A. Vinagre-Aragon, G. Olmedo-Saura, I. Rouco Axpe, A. D. Adarmes Gomez, P. Perez Torre, B. Alemany-Perna, B. Castillo Calvo, M. F. Pacheco Mendoza, L. Garayoa Telletxea, R. Baviera-Munoz, G. Moris, I. Albajar Gomez, S. Marti, S. Colina, J. Alonso Perez, V. Velez-Santamaria, J. Bocos Portillo, L. Manrique, J. Gazulla, L. Rojas-Bartolome, E. Bellosta Diago, A. Mendez Guerrero, A. avila, M. J. Sobrido, M. a. Rubio, D. Lopez Dominguez, S. Fourcade, R. Sivera, S. Kapetanovic, I. Kortazar, E. Munoz, A. M. Mirea, C. Gil Polo, V. Garcia-Solaesa, C. Catalli, Pellerin
Background Heterozygous GAA-TTC repeat expansions in the FGF14 gene cause spinocerebellar ataxia 27B (SCA27B), a late-onset cerebellar ataxia (LOCA) increasingly recognized in populations of European ancestry. Objective To characterize the clinical and genetic features of SCA27B and compare its phenotype and progression with those of unexplained idiopathic LOCA (ILOCA) in a large multicenter cohort. Methods We conducted a nationwide multicenter study of patients with unexplained LOCA recruited from 21 Spanish hospitals. FGF14 GAA-TTC repeat expansions were analyzed using a standardized molecular protocol. Clinical, neuroimaging, and longitudinal data were compared between patients with genetically confirmed SCA27B and those with ILOCA. Longitudinal changes in the Scale for the Assessment and Rating of Ataxia (SARA) were analyzed using linear mixed-effects models. Results Among 430 patients with unexplained LOCA, 111 (25.8%) carried FGF14 expansions >250 repeats, and 16 additional patients (3.7%) had intermediate expansions of 200-249 repeats. Including 90 externally recruited genetically confirmed cases, the SCA27B cohort comprised 217 patients. Compared with 283 patients with ILOCA, SCA27B patients had a later age at onset (median 63 vs 55 years, p<0.001), more frequent episodic symptoms (45.2% vs 12.7%), and more frequent oculomotor abnormalities (82.5% vs 71.6%). Downbeat nystagmus was particularly frequent in SCA27B (67.4% vs 32.9%). Conversely, extracerebellar features, including pyramidal and sensory signs, were more common in ILOCA. Among patients receiving 4-aminopyridine (4-AP), subjective improvement was reported more frequently in SCA27B than ILOCA (72.5% vs 36.0%). Longitudinal SARA analysis showed similar rates of progression between groups (SCA27B slope 0.37 vs ILOCA 0.35 points/year; interaction p=0.56). Conclusions SCA27B was a frequent genetic cause of unexplained LOCA in this nationwide Spanish cohort and showed a distinct clinical phenotype characterized by later onset, episodic symptoms, oculomotor abnormalities, and frequent subjective response to 4-AP. Disease progression was similar to that observed in ILOCA. These findings support systematic FGF14 testing in patients with late-onset cerebellar ataxia, particularly those with characteristic clinical features.