RESOLVING HETEROGENEITY IN EPILEPSY WITH GENETIC MARKERS

本研究将利用连锁分析来研究 特发性全身性癫痫（IGE），占40%以上 所有癫痫 我们将研究IGE的三种具体形式： 青少年肌阵挛性癫痫（JME） (AGM)癫痫伴随机性大发作（RGM）。 JME已被证明 与6号染色体的HLA区域有遗传联系。 这个JME基因座 被命名为EJM-1 由于JME的家族特征， 据认为，其他几种形式的政府间会议也将相互联系， 与HLA基因座的关联 我们在上一次拨款时验证了这个假设 期 我们发现，RGM显然是不连锁的HLA位点。 然而，AGM，虽然不同于JME临床上，可能是遗传 一模一样 我们在遗传学方面的进一步工作有以下四个目标： IGE： 1. 为了验证在上一个授予期开发的假设， 与6号染色体上的HLA基因座相连 2. 寻找一个基因位点，导致癫痫与随机大发作 (RGM)我们已经证明了它与临床上的 类似AGM和JME。 3. 同时，为了寻找参与表达的第二个位点， IGC的三种形式。 4. 找到EJM-1基因座的侧翼标记。 我们将招募通过JME、RGM和AGM患者确定的家庭; 收集所有家庭成员的血液、脑电图和家族史;以及 为受试者的整个基因组进行标记。 我们将测试 AGM与HLA基因座的连锁，并测试所有三种形式，但特别是 RGM，用于与遗传标记的连锁。 我们将测试特定的候选人 与IGE的任何或所有三种形式连锁的基因座。 我们在上一个资助期的发现--年度股东大会可能与EJM有关-- 1和RGM没有联系-表明遗传连锁数据可用于 阐明临床异质性。 他们证明， 不同形式的癫痫--这是世界上最困难的问题之一 研究和临床实践--可以通过搜索 疾病的遗传原因。 它们还表明， 正确的表型是进行常见复合体遗传研究的关键 疾病

This study will use linkage analysis to investigate the genetics of idiopathic generalized epilepsy (IGE), which accounts for more than 40% of all epilepsy. We will investigate three specific forms of IGE: juvenile myoclonic epilepsy (JME), epilepsy with awakening grand mal (AGM), and epilepsy with random grand mal (RGM). JME has been shown to be genetically linked to the HLA region of chromosome 6. This JME locus has been designated EJM-1. Because of the family characteristics of JME, it was thought that several other forms of IGC would be also be linked to the HLA locus. We tested this hypothesis during the last grant period. We found that RGM is apparently not linked to the HLA locus. However, AGM, although different from JME clinically, may be genetically identical. We have the following four goals for our further work on the genetics of IGE: 1. To test the hypothesis, developed in the last grant period, that AGM is linked to the HLA locus on chromosome 6. 2. To search for a gene locus that causes epilepsy with random grand mal (RGM) which we have shown to be genetically different from the clinically similar AGM and JME. 3. Simultaneously, to look for a second locus involved in the expression of all three forms of IGC. 4. To find flanking markers for the EJM-1 locus. We will recruit families identified through JME, RGM and AGM patients; collect blood, EEGs, and family histories from all family members; and type the subjects for markers throughout the genome. We will test for linkage of AGM to the HLA locus and test all three forms, but especially RGM, for linkage to a genetic marker. We will test specific candidate loci for linkage to any or all three forms of IGE. Our findings during the last grant period--that AGM may be linked to EJM- 1 and RGM is not linked -- show that genetic linkage data can be used to unravel clinical heterogeneity. They demonstrate that differentiating the different forms of epilepsy--one of the most difficult problems in both research and clinical practice -- can be resolved by searching for the genetic cause of disease. They also show that definition of the proper phenotype is critical for genetic studies of common complex disease.