Clinical, Genetic, and Imaging Characteristics of SCA27B: Insights from a Large Dutch Cohort

Abstract

Background: Deep intronic GAA repeat expansions in intron 1 of the FGF14 gene were identified in 2023 as cause of late-onset cerebellar ataxia. Since then, GAA-FGF14-related ataxia (SCA27B) has emerged as one of the most common genetic causes of late-onset cerebellar ataxia. Objectives: To describe the clinical, genetic, and imaging features of a large Dutch cohort. Methods: The Radboudumc genetic database was queried for GAA-FGF14 expansions ≥200. Repeat length was assessed using locus-spanning polymerase chain reaction (PCR), repeat-primed PCR, and PacBio sequencing. A subset was validated using Oxford Nanopore. Clinical and imaging data were retrospectively reviewed. Results: 127 individuals with GAA-FGF14 expansions ≥200 were identified; clinical data were available from 116, including 109 symptomatic and 7 asymptomatic/presymptomatic individuals. Fifteen individuals carried GAA200-249 expansions; 60% exhibited at least one core SCA27B feature. Episodic symptoms occurred in 72.5%; 24% had prior emergency department or outpatient transient ischemic attack clinic visits. Brain magnetic resonance imaging frequently showed non-specific white matter abnormalities (>90%); Superior cerebellar peduncle sign was present in 67.7%. Among those treated, 54.1% reported symptomatic benefit from 4-aminopyridine. Nanopore and PacBio sequencing results showed high correlations. We observed an inverse relationship between age at onset and disease progression. Conclusions: Core SCA27B features emerge in those carrying GAA200-249 expansions. SCA27B may mimic stroke in patients with episodic symptoms. In our cohort, later onset was associated with faster disease progression. The superior cerebellar peduncle sign may aid diagnosis, while relevance of white matter changes remains unclear. Positive response to 4-aminopyridine was reported in approximately half of patients.