Characterization and outcome of 41 patients with beta‐ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam

Nguyen, Khanh Ngoc; Abdelkreem, Elsayed; Colombo, Roberto; Hasegawa, Yuki; Can, Ngoc Thi Bich; Bui, Thao Phuong; Le, Hai Thanh; Tran, Mai Thi Chi; Nguyen, Hoan; Trinh, Hung Thanh; Aoyama, Yuka; Sasai, Hideo; Yamaguchi, Seiji; Fukao, Toshiyuki; Vu, Dung

doi:10.1007/s10545-017-0026-6

Cited by 19 publications

(51 citation statements)

References 25 publications

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“…It has been detected in 28 families, most of which are Vietnamese. This variant accounts for 66% of all ACAT1 variant alleles identified in Vietnamese patients with T2 deficiency (Nguyen et al, ). Recent evidence indicates that the c.622C>T variant has been introduced by an ancient common founder to Vietnamese Kinh ethnic population 1900–2500 years ago (Nguyen et al, ).…”

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

“…This variant accounts for 66% of all ACAT1 variant alleles identified in Vietnamese patients with T2 deficiency (Nguyen et al, ). Recent evidence indicates that the c.622C>T variant has been introduced by an ancient common founder to Vietnamese Kinh ethnic population 1900–2500 years ago (Nguyen et al, ). This highly conserved residue is changed into glutamine (c.623G>A, p.Arg208Gln) in two other families (Sakurai et al, ).…”

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

“…Furthermore, five large deletions/insertions/duplications have been reported in the ACAT1 gene. g.20623_29833delinsGTAA includes deletion of exons 6–11 (Nguyen et al, ). c.731–46_752del (a 68‐bp deletion) involves the splice acceptor site of intron 7, causing exon 8 skipping (Fukao, Song, 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).…”

mentioning

confidence: 99%

“…Disease-associated ACAT1 variants are found in every exon ( Figure 4). Exon 11 contains the highest number (n = 15), followed by exon 6 (n = 11), exon 5 (n = 9), and exons 7 and 9 (each = 8 (Nguyen et al, 2017). This highly conserved residue is changed into glutamine (c.623G>A, p.Arg208Gln) in two other families (Sakurai et al, 2007).…”

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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%

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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Beta‐ketothiolase deficiency: A case with unusual presentation of nonketotic hypoglycemic episodes due to coexistent probable secondary carnitine deficiency

et al. 2019

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Beta‐ketothiolase (T2, mitochondrial acetoacetyl‐CoA thiolase) deficiency is an autosomal recessive disorder of isoleucine catabolism and ketone body metabolism that is characterized by increased urinary excretion of 2‐methylacetoacetate, 2‐methyl‐3‐hydroxybutyrate, and tiglylglycine. Most patients with T2 deficiency develop their first severe ketoacidotic events between 5 and 24 months of age. We encountered a case of T2 deficiency who developed the first hypoglycemic crisis without ketosis during her neonatal period and repeated such nonketotic hypoglycemic crisis during her infancy and early childhood. This is a very atypical clinical phenotype in T2 deficiency. We finally realized that she also has severe carnitine deficiency which might suppress beta‐oxidation resulting in nonketotic hypoglycemia. After carnitine supplementation, she actually developed episodes with ketonuria. Her carnitine deficiency was probably a secondary deficiency which is rare in T2 deficiency but if present, may modify the clinical manifestation of T2 deficiency from ketoacidotic events to hypoketotic hypoglycemic events.

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Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene

Ling

Lin

et al. 2017

Metab Brain Dis

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Hydroxysteroid (17β) dehydrogenase 10 (HSD10) and mitochondrial acetoacetyl-CoA thiolase (β-KT) are two adjacent enzymes for the degradation of isoleucine, thus HSD10 and β-KT deficiencies are confusing at an early stage because of nearly the same elevation of typical metabolites in urine, such as 2-methyl-3-hydroxybutyric acid (2M3HBA) and tiglylglycine (TG). In order to better understand the differences between these two disorders, we described the clinical and molecular characteristics of two HSD10 deficiency patients and four β-KT deficiency patients. β-KT deficiency patients had a much more favorable outcome than that of HSD10 deficiency patients, indicating that the multifunction of HSD10, especially neurosteroid metabolic activity, other than only enzymatic degradation of isoleucine, is involved in the pathogenesis of HSD10 deficiency. Two different mutations, a novel mutation p.Ile175Met and a reported mutation p.Arg226Gln, were detected in the HSD17B10 gene of HSD10 deficiency patients. Six different mutations, including four known mutations: p.Ala333Pro, p.Thr297Lys, c.83_84delAT, c.1006-1G > C, and two novel mutations: p.Thr277Pro and c.121-3C > G were identified in the ACAT1 gene of β-KT deficiency patients. In general, DNA diagnosis played an important role in distinguishing between these two disorders.

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Characterization and outcome of 41 patients with beta‐ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam

Cited by 19 publications

References 25 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

Beta‐ketothiolase deficiency: A case with unusual presentation of nonketotic hypoglycemic episodes due to coexistent probable secondary carnitine deficiency

Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene

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