AB120. Correlation of genotype with biochemical profile in patients with Glutaric Acidemia type I: a study from India

Background and objective: Mutations in glutaryl-CoA dehydrogenase gene causes Glutaric Acidemia type I (GA-I), an autosomal recessive, metabolic disorder which leads to accumulation of Glutaric Acid, 3-Hydroxyglutaric acid, Glutaconic Acid and Glutarylcarnitine (C5DC). There are no studies that correlate the genotype with biochemical profile in patients with GA-I from India. The objective of this study was to screen Indian patients with GA-I, for common mutations such as R402W, A421V, A293T, R227P and V400M and to correlate the genotype profile of the patients with C5DC levels.

Materials and methods: The study was approved by the institutional Human Ethics Committee. Fifty confirmed GA-I patients from unrelated families were recruited based on clinical, biochemical and neuroimaging studies. Informed consent was obtained before taking blood spots on the filter paper. The dried blood spots were used for measuring C5DC levels by tandem mass spectroscopy and for screening mutations by RFLP or by direct sequencing of PCR products. Mutations screened by RFLP were further confirmed by sequencing. Those patients with mutant homozygous alleles were considered for correlation studies.

Results: The mutation R402W was found in 11 (22%) patients, among them, 7 (14%) were homozygous and 5 (8%) were heterozygous. During genotyping, known mutation such as F236L was found in 1 (2%) and R313W in 1 (2%). Novel mutations, P286S was found in 2 (4%), W225X in 1 (2%), H403Y in 1 (2%), Y295Y in 1 (2%) and 1606 G>T at 3’UTR in 1 (2%). Conversely, none of the GA-I patients had A421V, A293T, R227P and V400M mutations. Patients homozygous for R402W, W225X, H403Y and g.13670 G>T at 3’UTR were considered for correlation studies. The mean C5DC levels, in patients with R402W mutation was found to be 1.83 µmol/L, patients with 3’UTR g.13670 G>T, W225X and H403Y mutations were found to have 1.74, 1.28 and 1.21 µmol/L respectively.

Conclusions: In conclusion, R402W and novel P286S are the most prevalent mutations among Indian patients with GA-I. Patients with R402W were found to have highest elevated levels of C5DC as compared to other homozygous mutations in our study. Mutation such as A421V, A293T, R227P and V400M were found to be absent in our population.

Keywords: Glutaric Acidemia type I (GA-I); Glutaryl carnitine; genotyping