發(fā)布時(shí)間：2018-06-05 16:59

  本文選題：家族性皮質(zhì)肌陣攣震顫性癲癇 + 基因　； 參考：《吉林大學(xué)》2016年博士論文

【摘要】：實(shí)驗(yàn)背景家族性皮質(zhì)肌陣攣震顫性癲癇(Familial cortical myoclonic tremor with epilepsy,FCMTE)是一種罕見的神經(jīng)系統(tǒng)常染色體顯性遺傳疾病,又稱良性成人家族性肌陣攣性癲癇(Benigh adult familial myoclonic epilepsy,BAFME),成年期發(fā)病,主要表現(xiàn)為四肢細(xì)微震顫或肌陣攣,以遠(yuǎn)端為著,伴或不伴癲癇發(fā)作,情緒緊張、光刺激或睡眠剝奪時(shí)易被誘發(fā),抗癲癇藥物可有效控制癲癇發(fā)作,而飲酒或使用β受體阻滯劑治療無效,病程為非進(jìn)展性。軀體誘發(fā)電位顯示肌陣攣或震顫來源于大腦皮質(zhì)。迄今,已有一百多個(gè)FCMTE家系被報(bào)道,以日本和意大利兩國居多,我國所做的相關(guān)報(bào)道屈指可數(shù)。其發(fā)病機(jī)制尚不明確,可能與離子通道缺陷有關(guān),也有人認(rèn)為可能與小腦-丘腦-皮質(zhì)投射環(huán)路中GABA受體的缺陷導(dǎo)致皮質(zhì)的興奮性增高有關(guān)。目前,國內(nèi)外遺傳分析已經(jīng)發(fā)現(xiàn)了5p15.31-p15、2p11.1-q12.2、3q26.32-3q28、8q23.3-24.1和10p15等多個(gè)該病致病基因位點(diǎn),并且已經(jīng)對DRPLA基因、CSMD3基因、ACMSD基因等多個(gè)候選基因進(jìn)行研究,但目前仍未發(fā)現(xiàn)該病的致病基因。雖然我國對該病的遺傳學(xué)研究有個(gè)別報(bào)道,卻也只是鳳毛麟角。實(shí)驗(yàn)?zāi)康奈覍?shí)驗(yàn)室對臨床發(fā)現(xiàn)的一個(gè)擬診的家族性皮質(zhì)肌陣攣震顫性癲癇大家系進(jìn)行臨床特點(diǎn)分析和遺傳學(xué)特征研究,嘗試定位或發(fā)現(xiàn)這一家系的致病基因,探討疾病的發(fā)病機(jī)制和識別疾病的易感基因,從而對風(fēng)險(xiǎn)人群生活方式及環(huán)境因子進(jìn)一步調(diào)整和干預(yù),有利于指導(dǎo)該病的臨床治療。實(shí)驗(yàn)方法與家系成員溝通,征得受試者同意(簽訂知情同意書)后,收集相關(guān)臨床信息,主要包括病史采集、體格檢查及相關(guān)輔助檢測,對收集結(jié)果進(jìn)行綜合分析,總結(jié)該家系的臨床特點(diǎn),確定其遺傳方式并繪制受試者的家系圖譜。采FCMTE家系患病成員及健康對照者外周靜脈血,利用血液基因組DNA提取試劑盒提取擬診的FCMTE家系受試者基因組DNA,選擇STR多態(tài)性標(biāo)記物,針對國內(nèi)外已報(bào)道的5個(gè)染色體區(qū)段(2p11.1-q12.2、5p15.31-p15、8q23.3-q24.1、3q26.32-3q28及10p15對應(yīng)短臂2-8M區(qū)段)進(jìn)行連鎖分析,明確上述染色體區(qū)段中是否存在該FCMTE家系的致病基因位點(diǎn)。最后應(yīng)用聚合酶鏈?zhǔn)椒磻?yīng)(PCR)以及PCR產(chǎn)物測序法,對先證者BASP1基因、SEMA5A基因和CTNND2基因進(jìn)行初步篩查,明確上述基因是否存在突變,從而推測其是否可能為該家系的致病基因。實(shí)驗(yàn)結(jié)果根據(jù)詳細(xì)的病史采集、體征及輔助檢查結(jié)果確定我們發(fā)現(xiàn)的家系為家族皮質(zhì)肌陣攣性癲癇家系。該家系4代46人中,8例患病(女6例,男2例),1例(男)可疑,大部分患者伴隨頭痛癥狀。該家系患病成員符合FCMTE的診斷標(biāo)準(zhǔn):呈常染色體顯性遺傳;有成人發(fā)病傾向;呈良性病程;表現(xiàn)為四肢遠(yuǎn)端的震顫或肌陣攣運(yùn)動(dòng),以雙手為著;伴隨癲癇發(fā)作,表現(xiàn)為強(qiáng)直-陣攣發(fā)作;服用β受體阻滯劑或酒精治療無效,應(yīng)用抗癲癇藥物有效;神經(jīng)電生理檢查提示震顫或陣攣來自大腦皮質(zhì)。將家系受試者就國內(nèi)外已報(bào)道的候選染色體片段進(jìn)行STR多態(tài)性標(biāo)記物連鎖分析發(fā)現(xiàn),選擇多個(gè)STR標(biāo)記分別對2p11.1-q12.2、3q26.32-3q28、8q23.3-q24.1、10p15對應(yīng)短臂2-8M區(qū)段進(jìn)行連鎖分析時(shí),當(dāng)θ=0.0時(shí),LOD值均小于-2,從而否定連鎖,說明上述4個(gè)染色體區(qū)段不是我們所研究的FCMTE家系的致病基因位點(diǎn)。選擇12個(gè)STR標(biāo)記針對5p15.31-p15進(jìn)行連鎖分析,結(jié)果顯示其中兩個(gè)STR標(biāo)記即D5S1957和D5S2095在θ=0.0時(shí),LOD值分別為2.16和1.34,支持致病基因位于該區(qū)段。應(yīng)用聚合酶鏈?zhǔn)椒磻?yīng)(PCR)及PCR產(chǎn)物測序法,對先證者BASP1基因、SEMA5A基因和CTNND2基因進(jìn)行初步篩查時(shí),BASP1基因PCR未擴(kuò)增出相應(yīng)產(chǎn)物,故不能對該基因進(jìn)行突變檢測。而對SEMA5A基因和CTNND2基因PCR擴(kuò)增產(chǎn)物測序的結(jié)果均未發(fā)現(xiàn)明確的突變。實(shí)驗(yàn)結(jié)論通過對家系的臨床特點(diǎn)綜合分析明確了此家系為FCMTE家系,利用基因連鎖分析方法,將其致病基因位點(diǎn)初步確定為5p15.31-p15染色體區(qū)段。但目前該家系未發(fā)現(xiàn)位于5號染色體上的SEMA5A基因和CTNND2基因存在突變。因FCMTE具有遺傳異質(zhì)性,是否會(huì)有其他的致病基因位點(diǎn)或致病基因仍是亟待進(jìn)一步解決的難題。但此家系的發(fā)現(xiàn)為探索FCMTE的發(fā)病機(jī)制提供了一份很好的研究資料。
[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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R742.1

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