Different clinical presentation in siblings with mitochondrial acetoacetyl-CoA thiolase deficiency and identification of two novel mutations.

Mitochondrial acetoacetyl-CoA thiolase (T2) catalyzes 2-methylacetoacetyl-CoA cleavage into acetyl-CoA and propionyl-CoA in isoleucine catabolism and interconversion between acetyl-CoA and acetoacetyl-CoA in ketone body metabolism. T2 deficiency is a rare metabolic disease of autosomal recessive inheritance. The disorder is characterized by intermittent ketoacidotic episodes. The onset of clinical symptoms is in the infant or toddler period. The frequency of episodes declines with age, stopping before adolescence. Here we report two siblings with this disorder. The proband (GK65) is a French girl born from non-consanguineous parents. She presented several ketoacidotic episodes with 5 hospitalizations from age 2 to 4 years, the first of them complicated by ketoacidotic coma. Minor episodes, which are generally provoked by infections or high protein intake, still persist at age of 16 years. Molecular analysis of the T2 gene has revealed the compound heterozygosity of c.578T>C (M193T) and IVS8+5g>t. The latter mutation results in skipping of exon 8. In contrast, the younger brother (GK65b) had a unique ketoacidotic crisis at the age of 6 years that is the oldest-age first crisis among T2-deficient patients reported thus far. Despite the mild phenotype, he carried the same T2 gene mutations as his sister (GK65). Furthermore, T2 catalytic activity and T2 protein were not detected in the fibroblasts derived from GK65 and GK65b. In conclusion, the siblings with the same T2 gene mutations present different clinical severity. Diagnostic testing for asymptomatic siblings is important in the management of T2-deficient families.