PDF(Pubmed)
Abstract：
Lipid storage myopathy (LSM) is a diverse group of lipid metabolic disorders with great variations in the clinical phenotype and age of onset. Classical multiple acyl-CoA dehydrogenase deficiency (MADD) is known to occur secondary to mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene. Whole exome sequencing (WES) with clinical correlations can be useful in identifying genomic alterations for targeted therapy.
We report a patient presented with severe muscle weakness and exercise intolerance, suggestive of LSM. Diagnostic testing demonstrated lipid accumulation in muscle fibres and elevated plasma acyl carnitine levels. Exome sequencing of the proband and two of his unaffected siblings revealed compound heterozygous mutations, c.250G > A (p.Ala84Thr) and c.770A > G (p.Tyr257Cys) in the ETFDH gene as the probable causative mutations. In addition, a previously unreported variant c.1042C > T (p.Arg348Trp) in ACOT11 gene was found. This missense variant was predicted to be deleterious but its association with lipid storage in muscle is unclear. The diagnosis of MADD was established and the patient was treated with riboflavin which resulted in rapid clinical and biochemical improvement.
Our findings support the role of WES as an effective tool in the diagnosis of highly heterogeneous disease and this has important implications in the therapeutic strategy of LSM treatment.
We report a patient presented with severe muscle weakness and exercise intolerance, suggestive of LSM. Diagnostic testing demonstrated lipid accumulation in muscle fibres and elevated plasma acyl carnitine levels. Exome sequencing of the proband and two of his unaffected siblings revealed compound heterozygous mutations, c.250G > A (p.Ala84Thr) and c.770A > G (p.Tyr257Cys) in the ETFDH gene as the probable causative mutations. In addition, a previously unreported variant c.1042C > T (p.Arg348Trp) in ACOT11 gene was found. This missense variant was predicted to be deleterious but its association with lipid storage in muscle is unclear. The diagnosis of MADD was established and the patient was treated with riboflavin which resulted in rapid clinical and biochemical improvement.
Our findings support the role of WES as an effective tool in the diagnosis of highly heterogeneous disease and this has important implications in the therapeutic strategy of LSM treatment.
摘要：
脂质贮积性肌病（LSM）是一组不同的脂质代谢紊乱，其临床表型和发病年龄差异很大。已知经典的多酰基辅酶A脱氢酶缺乏症（MADD）继发于电子转移黄素蛋白脱氢酶（ETFDH）基因的突变。具有临床相关性的全外显子组测序(WES)可用于鉴定靶向治疗的基因组改变。
我们报告一名患者出现严重的肌肉无力和运动不耐受，暗示LSM。诊断测试表明，肌纤维中脂质积累和血浆酰基肉碱水平升高。先证者和他的两个未受影响的兄弟姐妹的外显子组测序显示出复合杂合突变，c.250G>A（p。Ala84Thr）和c.770A>G（p。Tyr257Cys）在ETFDH基因中作为可能的致病突变。此外,以前未报告的变体c.1042C>T（p。在ACOT11基因中发现Arg348Trp)。预计这种错义变体是有害的，但其与肌肉中脂质储存的关系尚不清楚。确定了MADD的诊断，并对患者进行了核黄素治疗，从而迅速改善了临床和生化指标。
我们的发现支持WES作为诊断高度异质性疾病的有效工具的作用，这在LSM治疗的治疗策略中具有重要意义。
我们报告一名患者出现严重的肌肉无力和运动不耐受，暗示LSM。诊断测试表明，肌纤维中脂质积累和血浆酰基肉碱水平升高。先证者和他的两个未受影响的兄弟姐妹的外显子组测序显示出复合杂合突变，c.250G>A（p。Ala84Thr）和c.770A>G（p。Tyr257Cys）在ETFDH基因中作为可能的致病突变。此外,以前未报告的变体c.1042C>T（p。在ACOT11基因中发现Arg348Trp)。预计这种错义变体是有害的，但其与肌肉中脂质储存的关系尚不清楚。确定了MADD的诊断，并对患者进行了核黄素治疗，从而迅速改善了临床和生化指标。
我们的发现支持WES作为诊断高度异质性疾病的有效工具的作用，这在LSM治疗的治疗策略中具有重要意义。
