Beta-ketothiolase deficiency

Stable Identifier
R-HSA-9915355
Type
Pathway
Species
Homo sapiens
Synonyms
Alpha-methylacetoacetic aciduria
ReviewStatus
5/5
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Beta-ketothiolase deficiency
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ACAT1 is a mitochondrial enzyme that plays a role in metabolism of ketone bodies and isoleucine catabolism (Fukao et al, 1991; Haapalainen et al, 2007; reviewed in Fukao et al, 2019). As part of isoleucine catabolism in the mitochondria, ACAT1 catalyzes the thiolytic degradation of alpha-methylacetoacetyl-CoA to propionyl-CoA and acetyl-CoA (Fukao et al, 1991; Happalainen et al, 2007). Mutations in ACAT1 that affect protein stability and enzymatic activity are associated with beta-ketothiolase deficiency, also known as alpha-methylacetoacetic aciduria, an inborn error of metabolism that is identified by the presence of isoleucine intermediate metabolites in bodily fluids (Daum et al, 1973; Schutgens et al, 1982; Fukao et al, 1991; Fukao et al, 1992; Wakazono et al, 1995; Fukao et al, 1998; Sakurai et al, 2007; reviewed in Korman, 2006; Fukao et al, 2019). Neonatal onset is rare and most affected individuals present between 6 and 18 months with metabolic acidosis, lethargy, vomiting and sometimes coma (reviewed in Korman, 2006). As with other disorders of branched-chain metabolism, there is not a direct correlation between genotype and severity of phenotypic presentation (reviewed in Korman, 2006).
Literature References
PubMed ID Title Journal Year
1346617 Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency

Osumi, T, Hashimoto, T, Orii, T, Yamaguchi, S, Fukao, T, Schutgens, RB

J Clin Invest 1992
16950638 Inborn errors of isoleucine degradation: a review

Korman, SH

Mol Genet Metab 2006
9744475 Characterization of N93S, I312T, and A333P missense mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency

Nakamura, K, Orii, KE, Hashimoto, T, Kano, M, Orii, T, Nakamura, H, Kondo, N, Yamaguchi, S, Fukao, T, Kohno, Y, Song, XQ

Hum Mutat 1998
17236799 Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure

Kondo, N, Wanders, RJ, Zhang, G, Haapalainen, AM, Fukao, T, Sakurai, S, Wierenga, RK, Yano, S, Gibson, MK, Mitchell, GA, Lilliu, F, Yamada, K, Robinson, P

Mol Genet Metab 2007
7173255 Beta-ketothiolase deficiency in a family confirmed by in vitro enzymatic assays in fibroblasts

vd Blij, JF, Middleton, B, Vulsma, T, Tegelaers, WH, Veder, HA, Schutgens, RB, Oorthuys, JW

Eur J Pediatr 1982
1715688 Evidence for a structural mutation (347Ala to Thr) in a German family with 3-ketothiolase deficiency

Osumi, T, Hashimoto, T, Schrod, L, Orii, T, Frauendienst-Egger, G, Yamaguchi, S, Fukao, T, Tomatsu, S

Biochem Biophys Res Commun 1991
4690360 An inherited disorder of isoleucine catabolism causing accumulation of alpha-methylacetoacetate and alpha-methyl-beta -hydroxybutyrate, and intermittent metabolic acidosis

Delvin, E, Goldman, H, Daum, RS, Lamm, P, Mamer, OA, Scriver, CR

Pediatr Res 1973
17371050 Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function

Kondo, N, Haapalainen, AM, Fukao, T, Pirilä, PL, Wierenga, RK, Meriläinen, G

Biochemistry 2007
30393371 Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency

Otsuka, H, Sasai, H, Ago, Y, Matsumoto, H, Fukao, T, Abdelkreem, E, Aoyama, Y

J Hum Genet 2019
7728148 Molecular, biochemical, and clinical characterization of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in two further patients

Wakazono, A, Lambert, M, Hashimoto, T, Mitchell, GA, Orii, T, Yamaguchi, S, Fukao, T, Lee, GW, Hori, T

Hum Mutat 1995
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
amino acid metabolic disorder DOID:9252 inborn errors of amino acid metabolism
beta-ketothiolase deficiency DOID:14723 3-ketothiolase deficiency, 3-oxothiolase deficiency, Mitochondrial acetoacetyl-CoA Thiolase deficiency, 2-methyl-3-hydroxybutyricacidemia, alpha-methylacetoaceticaciduria, peroxisomal thiolase deficiency
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-07-04)
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