Different Clinical Presentation in Siblings with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency and Identification of Two Novel Mutations

Thümmler, Susanne; Dupont, Didier; Acquaviva, Cécile; Fukao, Toshiyuki; Ricaud, Dominique De

doi:10.1620/tjem.220.27

Cited by 16 publications

(18 citation statements)

References 16 publications

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“…This is evident from the provided comprehensive list of patients with T2 deficiency reported in the literature (Supporting Information Table). Environmental/acquired factors, such as ketogenic triggers, considerably contribute to the clinical presentation (Thümmler, Dupont, Acquaviva, Fukao & De Ricaud, ). 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, ; Fukao et al, ; Köse et al, ; Nguyen et al, ; Thümmler et al, ).…”

Section: Clinical Significancementioning

confidence: 99%

“…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%

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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: Clinical Significancementioning

confidence: 99%

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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“…Our patient was a typical case of the disease. These patients are marked by recurrent attacks of severe ketosis mostly caused by ketolysis defects, the main probable mechanism of excessive production of acetoacetate (7). There is significant variety in reported cases, but the specific characteristics are the episodes of massive ketosis and acidosis.…”

Section: Discussionmentioning

confidence: 99%

First Report of 3-Oxothiolase Deficiency in Iran

Arani

Soltani

2014

Int J Endocrinol Metab

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Introduction:Mitochondrial acetoacetyl-CoA thiolase (3-oxothiolase) deficiency is a rare metabolic disorder involving ketone body metabolism characterized by acute attacks of vomiting, acidosis, ketosis, and lethargy along with some laboratory criteria including excessive excretion of 2-methyl-3-hydroxybutyric acid in urine.Case Presentation:This is a case report of 3-oxothiolase deficiency in a young Iranian boy with presentation of intractable vomiting and severe metabolic acidosis following a common cold in six months of age with abundant urinary 2-methyl-3- hydroxybutyric acid.Discussion:This is the first Iranian 3-oxothiolase deficiency case report as searched in the literature. Because of the high rate of consanguineous marriages in Iran, physicians should consider the 3-oxothiolase deficiency in the differential diagnosis of any patient with intractable vomiting and severe metabolic acidosis.

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“…T2 deficiency was first described in 1971, 25 and more than 100 patients have been reported. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Patients develop ketoacidosis during ketogenic stress such as starvation, febrile conditions and physical stresses because ketone bodies produced in the liver accumulate due to defective utilization in extrahepatic tissues. In physiological ketosis in normal children, both FFA and total ketone bodies (TKB) are elevated proportionally in the blood.…”

Section: Clinical Symptoms and Laboratory Findingsmentioning

confidence: 99%

Inborn errors of ketone body utilization

Hori

Yamaguchi

Shinkaku

et al. 2015

Pediatrics International

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Different Clinical Presentation in Siblings with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency and Identification of Two Novel Mutations

Abstract: Keywords: T2 deficiency/mitochondrial acetoacetyl-CoA thiolase deficiency/β -ketothiolase deficiency/genotype/ phenotype correlation/mutation Tohoku J.

Cited by 16 publications

References 16 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

First Report of 3-Oxothiolase Deficiency in Iran

Inborn errors of ketone body utilization

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