Beta-Ketothiolase Deficiency

Abdelkreem, Elsayed; Otsuka, Hiroki; Sasai, Hideo; Aoyama, Yuka; Hori, Tomohiro; Aal, Mohamed Abd El; Mahmoud, Shaimaa; Fukao, Toshiyuki

doi:10.1177/2326409816636644

Cited by 20 publications

(9 citation statements)

References 66 publications

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“…T2 deficiency is a rare genetic disorder that results from biallelic pathogenic variants of ACAT1 gene located on the chromosome 11q22.3 [2,3]. T2 enzyme cleaves 2-methylacetoacetyl-CoA in isoleucine metabolism, and is also responsible for the last step in ketogenesis in liver and in ketolysis in extra-hepatic tissues [1] (see Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…The typical presentation is in early childhood, with vomiting, hyperpnoea, drowsiness, lethargy and coma triggered by a ketogenic stress such as fasting, infection and physical exertion [3]. Some may have atypical presentations like metabolic stroke and metabolic encephalopathy and delayed onset as in our case [1]. Though rare, neonates can present with vomiting, poor suckling and lethargy [5].…”

Section: Discussionmentioning

confidence: 99%

“…Individuals with succinyl CoA:3-oxoacid CoA transferase (SCOT) deficiency can mimic attacks of T2 deficiency, but owing to its neonatal onset, permanent ketosis and non-specific urinary organic acid profile, SCOT deficiency was effectively excluded [1]. MHBD is an X-linked disorder having a similar clinical picture as in T2 deficiency, and urine will contain increased level of 2M3HB and TIG with no increase in 2MAA [1]. Therefore, MHBD was a differential diagnosis in this case.…”

Section: Discussionmentioning

confidence: 99%

“…Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) is a key enzyme needed for ketone metabolism and isoleucine catabolism [1]. T2 deficiency is a rare autosomal recessive disorder with an incidence of less than one per 1,000,000 newborns (1]. Owing to diagnostic challenges and lack of awareness, many cases have been missed during their initial presentation [2].…”

Section: Introductionmentioning

confidence: 99%

“…Owing to diagnostic challenges and lack of awareness, many cases have been missed during their initial presentation [2]. It typically manifests between 6-18 months of age as acute and recurrent ketoacidotic episodes triggered by ketogenic stress [1,2]. Patients are typically asymptomatic between episodes, and the episode frequency decreases with age [2].…”

Section: Introductionmentioning

confidence: 99%

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A Novel Mutation in ACAT1 Causing Beta-Ketothiolase Deficiency in a 4-Year-Old Sri Lankan Boy with Metabolic Ketoacidosis

et al. 2019

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Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency is a rare genetic disorder of ketone utilization and isoleucine catabolism caused by mutations in the ACAT1 gene. Here we report the first Sri Lankan case of T2 deficiency confirmed by genetic analysis. A 4-year-old boy presented with the first episode of severe metabolic ketoacidosis after a febrile illness. On admission, the child was drowsy and had circulatory collapse needing intubation. Initial investigations were not detective of a cause and symptomatic management did not improve the condition. During the acute episode, his urine organic acid profile revealed elevations in 3-OH-2-methylbutyric acid and tiglylglycine whilst 2-methylacetoacetic acid was not detected. The differential diagnoses for the urine organic acid profile included deficiency in T2 or 2-methyl-3-OH-butyryl-CoA dehydrogenase enzymes. Genetic analysis using polymerase chain reaction and DNA sequencing of ACAT1 gene revealed that the proband is homozygous for the novel missense likely pathogenic variant c.152C [ T p.(Pro51Leu) confirming the diagnosis of T2 deficiency. This case highlights the importance of suspecting T2 deficiency in the differential diagnosis of pediatric metabolic ketoacidosis in preventing life threatening consequences of an otherwise benign disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Mutation in ACAT1 Causing Beta-Ketothiolase Deficiency in a 4-Year-Old Sri Lankan Boy with Metabolic Ketoacidosis

et al. 2019

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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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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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Beta-Ketothiolase Deficiency

Cited by 20 publications

References 66 publications

A Novel Mutation in ACAT1 Causing Beta-Ketothiolase Deficiency in a 4-Year-Old Sri Lankan Boy with Metabolic Ketoacidosis

A Novel Mutation in ACAT1 Causing Beta-Ketothiolase Deficiency in a 4-Year-Old Sri Lankan Boy with Metabolic Ketoacidosis

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

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

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