家族性皮质肌阵挛震颤性癫痫一家系的临床特点分析和遗传学研究

发布时间：2018-06-05 16:59

本文选题：家族性皮质肌阵挛震颤性癫痫 + 基因　；参考：《吉林大学》2016年博士论文

【摘要】：实验背景家族性皮质肌阵挛震颤性癫痫(Familial cortical myoclonic tremor with epilepsy,FCMTE)是一种罕见的神经系统常染色体显性遗传疾病,又称良性成人家族性肌阵挛性癫痫(Benigh adult familial myoclonic epilepsy,BAFME),成年期发病,主要表现为四肢细微震颤或肌阵挛,以远端为著,伴或不伴癫痫发作,情绪紧张、光刺激或睡眠剥夺时易被诱发,抗癫痫药物可有效控制癫痫发作,而饮酒或使用β受体阻滞剂治疗无效,病程为非进展性。躯体诱发电位显示肌阵挛或震颤来源于大脑皮质。迄今,已有一百多个FCMTE家系被报道,以日本和意大利两国居多,我国所做的相关报道屈指可数。其发病机制尚不明确,可能与离子通道缺陷有关,也有人认为可能与小脑-丘脑-皮质投射环路中GABA受体的缺陷导致皮质的兴奋性增高有关。目前,国内外遗传分析已经发现了5p15.31-p15、2p11.1-q12.2、3q26.32-3q28、8q23.3-24.1和10p15等多个该病致病基因位点,并且已经对DRPLA基因、CSMD3基因、ACMSD基因等多个候选基因进行研究,但目前仍未发现该病的致病基因。虽然我国对该病的遗传学研究有个别报道,却也只是凤毛麟角。实验目的我实验室对临床发现的一个拟诊的家族性皮质肌阵挛震颤性癫痫大家系进行临床特点分析和遗传学特征研究,尝试定位或发现这一家系的致病基因,探讨疾病的发病机制和识别疾病的易感基因,从而对风险人群生活方式及环境因子进一步调整和干预,有利于指导该病的临床治疗。实验方法与家系成员沟通,征得受试者同意(签订知情同意书)后,收集相关临床信息,主要包括病史采集、体格检查及相关辅助检测,对收集结果进行综合分析,总结该家系的临床特点,确定其遗传方式并绘制受试者的家系图谱。采FCMTE家系患病成员及健康对照者外周静脉血,利用血液基因组DNA提取试剂盒提取拟诊的FCMTE家系受试者基因组DNA,选择STR多态性标记物,针对国内外已报道的5个染色体区段(2p11.1-q12.2、5p15.31-p15、8q23.3-q24.1、3q26.32-3q28及10p15对应短臂2-8M区段)进行连锁分析,明确上述染色体区段中是否存在该FCMTE家系的致病基因位点。最后应用聚合酶链式反应(PCR)以及PCR产物测序法,对先证者BASP1基因、SEMA5A基因和CTNND2基因进行初步筛查,明确上述基因是否存在突变,从而推测其是否可能为该家系的致病基因。实验结果根据详细的病史采集、体征及辅助检查结果确定我们发现的家系为家族皮质肌阵挛性癫痫家系。该家系4代46人中,8例患病(女6例,男2例),1例(男)可疑,大部分患者伴随头痛症状。该家系患病成员符合FCMTE的诊断标准:呈常染色体显性遗传;有成人发病倾向;呈良性病程;表现为四肢远端的震颤或肌阵挛运动,以双手为著;伴随癫痫发作,表现为强直-阵挛发作;服用β受体阻滞剂或酒精治疗无效,应用抗癫痫药物有效;神经电生理检查提示震颤或阵挛来自大脑皮质。将家系受试者就国内外已报道的候选染色体片段进行STR多态性标记物连锁分析发现,选择多个STR标记分别对2p11.1-q12.2、3q26.32-3q28、8q23.3-q24.1、10p15对应短臂2-8M区段进行连锁分析时,当θ=0.0时,LOD值均小于-2,从而否定连锁,说明上述4个染色体区段不是我们所研究的FCMTE家系的致病基因位点。选择12个STR标记针对5p15.31-p15进行连锁分析,结果显示其中两个STR标记即D5S1957和D5S2095在θ=0.0时,LOD值分别为2.16和1.34,支持致病基因位于该区段。应用聚合酶链式反应(PCR)及PCR产物测序法,对先证者BASP1基因、SEMA5A基因和CTNND2基因进行初步筛查时,BASP1基因PCR未扩增出相应产物,故不能对该基因进行突变检测。而对SEMA5A基因和CTNND2基因PCR扩增产物测序的结果均未发现明确的突变。实验结论通过对家系的临床特点综合分析明确了此家系为FCMTE家系,利用基因连锁分析方法,将其致病基因位点初步确定为5p15.31-p15染色体区段。但目前该家系未发现位于5号染色体上的SEMA5A基因和CTNND2基因存在突变。因FCMTE具有遗传异质性,是否会有其他的致病基因位点或致病基因仍是亟待进一步解决的难题。但此家系的发现为探索FCMTE的发病机制提供了一份很好的研究资料。
[Abstract]:Experimental background familial myoclonus tremor epilepsy (Familial cortical myoclonic tremor with epilepsy, FCMTE) is a rare autosomal dominant genetic disorder of the nervous system, also known as the benign adult familial myoclonic epilepsy (Benigh adult familial myoclonic epilepsy,), adult onset, mainly manifested in the extremities. Slight tremor or myoclonus, with far end, is easily induced with or without seizures, emotional stress, light stimulation or sleep deprivation. Antiepileptic drugs can effectively control epileptic seizures, while alcohol or beta blockers are not effective and the course of the disease is non progressing. The somatic induced potential shows myoclonus or tremor from the cerebral cortex. Now, more than 100 FCMTE families have been reported in Japan and Italy, and there are few related reports in our country. Its pathogenesis is not clear, it may be related to ion channel defects, and some people think it may be related to the deficiency of the GABA body in the cerebellum thalamocortical projection loop, which is related to the increase of the excitability of the cortex. Before, genetic analysis of 5p15.31-p15,2p11.1-q12.2,3q26.32-3q28,8q23.3-24.1 and 10p15 has been found at home and abroad, and many gene loci of the disease have been found, and many candidate genes, such as DRPLA gene, CSMD3 gene and ACMSD gene, have been studied, but the pathogenic gene of the disease has not been found. There are some reports, but it is only rare. Our laboratory studies the clinical characteristics and genetic characteristics of a clinically diagnosed familial myoclonus tremor, trying to locate or discover the pathogenic genes of the family, to explore the pathogenesis of the disease and to identify the susceptible basis of the disease. Therefore, further adjustment and intervention to the lifestyle and environmental factors of the risk population is conducive to the guidance of the clinical treatment of the disease. The experimental method is communicated with the family members, and after the consent of the subjects is obtained, the relevant clinical information is collected, including the collection of medical history, the physical examination and the related auxiliary tests, and the results of the collection are entered. A comprehensive analysis was made to summarize the clinical characteristics of the family, determine its genetic pattern and draw the family map of the subjects. The peripheral venous blood of the FCMTE family members and healthy controls was collected, and the genomic DNA extraction kit of the blood genome was used to extract the genomic DNA of the subjects of the FCMTE family, and the STR polymorphic markers were selected, which were reported at home and abroad. 5 chromosomal segments (2p11.1-q12.2,5p15.31-p15,8q23.3-q24.1,3q26.32-3q28 and 10p15 corresponding to the 2-8M section of the short arm) were used for linkage analysis to determine whether there was a genetic locus in the FCMTE family. Finally, the polymerase chain reaction (PCR) and the sequencing of PCR products were used for the BASP1 gene, SEMA5A, SEMA5A, SEMA5A, SEMA5A, SEMA5A, and SEMA5A. The gene and the CTNND2 gene were screened to determine whether there was a mutation to determine whether it might be a pathogenic gene in the family. 6 cases, male 2 cases, 1 cases (male) suspicious, most of the patients accompanied with headache symptoms. The family members conformed to the FCMTE diagnostic criteria: autosomal dominant inheritance; adult onset tendency; a benign course of disease; showing the tremor or myoclonus movement of the extremities, with both hands; accompanied by seizures, manifested by tonic clonic seizures; Anti epileptic drugs were effective with beta blockers or alcohol treatment, and electrophysiological tests suggested that tremor or clonus were from the cerebral cortex. The family subjects were linked to the STR polymorphic markers of the reported candidate chromosomes at home and abroad, and multiple STR markers were selected for 2p11.1-q12.2,3q26.32-3q28,8q2 When 3.3-q24.1,10p15 corresponds to the linkage analysis of the short arm 2-8M section, when theta =0.0 is less than -2, the LOD value is less than -2, indicating that the 4 chromosomal segments are not the pathogenetic loci of the FCMTE family we studied. 12 STR markers are selected for the linkage analysis of 5p15.31-p15, and the results show that two STR markers are D5S1957 and D5S1957. When D5S2095 was at theta =0.0, the LOD values were 2.16 and 1.34, respectively, which support the pathogenic genes in the section. By using the polymerase chain reaction (PCR) and the sequencing of PCR products, the BASP1 gene PCR did not amplify the corresponding products when the BASP1 gene, SEMA5A gene and CTNND2 gene were screened for the precursor, so the gene could not be detected by mutation. No clear mutation was found in the sequencing of the PCR amplification products of the gene and the CTNND2 gene. The conclusion was made that the family was a FCMTE family by a comprehensive analysis of the clinical characteristics of the family, and the genetic linkage analysis method was used to determine the pathogenicity site of the family as a 5p15.31-p15 chromophore area. However, the family was not found to be located at 5. There is a mutation in the SEMA5A and CTNND2 genes on the chromosome. Because FCMTE has genetic heterogeneity, whether there will be other pathogenic gene loci or pathogenic genes is still a difficult problem to be solved. However, the discovery of this family provides a good research data for exploring the pathogenesis of FCMTE.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R742.1

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