GENETIC EPIDEMIOLOGY OF FAMILIAL EPILEPSY

在本申请中，我们建议扩展我们对以下作用的研究： 癫痫的遗传通过进行遗传连锁分析， 并在染色体上定位特定的基因， 易患癫痫。 大约有32个家庭在 该项目的最初资助阶段，已知至少包含三个 癫痫患者（先证者和至少两个一级 亲属），将被纳入联系研究。 计算机模拟 将用于评估（1）哪些谱系可能产生 最高的lod分数，（2）哪些人需要接受采访，以获得 （3）其他家族史信息;（3）哪些人需要 在每个谱系中取样。 根据这些模拟的结果， 将进行额外的面谈，并从以下人员采集血样： 信息的家庭成员。 取样个体的基因型将是 在检测为限制性内切酶的一系列遗传标记中的每一个处确定 片段长度多态性 那么联系的几率和 每个遗传标记与一个 估计癫痫的假定易感基因。 异质性 将测试重组分数中的家族之间的差异， 关于哪些家庭可能显示出联系的假设， 比较不同发病年龄、病因和 先证者的癫痫发作类型 由基因引起的表型 将通过比较以下结果来研究易感基因： 受影响亲属的几种不同定义，包括所有 癫痫，仅特发性癫痫，仅全身性癫痫，部分性 仅癫痫，癫痫和热性惊厥，以及癫痫 和孤立的无端癫痫 最后，如果证明了链接， 将通过比较标记来研究连锁不平衡的存在。 研究中受影响和未受影响个体的等位基因频率 人口整体。 癫痫易感基因的鉴定将有助于早期 识别易感个体，这将是第一步， 分子研究旨在确定生理机制， 敏感性提高。 这些研究可能会增加 了解癫痫发病机制中的基本因素， 对新的治疗和预防策略的相应影响。

In this application, we propose to extend our investigations of the role of inheritance in epilepsy by performing genetic linkage analysis to identify and chromosomally locate specific genes that have a major influence on susceptibility to epilepsy. Approximately 32 families ascertained in the initially funded stage of the project, and known to contain at least three individuals with epilepsy (the proband and at least two first-degree relatives), will be included in the linkage study. Computer simulations will be used to assess (1) which pedigrees are likely to produce the highest lod score, (2) which individuals need to be interviewed to obtain additional family history information, and (3) which individuals need to be sampled within each pedigree. Based on the results of these simulations, additional interviews will be conducted and blood samples collected from informative family members. The genotypes of sampled individuals will be determined at each of a series of genetic markers detected as restriction fragment length polymorphisms. Then the odds of linkage and the maximum likelihood recombination fraction between each genetic marker and a putative susceptibility gene for epilepsy will be estimated. Heterogeneity between families in the recombination fraction will be tested both without assumptions about which families are likely to show linkage, and by comparing families defined by different ages at onset, etiologies, and seizure types in the probands. The phenotype that results from the susceptibility gene will be investigated by comparing the results under several different definitions of affected relatives, including all epilepsy, idiopathic epilepsy only, generalized epilepsies only, partial epilepsies only, both epilepsy and febrile convulsions, and both epilepsy and isolated unprovoked seizures. Finally, if linkage is demonstrated, the presence of linkage disequilibrium will be investigated by comparing marker allele frequencies in affected and unaffected individuals in the study population as a whole. Identification of a susceptibility gene for epilepsy would facilitate early identification of susceptible individuals, and would be a first step in molecular studies designed to identify the physiological mechanism by which susceptibility is raised. Such studies could lead to increased understanding of fundamental factors in the pathogenesis of epilepsy, with corresponding implications for new strategies of treatment and prevention.