Newly published in the Journal of Neurology, Neurosurgery, and Psychiatry, findings showed frequent intronic FGF14 GAA repeat expansions in patients with RFC1-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS)-like phenotype. These findings suggest GAA-FGF14-related disease is a common cause of cerebellar ataxia with polyneuropathy and/or bilateral vestibulopathy (BVP) and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum.1
Among 45 patients, the frequency of FGF14 GAA repeat expansions was 38% (n = 17) in the whole cohort, 38% (n = 5) in the subgroup with cerebellar ataxia plus polyneuropathy (n = 13), 43% (n = 9) in the subgroup with cerebellar ataxia plus BVP (n = 21) and 27% (n = 3) in patients with all 3 features (n = 11). BVP was observed in 75% (n = 12) of GAA-FGF14-positive patients (n = 16). Polyneuropathy was at most mild and of mixed sensorimotor type in 6 of 8 patients who were GAA-FGF14-positive.
Top Clinical Takeaways
- FGF14 GAA repeat expansions emerged as a common cause of cerebellar ataxia, influencing the diagnostic landscape and requiring consideration in RFC1 CANVAS cases.
- GAA-FGF14-positive patients exhibit notable differences, including a higher prevalence of familial history of ataxia and episodic symptoms, offering potential markers for differentiation.
- While the study sheds light on GAA-FGF14-related disease, larger natural history studies are crucial to comprehensively define its phenotypic spectrum and assess its prevalence in clinically definite CANVAS cases.
“Our findings also suggest that episodic symptoms are a frequent feature in GAA-FGF14-positive patients, which may help to discriminate these patients from RFC1-positive patients in whom episodic symptoms are rare,” senior author Matthis Synofzik, MD, head division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, in Germany, and colleagues, wrote.1
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Investigators recruited patients negative for biallelic RFC1 repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or BVP from 7 different centers in Europe. The researchers conducted deep phenotyping through review of medical records for both GAA-FGF14-positive and GAA-FGF14-negative patients to genotype the FGF14 repeat locus.2 Following that, the identified phenotypic features of GAA-FGF14-positive were compared with the GAA-FGF14-negative patients.
In the study, investigators also observed that a family history of ataxia was significantly more frequent (59% vs 15%; P = .007) in GAA-FGF14-positive-patients. In addition, permanent cerebellar dysarthria (12% vs 54%; P = .009) was significantly less frequent in GAA-FGF14-positive compared with in GAA-FGF14-negative patients. Notably, the age at onset for patients was inversely correlated with the size of the repeat expansion (Pearson's r, -0.67; R2=0.45; P = .0031).
Overall, the study had a small cohort size and only 29% (n = 13) of patients underwent brain MRI, nerve conduction studies and video head impulse test. The authors also recommended that larger natural history studies should be conducted to fully define the phenotypic spectrum of GAA-FGF14-related disease and to explore its frequency in patients meeting the proposed diagnostic criteria for clinically definite CANVAS negative for biallelic RFC1 repeat expansions. These studies could then also investigate the degree to which polyneuropathy is pathologically related to GAA-FGF14-related disease, according to the authors.
“In conclusion, we showed that FGF14 GAA repeat expansions are a common cause of cerebellar ataxia plus polyneuropathy and/or BVP in patients negative for biallelic RFC1 repeat expansions, thus expanding the phenotypic spectrum of this recently described disorder. Our results further suggest that GAA-FGF14-related disease should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum,” Synofzik et al noted.1
REFERENCES
1. Pellerin D, Wilke C, Traschütz A, et al. Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. J Neurol Neurosurg Psychiatry. 2024;95(2):175-179. Published 2024 Jan 11. doi:10.1136/jnnp-2023-331490
2. Cortese A, Simone R, Sullivan R, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia [published correction appears in Nat Genet. 2019 May;51(5):920]. Nat Genet. 2019;51(4):649-658. doi:10.1038/s41588-019-0372-4
