Yu et al. (2005) reported a 6-generation family with autosomal dominant pure spinocerebellar ataxia. The proband presented at age 40 years with a 13-year history of slowly progressive gait ataxia, upper limb ataxia, and dysarthria. Family history revealed ... Yu et al. (2005) reported a 6-generation family with autosomal dominant pure spinocerebellar ataxia. The proband presented at age 40 years with a 13-year history of slowly progressive gait ataxia, upper limb ataxia, and dysarthria. Family history revealed that multiple other members were affected, and 15 members were examined. Age at onset ranged from 26 to 60 years (mean, 42 years). The disorder was characterized by pure cerebellar signs, including ataxia of the trunk and limbs, dysarthria, and irregular visual pursuit movements. Intelligence was normal. MRI showed atrophy of the cerebellum sparing the pons and medulla. Anticipation was not observed. The family was of Norwegian ancestry and had immigrated to North Dakota. Hekman et al. (2012) conducted neuropathologic examination of 2 affected individuals from the family reported by Yu et al. (2005). Both showed significant loss of Purkinje cells in the cerebellar vermis with minimal or no neuronal loss in other brain regions.
In affected members of a family of Norwegian origin with autosomal dominant late-onset spinocerebellar ataxia-26, previously reported by Yu et al. (2005), Hekman et al. (2012) identified a heterozygous mutation in the EEF2 gene (P596H; 130610.0001). Detailed studies ... In affected members of a family of Norwegian origin with autosomal dominant late-onset spinocerebellar ataxia-26, previously reported by Yu et al. (2005), Hekman et al. (2012) identified a heterozygous mutation in the EEF2 gene (P596H; 130610.0001). Detailed studies of the equivalent mutation in yeast (P580Y) showed that it caused impaired translocation with an increased rate of -1 programmed ribosomal frameshift read-through during translation. Yeast carrying this mutation also showed greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge. The results suggested that the mutation disrupted the normal mechanical processes involved in translocation, and indicated that proteostatic disruption can cause a neurodegenerative disease.