Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G&gt;A

Wang, Zhiqiang; Chen, Xue-Jiao; Murong, Shen-Xing; Wang, Ning; Wu, Zhi‐Ying

doi:10.1007/s00109-011-0725-7

Cited by 76 publications

(69 citation statements)

References 28 publications

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“…The mean age at onset of 146 patients with late-onset MADD of whom detailed information was given in the literature is 14.3 years. Of additional 56 cases reported by Wang et al [[55]] and 71 cases reported by Xi et al [[28]] only the mean age at onset (24.5 ± 12.6 years with a range from 4 to 55 years and 25.0 ± 13.3 years with a range from 4 to 36 years, respectively) is known. If these cases are also taken into account, the mean age at onset in this study cohort is 19.2 years.…”

Section: Resultsmentioning

confidence: 99%

“…Most mutations seem to be private. Three common mutations in the ETFDH gene have been described which are mainly found in the Chinese and Taiwanese population: c.250G > A (p.A84T), c.770A > G (p.Y257C), c.1227A > C (p.L409F) [[23],[28],[55]]. As this literature review has shown, the vast majority of late-onset patients harbour mutations in the ETFDH gene, while ETFA or ETFB mutations are found in only about 7% of individuals.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Grünert

2014

Orphanet J Rare Dis

157

156

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BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases.MethodsAll 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment.ResultsMean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remained asymptomatic until a maximum age of 14 years. Diagnosis may be difficult as a relevant number of patients do not display typical biochemical patterns of urine organic acids and blood acylcarnitines during times of wellbeing. The vast majority of patients carry mutations in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are the exceptions. Almost all patients with late-onset MADD (98%) are clearly responsive to riboflavin.ConclusionsLate-onset MADD is probably an underdiagnosed disease and should be considered in all patients with acute or chronic muscular symptoms or acute metabolic decompensation with hypoglycemia, acidosis, encephalopathy and hepatopathy. This may not only prevent patients from invasive diagnostic procedures such as muscle biopsies, but also help to avoid fatal metabolic decompensations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Grünert

2014

Orphanet J Rare Dis

157

156

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“…Nevertheless, the carrier frequency of c.250G > A is estimated to be 1.35% amongst the population in southern China. Thus, ~1:22,000 Han Chinese are expected to suffer from riboflavin-responsive MADD [7]. Intriguingly, p.Ala84Thr has been identified in Asian countries including Taiwan, Hong Kong, Singapore, Thailand and southern China [6-11].…”

Section: Introductionmentioning

confidence: 99%

Computational analysis of a novel mutation in ETFDH gene highlights its long-range effects on the FAD-binding motif

Chen

Liu

et al. 2011

BMC Struct Biol

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BackgroundMultiple acyl-coenzyme A dehydrogenase deficiency (MADD) is an autosomal recessive disease caused by the defects in the mitochondrial electron transfer system and the metabolism of fatty acids. Recently, mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, encoding electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) have been reported to be the major causes of riboflavin-responsive MADD. To date, no studies have been performed to explore the functional impact of these mutations or their mechanism of disrupting enzyme activity.ResultsHigh resolution melting (HRM) analysis and sequencing of the entire ETFDH gene revealed a novel mutation (p.Phe128Ser) and the hotspot mutation (p.Ala84Thr) from a patient with MADD. According to the predicted 3D structure of ETF:QO, the two mutations are located within the flavin adenine dinucleotide (FAD) binding domain; however, the two residues do not have direct interactions with the FAD ligand. Using molecular dynamics (MD) simulations and normal mode analysis (NMA), we found that the p.Ala84Thr and p.Phe128Ser mutations are most likely to alter the protein structure near the FAD binding site as well as disrupt the stability of the FAD binding required for the activation of ETF:QO. Intriguingly, NMA revealed that several reported disease-causing mutations in the ETF:QO protein show highly correlated motions with the FAD-binding site.ConclusionsBased on the present findings, we conclude that the changes made to the amino acids in ETF:QO are likely to influence the FAD-binding stability.

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“…Acute metabolic crisis can be lethal when it is severe. Gastrointestinal symptoms, including abdominal pain, vomiting, diarrhea and hepatomegaly, are frequently observed . Cardiomyopathy and brain involvement have also been reported in MADD …”

Section: Clinical Featuresmentioning

confidence: 99%

Riboflavin‐responsive multiple acyl‐CoA dehydrogenase deficiency: A frequent condition in the southern Chinese population

Liang

Nishino

2013

Neurology & Clinical Neurosc

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Multiple acyl-CoA dehydrogenase deficiency (MADD) is caused by the recessive mutations in any of ETFA, ETFB and ETFDH, respectively, encoding electron transfer flavoprotein (ETF)-a, ETF-b and ETF-ubiquinone oxidoreductase (ETF-QO), resulting in defects in the transfer of high-energy electrons from acyl-CoA dehydrogenases in mitochondria and leading to dysfunction of all ETF-dependent acyl-CoA dehydrogenases. MADD seems to be very rare, at least in the Japanese population, but not among the southern Chinese population because of the presence of the common c.250G>A (p.Ala84Thr) mutation in ETFDH, with an estimated carrier frequency of approximately 1%. This mutation was originally identified in MADD patients in Taiwan; but later, several reports of the same mutation, including those from southern China, ensued this. So far, this mutation has not been identified in any other population, except for only a few patients in northern China, probably as a result of migration. High-dose riboflavin supplementation therapy has been shown to be efficacious in MADD patients with certain ETFDH mutations, including p.Ala84Thr, suggesting that MADD in most southern Chinese patients might be treatable. Therefore, the possibility of MADD should be highly suspected in southern Chinese patients with relevant clinical manifestations.

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Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A

Cited by 76 publications

References 28 publications

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Computational analysis of a novel mutation in ETFDH gene highlights its long-range effects on the FAD-binding motif

Riboflavin‐responsive multiple acyl‐CoA dehydrogenase deficiency: A frequent condition in the southern Chinese population

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