A novel missense mutation of Isovaleryl-CoA dehydrogenase gene associated with chronic intermittent Isovaleric Acidemia in a Bangladeshi patient

Isovaleric acidemia (IVA) is an organic acidemia characterized by the deficiency of isovaleryl-CoA dehydrogenase (IVD) enzyme, of the third step in the leucine degradation pathway in humans. We present here the case of a 9-year-old patient diagnosed with IVA at 2 years of age using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) analysis, as observed by elevated levels of signature disease markers- isovaleryl (C5)-carnitine and isovalerylglycine (IVG) in blood and urine samples, respectively. Over the ensuing seven year follow-up, his most prominent symptoms were hyperammonemia which peaked at >109 μmol/L complimented by developmental and motor dysfunctions. Delayed intervention using sodium benzoate, levocarnitine, multivitamins and a leucine free-diet appeared to gradually regulate his metabolite levels to normal, improving his overall health, although failed to mitigate his impaired mental status. Sequencing of the IVD gene unearthed a novel point mutation carried as a single allele by each parent, c.969G > T in exon-9 whose pathogenicity was predicted by three bioinformatics tools, SIFT, PolyPhen-2 and PhD-SNP. These bioinformatics investigations revealed a missense mutation imparting an amino acid change from a highly conserved glutamine residue to a histidine at a site proximal to the binding of an essential cofactor, FAD, which was implicated in his chronic intermittent, clinical manifestation.