A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening

Abstract

Isovaleric acidemia (IVA) is an inborn error of leucine metabolism that can cause significant morbidity and mortality. Since the implementation, in many states and countries, of newborn screening (NBS) by tandem mass spectrometry, IVA can now be diagnosed presymptomatically. Molecular genetic analysis of the IVD gene for 19 subjects whose condition was detected through NBS led to the identification of one recurring mutation, 932C-->T (A282V), in 47% of mutant alleles. Surprisingly, family studies identified six healthy older siblings with identical genotype and biochemical evidence of IVA. Our findings indicate the frequent occurrence of a novel mild and potentially asymptomatic phenotype of IVA. This has significant consequences for patient management and counseling.

Figure 1

Restriction-enzyme analysis for the detection of the 932C→T (A282V) mutation. The 213-bp product is cleaved into two fragments, of 146 bp and 67 bp, in the presence of the wild-type sequence (CC). The mutated sequence is not cleaved (see lanes CT and TT).

Figure 2

Algorithm for the diagnostic evaluation of newborns with an elevated C₅ acylcarnitine concentration in an NBS blood spot. An asterisk (*) indicates that NBS was not available as a clinical test (research only). AC = acylcarnitine analysis; AG = acylglycine analysis; C₅AC = C₅ acylcarnitine; H = abnormally elevated; IVC = isovalerylcarnitine; IVG = isovalerylglycine; MBC = 2-methylbutyrylcarnitine; MBG = 2-methylbutyrylglycine; N = normal; ND = 932C→T mutation not detected; OA = organic acid analysis; PVA = pivalic acid (a component of several antibiotic medications [Abdenur et al. 1998]); SBCAD-D = short/branched-chain acyl-CoA dehydrogenase deficiency (2-methylbutyrylglycinuria).