良性成人家族性肌阵挛性癫痫的遗传学特征及致病基因的定位
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摘要
良性成人家族性肌阵挛癫痫(benign adult familial myoclonic epilepsy, BAFME)是一种常染色体显性遗传的，主要以四肢远端震颤、肌阵挛伴或不伴全面强直-阵挛发作的癫痫综合征。至今，全世界约有100个家系在日本、意大利、荷兰、法国、土耳其及中国等地被相继发现并报道。但本病尚未被纳入到2001年国际抗癫痫联盟的癫痫综合征的分类当中。
本病早期报道源于日本，日本学者Wakeno在1975年报道了一个以家族性震颤和癫痫发作为表现的家系，而后陆续报道了多个类似家系，并经电生理研究确定其震颤均来源于大脑皮质，且均为常染色体显性遗传。1991年Yasuda在报道两个家系的基础上，总结了本病具有良性病程和常染色体显性遗传的特点，首次提出了“良性成人家族性肌阵挛癫痫”的概念。在1999年，Mikami使用连锁分析的方法将患有该病的一个3代27人的家系致病基因定位于8q23.3-24.1，从而发现了本病的第一个致病基因位点。2003年，Strianon对一个意大利的BAFME家系进行基因连锁分析后发现，其致病基因与2p11-q12.2具有连锁关系，又发现了一个新的致病基因位点，从而说明了该病的遗传异质性。2006年，我国邓飞燕等人通过对一BAFME大家系的遗传学分析，将致病基因定位于10p15；2010年Depienne等人将一法国FCMTE家系致病基因定位于5p15.31-p15；2012年Yeetong将一泰国BAFME家系致病基因定位在3q26.32-3q28。然而，目前为止尚未克隆出该病的致病基因。仅有日本学者Atsushi等人在2003年提出了CSMD3可能为BFAME的致病候选基因。CSMD3是一种编码跨膜蛋白的较大的基因，位于人类染色体8q23.3-q24.1区段，即BAFME被定位的区段。该基因包含73个外显子，长度跨越1.2Mb。主要在成人及胎儿的脑组织中表达。
自1991年Yasuda首次提出了BAFME的概念以来，BAFME综合征的研究不超过20余年历史，其中大多为病例报道，仅有屈指可数的几个遗传学研究报道，虽取得了一些研究成果，但是尚缺乏系统的对BAFME致病基因研究报道。尤其我国对BAFME家系很少有研究报道，对多代多人发病的大家系报道更是少见。我国作为人口大国，家系患病人群数量也相对较多，而BAFME的基因突变特点却不明确，因此对于中国BAFME家系的调查研究有很大意义。而且积极开展本病的临床及分子遗传学研究有助于提高临床医生对本病的认识、了解本病及其他特发性癫痫的分子发病机制，并为本病的诊断、治疗及遗传咨询提供基础。
课题组调查的为辽宁省沈阳市的一个家系，对家系调查分析后，确诊为良性成人家族性肌阵挛性癫痫。课题组与该家系成员进行沟通并讲述实验研究的目的以及意义，在其签署知情同意书后，对其进行遗传学调查、病史采集、临床资料搜集、辅助检查及采集外周血。该家系共4代43人，患者9人，其中男患2人，女患7人。现存4代40人，男女患病机会均等，除第4代尚未到发病年龄外，其余每代均有发病患者，符合常染色体显性遗传特点。患者发病年龄多在30～40岁左右，呈良性病程。所有发病患者的临床表现都比较相似，大多以四肢远端震颤为首发症状，随后或几年后出现全身性强直-阵挛发作，服用抗癫痫药物对缓解症状有效，β受体阻滞剂或饮酒无效，可除外原发性震颤。该家系是一个遗传关系很明确，发病人数较多的呈常染色体显性遗传的BAFME大家系。
采集该家系成员及部分成员配偶的外周血，提取白细胞DNA进行致病基因定位研究。实验思路为首先采用聚合酶链式反应（PCR）及PCR产物测序法对家系中先证者进行BAFME可疑致病基因CSMD3的突变检测；如果结果为阴性，则对已知的BAFME基因进行STR荧光标记物连锁分析，明确是否与目前已知的几个染色体区段连锁，尽可能将该家系的致病基因定位到某个染色体区段；如果结果仍为阴性，与现已知的基因位点均不连锁，致病基因不在几个候选染色体区段，则可以选择全基因组扫描定位法。将致病基因定位在某染色体的特定区域后，进行候选基因筛选，选择该区域内与癫痫有关的基因进行突变检测，从而明确该家系的致病基因。
首先，应用PCR产物测序分析法对先证者CSMD3基因的73个外显子进行PCR扩增产物测序，测序结果与GenBank人类CSMD3gDNA序列进行比较，未发现任何DNA序列变异，既没有发现多态也没有发现与疾病相关的突变，说明本家系不存在CSMD3基因突变。而后，对目前已报道的5个染色体区段进行连锁分析，结果显示染色体8q23.3-q24.1、2p11.1-q12.2、3q26.32-3q28、10p15区段的多个STR标记连锁分析结果显示不支持连锁，因此考虑本家系致病基因并不在上述4个染色体区段。而针对5p15.31-p15首先选择了4个STR标记，连锁分析结果表明现不能完全肯定与否定致病基因是否位于该区段，之后，为进一步明确结果，我们在该区段增加了8个STR位点，结果显示，D5S486在θ=0.0时，LOD值为2.8，实验结果支持该家系致病基因与该位点的连锁,考虑致病基因在5p15.31-p15染色体区段。
本实验研究了一良性成人家族性肌阵挛性癫痫的临床症状、遗传学特点并定位了致病基因位点。为良性成人家族性肌阵挛性癫痫的研究提供了经验，也为该病的遗传学研究提供了思路,并首次将国内的良性成人家族性肌阵挛性癫痫家系致病基因定位在染色体5p15.31-p15区段。
Benign adult familial myoclonic epilepsy (BAFME), is an autosomal dominant,idiopathic epileptic syndrome, characterized by adult-onset tremulous fingermovement, myoclonus, epileptic seizures, and non-progressive course. Up to now, theworld there are about100family in Japan, Italy, the Netherlands, France, Turkey andChina were successively found and reported.But the disease has not yet beenincorporated into the2001international epilepsy syndrome classification ofantiepileptic alliance.
The disease early reports are from Japan, the Japanese scholar Wakeno in1975reported a familial tremor and epilepsy as the ancestry of the performance, and thenhave reported more like family, and the electrophysiological study to determine itstremors are derived from the cerebral cortex, and all is autosomal dominantinheritance.In1991, Yasuda reported in two pedigrees, on the basis of this diseasewere summarized with a benign course and the characteristics of autosomal dominantinheritance, for the first time put forward the concept of benign familial myoclonicseizures in adults. In1999, Mikami using linkage analysis method to a3generation of27people suffering from the disease of the disease-causing gene location in8q23.3-24.1, to found the first gene loci of the disease.In2003, Strianon on an ItalianBAFME family genetic linkage analysis found that the gene loci on2p11-q12.2,which illustrates the genetic heterogeneity of the disease; In China in2006, deng feiyan, analized a BFAME pedigree, and found the pathogenic gene location to10p15;In2010, Depienne found a French FCMTE family pathogenic gene mapping in5p15.31-p15. In2012, Yeetong found a Thai BAFME pedigree pathogenic genelocation in3q26.32-3q28.
So far, the gene of this disease has not been clone. Only Japanese scholarsAtsushi, In2003put forward CSMD3as the candidate genes that cause BFAME.CSMD3is a giant gene of1.2Mb consisting of73exons, it encodes a transmembraneprotein of CUB and sushi multiple domains and it is expressed mainly in fetal andadult brains, suggesting a good candidate for the pathogenic gene for the benign adultfamilial myoclonic epilepsy which has been mapped to8q23.3-q24.1.
Since1991, Yasuda first puts forward the concept of BAFME, the research forBAFME only20years, however, most of them are reported cases, only a handful ofgenetics research reports, although made some research achievements, but it is lack ofsystem of pathogenic gene research report. Especially in our country, the study ofBAFME family reported is less, the big family is more rare. We have a big population,there are mang person have this disease, but our BAFME gene mutationcharacteristics is also not clear, so the Chinese BAFME genealogy research has greatsignificance. And actively carry out clinical and molecular genetics of this research ishelpful to improve clinicians understanding of the disease, to understanding themolecular pathogenesis of this disease and other idiopathic epilepsy. And provide thebasis for the disease diagnosis, treatment and genetic counseling.
The research survey from a family in shenyang, liaoning province, afterinvestigation and analysis, diagnosed with BAFME. Communication with familymembers in details about the purpose and significance of the experimental studies,after signing of the informed consent, begin comprehensive genetic investigation,detailed medical history collection, auxiliary examination and collecting peripheralblood.The family comprised43individuals across four generations. Nine of thefamily members were affected(male2,femal7), with males and females affectedequally. This was consistent with autosomal dominant inheritance. Patients with onsetage at about30~40years old, a benign course.All patients with the similar clinicalmanifestations, distal limbs tremor as starting a symptom more, then, or a few yearslater attacks of systemic rigidity-clonus. Taking antiepileptic drugs can relieve symptoms effectively, beta blockers or drinking is invalid. The family has a cleargenetic relationship, is an autosomal dominant BAFME pedigree.
Collecting peripheral blood of family members and some spouses, extract theleukocyte DNA for disease gene location. Ideas for the first experiment using PCRand PCR-DNA sequencing method to scan BAFME CSMD3gene mutation. If theresult is negative, then use the STR fluorescent marker gene linkage analysis toanalysis the BAFME gene which is known, attempt to mapping the disease gene to achromosomal region; if the current loci are all negative results, we use the wholegenome scan method to location disease gene. After orientation to the specificchromosomal region, select the gene near the loci which associated with epilepsy, toscan whether mutations exist in this familial BAFME, and to locate the specific genemutations in this BAFME family.
First of all, the application of PCR product sequencing analysis propositus theCSMD3gene73exon of the PCR amplification product sequencing, the sequencingresults comparing with human GenBank CSMD3gDNA sequences, and found noDNA sequence variations, neither found polymorphic nor mutations associated withthe disease, suggests that his department does not exist CSMD3gene mutations.Thelinkage analysis excluded linkage to the chromosome region8q23.3-q24.1,2p11.1-q12.2,3q26.32-3q28,10p15, so we consider the causative genes for this family arenot in the above four chromosome region. And we selected four STR markers for5p15.31-p15, the linkage analysis results show that it is neither affirmation nornegation located in the region, and then, in order to find the clear results, we add eightSTR loci, the linkage analysis data showed that the LOD score was2.80for D5S486at no recombination. This suggested linkage to5p15.31-p15.1.This study suggeststhat the causative gene responsible for BAFME in the Chinese pedigree may belocated on chromosome5p15.31-p15.1.
This experimental study learn the clinical feature, genetic characteristics andcausative gene loci of BAFME.The study provides experience for BAFME research, also gives the genetic studies of the disease a train of thought, and it is the first timeto report that the causative gene responsible for BAFME in the Chinese pedigreelocated on chromosome5p15.31-p15.1.
本病早期报道源于日本，日本学者Wakeno在1975年报道了一个以家族性震颤和癫痫发作为表现的家系，而后陆续报道了多个类似家系，并经电生理研究确定其震颤均来源于大脑皮质，且均为常染色体显性遗传。1991年Yasuda在报道两个家系的基础上，总结了本病具有良性病程和常染色体显性遗传的特点，首次提出了“良性成人家族性肌阵挛癫痫”的概念。在1999年，Mikami使用连锁分析的方法将患有该病的一个3代27人的家系致病基因定位于8q23.3-24.1，从而发现了本病的第一个致病基因位点。2003年，Strianon对一个意大利的BAFME家系进行基因连锁分析后发现，其致病基因与2p11-q12.2具有连锁关系，又发现了一个新的致病基因位点，从而说明了该病的遗传异质性。2006年，我国邓飞燕等人通过对一BAFME大家系的遗传学分析，将致病基因定位于10p15；2010年Depienne等人将一法国FCMTE家系致病基因定位于5p15.31-p15；2012年Yeetong将一泰国BAFME家系致病基因定位在3q26.32-3q28。然而，目前为止尚未克隆出该病的致病基因。仅有日本学者Atsushi等人在2003年提出了CSMD3可能为BFAME的致病候选基因。CSMD3是一种编码跨膜蛋白的较大的基因，位于人类染色体8q23.3-q24.1区段，即BAFME被定位的区段。该基因包含73个外显子，长度跨越1.2Mb。主要在成人及胎儿的脑组织中表达。
自1991年Yasuda首次提出了BAFME的概念以来，BAFME综合征的研究不超过20余年历史，其中大多为病例报道，仅有屈指可数的几个遗传学研究报道，虽取得了一些研究成果，但是尚缺乏系统的对BAFME致病基因研究报道。尤其我国对BAFME家系很少有研究报道，对多代多人发病的大家系报道更是少见。我国作为人口大国，家系患病人群数量也相对较多，而BAFME的基因突变特点却不明确，因此对于中国BAFME家系的调查研究有很大意义。而且积极开展本病的临床及分子遗传学研究有助于提高临床医生对本病的认识、了解本病及其他特发性癫痫的分子发病机制，并为本病的诊断、治疗及遗传咨询提供基础。
课题组调查的为辽宁省沈阳市的一个家系，对家系调查分析后，确诊为良性成人家族性肌阵挛性癫痫。课题组与该家系成员进行沟通并讲述实验研究的目的以及意义，在其签署知情同意书后，对其进行遗传学调查、病史采集、临床资料搜集、辅助检查及采集外周血。该家系共4代43人，患者9人，其中男患2人，女患7人。现存4代40人，男女患病机会均等，除第4代尚未到发病年龄外，其余每代均有发病患者，符合常染色体显性遗传特点。患者发病年龄多在30～40岁左右，呈良性病程。所有发病患者的临床表现都比较相似，大多以四肢远端震颤为首发症状，随后或几年后出现全身性强直-阵挛发作，服用抗癫痫药物对缓解症状有效，β受体阻滞剂或饮酒无效，可除外原发性震颤。该家系是一个遗传关系很明确，发病人数较多的呈常染色体显性遗传的BAFME大家系。
采集该家系成员及部分成员配偶的外周血，提取白细胞DNA进行致病基因定位研究。实验思路为首先采用聚合酶链式反应（PCR）及PCR产物测序法对家系中先证者进行BAFME可疑致病基因CSMD3的突变检测；如果结果为阴性，则对已知的BAFME基因进行STR荧光标记物连锁分析，明确是否与目前已知的几个染色体区段连锁，尽可能将该家系的致病基因定位到某个染色体区段；如果结果仍为阴性，与现已知的基因位点均不连锁，致病基因不在几个候选染色体区段，则可以选择全基因组扫描定位法。将致病基因定位在某染色体的特定区域后，进行候选基因筛选，选择该区域内与癫痫有关的基因进行突变检测，从而明确该家系的致病基因。
首先，应用PCR产物测序分析法对先证者CSMD3基因的73个外显子进行PCR扩增产物测序，测序结果与GenBank人类CSMD3gDNA序列进行比较，未发现任何DNA序列变异，既没有发现多态也没有发现与疾病相关的突变，说明本家系不存在CSMD3基因突变。而后，对目前已报道的5个染色体区段进行连锁分析，结果显示染色体8q23.3-q24.1、2p11.1-q12.2、3q26.32-3q28、10p15区段的多个STR标记连锁分析结果显示不支持连锁，因此考虑本家系致病基因并不在上述4个染色体区段。而针对5p15.31-p15首先选择了4个STR标记，连锁分析结果表明现不能完全肯定与否定致病基因是否位于该区段，之后，为进一步明确结果，我们在该区段增加了8个STR位点，结果显示，D5S486在θ=0.0时，LOD值为2.8，实验结果支持该家系致病基因与该位点的连锁,考虑致病基因在5p15.31-p15染色体区段。
本实验研究了一良性成人家族性肌阵挛性癫痫的临床症状、遗传学特点并定位了致病基因位点。为良性成人家族性肌阵挛性癫痫的研究提供了经验，也为该病的遗传学研究提供了思路,并首次将国内的良性成人家族性肌阵挛性癫痫家系致病基因定位在染色体5p15.31-p15区段。
Benign adult familial myoclonic epilepsy (BAFME), is an autosomal dominant,idiopathic epileptic syndrome, characterized by adult-onset tremulous fingermovement, myoclonus, epileptic seizures, and non-progressive course. Up to now, theworld there are about100family in Japan, Italy, the Netherlands, France, Turkey andChina were successively found and reported.But the disease has not yet beenincorporated into the2001international epilepsy syndrome classification ofantiepileptic alliance.
The disease early reports are from Japan, the Japanese scholar Wakeno in1975reported a familial tremor and epilepsy as the ancestry of the performance, and thenhave reported more like family, and the electrophysiological study to determine itstremors are derived from the cerebral cortex, and all is autosomal dominantinheritance.In1991, Yasuda reported in two pedigrees, on the basis of this diseasewere summarized with a benign course and the characteristics of autosomal dominantinheritance, for the first time put forward the concept of benign familial myoclonicseizures in adults. In1999, Mikami using linkage analysis method to a3generation of27people suffering from the disease of the disease-causing gene location in8q23.3-24.1, to found the first gene loci of the disease.In2003, Strianon on an ItalianBAFME family genetic linkage analysis found that the gene loci on2p11-q12.2,which illustrates the genetic heterogeneity of the disease; In China in2006, deng feiyan, analized a BFAME pedigree, and found the pathogenic gene location to10p15;In2010, Depienne found a French FCMTE family pathogenic gene mapping in5p15.31-p15. In2012, Yeetong found a Thai BAFME pedigree pathogenic genelocation in3q26.32-3q28.
So far, the gene of this disease has not been clone. Only Japanese scholarsAtsushi, In2003put forward CSMD3as the candidate genes that cause BFAME.CSMD3is a giant gene of1.2Mb consisting of73exons, it encodes a transmembraneprotein of CUB and sushi multiple domains and it is expressed mainly in fetal andadult brains, suggesting a good candidate for the pathogenic gene for the benign adultfamilial myoclonic epilepsy which has been mapped to8q23.3-q24.1.
Since1991, Yasuda first puts forward the concept of BAFME, the research forBAFME only20years, however, most of them are reported cases, only a handful ofgenetics research reports, although made some research achievements, but it is lack ofsystem of pathogenic gene research report. Especially in our country, the study ofBAFME family reported is less, the big family is more rare. We have a big population,there are mang person have this disease, but our BAFME gene mutationcharacteristics is also not clear, so the Chinese BAFME genealogy research has greatsignificance. And actively carry out clinical and molecular genetics of this research ishelpful to improve clinicians understanding of the disease, to understanding themolecular pathogenesis of this disease and other idiopathic epilepsy. And provide thebasis for the disease diagnosis, treatment and genetic counseling.
The research survey from a family in shenyang, liaoning province, afterinvestigation and analysis, diagnosed with BAFME. Communication with familymembers in details about the purpose and significance of the experimental studies,after signing of the informed consent, begin comprehensive genetic investigation,detailed medical history collection, auxiliary examination and collecting peripheralblood.The family comprised43individuals across four generations. Nine of thefamily members were affected(male2,femal7), with males and females affectedequally. This was consistent with autosomal dominant inheritance. Patients with onsetage at about30~40years old, a benign course.All patients with the similar clinicalmanifestations, distal limbs tremor as starting a symptom more, then, or a few yearslater attacks of systemic rigidity-clonus. Taking antiepileptic drugs can relieve symptoms effectively, beta blockers or drinking is invalid. The family has a cleargenetic relationship, is an autosomal dominant BAFME pedigree.
Collecting peripheral blood of family members and some spouses, extract theleukocyte DNA for disease gene location. Ideas for the first experiment using PCRand PCR-DNA sequencing method to scan BAFME CSMD3gene mutation. If theresult is negative, then use the STR fluorescent marker gene linkage analysis toanalysis the BAFME gene which is known, attempt to mapping the disease gene to achromosomal region; if the current loci are all negative results, we use the wholegenome scan method to location disease gene. After orientation to the specificchromosomal region, select the gene near the loci which associated with epilepsy, toscan whether mutations exist in this familial BAFME, and to locate the specific genemutations in this BAFME family.
First of all, the application of PCR product sequencing analysis propositus theCSMD3gene73exon of the PCR amplification product sequencing, the sequencingresults comparing with human GenBank CSMD3gDNA sequences, and found noDNA sequence variations, neither found polymorphic nor mutations associated withthe disease, suggests that his department does not exist CSMD3gene mutations.Thelinkage analysis excluded linkage to the chromosome region8q23.3-q24.1,2p11.1-q12.2,3q26.32-3q28,10p15, so we consider the causative genes for this family arenot in the above four chromosome region. And we selected four STR markers for5p15.31-p15, the linkage analysis results show that it is neither affirmation nornegation located in the region, and then, in order to find the clear results, we add eightSTR loci, the linkage analysis data showed that the LOD score was2.80for D5S486at no recombination. This suggested linkage to5p15.31-p15.1.This study suggeststhat the causative gene responsible for BAFME in the Chinese pedigree may belocated on chromosome5p15.31-p15.1.
This experimental study learn the clinical feature, genetic characteristics andcausative gene loci of BAFME.The study provides experience for BAFME research, also gives the genetic studies of the disease a train of thought, and it is the first timeto report that the causative gene responsible for BAFME in the Chinese pedigreelocated on chromosome5p15.31-p15.1.
引文
[1] Anderson VA, Hauser WA, Genetics.In: laidlaw J,et al,eds.A textbook ofepilepsy.3rd.EdinburghChurchill Livingstone.1998:49–72
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[向燕群,唐北沙,沈璐,等.良性家族性婴儿惊厥疾病基因定位的初步研究.中华神经科杂志,2000,33:286-289.]
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[19] Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1causejuvenile myoclonic epilepsy. Nature Genet,2004,36:842-849
[20] Zupanc ML, Legros B. Progressive myoclonic epilepsy. Cerebellum,2004,3(3):156-171.
[21] Minassian BA, Lee JR, Herbrick JA, et al. Mutations in a gene encoding a novelprotein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet,1998,20(2):171-174.
[22] Chan EM, Bulman DE, Paterson AD, et al. Genetic mapping of a new Laforaprogressive myoclonus epilepsy locus (EPM2B) on6p22. J Med Genet,2003,40(9):671-675.
[23] Joensuu T, Lehesjoki AE, Kopra O. Molecular background of EPM1-Unverricht-Lundborg disease. Epilepsia,2008,49(4):557-563.
[24] de Siqueira LF. Progressive myoclonic epilepsies: review of clinical, molecularand therapeutic aspects. J Neurol,2010,257:1612-1619．
[25] Williams RE, Aberg L, Autti T, et al. Diagnosis of the neuronal ceroidlipofuscinoses: an update. Biochim Biophys Acta,2006,1762:865-872.
[26] Yasuda T．Benigh adult familial myoclonic epilepsy(BAFME)[J]．KawasakiMed J，1991.17：1-13．
[27] Mikami M，Yasuda T，Terao A．et a1．Localization of a gene for benign adultfamilial myoclonic epilepsy to chromosome8q23．3-q24．1[J]．Am J HumGenet，1999，65(3):745-51.
[28] Striano P，Chifari R，Strino S，el a1．A new benign adult familial myoclonicepilepsy (BAFME) pedigree suggesting linkage to chromosome2p11．1-q12.2[J].Epilepsia,2004，45：190-2．
[29] Depienne C, Magnin E, Bouteiller D,et al. Familial cortical myoclonic tremorwith epilepsy: the third locus (FCMTE3) maps to5p. Neurology.2010Jun15;74(24):2000-3.
[30] Yeetong P, Ausavarat S, Bhidayasiri R. et al. A newly identified locus for benignadult familial myoclonic epilepsy on chromosome3q26.32-3q28. Eur J HumGenet.2013Feb;21(2):225-8.
[31] Wallace RH, Berkovic SF, How ll RA, et al. Suggestion of a major gene forfamilial febrile convulsions mapping to8q13-21. JMed Genet,1996,33∶308-312.
[32] Baulac S, Gourfink el-An I, Picard F, et al.A second locus for familialgeneralized epilepsy with febrile seizures plus maps to chromosome2q21-q33.Am J Hum Gen et,1999,65:1079-1085.
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[34] Escayg A, Macdonald BT, Meisler MH, et al. Mutations of SCN1A, encodinga neuronal sodium channel, in two families with GEFS+2. NatGenet,2000,24∶343-345.
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[38] Fong Y, Shah U, Gee N, et al. Childhood absence epilepsy with tonic-clonicseizures and electroencephalogram3-4Hz spike and multispike-slow wavecomplexes: linkage to chromosome8q24. Am J Hum Genet,1998,63:1117-1129
[39] Everett K, et al. Linkage and mutational analysis of CLCN2in childhood absenceepilepsy［J］. Epilepsy Res,2007,75(2-3):145–53.
[40] Haug K, Warnstedt M, Aleko AK, et al. Mutations in CLCN2encoding avoltage-gated chloride channel are associated with idiopathic generalizedepilepsies. Nature Genetics,2003,33:527-532
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[42] Steinlein OK, Magnusson A, Stoodt J, et al. An insertion mutation of theCHRNA4gene in a family with autosomal dominant nocturnal frontal lobeepilepsy. Hum Mol Genet,1997,6:943-947.
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[45] Phillips HA, Favre I, Kirkpatrick M, et al. CHRNB2is the second acetyl cholinerecept or subunit as sociated with autosomal dominant nocturnal frontal lobeepilepsy. Am J Hum Genet,2001,68∶225-231.
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