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

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

Results: Frequency of 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--positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA--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--positive than in GAA--negative patients. Age at onset was inversely correlated to the size of the repeat expansion (Pearson's r, -0.67; R=0.45; p=0.0031).

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