Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency
Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency
复制标题
三名晚发性多酰基辅酶A脱氢酶缺乏症中国患者具有相似ETFDH基因型的显着临床异质性
DOI：
10.1007/s10072-016-2549-2
复制
发表时间：
2016-07-01
影响因子：
3.3
通讯作者：
Wang, Ning
中科院分区：
文献类型：
--
作者：
Fu, Hong-xia;Liu, Xin-yi;Wang, Ning
伴有电子传递黄素蛋白脱氢酶（ETFDH）基因突变的迟发性多酰基辅酶A脱氢酶缺乏症（MADD）是中国最常见的脂质沉积性肌病（LSM）。其临床特征差异很大，对诊断构成挑战。我们通过收集临床信息、肌肉组织学和基因分析，展示了3例具有相似ETFDH基因型的中国迟发性MADD患者之间显著的临床异质性。鉴定出ETFDH基因的3种新的复合杂合变异：c.892C>T（p.Pro298Ser）、c.453delA（p.Glu152ArgfsTer15）和c.449_453delTAACA（p.Leu150Ter）。此外，所有患者都携带热点突变c.250G>A（p.Ala84Thr）。对患者肌肉组织的蛋白质印迹分析显示ETFDH表达显著降低，而电子传递黄素蛋白A（ETFA）和电子传递黄素蛋白B（ETFB）表达正常。2例具有相似基因型（c.453delA和c.449_453delTAACA）的患者表现出显著的临床异质性。其中，1例以肌无力和运动不耐受为首发和主要症状，另1例在晚年出现严重肌无力之前表现为发作性反复胃肠道症状。ETFDH中的新变异及相应的临床特征丰富了迟发性MADD的变异谱，并为基因型 - 表型关系提供了新的见解。迟发性MADD应与慢性消化系统疾病一起纳入成人肌病的鉴别诊断中。
Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) with electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations is the most common lipid storage myopathy (LSM) in China. Its clinical features vary widely and pose a challenge for diagnosis. We presented the significant clinical heterogeneity among three Chinese late-onset MADD patients with similar ETFDH genotype by collecting clinical information, muscle histology, and genetic analysis. Three novel compound heterozygous variants of ETFDH gene were identified: c.892C > T (p.Pro298Ser), c.453delA (p.Glu152ArgfsTer15), and c.449_453delTAACA (p.Leu150Ter). Moreover, all patients carried a hotspot mutation c.250G > A (p.Ala84Thr). Western blot analysis of the patients’ muscular tissue showed a significantly reduced ETFDH expression, and normal electron transfer flavoprotein A (ETFA) and electron transfer flavoprotein B (ETFB) expression. Two patients with similar genotypes (c.453delA and c.449_453delTAACA) presented a significant clinical heterogeneity. Among them, one exhibited muscle weakness and exercise intolerance as initial and major symptoms, and the other showed episodic recurrent gastrointestinal symptoms before a serious muscle weakness appeared in later life. Late-onset MADD should be included in differential diagnosis for adult myopathy along with chronic digestive disease.