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ABSTRACT

  • 2-Ketoadipic acid, an intermediate in the metabolism of L-lysine, hydroxy-L-lysine, and L-tryptophan, undergoes successive oxidative decarboxylations by 2-ketoadipic dehydrogenase and glutaryl-CoA dehydrogenase to form glutaryl-CoA and crotonyl-CoA, respectively.

  • Deficiency of 2-ketoadipic dehydrogenase causes 2-ketoadipic acidemia (MIM 245130), a condition characterized by accumulation and excretion of 2-ketoadipic, 2-aminoadipic, and 2-hydroxyadipic acids, probably without adverse phenotypic effects.

  • Deficiency of glutaryl-CoA dehydrogenase causes glutaric acidemia type I (MIM 231670), a disorder characterized clinically by dystonia and dyskinesia appearing during the first years of life, chemically by excretion of glutaric and 3-hydroxyglutaric acids in urine, and pathologically by neuronal degeneration of the caudate and putamen. CT and MRI scans often show frontotemporal atrophy and/or arachnoid cysts before the onset of symptoms.

  • Glutaryl-CoA dehydrogenase deficiency is inherited as an autosomal recessive trait. More than 60 pathogenic mutations have been identified in the GCD gene (19p13.2), and because no one mutation is prominent outside of inbred groups, most GA1 patients are heterozygous for two different mutant alleles. Identification of heterozygous carriers, while possible by demonstration of activity of intermediate enzymes in cultured fibroblasts and peripheral leukocytes, is most accurately done by mutation analysis.

  • Striatal damage and neurologic phenotype do not develop in all patients, and there is evidence that early supplementation with L-carnitine, vigorous treatment of intercurrent infections with fluids, glucose and insulin, and (perhaps) dietary restriction of lysine and tryptophan can prevent their development in most instances.

  • Prenatal diagnosis is possible and is based on demonstrating increased concentrations of glutaric acid in amniotic fluid, deficiency of glutaryl-CoA dehydrogenase in cultured amniocytes or (probably) material obtained by CVS, or, in appropriate families, by mutation analysis.

BIOCHEMISTRY

Steps in the conversion of L-lysine to 2-ketoadipic acid and defects in this pathway have been discussed in Chap. 111. 2-Ketoadipic acid, which is also an intermediate in the oxidation of hydroxy-L-lysine and L-tryptophan, is converted to crotonyl-CoA, an intermediate in fatty acid oxidation, by the sequential action of two enzymes, 2-ketoadipic dehydrogenase and glutaryl-CoA dehydrogenase (Fig. 124-1) Inherited defects in these proteins cause 2-ketoadipic acidemia and glutaric acidemia, respectively.

Fig. 124-1

Synthesis and oxidation of 2-ketoadipic acid in mammals. (1) Transaminase, (2) 2-ketoadipic dehydrogenase, (3) glutaryl-CoA dehydrogenase.

2-Ketoadipic dehydrogenase is a mitochondrial enzyme and has not been separated from 2-ketoglutaric acid dehydrogenase (EC 1.2.4.1), the citric acid cycle enzyme that forms succinyl-CoA.1 The enzyme has at least three subunits analogous to those of pyruvate dehydrogenase (see Chap. 129): a thiamine-containing E-1 subunit that decarboxylates 2-ketoadipic acid to active glutaraldehyde (and possibly also 2-ketoglutaric acid to active succinaldehyde), an E-2 transacetylase, and an E-3 lipoamide dehydrogenase. It is likely that the E-3 subunit is the same protein as the E-3 subunits of pyruvate dehydrogenase and of branched-chain ketoacid dehydrogenase, and it may also form part of the glycine cleavage enzyme. Electrons from ...

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