Two Libyan siblings with beta-ketothiolase deficiency: A case report and review of literature

Abdelkreem, Elsayed; Alobaidy, Hanna; Aoyama, Yuka; Mahmoud, Shaimaa; Aal, Mohamed Abd El; Fukao, Toshiyuki

doi:10.1016/j.ejmhg.2016.11.001

Cited by 7 publications

(11 citation statements)

References 29 publications

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“…Environmental/acquired factors, such as ketogenic triggers, considerably contribute to the clinical presentation (Thümmler, Dupont, Acquaviva, Fukao & De Ricaud, 2010). 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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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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“…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].…”

Section: Discussionmentioning

confidence: 78%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Though rare, neonates can present with vomiting, poor suckling and lethargy [5]. T2 deficiency may mimic central nervous system infection, diabetic ketoacidosis, if associated with stress hyperglycemia; or even salicylate poisoning [3]. Patients are reported to be asymptomatic between episodes [6].…”

Section: Discussionmentioning

confidence: 99%

“…The characteristic laboratory finding is the elevation of urine organic acids; tiglylglycine (TIG) 2-methylacetoacetic acid (2MAA) and 3-OH-2-methyl-butyric acid (2M3HB). More than 70 different mutations of the mitochondrial ACAT1 gene have been identified to date as causative for T2 deficiency [3]. Only one case of T2 deficiency has been reported from Sri Lanka, detected by gas chromatography/mass spectrometry (GC/MS), but the diagnosis was not confirmed by genetic studies or enzyme analysis [4].…”

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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T2 Deficiency

Heidari

2023

Genetic Syndromes

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Two Libyan siblings with beta-ketothiolase deficiency: A case report and review of literature

Cited by 7 publications

References 29 publications

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

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

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

T2 Deficiency

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