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Deficiency of acetyl-CoA acetyltransferase

MedGen UID:
280689
Concept ID:
C1536500
Disease or Syndrome
Synonyms: 2-methyl-3-hydroxybutyricacidemia; 3-ketothiolase deficiency; 3-oxothiolase deficiency; Alpha-methylacetoaceticaciduria; Beta ketothiolase deficiency; Ketothiolase Deficiency; Mitochondrial acetoacetyl-CoA Thiolase deficiency
SNOMED CT: Acetoacetyl-CoA thiolase deficiency (124258007); 3-Ketothiolase deficiency (124258007); Deficiency of acetoacetyl-CoA thiolase (124258007); Deficiency of acetyl-CoA acetyltransferase (124258007); alpha-Methylacetoacetic aciduria (124258007); 3-Methylhydroxybutyric acidemia (124258007); Deficiency of acetyl-coenzyme A acetyltransferase (124258007); Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency - potassium stimulated (237953006); Beta-ketothiolase deficiency (237953006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ACAT1 (11q22.3)
 
Monarch Initiative: MONDO:0008760
OMIM®: 203750
Orphanet: ORPHA134

Definition

Alpha-methylacetoacetic aciduria, also known as 3-ketothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone. [from OMIM]

Additional description

From MedlinePlus Genetics
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.\n\nThe 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.  https://medlineplus.gov/genetics/condition/beta-ketothiolase-deficiency

Clinical features

From HPO
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
A broad category of disorders characterized by an impairment to the intelligence an individual possesses. These impairments can result from trauma, birth, or disease and are not restricted to any particular age group.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Episodic ketoacidosis
MedGen UID:
349256
Concept ID:
C1859860
Finding
Intermittent episodes of ketoacidosis.

Recent clinical studies

Etiology

de Sousa J, Vencálek O, Hron K, Václavík J, Friedecký D, Adam T
Anal Chim Acta 2020 Feb 8;1097:49-61. Epub 2019 Nov 16 doi: 10.1016/j.aca.2019.11.006. PMID: 31910969
Delgado CA, Balbueno Guerreiro GB, Diaz Jacques CE, de Moura Coelho D, Sitta A, Manfredini V, Wajner M, Vargas CR
Arch Biochem Biophys 2019 Jun 15;668:16-22. Epub 2019 Apr 30 doi: 10.1016/j.abb.2019.04.008. PMID: 31047871
Su L, Li X, Lin R, Sheng H, Feng Z, Liu L
Metab Brain Dis 2017 Dec;32(6):2063-2071. Epub 2017 Sep 5 doi: 10.1007/s11011-017-0097-y. PMID: 28875337
Paquay S, Bourillon A, Pichard S, Benoist JF, de Lonlay P, Dobbelaere D, Fouilhoux A, Guffon N, Rouvet I, Labarthe F, Mention K, Touati G, Valayannopoulos V, Ogier de Baulny H, Elmaleh-Bergès M, Acquaviva-Bourdain C, Vianey-Saban C, Schiff M
J Inherit Metab Dis 2017 May;40(3):415-422. Epub 2017 Mar 2 doi: 10.1007/s10545-017-0021-y. PMID: 28255778
Pipitone A, Raval DB, Duis J, Vernon H, Martin R, Hamosh A, Valle D, Gunay-Aygun M
Am J Med Genet A 2016 Jun;170(6):1600-2. Epub 2016 Mar 21 doi: 10.1002/ajmg.a.37620. PMID: 26997609Free PMC Article

Diagnosis

Abdelkreem E, Harijan RK, Yamaguchi S, Wierenga RK, Fukao T
Hum Mutat 2019 Oct;40(10):1641-1663. Epub 2019 Jul 3 doi: 10.1002/humu.23831. PMID: 31268215Free PMC Article
Rajan D, Constance LSL, Brandon P
Med J Malaysia 2019 Apr;74(2):174-175. PMID: 31079130
Kılıç-Yıldırım G, Durmuş-Aydoğdu S, Ceylaner S, Sass JO
Turk J Pediatr 2017;59(4):471-474. doi: 10.24953/turkjped.2017.04.016. PMID: 29624230
Paquay S, Bourillon A, Pichard S, Benoist JF, de Lonlay P, Dobbelaere D, Fouilhoux A, Guffon N, Rouvet I, Labarthe F, Mention K, Touati G, Valayannopoulos V, Ogier de Baulny H, Elmaleh-Bergès M, Acquaviva-Bourdain C, Vianey-Saban C, Schiff M
J Inherit Metab Dis 2017 May;40(3):415-422. Epub 2017 Mar 2 doi: 10.1007/s10545-017-0021-y. PMID: 28255778
Fukao T, Akiba K, Goto M, Kuwayama N, Morita M, Hori T, Aoyama Y, Venkatesan R, Wierenga R, Moriyama Y, Hashimoto T, Usuda N, Murayama K, Ohtake A, Hasegawa Y, Shigematsu Y, Hasegawa Y
J Hum Genet 2014 Nov;59(11):609-14. Epub 2014 Sep 18 doi: 10.1038/jhg.2014.79. PMID: 25231369

Therapy

Delgado CA, Balbueno Guerreiro GB, Diaz Jacques CE, de Moura Coelho D, Sitta A, Manfredini V, Wajner M, Vargas CR
Arch Biochem Biophys 2019 Jun 15;668:16-22. Epub 2019 Apr 30 doi: 10.1016/j.abb.2019.04.008. PMID: 31047871
Muñoz-Bonet JI, Ortega-Sánchez MD, León Guijarro JL
Ital J Pediatr 2017 Jan 19;43(1):12. doi: 10.1186/s13052-017-0333-4. PMID: 28257639Free PMC Article
Yoo S, Kim JB
Biol Pharm Bull 2015;38(6):913-8. doi: 10.1248/bpb.b14-00712. PMID: 26027833
Köksal T, Gündüz M, Özaydın E, Azak E
Indian J Pediatr 2015 Jul;82(7):645-8. Epub 2015 Feb 25 doi: 10.1007/s12098-015-1722-6. PMID: 25708061
Xu G, Watanabe T, Iso Y, Koba S, Sakai T, Nagashima M, Arita S, Hongo S, Ota H, Kobayashi Y, Miyazaki A, Hirano T
Circ Res 2009 Aug 28;105(5):500-10. Epub 2009 Jul 30 doi: 10.1161/CIRCRESAHA.109.193870. PMID: 19644050

Prognosis

Václavík J, Coene KLM, Vrobel I, Najdekr L, Friedecký D, Karlíková R, Mádrová L, Petsalo A, Engelke UFH, van Wegberg A, Kluijtmans LAJ, Adam T, Wevers RA
J Inherit Metab Dis 2018 May;41(3):407-414. Epub 2017 Nov 14 doi: 10.1007/s10545-017-0109-4. PMID: 29139026
Aoyama Y, Sasai H, Abdelkreem E, Otsuka H, Nakama M, Kumar S, Aroor S, Shukla A, Fukao T
Mol Med Rep 2017 Jun;15(6):3879-3884. Epub 2017 Apr 4 doi: 10.3892/mmr.2017.6434. PMID: 28393214
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y
J Inherit Metab Dis 2014 Jul;37(4):541-51. Epub 2014 Apr 8 doi: 10.1007/s10545-014-9704-9. PMID: 24706027
Puisac B, Teresa-Rodrigo ME, Arnedo M, Gil-Rodríguez MC, Pérez-Cerdá C, Ribes A, Pié A, Bueno G, Gómez-Puertas P, Pié J
Mol Genet Metab 2013 Apr;108(4):232-40. Epub 2013 Feb 4 doi: 10.1016/j.ymgme.2013.01.019. PMID: 23465862
Catanzano F, Ombrone D, Di Stefano C, Rossi A, Nosari N, Scolamiero E, Tandurella I, Frisso G, Parenti G, Ruoppolo M, Andria G, Salvatore F
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S91-4. Epub 2010 Feb 16 doi: 10.1007/s10545-009-9028-3. PMID: 20157782Free PMC Article

Clinical prediction guides

Roland D, Jissendi-Tchofo P, Briand G, Vamecq J, Fontaine M, Ultré V, Acquaviva-Bourdain C, Mention K, Dobbelaere D
Mol Genet Metab 2017 Jun;121(2):111-118. Epub 2017 Mar 30 doi: 10.1016/j.ymgme.2017.03.006. PMID: 28396157
Aoyama Y, Sasai H, Abdelkreem E, Otsuka H, Nakama M, Kumar S, Aroor S, Shukla A, Fukao T
Mol Med Rep 2017 Jun;15(6):3879-3884. Epub 2017 Apr 4 doi: 10.3892/mmr.2017.6434. PMID: 28393214
Paquay S, Bourillon A, Pichard S, Benoist JF, de Lonlay P, Dobbelaere D, Fouilhoux A, Guffon N, Rouvet I, Labarthe F, Mention K, Touati G, Valayannopoulos V, Ogier de Baulny H, Elmaleh-Bergès M, Acquaviva-Bourdain C, Vianey-Saban C, Schiff M
J Inherit Metab Dis 2017 May;40(3):415-422. Epub 2017 Mar 2 doi: 10.1007/s10545-017-0021-y. PMID: 28255778
Köksal T, Gündüz M, Özaydın E, Azak E
Indian J Pediatr 2015 Jul;82(7):645-8. Epub 2015 Feb 25 doi: 10.1007/s12098-015-1722-6. PMID: 25708061
Puisac B, Teresa-Rodrigo ME, Arnedo M, Gil-Rodríguez MC, Pérez-Cerdá C, Ribes A, Pié A, Bueno G, Gómez-Puertas P, Pié J
Mol Genet Metab 2013 Apr;108(4):232-40. Epub 2013 Feb 4 doi: 10.1016/j.ymgme.2013.01.019. PMID: 23465862

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