Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan

Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by cerebellar ataxia, cognitive decline, and hypogonadism. Additionally, several heterozygous mutations in STUB1 have recently been described as a cause of autosomal dominant spinocerebellar ataxia type 48. STUB1 encodes C-terminus of HSC70-interacting protein (CHIP), which functions as an E3 ubiquitin ligase and co-chaperone and has been implicated in several neurodegenerative diseases. In this study, we identified two SCAR16 pedigrees from 512 Taiwanese families with cerebellar ataxia. Two compound heterozygous mutations in STUB1, c.[433A>C];[721C>T] (p.[K145Q];[R241W]) and c.[433A>C];[694T>G] (p.[K145Q];[C232G]), were found in each SCAR16 family by Sanger sequencing, respectively. Among them, STUB1 p.R241W and p.C232G were novel mutations. SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia. Clinically, the three patients from the two SCAR16 families presented with cerebellar ataxia alone or in combination with cognitive impairment. The brain MRIs showed a marked cerebellar atrophy of the patients. In conclusion, SCAR16 is an important but often neglected diagnosis of cerebellar ataxia of unknown cause, and the isolated cerebellar ataxia without involvement of other systems cannot be a basis to exclude the possibility of STUB1-related disease.