Inborn errors of ketone body utilization

Hori, Tomohiro; Yamaguchi, Seiji; Shinkaku, Haruo; Horikawa, Reiko; Shigematsu, Yosuke; Takayanagi, Masaki; Fukao, Toshiyuki

doi:10.1111/ped.12585

Cited by 34 publications

(89 citation statements)

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“…ACAT1 mutations are highly diverse, with more than 70 different mutations having been identified to date, and with only a few common mutations (Fukao et al 2010;Hori et al 2015). p.Met193Arg accounts for about half the identified mutant alleles in Indian patients with T2 deficiency, suggesting a founder effect in this Indian region.…”

Section: Discussionmentioning

confidence: 99%

“…Beta-ketothiolase deficiency, also referred to as mitochondrial acetoacetyl-CoA thiolase (T2) (EC 2.3.1.9, gene symbol ACAT1) deficiency (Online Mendelian Inheritance in Man [OMIM] 203750, 607809), is an autosomal recessive disease of isoleucine catabolism and ketone body utilization Hori et al 2015). Since the first description of T2 deficiency in 1971, more than 100 patients with the condition have been identified worldwide with no ethnic predisposition (Abdelkreem et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Abdelkreem

Akella

Dave³

et al. 2016

JIMD Reports

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Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase (T2) deficiency) is an inherited disease of isoleucine catabolism and ketone body utilization caused by ACAT1 mutations. We identified ten Indian patients who manifested with ketoacidotic episodes of variable severity. The patients showed increased urinary excretion of isoleucine-catabolic intermediates: 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Abdelkreem

Akella

Dave³

et al. 2016

JIMD Reports

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“…However, several reports show that T2 deficiency has variable clinical phenotypes even among patients who share not only identical genotype but also similar environmental factors (Abdelkreem, Alobaidy, et al, 2017;Fukao et al, 2012;Köse et al, 2016;Nguyen et al, 2017;Thümmler et al, 2010). Proper acute and preventive treatment seems crucial for a favorable outcome (Hori et al, 2015;Nguyen et al, 2017).…”

Section: Biochemical and Laboratory Significancementioning

confidence: 99%

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

et al. 2019

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Mitochondrial acetoacetyl‐CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. It typically manifests with episodic ketoacidosis. The presence of isoleucine‐derived metabolites is the key marker for biochemical diagnosis. To date, 105 ACAT1 variants have been reported in 149 T2‐deficient patients. The 56 disease‐associated missense ACAT1 variants have been mapped onto the crystal structure of T2. Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability. Expression and activity data of 30 disease‐associated missense ACAT1 variants have been measured by expressing them in human SV40‐transformed fibroblasts. Only two variants (p.Cys126Ser and p.Tyr219His) appear to have equal stability as wild‐type. For these variants, which are inactive, the side chains point into the active site. In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening.

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“…Beta-ketothiolase deficiency is also known by other names including T2 deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency, 3-oxothiolase deficiency, 3-ketothiolase deficiency, and 2-methyl-3-hydroxybutyric acidemia. [1][2][3] In this review, betaketothiolase is abbreviated as T2.…”

Section: Introductionmentioning

confidence: 99%

Beta-Ketothiolase Deficiency

Abdelkreem

Otsuka

Sasai

et al. 2016

Journal of Inborn Errors of Metabolism and Screening

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Beta-ketothiolase deficiency is an inherited disorder of ketone body metabolism and isoleucine catabolism. It typically manifests as recurrent ketoacidotic episodes with characteristic abnormalities in the urinary organic acid profile. However, several challenges in the diagnosis of beta-ketothiolase deficiency have been encountered: atypical presentations have been reported and some other disorders, such as succinyl-CoA:3-oxoacid CoA transferase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiencies, can mimic the clinical and/or biochemical signs of betaketothiolase deficiency. A final diagnosis of beta-ketothiolase deficiency requires an enzymatic assay and/or a molecular analysis, but some caveats must be considered. Despite the reported missed cases, screening programs have successfully identified an increasing number of patients with beta-ketothiolase deficiency. Early diagnosis and management of betaketothiolase deficiency will enable prevention of its serious acute and chronic complications and ultimately improve the prognosis.

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Inborn errors of ketone body utilization

Abstract: Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl-CoA thiolase (betaketothiolase or

Cited by 34 publications

References 60 publications

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

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

Beta-Ketothiolase Deficiency

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