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  • Updated 04.30.2024
  • Released 09.22.2003
  • Expires For CME 04.30.2027

Isovaleric acidemia



In this article, the author describes the different manifestations of this inborn error of leucine catabolism and explains disease diagnosis and treatment. Opportunities and challenges of extended newborn screening programs are discussed; patients identified early through newborn screening have a highly improved prognosis, and a newly recognized subcohort may have a mild or even asymptomatic clinical course.

Key points

• Isovaleric aciduria due to isovaleryl-CoA dehydrogenase deficiency presents with two distinct phenotypes: (1) acute neonatal onset with severe metabolic crisis that, without appropriate treatment, quickly evolves into coma and death or (2) a chronic intermittent disease with episodes of metabolic acidosis and psychomotor retardation.

• Key metabolites leading to diagnosis are isovalerylglycine in urine and isovaleryl carnitine in plasma or dried blood spots.

• Treatment must be supervised by an experienced metabolic center and must continue for life. Special care must be taken to ensure efficient emergency procedures at all times (including travel and holidays).

• Isovaleric acidemia can be readily diagnosed in newborn screening programs

• If treatment is initiated before the development of severe metabolic decompensation, the patient’s prognosis is significantly improved. Patients who are diagnosed by newborn screening usually have normal psychomotor development.

• Patients identified by newborn screening who carry the common mutation (A282V, 932C> T) are asymptomatic and most likely do not need treatment.

Historical note and terminology

Isovaleric acidemia is caused by a deficiency of isovaleryl-CoA dehydrogenase, an enzyme located proximally in the catabolic pathway of the essential branched-chain amino acid leucine.

Essential branched-chain amino acid L-leucine

(Source: Harbin, December 5, 2008. Public domain.)

The disease may manifest in the neonatal period with a severe metabolic crisis that without appropriate treatment quickly evolves into coma and death. Alternatively, patients may have a chronic intermittent disease with episodes of metabolic acidosis. The key metabolites leading to diagnosis are isovalerylglycine in urine and isovaleryl carnitine in plasma.

The first description of the clinical and biochemical phenotype was made by Japanese-American geneticist Kay Tanaka (1929-1975) and colleagues (61; 03), making isovaleric acidemia the first recognized organic acid disorder. The identification of the specific enzyme isovaleryl-CoA dehydrogenase was challenging because it was unclear whether a distinct enzyme existed for the degradation of isovaleryl-CoA or whether a common enzyme accomplished both the degradation of short-chain acyl-CoA esters in fatty acid oxidation and isovaleryl-CoA in leucine catabolism.

Human isovaleryl-CoA dehydrogenase homotetramer

Also shown are 4 flavin adenine dinucleotide (FAD; light blue-red) + 4 Coenzyme A (CoA; green-red). (Illustration by Tiffany KA, Roberts DL, Wang M, et al. Creative Commons Attribution-Share Alike 4.0 International license. htt...

Tanaka and colleagues hypothesized the existence of a dehydrogenase specific for isovaleryl-CoA because of the distinct elevation of isovaleryl metabolites in the absence of elevations of other short-chain acids. In 1980, Rhead and Tanaka proved that this assumption was correct (53). In contrast to normal activity of butyryl-CoA dehydrogenase, deficient activity of isovaleryl-CoA dehydrogenase was demonstrated in fibroblasts of a patient with isovaleric acidemia. Human isovaleryl-CoA dehydrogenase was isolated from liver tissue in 1987 (17). The gene was mapped to chromosome 15q14-q15 (60; 51). Several different mutations causing isovaleric acidemia have subsequently been identified (65).

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