Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases 2nd Edition

N. Blau . M. Duran M. E. Blaskovics . K. M. Gibson (Eds.)

Physician's Guide to the Laboratory Diagnosis of Metabolic O·seases

Second Edition

Foreword by C. R. Scriver

With 100 Figures and 270 Tables

~ Springer

Nenad Blau Division of Clinica} Chemistry and Biochemistry University Children's Hospital Steinvviesstrasse 75 8032 Ziirich Svvi tzer land e-mail: nenad.blau@kispi.unizh.ch

Milan E. Blaskovics 3639 Amesbury Road Los Angeles, CA 90027 USA e-mail: blaskk@earthlink.net

Marinus Duran Academic Medical Center Dept. of Pediatrics and Clinica! Chemistry Meibergdreef 9 1105 AZ Amsterdam The Netherlands e-mail: m.duran@amc.uva.nl

K. Michael Gibson Biochemical Genetics Laboratory Dept. of Molecular and Med. Genetics Oregon Health & Science University 2525 SW 3rd Avenue, Suite 350 Portland, Oregon 97201, USA e-mail: gibsonm@ohsu.edu

ISBN 978-3-642-62709-5 ISBN 978-3-642-55878-8 (eBook) DOI 10.1007/978-3-642-55878-8

Title of the 1st Edition: N. Blau, M. Duran, M.E. Blaskovics Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases © 1996 Chapman & Hali

Library of Congress Cataloging-in-Publication Data Physician's guide to the laboratory diagnosis of metabolic diseases/ [edited by] N. Blau .. [el al.].- 2nd ed. p.; cm. Includes bibliographical references and index.

ISBN 978-3-642-62709·5 (hd.: alk.paper) 1. Metabolism - Disorders - Diagnosis - Handbooks, manuals, etc. 2. Metabolism, Inborn errors of- Diagnosis - Handbooks, manuals, etc. 3. Diagnosis, Laboratory- Handbooks, manuals, etc. !. Blau, N. (Nenad), 1946 -[DNLM: 1. Metabolism, Inborn Errors - diagnosis. 2. Diagnosis, Differential. 3. Laboratory Techniques and Procedures. VVD 205 P578 2002] RB147.P476 2002 616.3'9075-dc21 2002021642

This work is subject to copyright. Ali 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 provisions 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 for prosecution under the German Copyright Law.

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© Springer-Verlag Berlin Heidelberg 2003 Originally published by Springer-Verlag Berlin Heidelberg New York in 2003 Softcover reprint of the hardcover 2nd edition 2003

The use of general descriptive names, registered names, 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. Produc! liability: The publishers cannot guar­antee the accuracy of any information about the application of operative techniques and medications contained in this book. In every individual case the user must check such information by consulting the relevant literature.

Graphics: Giinther Hippmann, Niirnberg Cover-Design: Erich Kirchner, Heidelberg

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SPIN 11319092 24/3150 PF 5 4 3 2 1 o

Foreword to 2nd Edition

The first edition of this book, published in 1996, was a success (at least in one way - it is sold out) because it provides useful information and thus enhances the care of patients with hereditary metabolic diseases. One mes­sage in the original Foreword is having a particular impact; the present edi­tion of the Book will have a CD-ROM format, allowing authors to provide pictures, chromatograms or even short videos. All of the books serving our field are moving in this direction.

Significant developments have occurred over the past six years between editions of the Physician's Guide. For example, a draft sequence of the Hu­man Genome is now available. As genes are identified there has been a pro­liferation of locus specific mutation databases (http://ariel.ucs.unimelb. edu.au:80/-cotton/mdi.htm), many of them linked to OM1M (http:// www.ncbi.nlm.nih.gov/Omim/). These databases and much other valuable information are also accessible through the Human Genome Sequencing Consortium and Human Genome Central (http://www.ensembl.org/genome/ central). The relevance of mutation analysis at loci associated with disease and its practical role in medicine have become significant concerns and they will form a leitmotif in this Book.

Meantime, the number of so-called orphan genetic diseases, among them the hereditary metabolic diseases, increases. One can identify many of them through OM 1M, the "genomic catalogue" of human phenotypic variation. The fact of this increase means that the Physician's Guide is ever challenged; it will always be attempting to keep up with what is new. When it is on-line and becomes a continuously expanding Physician's Guide, it will be able to do that; it will become a complementary resource to those many others serving genetic medicine.

Tandem mass spectrometry has entered the diagnostic arena; this powerful technology is now in place at referral centers across the world. As an important resource in laboratory diagnosis of metabolic diseases, it is expanding the repertoire of diagnoses and problems to address. Here is an­other reason for continuing relevance of the Physician's Guide.

The range of resources for patients and for those who care for them also grows. For example, GeneTests (http://www.genetests.org) is a reliable curated knowledge base in which many inborn errors of metabolism ap-

VI Foreword to 2nd Edition

pear with links to other resources. Yet another for readers of this book, is Metab-L (http://www.franken.de/lists/metab-l!) a listserve acting as a site for information exchange. It is not hard to predict a long and useful life for the Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases, in its present form, its transformations and its links.

Charles R. Scriver

Foreword to 1 st Edition

The medical model of disease, which has served the practice of medicine well, proposes that a cause of disease - no matter what the cause or the disease - initiates a deviant process - called pathogenesis - which culmi­nates in manifestations of the disease. The manifestations are its taxonomy and from them one initiates another process leading to diagnosis. Correct treatment depends upon diagnosis. All error in, or an absence of, diagnosis leaves manifestations naked, pathogenesis is not reversed and cause con­tinues to initiate the disease.

This book is about diagnosis. The necessary or sufficient causes of the diseases described here are mutations in genes responsible for important steps in the metabolic mosaic that underlies health. Garrod recognized that inborn errors of metabolism are manifestations of biochemical individual­ity. The importance of this observation was recognized by biologists but they made little impression on the practitioners of medicine during Gar­rod's lifetime. Even today, the inborn errors of metabolism are believed to be rare encounters in medicine and likely never to be seen in a typical medical practice. How wrong it would be to see things that way in 1996. The inborn errors of metabolism induce disease manifestations in every or­gan and at every life interval from the fetus to the geriatric patient, and they are ubiqitous in their appearance, with little regard for the qualifica­tions of the physician - generalist or specialist.

It is a sign of the times that this book is called Physician's Guide .. , Such a book is something Garrod might have hoped for but was realist enough not to expect its appearance in his library. Even in the half century since Garrod's death in 1935 few physicians have experienced the excitement in diagnosis of an hereditary metabolic disease. A generation ago an enter­prising publishing firm sponsored a series of advanced monographs for practitioners; those that dealt with problems affecting patients in large numbers with overt clinical problems that could be addressed by readily available resources and technologies did well and went into further edi­tions; those devoted to genetic and metabolic themes did not. The present adventurous text implies that the times have changed.

Whereas screening programs have become widely established to detect selected inherited metabolic diseases long before the clinical signs appear,

VIII Foreword to 1st Edition

the majority of diseases discussed in Physician's Guide will present first to the practising physician; he or she will identify the patient's disease first; it will be a challenge, and that is why the clinical features of these diseases are given prominence first here.

Why would already overworked editors and authors be willing to devote their time to preparing the texts, tables and appendices that comprise Phy­sician's Guide? May I offer these reasons?

• In aggregate, the inborn errors are indeed not rare, they are prevalent and they involve an increasingly large number of humans requiring in­tensive, often lifelong, health care. Accordingly, diagnosis to set them on the right path is important.

• The methods of diagnosis described in this book will also be those used to monitor treatment and management of the patient's disease.

• The inborn errors of metabolism constitute a group of diseases about which there is an enormous amount of information; more in fact than for almost any other set of diseases. Such knowledge is beneficial to practitioner and patient.

• Should one still believe that the inborn errors of metabolism are eso­teric, consult any major general textbook of pediatric or general medi­cine, or the Oxford Medical Companion, second edition. All of the for­mer describe these problems; the latter - a vastly informative encyclope­dia about the science and the practice of medicine - has a fine entry on the inborn errors of metabolism. The topic has found numerous harbors in the medical seascape.

The core of information common to each chapter of the Physician's Guide comprises:

• The major clinical and chemical signs initiating the diagnostic journey. In many cases they are translated into diagnostic algorithms. Perhaps they will be translated further into versions accessible on CD-ROM.

• Simple tests, both those that serve screening programs and those that can be done at the bedside, in physicians' offices or in nonspecialist lab­oratories. This information will replace a number of well-worn manuals and publications of a generation ago.

• Special tests done primarily at referral centers and whose interpretation is part of the Physician's Guide's lode of information. Useful practical matters such as how to collect and store the particular sample are described.

• Phenotype tests, primarily at chemical and biochemical levels (metabo­lites and enzymes) are emphasized. Genetic information is provided to indicate how much genetic and allelic heterogeneity may be associated with the phenotype. A later edition of this book may expand into the area of mutation detection and DNA diagnostics, but at present the phe­notype tests are robust and remain powerful.

Foreword to 1st Edition IX

• The authors have also gone beyond diagnosis to provide useful informa-tion about initial and emergency treatments.

The Physician's Guide is a work of dedication and if there is fairness in the scheme of things it will find a place on many a practitioner's shelf. Those who use it will no longer be limited to a small group of specialists - I re­peat, because diagnosis and care of the patient with hereditary metabolic disease is expanding beyond that small original community of practitioners into all medical specialties, and into internal medicine as the child patients grow into adulthood, thanks to advances in diagnosis and treatment. Ac­cordingly, this book will not only be a guide, it will be a companion and it will complement very nicely the other major texts in the field.

Charles R. Scriver

Preface to 2nd Edition

The premise upon which the first edition of this book was based has not changed. Specialization in medicine has decreased, more generalists are en­couraged, and governments have reduced programs for postdoctoral train­ing. As a consequence, the little that is taught in Medical schools about in­born errors of metabolism is, if anything, less than before.

The area of molecular genetics dealing with the mechanisms and the ba­sic fault in an inborn error of metabolism, on the other hand, has in­creased almost exponentially. Unfortunately, this area of science can only operate to deduce the problem after a fault has been recognized.

It is the recognition of the patient with a fault, the so-called "inherited" defects that this book is about. The book is therefore targeted towards phy­sicians and other individuals dealing with diagnosing these relatively rare disorders. Recognizing an individual with these disorders is often difficult because of the fact that they "blend in" with many common medical condi­tions. The signs and symptoms often do not stand out so that a patient may live for years with recurring problems and the condition never cor­rectly diagnosed.

This book presents the signs and symptoms of most of the recognized inborn errors of metabolism in relation to age. There is a chronological se­quence of signs and symptoms from infancy through childhood, adoles­cence and adulthood, and in addition, normal and pathological values are provided for each of the disorders so that one does not have to wonder about the significance of laboratory tests and reported values.

Recognized authorities describe each disorder. Based upon their experi­ence, they have created flow charts and diagnostic algorithms and recom­mend confirmatory tests and initial treatment schemes to help the unini­tiated.

Since the first edition was published in 1996, 43 new disorders have been recognized and are described in this edition. There is little doubt that more new disorders will be recognized, so that this current effort is really a "work in progress".

To that end, this edition is utilizing the progress made with computer technology to make accessing the data a little easier. A CD-ROM is in-

XII Preface to 2nd Edition

eluded with this edition that will allow the user to find a disorder and search via a program which uses key words.

Nenad Blau Marinus Duran Milan E. Blaskovics K. Michael Gibson

List of Contributors

Generoso Andria Dipartimento di Pediatria Universita Federico II Via S. Pansini 5 80131 Napoli Italy e-mail: andria@unina.it

Kurt Baerlocher Children's Hospital Claudiusstrasse 6 9006 St. Gallen Switzerland e-mail: kbaerlocher@dplanet.ch

Claude Bachmann CHUV Lab. Central de Clin. Chern. 1011 Lausanne Switzerland e-mail: Claude.Bachmann@chuv.hospvd.ch

Peter G. Barth Academic Medical Center Dept. of Pediatrics Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Michael Beck Universitats-Kinderklinik Langenbeckstrasse 1 55101 Mainz Germany e-mail: beck@kinder.klinik.uni-mainz.de

Anna Biason-Lauber Dept. of Pediatrics Division of Clinical Chemistry and Biochemistry University of Zurich Steinwiesstrasse 75 8032 Zurich Switzerland e-mail: anna.lauber@kispi.unizh.ch

Milan E. Blaskovics 3639 Amesbury Road Los Angeles, CA 90027 USA e-mail: blaskk@earthlink.net

Nenad Blau Division of Clinical Chemistry and Biochemistry University Children's Hospital Steinwiesstrasse 75 8032 Zurich Switzerland e-mail: nenad.blau@kispi.unizh.ch

Luisa Bonafe Division of Metabolism and Molecular Pediatrics University Children's Hospital Steinwiesstrasse 75 8032 Zurich Switzerland e-mail: luisa.bonafe@hospvd.ch

XIV List of Contributors

Peter T. Clayton Institute of Child Health Division of Biochemistry & Genetics 30 Guilford Street London WC1N 1EH UK e-mail: pclayton@ich.ucl.ac.uk

Tom de Koning University Medical Centre Department of Pediatric Metabolic Diseases 3508 AB Utrecht The Netherlands e-mail: T.deKoning@wkz.azu.nl

Katrina M. Dipple UCLA Department of Pediatrics Division of Genetics 10833 LeConte Avenue Los Angeles, CA 90095-1752 USA e-mail: kdipple@ucla.edu

Marinus Duran Academic Medical Center Dept. of Pediatrics and Clinical Chemistry Meibergdreef 9 1105 AZ Amsterdam The Netherlands e-mail: m.duran@amc.uva.nl

Orly N. Elpeleg Metabolic Disease Unit Shaare-Zedek Medical Center Jerusalem 91031 Israel e-mail: elpeleg@cc.huji.ac.il

Udo Engelke University Medical Centre Nijmegen Institute Neurology Reinier Postlaan 4 6525GC Nijmegen The Netherlands

Patrik Feyh Universitats-Kinderklinik 1m Neuenheimer Feld 150 69120 Heidelberg Germany

K. Michael Gibson Biochemical Genetics Laboratory Dept. of Molecular and Medical Genetics Oregon Health & Science University 2525 SW 3rd Avenue, Suite 350 Portland, Oregon 97201 USA e-mail: gibsonm@ohsu.edu

Erik Harms Universitats-Kinderklinik Albert Schweitzer-Strasse 33 48129 MUnster Germany e-mail: harms@uni-muenster.de

Georg F. Hoffmann Universitats-Kinderklinik 1m Neuenheimer Feld 150 69120 Heidelberg Germany e-mail: GeorR-Hoffmann@med.uni-heidelberg.de

Elisabeth Holme Department of Clinical Chemistry Sahlgrenska University Hospital 41345 Gothenburg Sweden e-mail: Elisabeth.Holme@clinchem.gu.se

Keith Hyland Institute of Metabolic Disease Baylor University Medical Center 3812 Elm Street Dallas, TX 75226 USA e-mail: k.hyland@baylordallas.edu

Chike B. Item Universitats-Kinderklinik Department of Pediatrics and National Newborn Screening Laboratory Wiihringer Giirtel 18-20 1090 Wien Austria

Michinori Ito University of Tokushima Department of Pediatrics Kuramoto-cho 3 Tokushima 770 Japan

Jaak Jaeken University Hospital Gasthuisberg Dept. of Pediatrics Div. of Metabolic Diseases 3000 Leuven Belgium e-mail: jaak.jaeken@uz.kuleuven.ac.be

Cornelis Jakobs VU University Medical Center Department of Clinical Chemistry De Boelelaan 1117 1081 HV Amsterdam The Netherlands e-mail: C.Jakobs@vumc.nl

Richard I. Kelley Kennedy Krieger Institute 707 N. Broadway Baltimore, MD 21205 USA e-mail: kelle_ri@jhuvms.hcf.jhu.edu

Lisa E. Kratz Kennedy Krieger Institute 707 North Broadway Baltimore, MD 21205 USA e-mail: kratz@kennedykrieger.org

Yasuhiro Kuroda University of Tokushima Department of Pediatrics Kuramoto-cho 3 Tokushima 770 Japan

List of Contributors XV

e-mail: pekuroda@clin.med.tokushima-u.ac.jp

Agne Larsson Department of Pediatrics Karolinska Institute Huddinge Univ. Hospital 14186 Stockholm Sweden e-mail: agne.larsson@klinvet.ki.se

Kay Latta Kinderklinik der Medizinischen Hochschule Hannover Department Pediatric Nephrology and Metabolic Disorders Carl-Neuberg-Str. 1 30625 Hannover Germany e-mail: kaylatta@web.de

Hugh A. Lemonde Institute of Child Health Division of Biochemistry & Genetics 30 Guilford Street London WClN 1EH UK

Gert Matthijs University Hospital Gasthuisberg Dept. of Pediatrics Div. of Metabolic Diseases 3000 Leuven Belgium

XVI List of Contributors

Ertan Mayatepek Division of Metabolic and Endocrine Diseases University Children's Hospital 1m Neuenheimer Feld 150 69120 Heidelberg Germany ertan_mayatepek@med.uni-heidelberg.de

Edward R.B. McCabe UCLA School of Medicine Department of Pediatrics 22-412 MDCC Los Angeles, CA 90095-1752 USA e-mail: emccabe@mednet.ucla.edu

David S. Millington Division of Medical Genetics Department of Pediatrics Box 3028 Duke University Medical Center Durham, NC 27710 USA e-mail: dmilli@acpub.duke.edu

Elisabeth I. Minder Stadtspital Triemli Chemie Zentrallabor 8000 Zurich Switzerland e-mail: eminder@swissonline.ch

Sytske Moolenaar University Medical Centre Nijmegen Institute Neurology Reinier Postlaan 4 6525GC Nijmegen The Netherlands

D. Holmes Morton Clinic for Special Children Box 128

535 Bunker Hill Road Strasburg, Pennsylvania 17579 USA

Adolf Muhl Universitats-Kinderklinik Department of Pediatrics and National Newborn Screening Laboratory Wahringer Gurtel 18-20 1090 Wien Austria

Won G. Ng Children's Hospital of Los Angeles 4650 Sunset Boulevard Los Angeles, CA 90027 USA e-mail: wng@chla.usc.edu

William L. Nyhan Univ. California San Diego Dept. of Pediatrics 9500 Gilman Drive (0609A) La Jolla, CA 92095-0609 USA e-mail: wnyhan@ucsd.edu

Giancarlo Parenti Dipartimento di Pediatria Universita Federico II Via S. Pansini 5 80131 Napoli Italy e-mail: parenti@unina.it

Bwee Tien Poll The Academic Medical Center Dept. of Pediatrics Meibergdreef 9 1105 AZ Amsterdam The Netherlands e-mail: b.t.pollthe@amc.uva.nl

Hildegard Przyrembel Federal Inst. for Health Protection of Consumers and Veterinary Medicine Div. of Nutritional Medicine PO Box 330013 14191 Berlin Germany e-mail: h.przyrembel@bgvv.de

Daniel J. Rader University of Pennsylvania School of Medicine 654 BRBII/III Laboratories 421 Curie Blvd Philadelphia, PA 19104 USA e-mail: rader@mail.med.upenn.edu

Ellinor Ristoff Department of Pediatrics Karolinska Institute Huddinge Univ. Hospital 14186 Stockholm Sweden e-mail: ellinor.ristoff@klinvet.ki.se

Thomas F. Roe Children's Hospital of Los Angeles 4650 Sunset Boulevard Los Angeles, CA 90027 USA e-mail: troe34@attbi.com

Wim Ruitenbeek Laboratory of Pediatrics and Neurology University Medical Center Nijmegen Geert Grooteplein 10 PO Box 9101 6500 HB Nijmegen The Netherlands e-mail: W.Ruitenbeek@ckslkn.azn.nl

List of Contributors XVII

Rene Santer UniversWits-Kinderklinik Abt. Allgemeine Padiatrie Schwanenweg 20 24105 Kiel Germany e-mail: santer@pediatrics.uni-kiel.de

Christian von Schnakenburg Kinderkardiologie und Padiatrische Intensivmedizin Universitatsklinikum G6ttingen Robert-Koch-Str. 40 37075 G6ttingen Germany e-mail: Christian. Schnakenburg@medizin. uni -goettingen.de

Xiaoye Schneider-Yin Stadtspital Triemli Chemie Zentrallabor 8000 Zurich Switzerland

Susanne Schweitzer-Krantz Evangelisches Krankenhaus Dusseldorf Postfach 102254 40013 Dusseldorf Germany e-mail: Schweitzer-Krantz@t-online.de

Charles R. Scriver McGill University Health Center Montreal Children's Hospital DeBelle Laboratory, A717 2300 Tupper Street Montreal, Quebec, H3H IP3 Canada e-mail: charles.scriver@mcgill.ca

XVIII List of Contributors

Rob Sengers Nijmegen Center for Mitochondrial Disorders Department of Pediatrics University Medical Center Nijmegen Geert Grooteplein 10 PO Box 9101 6500 HB Nijmegen The Netherlands e-mail: S.Eichelsheim@cukz.umcn.nl

Vivian E. Shih Harvard Medical School Massachusetts General Hospital East Amino Acid Disorders Laboratory Building 149, 13th Street Boston, MA 02129 USA e-mail: vshih@partners.org

H. Anne Simmonds Purine Research Laboratory UMDS Guy's Hospital 18th Floor, Guy's Tower St. Thomas' Street London SEI 9RT UK e-mail: anne.simmonds@kcl.ac.uk

Flemming Skovby Department of Clinical Genetics Rigshospitalet 4062 Blegdamsvej 9 21 00 Copenhagen Denmark e-mail: fskovby@rh.dk

Jan Smeitink Nijmegen Center for Mitochondrial Disorders Department of Pediatrics University Medical Center Nijmegen Geert Grooteplein 10 PO Box 9101 6500 HB Nijmegen The Netherlands e-mail: J.Smeitink@cukz.umcn.nl

Peter G.A. Smit Dept. Metabolic Diseases Beatrix Children's Hospital PO Box 30001 9700 RB Groningen The Netherlands e-mail: g.p.a.smit@bkk.azg.nl

Marc Solioz Department of Clinical Pharmacology Murtenstrasse 35 3010 Bern Switzerland e-mail: marc.solioz@ikp.unibe.ch

Sylvia Stockler-Ipsiroglu Universitats-Kinderklinik Department of Pediatrics and National Newborn Screening Laboratory Wahringer Gurtel 18-20 1090 Wien Austria e-mail: stoeckler@metabolic-screening.at

Carmen Stromberger Universitats-Kinderklinik Department of Pediatrics and National Newborn Screening Laboratory Wahringer Gurtel 18-20 1090 Wien Austria

Andrea Superti-Furga Division of Metabolic and Molecular Pediatrics University Children's Hospital Steinwiesstrasse 75 8032 Zurich Switzerland e-mail: asuperti@access.unizh.ch

Jerry N. Thompson University of Alabama at Birmingham

Department of Pediatrics

Metabolic Disease Center 775 Sparks Center 1720 7th Ave South Birmingham, AL 35294 USA e-mail: jthompson@peds.uab.edu

Frans Trijbels Nijmegen Center for Mitochondrial Disorders Laboratory of Pediatrics and Neurology University Medical Center Nijmegen Geert Grooteplein 10 PO Box 9101 6500 HB Nijmegen The Netherlands e-mail: F.Trijbels@ckslkn.azn.nl

Bert van den Heuvel Nijmegen Center for Mitochondrial Disorders Laboratory of Pediatrics and Neurology University Medical Center Nijmegen Geert Grooteplein 10 PO Box 9101 6500 HB Nijmegen The Netherlands e-mail: B.vandeHeuvel@ckslkn.azn.nl

Marjo S. van der Knaap VU University Medical Center Department of Pediatrics De Boelelaan 1117 1081 HV Amsterdam The Netherlands e-mail: ms.vanderknaap@vumc.nl

Albert H. van Gennip Academic Medical Center Dept. of Pediatr. and Clin. Chern. Meibergdreef 9 1105 AZ Amsterdam The Netherlands

List of Contributors XIX

Johan van Hove

University Hospital Gasthuisberg

Dept. of Pediatrics Div. of Metabolic Diseases 3000 Leuven Belgium

Nanda M. Verhoeven VU University Medical Center Department of Clinical Chemistry De Boelelaan 1117 1081 HV Amsterdam The Netherlands e-mail: N.Verhoeven@vumc.nl

Ronald J.A. Wanders Academic Medical Center Dept. of Pediatr. and Clin. Chern. Meibergdreef 9 1105 AZ Amsterdam The Netherlands e-mail: wanders@amc.uva.nl

Rebecca S. Wappner Riley Hospital for Children Section of Pediatric Metabolism/Genetics 702 Barnhill Drive Room 0907 Indianapolis, Indiana 46202-5225 USA e-mail: beckywappner@aol.com

Ron A. Weyers University Medical Center Nijmegen Institute Neurology Reinier Postlaan 4 6525GC Nijmegen The Netherlands e-mail: r.wevers@cukz.umcn.nl

How To Use This Book

This book is meant to supply clinicians and clinical biochemists with data to facilitate the rapid diagnosis of an inherited metabolic disease. No infor­mation about detailed laboratory methods is given, rather, the relationship between laboratory data and clinical signs and symptoms is stressed. Entry to the book is by scanning either of the indices, i.e. the signs and symp­toms index, the tests index or the disorders index. Due to the great clinical variability of inherited metabolic diseases one should not restrict oneself to one disorder when observing a given symptom or sign.

Most chapters have a uniform layout as given below. In a few chapters, however, this was not possible and information is given for the entire re­lated group of disorders in the chapter.

Introduction The introduction gives a brief overview of the clinical conditions described in the chapter and relates them to the biochemical abnormalities. Key refer­ences for further reading are given here.

No menclatu re Disorders in each chapter are numbered in accordance with the corre­sponding MIM number [1] and chromosomal localization if known.

Metabolic Pathway Disorders are identified by corresponding reference numbers at the step where the defect is localized. Pathological metabolites Cmarkers') are given in most chapters.

Signs and Symptoms The tables describe most, if not all, of the signs and symptoms for each disorder, including its reference number, and most important laboratory tests, in relation to age. In all instances, the signs and symptoms are in the untreated (natural) state.

± indicates that a sign or symptom may occur but is not inevitably pres­ent.

XXII How To Use This Book

+ indicates that a sign or symptom is always or nearly always present. If there are significant clinical signs and symptoms which exceed the usual, or if changes occur, this is indicated with + to + + +, etc.

n (normal) is used only when it is significant and may be useful in distin-guishing one condition from another.

Relative increases or decreases of substances, compounds, metabolites etc. are indicated with the use of arrows; for example, metabolite X i to t t t. Where metabolite X may change, it would be indicated by n-i for a possi­ble increase or t -n for a possible decrease, whatever the case.

In all tables, the test substance, material, compound or metabolite, etc., is listed and the source - (U), (B), (CSF), (P), or (RBC) - is given in paren­theses, with an arrow or arrows indicating increase/decrease or relative in­crease/ decrease.

Body fluids, cells, tissues, etc. are defined as:

P plasma S serum B blood U urine CSF cerebrospinal fluid RBC red blood cells LYM lymphocytes FB fibroblasts

Age groups are defined as:

Neonatal Infancy Childhood Adolescence Adulthood

birth to 1 month 1-18 months 1.5-11 yr 11-16 yr >16 yr

CV chorionic villi AF amniotic fluid AFC amniocytes CCV cultured chorionic villi PLT platelets WBC white blood cells Hb hemoglobin creat creatinine

Normal Values/Pathological Values/Differential Diagnosis Reference and pathological values are listed for all parameters relevant to the diagnosis according to the specimen (e.g. P, U, CSF, etc.) and age. For some parameters, normal values depend on methodology and may differ from chapter to chapter. Methods are specified where necessary. Pathologi­cal values are listed either as absolute values or with symbols (e.g. i, L etc.) according to the disorder. Values are limited to the analyses which can be performed in a well-equipped laboratory for selective screening. Data on enzyme studies are not given in most cases.

How To Use This Book XXIII

Loading Tests There is a brief description of the tests, with a table or figure to illustrate the interpretation.

Diagnostic Flow Chart The flow charts use simple yes/no algorithms to demonstrate the sequence for differential diagnosis; starting with clinical symptoms or general tests and proceeding to specific tests and a final diagnosis.

Specimen Collection This table lists preconditions, material, handling and pitfalls for each pa­rameter used in the diagnosis.

Prenatal Diagnosis This table lists the tissue or specimen, timing and pitfalls for each disorder.

DNA Analysis This table lists the tissue or specimen and methodology for each disorder.

Initial Treatment This section outlines briefly urgent treatment to consider before a defini­tive diagnosis is established for each (or each group of) disorder(s). Long­term treatment is not considered in this book; other books cover this topic.

Indices Three indices are included: (1) Disorders; (2) Signs and Symptoms, and (3) Tests. Each entry is linked to the corresponding disorder or page.

Reference 1. OMIM, Online Mandelian Inheritance in Man,

http://www3.ncbi.nlm.nih.gov/omim/, 2002

Contents

Part One: Approach to Diagnosis ........................... .

A Simple Tests in Urine and Blood .......................... 3 NENAD BLAU, MILAN E. BLASKOVICS, MARINUS DURAN

B Amino Acid Analysis VIVIAN E. SHIH

11

C Organic Acid Analysis .................................. 27 GEORG F. HOFFMANN, PATRIK FEYH

D Miscellaneous Analyses MARINUS DURAN

E Tandem Mass Spectrometry in Clinical Diagnosis DAVID S. MILLINGTON

45

57

F Proton NMR Spectroscopy of Body Fluids ................... 77 RON WEVERS, UDO ENGELKE, SYTSKE MOOLENAAR

Part Two: Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 87

1 Disorders of Phenylalanine and Tetrahydrobiopterin Metabolism .. 89 NENAD BLAU, LUISA BONAFE, MILAN E. BLASKOVICS

2 Disorders of Neurotransmitter Metabolism .................. 107

3

KEITH HYLAND

Disorders of GABA, Glycine, Serine and Proline JAAK JAEKEN, TOM DE KONING, JOHAN VAN HOVE

123

4 Disorders of Tyrosine Degradation . . . . . . . . . . . . . . . . . . . . . . . .. 141 ELISABETH HOLME

XXVI Contents

5 Disorders of Histidine Metabolism 155 YASUHIRO KURODA, MICHINORI ITO

6 Disorders of Leucine Metabolism .......................... 165 K. MICHAEL GIBSON, ORLY N. ELPELEG, D. HOLMES MORTON,

REBECCA S. WAPPNER

7 Disorders of Valine-Isoleucine Metabolism ................... 191 WILLIAM L. NYHAN, K. MICHAEL GIBSON

8 Various Organic Acidurias ............................... 215 CORNELIS JAKOBS, NANDA M. VERHOEVEN,

MARJO S. VAN DER KNAAP

9 Disorders of the y-Glutamyl Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . 233 AGNE LARSSON, ELLINOR RISTOFF

10 Disorders of Sulfur Amino Acids .......................... 243 FLEMMING SKOVBY

11 Inherited Hyperammonemias ............................. 261 CLAUDE BACHMANN

12 Disorders of Ornithine, Lysine and Tryptophan ............... 277 HILDEGARD PRZYREMBEL

13 Defective Transcellular Transport of Amino Acids . . . . . . . . . . . . . . 301 SUSANNE SCHWEITZER-KRANTZ

14 Disorders of Mitochondrial Fatty Acid Oxidation and Ketone Body Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 MARINUS DURAN

15 Disorders of Carbohydrate and Glycogen Metabolism ........... 335 THOMAS F. ROE, WON G. NG, PETER G.A. SMIT

16 Disorders of Glucose Transport ............................ 357 RENE SANTER

17 Disorders of Glycerol Metabolism .......................... 369 KATRINA M. DIPPLE, EDWARD R. B. MCCABE

18 The Mucopolysaccharidoses JERRY N. THOMPSON

377

Contents XXVII

19 Oligosaccharidoses and Related Disorders ................... 399 GENEROSO ANDRIA, GIANCARLO PARENTI

20 Congenital Disorders of Glycosylation ...................... 411 JAAK JAEKEN, GERT MATTHIJS

21 Cystinosis............................................ 423 ERIK HARMS

22 Other Storage Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 431 MICHAEL BECK

23 Purine and Pyrimidine Disorders . . . . . . . . . . . . . . . . . . . . . . . . .. 445 H. ANNE SIMMONDS, ALBERT H. VAN GENNIP

24 Disorders of Creatine Metabolism ......................... 467 SYLVIA STOCKLER-IpSIROGLU, CARMEN STROMBERGER,

CHIKE B. ITEM, ADOLF MUHL

25 Peroxisomal Disorders .................................. 481 RONALD J. A. WANDERS, PETER G. BARTH, BWEE TIEN POLL-THE

26 Hyperoxaluria ........................................ 509 CHRISTIAN VON SCHNAKENBURG, KAY LATTA

27 Mitochondrial Energy Metabolism. . . . . . . . . . . . . . . . . . . . . . . .. 519 JAN SMEITINK, BERT VAN DEN HEUVEL, FRANS TROBELS,

WIM RUITENBEEK, ROB SENGERS

28 Genetic Dyslipoproteinemias .............. . .............. 537 DANIEL J. RADER

29 Disorders of Steroid Synthesis and Metabolism ............... 551 ANNA BIASON-LAUBER

30 Inborn Errors of Cholesterol Biosynthesis ................... 573 LISA E. KRATZ, RICHARD I. KELLEY

31 The Porphyrias ....................................... 593 ELISABETH I. MINDER, XIAOYE SCHNEIDER-YIN

32 Disorders of Bile Acid Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . .. 615 PETER T. CLAYTON, HUGH A. LEMONDE

XXVIII Contents

33 Disorders of Copper, Zinc and Iron Metabolism ............... 631 KURT BAERLOCHER, MARC SOLIOZ

34 Leukotrienes .......................................... 659 ERTAN MAYATEPEK

35 Other Metabolic Disorders ............................... 669 ANDREA SUPERTI-FURGA

Part Three: Indices ........................................ 675

Disorders Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677

Signs and Symptoms Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689

Tests Index ........................................... 703

~4A

AA AADC abn. ACTH ADA ADDP ADE ADP AE AF

AFC

AGAT AGT AHC AlCA AlP Ala 5-ALA ALAD ALAT ALD Aldo ALP a.m. AMPD AnA ANT apo APRT Arg ARG ASA AS AT

Abbreviations

Androstenedione Amino acid Aromatic L-amino acid decarboxylase Abnormal Adrenocorticotropic hormone Adenosine deaminase 6-Aminolevulinic acid dehydratase-deficient porphyria Adenine Adenosine diphosphate Acrodermatitis enteropathica Amniotic fluid Amniotic fluid cells (Amniocytes) Arginine: glycine amidinotransferase Alanine: glyoxylate aminotransferase Adrenal hypoplasia congenita Aminoimidazole carboxamide Acute intermittent porphyria Alanine 6-Aminolevulinic acid 6-Aminolevulinic acid dehydratase Alanine aminotransferase Adrenoleukodystrophy Aldosterone Alkaline phosphatase Before noon Adenosine monophosphate deaminase Anthranilic acid Adenine nucleotide translocator Apolipoprotein Adenine phosphoribosyltransferase Arginine Argininemia Argininosuccinic aciduria Aspartate aminotransferase

xxx

Asn Asp ATP ATPase AV B

BfA BAEP BCKD BH4 Bio Br BUN bw CAC CAD CAFC CAH CAT cbl CBS ccv CDP CD PC CE CETP CFTR Chol. CITR CK CMP CNS CoA CPC CPS CPT Creat CRTR CSF CT CTH CTP CTX cv

Abbreviations

Asparagine Aspartic acid Adenosine triphosphate Adenosine triphosphatase Aortic valve Blood 3-Hydroxybutyratef acetoacetate Brainstem acoustic evoked potential Branched -chain a-keto acid dehydrogenase Tetrahydrobiopterin Biopterin Brain Blood urea nitrogen Body weight Carnitine acylcarnitine carrier Coronary artery disease Cultured amniotic fluid cells Congenital adrenal hyperplasia Computer-assisted tomography Cobalamin Cystathionine ,B-synthase Cultured chorionic villi Cytidine diphosphate Cytidine diphosphate choline Capillary electrophoresis Cholesteryl ester transfer protein Cystic fibrosis transmembrane regulator Cholesterol Citrullinemia Creatine kinase Cytidine monophosphate Central nervous system Coenzyme A Cetylpyridinium chloride Carbamylphosphate synthetase Carnitine palmitoyltransferase Creatinine Creatine transporter Cerebrospinal fluid Computed tomography y-Cystathionase Cytidine triphosphate Cerebrotendinous xanthomatosis Chorionic villi

Cys DA dAdo dATP dBS Dj3H dCDP dCyK DD def. DGGE dGuo dGTP DH 2,8-DHA DHAP DHAPAT DHEA DHPA DHPD DHPR DHT dIno DMB DMD DNA DNPH DOC DOCA DOPA DOPAC DOPS DRD DS dUr E EC ECG EDTA EEG EMG ERG ETF ETF-DH

Cysteine Dopamine Deoxyadenosine Deoxyadenosine triphosphate Dried blood spot Dopamine {J-hydroxylase Deoxycytidine diphosphate Deoxycytidine kinase Developmental delay Deficiency Denaturating gradient gel electrophoresis Deoxyguanosine Deoxyguanosine triphosphate Dehydrogenase 2,8-Dihydroxyadenine Dihydroxyacetonephosphate Dihydroxyacetonephosphate acyltransferase Dehydroepiandrosterone Dihydropyrimidinase Dihydropyrimidine dehydrogenase Dihydropteridine reductase Dihydrotestosterone Deoxyinosine Dimethylmethylene blue Duchenne muscular dystrophy Deoxyribonucleic acid Dinitrophenylhydrazine Deoxycorticosterone Deoxycortisone acetate Dihydroxyphenylalanine Dihydroxyphenylacetic acid Dihydroxyphenylserine DOPA-responsive dystonia Dermatan sulfate Deoxyuridine Epinephrine Electrochemical Electrocardiogram Ethylenediaminotetraacetic acid Electroencephalogram Electromyogram Electroretinogram Electron transfer flavoprotein

Abbreviations XXXI

Electron transfer flavoprotein dehydrogenase

XXXII

F FA FAAH FAB FADHz FB FD FDB FFA FH Figlu FISH Fru-I-P FSH 5-FU GAA GABA GAD GAGs Gal Gal-I-P GALK GALT GAMT GC GCMS GCS general. GFR GI GK Glc GIn Glu Gly G3P GSD yGT GT GTP GTPCH GTT GUA Guo

Abbreviations

Fluorescence Fumaric acid Fumarylacetoacetase Fast atom bombardment Reduced flavin adenine dinucleotide Fibroblasts Familial dysbetalipoproteinemia Familial defective apolipoprotein B-100 Free fatty acids Familial hypercholesterolemia Formiminoglutamic acid Fluorescence in situ hybridization Fructose-I-phosphate Follicle stimulating hormone 5-Fluorouracil Guanidinoacetate y-Aminobutyric acid Glutamic acid decarboxylase Glycosaminoglycans Galactose Galactose-I-phosphate Galactokinase Galactose-I-phosphate uridyltransferase Guanidinoacetate methyltransferase Gas chromatography Gas chromatography/mass spectrometry Glycine cleavage system Generalized Glomerular filtration rate Gastrointestinal Glycerol kinase Glucose Glutamine Glutamic acid Glycine Glycerol-3-phosphate Glycogen storage disorders y-Glutamyl transpeptidase GABA transaminase Guanosine triphosphate GTP cyclohydrolase 1 Glucose tolerance test Guanine Guanosine

Abbreviations XXXIII

GVHD Graft versus host disease HA Homogentisic acid Haw Hawkinsin Hb Hemoglobin HCS Holocarboxylase synthetase HDL High-density lipoproteins HDL-C High-density lipoprotein cholesterol HFI Hereditary fructose intolerance HGA Hydroxyglutaric acid (D-2, L-2, or 3-) HHH Hyperornithinemia -hyperammonemia -homocitrullinuria SHIAA 5-Hydroxyindoleacetic acid His Histidine HL Hepatic lipase HMG-CoA 3-Hydroxy-3-methylglutaryl-CoA HOGA Hyperornithinemia gyrate atrophy HPLC High-performance liquid chromatography HPO Hydroxyproline oxidase HPRT Hypoxanthine phosphoribosyltransferase HS Heparan sulfate 17/3-HSD 17/3-Hydroxysteroid dehydrogenase 3/3-HSDH 3/3-Hydroxy-i15 -C2Tsteroid dehydrogenase SHT Serotonin SHTP S-Hydroxytryptophan HVA Homovanillic acid HYP IEF He 1M Ino IPyA IR IRD ISSD ITP IV K 2-KGA 2-KGD KS KSS KynA L LCAD LCAT

Hypoxanthine Isoelectric focusing Isoleucine Intramuscular(ly) Inosine Imidazolepyruvic acid Infrared Infantile Refsum disease Intralysosomal sialic acid storage disease Idiopathic thrombocytopenic purpura Intravenous Kidney 2-Ketoglutaric acid 2-Ketoglutarate dehydrogenase Keratan sulfate Kearns-Sayre syndrome Kynurenic acid Liver Long-chain acyl-CoA dehydrogenase Lecithin: cholesterol acyltransferase

XXXIV

LCHAD LCT LDH LDL LDLR Leu LH LHON LIP LPI LPL LSIMS LYM Lys M MA MAD MAO MAT MCAD MCT MD MELAS

MERRF Met Met-Hb MHPG MI MITEM MMA MNGIE MPS MR MR/DD MRI MRS MSUD 3MT mtDNA MTHF MTHFR MTP MU

Abbreviations

Long -chain 3-hydroxyacyl-CoA dehydrogenase Long-chain triglyceride Lactate dehydrogenase Low-density lipoproteins Low-density lipoprotein receptor Leucine Luteinizing hormone Leber hereditary optic neuropathy Lactate/pyruvate Lysinuric protein intolerance Lipoprotein lipase Liquid secondary ion mass spectrometry Lymphocytes Lysine Muscle Malonic acid Multiple acyl-CoA dehydrogenation defects Monoamine oxidase Methionine adenosyltransferase Medium-chain acyl-CoA dehydrogenase Medium-chain triglyceride Menkes disease Mitochondrial encephalopathy, lactic acidosis, stroke-like epi­sodes Myoclonus epilepsy, ragged-red fibers Methionine Methemoglobin 3-Methoxy-4-hydroxyphenylglycol Myocardial infarction Mitochondrial energy metabolism Methylmalonic acid Mitochondrial neurogastrointestinal encephalomyopathy Mucopolysaccharidoses Mental retardation Mental retardation/developmental delay Magnetic resonance imaging Magnetic resonance spectroscopy Maple syrup urine disease 3-Methoxytyramine Mitochondrial DNA 5-Methyltetrahydrofolate 5,10-Methylenetetrahydrofolate reductase Microsomal transfer protein Methylene units

n

N/A NADH NAGA NAGS NALD NARP NCV n.d. NE Neo NKH NMN NMR OAT ODC 30HAnA 30H-Kyn 170HP OHS 30MD OPRT Orn OTC P PAA PAH PBG PBGD P5C PCD P5CDH PCR PCRE PEG PEO PH Phe PHYT PKU PLT p.m. PNP p.o.

Normal Not applicable Reduced nicotinamide adenine dinucleotide a-N-acetylgalactosaminidase N-acetylglutamate synthase Neonatal adrenal leukodystrophy

Abbreviations XXXV

Neurogenic muscle weakness, ataxia, retinitis pigmentosa Nerve conduction velocity Not detectable Norepinephrine Neopterin N onketotic hyperglycinemia Normetanephrine Nuclear magnetic resonance Ornithine aminotransferase Orotidine monophosphate decarboxylase 3-Hydroxyanthranilic acid 3-Hydroxykynurenine 17 -Hydroxyprogesterone Occipital horn syndrome 3-0-methyldopa Orotate phosphoribosyltransferase Ornithine Ornithine transcarbamylase Plasma Plasma amino acids Phenylalanine-4-hydroxylase Porphobilinogen Porphobilinogen deaminase Pyrroline-5-carboxylic acid Pterin-4a-carbinolamine dehydratase Pyrroline-5-carboxylate dehydrogenase Polymerase chain reaction Plasma creatinine Polyethylene glycol Progressive external ophthalmoplegia Primary hyperoxaluria Phenylalanine Phytanic acid Phenylketonuria Platelets Afternoon Purine nucleoside phosphorylase Orally

XXXVI

PO pp PPribP PRA PRIS Pro Prot. PRPP PRPS PTPS R-S-P RBC RCDP RNA r.p.m. rRNA RT S SA SAA SAdo SAICAr SAM s.c. SCAD SCHAD scm SD SDH Ser SGA SLE SO SSD STAR subst. T TAA TAT TG TH THAM THCA THC

Abbreviations

Proline oxidase Postprandial Phosphoribosylpyrophosphate Plasma renin activity Pristanic acid Proline Protein Phosphoribosylpyrophosphate Phosphoribosylpyrophosphate synthetase 6-Pyruvoyltetrahydropterin synthase Ribose-S-phosphate Red blood cells Rhizomelic chondrodysplasia punctata Ribonucleic acid Revolutions/minute Ribosomal RNA Room temperature Serum or Sepiapterin Succinylacetone Succinylacetoacetate Succininyladenosine Succininyl-aminoimidazole carboxamide riboside S-Adenosyl methionine Subcutaneously Short-chain acyl-CoA dehydrogenase Short-chain 3-hydroxyacyl-CoA dehydrogenase Severe combined immunodeficiency Standard deviation Sarcosine dehydrogenase Serine Small for gestational age Systemic lupus erythematosus Sulfite oxidase Succinic semialdehyde dehydrogenase Steroidogenic acute response protein Substance Testosterone Tubular amino acid reabsorption Tyrosine aminotransferase Triglycerides Tyrosine hydroxylase Tris(hydroxyaminomethyl) buffer Trihydroxycholestanoic acid Tetrahydrocortisone

THF Thr TIA/CVA TID TLC TMS tRNA Trp Tyr U UAA UCRE UDP UMP UMPH UMPS UroA UTI UTP UV Val VDAC YEP VLA VLCAD VLCFA VLDL VMA WBC WD XA X-ALD Xan XDH ZS

Tetrahydrofolic acid or Tetrahydrocortisol Threonine

Abbreviations XXXVII

Transient ischemic attack/cerebrovascular accident Three times/day Thin -layer chromatography Tandem mass spectrometry Transfer RNA Tryptophan Tyrosine Urine Urinary amino acids Urine creatinine Uridine diphosphate Uridine monophosphate Uridine monophosphate hydrolase Uridine monophosphate synthase Urocanic acid Urinary tract infection Uridine triphosphate Ultraviolet Valine Voltage-dependent anion channel Visual evoked potential Vanillactic acid Very-long-chain acyl-CoA dehydrogenase Very-long-chain fatty acid(s) Very-low-density lipoproteins Vanillylmandelic acid White blood cells Wilson disease Xanthurenic acid X-linked adrenoleukodystrophy Xanthine Xanthine oxidase/dehydrogenase Zellweger syndrome