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 . IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3- methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Biochemical metabolites characteristic of IVA include C5 acylcarnitine and 2-methylbutyrylcarnitine . Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in affected individuals. IVA can cause significant morbidity and mortality with both intra- and interfamilial variability. IVA is characterized by three phenotypes with either acute neonatal, chronic intermittent or asymptomatic presentations. Neonatal symptoms are non-specific and include poor feeding, vomiting, lethargy and seizures. Acute episodes of metabolic acidosis and moderate ketosis are observed. The chronic intermittent form is characterized by periodic episodes of metabolic acidosis. Infants with the neonatal form may later exhibit symptoms of the chronic intermittent. Neutropenia, thrombocytopenia, or, rarely, pancytopenia often occurs with acidotic episodes. A characteristic smell of "sweaty feet" may be present when the patient is acutely sick. Acidosis with an unexplained anion gap, hyperammonemia, hyper- or hypoglycemia and hypocalcemia may be present. IVA is caused by mutations to the IVD gene at 15q14) . One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who are asymptomatic. 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. Gene sequence analysis is available to test for mutations to the IVD gene (HF).
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- Confirmation of clinical/biochemical diagnosis of IVA
- Carrier testing in adults with a family history of IVA
Prevalence: IVA has an estimated incidence of 1:62,500 live births .
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
- Plasma Amino Acid (AA) Analysis, Urine Organic Acids (OA), and Pplasma Acylcarnitine Profile (AR) are used in the diagnoses of a patient with IVA
- Custom Diagnostic Mutation Analysis (KM) is available to family members if mutations are identified by sequencing.
- Prenatal testing is available for known familial mutations only. Please call the Laboratory Genetic Counselor before collecting a fetal sample.