Objective:

Repeat expansions in the FGF14 gene cause spinocerebellar ataxia 27B (SCA27B), a slowly progressive adult-onset cerebellar ataxia. This may be a common genetic cause of adult-onset ataxia, with cohort studies suggesting diagnostic rates of between 10-61% in various populations worldwide, however, prevalence studies have yet to be performed in the United States.

Background:

An estimated 50% of patients with genetic cerebellar ataxia remain undiagnosed despite rigorous genetic testing, most likely due to genetic etiologies undetectable by current genetic testing. 

Design/Methods:

A cohort of 732 predominantly adult-onset patients with undiagnosed cerebellar ataxia was evaluated and excluded for common genetic causes. Average age was 56.4 years (±16.8 years, range: 1-89 years), gender was 52.5% female, and the ancestral makeup was 71.7% white, 9.6% Asian, 2.7% Black, 1.0% Native American, with 8.1% of Hispanic/Latino ethnicity. Patients were screened with long-range and bidirectional repeat-primed PCR and products were analyzed by capillary and agarose gel electrophoresis to identify expanded FGF14 alleles and determine their approximate size.

Results:

Repeat expansions of ≥250 GAA tandem repeats were observed in 55 patients (7.5%) within the cohort. Of these 55 expansions, 31 (56%, 4.2% of cohort) were deemed fully pathogenic, with uninterrupted expansions >300 GAA tandem repeats, and 24 (44%, 3.3% of cohort) were designated low-penetrance pathogenicity, with uninterrupted expansions between 250-300 GAA tandem repeats. Clinically, of the 55 patients with diagnostic findings, 45 (81.8%) experienced unsteadiness, 45 (81.8%) demonstrated gait ataxia, 33 (60%) had episodic onset of symptoms, 27 (49.1%) experienced dizziness, 26 (47.2%) showed saccadic pursuit of eye movements, and 24 (43.6%) showed cerebellar atrophy on MRI.

Conclusions:

In a large undiagnosed ataxia patient cohort from the U.S. comprised of 732 individuals, repeat expansions of ≥250 FGF14-GAA tandem repeats were observed in 7.5%. Testing for SCA27B should be strongly considered in all adult undiagnosed ataxia patients, particularly those with episodic onset.