This page intentionally left blank A Clinical Guide to Inherited Metabolic Diseases This user-friendly clinical handbook provides a clear and concise overview of how to go about recognizing and diagnosing inherited metabolic diseases. The reader is led through the diagnostic process from the identification of those features of an illness suggesting that it might be metabolic through the selection of appropriate laboratory investigation to a final diagnosis. The book is organized into chapters according to the most prominent presenting problem of patients with inherited metabolic diseases: neurologic, hepatic, cardiac, metabolic acidosis, dysmorphism, and acute catastrophic illness in the newborn. It also includes chapters on general principles, laboratory investigation, neonatal screening, and the principles of treatment. This new edition includes much greater depth on mitochondrial disease and congenital disor- ders of glycosylation. The chapters on neurological syndrome and newborn screening are greatly expanded, as are those on laboratory investigation and treatment, to take account of the very latest technological developments. Dr J. T. R. Clarke is Professor of Paediatrics at the University of Toronto and a Senior Associate Scientist in the Research Institute of the Hospital for Sick Children, as well as continuing Head of the Genetic Metabolic Diseases Program of the Hospital. He is a Fellow of the Royal College of Physicians of Canada and the Canadian College of Medical Geneticists. He has won awards for postgraduate paediatric teaching and for excellence in paediatric medical care. He is consulted extensively by government and industry on matters relating to the management of inherited metabolic diseases and newborn screening. He is internationally respected for his expertise in the general area of metabolic genetics and is widely sought as a speaker and educator in this field. He has given over 100 invited lectures on inherited metabolic diseases in countries around the globe. This page intentionally left blank A Clinical Guide to Inherited Metabolic Diseases Third Edition JoeT.R.Clarke, MD, PhD, FRCPC Division of Clinical & Metabolic Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8 CANADA cambridge university press Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge cb2 2ru,UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Informationonthistitle:www.cambridge.org/9780521614993 © Joe T.R.Clarke 2005 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2005 isbn-13 978-0-511-13453-1 eBook (MyiLibrary) isbn-10 0-511-13453-3 eBook (MyiLibrary) isbn-13 978-0-521-61499-3 paperback isbn-10 0-521-61499-6 paperback Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Contents Reviewsoffirstedition page x Reviews ofsecond edition xi List of tables xii List of figures xvi Preface xix 1General principles 1 Introduction 1 Some general metabolic concepts 2 Disease results from point defects in metabolism 4 Accumulation of substrate 4 Accumulation of a normally minor metabolite 6 Deficiency of product 7 Secondary metabolic phenomena 9 Inborn errors of metabolism are inherited 9 Autosomal recessive disorders 9 X-linked recessive disorders 11 Autosomal dominant disorders 13 Mitochondrial inheritance 14 Inherited metabolic diseases may present at any age 16 Three sources of diagnostic confusion 17 Confusion with common acquired conditions 17 Confusion caused by association with intercurrent illness 20 Confusion arising from genetic heterogeneity 21 Congenital malformations and inborn errors of metabolism 21 The internet is particularly important 21 Suggested reading 27 2Neurologic syndrome 28 Chronic encephalopathy – without non-neural involvement 29 Gray matter disease (poliodystrophy) 29 Psychomotor retardation or dementia 29 Seizures 34 White matter disease (leukodystrophy) 47 v vi Contents Chronic encephalopathy – with non-neural tissue involvement 50 Acute encephalopathy 53 Hyperammonemia 55 Leucine encephalopathy (maple syrup urine disease – MSUD) 61 Reye-like acute encephalopathy (fatty acid oxidation defects) 61 Acute encephalopathy with metabolic acidosis 63 Hypoglycemia 63 Stroke 63 Movement disorder 63 Ataxia 63 Choreoathetosis and dystonia 69 Parkinsonism 71 Myopathy 72 Acute intermittent muscle weakness 72 Progressive muscle weakness 73 Myoglobinuria (myophosphorylase deficiency phenotype) 74 Myoglobinuria (CPT II deficiency phenotype) 77 Myopathy as a manifestation of multisystem disease (mitochondrial myopathies) 77 Autonomic dysfunction 79 Psychiatric problems 79 Suggested reading 87 3Metabolic acidosis 90 Buffers, ventilation, and the kidney 90 Is the metabolic acidosis the result of abnormal losses of bicarbonate or accumulation of acid? 92 Metabolic acidosis caused by abnormal bicarbonate losses 92 Metabolic acidosis resulting from accumulation of organic anion 94 Lactic acidosis 94 Pyruvate accumulation 95 PDH deficiency 98 PC deficiency 99 Multiple carboxylase deficiency 99 NADH accumulation 100 Ketoacidosis 101 Mitochondrial acetoacetyl-CoA thiolase deficiency (␤-ketothiolase deficiency) 102 Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency 103 Organic aciduria 104 Methylmalonic acidemia (MMA) 104 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency 110 Glutaric aciduria 110 Dicarboxylic aciduria 112 Ethylmalonic aciduria 113 D-Lactic acidosis 113 vii Contents Adventitious organic aciduria 114 Suggested reading 115 4Hepatic syndrome 116 Jaundice 116 Unconjugated hyperbilirubinemia 116 Conjugated hyperbilirubinemia 118 Hepatomegaly 118 Hypoglycemia 120 Ways to increase glucose production 120 Ways to decrease peripheral glucose utilization 122 An approach to the differential diagnosis of hypoglycemia 125 Hepatocellular dysfunction 133 Investigation 139 Liver function tests 139 Fasting tests 139 Suggested reading 141 5Cardiac syndromes 143 Cardiomyopathy 143 Initial investigation of possible inherited metabolic cardiomyopathy 148 Glycogen storage disease, type II (GSD II or Pompe disease) 149 Primary systemic carnitine deficiency 151 Fabry disease 151 Mitochondrial cardiomyopathies 152 Arrhythmias 153 Coronary artery disease 155 Familial hypercholesterolemia 155 Suggested reading 159 6Storage syndrome and dysmorphism 162 General characteristics of the dysmorphism resulting from inborn errors of metabolism 162 What are the types of inherited metabolic diseases in which dysmorphism might be expected to be prominent? 164 Lysosomal disorders 165 Peroxisomal disorders 178 Mitochondrial disorders 182 Biosynthetic defects 183 What sort of metabolic studies are most likely to be diagnostically productive in the investigation of dysmorphism? 195 Suggested reading 196 7Acute metabolic illness in the newborn 198 Suspicion 198 Initial laboratory investigation 200 Five clinical ‘syndromes’ 202 viii Contents Encephalopathy without metabolic acidosis 203 Maple syrup urine disease (MSUD) 203 Urea cycle enzyme defects (UCED) 205 Nonketotic hyperglycinemia (NKHG) 208 Pyridoxine-dependent seizures 209 Peroxisomal disorders (Zellweger syndrome) 209 Molybdenum cofactor deficiency (sulfite oxidase/xanthine oxidase deficiency 209 Encephalopathy with metabolic acidosis 210 Organic acidurias 210 Congenital lactic acidosis 213 Dicarboxylic aciduria 214 Neonatal hepatic syndrome 215 Jaundice 215 Severe hepatocellular dysfunction 217 Hypoglycemia 220 Cardiac syndrome 222 Intractable cardiac arrhythmias 222 Cardiomyopathy 222 Nonimmune fetal hydrops 223 Initial management 223 Summary comments 226 Suggested reading 226 8Newborn screening 228 Screening for medical intervention 230 Screening for reproductive planning 230 Screening to answer epidemiological questions 231 Case-finding 232 Problems created by false positive screening tests 232 Screening technology 233 Bacterial inhibition assays – the ‘Guthrie test’ 233 Tandem MSMS 235 Radioimmunoassay 238 Enzyme assay 238 Specific mutation testing 239 Suggested reading 239 9 Laboratory investigation 241 Studies on the extent and severity of pathology 245 Studies directed at the classification of disease processes (the ‘metabolic screen’) 245 Investigation of ‘small molecule disease’ 246 Plasma ammonium 246 Plasma lactate and pyruvate 246 Plasma ketones and free fatty acids 246 Amino acid analysis 247 Neurotransmitters 253 Organic acid analysis 254 Acylcarnitines and acylglycines 256 Porphyrins 260 Approaches to the investigation of metabolic disorders 263 ix Contents Cellular metabolic screening studies 263 Provocative testing 267 Enzymology 270 Molecular genetic studies 271 Investigation of ‘organelle disease’ 274 Lysosomal disorders 274 Disorders of mitochondrial energy metabolism 285 Peroxisomal disorders 291 Suggested reading 295 10 Treatment 297 Control of accumulation of substrate 297 Restricted dietary intake 297 Control of endogenous production of substrate 301 Acceleration of removal of substrate 303 Replacement of product 306 Reaction product replacement 306 Gene product replacement 307 Gene product