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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
Source: Orphanet
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.

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.  https://medlineplus.gov/genetics/condition/beta-ketothiolase-deficiency

Clinical features

From HPO
Elevated urinary 2-methyl-3-hydroxybutyric acid level
MedGen UID:
1054164
Concept ID:
CN377435
Finding
The amount of 2-methyl-3-hydroxybutyric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
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
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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.
Reduced mitochondrial acetyl-CoA acetyltransferase activity in cultured fibroblasts
MedGen UID:
1052113
Concept ID:
CN375675
Finding
Concentration or activity of mitochondrial acetyl-CoA acetyltransferase (EC 2.3.1.9) as measured in cultured fibroblasts is below the limits of normal.

Professional guidelines

PubMed

Huang Z, Liu Y, Huang X, Hu Z, Liu H, Wang L, Liu C, Ren Y
J Mass Spectrom 2019 Feb;54(2):134-140. doi: 10.1002/jms.4314. PMID: 30468550
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Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022

American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

Recent clinical studies

Etiology

Filali-Mouncef Y, Hunter C, Roccio F, Zagkou S, Dupont N, Primard C, Proikas-Cezanne T, Reggiori F
Autophagy 2022 Jan;18(1):50-72. Epub 2021 Apr 2 doi: 10.1080/15548627.2021.1895658. PMID: 33794741Free PMC Article
Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, Davis SS, Llapashtica C, Wang J, Kim DJ, Xia D, Lucas A, Baskaran S, Haddick PCG, Lenser M, Earr TK, Shi J, Dugas JC, Andreone BJ, Logan T, Solanoy HO, Chen H, Srivastava A, Poda SB, Sanchez PE, Watts RJ, Sandmann T, Astarita G, Lewcock JW, Monroe KM, Di Paolo G
Neuron 2020 Mar 4;105(5):837-854.e9. Epub 2020 Jan 2 doi: 10.1016/j.neuron.2019.12.007. PMID: 31902528
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
Davies MN, Kjalarsdottir L, Thompson JW, Dubois LG, Stevens RD, Ilkayeva OR, Brosnan MJ, Rolph TP, Grimsrud PA, Muoio DM
Cell Rep 2016 Jan 12;14(2):243-54. Epub 2015 Dec 31 doi: 10.1016/j.celrep.2015.12.030. PMID: 26748706Free PMC Article
Krisans SK
Am J Respir Cell Mol Biol 1992 Oct;7(4):358-64. doi: 10.1165/ajrcmb/7.4.358. PMID: 1356376

Diagnosis

Filali-Mouncef Y, Hunter C, Roccio F, Zagkou S, Dupont N, Primard C, Proikas-Cezanne T, Reggiori F
Autophagy 2022 Jan;18(1):50-72. Epub 2021 Apr 2 doi: 10.1080/15548627.2021.1895658. PMID: 33794741Free PMC Article
Grünert SC, Schmitt RN, Schlatter SM, Gemperle-Britschgi C, Balcı MC, Berg V, Çoker M, Das AM, Demirkol M, Derks TGJ, Gökçay G, Uçar SK, Konstantopoulou V, Christoph Korenke G, Lotz-Havla AS, Schlune A, Staufner C, Tran C, Visser G, Schwab KO, Fukao T, Sass JO
Mol Genet Metab 2017 Sep;122(1-2):67-75. Epub 2017 Jun 27 doi: 10.1016/j.ymgme.2017.06.012. PMID: 28689740
Grünert SC, Schlatter SM, Schmitt RN, Gemperle-Britschgi C, Mrázová L, Balcı MC, Bischof F, Çoker M, Das AM, Demirkol M, de Vries M, Gökçay G, Häberle J, Uçar SK, Lotz-Havla AS, Lücke T, Roland D, Rutsch F, Santer R, Schlune A, Staufner C, Schwab KO, Mitchell GA, Sass JO
Mol Genet Metab 2017 Jul;121(3):206-215. Epub 2017 May 22 doi: 10.1016/j.ymgme.2017.05.014. PMID: 28583327
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
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

Therapy

Amengual J, Ogando Y, Nikain C, Quezada A, Qian K, Vaisar T, Fisher EA
Mol Pharmacol 2021 Mar;99(3):175-183. Epub 2020 Dec 31 doi: 10.1124/molpharm.120.000108. PMID: 33384285Free PMC Article
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
Wierzbicki AS, Hardman TC, Viljoen A
Int J Clin Pract 2012 Mar;66(3):270-80. doi: 10.1111/j.1742-1241.2011.02867.x. PMID: 22340447

Prognosis

Grünert SC, Sass JO
Orphanet J Rare Dis 2020 Apr 28;15(1):106. doi: 10.1186/s13023-020-01357-0. PMID: 32345314Free PMC Article
Grünert SC, Schmitt RN, Schlatter SM, Gemperle-Britschgi C, Balcı MC, Berg V, Çoker M, Das AM, Demirkol M, Derks TGJ, Gökçay G, Uçar SK, Konstantopoulou V, Christoph Korenke G, Lotz-Havla AS, Schlune A, Staufner C, Tran C, Visser G, Schwab KO, Fukao T, Sass JO
Mol Genet Metab 2017 Sep;122(1-2):67-75. Epub 2017 Jun 27 doi: 10.1016/j.ymgme.2017.06.012. PMID: 28689740
Grünert SC, Schlatter SM, Schmitt RN, Gemperle-Britschgi C, Mrázová L, Balcı MC, Bischof F, Çoker M, Das AM, Demirkol M, de Vries M, Gökçay G, Häberle J, Uçar SK, Lotz-Havla AS, Lücke T, Roland D, Rutsch F, Santer R, Schlune A, Staufner C, Schwab KO, Mitchell GA, Sass JO
Mol Genet Metab 2017 Jul;121(3):206-215. Epub 2017 May 22 doi: 10.1016/j.ymgme.2017.05.014. PMID: 28583327
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
Richtrova E, Mrazova LS, Musalkova D, Luksan O, Stolnaya L, Minks J, Lukas J, Dvorakova L, Jirsa M, Hrebicek M
Gene 2016 Oct 30;592(1):36-42. Epub 2016 Jul 22 doi: 10.1016/j.gene.2016.07.051. PMID: 27452122

Clinical prediction guides

Filali-Mouncef Y, Hunter C, Roccio F, Zagkou S, Dupont N, Primard C, Proikas-Cezanne T, Reggiori F
Autophagy 2022 Jan;18(1):50-72. Epub 2021 Apr 2 doi: 10.1080/15548627.2021.1895658. PMID: 33794741Free PMC Article
Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, Davis SS, Llapashtica C, Wang J, Kim DJ, Xia D, Lucas A, Baskaran S, Haddick PCG, Lenser M, Earr TK, Shi J, Dugas JC, Andreone BJ, Logan T, Solanoy HO, Chen H, Srivastava A, Poda SB, Sanchez PE, Watts RJ, Sandmann T, Astarita G, Lewcock JW, Monroe KM, Di Paolo G
Neuron 2020 Mar 4;105(5):837-854.e9. Epub 2020 Jan 2 doi: 10.1016/j.neuron.2019.12.007. PMID: 31902528
Genoula M, Marín Franco JL, Dupont M, Kviatcovsky D, Milillo A, Schierloh P, Moraña EJ, Poggi S, Palmero D, Mata-Espinosa D, González-Domínguez E, León Contreras JC, Barrionuevo P, Rearte B, Córdoba Moreno MO, Fontanals A, Crotta Asis A, Gago G, Cougoule C, Neyrolles O, Maridonneau-Parini I, Sánchez-Torres C, Hernández-Pando R, Vérollet C, Lugo-Villarino G, Sasiain MDC, Balboa L
Front Immunol 2018;9:459. Epub 2018 Mar 9 doi: 10.3389/fimmu.2018.00459. PMID: 29593722Free PMC Article
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
Richtrova E, Mrazova LS, Musalkova D, Luksan O, Stolnaya L, Minks J, Lukas J, Dvorakova L, Jirsa M, Hrebicek M
Gene 2016 Oct 30;592(1):36-42. Epub 2016 Jul 22 doi: 10.1016/j.gene.2016.07.051. PMID: 27452122

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

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