中国华东地区腓骨肌萎缩症患者临床、电生理及致病基因突变特点的研究

发布时间：2018-02-11 00:08

本文关键词： 腓骨肌萎缩症临床特点电生理致病基因基因型表型　出处：《复旦大学》2014年博士论文　论文类型：学位论文

【摘要】：目的：描述中国华东地区腓骨肌萎缩症(Charcot-Marie-Tooth disease, CMT)患者的临床、电生理及致病基因突变特点。探讨临床指标间的关系和基因型表型关联,并与国内外相似研究比较,总结异同。方法：纳入2007-2013年间上海华山医院及福建医科大学附属第一医院就诊并接受基因诊断的CMT患者,共计148个家系,入组家系的先证者由神经内科专病医生进行临床及电生理评估。采用FDS评分及CMTNS评分评价患者疾病相关功能障碍。SPSS18.0软件用于统计分析。抽取枸橼酸钠抗凝外周静脉血各3 mL,标准法提取基因组DNA。 MLPA方法检测PMP22基因扩增与缺失突变,Sanger测序法检测GJB1, MPZ, MFN2, GDAP-1基因编码区及其侧翼部位的突变。分析基因型与临床表型的关系。结果：1 临床特点。入组病例中,男女比例1.4：1,平均就诊年龄24岁。其中CMTl型患者比例最高,其次是CMT2型及HNPP,各型比例依次为54.1%,28.8%,17.1%。入组病例中,有阳性家族史占45.0%,主要是常染色体显性遗传。58.5%患者20岁以前起病,病情缓慢进展,致残率低。CMT常见的临床表现包括四肢远端肌无力及萎缩,腱反射减退或消失,足部畸形,麻木或感觉减退。不常见的临床表现有：近端严重受累,上肢先起病,颅神经受累,病理征,腱反射亢进等。CMTl型患者中,CMTNS评分与病程呈正相关,与CMAP呈负相关。与发病年龄及MNCV无显著相关性。CMT2型患者中未见上述指标间的显著相关性。67%的CMT患者肌酶轻度升高,符合神经源性损害特点。2 致病基因突变特点。PMP22基因扩增突变是最常见的突变类型(13.5%),其次是PMP22基因缺失(11.5%). GJB1基因突变、MPZ基因突变和MFN2基因突变各占8.8%、2.0%和0.7%,且MPZ基因突变多发生在3号外显子。相关基因测序中共发现了4种新突变类型,均为GJB1基因突变。在GDAP-1基因未找到突变。3 基因型表型关系。CMT1A型患者阳性家族史比例高(70%),常表现为经典的CMT症状。正中神经MNCV普遍低于30m/s,一半以上低于20m/s。HNPP患者症状常反复发作,亦有既往正常者,受压后肢体麻木是最常见的主诉,肌电图诊断与基因诊断吻合度高。CMTIX型患者症状男性较女性严重,正中神经MCV轻度下降甚至正常,多在25-45m/s。 CMT1B,分为早发-重症和晚发-轻症两种表型。即使在同一位点突变,不同家系成员间的临床表现可以有很大差异。讨论：本研究患者队列为国内目前最大的CMT患者队列之一。入组患者中各临床亚型的分布与国外研究相似。患者的疾病相关功能障碍中国及其他亚洲人群的PMP22基因扩增突变频率比欧美人群偏低。在对CMT患者行基因筛查前应先行肌电图检查。
[Abstract]:Objective: to describe the clinical, electrophysiological and pathogenetic gene mutations of Charcot-Marie-Tooth disease (CMT) patients in eastern China. Methods: a total of 148 families of CMT patients who received genetic diagnosis in Shanghai Huashan Hospital and the first affiliated Hospital of Fujian Medical University from 2007 to 2013 were included in this study. The proband was evaluated clinically and electrophysiologically by the neurologist. The FDS score and CMTNS score were used to evaluate the disease related dysfunction. SPSS 18.0 software was used for statistical analysis. Sodium citrate anticoagulant peripheral static was extracted. The genomic DNA was extracted by standard method. MLPA was used to detect PMP22 gene amplification and deletion mutation. Sanger sequencing was used to detect mutations in the coding region and flanking region of GJB1, MPZ, MFN2, GDAP-1 gene. The relationship between genotype and clinical phenotype was analyzed. Clinical features. The ratio of male to female was 1.4: 1, and the average age was 24 years old. The proportion of CMTl type was the highest, followed by CMT2 type and HNPP type. The proportion of each type was 54.1% and 28.8% (17.1%). Among the cases, the positive family history was 45.0%, which was mainly autosomal dominant heredity .58.5% of the patients had been ill before 20 years old. The common clinical manifestations of CMT include weakness and atrophy of the distal muscles of the extremities, loss or disappearance of tendon reflex, deformity of the foot, numbness or hypothermia. The score of CMTNS was positively correlated with the course of disease in patients with cranial nerve involvement, pathological sign and tendon hyperreflexia. There was no significant correlation with the age of onset and MNCV. There was no significant correlation between the above indexes. 67% of the patients with CMT had a slight increase in muscle enzyme. PMP22 gene amplification mutation is the most common mutation type, followed by PMP22 gene deletion 11.5T. GJB1 gene mutation MPZ gene mutation and MFN2 gene mutation accounted for 8. 8% and 0. 7% respectively, and MPZ gene mutation accounted for 8. 8% and 0. 7% respectively. Most of the mutations occurred in exon 3. Four new mutation types were found by gene sequencing. All of them were mutations of GJB1 gene. There was no phenotypic relationship between GDAP-1 gene and genotype 3.The proportion of positive family history of GDAP-1 gene was 70%, which often showed classic CMT symptoms. The median nerve MNCV was generally lower than 30 m / s, and more than half of the patients under 20 m / s 路HNPP had recurrent symptoms. There were also normal people. Limb numbness after compression was the most common complaint. Electromyography (EMG) diagnosis and gene diagnosis were highly consistent. The symptoms of CMTIX type were more serious in males than in females, and MCV of median nerve decreased slightly or even normally. Most of them are 25-45m / s 路CMT1B, which are divided into two phenotypes: early onset severe disease and late onset mild disease. Even at the same locus mutation, The clinical manifestations of different family members may vary greatly. Discussion: the cohort of patients in this study is one of the largest cohorts of CMT patients in China. The frequency of PMP22 gene mutation in Chinese and other Asian populations with disease related dysfunction was lower than that in Europe and America. Electromyography should be performed before gene screening in patients with CMT.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R746

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