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

Abdelkreem, Elsayed; Akella, Radha Rama Devi; Dave, Usha; Sane, Sudhir V; Otsuka, Hiroki; Sasai, Hideo; Aoyama, Yuka; Nakama, Mina; Ohnishi, Hiroyuki; Mahmoud, Shaimaa; Aal, Mohamed Abd El; Fukao, Toshiyuki

doi:10.1007/8904_2016_26

Cited by 17 publications

(28 citation statements)

References 20 publications

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“…This is followed by c.455G>C (p.Gly152Ala) that was found in six families. Transient expression analysis of both p.Met193Arg and p.Gly152Ala variant T2 cDNAs revealed no residual enzyme activity (Abdelkreem, Akella, et al, ; Zhang et al, ).…”

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

“…Since Daum, Lamm, Mamer, and Scriver (1971), for the first time, characterized T2 deficiency, at least 159 patients (Supporting Information Table) with the disease have been confirmed (through enzyme assay and/or genetic analysis) worldwide without ethnic preference. The incidence of T2 deficiency has been estimated in some regions, as one per 232,000 newborns in Minnesota, one per 190,000 newborns in northern Vietnam, and one per 111,000 newborns in Hyderabad (India) (Abdelkreem, Akella, et al, 2017;Nguyen et al, 2017;Sarafoglou et al, 2011).…”

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confidence: 99%

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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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Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

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confidence: 99%

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

et al. 2019

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“…In 2017, Paquay et al described 26 French patients born between 1986 and 2014 [2], and Nguyen et al 41 patients born in Vietnam between 2002 and 2016 [3]. In the same year 2017, Abdelkreem et al reported 10 MATD patients from Southern India [4] and Grünert et al 32 patients who were mainly of European/Turkish origin [5]. In 2019, Abdelkreem et al have provided an update on ACAT1 variants and their molecular consequences [6].…”

Section: Introductionmentioning

confidence: 99%

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

Grünert

Sass

2020

Orphanet J Rare Dis

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Background: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetylcoenzyme A thiolase T2/ "beta-ketothiolase") is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1. Methods: We performed a systematic literature search for all available clinical descriptions of patients with MATD. Two hundred forty-four patients were identified and included in this analysis. Clinical course and biochemical data are presented and discussed. Results: For 89.6% of patients at least one acute metabolic decompensation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). More than 82% of patients presented in the first 2 years of life, while manifestation in the neonatal period was the exception (3.4%). 77.0% (157 of 204 patients) of patients showed normal psychomotor development without neurologic abnormalities. Conclusion: This comprehensive data analysis provides a systematic overview on all cases with MATD identified in the literature. It demonstrates that MATD is a rather benign disorder with often favourable outcome, when compared with many other organic acidurias.

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“…In 13 patients (13/204; 6.3%) movement disorders were reported, including dyskinesia, dystonia, choreoathetosis, dysarthria and myoclonic jerks. Seizures were rare in this cohort and only reported in 2 (surviving) patients apart from metabolic decompensations [10,11]. Imaging data (MRI or CT) were available of 71 patients.…”

Section: Resultsmentioning

confidence: 96%

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

Grünert

Sass

2019

Preprint

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Background: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetyl-coenzyme A thiolase T2/ “beta-ketothiolase”) is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1. Methods: We performed a systematic literature search for all available clinical descriptions of patients with MATD. 244 patients were identified and included in this analysis. Clinical course and biochemical data are presented and discussed. Results: For 89.6 % of patients at least one acute metabolic decompensation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). More than 82% of patients presented in the first two years of life, while manifestation in the neonatal period was the exception (3.4%). 77.0% (157 of 204 patients) of patients showed normal psychomotor development without neurologic abnormalities.Conclusion: This comprehensive data analysis provides a systematic overview on all cases with MATD identified in the literature. It demonstrates that MATD is a rather benign disorder with often favourable outcome, when compared with many other organic acidurias.

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

Cited by 17 publications

References 20 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

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

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

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