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. 365) 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 1,000 newborns. Almost all are transmitted as autosomal recessive traits.
The features of inherited disorders of amino acid catabolism are summarized in Table 364-1. In general, these disorders are named for the compound that accumulates to highest concentration in blood (-emias) or urine (-urias). For many conditions (often called aminoacidopathies), the parent amino acid is found in excess; for others, generally referred to as organic acidemias, products in the catabolic pathway accumulate. 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, seven forms of homocystinuria, and seven types of methylmalonic acidemia are recognized. Such heterogeneity reflects the presence of an even larger array of molecular defects.
Table 364-1 Inherited Disorders of Amino Acid Metabolism |Favorite Table|Download (.pdf)
Table 364-1 Inherited Disorders of Amino Acid Metabolism
|Amino acid(s)||Condition||Enzyme Defect||Clinical Findings||Inheritance|
|Phenylalanine||Phenylketonuria||Phenylalanine hydroxylase||Mental retardation, microcephaly, hypopigmented skin and hairs, eczema, “mousy” odor||AR|
|DHPR deficiency hyperphenylalaninemia||Dihydropteridine reductase||Mental retardation, hypotonia, spasticity, myoclonus||AR|
|PTS deficiency hyperphenylalaninemia||6-Pyruvoyl-tetrahydropterin synthase||Dystonia, neurologic deterioration, seizures, mental retardation||AR|
|GCH1 deficiency hyperphenylalaninemia||GTP cyclohydrolase I||Mental retardation, seizures, dystonia, temperature instability||AR|
|Carbinolamine dehydratase deficiency||Pterin-4α-carbinolamine dehydratase||Transient hyperphenylalaninemia (benign)||AR|
|Tyrosine||Tyrosinemia type I (hepatorenal)||Fumarylacetoacetate hydrolase||Liver failure, cirrhosis, rickets, failure to thrive, peripheral neuropathy, “boiled cabbage” odor||AR|
|Tyrosinemia type II (oculocutaneous)||Tyrosine transaminase||Palmoplantar keratosis, painful corneal erosions with photophobia, mental retardation (?)||AR|
|Tyrosinemia type III||4-Hydroxyphenylpyruvate dioxygenase||Hypertyrosinemia with normal liver function, occasional mental delay||AR|
|Hawkinsinuria||4-Hydroxyphenylpyruvate dioxygenase||Transient failure to thrive, metabolic acidosis in infancy||AD|
|Alkaptonuria||Homogentisic acid oxidase||Ochronosis, arthritis, cardiac valve involvement, coronary artery calcification||AR|
|Albinism (oculocutaneous)||Tyrosinase||Hypopigmentation of hair, skin, and optic fundus; visual loss; photophobia||AR|
|Albinism (ocular)||Different enzymes or transporters||Hypopigmentation of optic fundus, visual loss||AR, XL|
|DOPA-responsive dystonia||Tyrosine hydroxylase||Rigidity, truncal hypotonia, tremor, mental retardation||AR|
|GABA||4-Hydroxybutyric aciduria||Succinic semialdehyde dehydrogenase||Seizures, mental retardation, ataxia||AR|
|Tryptophan||Kynurenic aciduria||Kynurenine-3-monooxygenase||Niacin ...|
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