Natural History of Spinocerebellar Ataxia Type 7 (SCA7)

脊髓小脑型共济失调7型是一种由ATXN7基因编码区CAG三核苷酸重复序列扩增引起的神经退行性疾病。它与其他常染色体显性遗传性脊髓小脑性共济失调的区别在于伴有视网膜变性。因此，视力丧失是影响这些患者生活质量的重要并发症，然而，目前的治疗仅限于改变生活方式。眼睛是潜在治疗研究的极佳目标，因为它具有相对免疫的特权，可以通过手术获得，而且很容易检查和成像。因此，在应用于其他中枢神经系统之前，在SCA7中建立眼部疾病治疗的概念验证是非常有吸引力的。虽然在全球各地的人群中已经报告了大量的病例报告或小病例系列，但分子证实的SCA7个体视网膜变性的纵向临床过程尚未被记录在案。通过这项研究，我们希望收集这些信息，为未来的临床试验做准备。 目标1：建立一个分子确认的SCA7参与者队列 参与者将进行为期一周的访问，其中包括眼科诊所的评估、眼球运动记录与听力学、神经学检查、神经心理评估和神经成像。参与者将返回进行年度访问，至少五次门诊研究访问。参与者来自全国各地的神经学、遗传学和眼科诊所，以及国家共济失调基金会。目前，已有超过35名患者表示有兴趣参与这项研究，15名患者已经进行了筛选，11名分子确认的SCA7患者已经入选并成功完成了他们的基线评估。两名患者已返回接受为期一年的随访评估。 目标2：从SCA7参与者的累积队列中创建血浆、DNA和皮肤成纤维细胞样本库 所有登记的参与者在研究过程中都提供了供分析的血液样本。参与者也可以选择提供皮肤样本，尽管这对本研究并不是必需的。样本将被编码、存储，并可用于IRB预期批准的进一步研究。 目标3/4：获取和执行初步的数据分析，这些数据可以促进我们对与分子确认的SCA7相关的视网膜和神经变性进展的理解，并为未来的研究制定临床结果衡量标准 11名登记的参与者接受了标准化的医疗/眼科病史、完整的基线眼科检查以及色觉测试、视野测试、视网膜电描记术、心理生理学、眼科成像和眼动记录。此外，参与者还接受了详细的神经学检查、神经成像和神经心理学评估。登记的受试者有40到66个扩展的CAG重复序列(正常和18个)，并以不同的疾病严重程度呈现。最佳矫正视力从20/32到20/500，中央黄斑有异常的颜色辨别和视网膜敏感度降低。参与者表现出不同程度的明视和暗视反应减弱。随着更多的参与者跟进，我们希望为未来的试验确定临床结果衡量标准。

Spinocerebellar Ataxia Type 7 is a neurodegenerative disease caused by an expansion of a CAG trinucleotide repeat in the coding region of the ATXN7 gene. It is distinguished from other autosomal dominant spinocerebellar ataxias by its associated retinal degeneration. Vision loss is therefore a significant comorbidity affecting the quality of life of these patients however at this time, treatment is limited to lifestyle modification. The eye presents itself as an excellent target for research on potential therapies as it is relatively immune privileged, surgically accessible and easily examined and imaged. Establishing proof-of-concept for a therapy in ocular disease is therefore very attractive in SCA7 before application in other CNS systems. While numerous case reports or small case series have been reported in populations from across the globe, the longitudinal clinical course of retinal degeneration in molecularly-confirmed SCA7 individuals has not yet been documented. With this study, we hope to gather this information in anticipation of future clinical trials. Aim 1: Establish a cohort of participants with molecularly-confirmed SCA7 Participants will present for a one week visit which will include evaluations in the eye clinic, eye movement recordings with audiology, neurologic examination, neuropsychological assessment and neuroimaging. The participants will return for annual visits with a minimum of five outpatient study visits. Participants have been recruited from neurology, genetics, and ophthalmology practices across the nation, as well as from The National Ataxia Foundation. At this time, over thirty five patients have expressed interest in participating in the study, 15 have been screened and 11 patients who have molecularly-confirmed SCA7 have been enrolled and successfully completed their baseline evaluations. Two patients have returned for their one year follow up evaluation. Aim 2: Create a repository of plasma, DNA, and skin fibroblast samples from the accrued cohort of SCA7 participants All enrolled participants provide a blood sample for analysis during the course of the study. Participants will have the option to provide a skin sample as well, although it is not required for this study. The samples will be coded, stored, and available for additional research, as prospectively approved by the IRB. Aims 3/4: Acquire and perform preliminary analyses of data that may advance our understanding of the progression of retinal and neurodegeneration associated with molecularly-confirmed SCA7 as well as formulate clinical outcome measures for future studies The 11 enrolled participants underwent a standardized medical/ophthalmic history, complete baseline eye examination as well as color vision testing, visual field testing, electroretinography, psychophysiology, ophthalmic imaging and eye movement recordings. Additionally, participants underwent a detailed neurology exam, neuroimaging and neuropsychological assessment. The enrolled subjects have a range of 40 to 66 expanded CAG repeats (normal <18) and presented at different levels of disease severity. Best corrected visual acuity has ranged from 20/32 to 20/500, with abnormal color discrimination and decreased retinal sensitivity in the central macula. Participants demonstrate diminished photopic and scotopic responses to varying degrees. As more participants follow up, we hope to identify clinical outcome measures for future trials.