Molecular identification of glutaryl CoA dehydrogenase gene variations and clinical course in three glutaric aciduria type I patients

Glutaric aciduria type-I (GA-I) is a rare autosomal recessive organic-aciduria caused due to glutaryl-CoA-dehydrogenase (GCDH) gene mutations leading to the accumulation of neurotoxins. In this article, we describe the molecular study of three GA-I families from southern India. Clinical features and biochemical parameters were examined. DNA was isolated from dried blood spots and GCDH gene analysis was performed using polymerase chain reaction and Sangers sequencing. Computational assessment of the mutations was performed to analyse their pathogenicity. Median age of the patients was 8 months and parental consanguinity was seen in all the three families. All GA-I patients had a mild clinical course, with brain atrophies. Macrocephaly was not noted. Mutation analysis identified three likely pathogenic mutations including two novel GCDH gene variants (S189T and W225S) and one previously reported variant (R386P). In-silico tools determined R386P and W225S mutations to be deleterious, while S189T to be neutral to the GCDH protein. The S189T was associated with a low excretor phenotype. In conclusion, identification of mutations by genotyping tests in distinct populations can accomplish early DNA based GA-I screening and is useful in definitive diagnosis of GA-I without the prior need of biochemical or enzyme assay. •Glutaric aciduria type-I is caused due to mutations in glutaryl-CoA-dehydrogenase (GCDH) gene.•GCDH gene mutations i.e. S189T and W225S (Novel) and R386P (known) were found in this study.•S189T mutation is associated with low excretor phenotype.•DNA based mutation screening is necessary for definitive diagnosis of GA-I.