Objective: To report on the frequency of intronic GAA expansions in the fibroblast growth factor 14 (FGF14) gene in patients with an unexplained cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS)-like phenotype.

Background: Dominantly inherited intronic GAA repeat expansions in FGF14 have recently been shown to be a common cause of hereditary ataxia (spinocerebellar ataxia 27B; GAA-FGF14 ataxia). Initial observations of cerebellar ataxia and bilateral vestibulopathy (BVP) in a subset of patients carrying an FGF14 GAA expansion suggested partial phenotypic overlap between SCA27B and CANVAS [1,2]. Biallelic intronic pentanucleotide expansions in the replication factor C subunit 1 (RFC1) gene are a frequent cause of CANVAS, accounting for 70% to 100% of cases in various series. While biallelic RFC1 expansions are the main cause of CANVAS-spectrum disease, other causative genes are yet to be identified, especially in the subgroup of patients with partial features of CANVAS.

Method: We recruited 45 patients negative for biallelic RFC1 expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP). We genotyped the FGF14 repeat locus using long-range and repeat-primed PCR [3]. Phenotypic features of GAA-FGF14-positive versus GAA-FGF14-negative patients were compared.

Results: Frequency of FGF14 GAA 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 3 features. BVP was observed in 75% (12/16) of GAA-FGF14-positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in 6 of 8 GAA-FGF14-positive patients. Family history of ataxia (p=0.007) was significantly more frequent and dysarthria (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 expansion (Pearson’s r, -0.68; R²=0.46; p=0.003).

Conclusion: SCA27B is a common cause of cerebellar ataxia with polyneuropathy and/or BVP in patients negative for biallelic RFC1 expansions, and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum.

References: [1] Pellerin D, Danzi MC, Wilke C, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. Jan 12 2023;388(2):128-141. doi:10.1056/NEJMoa2207406
[2] Rafehi H, Read J, Szmulewicz DJ, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genet. Jan 5 2023;110(1):105-119. doi:10.1016/j.ajhg.2022.11.015
[3] Bonnet C, Pellerin D, Roth V, et al. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia. medRxiv. 2023:2023.02.02.23285206. doi:10.1101/2023.02.02.23285206

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intronic-fgf14-gaa-repeat-expansions-are-a-common-cause-of-ataxia-syndromes-with-neuropathy-and-bilateral-vestibulopathy/