Role of CCG Interruptions on Disease Penetrance in Families with Spinocerebellar Ataxia Type 8

Abstract

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder which causes neurons in the cerebellum to die. SCA8 patients exhibit slowly progressive symptoms including staggering, slurred speech, and abnormalities in eye movements. Age of onset is approximately 20-40 years of age, but mutation carriers can develop the disease earlier or go through life without symptoms at all. SCA8 is caused by a CTG*CAG repeat expansion mutation on chromosome 13q21. Preliminary findings in the Ranum Lab support the hypothesis that patients with CCG*CCG interruptions within the repeat tracts are more likely to have family members with expansions that cause the disease. Because CCG interruptions are associated with higher disease penetrance, I predict that CCG or a similar mutation will be found in a group of newly identified patients with SCA8 expansions and juvenile onset (<5 years of age). To test this hypothesis, I am genotyping and sequencing the expansions in multiple SCA8 families and finding the correlations between interruptions in the repeat sequence and penetrance/age of onset. Understanding the role of these interruptions will give a better picture of how this disease is transmitted from parent to child and assist genetic counselors when helping affected families.