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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). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	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.

See: Feature record | Search on this feature

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.

See: Feature record | Search on this feature

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.

See: Feature record | Search on this feature

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.

See: Feature record | Search on this feature

Episodic ketoacidosis

MedGen UID:: 349256
•Concept ID:: C1859860
•: Finding

Intermittent episodes of ketoacidosis.

See: Feature record | Search on this feature

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.

See: Feature record | Search on this feature

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Abnormality of metabolism/homeostasis
Abnormality of the digestive system
- Vomiting
Abnormality of the genitourinary system
- Elevated urinary 2-methyl-3-hydroxybutyric acid level
Abnormality of the nervous system
- Intellectual disability

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVDisorder of organic acid metabolism

Classic organic aciduria
- Deficiency of acetyl-CoA acetyltransferase

Follow this link to review classifications for Deficiency of acetyl-CoA acetyltransferase in Orphanet.

Professional guidelines

PubMed

Newborn screening for 3-hydroxy-3-methylglutaric aciduria using direct analysis in real-time mass spectrometry.

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

Prenatal diagnosis of succinyl-coenzyme A:3-ketoacid coenzyme A transferase deficiency.

Fukao T, Song XQ, Watanabe H, Hirayama K, Sakazaki H, Shintaku H, Imanaka M, Orii T, Kondo N
Prenat Diagn 1996 May;16(5):471-4. doi: 10.1002/(SICI)1097-0223(199605)16:5<471::AID-PD898>3.0.CO;2-E. PMID: 8844009

Prenatal diagnosis in a family with mitochondrial acetoacetyl-coenzyme A thiolase deficiency with the use of the polymerase chain reaction followed by the heteroduplex detection method.

Fukao T, Wakazono A, Song XQ, Yamaguchi S, Zacharias R, Donlan MA, Orii T
Prenat Diagn 1995 Apr;15(4):363-7. doi: 10.1002/pd.1970150411. PMID: 7617578

See all (4)

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

The ménage à trois of autophagy, lipid droplets and liver disease.

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: 33794741 Free PMC Article

TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.

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

Significance of l-carnitine for human health.

Adeva-Andany MM, Calvo-Castro I, Fernández-Fernández C, Donapetry-García C, Pedre-Piñeiro AM
IUBMB Life 2017 Aug;69(8):578-594. Epub 2017 Jun 26 doi: 10.1002/iub.1646. PMID: 28653367

Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.

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

Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies.

Gilkes JA, Heldermon CD
Pediatr Endocrinol Rev 2014 Sep;12 Suppl 1:133-40. PMID: 25345095

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Diagnosis

The ménage à trois of autophagy, lipid droplets and liver disease.

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.

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: 31268215 Free PMC Article

Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.

Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies.

Gilkes JA, Heldermon CD
Pediatr Endocrinol Rev 2014 Sep;12 Suppl 1:133-40. PMID: 25345095

Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) gene.

Feldhammer M, Durand S, Mrázová L, Boucher RM, Laframboise R, Steinfeld R, Wraith JE, Michelakakis H, van Diggelen OP, Hrebícek M, Kmoch S, Pshezhetsky AV
Hum Mutat 2009 Jun;30(6):918-25. doi: 10.1002/humu.20986. PMID: 19479962

See all (58)

Therapy

Prevention by L-carnitine of DNA damage induced by 3-hydroxy-3-methylglutaric and 3-methylglutaric acids and experimental evidence of lipid and DNA damage in patients with 3-hydroxy-3-methylglutaric aciduria.

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

A readout of metabolic efficiency in arylamine N-acetyltransferase-deficient mice reveals minor energy metabolism changes.

Denis RGP, Busi F, Castel J, Morel C, Zhang W, Bui LC, Sugamori KS, Prokopec SD, Boutros PC, Grant DM, Rodrigues-Lima F, Luquet S, Dupret JM
FEBS Lett 2019 Apr;593(8):831-841. Epub 2019 Mar 22 doi: 10.1002/1873-3468.13357. PMID: 30883722

Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

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: 28257639 Free PMC Article

New lipid-lowering drugs: an update.

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

Characterization of the biosynthesis, processing and kinetic mechanism of action of the enzyme deficient in mucopolysaccharidosis IIIC.

Fan X, Tkachyova I, Sinha A, Rigat B, Mahuran D
PLoS One 2011;6(9):e24951. Epub 2011 Sep 21 doi: 10.1371/journal.pone.0024951. PMID: 21957468 Free PMC Article

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Prognosis

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways.

Grünert SC, Sass JO
Orphanet J Rare Dis 2020 Apr 28;15(1):106. doi: 10.1186/s13023-020-01357-0. PMID: 32345314 Free PMC Article

Structural elucidation of novel biomarkers of known metabolic disorders based on multistage fragmentation mass spectra.

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

Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

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: 28257639 Free PMC Article

Ketone body metabolism and its defects.

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

Inborn errors of isoleucine degradation: a review.

Korman SH
Mol Genet Metab 2006 Dec;89(4):289-99. Epub 2006 Sep 6 doi: 10.1016/j.ymgme.2006.07.010. PMID: 16950638

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