26例核黄素反应性脂质沉积性肌病患者的临床及ETFDH基因突变特点分析

Clinical characteristics and electron transfer flavoprotein dehydrogenase genetic mutations in 26 patients with riboflavin reactive lipid deposition myopathy

目的探讨核黄素反应性脂质沉积性肌病(RR-LSM)的临床及电子转移黄素蛋白脱氧酶(ETFDH)基因突变特点。方法回顾性分析自2009年1月至2021年6月于焦作市人民医院及河南省人民医院神经肌肉病中心确诊的26例核黄素治疗有效的脂质沉积性肌病患者的临床及肌肉病理资料。所有患者均提取外周静脉血DNA,采用全外显子组测序技术检测并分析ETFDH基因突变情况。结果26例患者均以肢体近端无力起病,17例有抬头费力,12例伴咀嚼无力,6例有吞咽困难,5例伴恶心呕吐,合并横纹肌溶解和可逆性胼胝体压部病变综合征各一例。肌肉病理表现为以Ⅰ型肌纤维受累为主的肌纤维内脂滴异常沉积,少数可见变性坏死肌纤维。26例患者均检测到ETFDH基因突变,其中23例为复合杂合突变,2例为单一杂合突变,1例为纯合突变;共发现25个不同的突变位点,以错义突变为主,其中c.770A>G出现频率最高,占等位基因的20%(10/50),c.1115A>G和c.1781T>C为新发现的致病突变。结论RR-LSM主要表现为四肢近端肌无力和疲劳不耐受,常伴有颈伸肌和咀嚼肌受累;c.770A>G是患者ETFDH基因突变的主要位点。

Objective To investigate the clinical characteristics and electron transfer flavoprotein dehydrogenase(ETFDH)genetic mutations in patients with riboflavin responsive lipid storage myopathy(RR-LSM).Methods A retrospective analysis was performed.The clinical data and muscular pathology of 26 patients with RR-LSM,admitted to our hospital from January 2009 to June 2021,were collected.Peripheral venous blood DNA was extracted,and the mutations of ETFDH gene were detected and analyzed by whole exome sequencing.Results These 26 patients had onset of proximal limb myasthenia,17 patients had difficulty in raising their head,12 patients had mastication weakness,6 had dysphagia,5 had nausea and vomiting,and one was complicated with rhabdomyolysis and one was with reversible splenic lesion syndrome.Muscle biopsy indicated pathological deposition of lipid droplet,which type I fibers were involved mainly;degenerative necrotic muscle fibers were seen in a few cases.ETFDH gene mutations were detected in 26 patients;23 patients had compound heterozygous mutation,two had single heterozygous mutation and one had homozygous mutation;25 different mutation sites were found,mainly missense mutations;the C.770A>G frequency was the highest,accounting for 20%alleles(10/50);two novel mutation sites were found:c.1115A>G and c.1781T>C.Conclusion RR-LSM is mainly characterized by proximal limb muscle weakness and fatigue intolerance,often accompanied by neck extensor and masticatory weakness;c.770A>G is the hot site of ETFDH genetic mutations in RR-LSM patients.