Biomarkers in Inborn Errors of Metabolism

Clinical Aspects and Laboratory Determination

Uttam Garg,Laurie D. Smith

• Publisher: Elsevier
• Year: 2017
• ISBN:
  9780128029183
• Topic: Medicina
• Subtopic: Endocrinologia e metabolismo

Biomarkers of Inborn Errors in Metabolism: Clinical Aspects and Laboratory Determination is structured around the new reality that laboratory testing and biomarkers are an integral part in the diagnosis and treatment of inherited metabolic diseases. The book covers currently used biomarkers as well as markers that are in development. Because biomarkers used in the initial diagnosis of disease may be different than the follow-up markers, the book also covers biomarkers used in both the prognosis and treatment of inherited metabolic disorders.

With the introduction of expanded new-born screening for inborn metabolic diseases, an increasing numbers of laboratories are involved in follow-up confirmatory testing. The book provides guidance on laboratory test selection and interpreting results in patients with suspected inherited metabolic diseases. The book provides comprehensive guidance on patient diagnosis and follow-up through its illustrative material on metabolic pathways, genetics and pathogenesis, treatment and prognosis of inherited metabolic diseases, along with essential information on clinical presentation.

Each chapter is organized with a uniform, easy-to-follow format: a brief description of the disorder and pathway; a description of treatment; biomarkers for diagnosis; biomarkers followed for treatment efficacy; biomarkers followed for disease progression; confounding conditions that can either: affect biomarker expression or mimic IEMs; other biomarkers: less established, future.

• Provides comprehensive information on the tests/biomarkers selection in newborn screening and follow-up of newborn screens
• Categorizes biomarkers into diagnostic markers, disease follow-up markers, and prognostic biomarkers
• Covers confounding factors that can alter biomarkers in the absence of inborn errors of metabolism
• Offers guidance on how to distinguish acquired causes from inborn errors of metabolism

Chapter 1

Introduction to laboratory diagnosis and biomarkers in inborn error of metabolism

U. Garg^1,3 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

Abstract

Inborn errors of metabolism (IEM) are genetic disorders of intermediary metabolism that result in metabolic defects due to deficiency of enzymes, membrane transporters, or other functional proteins. Many of these disorders are detected through newborn screening or clinical suspicion. Laboratory tests and use of biomarkers are essential in the diagnosis and follow-up of patients with IEM. Specialized tests are not available in most hospitals, and need special attention in specimen collection, processing, and transport. Routine tests, although not necessarily diagnostic, are important in initial patient management and in providing guidance for further testing and management. Furthermore, there may be conditions that present with biochemical findings that mimic or confound a diagnosis. Unlike routine laboratory tests that are generally automated, most biochemical genetics tests are developed in-house. Method development and quality control can be challenging due to lack of standardized reagents and limited availability of external assessment programs. Treatment and prognosis of these disorders varies significantly, from dietary management to enzyme replacement therapies.

Keywords

Inborn errors of metabolism; inherited metabolic disorders; amino acids; organic acids; acylcarnitine; quality control; reference ranges; method evaluation

1.1 Introduction

Inborn errors of metabolism (IEM) are genetic disorders of intermediary metabolism. 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 presentation 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, lethargy, 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 inherited 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 progressive 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 involvement 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 to conventional treatment. Labora...