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. They will also be evaluated by the Physical Medicine and Rehabilitation Department (speech and swallowing at baseline and then yearly; occupational therapy, physical therapy, etc., as needed). 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 patients have expressed interest in participating in the study and we have enrolled two patients who have molecularly-confirmed SCA7 and have successfully completed their baseline evaluations.
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 two enrolled patients did not provide a skin sample at the first baseline visit. The samples will be coded, stored, and available for additional research, as prospectively approved by the CNS IRB. If whole exome/whole genome sequencing is required, separate informed consent will be obtained under another NEI protocol.
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 two 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 two enrolled subjects have 45 and 66 expanded CAG repeats (normal <18) and presented at different levels of disease severity. Both participants were found to have decreased visual acuity (ranging from 20/100 to 20/500), abnormal color discrimination (ranging from enlarged achromatic area on Cambridge Color testing to functionally achromatic) and decreased retinal sensitivity in the central macula. In terms of electrophysiologic data, both had diminished photopic and scotopic responses, however the patient with the higher number of CAG repeats had a nearly extinguished ERG. Progression cannot be assessed at this time as these two patients have only undergone one study visit, however we hope to identify clinical outcome measures for future trials as more data is collected.
