Abstract Details

RFC1 expansions have been identified as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). The description of the first cohorts of RFC1 patients and the extension of genetic testing to broader categories of patients revealed a significant heterogeneity in clinical manifestations, course and severity of RFC1 CANVAS and disease spectrum. AAGGG expansions size, as measured by Southern Blotting, ranges from hundreds to thousands repeats but its prognostic role has not been investigated yet.

Patients were 128 (52%) females and 116 (48%) males. Median age of onset of imbalance was 55 years (range 30-76) and median disease duration at last follow up was 10 years (range 1-43). At last examination, 43% of patients had with full-blown CANVAS, 18% isolated sensory neuropathy and 39% neuropathy with cerebellar or vestibular involvement. RFC1 expansion as measured by Southern Blotting ranged from 249 to 2360 repeat units for the smaller allele, and from 294 to 3885 repeat units for the larger allele. An inverse correlation was observed between the size of expansions and age at neurological onset, age at onset of dysarthria and/or dysphagia and age at use of one stick. The correlation was stronger between clinical variables and the smaller allele.  

RFC1-related disorders show heterogenous clinical presentation and disease course. A smaller expansion has a protective role and is associated with later disease onset, later appearance of cerebellar symptoms and delayed need for walking aids. The finding also further supports a direct pathogenic role of AAGGG expansion in RFC1 CANVAS and disease spectrum.