Molecular characterization of Familial dyskinesias

描述（由申请人提供）：运动障碍是运动过度 不自主运动，通常表现为不连续的发作或 发作它们与其他阵发性神经系统疾病有相似之处， 例如癫痫和偏头痛。它们以散发和家族形式发生， 由各种刺激（例如，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 进一步分为运动诱发的（运动诱导的）和非运动诱发的 （自发的）形式。我们已经在基因图谱上找到了一个 染色体2q的家族性阵发性运动障碍（FPD）的非运动诱发形式 （FPD1）和16号染色体的运动诱发形式（FPD2）。此外，我们有 确定了其他家庭不与任何一个位点，进一步证明 遗传异质性我们计划识别和描述基因， 导致家族性阵发性运动障碍的突变家庭中， 疾病与FPD1或FPD2无关，将使用一般遗传学方法进行研究。 连锁方法来鉴定额外的FPD基因座。我们将进行变异 与FPD位点连锁的候选基因分析。多种定位克隆 如果候选基因分析不成功，则使用策略。 FPD基因的鉴定，加上广泛的临床数据，将允许 我们来描述由单个突变引起的表型谱， 基因，并比较不同基因座突变患者的表型。的 特别令人感兴趣的是，具体的 基因和突变与治疗反应，以及突出的，但多样的 酒精和咖啡因等神经活性剂对这些神经系统的影响 紊乱 FPD的分子特征将导致一种新的遗传 分类和更好地了解这些疾病。表征 FPD的致病机制将导致改善 诊断，可能会提出新的治疗策略，并将阐明 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.