Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy.

BACKGROUND: Intronic GAA repeat expansions in the fibroblast growth factor 14 gene ( FGF14 ) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1 -related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic FGF14 GAA repeat expansions in patients with an unexplained CANVAS-like phenotype.

METHODS: We recruited 45 patients negative for biallelic RFC1 repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP), and genotyped the FGF14 repeat locus. Phenotypic features of GAA- FGF14 -positive versus GAA- FGF14 -negative patients were compared.

RESULTS: Frequency of FGF14 GAA repeat expansions was 38% (17/45) in the entire cohort, 38% (5/13) in the subgroup with cerebellar ataxia plus polyneuropathy, 43% (9/21) in the subgroup with cerebellar ataxia plus BVP and 27% (3/11) in patients with all three features. BVP was observed in 75% (12/16) of GAA- FGF14 -positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA- FGF14 -positive patients. Family history of ataxia (59% vs 15%; p=0.007) was significantly more frequent and permanent cerebellar dysarthria (12% vs 54%; p=0.009) significantly less frequent in GAA- FGF14 -positive than in GAA- FGF14 -negative patients. Age at onset was inversely correlated to the size of the repeat expansion (Pearson's r, -0.67; R2 =0.45; p=0.0031).

CONCLUSIONS: GAA- FGF14 -related disease is a common cause of cerebellar ataxia with polyneuropathy and/or BVP, and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum.