Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of isovaleric acidemia, isovaleric aciduria, isovaleryl-CoA dehydrogenase deficiency, and IVD deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this article, the authors describe the different manifestations of this inborn error of leucine catabolism and explain 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.
• 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 or 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.
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. The disease may manifest in the neonatal period with 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 and psychomotor retardation. The key metabolites leading to diagnosis are isovalerylglycine in urine and isovaleryl carnitine in plasma.
First descriptions of the clinical and biochemical phenotype were made by Tanaka and colleagues (39; 03), making isovaleric acidemia the first recognized organic acid disorder. The identification of the specific enzyme isovaleryl-CoA dehydrogenase was challenging. It was not known whether a distinct enzyme existed for the degradation of isovaleryl-CoA or whether the degradation of short-chain acyl-CoA esters in fatty acid oxidation and isovaleryl-CoA in leucine catabolism was accomplished by a common enzyme. 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 were able to prove this assumption (33). 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 (12). The gene was mapped to chromosome 15q14-q15 (38; 31). Several different mutations causing isovaleric acidemia have subsequently been identified (43).
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