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The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients.
Mol Genet Metab 2001; 72(2):109-14MG

Abstract

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 DNA nucleotide sequence. Thirty different disease-associated alleles were identified. 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 collected (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 in clinical severity between patients with null-conferring or residual-conferring genotypes for T2 activity; only the absence of or a low urinary excretion of tiglyglycine during ketoacidosis correlated with a mild genotype. In general, T2 deficiency has a favorable outcome and 23 of 26 patients developed normally; one died during the first ketoacidotic episode and two have developmental delay. The median age at onset for the first ketoacidotic episode is 15 months (range 3 days to 48 months). The frequency of attacks falls with age, the last in our series occurring at 10 years of age; 11 patients had only one episode and 3 patients had none. We conclude that clinical consequences of T2 deficiency are avoidable with early diagnosis, appropriate management of ketoacidosis, and modest protein restriction.

Authors+Show Affiliations

Department of Pediatrics, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu, 500-8076, Japan. toshi-gif@umin.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11161836

Citation

Fukao, T, et al. "The Clinical Phenotype and Outcome of Mitochondrial acetoacetyl-CoA Thiolase Deficiency (beta-ketothiolase or T2 Deficiency) in 26 Enzymatically Proved and Mutation-defined Patients." Molecular Genetics and Metabolism, vol. 72, no. 2, 2001, pp. 109-14.
Fukao T, Scriver CR, Kondo N, et al. The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab. 2001;72(2):109-14.
Fukao, T., Scriver, C. R., & Kondo, N. (2001). The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Molecular Genetics and Metabolism, 72(2), pp. 109-14.
Fukao T, et al. The Clinical Phenotype and Outcome of Mitochondrial acetoacetyl-CoA Thiolase Deficiency (beta-ketothiolase or T2 Deficiency) in 26 Enzymatically Proved and Mutation-defined Patients. Mol Genet Metab. 2001;72(2):109-14. PubMed PMID: 11161836.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. AU - Fukao,T, AU - Scriver,C R, AU - Kondo,N, AU - ,, PY - 2001/2/13/pubmed PY - 2001/5/1/medline PY - 2001/2/13/entrez SP - 109 EP - 14 JF - Molecular genetics and metabolism JO - Mol. Genet. Metab. VL - 72 IS - 2 N2 - 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 DNA nucleotide sequence. Thirty different disease-associated alleles were identified. 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 collected (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 in clinical severity between patients with null-conferring or residual-conferring genotypes for T2 activity; only the absence of or a low urinary excretion of tiglyglycine during ketoacidosis correlated with a mild genotype. In general, T2 deficiency has a favorable outcome and 23 of 26 patients developed normally; one died during the first ketoacidotic episode and two have developmental delay. The median age at onset for the first ketoacidotic episode is 15 months (range 3 days to 48 months). The frequency of attacks falls with age, the last in our series occurring at 10 years of age; 11 patients had only one episode and 3 patients had none. We conclude that clinical consequences of T2 deficiency are avoidable with early diagnosis, appropriate management of ketoacidosis, and modest protein restriction. SN - 1096-7192 UR - https://www.unboundmedicine.com/medline/citation/11161836/The_clinical_phenotype_and_outcome_of_mitochondrial_acetoacetyl_CoA_thiolase_deficiency__beta_ketothiolase_or_T2_deficiency__in_26_enzymatically_proved_and_mutation_defined_patients_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(00)93113-5 DB - PRIME DP - Unbound Medicine ER -