swanson PD. Cerebrotendinous xanthomatosis. Arch Neurol 1968; 18: 688–698 Siebner HR, Berndt S, Conrad B. Cerebrotendinous xanthomatosis without tendon xanthomas mimichking Marinesco-Sjoegren syndrome: a case report. J Neurol Neurosurg Psychiatry 1996; 60: 582–585 Soffer D, Benharroch D, Berginer V. The neuropathology of cerebrotendinous xanthomatosis revisited: a case report and review of the literature. Acta Neuropathol (Berl) 1995; 90: 213–220 Tai KS, Brockwell J, Chan FL, Janus ED, Lam KSL. Magnetic resonance imaging of cerebrotendinous xanthomatosis. Australas Radiol 1995; 39: 61–65 Tokimura Y, Kuriyama M, Arimura K, Fujiyama J, Osame M. Electrophsiological studies in cerebrotendinous xanthomatosis. J Neurol Neurosurg Psychiatry 1992; 55: 52–55

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Van Heijst AFJ,Wevers RA,Tangerman A,Cruysberg JRM,Renier WO, Tolboom JJM. Chronic diarrhoea as a dominating symptom in two children with cerebrotendinous xanthomatosis. Acta Paediatr 1996; 85: 932–936 Van Heijst AFJ,Verrips A,Wevers RA,Cruysberg JRM,Renier WO, Tolboom JJM. Treatment and follow-up of childeren with cerebrotendinous xanthomatosis. Eur J Pediatr 1998; 157: 313–316 Van Rietvelde F, Lemmering M, Mespreuve M, Crevits L, De Reuck J, Kunnen M. MRI of the brain in cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease). Eur Radiol 2000; 10: 576–578 Verrips A, Lycklama à Nijeholt, GJ, Barkhof F, van Engelen BGM, Wesseling P, Luyten JAFM, Wevers RA, Stam J, Wokke JHJ, Van den Heuvel LPWJ, Keyser A, Gabreëls FJM. Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Brain 1991; 122: 1589–1595 Verrips A,Wevers RA, van Engelen BGM, Keyser A,Wolthers BG, Barkhof F, Stalenhoef A, De Graaf R, Jansen-Zijlstra F, Van Spreeken A, Gabreëls FJM. Effect of Simvastatin in addition to chenoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism 1999; 48: 233–238 Verrips A, van Engelen BGM, Ter Laak H, Gabreëls-Festen A, Janssen A, Zwarts M, Wevers RA, Gabreëls FJM. Cerebrotendinous xanthomatosis controversies about nerve and muscle: observations in ten patients. Neuromusc Disord 2000; 10: 407–414 Verrips A, van Engelen BGM,Wevers RA, van Geel BM, Crusberg JRM, van den Heuvel LPWJ, Keyser A, Gabreëls FJM. Presence of diarrhea and abcense of tendom xanthomas in patients with cerebrotendinous xanthomatosis. Arch Neurol 2000; 57: 520–524 Verrips A, Hoefsloot LH, Steenbergen GCH, Theelen JP, Wevers RA, Gabreëls JM, van Engelen BGM, Van den Heuvel LPWJ. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 2000; 123: 908–919 Wakamatsu N, Hayashi M, Kawai H, Kondo H, Gotoda Y, Nishida Y, Kondo S, Matsumoto T. Mutations producing premature termination of translation and an an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism. J Neurol Neurosurg Psychiatry 1999; 67: 195–198 Wevers RA,Cruysberg JRM,van Heijst AFJ,Janssen-Zijlstra FSM, Renier WO,van Engelen BGM,Tolboom JJM.Paediatric cerebrotendinous xanthomatosis. J Inherit Metab Dis 1992; 15: 374–376

32 Cockayne Syndrome Balajee AS, De Santis LP, Brosh Jr RM, Selzer R, Bohr VA. Role of the ATPase domain of the Cockayne syndrome group B protein in UV induced apoptosis. Oncogene 2000; 19: 477–489 Berneberg M, Lowe JE, Nardo T, Araújo S, Fousteri MI, Green MHL, Krutmann J, Wood RD, Stefanini M, Lehmann AR. UV damage causes uncontrolled DNA breakage in cells from patients with combined features of XP-D and Cockayne syndrome. EMBO J 2000; 19: 1157–1166 Berneburg M, Lehmann AR. Xeroderma pigmentosum and related disorders: defect in DNA repair and transcription. Adv Genet 2000; 43: 71–102 Bohr VA. Human premature aging syndrome and genomic instability. Mech Ageing Dev 2002; 123: 987–993

Boltshauser E, Yalcinkaya C, Wichmann W, Reutter F, Prader A, Valavanis A. MRI in Cockayne syndrome type I. Neuroradiology 1989; 31: 276–277 Castillo M, Thomas D, Mukherji SK. Facies to remember. Int J Neuroradiol 1997; 3: 35–41 Cirillo Silengo M, Franceschini P, Bianco R, Biagioli M, Pastorin L, Vista N, Baldassar A, Benso L. Distinctive skeletal dysplasia in Cockayne syndrome. Pediatr Radiol 1986; 16: 264–266 Citterio E, Van der Boom V, Schnitzler G, Kanaar R, Bonte E, Kingston RE, Hoeijmakers JHJ, Vermeulen W. ATP-dependent chromatin remodeling by the Cockayne syndrome B DNA repair–transcription-coupling factor. Mol Cell Biol 2000; 20: 7643–7653 Colabucci F, Rossodivita A, Parigi A, Colavita N. A clinical and radiological study of two brothers affected by Cockayne syndrome type II. Rays 1987; 12: 57–63 Dabbagh O, Swaiman KF. Cockayne syndrome: MRI correlates of hypomyelination. Pediatr Neurol 1988; 4: 113–116 Del Bigio MR, Greenberg CR, Rorke LB, Schnur R, McDonaldMcGinn DM, Zackai EH.Neuropathological findings in eight children wit cerebro-oculo-facio-skeletal (COFS) syndrome. J Neuropathol Exp Neurol 1997; 56: 1147–1157 Demaerel P,Wilms G,Verdru P, Carton H, Baert AL. MRI in the diagnosis of Cockayne’s syndrome. One case. J Neuroradiol 1990; 17: 157–160 Demaerel P, Kendall BE, Kingsley D. Cranial CT and MRI in diseases with DNA repair defects. Neuroradiology 1992; 34: 117–121 Friedberg EC. Cockayne syndrome – a primary defect in DNA repair, transcription, both or neither? Bioessays 1996; 18: 731–738 Graham JM Jr, Anyane-Yeboa K, Raams A, Appeldoorn E, Kleijer WJ, Garritsen VH, Busch D, Edersheim TG, Jaspers NGJ. Cerebo-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. Am J Hum Genet 2001; 69: 291–300 Grunnet ML, Zimmerman AW, Lewis RA. Ultrastructure and electrodiagnosis of peripheral neuropathy in Cockayne’s syndrome. Neurology 1983; 33: 1606–1609 Hanawalt PC. The basis for Cockayne syndrome. Nature 2000; 405: 415–416 Harbord MG, Finn JP, Hall-Craggs MA, Brett EM, Baraitser M. Early onset leukodystrophy with distict facial features in 2 siblings. Neuropediatrics 1989; 20: 154–157 Hayashi M, Hayakawa K, Suzuki F, Sugita K, Satoh J, Morimatsu Y. A neuropathological study of early onset Cockayne syndrome with chromosomal anomaly 47XXX. Brain Dev 1992; 14: 63–67 Hayashi M, Itoh M, Araki S, Kumada S, Shioda K, Tamagawa K, Mizutaini T, Morimatsu Y, Minagawa M, Oda M. Oxidative stress and disturbed glutamate transport in hereditary nucleotide repair disorders. J Neuropathol Exp Neurol 2001; 60: 350–356 Houston CS, Zaleski WA, Rozdilsky B. Identical male twins and brother with Cockayne syndrome. Am J Med Genet 1982; 13: 211–223 Itoh M, Hayashi M, Shioda K, Minagawa M, Isa F, Tamagawaa K, Morimatsu Y, Oda M. Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 1999; 21: 326–333 Kohji T, Hayashi M, Shioda K, Minagawa M, Morimatsu Y, Tamagawa K, Oda M. Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci Lett 1998; 243: 133–136

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960 References and Further Reading Lee S-K, Yu S-L, Prakash L, Prakash S. Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription: implications for Cockayne syndrome. Cell 2002; 109: 823–834 Leech RW, Brumback RA, Miller RH, Otsuka F, Tarone RE, Robbins JH. Cockayne syndrome: clinicopathologic and tissue culture studies of affected siblings. J Neuropathol Exp Neurol 1985; 44: 507–519 Lehmann AR, Thompson AF, Harcourt SA, Stefanini M, Norris PG. Cockayne’s syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation. J Med Genet 1993; 30: 679–682 Licht CL, Stevsner T, Bohr VA. Cockayne syndrome group B cellular and biochemical functions. Am J Hum Genet 2003; 73: 1217–1239 Lindahl T, Karran P, Wood RD. DNA excision repair pathways. Curr Opin Genet Dev 1997; 7: 159–169 Lindenbaum Y, Dickson DW, Rosenbaum PS, Kraemer KH, Robbins JH, Rapin I. Xeroderma pigmentosum / Cockayne syndrome complex: first neuropathological study and review of eight other cases. Eur J Pediatr Neurol 2001; 5: 225–242 Lowry RB. Early onset of Cockayne syndrome. Am J Med Genet 1982; 13: 209–210 Mallery DL,Tanganelli B, Colella S, Steingrimsdottir H,Van Gool AJ,Troelstra C, Stefanini M, Lehmann AR. Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome. Am J Hum Genet 1998; 62: 77–85 Meira L, Graham Jr JM, Greenberg CR, Busch DB, Doughty ATB, Ziffer DW, Coleman DM, Savre-Train I, Friedberg EC. Manitona aboriginal kindred with original cerebro-oculo-facioskeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene. Am J Hum Genet 2000; 66: 1221–1228 Moyer DB, Marquis P, Shertzer ME, Burton BK. Cockayne syndrome with early onset of manifestations. Am J Med Genet 1982; 13: 225–230 Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992; 42: 68–84 Nishio H, Kodama S, Matsuo T, Ichihashi M, Ito H, Fujiwara Y. Cockayne syndrome: magnetic resonance images of the brain in a severe form with early onset. J Inherit Metab Dis 1988; 11: 88–102 Norman RM, Tingey AH. Syndrome of micrencephaly, striocerebellar calcifications, and leucodystrophy. J Neurol Neurosurg Psychiatry 1966; 29: 157–163 Ohnishi A, Mitsudome A, Murai Y. Primary segmental demyelination in the sural nerve in Cockayne’s syndrome. Muscle Nerve 1987; 10: 163–167 Özdirim E,Topçu M, Özön A, Cila A. Cockayne syndrome: review of 25 cases. Pediatr Neurol 1996; 15: 312–316 Patton MA, Giannelli F, Francis AJ, Baraiser M, Harding B, Williams AJ. Early onset Cockayne’s syndrome: case reports with neuropathological and fibroblast studies.J Med Genet 1989; 26: 154–159 Pena SDJ, Shokeir MHK. Autosomal recessive cerbro-oculo-facio-skeletal (COFS) syndrome. Clin Genet 1974; 5: 285–293 Pena SDJ, Evans J, Hunter AGW. COFS syndrome revisited. Birth Defects 1978; XIV: 205–213 Rapin I. Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. DNA repair disorders with overlaps and paradoxes. Neurology 2000; 55: 1442–1449 Roy S, Srivastava RN, Gupta PC, Meyekar G. Ultrastructure of pheripheral nerve in Cockayne’s syndrome. Acta Neuropathol (Berl) 1973; 24: 345–349

Sakai T, Kikuchi F,Takashima S, Matsuda H,Watanabene N. Neuropathological findings in the cerebro-oculo-facio-skeletal (Pena-Shokeir II) syndrome. Brain Dev 1997; 19: 58–62 Sasaki K,Tachi N, Shinoda M, Satoh N, Minami R, Ohnishi A. Demyelinating peripheral neuropathy in Cockayne syndrome: a histopathologic and morphometric study. Brain Dev 1992; 14: 114–117 Sato H, Saito T, Kurosawa K, Ootaka T, Furuyama T,Yoshinaga K. Renal lesions in Cockayne’s syndrome. Clin Nephrol 1988; 29: 206–209 Savary JB, Vasseur F, Deminatti MM. Routine autorediographic analysis of DNA excision-repair. Report of prenatal and postnatal diagnosis in eleven families. Ann Genet 1991; 2: 76–81 Smits MG, Gabreëls FJM, Renier WO, Joosten EMG, GabreelsFesten AAWM, ter Laak HJ, Pinckers AJL, Hombergen GCJ, Notermans SLH, Thijssen HOM. Peripheral and central myelinopathy in Cockayne’s syndrome. Neuropediatrics 1982; 13: 161–167 Soffer D, Grotsky HW, Rapin I, Suzuki K. Cockayne syndrome: unusual neuropathological findings and review of the literature. Ann Neurol 1979; 6: 340–348 Sugita K,Takanashi J, Ishii M, Niimi H. Comparison of MRI white matter changes with neuropsychologic impairment in Cockayne syndrome. Pediatr Neurol 1992; 8: 295–298 Takada K, Becker LE. Cockayne’s syndrome: report of two autopsy cases associated with neurofibrillary tangles. Clin Neuropathol 1986; 5: 64–68 Talwar D, Smith SA. Camfak syndrome: a demyelinating inherited disease similar to Cockayne syndrome. Am J Med Genet 1989; 34: 194–198 Traboulsi EI,de Becker I,Maumenee IH.Ocular findings in Cockayne syndrome. Am J Ophthalmol 1992; 114: 579–583 Van Gool AJ, van der Horst GTJ, Citterioo E, Hoeijmakers JHJ. Cockayne syndrome: defective repair of transcription? EMBO J 1997; 16: 4155–4162 Van Hoffen A, Kalle WHJ, De Jong-Versteeg A, Lehmann AR,Van Zeeland AA, Mullenders LHF. Cells from XP-D and XP-D-CS patients exhibit equally inefficient of UV-repair damage in transcribed genes but different capacity to recover UV-inhibited transcription. Nucl Acids Res 1999; 27: 2898–2904 Vos A, Gabreëls-Festen A, Joosten E, Gabreëls F, Renier W, Mullaart R. The neuropathy of Cockayne syndrome. Acta Neuropathol (Berl) 1983; 61: 153–156 Weliky-Conaway J, Conaway RC. Transcription elongation and human disease. Annu Rev Biochem 1999; 68: 301–319 Winter RM, Donna D, d’A Crawfurd M. Syndromes of microcephaly, microphtalmia, cataracts, and joint contractures. J Med Genet 1981; 18: 29–133 Zafeiriou DI,Thorel F, Andreou A, Kleijer WJ, Raams A, Garritsen VH, Gombakis N, Jaspers NGJ, Clarkson SG. Xeroderma pigmentosum group G with severe neurological involvement and features of Cockayne syndrome in infancy. Pediatr Res 2001; 49: 407–412

33 Trichothiodystrophy with Photosensitivity Battistella PA, Peserico A. Central nervous system dysmyelinatoion in PIBI(D)S syndrome: a further case. Childs Nerv Syst 1996; 12: 110–113 Bergmann E,Egly J-M.Trichothiodystrophy,a transcription syndrome.Trends Genet 2001; 17: 279–286

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McGuaig C,Marcoux D,Rasmussen JE,Werner MM,Gentner NE. Trichothiodystrophy associated with photosensitivity, gonadal failure, and striking osteosclerosis. J Am Acad Dermatol 1993; 28: 820–826 Murrin KL, Clarke DJ. Behavioral aspects of Pollitt syndrome: a 32-year follow-up of a case described by R.J. Pollitt and colleagues in 1968. J Intellect Disabil Res 2002; 46: 273–278 Østergard JR, Christensen T. The central nervous system in Tay syndrome. Neuropediatrics 1996; 27: 326–330 Pescerico A, Battistella PA, Bertoli P. MRI of a very rare hereditary ectodermal dysplasia: PIBI(D)S. Neuroradiology 1992; 34: 316–317 Porto L, Weis R, Schulz C, Reichel P, Lanfermann H, Zanella FE. Tay’s syndrome: MRI. Neuroradiology 2000; 42: 849–851 Queille S, Drougard C, Sarasin A, Daya-Grosjean L. Effects of XPD mutations on ultraviolet-induced apoptosis in relation to skin cancer-proneness in repair-deficient syndromes. J Invest Dermatol 2001; 117: 1162–1170 Racioppi L, Cancrini C, Romiti ML, Angelini F, di Cesare S, Bertini E, Livadiotti S, Gambarara MG, Matarese G, Lago Paz F, Stefanini M, Rossi P. Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia. Clin Exp Immunol 2001; 126: 511–518 Savary JB, Vasseur F, Vinatier D, Manouvrier S, Thomas P, Deminatti MM. Prenatal diagnosis of PIBIDS. Prenat Diagn 1991; 11: 859–866 Stefanini M, Giliani S, Nardo T, Marinoni S, Nazzaro V, Rizzo R, Trevisan G. DNA repair investigations in the nine Italian patients affected by trichothiodystrophy. Mutat Res DNA Repair 1992; 273: 119–125 Takayama K, Salazar EP, Brougthon BC, Lehmann AR, Sarasin A, Thompson LH, Weber CA. Defects in the DNA repair and transcription gene CRCC2(XPD) in trichothiodystrophy. Am J Hum Genet 1996; 58: 263–270 Taylor EM, Broughton BCM Botta E, Stefanini M, Sarasin A, Jaspers NGJ, Fawcett H, Harcourt SA, Arlett CF, Lehmann AR. Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. Proc Natal Acad Sci 1997; 94: 8658–8663 Vandenberghe K, Casteels I, Vandenbussche E, de Zegher F, de Boeck K. Bilateral cataract and high myopia in a child with trichothiodystrophy: a case report. Bull Soc Belge Ophthalmol 2001; 282: 15–18 Vermeulen W, Bergmann E, Auriol J, Rademakers S, Frit P, Appeldoorn E, Hoeijmakers JHJ, Egly J-M. Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder. Nat Genet 2000; 26: 307–313 Vermeulen W, Rademakers S, Jaspers NGJ, Appeldoorn E, Raams A, Klein B, Kleijer WJ, hansen LK, Hoeijmakers JHJ. A temperature-sensitive disorder in basal transcription and DNA repair in humans. Nat Genet 2001; 27: 299–303 Viprakasit V, Gibbons RJ, Broughton BC, Tolmie JL, Brown D, Lunt P, Winter RM, Marioni S, Stefanini M, Brueton L, Lehmann AR, Higgs DR. Mutations in the general transcription factor TFIIH result in b-thalassaemia in individuals with trichthiodystrophy. Hum Mol Genet 2001; 10: 2797–2802 Weeda G, Eveno E, Donker I, Vermeulen W, Chevallier-Lagente O, Taïeb A, Stary A, Hoeijmakers JHJ, Mezzina M, Sarasin. A mutation in the XPB/ERCC2 DNA repair transcription gene, associated with trichothiodystrophy. Am J Hum Genet 1997; 60: 320–329

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34 Pelizaeus-Merzbacher Disease André M, Monin P, Moret C, Braun M, Picard L. Maladie de Pelizaeus-Merzbacher. J Neuroradiol 1990; 17: 216–221 Apkarain P, Koetsveld-Baart JC, Barth PG. Visual evoked potential characteristics and early diagnosis of PelizaeusMerzbacher disease. Arch Neurol 1993; 50: 981–985 Battini R, Biancji MC, Boespflug-Tanguy O,Tosetti M, Bonanni P, Canapicchi R, Cioni G. Unusual clinical and magnetic resonance imaging findings in a family with proteolipid protein gene mutation. Arch Neurol 2003; 60: 268–272 Boltshauser E, Schinzel A, Wichmann W, Haller D, Valavanis A. Pelizaeus-Merzbacher disease: identification of heterozygotes with magnetic resonance imaging? Hum Genet 1988; 80: 393–394 Bonavita S, Schiffmann R, Moore DF, Frei K, Choi B, Patronas N, Virta A, Boespflüg-Tanguy O, Tedeschi G. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology 2001; 56: 758–788 Bond C, Si X, Crisp M,Wong P, Paulson GW, Boesel CP, Dlouhy SR, Hodes ME. Family with Pelizaeus-Merzbacher disease / X-linked spastic paraplegia and a nonsense mutation in exon 6 of the proteolipid protein gene.Am J Med Genet 1997; 71: 357–360 Boulloche J, Aicardi J. Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol 1986; 1: 233–239 Bourre JM, Jacque C, Nguyen-Legros J, Bornhofen JH, Araoz CA, Daudu O, Baumann NA. Pelizaeus-Merzbacher disease: biochemical analysis of isolated myelin (electron-microscopy: protein, lipid and unsubstituted fatty acids analysis). Eur Neurol 1978; 17: 317–326 Bridge PJ, MacLeod PM, Lillicrap DP. Carrier detection and prenatal diagnosis of Pelizaeus-Merzbacher disease using a combination of anonymous DNA polymorphisms and the proteolipid protein (PLP) gene cDNA. Am J Med Genet 1991; 38: 616–621 Cailloux F, Gauthier-Barichard F, Mimault C, Isabelle V, Courtois V,Giraud G, Dastugue B,Boespflug-Tanguy O for Clinical European Network on Brain Dysmyelinating Disease. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Eur J Hum Genet 2000; 8: 837–845 Cambi F,Tang X-M, Cordray P, Fain PR, Keppen LD, Barker DF. Refined genetic mapping and proteolipid protein mutations analysis in X-linked pure hereditary spastic paraplegia. Neurology 1996; 46: 1112–1117 Cambi F,Tartaglino L, Lublin F, McCarren D. X-linked pure familial spastic parapresis. Characterization of a large kindred with magnetic resonance imaging studies. Arch Neurol 1995; 52: 665–669 Caro PA, Marks HG. Magnetic resonance imaging and computed tomography in Pelizaeus-Merzbacher disease. Magn Reson Im 1990; 8: 791–796 Cuddon PA, Lipsitz D, Duncan ID. Myelin mosaicism and brain plasticity in heterozygous females of a canine X-linked trait. Ann Neurol 1998; 44: 771–779 Ellis D, Malcom S. Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease. Nat Genet 1994; 6: 333–334 Fanarraga ML, Griffiths IR, McCulloch MC, Barrie JA, Cattanach BM, Brophy PJ, Kennedy PGE. Rumpshaker: an X-linked mutation affecting CNS myelination.A study of the female heterozygote. Neuropathol Appl Neurobiol 1991; 17: 323–334

Fanarraga ML, Griffiths IR, McCulloch MC, Barrie JA, Kennedy PGE, Brophy PJ. Rumpshaker: an X-linked mutation causing hypomyelination and glial cells between the optic nerve and spinal cord. Glia 1992; 5: 161–170 Feldman JI, Kearns DB, Seid AB, Pransky SM, Jones MC.The otolaryngologic manifestations of Pelizaeus-Merzbacher disease. Arch Otolaryngol Head Neck Surg 1990; 116: 613–616 Garbern JY, Cambi F, Lewis R, Shy M, Sima A, Kraft G, Vallat JM, Bosch EP, Hodes ME, Dlouhy S, Raskind W, Bird T, Macklin W, Kamholz J. Peripheral neuropathy caused by proteolipid protein gene mutations. Ann NY Acad Sci 1999; 883: 351–365 Garbern J, Cambi F, Shy M, Kamholz J.The molecular pathogenesis of Pelizaeus-Merzbacher disease. Arch Neurol 1999; 56: 1210–1214 Garbern J, Shy M, Krajewski K, Kamholz J, Hobson G, Cambi F. Evidence of neuroaxonal injury in patients with proteolipid gene mutations. Neurology 2001; 57: 1938–1939 Garbern J,Yool DA, Moore GJ,Wilds IB, Faulk MW, Klugmann M, Nave K-A,Sistermans EA,van der Knaap MS,Bird TD,Shy ME, Kamholz JA, Griffiths IR. Patients lacking the major myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002; 125: 551–561 Garg BP, Markand ON, DeMyer WE. Usefulness of BAER studies in the early diagnosis of Pelizaeus-Merzbacher disease. Neurology 1983; 33: 955–956 Gencic S, Abuelo D, Ambler M, Hudson LD. PelizaeusMerzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am J Hum Genet 1989; 45: 435–442 Gow A, Lazzarini RA. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet 1996; 13: 422–428 Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, Nave K-A. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 1998; 280: 1610–1613 Griffiths I, Klugmann M, Anderson T,Thomson C,Vouyiouklis D, Nave K-A. Current concepts of PLP and its role in the nervous system. Microsc Res Tech 1998; 41: 344–358 Griffiths IR, Montague P, Dickinson P. The proteolipid protein gene. Neuropathol Appl Neurobiol 1995; 21: 85–96 Grinspan JB, Coulalaglou M, Beesley JS, Carpio DF, Scherer SS. Mutation-dependent apoptic cell death of oligodendrocytes in myelin-deficient rats. J Neurosci Res 1998; 54: 623–634 Gutmann DH, Fischbeck KH, Kamholz J. Complicated hereditary spastic paraparesis with cerebral white matter lesions. Am J Med Genet 1990; 36: 251–257 Hobson GM, Davis AP, Stowell NC, Kolodny EH, Sistermans EA, De Coo IFM, Funanage VL, Marks HG. Mutations in noncoding regions of the proteolipid protein gene in PelizaeusMerzbacher disease. Neurology 2000; 55: 1089–1096 Hodes ME, DeMyer WE, Pratt VM, Edwards MK, Dlouhy SR. Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene. Am J Med Genet 1995; 55: 397–401 Hodes ME, Blank CA, Pratt VM, Morales J, Napier J, Dlouhy SR. Nonsense mutation in exon 3 of the proteollipid protein gene (PLP) in a family with with an unusual form of Pelizaeus-Merzbacher disease. Am J Med Genet 1997; 69: 121–125

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Hodes ME, Zimmermann AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD, Dlouhy SR. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2).Am J Med Genet 1999; 82: 132–139 Hodes ME, Woodward K, Spinner NB, Emanuel BS, Enrico-Simon A, Kamholz J, Stambolian D, Zackai EH, Pratt VM, Thomas IT, Crandall K, Dlouhy SR, Malcolm S. Additional copies of the proteolipid protein gene causing PelizaeusMerzbacher disease arise by separate integration into the X chromosome. Am J Hum Genet 2000; 67: 14–22 Hudson LD. Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol 2003; 18: 616–624 Hudson LD, Puckett C, Berndt J, Chan J, Gencic S. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc Natl Acad Sci 1989; 86: 8128–831 Inoue K, Osaka H, Imaizumi K, Nezu A, Takanashi J-I, Arii J, Murayama K, Ono J, Kikawa Y, Mito T, Shaffer LG, Lupski JR. Proteolipid protein gene duplications causing PelizaeusMerzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol 1999; 45: 624–632 Inoue K,Tanaka H, Scaglia F, Araki A, Shaffer LG, Lupski JR. Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann Neurol 2001; 50: 747–754 Journel H, Roussey M, Gandon Y, Allaire C, Carsin M, le Marec B. Magnetic resonance imaging in Pelizaeus-Merzbacher disease. Neuroradiology 1987; 29: 403–405 Jung M, Sommer I, Schachner M, Nave K-A. Monoclonal antibody 010 defines a conformationally sensitive cell-surface epitope of proteolipid protein (PLP): evidence that PLP misfolding underlies dysmyelination in mutant mice. J Neurosci 1996; 16: 7920–7929 Kaga M, Murakami T, Naitoh H, Nihei K. Studies on pediatric patients with absent auditory brainstem response (ABR) later components. Brain Dev 1990; 12: 380–384 Kagawa T, Ikenaka K, Inoue Y, Kuriyama S,Tsujii T, Nakao J, Nakajima K, Aruga J, Okano H, Mikoshiba K. Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron 1994; 13: 427–442 Karthigasan J, Evans EL,Vouyiouklis DA, Inouye H, Borenshteyn N, Ramamurthy GV, Kirschner DA. Effects if Rumpsaker mutation on CNS myelin composition and structure. J Neurochem 1996; 66: 338–345 Kaye EM, Doll RF, Natowicz MR, Smith FI. Pelizaeus-Merzbacher disease presenting as spinal muscular atrophy: clinical and molecular studies. Ann Neurol 1994; 36: 916–919 Kobayashi H, Hoffman EP. The rumpshaker mutation in spastic paraplegia. Nat Genet 1994; 7: 351–352 Koeppen AH, Robitaille Y.Pelizaeus-Merzbacher disaese.J Neuropathol Exp Neurol 2002; 61: 747–759 Koeppen AH, Ronca NA, Greenfield EA, Hans MB. Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease. Ann Neurol 1987; 21: 159–170 Komaki H Sasaki M, Yamamoto T, Iai M, Takanshima S. Connatal Pelizaeus-Merzbacher disease associated with the Jimpymsd mice mutation. Pediatr Neurol 1999; 20: 309–311 Learish RD, Brüstle O, Zhang S-C, Duncan ID. Intraventricular transplantation of oligodendrocyte progenitors into a fetal myelin mutant results in widespread formation of myelin. Ann Neurol 1999; 46: 716–722

Merzbacher L. Eine eigenartige familiär-hereditäre Erkrankungsform (aplasia axialis extracorticalis congenita). Z Ges Neurol Psychiatrie 1910; 3: 1–138 Mimault C, Giraud G, Courtois V, Cailloux FN, Boire JY, Dastugue B, Boespflug-Tanguy O, The Clinical European Network on Brain Dysmyelination Disease. Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. Am J Hum Genet 1999; 65: 360–369 Naidu S, Dlouhy SR, Geraghty MT, Hodes ME. A male child with the rumpshaker mutation, X-linked spastic paraplegia/ Pelizaeus-Merzbacher disease and lysinuria.J Inherit Metab Dis 1997; 20: 811–816 Nance MA,Boyadjiev S,Pratt VM,Taylor S,Hodes ME,Dlouhy SR. Adult-onset neurodegenerative disorder due to proteolipid protein gene mutation in the mother of a man with Pelizaeus-Merzbacher disease. Neurology 1996; 47: 1333– 1335 Nezu A, Kimura S, Takeshita S, Osaka H, Kimura K, Inoue K. An MRI and MRS study of Pelizaeus-Merzbacher disease. Pediatr Neurol 1998;18: 334–337 Pelizaeus F. Ueber eine eigenartige familiäre Entwickelungshemmung vornehmlich auf motorischem Gebiet. Arch Psychiatr Nervenkr 1899; 31: 100–104 Plecko B, Stockler-Ipsiroglu S, Gruber S, Mlynarik V, Moser E, Simbrunner J, Ebner F, Bernert G, Harrer G, Gal A, Prayer D. Degree of hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype. Neuropediatrics 2003; 34: 127–136 Readhead C, Schneider A, Griffiths I, Nave K-A. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 1994; 12: 583–595 Renier WO, Gabreeels FJM, Hustinx TWJ, Jaspar HHJ, Geelen JAG, van Haelst UJG, Lommen EJP, ter Haar BGA. Connatal Pelizaeus-Merzbacher disease with congenital stridor in two maternal cousins. Acta Neuropathol (Berl) 1981; 54: 11–17 Saugier-Veber P, Munnich A, Bonneau D, Rozet J-M, Le Merrer M, Gil R, Boespflug-Tanguy O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 1994; 6: 257–262 Scheffer IE, Baraitser M,Wilson J, Harding B, Kendall B, Brett EM. Pelizaeus-Merzbacher disease: classical or connatal? Neuropediatrics 1991; 22: 71–78 Schneck L, Adachi M, Volk BW. Congenital failure of myelinization: Pelizaeus-Merzbacher disease? Neurology 1971; 21: 817–824 Shy ME, Hobson G, Jain M, Boespflug-Tanguy O, Garbern J, Sperle K, Li W, Gow A, Rodrihuez D, Bertini E, Mancias P, Krajewski K, Lewis R, Kamholz J. Schwann cell expression of PLP1 but not DM 20 is necessary to prevent neuropathy. Ann Neurol 2003; 53: 354–365 Silverstein AM, Hirsh DK, Trobe JD, Gebarski SS. MR imaging of the brain in five members of a family with PelizaeusMerzbacher disease. AJNR Am J Neuroradiol 1990; 11: 495–499 Simons M, Krämer E-M, Macchi P, Rathke-Hartlieb S, Trotter J, Nave K-A, Schulz JB. Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease. J Cell Biol 2002; 157: 327–336

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964 References and Further Reading Sistermans EA, De Wijs IJ, De Coo RFM, Smit LME, Menko FH, Van Oost BA. A (G-to-A) mutation in the intiation condon of the proteolipid protein gene causing a reletively mild form of Pelizaeus-Merzbacher disease in a Dutch family. Hum Genet 1996; 97: 337–339 Sistermans EA, De Coo, RFM, De Wijs IJ, Van Oost BA. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 1998; 50: 1749– 1754 Sivakumar K, Sambuughin N, Selenge B, Nagle JW, Baasanjav D, Hudson LD, Goldfarb LG. Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol 1999; 45: 680–683 Southwood CM, Garbern J, Jiang W, Gow A. The unfolded protein response modulates disease severity in PelizaeusMerzbacher disease. Neuron 2002; 36: 585–596 Spalice A, Popolizio T, Parisi P, Scarabino T, Iannetti P. Proton MR spectroscopy in connatal Pelizaeus-Merzbacher disease. Pediatr Radiol 2000; 30: 171–175 Spörkel O, Uschkureit T, Büssow H, Stoffel W. Oligodendrocytes expressing exclusively the DM 20 isoform of the proteolipid protein gene: myelination and development. Glia 2002; 37: 19–30 Takanashi J-I, Sugita K, Osaka H, Ishii M, Niimi H. Proton MR spectroscopy in Pelizaeus-Merzbacher disease. AJNR Am J Neuroradiol 1997; 18: 533–535 Takanashi J-I, Sugita K,Tanabe Y, Nagasawa K, Inoue K, Osaka H, Kohno Y. MR-Revealed myelination in the cerebral corticospinal tract as a marker for Pelizaeus-Merzbacher’s disease with proteolipid protein gene duplication. AJNR Am J Neuroradiol 1999; 20: 1822–1828 Takanashi J, Inoue K, Tomita M, Kurihara A, Morita F, Ikehira H, Tandana S,Yoshitome E, Kohno Y. Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication. Neurology 2002; 58: 237–241 Thomson CE,Montague P,Jung M,Nave K-A,Griffiths IR.Phenotypic severity of murine PLp mutants reflects in vivo and in vitro variations in transport of PLP isoproteins. Glia 1997; 20: 322–332 Ulrich J, Herschkowitz N. Seitelberger’s connatal form of Pelizaeus-Merzbacher disease. Acta Neuropathol (Berl) 1977; 40: 129–136 van der Knaap MS, Valk J. The reflection of histology in MR imaging of Pelizaeus-Merzbacher disease. AJNR Am J Neuroradiol 1989; 10: 99–103 Vaurs-Barriere C, Wong K, Weibel TD, Abu-Asab M, Weiss MD, Kaneski CR, Mixon TH, Bonavita S, Creveaux I, Heiss JD, Tsokos M, Goldin E, Quarles RH, Boespflug-Tanguy O, Schiffmann R. Insertion of mutant proteolipid protein results in missorting of myelin proteins. Ann Neurol 2003; 54: 769–780 Watanabe I, McCaman R, Dyken P, Zeman W. Absence of cerebral myelin sheaths in a case of presumed PelizaeusMerzbacher disease. J Neuropathol Exp Neurol 1969; 28: 243–256 Watanabe I, Patel V, Goebel HH, Siakotos AN, Zeman W, Demyer W, Schroder Dyer J. Early lesion of Pelizaeus-Merzbacher disease: electron microscopic and biochemical study. J Neuropathol Exp Neurol 1973; 32: 313–333 Witter B, Debuch H, Klein H. Lipid investigation of central and peripheral nervous system in connatal PelizaeusMerzbacher’s disease. J Neurochem 1980; 34: 957–962

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35 18q– Syndrome Davis Ghidoni P, Hale DE, Cody JD, Gay CT, Thompson NM, McClure EB, Danny MM, Leach RJ, Kaye CI. Growth hormone deficiency associated in the 18q deletion syndrome. Am J Med Genet 1997; 69: 7–12 Felding I,Kristoffersson U,Sjöström H,Noren O.Contribution to the 18q– syndrome. A patient with del (18) (q22.3qter). Clin Genet 1987; 31: 206–210 Fryns JP, Logghe N, van Eygen M, van den Berghe H. 18q– Syndrome in mother and daughter. Eur J Pediatr 1979; 130: 189–192 Gabrielli O, Coppa GV, Carloni I, Salvolini U. 18q– Syndrome and white matter alterations. AJNR Am J Neuroradiol 1998; 39: 398–399 Gay CT, Hardies LJ, Rauch RA, Lancaster JL, Plaetke R, DuPont BR, Cody JD, Cornell JE, Herndon RC, Ghidoni PD, Schiff JM, Kaye CI, Leach RJ, Fox PT. Magnetic Resonance Imaging demonstrates incomplete myelination in 18q– syndrome: evidence for myelin basic protein haploinsufficiency. Am J Med Genet 1997; 74: 422–431 Jayarajan V, Swan IRC, Patton MA. Hearing impairment in 18q deletion syndrome. J Laryngol Otol 2000; 114: 963–966 Kamholz J, Spielman R, Gogolin K, Modi W, O’Brien S, Lazzarini R. The human myelin-basic-protein gene: chromosomal localization and RFLP analysis. Am J Hum Genet 1987; 40: 365–373 Keppler-Noreuil KM, Carroll AJ, Finley SC, Descartes M, Cody JD, DuPont BR, Gay CT, Leach RJ. Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss. Am J Med Genet 1998; 76: 372–378 Kline AD,White ME,Wapner R, Rojas K, Biesecker LG, Kamholz J, Zackai EH, Muenke M, Scott Jr CI, Overhauser J. Molecular analysis of the 18q– syndrome – and correlation with phenotype. Am J Hum Genet 1993; 52: 895–906 Lemke G. Unwrapping the genes of myelin. Neuron 1988; 1: 535–543 Linnankivi TT, Autti TH, Pikho SH, Somer MS, Tienari PJ, Wirtavuori KO,Valanne LK. 18q– syndrome: brain MRI shows poor differentiation of gray and white matter on T2weighted images. J Magn Reson Imag 2003; 18: 414–419 Loevner LA, Shapiro RM, Grossmann RI, Overhauser J, Kamholz J. White matter changes associated with deletions of the long arm of chromosome 18 (18q– syndrome): a dysmyelinating disorder? AJNR Am J Neuroradiol 1996; 14: 1843– 1848

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36 Phenylketonuria Alvord EC, Stevenson LD, Vogel FS, Engle RL. Neuropathological findings in phenyl-pyruvic oligophrenia (phenyl-ketonuria). J Neuropathol Exp Neurol 1950; 9: 298–310 Anderson PJ, Wood SJ, Francis D, Coleman L, Warwick L, Casanelia S, Anderson VA, Boneh A. Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol 2004; 46: 230–238 Arnold GL,Vladutiu CJ, Kirby RS, Blakely EM, DeLuca JM. Protein insufficiency and linear growth restriction in phenylketonuria. J Pediatr 2002; 141: 243–246 Battistini S, de Stefano N, Parlanti S, Federico A. Unexpected white matter changes in an early treated PKU case and improvement after dietary treatment. Funct Neurol 1991; 6: 177–180 Bick U, Fahrendorf G, Ludolph AC, Vassallo P, Weglage J, Ullrich K. Disturbed myelination in patients with treated hyperphenylalaninaemia: evaluation with magnetic resonance imaging. Eur J Pediatr 1991; 150: 185–189 Blau N, Branes I, Dhondt JL. International database of tetrahydrobiopterin deficiencies.J Inherit Metab Dis 1996; 19: 8–14 Bonafé L, Blau N, Burlina AP, Romstad A, Gütter F, Burlina AB. Treatable neurotransmitter deficiency in mild phenylketonuria. Neurology 2001; 57: 908–911 Brenton DP, Pietz J. Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr 2000; 159: S114-S120

Breysem L, Smet M-H, Johannik K, van Hecke P, François B, Wilms B, Bosmans H. Marchal G, Jaeken J, Demaerel P. Brain MR imaging in dietary treatment phenylketonuria. Eur Radiol 1994: 4: 329–331 Brismar J, Aqeel A, Gascon G, Ozand P. Malignant hyperphenylalaninemia: CT and MR of the brain. AJNR Am J Neuroradiol 1990; 11: 135–138 Burgard P. Development of intelligence in early treated phenylketonuria. Eur J Pediatr 2000; 159: S74-S79 Burri R, Steffen CH, Stieger S, Brodbeck U, Colombo JP, Herschkowitz N. Reduced myelinogenesis and recovery in hyperphenylalaninemic rats. Mol Chem Neuropathol 1990; 13: 57–69 Cerone R, Schiaffino MC, Di Stefano S, Veneselli E. Phenylketonuria: diet for life or not? Acta Paediatr 1999; 88; 664–666 Chien Y-H, Peng S-F, Wang T-R, Hwu W-L. Cranial MR spectroscopy of tetrahydrobiopterin deficiency. AJNR Am J Neuroradiol 2002; 23: 1055–1058 Cleary MA, Walter JH. Assessment of adult phenylketonuria. Ann Clin Biochem 2001; 38: 450–458 Cleary MA, Walter JH, Wraith JE, Jenkins JPR, Alani SM, Tyler K, Whittle D. Magnetic resonance imaging of the brain in phenylketonuria. Lancet 1994; 334; 87–90 Cleary MA, Walter JH, Wraith JE, Jenkins JPR. Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 1995; 127: 251–255 Costa LG, Guizzetti M, Burry M, Oberdoerster J. Developmental neurotoxicity: do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria.Toxicol Lett 2002; 127: 197–205 Dezortová M, Hájek M, Tintra, Hejcmanová L, Syková E. MR in phenylketonuria-related brain lesions.Acta Radiol 2001; 42: 459–466 Dhondt JL, Farriaux JP, Boudha A, Largillière C, Ringel J, Roger MM, Leeming RJ. Neonatal hyperphenylalaninemia presumably caused by guanosine triphosphate-cyclohydrolase deficiency. J Pediatr 1985; 106: 954–956 Erlandsen H, Stevens RC. The structural basis of phenylketonuria. Mol Genet Metab 1999; 68: 103–125 Erlandsen H, Stevens RC. A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninaemia and phenylketonuria. J Inherit Metab Dis 2001; 24: 213–230 Fisch RO, Burke B, Bass J, Ferrara TB, Mastri A. Maternal phenylketonuria – chronology of the detrimental effects on embryogenesis and fetal development: pathological report, survey, clinical application. Pediatr Pathol 1986; 5: 449–461 Fisch RO, Chang P-N, Weisberg S, Guldberg P, Güttler F, Tsai MY. Phenylketonuric patients decades after diet. J Inherit Metab Dis 1995; 18: 347–353 Gerstl B, Malamud N, Eng LF, Hayman RB. Lipid alterations in human brains in phenylketonuria. Neurology 1967; 17: 51–57 Giovannini M, Biasucci G, Brioschi M, Ghiglioni D, Riva E. Cofactor defects and PKU: diagnosis and treatment. Int Pediatr 1991; 6: 26–31 Gudinchet F, Maeder P, Meuli RA, Deonna T, Mathieu JM. Cranial CT and MRI in malignant phenylketonuria. Pediatr Radiol 1992; 22: 223–224 Güttler F, Guldberg P. Mutation analysis anticipates dietary requirements in phenylketonuria. Eur J Pediatr 2000; 159; S150-S153

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966 References and Further Reading Huijbreghts SCJ, de Sonneville LMJ, Licht R, van Spronsen FJ, Sergeant JA. Short-term dietary erventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. J Inherit Metab Dis 2002; 25: 419–430 Huttenlocher PR.The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 2000: 159; S102-S106 Jones SJ, Turano G, Kriss A, Shawkat F, Kendall B, Thompson AJ. Visual evoked potentials in phenylketonuria: association with brain MRI, dietary state, and IQ. J Neurol Neurosurg Psychiatry 1995; 59: 260–265 Knudden GM,Hasselbalch S,Toft PB,Christensen E,Paulson OB, Lou H. Blood–brain barrier transport of amino acids in healthy controls and in patients with phenylketonuria. J Inherit Metab Dis 1995; 18: 653–664 Koch R, Hanley W, Levy H, Matalon R, Rouse B, Trefz F, Guttler F, Azen C, Friedman E, Platt L, de la Cruz F. maternal phenylketonuria: an international study. Mol Genet Metab 2000; 71: 233–239 Koch R, Burton B, Hoganson G, Peterson R, Rhead W, Rouse B, Scott R, Wolff J, Stern AM, Guttler F, Nelson M, de la Cruz F, Coldwell J, Erbe R, Geraghty MT, Shear C, Thomas J, Azen C. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 2002; 25: 333–346 Lässker U, Zschocke J, Blau N, Santer R.Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings. J Inherit Metab Dis 2002; 25: 65–70 Leuzzi V, Gualdi GF, Fabbrizi F, Trasimeni G, DiBiasi C, Antonozzi I.Neuroradiological (MRI) abnormalities in phenylketonuric subjects: clinical and biochemical correlations. Neuropediatrics 1993; 24: 302–306 Leuzzi V, Traisimeni G, Gualdi GF, Antonozzi I. Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients. J Inherit Metab Dis 1995; 18: 624–634 Levy HL, Lobbregt D, Sansaricq C, Snyderman SE. Comparison of phenylketonuric and nonphenylketonuric sibs from untreated pregnancies in a mother with phenylketonuria. Am J Med Genet 1992; 44: 439–442 Longhi R,Valsasina R, Buttè C, Paccanelli S, Riva E, Giovannini M. Cranial computerized tomography in dihydropterine reductase deficiency. J Inherit Metab Dis 1985; 8: 109–112 Lou HC, Toft PB, Andressen J, Mikkelsen I, Olsen B, Güttler F, Wieslander S, Henriksen O. An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninaemia. J Inherit Metab Dis 1992; 15: 687–695 Magee AC, Ryan K, Moore A, Trimble ER. Follow up of fetal outcome in cases of maternal phenylketonuria in Northern Ireland. Arch Dis Child 2002; 87: F141-F143 Malamud N. Neuropathology of phenylketonuria. J Neuropathol Exp Neurol 1966; 25: 254–268 McCombe PA, McLaughlin DB, Chalk JB, Brown NN, McGill JJ, Pender MP. Spasticity and white matter abnormalities in adult phenylketonuria. J Neurol Neurosurg Psychiatry 1992; 55: 359–361 Menkes JH. The pathogenesis of mental retardation in phenylketonuria and other inborn errors of amino acid metabolism. Pediatrics 1967; 39: 297–308 Milandi N, Larnaout A, Dhondt J-L, Vincent M-F, Kaabachi N, Hentati F. Dihydropteridine reductase deficiency in a large consanguineous Tunisian family: clinical, biochemical, and neuropathologic findings. J Child Neurol 1998; 13: 475–480 Moats RA, Koch R, Moseley K, Guldberg P, Guttler F, Boles RG, Nelson Jr, MD. Brain phenylalanine concentration of adults with phenylketonuria. J Inherit Metab Dis 2000, 23: 7–14

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37 Glutaric Aciduria Type I Al-Essa M, Bakheet S, Patay Z, Al-Watban J, Powe J, Joshi S, Ozand PT. Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in glutaric aciduria type I: clinical and MRI correlations. Brain Dev 1998; 20: 295–301 Alkan A, Baysal T,Yakinici C Sig˘erici A, Kutlu R. Glutaric aciduria type I diagnosed after poliovirus immunization: magnetic resonance findings. Pediatr Neurol 2002; 26: 405–407 Altman NR, Rovira MJ, Bauer M. Glutaric aciduria type 1: MR findings in two cases. AJNR Am J Neuroradiol 1991; 12: 966–968 Amir N, Peleg OE, Shalev RS, Christensen E. Glutaric aciduria type I: clinical heterogeneity and neuroradiologic features. Neurology 1987; 37: 1654–1657 Amir N, Elpeleg ON, Shalev RS, Christensen E. Glutaric aciduria type I: enzymatic and neuroradiologic investigations of two kindreds. J Pediatr 1989; 114: 983–989 Bähr O, Mader I, Zschoke J, Dichgans J, Schultz JB. Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology 2002; 59: 1802–1804 Bariæ I, Zschocke J, Christensen E, Duran M, Goodman SI, Leonard JV, Muller E, Morton DH, Superti-Furga A, Hoffmann GF. Diagnosis and management of glutaric aciduria type I. J Inherit Metab Dis 1998; 21: 326–340 Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF. Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 1999; 22: 867–882 Bennett MJ, Marlow N, Pollitt RJ, Wales JKH. Glutaric aciduria type I: biochemical investigations and postmortem findings. Eur J Pediatr 1986; 145: 403–405 Bennett MJ, Pollitt RJ, Goodman SI, Hale DE,Vamecq J. Atypical riboflavin-responsive glutaric aciduria, and deficient peroxisomal glutaryl-CoA oxidase activity: a new peroxisomal disorder. J Inherit Metab Dis 1991; 14: 165–173 Bergman I, Finegold D, Gärtner JC, Zitelli BJ, Claassen D, Scarano J, Roe CR, Stanley C, Goodman SI. Acute profound dystonia in infants with glutaric acidemia. Pediatrics 1989; 83: 228–234 Bismar J, Ozand PT. CT and MR of the brain in glutaric aciduria type I: a review of 59 published cases and a report of 5 new patients. AJNR Am J Neuroradiol 1995; 16: 675–683 Busquets C, Coll MR, Christensen E, Campistol J, Clusellas N, Vilaseca MA, Ribes A. Feasibility of molecular prenatal diagnosis of glutaric aciduria type I in chorionic villi. J Inherit Metab Dis 1998; 21: 243–246 Busquets C, Coll MJ, Merinero B, Ugarte M, Ruiz MA, Martinez Bermejo A, Ribes A. Prenatal molecular diagnosis of glutaric aciduria type I by direct mutation analysis. Prenat Diagn 2000; 20: 761–764

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968 References and Further Reading Busquets C, Soriano M, Taveres de Almeida I, Garavaglia B, Rimoldi M,Rivera I,Uziel G,Cabral A,Coll MJ,Ribes A.Mutation analysis of the GCDH gene in Italian and Portuguese patients with glutaric aciduria type I. Mol Genet Metab 2000; 71: 535–537 Busquets C, Merinero B, Christensen E, Gelpi JL, Campistol J, Pineda M, Fernández-Alverez E, Prats JM, Sans A, Arteaga R, Martí M, Campos J, Martínez-Pardo M, Martinez-Bermejo A, Ruiz-Falcó ML, Vaquerizo J, Orozco M, Ugarte M, Coll MJ, Ribes A. Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct. Pediatr Res 2000; 48: 315–322 Campistol J, Ribes A, Alvarez L, Christensen E, Millington DS. Glutaric aciduria type I: unusual biochemical presentation. J Pediatr 1992; 121: 83–86 Chow CW, Haan EA, Goodman SI, Anderson RM, Evans WA, Kleinschmidt-de Masters BK, Wise G, McGill JJ, Danks DM. Neuropathology in glutaric acidaemia type I. Acta Neuropathol (Berl) 1988; 76: 590–594 Desai NK, Runge VM, Crisp DE, Crisp MB, Naul LG. Magnetic resonance imaging of the brain in glutaric acidemia type I: a review of the literature and a report of four new cases with attention to the basal ganglia and imaging technique. Invest Radiol 2003; 38: 489–496 Drigo P, Piovan S, Battistella PA, Della Puppa A, Burlina AB. Macrocephaly, subarachnoid fluid collection, and glutaric aciduria type I. J Child Neurol 1996; 11: 414–417 Francois B, Jaeken J, Gillis P. Vigabatrin in the treatment of glutaric aciduria type I. J Inherit Metab Dis 1990; 13: 352–354 Goodman SE, Norenberg MD, Shikes RH, Breslich DJ, Moe PG. Glutaric aciduria: biochemical and morphologic considerations. J Pediatr 1990; 90: 746–750 Hald JK, Nakstad PH, Skjeldal OH, Strømme P. Bilateral arachnoid cysts of the temporal fossa in four children with glutaric aciduria type I. AJNR Am J Neuroradiol 1991; 12: 407–409 Hartley LM, Khwaja OS, Verity CM. Glutatic aciduria type I and nonaccidental head injury. Pediatrics 2001; 107: 174–175 Hauser S, Peters H. Glutaric aciduria type I: an underdiagnosed cause of encephalopathy and dystonia-dyskinesia syndrome in children. J Paediatr Child Health 1998; 34: 302– 304 Hauser SEP, Boneh A. Severe clincal cause with recurrent hyperpyrexia in a patient with glutaric aciduria type I. Neuropediatrics 1999; 30: 51–52 Haworth JC, Booth FA, Chudley AE, de Groot GW, Dilling LA, Goodman SI,Greenberg CR,Mallory CJ,McClarty BM,Seshia SS, Seargeant LE. Phenotypic variability in glutaric aciduria type I: report of fourteen cases in five Canadian Indian kindreds. J Pediatr 1991; 118: 52–58 Hoffmann GF, Trefz FK, Barth PG, Böhles HJ, Lehnert W, Christensen E, Valk J, Rating D, Bremer HJ. Macrocephaly: an important indication for organic acid analysis. J Inherit Metab Dis 1991; 14: 329–332 Hoffmann GF, Trefz FK, Barth PG, Böhles HJ, Biggemann B, Bremer HJ, Christensen E, Frosch M, Hanefeld F, Hunneman DH, Jacobi H, Kurlemann G, Lawrenz-Wolf B, Rating D, Roe CR, Schutgens RBH, Ullrich K, Weisser J, Wendel U, Lehnert W. Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy. Pediatrics 1991; 88: 1194–1203 Hoffmann GF, Böhles HJ, Burlina A, Duran M, Herwig J, Lehnert W, Leonard JV, Muntau A, Plecko-Starting FK, Superti-Furga A,Trefz FK, Christensen E.Early signs and cause of disease of glutaryl-CoA dehydrogenase deficiency.J Inherit Metab Dis 1995; 18: 173–176

Hoffmann GF, Althanassopoulos S, Burlina AB, Duran M, de Klerk BC, Lehnert W, Leonard JV, Moravari AA, Müller E, Muntau AC, Naugten ER, Plecko-Starting B, Superti-Furga A, Zschocke J, Christensen E. Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 1996; 27: 115–123 Hoffmann GF, Zschocke J. Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis 1999; 22: 381–391 Iafolla AK, Kahler SG. Megalencephaly in the neonatal period as the initial manifestation of glutaric aciduria type I. J Pediatr 1989; 114: 1004–1006 Jamjoom ZAB, Okamoto E, Jamjoom A-H B, Al Hajery O, AbuMelha A. Bilateral arachnoid cysts of the sylvian region in female siblings with glutaric aciduria type I. J Neurosurg 1995; 82: 1078–1081 Kafil-Hussain NA, Monvarvi A, Bowell R, Thornton P, Naughten E, O’Keefe M. Ocular findings in glutaric aciduria type I. J Pediatr Ophthalmol Strabismus 2000; 37: 289–293 Kölker S, Ahlemeyer B, Kriegelstein J, Hoffmann GF. 3-Hydroxyglutaric and glutaric acids are neurotoxic through NMDA receptors in vitro. J Inherit Metab Dis 1999; 22: 259–2623 Kölker S, Ahlemeyer B, Kriegelstein J, Hoffmann GF. Evaluation of trigger factors of acute encephalopathy in glutaric aciduria type I: fever and tumour necrosis factor-a. J Inherit Metab Dis 2000; 23: 359–362 Kölker S,Ahlemeyer B,Kriegelstein J,Hoffmann GF.Maturationdependent neurotoxicity of 3-hydroxyglutaric and glutaric acids in vitro:a new pathophysiologic approach to glutarylCoA dehydrognase deficiency. Pediatr Res 2000; 47: 495– 503 Kölker S, Ramaekers VT, Zschocke J, Hoffmann GF. Acute encephalopathy despite early therapy in a patient with homozygosity for E365 K in the glutaryl-coenzyme A dehydrogenase gene. J Pediatr 2001; 138: 277–279 Kölker S, Hoffmann GF, Schor DS, Feyh P, Wagner L, Jeffrey I, Pourfarzam M, Okun JG, Zschocke J, Baric I, Bain MD, Jakobs C, Chalmers RA. Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 2003; 34: 253–260 Kyllerman M, Skjeldal OH, Lundberg M, Holme I, Jellum E, von Döbeln U, Fossen A, Carlsson G. Dystonia and dyskinesia in glutaric aciduria type I: clinical heterogeneity and therapeutic considerations. Mov Dis 1994; 9: 22–30 Land JM, Goulder P, Johnson A, Hockaday J. Glutaric aciduria type I. An atypical presentation together with some observations upon treatment and the possible cause of cerebral damage. Neuropediatrics 1992; 23: 322–326 Leibel RL, Shih VE, Goodman SI, Bauman ML, McCabe ERB, Zwerdling RG, Bergman I, Costello C.Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis. Neurology 1980; 30: 1163–1168 Lipkin PH, Roe CR, Goodman SI, Batshaw ML. A case of glutaric acidemia type I: effect of riboflavin and carnitine. J Pediatr 1988; 112: 62–65 Lütcherath V,Waaler PE, Jellum E,Wester K. Children with bilateral temporal arachnoid cysts may have glutaric aciduria type I (GATI); operation without knowing that may be harmful. Acta Neurochir (Wien) 2000; 142: 1025–1030 Mandel H, Braun J, El-Peleg O, Christensen E, Berant M. Glutaric aciduria type I. Brain CT features and a diagnostic pitfall. Neuroradiology 1991; 33: 75–78

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38 Propionic Acidemia Bergman AJIW,van der Knaap MS,Smeitink JAM,Duran M,Dorland L,Valk J, Poll-The BT. Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: clinical and biochemical considerations. Pediatr Res 1996; 40: 404– 409 Böhles H, Lehnert W. The effect of intravenous l-carnitine on propionic acid excretion in acute propionic acidaemia. Eur J Pediatr 1984; 143: 61–63 Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. AJNR Am J Neuroradiol 1994; 15: 1459–1473 Burlina AB, Dionisi-Vici C, Piovan S, Saponara I, Bartuli A, Sabetta G, Zacchello F. Acute pancreatitis in propionic acidaemia. J Inherit Metab Dis 1995; 18:169–172 Chemelli AP, Schocke M, Sperl W, Trieb T, Aichner F, Felber S. Magnetic resonance spectroscopy (MRS) in five patients with treated propionic acidemia. J Magn Reson Imaging 2000; 11: 596–600 Clavero S, Martínez MaA, Pérez B, Pérez-Cerdá C, Ugarte M, Desviat LR. Functional characterization of PCCA mutations causing propionic acidemia. Biochim Biophys Acta 2002; 1588: 119–125 Gebarski SS, Gabrielsen TO, Knake JE, Latack JT. Cerebral CT findings in methylmalonic and propionic acidemias. AJNR Am J Neuroradiol 1983; 4: 955–957 Gravel RA, Akerman BR, Lamhonwah AM, Loyer M, Léon-delRio A, Italiano I. Mutations participating in interallelic complementation in propionic acidemia. Am J Hum Genet 1994; 55: 51–58 Haas RH, Marsden DL, Capistrano-Estrada S, Hamilton R, Grafe MR, Wong W, Nyhand WL. Acute basal ganglia infarction in propionic acidemia. J Child Neurol 1995; 10: 18–22 Hamilton RL, Haas RH, Nyhan WL, Powell HC, Grafe MR. Neuropathology of propionic acidemia:a report of two patients with basal ganglia lesions. J Child Neurol 1995; 10: 25–30 Harding BN, Leonard JV, Erdohazi M. Propionic acidaemia: a neuropathological study of two patients presenting in infancy. Neuropathol Appl Neurobiol 1991; 17: 133–138 Hommes FA, Kuipers JRG, Elema JD, Jansen JF, Jonxis JHP. Propionicacidemia, a new inborn error of metabolism. Pediatr Res 1968; 2: 519–524 Inoue Y, Kuhara T. Rapid and sensitive method for prenatal diagnosis of propionic acidemia using stable isotope dilution gas chromatography-mass spectroscopy and urease pretreatment. J Chromatogr B Biomed Sci Appl 2002; 776: 71–77

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972 References and Further Reading Toone JR, Applegarth DA, Coulter-Mackie M, James ER. Identification of the first reported splice site mutation (IVS7–1GA) ion th aminomethyltransferase (T-protein) gene (AMT) of the glycine cleavage complex in 3 unrelated families with nonketotic hyperglycinemia. Hum Mutat 2000; 17: 76–81 Tauner DA, Page T, Green C, Sweetman L, Kulovich S, Nyhan WL. Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia. J Pediatr 1981; 98: 272–275 Van Hove JLK, Kishnani PS, Damaerel P, Kahler SG, Miller C, Jaeken J, Rutledge SL. Acute hydrocephalus in nonketotic hyperglycinemia. Neurology 2000; 54: 754–756 Wiltshire EJ, Poplawski NK, Harrison JR, Fletcher JM. Treatment of late-onset nonketotic hyperglycinaemia:effectiveness of imipramine and benzoate. J Inherit Metab Dis 2000; 23: 15–21 Wraith JE. Non-ketotic hyperglycinemia: prolonged survival in a patient with a mild variant. J Inherit Metab Dis 1996; 19: 695–696 Zammarchi E, Donati MA, Ciani F, Pasquini E, Pela I, Fiorini P. Failure of early dextromethorphan and sodium benzoate therapy in an infant with nonketotic hyperglycinemia. Neuropediatrics 1994; 25: 274–276 Zammarchi E, Donati MA, Ciani F.Transient neonatal nonketotic hyperglycinemia: a 13-year follow-up. Neuropediatrics 1995; 26: 328–330

40 Maple Syrup Urine Disease Backhouse O, Leitch RJ,Thompson D, Kriss A, Charris D, Clayton P, Russel-Eggitt I. A case of reversible blindness in maple syrup urine disease. Br J Ophthalmol 1999; 83: 250–251 Berry GT, Heidenreich R, Kaplan P, Levine F, Mazur A, Palmieri MJ,Yudkoff M,Segal S.Branched-chain amino acid-free parenteral nutrition in the treatment of acute metabolic decompensation in patients with maple syrup urine disease. N Engl J Med 1991; 324: 175–179 Biggemann B, Zass R, Wendel U. Postoperative metabolic decompensation in maple syrup urine disease is completely prevented by insulin. J Inherit Metab Dis 1993; 16: 912–913 Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P. Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. AJNR Am J Neuroradiol 1990; 11: 1219–1228 Cavelleri F, Berardi A, Burlina AB, Ferrari F, Mavilla L. Diffusionweighted MRI of maple syrup urine disease encephalopathy. Neuroradiology 2002; 44: 449–502 Chuang DT, Davie JR, Max Wynn R, Chuang JL, Koyata H, Cox RP. Molecular basis of maple syrup urine disease and stable correction by retroviral gene transfer. J Nutr 1995; 125: 1766S–1772S Chuang JL, Chuang DT. Diagnosis and mutational analysis of maple syrup urine disease using cell cultures. Methods Enzymol 2000; 324: 413–464 Delis D, Michelakakis H, Katsarou E, Bartsocas CS. Thiamin-responsive maple syrup urine disease: seizures after 7 years of satisfactory metabolic control. J Inherit Metab Dis 2001; 24: 683–684 Fariello G, Dionisi-Vice C, Orazi C, Malena S, Bartuli A, Schingo P, Carnavale E, Saponara I, Sabetta G. Cranial ultrasonography in maple syrup urine disease. AJNR Am J Neuroradiol 1996; 17: 311–315

Felber SR, Sperl W, Chemelli A, Murr Ch,Wendel U. Maple syrup urine disease: metabolic decompensation monitored by proton magnetic resonance imaging and spectroscopy. Ann Neurol 1993; 33: 396–401 Giacoia GP, Berry GT. Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease. Am J Dis Child 1993; 147: 954–956 Gouyon JB, Semama D, Prévot A, Desgres J. Removal of branched-chain amino acids and a-ketoisocaproate by haemofiltration and haemodiafiltration. J Inherit Metab Dis 1996;19: 610–620 Ha JS, Kim TK, Eun BL, Lee HS, Lee KY, Seol HY, Cha SH. Maple syrup urine disease encephalopathy: a follow-up study in the acute stage using diffusion-weighted MRI. Pediatr Radiol 2004; 34: 163–166 Hilliges C, Awiszus D, Wendel U. Intellectual performance of children with maple syrup urine disease. Eur J Pediatr 1993; 152: 144–147 Indo Y, Akaboshi I, Nobukumi Y, Endo F, Matsuda I. Maple syrup urine disease: a possible biochemical basis for the clinical heterogeneity. Hum Genet 1988; 80: 6–10 Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003; 45: 393–399 Jouvet P, Poggi F, Rabier D, Michel JL, Hubert P, Sposito M, Saudurbray JM, Man NK. Continuous venovenous haemodiafiltration in the acute phase of neonatal maple syrup disease. J Inherit Metab Dis 1997; 20: 463–477 Jouvet P, Rustin P, Taylor DL, Pocock JM, Felderhoff-Mueser U, Mazarakis ND, Sarraf C, Joashi U, Kozma M, Greenwood K, Edwards DA, Mehmet H. Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell 2000; 11: 1919–1932 Jouvet P, Jugie M, Rabier D, Desgrès J, Hubert P, Saudubray JM, Man NK. Combined nutritional support and continuous extracorporeal removal therapy in the severe acute phase of maple syrup urine disease. Intensive Care Med 2001; 27: 1798–1806 Kamei A, Takashima S, Chan F, Becker LE. Abnormal dendritic development in maple syrup urine disease. Pediatr Neurol 1992; 8: 145–147 Kaplan P, Mazur A, Field M, Berlin JA, Berry GT, Heidenreich R, Yudkoff M, Segal S. Intellectual outcome in children with maple syrup urine disease. J Pediatr 1991; 119: 46–50 Kleopa KA, Raizen DM, Friedrich CA, Brown MJ, Bird SJ. Acute axonal neuropathy in maple syrup urine disease. Muscle Nerve 2001; 24: 284–287 Menkes JH, Philippart M, Fiol RE. Cerebral lipids in maple syrup disease. J Pediatr 1965; 66: 584–594 Menkes JH, Solcher H. Maple syrup disease. Arch Neurol 1967; 16: 486–491 Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelly RI. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 2002; 109: 999–1008 Müller K, Kahn T,Wendel U. Is demyelination a feature of maple syrup urine disease? Pediatr Neurol 1993; 9: 375–382 Nellis MM, Danner DJ. Gene preference in maple syrup urine disease. Am J Hum Genet 2001; 68: 232–237 Nobukuni Y, Mitsubuchi H, Akaboshi I, Indo Y, Endo F, Matsuda I.Maple syrup urine disease: clinical and biochemical significance of gene analysis. J Inherit Metab Dis 1991; 14: 787– 792

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Nord A, van Doorninck WJ, Greene C. Developmental profile of patients with maple syrup urine disease.J Inherit Metab Dis 1991; 14: 881–889 Northrup H, Sigman ES, Hebert AA. Exfoliative erythroderma resulting from inadequate intake of branched-chain amino acids in infants with maple syrup urine disease. Arch Dermatol 1993; 129: 384–385 Nyhan WL, Rice-Kelts M, Klein J, Barshop BA. Treatment of the acute crisis in maple syrup urine disease. Arch Pediatr Adolesc Med 1998; 152: 593–598 Ogier de Baulny H, Saudurbray JM. Branched-chain organic acidurias. Semin Neonatol 2002; 7: 65–74 Parini R, Sereni LP, Bagozzi DC, Corbetta C, Rabier D, Narcy C, Hubert P, Saudubray JM. Nasogastric drip feeding as the only treatment of neonatal maple syrup urine disease. Pediatrics 1993; 92: 280–283 Parmar H, Sitoh YY, Ho L. Maple syrup urine disease. Diffusionweighted and diffusion-tensor magnetic resonance imaging findings. J Comput Assist Tomogr 2004; 28: 93–97 Parsons HG, Carter RJ, Unrath M, Snyder FF. Evaluation of branched-chain amino acid intake in children with maple syrup urine disease and methylmalonic aciduria. J Inherit Metab Dis 1990; 13: 125–136 Prensky AL, Moser HW. Brain lipids, proteolipids, and free amino acids in maple syrup urine disease. J Neurochem 1966; 13: 863–874 Puliyanda DP, Harmon WE, Peterschmitt MJ, Irons M, Somers MJG. Utility of hemodialysis in maple syrup urine disease. Pediatr Nephrol 2002; 17: 239–242 Riviello JJ, Rezvani I, DiGeorge AM, Foley CM. Cerebral edema causing death in children with maple syrup urine disease. J Pediatr 1991; 119: 42–45 Schönberger S, Schweiger B, Schwahn B, Schwarz M,Wendel U. Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab 2004; 82: 69–75 Scriver CR, Clow CL, Mackenzie S, Delvin E. Thiamine-responsive maple-syrup-urine disease. Lancet 1971; I: 310–312 Scriver CR, Clow CL, George H. So-called thiamin-responsive maple syrup urine disease: 15-year follow-up of the original patient. J Pediatr 1985; 107: 763–765 Sener RN.Diffusion magnetic resonance imaging in intermediate form of maple syrup urine disease. J Neuroimaging 2002; 12: 368–390 Silberberg DH. Maple syrup urine disease metabolites studies in cerebellum cultures. J Neurochem 1969; 16: 1141–1146 Silberman J, Dancis J, Feigin I. Neuropathological observations in maple syrup urine disease. Arch Neurol 1961; 5: 351–363 Taccone A, Schiaffino MC, Cerone R, Fondelli MP, Romano C. Computed tomography in maple syrup urine disease. Eur J Radiol 1992; 14: 207–212 Tharp BR. Unique EEG pattern (comb-like rhythm) in neonatal maple syrup urine disease. Pediatr Neurol 1992; 8: 65–68 Thompson GN, Francis DEM, Halliday D. Acute illness in maple syrup urine disease: dynamics of protein metabolism and implications for management. J Pediatr 1991; 119: 35–41 Tornqvist K, Tornqvist H. Corneal de-epithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease. Acta Ophthalmol Scand 1996; 74: 48–49 Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR. Maple syrup urine disease: interrelations between branched-chain amino, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis 1992; 15: 121–135

Tsuruta M, Mitsubuchi H, Mardy S, Miura Y, Hayashida Y, Kinugasa A, Ishitsu T, Matsuda I, Indo Y. Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain (ALPHA)-keto acid dehydrogenase complex. J Hum Genet 1998; 43: 91–100 Uziel G, Savoiardo M, Nardocci N. CT and MRI in maple syrup urine disease. Neurology 1988; 38: 486–488 Verdu A, Lopez-Herce J, Pascual-Castroviejo I, Martinez-Bermejo A, Ugarte M, Garcia MJ. Maple syrup urine disease variant form: presentation with psychomotor retardation and CT scan abnormalities. Acta Paediatr Scand 1985; 74: 815–818 Wanjer M, Coelho DM, Barschak AG, Araújo PR, Pires RF, Lulhier FLG, Vargas CR. Reduction of large neutral amino acid concentrations in plasma and CSF of patients with maple syrup urine disease during crisis. J Inherit Metab Dis 2000; 23: 505–512 Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup disease. Eur J Pediatr 1999; 158: S60-S64 Wynn RM, Ho R, Chuang JL, Chuang DT. Roles of active site and novel K+ ion-binding site residues in human mitochondrial branched chain a-ketoacid decarboxylase/dehydrogenase. J Biol Chem 2001; 9: 4168–4174 Yoshino M,Aoki K,Akeda H,Hashimoto K,Ikeda T,Inoue F,Ito M, Kawamura M, Kohno Y, Koga Y, Kuroda Y, Maesaka H, Murakami-Soda H, Sugiyama N, Suzuki Y, Yano S, Yoshioka A. Management of acute metabolic decompensation in maple syrup urine disease: a multi-center study. Pediatr Int 1999; 41: 132–173 Zneimer SM, Lau KS, Eddy RL, Shows TB, Chuang JL, Chuang DT, Cox RD. Regional assignment of two genes of the human branched-chain (ALPHA)-keto acid dehydrogenase complex: the E1b gene (BCKDHB) to chromosome 6p21–22 and the E2 gene (DTB) to chromosome 1p31. Genomics 1991; 10: 740–747

41 3-Hydroxy-3-Methylglutaryl CoA Lyase Deficiency Bakker HD, Wanders RJA, Schutgens RBH, Abeling NGGM, van Gennip AH. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency: absence of clinical symptoms due to a self-imposed dietary fat and protein restriction. J Inherit Metab Dis 1993; 16: 1061–1062 Ferris JN,Tien RD. Cerebral MRI in 3-hydroxy-3-methylglutarylcoenzyme A lyase deficiency: case report. Neuroradiology 1993; 35: 559–560 Gibson KM, Breuer J, Kaiser K, Nyhan WL, McCoy EE, Ferreira P, Greene CL, Blitzer MG, Shapira E, Reverte F, Conde C, Bagnell P, Cole DEC. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients. J Inherit Metab Dis 1988; 11: 76–87 Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methylglutarylcoenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr 1988: 148: 180–186 Gibson KM, Cassidy SB, Seaver LH,Wanders RJA, Kennaway NG, Mitchell GA, Sprak RP. Fatal cardiomyopathy associated with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. J Inherit Metab Dis 1994: 17: 291–294 Gordon K, Riding M, Camfield P, Bawden H, Ludman M, Bagnell P. CT and MR of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. AJNR Am J Neuroradiol 1994: 15: 1474– 1476

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974 References and Further Reading Huemer M, Muehl A, Wandl-Vergesslich K, Strobl W, Wanders RJA, Stoeckler-Ipsiroglu S. Stroke-like encephalopathy in an infant with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Eur J Pediatr 1998; 157: 743–746 Leupold D, Bojasch M, Jacobs C. 3-Hydroxy-3-methylglutarylcoenzyme A lyase deficiency in an infant with macrocephaly and mild metabolic acidosis. Eur J Pediatr 1982; 138: 73–76 Lisson G, Leupold D, Bechinger D, Wallesch C. CT findings in a case of deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase. Neuroradiology 1981; 22: 99–101 Mitchell GA, Jakobs C, Gibson KM, Robert M-F, Burlina A, Dionisi-Vici C, Dallaire L. Molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Prenat Diagn 1995; 15: 725–729 Ozand PT, Al Aqeel A, Gascon G, Brismar J,Thomas E, Gleispach H. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia. J Inherit Metab Dis 1991; 14: 174–188 Robinson BH,Oei J,Sherwood G,Slyper AH,Heininger J,Mamer OA. Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome. Neurology 1980; 30: 714–718 Thompson GN, Chalmers RA, Halliday D. The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria. Eur J Pediatr 1990; 149: 346–350 van der Knaap MS, Bakker HD, Valk J. MR imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. AJNR Am J Neuroradiol 1998; 19: 378–382 Walter JH, Clayton PT, Leonard JV. 3-Hydroxy-3-methylglutarylcoenzyme A lyase deficiency. J Inherit Metab Dis 1986; 9: 287–288 Wang SP, Robert M-F, Gibson KM, Wanders RJA, Mitchell GA. 3Hydroxy-3-methylglutaryl-CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients. Genomics 1996; 33: 99–104 Wilson WG, Cass MB, Søvik O, Gibson KM, Sweetman L. A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Eur J Pediatr 1984; 142: 289–291 Wysocki SJ, Hähnel R. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: a review. J Inherit Metab Dis 1986; 9: 225–233 Yalçinkaya C, Dinçer A, Gündüz E, Fiçiciog˘lu C, Koçer N, Aydin A. MRI and MRI in HMG-CoA lyase deficiency. Pediatr Neurol 1999; 20: 375–380 Zoghbi HY, Spence JE, Beaudet AL, O’Brien WE, Goodman CJ, Gibson KM. Atypical presentation and neuropathological studies in 3-hydroxy-3-methylglutaryl-CoA layase deficiency. Ann Neurol 1986; 20: 367–369

42 Canavan Disease Adachi M, Wallace BJ, Schneck L, Volk BW. Fine structure of spongy degeneration of the central nervous system (van Bogaert and Betrand type). J Neuropathol Exp Neurol 1966; 25: 598–616 Adachi M,Volk BW. Protracted form of spongy degeneration of the central nervous system.Neurology 1968; 18:1084–1092 Adachi M,Torii J, Schneck L, Volk BW. Electron microscopic and enzyme histochemical studies of the cerebellum in spongy degeneration. Acta Neuropathol (Berl) 1972; 20: 22–31

Adachi M, Schneck L, Cara J, Volk BW. Spongy degeneration of the central nervous system (Van Bogaert and Bertrand type; Canavan’s disease). Hum Pathol 1973; 4: 331–347 Austin SJ,Connelly A,Gadian DG,Benton JS,Brett EM.Localized 1H NMR spectroscopy in Canavan’s disease: a report of two cases. Magn Reson Med 1991; 19: 439–445 Banker BQ, Robertson JT, Victor M. Spongy degeneration of the central nervous system in infancy. Neurology 1964; 14: 981–1001 Barker PB, Bryan RN, Kumar AJ, Naidu S. Proton NMR spectroscopy of Canavan’s disease. Neuropediatrics 1992; 23: 263–267 Baslow MH. Molecular water pumps and the aetiology of Canavan’s disease: a case of sorcerer’s apprentice. J Inherit Metab Dis 1999; 22: 99–101 Baslow MH. Canavan’s spongiform leukodystrophy. A clinical anatomy of a genetic metabolic CNS disease. J Mol Neurosci 2000; 15: 61–69 Baslow MH. Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 2002; 40: 295–300 Baslow MH. Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease. J Mol Neurosci 2003; 21: 185–189 Baslow MH, Resnik TR. Canavan Disease. Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms. J Mol Neurosci 1997; 9: 109–125 Baslow MH, Suckow RF,Sapirstein V,Hungund BL.Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes.J Mol Neurosci 1999; 13: 47–53 Bennett MJ, Gibson KM, Sherwood WG, Divry P, Rolland MO, Elpeleg ON, Rinaldo P, Jakobs C. Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis. J Inherit Metab Dis 1993; 16: 831–836 Besley GTN, Elpeleg ON, Shaag A, Manning NJ, Jakobs C,Walter JH. Prenatal diagnosis of Canavan disease. Problems and dilemmas. J Inherit Metab Dis 1999; 22: 263–366 Brismar J, Brismar G, Gascon G, Ozand P. Canavan disease: CT and MR imaging of the brain. AJNR Am J Neuroradiol 1990; 11: 805–810 Brown LW, Rorke LB, Deray MJ, Smith SB, Altman N. Psychomotor retardation and macrocephaly in an infant. Pediatr Neurosci 1985–1986; 12: 266–271 Burlina AP, Ferrari V, Divry P, Gradowska W, Jakobs C, Bennett MJ, Sewell AC, Dionisi-Vici C, Burlina AB. N-Acetylaspartylglutamate in Canavan disease: an adverse effector? Eur J Pediatr 1999; 158: 406–409 De Coo IFM, Gabreëls FJM, Renier WO, de Pont JJHHM, Hälst UJGM, Veerkamp JH, Trijbels JMF, Jaspar HHJ, Renkawek. Canavan disease: neuromorphological and biochemical analysis of a brain biopsy specimen.Clin Neuropathol 1991; 10: 73–78 Echenne B, Divry P, Vianey-Liaud C. Spongy degeneration of the neuraxis (Canavan-Van Bogaert disease) and N-acetylaspartic aciduria. Neuropediatrics 1989; 20: 70–81 Engelbrecht V, Scherer A, Rassek M, Witsack HJ, Mödder U. Diffusion-weighted MR imaging in the brain in children: findings in the normal brain and in the brain with white matter diseases. Radiology 2002; 222: 410–418 Gascon GG, Ozand PT, Mahdi A, Jamil A, Haider A, Brismar J, Al-Nasser M. Infantile CNS spongy degeneration–14 cases: clinical update. Neurology 1990; 40: 1876–1882

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Matalon R, Kaul R, Gao GP, Michals K, Gray RGF, Bennett-Briton S,Norman A,Smith M,Jakobs C.Prenatal diagnosis for canavan disease: the use of DNA markers. J Inherit Metab Dis 1995; 18: 215–217 Matalon R, Rady PL, Platt KA, Skinner HB, Quast MJ, Campbell GA, Metalon K, Ceci JD,Tyring SK, Nehls M, Surendran S,Wei J, Ezell EL, Szucs S. Knock-out mouse for Canavan disease: a model for gene transfer tot the central nervous system. J Gene Med 2000; 2: 165–175 Meyding-Lamadé U, Sartor K. Magnetresonanztomographie bei neurodegenerativen Erkrankungen im Kindesalter. Klin Neuroradiol 1993; 3: 52–61 Toft PB, Geiß-Holtorff R, Roland MO, Pryd SO, Mueller-Forell W, Christensen E,Lehnert W,Lou HC,Ott D,Hennig J,Henriksen O. Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr 1993; 152: 750–753 Topçu M, Erdem G, Saatçi I, Aktan G, S¸ims¸ek A A, Renda Y, Schutgens RBH,Wanders RJA,Jacobs C.Clinical and magnetic resonance imaging features of L-2-hydroxyglutaric academia: report of three cases in comparison with Canavan disease. J Child Neurol 1996; 11: 373–377 Traeger E, Rapin I.The clinical course of Canavan disease. Pediatr Neurol 1998; 18: 207–212 Van Bogaert L, Bertrand I. Les leucodystrophies progressives familiales. Rev Neurol 1933; 2: 249–286 Wittsack HJ, Kugel H, Roth B, Heindel W. Quantitative measurements with localized 1H MR spectroscopy in children with Canava’s disease. J Magn Reson Imaging 1996; 6: 889–893 Zafeiriou D, Kleijer WJ, Maropoulos G, Anastasiou AL, Augoustidou-Savvopoulou P, Papadopoulou F, Kontopuolos EE, Fagan E, Payne S. Protracted course of N-acetylaspartic aciduria in two non-Jewish siblings: identical clinical and magnetic resonance imaging findings. Brain Dev 1999; 21: 205–208 Zelnik N, Amir N, Luder AS, Hemli JA, Elpeleg ON, Fatal A, GrossTsur V, Harel S. Protracted clinical course for patients with Canavan disease. Dev Med Child Neurol 1993; 35: 346–358

43 L-2-Hydroxyglutaric Aciduria Aydin K, Ozmen M, Tatli B, Sencer S. Single-voxel MR spectroscopy and diffusion-weighted MRI in two patients with L-2hydroxyglutaric aciduria. Pediatr Radiol 2003; 33: 872–876 Barbot C, Fineza I, Diogo L, Maia M, Melo J, Guimarães A, Pires MM, Cardoso ML, Vilarinho L. L-2-Hydroxyglutaric aciduria: clinical biochemical and magnetic resonance imaging in six Portuguese pediatric patients. Brain Dev 1997; 19: 268– 273 Barth PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, van Gennip AH, Duran M, Valk J, Schutgens RBH, Trefz FK, Reimann G, Hartung HP. L-2-Hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992; 32: 66–71 Barth PG, Hoffmann GF, Jaeken J, Wanders RJA, Duran M, Jansen GA, Jakobs C, Lehnert W, Hanefeld F, Valk J, Schutgens RBH, Trefz FK, Hartung HP, Chamoles NA, Sfaello Z, Caruso U. L-2-Hydroxyglutaric acidaemia: clinical and biochemical findings in 12 patients and preliminary report on L-2-hydroxyacid dehydrogenase. J Inherit Metab Dis 1993; 16: 753–761 Barth PG,Wanders RJA, Scholte HR, Abeling N, Jakobs C, Schutgens RBH, Vreken P. L-2-Hydroxyglutaric aciduria and lactic acidosis. J Inherit Metab Dis 1998; 21: 251–254

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976 References and Further Reading Chen E, Nyhan WL, Jakobs C, Greco CM, Barkovich AJ, Cox VA, Packman P. L-2-Hydroxyglutaric aciduria: neuropathological correlations and first report of severe neurodegenerative disease and neonatal death. J Inherit Metab Dis 1996; 19: 335–343 Clerc C,Bataillard M,Richard P,Divry P,Kreahenbuhl J,Rumbach L. An adult form of L-2-hydroxyglutaric aciduria revealed by tremor. Eur Neurol 2000; 43: 119–120 De Klerk JBC, Huijmans JGM, Stroink H, Robben SGF, Jakobs C, Duran M. L-2-Hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship. Neuropediatrics 1997; 28: 314–317 D’Incenti, Farina L, Moroni I, Uziel G, Savoiardo M. L-2-Hydroxyglutaric aciduria: MRI in seven cases. Neuropathology 1998; 40: 727–733 Diogo L, Fineza I, Canha J, Borges L, Cardoso ML, Vilarinho L. Macrocephaly as the presenting feature of L-2-hydroxyglutaric aciduria in a 5-month-old-boy. J Inherit Metab Dis 1996; 19: 369–370 Divry P, Jakobs C, Vianey-Saban C, Gibson KM, Michelakakis H, Papadimitriou A, Divari R, Chabrol B, Cournelle MA, Livet MO. L-2-Hydroxyglutaric aciduria: two further cases. J Inherit Metab Dis 1993; 16: 505–507 Duran M,Kamerling JP,Bakker HD,van Gennip AH,Wadman SK. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism. J Inherit Metab Dis 1980: 3:109–112 Fujitake J, Ishikawa Y, Fujii H, Nishimura K, Inoue F, Terada N, Okochi M, Tatsuoka Y. L-2-Hydroxyglutaric aciduria: two Japanese adult cases in one family. J Neurol 1999; 246: 378–382 Hoffmann GF, Jakobs C, Holmes B, Mitchell L, Becker G, Hartung H-P, Nyhan WL. Organic acids in cerebrospinal fluid and plasma of patients with L-2-hydroxyglutaric aciduria. J Inherit Metab Dis 1995; 18: 189–193 Jansen GA, Wanders RJA. L-2-Hydroxyglutarate dehydrogenase:identification of a novel enzyme activity in rat and human liver. Implications for L-2-hydroxyglutaric aciduria. Biochim Biophys Acta 1993; 1225: 53–56 Kaabachi N, Larnaout A, Rabier D, Jakobs C, Belal S, Hentati F, Parvey P, Bardet J, Ben Hamida M, Mebazaa A, Kamoun P. Familial encephalopathy and L-2-hydroxyglutaric aciduria. J Inherit Metab Dis 1993; 16: 893 Kossoff EH, Keswani SC, Raymond GV. L-2-Hydroxyglutaric aciduria presenting as migraine. Neurology 2001; 57: 1731– 1732 Larnaout A, Hentati F, Belal S, Ben Hamida C, Kaabachi N, Ben Hamida M. Clinical and pathological study of three Tunisian siblings with L-2-hydroxyglutaric aciduria. Acta Neuropathol (Berl) 1994; 88: 367–370 Moroni I, D’Incerti L, Farina L, Rimoldi M, Uziel G. Clinical, biochemical and neuroradiological findings in L-2-hydroxyglutaric aciduria. Neurol Sci 2000; 21: 103–108 Moroni I, Bugiani M, D’Incerti L, Maccagnano C, Rimoldi M, Bissola L, Pollo B, Finocchiaro G, Uziel G. L-2-Hydroxyglutaric aciduria and brain malignant tumors. A predisposing condition? Neurology 2004; 62: 1882–1884 Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci USA 2004; 101: 16849–16854 Sztriha L, Gururaj A, Vreken P, Nork M, Lestringant GG. L-2-Hydroxyglutaric aciduria in two siblings. Pediatr Neurol 2002; 27: 141–144

Topçu M, Erdem G, Saatçi I, Aktan G, S¸ims¸ek A A, Renda Y, Schutgens RBH,Wanders RJA,Jacobs C.Clinical and magnetic resonance imaging features of L-2-hydroxyglutaric aciduria academia: report of three cases in comparison with Canavan disease. J Child Neurol 1996; 11: 373–377 Topçu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Gerceker FO, Wanders RJA, Prud’homme JF, Lathrop M, Özguc M, Fischer J. L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 2004; 13: 2803–2811 Wanders RJA, Vilarinho L, Hartung HP, Hoffmann GF, Mooijer PAW, Jansen GA, Huijmans JGM, de Klerk JBC, ten Brink HJ, Jakobs C, Duran M. L-2-Hydroxyglutaric aciduria: normal L2-hydroxyglutarate dehydrogenase activity in liver from two new patients. J Inherit Metab Dis 1997; 20: 725–726 Wilcken B, Pitt J, Heath F,Walsh P,Wilson G, Bachanan N. L-2-Hydroxyglutaric aciduria: three Australian cases. J Inherit Metab Dis 1993; 16: 501–504 Zafeiriou DI, Sewell A, Savvopoulou-Augoustidou P, Gombakis N, Katzos G. L-2-Hydroxyglutaric aciduria presenting as a status epilepticus. Brain Dev 2001; 23: 255–257

44

D-2-Hydroxy

Glutaric Aciduria

Achouri Y, Noël G,Vertommen D, Rider MH,Veiga-Da-Cunha M, Van Schaftingen E. Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J 2004; 381: 35-42 Amiel J, de Lonay P, Francannet C, Picard A, Bruel H, Rabier D, Le Merrer M, Verhoeven N, Jakobs C, Lyonnet S Munnich A. Facial anomalies in D-2-hydroxyglutaric aciduria. Am J Med Genet 1999; 86: 124–129 Baker NS, Sarnat HB, Jack RM, Patterson K, Shaw DW, Herndon SP. D-2-hydroxyglutaric aciduria: hypertonia, cortical blindness, seizures, cardiomyopathy and cylindrical spirals in skeletal muscle. J Child Neurol 1997; 12: 31–36 Chalmers RA, Lawson AM, Watts WE, Tavill AS. D-2-Hydroxyglutaric aciduria: case report and biochemical studies. J Inherit Metab Dis 1980; 3: 11–15 Clarcke NF,Andrews I,Carpenter K,Jakobs C,van der Knaap MS, Kirk EP. D-2-Hydroxyglutaric aciduria: a case with an intermediate phenotype and prenatal diagnosis of two affected fetuses. Am J Med Genet 2003; 120A: 523–527 Craigen WJ, Jakobs C, Sekul EA, Levy ML, Gibson KM, Butler IJ, Herman GE. D-2-Hydroxyglutaric aciduria in neonate with seizures and CNS dysfunction. Pediatr Neurol 1994; 10: 49–53 Da Silva CG, Ribeiro CAJ, Leipnitz G, Duntra-Filho CS,Wyse ATS, Wannmacher CMD, Sarkis JJF, Jakobs C,Wajner M.Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by D-2-hydroxyglutaric acid in vitro. Biochim Biophys Acta 2002; 1586: 81–91 Eeg-Olofsson O, Zhang WW, Olsson Y, Jagell S, Hagenfeldt L. D-2-Hydroxyglutaric aciduria with cerebral, vascular, and muscular abnormalities in a 14-year-old boy. J Child Neurol 2000; 15: 488–492 Geerts Y, Renier WO, Bakkeren J, de Jong J. 2-Hydroxyglutaric aciduria:a case report on an infant with the D-isomeric form with review of the literature. J Neurol Sci 1996; 143: 166–169 Gibson KM, Craigen W, Herman GE, Jakobs C. D-2-Hydroxyglutaric aciduria in a newborn with neurological abnormalities: a new neurometabolic disorder? J Inherit Metab Dis 1993; 16: 497–500

References and Further Reading

Gibson KM, ten Brink HJ, Schor SM, Kok RM, Bootsma AH, Hoffmann GF, Jakobs C. Stable isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias. Pediatr Res 1993; 34: 277–280 Kwong KL, Mak T, Fong CM, Poon KH, Wong SN, So KT. D-2-Hydroxyglutaric aciduria and subdural haemorrhage. Acta Paediatr 2002; 91: 716–718 Muntau AC, Röschinger W, Merkenschlager A, van der Knaap MS, Jakobs C, Duran M, Hoffmann GF, Roscher AA. Combined D-2- and L-2-hydroxyglutaric aciduria with neonatal onset encephalopathy: a third biochemical variant of 2-hydroxyglutaric aciduria? Neuropediatrics 2000; 31: 137–140 Nyhan WL, Shelton D, Jakobs C, Holmes B, Bowe C, Curry CJR, Vance C, Duran M, Sweetman L. D-2-Hydroxyglutaric aciduria. J Child Neurol 1995; 10: 137–142 Struys EA, Verhoeven NM, Roos B, Jakobs C. Disease-related metabolites in culture medium of fibroblasts from patients with D-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria and combined D-/L-2-hydroxyglutaric aciduria. Clin Chem 2003; 49: 1133–1138 Struys EA,Verhoeven NM, Brunengraber H, Jakobs C. Investigations by mass isotopomer analysis of the formation of D-2hydroxyglutarate by cultured lymphoblasts from two patients with D-2-hydroxyglutaric aciduria. FEBS Lett 2004; 557: 115–120 Struys EA, Salomons GS, Achouri Y, van Schaftingen E, Grosso S, Craigen WJ, Verhoeven NM, Jakobs C. Mutations in the D-2hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet 2005; 76 358–360 Sugita K, Kakinuma H, Okajima Y, Ogawa A, Watanabe H, Niimi H. Clinical and MRI findings in a case of D-2-hydroxyglutaric aciduria. Brain Dev 1995; 17: 139–141 van der Knaap MS, Jakobs C, Hoffmann GF, Nyhan WL, Renier WO, Smeitink JAM, Catsman-Berrevoets CE, Hjalmarson O, Vallance H, Sugita K, Bowe CM, Herrin JT, Caigen WJ, Buist NRM, Brookfield DSK, Cahlmers RA. D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity? Ann Neurol 1999a; 45: 111–119 van der Knaap MS, Jakobs C, Hoffmann GF, Duran M, Muntau AC, Schweitzer S, Kelley RI, Parrot-Rouland F, Amiel J, De Lonay P, Rabier D, Eeg-Olofsson O. D-2-Hydroxyglutaric aciduria: further clinical delineation. J Inherit Metab Dis 1999b; 22: 404–413 Wagner L, Hoffmann GF, Jakobs C. D-2-Hydroxyglutaric aciduria: evidence of clinical and biochemical heterogeneity. J Inherit Metab Dis 1998; 21: 247–250 Wajner M, Vargas CR, Funayama C, Fernandez A, Elias MLC, Goodman SI, Jakobs C, van der Knaap MS. D-2-Hydroxyglutaric aciduria in a patient with a severe clinical phenotype and unusual MRI findings. J Inherit Metab Dis 2002; 25: 28–34 Wanders RJA, Mooyer P. D-2-Hydroxyglutaric aciduria: identification of a new enzyme, D-2-hydroxyglutarate dehydrogenase, localized in mitochondria. J Inherit Metab Dis 1995; 18: 194–196

45 Hyperhomocysteinemias Defects in the Transsulfuration Pathway Abeling NGGM, van Gennip AH, Blom H, Wevers RA, Vreken P, van Tinteren HLG, Bakker HD. Rapid diagnosis and methionine administration: basis for a favourable outcome in a patient with methylene tetrahydrofolate reductase deficiency. J Inherit Metab Dis 1999; 22: 240–242 Al-Essa MA, Al Amir A, Rashed M, Al Jishi E, Abutaleb A, Mobaireek K, Shin YS, Ozand PT. Clinical, flurorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. Brain Dev 1999; 21: 345–349 Baethmann M, Wendel U, Hoffmann GF, Göhlich-Ratmann G, Kleinlein B, Seiffert P, Blom H,Voit T. Hydrocephalus internus in two patients with 5,10-mehylenetetrahydrofolate reductase deficiency. Neuropediatrics 2000; 31: 314–317 Beckman DR, Hoganson G, Berlow S, Gilbert EF. Pathological findings in 5,10-methylene tetrahydrofolate reductase deficiency. Birth Defects 1987; 23: 47–64 Beradelli A,Thompson PD, Zaccagnini M, Giardini O, D’Eufemia P, Massoud R, Manfredi M.Two sisters with generalized dystonia associated with homocystinuria. Mov Disord 1991; 6: 163–165 Carson NAJ, Dent CE, Field CMB, Gaull GE. Homocystinuria. J Pediatr 1965; 66: 565–583 Chou SM, Waisman HA. Spongy degeneration of the central nervous system. Arch Pathol Lab Med 1965; 79: 357–363 Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 1986; 49: 920–927 Dunn HG, Perry TL, Dolman CL. Homocystinuria. A recently discovered cause of mental defect and cerebrovascular thrombosis. Neurology 1966; 16: 407–420 Engelbrecht V,Rassek M,Huismann J,Wendel U.MR and proton MR spectroscopy of the brain in hyperhomocysteinemia caused by methylenetetrahydrofolate reductase deficiency. AJNR Am J Neuroradiol 1997; 18: 536–539 Fattal-Valevski A, Bassan H, Korman SH, Lerman-Sagie T, Gutman A, Harel S. Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis. J Child Neurol 2000; 15: 539–543 Fowler B. Disorders of homocysteine metabolism. J Inherit Metab Dis 1997; 20: 270–285 Gerritsen T, Waisman HA. Homocystinuria, an error in the metabolism of methionine. Pediatrics 1964; 33: 413–420 Haworth JC, Dilling LA, Surtees RAH, Seargeant LE, Shing HL, Cooper BA, Rosenblatt DS. Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 1993; 45: 572–576 Hyland K, Smith I, Bottiglieri T, Perry J, Wendel U, Clayton PT, Leonard JV. Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurology 1988; 38: 459–462 Kelly PJ, Furie KL, Kistler JP, Barron M, Picard EH, Mandell R, Shih VE. Stroke in young patients with hyperhomocsyteinemia due to cystathionine beta-synthase deficiency. Neurology 2003; 60: 275–279 Keskin S, Yalcin E. Case report of homocystinuria: clinical, electroencephalographic, and magnetic resonance imaging findings. J Child Neurol 1994; 9: 210–211

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Van Diemen-Steenvoorde R, van Nieuwenhuizen O, de Klerk JBC, Duran M. Quasi-Moyamoya disease and heterozygosity for homocystinuria in a five-year-old girl. Neuropediatrics 1990; 21: 110–112 Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, Breteler MMB. Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam scan study. Ann Neurol 2002; 51: 285–289 Vermeulen EGJ, Stehouwer CDA, Valk J, van der Knaap MS, van den Berg M,Twisk JWR,Prevoo W,Rauwerda JA.Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on cerebrovascular atherosclerosis and white matter abnormalities as determined by MRA and MRI: a placebo-controlled, randomized trial. Eur J Clin Invest 2004; 34: 256–261 Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: 1042–1050 Wilcken DEL, Wilcken B.The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis 1997; 20: 295–300

Folate Deficiency Giles WH, Kittner SJ, Anda RF, Croft JB, Casper ML. Serum folate and risk factor for ischemic stroke. First national health and nutrition examination survey. Epidemiologic follow-up study. Stroke 1995; 26: 1166–1170 Hoffbrand AV, Weir DG. The history of folic acid. Br J Haematol 2001; 113: 579–589 Lever EG, Elwes RDC, Williams A, Reynolds EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry 1986; 49: 1203–1207 Robertson DM, Dinsdale HB, Campbell RJ, Kingston ChB. Subacute combined degeneration of the spinal cord. No association with vitamin B12 deficiency. Arch Neurol 1971: 24: 203–207 Scott JM, Weir DG. The methyl folate trap. Lancet 1981: 2: 337– 340 Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging 2002; 6: 39–42 Van der Weyden MB, Hayman RJ, Rose IS, Brumley J. Folate-deficient human lymphoblasts: changes in deoxynucleotide metabolism and thymidylate cycle activities. Eur J Haematol 1991: 47: 109–114 Weir DG, Scott JM. Brian function in the elderly: role of vitamin B12 and folate. Br Med Bull 1999; 55: 669–682

Inborn Errors of Cobalamin Metabolism Augoustides-Savvopouloou P, Mylonas I, Sewell AC, Rosenblatt DS.Reversible dementia in an adolescent with clbC disease: clinical heterogeneity within the same family. J Inherit Metab Dis 1999; 22: 759–758 Bartholomew DW, Batshaw ML, Allen RH, Roe CR, Rosenblatt D, Valle DL, Francomano CA. Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 1988; 112: 32–39 Bellini C, Cerone R, Bonacci W, Caruso U, Magliano CP, Serra G, Fowler B, Romano C. Biochemical diagnosis and outcome of 2 years’ treatment in a patient with combined methylmalonic aciduria and homocystinuria. Eur J Pediatr 1992; 151: 818–820

Bianheri R, Cerone R, Schiaffino MC, Caruso U, Veneselli E, Perrone MC, Rossi A, Gatti R. Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiological findings in 14 cases. Neuropediatrics 2001; 32: 14–22 Bibi H, Gelman-Kohan Z, Baumgartner ER, Rosenblatt DS. Transcobalamin II deficiency with methylmalonic aciduria in three sisters. J Inherit Metab Dis 1999; 22: 765–772 Carmel R, Watkins D, Goodman SI, Rosenblatt DS. Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 1988; 318: 1738–1741 Dayan AD, Ramsey RB. An inborn error of vitamin B12 metabolism associated with cellular deficiency of coenzyme forms of the vitamin. J Neurol Sci 1974; 23: 117–128 Enns GM, Barkovich AJ, Rosenblat DS, Fredrick DR, Weisiger K, Ohnstad C, Packman S. Progressive neurological deterioration and MRI changes in clbC methylmalonic acidaemia treated with hydroxocobalamin. J Inherit Metab Dis 1999; 22: 599–607 Fenton WA, Rosenberg LE. Genetic and biochemical analysis of human cobalamin mutants in cell culture. Annu Rev Genet 1978; 12: 223–248 Linnell JC, Ray Bhatt H. Inherited errors of cobalamin metabolism and their management. Balliere’s Clin Haematol 1995; 8: 567–601 Mitchell GA, Watkins D, Melançon SB, Rosenblatt DS, Geoffroy G, Orquin J, Homsy MB, Dallaire L. Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 1986; 108: 410–415 Powers JM, Rosenblatt DS, Schmidt RE, Cross AH, Black JT, Moser AB, Moser HW, Morgan DJ. Neurological and neuropathological heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol 2001; 49: 396–400 Rossi A, Biancheri R, Tortori-Donati P. The pathogenesis of hydrocephalus in inborn errors of the single carbon transfer pathway. Neuropediatrics 2001a; 32: 335–336 Rossi A, Cerone R, Biancheri R, Gatti R, Schiaffino MC, Fonda C, Zammarchi E, Tortori-Donati P. Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol 2001b; 22: 554–563 Schuh S, Rosenblatt DS, Cooper BA, Schroeder M-L, Bishop AJ, Seargeant LE, Haworth JC. Homocystinuria and megaloblastic anemia responsive to vitamin B12 therapy. An inborn error of metabolism due to a defect in cobalamin metabolism. N Engl J Med 1984; 310: 686–690 Shinnar S, Singer HS. Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence. N Engl J Med 1984; 311: 451–454 Steen C, Rosenblat DS, Scheying H, Braeuer JC, Kohlstütter A. Cobalamin E (clbE) disease: a severe neurological disorder with megaloblastic anaemia, homocystinuria and slow serum mehionine. J Inherit Metab Dis 1997; 20: 705–706 Surtees R. Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 1998; 157: S118-S121 Thomas PK, Hoffbrand AV. Hereditary transcobalamin II deficiency: a 22 year follow up. J Neurol Neurosurg Psychiatry 1997; 62: 197 Tuchman M, Kelly P, Watkins D, Rosenblatt DS. Vitamin B12-responsive megaloblastic anemia, homocystinuria, and transient methylmalonic aciduria in cblE disease. J Pediatr 1988;113: 1052–1055 Watkins D, Rosenblatt DS. Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups: cblE and cblG. J Clin Invest 1988; 81: 1690–1694

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Cobalamin Deficiency Bassi SS, Bulundwe KK, Greeff GP, Labuscagne JH, Gledhill RF. MRI of the spinal cord in myelopathy complicating vitamin B12 deficiency: two additional cases and a review of the literature. Neuroradiology 1999; 41: 271–274 Brattström L, Israelsson B, Lindgärde F, Hultberg B. Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine b-synthase deficiency. Metabolism 1988;37: 175–178 Carmel R. Pernicious anemia. Arch Intern Med 1988; 148: 1712–1714 Chatterjee A,Yapundich R, Palmer CA, Marson DC, Mitchell GW. Leukoencephalopathy associated with cobalamin deficiency. Neurology 1996; 16: 832–834 Clementz CL, Schade SG.The spectrum of vitamin B12 deficiency. Am Fam Physician 1999; 41:150–162 Duprez TP, Gille M, vande Berg BC, Malghem J, Grandin CB, Michel P, Ghariani S, Maldague BE. MRI of the spine in cobalamin deficiency: the value of examining both spinal cord and bone marrow. Neuroradiology 1996; 38: 511–515 Fine EJ, Soria E, Paroski MW, Petryk D, Thomasula L. The neurophysiological profile of vitamin B12 deficiency. Muscle Nerve 1990; 13: 158–164 Flippo TS, Holder WD. Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch Surg 1993; 128: 1391–1395 Garewal G, Narang A, Das KC. Infantile tremor syndrome: a vitamin B12 deficiency syndrome in infants. J Trop Pediatr 1988; 34: 174–178 Gilois C,Wierzbicki AS, Hirani N, Norman PM, Jones SJ, Ponsford S, Alani SM, Kriss A. The hematological and electrophysiological effects of cobalamin. Deficiency secondairy to vegetarian diets. Ann N Y Acad Sci 1992; 669: 345–348 Graham SM, Arvela OM,Wise GA. Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants. J Pediatr 1992; 121: 710–714 Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord 1997; 12: 39–46 Green R,Kinsella LJ.Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995; 45: 1435–1440 Healton EB, Savage DG, Brust JCM, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine 1991; 70: 229–245 Heckmann JG, Lang CJG, Ganslandt O, Tomandl B, Neundörfer B. Reversible leukoencephalopathy due to vitamin B12 deficiency in an acromegalic patient. J Neurol 2003; 250: 366–368 Hector M,Burton JR.What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc 1988; 36: 1105– 1112 Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lücking CH. Subacute combined deterioration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 1998; 65: 822–827

Higginbottom MC, Sweetman L, Nyhan WL. A syndrome of methylmalonic aciduria, homocystinuria, megalobastic anemia and neurologic abnormalities in a vitaman B12 deficient breast-fed infant of a strict vegetarian. N Engl J Med 1978; 299: 317–323 Hoffbrand AV, Jackson BFA. Correction of the DNA synthesis defect in vitamin B12 deficiency by tetrahydrofolate: evidence in favour of the methyl-folate trap hypothesis as the cause of megaloblastic anaemia in vitamin B12 deficiency. Br J Haematol 1993; 83: 643–647 Holloway KL, Alberico AM. Postoperative myeloneuropathy: a preventable complication in patients with B12 deficiency. J Neurosurg 1990; 72: 732–736 Karnaze DS, Carmel R. Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states, including deficiency without anemia and with normal absorption of free cobalamin. Arch Neurol 1990; 47: 1008–1012 Katsaros VK, Glocker FX, Hemmer B, Schumacher M. MRI of spinal cord and brain lesions in subacute combined degeneration. Neuroradiology 1998; 40: 716–719 Kealey SM, Provenzale JM. Tensor diffusion imaging in B12 leukoencephalopathy. J Comput Assist Tomogr 2002; 26: 952–955 Kühne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr 1991; 150: 205–208 Küker W, Hesselmann V, de Simone A. MRI demonstration of reversible impairment of the blood-CNS barrier function in subacute combined degeneration of the spinal cord.J Neurol Neurosurg Psychiatry 1997; 62: 298–299 Lindenbaum J, Healton EB, Savage DG, Brust JCM, Garrett TJ, Podell ER, Marcell PD, Stabler SP, Allen RH. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318: 1720–1728 Lövblad K-O, Ramelli G, Remonda L, Nirkko AC, Ozdoba C, Schroth G. Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Pediatr Radiol 1997; 27: 155–158 Morita S, Miwa H, Kihira T, Kondo T. Cerebellar ataxia and leukoencephalopathy associated with cobalamin deficiency. J Neurol Sci 2003; 216: 183–184 Murata S, Naritomi H, Sawada T. MRI in subacute combined degeneration. Neuroradiology 1994; 36: 408–409 Narayanan MN, Dawson DW, Lewis MJ. Dietary deficiency of vitamin B12 is associated with low serum cobalamin levels in non-vegetarians. Eur J Haematol 1991; 47: 115–118 Perry J, Chanarin I, Deacon R, Lumb M. Methylation of DNA in megaloblastic anaemia. J Clin Pathol 1990; 43: 211–212 Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamine B12 deficiency in children and adolescents. J Pediatr 2001; 138: 10–17 Reynolds EH, Bottiglieri T, Laundy M, Stern J, Payan J, Linnell J, Faludy J. Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein. Arch Neurol 1993;50: 739–742 Saracaceanu E, Tramoni AV, Henry JM. An association between subcortical dementia and pernicious anemia. A psychiatric mask. Compr Psychiatry 1997; 38: 349–351 Scott JM, Wilson P, Dinn JJ, Weir DG. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981; 2: 334–337 Shevell MI, Rosenblatt DS. The neurology of cobalamin. Can J Neurol Sci 1992; 19: 472–486

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46 Urea Cycle Defects Aida S, Ogata T, Kamota T, Nakamura N. Primary ornithine transcarbamylase deficiency. Acta Pathol Jpn 1989; 39: 451–456 Albayram S, Murphy KJ, Gailloud P, Moghekar A, Brunberg JA. CT findings in the infantile form of citrullinemia. AJNR Am J Neuroradiol 2002; 23: 334–336 Bachmann C.Ornithine carbamoyl transferase deficiency: findings, models and problems. J Inherit Metab Dis 1992;15: 578–591 Bajaj SK, Kurlemann G, Schuierer G, Peters PE. CT and MRI findings in a girl with late-onset ornithine transcarbamylase deficiency: case report. Neuroradiology 1996; 38: 796–799 Batshaw ML. Inborn errors of urea synthesis. Ann Neurol 1994; 35: 133–141 Brockstedt M, Smit LME, de Grauw AJC, van der Klei-van Moorsel JM, Jakobs C. A new case of hyperargininaemia: neurological and biochemical findings prior to and during dietary treatment. Eur J Pediatr 1990; 149: 341–343 Brusilow SW. Arginine, an indespensible amino acid for patients with inborn errors of urea synthesis. J Clin Invest 1984; 74: 2144–2148 Bruton CJ, Corsellis JAN, Russell A. Hereditary hyperammonaemia. Brain 1970; 93: 423–434 Cerone R, Caruso U, Barabino A. Gatt R, Jakobs C, Jacquemyn I, Marescau B, De Deyn PP. Hyperargininemia: pre-natal diagnosis and treatment from birth. In: De Deyn PP, Marescau B, Qureshi IA, Mori A, eds. Guanidino compounds. Eastleigh: John Libbey 1997, pp 71–76 Chen Y-F, Huang Y-C, Liu H-M, Hwu W-L. MRI in a case of adult onset citrullinemia. Neuroradiology 2001; 43: 845–847 Choi C-G,Yoo HW.Localized proton MR spectroscopy in infants with urea cycle defect. AJNR Am J Neuroradiol 2001; 22: 834–837

Christodoulou J, Qureshi IA, McInnes RR, Clarke JTR. Ornithine transcarbamylase deficiency presenting with strokelike episodes. J Pediatr 1993; 122: 423–425 Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 1993; 33: 77–81 Dolman CL, Clasen RA, Dorovini-Zis K. Severe cerebral damage in ornithine transcarbamylase deficiency. Clin Neuropathol 1988; 7: 10–15 Donn SM, Thoene JG. Prospective prevention of neonatal hyperammonaemia in argininosuccinic acidura by arginine therapy. J Inherit Metab Dis 1985; 8: 18–20 Finkelstein JE, Hauser ER, Leonard CO, Brusilow SW. Late-onset ornithine transcarbamylase deficiency in male patients. J Pediatr 1990; 117: 897–902 Gallagher JV, Rifai N, Conry J, Soldin SJ. Role of the clinical laboratory in evaluation of argininosuccinate lyase deficiency. Clin Chem 1991; 37: 1384–1389 Gerrits GPJM, Gabreëls FJM, Monnens LAH, De Abreu RA, van Raaij-Selten B, Niezen-Koning KE, Trijbels JMF. Arginiosuccinic aciduria: clinical and biochemical findings in three children with the late onset form, with special emphasis on cerebrospinal fluid findings of amino acids and pyrimidines. Neuropediatrics 1993; 21: 15–18 Grody WW, Kern RM, Klein D, Dodson AE, Wissman PB, Barsky SH, Cederbaum SD. Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme. Hum Genet 1993; 91: 1–5 Grompe M, Caskey CT, Fenwick RG. Improved molecular diagnostics for ornithine transcarbamylase deficiency. Am J Hum Genet 1991; 48: 212–222 Harding BN, Leonard JV, Erdohazi M. Ornithine carbamoyl transferase deficiency: a neuropathological study. Eur J Pediatr 1984; 141: 215–220 Hommes FA, de Groot CJ, Wilmink CW, Jonxis JHP. Carbamylphosphate synthetase deficiency in an infant with severe cerebral damage. Arch Dis Childh 1969; 44: 688–693 Honeycutt D, Callahan K, Rutledge L, Evans B. Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy. Neurology 1992; 42: 666–668 Horiuchi M, Imamura Y, Nakamura N, Maruyama I, Saheki T. Carbamoylphosphate synthetase deficiency in an adult: deterioration due to administration of valproic acid. J Inherit Metab Dis 1993;16: 39–45 Kleijer WJ,Garritsen VH,Linnebank M,Mooyer P,Huijmans JGM, Mustonen A, Simola KOJ, Arslan-Kirchner M, Battini R, Briones P,Cardo E,Mandel H,Tschiedel E,Wanders RJA, Koch HG. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families. J Inherit Metab Dis 2002; 25: 399–410 Kornfeld M, Woodfin BM, Papile L, Davis LE, Bernard LR. Neuropathology of ornithine carbamyl transferase deficiency. Acta Neuropathol (Berl) 1985; 65: 261–264 Kurihara A, Takanashi J-i, Tomita M, Kobayashi K, Ogawa A, Kanazawa M, Yamamoto S, Kohno Y. Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency. Brain Dev 2003; 25: 40–44 Lee B, Goss J. Long-term correction of urea cycle disorders. J Pediatr 2001; 138: S62-S71 Legras A, Labarthe F, Maillot F, Garrigue M-A, Kouatchet A, Ogier de Baulny H. Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations. Crit Care Med 2002; 30: 241–244

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982 References and Further Reading Maestri NE, Hauser ER, Bartholomew D, Brusilow SW. Prospective treatment of urea cycle disorders. J Pediatr 1991; 119: 923–928 Maestri NE, McGowan KD, Brusilow SW. Plasma glutamine concentration: a guide in the management of urea cycle disorders. J Pediatr 1992; 121: 259–261 Maestri NE, Brusilow SW, Clissold DB, Bassett SS. Long-term treatment of girl with ornithine transcarbylase defiency. N Engl J Med 1996; 335: 855–859 Mamourian AC, du Plessis A. Urea cycle defect: a case with MR and CT findings resembling infarct. Pediatr Radiol 1991; 21: 594–595 Marescau B, de Deyn PP, Lowenthal A, Qureshi IA, Antonozzi I, Bachmann C, Cederbaum SD, Cerone R, Chamoles N, Colombo JP,Hyland K,Gatti R,Kang SS,Letarte J,Lambert M, Mizutani N, Possemiers I, Rezvani I, Snyderman SE, Terheggen HG, Yoshino M. Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: follow-up of guanidino compound levels during therapy. Pediatr Res 1990; 27: 297–303 Martin JJ, Farriaux JP, de Jonghe P. Neuropathology of citrullinaemia. Acta Neuropathol (Berl) 1982; 56: 303–306 Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: role of the nephrologist. Am J Kidney Dis 2001; 37: 1069–1080 Matsuda I, Nagata N, Matsuura T, Oyanagi K,Tada K, Narisawa K, Kitagawa T, Sakiyama T, Yamashita F, Yoshino M. Retrospective survey of urea cycle disorders. 1. Clinical and laboratory observations of thirty-two Japanese male patients with ornithine transcarbamylase deficiency. Am J Med Genet 1991; 38: 85–89 Matsuura T, Hoshide R, Fukushima M, Sakiyama T, Owada M, Matsuda I. Prenatal monitoring of ornithine transcarbamoylase deficiency in two families by DNA analysis. J Inherit Metab Dis 1993; 16: 31–38 Mattson LR, Lindor NM, Goldman DH, Goodwin JT, Groover RV, Vockley J. Central pontine myelinosis as a complication of partial ornithine carbamoyl transferase deficiency. Am J Med Genet 1995; 60: 210–213 McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet 2000; 93: 313–319 Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. N Engl J Med 1984; 310: 1500–1505 Oechsner M, Steen C, Stürenberg HJ, Kohlschütter A. Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognized ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry 1998; 64: 680–682 Olier J, Gallego J, Digon E. Computerized tomography in primary hyperammonemia. Neuroradiology 1989; 31: 356– 257 Osafune K, Ichikawa K, Yasui Y, Sekikawa A, Takeoka H, Kanatsu K, Kohigashi K, Koshiyama H. An adult-onset case of argininosuccinate synthetase deficiency presenting with atypical citrullinemia. Intern Med 1999; 38: 590–596 Oshiro S, Kochinda T, Tana T,Yamazato M, Kobayashi K, Komine Y, Muratani H, Saheki T, Iseki K, Takishita S. A patient with adult-onset type II citrullinemia on long-term hemodialysis: reversal of clinical symptoms and brain MRI findings. Am J Kidney Dis 2002; 39: 189–192

Picker JD, Puga AC, Levy HL, Marsden D, Shih VE, DeGirolami U, Ligon KL, Cederbaum SD, Kern RM, Cox GF. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr 2003; 142: 349–352 Potter M, Hammond JW, Sim K-G, Green AK, Wilcken B. Ornithine carbamoyltransferase deficiency: improved sensitivity of testing for protein tolerance in the diagnosis of heterozygotes. J Inherit Metab Dis 2001; 24: 5–14 Prasad AN, Breen JC, Ampola MG, Rosman NP. Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. J Child Neurol 1997; 12: 301–309 Pridmore CL, Clarke JTR, Blaser S. Ornithine transcarbamylase deficiency in females: an often overlooked cause of treatable encephalopathy. J Child Neurol 1995; 10: 369–374 Solitare GB, Shih VE, Nelligan DJ, Dolan Jr DJ, Arigininosuccinic aciduria: clinical, biochemical, anatomical and neuropathological observations. J Ment Defic Res 1969; 13: 153–170 Sperl W, Felber S, Skladal D, Wermuth B. Metabolic stroke in carbamyl phosphate synthetase deficiency. Neuropediatrics 1997; 28: 229–234 Takanashi J, Kurihara A, Tomita M, Kanazawa M, Yamamoto S, Morita F, Ikehira H, Tanada H, Tanada S, Kohno Y. Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology 2002; 59: 210–214 Takanashi J-I, Barkovic AJ, Cheng SF, Weisiger K, Zlatunich CO, Mudge C, Rosenthal P, Tuchman M, Packman S. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol 2003; 24: 1184–1187 Takanashi J-I, Barkovic AJ, Cheng SF, Kostiner D, Baker JC, Packman S. Brain MR imaging in acute hyperammonemic encephalopathy arising form late-onset ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol 2003; 24: 390–393 Takeoka M, Soman TB, Shih VE, Caviness VS, Krishnamoorthy KS.Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy. Pediatr Neurol 2001; 24: 193–199 Tomomasa T, Kobayashi K, Kaneko H, Shimura H, Fukusato T, Tabata M, Ioue Y, Ohwada S, Kasahara M, Morishita Y, Kimura M, Saheki T, Morikawa A. Possible clinical and histological manifestations of adult-onset type II citrullinemia in early infancy. J Pediatr 2001; 138: 741–743 Travers H, Reed JS, Kennedy JA. Ultrastructural study of the liver in argininosuccinase deficiency. Pediatr Pathol 1986; 5: 307–318 Tuchman M.The clinical, biochemical, and molecular spectrum of ornithine transcarbamylase deficiency. J Lab Clin Med 1992; 120: 836–850 Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase gene. Hum Mutat 1993; 2: 174– 178 Tuchman M, Mauer SM, Holzknecht RA, Summar ML, VnencakJones CL. Prospective versus clinical diagnosis and therapy of acute neonatal hyperammonaemia in two sisters with carbamyl phosphate synthetase deficiency. J Inherit Metab Dis 1992; 15: 269–277 Whitington PF, Alonso EM, Boyle JT, Molleston JP, Rosenthal P, Emond JC, Millis JM. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis 1998; 21: 112–118

References and Further Reading

Widhalm K, Koch S, Scheibenreiter S, Knoll E, Colombo JP, Bachmann C, Thalhammer O (1992) Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics 87: 1182–1184

47 Serine Synthesis Defect De Koning TJ. 3-Phosphoglycerate dehydrogenase in disease and development. Thesis, University of Utrecht. Utrecht: Zuidam en Uithof, 2001 De Koning TJ, Duran M, Dorland M, Dorland L, Gooskens R, van Schaftingen E, Jeaken J, Blau N, Berger R, Poll-The BT. Beneficial effects of l-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency. Ann Neurol 1998; 44: 261–265 De Koning TJ, Poll-The BT, Jaeken J. Continuing education in neurometabolic disorders – serine deficiency disorders. Neuropediatrics 1999; 30: 1–4 De Koning TJ, Jaeken J, Pineda M, van Maldergem L, Poll-The BT, van der Knaap MS. Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency. Neuropediatrics 2000; 31: 287–292 De Koning TJ, Duran M, van Maldergem L, Pineda M, Dorland L, Gooskens R, Jaeken J, Poll-The BT. Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. J Inherit Metab Dis 2002; 25: 119–125 De Koning TJ, Snell K, Duran M, Berger R, Poll-The BT, Surtees R. L-Serine in disease and development. Biochem J 2003; 371: 653–661 Häusler MG, Jaeken J, Mönch E, Ramaekers VT. Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings. Neuropediatrics 2001; 32: 191–195 Jaeken J, Detheux M, van Maldegem L, Foulon M, Carchon H, van Schaftingen E.3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child 1996; 74: 542–545 Jaeken J, Detheux M, van Maldegem L, Frijns JP, Alliet P, Foulon M, Carchon H, van Schaftingen E. 3-Phosphoglycerate dehydrogenase deficiency and 3-phosphosine phosphatase deficiency: inborn errors of serine biosynthesis. J Inherit Metab Dis 1996; 19: 223–226 Klomp LWJ, de Koning TJ, Malingré HEM, van Beurden EACM, Brink M, Opdam FL, Duran M, Jaeken J, Pineda M, van Maldergem L, Poll-The BT, Van den Berg IET, Berger R. Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency – a neurometabolic disorder associated with reduced l-serine biosynthesis. Am J Hum Genet 2000; 67: 1389–1399 Pineda M,Vilaseca MA,Artuch R,Santos S,Garcia González MM, Sua I, Aracil A, van Schaftingen E, Jaeken J. 3-Phosphoglycerate dehydrogenase deficiency in a patient with West syndrome. Dev Med Child Neurol 2000; 42: 629–633

48 Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase Deficiency Appignani BA, Kaye EM,Wolpert SM. CT and MR appearance of the brain in two children with molybdenum cofactor deficiency. AJNR Am J Neuroradiol 1996; 17: 317–320 Arslanoglu S, Yalaz M, Göklpen, Çoker M, Tütüncüog˘lu S, Akisu M, Darcan Sˆ, Kultursay N, Çiris M, Demirtasˆ E. Molybdenum cofactor deficiency associated with Dandy-Walker complex. Brain Dev 2001; 23: 815–818 Barbot C, Martins E, Vilarinho L, Dorche C, Cardoso ML. A mild form of infantile isolated sulphite oxidase deficiency. Neuropediatrics 1995; 322: 322–324 Brown GK, Scholem RD, Croll HB,Wraith JE, McGill JJ. Sulfite oxidase deficiency: clinical, neuroradiologic, and biochemical features in two new patients. Neurology 1989; 39: 252–257 Dublin AB, Hald JK,Wootton-Gorges SL. Isolated sulfite oxidase deficiency: MR images features. AJNR Am J Neuroradiol 2002; 23: 484–485 Duran M, Beemer FA, van der Heijden C, Korteland J, de Bref PK, Brink M, Wadman SK. Combined deficiency of xanthine oxidase and sulphite oxidase: a defect of molybdenum metabolism or transport. J Inherit Metab Dis 1978; 1; 175–178 Endres W, Shin YS, Günther R, Ibel H, Duran M, Wadman SK. Report on a new patient with combined deficiencies of sulphite oxidase and xanthine dehydrogenase due to molybdenum cofactor deficiency. Eur J Pediatr 1988; 148: 246–249 Feng G,Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 1998; 282: 1321–1324 Hänzelmann P, Schwartz G, Mendel RR. Functionality of alternative splice forms of the first enzymes involved in human molybdenum cofactor biosynthesis. J Biol Chem 2002; 227: 18303–18312 Hughes EF,Fairbanks L,Simmonds HA,O’Robinson R.Molybdenum cofactor deficiency – phenotypic variability in a family with late-onset variant. Dev Med Child Neurol 1998; 40: 57–61 Johnson JL, Coyne E, Rajagopalan KV, van Hove JLK, Mackay M, Pitt J,Boneh A.Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency. Am J Med Genet 2001; 104: 169–173 Johnson JL, Coyne KE, Garret RM, Zabot M-T, Dorche C, Kisker C, Rajagopalan KV. Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients. Hum Mutat 2002; 20: 74–79 Lee HF, Mak BSC, Chi CS, Tsai CR, Chen CH, Shu SG. A novel mutation in neonatal isolated sulphite oxidase deficiency. Neuropediatrics 2002; 33: 174–179 Mize C, Johnson JL, Rajagopalan KV. Defective molybdopterin biosynthesis: clinical heterogeneity associated with molybdenum cofactor deficiency. J Inherit Metab Dis 1995; 18: 283–290 Reiss J. Genetics of molybdenum cofactor deficiency. Hum Genet 2000; 106: 157–163 Reiss J, Johnson LJ. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum Mutat 2003; 21: 569–576 Reiss J, Cohen N, Dorche C, Mandel H, Mendel RR, Stallmeyer B, Zabot MT, Dierks T. Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency. Nat Genet 1998; 20: 51–53

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984 References and Further Reading Reiss J, Christensen E, Kurlemann G, Zabot M-T, Dorche C. Genomic structure and mutation spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. Hum Genet 1998; 103: 639–644 Reiss J, Dorche C, Stallmeyer B, Mendel RR, Cohen N, Zabot MT. Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Am J Hum Genet 1999; 64: 706–711 Reiss J, Gross-Hart S, Christensen E, Schmidt P, Mendel RR, Schwartz G. A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. Am J Hum Genet 2001; 68: 208–213 Rupar CA, Gillett J, Gordon BA, Ramsay DA, Johnson JL, Garrett RM, Rajagopalan KV, Jung JH, Bacheyie GS, Sellers AR. Isolated sulfite oxidase deficiency. Neuropediatrics 1996; 27: 299–304 Salvan AM, Chambrol B, Lamoureux S, Confort-Gouny S, Cozzone PJ, Vion-Dury J. In vivo brain proton MR spectroscopy in a case of molybdenum cofactor deficiency. Pediatr Radiol 1999; 29: 846–848 Schuierer G, Kurlemann G, Bick U, Stephani U. Molybdenumcofactor deficiency; CT and MR findings. Neuropediatrics 995; 26: 5–54 Shalata A, Mandel H, Reiss J, Szargel R, Cohen-Akenine A, Dorche C,Zabot M-T,Van Gennip A,Abeling N,Berant M,Cohen N. Localisation of a gene for molybdenum cofactor deficiency, on the short arm of chromosome 6, by homozygosity mapping. Am J Hum Genet 1998; 63: 148–154 Shih VE, Abroms IF, Johnson JL, Carney M, Mandell R, Robb RM, Cloherty JP, Rajagopalan KV. Sulfite oxidase deficiency. Biochemical and clinical investigations of a hereditary metabolic disorder in sulfur metabolism. N Engl J Med 1977; 207: 1022–1028 Topçu M, Coskun T, Haliloglu G, Saatci I. Molybdenum cofactor deficiency: report of three cases presenting as hypoxic-ischemic encephalopathy. J Child Neurol 2001; 16: 264–270 Touati G, Rusthoven E, Depondt, Dorche C, Duran M, Héron B, Rabier D, Russo M, Saudubray JM. Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. Evidence for clinical and biochemical improvement. J Inherit Metab Dis 2000; 23: 45–53 Van der Klei-van Moorsel JM, Smit LM, Brockstedt M, Jacobs C, Dorche C, Duran M. Infantile isolated sulphite oxidase deficiency: report of a case with negative sulphite test and normal sulphate excretion. Eur J Pediatr 1991; 150: 196–197

49 Galactosemia Acosta PH, Gross KC. Hidden sources of galactose in the environment. Eur J Pediatr 1995; 154: S87-S92 Beigi B, O’Keefe M, Bowell R, Naughten E, Badawi N, Lanigan B. Ophthalmic findings in classical galactosaemia – prospective study. Br J Ophthalmol 1993; 77: 162–164 Berry GT. The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr 1995; 154: S53-S64 Berry GT, Palmieri M, Gross KC, Acosta PB, Henstenburg JA, Mazur A, Reynolds R, Segal S.The effect of dietary fruits and vegetables on urinary galactitol excretion in galactose-1phosphate uridyltransferase deficiency. J Inherit Metab Dis 1993; 16: 91–100 Böhles H, Wenzel D, Shin YS. Progressive cerebellar and extrapyramidal motor disturbances in galactosaemic twins. Eur J Pediatr 1986; 145: 413–417

Bosch AM,Bakker HD,van Gennip AH,van Kempen JV,Wanders RJA, Wijburg FA. Clinical features of galactokinase deficiency: a review of the literature. J Inherit Metab Dis 2002; 25: 629–634 Burke JP, O’Keefe M, Bowell R, Naughten ER. Ophthalmic findings in classical galactosemia – a screened population. J Pediatr Ophthalmol Strabismus 1989; 26: 165–168 Cleary MA, Heptinstall LE, Wraith JE, Walter JH. Galactosemia: relationship of IQ to biochemical control and genotype. J Inherit Metab Dis 1995; 18: 151–152 Crome L. A case of galactosaemia with the pathological and neuropathological findings. Arch Dis Child 1962; 37: 415– 429 Friedman JH,Levy HL,Boustany R-M.Late onset of distinct neurologic syndromes in galactosemic siblings. Neurology 1989; 39: 741–742 Gitzelmann R. Galactose-1-phosphate in the pathophysiology of galactosemia. Eur J Pediatr 1995; 154: S45–S49 Gitzelmann R, Steinmann B, Mitchell B, Haigis E. Uridine diphosphate galactose 4-epimerase deficiency. Report of eight cases in three families. Helv Paediatr Acta 1976; 31: 441–452 Haberland C, Perou M, Brunngraber EG, Hof H. The neuropathology of galactosemia. J Neuropathol Exp Neurol 1971; 30: 431–447 Henderson MJ, Holton JB. Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.J Inherit Metab Dis 1983; 6: 17–20 Holton JB. Effects of galactosemia in utero. Eur J Pediatr 1995; 154: S77–S81 Holton JB. Galactosemia: pathogenesis and treatment. J Inherit Metab Dis 1996; 19: 3–7 Holton JB, Allen JT, Gillett MG. Prenatal diagnosis of disorders of galactose metabolism. J Inherit Metab Dis 1989; 12 (suppl 1): 202–206 Keevill NJ, Holton JB, Allen JT. UDP-glucose and UDP-galactose concentrations in cultured skin fibroblasts of patients with classical galactosaemia. J Inherit Metab Dis 1994; 17: 23–26 Kliegman RM, Sparks JW. Perinatal galactose metabolism. J Pediatr 1985; 107: 831–841 Koch TK,Schmidt KA,Wagstaff JE,Won G,Packman S.Neurologic complications in galactosemia. Pediatr Neurol 1992; 8: 217–220 Landing BH, Ang SM, Villarreal-Engelhardt G, Donnell GN. Galactosemia: clinical and pathologic features, tissue staining patterns with labeled galactose- and galactosaminebinding lectins, and possible loci of nonenzymatic galactosylation. Perspect Pediatr Pathol 1993; 17: 99–124 Lesgold Belman A, Moshe SL, Zimmerman RD. Computed tomographic demonstration of cerebral edema in a child with galactosemia. Pediatrics 1986; 78: 606–609 Liu G, Hale GE, Hughes CL. Galactose metabolism and ovarian toxicity. Reprod Toxicol 2000; 14: 377–384 Nelson CD, Waggoner DD, Donnell GN, Tuerck JM, Buist NRM. Verbal dyspraxia in treated galactosemia. Pediatrics 1991; 88: 346–350 Nelson MD,Wolff JA, Cross CA, Donnell GN, Kaufman FR. Galactosemia: evaluation with MR imaging. Radiology 1992; 184: 255–261 Olambiwonnu NO, McVie R, Won G, Frasier SD, Donnell GN. Galactokinase deficiency in twins: clinical and biochemical studies. Pediatrics 1974; 53: 314–318

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Ornstein KS, McGuire EJ, Berry GT, Roth S, Segal S. Abnormal galactosylation of complex carbohydrates in cultured fibroblasts from patients with galactose-1-phosphate uridyltransferase deficiency. Pediatr Res 1992; 31: 508–511 Ratner Kaufman F,McBride-Chang C, Manis FR,Wolff JA, Nelson MD. Cognitive functioning, neurologic status and brain imaging in classical galactosemia. Eur J Pediatr 1995; 154: S2–S5 Ratner Kaufman F, Horton EJ, Gott P, Wolff JA, Neson Jr. MD, Azen C. Manis FR. Abnormal somatosensory evoked potentials in patients with classic galactosemia: correlation with neurologic outcome. J Child Neurol 1995; 10: 32–36 Sardharwalla IB,Wraith JE, Bridge C, Fowler B, Roberts SA. A patient with severe type of epimerase deficiency galactosaemia. J Inherit Metab Dis 1988; 11 (suppl 2): 249–251 Schwarz HP, Schaefer T, Bachmann C. Galactose and galactitol in the urine of children with compound heterozygosity for Duarte variant and classical galactosemia (GtD/gt) after an oral galactose load. Clin Chem 1985; 31: 420–422 Schweitzer S, Shin Y,Jakobs C, Brodehl J.Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 1993; 152: 36–43 Segal S. Galactosemia unsolved. Eur J Pediatr 1995; 154: S97–S102 Segal S, Rutman JY, Frimptr GW. Galactokinase deficiency and mental retardation. J Pediatr 1979; 95: 750–753 Smetana HF, Olen E. Hereditary galactose disease. Am J Clin Pathol 1962; 38: 3–25 Sokol RJ, McCabe ERB, Kotzer AM, Langendoerfer SI. Pitfalls in diagnosing galactosemia: false negative newborn screening following red blood cell transfusion. J Pediatr Gastroenterol Nutr 1989; 8: 266–268 Tyfield LA,Reichardt J,Fridovich-Keil J,Croke Dt,Elas II LJ,Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Dolores Boleda M. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat 1999; 13: 417–430 Tyfield LA. Galactosemia and allelic variation at the galactoseme-1-phosphate uridyltransferase gene: a complex relationship between genotype and phenotype. Eur J Pediatr 2000; 159: S204–S207 Waggoner DD, Buist NRM. Long-term complications in treated galactosemia. Int Pediatr 1993; 8: 97–100 Waggoner DD, Buist NRM, Donnell GN. Long-term prognosis in galactosaemia: results of a survery of 350 cases. J Inherit Metab Dis 1990; 13: 802–818

50 Sjögren-Larsson Syndrome Altmok D,Yildiz YT, Seçkin D, Altmok G, Tacal T, Eryilmaz M. MRI of three siblings with Sjögren-Larsson syndrome. Pediatr Radiol 1999; 29: 776–769 Auada MP, Taube MBZ, Collares EF, Tanaka AMU, Cintra ML. Sjögren-Larsson syndrome: biochemical defects and follow up in three cases. Eur J Dermatol 2002; 12: 263–266 De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Steinert SP, Compton JG, Markova N, Rizzo WB. Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet 1996; 12: 52–57 Di Rocco M,Filocamo M,Tortori-Donati P,Veneselli E,Borrone C, Rizzo WB. Sjögren-Larsson syndrome: nuclear magnetic resonance imging of the brain in a 4-year-old boy. J Inherit Metab Dis 1994; 17: 112–114

Gomori JM, Leibovici V, Zlotogorski A, Wirguin I, Haham-Zadeh S. Computed tomography in Sjögren-Larsson syndrome. Neuroradiology 1987; 29: 557–559 Hussain MZ, Aihara M, Oba H, Ohtomo K, Uchiyama G, Hayashibe H, Nakazawa S. MRI of white matter changes in the Sjögren-Larsson syndrome. Neuroradiology 1995; 37: 576–577 Kelson TL, Craft DA, Rizzo WB. Carrier detection for SjögrenLarsson syndrome. J Inherit Metab Dis 1992; 15: 105–111 Kelson TL, Secor McVoy JR, Rizzo WB. Human liver fatty aldehyde dehydrogenase: microsomal localization, purification, and biochemical characterization. Biochim Biophys Acta 1997; 1335: 99–110 Lake BD, Smith VV, Judge MR, Harper JI, Besley GTN. Hexanol dehydrogenase activity shown by enzyme histochemistry on skin biopsies allows differentiation of Sjögren-Larsson syndrome from other ichthyoses. J Inherit Metab Dis 1991; 14: 338–340 Mano T, Ono J, Taminaga T, Imai K, Sakurai K, Harada K, Nagai T, Rizzo WB, Okada S. Proton MR spectroscopy of SjögrenLarsson’s syndrome. AJNR Am J Neuroradiol 1999; 20: 1671–1673 Miyanomae Y,Ochi M,Yoshioka H,Takaya K,Kizaki Z,Inoue F,Furuya S, Naruse S. Cerebral MRI and spectroscopy in SjögrenLarsson syndrome: case report. Neuroradiology 1995; 37: 225–228 Mulder LJMM, Oranje AP, Loonen MCB. Cranial CT in the Sjögren-Larsson syndrome. Neuroradiology 1987; 29: 560–561 Rizzo WB. Inherited disorders of fatty alcohol metabolism. Mol Genet Metab 1998; 65: 63–73 Rizzo WB. Sjögren-Larsson syndrome. Explaining the skin– brain connection. Neurology 1999; 52: 1307–1308 Rizzo WB, Craft DA. Sjögren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol: NAD+ oxidoreductase in cultured fibroblasts. J Clin Invest 1991; 88: 1643–1648 Rizzo WB, Craft DA. Sjögren-Larsson syndrome: accumulation of free fatty alcohols in cultured fibroblasts and plasma. J Lipid Res 2000; 41: 1077–1081 Rizzo WB, Carney G, Lin Z.The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. Am J Hum Genet 1999; 65: 1547–1560 Rizzo WB, Heinz E, Simon M, Craft DA. Microsomal fatty aldehyde dehydrogenase catalyzes the oxidation of aliphatic aldehyde derived form ether glycerolipid catabolism: implications for Sjögren-Larsson syndrome. Biochim Biophys Acta 2000; 1535: 1–9 Rizzo WB, Lin Z, Carney G. Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analysis in Sjögren-Larsson syndrome. Chem Biol Interact 2001; 130–132: 297–307 Sillén A, Anton-Lamprecht I, Braun-Quentin C, Kraus CS, Sitki Sayli B, Ayuso C, Jagell S, Küster W, Waledius C. Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome. Hum Mutat 1998; 12: 377–384 Sylvester PE. Pathological findings in Sjögren-Larsson syndrome. J Ment Defic Res 1969; 13: 267–275 Tabsh K, Rizzo WB, Holbrook K,Theroux N.Sjögren-Larsson syndrome: technique and timing of prenatal diagnosis. Obstet Gynecol 1993; 82 (suppl II): 700–703 Taube B, Billeaud C, Labrèze C, Entressangles B, Fontan D,Taïeb A. Sjögren-Larsson syndrome: early diagnosis, dietary management and biochemical studies in two cases. Dermatology 1999; 198: 340–345

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986 References and Further Reading Tsukamoto N, Chang C, Yoshida A. Mutations associated with Sjögren-Larsson syndrome. Ann Hum Genet 1997; 61: 235–242 Van Domburg PHMF, Willemsen MAAP, Rotteveel JJ, de Jong JGN, Thijssen HOM, Heerschap A, Cruysberg JRM, Wanders RJA, Gabreëls FJM, Steijlen PM. Sjögren-Larsson syndrome. Clinical and MRI/MRS findings in FALDH-deficient patients. Neurology 1999; 52: 1345–1352 Van Mieghem F, van Goethem JWM, Parizel PM, Cras P, van den Hauwe L, de Meirleire J, de Schepper AM. MR of the brain in Sjögren-Larsson syndrome. AJNR Am J Neuroradiol 1997; 18: 1561–1563 Verhoeven NM, Jacobs C, Carney G, Somers MP, Wanders RJA, Rizzo WB. Involvement of microsomal fatty aldehyde dehydrogenase in the a-oxidation of phytanic acid. FEBS Lett 1998; 429: 225–228 Wester P, Bergström U, Brun A, Jagell S, Karlsson B, Eriksson A. Monoaminergic dysfunction in Sjögren-Larsson syndrome. Mol Chem Neuropathol 1991; 15: 13–28 Willemsen MAAP, Rotteveel JJ, Steijlen PM, Heerschap A, Mayatepek E. 5-Lipoxygenase inhibition: a new treatment strategy for Sjögren-Larsson Syndrome. Neuropediatrics 1999; 31: 1–3 Willemsen MAAP, Rotteveel JJ, Domburg v PHMF, Gabreëls FJM, Mayatepek E, Sengers RCA. Preterm birth in SjogrenLarsson syndrome. Neuropediatrics 1999; 30: 325–327 Willemsen MAAP, de Jong JGN, van Domburg PHMF, Rotteveel JJ, Wanders RJA, Mayatepek E. Defective inactivation of leukotriene B4 in patients with Sjögren-Larsson syndrome. J Pediatr 1999; 136: 258–260 Willemsen MAAP, Cruysberg RM, Rotteveel JJ, Aandekerk AL, van Domburg PHMF, Deuteman AF. Juvenile Macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome. Am J Ophthalmol 2000; 130: 782–789 Willemsen MAAP,Lutt MAJ,Steijlen PM,Cruysberg JRM,van der Graaf M, Nijhuis-van der Sanden MWG, Pasman JW, Mayatepek E, Rotteveel JJ. Clinical and biochemical effects of zileuton in patients with the Sjögren-Larsson syndrome. Eur J Pediatr 2001; 160: 711–717 Willemsen MAAP, Rotteveel JJ, de Jong JGN, Wanders RJA, Ijlst L, Hoffmann GF, Mayatepek E. Defective metabolism of leukotriene B4 in the Sjögren-Larsson syndrome. J Neurol Sci 2001; 183: 61–67 Willemsen MAAP, IJlst L, Steijlen PM, Rotteveel JJ, de Jong JGN, van Domburg PHMF, Mayatepek E, Gabreëls FJM, Wanders RJA. Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome. Brain 2001; 124: 1426–1437 Willemsen MAAP, van der Graaf M, van der Knaap MS, Heerschap A, van Domburg PHMF, Gabreëls FJM, Rotteveel JJ. MR imaging and proton MR spectroscopic studies in Sjögren-Larsson syndrome: characterization of the leukoencephalopathy. AJNR Am J Neuroradiol 2004; 25: 649–657

51 Lowe Syndrome Athreya BH, Schumacher HR, Getz HD, Norman ME, Borden S, Witzleben CL. Arthropathy of Lowe’s (oculocerebrorenal) syndrome. Arthritis Rheum 1983; 26: 728–735

Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR, Nussbaum RL. The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 1992; 358: 239–242 Carroll WJ, Woodruff WW, Cadman TE. MR findings in oculocerebrorenal syndrome. AJNR Am J Neuroradiol 1993; 14: 449–451 Charnas LR, Gahl WA. The oculocerebrorenal syndrome of Lowe. Adv Pediatr 1991; 38: 75–107 Charnas L, Bernar J, Pezeshkpour GH, Dalakas M, Harper GS, Gahl WA. MRI findings and peripheral neuropathy in Lowe’s syndrome. Neuropediatrics 1988; 19: 7–9 Charnas LR, Bernardini I, Rader D, Hoeg JM, Gahl WA. Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med 1991; 324: 1318–1325 Cibis GW, Waeltermann JM, Whitcraft CT, Tripathi RC, Harris DJ. Lenticular opacities in carriers of Lowe’s syndrome. J Ophthalmol 1986; 93: 1041–1045 De Camilli P, Emr SD, McPherson PS, Novick P. Phosphoinositides as regulators in membrane traffic. Science 1996; 271: 1533–1539 Demmer LA, Wippold FJ, Dowton SB. Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome. Pediatr Radiol 1992; 22: 76–77 Dressman MA, Olivos-Glander IM, Nussbaum RL, Suchy SF. Ocrl1, a PtdIns(4,5)P2 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells. J Histochem Cytochem 2000; 48: 179–189 Fivush BA, Rausen C, Christenson MJ, Olson JL. Acute tubular necrosis associated with Lowe’s syndrome: possible role of rhabdomyolysis. Am J Kidney Dis 1992; 20: 396–399 Garzuly F, Jellinger K, Szabo L,Toth K. Morbid changes in Lowe’s oculo-cerebro-renal syndrome. Neuropediatrics 1973; 4: 304–313 Giannakopoulos P, Bouras C, Vallet P, Constantinidis J. Lowe syndrome: clinical and neuropathological studies of an adult case. J Ment Defic Res 1990; 34: 491–500 Irvine R. Second messengers and Lowe syndrome. Nat Genet 1992; 1: 315–316 Kenworthy L, Park T, Charnas LR. Cognitive and behavioral profile of the oculocerebrorenal syndrome of Lowe. Am J Med Genet 1993; 46: 297–303 Kohyama J, Niimura F, Kawashima K, Iwakawa Y, Nonaka I. Congenital fiber type disproportion myopathy in Lowe syndrome. Pediatr Neurol 1989; 5: 373–376 Lin T, Orrison BM, Leahey A-M, Suchy SF, Bernard DJ, Lewis RA, Nussbaum RL. Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet 1997; 60: 1384–1388 Lin T, Orrison BM, Suchy SF, Lewis RA, Nussbaum RL. Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. Mol Genet Metab 1998; 64: 58–61 Monnier N, Satre V, Lerouge E, Berthoin F, Lunardi J. OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Hum Mutat 2000; 16: 157–165 Mueller OT, Hartsfield JK, Gallardo LA, Essig YP, Miller KL, Papenhausen PR, Tedesco TA. Lowe oculocerebrorenal syndrome in a female with a balanced X;20 translocation: mapping of the X chromosome breakpoint. Am J Hum Genet 1991; 49: 804–810

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Nielsen KF, Steffensen GK. Congenital nephritic syndrome associated with Lowe’s syndrome. Child Nephrol Urol 1990; 10: 92–95 Olivos-Glander IM, Jänne PA, Nussbaum RL. The oculocerebrorenal syndrome gene product is a 105-kD protein localized tot the Golgi complex. Am J Hum Genet 1995; 57: 817–823 Ono J,Harada K,Mano T,Yamamoto T,Okada S.MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome. Pediatr Neurol 1996; 14: 162–164 O’Tuama LA, Laster DW. Oculocerebrorenal syndrome: case report with CT and MR correlates. AJNR Am J Neuroradiol 1987; 8: 555–557 Pueschel SM, Brem AS, Nittoli P. Central nervous system and renal investigations in patients with Lowe syndrome. Childs Nerv Syst 1992; 8: 45–48 Satre V, Monnier N, Berthoin F, Ayuso C, Joannard A, Jouk P-S, Lopex-Pajares I, Megabarne A, Philipe HJ, Plauchu H, Torres ML, Lunardi J. Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene. Am J Hum Genet 1999; 65: 68–76 Savolaine ER,Bielke DJ.Cranial magnetic resonance imaging in Lowe’s syndrome. Clin Imaging 1993; 17: 133–136 Schneider JF, Boltshauser E, Neuhaus TJ, Rauscher C, Martin E. MRI and proton spectroscopy in Lowe syndrome. Neuropediatrics 2001; 32: 45–48 Shields D, Arvan P. Disease models provide insight into postGolgi protein trafficking, localization and processing. Curr Opin Cell Biol 1999; 11: 489–494 Suchy SF, Nussbaum RL. The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization. Am J Hum Genet 2002; 71: 1420–1427 Suchy SF, Olivos-Glander IM, Nussbaum RL. Lowe syndrome, a deficiency of a phosphatidyl-inositol 4,5-biphosphate 5phosphatase in the Golgi apparatus. Hum Mol Genet 1995; 4: 2245–2250 Terslev E. Two cases of aminoaciduria, ocular changes and retarded mental and somatic development (Lowe’s syndrome). Acta Paediatr Scand 1960; 49: 635–644 Tripathi RC, Cibis GW, Tripathi BJ. Pathogenesis of cataracts in patients with Lowe’s syndrome. J Ophthalmol 1986; 93: 1046–1051 Zhang X,Majerus PW.Phosphatidylinositol signaling reactions. Semin Cell Dev Biol 1998; 9: 153–160 Zhang X, Jefferson AB, Auethavekiat V, Majerus PW.The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5biphosphate 5-phosphatase. Proc Natl Acad Sci 1995; 92: 4853–4856

52 Wilson Disease Aisen AM, Martel W, Gabrielsen TO, Glazer GM, Brewer G,Young AB, Hill G.Wilson disease of the brain: MR imaging. Radiology 1985; 157: 137–141 Albernaz VS, Castillo M, Mukherji SK, Siatkowski M, Naidich TP. Facies to remember. Int J Neuroradiol 1997; 3: 206–217 Bertrand E, Lewandowska E, Szpak GM, Hoogenraad T, Blaauwgers HG, Czlonkowska A, Dymecki J. Neuropathological analysis of pathological forms of astroglia in Wilson’s disease. Folia Neuropathol 2001; 39: 73–79 Brewer GJ. Penicillamine should not be used as initial therapy in Wilson’s disease. Mov Disord 1999; 14: 551–554

Brewer GJ. Recognition, diagnosis, and management of Wilson’s disease. Proc Soc Exp Biol Med 2000; 233: 39–46 Brewer GJ, Askari F. Transplant livers in Wilson’s disease for hepatic, not neurologic, indications. Liver Transplant 2000; 6: 662–664 Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine 1992; 71: 139–164 Brewer GJ, Fink JK, Hedera P. Diagnosis and treatment of Wilson’s disease. Semin Neurol 1999; 19: 261–270 Brewer GJ, Johnson VD, Dick RD, Hedera P, Fink JK, Kluin KJ. Treatment of Wilson’s disease with zinc.XVII.Treatment during pregnancy. Hepatology 2000; 31: 364–370 Brewer GJ, Dick RD, Johnson VD, Fink JK, Kluin KJ, Daniels S. Treatment of Wilson’s disease with zinc. XVI.Treatment during the pediatric years. J Lab Clin Med 2001; 137: 191–198 Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK. Treatment of Wilson disease with ammonium tetrathiomolybdate. Arch Neurol 2003; 60: 379–385 Bingle CD, Srai SKS, Epstein O. Copper metabolism in hypercupremic human livers. Studies of its subcellular distribution, association with binding proteins and expressions of mRNAs. J Hepatol 1992; 15: 94–101 Brugieres P, Combes C, Ricolfi F, Degos JD, Poirier J, Gaston A. Atypical MR presentation of Wilson disease: a possible consequence of paramagnetic effect of copper? Neuroradiology 1992; 34: 222–224 Bull PC,Thomas GR, Rommens JM, Forbes JR,Wilson Cox D.The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 1993; 5: 327–337 Castilla-Higuero L,Romero-Gomez M,Suarez E,Castro M.Acute hepatitis after starting zinc therapy in a patient with presymptomatic Wilson’s disease. Hepatology 2000; 32: 877 Chelly J, Monaco AP. Cloning the Wilson disease gene. Nat Genet 1993; 5: 317–318 De Haan J, Grossman RI, Civitello L, Hackney DB, Golberg HI, Bilaniuk LT, Zimmerman RA. High-field magnetic resonance imaging of Wilson’s disease. J Comput Assist Tomogr 1987; 11: 132–135 Demirkiran M, Jankovic J, Lewis RA, Cox DW. Neurologic presentation of Wilson disease without Kayser-Fleischer rings. Neurology 1996; 46: 1040–1043 Dening TR, Berrios GE, Walshe JM. Wilson’s disease and epilepsy. Brain 1988; 111: 1139–1155 Di Donato M, Sarkar B. Copper transport and its alterations in Menkes and Wilson diseases. Biochim Biophys Acta 1997; 1360: 3–16 Emre S, Atillasoy EO, Ozdemir S, Schilsky M, Rathna Varma CVR, Thung SN, Sternlieb I, Guy SR, Sheiner PA, Schwartz ME, Miller CM. Orthotopic liver transplantation for Wilson’s disease: a single-center experience. Transplantation 2001; 72: 1232–1236 Engelbrecht V, Schlaug G, Hefter H, Kahn T, Mödder U. MRI of the brain in Wilson disease: T2 signal loss under therapy. J Comput Assist Tomogr 1995; 19: 635–638 Gaffney D,Walker JL, O’Donnell JG, Fell GS, O’Neill KF, Park RHR, Russell RI. DNA-based presymptomatic diagnosis of Wilson disease. J Inherit Metab Dis 1992; 15: 161–170 Giagheddu M, Tamburini G, Piga M, Tacconi P, Giagheddu A, Serra A, Siotto P, Satta L, Demilia L, Marrosu F.Comparison of MRI, EEG, EPS and ECD-SPECT in Wilson’s disease. Acta Neurol Scand 2001; 103: 71–81 Gow PJ, Smallwood RA, Angus PW, Smith AL,Wall AJ, Sewell RB. Diagnosis of Wilson’s disease: an expience over three decades. Gut 2000; 46: 415–419

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988 References and Further Reading Grimm G, Madl C, Katzenschlager R, Oder W, Ferenci P, Gangl A. Detailed evaluation of evoked potentials in Wilson’s disease. Electroencephalogr Clin Neurophysiol 1992; 82: 119–124 Heckmann JM, Eastman RW.Wilson’s disease: neurological and magnetic resonance imaging improvement on zinc treatment. J Neurol Neurosurg Psychiatry 1994; 57: 1273–1274 Hedera P, Brewer GJ, Arbor A, Fink JK. White matter changes in Wilson disease. Arch Neurol 2002; 59: 866–867 Hefter H, Rautenberg W, Kreuzpainter G, Arendt G, Freund H-J, Pichlmayr R, Strohmeyer G. Does orthopic liver transplantation heal Wilson’s disease? Clinical follow-up of two livertransplanted patients.Acta Neurol Scand 1991; 84: 192–196 Hoogenraad TU, Koevoet R, de Ruyter-Korver EGWM. Oral zinc sulphate as long term treatment in Wilson’s disease. Eur Neurol 1979; 18: 205–211 Houwen RHJ,Roberts EA,Thomas GR,Cox DW.DNA markers for the diagnosis of Wilson disease. J Hepatol 1993; 17: 269– 276 Huang C-C, Chu N-S. Acute dystonia with thalamic and brainstem lesions after initial penicillamine treatment in Wilson’s disease. Eur Neurol 1998; 39: 32–37 Huang C-C, Chu N-S.Wilson’s disease: resolution of MRI lesions following long-term oral zinc therapy. Acta Neurol Scand 1996; 93: 215–218 Imlya M, Ichikawa K, Matsushima H, Kageyama Y, Fujioka A. MR of the base of the pons in Wilson disease. AJNR Am J Neuroradiol 1992; 13: 1009–1012 Ishino H,Mii T,Hayashi Y,Saito A,Otsuki S.A case of Wilson’s disease with enormous cavity formation of cerebral white matter. Neurology 1972; 22: 905–909 Keller R, Torta R, Lagget M, Crasto S, Bergamosso B. Psychiatric symptoms as late onset of Wilson’s disease: neuroradiological findings,clinical features and treatment.Ital J Neurol Sci 1999; 20: 49–54 Kobayashi S, Ochiai T, Hori S, Suzuki T, Shimizu T, Gunji Y, Shimada H, Yamamoto S, Ogawa A, Kohno Y, Sunaga M, Shimazu M, Takena K. Copper metabolism after living donor liver transplantation for hepatic failure of Wilson’s disease from a gene mutated donor. Hepatogastroenterology 2001; 48: 1259–1261 Komatsu H, Fujisawa T, Inui A, Soga T, Sekine I, Kodama H, Uemoto S,Tanaka K. Hepatic copper concentration in children undergoing living related liver transplantation due to Wilsonian fulminant hepatic failure. Clin Transplant 2002; 16: 227–232 Lang CJG, Rabas-Kolominsky P, Engelhart A. Fatal deterioration of Wilson’s disease after institution of oral zinc therapy. Arch Neurol 1993; 50: 1007–1008 Longhi R, Riva E, Rottoli A, Valsasina R, Pinelli P, Giovannini M. Nuclear magnetic resonance brain study in a case of Wilson disease. J Inherit Metab Dis 1989; 12 (suppl) 386–388 Lui CC, Chen CL, Cheng YF, Lee TY. Recovery of neurological deficits in a case of Wilson’s disease after liver transplantation.Transplant Proc 1998; 30: 3324–3325 Magalhaes ACA, Caramelli P, Menezes JR, Lo LS, Bacheschi LA, Barbosa ER, Rosemberg LA. Wilson’s disease: MRI with clinical correlation. Neuroradiology 1994; 36: 97–100 Mason AL, Marsh W, Alpers DH. Intractable neurological Wilson’s disease treated with orthotopic liver transplantation. Dig Dis Sci 1993; 38: 1746–1750 Matsuura T, Sasaki H,Tashiro K. Atypical MR findings in Wilson’s disease: pronounced lesions in the dentate nucleus causing tremor. J Neurol Neurosurg Psychiatry 1998; 64: 160

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53 Menkes Disease Ambrosini L, Mercer JFB. Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper treated classical Menkes disease.Hum Mol Genet 1999; 8: 1545–1555 Aynaci FM, Mocan H, Bahadir S, Sari A, Aksoy A. A case of Menkes’ syndrome associated with deafness and inferior cerebellar vermian hypoplasia. Acta Paediatr 1997; 87: 121–123 Barnard RO, Best PV, Erdohazi M. Neuropathology of Menkes’ disease. Dev Med Child Neurol 1978; 20: 586–597 Blaser SI, Berns DH, Ross JS, Lanska MJ,Weissman BM. Serial MR studies in Menkes disease. J Comput Assist Tomogr 1989; 13: 113–115 Camakaris J, Voskoboinik I, Mercer JF. Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun 1999; 261: 225–232 Chelly J, Tümer Z, Tønnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet 1993; 3: 14–19 Christodoulou J, Danks DM, Sarkar B, Baerlocher KE, Casey R, Horn N,Tümer Z, Clarke JTR. Early treatment of Menkes disease with parenteral cooper-histidine: long-term follow-up of four treated patients. Am J Med Genet 1998; 76: 154–164 Dagenais SL, Adam AN, Innis JW, Glover TW. A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease. Am J Hum Genet 2001; 69: 420–427 DiDonato M, Sarkar B. Copper transport and its alterations in Menkes and Wilson diseases. Biochim Biophys Acta 1997; 1360: 3–16 Faerber EN, Grover WD, DeFilipp GJ, Capitanio MA, Lui T-H, Swartz JD. Cerebral MR of Menkes kinky-hair disease. AJNR Am J Neuroradiol 1989; 10: 190–192 Gasch AT, Caruso RC, Kaler SG, Kaiser-Kupfer M. Menkes’ syndrome. Ophthalmic findings. Ophthalmology 2002; 109: 1477–1483 Geller TJ, Pan Y, Martin DS. Early neuroradiologic evidence of degeneration in Menkes’ disease. Pediatr Neurol 1997; 17: 255–258 George DH,Casey RE.Menkes disease after copper histidine replacement therapy: case report. Pediatr Dev Pathol 2001; 4: 281–288 Gu Y-H, Kodoma H, Murata Y, Mochizuki D, Yanagawa Y, Ushijima H, Shiba T, Lee C-C. ATP7A Gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. Am J Med Genet 2001; 99: 217–222 Guimarães Santos LM, da Silva Teixeira C, Pereira Vilanova LC, Micheletti C, Curiati Mendes CS, Borri ML, Martins AM. Menkes disease. Case report of an uncommon presentation with white matter lesions.Arq Neuropsiquiatr 2001; 59: 125–127

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54 Fragile X Premutation Beilina A,Tassone F,Schwartz PH,Sahota P,Hagerman PJ.Redistribution of transcription starts sites within the FMR1 promotor region with expansion of the downstream CGG-repeat element. Hum Mol Genet 2004; 13: 543–549 Berry-Kravis E, Lewin F, Wuu J, Leehey M, Hagerman R, Hagerman P, Goetz CG.Tremor and ataxia in fragile X premutation carriers: blinded videotape study. Ann Neurol 2003; 53: 616–623 Brunberg JA, Jacquemont S, Hagerman RJ, Berry-Kravis EM, Grigsby J, Leehey MA, Tassone F, Brown TW, Greco CM, Hagerman PJ. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. AJNR Am J Neuroradiol 2002; 23: 1757–1766 Chen L-S, Tassone F, Sahota P, Hagerman PJ. The (CGG)n repeat element within the 5’untranslated region of the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter. Hum Mol Genet 2003; 12: 3067–3074

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55 Hypomelanosis of Ito Ardinger HH, Bell WE. Hypomelanosis of Ito. Wood’s light and magnetic resonance imaging as diagnostic measures. Arch Neurol 1986; 43: 848–850 Auriemma A, Agostinis C, Bianchi P, Bellan C, Salvoni L, Manara O, Colombo A. Hemimegalencephaly in hypomelanosis of Ito: early sonographic pattern and peculiar MR findings in a newborn. Eur J Ultrasound 2000; 12: 61–67 Battistella PA, Peserico A, Bertoli P, Drigo P, Laverda AM, Casara GL. Hypomelanosis of Ito and hemimegalencephaly. Childs Nerv Syst 1990; 6: 421–423 Bermejo F, Dooms G. Cerebral magnetic resonance imaging in a 2-year-old Caucasian girl, with hypomelanosis of Ito. J Neuroradiol 1996; 23: 248–250 Bhushan V, Gupta RR, Weinreb J, Kairam R. Unusual brain MRI findings in a patient with hypomelanosis of Ito. Pediatr Radiol 1989; 20: 104–106 Echenne BP, Leboucq N, Humbertclaude V. Ito hypomelanosis and moyamoya diasease. Pediatr Neurol 1995; 13: 169–171 Fryburg JS, Lin KY, Matsumoto J. Abnormal head MRI in a neurologically normal boy with hypomelanosis of Ito. Am J Med Genet 1996; 66: 200–203 Fujino O, Hashimoto K, Fujita T, Enokido H, Komatsuzaki H, Asano G, Sato J, Morimatsu Y. Clinico-neuropathological study of incontinentia pigmenti achromians – an autopsy case. Brain Dev 1995; 17: 425–427 Glover MT, Brett EM, Atherton DJ. Hypomelanosis of Ito: spectrum of the disease. J Pediatr 1989; 115: 75–80 Griebel V, Krägeloh-Mann I, Michaelis R. Hypomelanosis of Ito – report of four cases and survey of the literature.Neuropediatrics 1989; 20: 234–237 Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol 1993; 129: 1460 –1470 Happle R. New aspects of cutaneous mosaicism. J Dermatol 2002; 29: 681–692 Kimura M,Yoshino K,Maeoka Y,Suzuki N.Hypomelanosis of Ito: MR findings. Pediatr Radiol 1994; 24: 68–69 Kuwahara RT, Henson T, Tunca Y, Wilroy SW. Hyperpigmentation along the lines of Blaschko with associated chromosome 14 mosaicism. Pediatr Dermatol 2001; 18: 360–361 Malherbe V,Pariente D,Tardieu M,Lacroix C,Venencie PY,Hibon D,Vedrenne J, Landrieu P. Central nervous system lesions in hypomelanosis of Ito: an MRI and pathological study.J Neurol 1993; 240: 302–304 Mendiratta V,Sharma RC,Arya L,Sardana K.Linear and whorled nevoid hypermelanosis. J Dermatol 2001; 28: 58–59 Montagna P, Procaccianti G, Galli G, Ripamonti L, Patrizi A, Baruzzi A. Familial hypomelanosis of Ito. Eur Neurol 1991; 31: 345–347 Pascual-Castroviejo I, López-Rodriquez L, de la Cruz Medina M, Salamanca-Maesso C, Herrero CR. Hypomelanosis of Ito. Neurological complications in 34 cases. Can J Neurol Sci 1988; 15: 124–129 Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, Arcas J, Lopez-Martin V,Tendero A, Esquiroz JLH, Pascual-Pascual SI. Hypomelanosis of Ito. A study 76 infantile cases. Brain Dev 1998; 20: 36–43

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56 Incontinentia Pigmenti Aydingöz Ü, Midia N. Central nervous system involvement in incontinentia pigmenti: cranial MRI of two siblings. Neuroradiology 1998; 40: 364–366 Chatkupt S, Gozo AO, Wolansky LJ, Sun S. Characteristic MR findings in a neonate with incontinentia pigmenti.Am J Radiol 1993; 160: 372–374 Cohen BA. Incontinentia pigmenti. Neurol Clin 1987; 5: 361–377 Fiorillo L, Sinclair DB, O’Byrne ML, Krol AL. Bilateral cerebrovascular accidents in incontinentia pigment. Pediatr Neurol 2003; 29: 66–68 Goldberg MF. The blinding mechanisms of incontinentia pigmenti. Ophthalmic Genet 1994; 2: 69–76 Goldberg MF, Custis PH. Retinal and other manifestations of incontinentia pigmenti (Bloch-Sulzberger syndrome). Ophthalmology 1993; 100: 1645–1654 Hennel SJ, Ekert PG, Volpe JJ, Inder TE. Insights into the pathogenesis of cerebral lesions in incontinentia pigmenti: Pediatr Neurol 2003; 29: 148–150 Kasai T, Kato Z, Matsui E, Sakai A, Nishida T, Kondo N, Taga T. Cerebral infarction in incontinentia pigmenti: the first report of a case evaluated by single photon emission computed tomography. Acta Paediatr 1997; 86: 665–667 Mangano S, Barbagallo A. Incontinentia pigmenti: clinical and neuroradiologic features. Brain Dev 1993; 15: 362–366

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57 Alexander Disease Aoki Y, Haginoya K, Munakata M,Yokoyama H, Nishio T,Tagashi N, Ito T, Suzuki Y, Kure S, Linuma K, Brenner M, Matsubara Y. A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease. Neurosci Lett 2001; 312: 71–74 Bobele GB, Garnica A, Schaefer GB, Leonard JC,Wilson D, Marks WA, Leech RW, Brumback RA. Neuroimaging findings in Alexander’s disease. J Child Neurol 1990; 5: 253–258 Borrett D, Becker LE. Alexander’s disease. A disease of astrocytes. Brain 1985; 108: 367–385 Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriquez D, Goldman JE, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001; 27: 117–120 Brockmann K, Dechent P, Meins M, Haupt M, Sperner J, Stephani U, Frahm J, Hanefeld F. Cerebral proton magnetic resonance spectroscopy in infantile Alexander disease. J Neurol 2003; 250: 300–306 Clifton AG, Kendall BE, Kingsley DPE, Cross JH, Andar U. Computed tomography in Alexander’s disease. An atypical case with extensive low density in both frontal lobes. Neuroradiology 1991; 33: 438–440 Cole G, de Villiers F, Proctor NSF, Freiman I, Bill P.Alexander’s disease: case report including histopathological and electron microscopic features. J Neurol Neurosurg Psychiatry 1979; 42: 619–624 Crome L. Megalencephaly associated with hyaline pan-neuropathy. Brain 1953; 76: 215–228 Deprez M, D’Hooge M, Misson JP, de Leval L, Ceuterick C, Reznik M, Martin JJ. Infantile and juvenile presentations of Alexander’s disease:a report of two cases.Acta Neurol Scand 1999; 99: 158–165 Duckett S, Schwartzman RJ, Osterholm J, Rorke LB, Friedman D, McLellan TL. Biopsy diagnosis of familial Alexander’s disease. Pediatr Neurosurg 1992; 18: 134–138

Farrell K, Chuang S, Becker LE. Computed tomography in Alexander’s disease. Ann Neurol 1984; 15: 605–607 French TA, Bower BD, Cameron AH. Alexander’s disease presenting as astrocytoma. J Neurol Neurosurg Psychiatry 1976; 39: 803–809 Friede RL. Alexander’s disease. Arch Neurol 1964; 11: 414–422 Friedman JH, Ambler M Progressive parkinsonism associated with Rosenthal fibers: senile-onset Alexander’s disease? Neurology 1992; 42: 1733–1735 Garcia L, Gascon G, Ozand P, Yaish H. Increased intracranial pressure in Alexander disease: a rare presentation of whitematter disease. J Child Neurol 1992; 7: 168–171 Garret R,Ames RP.Alexander disease.Case report with electron microscopical studies and review of the literature. Arch Pathol 1974; 98: 379–385 Gingold MK, Bodensteiner JB, Schochet SS, Jaynes M. J Child Neurol 1999; 14: 325–329 Goebel HH, Bode G. Ceasar R, Kohlschütter A. Bulbar palsy with Rosenthal fiber formation in the medulla of a 15-year-old girl.Localized form of Alexander’s disease? Neuropediatrics 1981; 12: 382–391 Gorespe JR, Naidu S, Johnson AB, Puri V, Raymond GV, Jenkins SD, Pedersen RC, Lewis D, Knowles P, Fernandez R, de Vivo D, van der Knaap MS, Messing A, Brenner M, Hoffman EP. Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.Neurology 2002; 58:1494–1500 Guthrie SO, Burton EM, Knowles P, Marshall R. Alexander’s disease in a neurologically normal child: a case report. Pediatr Radiol 2003; 33: 47–49 Habib M, Hassoun J, Ali-Cherif A, Alonzo B,Toga M, Khalil R.Maladie d’Alexander de l’adulte.Rev Neurol 1984; 140:179–189 Honnorat J, Flocard F, Ribot C, Saint-Pierre G, Pineau D, Peysson P, Kopp N. Maladie d’Alexander de l’adulte et gliomatose cérébrale diffuse chez deux members d’une famille. Rev Neurol 1993; 149: 781–787 Imamura A, Orii KE, Mizuno S, Hoshi H, Kondo T. MR imaging and 1H-MR spectroscopy in a case of juvenile Alexander disease. Brain Dev 2002; 24: 723–726 Jacob J, Robertson NJ, Hilton DA. Short report. The clinicopathological spectrum of Rosenthal fibre encephalopathy and Alexander’s disease: a case report and review of the literature. J Neurol Neurosurg Psychiatry 2003; 74: 807–810 Johnson AB. Alexander disease: a review and the gene. Int J Dev Neurosci 2002; 20: 391–394 Johnson AB, Brenner M. Alexander’s disease: clinical, pathologic, and genetic features. J Child Neurol 2003; 18: 625–632 Klein EA, Anzil AP. Prominent white matter cavitation in an infant with Alexander’s disease. Clin Neuropathol 1994; 13: 31–38 Li R, Messing A, Goldman JE, Brenner M. GFAP mutations in Alexander disease. Int J Dev Neurosci 2002;20: 259–268 Liedtke W, Edelmann W, Bieri PL, Chiu F-C, Cowan NJ, Kucherlapati R, Raine CS. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 1996; 17: 607–615 Madsen JR, Partington MD, Hay TC, Tyson RW. A 2-month-old female infant with progressive macrocephaly and irritability. Pediatr Neurosurg 1999; 30: 157–163 Martidis A,Yee RD, Azzarelli B, Biller J. Neuro-ophthalmic, radiographic, and pathologic manifestations of adult-onset Alexander disease. Arch Ophthalmol 1999; 117: 265–267 Mastri AR, Sung JH. Diffuse Rosenthal fiber formation in the adult:a report of four cases.J Neuropathol Exp Neurol 1973; 32: 424–436

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994 References and Further Reading Meins M, Brockmann K, Yadav S, Haupt M, Sperner J, Stephani U, Hanefeld F. Infantile Alexander disease: a GFAP mutation in monozygotic twins an novel mutations in two other patients. Neuropediatrics 2002; 33: 194–198 Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M. Fatal encephalopathy with astrocytes inclusions in GFAP transgenic mice. Am J Pathol 1998; 152: 391–398 Messing A, Goldman JE, Johnson AB, Brenner M. Alexander disease: new insights from genetics. J Neuropathol Exp Neurol 2001; 60: 563–573 Mignot C, Boespflug-Tanguy O, Gelot A, Dautigny A, PhamDinh D, Rodriguez D. Alexander disease: putative mechanisms of an astrocytic encephalopathy. Cell Mol Life Sci 2004; 61: 369–385 Namekawa M, Takiyama Y, Aoki Y, Takayashiki N, Sakoe K, Shimazaki H,Taguchi T,Tanaka Y, Nishizawa M, Saito K, Matsubara Y, Nakano I. Identification of GFAP gene mutation in hereditary adult-onset Alexander’s disease. Ann Neurol 2002; 52: 779–785 Neal JW, Cave EM, Singhrao SK, Cole G, Wallace SJ. Alexander’s disease in infancy and childhood: a report of two cases. Acta Neuropathol (Berl) 1992; 84: 322–327 Neumaier Probst E, Hagel C, Weisz V, Nagel S, Wittkugel O, Zeumer H, Kohlschütter A. Atypical focal MRI lesions in a case of juvenile Alexander’s disease. Ann Neurol 2003; 53: 118–120 Ni Q, Johns GS, Manepalli A, Martin DS, Geller TJ, Infantile Alexander’s disease: serial neuroradiologic findings. J Child Neurol 2002; 17: 463–466 Okamoto Y, Mitsuyama H, Jonosono M, Hirata K, Arimura K, Osame M, Nakagawa M. Autosomal dominant palatal myoclonus and spinal cord atrophy. J Neurol Sci 2002; 195: 71–76 Pridmore CL, Baraitser M, Harding B, Boyd SG, Kendall B, Brett EM. Alexander’s disease: clues to diagnosis. J Child Neurol 1993; 8: 134–144 Reichard EAP, Ball WS Jr, Bove KE. Alexander disease: a case report and review of the literature. Pediatr Pathol Lab Med 1996; 16: 327–343 Riggs JE, Schochet SS Jr, Nelson J. Asymptomatic adult Alexander’s disease: entity or nosological misconception? Neurology 1988; 38: 152–154 Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N’guyen S, Goizet C, Gelot A, Surtees R, Predespan J-M, Hernandorena X, Troncoso M, Uziel G, Messing A, Ponsot G, Pham-Dinh D, Dautigny A, Boespflug-Tanguy O. Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet 2001; 69: 1134–1140 Russo LS Jr, Aron A, Anderson PJ. Alexander’s disease: a report and reappraisal. Neurology 1976; 26: 607–614 Sawaishi Y, Yano T, Takaku I, Takada G. Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene. Neurology 2002; 58: 1541–1543 Schochet CSS Jr, Lampert PW, Earle KM. Alexander’s disease. A case report with electron microscopic observations.Neurology 1968; 18: 543–549 Schuster V, Horwitz AE, Kreth HW. Alexander’s disease: cranial MRI and ultrasound findings. Pediatr Radiol 1991; 21: 133– 134 Schwankhaus JD, Parisi JE, Gulledge WR, Chin L, Currier RD. Hereditary adult-onset Alexander’s disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia. Neurology 1995; 45: 2266–2271 Seil FJ,Schochet SS Jr,Earle KM.Alexander’s disease in an adult. Report of a case. Arch Neurol 1968; 19: 494–502

Shah M, Ross JS. Infantile Alexander disease: MR appearance of a biopsy-proved case. AJNR Am J Neuroradiol 1990; 11: 1105–1106 Sherwin RM, Berthrong M. Alexander’s disease with sudanophilic leukodystrophy. Arch Pathol 1970; 89: 321–328 Shiroma N, Kanazawa N, Izumi M, Sugai K, Fukumizu M, Sasaki M,Hanaoka S,Kaga M,Tsujino S.Diagnosis of Alexander disease in a Japanese patient by molecular genetic analysis. J Hum Genet 2001; 46: 579–582 Soffer D, Horoupian DS. Rosenthal fibers formation in the central nervous system. Its relation to Alexander’s disease. Acta Neuropathol (Berl) 1979; 47: 81–84 Spalke G, Mennel HD. Alexander’s disease in an adult: clinicopathologic study of a case and review of the literature. Clin Neuropathol 1982; 1: 106–112 Springer S, Erlewein R, Naegele T, Becker I, Auer D, Grodd W, Krägeloh-Mann I. Alexander disease – classification revisited and isolation of a neonatal form. Neuropediatrics 2000; 31: 86–92 Stumpf E, Masson H, Duquette A, Berthelet F, McNabb J, Lortie A, Lesage J, Montplaisir J, Brais B, Cossette P. Adult Alexander disease with autosomal dominant transmission. A distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol 2003; 60: 1307–1312 Takanashi J-I, Sugita K, Tanabe Y, Niimi H. Adolescent case of Alexander disease: MR imaging an MR spectroscopy. Pediatr Neurol 1998; 18: 67–70 Torreman M, Smit LME, van der Valk P, Valk J, Scheltens Ph. A case of macrocephaly, hydrocephalus, megacerebellum, white matter abnormalities and Rosenthal fibres. Dev Med Child Neurol 1993; 35: 732–736 Towfighi J, Young R, Sassani J, Ramer J, Horoupian DS. Alexander’s disease: further light- and electron-microscopic observations. Acta Neuropathol (Berl) 1983; 61: 36–42 van der Knaap MS, Naidu S, Breiter SN, Blaser S, Stroink H, Springer S, Begeer JC, van Coster R, Barth PG, Thomas NH, Valk J, Powers JM. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22: 541–552 Vogel PS, Hallervorden J. Leukodystrophy with diffuse Rosenthal fiber formation. Acta Neuropathol (Berl) 1962; 2: 126–143 Walls TJ, Jones RA, Cartlidge NEF, Saunders M. Alexander’s disease with Rosenthal fibre formation in an adult. J Neurol Neurosurg Psychiatry 1984; 47: 399–403 Wohlwill FJ, Bernstein J, Yakovlev PI. Dysmyelinogenic leukodystrophy. J Neuropathol Exp Neurol 1959; 18: 359–383

58 Giant Axonal Neuropathy Bomont P, Cavalier L, Blondeau F, Ben Hamida C, Belal S,Tazir M, Demir E, Topaloglu H, Koninthenberg R,Tüysüz B, Landrieu P, Hentati F, Koenig M.The gene encoding gigaxonin, a new member of the cytoskeletal BTB / kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet 2000; 26: 370–374 Bomont P, Ioos C, Yalcinkaya C, Korinthenberg R, Vallat JM, Assami S, Munnich A, Chabrol B, Kurlemann G, Tazir M, Koenig M. Identification of seven novel mutations in the GAN gene. Hum Mutat 2003; 21: 446 Brockmann K, Pouwels PJW, Dechent P, Flanigan KM, Frahm J, Hanefeld F. Cerebral proton magnetic resonance spectroscopy of a patient with giant axonal neuropathy. Brain Dev 2003; 25: 45–50

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59 Megalencephalic Leukoencephalopathy with Subcortical Cysts Aoki K, Uchihara T,Tsuchiya K, Nakamura A, Ikeda K,Wakayama Y.Enhanced expression of aquaporin 4 in human brain with infarction. Acta Neuropathol (Berl) 2003; 106: 121–124 Ben-Zeev B, Gross V, Kushnir T, Shalev R, Hoffman C, Shinar Y, Pras E, Brand N. Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients. J Child Neurol 2001; 16: 93–99 Ben-Zeev B, Levy-Nissenbaum E, Lahat H, Anikster Y, Shinar Y, Brand N, Gross-Tzur V, MacGregor D, Sidi R, Kleta R, Frydman M, Pras E.Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews. Hum Genet 2002; 111: 214–218 Besˇenski N, Bosˇnjak V, Cop S, Pavic D, Mikulic D, Oroliæ K. Neuroimaging and clinically distinctive features in van der Knaap megalencephalic leukoencephalopathy.Int J Neuroradiol 1997; 3: 244–249 Biancheri R, Pisaturo C, Perrone MV, Passagno A, Rossi A, Veneselli E. Presence of delayed myelination and macrocephaly in the sister of a patient with vacuolating leukocencephalopathy with subcortical cysts. Neuropediatrics 2000; 31: 321–324 Blattner R, von Moers A, Leegwater PAJ, Hanefeld FA, van der Knaap MS, Köhler W. Clinical and genetic heterogeneity in megalencepahlic leukoencephalopathy with subcortical cysts (MLC). Neuropediatrics 2002; 34: 215–218 Boor PKI, de Groot K, Waisfisz Q, Kamphorst W, Oudejans CBM, Powers JM, Pronk JC, Scheper GC, van der Knaap MS. MLC1: a novel protein in distal astroglial processes. J Neuropathol Exp Neurol 2005 (in press) Brockmann K, Finsterbusch J, Terwey B, Frahm J, Hanefeld F. Megalencephalic leukoencephalopathy with subcortical cysts in an adult: quantitative proton MR spectroscopy and diffusion tensor MRI. Neuroradiology 2003; 45: 137–142 Bugiani M, Moroni I, Bizzi A, Nardocci N, Bettecken T, Gärtner J, Uziel G. Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts. Neuropediatrics 2003; 34: 211–214 Chandrashekar HS, Guruprasad AS, Jayakumar PN, Srikanth SG, Taly AB. Megalencephalic leukoencephalopathy with subcortical cysts: MRI and proton spectroscopic features. Neurol India 2003; 51: 525–527 De Stefano N, Balestri P, Dotti MT, Grosso S, Mortilla M, Morgese G, Frederico A. Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study. J Neurol 2001; 248: 403–409 Gelal F, Call C, Apaydin M, Erdem G. Van der Knaap’s leukoencephalopathy: report of five new cases with emphasis on diffusion-weighted MRI findings. Neuroradiology 2002; 4: 625–630 Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, Hoffman EP, Naidu S. Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurology 2004; 62: 878–882 Goutières F, Boulloche J, Bourgeois M, Aicardi J. Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report of five new cases. J Child Neurol 1996; 11: 439–444 Gulati S, Kabra M, Gera S, Ghosh M, Menon PSN, Kalra V. Infantile-onset leukoencephalopathy with discrepant mild clinical course. Indian J Pediatr 2000; 67: 769–773

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996 References and Further Reading Harbord MG, Harden A, Harding B, Brett EM, Baraitser M. Megalencephaly with dysmyelination, spasticity, ataxia, seizures and distinctive neurophysiological findings in two siblings. Neuropediatrics 1990; 21: 164–168 Higuchi Y,Hattori H,Tsuji M,Asato R,Nakahata T.Partial seizures in leukoencephalopathy with swelling and a discrepantly mild clinical course. Brain Dev 2000; 22: 287–389 Koeda T, Takeshita K. Slowly progressive cystic leukoencephalopathy with megalencephaly in a Japanese boy. Brain Dev 1998; 20: 245–249 Leegwater PAJ, Qiang Yuan B, van der Steen J, Mulders J, Könst AAM, Ilja Boor PK, Mejaski-Bosnjak V, Van der Maarel SM, Frants RR, Oudejans CBM, Schutgens RBH, Pronk JC, van der Knaap MS. Mutations of MCL1 (KIAA0027), encoding a putative membrane protein cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001; 68: 831–838 Leegwater PAJ, Boor PKI, Yuan BQ, van der Steen J, Visser A, Könst AAM, CBM Oudejans, Schutgens RBH, Pronk JC, van der Knaap MS. Identifications of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. Hum Genet 2002; 110: 279–283 Mejasˇki-Bosˇnjak V, Beenski N. Megalencephalic leukoencephalopathy: a further case of a new neurodegenerative white matter disease. Dev Med Child Neurol 1997; 39: 561–563 Mejasˇki-Bosˇnjak V, Besˇenski N, Brockmann K, Pouwels PJW, Frahm J, Hanefeld FA. Cystic leukoencephalopathy in a megalencephalic child: clinical and magnetic resonance imaging/magnetic resonance spectroscopy findings. Pediatr Neurol 1997; 16: 347–350 Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME. Syntrophin-dependent expression and localization of aquaporin-4 water channel protein. Proc Natl Acad Sci USA 2001; 98: 14108–14113 Patrono C, di Giacinto G, Eymard-Pierre E, Santorelli FM, Rodriguez D, de Stefano N, Federico A, Gatti R, Benigo V, Megarbané A, Tabarki B, Boespflug-Tanguy O, Bertini E. Genetic heterogeneity of megalencephalic leukoencephalopathy with subcortical cysts. Neurology 2003; 61: 534–537 Rubie C, Lichtner P, Gärtner J, Siekiera M, Uziel G, Kohlmann B, Kohlschütter A,Meitinger T, Stöber G, Bettecken T. Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders? Hum Mutat 2002; 21: 45–53 Saijo H, Nakayama H, Ezoe T, Araki K, Sone S, Hamaguchi H, Suzuki H, Shiroma N, Kanazawa N, Tsujino S, Hirayama Y, Arima M. A case of megalencephalic leukoencephalopathy with subcortical cysts (van der Knaap disease): molecular genetic study. Brain Dev 2003; 25: 362–366 Schmitt A, Gofferje V, Weber M, Meyer J, Mössner R, Lesch K-P. The brain-specific protein MLC1 implicated in megalencephalic leukoencephalopathy with subcortical cysts is expressed in glial cells in the murine brain. Glia 2003; 44: 283–295 Sener RN. Van der Knaap syndrome: MR imaging findings including FLAIR, diffusion imaging, and proton MR spectroscopy. Eur Radiol 2000; 10: 1452–1455 Shinar Y, Ben-Zeev B, Brand N, Lahat H, Gross-Zur V, MacGregor D, Bahan T, Kastner DL, Pras E. A common ancestral haplotype in carrier chromosomes form different ethnic backgrounds in vacuolating megalencephalic leukoencephalopathy with subcortical cysts. J Med Genet 2002; 39: 54–57

Singhal BS, Gursahani RD, Udami VPk Biniwale AA. Megalencephalic leukodystrophy in an Asian Indian Ethnic Group. Pediatr Neurol 1996; 14: 291–296 Singhal BS, Gorospe JR, Naidu S. Megalencephalic leukoencephalopathy with subcortical cysts. J Child Neurol 2003; 18: 646–652 Takanashi J-I, Sugita K, Kohno Y. Vacuolating leukoencephalopathy with subcortical cysts with late onset athetotic movements. J Neurol Sci 1999; 165: 90–93 Teijido O, Martinez A, Pusch M, Zorzano A, Soriano E, Del Rio JA, Palacin M,Estevez R.Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet 2004; 13: 2581–2594 Thele T, Balslev T, Christenen T. Van der Knaap’s vacuolating leukoencephalopathy: two additional cases. Eur J Pediatr Neurol 1999; 3: 83–86 Topçu M, Saatci I, Topcuoglu MA, Kose G, Kunak B. Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases. Brain Dev 1998; 20: 142–153 Topçu M, Gartioux C, Ribierre F,Yalçinkaya C,Tokus E, Öztekin N, Beckmann JS, Ozguc M, Seboun E. Vacuolating megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet 2000; 66: 733–739 Tsujino S, Kanazawa N, Yoneyama H, Shimono M, Kawakami A, Hatanaka Y, Shimizu T, Oba H. A common mutation and a novel mutation in Japanese patients with van der Knaap disease. J Hum Genet 2003; 48: 605–608 van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts WFM,Hoogenraad F,Valk J.Leukoencephalopathy with swelling and a discrepantly mild clinical course in 8 children. Ann Neurol 1995; 37: 324–334 van der Knaap, Valk J, Barth PG, Smit LME, Van Engelen BGM, Tortori Donati P. Leukoencephalopathy with swelling in children and adolenscents: MRI pattern and differential diagnosis. Neuroradiology 1995; 37: 679–686 van der Knaap, Barth PG, Vrensen GFJM, Valk J. Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol (Berl) 1996; 92: 206–212 Yakinci C, Soylu H, Kutlu NO, Sener RN. Leukoencephalopathy with a mild clinical course: a case report. Comput Med Imaging Graph 1999; 23: 169–172 Yalçinkaya C, Çomu S, Koçer N, Yüksel A, Güdüz E, Dermirbilek V, Öcal A. Siblings with cystic leukoencephalopathy and megalencephaly. J Child Neurol 2000; 15: 690–693 Yalçinkaya C, Yüksel A, Çomu S, Kiliç G, Çokar Ö, Dervent A. Epilepsy in vacuolating megalencephalic leukoencephalopathy with subcortical cysts. Seizure 2003; 12: 388–396

60 Congenital Muscular Dystrophies Walker-Warburg Syndrome Asano Y, Minagawa K, Okuda A, Matsui T, Ando K, Kondo-Iida E, Kobayashi O,Toda T, Nonaka I, Tanizawa T. A case of WalkerWarburg syndrome. Brain Dev 2000; 22: 454–457 Barkovic AJ. Neuroimaging manifestations and classification of congenital muscular dystrophies. AJNR Am J Neuroradiol 1998; 19: 1389–1396

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Muscle-Eye-Brain Disease Auranen M, Rapola J, Pihki H, Haltia M, Leivo I, Soinila S, Virtanen I, Kalimo H, Anderson LVB, Santavuori P, Somer H. Muscle membrane–skeleton protein changes and histopathological characterization of muscle-eye-brain disease. Neuromusc Disord 2000; 10: 16–23 Chiba A, Matsumura K, Yamada H, Inazu T, Shimizu T, Kusunoki S, Kanazawa I, Kobata A, Endo T. Structures of sialylated Olinked oligosaccharides of bovine peripheral nerve a-dystroglycan. The role of a novel O-manniosyl-type oligosaccharide in the binding of a-dystroglycan with laminin. J Biol Chem 1997; 272: 2216–262 Cormand B, Avela K, Pihko H, Santavouri P, Talin B, Topalogly H, de la Chapelle A, Lehesjoki A-E. Assignment of the muscleeye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping. Am J Hum Genet 1999; 64: 126–135

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Pegoraro E, Marks H, Garcia CA, Crawford T, Mancias P, Connolly AM, Fanin M, Martinello F,Trevisan CP, Angelini C, Stella A, Scavina M, Munk RL, Servidei S, Bönnemann CC, Bertorini T, Acsadi G, Thompson CE, Gagnon D, Hoganson G, Carver V, Zimmerman RA, Hoffman EP. Laminin a2 muscular dystrophy genotype/phenotype studies of 22 patients. Neurology 1998; 51: 101–110 Pegoraro E, Fanin M,Trevisan CP, Angelini C, Hoffman EP. A novel laminin a2 isoform in severe laminin a2 deficient congenital muscular dystrophy. Neurology 2000; 55: 1128– 1134 Philpot J,Sewry C,Pennock J,Dubowitz V.Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle.Neuromusc Disord 1995; 5: 301–305 Philpot J, Cowan F, Pennock J, Sewry C, Dubowitz V, Bydder G, Muntoni F. Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging. Neuromusc Disord 1999; 9: 81–85 Pini A,Merlini L,Tomé FMS,Chevallay M,Gobbi G.Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families. Brain Dev 1996; 18: 316–322 Reed U,Marie SK,Vainzof M,Salum PB,Levy JA,Zatz M,Diament A. Congenital muscular dystrophy with cerebral white matter hypodensity. Correlation of clinical features and merosin deficiency. Brain Dev 1996; 18: 53–58 Sanuda Y, Edgar TS, Lotz BP, Rust RS, Campbell KP. Merosin-negative congenital muscular dystrophy associated with extensive brain abnormalities. Neurology 1995; 45: 2084– 2089 Schorer Z, Philpot J, Muntoni F, Sewry C, Dubowitz V. Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy. J Child Neurol 1995; 10: 472– 475 Sewrey CA, Philpot J, Mahonoy D, Wilson LA, Muntoni F, Dubowitz V. Expression of laminin subunits in congenital muscular dystrophy. Neuromusc Disord 1995; 5: 307–316 Sewrey CA, Philpot J, Sorokin LM, Wilson LA, Naom I, Goodwin F,D’Allesandro M,Muntoni F.Diagnosis of merosin (laminin2) deficient congenital muscular dystrophy by skin biopsy. Lancet 1996; 347: 582–584 Sewrey CA, Naom I, D’Allesandro M, Sorokin L, Bruno S, Wildon LA, Dubowitz V, Muntoni F. Variable clinical phenotype in merosin-deficient congenital muscular dystrophy associated with differential immunolabelling of two fragments of the laminin a2 chain. Neuromusc Disord 1997; 7: 169–175 Sewrey CA, D’Alessandro M, Wilson LA, Sorokin LM, Naom I, Bruno S, Ferlini A, Dubowitz V, Muntoni F. Expression of laminin chains in skin in merosin-deficient congenital muscular dystrophy. Neuropediatrics 1997; 28: 217–222 Sewrey CA, Naom I, D’Allesandro M, Sorokin L, Bruno S, Wilson LA, Dubowitz V, Muntoni F. Variable clinical phenotype in merosin-deficient congenital muscular dystrophy associated with differential immunolabelling of two fragments of the laminin a2 chain. Neuromusc Disord 1997; 7: 169–175 Tachi N,Kamimura S,Ohya K,Chiba S,Sasaki K.Congenital muscular dystrophy with partial deficiency of merosin. J Neurolog Sci 1997; 151: 25–27 Tan E,Topaloglu H, Sewry C, Zorlu Y, Naom I, Erdem S, D’Allesandro M, Muntoni F, Dubowitz V. Late onset muscular dystrophy with cerebral white matter changes due to partial merosin deficiency. Neuromusc Disord 1997; 7: 85–89

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Taratuto AL, Lubieniecki F, Díaz D, Schultz M, Ruggieri V, Saccoliti M, Dubrovski A. Merosin-deficient congenital muscular dystrophy associated with abnormal cerebral cortical gyration: an autopsy study. Neuromusc Disord 1999; 9: 86–94 Tezak Z, Prandini P, Boscaro M, Marin A, Devaney J, Marino M, Fanin M, Trevisan CP, Park J, Tyson W, Finkel R, Garcai C, Algelini C, Hoffman EP, Pagoraro E. Clinical and molecular study in congenital muscular dystrophy with partial laminin a2 (LAMA2) deficiency. Hum Mutat 2003; 21: 103– 111 Tomé FMS, Evangelista T, Leclerc A, Sunada Y, Manole E, Estournet B, Barois A, Campbell KP, Fardeau M. Congenital muscular dystrophy with merosin deficiency. Life Sci 1994; 317: 351–357 Trevisan CP, Martinello F, Ferruzza E, Angelini C. Divergence of central nervous system involvement in 2 Italian sisters with congenital muscular dystrophy: a clinical and neuroradiological follow-up. Eur Neurol 1995; 35: 230–235 Trevisan CP,Martinello F,Ferruzza E,Fanin M,Chevallay M,Tomé FMS. Brain alterations in the classical form of congenital muscular dystrophy. Child Nerv Syst 1996; 12: 604–610 Tsao CY, Mendell JR, Rusin J, Luquette M. Congenital muscular dystrophy with complete laminin-a2-deficiency, cortical dysplasia, and cerebral white-matter changes in children. J Child Neurol 1998; 13: 253–256 Van Engelen BGM, Leyten QH, Bernsen PLJA, Gabreëls FJM, Barkhof F, Joosten EMG, Hamel BCJ, ter Laak HJ, Ruijs MBM, Cruysberg JRM,Valk J.Familial adult-onset muscular dystrophy with leukoencephalopathy. Ann Neurol 1992; 32: 577–580 Villanova M, Malandrini A, Toti P, Salvestroni R, Six J, Martin JJ, Guazzi GC. Localization of merosin in the normal human brain: implications for congenital muscular dystrophy with merosin deficiency. J Submicrosc Cytol Pathol 1996; 28: 1–4 Villanova M, Malandrini A, Sabatelli P, Sewry CA, Toti P, Torelli S, Six J, Scarfó G, Palma L, Muntoni F, Squarzoni S,Tosi P, Maraldi NM, Guazi GC. Localization of laminin a2 chain in normal human central nervous system: an immunofluorescence and ultrastructural study. Acta Neuropathol (Berl) 1997; 94: 567–571 Wewer UM, Engvall E. Merosin/laminin-2 and muscular dystrophy. Neuromusc Disord 1996; 6: 409–418 Yurchenco PD, Cheng Y-S, Campbell K, Li S. Loss of basement membrane, receptor and cytoskeletal lattices in a laminindeficient muscular dystrophy. J Cell Sci 2004; 117: 735–742

MDC1C Brockington M, Blake DJ, Prandini P, Brown SC,Torelli S, Benson MA, Ponting CP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F. Mutations in the Fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin a2 deficiency and abnormal glycosylation of a-dystroglycan. Am J Hum Genet 2001; 69: 1198–1209 Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S, Benson MA, Herrmann R, Anderson LVB, Bashir R, Burgunder J-M, Fallet S, Romero N, Fardeau M, Straub V, Storey G, Pollitt C, Richard I, Sewry CA, Bushby K, Voit T, Blake DJ, Muntoni F. Mutations in the Fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2 l as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 2001; 10: 2851–2859

Brown SC, Torelli S, Brockington M, Yuva Y, Jimenez C, Feng L, Anderson L, Ugo I, Kroger S, Bushby K, Voit T, Sewry C, Muntoni F. Abnormalities in a-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol 2004; 164: 727–737 De Paula F, Vieira N, Starling A, Uraco Yamamoto L, Lima B, De Cássia Pavanello R, Vainzof M, Nigro V, Zatz M. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet 2003; 11: 923–930 Driss A, Noguchi S, Amouri R, Kefi M, Sasaki T, Surgie K, Souilem S, Hayashi YK, Shimizu N, Minoshima S, Kudoh J, Hentati F, Nishino I. Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I. Neurology 2003; 60: 1341–1344 Harel T,Goldberg Y,Shalev SA, Chervinski I, Ofir R, Birk OS.Limbgirdle muscular dystrophy 2I: phenotypic variability within a large consanguineous Bedouin family associated with a novel FKRP mutation. Eur J Hum Genet 2004; 12: 38–43 Louhichi N,Triki C, Quijano-Roy S, Richard P, Makri S, Méziou M, Estournet B, Mrad S, Romero NB, Ayadi H, Guicheney P, Fakhfakh F. New FRKP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunesian families. Neurogenetics 2004; 5: 27–34 Mercuri E, Sewry CA, Brown SC, Brockington M, Jungbluth H, DeVille C, Counsell S, Muntioni F. Congenital muscular dystrophy with secondary merosin deficiency and normal brain MRI: a novel entity? Neuropediatrics 2000; 31: 186–189 Mercuri E, Brockington M, Straub V, Quijano-Roy S, Yuva Y, Hermann R, Brown SC, Torelli S, Dubowitz V, Blake DJ, Romero NB, Estournet B, Sewry CA, Guicheney P, Voit T, Muntoni F. Phenotype spectrum associated with mutations in the Fukutin-related protein gene. Ann Neurol 2003; 53: 537– 542 Topaloglu H, Brockington M, Yuva Y, Talim B, Haliloglu G, Blake D, Torelli S, Brown SC, Muntoni F. FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 2003; 60: 988–992

MDC1D Endo T, Toda T. Glycosylation in congenital muscular dystrophies. Biol Pharm Bull 2003; 26: 1641–1647 Grewal PK, Hewitt JE. Glycosylation defects: a new mechanism for muscular dystrophy? Hum Mol Genet 2003; 12: R259R264 Hewitt JE, Grewal PK, Glycosylation defects in inherited muscle disease. Cell Mol Life Sci 2003; 60: 251–258 Longman C, Brockington M, Torelli S, Jimenez-Mallebrera C, Kennedy C, Khalil N, Feng L, Saran RK,Voit T, Merlini L, Sewry CA, Brown SC, Muntoni F. Mutations in the human LARGE gene caus MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of a-dystroglycan. Hum Mol Genet 2003; 12: 2853–2861 Martin PT, Freeze HH. Glycobiology of neuromuscular disorders. Glycobiology 2003; 13: 67R-75R Martin-Rendon E, Blake DJ. Protein glycosylation in disease: new insights into the congenital muscular dystrophies. Trends Pharmacol Sci 2003; 24: 178–183

1002 References and Further Reading Muntoni F, Valero de Bernabe B, Bittner R, Blake D, van Bokhoven H, Brockington M, Brown S, Bushby K, Campbell KP, Fiszman M, Gruenewald S, Merlini L, Quijano-Roy S, Romero N, Sabatelli P, Sewry CA, Straub V,Talim B,Topalog˘lu H, Voit T, Yurchenco PD, Urtizberea JA, Wewer UM, Guicheney P. 114th ENMC International Workshop on Congenital Muscular Dystrophy (CMD) (8th Workshop of the International Consortium on CMD; 3rd Workshop of the Myo-cluster Project GENRE). Neuromusc Disord 2003; 13: 579–588 Muntoni F, Brockington M,Torelli S, Brown SC. Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol 2004; 17: 205–209

Rest Arahata K, Brockington M, Bushby K, Cormand B, Dubowitz V, Engvall E, Flanigan K, Guicheney P, Moghadaszadeh B, Morandi L, Nuntoni F, Naom I, Pihko H, Sewry C, Soininen R, Straub V, Toda T, Tomé F, Topalog˘lu H, Urizberea A, Villanova M, Vilquin J-T, Voit T. 68th ENMC International Workshop (5th International Workshop): on congenital muscular dystrophy. Neuromusc Disord 1999; 9: 446–454 De Stefano N, Dotti MT, Villanova M, Scarano G, Federico A. Merosin positive congenital muscular dystrophy with severe involvement of the central nervous system. Brain Dev 1996; 18: 323–326 Echenne B, Rivier F, Jallali AJ, Azais M, Mornet D, Pons F. Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cerebral white matter. Neuromusc Disord 1997; 7: 187–190 Kobayashi O, Hayashi Y, Arahata K, Ozawa E, Nonaka I. Congenital muscular dystrophy: clinical and pathologic study of 50 patients with the classical (occidental) merosin-positive form. Neurology 1996; 46: 815–818 Topalog˘lu H, Kale G, Yalnizog˘lu D, Taödemir AH, Karaduman A, Topçu M, Kotiog˘lu E. Analysis of “pure” congenital muscular dystrophies in thirty-eight cases. How different is the classical type I from the occidental type cerebromuscular dystrophy? Neuropediatrics 1994; 25: 94–100 Triki C, Louhichi N, Méziou M, Choyakh F, Kéchaou MS, Jlidi R, Mhiri C, Fakhfakh F, Ayadi H. Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts, unlinked to the LAMA2, FCMD, MEB and CMD1B loci, in three Tunesian patients. Neuromusc Disord 2003; 13: 4–12 Voit T, Cohn RD, Sperner J, Leube B, Sorokin L,Toda T, Herrmann R. Merosin-positive congenital muscular dystrophy with transient brain dysmyelination, pontocerebellar hypoplasia and mental retardation. Neuromusc Disord 1999; 9: 95–101

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62 Myotonic Dystrophy Type 2 Bönsch D, Neumann C, Lang-Roth R, Witte O, Lamprecht-Dinnesen A, Deufel T. PROMM and deafness: excluding of ZNF9 as the disease in DFNA18 suggests a polygenic origin of the PROMM/DM 2 phenotype. Clin Genet 2003; 63: 73–75 Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LPW. Myotonic dystrophy type 2. Molecular, diagnostic and clinical spectrum. Neurology 2003; 60: 657–664 Finsterer J, Monotonic dystrophy type 2. Eur J Neurol 2002; 9: 441–447 Hund E, Jansen O, Koch MC, Ricker K, Fogel W, Niedermaier N, Otto M, Kuhn E, Meinck HM. Proximal myotonic myopathy with MRI white matter abnormalities of the brain. Neurology 1997; 48: 33–37 Kress W,Mueller-Myhsok B,Ricker K,Schneider C,Koch MC,Toyka KV, Mueller CR, Grimm T. Proof of genetic heterogeneity in the proximal myotonic myopathy syndrome (PROMM) and its relationship to myotonic dystrophy type 2 (DM). Neuromusc Disord 2000; 10: 478–480 Liquiori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LPW. Myotonic dystrophy type 2 caused by a CCTG expansion in Intron 1 of ZNF9. Science 2001; 293: 864–867 Mastaglia FL, Harker N, Philips BA, Day TJ, Hankey GJ, Laing NG, Fabian V, Kakulas BA. Dominantly inherited proximal myotonic myopathy and leukoencephalopathy in a family with an incidental CLCN1 mutation. J Neurol Neurosurg Psychiatry 1998; 64: 543–547 Meola G. Clinical and genetic heterogeneity in myotonic dystrophies. Muscle Nerve 2000; 23: 1789–1799 Meola G. Motonic dystrophies. Curr Opin Neurol 2000; 13: 519–525

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63 X-linked Charcot-Marie-Tooth Disease Abrams CK, Oh S, Ri Y, Bargiello TA. Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease. Brain Res Rev 2000; 32:203–214 Abrams CK, Freidin MM, Verselis VK, Bennett MVL, Bargiello TA. Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res 2001; 300: 9–25 Abrams CK, Bennett MVL, Verselis VK, Bargiello TA. Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked CharcotMarie-Tooth disease. Proc Natl Acad Sci USA 2002; 99: 3980–3984 Bähr M, Andres F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans J. Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatry 1999; 66: 202–206 Bergoffen J, Scherer SS, Wang S, Oronzi Scott M, Bone LJ, Paul DL, Chen K, Lensch MW, Chance PF, Fischbeck KH. Commexin mutations in X-linked Charcot-Marie-Tooth disaese. Science 1993; 262: 2039–2042

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Senderek J, Hermanns B, Bergmann C, Boroojerdi B, Bajbouj M, Hungs M, Ramaekers VT, Quasthoff S, Karch D, Micheal Schröder J. X-linked dominant Charcot-Marie-Tooth neuropathy: clinical electrophysiological, and morphological phenotype in four families with different connexin32 mutations. J Neurologic Sci 1999; 167: 90–101 Stojkovic T, Latour P. Vanderberghe A, Hurtevent JF, Vermersch P. Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q). Neurology 1999; 52: 1010–1014 Sutor B, Schmolke C, Teubner B, Schirmer C, Willecke K. Myelination defects and neuronal hyperexcitability in the neocortex of connexin 32-deficient mice. Cerebr Cortex 2000; 10: 684–697

64 Oculodentodigital Dysplasia Ginsberg LE, Jewett T, Grub R, McLean WT. Oculodental digital dysplasia: neuroimaging in a kindred. Neuroradiology 1996; 38: 84–86 Gladwin A, Donnai D, Metcalfe K, Schrander-Stumpel C, Brueton L, Verloes A, Aylsworth A, Torrielo H, Winter R, Dixon M. Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-q24. Hum Mol Genet 1997; 6: 123–127 Gutmann DH,Zackai EH,McDonald-McGinn DM,Fischbeck KH, Kamholz J. Oculodentodigital dysplasia syndrome associated with abnormal cerebral white matter. Am J Med Genet 1991; 41: 18–20 Loddenkemper T, Grote K, Evers S, Oelerich M, Stögbauer F. Neurological manifestations of the oculodentodigital dysplasia syndrome. J Neurol 2002; 249: 584–595 Norton KK, Carey JC, Gutmann DH. Oculodentodigital dysplasia with cerebral white matter abnormalities in a two-generation family. Am J Med Genet 1995; 57: 458–461 Patton MA, Laurence KM. Three new cases of oculodentodigital (ODD) syndrome: development of the facial phenotype. J Med Genet 1985; 22: 386–389 Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia.Am J Hum Genet 2003; 72: 408–418 Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B. A homozygous GJA1 gene mutation causes a Hallerman-Streiff/ODDD spectrum phenotype. Hum Mutat 2004; 23: 286 Richardson RR, Donnai D, Meire F, Dixon MJ. Expression of Gja1 correlates with the phenotype observed in oculodentodigital syndrome/type III syndactyly. J Med Genet 2004; 41: 60–67 Schrander-Stumpel CTRM, Franke CL. Central nervous system abnormalities in oculodentodigital dysoplasia. Genet Couns 1996; 7: 233–235 Schrander-Stumpel CTRM, de Groot-Wijnands JBG, de DieSmulders C, Fryns JP. Type III syndactyly and odulodentodigital dysplasia: a clinical spectrum. Genet Couns 1993; 4: 271–276 Shapiro RE, Griffin JW, Stine OC. Evidence for genetic anticipation in the oculodentodigital syndrome. Am J Med Genet 1997; 71: 36–41

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65 Vanishing White Matter Abbott CM, Proud CG. Translation factors: in sickness and in health.Trends Biochem Sci 2004; 29: 25–31 Alorainy IA, Patenaude YG, O’Gorman AM, Black DN, MeagherVillemure K. Cree leukoencephalopathy: neuroimaging findings. Radiology 1999; 213: 400–406 Anzil AP, Gessaga E. Late-life cavitating dystrophy of the cerebral and cerebellar white matter. Eur Neurol 1972; 7: 79–94 Biancheri R, Rossi A, Di Rocco M, Filocamo M, Pronk JC, van der Knaap MS, Tortori-Domati P. Leukoencephalopathy with vanishing white matter: an adult onset case. Neurology 2003; 61: 1818–1819 Black DN, Booth F, Watters GV, Andermann E, Dumont C, Halliday WC, Hoogstraten J, Kabay ME, Kaplan P, Meagher-Villemure K, Michaud J, O’Gorman G. Leukoencephalopathy among native Indian infants in northern Quebec and Manitoba. Ann Neurol 1988; 24: 490–496 Blüml S, Philippart M, Schiffmann R, Seymour K, Ross BD. Membrane phospholipids and high-energy metabolites in childhood ataxia with CNS hypomyelination. Neurology 2003; 61: 648–654 Boesen T, Mohammed SS, Pavitt GD, Andersen GR. Structure of the catalytic fragment of translation initiation factor 2B and identification of a critically important catalytic residue. J Biol Chem 2004; 279: 10584–10592 Boltshauser E, Barth PG,Troost D, Martin E, Stallmach T.“Vanishing white matter” and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype. Neuropediatrics 2002; 33: 57–62 Brück W, Herms J, Brockmann K, Schulz-Schaeffer W, Hanefeld F. Myelinopathia centralis diffusa (vanishing white matter disease): evidence of apoptotic oligodendrocyte degeneration in early lesion development. Ann Neurol 2001; 50: 532–536 Deisenhammer E, Jellinger K. Höhlenbildende Neurtralfettleukodystrophie mit Schubverlauf. Neuropediatrics 1976; 7: 111–121 Duncan RF, Hershey JW. Protein synthesis and protein phosphorylation during heat stress, recovery, and adaptation. J Cell Biol 1989; 109: 1467–1481 Eicke WJ. Polycystische Umwandlung des Marklagers mit progredientem Verlauf. Atypische diffuse Sklerose? Arch Psychiatr Nervenkr 1962; 203: 599–602 Espay AJ, Bodensteiner JB, Patel H. Episodic coma in a new leukodystrophy. Pediatr Neurol 2002; 26: 139–142 Fogli A, Dionisi-Vici C, Deodato F, Bartuli A, Boespflug-Tanguy O, Bertini E. A severe variant of childhood ataxia with central hypomyelination / vanishing white matter leukoencephalopathy related to EIF21B5 mutation. Neurology 2002; 59: 1966–1968 Fogli A, Wong K, Eymard-Pierre E, Wenger J, Bouffard JP, Goldin E, Black DN, Boespflug-Tanguy O, Schiffmann R. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol 2002; 52: 506–510

Fogli A, Rodriguez D, Eymard-Pierre E, Bouhour F, Labauge P, Meaney BF, Zeesman S, Kaneski CR, Schiffmann R, Boespflug-Tanguy O. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003 72: 1544–1550 Fogli A, Schiffmann R, Hugendubler L, Combes P, Bertini E, Rodriguez D, Kimball SR, Boespflug-Tanguy O. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet 2004; 12: 561–566 Fogli A, Schiffmann R, Bertini E, Ughetto S, Combes P, EymardPierre E, Kaneski CR, Pineda M, Troncoso M, Uziel G, Surtees R, Pugin D, Chaunu M-P, Rodriguez D, Boespflug-Tanguy O. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 2004; 62: 1509–1517 Francalanci P, Eymard-Pierre E, Dionisi-Vici C, Bolderini R, Piemonte F, Virgili R, Fariello G, Bosman C, Santorelli FM, Boespflug-Tanguy O, Bertini E. Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27. Neurology 2001; 57:265–70 Gallo A, Rocca MA, Falini A, Scaglione C, Salvi F, Gambini A, Guerrini L, Mascalchi M, Pronk JC, van der Knaap MS, Filippi M. Multiparametric MRI in a patient with adult-onset leukoencephalopathy with vanishing white matter.Neurology 2004; 62: 323–326 Gautier JC, Gray F, Awada A, Escourolle R. Leucodystrophie orthochromatique cavitaire de l’adulte. Prolifération et inclusion oligodendrogliales. Rev Neurol 1984; 140: 493–501 Girard PF, Tommassi M, Rochet M, Boucher M. Leucoencéphalopathie avec cavitations massives, bilatérales et symétriques. Syndrome de décortication post-traumatique. Presse Med 1968; 76: 163–166 Gow A,Sharma R.The unfolded protein response in protein aggregating diseases. Neuromol Med 2003; 4: 73–94 Graveleau P, Gray F, Plas J, Graveleau J, Brion S.Leucodystrophie orthochromatique cavitaire avec modifications oligodendrogliales. Un cas sporadique adulte. Rev Neurol 1985; 141: 713–718 Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen HJ, Frahm J. Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993; 24: 244–248 Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397:271–274 Harding HP, Novoa I, Zhang Y, Zeng H,Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6: 1099–1108 Hershey JWB, Merrick WC.The pathway and mechanism of initiation of protein synthesis. In: Sonenberg N, Hershey JWB, Mathews MB, eds.Translational control of gene expression. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2000, pp 33–88 Hinnebusch AG. Mechanism and regulation of initiator methionyl-tRNA binding to ribosomes. In: Sonenberg N, Hershey JWB, Mathews MB, eds. Translational control of gene expression. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2000, pp 185–243 Kleijn M, Scheper GC, Voorma HO, Thomas AA. Regulation of translation initiation factors by signal transduction. Eur J Biochem 1998; 253: 531–544

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66 Aicardi-Goutières Syndrome Abdel-Salam GMH, Zaki MS, Lebon P, Meguid NA. AicardiGoutières syndrome: clinical and neuroradiological findings of 10 new cases. Acta Paediatr 2004; 93: 929–936 Aicardi J. Aicardi-Goutières syndrome: special type early-onset encephalopathy. Eur J Paediatr 2002; 6: A1-A7 Aicardi J, Goutières F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15: 49–54 Aicardi J, Goutières F. Systemic lupus erythematosus or Aicardi-Goutières syndrome? Neuropediatrics 2000; 31: 113 Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, Lindsay Whitton J, Bloom FE, Campbell IL.Transgenic expression of IFN-a the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol 1998; 161: 5016–5026 Al-Dabbous R, Sabry MA, Farah S, Al-Awadi SA, Sineonov S, Farag TI. The autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease: report of another Bedouin family. Clin Dysmorphol 1998; 7: 127–130 Babitt DP, Tang T, Dobbs J, Berk R. Idiopathic familial cerebrovascular ferrocalcinosis (Fahr’s disease) and review of differential diagnosis of intracranial calcification in children. Am J Roentgenol Radiat Ther Nucl Med 1969; 105: 352–358 Baraitser M, Brett EM, Piesowicz AT. Microcephaly and intracranial calcification in two brothers. J Med Gen 1983; 20: 210– 212 Barth PG.The neuropathology of Aicardi-Goutières syndrome. Eur J Paediatr Neurol 2002; 6: A27-A31 Barth PG, Walter A, van Gelderen I. Aicardi-Goutières syndrome: a genetic microangiopathy? Acta Neuropathol (Berl) 1999; 98: 212–216 Billard C, Dulac O, Bouloche J, Echenne B, Lebon P, Motte J, Robain O, Santini JJ. Encephalopathy with calcifications of the basal ganglia in children. A reappraisal of Fahr’s syndrome with respect to 14 new cases. Neuropediatrics 1989; 20: 12–19 Black DN, Watters GV, Andermann E, Dumont C, Kabay ME, Kaplan P,Meagher-Villemure K,Michaud J,O’Gorman G,Reece E, Tsoukas C, Wainberg MA. Encephalitis among cree children in Northern Quebec. Ann Neurol 1988; 24: 483–489 Blau N, Bonafé L, Krägeloh-Mann I,Thöny B, Kierat L, Häusler M, Ramaekers V. Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome. A new phenotype. Neurology 2003; 61: 642–647 Boltshauser E,Steinlin M, Boesch C, Martin E,Schubiger G.Magnetic resonance imaging in infantile encephalopathy with cerebral calcification and leukodystrophy. Neuropediatrics 1991; 22: 33–35

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1008 References and Further Reading McEntagart M, Kamel H, Lebon P, King MD. Aicardi-Goutières syndrome: an expanding phenotype. Neuropediatrics 1998; 29: 163–167 Mehta L, Trounce JQ, Moore JR, Young ID. Familial calcification of the basal ganglia with cerebrospinal fluid pleocytosis. J Med Genet 1986; 23: 157–160 Monastiri K, Salem N, Korbi S, Snoussi N. Microcephaly and intracranial calcification: two new cases. Clin Genet 1997; 51: 142–143 Østergaard JR, Christensen T, Nehen AM. A distinct difference in clinical expression of two siblings with Aicardi-Goutières syndrome. Neuropediatrics 1999; 30: 38–41 Polizzi A, Pavone P, Parana E, Incorpora G, Ruggieri M. Lack of progression of brain atrophy in Aicardi-Goutières syndrome. Pediatr Neurol 2001; 24: 300–302 Razavi-Encha F, Larroche JC, Gaillard D. Infantile familial encephalopathy with cerebral calcifications and leukodystrophy. Neuropediatrics 1988; 19: 72–79 Reardon W,Hockey A,Silberstein P,Kendall B,Farag TI,Swash M, Stevenson R, Baraitser M. Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease. Am J Med Genet 1994; 52: 58–65 Schwarz KB, Ferrie CD, Woods CG. Two siblings with a new Aicardi-Goutières -like syndrome. Dev Med Child Neurol 2002; 44: 422–425 Slee J, Lam G, Walpole I. Syndrome of microcephaly, microphthalmia, cataracts, and intracranial calcification. Am J Med Genet 1999; 84: 330–333 Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JBP. The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 1995; 32: 881–884 Troost D, van Rossum A, Veiga Pires J, Willemse J. Cerebral calcifications and cerebellar hypoplasia in two children: clinical, radiologic and neuropathological studies – a separate neurodevelopmental entity. Neuropediatrics 1984; 15: 102–109 Verrips A, Hiel JAP, Gabreëls FJM, Wesseling P, Rotteveel JJ. The Aicardi-Goutières syndrome: variable clinical expression in two siblings. Pediatr Neurol 1997; 16: 323–325 Vivarelli R, Grosso S, Cioni M, Galluzzi P, Monti L, Morgese G, Balestri P. Pseudo-TORCH syndrome or Baraitser-Reardon syndrome: diagnostic criteria. Brain Dev 2001; 23: 18–23 Wieczorek D, Gillessen-Kaesbach G, Passarge E. A nine-monthold boy with microcephaly, cataracts, intracerebral calcifications and dysmorphic signs: an additional observation of an autosomal recessive congenital infection-like syndrome? Genet Couns 1995; 6: 297-302

67 Leukoencephalopathy with Calcifications and Cysts Aynaci FM, Celep F, Ahmetoglu A. Encephalopathy with intracranial calcification, dwarfism, leucodystrophy and neuropathy: a new clinical entity? Brain Dev 2002; 24: 639–640 Crow YJ, McMenamin J, Haenggeli CA, Hadley DM, Tirupathi S, Tracy EP, Zuberi SM, Browne BH, Tolmie JL, Stephanson JBP. Coats’ plus: a progressive syndrome of bilateral Coats’ disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument. Neuropediatrics 2004; 35: 10–19

Gayatri NA, Hughes MI, Lloyd IC, Wynn RF. Association of the congenital bone marrow failure syndromes with retinopathy, intracerebral calcification and progressive neurological impairment. Eur J Paediatr Neurol 2002; 6: 125–128 Goutières F, Dollfus H, Becquet F, Dufier J-L. Extensive brain calcification in two children with bilateral Coats’ disease. Neuropediatrics 1990; 30: 19–21 Kajtár P, Méhes K. Bilateral coats retinopathy associated with aplastic anaemia and mild dyskeratotic signs. Am J Med Genet 1994; 49: 374–377 Labrune P, Lacroix C, Goutières F, de Laveaucoupet J, Chevalier P, Zerah M, Husson B. Landrieu P. Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology 1996; 46: 1297–1301 Nagae-Poetscher LM, Bibat G, Philippart M, Rosemberg S, Fatemi A, Lacerda MTC, Costa MOR, Kok F, Costa Leite C, Horská A, Barker PB, Naidu S. Leukoencephalopathy, cerebral calcifications, and cysts. New observations. Neurology 2004; 62: 1206–1209 Niedermeyer I, Reiche W, Graf N, Mestres P, Feiden W. Cerebroretinal vasculopathy and leukoencephalopathy mimicking a brain tumor. Clin Neuropathol 2000; 19: 285–295 Revesz T, Fletcher S, Al-Gazali LI, DeBuse P. Bilateral retinopathy, aplastic anaemia, and central nervous system abnormalities: a new syndrome? J Med Genet 1992; 29: 673–675 Sazgar M, Leonard NJ, Renaud DL, Bhargava R, Sinclair DB. Intracranial calcification, retinopathy, and osteopenia: a new syndrome? Pediatr Neurol 2002; 26: 324–328 Tolmie JL, Browne BH, McGettrick PM, Stephenson JBP. A familial syndrome with Coats’ reaction retinal angiomas, hair and nail defects and intracranial calcification. Eye 1988; 2: 297–303

68 Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated Lactate Linnankivi T, Lundbom N, Autti T, Häkkinen AM, Koillinen H, Kuusi T, Lönnqvist T, Saino K, Valanne L, Äärimaa T, Pihko H. Five new cases of a recently described leukoencephalopathy with high brain lactate. Neurology 2004; 63: 688–693 Serkov SV,Pronin IN,Bykova OV,Maslova OI,Arutyunov NV,Muravina TI, Kornienko VN, Fadeeva LM, Marks H, Bönnemann C, Schiffmann R, van der Knaap MS. Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate. Neuropediatrics 2004; 35: 1–5 van der Knaap MS, van der Voorn P, Barkhof F, van Coster R, Krägeloh-Mann I, Feigenbaum A, Blaser S, Vles JSH, Rieckmann P, Pouwels PJW. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003; 53: 252–258

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69 Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum van der Knaap MS, Naidu S, Pouwels PJW, Bonavita S, van Coster R, Lagae L, Sperner J, Surtees R, Schiffmann R, Valk J. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol 2002; 23: 1466–1474

70 Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids Axelsson R, Röyttä M, Sourander P, Åkesson HO, Andersen O. Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand 1984; 69 (suppl 314): 7–65 Browne L, Sweeney BJ, Farrell MA. Late-onset neuraxonal leucoencephalopathy with spheroids and vascular amyloid. Eur Neurol 2003; 50: 85–90 Goodman LA, Dickson DW. Nonhereditary diffuse leukoencephalopathy with spheroids presenting as early-onset rapidly progressive dementia. J Neuropathol Exp Neurol 1995; 54: 471 Hancock N, Poon M, Taylor B, McLean C. Hereditary diffuse leukoencephalopathy with spheroids. J Neurol Neurosurg Psychiatry 2003; 74: 1345–1347 Lampert PW. A comparative electron microscopic study of reactive, degenerating, regenerating, and dystrophic axons. J Neuropathol Exp Neurol 1967; 26: 345–368 Matsuyama H, Watanabe I, Mihm MC, Richardson EP. Dermatoleukodystrophy with neuroaxonal spheroids. Arch Neurol 1978; 35: 329–336 Moro-de-Casillas ML, Cohen ML, Riley DE. Leucoencephalopathy with neuroaxonal spheroids (LENAS) presenting as the cerebellar subtype of multiple system atrophy. J Neurol Neurosurg Psychiatry 2004; 75: 1070–1072 Seitelberger F. Neuropathological conditions related to neuroaxonal dystrophy. Acta Neuropathol (Berl) 1971; 21 (suppl V); 17–29 Torack R, Hughes CP. Neuroaxonal dystrophy in subacute dementia. Acta Neuropathol (Berl) 1972; 22: 267–268 van der Knaap MS, Naidu S, Kleinschmidt-DeMasters BK, Kamphorst W, Weinstein HC. Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids.Neurology 2000; 54: 463–468 Yamashita M,Yamamoto T. Neuroaxonal leukoencephalopathy with axonal spheroids. Eur Neurol 2002; 48: 20–25 Yazawa I, Nakano I,Yamada H, Oda M. Long tract degeneration in familial sundanophilic leukodystrophy with prominent spheroids. J Neurol Sci 1997; 147: 185–191

71 Dentatorubropallidoluysian Atrophy Becher MW, Rubinztein DC, Loggo J, Wagster MV, Stine OC, Ranen NG,Franz ML,Abbott MH,Sherr M,MacMillan JC,Barron L, Porteous M, Harper PS, Ross CA. Dentatorubral-pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed North American and European Pedigrees. Mov Disord 1997; 12: 519–530

Burke JR, Wingfield MS, Lewis KE, Roses AD, Lee JE, Hulette C, Pericak-Vance MA,Vance JM.The Haw River syndrome: dentatorubral-pallidoluysian atrophy (DRPLA) in an AfricanAmerican family. Nat Genet 1994: 7: 521–524 Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, Calabrese O, Salvatore E, De Michelle G, Riggio MC, Pareyson D, Gellera C, Di Donato S. Relative frequencies of CAG expansions in spinocereballar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol 2000; 44: 31–36 Imamura A,Ito R,Tanaka S,Fukutomi O,Shimozawa N,Nishimura M, Suzuki Y, Kondo N, Yamada M, Orii T. High-intensity proton and T2-weighted MRI signals in the globus pallidus juvenile-type of dentatorubral and pallidoluysian atrophy. Neuropediatrics 1994; 25: 234–237 Koide R, Onodera O, Ikeuchi T, Kondo R, Tanaka H, Tokiguchi S, Tomoda A, Miike T, Isa F, Beppu H, Shimizu N, Watanabe Y, Horikawa Y, Shimohata T; Hirota K, Ishikawa A, Tsuji S. Atrophy of the cerebellum and brain stem in dentatorubral-pallidoluysian atrophy. Influence of GAG repeat size on MR findings. Neurology 1997; 49: 1605–1612 Lee I-H, Soong B-W, Lu Y-C, Chang Y-C. Dentatorubral-pallidoluysian atrophy in Chinese. Arch Neurol 2001; 58: 1905–1908 Lopez-Cendez I, Teive HGA, Calcagnotto ME, Da Costa JC, Cardoso F, Viana E, Maciel JA, Radvany J, Arruda WO, TrevisolBittencourt PC,Neto PR,Silveira I,Steiner CE,Pinto Jr.W,Santos AS, Neto YC, Werneck LC, Araújo AQC, Carakushansky G, Mello LR, Jardim LB, Rouleau GA. Frequency of the different mutations causing spinobellar ataxia (SCA1, SCA2, MJD/ SCA3 and DRPLA) in a large group of Brazilian patients. Arq Neuropsiquiatr 1997; 55: 519–529 Melberg A, Dahl N, Hetta J,Valind S, Nennesmo I, Lundberg PO, Raininko R. Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and narcolepsy. Neurology 1999; 53: 2190–2192 Miyazaki M, Hashimoto T, Yoneda Y, Tayama M, Harada M, Miyoshi H, Kawano N, Murayama N, Kondo I, Kuroda Y. Proton magnetic resonance spectroscopy in childhood-onset dentatorubral-pallidoluysian atrophy (DRPLA). Brain Dev 1966; 18: 142–146 Mizukami K, Sasaki M, Shiraishi H, Koizumi J, Ogata T, Kosaka K. An autopsied case of dentatorubropallidoluysian atrophy with atypical pathological features. Jpn J Psy Neurol 1992; 46: 749–754 Miyazaki M, Kato T, Hashimoto T, Harada M, Kondo I, Kuroda Y. MR of childhood-onset dentatorubral-pallidoluysian atrophy. AJNR Am J Neuroradiol 1995; 16: 1834–1836 Muñoz E, Milà M, Sánchez A, Latorre P, Ariza A, Codina M, Ballesta F. Tolosa E. Dentatorubral-pallidoluysian atrophy in a Spanish family: a clinical, radiological, pathological, and genetic study. J Neurol Neurosurg Psychiatry 1999; 67: 811–814 Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M,Takeda T,Tadokoro K, Kondo I, Murayama N,Tanaka Y, Kikushima H, Umino K, Kurosawa H, Furukawa T, Nihei K, Inoue T, Sano A, Komue O, Takahashi M, Yoshizawa T, Kanazawa I, Yamada M. Detatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 1994; 6: 14–18 Nagaoka U, Suzuki Y, Kawanami T, Kurita K, Shikama Y, Honda K, Abe K, Nakajima T, Kato T. Regional differences in genetic subgroup frequency in hereditary cerebellar ataxia, and a morphometrical study of brain MR images in SCA1, MJD and SCA6. J Neurol Sci 1999; 164: 187–194

1010 References and Further Reading Robitaille Y,Lopez-Cendez I,Becher M,Rouleau G,Clark AW.The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 1997; 7: 901–926 Silveira I, Miranda C, Guimarães, Moreira M-C, Alonso I, Mendonça P, Ferro A, Pinto-Basto J, Coelho J, Ferreirinha F, Poirier J, Parreira E, Vale J, Januário C, Barbot C, Tuna A, Barros J, Koide R, Tsuji S, Holmes SE, Margolis RL, Jardim L, Pandolfo M, Coutinho P, Seqeiros J.Trinucleide repeats in 202 families with ataxia. Arch Neurol 2002; 59: 623–629 Smith JK, Gonda VE, Malamud N. Unusual form of cerebellar ataxia: combined dentatorubral and pallidoluysian degeneration. Neurology 1958; 13: 266–269 Tsuchiya K, Oyanani S, Arima K, Ikeda K, Akashi T, Ando S. Kurosawa T, Ikeuchi T, Tsuji S. Dentatorubropallidoluysian atrophy: clinicopathological study of dementia and involvement of the nucleus basalis of Meynert in seven autopsy cases. Acta Neuropathol (Berl) 1998; 96: 502–508 Uyama E, Kondo I, Uchino M, Fukushima T, Murayama N, Kuwano A, Inokuchi N, Ohtani Y, Ando M. Dentatorubralpallidoluysian atrophy (DRPLA): clinical, genetic and neuroradiologic studies in a family. J Neurol Sci 1995; 130: 146–153 Violante V, Luongo A, Pepe S, Annunziata S, Gentile V.Transglutaminase-dependent formation of protein aggregates as possible biochemical mechanism for polyglutamine diseases. Brain Res Bull 2001; 56: 169–172 Warner TT, Lennox GC, Janota I, Harding E. Autosomal-dominant dentatorubropallidoluysian atrophy in the United Kingdom. Mov Disord 1994; 3: 289–296 Warner TT,Williams LD,Walker RWH, Flinter F, Robb SA, Bundey SE, Honavar M, Harding AE. A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families. Ann Neurol 1995; 37: 452–459 Yabe I, Sasaki H, Kikuchi S, Nonaka M, Moriwake F, Tashiro K. Late onset ataxia phenotype in dentatorubro-pallidoluysian atrophy (DRPLA). J Neurol 2002; 249: 432–436 Yamada M, Sato T,Tsuji S,Takahashi H. Oligodendrocytic polyglutamine pathology in dentatorubral-pallidoluysian atrophy. Ann Neurol 2002; 52: 670–674 Yoshii F, Tomiyashu H, Shinohara Y. Fluid attenuation inversion recovery (FLAIR) images of dentatorubropallidoluysian atrophy: case report. J Neurol Neurosurg Psychiatry 1998; 65: 396–399 Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Ann Rev Neurosci 2000; 23: 217–247

72 Cerebral Amyloid Angiopathy Abrahamson M, Jonsdottir S, Olafsson I, Jensson O, Grubb A. Hereditary cystin C amyloid angiopathy: indentification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis. Hum Genet 1992; 89: 377–380 Atwood CS, Bishop GM, Perry G, Smith MA. Amyloid-b: a vascular sealant that protects against hemorrhage? J Neurosci Res 2002; 70: 356 Baumann MH, Wisniewski T, Levy E, Plant GT, Ghiso J. C-Terminal fragments of a- and b-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial cerebral amyloid angiopathy, British type. Biochem Biophys Res Commun 1996; 219: 238–242

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1012 References and Further Reading Oide T, Takahashi H, Yutani C, Ishihara T, Ikeda S-I. Relationship between lobar intracerebral hemorrhage and leukoencephalopathy associated with cerebral amyloid angiopathy: clinicopathological study of 64 Japanese patients. J Protein Folding Disord 2003; 10: 136–143 Ólafsson Í, Grubb A.Hereditary cystatin C amyloid angiopaghy. Int J Exp Clin Invest 2000; 7: 70–79 Olichney JM, Hansen LA, Hofstetter R, Grundman M, Katzman R, Thal LJ. Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol 1995; 52: 702–708 Olichney JM, Hansen LA, Lee JH, Hofstetter CR, Katzman R,Thal LJ. Relationship between severe amyloid angiopathy, apolipoprotein E genotype and vascular lesions in Alzheimer’s disease. Ann NY Acad Sci 2000; 903: 138–143 O’Riordan S, McMonagle P, Janssen JC, Fox NC, Farell M, Collinge J, Rossor MN, Hutchinson M. Preselin-1 mutation (E280G), spastic paraparesis, and cranial MRI white matter abnormalities. Neurology 2002; 59: 1108–1110 Osumi AK, Tien RD, Felsberg GJ, Rosenbloom M. Cerebral amyloid angiopathy presenting as a brain mass. AJNR Am J Neuroradiol 1995; 16: 911–915 Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and congnitive function. Neurology 2002; 58: 1629–1634 Prior R, Wihl G, Urmoneit B. Apolipoprotein E, smooth muscle cells and the pathogenesis of cerebral amyloid angiopathy: the potential role of impaired cerebrovascular Ab clearance. Ann NY Acad Sci 2000; 903: 180 – 186 Revasz T, Holton JL, Lashley T, Plant G, Rostagno A, Ghiso J, Frangione B. Sproradic and familial cerebral amyloid angiopathies. Brain Pathol 2002; 12: 343–357 Roob G, Fazekas F. Magnetic resonance imaging of cerebral microbleeds. Curr Opin Neurol 2000; 13: 69–73 Sarazin M, Amarenco P, Mikol J, Dimitri D, Lot G, Bousser MG. Reversible leukoencephalopathy in cerebral amyloid angiopathy presenting as subacute dementia. Eur J Neurol 2002; 9: 353–358 Schubert P, Morino T, Miyazaki H, Ogata T, Nakamura Y, Marchini C, Ferroni S. Cascading glia reactions: a common pathomechanism and its defferentiated control by cycling neucleotide signaling. Ann NY Acad Sci 2000; 903: 24–33 Scully RE, Mark EJ, McNeely WF, Ebeling SH, Ellender SM. Presentation of case. N Engl J Med 2000; 342: 957–965 Shimode K, Kobayashi S, Imaoka K, Umegae N, Nagai A. Leukoencephalopathy-related cerebral amyloid angiopathy with cystatin C deposition. Stroke 1996; 27; 1417– 1419 Sillus M, Saeger W, Linke RP, Müller D,Voigt C. Cerebral amyloid angiopathy. Frequency, significance and immunohistochemistry. Zentrabl Pathol 1993; 139: 2074–215 Sveinbjörnsdóttir S, Blöndal H, Gudmundsson G, Kjartansson O, Jónsdóttir S, Gudmundsson G. Progressive dementia and leukoencephalopathy as the initial presentation of late onset hereditary cystatin-C amyloidosis. Clinical presentation of two cases. J Neurol Sci 1996; 140: 101–108 Van Duinen SG, Maat-Schieman MLC, Bruijn JA, Haan J, Roos RAC. Cortical tissue of patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) contains various extracellular matrix deposits. Lab Invest 1995; 73: 183–189 Van Nostrand WE, Melchor J, Wagner M, Davis J. Cerebrovascular smooth muscle cell surface fibrillar Ab. Alteration of the proteolytic environment in the cerebral vessel wall. Ann NY Acad Sci 2000; 903: 89 – 96 Vinters HV. Cerebral amyloid angiopathy and Alzheimer’s disease: two entities or one? J Neurol Sci 1992; 112: 1–3

Vonsattel JPG, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr.Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 1991; 30: 637–649 Walker LC. Animal models of cerebral ß-amyloid angiopathy. Brain Res Rev 1997: 25: 70–84 Wattendorf AR, Frangione B, Luyendijk W, Bots GTAM. Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D): clinicopathological studies. J Neurol Neurosurg Psychiatry 1995; 58: 699–705 Weller RO, Massey A, Kuo Y-M, Rohler AE. Cerebral amyloid angiopathy: accumulation of Aß in interstitial fluid drainage pathways in Alzheimer’s disease. Ann NY Acad Sci 2000; 903: 110–117 Yamada M. Cerebral amyloid angiopathy: an overview. Neuropathology 2000; 1: 8–22 Yoshimura M, Yamanouchi H, Kuzuhara S, Mori H, Sugiura S, Mizutani T, Shimada H, Tomonaga M, Toyokura Y. Dementia in cerebral amyloid angiopathy: a clinicopathological study. J Neurol 1992; 239: 441–450

73 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukencephalopathy Abe K, Murakami T, Matsubara E, Manabe Y, Nagano I, Shoji M. Clinical features of CADASIL. Ann NY Acad Sci 2002; 977: 266–272 Arbodela-Valasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D,Gutierrez JE,Vargas S,Medina M,Martinez de Arieta C, Lebo RV, Slangenhaupt SA, Betensky RA, Villegas A, Arcos-Burgos M, Rivers D, Restrepo JC, Kosik KS. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology 2002; 59: 277–279 Auer DP, Schirmer T, Heidenreich JO, Herzog J, Pütz B, Dichgans M. Altered white and gray matter metabolism in CADASIL. A proton MR spectroscopy and 1H-MRSI study. Neurology 2001; 56: 635–642 Auer DP, Pütz B, Gössl C, Elbel G-K, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001; 218: 443–451 Bruening R, Dichgans M, Berchtenbreiter C,Yousry T, Seelos KC, Wu RH, Mayer M, Brix G, Reiser M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: decrease in regional cerebral blood volume in hyperintense subcortical lesions inversely correlates with disability and cognitive performance. AJNR Am J Neuroradiol 2001; 22: 1268–1274 Brulin P, Godfraind C, Leteurtre E, Ruchoux M-M. Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications. Acta Neuropathol (Berl) 2002; 104: 241–248 Ceroni M, Poloni TE, Tonietti S, Fabozzi D, Uggetti C, Frediani F, Simonetti F, Malaspina A, Alimonti D, Celano M, Ferrari M, Carrera P. Migraine with aura and white matter abnormalities: notch3 mutation. Neurology 2000: 54: 1869–1871 Chabriat H, Mrissa R, Levy C, Vahedi K, Taillia H, Iba-Zizen MT, Joutel A, Tournier-Lasserve E, Bousser MG. Brian stem MRI signal abnormalities in CADASIL. Stroke 1999; 30: 457–459

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Furby A, Vahedi K, Force, Larrouy S, Ruchoux M-M, Joutel A, Tournier-Lasserve E. Differential diagnosis of a vascular leukoencephalopathy within a CADASIL family: use of skin biopsy electron microscopy study and direct genotypic screening. J Neurol 1998; 245: 734–740 Iannucci G, Dichgans M, Rovaris M, Brüning R, Gasser T, Giacomotti L, Yousry TA, Filippi M. Correlations between clinical findings and magnetization transfer imaging metrics of tissue damage in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2001; 32: 643–648 Ito D, Tanahasi N, Murata M, Sato H, Saito I, Wanatabe K, Fukkuchi Y. Notch3 gene polymorphism and ischaemic cerebrovascular disease. J Neurol Neurosurg Psychiatry 2002; 72: 382–384 Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Maréchal E, Maciazek J, Vayssière C, Cruaud C, Cabanis E-A, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383: 707–710 Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, Cruaud C, Maciazek M, Weissenbach J, Bousser M-G, Bach J-F, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997; 350: 1511–1515 Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 2000; 105: 597–605 Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG. De novo mutation in the notch3 gene causing CADASIL. Ann Neurol 2000; 47: 388–391 Joutel A, Monet M, Domega V, Riant F, Tournier-Lasserve E. Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect jagged1 binding and Notch3 activity via the RBP/JK signaling pathway. Am J Hum Genet 2004; 74: 338–347 Kalimo H,Viitanen M, Amberlat K, Juvonen V, Marttila R, Pöyhönen M, Rinne JO, Savontaus M-L, Tuisku S, Winblad B. CADASIL: hereditary disease of arteries causing brain infarcts and dementia. Neuropathol Appl Neurobiol 1999; 25: 257–265 Karlström H, Beatus P, Dannaeus K, Chapman G, Lendahl U, Lundkvist J. A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci 2002; 99: 17119–17124 LaPoint SF, Patel U, Rubio A. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Adv Anat Pathol 2000; 7: 307–321 Le Bler I, Carluer L, Derache N, Lalevée C, Ledoze F, Defer GL. Unusual presentation of CADASIL with reversible coma and confusion. Neurology 2002; 59: 1115–1116 Lesnik Oberstein SAJ, van den Boom R, Middelkoop HAM, Ferrari MD, Knaap YM, van Houwelingen HC, Breuning MH, van Buchem MA, Haan J. Incipient CADASIL. Arch Neurol 2003; 60: 707–712 Lesnik Oberstein SAJ, van Duinen SG, van den Boom R, MaatSchieman MLC, van Buchem MA, van Houwelingen HC, Hegeman-Kleinn IM, Ferrari MD, Breuning MH, Haan J. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol (Berl) 2003; 106: 107–111

1014 References and Further Reading Malandrini A, Carrera P, Palmeri S, Cavellaro T, Fabrizi GM, Villanova M, Fattapposta M, Vismara L, Brancolini V, Tanganelli P, Calì A, Morocutti C, Zeviani M, Ferrari M, Guazzi GC. Clinicopathological and genetic studies of two further Italian families with cerebral dominant arteriopathy. Acta Neuropathol (Berl) 1996; 92: 115–122 Malandrini A, Carrera P, Giacci G, Gonelli Villanova M, Palmeri S, Vismara L, Brancolini V, Signorini E, Ferrari, Guazzi GC. Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy. Neurology 1997; 48: 1200–1203 Malandrini A, Albani F, Palmeri S, Fattapposta F, Gambelli S, Berti G, Bracco A, Tammaro A, Calzavara S, Villanova M, Ferrari M, Rossi A, Carrera P. Asymptomatic and paracrystalline mitochondrial inclusions in CADASIL. Neurology 2002; 59: 617–620 Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF. Diagnostic strategies in CADASIL. Neurology 2002; 59: 1134–1138 Mayer M, Straube A, Bruening R, Uttner I, Pongratz D, Gasser T, Dichgans M, Müller-Höcker J. Muscle and skin biopsies are sensitive diagnostic tool in the diagnosis of CADASIL. J Neurol 1999; 246: 526–532 Molko N, Pappata S, Magnin JF, Poupon C, Vahedi K, Jobert A, LeBihan D, Bousser MG, Chabriat H. Diffusion tensor imaging study of subcortical gray matter in CADASIL. Stroke 2001; 32: 2049–2054 Molko N, Pappata S, Mangin J-F, Poupon F, LeBihan D, Bousser M-G, Chabriat H. Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging. A study with whole brain histogram analysis. Stroke 2002; 33: 2902–2908 Okeda R,Arima K,Kawai M.Arterial changes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter. Examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case. Stroke 2002; 33: 2565–2569 O’Sullivan, M Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 2001; 56: 628–634 O’Sullivan M, Rich PM, Barrick TH, Clark CA, Markus HS. Frequency of subclinical lacunar infarcts in ischemic leukoaraiosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AJNR Am J Neuroradiol 2003; 24: 1348–1354 Robinson W, Galetta SL, McCluskey L, Forman MS, Balcer LJ. Retinal findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalpathy (CADASIL). Surv Ophthalmol 2001; 45: 445–448 Rocca MA, Filippi M, Herzog J, Sormani MP, Dichgans M,Yousry TA. A magnetic resonance imaging study of the cervical cord of patients with CADASIL. Neurology 2001; 56: 1392– 1394 Rubio A, Rifkin D, Powers JM, Patel U, Stewart J, Faust P, Goldman JE, Mohr JP, Numaguchi Y, Jensen K. Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol (Berl) 1997; 94: 247–254 Ruchoux M-M, Muarage C-A. CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 1997; 56: 947– 964

Santa Y, Uyama E, Chui de H, Arima M, Kotorii S, Takahashi K, Tabira T. Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis. J Neurol Sci 2003; 212: 79–84 Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS.“CADASIL coma”: an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry 2003: 74: 249–252 Schultz A, Santoianni R, Hewan-Lowe D. Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol 1999; 23: 241–247 Thomas NJ, Morris CM, Scaravilli F, Johansson J, Rossor M, de Lange R, St Clair D, Nicoll J, Blank C, Coulthard A, Bushby K, Ince PG, Burn D, Kalaria RN. Hereditary vascular dementia linked to notch 3 mutations. CADASIL in British families. Ann N Y Acad Sci 2000; 903: 293–298 Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas J-L, Cabanis E-A, Baudrimont M, Maciazek J, Bach M-A, Bousser M-G. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993; 3: 256–259 Trojano L, Ragno M, Manca A, Caruso G. A kindred affect by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A 2-year neuropsychological follow-up. J Neurol 1998; 245: 217–222 Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne JO, Tuisku S, Kurki T, Marttila R, Pöyhönen M, Savontaus M-L, Viitanen M, Kalimo H. Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R113C Notch3 mutation. Stroke 2001; 32: 1767– 1774 Utatsu Y,Takashima H,Michizono K,Kanda N,Endou K,Mitsuyama Y, Fujimoto T, Nagai M, Umehara F, Higuchi I, Arimura K, Nakagawa M, Osame M. Autosomal dominant early onset dementia and leukoencephalopathy in a Japanese family: clinical, neuroimaging and genetic studies. J Neurol Sci 1997; 147: 55–62 Van den Boom R, Lesnik Oberstein SAJ, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA. Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology 2002; 224: 791–796 Van den Boom R, Lesnik Oberstein SAJ, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR findings at different ages – 3rd–6th decades. Radiology 2003; 229: 683–690 Viitanen M, Kalimo H. CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. Ann N Y Acad Sci 2000; 903: 273–284 Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 2001; 108: 161–164 Wang T, Sharma SD, Fox N, Rossor M, Brown MJ, Sharma P. Description of a simple test for CADASIL disease and determination of mutation frequencies in sporadic ischaemic stroke and dementia patients. J Neurol Neurosurg Psychiatry 2000; 69: 652–654

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74 Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukencephalopathy (CARASIL) Fukutake T. Young-adult-onset hereditary subcortical vascular dementia: cerebral autosomal recessive arteriosclerosis with subcortical infarcts and leukoencephalopathy (CARASIL). Clin Neurol 1999: 39: 50–52 Fukutake T, Hirayama K. Familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension. Eur Neurol 1995; 35: 69–79 Maeda S, Nakayama H, Isaka K, Aihara Y, Nemoto S. Familial unusual encephalopathy of Binswanger’s type without hypertension. Folia Psychiatr Neurol Jap 1976; 30: 165–177 Uchino M, Hirano T, Uyama E, Hashimoto Y. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and CADASIL-like disorders in Japan. Ann NY Acad Sci 2002; 977: 273–278 Yamamura T, Nishimura M, Shirabe T, Fujita M. Subcortical vascular encephalophy in a normotensive, young adult with premature baldness and spondylitis deformans. A clinocopathological study and review of the literature. J Neurol Sci 1987; 78: 175–188 Yanagawa S, Ito N, Arima K, Ikeda S-I. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Neurology 2002; 58: 817–820 Yokoi S, Nakayama H. Chronic progressive leukoencephalopathy with systemic arteriosclerosis in young adults. Clin Neuropathol 1985; 4: 165–173

75 Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (Nasu-Hakola Disease) Amano N, Iwabuchi K, Sakai H,Yaghishita S, Itho Y, Eseki E,Yokoi S, Arai N, Kinoshita J. Nasu-Hakola’s disease (membranous lipodystrophy). Acta Neuropathol (Berl) 1987; 74: 294–299 Araki T,Ohba H,Monzawa S,Sakuyama K,Hachiya J,Seki T,Takahashi Y, Yamaguchi M. Membranous lipodystrophy: MR imaging appearance of the brain. Radiology 1991; 180: 793–797

Bianchin MM, Capella HM, Chaves DL, Steindel M, Grisard EC, Ganev GG, Péricles da Silva J, Neto ES, Poffo MA,Walz R, Carlotti CG, Sakamoto AC. Nasu-Hakola disaease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy – PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol 2004; 24: 1–24 Bird TD, Koerker RM, Leaird BJ, Vlcek BW, Thorning DR. Lipomembranous polycystic osteodysplasia (brain, bone, and fat disease): a genetic cause of presenile dementia. Neurology 1983; 33: 81–86 Chaabane M, Larnaout A, Sebai R, Nagi S, Touibi S, Hentati F. Nasu-Hakola disease in two Tunisian siblings: new radiological findings. Neuroradiology 2000; 42: 375–378 Hakola HPA, Järvi OH, Sourander P. Osteodysplasia polycystica hereditaria combined with sclerosing leukoencephalopathy, a new entity of the dementia praesenilis group. Acta Neurol Scand 1970; 46: 79–80 Hakola HPA. Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. Acta Psychiatr Scand 1972; 232: 1–173 Hakola HPA, Livanainen M. A new hereditary disease with progressive dementia and polycystic osteodysplasia: neuroradiological analysis of seven cases. Neuroradiology 1973; 6: 162–168 Hakola HPA, Partanen VSJ. Neurophysiological findings in the hereditary presenile dementia characterized by polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy. J Neurol Neurosurg Psychiatry 1983; 46: 515–520 Hakola HPA, Puranen M. Neuropsychiatric and brain CT findings in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Acta Neurol Scand 1993; 88: 370–375 Haruta K, Matsunaga S, Ito H, Hayashi K, Yokouchi M, Onishi T, Komiya S. Membranous lipodystrophy (Nasu-Hakola disease) presenting an unusually benign clinical course. Oncol Rep 2003; 10: 1007–1010 Livanainen M, Hakola P, Erkinjuntti T, Sipponen JT, Ketonen L, Sulkava R, Sepponen RE. Cerebral MR and CT imaging in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. J Comput Assist Tomogr 1984; 8: 940–943 Kalimo H, Sourander P, Järvi O, Hakola P. Vascular changes and blood-brain barrier damage in the pathogenesis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (membranous lipodystrophy). Acta Neurol Scand 1994; 89: 353–361 Kitajima I, Suganuma T, Murata F, Nagamatsu K. Ultrastructural demonstration of Maclura pomifera agglutinin bindings sites in the membranocystic lesions of membranous lipodystrophy (Nasu-Hakola disease). Virchows Arch [A] 1988; 413: 475–483 Kitajima I, Kuriyama M, Usuki F, Izumo S, Osame M, Suganuma T, Murata F, Nagamatsu K. Nashu-Hakola disease (membranous lipodystrophy). Clinical, histopathological and biochemical studies of three cases. J Neurol Sci 1989; 91: 35–52 Kobayashi K, Kobayashi E, Miyazu K, Muramori F, Hiramatsu S, Aoki T, Nakamura I, Koshino Y. Hypothalamic haemorrhage and thalamus degeneration in a case of Nasu-Hakola disease with hallucinatory symptoms and central hypothermia. Neuropathol Appl Neurobiol 2000; 26: 98–101

1016 References and Further Reading Malandrini A, Scarpini C, Palmeri S, Villanova M, Parrotta E, Tripodi S, Giani S, DeFalco D, Guazzi GC. Palatal myoclonus and unusual MRI findings in a patient with membranous lipodystrophy. Brain Dev 1996; 18: 59–63 Matsushita M, Oyanagi S, Hanawa S, Shiraki H, Kosaka K. NasuHakola’s disease (membranous lipodystrophy). A case report. Acta Neuropathol (Berl) 1981; 54: 89–93 Mii Y, Miyauchi Y, Yoshikawa T, Honoki K, Aoki M, Tsutsumi M, Maruyama H, Funauchi M, Konishi Y,Tamai S. Ultrastructural lipid and glycoconjugate cytochemistry of membranous lipodystrophy (Nasu-Hakola disease). Virchows Archiv [A] 1991; 419: 137-142 Minagawa M, Maeshiro H, Kato K, Shioda K. A rare case of leucodystrophy-neuroaxonal leucodystrophy (Seitelberger). Psychiatry Neurol Jpn 1980; 82: 488–503 Minagawa M, Maeshiro H, Shioda K, Hirano A. membranous lipodystrophy (Nasu disease): clinical and neuropathological study of a case. Clin Neuropathol 1985; 4: 38–45 Miyazu K, Kobayashi K, Fukutani Y, Nakamura I, Hasegawa H,Yamaguchi N, Saitoh T. Membranous lipodystrophy (NasuHakola disease) with thalamic degeneration: report of an autopsied case. Acta Neuropathol (Berl) 1991; 82: 414–419 Motohasi N, Shinohara M, Shioe K, Fukuzawa H, Akiyama Y, Kariya T. A case of membranous lipodystrophy (Nasu-Hakola disease) with unique MRI findings. Neuroradiology 1995; 37: 549–550 Nasu T, Tsukahara Y, Terayama K. A lipid metabolic disease – “membranous lipodystrophy” – an autopsied case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues. Acta Pathol Jpn 1973; 23: 539–558 Oishi M, Mori N, Takasu T, Osaka S, Yamamoto M, Uchiyama T, Sawada S.Nasu-Hakola disease.A case accompanied by abnormalities in fatty acid composition of serum total lipids and amino acid analysis. Acta Neurol (Napoli) 1993; 15: 53–61 Paloneva J, Kestilä M,Wu J, Salminen A, Böhling T, Ruotsalainen V, Hakola P, Bakker ABH, Phillips JH, Pekkarinen, Lanier LL,Timonen T, Peltonen L. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 2000; 25: 357–361 Paloneva J, Autti T, Raininko R, Partanen J, Salonen O, Puranen M, Hakola P, Haltia M. CNS manifestations of Nasu-Hakola disease. A frontal dementia with bone cysts. Neurology 2001; 56: 1552–1558 Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjærg Y, Konttinen Y, Peltonen L. Mutations in two genes encoding different subunits of a receptor signaling complex results in an identical disease phenotype. Am J Hum Genet 2002; 71: 656–662 Pekkarinen P, Hovatta I, Hakola P, Järvi O, Kestilä M, Lenkkeri U, Adolfsson R, Holmgren G, Nylander P-O, Tranebjærg L, Terwilliger JD, Lönnqvist J, Peltonen L. Assignment of the locus for PLO-SL, a frontal lobe dementia with bone cysts, to 19q13. Am J Hum Genet 1998; 62: 362–372 Snow JL, Su WPD, Gibson LE. Lipomembranous (membranocystic) changes associated with morphea: a clinicopathologic review of three cases. J Am Acad Dermatol 1994; 31: 246–250 Tanaka J. Leukoencephalopathic alteration in membranous lipodystrophy. Acta Neuropathol (Berl) 1980; 50: 193–197 Tanaka J. Nasu-Hakola disease: a review of its leukoencephalopathic and membranolipodystrophic features. Neuropathology 2000; 20: S25-S29

Ueki Y, Kohara N, Oga T, Fukuyama H, Akiguchi I, Kimura J, Shibasaki H. Membranous lipodystrophy presenting with palilalia: a PET study of cerebral glucose metabolism. Acta Neurol Scand 2000; 102: 60–64 Verloes A, Maquet P, Sadzot B, Vivario M, Thiry A, Franck G. Nasu-Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and presenile dementia. J Med Genet 1997; 34: 753–757 Yagishita S, Ito Y, Sakai H, Amano N. Membranocystic lesions of the lung in Nasu-Hakola disease. Virchows Arch [A] 1985; 408: 211–217

76 Pigmentary Orthochromatic Leukodystrophy Belec L, Gray F, Louarn F, Gherardi R, Morelot D, Destée A, Poirier J, Castaigne P. Leucodystrophie orthochromatique pigmentaire. Rev Neurol 1988; 144: 347–357 Constantinidis J,Wisniewski TM.The dominant form of the pigmentairy orthochromatic leukodystrophy. Acta Neuropathol (Berl) 1991; 82: 483–487 Dousset V,Tison F,Vital A, Henry P. Leucodystrophie orthochromatique d’évolution rapide chez l’adulte. Rev Neurol 1998; 154: 415–418 Gray F,Destee A,Bourre J-M,Gherardi R,Krivosic I,Warot P,Poirier J. Pigmentary type of orhtochromatic leukodystrophy (OLD); a new case with ultrastructural and biochemical study. J Neuropathol Exp Neurol 1987; 46: 585–596 Knopman D,Sung JH,Davis D.Progressive familial leukodystrophy of late onset. Neurology 1996; 46: 429–434 Marotti JD, Tobias S, Fratkin JD, Powers JM, Rhodes CH. Adult onset leukodystrophy with neuroaxonal spheroids and pigmented glia: report of a family, historical perspective, and review of the literature. Acta Neuropathol (Berl) 2004; 107: 481–488 Okeda R,Matsuo T,Kawahara Y,Eishi Y,Tamai Y,Tanaka M,Kamaki M, Tsubota N, Yamadera H. Adult pigment type (Pfeiffer) of sudanophilic leukodystrohy. Pathological and morphometrical studies on two autopsied cases of siblings. Acta Neuropathol (Berl) 1989; 78: 433–542 Pietrini V, Tagliavini F, Pilleri G, Trabattoni CR, Lechi A. Orthochromatic leukodystrophy with pigmented glial cells. An adult case with clinical-anatomical study. Acta Neurol Scand 1979; 59: 140–147 Seiser A,Jellinger K,Brainin.Pigmentary type of orthochromatic leukodystrophy with early onset and protracted course. Neuropediatrics 1990; 21: 48–52 Shannon P, Wherrett JR, Nag S. A rare form of adult onset leukodystrophy: orthochromatic leukodystrophy with pigmented glia. Can J Neurol Sci 1997; 24: 146–150 Verghese J, Weidenheim K, Malik S, Rapin I. Adult onset pigmentary orthochromatic leukodystrophy with ovarian dysgenesis. Eur J Neurol 2002; 9: 663–670

77 Adult-onset Autosomal Dominant Leukoencephalopathies Abe K, Ikeda M,Watase K,Tanabe H, Fujimura H,Yorifuji S, Ueno S, Mezaki T, Mori T. A kindred of hereditary adult-onset leukodystrophy with sparing of the optic radiations.Neuroradiology 1993; 35: 281–283

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81 Acquired Immunodeficiency Syndrome Abdoulafia DM, Taylor L. Vacuolar myelopathy and vacuolar cerebellar leukoencephalopathy: a late complication of AIDS after highly active antiretroviral therapy-induced immune reconstruction. AIDS Pat Care 2002; 16: 579–584 Albright AV, Soldan SS, Gonzalez-Scarano F. Pathogenesis of human immunodeficiency virus-induced neurological disease. J Neurovirol 2003; 9: 222–227 Anderson E, Zink W, Xiong H, Gendelman HE. HIV-1-associated dementia: a metabolic encephalopathy perpetrated by virus-infected and immune-competent mononuclear phagocytes.J Acquir Immune Defic Syndr 2002; 31:S43-S54 Annunziata P. Blood–brain barrier changes during invasion of the central nervous system by HIV-1. J Neurol 2003; 250: 901–906 Avison MJ,Nath A,Berger JR.Understanding pathogenesis and treatment of HIV dementia: a role for magnetic resonance? Trends Neurosci 2002; 25: 468–473 Barret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, Desguerre I, Dollfus C, Mayaux M-J, Blance S. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17: 1769–1785 Belman AL, Ultmann MH, Horoupian D, Novick B, Spiro AJ, Rubinstein A, Kurtzberg D, Cone-Wesson B. Neurological complications in infants and children with acquired immune deficiency syndrome. Ann Neurol 1985; 18: 560–566 Bencherif B, Rottenberg DA. Neuroimaging of the AIDS dementia complex. AIDS 1998; 12: 233–244 Berger JR, Sheremata WA, Resnick L, Atherton S, Fletcher MA, Norenberg M. Multiple sclerosis-like illness occurring with human immunodeficiency virus infection. Neurology 1989; 39: 324–329 Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, Ciraru-Vigneron N, Lacroix C, Rouzioux C, Mabdelbrot L, Desguerre I, Rötig A, Mayaux M-J, Delfraissy JF. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354: 1084– 1089 Camacho DLA, Smith JK, Castillo M. Differentiation of toxoplasmosis and lymphoma in AIDS patients by using apparent diffusion coefficients. AJNR Am J Neuroradiol 2003; 24: 633–637 Cedis Meltzer C,Wells SW, Bechner MW, Flanigan KM, Oyler GA, Lee RR. AIDS-related MR hyperintensity of the basal ganglia. AJNR Am J Neuroradiol 1998; 19: 83–89

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82 Progressive Multifocal Leukoencephalopathy Agostini HT, Ryschkewitsch CF, Baumhefner RW, Tourtelotte WW, Singer EJ, Komoly S, Stoner GL. Influence of JC virus coding region genotype on risk of multiple sclerosis and progressive multifocal leukoencephalopathy. J Neurovirol 2000; 6: S101-S108 Aksamit AJ, Gendelman HE, Orenstein JM, Pezeshkpour GH. AIDS-associated progressive multifocal leukoencephalopathy (PML): comparison to non-AIDS PML with situ hybridization and immunohistochemistry. Neurology 1990; 40: 1073–1078 Arai Y, Tsutsui Y, Nagashima K, Shinmura Y, Kosugi T, Wakai M, Nishikage H, Yamamoto J. Autopsy case of the cerebellar form of progressive multifocal leukoencephalopathy without immunodeficiency. Neuropathology 2002; 22: 48–56 Berger JR, Pall L, Lanska D,Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 1998; 4: 59–68

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1028 References and Further Reading Sabath BF, Major EO.Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis 2002; 186: S180-S186 Safdar A, Rubocki J, Horvath JA, Narayan K, Waldron RL. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstruction. Clin Infect Dis 2002; 35: 1250–1257 Seth P, Diaz F, Major EO. Advances in the biology of JC virus and induction of progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9: 236–246 Shapiro RA, Mullane KM, Camras L, Flowers C, Sutton S. Clinical and magnetic resonance imaging regression of progressive multifocal leukoencephalopathy in an AIDS patient after intensive antiretroviral therapy. J Neuroimaging 2001; 11: 336–339 Sima AAF, Finkelstein SD, McLachlan DR. Multiple malignant astrocytomas in a patient with spontaneous progressive multifocal leukoencephalopathy. Ann Neurol 1983; 14: 183–188 Steiger MJ, Tarnesby G, Gabe S, McLaughlin J, Schapira AHV. Successful outcome of progressive multifocal leukoencephalopathy with cytarabine and interferon. Ann Neurol 1993; 33: 407–411 Stohlman SA, Hinton DR. Viral induced demyelination. Brain Pathol 2001;11:92–106 Sugimoto C, Ito D, Matsuda H, Saito H, Sakai H, Fujihara K, Itoyama Y, Yamada T, Kira J, Matsumoto R, Mori M, Nagashima K, Yogo Y. Amplification of JC virus regulatory DNA sequences from cerebrospinal fluid: diagnostic value for progressive multifocal leukoencephalopathy. Arch Virol 1998; 143: 249–262 Thurnher MM, Donovan Post MJ, Rieger A, Kleibl-Popov C, Loewe C, Schindler E.Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol 2001; 22: 977–984 Trotot PM Vazeux R, Yamashita HK, Sandoz-Tronca C, Mikol J, Vedrenne C, Thiébaut JB, Gray F, Cikurel M, Pialoux G, Levillain R. MRI pattern of progressive multifocal leukoencephalopathy (PML) in AIDS. J Neuroradiol 1990; 17: 233– 254 Weber T, Major EO. Progressive multifocal leukoencephalopathy: molecular biology, pathogenesis and clinical impact. Intervirology 1997; 40: 98–111 Zachoval R, Hunstein W, Ho AD. Progressive multifocal leukoencephalopathy in a patient with Hodgkin’s disease. Blut 1980; 41: 451–454

83 Brucellosis Akdeniz H, Irmak H, Anlar O, Demiroz AP. Central nervous system brucellosis: presentation, diagnosis and treatment. J Infect 1998; 36: 297–301 Al Deeb SM, Yaqub BA, Sharif HS, Phadke JG. Neurobrucellosis: clinical characteristics, diagnosis, and outcome. Neurology 1989; 39: 498–501 Al-Eissa YA. Unusual suppurative complications of brucellosis in children. Acta Paediatr 1993; 82: 987–992 Al-Sous MW, Bohlega S, Al-Kawi MZ, Alwatban J, McLean DR. Neurobrucellosis: clinical and neuroimaging correlation. AJNR Am J Neuroradiol 2004; 25: 395–401

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84 Subacute Sclerosing Panencephalitis Akdal G, Baklan B, Çakmakçi H, Kovanlikaya A. MRI follow-up of basal ganglia involvement in subacute sclerosing panencephalitis. Pediatr Neurol 2001; 24: 393–395 Alexander M, Singh S, Gnanamuthu C, Chandi S, Korah IP. Subacute sclerosing panencephalitis: CT and MR imaging in a rapidly progressive case. Neurol India 1999; 47: 304–307 Alkan A, Sarac K, Kutlu R, Yakinci C, Sigirci A, Aslan M, Baysal T. Early- and late-state subacute sclerosing panencephalitis; chemical shift imaging and single-voxel MR spectroscopy. AJNR Am J Neuroradiol 2003; 24: 501–506 Allen IV, McQuaid S, McMaron J, Kirk J, McConnell R.The significance of measles virus antigen and genome distribution in the CNS in SSPE for mechanisms of viral spread and dymyelination.J Neuropathol Exp Neurol 1996;55:471–480 Anlar B, Saatçi I, Köse G, Yalaz K. MRI findings in subacute sclerosing panencephalitis. Neurology 1996; 47: 1278–1283 Anlar B, Yalaz K, Oktem F, Kose G. Long-term follow-up of patients with subacute sclerosing panencephalitis treated with intraventricular a-interferon. Neurology 1997; 48: 526–528 Anlar B, Yalaz K, Köse G, Saygi S. b-Interferon plus inosiplex in the treatment of subacute sclerosing panencephalitis. J Child Neurol 1998; 13: 557–559 Anlar B, Söylemenzog˘lu F, Aysun S, Köse G, Belen D,Yalaz K.Tissue inflammatory response in subacute sclerosing panencephalitis (SSPE). J Child Neurol 2001; 16: 895–900 Arora SC, Al-Tahan AR, Al-Zeer A, Al-Tahan F, Ozo CO, ur-Rahman N. Subacute sclerosing panencephalitis presenting as acute disseminated encephalomyelitis: a case report. J Neurol Sci 1997; 146: 13–18 Barthez Carpentier MA, Billard C, Maheut J, Jourdan ML, Degenne D, Ruchoux MM, Goudeau A, Santini JJ. Acute measles encephalitis of the delayed type: neuroradiological and immunological findings. Eur Neurol 1992; 32: 235–237 Bismar J, Gascon GG, Vult von Steyern K, Bohlega S. Subacute sclerosing panencephalitis; evaluation with CT and MR. AJNR Am J Neuroradiol 1996; 17: 761–772 Bohlega S, Al-Kawi MZ. Subacute sclerosing panencephalitis. J Neuroimaging 1994; 4: 71–76 Callebaut DP,Cras P,Martin JJ.Prolonged and atypical course in some cases of subacute sclerosing panencephalitis. Acta Neurol Belg 1997; 97: 39–44 Cathomen T, Naim HY, Cattaneo R. Measles viruses with altered envelope protein cytoplasmic tails gain cell infusion competence. J Virol 1998; 72: 1224–1234 Cruzado D, Massery-Spicher V, Roux L, Delavelle J, Picard F, Haenggeli C-A. Early onset and rapidly progressive subacute sclerosing panencephalitis after congenital measles infection. Eur J Pediatr 2002; 161: 438–441 Dimova P, Bojinova V. Subacute sclerosing panencephalitis with atypical onset: clinical, computed tomographic, and magnetic resonance imaging correlations. J Child Neurol 2000; 15: 258–260 Dlugos DJ, Liu GT. Subacute sclerosing panencephalitis in an American-born adult. Clin Infect Dis 2001; 32: 173–174 Dyken PR. Subacute sclerosing panencephalitis. Neurol Clin 1985; 3: 179–196 Dyken PR. Neuroprogressive disease of post-infectious origin: a review of a resurging subacute sclerosing panencephalitis (SSPE). Ment Retard Dev Disabl Res Rev 2001; 7: 217–225

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1030 References and Further Reading Lewandowska E, Lechowicz W, Szpak GM, Sobczyk W. Quantative evaluation of intranuclear inclusions in SSPE: correlation with disease duration. Folia Neuropathol 2001; 39: 237–241 Lum GB,Williams JP, Dyken PR, Machen BC, Dotson PM, Harpen MD, McLeod N. Magnetic resonance and CT imaging correlated with clinical status in SSPE. Pediatr Neurol 1986; 2: 75–79 Mawrin C, Lins H, Koenig B, Heinrichs T, Murayama S, Kirches E, Boltze C, Dietzmann K. Spatial and temporal disease progression of adult-onset subacte sclerosing panencephalitis. Neurology 2002; 58: 1568–1571 McCarron MO, McDonnell GV, Gibson JM. Rapid neurological deterioration in a 22-year-old man. Postgrad Med J 1997; 73: 344–347 McQuaid S, Campbell S, Wallace IJC, Kirk J, Cosby SL. Measles virus infection and replication in undifferentiated and differentiated human neuronal cells in culture. J Virol 198; 72: 5245–5250 Miki K, Komase K, Mgone CS, Kawanishi R, Iijima M, Mgone JM, Asuo PG, Alpers MP, Takasu T Mizutani T. Molecular analysis of measles virus infection genome derived from SSPE and acute measles patients in Papua, New Guinea. J Med Virol 2002; 68: 105–112 Modi G, Campbell H, Bill P. Subacute sclerosing panencephalitis: changes on CT scan during acute relapse. Neuroradiology 1989; 31: 433–434 Norrby E, Kristensson K. Measles virus in the brain. Brain Res Bull 1997; 44: 213–220 Ogura H, Ayata M, Hayashi K, Seto T, Matsuoka O, Hattori H, Tanaka K, Tanaka K, Takano Y, Murata R. Efficient isolation of subacte sclerosing panencephalitis virus from patient brains by reference to magnetic resonance and computed tomographic images. J Neurovirol 1997; 3: 304–309 Ohya T, Martinez AJ, Jabbour JT, Lemmi, Duenas DA. Subacute sclerosing panencephalitis: correlation of clinical, neurophysiologic and neuropathologic findings. Neurology 1974; 24: 211–218 Özturk A, Gürses C, Baykan B, Gökyig˘it A, Eraksoy M. Subacute sclerosing panencephalitis: clinical and magnetic resonance imaging evaluation of 36 patients. J Child Neurol 2002; 17: 25–29 Panagariya A, Sureka RK, Aurora A. Current developments in the management of subacute sclerosing panencephalitis. J Assoc Physicians India 1998; 46: 218–222 Patterson JB, Cornu TI, Redwine J, Dales S, Lewicki H, Holz A, Thomas D, Billeter MA, Oldstone MBA. Evidence that the hypermutated M protein of a subacute sclerosing panencephalitis measles virus actively contributes to the chronic progressive CNS disease. Virology 2001; 291: 215– 225 Salvan AM, Confort-Gouny S, Cozzone PJ, Vion-Dury J, Chabrol B, Manchini J. In vivo cerebral proton MRS in a case of subacute sclerosing panencephalitis. J Neurol Neurosurg Psychiatry 1999; 66: 547–555 Santoshkumar B, Radhakrishnan K. Substantial spontaneous long-term remission in subacute sclerosing panencephalitis (SSPE). J Neurol Sci 1998: 154: 83–88 Sawaiski Y, Yano Y, Watanabe Y, Takada G. Migratory basal ganglia lesions in subacute sclerosing panencephalitis (SSPE): clinical implications of axonal spread. J Neurol Sci 1999; 168: 137–140 Sawaishi Y, Abe T, Yano T, Ishikawa K, Takada G. SSPE following neonatal measles infection. Pediatr Neurol 1999; 20: 63–65

Schneider-Schaulies J, Niewiesk S, Schneider-Schaulies S, ter Meulen V.Measles virus in the CNS: the role of viral and host factors for the establishment and maintenance of a persistent infection. J Neurovirol 1999; 5: 613–622 Senol U, Haspolat S, Cevikol C, Saatçi I. Subacute sclerosing panencephalitis: brain stem involvement in a peculiar pattern. Neuroradiology 2000; 42: 913–916 Takayama S, Iwasaki Y, Yamanouchi H, Sugai K, Takashima S, Iwasaki A. Characteristic clinical features in a case of fulminant subacute sclerosing panencephalitis. Brain Dev 1994; 16: 132–135 Tomoda A, Shiraishi S, Hosoya M, Hamada A, Miike T. Combined treatment with interferon-alpha and ribavirin for subacute sclerosing panencephalitis. Pediatr Neurol 2001; 24: 54–59 Tsuchiya K,Yamauchi T, Furui S, Suda Y,Takenaka E. MR imaging vs CT in subacute sclerosing panencephalitis. AJNR Am J Neuroradiol 1988; 9: 943–946 Tuncay R, Akman-Demir G, Gökyigit A, Eraksoy M, Barlas M,Tolun R, Gürsoy G. MRI in subacute sclerosing panencephalitis. Neuroradiology 1996; 38: 636–640 Voudris KA, Skardoutsou A, Hasiotou M, Theodoropoulos B, Vagiakou EA. Long-term findings on brain magnetic resonance imaging in acute encephalopathy with bilateral striatal necrosis associated with measles. J Child Neurol 2002; 17: 776–777 Winer JB, Pires M, Kermode A, Ginsberg L, Rossor M. Resolving MRI abnormalities with progression of subacute sclerosing panencephalitis. Neuroradiology 1991; 33: 178–180 Woelk CH, Pybus OG, Jin L, Brown DWG, Holmes EC. Increased positive selection pressure in persistent (SSPE) versus acute measles virus infections. J Gen Virol 2002; 83: 1419–1430 Yalaz K, Anlar B, Oktem F, Aysun S, Ustacelebi S, Gurcay O, Gurcay O, Gucuyener K, Renda Y. Intraventricular interferon and oral inosiplex in the treatment of subacute sclerosing panencephalitis. Neurology 1992; 42: 488–491 Zilber N, Kahana E. Environmental risk factors for subacute sclerosing panencephalitis (SSPE). Acta Neurol Scand 1998; 98: 49–54

85 Congenital and Perinatal Cytomegalovirus Infection Adler SP. Immunoprophylaxis against cytomegalovirus disease. Scand J Infect Dis Suppl 1995; 99: 105–109 Adler SP. Current prospects for immunization against cytomegalovirus disease. Infect Agents Dis 1996; 85: 29–35 Ahlfors K, Ivarsson S-A, Harris S. Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature. Scand J Infect Dis 1999; 31: 443–457 Alford CA, Stagno S, Pass RF, Britt WJ. Congenital and perinatal cytomegalovirus infections. Rev Infect Dis 1990; 12: 45–53 Allen RD, Pellett PE, Stewart JA, Koopmans M. Nonradioactive PCR-enzyme-linked immunosorbent assay method for detection of human cytomegalovirus DNA. J Clin Microbiol 1995; 33: 725–728 Anderson KS, Amos CS, Boppana S, Pass R. Ocular abnormalities in congenital cytomegalovirus infection. J Am Optom Assoc 1996; 67: 273–278 Atkins JT, Demmler GJ, Williamson WD, McDonald JM, Istas AS, Buffone GJ. Polymerase chain reaction to detect cytomegalovirus DNA in the cerebrospinal fluid of neonates with congenital infection. J Infect Dis 1994; 169: 1334–1337

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1032 References and Further Reading Haginoya K, Ohura T, Kon K,Yagi T, Sawaishi Y, Ishii KK, Funato T, Higano S,Takahashi S, Iinuma K. Abnormal white matter lesions with sensorineural hearing loss caused by congenital cytomegalovirus infection: retrospective diagnosis by PCR using Guthrie cards. Brain Dev 2002; 24: 710–714 Hayward JC, Titelbaum DS, Clancy RR, Zimmerman RA. Lissencephaly-pachygyria associated with congenital cytomegalovirus infection. J Child Neurol 1991; 6: 109–114 Istas AS, Demmler GJ, Dobbins JG, Stewart JA. Surveillance for congenital cytomegalovirus disease: a report from the National Congenital Cytomegalovirus Disease Registry. Clin Infect Dis 1995; 20: 665–670 Jauniaux E, Jurkovic D, Gulbis B, Liesnard C, Lees C, Campbell S. Materno-fetal immunoglobulin transfer and passive immunity during the first trimester of human pregnancy. Hum Reprod 1995; 10: 3297–330 Johansson PJH, Jönsson M, Ahlfors K, Ivarsson SA, Svanberg L, Guthenberg C. Retrospective diagnostics of congenital cytomegalovirus infection performed by polymerase chain reaction in blood stored on filter paper. Scand J Infect Dis 1997; 29: 465–468 Jones CA, Isaacs D. Predicting the outcome of symptomatic congenital cytomegalovirus infection. J Paediatr Child Health 1995; 31: 70–71 Kimberlin DW,Lin C-Y,Sanches PJ,Demmler GJ,Danker W,Shelton M,Jacobs RF,Vaudry W,Pass RF,Kiell JM,Soong S-J,Whitley RJ. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003; 143: 16–25 Koedood M, Fichtel A, Meier P, Mitchell PJ. Human cytomegalovirus (HCMV) immediate-early enhancer/promoter specificity during embryogenesis defines target tissues of congenital HCMV infection. J Virol 1995; 69: 2194– 2207 Kohyama J, Kajiwara M, Shimohira M, Iwakawa Y, Okawa H. Human cytomegalovirus DNA in cerebrospinal fluid. Arch Dis Child 1994; 71: 414–418 Koi H, Zhang J, Parry S.The mechanisms of placental viral infection. Ann NY Acad Sci 2001; 943: 148–156 Koopmans M, Sánchez-Martinéz D, Patton J, Stewart J. Evaluation of antigen and antibody detection in urine specimens from children with congenital human cytomegalovirus infection. J Med Virol 1995; 46: 321–328 Lagasse N, Dhooge I, Govaert P. Congenital CMV-infection and hearing loss. Acta Otolaryngol Belg 2000; 54: 431–436 Lamy ME, Mulongo KN, Gadisseux J-F, Lyon G, Gaudy V, van Lierde M. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 1992; 166: 91–94 Lazzarotto T, Guerra B, Spezzacatena P, Varani S, Gabrielli L, Pradelli P, Rumpianesi F, Banzi C, Bovicelli L, Landini MP. Prenatal diagnosis of congenital cytomegalovirus infection. J Clin Microbiol 1998; 36: 3540–3544 Lazzarotto T, Spezzacatena P, Varani S, Gabrielli L, Pradelli P. Guerra B, Landini MP. Anticytomegalovirus (anti-CMV) immunoglobulin G avidity in identification of pregnant woman at risk of transmitting congenital CMV infection. Clin Diagn Lab Immunol 1999; 6: 127–129 Lazzarotto T Varani S, Gabrielli L, Spezzacatena P, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. II. Diagnostics and antiviral therapy. Intervirology 1999; 42: 390–397 Lazzarotto T,Varani S, Guerra B, Nicolosi A, Lanari M, Landini MP. Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 2000; 137: 90–95

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92 Posterior Reversible Encephalopathy Syndrome Çelik M, Forta H, Dalkiliç T, Babacan G. MRI reveals reversible lesions resembling posterior reversible encephalopathy in porphyria. Neuroradiology 2002; 44: 839–841 Chakravarty A, Chakrabarti SD. The neurology of eclampsia: some observations. Neurol India 2002; 50: 128–135 Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images. AJNR Am J Neuroradiol 2002; 23: 1038–1048 Delanty N, Vaughan C, Frucht S, Stubgen P. Erythropoietin-associated hypertensive posterior leukoencephalopathy. Neurology 1997; 49: 686–689 De Seze J, Mastain B, Stojkovic T, Ferriby D, Pruvo JP, Destée A, Vermersch P. Unusual MR findings of the brain stem in arterial hypertension.AJNR Am J Neuroradiol 2000; 21:391–394 Digre KB, Varner MW, Osborn AG, Crawford S. Cranial magnetic resonance imaging in severe preeclampsia vs eclampsia. Arch Neurol 1993; 50: 399–406 Eguchi K, Kasahara K, Nagashima A, Mori T, Nii T, Ibaraki K, Kario K, Shimada K.Two cases of malignant hypertension with reversible diffuse leukoencephalopathy exhibiting a reversible nocturnal blood pressure “riser”pattern.Hypertens Res 2002; 25: 467–473 Eichler FS,Wang P,Wityk RJ,Beauchamp NJ Jr,Barker PB.Diffuse metabolic abnormalities in reversible posterior leukoencephalopathy syndrome. AJNR Am J Neuroradiol 2002; 23: 833–837 Hauser RA, Lacey M, Knight MR.Hypertensive encephalopathy: magnetic resonance description of reversible cortical and white matter lesions. Arch Neurol 1988; 45: 1078–1083 Hinchey J, Chaves C, Appignani B, Breen J, Pao L,Wang A, Pessin MS, Lamy C, Mas JL, Caplan LR. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334: 494–500

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1040 References and Further Reading Tajima Y, Isonishi K, Kashiwaba T,Tashiro K.Two similar cases of encephalopathy, possibly a reversible posterior leukoencephalopathy syndrome: serial findings of magnetic resonance imaging, SPECT and angiography. Int Med 1999; 38: 54–58 Urushitani M, Seriu N, Udaka F, Kameyama M, Nishinaka K, Kodama M. MRI Demonstration of a reversible lesion in cerebral deep white matter in thrombotic trombocytopenic purpura. Neuroradiology 1996; 38: 137–138 Taylor MB, Jackson A, Weller JM. Dynamic susceptibility contrast enhanced MRI in reversible posterior leukoencephalopathy syndrome associated with haemolytic uraemic syndrome. Br J Radiol 2000; 73: 438–442 Thomas SV. Neurological aspects of eclampsia. J Neurol Sci 1998; 155; 37–43 Utz N, Kinkel B, Hedde JP, Bewermeyer H. MR imaging of acute intermittent porphyria mimicking reversible posterior leukoencephalopathy syndrome. Neuroradiology 2001; 43: 1059–1062 Wanatabe Y, Mitomo M, Tokuda Y, Yoshida K, Choi S, Hosoki T, Ban C. Eclamptic encephalopathy: MRI, including diffusionweighted images. Neuroradiology 2002; 44: 981–958 Weidauer S, Gaa J, Sitzer M, Hefner R, Lanfermann H, Zanella FE. Posterior encephalopathy with vasospasm: MRI and angiography. Neuroradiology 2003; 45: 869–876

93 Langerhans Cell Histiocytosis Adle-Biassette H, Chetritt J, Bergemer-Fouquet AM,Wechsler J, Mussini JM, Gray F. Pathology of the central nervous system in Chester-Erdheim disease: report of three cases. J Neuropathol Exp Neurol 1997; 56: 1207–1216 Aricò M, Haupt R, Russotto VS, Bossi G, Scappaticci S, Denasino C. Langerhans cell histiocytosis in two generations: a new family and review of the literature. Med Pediatr Oncol 2001; 36: 314–316 Bohlega S, Alwatban J, Tulbah A, Bakheet SM, Powe J. Cerebral manifestation of Erdheim-Chester disease:clinical and radiologic findings. Neurology 1997; 49: 1702–1705 Broadbent V, Gadner H. Current therapy for Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998; 12: 327– 338 Cervera A, García Penas JJ, Díaz MA, Gutiërres-Solana LG, Benito A, Ruiz-Falcó M-L. Villa M. CNS sequellae in Langerhans cell histiocytosis: progressive spinocerebellar degeneration as a late manifestation of the disease. Pediatr Hematol Oncol 1997; 14: 577–584 Chu T. Langerhans cell histiocytosis. Aus J Dermatol 2001; 42: 237–242 Evidente VGH, Adler CH, Giannini C, Conley CR, Parisi JE, Fletcher GP. Erdheim-Chester disease with extensive intraaxial brain stem lesions presenting as a progressive cerebellar syndrome. Mov Disord 1998; 13: 576–581 Fuzakawa T, Tsukishima E, Sasaki H, Hamada K, Hamada T, Tashiro K. Erdheim-Chester disease and slowly progressive cerebellar dysfunction. J Neurol Neurosurg Psychiatry 1995; 58: 238–240 Gaetani P,Tancioni F, di Rocco M, Rodriguez y Baena R. Isolated cerebellar involvement in Rosai-Dorfman disease: case report. Neurosurgery 2000; 46: 479–481 Goldberg-Stern H, Weitz R, Zaizov R, Gornish M, Gadoth N. Progressive spinocerebellar degeneration “plus” associated with Langerhans cell histiocytosis: a new paraneoplastic syndrome? J Neurol Neurosurg Psychiatry 1995; 58: 180–183

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Drug-related Vasculitis Aggerwal SK, Williams V, Levine SR, Cassin BJ, Garcia JH. Cocaine-associated intracranial hemorrhage: absence of vasculitis in 14 cases. Neurology 1996; 46: 1741–1743 Ashchi M, Wiedermann HP, James KB. Cardiac complication form use of cocaine and phenylephirine in nasal septoplasty. Arch Ontolaryngol 1995; 121: 681–684 Barbieri EJ, Ferko AP, DiGregoria GJ, Ruch EK. The presence of cocaine and benzoylecgoninen in rat cerebrospinal fluid after the intravenous administration of cocaine. Life Sci 1992; 51: 1739–1746 Bartzokis G, Goldstein IB, Hance DB, Beckson M, Shapiro D, Lu PH, Edwards N, Mintz J, Bridge P. The incidence of T2weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific. AJNR Am J Neuroradiol 1999; 20: 1628–1635 Benders MJ, Dorrepaal CA, van de Bor M, van Bel F. Acute effects of indometacin on cerebral hemodynamics and oxygenation. Biol Neonate 1995; 68; 91–99 Buttner A, Mall G, Penning R, Weis S. The neuroapathology of heroin abuse. Forensci Sci Int 2000; 113: 435–442 Cone EJ. Pharmacokinetics and pharmacodynamics of cocaine. J Anal Toxicol 1995; 19: 459–478 Cuellar ML. Drug-induced vasculitis. Curr Rheumatol Rep 2002; 4: 55–59 De Smet PA. A multidisciplinary overview of intoxicating snuff rituals in the western hemisphere. J Ethnopharmacol 1985; 13: 3–49 Fowler JS,Volkow ND,Wang GJ, Gatley SJ, Logan J. Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy. Nucl Med Biol 2001; 28: 561–572 Gradon JD, Wityk R. Diagnosis of probable cocaine-induced cerebral vasculitis by magnetic resonance angiography. South Med J 1995; 88: 1264–1266 He GQ, Zhang A, Altura BT, Altura BM. Cocaine-induced cerebrovasospasm and its possible mechanisms of action. J Pharmacol Exp Ther 1994; 268: 1532–1539 Heesch CM,Wilhelm CR, Ristch J, Adnane J, Bontempo FA,Wagner WR. Cocaine activates platelets and increases the formation of circulating platelet containing microagregates in humans. Heart 2000; 83: 688–695 Kaye BR, Fainstat M. Cerebral vasculitis associated with cocaine abuse. JAMA 1987; 258: 2104–2106 Lau CE, Iman A, Ma F, Falk JL. Acute effects of cocaine on spontaneous and discriminative motor functions: relation to route of administration and pharmacokinetics.J Pharmacol Exp Ther 1991; 257: 444–246 Margolis MT, Newton TH. Methamphetamine (“speed”) arteritis. Neuroradiology 1971; 2: 179–182 Martin K, Rogers T, Kavanaugh A. Central nervous system angiopathy associated with cocaine abuse.J Rheumatol 1995; 22: 780–782 McEvoy AW, Kitchen ND, Thomas DG. Intracerebral haemorrhage and drug abuse in young adults.Br J Neurosurg 2000; 14: 449–454 Merkel PA, Koroshetz WJ, Irizarry MC, Cudkowicz ME. Cocaineassociated cerebral vasculitis. Semin Arthritis Rheum 1995; 25: 172 Mockel M, Kampf D, Lobeck H, Frei U. Severe panarteritis associated with drug abuse. Intensive Care Med 1999; 25: 113–117

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Disorders Obstructing the Vascular Lumen Glauser TA, Siegel MJ, Lee BCP, DeBaun MR. Accuracy of neurologic examination and history in detecting evidence of MRI-diagnosed cerebral infarctions in children with sickle cell hemoglobinopathy. J Child Neurol 1995; 10: 88–92 Kenéz J, Barsi P, Majtèniy K, Molnár B, Kocher I, Stangi E, Kolomy S. Can intravascular lymphomatosis mimic thrombosis? A case report with 8 months’ follow-up and fatal outcome. Neuroradiology 2000; 42: 436–440 Martin-Duverneuil N, Mokhtari K, Behin A, Lafitte F, HoangXuan K, Chiras J. Intravascular malignant lymphomatosis. Neuroradiology 2002; 44: 749–754 Miller D, Hochberg F, Harris N, Gruber M, Louis D, Cohen H. Pathology with clinical correlations of primary central nervous system non-Hodgkin lymphoma: the Massachusetts General Hospital experience. Cancer 1994; 74: 1338–1397 Moran CJ, Siegel MJ, DeBaun MR. Sickle cell disease: imaging of cerebrovascular complications. Radiology 1998; 206; 311– 332 Moser FG, Miller ST, Bello JA, Pegelow CH, Zimmerman RA, Wang WC, Ohene-Frempong K, Schwartz A, Vichainsky EP, Gallagher D, Kinney TR. The spectrum of brain MR abnormalities in sickle-cell disease: a report from the cooperative study of sickle cell disease.AJNR Am J Neuroradiol 1996; 17: 965–972 Moussouttas M. Intravascular lymphomatosis presenting as posterior leukoencephalopathy. Arch Neurol 2002; 59: 640–641 Otrakji C,Voight W, Amador A, Gregorius J. Malignant angioendotheliomatosis: a true lymphoma. A case of intravascular lymphomatosis studied by Southern blot hybridization analysis. Hum Pathol 1988; 19: 475–478 Perniciaro C, Winkelmann RK, Daoud MS, Su WP. Malignant angioendotheliomatosis is an angiotropic intravascular lymphoma. Immunohistological, ultrastructural and molecular genetic study. Am J Dermatopathol 1995; 17: 242–248 Steen RG, Emudianughe T, Hankins GM, Wynn LW, Wang WC, Xiong X, Helton KJ. Brain imaging findings in pediatric patients with sickle cell disease. Radiology 2003; 228: 216–225 Steen RG, Miles MA, Helton KJ, Strawn S, Wang W, Xiong XZ, Mulherns RK. Cognitive impairment in children with hemoglobin SS sickle cell disease: relationship to MR imaging findings and hematocrit. AJNR Am J Neuroradiol 2003; 24: 382–389

Strickland-Marmol LB, Fessler RG, Rojiani AM. Necrotizing sarcoid granulomatosis mimicking an intracranial neoplasm: clinicopathologic features and review of the literature.Mod Pathol 2000; 13: 909–913 Tateishi U, Terae S, Ogata A, Sawamura Y, Suzuki Y, Abe S, Miyasaka K. MR imaging of the brain in lymphomatoid granulomatosis.AJNR Am J Neuroradiol 201; 22: 1283–1290 Wang WC, Langstem JW, Steen RG, Wynn LW, Mulhern RK, Williams JA, Kim FM, Figueroa RE. Abnormalities of the central nervous system in very young children with sickle cell anemia. J Pediatr 1998; 132: 994–998

101 Dural Arteriovenous Fistula Awad IA, Little JR, Akarawi WP, Ahl J. Intracranial dural arteriovenous malformations: factors predisposing to an aggressive neurological course. J Neurosurg 1990; 72: 839–850 Borden JA, Wu JK, Shucart WA. A proposed classification for spinal and cranial dural arteriovenous fistulous malformations and implications for treatment. J Neurosurg 1995; 82: 166–179 Brown RD Jr, Wiebers DO, Nichols DA. Intracranial dural arteriovenous fistulae: angiographic predictors of intracranial hemorrhage and clinical outcome in nonsurgical patients. J Neurosurg 1994; 81: 531–538 Cognard C, Gobin YP, Pierot L, Bailly AL, Houdart E, Casasco A, Chiras J, Merland JJ. Cerebral dural arteriovenous fistulas: clinical and angiographic correlation with a revised classification of venous drainage. Radiology 1995; 194: 671–680 Cognard C, Houdart E, Casasco A, Gabrillargues J, Chiras J, Merland JJ. Long-term changes in intracranial dural arteriovenous fistulae leading to worsening in the type of venous drainage. Neuroradiology 1997; 39: 59–66 Collice M, D’Aliberti G,Talamonti G, Branca V, Boccardi E, Scialfa G et al. Surgical interruption of leptomeningeal drainage as treatment for intracranial dural arteriovenous fistulas without dural sinus drainage. J Neurosurg 1996; 84: 810–817 Davies MA, TerBrugge K, Willinsky R, Coyne T, Saleh J, Wallace MC. The validity of classification for the clinical presentation of intracranial dural arteriovenous fistulas. J Neurosurg 1996; 85: 830–837 Davies MA, Saleh J, TerBrugge K, Willinsky R, Wallace MC. The natural history and management of intracranial dural arteriovenous fistulae. Part 1: Benign lesions. Interventional Neuroradiology 1997; 3: 295–302 Davies MA, TerBrugge K, Willinsky R, Wallace MC. The natural history and management of intracranial dural arteriovenous fistulae. Part 2: Aggressive lesions. Interventional Neuroradiology 1997; 3: 303–311 Duffau H, Lopes M, Janosevic V, Sichez JP, Faillot T, Capelle L, Ismail M,Bitar A,Arthuis F,Fohanno D.Early rebleeding from intracranial dural arteriovenous fistulas: report of 20 cases and review of the literature. J Neurosurg 1999; 90: 78–84 Greenough GP, Mamourian A, Harbaugh RE. Venous hypertension asociated with a posterior fossa dural arteriovenous fistula: another cause of bithalamic lesions on MR images. AJNR Am J Neuroradiol 1999; 20: 145–147 Houser OW, Campbell JK, Campbell RJ, Sundt TM. Arteriovenous malformation affecting the transverse dural venous sinus–an acquired lesion. Mayo Clin Proc 1979; 54: 651–661

1056 References and Further Reading Hurst RW, Bagley LJ, Galetta S, Glosser G, Lieberman AP, Trojanowski J, Sinson G, Stecker M, Zager E, Raps EC, Flamm ES. Dementia resulting from dural arteriovenous fistulas: the pathologic findings of venous hypertensive encephalopathy. AJNR Am J Neuroradiol 1998; 19: 1267–1273 Ito M, Sonokawa T, Mishina H, Sato K. Reversible dural arteriovenous malformation-induced venous ischemia as a cause of dementia: treatment by surgical occlusion of draining dural sinus: case report. Neurosurgery 1995; 3: 1187–1191 Jaillard AS, Peres B, Hommel M. Neuropsychological features of dementia due to dural arteriovenous malformation. Cerebrovasc Dis 1999; 9: 91–97 Lasjaunias P,Chiu M,ter Brugge K,Tolia A,Hurth M,Bernstein M. Neurological manifestations of intracranial dural arteriovenous malformations. J Neurosurg 1986; 64: 724–730 Lawton MT, Jacobowitz R, Spetzler RF. Redefined role of angiogenesis in the pathogenesis of dural arteriovenous malformations. J Neurosurg 1997; 8: 267–274 Malik GM, Pearce JE, Ausman JI, Mehta B. Dural arteriovenous malformations and intracranial hemorrhage. Neurosurgery 1984; 15: 332–339 Matsuda S, Waragai M, Shinotoh H, Takahashi N, Takagi K, Hattori T. Intracranial dural arteriovenous fistula presenting progressive dementia and parkinsonism. J Neurol Sci 1999; 165: 43–47 Mironov A. Selective transvenous embolization of dural fistulas without occlusion of the dural sinus. AJNR Am J Neuroradiol 1998; 19: 389–391 Newton TH, Cronqvist S. Involvement of dural arteries in intracranial arteriovenous malformations. Radiology 1969; 93: 1071–1078 Noguchi K, Melhem ER, Kanazawa T, Kubo M, Kuwayama N, Seto H. Intracranial dural arteriovenous fistulas: Evaluation with combined 3D Time-of -Flight MR angiography and MR digital subtraction angiography. AJR Am J Roentgenol 2004; 182: 183–190 Rothbart D, Awad IA, Lee J, Kim J, Harbaugh R, Criscuolo GR. Expression of angiogenic factors and structural proteins in central nervous system vascular malformations. Neurosurgery 1996; 38: 915–924 Satomi J, Van Dijk JM, TerBrugge KG, Willinsky RA, Wallace MC. Benign cranial dural arteriovenous fistulas: outcome of conservative management based on the natural history of the lesion. J Neurosurg 2002; 97: 767–770 Uranishi R, Nakase H, Sakaki T. Expression of angiogenic growth factors in dural arteriovenous fistula. J Neurosurg 1999; 91: 781–786 Van Dijk JM, Willinsky RA. Venous congestive encephalopathy related to cranial dural arteriovenous fistulas. Neuroimaging Clin N Am 2003; 13: 55–72 Van Dijk JM, TerBrugge KG, Willinsky RA, Wallace MC. Multiplicity of dural arteriovenous fistulas. J Neurosurg 2002; 96: 76–78 Van Dijk JM, TerBrugge KG, Willinsky RA, Wallace MC. Clinical course of cranial dural arteriovenous fistulas with longterm persistent cortical venous reflux. Stroke 2002; 33: 1233–1236 Willinsky R, TerBrugge K, Montanera W, Mikulis D, Wallace MC. Venous congestion: an MR finding in dural arteriovenous malformations with cortical venous drainage. AJNR Am J Neuroradiol 1994; 15: 1501–1507

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108 Magnetic Resonance Spectroscopy General Bottomley PA. Human in vivo NMR spectroscopy in diagnostic medicine: clinical tool or research probe? Radiology 1989; 170: 1–15 Brooks WM, Friedman SD, Stidley CA. Reproducibility of 1HMRS in vivo. Magn Reson Med 1999; 41: 193–197 Castillo M, Kwock L, Mukherji SK.Clinical applications of proton MR spectroscopy. AJNR Am J Neuroradiol 1996; 17: 1–15 Cox IJ. Development and applications of in vivo clinical magnetic resonance spectroscopy. Prog Biophys Mol Biol 1996; 65: 45–81 Kreis R. Quantitative localized 1H MR spectroscopy for clinical use. J Progr Nucl Magn Reson Spectr 1997; 31: 155–195 Novotny E, Ashwal S, Shevell M. Proton magnetic resonance spectroscopy: an emerging technology in pediatric neurology research. Pediatr Res 1998; 44: 1–10 Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993; 30: 672–679 Ross B, Bluml, S. Magnetic resonance spectroscopy of the human brain. Anat Rec [New Anat] 2001; 265: 54–84 Simmons A, Smail M, Moore E, Williams SCR. Serial precision of the metabolic peak area rations and water referenced metabolite peak areas in proton MR spectroscopy of the human brain. Magn Reson Imaging 1998; 16: 319–330 Tedeschi G,Bertolino A,Campbell G,Barnett AS,Duyn JH,Jacob PK, Moonen CTW, Alger JR, di Chiro G. Reproducibility of proton MR spectroscopy imaging findings. AJNR Am J Neuroradiol 1996; 17: 1871–1879 Van Zijl PCM, Barker PB. Magnetic resonance spectroscopy and spectroscopic imaging for study of brain metabolism. Ann N Y Acad Sci 1997; 820: 75–96

Normal Age-dependent and Regional Changes Azzopardi D, Wyatt JS, Hamilton PA, Cady EB, Delpy DT, Hope PL, Reynolds EOR. Phosphorus metabolites and intracellular pH in the brains of normal and small for gestational age infants investigated by magnetic resonance spectroscopy. Pediatr Res 1989; 25: 440–444 Blüml S, Seymour KJ, Ross BD. Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled 31P MRS in vivo human brain. Magn Reson Med 1999; 42: 643–654 Buchli R, Boesiger MP, Rumpel H. Developmental changes of phosphorus metabolite concentrations in the human brain: a 31P magnetic resonance spectroscopy study in vivo. Pediatr Res 1994; 35: 431–435 Buchli R, Duc CO, Martin E, Boesiger P. Assessment of absolute metabolite concentrations in human tissue by 31P MRS in vivo. 1. Cerebrum, cerebellum, cerebellar gray and white matter. Magn Reson Med 1994; 32: 447–452 Filippi CG, Ulug˘ AM, Deck MDF, Zimmerman RD, Heier LA. Developmental delay in children: assessment with proton MR spectroscopy. AJNR Am J Neuroradiol 2002; 23: 882–888 Hanaoka S,Takashima S,Morooka K.Study of the maturation of the child’s brain using 31P-MRS. Pediatr Neurol 1998; 18: 305–310

Horská A, Kaufmann WE, Brant LJ, Naidu S, Harris JC, Barker PB. In vivo quantitative proton MRSI study of brain development from childhood to adolescence. J Magn Reson Imaging 2002; 15: 137–143 Hüppi PS, Fusch C, Boesch C, Burri R, Bossi E, Amato M, Herschkowitz N. Regional metabolic assessment of human brain during development by proton magnetic resonance spectroscopy in vivo and high-performance liquid chromatography/gas chromatography in autopsy tissue. Pediatr Res 1995; 37: 145–150 Jacobs MA, Horská A, van Zijl PCM, Barker PB. Quantitative proton MR spectroscopy imaging of normal human cerebellum and brain stem. Magn Reson Med 2001; 46: 699–705 Kok RD, van den Berg PP, van den Bergh AJ, Nijland R, Heerschap A. Maturation of the human fetal brain as observed by 1H MR spectroscopy. Magn Reson Med 2002; 48: 611–616 Kreis R, Ernst T, Ross BD.Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn Reson Med 1993; 30: 424–437 Kreis R, Hofmann L, Kuhlmann B, Boesch C, Bossi E, Hüppi PS. Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 2002; 48: 949–958 Lam WWM, Wang ZJ, Zhao H, Berry GT, Kaplan P, Gibson J, Kaplan BS, Bilaniuk LT, Hunter JV, Haselgrove JC, Zimmermann RA. 1H MR Spectroscopy of the basal ganglia in childhood:a semiquantitative analysis.Neuroradiology 1998; 40: 315–323 Mader I, Seeger U, Karitzky J, Erb M, Schick F, Klose U. Proton magnetic resonance spectroscopy with metabolite nulling reveals regional differences of macromolecules in normal human brain. J Magn Reson Imaging 2002; 16: 538–546 Mascalchi M, Burgnoli R, Guerrini L, Belli G, Nistri M, Politi LS, Gavazzi C, Lolli F, Argenti G, Villari N. Single-voxel long TE 1 H-MR spectroscopy of the normal brainstem and cerebellum. J Magn Reson Imaging 2002; 16: 532–537 McLean MA,Woermann FG, Barker GJ, Duncan JS. Quantitative analysis of short echo time 1H-MRSI of cerebellar gray and white matter. Magn Reson Med 2000; 44: 401–411 Nakada T, Kwee IL. 31P localized spectroscopy of fetal brain in utero. Magn Reson Med 1993; 29: 122–124 Pouwels PJW, Frahm J. Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med 1998; 39: 53–60 Pouwels PJW,Brockmann K,Kruse B,Wilken B,Wick M,Hanefeld F, Frahm J. Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS. Pediatr Res 1999; 46: 474–485 Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993; 30: 672–679 Tedeschi G, Bertolino A, Righini A, Campbell G, Raman R, Duyn JH, Moonen CTW, Alger JR, di Chiro G. Brain regional distribution pattern of metabolite signal intensities in young adults by proton magnetic resonance spectroscopy imaging. Neurology 1995; 45: 1384–1391 Toft PB, Leth H, Lou HC, Pryds O, Henriksen O. Metabolite concentrations in the developing brain estimated with proton MR spectroscopy. J Magn Reson Imaging 1994; 4: 674–680

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van der Knaap MS,van der Grond J,van Rijen PC,Faber JAJ,Valk J, Willemse K. Age-dependent changes in localized proton and phosphorus MR spectroscopy of the brain. Radiology 1990; 176: 509–515 Vigneron DB,Barkovich AJ, Noworolski SM, von dem Busche M, Henry RG, Lu Y, Partridge JC, Gregory G, Ferriero DM. Threedimensional proton MR spectroscopic imaging of premature and term neonates. AJNR Am J Neuroradiol 2001; 22: 1424–1433

Metabolites: General Bhakoo KK, Williams IT, Williams SR, Gadian DG, Noble MD. Proton nuclear magnetic resonance spectroscopy of primary cells derived from nervous tissue. J Neurochem 1996; 66: 1254–1263 Govindaraju V, Young K, Mandsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 2000; 13: 129–153 Michaelis T, Merboldt KD, Hänicke W, Gyngell ML, Bruhn H, Frahm J. On the identification of cerebral metabolites in localized 1H NMR spectra of human brain in vivo. NMR Biomed 1991; 4: 90–98 Urenjak J, Williams SR, Gadian DG, Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981–989

Phosphomonoester / Phosphodiester Daly PF, Lyon RC, Faustino PJ, Cohen JS. Phospholipid metabolism in cancer cells monitored by 31P NMR spectroscopy. J Biol Chem 1987; 262: 14875–14878 Dawson RMC. Enzymic pathways of phospholipid metabolism in the nervous system. In: Eichberg J, ed. Phospholipids in nervous tissues. New York: Wiley, 1985, pp 45–78 Gyulai L, Bolinger L, Leigh JS Jr, Barlow C, Chance B. Phosphorylethanolamine – the major constituent of the phosphomonoester peak observed by 31P-NMR on developing dog brain. FEBS Lett 1984; 178: 137–142 Kilby PM, Bolas NM, Radda GK. 31P-NMR study of brain phospholipid structures in vivo. Biochim Biophys Acta 1991; 1085: 257–264 McNamara R, Arias-Mendoza F, Brown TR. Investigation of broad resonances in 31P NMR spectra of the human brain in vivo. NMR Biomed 1994; 7: 237–242 Murphy EJ, Rajagopalan B, Brindle KM, Radda GK. Phospholipid bilayer contribution to 31P NMR spectra in vivo. Magn Reson Med 1989; 12: 282–289 Porcellati G, Arienti G. Metabolism of phosphoglycerides. In: Lajtha A, ed. Handbook of neurochemistry, vol 3: Metabolism in the nervous system. New York, Plenum Press: 1983, pp 133–161 Stanley JA, Pettegrew JW. Postprocessing method to segregate and quantify the broad components underlying the phosphodiester spectral region of in vivo 31 P brain spectra. Magn Reson Med 2001; 45: 390–396 Sun GY, Foudin LL. Phospholipid composition and metabolism in the developing and aging nervous system. In: Eichberg J, ed. Phospholipids in nervous tissues. New York:Wiley, 1985, pp 79–134 Van der Grond J, Dijkstra G, Roelofsen B, Mali WPTM. 31P-NMR determination of phosphomonoesters in relation to phospholipid biosynthesis in testis of the rat at different ages. Biochim Biophys Acta 1991; 1074: 189–194

pH Madden A, Leach MO, Sharp JC, Collins DJ, Easton D. A quantitative analysis of the accuracy of in vivo pH measurements with 31P NMR spectroscopy: assessment of pH measurement methodology. NMR Biomed 1991; 4: 1–11 Moon RB, Richards JH. Determination of intracellular pH by 31P magnetic resonance. J Biol Chem 1973; 248: 7276–7278 Petroff OAC, Prichard JW, Behar KL, Alger JR, den Hollander JA, Shulman RG. Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy. Neurology 1985; 35: 781– 788 Pettegrew JW, Withers G, Panchalingham K, Post JFM. Considerations for brain pH assessment by 31P NMR. Magn Reson Imaging 1988; 6: 135–142

N-Acetylaspartate Baslow MH. Functions of N-acetyl-l-aspartate and N-acetyl-laspartylglutamate in the vertebrate brain: role in glial cellspecific signaling. J Neurochem 2000; 75: 453–459 Baslow MH. N-Acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 2003; 28: 941–953 Bates TE, Strangward M, Keelan J, Davey GP, Munro PMG, Clark JB. Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. Neuroreport 1996; 7: 1397–1400 Bhakoo KK, Pearce D. In vitro expression of N-acetyl aspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 2000; 74: 254–262 Birken DL, Oldendorf WH. N-acetyl-L-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of brain. Neurosci Biobehav Rev 1989; 13: 23–31 Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD. N-Acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol 2002; 51: 51–58 Block W, Träber, Flacke S, Jessen F, Pohl C, Schild H. In-vivo proton MR-spectroscopy of the human brain: assessment of Nacetylaspartate (NAA) reduction as a marker for neurodegeneration. Amino Acids 2002; 23: 317–323 Chakrabourty G, Mekala P,Yahya D,Wu G, Ledeen RW. Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 2001; 78: 736–745 De Stefano N,Matthews PM,Arnold DL.Reversible decreases in N-acetylaspartate after acute brain injury.Magn Reson Med 1995; 34: 721–727 Gasparovic C, Arfai N, Smid N, Feeney DM. Decrease and recovery of N-acetylaspartate/creatine in rat brain remote from focal injury. J Neurotrauma 2001; 18: 241–246 Patel TB, Clark JB. Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. Biochem J 1979; 184: 539–546 Pouwels PJW, Frahm J. Differential distribution of NAA and NAAG in human brain as determined by quantitative localized proton MRS. NMR Biomed 1997; 10: 73–78 Tallan HH, Moore S, Stein WH. N-Acetyl-l aspartic acid in brain. J Biol Chem 1956; 219: 257–264 Taylor DL,Davies SEC,Obrenovitch TP,Doheny MH,Patsalos PN, Clark JB, Symon L. Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 1995; 65: 275–281

1066 References and Further Reading Urenjak J,Williams SR, Gadian DG, Noble M. Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992; 59: 55–61

Creatine Chance B, Leigh JS Jr, Clark BJ, Maris J, Kent J, Nioka S, Smith D. Control of oxidative metabolism and oxygen delivery in human skeletal muscle: a steady-state analysis of the work/energy cost transfer function. Proc Natl Acad Sci 1985; 82: 8384–8388 Dringen R, Verleysdonk S, Hamprecht B, Willker W, Leibfritz D, Brand A. Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine and glutathione. J Neurochem 1998; 70: 835–840 Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000; 80: 1107–1213

Choline Gupta RK, Cloughesy TF, Sinha U, Garakian J, Lazareff J, Rubino G, Rubino L, Becker DP, Vinters HV, Alger JR. Relationships between choline magnetic resonance spectroscopy,apparent diffusion coefficient an quantitative histopathology in human glioma. J Neurooncol 2000; 50: 215–226 Miller BL. A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatine and choline. NMR Biomed 1991; 4: 47–52 Miller BL, Chang L, Booth R, Ernst T, Conford M, Nikas D, McBride D, Jenden DJ. In vivo 1H MRS choline: correlation with in vivo chemistry/histiology. Life Sci 1996; 58:1929–1935

Myo-inositol Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993; 15: 289–298 Glanville NT, Byers DM. Differences in the metabolism of inositol. Biochim Biophys Acta 1989; 104: 169–179 Häussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, Gerok W, Hennig J. Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 1994; 107: 1475–1480 Lee JH, Arginue E, Ross BD. Brief report: organic osmolytes in the brain of an infant with hypernatremia. N Engl J Med 1994; 331: 439–442 Michaelis T, Helms G, Merboldt KD, Hänicke W, Bruhn H, Frahm J. Identification of scyllo-inositol in proton NMR spectra of human brain in vivo. NMR Biomed 1993; 6: 105–109 Ross BD.Biochemical considerations in 1H spectroscopy.Glutamate and glutamine; myo-inositol and related metabolites. NMR Biomed 1991; 4: 59–63 Rumpel H, Lim WEH, Chang HM, Chan LL, Ho GL,Wong MC,Tan KP. Is myo-inositol a measure of glial swelling after stroke? A magnetic resonance study. J Magn Reson Imaging 2003; 17: 11–19 Seaquist ER, Gruetter R. Identification of a high concentration of scyllo-inositol in the brain of a healthy human subject using 1H- and 13C-NMR. Magn Reson Med 1998; 39: 313–316

Shonk T, Ross BD. Role of increased cerebral myo-inositol in the dementia of Down syndrome. Magn Reson Med 1995; 33: 858–861 Videen JS, Michaelis T, Pinto P, Ross BD. Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 1995; 95: 788–793

Lactate López-Villegas D, Lenkinski RE, Wehrli SL, Ho W-Z, Douglas SD. Lactate production by human monocytes / macrophages determined by proton MR spectroscopy. Magn Reson Med 1995; 34: 32–38 Petroff OAC, Graham GD, Blamire AM, Al-Rayess M, Rothman DL, Fayad PB, Brass LM, Shulman RG, Prichard JW. Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes. Neurology 1992; 42: 1349–1354 Prichard JW. What the clinician can learn from MRS lactate measurements. NMR Biomed 1991; 4: 99–102 Veech RL. The metabolism of lactate. NMR Biomed 1991; 4: 53–58

Glucose Gruetter R, Rothman DL, Novotny EJ, Shulman GI, Prichard JW, Shulman RG. Detection and assignment of the glucose signal in 1H NMR difference spectra of the human brain. Magn Reson Med 1992; 27: 183–188 Gruetter R, Novotny EJ, Boulware SD, Rothman DL, Shulman RG. 1H NMR Studies of glucose transport in the human brain. J Cereb Blood Flow Metab 1996; 16: 427–438 Rothman DL. Studies of metabolic compartmention and glucose transport using in vivo MRS. NMR Biomed 2001; 14: 149–160

Glutamine / Glutamate / GABA Chamuleau RAFM, Bosman DK, Bové WMMJ, Luyten PR, den Hollander JA. What the clinician can learn from MR glutamine/glutamate assays. NMR Biomed 1991; 4: 103–108 Govindaraju V, Basus VJ, Matson GB, Maudsley AA. Measurement of chemical shifts and coupling constants for glutamate and glutamine. Magn Reson Med 1998; 39: 1011– 1013 Keltner JR,Wald LL, Frederick BB, Renshaw PF. In vivo detection of GABA in human brain using a localized double-quantum filter technique. Magn Reson Med 1997; 37: 366–371 Ross BD.Biochemical considerations in 1H spectroscopy.Glutamate and glutamine; myo-inositol and related metabolites. NMR Biomed 1991; 4: 59–63 Rothman DL, Hanstock CC, Petroff OAC, Novotny EJ, Prichard JW, Shulman RG. Localized 1H NMR spectra of glutamate in the human brain. Magn Reson Med 1992; 25: 94–106 Sonnewald U, Westergaard N, Schousboe A, Svendsen JS, Unsgard G, Peterson SB. Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem Int 1993; 22:19–29 Sonnewald U, Westergaard N, Shousboe A. Glutamate transport and metabolites in astrocytes. Glia 1997; 21: 56–63

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Taurine Hardy DL, Norwood TJ. Spectral editing technique for the in vitro and in vivo detection of taurine. Nucl Magn Reson 1998; 133: 70–78 Trenkner E, Sturman JA. The role of taurine in the survival and function of cerebral cells in cultures of early postnatal cat. Int J Dev Neurosci 1991; 9: 77–88

Neuronal Degeneration Block W, Karitzky J, Träber F, Pohl C, Keller E, Mundegar R, Lamerichs R, Rink H, Ries F, Schild HH, Jerusalem F. Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease. Arch Neurol 1998; 55: 931–936 Brockmann K, Pouwels PJW, Christen H-J, Frahm J, Hanefeld F. Localized proton magnetic resonance spectroscopy of cerebral metabolic disturbances in children with neuronal ceroid lipofuscinosis. Neuropediatrics 1996; 27: 242–248 Chan S, Shungu DC, Douglas-Akinwande A, Lange DJ, Rowland LP. Motor neuron diseases: comparison of single-voxel proton MR spectroscopy of the motor cortex with MR imaging of the brain. Radiology 1999; 212: 763–769 Ellis CM, Simmons A, Andrews C, Dawson JM, Williams SCR, Leigh PN. A proton magnetic resonance spectroscopy study in ALS. Correlation with clinical findings. Neurology 1998; 51: 1104–1109 Frederico F, Simone IL, Lucivero V, de Mari M, Gianinni P, Iliceto G, Mezzapesa DM, Lamberti P. Proton magnetic resonance spectroscopy in Parkinson’s disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1997; 62: 239–242 Miyazaki M, Hashimoto T, Yonada Y, Tayama M, Harada M, Miyoshi H, Kawano N, Murayama N, Kondo I, Kuroda Y. Proton magnetic resonance spectroscopy on childhood-onset dentatorubral-pallidoluysian atrophy (DRPLA). Brain Dev 1996; 18: 142–146 Rooney WD, Miller RG, Gelinas D, Schuff N, Maudsley AA, Weiner MW. Decreased N-acetylaspartate in motor cortex and corticospinal tract in ALS. Neurology 1998; 50: 1800–1805 Tedeschi G,Bertolini A,Massaquoi SG,Campbell G,Patronas NJ, Bonavita S, Barnett AS, Alger JR, Hallett M. Proton magnetic resonance spectroscopic imaging in patients with cerebellar degeneration. Ann Neurol 1996; 39: 71–78 Tedeschi G, Litvan I, Bonavita S, Bertolini A, Lundbom N, Patronas NJ, Hallett M. Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson’s disease and corticobasal degeneration. Brain 1997; 120: 1541–1552 Tedeschi G, Bonavita S, Barton NW, Bertolino A, Frank JA, Patronas NJ, Alger JR, Shiffmann R. Proton magnetic resonance spectroscopic imaging in the clinical evaluation of patients with Niemann-Pick type C disease. J Neurol Neurosurg Psychiatry 1998; 65: 72–79

Demyelinination Brockmann K, Dechent P, Wilken B, Rusch O, Frahm J, Hanefeld F.Proton MRS profile of cerebral metabolic abnormalities in Krabbe disease. Neurology 2003; 60: 819–825

Degaonkar MN, Khubchandihani M, Dhawan JK, Jayasundar R, Jagannathan NR. Sequential proton MRS study of brain metabolite changes monitored during a complete pathological cycle of demyelination and remyelination in a lysophosphatidyl choline (LPC)-induced experimental demyelinating lesion model. MNR Biomed 2002; 15: 293–300 Farina L, Bizzi A, Finocchiaro G, Pareyson D, Sghirlanzoni A, Bertagnolio B, Savaoirdo M, Naidu SB, Singhal BS, Wenger DA. MR imaging and proton MR spectroscopy in adult Krabbe disease. AJNR Am J Neuroradiol 2000; 21: 1478– 1482 Kruse B, Hanefeld F, Christen HJ, Bruhn H, Michaelis T, Hänicke W, Frahm J. Alterations of brain metabolites in metachromatic leukodystrophy as detected by localized proton magnetic resonance spectroscopy in vivo. J Neurol 1993; 241: 68–74 Silver NC, Barker RA, MacManus DG, Barker GJ, Thom M, Thomas DGT, McDonald WI, Miller DH. Proton magnetic resonance spectroscopy in a pathologically confirmed acute demyelinating lesion. J Neurol 1997; 244: 204–207 van der Knaap MS, van der Grond J, Luyten PR, den Hollander JA, Nauta JJP, Valk J. 1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders. Ann Neurol 1992; 31: 202–211

Hypomyelination Bonavita S, Schiffmann R, Moore DF, Free K, Choi B, Patronas N, Virta A, Boespflüg-Tanguy O, Tedeschi G. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology 2001; 56: 785–788 Gebern JY,Yook DA,Moore GJ,Wilds IB,Faulk MW,Klugmann M, Nave K-A, Sistermans ES, van der Knaap MS, Bird TD, Shy ME, Kamholz JA, Griffiths IR. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002; 125: 551–561 Pizzini F, Fatemi AS, Barker PB, Nagae-Poetscher LM, Horská A, Zimmerman AW, Moser HW, Bibat G, Naidu S. Proton MR spectroscopic imaging in Pelizaeus-Merzbacher disease. AJNR Am J Neuroradiol 2003; 24: 1683–1689 Plecko B, Stöckler-Ipsirolglu S, Gruber S, Mlynarik V, Moser E, Simbrunner J, Ebner F, Bernert G, Harrer G, Gal A, Prayer D. Degree of hypomyelination and magnetic resonance spectroscopy findings in patient with Pelizaeus Merzbacher phenotype. Neuropediatrics 2003; 34: 127–136 Spalice A, Popolizio T, Parisi P, Scarabino T, Iannetti P. Proton MR spectroscopy in connatal Pelizaeus-Merzbacher disease. Pediatr Radiol 2000; 30: 171–175 Takanashi J, Inoue K, Tomita M, Kurihara A, Morita F, Ikehira H, Tanada S, Yoshitome E, Kohno Y. Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication. Neurology 2002; 58: 237–241 van der Knaap MS, Naidu S, Pouwels PJ, Bonavita S, van Coster R, Lagae L, Sperner J, Surtees R, Schiffmann R, Valk J. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol 2002; 23: 1466–1474

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Cystic White Matter Degeneration Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen H-J, Frahm J. Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993; 24: 244–248 Salvan A-M, Chabrol B, Lamoureux S, Confort-Gouny S, Cozzone PJ, Vion-Dury J. In vivo brain proton MR spectroscopy in a case of molybdenum cofactor deficiency. Pediatr Radiol 1999; 29: 846–848 Schiffmann R, Moller JR, Trapp BD, Shih HH-L, Farrer RG, Katz DA, Alger JR, Parker CC, Hauer PE, Kaneski CR, Heiss JD, Kaye EM, Quarles RH, Brady RO, Barton NW. Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994; 35: 331–340 Tedeschi G, Schiffmann R, Barton NW, Shih HH-L, Gospe SM Jr, Brady RO, Alger JR, di Chiro G. Proton magnetic resonance spectroscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination. Neurology 1995; 45: 1526–1532 van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E,Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998; 51: 540–547 van der Knaap MS, Barth PG, Gabreëls FJM, Franzoni E, Begeer JH, Stroink H, Rotteveel JJ, Valk J. A new leukoencephalopathy with vanishing white matter. Neurology 1997; 48: 845–855

Hyperammonemia Chol C-G,Yoo HW.Localized proton MR spectroscopy in infants with urea cycle defect. AJNR Am J Neuroradiol 2001; 22: 834–837 Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 1993; 33: 77–81 Haseler LJ, Sibbitt WL Jr, Mojtahezadeh HN, Reddy S, Aragwal VP, McCarthy DM. Proton MR spectroscopic measurement of neurometabolites in hepatic encephalopathy during oral lactulose therapy. AJNR Am J Neuroradiol 1998; 19: 1681–1686 Kraft E, Trenkwalder C, Bergh FT, Auer DP. Magnetic resonance proton spectroscopy of the brain in Wilson’s disease. J Neurol 1999; 246: 693–699 Kreis R, Farrow N, Ross BD. Localized 1H NMR spectroscopy in patients with chronic hepatic encephalopathy. Analysis of changes in cerebral glutamine, choline and inositols. NMR Biomed 1991; 4: 109–116 Kreis R,Ross BD,Farrow NA,Ackerman Z.Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy. Radiology 1992; 182: 19–27 Laubenberger J, Häussinger D, Bayer S, Gufler H, Hennig J, Langer M. Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology 1997; 112; 1610–1616 Lien YHH, Michaelis T, Moats RA, Ross BD. Scyllo-inositol depletion in hepatic encephalopathy. Life Sci 1994; 54: 1507– 1512

Naegele T,Grodd W,Viebahn R,Seeger U,Klose U,Seitz D,Kaiser S, Mader I, Mayer J, Lauchart W, Gregor M, Voight K. MR imaging and 1H spectroscopy of brain metabolites in hepatic encephalopathy: time course of renormalization after liver transplantation. Radiology 2000; 216: 683–691 Ross BD, Jacobson S,Villamil F, Korula J, Kreis R, Ernst T, Shonk T, Moats RA. Subclinical hepatic encephalopathy proton MR spectroscopic abnormalities. Radiology 1994; 193: 457–463 Van den Heuvel AG, van der Grond J, van Rooij LG, van Wassenaer-van Hall HN, Hoogenraad TU, Mali WPTM. Differential between portal-systemic encephalopathy and neurodegenerative disorders in patients in Wilson disease: H-1 MR spectroscopy. Radiology 1997; 203: 539–543

Osmolytes Davies SEC, Gotoh M, Richards DA, Obrenovitch TP. Hypoosmolarity induces an increase of extracellular N-acetylaspartate concentration in the rat striatum. Neurchem Res 1998; 23: 1021–1025 Heilig CW, Stromski ME, Blumenfeld JD, Lee JP, Gullans SR. Characterization of the major brain osmolytes that accumulate in salt-loaded rats. Am J Physiol 1989; 257: F1108–F1116 Lee JH, Arcinue E, Ross BD. Organic osmolytes in the brain of an infant with hypernatremia. N Engl J Med 1994; 331: 439–442 Lien Y-H H, Shapiro JI, Chan L. Study of brain electrolytes and organic osmolites during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis. J Clin Invest 1991; 88: 303–309 Strange K, Emma F, Paredes A, Morrison R. Osmoregulatory changes in myo-inositol content and Na+ / myo-inositol cotransport in rat cortical astrocytes. Glia 1994; 12: 35–43 Videen JS, Michaelis T, Pinto R, Ross BD. Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 1995; 95: 788–793

Perinatal Hypoxia–Ischemia Azzopardi D, Wyatt JS, Cady EB, Delphy DT, Baudin J, Stewart AL, Hope PL, Hamilton PA, Reynolds EOR. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 1989; 25: 445–451 Groenendaal F, Veenhoven RH, van der Grond J, Jansen GH, Witkamp TD, de Vries LS. Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy. Pediatr Res 1994; 35: 148–151 Groenendaal F, van der Grond J, Witkamp TD, de Vries LS. Proton magnetic resonance spectroscopic imaging in neonatal stroke. Neuropediatrics 1995; 26: 243–248 Groenendaal F, van der Grond J, Eken P, van Haastert IC, Rademaker KJ, Toet MC, de Vries LS. Early cerebral proton MRS and neurodevelopmental outcome in infants with cystic leukomalacia. Dev Med Child Neurol 1997; 39: 373–379 Hanrahan JD, Sargentoni J, Azzopardi D, Manji K, Cowan FM, Rutherford MA, Cox IJ, Bell JD, Bryant DJ, Edwards AD. Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopic study. Pediatr Res 1996; 39: 584–590

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Hanrahan JD, Cox IJ, Edwards AD, Cowan FM, Sargentoni J, Bell JD, Bryant DJ, Rutherford MA. Persistent increases in cerbral lactate concentration after birth asphyxia.Pediatr Res 1998; 44: 304–311 Hanrahan JD, Cox IJ, Azzopardi D, Ocwan FM, Sargentoni J, Bell JD, Bryant DJ, Edwards AD. Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age. Dev Med Child Neurol 1999; 41: 76–82 Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, Peebles D,Weylezinska M, Owen-Reece H, Kirkbridge V, Cooper CE, Aldridge RF, Roth SC, Brown G, Delpy DT, Reynolds EOR. Delayed (“secondary”) cerebral energy failure after acute hypoxia–ischemia in the newborn piglet: continuous 48hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 1994; 36: 699–706 Martin E, Buchli R, Ritter S, Schmid R, Largo RH, Boltshauser E, Fanconi S, Duc G, Rumpel H. Diagnostic and prognostic value of cerebral 31P magnetic resonance spectroscopy in neonates with perinatal asphyxia. Pediatr Res 1996; 40: 749–758 Moorcraft J, Bolas NM, Ives NK, Ouwerkerk R, Smyth J, Rajagopalan B, Hope PL, Radda GK. Global and depth resolved phosphorus magnetic resonance spectroscopy to predict outcome after birth asphyxia. Arch Dis Child 1991; 66: 1119–1123 Moorcraft J, Bolas NM, Ives NK, Sutton P, Blackledge MJ, Rajagopalan B, Hope PL, Radda GK. Spatially localized magnetic resonance spectroscopy of the brains of normal and asphyxiated newborns. Pediatrics 1991; 87: 273–282 Penrice J, Lorek A, Cady EB, Amess PN,Wylezinski M, Cooper CE, D’Souza P, Brown GC, Kirkbride V, Edwards AD, Wyatt JS, Reynolds EOR. Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet. Pediatr Res 1997; 41: 795–802 Robertson NJ, Lewis RH, Cowan FM, Allsop JM, Counsell SJ, Edwards AD, Cox IJ. Early increases in brain myo-inositol measured by proton magnetic resonance spectroscopy in term infants with neonatal encephalopathy.Pediatr Res 2001;50: 692–700 Roth SC, Azzopardi D, Edwards AD, Baudin J, Cady EB, Townsend J, Delpy DT, Stewart AL, Wyatt JS, Osmund E, Reynolds R. Relation between cerebral oxidative metabolism following birth asphyxia, and neurodevelopmental outcome and brain growth at one year.Dev Med Child Neurol 1992; 34: 285–295 Roth SC, Baudin J, Cady E, Johal K, Towsend JP, Wyatt JS, Reynolds EOR, Stewart AL. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years.Dev Med Child Neurol 1997; 39: 708–725

Chronic Hypoxia–Ischemia Auer DP, Schirmer T, Heidenreich JO, Herzog J, Pütz B, Dichans M. Altered white and gray matter metabolism in CADASIL. A proton MR spectroscopy and 1H-MRSI study. Neurology 2001; 56: 635–642 Brooks WM, Wesley MH, Kodituwakku PW, Garry PJ, Rosenberg GA. 1H-MRS Differentiates white matter hyperintensities in subcortical arteriosclerotic encephalopathy from those in normal elderly. Stroke 1997; 28: 1940–1943

Capizzano AA, Schuff N, Armend DL, Tanabe JL, Norman D, Maudsley AA, Jagust W, Chui HC, Fein G, Segal MR, Weiner MW. Subcortical ischemic vascular dementia: assessment with quantitative MR imaging and 1H MR spectroscopy. AJNR Am J Neuroradiol 2000; 21: 621–630 Oppenheimer SM, Bryan RN, Conturo TE, Soher BJ, Preziosi TJ, Barker PB. Proton magnetic resonance spectroscopy and gadolinium-DTPA perfusion imaging of asymptomatic MRI white matter lesions. Magn Reson Med 1995; 33: 61–68 Van der Grond J, Ramos LMP, Eikelboom BC, Mali WPTM. Cerebral metabolic differences between the severe and critical hypoperfused brain. Neurology 1996; 47: 399–404

Mitochondrial Defects Barbiroli B, Montagna P, Martinelli P, Lodi R, Iotti S, Cortelli P, Funicello R, Zaniol P. Defective brain energy metabolism shown by in vivo 31P MR spectroscopy in 28 patients with mitochondrial cytopathies. J Cereb Blood Flow Metab 1993; 13: 469–474 Barbiroli B, Montagna P, Cortelli P, Lotti S, Lod R, Barboni P, Monari L, Laguresi E, Frassineti C, Zaniol P. Defective brain and muscle energy metabolism shown by in vivo 31P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation. Neurology 1995; 45: 1364–1369 Bianchi MC,Tosetti M, Battini R, Manca ML, Mancuso M, Cioni G, Canapicchi R, Siciliano G. Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. AJNR Am J Neuroradiol 2003; 24: 1958–1966 Cross JH, Gadian DG, Connelly A, Leonard JV. Proton magnetic resonance spectroscopy studies in lactic acidosis and mitochondrial disorders. J Inherit Metab Dis 1993; 16: 800–811 Detre JA, Wang Z, Bogdan AR, Gusnard DA, Bay CA, Bingham PM, Zimmerman RA. Regional variation in brain lactate in Leigh syndrome by localized 1H magnetic resonance spectroscopy. Ann Neurol 1991; 29: 218–221 Eleff SM, Barker PB, Blackband SJ, Chatham JC, Lutz NW, Johns DR, Bryan RN, Hurko O. Phosphorus magnetic resonance spectroscopy of patients with mitochondrial cytopathies demonstrates decreased levels of brain phosphocreatine. Ann Neurol 1990; 27: 626–630 Herzberg NH, van Schooneveld MJ, Bleeker-Wagemakers E, Zwart R, Cremers FPM, van der Knaap MS, Bolhuis PA, de Visser M. Kearns-Sayre syndrome with a phenocopy of choroideremia instead of pigmentary retinopathy. Neurology 1993; 43: 218–221 Kamada K, Takeuchi F, Houkin K, Kitagawa M, Kuriki S, Ogata A, Tashiro K, Koyanagi I, Mitsumori K, Iwasaki Y. Reversible brain dysfunction in MELAS: MEG and 1H MRS analysis. J Neurol Neurosurg Psychiatry 2001; 70: 675–678 Krägeloh-Mann I, Grodd W, Niemann G, Haas G, Ruitenbeek W. Assessment and therapy monitoring of Leigh disease by MRI and proton spectroscopy.Pediatr Neurol 1992; 8:60–64 Krägeloh-Mann I, Grodd W, Schöning M, Marquard K, Nägele T, Ruitenbeek W. Proton spectroscopy in five patients with Leigh’s disease and mitochondrial enzyme deficiency. Dev Med Child Neurol 1993; 35: 769–776 Lin DDM, Crawford TO, Barker PB. Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. AJNR Am J Neuroradiol 2003; 24: 33–41

1070 References and Further Reading Lodi R, Montagna Pk Iotti S, Zaniol P, Barboni P, Puddu P, Barbioli B. Brain and muscle energy metabolism studied in vivo by 31P-magnetic resonance spectroscopy in NARP syndrome. J Neurol Neurosurg Psychiatry 1994; 57: 1492–1496 Matthews PM, Andermann F, Silver K, Karpati G, Arnold DL. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology 1993; 43: 2484–2490 Pavlakis SG, Kingsley PB, Kaplan GP, Stacpoole PW, O’Shea M, Lustbader D. Magnetic resonance spectroscopy. Use in monitoring MELAS treatment. Arch Neurol 1998; 55: 849–852 Rubio-Gozalbo ME, Heerschap A, Trijbels JMF, de Meirleir L, Thijssen HOM, Smeitink JAM. Proton MR spectroscopy in a child with pyruvate dehydrogenase complex deficiency. Magn Reson Imaging 1999; 17: 939–944 Shevell MI,Matthews PM,Scriver CR,Brown RM,Otero LJ,Legris ML, Brown GK, Arnold DL. Cerebral dysgenesis and lactate acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol 1994; 11: 224–229 Takahashi S, Oki J, Miyamoto A, Okuno A. Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome. Brain Dev 1999; 21: 200–204 Wilichowski E, Pouwels PJW, Frahm J, Hanefeld F. Quantitative proton magnetic resonance spectroscopy in patients with MELAS. Neuropediatrics 1999; 30: 256–263 Zand DJ, Simon EM, Pulitzer SB, Wang DJ, Wang ZJ, Rorke LB, Palmieri M, Berry GT. In vivo pyruvate detected by MR spectroscopy in neonatal pyruvate dehydrogenase deficiency. AJNR Am J Neuroradiol 2003; 24: 1471–1474

Tracey I, Carr CA, Guimareas AR, Worth JL, Navia BA, González RG. Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: a proton magnetic resonance spectroscopic study. Neurology 1996; 46: 783–788

Canavan Disease Austin SJ,Connelly A,Gadian DG,Benton JS,Brett EM.Localized 1H NMR spectroscopy in Canavan’s disease: a report of two cases. Magn Reson Med 1991; 19: 439–445 Barker PB, Bryan RN, Kumar AJ, Naidu S. Proton NMR spectroscopy of Canavan’s disease. Neuropediatrics 1992; 23: 263–267 Marks HG, Caro PA, Wang Z, Detre JA, Bogdan AR, Gusnard DA, Zimmerman RA. Use of computed tomography, magnetic resonance imaging, and localized 1H magnetic resonance spectroscopy in Canavan’s disease: a case report. Ann Neurol 1991; 30: 106–110 Wittsack H-J,Kugel H,Roth B,Heindel W.Quantitative measurements with localized 1H MR spectroscopy in children with Canavan’s disease. J Magn Reson Imaging 1996; 6: 889–893

NAA Synthesis Defect Barker PB. N-Acetyl aspartate – a neuronal marker? Ann Neurol 2001; 49: 423–424 Martin E, Capone A, Schneider J, Hennig J,Thiel T.Absence of Nacetylaspartate in the human brain: impact on neurospectroscopy? Ann Neurol 2001; 49: 518–521

Encephalitis Creatine Deficiency Syndromes Chang L, Ernst T, Tornatore C, Aronow H, Melchor R, Walot I, Singer E, Conford M. Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy. Neurology 1997; 48: 836–845 Iranzo A, Moreno A, Pujol J, Marti-Fàbregas J, Domingo P. Molet J, Ris J, Cadafalch J. Proton magnetic resonance spectroscopy pattern of progressive multifocal leukoencephalopathy in AIDS. J Neurol Neurosurg Psychiatry 1999; 66: 520–523 Laubenberger J, Häussinger D, Bayer S, Thielemann S, Schneider B, Mundinger A, Hennig J, Langer M. HIV-related metabolic abnormalities in the brain: depiction with short echo times. Radiology 1996; 199: 805–810 Meyerhoff DJ, MacKay S, Bachman L, Poole N, Dillon WP, Weiner MW, Fein G. Reduced brain N-acetylaspartate suggests neuronal loss in cognitive impaired neuronal loss in cognitively impaired human immunodeficiency virus-seropositive individuals. In vivo 1H magnetic resonance spectroscopic imaging. Neurology 1993; 43: 509–515 Sämann PG, Schlegel J, Müller G, Prantl F, Emminger C, Auer DP. Serial proton MR spectroscopy and diffusion imaging findings in HIV-related herpes simplex encephalitis. AJNR Am J Neuroradiol 2003; 24: 2015–2019 Takanashi J-I, Sugita K, Ishii M, Aoyagi M, Niimi H. Longitudinal MR imaging and proton MR spectroscopy in herplex simplex encephalitis. J Neurol Sci 1997; 149: 99–102

Cecil KM, Salomons GS, Ball WS Jr,Wong B, Chuck G,Verhoeven NM, Jakobs C, DeGrauw TJ. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect. Ann Neurol 2001; 49: 401–404 DeGrauw TJ, Salomons GS, Cecil KM, Chuck G, Newmeyer A, Shapiro MB, Jakobs C. Congenital creatine transporter deficiency. Neuropediatrics 2002; 33: 232–238 Salomons GJ, van Dooren SJM, Verhoeven NM, Cecil KM, Ball WS, DeGrauw TJ, Jakobs C. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 2001; 68: 1497–1500 Schultze A. Creatine deficiency syndromes. Mol Cell Biochem 2003; 244: 143–150 Stöckler S, Holzbach U, Hanefeld F, Marquart I, Helms G, Requart M, Hänicke W, Frahm J. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 1994; 36: 409–413 Stöckler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura. Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 1996; 58: 914–922 Stromberger C, Bodamer OA, Stöckler-Ipsiroglu S.Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis 2003; 26: 299–308 van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, Pouwels PJW, Onkenhout W, Peeters EAJ, Stöckler-Ipsiroglu S, Jakobs C. Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol 2000; 47: 450–543

References and Further Reading 1071

Nonketotic Hyperglycinemia

Salla Disease

Gabis L, Parton P, Roche P, Lenn N, Tudorica A, Huang W. In vivo 1 H magnetic resonance spectroscopic measurement of brain glycine levels in nonketotic hyperglycinemia. J Neuroimaging 2001; 11: 209–211 Heindel W, Kugel H, Roth B. Noninvasive detection of increased glycine content by proton MR spectroscopy in the brains of two infants with nonketotic hyperglycinemia. AJNR Am J Neuroradiol 1993; 14: 629–635 Huisman TAGM, Thiel T, Steinman B, Zeislinger G, Martin E. Proton magnetic resonance spectroscopy of the brain of a neonate with nonketotic hyperglycinemia: in vivo-in vitro (ex vivo) correlation. Eur Radiol 2002; 12: 858–861 Viola A, Chabrol B, Nicoli F, Confort-Gouny S, Viout P, Cozzone PJ. Magnetic resonance spectroscopy study of glycine in nonketotic hyperglycinemia. Pediatr Res 2002; 52: 292–300

Sewell AC, Murphy HC, Iles RA. Proton magnetic resonance spectroscopic detection of sialic acid storage disease. Clin Chem 2002; 48: 35–359 Varho T, Komhu M, Sonninen P, Holopainen I, Nyman S, Manner T, Sillapää M, Aula P, Lundbom N. A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla disease. Neurology 1999; 52: 1668–1672

Phenylketonuria

Sjö gren-Larsson Syndrome

Kreis R. Comments on in vivo proton magnetic resonance spectroscopy in phenylketonuria. Eur J Pediatr 2000; 159: S126-S128 Kreis R, Pietz J, Penzien J, Herschkowitz N, Boesch C. Identification and quantitation of phenylalanine in the brain of patients with phenylalanine by means of localized in vivo 1H magnetic-resonance spectroscopy. J Magn Reson B 1995; 107: 242–251 Leuzzi V, Bianchi MC, Tosetti M, Carducci Cl, Carducci Ca, Antonozzi I. Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria.J Inherit Metab Dis 2000; 23: 563–570 Moats RA, Scadeng M, Nelson MD Jr. MR imaging and spectroscopy in PKU. Ment Retard Dev Disab Res Rev 1999; 5: 132–135 Moats RA, Mosely KD, Koch R, Nelson M Jr. Brain phenylalanine concentrations in phenylketonuria:research and treatment of adults. Pediatrics 2003; 112: 1575–1579 Möller HE,Vermathen, Ullrich K,Weglage J, Koch H-G, Peters PE. In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerbral phenylalanine levels under dietary treatment. Neuropediatrics 1995; 26: 199–202 Möller HE, Ullrich K, Weglage J. In vivo proton magnetic resonance spectroscopy in phenylketonuria. Eur J Pediatr 2000; 159: S121-S125 Möller HE, Weglage J, Bick U, Wiedermann D, Feldmann R, Ullrich K. Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria. Pediatrics 2003; 112: 1580–1583 Novotny EJ Jr, Avison MJ, Herschkowitz N, Petroff OAC, Prichard JW, Seashore MR, Rothman DL. In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy. Pediatr Res 1995; 37: 244–249 Pietz J, Lutz T, Zwygart K, Hoffman GF. Phenylalanine can be detected in brain tissue of healthy subjects by 1H magnetic resonance spectroscopy. J Inherit Metab Dis 2003; 26: 683–691

Mano T, Ono J, Kaminaga T, Imai K, Sakura K, Harada K, Nagai T, Rizzo WB, Okada S. Proton MR spectroscopy of SjögrenLarsson’s syndrome. AJNR Am J Neuroradiol 1999; 20: 1671–1673 Van Domburg PHMF, Willemsen MAAP, Rotteveel JJ, de Jong JGN, Thijssen HOM Heerschap A, Cruysberg JRM, Wanders RJA, Gabreëls FJM, Steijlen PM. Sjögren-Larsson syndrome. Clinical and MRI/MRS findings in FALDH-deficient patients. Neurology 1999; 52: 1345–1352 Willemsen MAAP, van der Graaf M, van der Knaap MS, Heerschap A, van Domburg PHMF, Gabreëls FJM, Thijssen HOM, Rotteveel JJ. MR imaging and proton MR spectroscopy studies in Sjögren-Larsson syndrome: characterization of the leukoencephalopathy. AJNR Am J Neuroradiol 2004;25: 649–657

Maple Syrup Urine Disease Felber SR, Sperl W, Chemelli A, Murr C, Wendel U. Maple syrup urine disease: metabolic decompensation monitored by proton magnetic resonance imaging and spectroscopy. Ann Neurol 1993; 33: 396–401

Galactosemia Berry GT, Hunter JV,Wang Z, Dreha S, Mazur A, Brooks DG, Ning C, Zimmerman RA, Segal S. In vivo evidence of brain galactitol accumulation in an infant with galactosemia and encephalopathy. J Pediatr 2001; 138: 260–262 Möller HE, Ullrich K,Vermathen P, Schuierer G, Koch H-G. In vivo study of brain metabolism in galactosemia by 1H and 31P magnetic resonance spectroscopy. Eur J Pediatr 1995; 154: S8-S13 Wang ZJ, Berry GT, Dreha SF, Zhao G, Segal S, Zimmerman RA. Proton magnetic resonance spectroscopy of brain metabolites in galactosemia. Ann Neurol 2001; 50: 266–269

Defect in Polyol Metabolism Huck JHJ, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap MS. Ribose 5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 2004; 74: 745–751 van der Knaap MS, Wevers RA, Struys EA, Verhoeven NM, Pouwels PJW, Engelke UFH, Feikema W, Valk J, Jakobs C. Leukoencephalopathy associated with a disturbance in the metabolism of polyols. Ann Neurol 1999; 46: 925–928

1072 References and Further Reading

Kreis R, Ross BD. Cerebral metabolic disturbance in patients with subacute and chronic diabetes mellitus: detection with proton MR spectroscopy. Radiology 1992; 184: 123–130 Pan JW, Telang FW, Lee JH, de Graaf RA, Rothman DL, Stein DT, Hetherington HP. Measurement of b-hydorxybutyrate in acute hyperketonemia in human brain. J Neurochem 2001; 79: 539–544

Ross BD, Ernst T, Kreis R, Haseler LJ, Bayer S, Danielsen E, Blüml S, Shonk T, Mandigo JC, Caton W, Clark C, Jensen SW, Lehman NL, Arcinue E, Pudenz R, Shelden CH. 1H MRS in acute traumatic brain injury.J Magn Reson Imaging 1998; 8: 829–840 Signoretti S, Marmarou A, Tavazzi B, Lazzarino G, Beaumont A, Vagnozzi R. N-Acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury. J Neurotrauma 2001; 18: 977–991

X-Linked Adrenoleukodystrophy

Multiple Sclerosis

Eichler FS, Itoh R, Barker PB, Mori S, Garrett ES, van Zijl PCM, Moser HW, Raymond GV, Melhem ER. Proton MR spectroscopy and diffusion tensor brain MR imaging in X-linked adrenoleukodystrophy: initial experience. Radiology 2002; 225: 245–252 Eichler FS, Barker PB, Cox C, Edwin D, Ulug AM, Moser HW, Raymond GV.Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002; 58: 901–907 Korenke GC, Pouwels PJW, Frahm J, Hunneman DH, Stoeckler S, Krasemann E, Jost W, Hanefeld F. Arrested cerebral adrenoleukodystrophy: a clinical and proton magnetic resonance spectroscopy study in three patients. Pediatr Neurol 1996; 15: 103–107 Pouwels PJW, Kruse B, Korenke GC, Mao X, Hanefeld FA, Frahm J.Quantitative proton magnetic resonance spectroscopy of childhood adrenoleukodystrophy. Neuropediatrics 1998; 2: 254–264 Wilken B, Dechent P, Brockmann K, Finsterbusch J, Baumann M, Ebell W, Korenke GC, Pouwels PJW, Hanefeld FA, Frahm J. Quantitative proton magnetic resonance spectroscopy of children with adrenoleukodystrophy before and after hematopoietic stem cell transplantation. Neuropediatric 2003; 34: 237–246

Arnold DL, Wolinksky JS, Matthews PM, Falini A. The use of magnetic resonance spectroscopy in the evaluation of the natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry 1998; 64: S94–S101 Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, Brück W. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol 1999; 20: 1619–1627 Bjartmar C,Kidd G,Mörk S,Rudick R,Trapp BD.Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl asparate in chronic multiple sclerosis patients.Ann Neurol 2000; 48: 893–901 Bonneville F, Moriarty DM, Li BSY, Babb JS, Grossmann RI, Gonen O.Whole-brain N-acetylaspartate concentration: correlation with T2-weighted lesion volume and expanding disability status scale score in cases of relapsing-remitting multiple sclerosis. AJNR Am J Neuroradiol 2002; 23: 371– 375 Chard DT, Griffin CM, McLean MA, Kapeller P, Kapoor R,Thompson AJ, Miller DH. Brian metabolite changes in cortical gray and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 2002; 125: 2342–2352 Davie CA, Barker GJ, Thompson AJ, Tofts PS, McDonald WI, Miller DH. 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiatry 1997; 63: 736–742 De Stefano N, Matthews PM, Antel JP, Preul M, Francis G, Arnold DL. Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol 1995; 38: 901–909 De Stefano N, Mattews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL. Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998; 121; 1469–1477 De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 2001; 58: 65–70 Gonen O, Moriarty DM, Li BSY, Babb JS, He J, Listerud J, Jacobs D, Markowitz CE, Grossman RI. Relapsing–remitting multiple sclerosis and whole-brain N-acetylaspartate measurement: evidence for different clinical cohorts – initial observations. Radiology 2002; 225: 261–268 Husted CA, Goodin DS, Hugg JW, Maudsley AA, Tsuruda JS, de Bie SH, Fein G, Matson GB, Weiner MW. Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging. Ann Neurol 1994; 36: 157–165

Diabetes Mellitus

Diffuse Axonal Injury Auld KL, Ashwal S, Holshouser BA, Tomasi LG, Perkin RM, Ross BD, Hinshaw BD Jr. Proton magnetic resonance spectroscopy in children with acute central nervous system injury. Pediatr Neurol 1995; 12: 323–334 Friedman SD, Brooks WM, Jung RE, Hart BL, Yeo RA. Proton MR spectroscopic findings correspond to neuropsychological function in traumatic brain injury. AJNR Am J Neuroradiol 1998; 19: 1879–1885 Friedman SD, Brooks WM, Jung RE, Chiulli SJ, Sloan JH, Montoya BT, Hart BL, Yeo RA. Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology 1999; 52: 1384–1391 Garnett MR, Blamire AM, Corkill RG, Cadoux-Hudson TAD, Rajagopalan B, Styles P. Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain 2000; 123: 2046–2054 Haseler LJ, Arcinue E, Danielsen ER, Bluml S, Ross BD. Evidence from proton magnetic resonance spectroscopy for a metabolic cascade of neuronal damage in shaken baby syndrome. Pediatrics 1997; 99: 4–14

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Kapeller P, McLean MA, Griffin CM, Chard D, Parker GJM, Barker GJ, Thompson AJ, Miller DH. Preliminary evidence for neuronal damage in cortical grey matter and normal appearing white matter in short duration relapsing-remitting multiple sclerosis: a quantitative MR spectroscopy imaging study. J Neurol 2001; 248: 131–138 Leary SM, Davie CA, Parker GJM, Stevenson WL, Wang L, Barker GJ, Miller DH, Thompson AJ. 1H Magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis. J Neurol 1999; 246: 1023–1026 Mader I, Roser W, Kappos L, Hagberg G, Seeling J, Radue EW, Steinbrich W. Serial proton MR spectroscopy of contrastenhancing multiple sclerosis plaques: absolute metabolic values over 2 years during clinical pharmacological study. AJNR Am J Neuroradiol 2000; 21: 1220–1227 Mader I, Seeger U, Weissert R, Klose U, Naegele T, Melms A, Grodd W. Proton MR spectroscopy with metabolite-nulling reveals elevated macromolecules in acute multiple sclerosis. Brain 2001; 124: 953–961 Narayana PA,Doyle TJ,Lai D,Wolinsky JS.Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998; 43: 56–71 Sarchielli P, Presciutti O, Pellicioli GP,Tarducci R, Gobbi G, Chiarini P, Alberti A, Vicinanza F, Gallai V. Absolute quantification of brain metabolites by proton magnetic resonance spectroscopy in normal appearing white matter of multiple sclerosis patients. Brain 1999; 122: 513–521 Sarchielli P, Presciutti O, Tarducci R, Gobbi G, Alberti A, Pelliccioli GP, Chiarini P, Gallai V. Localized 1H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis. J Neurol 2002; 249: 902–910 Suhy J, Rooney WD, Goodkin DE, Capizzano AA, Soher BJ, Maudsley AA,Waubant E, Andersson PB,Weiner MW. 1H MRSI Comparison of white matter and lesions in primary progressive and relapsing-remitting MS. Mult Scler 2000; 6: 148–155 Tartaglia MS, Narayanan S, de Stefano N, Arnaoutelis R, Antel SB, Francis SJ, Santos AC, Lapierre Y, Arnold DL. Choline is increased in pre-lesional normal appearing white matter in multiple sclerosis. J Neurol 2002; 249: 1382–1390 Tourbah A, Stievenart JL, Gout O, Fontaine B, Liblau R, Lubetzki C, Cabanis EA, Lyon-Cean O. Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis. Neurology 1999; 53: 1091–1097 Van Walderveen MAA, Barkhof F, Pouwels PJW, van Schijndel RA, Polman CH, Castelijns JA. Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann Neurol 1999; 46: 79–87

109 Pattern Recognition in White Matter Disorders Barkhof F, van der Knaap MS. Differential diagnosis with leukodystrophies and non-vascular acquired white matter disorders. In: Erkinjuntti T, Gauthier S, eds. Vascular cognitive impairment. London: Martin Dunitz, 2002, pp 485–500

Blaser SI, Clarke JTR, Becker LE. Neuroradiology of lysosomal disorders. Neuroimaging Clin N Am 1994; 4: 283–298 Blois MS. Clinical judgment and computers. N Engl J Med 1980; 303: 192–197 Boltshauser E, Martin E, Wichmann W, Valavanis A. Grenzen der kernspintomographie aus neuropädiatrischer Sicht. Klin Neuroradiol 1993; 3: 79–82 Brismar J. CT and MRI of the brain in inherited metabolic disorders. J Child Neurol 1992; 7: S122–S131 Cassedy KJ, Edwards MK. Metabolic and degenerative diseases of childhood.Top Magn Reson Imaging 1993; 5: 73–95 Cheon JE, Kim IO, Hwang YS, Kim KJ, Wang KC, Cho BK, Chi JG, Kim CJ, Kim WS,Yeon KM. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002; 22: 461–476 Edwards MK. Imaging of metabolic diseases of the brain. Curr Opin Radiol 1991; 3: 25–30 Ford CC, Ceckler TL, Karp J, Herndon RM. Magnetic resonance imaging of experimental demyelination lesions. Magn Reson Med 1990; 14: 461–481 Forsting M.MR imaging of the brain: metabolic and toxic white matter diseases. Eur Radiol 1999; 9: 1061–1065 Getty DJ, Pickett RM, D’Orsi CJ, Swets JA. Enhanced interpretation of diagnostic images. Invest Radiol 1988; 23: 240–252 Kendall BE. Disorders of lysosomes, perosixomes and mitochondria. AJNR Am J Neuroradiol 1992; 13: 621–653 Kendall BE.Inborn errors and demyelination: MRI and the diagnosis of white matter disease. J Inherit Metab Dis 1993; 16:771–786 Kristjánsdóttir R, Uvebrant P, Hagberg B, Kyllerman M, Wiklund L-M, Blennow G, Flodmark O, Gustavsson L, Ekholm S, Månsson J-E. Disorders of the cerebral white matter in children. The spectrum of the lesions. Neuropediatrics 1996; 27: 295–298 Miller DH, Robb SA, Ormerod IEC, Pohl KRE, MacManus DG, Kendall BE, Moseley IF, McDonald WI. Magnetic resonance imaging of inflammatory and demyelinating white matter diseases of childhood. Dev Med Child Neurol 1990; 32: 97–107 Sackett DL, Haynes RB,Tugwell P. Clinical epidemiology: a basic science for clinical medicine. Boston: Little, Brown & Co, 1985 Valk J, van der Knaap MS. Selective vulnerability in toxic encephalopathies and metabolic disorders. Riv Neuroradiol 1996; 9: 749–760 Valk J, van der Knaap MS. Patterns of myelin breakdown. Eur Radiol 1999; 9: S3–S14 van der Knaap MS. Magnetic resonance in childhood white matter disorders. Dev Med Child Neurol 2001; 43: 715–712 van der Knaap MS, Valk J. Non-leukodystrophic white matter changes in inherited disorders. Int J Neuroradiol 1995; 1: 56–66 van der Knaap MS, Valk J, de Neeling N, Nauta JJP. Pattern recognition in magnetic resonance imaging. Neuroradiology 1991; 33: 478–493 van der Knaap MS, Breiter SN, Naidu S, Hart AAM, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213: 121– 133

Subject Index

A acquired immunodeficiency syndrome 616–627 – acute HIV-1 encephalopathy 616 – AIDS in infants and children 617 – AIDS-related dementia 616 – cellular immunodeficiency 616 – diagnostic criteria Centers of Disease Control 616 – diagnostic procedures 617 – high risk groups 616 – highly aggressive antiretroviral therapy (HAART) 622 – HIV-1 virions in brain tissue 617 – human immunodeficiency virus type 1 (HIV-1) 616 – lentovirinae subfamily of retroviruses 620 – magnetic resonance imaging 606–627 – major envelope proteins 620 – mode of infection 620 – MS-like encephalopathy 619 – opportunistic infections 616 – pneumocystis carinii pneumonia 616 – spinal cord involvement 619 – subacute HIV-1 encephalopathy 616 – therapeutic options 621–623 activator protein deficiency 74, 98, 104 acute disseminated encephalomyelitis and acute hemorrhagic encephalomyelitis 604–615 – auto-immune reaction 605 – clinical variants 604 – Guillain-Barré syndrome 604 – magnetic resonance imaging 606–615 – postvaccinal encephalopathy 604 – therapeutic options 605 – viral infections 604 acute intermittent porphyria 700 acute profound hypoxic-ischemic insults 718 adult polyglucosan body disease 147–151 – corpora amylacea 148 – cystic lesions 147 – genetic defect 148 – glucose polymers 148 – glycogen branching enzyme 148

– glycogen storage disease type IV 148 – magnetic resonance imaging 149–151 – polyglucosan bodies 147 – – intra-axonal and astrocytic location 147 – sural nerve biopsy 147 adult-onset autosomal dominant leukoencephalopathies 560–561 – clinical variants 560 Aicardi-Goutières syndrome 496–504 – atypical manifestations 496, 497 – calcium deposits 497, 498, 501 – clinical variants 496 – Cree encephalitis 497 – CSF lymphocytosis 497 – interferonopathy 498 – interferon-a 497 – magnetic resonance imaging 498–504 – pseudo-TORCH syndrome 497 Alexander disease 416–435 – aB-crystallin 416 – clinical variants 416 – genetic defect 418 – glial fibrillary astrocyte protein 418 – magnetic resonance imaging 419–435 – megalencephaly 416 – Rosenthal fibers 416, 417, 418 amyloid angiopathy 535–540 angiokeratomas (Fabry disease) 112 anti-phospholipid antibody syndrome 785 apparent diffusion coefficient (ADC) 840 arginase deficiency 360, 362, 367 argininosuccinate – lyase deficiency 360, 362, 364 – synthase deficiency 360, 362 astrocyte 5 ATP synthase deficiency 224, 225, 227 Ayala syndrome 709

B Baló concentric sclerosis 567, 600 basal ganglia damage after perinatal asphysica 718, 738, 739 Batten disease 137 Behçet disease 789, 791, 792 benign primary angiitis 776 big panda sign 397

Binswanger disease 767–772 biotin metabolism, defects 248 biotinidase deficiency 248–251 Bloch-Sulzberger syndrome 412–415 Borrelia burgdorferi 792 brain maturation – ADC values 847 – DWI-DTI changes 847 – MTR values 42, 857 brucellosis 635–639 – Brucella species 635 – clinical variability 635 – coccobacilli 635 – geographic distribution 635 – magnetic resonance imaging 636–639 – therapeutic options 636 – zoonosis 635

C CADASIL 541–548 Canavan disease 326–333 – aspartoacylase 327 – clinical variants 326 – genetic defect 327 – magnetic resonance imaging 328–333 – N-acetyl aspartate 327 – spongy degeneration 326 – vacuolating myelinopathy 326, 327 – Van Bogaert-Bertrand disease 326 CARASIL 549–551 carbon monoxide intoxication 755 carboxyl phosphate synthetase deficiency 360, 362 cataracts, microcephaly, failure to thrive, kyphoscoliosis syndrome (CAMFAK) 260 central cortical and subcortical pattern 718, 733, 737–740 central pontine and extrapontine myelinolysis 684–689 – alcohol abuse 685 – hyponatremia 685 – iatrogenic factor 685 – magnetic resonance imaging 686–689 – myelinolysis 684–685 – prevention 686 – rapid correction of hyponatremia 685 – therapeutic options 686

1076 Subject Index cerebral amyloid angiopathy 535–540 – amyloid – – cascade 537 – – precursor proteins 536 – – Bri fragment 537 – Ab protein subunits 536 – British variant (Worster-Drought syndrome) 535 – cystatin C 536 – Dutch variant 535 – Flemish variant 535 – genetic defects 536, 537 – Iceland variant 535 – lobar hemorrhage 535 – magnetic resonance imaging 537–540 – oculoleptomeningeal amyloidosis 535 – b-sheet content 536 – sporadic forms 535 – therapeutic options 537 – transthyretin 536 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 541–548 – absence of vascular risk factors 541 – diagnostic criteria 541 – epidermal growth factor motif 542 – familial Binswanger disease 541 – genetic defect 542 – granular osmiophilic material 541 – hereditary multi-infarct dementia 541 – magnetic resonance imaging 542–548 – migrainous headache 541 – therapeutic options 542 cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) 549–551 – alopecia 549 – clinical variants 549 – lumbago 549 – magnetic resonance imaging 549–551 cerebro-oculo-facio-skeletal syndrome (COFS) 260 cerebrotendinous xanthomatosis 252–259 – Achilles tendon 252 – bile acid metabolism 252, 253, 254 – cholestanol 253 – clinical variants 252 – genetic defect 253 – 27-hydroxylase 253 – magnetic resonance imaging 253–258 – xanthomas 253

Charcot-Marie-Tooth disease, X-Linked 476–478 – clinical variants 476 – connexin 32 476 – genetic defect 476 – magnetic resonance imaging 477, 478 chemotherapy-related encephalopathy 808–817 childhood ataxia with CNS hypomyelination 481–494 cholestanol 253 choline phosphoglycerides 7 Churg-Strauss syndrome 789 classification – of lysosomal storage disorders 69 – of mitochondrial disorders 200 – of mucopolysaccharidoses 123 – of neuronal ceroid lipofuscinoses (eponyms) 137 – of peroxisomal disorders 153 – of toxic encephalopathies 664–678 – of white matter disorders 20–24 cobalamin – deficiency 343, 346, 354, 356 – defects in metabolism 343, 347 Cockayne syndrome 259–267 – cachectic dwarfism 259 – CAMFAK syndrome 260 – clinical variants 259 – COFS syndrome 260 – complementation groups 261 – DNA-repair 261–262 – genetic defects 261 – magnetic resonance imaging 263–267 – therapeutic options 262 – trichothiodystrophy 261 – UV hypersensitivity 261 complex I deficiency 224, 226, 229 complex IV deficiency 224, 226, 232 conduction velocity 15 congenital and perinatal cytomegalovirus infection 645–657 – ganciclovir 647 – herpes viridae family 645 – magnetic resonance imaging 650–657 – maternal infection 645 – mental deficiency 646 – modes of infection 645 – retrospective diagnosis 646 – sensorineural hearing loss 646 – therapeutic options 648, 649 – TORCH infections 646 – viral gene products 648 congenital muscular dystrophy 451–468 – a-dystroglycan 453 – – hypoglycosylation 454, 455

– dystrophin-associated glycoprotein complex 454 – Fukuyama congenital muscular dystrophy 451 – genetic defects 454, 455 – laminin-a2 453–455 – limb girdle muscular dystrophy 21 452 – magnetic resonance imaging 457–468 – MDC1C 451 – MDC1D 451 – merosin-deficient congenital muscular dystrophy (MDC1A) 451 – muscle-eye-brain disease 451 – therapeutic options 457 – Walker-Warburg syndrome 451 cree leukoencephalopathy 481 CREST 786 Curschmann-Steinert disease 469–472 cyanide intoxication 755 cystathionine b-synthase deficiency 342, 347 cytochrome c oxidase deficiency 225, 227, 238 cytomegalovirus infection – congenital or perinatal 645–657 – in AIDS 624

D D-2-hydroxyglutaric aciduria 338–341 – clinical variants 338 – D-2-hydroxyglutarate dehydrogenase 338 – genetic defect 338 – magnetic resonance imaging 339–341 – secondary respiratory chain deficiency 338 delayed posthypoxic leukoencephalopathy 755–758 – carbon monoxide 755 – cyanide 755 – magnetic resonance imaging 756–758 – therapeutic options 756 demyelination 15, 17 – biochemical changes 17 – loss of function 18 dentatorubropallidoluysian atrophy 530–534 – anticipation 531 – atrophin-1 530 – CAG trinucleotide repeat 530 – clinical variants 530 – genetic defect 530 – magnetic resonance imaging 531–534 – polyglutamine repeat 531

Subject Index 1077

diabetes insipidus 709 diffuse axonal injury 823–831 – acceleration-deceleration trauma 823 – axonal damage 824 – Genneralli classification 824, 831 – magnetic resonance imaging 824–831 – outcome 824 – therapeutic options 824 diffusion sensitivity 840 diffusion weighted imaging 839–855 – apparent diffusion coefficient 840 – Brownian movement 839 – developmental changes 847 – diffusion sensitivity 840 – fractional anisotropy 843 – hypoxia-ischemia in neonates 733, 736, 738, 745, 747, 847, 848 – intravoxel coherent and incoherent motion 840 – relative anisotropy 843 – Stejskal-Tanner sequence 840 – trace diffusion-weighted images 843 dihydropteridine reductase deficiency 286, 291, 292, 293 DNA – content of brain 13 – repair disorders 259–267, 268–272 drug-induced vasculitis 797 dysmyelination 15, 17

E eclampsia 699 elderly with mild cognitive impairment 759 eosinophilic granuloma 709 Erdheim-Chester disease 709, 710, 711, 713 etat – criblé 767 – lacunaire 767 ethanolamine phosphoglycerides 6 extrapontine myelinolysis 684–689

F Fabry disease 112–118 – atypical variants 112 – early and late manifestations 112 – a-galactosidase 113 – – recombinant 113 – genetic defect 114 – glycosphingolipids accumulation 114 – heterozygous female patients 112 – magnetic resonance imaging 115–118 – pain 112 – therapeutic options 114 – vascular changes 113

fatty acid b-oxidation, peroxisomal 152 folate – defects in metabolism 347 – deficiency 343, 344 fragile X premutation 406–408 – clinical variants 406 – genetic defect 406 – magnetic resonance imaging 406–408 – mental retardation 406 – trinucleotide expansion 406 free sialic acid storage disorder 133–136 – bone abnormalities 134 – clinical types 133 – free sialic acid – – excretion in urine 133 – – transporter 134 – genetic defect 134 – magnetic resonance imaging 135–136 – Salla disease 133 – vacuolar inclusions in sural nerve biopsy 134 fucosidosis 119–122 – clinical variants 119 – fucose 119 – genetic defect 120 – internal organs enlargement 119 – a-L-fucosidase 117 – magnetic resonance imaging 120–122 – neuronal ballooning 119 – therapeutic options 117 Fukuyama congenital muscular dystrophy 451, 454, 459, 461

G Gagel granuloma 709 galactosemia 377–382 – clinical variants 377 – Duarte variants 378 – epimerase 379 – galacticol 378 – galactokinase 377 – galactosed-1-phosphate uridyltransferase 377 – genetic defects 378, 379 – incidence 377 – magnetic resonance imaging 380–382 – therapeutic options 379 – uridine diphosphate – – galactose 379 – – galactose-4-epimerase 377 gangliosides 7, 81, 95, 102, 104 Genneralli classification 824, 831 germinal layer related hemorrhage 720

giant axonal neuropathy 436–441 – aberrant neurofilaments 437 – genetic defect 437 – giant axonal swellings 437 – gigaxonin 437 – hair abnormalities 436 – magnetic resonance imaging 437–441 – Rosenthal fibers 436 giant cell arteriitis 775 gliomatosis cerebri 818–822 – clinical variants 818 – delayed gadolinium enhancement 821 – genetic patterns 818 – magnetic resonance imaging 818–822 – therapeutic options 820 globoid cell leukodystrophy (Krabbe disease) 87–95 – cerebrosides 89 – clinical variants 87 – galactocerebroside b-galactosidase 88 – genetic defect 89 – magnetic resonance imaging 91–95 – psychosine 89 – therapeutic options 90 – white matter involvement 89 glutaric aciduria type 1 294–300 – clinical variants 294, 295 – genetic defect 295 – glutaryl-CoA-dehydrogenase 295 – magnetic resonance imaging 296–299 – myelin splitting 295, 296 – therapeutic options 295, 296 glycosaminoglucans in urine 126 GM1 gangliosidosis 96–102 – activator protein 97 – bone deformities 96 – clinical variants 96 – b-galactosidase 98 – gangliosides 97 – genetic defect 98 – magnetic resonance imaging 100–102 – membranous cytoplasmic bodies 97 GM2 gangliosidosis 103–111 – bone deformities 104 – clinical variants 103 – gangliosides 106 – genetic defect 106 – glycolipid biosynthesis 107 – hexosaminidase A and B 104 – magnetic resonance imaging 108–111 – motor neuron disease 104 granulomatous angiitis 774, 775, 776

1078 Subject Index gyration 45 – iconography: preterm-term neonates 45–50

H Hachinski scale 760 Hand-Schüller-Christian disease 709 hemolytic-uremic syndrome 700 hepatolenticular syndrome 392–399 hereditary diffuse leukoencephalopathy with neuroaxonal spheroids 526–529 – axonal spheroids 526 – clinical variants 526 – dermatoleukodystrophy with neuroaxonal spheroids 526 – magnetic resonance imaging 527–529 – polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease) 526, 552–556 herpes zoster ophthalmica 797 histiocytosis X 709 holocarboxylase synthase deficiency 248–251 Hunter syndrome 83, 124, 130 Hurler-Scheie syndrome 123, 124, 130 Hurler syndrome 123, 124 3-hydroxy-3-methylglutaryl-CoA lyase deficiency 321–324 – clinical variants 321 – genetic defect 321 – HMG-CoA lyase 321 – hypoketotic hypoglycemia 322 – ketone bodies 321 – magnetic resonance imaging 321–325 – therapeutic options 322 hyperhomocysteinemia 342–359 – clinical variants 343, 344, 345 – cobalamin metabolism 342 – cystathione b-synthase 342 – folate metabolism 342 – genetic defects 347, 348 – homocysteine metabolism 342 – magnetic resonance imaging 348–359 – methyl-folate trap 345 – methylmalonic acidemia 343 – mild form 342 – pyridoxine (vitamin B6) 348 – subacute combined degeneration of the cord 345 – therapeutic options 348 – transsulfuration pathway 342 hypernatremia 690–694 – magnetic resonance imaging 691–694 – non-accidental intake of sodium 690

– regulation of fluid balance 691 – toxicity 690 hypertensive encephalopathy 699 hypomelanosis of Ito 409–411 – Blaschklo lines 409 – chromosomal or genetic mosaicism 409 – clinical phenotypes 409 – enlarged perivascular spaces 410 – incontinentia pigmenti achromians 409 – magnetic resonance imaging 410, 411 hypomyelination with atrophy of the basal ganglia and cerebellum 519–525 – clinical variants 519 – magnetic resonance imaging 519–525 hyponatremia 685 hypoxia-ischemia in neonates, DWI 733, 736, 738, 745, 747, 847, 848

I iatrogenic toxic encephalopathies 679–683 – host-versus-graft disease 679 – magnetic resonance imaging 680–683 – multifocal inflammatory leukoencephalopathy 679 – posterior reversible encephalopathy syndrome 681 incontinentia pigmenti 412–415 – Bloch-Sulzberger syndrome 412 – genetic defect 412 – magnetic resonance imaging 413–415 – NF-k-B activation 412 – proapoptotic signals 412 – skin lesions 412 – type II 412–415 infantile Refsum syndrome 154–166 inflammatory and infectious disorders 561–565 – acquired adaptive immune system 561 – acute phase proteins 561 – B-cell lymphocytes 561 – complement 561 – cytokines 563 – exotoxins 563 – human leukocyte antigen (HLA) 581 – immune system 561 – inflammatory mediators 561 – inflammatory process 561 – innate non-adaptive immune system 561 – interferons 561 – Langerhans and dendritic cells 563

– major histocompatibility complex (MHC) 561 – molecular and soluble components 561 – myelin involvement in inflammatory and infectious disorders 565 – natural killer cells 562 – oxygen radicals 562 – T-cell lymphocytes 561 intraperiod line 3 intravascular lymphomatosis 798

J Jansky Bielschowski disease

137

K Kearns-Sayre syndrome 215–220 – endocrine dysfunction 215 – genetic defects 216 – magnetic resonance imaging 217–220 – overlapping syndromes 216 – Pearson syndrome 215 – red ragged fibers 215 – therapeutic options 216 kinky hair disease 400 Krabbe disease 87–95 Kufs disease 137

L L-2-hydroxyglutaric aciduria 334–337 – clinical variants 334 – genetic defect 334 – L-2-hydroxyglutarate dehydrogenase 334 – magnetic resonance imaging 334–337 Langerhans cell histiocytosis 709–714 – diabetes insipidus 709 – eosinophilic granuloma 709 – Erdheim-Chester disease 709, 710 – Hand-Schüller-Christian disease 709 – histiocytosis X 709 – Letterer Siwe disease 709 – magnetic resonance imaging 710–714 Leber hereditary optic atrophy 212–214 – genetic defects 213 – magnetic resonance imaging 213–214 – multiple sclerosis association 212 – Uhthoff symptom 212 – visual dysfunction 212 Leigh syndrome and mitochondrial leukoencephalopathies 224–244 – ATP synthase deficiency 224, 227 – causes 224, 226 – clinical variants 224

Subject Index 1079

– complex I deficiency 224, 226 – cytochrome c oxidase deficiency 224, 227 – magnetic resonance imaging 228–244 – mitochondrial leukoencephalopathies 224–244 – pyruvate dehydrogenese complex deficiency 224, 226 – therapeutic options 227 Letterer Siwe disease 709 leukoaraiosis 759 leukodystrophy 15 leukoencephalopathy 15 leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate 510–518 – clinical variants 510 – magnetic resonance imaging 510–518 leukoencephalopathy with calcifications and cysts 505–509 – angiomatous changes 505 – calcifications 505, 507, 509 – clinical variants 505 – magnetic resonance imaging 505–509 – Rosenthal fibers 505 leukoencephalopathy and dural arteriovenous fistulas 801–808 – basic fibroblast growth factor 801 – classification of cranial AV fistulas 802 – magnetic resonance imaging 803–807 – therapeutic options 802 – vascular endothelial growth factor 801 leukoencephalopathy after radiotherapy and chemotherapy 808–817 – types of damage 808 – multifocal inflammatory leukoencephalopathy 808 – posterior reversible encephalopathy syndrome 808 – Magnetic Resonance Imaging 810–817 leukoencephalopathy with vanishing white matter 481–494 – childhood ataxia with CNS hypomyelination (CACH) 481 – clinical variants 487–494 – Cree leukoencephalopathy 481 – guanosine diphosphateguanosine triphosphate conversion 482 – guanosine exchange factor activity 482 – magnetic resonance imaging 483–494

– – – – – –

ovarioleukodystrophy 481 regulation of protein synthesis 482 stress conditions 482 sububits of eIF2B 482 therapeutic options 482 translation-initiation factor eIF2B 482 Lhermitte symptom 566 lipofuscine 137 Loes score 186 Lorentzo oil 181 Lowe syndrome 387–391 – genetic defect 388 – magnetic resonance imaging 388–391 – oculocerebrorenal syndrome 387 – phosphoinositides 388 – skeletal abnormalities 387 – therapeutic options 388 – type II phosphatases 388 Lyme disease 792, 793, 794 lysosomal storage disorders 68–73 – classification 69 – defects – – in activator proteins 71 – – in postsynthetic modification of lysosomal proteins 71 – – in protective protein 72 – – in structural lysosomal proteins 71 – – in transport systems 72 – lysosomal lipid metabolism 70 lysosomes 66 – biogenesis 66 – defects in individual hydrolases 68 – definition 66 – disorders 66–73 – functions 66 – pathochemistry 68

M magnetic resonance spectroscopy 859–881 – ATP 861 – basic principles 859 – chemical shift imaging (CSI) 859, 861 – choline 863 – creatine 863 – disease-specific abnormalities 865–873 – editing techniques 860 – Fourier transformation 860 – frequency domain signal 860 – GABA 864 – glutamate 864 – 1H-MRS peak assignment 862 – inorganic phosphate 861 – J-coupling 860 – lactate 863

– – – – – – – – – – – – – –

Larmor – frequency 859 – precession 859 myo-inositol 864 N-acetylaspartate 863 normal values 864 parts per million (ppm) 860 phosphocreatine 861 phosphodiesters 861 phosphomonoesters 861 31 P-MRS – peak assignment 861 – pH estimation 865 process-specific abnormalities 873–880 – time domain signal 860 magnetization transfer imaging 854–858 – developmental changes 42, 857 – magnetization transfer ratio (MTR) 855 – – histogram analysis 855 – – axonal density 856 major dense line 3 maple syrup urine disease 311–320 – branched-chain – – a-keto acid decarboxylase (E1) 312 – – a-keto acid dehydrogenase complex 312 – – amino acids 311 – clinical variants 311 – dihydrolipoyl – – acyltransferase (E2) 312 – – dehydrogenase (E3) 312 – genetic defects 312 – magnetic resonance imaging 312–320 – therapeutic options 313 Marchiafava-Bignami disease 695–699 – alcohol 695 – clinical variants 695 – corpus callosum splitting 696 – magnetic resonance imaging 697–698 – toxic factors 695 Maroteaux-Lamy syndrome 83, 125, 132 measles 640 megalencephalic leukoencephalopathy with subcortical cysts 442–450 – ethnic distribution 442 – genetic defect 443 – macrocephaly 442 – magnetic resonance imaging 443–450 – MLC1 protein 443 – phenotypic variation 443 – vacuolating myelinopathy 443

1080 Subject Index Menkes disease 400–405 – ceruloplasmin levels 401 – clinical variants 400 – copper – – -dependent enzyme processes 402 – – -transporting P-type ATPase 402 – – levels 401 – cranial exostoses 400 – genetic defect 402 – kinky hair disease 400 – magnetic resonance imaging 403–405 – occipital horn syndrome 400 – skeletal abnormalities 400 – therapeutic options 403 – tortuosity of cerebral vessels 403 – trichopoliodystrophy 400 – type IX Ehlers-Danlos syndrome 400 – X-linked cutis laxa 400 merosin-deficient congenital muscular dystrophy 451, 455, 466 metachromatic leukodystrophy 74–81 – arylsulfatase A 75 – clinical variants 74 – genetic defect 76 – magnetic resonance imaging 78–81 – metachromasia 75 – pseudodeficiency of arylsulfatase A 75 – sulfatide 75 – therapeutic options 78 5,10-methylenetetrahydrofolate – reductase deficiency 342, 347, 351 – thermolabile variant 342, 347 microscopic polyarteritis 789 mitochondria 195–204 – citric acid cycle 197 – mitochondrial DNA 198 – nuclear DNA 198 – oxidative phosphorylation 197 – respiratory chain 197 – structure and function 195 mitochondrial disorders 195–204 – classification 200 – maternal inheritance 199 – mitochondrial DNA defects 200–201 – – deletions, large single 201 – – duplications 201 – – point mutations 201 – genetics 198 – leukoencephalopathies 224–244 – nuclear DNA defects 201–202 – – types of genes 201 – – assembly factors 202 – – DNA maintenance 202

mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) 204–211 – calcium deposits 205 – clinical variants 204 – genetic defects 205 – magnetic resonance imaging 206–211 – MELAS-MERFF overlap 204 – red ragged fibers 204 – therapeutic options 205 mitochondrial leukoencephalopathies 224–244 mitochondrial neurogastrointestinal encephalomyopathy 221–223 – genetic defect 222 – magnetic resonance imaging 222–223 – synonyms 221 molybdenum cofactor deficiency 372–376 – isolated sulfite oxidase deficiency 372–376 – clinical variants 372 – sulphite oxidase 372 – genetic defects 372, 373 – molybdenum cofactor synthesis 372 – therapeutic options 373 – magnetic resonance imaging 373–376 Morquio syndrome 83, 125, 132 Moyamoya syndrome 777, 778, 779, 780 mucopolysaccharidoses 123–132 – classification 123 – degradation of mucoplysaccharides 126 – enzyme deficiencies (table) 123 – enzymes involved 123 – genetic defects 127 – glycosaminoglycans 127 – Magnetic Resonance Imaging 129–132 – mental deficiency 126 – proteoglycans 127 – therapeutic options 127 multicystic encephalopathy 720, 742, 743 multifocal inflammatory leukencephalopathy 679, 680, 808 multiple carboxylase deficiency 248–251 – biotinidase deficiency 248 – clinical variants 248 – genetic defect 249 – holocarboxylase synthase deficiency 248 – magnetic resonance imaging 250, 251 – skin abnormalities 248 – therapeutic options 250

multiple sclerosis 566–613 – Baló concentric sclerosis 567 – Barkhof criteria 568 – benign MS 566 – CD 4+ and CD 8+ T cell lymphocytes 572 – Charcot type 566 – clinical variants 566 – clinically isolated symptom (CIS) 566 – cluster of differentiation markers (CD) 569 – diagnostic criteria 567 – environmental factors 574 – experimental allergic encephalomyelitis (EAE) 572 – FA and ADC 849, 592, 593 – gadolinium enhancement 569 – genetic factors 573 – incidence 566 – Lhermitte symptom 566 – magnetic resonance imaging 577–613 – Marburg type 566 – McDonald criteria 568 – neuromyelitis optica 567 – oligoclonal banding 568 – perivenular inflammation 569 – primary progressive MS 566 – relapsing-remitting MS 566 – remyelination 570 – Schilder diffuse sclerosis 567 – secondary progressive MS 566 – spinal cord involvement 579, 587–589 – therapeutic options 575, 576 – tumefactive MS 566 – viral factors 573 multiple sulfatase deficiency 82–86 – clinical variants 82 – genetic defect 83 – magnetic resonance imaging 83–86 – mucopolysaccharidoses 82 – peripheral nerve involvement 83 – sulfatases involved 83 – zebra bodies 82 muscle-eye-brain disease 451, 454, 462 myelin – aging 14 – basic protein 7, 281 – biochemical composition 6 – compositional changes during development 13 – function 14 – introduction 1 – glycoproteins 7 – levels of involvement 16 – molecular architecture 9

Subject Index 1081

– morphology 1 – disorders – – classification 20–24 – – definitions 15 – – levels of myelin involvement 16 – turnover 14 – myelination 10, 11, 12 – myelinogenesis 10 – regulation of myelinogenesis 10 – retarded myelination 18 myelination 3, 4, 10, 11, 12, 37–65 – arrest 51 – delayed myelination 51 – diffusion tensor imaging 41 – diffusion weighted imaging 41 – Flechsig 37 – hypomyelination 51 – iconography: preterm-adult pattern 51–65 – irregular myelination 51 – magnetization transfer imaging 42 – marker sites 43 – MRI pulse sequences 39 – myelination: time tables 42 myelinogenesis 10 myoneurogastrointestinal encephalopathy (MNGIE) 221–223 myotonic dystrophy, type 1 469–472 – anticipation 469, 470 – clinical variants 469 – Curschmann-Steinert disease 469 – genetic defect 470 – magnetic resonance imaging 470–472 – therapeutic options 470 – unstable CTG repeat 469 myotonic dystrophy, type 2 473–475 – clinical variants 473 – genetic defect 474 – magnetic resonance imaging 474, 475 – proximal myotonic dystrophy 473 – therapeutic options 474 – unstable CCTG repeat 474

neuronal ceroid lipofuscinoses 137–146 – age pigment 141 – Batten disease 137 – classification (table) 137 – genes involved 141 – incidence 137 – lysosomal location 140 – magnetic resonance imaging 143–146 – myelin reduction 141 – neuronal lipofuscin storage 140 – protein defects 141 – storage material in subtypes (table) 137 neurosarcoidosis 787, 788 node of Ranvier 4, 15 nonketotic hyperglycinemia 306–311 – clinical variants 306 – genetic defect 307 – glycine cleavage system 306 – magnetic resonance imaging 309, 310 – P-, T-, H- and L-proteins 307 – therapeutic options 308 Northern epilepsy 137

O occipital horn syndrome 400 oculo-cerebro-renal syndrome 387–391 oculo-dento-digital dysplasia 479–480 – clinical variants 479 – connexin 43 479 – genetic defect 479 – magnetic resonance imaging 480 oculogastrointestinal muscular dystrophy (OGIMD) 221–223 oligodendrocyte 4 – specific protein 7 ornithine transcarbamylase deficiency 360, 362, 365 ovarioleukodystrophy 481

N

P

NARP syndrome 227, 244 Nasu-Hakola disease 552–556 neonatal adrenoleukodystrophy 154–166 neonatal hypoglycemia 749–754 – causes 749 – glucose transporters 749 – magnetic resonance imaging 752–754 – selective vulnerability in hypoglycemia 749, 750 – therapeutic options 750, 751 neuromyelitis optica 567, 597

pattern recognition – examples 891–904 – in unclassified white matter disorders 889 – in white matter disorders 881–904 – – computer-aided pattern recognition 886 – – general characteristics 884 – – non-computerized pattern recognition 882 – – practical applications 886 – – sensitivity and specificity 881 – – special characteristics 884 – – structural image elements 884

Pelizaeus-Merzbacher disease and X linked spastic paraplegia type II 272–284 – clinical variants 272 – DM20 274 – genetic defect 275 – magnetic resonance imaging 276–284 – proteolipid protein 274 – X-inactivation 275 periventricular leukomalacia 719, 720, 722, 726, 727 peroxisomal acyl-CoA oxidase deficiency 172–175 – cranio-facial dysmorphism 172 – fatty acyl-CoA oxidase 172 – gene defect 172 – magnetic resonance imaging 174–175 peroxisomal biochemical functions 151 peroxisomal D-bifunctional protein deficiency 167–171 – clinical phenotype 167 – gene defect 168 – magnetic resonance imaging 168–171 peroxisomal single enzyme defects 153 peroxisome biogenesis 151 – disorders 153, 154–166 – – clinical variants 154 – – Zellweger syndrome 154 – – neonatal adrenoleukodystrophy 154 – – infantile refsum syndrome 154 – – pathology 155 – – pathogenesis 157 – – genetic defects 157, 158 – – therapy 159 – – magnetic resonance imaging 160–166 peroxisomes and peroxisomal disorders 151–153 phenylalanine metabolism 284 phenylketonuria 284–293 – clinical variants 284 – genetic defect 287 – magnetic resonance imaging 289–294 – maternal phenylketonuria 285 – neonatal screening 285 – phenylalanine – – hydroxylase 284 – – metabolism 284 – tetrahydrobiopterin 284 – – synthesis 285 – therapeutic options 288 3-phosphoglygerate dehydrogenase deficiency 369–371 PIBIDS 268–272

1082 Subject Index pigmentary orthochromatic leukodystrophy 557–558 – magnetic resonance imaging 558 Pollit syndrome 268–272 polyarteritis nodosa 777, polycystic lipomembranous osteodysplasia with sclerosing leukencephalopathy 526, 552–556 – clinical variants 552 – genetic defects 553 – magnetic resonance imaging 553–556 – Nasu-Hakola disease 552 – skeletal abnormalities 552 polyneuropathy, ophthalmoplegia, leukoencephalopathy, intestinal pseudo-obstruction (POLIP) 221–223 posterior reversible encephalopathy syndrome 679, 680, 699–709, 808 – complication of medical treatment 699 – eclampsia, pre-eclampsia 699 – hypertensive encephalopathy 699 – magnetic resonance imaging 701–709 – related conditions 699 – reversible posterior leukoencephalopathy syndrome 699 – therapeutic options 700 – uremic encephalopathies 700 posthypoxic-ischemic encephalopathy in neonates 718–749 – basal ganglia damage 718 – central cortical and subcortical damage 718 – germinal layer hemorrhage 720 – magnetic resonance imaging 723–748 – multicystic encephalopathy 720 – periventricular leukomalacia 718, 719 – prognostic factors 719 – Sarnat classification 719 – subcortical leukomalacia 718 – therapeutic options 723 – venous infarction 720 posthypoxic-ischemic damage 714–719 – anti-oxidance capacity 715 – arachidonic acid 715 – calcium-entry blockers 715 – excitatory amino acids 716 – free radicals 714, 715 – – scavengers 714 – glutamate 716 – Haber-Weiss reaction 714 – nitric oxide 715 – N-methyl-D-aspartate (NMDA) 716 – oxygen paradox 714

– patterns of white matter damage in oxygen deprivation 716, 717 – reperfusion damage 714 – superoxide dismutase 714 progressive multifocal leukoencephalopathy 628–634 – B-cell infection 629 – JC virus infection 628 – magnetic resonance imaging 630–634 – oligodendrocyte infection 629 – Papova-Polyoma virus 628 – simian virus 40 (SV40) 629 – therapeutic options 630 – tumor induction 630 propionic acidemia 300–306 – biotin cofactor 300 – clinical variants 300 – genetic defect 301 – ketotic hyperglycinemia 300 – magnetic resonance imaging 303–305 – propionyl-CoA carboxylase 300 – therapeutic options 301 proteolipid protein 7, 274 psychosine (in Krabbe disease) 89 pyruvate carboxylase deficiency 245–247 – biotin dependent carboxylases 246 – clinical variants 245 – genetic defect 245 – magnetic resonance imaging 246–247 – pyruvate-oxalate conversion 246 – therapeutic options 246 pyruvate dehydrogenase complex deficiency 226, 229, 224

R Radiotherapy 808–817 – acute postradiotherapy syndrome 809 – early delayed postradiotherapy syndrome 809 – late postradiotherapy syndrome 809 recombinant a-galactosidase 113 Refsum disease (heredopathia atactica polyneuritiformis) 91–194 – cardiomyopathy 191 – clinical variants 191 – genetic defect 193 – hereditary sensory and motor neuropathy type 4 191 – ichthyosis 191 – magnetic resonance imaging 194 – phytanic acid levels 191, 192 – phytanoyl-CoA hydroxylase 193 – pipecolic acidemia 193 – skeletal deformities 191 – therapeutic options 194

remyelination 18 retarded myelination 18, 51, 42 reversible posterior leukoencephalopathy syndrome 699–709 rheumatoid disease 781

S Salla disease 133–136 saltatory conduction 15 Sandhoff disease 103–111 Sanfilippo syndrome 83 Santavuori disease 137, 144, 145 Sarnat classification 719 Scheie syndrome 123, 124 Schilder diffuse sclerosis 567, 598, 599 Schmidt-Lantermann cleft 4 Schwann cell 4 selective vulnerability 25–36 – causes of selective involvement 30–35 – topistic areas 25 serine synthesis defect 369–371 – genetic defect 369 – magnetic resonance imaging 370, 371 – 3-phosphoglycerate dehydrogenase 369 – treatment options 369 sialic acid 134 – transporter 134 sickle cell disease 798 Sjögren syndrome 786 Sjögren-Larsson Syndrome 383–386 – clinical triad 383 – fatty alcohol-NAD+ oxidoreductase 383 – fatty aldehyde dehydrogenase 384 – genetic defect 383 – leukotriene B4 384 – magnetic resonance imaging 384–386 – therapeutic options 384 Sly syndrome 125 Sneddon syndrome 785 Spielmeijer-Vogt disease 137 Stejskal-Tanner sequence 840 subacute combined degeneration of the cord 350 subacute sclerosing panencephalitis 640–644 – absence of M protein 642 – anti-measles virus antibody 640, 641 – M protein gene mutations 641 – magnetic resonance imaging 642–644 – measles infection 640 – paramyxoviridae family 641 – slow virus infection 640 – stages of disease 640, 641

Subject Index 1083

subcortical arteriosclerotic encephalopathy 767–772 – Binswanger disease 767–772 – criteria 767 – état – – criblé 767 – – lacunaire 767 – lacunar infarctions 767 – magnetic resonance imaging 768–772 – therapeutic options 768 – Virchow-Robin spaces 767 subcortical leukomalacia 718 sulfite oxidase deficiency 372–376 18q– syndrome 281–283 – clinical variants 281 – contiguous gene syndrome 281 – magnetic resonance imaging 282, 283 – myelin basic protein 281 syphilitic arteritis 795 systemic lupus erythematosus 781–784

T Takayasu arteritis 776, 777 Tay syndrome 268–272 Tay-Sachs disease 103–111 temporal arteritis 775 tetrahydrobiopterin deficiency 285 – synthesis 285 thrombotic thrombocytopenic purpura 699 toxic encephalopathies 664–678 – Bonhoeffer reaction types 664 – chemical affinity 665 – classification 667 – drug abuse 670 – endogenous intoxications 667 – exogenous-external intoxications 667 – fetal intoxications 677 – historic examples 664 – iatrogenic intoxications 669 – lipophilic substances 665 – magnetic resonance imaging (examples) 665–678 – mechanisms of selective vulnerability 665 – organic solvents 670 – topistic areas 664 trichothiodystrophy with photosensitivity 268–272 – basal transcription factor II H 269 – clinical variants 268 – DNA-repair 269 – genetic defects 269 – hair abnormalities 268 – magnetic resonance imaging 270–271

– Pollit syndrome 268 – Tay syndrome 268 – xeroderma pigmentosum tuberculosis 795, 796

269

U Uhthoff symptom 212 urea cycle 360 – disorders 360–369 – – arginase deficiency 360 – – argininosuccinate lyase deficiency 360 – – argininosuccinate synthetase deficiency 360 – – carbamyl phosphate synthetase deficiency 360 – – female heterozygotes of ornithine transcarbamylase deficiency 360 – – genetic defects 362 – – hyperargininemia 360 – – magnetic resonance imaging 363–369 – – ornithine transcarbamylase deficiency 360 – – therapeutic options 362 – – urea cycle defects 360

V Van Bogaert-Bertrand disease 326–333 vanishing white matter 481–494 varicella-zoster vasculitis 796 vasculitis 773–800 – ANCA test 789 – angiotensin converting enzyme 787 – anti-phospholipid antibody syndrome 785 – Behçet disease 789 – benign primary angiitis 776 – Borrelia burgdorferi 792 – Churg-Strauss syndrome 789 – classification 774 – CREST 786 – drug-induced vasculitis 797 – erythema migrans 793 – giant cell arteritis 775 – granulomatous angiitis 774 – herpes zoster ophthalmica 797 – hydroxyurea 799 – hypercoagulative states 798 – intravascular lymphomatosis 798 – Lyme disease 792 – magnetic resonance imaging 799–800 – microscopic polyarteritis 789 – Moyamoya syndrome 777 – neurosarcoidosis 787 – polyarteritis nodosa 777 – rheumatoid disease 781

– sickle cell disease 798 – Sjögren syndrome 786 – Sneddon syndrome 785 – syphilitic arteritis 795 – systemic lupus erythematosus 783 – Takayasu arteritis 776 – temporal arteritis 775 – tuberculosis 795 – varicella-zoster vasculitis 796 – Wegener disease 789 venous infarction 720, 724 vitamin B12 deficiency (see also cobalamin deficiency) 343, 346, 354, 356

W Walker-Warburg syndrome 451, 455, 466 Wallerian degeneration 832–837 – magnetic resonance imaging 834–838 – stages of myelin degradation 832, 833 Wegener disease 789, 790 Whipple disease 658–663 – clinical triad 658 – CNS involvement 658 – lipofuscin granules 658 – magnetic resonance imaging 659–663 – therapeutic options 659 – Tropheryma Whippelii 658 white matter lesions in the elderly 759–766 – age-related changes 759 – cerebral perfusion 760 – leukoaraiosis 759 – magnetic resonance imaging 761–766 – mild cognitive impairment 759 – MR grading of lesions 762 – quantitative MR techniques 759 – risk factors 760 Wilson disease 392–399 – ceruloplasmin 393 – clinical variants 392, 393 – copper – – concentration 393 – – homeostasis 394 – – toxicity 395 – genetic defect 394 – hepatolenticular degeneration 392 – Kayser-Fleischer rings 392 – magnetic resonance imaging 396–399 – metallothionein 394 – therapeutic options 395

X Xeroderma pigmentosum 260, 269 X-linked adrenoleukodystrophy 176–190

1084 Subject Index – – – – – – – –

ABCD2 gene 182 adrenal insufficiency 176 clinical variants 176 fatty acid chain elongation 180 female carriers 177 genetic defect 179 Loes score 186 Lorenzo oil 181

– magnetic resonance imaging 182–190 – MTR 187, 857, 858 – pathogenesis 180 – therapeutic options 181 – unusual forms of X-ALD 177 – very-long-chain fatty acids (VLCFA) 177

– VLCFA b-oxidation 179 – VLCFA-CoA synthase 179 X-linked ichthyosis 83

Z Zellweger syndrome

154–166