Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an inborn error of metabolism that affects isoleucine catabolism and ketone body metabolism. This disorder is clinically characterized by intermittent ketoacidotic crises under ketogenic stresses. In addition to a previous 26-case series, four series of T2-deficient patients were recently reported from different regions. In these series, most T2-deficient patients developed their first ketoacidotic crises between the ages of 6 months and 3 years. Most patients experienced less than three metabolic crises. Newborn screening (NBS) for T2 deficiency is performed in some countries but some T2-deficient patients have been missed by NBS. Therefore, T2 deficiency should be considered in patients with severe metabolic acidosis, even in regions where NBS for T2 deficiency is performed. Neurological manifestations, especially extrapyramidal manifestations, can occur as sequelae to severe metabolic acidosis; however, this can also occur in patients without any apparent metabolic crisis or before the onset of metabolic crisis.
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Daum RS, Lamm PH, Mamer OA, Scriver CRA. “new” disorder of isoleucine catabolism. Lancet. 1971;2:1289–90.
Daum RS, Scriver CR, Mamer OA, Delvin E, Lamm P, Goldman H. An inherited disorder of isoleucine catabolism causing accumulation of alpha-methylacetoacetate and alpha-methyl-beta -hydroxybutyrate, and intermittent metabolic acidosis. Pediatr Res. 1973;7:149–60.
Fukao T, Maruyama S, Ohura T, Hasegawa Y, Toyoshima M, Haapalainen AM, et al. Three Japanese patients with beta-ketothiolase deficiency who share a mutation, c.431A>C (H144P) in ACAT1: subtle abnormality in urinary organic acid analysis and blood acylcarnitine analysis using tandem mass spectrometry. JIMD Rep. 2012;3:107–15.
Yamaguchi S, Orii T, Sakura N, Miyazawa S, Hashimoto T. Defect in biosynthesis of mitochondrial acetoacetyl-coenzyme A thiolase in cultured fibroblasts from a boy with 3-ketothiolase deficiency. J Clin Invest. 1988;81:813–7.
Mitchell GA, Fukao T. Inborn errors of ketone body metabolism. In: Scriver CR, Beaudet AL, Sly WS & Valle D, editors. The metabolic & molecular basis of inherited disease. Vol. 2, Ch. 102 New York: McGraw-Hill; 2001. p. 2327–56.
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis. 2014;37:541–51.
Abdelkreem E, Otsuka H, Sasai H, Aoyama Y, Hori T, Abd El Aal M, et al. Beta-ketothiolase deficiency: resolving challenges in diagnosis. J Inborn Errors Metab Screen. 2016;4:1–9.
Fukao T, Yamaguchi S, Nagasawa H, Kano M, Orii T, Fujiki Y, et al. Molecular cloning of cDNA for human mitochondrial acetoacetyl-CoA thiolase and molecular analysis of 3-ketothiolase deficiency. J Inherit Metab Dis. 1990;13:757–60.
Fukao T, Yamaguchi S, Tomatsu S, Orii T, Frauendienst-Egger G, Schrod L, et al. Evidence for a structural mutation (347Ala to Thr) in a German family with 3-ketothiolase deficiency. Biochem Biophys Res Commun. 1991;179:124–9.
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;109:285–90.
Fukao T, Yamaguchi S, Orii T, Osumi T, Hashimoto T. Molecular basis of 3-ketothiolase deficiency: identification of an AG to AC substitution at the splice acceptor site of intron 10 causing exon 11 skipping. Biochim Biophys Acta. 1992;1139:184–8.
Fukao T, Yamaguchi S, Wakazono A, Okamoto H, Orii T, Osumi T, et al. Molecular basis of 3-ketothiolase deficiency: detection of gene mutations and expression of mutant cDNAs of mitochondrial acetoacetyl-CoA thiolase. J Inherit Metab Dis. 1992;15:815–20.
Wajner M, Sanseverino MT, Giugliani R, Sweetman L, Yamaguchi S, Fukao T, et al. Biochemical investigation of a Brazilian patient with a defect in mitochondrial acetoacetylcoenzyme-A thiolase. Clin Genet. 1992;41:202–5.
Masuno M, Kano M, Fukao T, Yamaguchi S, Osumi T, Hashimoto T, et al. Chromosome mapping of the human mitochondrial acetoacetyl-coenzyme A thiolase gene to 11q22.3----q23.1 by fluorescence in situ hybridization. Cytogenet Cell Genet. 1992;60:121–2.
Fukao T, Yamaguchi S, Orii T, Schutgens RB, Osumi T, Hashimoto T. 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. J Clin Invest. 1992;89:474–9.
Fukao T, Yamaguchi S, Scriver CR, Dunbar G, Wakazono A, Kano M, et al. Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families. Hum Mutat. 1993;2:214–20.
Fukao T, Yamaguchi S, Wakazono A, Orii T, Hoganson G, Hashimoto T. Identification of a novel exonic mutation at -13 from 5’ splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency. J Clin Invest. 1994;93:1035–41.
Fukao T, Song XQ, Yamaguchi S, Orii T, Wanders RJ, Poll-The BT, et al. Mitochondrial acetoacetyl-coenzyme A thiolase gene: a novel 68-bp deletion involving 3’ splice site of intron 7, causing exon 8 skipping in a Caucasian patient with beta-ketothiolase deficiency. Hum Mutat. 1995;5:94–96.
Fukao T, Kodama A, Aoyanagi N, Tsukino R, Uemura S, Song XQ, et al. Mild form of beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase deficiency) in two Japanese siblings: identification of detectable residual activity and cross-reactive material in EB-transformed lymphocytes. Clin Genet. 1996;50:263–6.
Fukao T, Song XQ, Yamaguchi S, Kondo N, Orii T, Matthieu JM, et al. Identification of three novel frameshift mutations (83delAT, 754insCT, and 435+1G to A) of mitochondrial acetoacetyl-coenzyme A thiolase gene in two Swiss patients with CRM-negative beta-ketothiolase deficiency. Hum Mutat. 1997;9:277–9.
Wakazono A, Fukao T, Yamaguchi S, Hori T, Orii T, Lambert M, et al. Molecular, biochemical, and clinical characterization of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in two further patients. Hum Mutat. 1995;5:34–42.
Fukao T, Nakamura H, Song XQ, Nakamura K, Orii KE, Kohno Y, et al. Characterization of N93S, I312T, and A333P missense mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency. Hum Mutat. 1998;12:245–54.
Sewell AC, Herwig J, Wiegratz I, Lehnert W, Niederhoff H, Song XQ, et al. Mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase) deficiency and pregnancy. J Inherit Metab Dis. 1998;21:441–2.
Nakamura K, Fukao T, Perez-Cerda C, Luque C, Song XQ, Naiki Y, et al. A novel single-base substitution (380C>T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab. 2001;72:115–21.
Fukao T, Scriver CR, Kondo N. 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;72:109–14.
Fukao T, Nakamura H, Nakamura K, Perez-Cerda C, Baldellou A, Barrionuevo CR, et al. Characterization of six mutations in five Spanish patients with mitochondrial acetoacetyl-CoA thiolase deficiency: effects of amino acid substitutions on tertiary structure. Mol Genet Metab. 2002;75:235–43.
Fukao T, Matsuo N, Zhang GX, Urasawa R, Kubo T, Kohno Y, et al. Single base substitutions at the initiator codon in the mitochondrial acetoacetyl-CoA thiolase (ACAT1/T2) gene result in production of varying amounts of wild-type T2 polypeptide. Hum Mutat. 2003;21:587–92.
Fukao T, Zhang GX, Sakura N, Kubo T, Yamaga H, Hazama A, et al. The mitochondrial acetoacetyl-CoA thiolase (T2) deficiency in Japanese patients: urinary organic acid and blood acylcarnitine profiles under stable conditions have subtle abnormalities in T2-deficient patients with some residual T2 activity. J Inherit Metab Dis. 2003;26:423–31.
Zhang GX, Fukao T, Rolland MO, Zabot MT, Renom G, Touma E, et al. Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with “mild” mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA. Pediatr Res. 2004;56:60–64.
Mrazova L, Fukao T, Halovd K, Gregova E, Kohut V, Pribyl D, et al. Two novel mutations in mitochondrial acetoacetyl-CoA thiolase deficiency. J Inherit Metab Dis. 2005;28:235–6.
Zhang G, Fukao T, Sakurai S, Yamada K, Michael Gibson K, Kondo N. Identification of Alu-mediated, large deletion-spanning exons 2-4 in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency. Mol Genet Metab. 2006;89:222–6.
Sakurai S, Fukao T, Haapalainen AM, Zhang G, Yamada K, Lilliu F, et al. 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. Mol Genet Metab. 2007;90:370–8.
Fukao T, Boneh A, Aoki Y, Kondo N. A novel single-base substitution (c.1124A>G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab. 2008;94:417–21.
Fukao T, Horikawa R, Naiki Y, Tanaka T, Takayanagi M, Yamaguchi S, et al. A novel mutation (c.951C>T) in an exonic splicing enhancer results in exon 10 skipping in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab. 2010;100:339–44.
Fukao T, Nguyen HT, Nguyen NT, Vu DC, Can NT, Pham AT, et al. A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab. 2010;100:37–41.
Thummler S, Dupont D, Acquaviva C, Fukao T, de Ricaud D. Different clinical presentation in siblings with mitochondrial acetoacetyl-CoA thiolase deficiency and identification of two novel mutations. Tohoku J Exp Med. 2010;220:27–31.
Fukao T, Aoyama Y, Murase K, Hori T, Harijan RK, Wierenga RK, et al. Development of MLPA for human ACAT1 gene and identification of a heterozygous Alu-mediated deletion of exons 3 and 4 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab. 2013;110:184–7.
Buhas D, Bernard G, Fukao T, Decarie JC, Chouinard S, Mitchell GA. A treatable new cause of chorea: beta-ketothiolase deficiency. Mov Disord. 2013;28:1054–6.
Akella RR, Aoyama Y, Mori C, Lingappa L, Cariappa R, Fukao T. Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India. Brain Dev. 2014;36:537–40.
Otsuka H, Sasai H, Nakama M, Aoyama Y, Abdelkreem E, Ohnishi H, et al. Exon 10 skipping in ACAT1 caused by a novel c. 949G>A mutation located at an exonic splice enhancer site. Mol Med Rep. 2016;14:4906–10.
Nguyen KN, Abdelkreem E, Colombo R, Hasegawa Y, Can NTB, Bui TP, et al. Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam. J Inherit Metab Dis. 2017;40:395–401.
Abdelkreem E, Akella RRD, Dave U, Sane S, Otsuka H, Sasai H. et al. Clinical and mutational characterizations of ten Indian patients with beta-ketothiolase deficiency. JIMD Rep. 2017;35:59–65.
Sasai H, Aoyama Y, Otsuka H, Abdelkreem E, Nakama M, Hori T, et al. Single-nucleotide substitution T to A in the polypyrimidine stretch at the splice acceptor site of intron 9 causes exon 10 skipping in the ACAT1 gene. Mol Genet Genom Med. 2017;5:177–84.
Abdelkreem E, Alobaidy H, Aoyama Y, Mahmoud S, Abd El Aal M, Fukao T. Two Libyan siblings with beta-ketothiolase deficiency: a case report and review of literature. Egypt J Med Human Genet. 2017;18:199–203.
Aoyama Y, Sasai H, Abdelkreem E, Otsuka H, Nakama M, Kumar S, et al. A novel mutation (c.12113T>A) in the polypyrimidine tract of the splice acceptor site of intron 2 causes exon 3 skipping in mitochondrial acetoacetyl-CoA thiolase gene. Mol Med Rep. 2017;15:3879–84.
Grunert SC, Schmitt RN, Schlatter SM, Gemperle-Britschgi C, Balci MC, Berg V, et al. Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency. Mol Genet Metab. 2017;122:67–75.
Paquay S, Bourillon A, Pichard S, Benoist JF, de Lonlay P, Dobbelaere D, et al. Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. J Inherit Metab Dis. 2017;40:415–22.
Sarafoglou K, Matern D, Redlinger-Grosse K, Bentler K, Gaviglio A, Harding CO, et al. Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics. 2011;128:e246–50.
Wojcik MH, Wierenga KJ, Rodan LH, Sahai I, Ferdinandusse S, Genetti CA, et al. Beta-ketothiolase deficiency presenting with metabolic stroke after a normal newborn screen in two individuals. JIMD Rep. 2017;39:45–54.
Estrella J, Wilcken B, Carpenter K, Bhattacharya K, Tchan M, Wiley V. Expanded newborn screening in New South Wales: missed cases. J Inherit Metab Dis. 2014;37:881–7.
Frazier DM, Millington DS, McCandless SE, Koeberl DD, Weavil SD, Chaing SH, et al. The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005. J Inherit Metab Dis. 2006;29:76–85.
Ozand PT, Rashed M, Gascon GG, al Odaib A, Shums A, Nester M, et al. 3-Ketothiolase deficiency: a review and four new patients with neurologic symptoms. Brain Dev. 1994;16:38–45.
Middleton B. The oxoacyl-coenzyme A thiolases of animal tissues. Biochem J. 1973;132:717–30.
Middleton B, Bartlett K. The synthesis and characterisation of 2-methylacetoacetyl coenzyme A and its use in the identification of the site of the defect in 2-methylacetoacetic and 2-methyl-3-hydroxybutyric aciduria. Clin Chim Acta. 1983;128:291–305.
Erdol S, Ture M, Yakut T, Saglam H, Sasai H, Abdelkreem E, et al. A Turkish patient with succinyl-CoA: 3-oxoacid CoA transferase deficiency mimicking diabetic ketoacidosis. J Inborn Errors Metab Screen. 2016;4:1–5.
Attia N, Sakati N, al Ashwal A, al Saif R, Rashed M, Ozand PT. Isovaleric acidemia appearing as diabetic ketoacidosis. J Inherit Metab Dis. 1996;19:85–86.
Dweikat IM, Naser EN, Abu Libdeh AI, Naser OJ, Abu Gharbieh NN, Maraqa NF, et al. Propionic acidemia mimicking diabetic ketoacidosis. Brain Dev. 2011;33:428–31.
Guven A, Cebeci N, Dursun A, Aktekin E, Baumgartner M, Fowler B. Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant. Pediatr Diabetes. 2012;13:e22–25.
Bonnefont JP, Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JB, et al. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr. 1990;150:80–85.
Zschocke J. HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherit Metab Dis. 2012;35:81–89.
Zschocke J, Ruiter JP, Brand J, Lindner M, Hoffmann GF, Wanders RJ, et al. Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. Pediatr Res. 2000;48:852–5.
Robinson BH, Sherwood WG, Taylor J, Balfe JW, Mamer OA. Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism. J Pediatr. 1979;95:228–33.
Fukao T, Song XQ, Mitchell GA, Yamaguchi S, Sukegawa K, Orii T, et al. Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res. 1997;42:498–502.
Gibson KM, Lee CF, Kamali V, Sovik O. A coupled assay detecting defects in fibroblast isoleucine degradation distal to enoyl-CoA hydratase: application to 3-oxothiolase deficiency. Clin Chim Acta. 1992;205:127–35.
Hori T, Yamaguchi S, Shinkaku H, Horikawa R, Shigematsu Y, Takayanagi M, et al. Inborn errors of ketone body utilization. Pediatr Int. 2015;57:41–48.
Shibata N, Hasegawa Y, Yamada K, Kobayashi H, Purevsuren J, Yang Y, et al. Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: selective screening vs. expanded newborn screening. Mol Genet Metab Rep. 2018;16:5–10.
Akagawa S, Fukao T, Akagawa Y, Sasai H, Kohdera U, Kino M, et al. Japanese male siblings with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) without neurological regression. JIMD Rep. 2017;32:81–85.
Middleton B, Bartlett K, Romanos A, Gomez Vazquez J, Conde C, Cannon RA, et al. 3-Ketothiolase deficiency. Eur J Pediatr. 1986;144:586–9.
Haas RH, Marsden DL, Capistrano-Estrada S, Hamilton R, Grafe MR, Wong W, et al. Acute basal ganglia infarction in propionic acidemia. J Child Neurol. 1995;10:18–22.
Hamilton RL, Haas RH, Nyhan WL, Powell HC, Grafe MR. Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions. J Child Neurol. 1995;10:25–30.
Heidenreich R, Natowicz M, Hainline BE, Berman P, Kelley RI, Hillman RE, et al. Acute extrapyramidal syndrome in methylmalonic acidemia: “metabolic stroke” involving the globus pallidus. J Pediatr. 1988;113:1022–7.
Thompson GN, Christodoulou J, Danks DM. Metabolic stroke in methylmalonic acidemia. J Pediatr. 1989;115:499–500.
Prada CE, Villamizar-Schiller IT. Globus pallidus involvement as initial presentation of methylmalonic acidemia. Mov Disord. 2014;29:870.
Scholl-Burgi S, Haberlandt E, Gotwald T, Albrecht U, Baumgartner Sigl S, Rauchenzauner M, et al. Stroke-like episodes in propionic acidemia caused by central focal metabolic decompensation. Neuropediatrics. 2009;40:76–81.
Cazorla MR, Verdu A, Perez-Cerda C, Ribes A. Neuroimage findings in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency. Pediatr Neurol. 2007;36:264–7.
Sass JO, Forstner R, Sperl W. 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: impaired catabolism of isoleucine presenting as neurodegenerative disease. Brain Dev. 2004;26:12–4.
Murin R, Mohammadi G, Leibfritz D, Hamprecht B. Glial metabolism of isoleucine. Neurochem Res. 2009;34:194–204.
Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I. Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab. 2008;94:4–15.
Rosa RB, Schuck PF, de Assis DR, Latini A, Dalcin KB, Ribeiro CA, et al. Inhibition of energy metabolism by 2-methylacetoacetate and 2-methyl-3-hydroxybutyrate in cerebral cortex of developing rats. J Inherit Metab Dis. 2005;28:501–15.
Leipnitz G, Seminotti B, Amaral AU, Fernandes CG, Dutra-Filho CS, Wajner M. Evidence that 2-methylacetoacetate induces oxidative stress in rat brain. Metab Brain Dis. 2010;25:261–7.
We thank Professor emeritus Tadao Orii (Gifu University) and Professor emeritus Seiji Yamaguchi (Shimane University) for their mentorship, Professor Grant Mitchell and Professor Oliver Sass for long-term collaborations and for discussions on defective ketone body metabolism. We also thank Ms Naomi Sakaguchi for her dedicated assistance with laboratory work. This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant Numbers 16K09962, 15K01693], by AMED under Grant Number JP17ek0109276, and by Health and Labour Sciences Research Grants (H29-nanchitou(nan)-ippan-051) for Research on rare and intractable diseases. We thank Jeremy Allen, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant Numbers 16K09962, 15K01693], by AMED under Grant Number JP17ek0109276, and by Health and Labour Sciences Research Grants [H29-nanchitou(nan)-ippan-051] for Research on rare and intractable diseases.
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The authors declare that they have no conflict of interest.
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Fukao, T., Sasai, H., Aoyama, Y. et al. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet 64, 99–111 (2019). https://doi.org/10.1038/s10038-018-0524-x
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