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Genetic disorder affecting the branched-chain organic acids, the most frequent of the leucine metabolism disorders. This inborn error of metabolism leads to body accumulation of isovaleric acid (and its metabolites) resulting in vomiting, dehydration, severe metabolic acidosis, and neurologic manifestations.

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Isovaleric Acid CoA Dehydrogenase Deficiency.

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Uncertain (lack of general population screening); more than 60 cases have been reported since the first description in 1966.

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Autosomal recessive; chromosome 15q14-q15.

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Isovaleryl-CoA dehydrogenase catalyzes the first step of branched-chain organic acid metabolism of leucine. The deficiency of isovaleryl-CoA dehydrogenase activity results in accumulation of abnormal metabolites (isovaleric acid, isovalerylglycine, hydroxyisovaleric acid, isovalerylglucuronide, isovalerylglutamic acid). The build-up of these metabolites is responsible for the disease. The precise mechanism of isovaleric acid toxicity is not well known, but it is an inhibitor of succinate CoA ligase in the Krebs cycle and inhibits liver mitochondrial oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. The neutropenia often seen in the disease may be attributed to inhibition of granulopoietic progenitor cell proliferation by isovaleric acid.

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Clinical course; occasionally foul odor of “sweaty feet” caused by isovaleric acid in body fluids; metabolic acidosis with mild-to-moderate ketonuria and lactic acidemia; hyperammonemia. Thrombocytopenia, neutropenia, and pancytopenia may be present, as well as hypocalcemia. The “sweaty feet” odor is suggestive of, but not specific for, isovaleric acidemia because it may be present in other organic acidurias (e.g., “maple syrup” urine disease, glutaric aciduria type II). Urine analysis for nonvolatile organic acids reveals marked elevation of isovalerylglycine acid with lesser elevation of hydroxyvaleric acid and smaller, but still significant, amounts of the other abnormal metabolites. Confirmation of the diagnosis of isovaleric acidemia comes from assays on patients' fibroblasts showing deficiency of isovaleryl-CoA dehydrogenase (improved tritium release assay or fluorometric assay). Prenatal diagnosis can be made by amniocentesis by stable isotope dilution analysis of elevated isovalerylglycine in amniotic fluid or by fluorometric assay of isovaleryl-CoA dehydrogenase activity.

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Two clinical categories: half of the patients present with an acute neonatal illness with poor feeding, dehydration, hypothermia, and coma, and if untreated, death secondary to severe metabolic acidosis, cerebral edema, cerebral hemorrhage, or infection. The other half of patients either are survivors of the acute neonatal episode or later developed symptoms and suffer from a chronic intermittent form with similar episodes. The majority of patients have normal psychomotor development, but some present with various degrees of developmental delay. The recurrent episodes often follow upper respiratory infection or intake of protein-rich food to which patients frequently develop aversion. Most diagnoses of the disease are made during the first episode. Acute episodes are treated symptomatically (protein restriction, hydration, correction of acid-base disturbances, glucose infusion). Along with symptomatic treatment are more specific therapeutic approaches, such as glycine and carnitine administration. Under stable conditions of a leucine-restricted diet, the optimal regimen is 150 mg/kg/day of glycine per os or per nasogastric tube. During acute crisis, increase glycine supplements to ...

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