Objective: To study the frequency and phenotype of GAA-FGF14 expansions in a large cohort of patients with bilateral vestibulopathy (BVP) syndromes.

Background: Intronic GAA repeat expansions in FGF14 cause spinocerebellar ataxia 27B (SCA27B), a common late-onset, slowly progressive cerebellar ataxia with episodic features and downbeat nystagmus (DBN). BVP has been reported as a recurrent feature of SCA27B, with some series reporting a frequency as high as 75%. However, whether FGF14 GAA repeat expansions represent a common cause of primary BVP syndromes remains to be established.

Method: We recruited 116 patients with BVP syndrome, including 92 with idiopathic BVP, 10 with biallelic RFC1 expansions, and 14 with a secondary cause. We conducted in-depth neurological and disease evolution phenotyping. Genotyping of the FGF14 repeat locus was performed, and expansions of at least 250 GAA repeat units were considered pathogenic.

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 developed cerebellar dysfunction, DBN, and BVP at ages 55 and 62, without episodic symptoms at onset. Both exhibited gait impairment but did not require walking aids. Their mean vestibulo-ocular reflex (VOR) gains on video head impulse testing were 0.22° and 0.59°, consistent with mild-to-moderate BVP. Their phenotype aligned with SCA27B. The GAA-FGF14-positive patient in the RFC1-positive group developed cerebellar dysfunction, sensory neuropathy, and BVP at age 70, consistent with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). He also exhibited DBN without episodic symptoms and remained mildly impaired after two years of progression. DBN was significantly more frequent in GAA-FGF14 expansion carriers than in idiopathic BVP patients (3/3, 100% vs 7/90, 7.8%; Fisher’s exact test, p=0.0009).

Conclusion: FGF14 GAA expansions are an uncommon cause of primary BVP syndromes and are associated with a phenotype characteristic of SCA27B. Co-occurrence with other genetic variants, such as RFC1 expansions, is possible and may influence the clinical presentation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/frequency-and-phenotype-of-gaa-fgf14-disease-in-bilateral-vestibulopathy-syndromes-insights-from-repeat-expansion-carriers-including-a-dual-diagnosis-with-rfc1-related-canvas/