NMR-based urinalysis for beta-ketothiolase deficiency

Law, Chun Yiu; Lam, Ching‐Wan; Ching, Chor Kwan; Yau, Kin-Cheong Eric; Ho, Tsz-wai; Lai, Chi-Kong; Mak, Chloe Miu

doi:10.1016/j.cca.2014.08.041

Cited by 7 publications

(7 citation statements)

References 24 publications

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“…Numerous different mutations (>50) have been identified in ACAT1, 20% of which cause aberrant splicing (10). Although the majority Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site of mutations that cause aberrant splicing are located at splice acceptor or donor sites (11)(12)(13)(14)(15), certain exonic mutations have been identified to activate cryptic splice sites within their exons or alter the consensus sequences of exonic splice enhancer (ESE) sites (16,17). The present study reports a novel exonic mutation, c.949G>A (nucleotide 9 in exon 10).…”

Section: Introductionmentioning

confidence: 78%

Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site

Otsuka¹,

Sasai²,

Nakama³

et al. 2016

Molecular Medicine Reports

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Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive disease caused by mutations in the acetyl‑CoA acetyltransferase 1 (ACAT1) gene. A German T2‑deficient patient that developed a severe ketoacidotic episode at the age of 11 months, was revealed to be a compound heterozygote of a previously reported null mutation, c.472A>G (p.N158D) and a novel mutation, c.949G>A (p.D317N), in ACAT1. The c.949G>A mutation was suspected to cause aberrant splicing as it is located within an exonic splicing enhancer sequence (c. 947CTGACGC) that is a potential binding site for serine/arginine‑rich splicing factor 1. A mutation in this sequence, c.951C>T, results in exon 10 skipping. A minigene construct was synthesized that included exon 9‑truncated intron 9‑exon 10‑truncated intron 10‑exon 11, and the splicing of this minigene revealed that the c.949G>A mutant construct caused exon 10 skipping in a proportion of the transcripts. Furthermore, additional substitution of G for C at the first nucleotide of exon 10 (c.941G>C) abolished the effect of the c.949G>A mutation. Transient expression analysis of the c.949G>A mutant cDNA revealed no residual T2 activity in the mutated D317N enzyme. Therefore, c.949G>A (D317N) is a pathogenic missense mutation, and diminishes the effect of an exonic splicing enhancer and causes exon 10 skipping. The present study demonstrates that a missense mutation, or even a synonymous substitution, may disrupt enzyme function by interference with splicing.

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Section: Introductionmentioning

confidence: 78%

Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site

Otsuka¹,

Sasai²,

Nakama³

et al. 2016

Molecular Medicine Reports

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“…The overall incidence of BKTD was 1 in 1,149,156 births (Table 1). In total, 29 Chinese patients were genetically diagnosed as BKTD in this cohort, 17 had been previously reported [12][13][14][15][16]. The median C4OH concentration was 1.38 ± 0.94 µmol/L (range 0.26-3.58 µmol/L, reference value 0.02-0.3 µmol/L), almost all patients (15/16, 94%) showed elevated C4OH levels except for one patient (Supplemental Table S1, No.…”

Section: Bktd Nbs and Acylcarnitine Analysismentioning

confidence: 99%

C4OH is a Potential Screening Marker - A Multicenter Retrospective Study of Patients with Beta-Ketothiolase Deficiency in China

Lin

Yang

Yang³

et al. 2020

Preprint

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Background: Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutations in ACAT1 that affects both isoleucine catabolism and ketolysis. Scant information is available regarding the incidence, newborn screening (NBS), and mutational spectrum in China.Methods: We collected NBS, biochemical, clinical, and ACAT1 mutation data from 18 provinces or municipalities in China between January 2009 and May 2020, and systematically assessed all available published Chinese BKTD patients data.Results: Totally 16,088,190 newborns were screened and 14 were identified through NBS, with an estimated incidence of 1 per 1 million newborns in China. Twenty-nine patients were genetically diagnosed as BKTD and 12 patients were newly identified. Most patients showed typical blood acylcarnitine and urinary organic acid profiles. In particular, almost all patients (15/16, 94%) showed elevated C4OH levels. Eighteen patients presented acute metabolic decompensations and displayed variable clinical symptoms. The acute episodes of 9 patients were triggered by infections, diarrhea, and vaccination. About two thirds of patients have favorable outcomes, one showed developmental delay, while three had died. Twenty-seven distinct variants were identified in ACAT1, among which 5 were found to be novel.Conclusion: This study presented the largest series of BKTD cohort in China. Our results indicated that C4OH is a useful marker for the detection of BKTD. The performance of BKTD NBS could be improved by adding C4OH to the current panel of C5OH and C5:1 markers in NBS. The mutational spectrum and molecular profiles of ACAT1 in Chinese population were expanded with 5 newly identified variants.

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“…To our knowledge, apart from the common R208X mutation that has been identified in Vietnamese cases, no other common mutations have been determined. 1,4,7 -15,17,20 -25,28,29,33 -59…”

Section: Molecular Analysis: Diagnostic Challengesmentioning

confidence: 99%

“…However, a case of MHBD deficiency mimicking T2 deficiency both clinically and in terms of the urinary organic acid profile (increased excretion of 2M3HB and TIG) has been reported. 2,29 Moreover, MHBD deficiency may produce the same abnormal results as T2 deficiency in a coupled assay. 1,30 Differentiation between T2 and MHBD deficiencies is based on the following: (1) MHBD deficiency is an X-linked disorder; (2) urinary excretion of 2MAA does not increase in MHBD deficiency, even after an oral isoleucine challenge (100 mg/kg body weight), although isoleucine challenge is usually not necessary 3 ; and (3) the potassium-dependent AA-CoA thiolase assay gives a normal result in cases of MHBD deficiency.…”

Section: Diagnostic Challengesmentioning

confidence: 99%

“…Vietnamese cases, no other common mutations have been determined. 1,4,[7][8][9][10][11][12][13][14][15]17,[20][21][22][23][24][25]28,29, T2 deficiency can be confirmed if genomic DNA analysis reveals mutations in ACAT1 gene that were previously identified as causative for T2 deficiency in a mutant complementary DNA (cDNA) expression assay. Screening of other family members for these mutations can identify asymptomatic patients without the need for other sophisticated biochemical or enzymatic assays.…”

Section: Molecular Analysismentioning

confidence: 99%

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Beta-Ketothiolase Deficiency

Abdelkreem

Otsuka

Sasai

et al. 2016

Journal of Inborn Errors of Metabolism and Screening

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Beta-ketothiolase deficiency is an inherited disorder of ketone body metabolism and isoleucine catabolism. It typically manifests as recurrent ketoacidotic episodes with characteristic abnormalities in the urinary organic acid profile. However, several challenges in the diagnosis of beta-ketothiolase deficiency have been encountered: atypical presentations have been reported and some other disorders, such as succinyl-CoA:3-oxoacid CoA transferase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiencies, can mimic the clinical and/or biochemical signs of betaketothiolase deficiency. A final diagnosis of beta-ketothiolase deficiency requires an enzymatic assay and/or a molecular analysis, but some caveats must be considered. Despite the reported missed cases, screening programs have successfully identified an increasing number of patients with beta-ketothiolase deficiency. Early diagnosis and management of betaketothiolase deficiency will enable prevention of its serious acute and chronic complications and ultimately improve the prognosis.

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NMR-based urinalysis for beta-ketothiolase deficiency

Cited by 7 publications

References 24 publications

Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site

Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site

C4OH is a Potential Screening Marker - A Multicenter Retrospective Study of Patients with Beta-Ketothiolase Deficiency in China

Beta-Ketothiolase Deficiency

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