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

• Published in: Meta Gene Vol. 20; p. 100557
• Main Authors: Sarker, Suprovath Kumar, Islam, Md Tarikul, Hasib, Saad Hassan, Sultana, Nusrat, Hossain, Shekh Rezwan, Biswas, Aparna, Sultana, Rosy, Bhuyan, Golam Sarower, Begum, Mst. Noorjahan, Konica, Fatema Ahmed, Qadri, Syeda Kashfi, Qadri, Syed Saleheen, Saha, Narayan, Qadri, Firdausi, Mannoor, Kaiissar
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2019
• Subjects: Bangladesh; Case report; FAD; Isovaleric acidemia; Isovaleryl-CoA dehydrogenase; Organic acidemia; Isovaleryl-CoA dehydrogenase; FAD; Case report; Bangladesh; Organic acidemia; Isovaleric acidemia
• ISSN: 2214-5400; 2214-5400
• DOI: 10.1016/j.mgene.2019.100557

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. •An uncharacterized IVD mutation c.969G > T (p.Gln323His) was uncovered in a 2-year-old IVA patient in Bangladesh.•His parents were heterozygous carriers of this mutation, manifesting homozygously in our study participant.•Decompensation episodes and hyperammonemia were stabilised using tailored therapy, yet cognitive impairment was irreversible.•A pathogenic, chronic intermittent manifestation is implicated by impairment of optimal enzyme activity due to the mutation.