Frequency and phenotype of GAA-FGF14 disease in bilateral vestibulopathy syndromes: insights from repeat expansion carriers, including a case of co-occurrence with RFC1-related CANVAS

Abstract Objectives Intronic FGF14 GAA repeat expansions cause spinocerebellar ataxia 27B (SCA27B) / GAA- FGF14 disease. Bilateral vestibulopathy (BVP) has been reported as a recurrent feature of this disease. Here, we aimed to determine whether GAA- FGF14 expansions represent a common cause of primary BVP syndromes. Methods FGF14 genotyping, and in-depth neurological, vestibular and disease evolution phenotyping of 116 consecutive patients meeting the diagnostic criteria for BVP, including 92 with idiopathic BVP, 10 with biallelic RFC1 expansions, and 14 with a secondary cause. Results Two patients in the idiopathic BVP group (2/92, 2.2%; 430 and 349 GAA repeats) and one in the RFC1 -positive BVP group (1/10, 10%; 255 GAA repeats) carried an FGF14 (GAA) ≥250 expansion. No expansions were detected in the secondary BVP group. In the idiopathic BVP group, the GAA- FGF14 -positive patients had mild-to-moderate BVP and a phenotype that aligned with SCA27B. The patient carrying both FGF14 and biallelic RFC1 expansions developed cerebellar dysfunction, downbeat nystagmus, sensory neuropathy, and BVP at age 70. Downbeat nystagmus was observed in all GAA- FGF14 expansion carriers (3/3, 100%) compared to only a minority of patients with idiopathic BVP (7/90, 8%; Fisher’s exact test, p = 0.0009). Discussion The phenotypic spectrum of GAA- FGF14 disease can include a relevant bilateral vestibular deficit (BVP); however, FGF14 GAA expansions are overall a rare cause of primary BVP syndromes. Given the possible co-occurrence of GAA- FGF14 and RFC1 expansions, dual diagnosis should be considered in patients presenting with unusual or broader phenotypes.