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

Abstract

Intronic GAA repeat expansions in the fibroblast growth factor 14 gene (<i>FGF14</i>) have recently been identified as a common cause of ataxia with potential phenotypic overlap with <i>RFC1</i>-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic <i>FGF14</i> GAA repeat expansions in patients with an unexplained CANVAS-like phenotype. We recruited 45 patients negative for biallelic <i>RFC1</i> repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP), and genotyped the <i>FGF14</i> repeat locus. Phenotypic features of GAA-<i>FGF14</i>-positive versus GAA-<i>FGF14</i>-negative patients were compared. Frequency of <i>FGF14</i> 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-<i>FGF14</i>-positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA-<i>FGF14</i>-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-<i>FGF14</i>-positive than in GAA-<i>FGF14</i>-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). GAA-<i>FGF14</i>-related disease is a common cause of cerebellar ataxia with polyneuropathy and/or BVP, and should be included in the differential diagnosis of <i>RFC1</i> CANVAS and disease spectrum.