Inborn Errors of Metabolism in Humans

Previous Symposia of the Society for the Study of Inborn Errors of Metabolism*

1. Neurometabolic Disorders in Childhood. Ed. K. S. Holt and J. Milner 1963 2. Biochemical Approaches to Mental Handicap in Children. Ed. J. D. Allan

and K. S. Holt 1964 3. Basic Concepts of Inborn Errors and Defects of Steroid Biosynthesis.

Ed. K. S. Holt and D. N. Raine 1965 4. Some Recent Advances in Inborn Errors of Metabolism. Ed. K. S. Holt and

v. P. Coffey 1966 5. Some Inherited Disorders of Brain and Muscle. Ed. J. D. Allan and D. N.

Raine 1969 6. Enzymopenic Anaemias, Lysosomes and other papers. Ed. J. D. Allan,

K. S. Holt, J. T. Ireland and R. J. Pollitt 1969 7. Errors of Phenylalanine Thyroxine and Testosterone Metabolism. Ed.

W. Hamilton and F. P. Hudson 1970 8. Inherited Disorders of Sulphur Metabolism. Ed. N. A. J. Carson and

D. N. Raine 1971 9. Organic Acidurias. Ed. J. Stern and C. Toothill 1972

10. Treatment of Inborn Errors of Metabolism. Ed. J. W. T. Seakins, R. A. Saunders and C. Toothill 1973

11. Inborn Errors of Skin, Hair and Connective Tissue. Ed. J. B. Holton and J. T. Ireland 1975

12. Inborn Errors of Calcium and Bone Metabolism. Ed. H. Bickel and J. Stern 1976

13. Medico-Social Management of Inherited Metabolic Disease. Ed. D. N. Raine 1977

14. The Cultured Cell and Inherited Metabolic Disease. Ed. R. A. Harkness and F. Cockburn 1977

15. Inborn Errors of Immunity and Phagocytosis. Ed. F. Guttier, J. W. T. Seakins and R. A. Harkness 1979

16. Inherited Disorders of Carbohydrate Metabolism. Ed. D. Burman, J. B. Holton and C. A. Pennock 1980

17. Transport and Inherited Disease. Ed. N. R. Belton and C. Toothill 1981

The Society exists to promote exchanges of ideas between workers in different disciplines who are interested in any aspect of inborn metabolic disorders. Particulars of the Society can be obtained from the Editors of this Symposium.

*- Symposia 1 10 published by E & $. Livingstone

Inborn Errors of Metabolism in Humans Monograph based upon Proceedings of the International Symposium held in Interlaken, Switzerland, September 2-5, 1980.

Edited by Forrester Cockburn and Richard Gitzelmann

MT~'i LIMITED International Medical Publishers

Published in the UK and Europe by MTP Press Limited

Falcon House Lancaster, England

British Library Cataloguing in Publication Data

Inborn errors of metabolism in humans.-(Symposium of the Society for the Study of Inborn Errors of Metabolism; 18) 1. Metabolism, Inborn errors of-Congresses I. Cockburn, Forrester II. Gitzelmann, R. III. Series 616.3'9042 RC627.8

ISBN-13: 978-94-009-7327-5 e-ISBN-13: 978-94-009-7325-1 001: 10.1007/978-94-009-7325-1

Copyright © 1982 The Society for the Study of Inborn Errors of Metabolism

Softcover reprint of the hardcover 1st edition 1 982

All rights reserved. No part of this publication may be reproduced, stored in a retrieval

system, or transmitted in any form or by any means, electronic, mechanical, photocopying,

recording or otherwise, without prior permission from the publishers.

Typeset by Macmillan India Ltd, Bangalore

by McCorquodale (Scotland) Ltd.

Contents

list of contributors

Opening remarks

Dedication

SECTION ONE

Pathogenic Mechanisms of Inborn Errors: Clinical Implications of Biochemical Diversity

1 Molecular aspects of genetic heterogeneity

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xiii

xv

H. Harris 3

2 Inborn errors of purine metabolism-The Milner Lecture W. L. Nyhan 13

3 Vitamin-responsive inherited metabolic disorders: propionic acidaemia and methylmalonic acidaemia L. E. Rosenberg 37

4 Homocystinuria: clinical and biochemical heterogeneity N. A. J. Carson 53

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vi CONTENTS

5 Hereditary defects of steroid biosynthesis A. Prader and M. Zachmann 69

6 Blood~brain barrier amino-acid transport: clinical implications W. M. Pardridge 87

SECTION TWO

Treatment: New Aspects and Limits, Transplantation, Replacement Therapy, Genetic Engineering

7 Recent studies on the maturation of lysosomal enzymes E. F. Neufeld 103

8 Enzyme substitution by fibroblast transplantation M. F. Dean, H. Muir, P. F. Benson and L. R. Button 111

9 Artificial cell-encapsulated enzymes and adsorbents in congenital metabolic disorders T. M. S. Chang 131

10 Prospects for enzyme replacement therapy in heritable metabolic disorders R. O. Brady, J. A. Barranger, P. G. Pentchev, F. S. Furbish and A. E. Gal 139

CONTENTS

11

12

13

14

15

SECTION THREE

Inborn Errors of Metabolism affecting Brain Development (Animal Models)

Inborn errors of metabolism affecting brain development -Introduction N. Herschkowitz

Mutations in mice affecting brain development and their correlations with human diseases N. Baumann, F. Lachapelle and J-C. Turpin

Murine mutations affecting myelination: models to study myelin diseases in the human J -M. Matthieu

The effect of phenylalanine on myelin metabolism in adolescent rats F. A. Hommes, A. G. Eller and E. H. Tay/or

Abnormal oligodendrocyte differentiation in a mouse mutant with defect in myelination L. B%ga-Sandru, H.-P. Siegrist, A. Z'graggen, U. Wiesmann and N. Herschkowitz

SECTION FOUR

Consequences of Inborn Errors of Metabolism for the Individual. the Family and Society

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157

161

173

193

201

viii CONTENTS

16 Inborn errors of metabolism-consequences of long-term treatment for the individual, as derived from observations in phenylketonuria H. Bickel and S. Grubel-Kaiser 211

17 Social aspects of the handicapped person Y. Pasternak 225

18 Psychological and educational aspects of handicap C. C. Cunningham 237

19 Repercussions of screening B. E. Clayton 255

20 Some principles in the management of inherited metabolic disease D. N. Raine 267

Index 287

List of contributors

J. A. BARRANGER Developmental and Metabolic Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke, NIH, Bethesda, MD 20205, USA

N. BAUMANN Laboratoire de Neurochimie, Inserm U. 134, Hopital de la Salpetriere, 47 Boulevard de l'Hopital, 75651 Paris Cedex 13, France

P. F. BENSON Paediatric Research Unit, Department of Surgery, Guy's Hospital Medical School, London Sf1 9RT, UK

H. BICKEL Universitats Kinderklinik, 1m Neuenheimer Feld 150, D-6903 Heidelberg, West Germany

L. BOLOGA-SANDRU Department of Pediatrics, University of Berne, 3010 Berne, Switzerland

R.O.BRADY Developmental and Metabolic Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke, NIH, Bethesda, MD 20205, USA

L. R. BUTTON Paediatric Research Unit, Department of Surgery, Guy's Hospital Medical School, London, Sfl 9RT, UK

N. A. J. CARSON Department of Child Health, The Queens University, Belfast 7, N. Ireland

T. M. S. CHANG Artificial Cells and Organs Research Centre, McGill University, 3655 Drummond Street, Montreal, P.Q., Canada H3G 1Y6

B. E. CLAYTON Department of Chemical Pathology and Human Metabolism, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, Hants S09 4XY, UK

F. COCKBURN University Department of Child Health, Royal Hospital for Sick Children, Yorkhill, Glasgow G38SJ, UK

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x LIST OF CONTRIBUTORS

C. C. CUNNINGHAM Hester Adrian Research Centre, The University of Manchester, Manchester, M13 9PL UK

M. F. DEAN Department of Biochemistry, Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith London W6 7DW, UK

A. G. ELLER Department of Cell and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA

F. S. FURBISH Developmental and Metabolic Neurology Branch National Institute of Neurological and Communicative Disorders and Stroke, NIH, Bethesda, MD 20205, USA

A. E. GAL Developmental and Metabolic Neurology Branch National Institute of Neurological and Communicative Disorders and Stroke, NIH, Bethesda, MD 20205, USA

R. GITZELMANN Division of Metabolism, University Paediatric Department, Kinderspital, 8032 Zurich Switzerland

S. GRUBEL-KAISER Universitats Kinderklinik, 1m Neuenheimer Feld 150, D-6903 Heidelberg, West Germany

H. HARRIS Department of Human Genetics, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA

N. HERSCHKOWITZ Department of Pediatrics, University of Berne, 3010 Berne, Switzerland

F. A. HOMMES Department of Cell and Molecular Biology, Medical Col/ege of Georgia, Augusta, GA 30912, USA

F. LACHAPELLE Laboratoire de Neurochimie, Inserm U. 134, Hopital de la Salpetriere, 47 Boulevard de l'Hopital, 75651 Paris Cedex 13, France

R.-S. MACH 4 rue de I'Athenee, 1205 Geneve, Switzerland

J.-M. MATTHIEU Neurochemistry Laboratory, Department of Pediatrics, University

LIST OF CONTRIBUTORS xi

Medical Center of Lausanne, CHUV, CH-1011 Lausanne, Switzerland

H. MUIR Department of Biochemistry, Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith London, W6 ,OW, UK

E. F. NEUFELD Genetics and Biochemistry Branch National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20205, USA

W. L. NYHAN Pediatrics Department University of California, San Diego School of Medicine, La Jolla, CA 92093, USA

W. M. PARDRIDGE Department of Medicine, Division of Endocrinology, UCLA School of Medicine, Los Angeles, CA 90024, USA

P.G.PENTCHEV Developmental and Metabolic Neurology Branch National Institute of Neurological and Communicative Disorders and Stroke, NIH, Bethesda, MD 20205, USA

Y. POSTERNAK University of Geneva, 36 B route du Vallor, 1224 Chene-Bougeries, Geneva, Switzerland

A.PRADER Department of Paediatrics, University of Zurich Kinderspital, Steinwiesstrasse 75, B032 Zurich Switzerland

D. N. RAINE (deceased) Department of Clinical Chemistry, The Children's Hospital, Ladywood, Birmingham B 16 BET, UK

L. E. ROSENBERG Department of Human Genetics, Yale University School of Medicine, 333 Cedar Street New Haven, CT 06510, USA

H.-P. SIEGRIST Department of Pediatrics, University of Berne, 3010 Berne, Switzerland

E. H. TAYLOR Department of Cell and Molecular Biology, Medical Col/ege of Georgia, Augusta, GA 30912, USA

J.-C. TURPIN Laboratoire de Neurochimie, Inserm U. 134, Hopital de la Salpetriere, 47 Boulevard de I 'Hop ita I, 75651 Paris Cedex 13, France

xii LIST OF CONTRIBUTORS

U. WIESMANN Department of Pediatrics, University of Berne, 3010 Berne, Switzerland

M. ZACHMANN Department of Paediatrics, University of Zurich Kinderspita/, Steinwiesstrasse 75, 8032 Zurich Switzerland

A. Z'GRAGGEN Department of Pediatrics, University of Berne, 3010 Berne, Switzerland

Opening Remarks

In the name of the Swiss Academy of Medical Sciences it is my pleasure to welcome you all, speakers and participants, to Interlaken.

My first remark goes to Hugo Aebi, to congratulate him for having set up and organized this meeting.

It is not quite by chance that this meeting on the biochemistry of genetic disorders is held in Switzerland; there are two reasons for that: firstly, the presence in Switzerland of good biochemists, and secondly, it is relevant to recall that Switzerland could be considered the birthplace of the DNA period of genetic research. It was Friedrich Miescher, who in 1869 in Basel (stimulated by his uncle, the embryologist His), isolated DNA for the first time. "That viscous substance". as Miescher referred to the DNA he had isolated from salmon, did not make headlines at the time, however, and Miescher would probably have been very surprised ifhe could have learned from Avery, more than 80 years later. that this DNA was indeed the chemical support of genetic information.

In the history of the relationship between medical research and inherited metabolic diseases. one can distinguish three overlapping periods. First, the description of the particular signs and symptoms which constitute a particular disease. Then. the elucidation of the biochemical defects involved. And finally, the understanding that these biochemical defects are themselves only the consequence of alterations at the level of DNA, which must be studied and explained in the light of the rapid progress of molecular genetics.

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xiv OPENING REMARKS

During the 50 years which elapsed between the formulation by Archibald Garrod of the concept of 'Inborn error of metabolism' in 1908 and the first printing of Stanbury's classical book on the biochemistry of inherited diseases, phenomenal progress has been made in the biochemistry of inherited metabolic disorders. The precise understanding of the biochemical defects must be completed by a study of the ultimate genetic origin of the diseases. And here the work of the biochemists and of the clinicians has been complemented by the progress of molecular biology during the last 30 years. An understanding of the origin of inherited diseases in molecular terms indeed draws heavily on that new science, from the concept of 'one gene - one enzyme' of Beadle and Tatum to the more recent discovery that most genes are indeed discontinuous or fragmented along our chromosomes.

Because of the rapid progress of the various areas which have made the field of inborn errors of metabolism what it is today, there is an inherent danger or risk for medical sciences and medicine. This danger is the gap between the professional scientists and medicine. More than ever we need people capable of conducting a dialogue between what sometimes appear to be different worlds. This meeting is a remarkable example of such a dialogue for the ultimate benefit of medicine. In the name of the Swiss Academy of Medical Sciences I am grateful for your contribution.

May your symposium be a great success. Thank you. RENE-S. MACH

Dedication

THIS VOLUME IS DEDICATED TO THE MEMORY OF DR D. N. RAINE

In opening this symposium Professor Mach pointed to the danger that physicians caring for patients and advising families might be unaware of or unable to comprehend the relevance to their patients of the work of scientists investigating inborn errors of metabolism.

The last contribution in this volume suggests practical steps which can be taken to meet and overcome this danger. Those present at the symposium will know that the author of "Some general principles in the co-ordinated management of inherited metabolic disease" was unable to attend and present this paper because of his terminal illness. With the help of his wife and son, Noel Raine completed the final chapter ofthis book shortly before he died. His friends in the Society for the Study of Inborn Errors of Metabolism thank Noel and his family and dedicate this volume to his memory.

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