Molecular characterization of Familial dyskinesias

描述(由申请人提供)：运动障碍是多动症 非自愿运动，通常表现为离散的发作性发作或 阵发性疾病。它们与其他阵发性神经疾病有相似之处， 比如癫痫和偏头痛。它们以零星和家族性的形式出现， 由各种刺激(如压力、疲劳、月经、酒精、 咖啡因)，并经常对抗惊厥药物有反应。运动障碍 进一步分为运动生成(运动诱导)和非运动生成 (自发)形式。我们已经从基因上定位了一个与 染色体2q的非运动性形式的家族性阵发性运动障碍 (FPD1)和16号染色体的运动发生形式(FPD2)。此外，我们还拥有 发现了与这两个基因座都没有关联的其他家族，进一步证明了 遗传异质性。我们计划识别和表征基因，以及 突变导致家族性发作性运动障碍。在这些家庭中 疾病与FPD1或FPD2无关，将使用普通遗传学进行研究 用连锁方法识别额外的FPD基因座。我们将进行变异 与FPD基因座连锁的候选基因分析多种位置克隆 如果候选基因分析不成功，将使用策略。 FPD基因的鉴定，加上大量的临床数据，将使 美国将表征由单个基因突变引起的表型谱 并比较不同基因突变患者的表型。的 特别令人感兴趣的是，具体的 具有治疗反应的基因和突变，以及突出但多样的 酒精和咖啡因等神经活性物质对这些细胞的影响 精神错乱。 对FPD的分子表征将导致一种新的基因 对这些疾病进行分类和更好的了解。表征 FPD潜在的致病机制将导致改善 诊断，可能会提出新的治疗策略，并将揭示 更复杂的阵发性疾病，如偏头痛和癫痫。

DESCRIPTION (provided by the applicant): Dyskinesias are hyperkinetic involuntary movements, which are often present as discrete episodic attacks or paroxysms. They share similarities with other paroxysmal neurologic disorders, such as epilepsy and migraine. They occur in sporadic and familial forms, are precipitated by various stimuli (e.g. stress, fatigue, menses, alcohol, caffeine), and frequently respond to anticonvulsant medications. Dyskinesias are further categorized into kinesigenic (movement-induced) and non-kinesigenic (spontaneous) forms. We have genetically mapped a locus associated with a non-kinesigenic form of familial paroxysmal dyskinesia (FPD) to chromosome 2q (FPD1) and a kinesigenic form to chromosome 16 (FPD2). Furthermore, we have identified other families not linked to either locus, demonstrating further genetic heterogeneity. We plan to identify and characterize genes, and mutations responsible for familial paroxysmal dyskinesias. Families in whom the disorder is not linked to FPD1 or FPD2 will be studied using a general genetic linkage approach to identify additional FPD loci. We will perform mutation analysis on candidate genes linked to FPD loci. A variety of positional cloning strategies will be utilized if candidate gene analysis is unsuccessful. Identification of FPD genes, coupled with extensive clinical data, will allow us to characterize the spectrum of phenotypes caused by mutations in a single gene and to compare phenotypes of patients with mutations at different loci. Of particular interest will be whether there is a correlation between specific genes and mutations with therapeutic responses, and the prominent but diverse effects that such neuroactive agents as alcohol and caffeine have on these disorders. Molecular characterization of the FPDs will lead to a new genetic classification and a better understanding of these disorders. Characterization of the pathogenic mechanisms underlying the FPDs will lead to improved diagnosis, may suggest novel therapeutic strategies, and will shed light on more complex paroxysmal disorders, such as migraine and epilepsy.