Natural History of Spinocerebellar Ataxia Type 7 (SCA7)

脊髓小脑共济失调7型是由ATXN 7基因编码区CAG三核苷酸重复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共济失调的区别在于其相关的视网膜变性。 因此，视力丧失是影响这些患者生活质量的重要合并症，但目前治疗仅限于改变生活方式。 眼睛是研究潜在疗法的一个很好的目标，因为它相对免疫特权，手术可及，易于检查和成像。 因此，在应用于其他CNS系统之前，在SCA 7中建立眼部疾病治疗的概念验证是非常有吸引力的。 虽然在来自地球仪的人群中报告了许多病例报告或小病例系列，但尚未记录经分子学证实的SCA 7个体中视网膜变性的纵向临床病程。 通过这项研究，我们希望收集这些信息，以期待未来的临床试验。 目的1：建立一个经分子学证实的SCA 7受试者队列 参与者将进行为期一周的访问，其中包括眼科诊所的评估，眼动记录与听力学，神经检查，神经心理评估和神经成像。 受试者将返回进行年度访视，至少进行5次门诊研究访视。 参与者来自全国各地的神经病学，遗传学和眼科实践，以及国家共济失调基金会。 目前，已有40多名患者表示有兴趣参与研究，20名患者已接受筛选，17名经分子学证实的SCA 7患者已入组并成功完成基线评价。14名患者返回进行了1年随访评价，11名患者完成了第2年访视。 目标2：从SCA 7参与者的累积队列中创建血浆、DNA和皮肤成纤维细胞样本库 所有入组的参与者在研究过程中提供血液样本用于分析。受试者也可以选择提供皮肤样本，尽管本研究不要求提供。将对样本进行编码、储存，并可用于IRB前瞻性批准的其他研究。 目标3/4：获取并进行初步数据分析，这些数据可能会促进我们对与分子确认的SCA 7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局指标 筛选了20名患者，17名入组的参与者接受了标准化的病史/眼科史、完整的基线眼部检查以及色觉测试、视野测试、视网膜电图、心理生理学、眼科成像和眼动记录。 此外，参与者接受了详细的神经病学检查，神经影像学，眼动记录和神经心理学评估，作为他们基线访视的一部分，如果能够参加。 入组了14名女性和6名男性，年龄范围为15.6 - 62.8岁（平均40.2岁）。入选的受试者具有40至69个扩增的CAG重复序列（正常<18）的范围，并且以不同的疾病严重程度水平呈现。 最佳矫正视力范围为20/16至20/400，R=0.97，p<0.0001，给定参与者眼睛之间的视力相关性。我们的队列的平均扫视速度慢于正常人群。颜色辨别缺陷的范围从正常的色觉到完全无色，并且在微视野检查中注意到中央黄斑的视网膜灵敏度降低。 在具有大于45个CAG重复的大多数患者中注意到视神经萎缩和视网膜神经纤维层变薄，在给定参与者的眼睛之间具有强相关性（R=0.88，p<0.0001），进一步支持该疾病过程对称地影响双眼。参与者表现出不同程度的明视和暗视反应减弱，锥细胞功能首先受到影响。对每个参与者的IS/OS的结构性损失进行量化，并注意到眼睛之间的相关性（R=0.95，p<0.0001）。随着患者继续入组并返回进行随访，我们希望完成进一步的纵向分析，并确定未来试验的临床结局指标。

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 referred from neurology, genetics, and ophthalmology practices across the nation, as well as from The National Ataxia Foundation. At this time, over 40 patients have expressed interest in participating in the study, 20 have been screened and 17 patients who have molecularly-confirmed SCA7 have been enrolled and successfully completed their baseline evaluations. Fourteen patients have returned for their one year follow up evaluation and 11 have completed their year two visit. 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 Twenty patients have been screened and the 17 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, eye movement recordings and neuropsychological assessment as part of their baseline visit if able to participate. Fourteen females and 6 males have enrolled, age ranging from 15.6 to 62.8 (mean 40.2) years. The enrolled subjects have a range of 40 to 69 expanded CAG repeats (normal <18) and presented at different levels of disease severity. Best corrected visual acuity has ranged from 20/16 to 20/400, with R=0.97, p<0.0001 correlation of acuity between eyes of a given participant. The mean saccadic velocities of our cohort are slower than that of the normal population. Color discrimination deficits range from normal color vision to completely achromatic and decreased retinal sensitivity in the central macula is noted on microperimetry testing. Optic atrophy and retinal nerve fiber layer thinning was noted in most patients with greater than 45 CAG repeats with a strong correlation (R=0.88, p<0.0001) between eyes of a given participant further supporting this disease process as affecting both eyes symmetrically. Participants demonstrate diminished photopic and scotopic responses to varying degrees with cone function primarily affected first. Structural loss of IS/OS was quantified for each participant and was noted to be correlated between eyes (R=0.95, p<0.0001). As patients continue to enroll and return for follow up visits, we hope to complete further longitudinal analysis and identify clinical outcome measures for future trials.