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INTRODUCTION

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Amino acids are not only the building blocks of proteins but also serve as neurotransmitters (glycine, glutamate, γ-aminobutyric acid) or as precursors of hormones, coenzymes, pigments, purines, or pyrimidines. Eight amino acids, referred to as essential, cannot be synthesized by humans and must be obtained from dietary sources. The others are formed endogenously. Each amino acid has a unique degradative pathway by which its nitrogen and carbon components are used for the synthesis of other amino acids, carbohydrates, and lipids. Disorders of amino acid metabolism and transport (Chap. 435e) are individually rare—the incidences range from 1 in 10,000 for cystinuria or phenylketonuria to 1 in 200,000 for homocystinuria or alkaptonuria—but collectively, they affect perhaps 1 in 1000 newborns. Almost all are transmitted as autosomal recessive traits.

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The features of inherited disorders of amino acid catabolism are summarized in Table 434e-1. In general, these disorders are named for the compound that accumulates to highest concentration in blood (-emias) or urine (-urias). In the aminoacidopathies, the parent amino acid is found in excess, whereas products in the catabolic pathway accumulate in organic acidemias. Which compound(s) accumulates depends on the site of the enzymatic block, the reversibility of the reactions proximal to the lesion, and the availability of alternative pathways of metabolic “runoff.” Biochemical and genetic heterogeneity are common. Five distinct forms of hyperphenylalaninemia, nine forms of homocystinuria, and methylmalonic acidemia are recognized. Such heterogeneity reflects the presence of a large array of molecular defects.

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The manifestations of these conditions differ widely (Table 434e-1). Some, such as sarcosinemia, produce no clinical consequences. At the other extreme, complete deficiency of ornithine transcarbamylase is lethal in the untreated neonate. Central nervous system (CNS) dysfunction, in the form of developmental retardation, seizures, alterations in sensorium, or behavioral disturbances, is present in more than half the disorders. Protein-induced vomiting, neurologic dysfunction, and hyperammonemia occur in many disorders of urea cycle intermediates. Metabolic ketoacidosis, often accompanied by hyperammonemia, is a frequent presenting finding in disorders of branched-chain amino acid metabolism. Some disorders produce focal tissue or organ involvement such as liver disease, renal failure, cutaneous abnormalities, or ocular lesions.

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The analysis of plasma amino acids (by ion-exchange chromatography), urine organic acids (by gas chromatography/mass spectrometry), and plasma acylcarnitine profile (by tandem mass spectrometry) is commonly used to diagnose and monitor most of these disorders. The diagnosis is confirmed by enzyme assay on cells or tissues from the patients or by DNA testing. The clinical manifestations in many of these conditions can be prevented or mitigated if a diagnosis is achieved early and appropriate treatment (e.g., dietary protein or amino acid restriction or vitamin supplementation) is instituted promptly. For this reason, newborn screening programs seek to identify several of these disorders. Infants with a positive screening test need additional metabolic testing (usually suggested by the newborn screening program) to confirm or exclude ...

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