Beta-ketothiolase deficiency is an inherited disorder in which the body cannot effectively process a protein building block (amino acid) called isoleucine. This disorder also impairs the body's ability to process ketones, which are molecules produced during the breakdown of fats.
The signs and symptoms of beta-ketothiolase deficiency typically appear between the ages of 6 months and 24 months. Affected children experience episodes of vomiting, dehydration, difficulty breathing, extreme tiredness (lethargy), and, occasionally, seizures. These episodes, which are called ketoacidotic attacks, sometimes lead to coma. Ketoacidotic attacks are frequently triggered by infections or periods without food (fasting), and increased intake of protein-rich foods can also play a role.
Beta-ketothiolase deficiency appears to be very rare. Fewer than 250 affected individuals have been reported in the medical literature.
Mutations in the ACAT1 gene cause beta-ketothiolase deficiency. This gene provides instructions for making an enzyme that is found in the energy-producing centers within cells (mitochondria). This enzyme plays an essential role in breaking down proteins and fats from the diet. Specifically, the ACAT1 enzyme helps process isoleucine, which is a building block of many proteins, and ketones, which are produced during the breakdown of fats.
Mutations in the ACAT1 gene reduce or eliminate the activity of the ACAT1 enzyme. A shortage of this enzyme prevents the body from processing proteins and fats properly. As a result, related compounds can build up to toxic levels in the blood. These substances may cause the blood to become too acidic (ketoacidosis) and can damage the body's tissues and organs, particularly in the nervous system.
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Other Names for This Condition
- 2-methylacetoacetyl-coenzyme A thiolase deficiency
- 3-alpha-oxothiolase deficiency
- 3-ketothiolase deficiency
- 3-oxothiolase deficiency
- Alpha-methylacetoacetic aciduria
- MAT deficiency
- Methylacetoacetyl-coenzyme A thiolase deficiency
- Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency - potassium stimulated
- Mitochondrial acetoacetyl-CoA thiolase deficiency
- T2 deficiency
- Β-ketothiolase deficiency
Additional Information & Resources
Genetic Testing Information
Genetic and Rare Diseases Information Center
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
- Abdelkreem E, Harijan RK, Yamaguchi S, Wierenga RK, Fukao T. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Hum Mutat. 2019 Oct;40(10):1641-1663. doi: 10.1002/humu.23831. Epub 2019 Jul 3. Review. Citation on PubMed or Free article on PubMed Central
- Fukao T, Yamaguchi S, Orii T, Hashimoto T. Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene. Hum Mutat. 1995;5(2):113-20. Review. Citation on PubMed
- Grünert SC, Sass JO. 2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways. Orphanet J Rare Dis. 2020 Apr 28;15(1):106. doi: 10.1186/s13023-020-01357-0. Citation on PubMed or Free article on PubMed Central
- Kano M, Fukao T, Yamaguchi S, Orii T, Osumi T, Hashimoto T. Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene. Gene. 1991 Dec 30;109(2):285-90. Citation on PubMed