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.
