UNDERSTANDING FXTAS AMONG MALES WITH THE FMR1 PREMUTATION

了解 FMR1 提前突变的男性 FXTAS

• 批准号: 7483335
• 负责人: Stephanie L. Sherman
• 金额: $ 19.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483335
• 关键词: Accelerated Phase; Address; Age; Age of Onset; Age-Years; Ataxia; Autonomic Dysfunction; Behavior Disorders; Budgets; Classification; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive deficits; Cohort Studies; Cross-Sectional Studies; Data; Development; Diagnosis; Disease; Ensure; Erectile dysfunction; Evidence based treatment; FMR1 Premutation; FXTAS; Failure; Family; Fecal Incontinence; Fragile X Syndrome; Functional disorder; Funding; Future; Genetic; Goals; Grant; Impaired cognition; Individual; Institution; Intervention; Laboratories; Longitudinal Studies; Measures; Medical History; Messenger RNA; Motor; Neurodegenerative Disorders; Neurologic; Neuropsychology; Neurosecretory Systems; Parkinsonian Disorders; Participant; Pathology; Patients; Pattern; Phase; Phenotype; Pilot Projects; Population; Population Study; Range; Rate; Recruitment Activity; Relative (related person); Research Personnel; Research Project Grants; Restless Legs Syndrome; Risk; Sampling; Sampling Studies; Screening procedure; Severities; Siblings; Site; Sleep Apnea Syndromes; Snoring; Specific qualifier value; Structure; Symptoms; Testing; Testosterone; Time; Toxic effect; Translational Research; Tremor; Woman; Work; Yang; base; cognitive change; demographics; experience; follow-up; insight; male; men; rapid eye movement; research study; urinary

Dr. Sherman's project will utilize the study population of well-phenotyped FMR1 premutation carrier males and their noncarrier siblings created in the previous funding period to test specific hypotheses that will delineate the disease course of fragile X-associated tremor/ataxia syndrome (FXTAS), a debilitating neurodegenerative disorder. Our current cross-sectional study includes neuropsychologic and neurologic assessments, demographics and medical history obtained from individuals recruited from families identified with fragile X syndrome (FXS). In this funding period, we will extend the phenotype battery to further characterize non-motor symptoms that, in our experience, often pre-date the onset of motor symptoms. We will leverage our existing population to obtain a second follow-up time point in these individuals. We will develop an abbreviated test battery derived from the analysis of the two time points, one that will be more suitable for future longitudinal studies. We are working with other established FXTAS consortia to ensure that this test battery, or a modified version, becomes a deliverable product available for future clinical trials. As this neurodegenerative disorder is known to be incompletely penetrant with variable age of onset, severity and progression, assessment of pre-motor symptoms will be essential if neuroprotective therapy is to be considered in the future. Because of the budgetary constraints of this application and our preliminary data indicating a significantly reduced risk for FXTAS among women, we have proposed a focused clinical research study on males only, but emphasize that this project will serve as a launching pad for future studies. The over-arching goal of this project is to test hypotheses that will provide insight into the pathology and disease course of FXTAS in order to: 1) specify time points for neuroprotective interventions and 2) provide evidence-based treatment strategies of FXTAS-related symptoms. Because of the budget constraints, we have developed a small, focused clinical research project primarily examining non-motor symptoms and their progression, taking advantage of our current study sample. However, we envision this project as a pilot project that can be enhanced within the structure of the Fragile X Center, one that extends the current ongoing projects at Emory and Baylor that address fragile X-associated disorders. For example, our study cohort that has been carefully phenotyped using funding from the current Fragile X Center grant will be available for future studies that examine genetic and environmental modifiers of FXTAS based on exciting data from Dr. Peng Jin's laboratory. Dr. Jin is a young investigator in our department who has contributed significantly to the understanding of the toxic effect of the premutation mRNA (e.g., Duan and Jin, 2006; e.g., Jin et al., 2003; Yang et al., 2007). Our plan is to use data derived from this proposed pilot study and those from other collaborators within our institutions to spin off new projects that have the same basic goal to ameliorate the symptoms of FXTAS. In parallel, we have moved outside our Fragile X Center "walls" and have established a FXTAS Working Group with other investigators who are working on FXTAS. Our goal is to establish phenotype measures that document the course of the disorder, are portable and can be shared across studies being conducted at multiple sites. This data-sharing will be an essential component of future clinical and translational research on FXTAS.

Sherman 博士的项目将利用表型良好的 FMR1 前突变携带者男性研究群体 以及他们在上一个资助期间创建的非携带者兄弟姐妹，以测试将 描述脆性 X 相关震颤/共济失调综合征 (FXTAS) 的病程，这是一种使人衰弱的疾病 神经退行性疾病。我们目前的横断面研究包括神经心理学和神经病学 从已确定的家庭招募的个人中获得的评估、人口统计数据和病史 患有脆性 X 综合征 (FXS)。在本次资助期间，我们将扩展表型电池以进一步 根据我们的经验，非运动症状的特征通常早于运动症状的出现。我们将 利用我们现有的人群来获得这些个体的第二个随访时间点。我们将开发一个 通过对两个时间点的分析得出的简化测试电池，其中一个更适合 未来的纵向研究。我们正在与其他已成立的 FXTAS 联盟合作，以确保此测试 电池或修改版本成为可用于未来临床试验的可交付产品。正如这个 众所周知，神经退行性疾病具有不完全渗透性，其发病年龄、严重程度和发病年龄各不相同。 如果要进行神经保护治疗，则运动前症状的评估至关重要 将来考虑。由于该应用程序的预算限制以及我们的初步数据 表明女性 FXTAS 风险显着降低，我们提出了一项重点临床研究 仅针对男性进行研究，但强调该项目将作为未来研究的起点。 该项目的首要目标是测试假设，以深入了解病理学和 FXTAS 的疾病进程，以便：1) 指定神经保护干预的时间点，2) 提供 FXTAS 相关症状的循证治疗策略。由于预算限制，我们 开发了一个小型的、重点突出的临床研究项目，主要检查非运动症状及其 进展，利用我们当前的研究样本。但是，我们将该项目视为一个试点项目 可以在脆弱 X 中心的结构内得到增强，该中心扩展了当前正在进行的 埃默里大学和贝勒大学的项目致力于解决脆弱的 X 相关疾病。例如，我们的研究队列 已使用当前脆弱 X 中心赠款的资金进行了仔细的表型分析，该资金将用于未来 基于彭博士令人兴奋的数据检查 FXTAS 的遗传和环境修饰剂的研究 金的实验室。金博士是我们科室的一位年轻研究员，为该领域的研究做出了重大贡献。 了解前突变 mRNA 的毒性作用（例如，Duan 和 Jin，2006；例如，Jin 等人，2003； 杨等人，2007）。我们的计划是使用从这项拟议的试点研究和其他研究中获得的数据 我们机构内的合作者可以衍生出具有相同基本目标的新项目，以改善 FXTAS 的症状。与此同时，我们已经走出了脆弱 X 中心的“围墙”，并建立了一个 FXTAS 工作组与其他从事 FXTAS 工作的调查人员一起。我们的目标是建立表型 记录疾病进程的测量方法是可移植的，并且可以在研究之间共享 在多个地点进行。这种数据共享将成为未来临床和转化的重要组成部分 FXTAS 的研究。