IVA is inherited in an autosomal recessive pattern. Normally a person has two functional genes. In people with IVA, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with IVA typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.
Carriers of IVA do not typically have symptoms.
There are two forms of IVA, neonatal-onset and late-onset.
Neonatal-onset: The neonatal-onset form of this disorder is severe and symptoms typically begin in the first few days of life. Symptoms begin as vomiting and poor feeding, but progress to seizures, coma and eventually death. Newborns with IVA have a distinctive odor of sweaty feet.
Late-onset: The symptoms of late-onset IVA may be brought on by illness, fasting or eating a protein rich meal. Symptoms may include vomiting and seizures. Long-term symptoms include growth impairment and intellectual disability. Rarely, people with IVA remain asymptomatic.
- Incidence: The incidence of IVA is estimated to be 1 in 250,000.
- New York State Method of Screening (First Tier): Screening for IVA is accomplished by measuring the acylcarnitine C5 by tandem mass spectrometry (MS/MS).
- Second Tier Screening: None
- Testing can be affected by: Newborn screening cannot distinguish between IVA and 2-Methylbutyrylglycinuria (2-MBCD). Pivalic acid, common in many medications (including some antibiotics), produces an elevated C5 and thus a false positive newborn screen.
- Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
- Referral to Specialty Care Center: Patients with an abnormal newborn screen for IVA are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of IVA.
Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis, enzyme analysis and genetic testing of the IVD gene.
Treatment is typically dietary management, including careful monitoring of protein intake and supplementing with specialized leucine-free formula. Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.
Outcome of the neonatal-onset form is poor, although early treatment improves prognosis. Outcome of the late-onset form is variable and dependent on multiple factors, including the severity of disease and response to treatments.
Isovaleric acidemia (IVA) is a disorder of organic acid metabolism (inherited metabolic disorder).
IVA is caused by mutations in the IVD gene. A component of protein, the amino acid leucine, is broken down as part of normal metabolism. Mutations in the IVD gene cause a deficiency of an important enzyme, isovaleryl-CoA dehydrogenase. Without this enzyme, leucine is not broken down; the toxic metabolite isovaleric acid accumulates and causes neurologic symptoms.