Clinical Information

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism associated with germline mutations of the isovaleryl-CoA dehydrogenase (IVD) gene. Mutations in this gene cause isovaleryl-CoA dehydrogenase (IVD) deficiency. This enzyme defect results in the accumulation of derivatives of isovaleryl-CoA, including free isovaleric acid, 3-OH valeric acid, N-isovalerylglycine, and isovalerylcarnitine. Diagnosis relies primarily on the identification of these metabolites in urine by organic acid and acylglycine analyses, and in plasma by acylcarnitine analysis.

Patients with IVA may present with various phenotypes, from the acute, neonatal phenotype to the chronic intermittent phenotype. Typically patients present with fairly nonspecific features including poor feeding and vomiting. During these episodes, a characteristic smell of "dirty socks" may be present. In the past, many patients with neonatal onset died during the first episode, while survivors of acute manifestations often suffered neurological sequelae due to incurred central nervous system damage. Therefore, early diagnosis and treatment is of the utmost importance. Newborn screening for IVA was established to allow for early detection by acylcarnitine analysis and presymptomatic initiation of treatment. This early detection has led to improved prognosis for IVA patients.

Molecular follow-up testing for patients with positive newborn screening for IVA has led to the identification of specific mutant alleles. One such mutant allele A282V (historic nomenclature:A282V, current nomenclature: A314V)  has been found to be overrepresented in patients detected by newborn screening. Clinical evaluation of patients with the A282V mutant allele suggests that this specific mutant allele may confer a milder clinical phenotype. Accordingly, determination of the patient's genotype with respect to the A282V mutation has implications for patient management and genetic counseling.