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LEARNING OBJECTIVES
List laboratory results associated with a variety of inborn errors of metabolism.
Explain the molecular basis for a broad array of inborn errors of metabolism.
Describe the clinical presentation of an array of inborn errors of metabolism.
Describe the various effective treatment modalities for inborn errors of metabolism.
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The clinical recognition and eventual laboratory diagnosis of many inborn errors of metabolism (IEMs) is challenging due to an often long presymptomatic phase and nonspecific clinical presentation. Missed or delayed diagnoses can have severe and long-lasting consequences. In 2006, the American College of Medical Genetics (ACMG) reported on its examination of dozens of metabolic conditions and their suitability for newborn screening. The report recommended screening for 29 core conditions and a number of secondary targets.1 The following chapter will primarily focus on the clinical presentation, molecular genetic basis, and diagnosis of the “core panel” IEMs. These include branched-chain and aromatic aminoacidopathies, some urea cycle disorders, mitochondrial fatty acid oxidation disorders, and cofactor metabolism abnormalities. The final section will summarize the treatment strategies associated with these disease states. The reader should be aware that currently there are over 500 single gene IEMs and that these 29 ACMG recommended conditions for screening represent some of the more significant conditions in terms of diagnosis and treatment. For an extensive review of all IEM's, the reader is recommended to read the online version of Metabolic and Molecular Bases of Inherited Diseases (oMMBID).
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Branched-Chain Aminoacidopathies
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The branched-chain amino acids (BCAA) are leucine, isoleucine, and valine. These amino acids are “essential” because they cannot be synthesized by mammals and must be obtained through the diet. The branched-chain amino acids comprise approximately 35% of the total essential amino acids in muscle protein and 40% of the dietary amino acids required by mammals.2 The carbon skeletons of BCAAs can generate ketone bodies or provide succinate for TCA cycle function, thus providing substrates for energy production. Derived carbon skeletons from these amino acids also provide precursors for fatty acid and cholesterol synthesis. Some of the most common signs and symptoms of branched-chain amino acid disorders include encephalopathy, coma, or death if not diagnosed and treated promptly. Common biochemical findings include but are not limited to metabolic acidosis, hyperammonemia, hypoglycemia with appropriate or increased ketosis, liver dysfunction, and the presence of reducing substances in the urine. A high level view of branched-chain amino acid catabolism is shown in Figure 3-1. Some of the most common disorders are described here.
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