Table Of ContentBiomarkers in Inborn
Errors of Metabolism
Clinical Aspects and Laboratory Determination of Biomarkers Series
Series Editors: Uttam Garg and Laurie D. Smith
Volume 1
Alcohol and Its Biomarkers: Clinical Aspects and Laboratory Determination
Volume 2
Biomarkers in Inborn Errors of Metabolism: Clinical Aspects and Laboratory
Determination
Volume 3
Endocrine Biomarkers: Clinical Aspects and Laboratory Determination
Biomarkers in Inborn
Errors of Metabolism
Clinical Aspects and
Laboratory Determination
Uttam Garg
Children’s Mercy Hospitals and Clinics,
Kansas City, MO, United States;
University of Missouri School of Medicine,
Kansas City, MO, United States
Laurie D. Smith
University of North Carolina School of Medicine,
Chapel Hill, NC, United States
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
Copyright © 2017 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, recording, or any information storage
and retrieval system, without permission in writing from the publisher. Details on how to
seek permission, further information about the Publisher’s permissions policies and our
arrangements with organizations such as the Copyright Clearance Center and the Copyright
Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by
the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional practices,
or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge
in evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety and
the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of
products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-802896-4
For Information on all Elsevier publications
visit our website at https://www.elsevier.com/books-and-journals
Publisher: Mica Haley
Acquisition Editor: Tari Broderick
Editorial Project Manager: Fenton Coulthurst
Production Project Manager: Karen East and Kirsty Halterman
Designer: Mark Rogers
Typeset by MPS Limited, Chennai, India
This book is dedicated to
My family, wife Jyotsna, and daughters Megha and
Mohini who are my inspiration (Uttam Garg).
My family and, most importantly, to the patients and
their parents who have taught me so much by allowing me
to be a part of their lives (Laurie D. Smith).
List of Contributors
R. Artuch
Hospital Sant Joan de Déu, Barcelona, Spain
M.J. Bennett
The Children’s Hospital of Philadelphia and University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA, United States
N. Couser
University of North Carolina, Chapel Hill, NC, United States
M. Dasouki
King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;
University of Kansas Medical Center, Kansas City, KS, United States
P.D. DeArmond
Nationwide Children’s Hospital, Columbus, OH, United States
D.J. Dietzen
Washington University School of Medicine, St. Louis, MO, United States;
St. Louis Children’s Hospital, St. Louis, MO, United States
A.M. Ferguson
University of Missouri School of Medicine, Kansas City, MO, United States;
Children’s Mercy Hospitals and Clinics, Kansas City, MO, United States
R. Ganetzky
University of Pennsylvania, Philadelphia, PA, United States
A. Garcia-Cazorla
Hospital Sant Joan de Déu, Barcelona, Spain
U. Garg
Children’s Mercy Hospitals and Clinics, Kansas City, MO, United States;
University of Missouri School of Medicine, Kansas City, MO, United States
M. Gucsavas-Calikoglu
University of North Carolina, Chapel Hill, NC, United States
M. He
University of Pennsylvania, Philadelphia, PA, United States
L. Hubert
Baylor College of Medicine, Houston, TX, United States; Baylor Genetics
Laboratories, Houston, TX, United States
P.M. Jones
Children’s Medical Center of Dallas and University of Texas Southwestern
Medical Center, Dallas, TX, United States
S.F. Lo
Children’s Hospital of Wisconsin, Milwaukee, WI, United States
xxi
xxii List of Contributors
M. Molero-Luis
Hospital Sant Joan de Déu, Barcelona, Spain
M.A. Morrissey
Wadsworth Center, Albany, NY, United States
A. Ormazabal
Hospital Sant Joan de Déu, Barcelona, Spain
A.L. Pyle-Eilola
Nationwide Children’s Hospital, Columbus, OH, United States; The Ohio State
University, Columbus, OH, United States
F.J. Reynoso
University of Pennsylvania, Philadelphia, PA, United States
L.D. Smith
University of North Carolina School of Medicine, Chapel Hill, NC, United States
Q. Sun
Baylor College of Medicine, Houston, TX, United States
V.R. Sutton
Baylor College of Medicine, Houston, TX, United States; Baylor Genetics
Laboratories, Houston, TX, United States; Texas Children’s Hospital, Houston,
TX, United States
C. Yu
Icahn School of Medicine at Mount Sinai, New York, NY, United States
Biographies
Uttam Garg
Uttam Garg, PhD, is Director of Laboratory Medicine at Children’s Mercy Hospital,
and Professor of Pathology at the University of Missouri, School of Medicine in
Kansas City. Before joining Children’s Mercy Hospital, he served as faculty at the
New York University Medical Center and the University of Minnesota Medical
School. He is board certified in clinical chemistry, and has extensive laboratory expe-
rience in the areas of clinical chemistry and biochemical genetics. He served on
the Board of Directors of the American Board of Clinical Chemistry and National
Registry of Certified Chemists. He is a member of expert panel on newborn screen-
ing of Clinical Laboratory Standards Institute. He has published over 150 research
papers, review articles, and book chapters in the area of clinical biochemistry, and
has edited/coedited 4 books. His research interests include methods development in
clinical laboratory diagnosis.
Laurie D. Smith
Laurie D. Smith, MD, PhD, is Associate Professor of Pediatrics at the University of
North Carolina in Chapel Hill. She is a board certified pediatrician, clinical geneti-
cist, and clinical biochemical geneticist with extensive experience in the diagnosis
and management of patients with inborn errors of metabolism. She serves or has
served on a number of national, regional, and state committees and organizations
and is a fellow of the American Academy of Pediatrics and the American College of
Medical Genetics. She has published numerous research papers and book chapters in
the area of metabolic disorders. She has coedited one book.
xxiii
Preface
Inborn errors of metabolism are biochemical genetic disorders that result from the
deficiency of enzymes, membrane transporters, or other functional proteins. Patients
with these disorders may present with either acute overwhelming sickness or a pro-
longed, smoldering illness. For the former, rapid diagnosis is vital in the diagnosis
and follow-up of these patients to limit morbidity and mortality. For the latter, diag-
nosis is important for the initiation of appropriate clinical care. Clinical presentation
resulting from these disorders can be quite variable. Therefore, use of laboratory tests
and biomarkers are indispensable in the diagnosis and follow-up of these disorders.
Rapid tests are generally available for the initial presumptive diagnosis and manage-
ment of acutely ill patients. Specialized tests involving laboratory biomarkers are not
available in most medical centers, and are needed for the confirmation and follow-up
of these disorders. Moreover, laboratory biomarkers are used in newborn screening
to diagnose biochemical genetic disorders in asymptomatic patients.
In this book, Biomarkers in Inborn Errors of Metabolism, the major emphasis is
on the test selection and biomarkers used in the diagnosis and follow-up. When possi-
ble, biochemical pathways and illustrative chromatograms are provided. In addition,
basic information on clinical presentation, pathogenesis, treatment, and prognosis is
also presented. Furthermore, confounding factors that may mimic biomarkers used
in the diagnosis of inborn error of metabolisms are also covered.
We are indebted to our authors and colleagues for their excellent contributions
and making this book possible. We are also thankful to our patients and families who
have taught us a lot. Last but not the least, we would like to acknowledge the support
of Jeffery Rossetti and Fenton Coulthurst, editorial project managers, for their sup-
port during the preparation of this book.
Uttam Garg and Laurie D. Smith
xxv
CHAPTER
1
Introduction to laboratory
diagnosis and biomarkers in
inborn error of metabolism
U. Garg1,3 and L.D. Smith2
1Children’s Mercy Hospitals and Clinics, Kansas City, MO, United States;
2University of North Carolina School of Medicine, Chapel Hill, NC, United States;
3University of Missouri School of Medicine, Kansas City, MO, United States
1.1 INTRODUCTION
Inborn errors of metabolism (IEM) are genetic disorders of intermediary metabo-
lism. The majority of these disorders are due to single gene defects resulting in the
deficiency of an enzyme, membrane transporter, or other functional protein. Timely
biochemical genetic testing, and, in many cases, newborn screening are important
in early recognition and treatment of these disorders. Often there is accumulation of
toxic substrates or metabolites or deficiency of essential products. Clinical presen-
tation resulting from IEM can be quite variable. Broadly, IEM can be divided into
those that involve defects in metabolism of complex molecules, those that result in
acute intoxication and those that result in energy deficiency.1,2 Patients with IEM
are diagnosed through clinical suspicion or newborn screening. A family history can
provide clues but does not exclude an underlying IEM. One of the scenarios that
might suggest an IEM in a neonate is an acute sepsis-like illness, poor feeding, leth-
argy, poor growth, and so on, that does not respond to conventional treatment. In an
older child, symptoms such as vomiting, metabolic acidosis, ataxia, or coma might
suggest an IEM. Further testing is needed to confirm a clinical suspicion of an IEM.
In addition to making a diagnosis of an IEM in a symptomatic patient, a significant
number of patients are diagnosed through newborn screening programs. In recent
years, newborn screening programs have expanded to include more than 50 inher-
ited metabolic disorders, including aminoacidopathies, organic acidemias, fatty acid
oxidation disorders, and lysosomal storage disorders.3–6 Newborn screening results
are considered presumptive positive and are confirmed by more definitive laboratory
tests.6,7 Many of these disorders may present later in life with chronic and progres-
sive multisystem (skeletal muscle, liver, kidneys, gastrointestinal tract, eyes, skin, or
central nervous system) symptoms. Lysosomal disorders involving the accumulation
of complex molecules may present with behavioral changes, coarsening of facial
features, or joint contractures. The IEM can also present with specific organ involve-
ment such as a cardiomyopathy or hepatic dysfunction. Generally, an IEM should be
considered in any patient who does not have a clear diagnosis and does not respond
Biomarkers in Inborn Errors of Metabolism. DOI:http://dx.doi.org/10.1016/B978-0-12-802896-4.00001-8 1
© 2017Elsevier Inc. All rights reserved.
