J. Fernandes· J.-M. Saudubray . G. Van den Berghe (Eds.): Inborn Metabolic Diseases Springer-Verlag Heidelberg GmbH J. Fernandes J.-M. Saudubray G. Van den Berghe (Eds.)

Inborn Metabolic Diseases

Diagnosis and Treatment

3rd, Revised Edition

With 66 Figures and 57 Tables

, Springer Dr. JOHN FERNANDES Professor Emeritus of Pediatrics Veldweg 87 8051 NP Hattem, The

Professor JEAN-MARIE SAUDUBRAY Hospital Necker-Enfants Malades 149 Rue de Sevres 75743 Paris Cedex 15, France

Professor GEORGES VAN DEN BERGHE Christian de Duve Institute of Cellular Pathology Universite Catholique de Louvain Avenue Hippocrate 75 1200 Brussels, Belgium

Cover Illustration: Putti by della Robbia at Spedale degli Innocenti, Firenze, Italy

Library of Congress Cataloging in Publication Data applied for. Die Deutsche Bibliothek - CIP-Einheitsaufnahme Inborn metabolic diseases: diagnosis and treatment/I. Fernandes ... - 3., rev. ed.

ISBN 978-3-662-04287-8 ISBN 978-3-662-04285-4 (eBook) DOI 10.1007/978-3-662-04285-4

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© Springer-Verlag Berlin Heidelberg 2000 Originally published by Springer-Verlag Berlin Heidelberg New in 2000 Softcover reprint of the hardcover 3rd edition 2000

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Printed on acid-free paper SPIN: 10708260 22/3134/goh - 5 4 3 2 1 0 Preface

Five years have passed since the second edition of With respect to the contents of the book, most Inborn Metabolic Diseases; Diagnosis and Treatment chapters have been rewritten or extensively revised. A was published. The third edition, now being presented, few chapters from the second edition have been has been thoroughly updated and revised. Again, the deleted, since their contents are discussed in other clinical presentation, the methods to arrive at the chapters of the present edition. A few new chapters diagnosis and the treatment of the patient have have been introduced, such as a general chapter on remained the focus of the book, that for a large part treatment, which gives a comprehensive list of present has been written by clinicians for clinicians. The scope treatments and new trends, a chapter on persistent of the readership has enlarged: from the original teams hyperinsulinemic hypoglycemia, a combined chapter of pediatricians, biochemists and dieticians it now also on disorders of ketogenesis and ketolysis, a chapter on encompasses neurologists, internists, geneticists and disorders of proline and serine metabolism, a chapter psychosocial workers. This reflects the fact that for on disorders of cholesterol synthesis, and a chapter on many inborn metabolic diseases the survival of the defective leukotriene synthesis. For more detailed patients and their quality of life have improved. A information, particularly with respect to pathophysiol• combination of facts has contributed to this: above all ogy and genetics, we recommend the eighth edition of refined methods for biochemical monitoring of the the Molecular and Metabolic Bases of Inherited Disease, condition of the patients, and treatments tailored to edited by Charles R. Scriver et al (Mc Graw-Hill, 2000). various stages of the disease and ages of the patients. In view of the rapidly expanding knowledge of Furthermore, refined molecular genetic investigation clinical, metabolic and genetic variability and their has uncovered not only a great heterogeneity of most influence on prognosis and treatment, it is important to metabolic disorders, but also contributed to genetic be aware of the existence of networks of experts and counselling. laboratories specialized in the diagnosis and treatment The book can be used in two main situations. When of inherited metabolic disorders. For countries of the the diagnosis is already suspected, the reader can go European Union such a list is compiled by the Society dir"ectly to the relevant chapter, which is always for the Study of Inborn Errors of Metabolism (SSIEM), presented in the design common to all chapters. for the United States and Canada, Japan and Australia However, when the diagnosis is unknown, the physi• by the American, Japanese and Australian Societies of cian can first refer to Chapter 1, which presents Inherited Metabolic Diseases (SIMD, JIMD, and AIMD, symptoms according to four main entries: symptoms respectively) . in the newborn infant, acute symptoms of later onset The editors welcome new authors of old and new and recurrent attacks, chronic and general progressive chapters and pay tribute to the authors who, though symptoms, or symptoms related to an organ (system). not participating this time, laid the framework for this Each symptom can be found in the index list of the book. chapter, which refers either to the text, a table, a figure, an algorithm or a list of disorders, or a combination of John Fernandes these. From this introductory information it is easy to Jean-Marie Saudubray proceed to a relevant chapter in order to obtain more Spring 2000 Georges van den Berghe specific information. Contents

Part I 13. Defects of the Respiratory Chain Diagnosis and Treatment: A. Munnich ...... 157 General Principles

1. Clinical Approach to Inherited Metabolic Diseases Part IV J.-M. Saudubray, H. Ogier de Baulny, Disorders of Amino Acid Metabolism and C. Charpentier ...... 3 and Transport

2. Diagnostic Procedures: 14. The Hyperphenylalaninaemias Function Tests and Postmortem Protocol I. Smith and P. Lee ...... 171 J. Fernandes, J.-M. Saudubray, and J. Huber 43 15. Disorders of Tyrosine Metabolism 3. Emergency Treatments E.A. Kvittingen and E. Holme ...... 185 H. Ogier de Baulny and J.-M. Saudubray 53 16. Branched-Chain Organic Acidurias 4. Psychosocial Care of the Child and Family H. Ogier de Baulny and J.-M. Saudubray ...... 195 J.C. Harris ...... 63 17. Disorders of the Urea Cycle 5. Treatment: Present Status and New Trends J.V. Leonard ...... 213 J.H. Walter and J.E. Wraith ...... 75 18. Disorders of Sulfur Amino Acid Metabolism G. Andria, B. Fo",ler, and G. Sebastio 223 Part II Disorders of Carbohydrate Metabolism 19. Disorders of Ornithine and Creatine Metabolism 6. The Glycogen-Storage Diseases V.E. Shih and S. Stockler-Ipsiroglu ...... 233 J. Fernandes and G.P.A. Smit ...... 87 20. Disorders of Lysine Catabolism 7. Disorders of Galactose Metabolism and Related Cerebral Organic-Acid Disorders 103 R. Gitzelmann ...... G.F. HoffInann ...... 241

8. Disorders of Fructose Metabolism 21. Nonketotic Hyperglycinemia G. van den Berghe ...... 111 K. Tada ...... 255

9. Persistent Hyperinsulinemic Hypoglycemia 22. Disorders of Proline and Serine Metabolism P. de Lonlay and J.-M. Saudubray ...... 117 J. Jaeken ...... 259

Part III 23. Transport Defects of Amino Acids Disorders of Mitochondrial Energy at the Cell Membrane: Cystinuria, Hartnup Metabolism Disease, and Lysinuric Protein Intolerance O. Simell, K. Parto, and K. Niinto-Salonen ...... 265 10. Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle D.S. Kerr, I.D. Wexler, and A.B. Zinn 127 Part V 11. Disorders of Fatty Acid Oxidation Vitamin-Responsive Disorders C.A. Stanley ...... 139 24. Biotin-Responsive Multiple Carboxylase 12. Disorders of Ketogenesis and Ketolysis Deficiency A.A.M. Morris ...... 151 E.R. Baumgartner and T. Suormala ...... 277 VIII Contents

25. Disorders of Cobalamin and Folate Transport Part IX and Metabolism Disorders of Metal Transport D.S. Rosenblatt ...... 33. Copper Transport Disorders: Wilson Disease and Menkes Disease Part VI D.W. Cox and Z. Turner ...... 385 Neurotransmitter and Small Peptide Disorders 34. Genetic Defects Related to Metals Other Than Copper 26. Disorders of N eurotransmission F. Jochum and 1. Lombeck ...... 393 J. Jaeken, C. Jakobs, and R. Weyers 301 27. Disorders in the Metabolism of Glutathione and Imidazole Dipeptides A. Larsson and J. Jaeken ...... 313 Part X Organelle-Related Disorders: Part VII Lysosomes, Peroxisomes, and Golgi Disorders of Lipid and Bile Acid Metabolism and Pre-Golgi Systems 28. Dyslipidemias 35. Disorders of Sphingolipid Metabolism A. Rodriguez-Oquendo and P.G. Barth ...... 401 P.O. Kwiterovich Jr...... 321 36. Mucopolysaccharidoses 29. Disorders of Cholesterol Synthesis and Oligosaccharidoses G.F. Hoffmann and D. Haas ...... 337 M. Beck ...... 413 30. Disorders of Bile-Acid Synthesis 37. Peroxisomal Disorders P.T. Clayton ...... 343 B.T. Poll-The and J.-M. Saudubray ...... 423 38. Congenital Defects of Glycosylation: Part VIII Disorders of N-Glycan Synthesis Disorders of Nucleic Acid J. Jaeken ...... 433 and Heme Metabolism 39. Cystinosis 31. Disorders of Purine M. Broyer ...... 439 and Pyrimidine Metabolism G. Van den Berghe, M.-F. Vincent, 40. Primary Hyperoxalurias and S. Marie ...... 355 P. Cochat and M.-O. Rolland ...... 445

32. The Porphyrias 41. Leukotriene-C4-Synthesis Deficiency N.G. Egger, D.E. Goeger, and K.E. Anderson .... 369 E. Mayatepek ...... 453 List of Contributors

K.E. ANDERSON D.W. Cox Department of Preventive Medicine Department of Medical Genetics, and Community Health, University of Alberta, The University of Texas Medical Branch, 8-39 Medical Sciences Building, Galveston, TX 77555-1109, USA Edmonton, AB T6G 2H7, Canada

G. ANDRIA N.G. EGGER Department of Pediatrics, Department of Preventive Medicine Federico II University, and Community Health, Via Sergio Pansini 5, The University of Texas Medical Branch, 80131 Naples, Italy Galveston, TX 77555-1109, USA

FERNANDES P.G. BARTH J. Department of Pediatrics, Pediatric Neurology Unit, University Hospital, Emma Children's Hospital, Private address: University of Amsterdam, Veldweg 87, 8051NP Hattem, P.O.B. 22700, 1100 DE Amsterdam, The Netherlands The Netherlands B. FOWLER E.R. BAUMGARTNER Basler Kinderspital, Basel University, University Children's Hospital Basel, Romergasse 8, 4005 Basel, Metabolic Unit, Switzerland Romergasse 8, 4005 Basel, Switzerland R. GITZELMANN Abteilung fUr Stoffwechsel M. BECK und Molekularkrankheiten U niversitatskinderklinik, Universitatskinderklinik, Langenbeckstrasse 1, Steinwiesstrasse 75, 55101 Mainz, Germany 8032 Zurich, Switzerland

M. BROYER D.E. GOEGER N ephrologie Pediatrique Department of Preventive Medicine Hopital Necker Enfants Malades, and Community Health, 149 Rue de Sevres, The University of Texas Medical Branch, 75743 Paris Cedex 15, France Galveston, TX 77555-1109, USA D. HAAS C. CHARPENTIER Universitatskinderklinik, Hopital Necker Enfants Malades, 1m Neuenheimer Feld 150, 149 Rue de Sevres, 69120 Heidelberg, Germany 75743 Paris Cedex 15, France J.C. HARRIS P.T. CLAYTON Department of Psychiatry Institute of Child Health, and Behavioral Sciences, 30 Guilford Street, Johns Hopkins Medical Institutions, WCIN lEH, UK 600 North Wolfe Street, CMSC 341, Baltimore, MD 21287-3325, USA P. COCHAT Unite de Nephrologie Pediatrique, G.F. HOFFMANN Hopital Edouard Herriot U niversitatskinderklinik, and Universite Claude Bernard, 1m Neuenheimer Fe1d 150, 69437 Lyon Cedex 03, France 69120 Heidelberg, Germany X List of Contributors

E. HOLME A. LARSSON Department of Clinical Chemistry, Dept. of Pediatrics, Karolinska Institutet, Goteborg University, Huddinge University Hospital, Sahlgrenska University Hospital, 141-86 Huddinge, Sweden 41345 Gothenburg, Sweden Ph. LEE J. HUBER Metabolic Unit, The Middlesex Hospital, Pathology Department, The University College Hospitals, Wilhelmina Children's Hospital, NHS Trust, Mortimer Street, University of Utrecht, London, WIN 8AA, UK P.O. Box 85090, J.V. LEONARD 3508 AB Utrecht, The Netherlands Biochemistry, Endocrinology and Metabolic Unit, J. JAEKEN Institute of Child Health, Centre for Metabolic Disease, 30 Guilford Street, Department of Paediatrics, London WCIN lEH, UK University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium 1. LOMBECK Medizinische Einrichtungen C. JAKOBS der Heinrich Heine Universitat, Metabolic Unit 949B, Zentrum fUr Kinderheilkunde, Department of Clinical Chemistry, Postfach 101007, Free University Hospital Amsterdam, 40001 Dusseldorf, Germany De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands P. dE LONLAY Hopital Necker-Enfants Malades, F. JOCHUM 149 Rue de Sevres, Charite Universitatsklinikum 75743 Paris Cedex 15, France der Humboldt-Universitat zu Berlin, Campus Virchow-Klinikum, S. MARIE Klinik fUr Neonatologie, Laboratory of Physiological Chemistry, Augustenburger Platz 1, Christian de Duve Institute 13353 Berlin, Germany of Cellular Pathology, University of Louvain Medical School, D.S. KERR Avenue Hippocrate 75.39, Center for Human Genetics, 1200 Brussels, Belgium Rainbow Babies' and Children's Hospital, E. MAYATEPEK Case Western Reserve University, Department of General Pediatrics, 11100 Euclid Ave., U niversitatskinderklinik, Cleveland, OH 44106-6004, USA 1m Neuenheimer Feld 150, 69120 Heidelberg, Germany E.A. KVITTINGEN Institute of Clinical Biochemistry, A.A.M. MORRIS University of Oslo, Department of Child Health, Rikshospitalet, University of , 0027 Oslo, Norway Royal Victoria Infirmary, Newcastle upon Tyne, NEI 4LP, UK P.O. KWITEROVICH Jr. Lipid Research-Atherosclerosis Division, A. MUNNICH Department of Pediatrics, Department of Genetics, The Johns Hopkins Hospital, Hopital Necker-Enfants Malades, 600 N. Wolfe Street, 149 rue de Sevres, Baltimore, MD 21287-3654, USA 75743 Paris Cedex 15, France List of Contributors XI

K. NANTO-SALONEN G. SEBASTIO Department of Pediatrics, Department of Pediatrics, University of Turku, Federico II University, Kiinamyllynkatu 4-8, Via Sergio Pansini 5, 20520 Turku, Finland 80131 Naples, Italy

OGIER BAULNY H. de V.E. SHIH Service de Neuropediatrie, Amino Acid Disorder Laboratory, Maladies Metaboliques, Pediatrics and Neurology Services, H6pital Robert Debre, Massachusetts General Hospital, 48 Boulevard Serurier, Building 149, 13th Street, 75019 Paris, France Boston, MA 02129, USA

K. PARTO O. SIMELL Department of Pediatrics, Department of Pediatrics, University of Turku, University of Turku, Kiinamyllynkatu 4-8, Kiinamyllynkatu 4-8, 20520 Turku, Finland 20520 Turku, Finland

B.T. POLL-THE Wilhelmina Children's Hospital, G.P.A. SMIT University of Utrecht, Pediatrics Department, P.O. Box 85090, University Hospital, 3508 AB Utrecht, The Netherlands P.O. Box 30001, 9700 RB Groningen, E.A. Roberts The Netherlands Division of Gastroentrology and Nutrition, I. SMITH University of Toronto, Metabolic Unit, 555 University Avenue, The Hospital for Sick Children, Toronto, Ontario M5GIX8, NHS Trust, Canada Great Ormond Street, London, WC1N 3JH, UK A. RODRIGUEZ-OQUENDO

Department of Medicine, C.A. STANLEY Sinai Hospital of Baltimore, Endocrine Division, Baltimore, MD 21287-3654, USA The Children's Hospital of Philadelphia, 34th Street & Civic Center Boulevard, M.-O. ROLLAND Philadelphia, P A 19104, USA Unite de Nephrologie Pediatrique, H6pital Edouard Herriot S. STOCKLER-IpSIROGLU and Universite Claude Bernard, Department of Pediatrics, 69437 Lyon Cedex 03, France National Newborn-Screening Laboratory,

D.S. ROSENBLATT University of Vienna, Division of Medical Genetics, Wiihringer GiirteI18-20, 1090 Vienna Department of Medicine, Austria McGill University Health Centre, 687 Pine Avenue West, T. SUORMALA Montreal, Quebec H3A 1A1, Canada University Children's Hospital Basel, Metabolic Unit, Romergasse 8, J.M. SAUDUBRAY 4005 Basel, Switzerland Service de Maladies Metaboliques, Departement de Pediatrie, K. TADA H6pital Necker Enfants Malades, NTT Tohoku Hospital, 149 Rue de Sevres, 2-29-1, Yamatomachi, 75043 Paris Cedex 15, France Wakabayashi, Sendai 983, Japan XII List of Contributors

Z. TOMER R. WEYERS Department of Medical Genetics, Institute of Neurology, University of Copenhagen, University Hospital , Panum Institute, Reinier Postlaan 4, Blegdamsvej 3, PO Box 9101, 6500 HB Nijmegen, 2200 KBH N Copenhagen, The NetlIerlands Denmark I.D. WEXLER G. VAN den BERGHE Department of Pediatrics, Laboratory of Physiological Chemistry, Case Western Reserve University, Christian de Duve Institute 11100 Euclid Ave., of Cellular PatlIology, Cleveland, OH 44106-6004, USA University of Louvain Medical School, Avenue Hippocrate 75, J.E. WRAITH 1200 Brussels, Belgium Willink Biochemical Genetics Unit, M.-F. VINCENT Royal Manchester Children's Hospital, Laboratory of Physiological· Chemistry, Manchester, M27 4HA, UK Christian de Duve Institute of Cellular Pathology, A.B. ZINN University of Louvain Medical School, Center for Human Genetics, Avenue Hippocrate 75, University Hospital of Cleveland, 1200 Brussels, Belgium Case Western Reserve University, 11100 Euclid Ave., J.H. WALTER Cleveland, OH 44106-6004, USA Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, M27 4HA, UK