电子转移黄素蛋白脱氢酶基因突变所致的核黄素反应性脂质沉积性肌病的临床、病理和基因特征分析

目的分析电子转移黄素蛋白脱氢酶(ETFDH)突变所致的核黄素反应性脂质沉积性肌病(RR-MADD)的临床特点、肌肉病理以及血、尿质谱筛查结果和基因突变特点,旨在为早期诊断和治疗提供帮助。方法回顾性分析该院2009年至2019年确诊的15例ETFDH突变所致的脂质沉积性肌病患者的各项资料。结果 15例患者平均发病年龄为(32.1±13.6)岁,均以肢体无力为首发症状,其中四肢起病者占53.3%,双下肢起病者占46.7%。所有患者的肌酶水平均升高;肌电图结果提示80%呈肌源性损害,13.3%为肌源性合并神经源性损害,6.7%结果正常。血、尿质谱的阳性检出率分别为66.7%和22.2%;基因检测提示所有患者存在ETFDH基因不同位点突变,其中单一杂合突变和复合杂合突变各占40%,纯合突变占20%。结论该病以波动性肌无力伴肌酶升高为主要表现,患者应尽快行肌肉病理检查,同时联合血、尿代谢筛查和基因检测有助于RR-MADD患者早期诊断和及时治疗。     

核黄素反应性脂质沉积性肌病20个家系的电子转移黄素蛋白脱氢酶基因存在热点突变

目的 报道20个核黄素反应性脂质沉积性肌病(RR-LSM)患者的电子转移黄素蛋白脱氧酶(ETFDH)基因检查结果.方法 对2003年1月至2010年5月我院神经科收治的24例RRLSM患者(来自20个我国大陆北方地区RR-LSM家系,其中16个家系各有1例患者,其余4个家系各有2例发病者)的临床特点进行分析.对24例患者、11名无症状家系成员以及100名健康人行ETFDH基因检查.结果 24例患者发病年龄为(27.9±9.9)岁,主要症状为四肢无力(21例,87.5%)、咀嚼困难(15例,62.5%)、颈肌无力(14例,58.3%)和肌痛(14例,58.3%)等.18例患者的血代谢筛查均提示脂酰肉碱升高,17例患者中有15例存在戊二酸尿症.我们发现19个家系存在17种ETFDH基因点突变,包括13种错义突变、2种剪切突变和2种无义突变.其中患者的c.998A>G、c.1450T>C、c.1703T>C、c.11717C>T、c.821G>A、c.643G>A、c.25IC>T、c.1763A>T、c.IVS7+2T>C、c.IVS6+1G>A没有出现在100名健康人中.有9个家系存在c.770A>G(P.Y257C)突变;5个家系存在c.1227A>C(P.L409F)突变.结论 诸多ETFDH基因新突变提示国人RR-LSM可能存在特殊的基因突变谱,其中P.Y257C与P.L409F突变可能为我国大陆北方地区的热点突变.

Abstract：

Objective To report the spectrum of electron transfer flavoprotein dehydrogenase (ETFDH)gene mutations in 20 Chinese RR-LsM families.Methods Twenty-four RR-LSM patients in the First Hospital of Peking University from January 2003 to May 2010 were collected and the clinical characteristics were analyzed.These patients came from 20 families in North Mainland China.Sixteen families had 1 patient each.and the other 4 families had 2 patients.ETFDH gene analysis was performed in all patients,11 family members and 100 healthy controls.Results The mean onset age was(27.9±9.9)years.The main symptoms were limb weakness(21,87.5%),dysmasesia(15,62.5%),neck weakness (14,58.3%)and myalgia(14,58.3%).Eighteen patients had high level of acyleamitine.Fifteen of 17patients had glutaric aciduria.Seventeen ETFDH mutations,including 13 missense mutations,2 splice mutations,and 2 nonsense mutations,were identified in 19 families:c.998A>G,c.1450T>C,c.1703T>C,c.1717C>T,c.821G>A,c.643G>A,c.251C>T,c.1763A>T,c.IVS7+2T>C and c.IVS6+1G>A were Hovel mutations which were not found in 100 healthy controls.Nine families had the mutation of c.770A>G(P.Y257C)and 5 families had the mutation of c.1227A>C(P.L409F).Conclusions The numerous novel mutations in ETFDH gene indicate that Chinese RR-LSM might have special mutation pattern.c.770A>G(P.Y257C)and c.1227A>C(p.L409F)may be hot spot mutations in North Mainland China.     

核黄素反应性脂质沉积性肌病二例

目的探讨核黄素反应性脂质沉积性肌病(LSM)的临床、病理及基因突变特征。方法分析两例核黄素反应性LSM患者的临床资料。结果本组两例患者表现为慢性起病的四肢和躯干肌无力,不能耐受疲劳,例2累及吞咽功能,例1累及咀嚼功能。两例肌肉活检发现肌纤维内大量脂肪沉积,未见肌纤维坏死和再生,改良Gomori三色染色、琥珀酸脱氢酶染色未发现线粒体酶活性缺失。两例患者均有2个以上位点突变,有明确临床意义的突变均为ETFDH外显子改变,应用核黄素治疗后两例明显好转。结论本病多累及躯干和四肢肌,表现为肌无力和疲劳不耐受;病理特征为肌肉脂肪沉积,基因突变多为ETFDH改变。核黄素单一治疗对本病有显著疗效。     

脂质沉积性肌病合并腕管综合征1例报告

脂质沉积性肌病(Lipid storage myopathy,LSM)是一组因脂肪代谢障碍导致的肌纤维内脂肪沉积为病理特征的肌病,临床表现为进行性肌无力和运动不耐受,病程可有波动性[1]. 该病也可以同时累及其他部位,如周围神经、心脏、骨骼系统、消化系统、眼睛等[2,3],但合并周围神经损害的未见报道.现报道1例脂质沉...     

核黄素反应性脂质沉积性肌病的临床和病理特征

目的 探讨核黄素反心性脂质沉积性肌病的临床和病理特征。方法 回顾性分析4例核黄素反应性脂质沉积性肌病患者的临床资料结果本组4例患者表现为亚急性起病的四肢近端和躯干肌无力,不能耐受疲劳,3例患者有颈肌和脊旁肌萎缩、无力,2例有明显的咀嚼肌无力。2例肌电图示肌源性损害,1例示双侧胫神经传导速度轻度减慢。肌肉活检发现肌纤维内大量脂肪沉积,未见肌纤维坏死和再生,改良Gomorii色染色、琥珀酸脱氢酶和细胞色素C氧化酶染色以及电镜观察未发现有线粒体酶活性缺失,以及线粒体结构和数量的异常改变。应用维小素B2单药治疗后2例明显好转,2例痊愈。2例患者分别在治愈后1年、5年复发,重新给予维生素B2治疗仍然有效。结论 本病多以颈肌、脊旁肌和咀嚼肌受累,病理特征为肌肉脂肪沉积,无线粒体异常改变。维生素B2单一治疗对本病有显著疗效,此亦可与其他肌病鉴别。     

以感觉障碍为首发症状的脂质沉积性肌病1例报告

脂质沉积性肌病 (lipidstoragemyopathy ,LSM)是指由于肌纤维内脂肪代谢障碍 ,致使肌细胞内脂肪堆积而引起的肌病。自 70年代起 ,文献中陆续报道该病的临床病理表现 ,但以感觉障碍为首发症状的LSM现未见报道 ,现报道 1例如下。1　病例介绍患者 ,女 ,2 1岁 ,农民。 2 0 0 1年 11月 2 3日入院。 3年前无明显诱因出现双脚的麻木 ,逐渐向上发展至大腿手指麻木 ,走路似踩棉花感 ,3天后出现四肢无力走路不稳 ,逐渐加重 ,发病至 2个月时不能下床。近 6个月症状加重 ,下蹲不能站起 ,不能远距离行走 ,咀嚼无力 ,抬头困难而入院。且于劳累、生气、…     

多发性肌炎伴脂质沉积性肌病2例报告

多发性肌炎 (polymyositis)为横纹肌弥漫性炎性疾病 ,常常引起进行性、对称性的肢带肌、颈肌和咽部肌肉的无力及萎缩 ,它可以作为一种独立的疾病而就诊于神经内科 ,也可以与许多结缔组织疾病并存 ,但与脂质沉积性肌病 (LSM )合并存在的情况国内未见报道。我们在诊治多发性肌炎患者中发现 2例合并脂质沉积性肌病。肌活检提示 :肌炎伴脂质代谢异常。现就 2例病例的临床病理报告如下。1　病例资料2例患者均为男性 ,年龄为 3 4岁及 65岁 ,双下肢无力伴吞咽及行走异常 2例 ,吞咽困难及构音障碍 2例 ,颈肌无力 1例 ,2者均伴有肌肉及关节部的疼痛…     

脂质沉积性肌病35例的临床特点及电子转移黄素蛋白脱氢酶基因突变分析

目的 探讨脂质沉积性肌病(LSM)的临床特点及电子传递黄素蛋白脱氢酶(ETFDH)基因突变所致的多种脂酰辅酶A脱氢酶缺乏症在该病中所占比例.方法 收集35例经病理明确诊断的LSM患者的临床资料,并对所有患者的ETFDH基因的全部13个外显子进行PCR扩增,产物纯化后直接测序.同时对来自50名健康对照的100条染色体进行检测,以验证发现的ETFDH新突变.结果 35例患者均存在不同程度的肌肉无力,包括10例存在咀嚼吞咽无力,28例存在抬头无力.在随访的32例患者中,29例患者经维生素B2及辅酶Q10治疗后症状明显改善.30例(86%)存在不同形式的ETFDH基因突变:8例为纯合突变,20例为复合杂合突变,2例患者仅存在1个杂合突变.本组患者共发现14个新突变:9个错义突变(c.3G>C、c.152G>A、c.191G>A、c.349G>C、c.433G>C、c.949C>A、c.1454C>G、c.1744A>T和c.1763A>G),1个无义突变(c.172G>T),2个缺失突变(c.1282_1283del和c.1773_1774del)和2个剪切位点突变(c.405+1G>T和c.1691-3C>G).所有患者中,9例存在c.250G>A突变,6例存在c.770A>G突变.结论 LSM可表现近端肌受累为主的肢体无力.基因分析发现本组KSM患者以ETFDH突变引起的多种酰基辅酶A脱氢酶缺乏为主.c.250G>A和c.770A>G是其最常见的突变位点.

Abstract：

Objective To investigate the clinical features and electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations in 35 Chinese patients with lipid storage myopathy. Methods The clinical data of 35 cases with lipid storage myopathy confirmed by muscle biopsy were collected. The sequences of all 13 exons of ETFDH were analyzed. Results All 35 patients showed proximal weakness. Ten of them demonstrated masseter weakness and 28 of them showed weakness in neck flexion. Twenty-nine of 32 patients who were followed up showed improvement after treatment with VitB2 and CoQ10. Mutations of ETFDH were found in 30 of 35 patients,which included 8 homozygosises,20 compound heterozygosises and 2 single heterozygosises. Fourteen novel mutations were found, including 9 missense mutations ( c. 3G > C, c. 152G>A, c. 191G > A, c.349G>C, c.433G>C, c. 949C > A, c. 1454C > G, c. 1744A >T and c. 1763A>G), 1 nonsense mutation(c. 172G>T), 2 deletions(c. 1282_1283del and 1773_1774del) and 2 splice mutations (c. 405 + 1G > T and c. 1691 -3C > G). Nine of them showed c. 250G > A mutation and 6 of them showed c. 770A > G mutation. Conclusions Lipid storage myopathy is presented as proximal weakness. Multiple acyl-CoA dehydrogenase deficiency caused by mutations of ETFDH is the major cause of lipid storage disease in this group. ETFDH c. 250G > A and c. 770A > G mutations show a high frequency.     

核黄素反应性脂质沉积性肌病临床特征与基因突变分析:两家系三例报告并文献复习

目的分析核黄素反应性脂质沉积性肌病临床特征和基因型,以实现早期诊断与治疗。方法与结果两家系3例核黄素反应性脂质沉积性肌病患者主要表现为进行性呼吸肌、四肢近端肌无力,肌电图呈肌源性损害,油红O染色肌纤维内可见脂肪滴沉积。3例患者均存在电子转移黄素蛋白脱氢酶(ETFDH)基因突变,分别为c.250GA(Ala84Thr)纯合突变和c.250GA(Ala84Thr)、c.524GA(Arg175His)复合杂合突变。维生素B2治疗后症状明显改善,1例治疗10个月后呼吸肌和四肢近端肌无力症状完全消失,恢复正常运动功能;1例治疗2个月后行走、跑步如常,颈部肌肉恢复至正常状态;1例治疗2个月后可参加剧烈运动且无疲劳感。结论核黄素反应性脂质沉积性肌病虽然以四肢近端和躯干肌无力,以及运动不耐受为主要表现,但也需注意少数以呼吸肌无力为首发症状的病例,避免漏诊和误诊。维生素B2单药治疗效果极佳,症状可明显好转或痊愈。因此,临床疑似核黄素反应性脂质沉积性肌病患者可尝试维生素B2诊断性治疗。     

脂质沉积性肌病

脂质沉积性肌病是先天性脂质代谢障碍,致脂质沉积在肌纤维中而引起的一组肌病。肌活检示肌纤维中有大量脂肪颗粒沉积,以Ⅰ型肌纤维受累为重。经低脂饮食及药物治疗,病情可控制。本文对该病的发病机制,临床表现,肌电图,肌肉病理特点,诊断,鉴别诊断及治疗等作一综述。     

Investigation of adult-onset multiple acyl-CoA dehydrogenase deficiency associated with peripheral neuropathy

Multiple Acyl-CoA dehydrogenase deficiency (MADD), one of the most common lipid storage myopathies (LSMs), is a heterogeneous inherited muscular disorder that is pathologically characterized by numerous lipid droplets in muscle fibers due to lipid metabolism disturbance. MADD exhibits a wide range of clinical features, including skeletal muscle weakness and multisystem dysfunctions. However, MADD, as well as other types of LSM, associated with peripheral neuropathy has rarely been reported during the past four decades. Here, we present four Chinese patients affected by MADD with peripheral neuropathy in our neuromuscular center. Clinically, these four patients showed skeletal muscle weakness and prominent paresthesia. Muscle biopsy detected characteristic myopathological patterns of LSM, such as obvious lipid droplets in muscle fibers. Sural nerve biopsy revealed a severe reduction in number of myelinated nerve fibers, which is a typical neuropathological pattern of peripheral neuropathy. Causative ETFDH mutations were found in all four cases. The skeletal muscle weakness was rapidly improved after some treatments while paresthesia showed unsatisfactory improvement. The features of previously reported patients of this specific type are also summarized in this paper. We propose that MADD with peripheral neuropathy may be a new phenotypic subtype because the pathology and reaction to riboflavin treatment are different from those of traditional MADD, although further research on the precise pathogenesis and mechanisms is needed.     

Fulminant lipid storage myopathy due to multiple acyl‐coenzyme a dehydrogenase deficiency

Introduction: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. Methods: We describe a rapidly progressive myopathy in a previously healthy 33‐year‐old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. Results: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. Conclusions: This report illustrates a late‐onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy. Muscle Nerve 52 : 289–293, 2015