The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients

Mitochondrial acetoacetyl-CoA thiolase (T2 enzyme) deficiency (MIM 203750) is an autosomal recessive disorder of isoleucine and ketone-body metabolism . We determined the molecular basis of T2 enzyme deficiency in 26 patients at the levels of skin fibroblast enzyme activity, protein integrity, and DN A nucleotide sequence. Thirty different disease-associated alleles were ide ntified. From these data we predicted that T2 in 6 of the 26 patients would have a mild effect on the enzyme protein and 20 would have a severe effect from their mutant genotypes. The corresponding clinical data were collecte d (by interviews and questionnaires) for the patients in the two groups. We found that genotype does not predict clinical severity and mutant sibs can have different clinical phenotypes; there were no consistent differences i n clinical severity between patients with null-conferring or residual-confe rring genotypes for T2 activity; only the absence of or a low urinary excre tion of tiglyglycine during ketoacidosis correlated with a mild genotype. I n general, T2 deficiency has a favorable outcome and 23 of 26 patients deve loped normally; one died during the first ketoacidotic episode and two have developmental delay. The median age at onset for the first ketoacidotic ep isode is 15 months (range 3 days to 48 months). The frequency of attacks fa lls with age, the last in our series occurring at 10 years of age; 11 patie nts had only one episode and 3 patients had none. We conclude that clinical consequences of T2 deficiency are avoidable with early diagnosis, appropri ate management of ketoacidosis, and modest protein restriction. (C) 2001 Ac ademic Press.