First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China

Liang, Cuili; Jiang, Mao Fa; Sheng, Huiying; Cai, Yamei; Wu, Dayong; Yin, Xi; Peng, Minzhi; Liu, Li

doi:10.1515/jpem-2014-0058

Cited by 6 publications

(7 citation statements)

References 5 publications

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“…These data differ to those for the Chinese population: the c.985A>G mutation was not detected either in the present study or in another Chinese MCADD patient . Of the six mutations detected in the present study, however, a previously reported mutation in Chinese patients, that is, c.449_452del detected in patients 4, 5, and 6, occurred in 3/12 alleles in this study. This mutation is estimated to be relatively common in affected East Asian individuals, accounting for approximately 45% of mutant alleles in Japanese MCADD patients .…”

Section: Discussioncontrasting

confidence: 99%

“…Of the pathogenic mutations, approximately 81% of MCADD patients have a c.985A>G mutation, while another 18% have a heterozygous c.985A>G and an additional heterozygous mutation . These data differ to those for the Chinese population: the c.985A>G mutation was not detected either in the present study or in another Chinese MCADD patient . Of the six mutations detected in the present study, however, a previously reported mutation in Chinese patients, that is, c.449_452del detected in patients 4, 5, and 6, occurred in 3/12 alleles in this study.…”

Section: Discussioncontrasting

confidence: 98%

“…Separately, MCADD is the most common of the types of FAOD in previous research, especially in affected Caucasian individuals . Not many cases of MCADD, however, have been documented in mainland China to date . Therefore, here, we report the clinical, biochemical, and mutation spectra of six Chinese MCADD patients.…”

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confidence: 88%

“…[16][17][18] Not many cases of MCADD, however, have been documented in mainland China to date. [19][20][21] Therefore, here, we report the clinical, biochemical, and mutation spectra of six Chinese MCADD patients.…”

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confidence: 99%

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Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Zhu

Liu

et al. 2019

Pediatrics International

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Background Medium‐chain acyl‐coenzyme A dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder that affects the degradation of medium‐chain fatty acids. Few cases of MCADD have been documented to date in mainland China. Methods Medium‐chain acyl‐coenzyme A dehydrogenase deficiency was diagnosed in six patients (three girls and three boys) from six unrelated Chinese families at ages ranging from 10 days to 3 years old. The diagnosis was confirmed by the identification of a primary biomarker of serum octanoyl‐carnitine (C8) and genetic pathogenic mutations. Results Only two patients were admitted because of vomiting, diarrhea, myasthenia, and coma; the other four patients were diagnosed via the newborn screening process. Six mutations were found in acyl‐CoA dehydrogenase medium chain (ACADM). One mutation (c.727C>T) was novel and the others (c.158G>A, c.387+1delG, c.449_452del, c.1045C>T, and c.1085G>A) have been previously reported. Conclusions Six Chinese cases of MCADD were identified. One novel mutation was found. c.449_452del and c.1085G>A were common mutations in this study.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 98%

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confidence: 88%

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confidence: 99%

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Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Zhu

Liu

et al. 2019

Pediatrics International

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“…Mutations p.T150Rfs * 4, p.R17H, p.G362E, p.R53C, and p.R281S accounted for approximately 60% of all alleles in a large cohort of Japanese MCADD patients, and mutation p.T150Rfs * 4 was the most prevalent (Tajima et al, 2016). In Chinese patients, seven mutations have been previously reported, including p.T150Rfs * 4, p.T121I, p.R243X, p.R53H, p.R349X, p.G362E, and c.387+1delG, with p.T150Rfs * 4 being the most common (Liang et al, 2015;Li et al, 2019). We observed 24 ACADM gene mutations, including 17 novel variants.…”

Section: Discussionmentioning

confidence: 97%

Clinical, Biochemical, and Molecular Analyses of Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Chinese Patients

et al. 2021

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ObjectiveMedium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation. The present study aimed to evaluate clinical and biochemical manifestations, and the mutation spectrum of this disorder in a large cohort of Chinese patients.MethodsA total of 24 patients were enrolled, and blood acylcarnitine and urinary organic acid levels were measured by tandem mass spectrometry and gas chromatography–mass spectrometry (GC–MS), respectively. Mutations in the ACADM gene were detected by Sanger or next-generation sequencing. Clinical progression, acylcarnitine spectra, and mutations were analyzed and described in detail.ResultsAmong the 24 patients, six cases were diagnosed because of disease onset with symptoms such as vomiting, diarrhea, convulsion, and hypoglycemia; 18 patients without symptoms were diagnosed by newborn screening (NBS). All patients who accepted treatment after diagnosis developed normal intelligence and physique. The concentrations of octanoylcarnitine, the octanoylcarnitine/decanoylcarnitine ratio, and the octanoylcarnitine/acetylcarnitine ratio in the blood and urinary dicarboxylic acid concentrations were consistently elevated. Blood biomarkers failed to decrease after treatment. DNA sequencing revealed seven known and 17 novel mutations in the ACADM gene of patients. Mutation p.T150Rfs∗4 was most frequent, followed by p.R31C, p.F103Y, p.I223T, p.G362E, and c.387+1delG.ConclusionDespite biochemical abnormalities, medium-chain acyl-CoA dehydrogenase deficiency showed relatively mild clinical phenotypes with low mortality and optimistic prognoses in China. NBS is crucial for early diagnosis, treatment, and prognosis.

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Vulnerable exons, like ACADM exon 5, are highly dependent on maintaining a correct balance between splicing enhancers and silencers

et al. 2021

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It is now widely accepted that aberrant splicing of constitutive exons is often caused by mutations affecting cis‐acting splicing regulatory elements, but there is a misconception that all exons have an equal dependency on splicing regulatory elements and thus a similar susceptibility to aberrant splicing. We investigated exonic mutations in ACADM exon 5 to experimentally examine their effect on splicing and found that 7 out of 11 tested mutations affected exon inclusion, demonstrating that this constitutive exon is particularly vulnerable to exonic splicing mutations. Employing ACADM exon 5 and 6 as models, we demonstrate that the balance between splicing enhancers and silencers, flanking intron length, and flanking splice site strength are important factors that determine exon definition and splicing efficiency of the exon in question. Our study shows that two constitutive exons in ACADM have different inherent vulnerabilities to exonic splicing mutations. This suggests that in silico prediction of potential pathogenic effects on splicing from exonic mutations may be improved by also considering the inherent vulnerability of the exon. Moreover, we show that single nucleotide polymorphism that affect either of two different exonic splicing silencers, located far apart in exon 5, all protect against both immediately flanking and more distant exonic splicing mutations.

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First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China

Cited by 6 publications

References 5 publications

Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Clinical, Biochemical, and Molecular Analyses of Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Chinese Patients

Vulnerable exons, like ACADM exon 5, are highly dependent on maintaining a correct balance between splicing enhancers and silencers

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