Isovaleric Acidemia · IVA

Description

Isovaleric acidemia, IVA, is an autosomal recessive organic acid disorder of leucine catabolism. The enzyme isovaleryl-CoA dehydrogenase, encoded by IVD on chromosome 15, catalyzes the third step of leucine breakdown. Pathogenic variants in IVD reduce or abolish enzyme activity. Isovaleric acid, 3-hydroxyisovaleric acid, isovalerylglycine, and isovalerylcarnitine accumulate in blood and urine. Free isovaleric acid produces a characteristic odor described as sweaty feet, and the smell is sometimes the first clue at the bedside.

Two phenotypes are recognized. The acute neonatal form presents in the first days to two weeks of life with poor feeding, vomiting, lethargy, hypotonia, severe metabolic acidosis with elevated anion gap, ketonemia, hyperammonemia, and progression to coma or death without treatment. The chronic intermittent form presents later in infancy or childhood with episodes of vomiting, ketoacidosis, and lethargy triggered by infection or protein load, and is asymptomatic between episodes. Both phenotypes can occur in the same family and reflect variant-specific residual enzyme activity rather than separate genetic disorders. A milder phenotype associated with the c.932C>T (p.Ala282Val) variant is now the most commonly identified form in newborn screening cohorts and is often clinically silent.

Detection is by newborn screening on the dried blood spot, using tandem mass spectrometry to identify elevated isovalerylcarnitine, C5. The C5 marker also reflects the related compound 2-methylbutyrylcarnitine, and second-tier testing distinguishes isovaleric acidemia from short and branched-chain acyl-CoA dehydrogenase deficiencies and from pivaloylcarnitine produced by certain antibiotics. Confirmation uses urine organic acids showing isovalerylglycine and 3-hydroxyisovaleric acid, plasma acylcarnitines, and IVD sequencing. Reported incidence in expanded newborn screening programs is roughly 1 in 50,000 to 1 in 250,000 live births, with the higher detected rates reflecting inclusion of mild variant-associated cases.

Treatments to date

There is no FDA-approved disease-specific drug therapy for isovaleric acidemia. Standard of care has three components: a leucine-restricted diet using a leucine-free medical formula combined with measured natural protein, oral glycine supplementation, and oral L-carnitine supplementation. Glycine and carnitine each conjugate isovaleric acid in the body, forming isovalerylglycine and isovalerylcarnitine that the kidney excretes; the two conjugation pathways operate in parallel and are typically used together. A metabolic dietitian supervises calorie adequacy, growth, and protein sufficiency.

Acute decompensations are managed with intravenous dextrose at high infusion rates, correction of acidosis, fluid resuscitation, intravenous L-carnitine, and ammonia scavengers when hyperammonemia is present. Hemofiltration or hemodialysis is reserved for severe acidosis or refractory hyperammonemia. Outcomes for children identified by newborn screening and started on diet, glycine, and carnitine within the first weeks of life are generally good, and most reach adulthood with normal cognitive development. Outcomes for children who survive an unrecognized neonatal crisis depend on the severity of the initial decompensation. Liver transplantation has been performed in selected severe cases and reduces metabolite production while not eliminating the underlying defect outside the liver.