A Large Spanish Cohort Study Defines SCA27B Distinct Clinical Phenotype and its Longitudinal Progression
Abstract
BackgroundHeterozygous 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.
ObjectiveTo 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.
MethodsWe 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.
ResultsAmong 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).
ConclusionsSCA27B 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.
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BibTeX
@misc{vinagrearagon2026large,
title = {{A Large Spanish Cohort Study Defines SCA27B Distinct Clinical Phenotype and its Longitudinal Progression}},
author = {A. Vinagre-Aragon and G. Olmedo-Saura and I. Rouco Axpe and A. D. Adarmes Gomez and P. Perez Torre and B. Alemany-Perna and B. Castillo Calvo and M. F. Pacheco Mendoza and L. Garayoa Telletxea and R. Baviera-Munoz and G. Moris and I. Albajar Gomez and S. Marti and S. Colina and J. Alonso Perez and V. Velez-Santamaria and J. Bocos Portillo and L. Manrique and J. Gazulla and L. Rojas-Bartolome and E. Bellosta Diago and A. Mendez Guerrero and A. avila and M. J. Sobrido and M. a. Rubio and D. Lopez Dominguez and S. Fourcade and R. Sivera and S. Kapetanovic and I. Kortazar and E. Munoz and A. M. Mirea and C. Gil Polo and V. Garcia-Solaesa and C. Catalli and Pellerin},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.26362788},
url = {https://www.medrxiv.org/content/10.64898/2026.09.11.26362788v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A Large Spanish Cohort Study Defines SCA27B Distinct Clinical Phenotype and its Longitudinal Progression
AU - A. Vinagre-Aragon
AU - G. Olmedo-Saura
AU - I. Rouco Axpe
AU - A. D. Adarmes Gomez
AU - P. Perez Torre
AU - B. Alemany-Perna
AU - B. Castillo Calvo
AU - M. F. Pacheco Mendoza
AU - L. Garayoa Telletxea
AU - R. Baviera-Munoz
AU - G. Moris
AU - I. Albajar Gomez
AU - S. Marti
AU - S. Colina
AU - J. Alonso Perez
AU - V. Velez-Santamaria
AU - J. Bocos Portillo
AU - L. Manrique
AU - J. Gazulla
AU - L. Rojas-Bartolome
AU - E. Bellosta Diago
AU - A. Mendez Guerrero
AU - A. avila
AU - M. J. Sobrido
AU - M. a. Rubio
AU - D. Lopez Dominguez
AU - S. Fourcade
AU - R. Sivera
AU - S. Kapetanovic
AU - I. Kortazar
AU - E. Munoz
AU - A. M. Mirea
AU - C. Gil Polo
AU - V. Garcia-Solaesa
AU - C. Catalli
AU - Pellerin
PY - 2026
DA - 2026/09/11
PB - medRxiv
DO - 10.64898/2026.09.11.26362788
UR - https://www.medrxiv.org/content/10.64898/2026.09.11.26362788v1
AB - BackgroundHeterozygous 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. ObjectiveTo 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. MethodsWe 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. ResultsAmong 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). ConclusionsSCA27B 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.
ER -