Genotype-Phenotype Relationships in Fragile X Families

摘要 脆性X相关震颤/共济失调综合征(FXTAS)是一种神经退行性疾病，具有变量 由FMR1前突变引起的进展。各种分子变化已被记录在案。 在FXTAS中，包括线粒体功能障碍，CGG重复序列对特定蛋白质的隔离- 包含FMR1 mRNA的发夹环、慢性DNA损伤修复和FMRPolyG的产生 多肽通过RAN翻译。虽然有许多关于FXTAS临床表型的报道，但FXTAS的临床表型尚未见报道。 从来没有对那些受FXTAS影响的人进行纵向研究，因此，没有已知的 进展的生物标记物。拟议的项目将通过预期的方式满足这一关键需求 加州大学心理研究所对100名患有FXTA的人(60名男性和40名女性)的纵向研究 戴维斯。Mind Institute每两年将对100名患者进行跟踪调查，另外还将对20名患者进行跟踪 通过FXTAS，将在澳大利亚的拉特洛贝大学看到，以在头脑中复制和验证发现。 我们将通过对特定临床措施的重复评估来量化FXTAS的进展， 包括神经/运动、精神、认知、事件相关电位(ERP)、眼球跟踪研究，以及 MRI/DTI测量。此外，我们还将记录FXTAS每个阶段的分子/生化标记 并将这些标记物与包括MRI/DTI成像在内的临床领域的进展速度相关联。 我们还将确定FXTAS的共病情况或诊断，如自身免疫性疾病， 帕金森氏症的特征，药物滥用，高血压和糖尿病；我们将评估这些共同的 病态条件影响FXTAS的进展。我们将记录FXTAS进程的可变性 跨域。我们将评估女性是否比男性进展更慢，即使是那些 患免疫调节疾病的风险更高。我们计划开发分子和生化标记 在未来的临床试验中可用于结果衡量的进展和量化临床措施 对FXTAS的治疗。生化/分子标记将包括线粒体功能障碍的测量， 氧化应激、活性氧物种、ASFMR1亚型、活化率、CGG重复、AGG锚定和 长的非编码RNA。作为一个探索性的目标，我们将尝试在组织中检测FMRPolyG蛋白，包括 在临床护理过程中收集的成纤维细胞、淋巴细胞和其他组织，以及 死后可供收藏的大脑。我们还将评估生活方式因素，如肥胖， 运动、酗酒和吸毒可能影响FXTAS的进展。

ABSTRACT Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with variable progression caused by the FMR1 premutation. A variety of molecular changes have been documented in those with FXTAS, including mitochondrial dysfunction, sequestration of specific proteins by the CGG-repeat– containing hairpin loops of the FMR1 mRNA, chronic DNA damage repair, and production of the FMRpolyG polypeptide through RAN translation. Although there are many reports of the clinical phenotype of FXTAS, there has never been a longitudinal study of those affected by FXTAS, and consequently, there are no known biomarkers of progression. The proposed project will address this critical need through a prospective longitudinal study of 100 individuals (60 males and 40 females) with FXTAS seen at the MIND Institute at UC Davis. One hundred patients will be followed every 2 years at the MIND Institute, and an additional 20 patients with FXTAS will be seen at La Trobe University in Australia to replicate and validate the findings at the MIND. We will quantify the progression of FXTAS through repetitive assessment of specific clinical measures, including neurological/motor, psychiatric, cognitive, event related potentials (ERP), eye-tracking studies, and MRI/DTI measures. In addition, we will document the molecular/biochemical markers for each stage of FXTAS and correlate these markers with the rate of progression in the clinical domains, including MRI/DTI imaging. We will also identify comorbid conditions or diagnoses that occur with FXTAS, such as autoimmune disease, Parkinsonian features, substance abuse, hypertension, and diabetes; we will evaluate whether these co- morbid conditions affect the progression of FXTAS. We will document the variability of FXTAS progression across domains. We will assess whether females progress more slowly than males with FXTAS, even for those at higher risk for immune-mediated disorders. We plan to develop molecular and biochemical markers of progression and quantitative clinical measures that can be utilized for outcome measures in future clinical trials of treatment of FXTAS. The biochemical/molecular markers will include measures of mitochondrial dysfunction, oxidative stress, reactive oxygen species, ASFMR1 isoforms, activation ratio, CGG repeats, AGG anchors, and long non-coding RNAs. In an exploratory aim, we will try to detect FMRpolyG protein in tissues, including fibroblasts, lymphocytes, and other tissues that are collected during the course of clinical care, as well as in the brains that are available for collection after death. We will also assess lifestyle factors such as obesity, exercise, and alcohol and drug abuse that may affect the progression of FXTAS.