Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Abstract

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra-and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.

Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

“…In fact, it has been suggested already that the intake of VPA should be avoided in patients with inborn errors affecting mitochondrial metabolism (Silva et al, 2008). For that reason, we conclude that VPA administration should be avoided in cases of inborn deficiencies affecting certain ACDs or affecting the leucine and isoleucine oxidative pathways (Korman, 2006;Vockley and Ensenauer, 2006).…”

Newborn Screening for Isovaleric Acidemia Using Tandem Mass Spectrometry: Data from 1.6 Million Newborns

“…Characteristic but unspecific clinical signs include episodes of recurrent vomiting, and there is a risk of coma and death. IVA manifestation varies from the acute neonatal type, with early onset of metabolic decompensation, to the chronic intermittent type, with onset in infancy or childhood that presents as developmental delay and/or failure to thrive (1 ).…”

Aspects of Newborn Screening in Isovaleric Acidemia

“…Long-term treatment strategies aim to: (1) reduce the production of toxic metabolites by the restriction of protein or leucine intake; and to (2) enhance the conjugation of potentially toxic free isovaleric acid to its non-toxic conjugates isovalerylcarnitine and isovalerylglycine, which are excreted by the kidneys via supplementation of L-carnitine and/or L-glycine [44,80,81].…”

“…Because it remains unknown if subjects with the mild IVA phenotype detected by NBS might experience metabolic crises or long-term neurological manifestations, these individuals may be advised to take L-carnitine, although it is unclear whether it prevents metabolic crises. A low dosage of 30 to 50 mg/kg × day has been proposed for these individuals [44]. L-glycine may be omitted from long-term treatment, especially in individuals with the mild phenotype.…”