Biomarkers 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. 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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.