Elucidating and understanding the genetic basis of movement disorders

描述（由申请人提供）： 复杂运动障碍（CMD），定义为患者受一种以上运动障碍（如帕金森综合征和肌张力障碍，或肌阵挛和震颤）影响的疾病，是诊断和治疗的持续挑战。CMD通常是进行性的，阻止患者进行基本的日常功能，如行走，进食和说话，并导致患者及其家人的疾病相关的经济和个人负担。此外，与运动障碍基因相关的已知表型和病因异质性是相当惊人的，并对治疗提出了重大挑战。因此，早期诊断对于适当的治疗以恢复运动活动和改善患者的生活质量至关重要。由于运动障碍（MD）的遗传学研究已经证明了他们在发现潜在的病理过程中的成功，并帮助研究人员了解疾病的表现和进展，识别潜在的遗传因素，或有助于MD的发展提供了一个强大的工具，了解其相关的病理。因此，在试图确定与这些CMD相关的分子网络，并促进新的治疗方法，该建议侧重于招募家族性和散发性CMD患者，并确定其致病等位基因。因为全外显子组测序（WES）已经证明了它能够识别遗传性疾病的致病等位基因，即使是在以前被认为是统计学上的家族中， 对于定位克隆而言，WES的能力不足，并且已经成为孟德尔和更复杂性状的基因鉴定的富有成效的策略，WES与基于SNP的阵列一起沿着将减少对因果变体的搜索，在本提案中将用于致病突变鉴定。 我们相信，对这些疾病的深入研究是阐明CMD和更常见疾病（如帕金森病）的疾病机制的有力方法，并将导致诊断和治疗的改进。总之，这项研究将大大有助于新的CMD基因的识别和表征其表型，这不仅是理解的病因和病理生理学的CMD，但也为开发更有针对性的和有效的治疗策略，这将是非常有益于人类健康。

DESCRIPTION (provided by applicant): Complex movement disorders (CMDs), defined as disorders in which patients are affected by more than one movement disorder (such as parkinsonism and dystonia, or myoclonus and tremor), are a continuing challenge for diagnosis and treatment. CMDs are usually progressive, prevent patients from performing basic daily functions such as walking, eating, and talking, and result in high disease-associated financial and personal burden for patients and their families. Moreover, the already-known phenotypic and etiologic heterogeneity associated with movement disorder genes is quite striking and presents a significant challenge for treatment. Therefore, early diagnosis is crucial for appropriate treatment to restore motor activities and improve patients' quality of life. Since genetic studies in movement disorders (MDs) have demonstrated their success in the discovery of underlying pathologic processes and have helped researchers to understand both disease manifestation and progression, the identification of genetic factors underlying, or contributing to, the development of MDs provides a powerful tool for understanding their associated pathology. Accordingly, in an attempt to identify molecular networks associated with these CMDs and to facilitate novel treatments, this proposal focuses on the recruitment of familial and sporadic patients with CMDs, and the identification of their disease-causing alleles. Because whole exome sequencing (WES) has proved its ability to identify causative alleles for inherited diseases, even in families previously deemed statistically underpowered for positional cloning, and has become a fruitful strategy for gene identification in both Mendelian and more complex traits, WES, along with SNP-based arrays, which will reduce the search for causal variants, will be used for disease- causing mutation identification in this proposal. We believe that intense study of these disorders represents a powerful approach to elucidate disease mechanism for both CMDs and for more common disorders such as Parkinson's disease, and will lead to improvements in both diagnoses and treatments. In conclusion, this study will contribute enormously to the identification of novel CMD genes and the characterization of their phenotype, which not only are essential for understanding the etiology and pathophysiology of CMDs, but also for developing more targeted and efficient therapeutic strategies that will be of great benefit to human health.