Isovaleric Acidemia via the IVD Gene

Isovaleric acidemia (OMIM 243500) is a metabolic defect in the catabolism of the branched-chain amino acid leucine. Isovaleric acidemia patients have deficiency in the activity of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (Rhead and Tanaka. Proc Nat Acad Sci USA 77:580-583, 1980). This deficiency leads to abnormally high concentrations of isovaleric acid in cells, blood, and urine. Isovaleric acid is toxic to the CNS. Clinically, isovaleric acidemia exhibits wide variation in severity. The acute, neonatal form presents with massive metabolic acidosis in the first days of life. Poor feeding, vomiting, and seizures follow and coma and death are often the outcomes. At the other end of the spectrum, the chronic form of isovaleric acidemia exhibit periodic crisis of severe ketoacidosis, but otherwise asymptomatic intervening periods. Intermediate forms may have a childhood onset and are characterized by varying degrees of developmental delay and recurrent episodes of vomiting and lethargy. Patients often have the distinctive “sweaty feet” odor of isovaleric acid during acute illness. Patients can sometimes suffer stroke, and cerebellar hemorrhage has been described in some organic acidemias, including isovaleric acidemia (Testai and Gorelick. Arch Neurol 67:148-153, 2010). Isovaleric acidemia can mimic propionic acidemia and methylmalonic acidemia by producing hyperglycinemia, leukopenia, and episodic ketoacidosis (Ando et al. Pediat Res 5:827-832, 1971). Early diagnosis appears to be highly beneficial for patients.

Isovaleric acidemia is an autosomal recessive disorder. Nearly 40 different IVD causative variants have been reported. The majority of these variants result in amino acid substitutions. Ensenauer et al. (Am J Hum Genet 75:1136- 42, 2004) reported that one common variant, c.941C>T (p.Ala314Val; also referred to in the literature as c.932C>T [p.Ala311Val or p.Ala282Val]), comprises ~50% of variants in patients detected through newborn screening. Importantly, these authors found the same abnormal genotype among siblings who had biochemical evidence of isovaleric acidemia but no clinical symptoms of the disease.

Analytical sensitivity should be high because all reported variants are detectable by sequencing. Clinical sensitivity should also be high. For example, Ensenauer et al.  reported the detection by DNA sequencing of two likely causative IVD variants in 18 out of 19 patients identified through newborn screening. Only one causative variant was found in the 19th child (Ensenauer et al. Am J Hum Genet 75:1136-1142, 2004).

This test provides full coverage of all coding exons of the IVD gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).