Beta-ketothiolase (T2) deficiency is an autosomal recessive metabolic disease caused by mutations in ACAT1 gene. This disease affects isoleucine catabolism and ketone body utilization and characterized clinically by intermittent ketoacidotic episodes.

  We report 9 Indians with beta-ketothiolase deficiency. They were suspected based on their clinical presentations (ketoacidotic episodes) and increased urinary isoleucine catabolic metabolites. Genomic DNA analysis revealed 6 different mutations in ACAT1 gene; M193R, E85del, c.1124A>G, I323T, 1015-1016insAAAG, and IVS7+1g>a, in which the last 3 are novel ones. IVS7+1g>a mutation affects a critical point of the splice donor site of intron 7, thus aberrant splicing is the usual consequence. Transient expression of mutant cDNAs was done at 37°C, followed by T2 enzyme assay, revealed that 1015-1016insAAAG mutation has no activity while I323T retains some.

  The molecular analysis of ACAT1 gene in suspected T2 deficient cases not just confirms the diagnosis, leading to a better prognosis in such cases, but also provides an efficient screening tool for detection of asymptomatic patients in other family members before the development of any acute or chronic clinical manifestations.