Screening for SCA27B, CANVAS and other repeat expansion disorders in Greek patients with late-onset cerebellar ataxia suggests a need to update current diagnostic algorithms

Objective

Late-onset cerebellar ataxia (LOCA) is a slowly progressive cerebellar disorder with symptom onset ≥30 years of age. Intronic tandem repeat expansions (TREs) in RFC1 and FGF14 have recently emerged as common causes of LOCA. The relative contribution of classic vs. newly discovered TREs has not been systematically investigated in LOCA cohorts.

Methods

Over 28 years, 206 consecutive Greek LOCA index patients were referred for genetic testing and, based on clinical data and inheritance pattern, screened for FRDA, SCA1,2,3,6,7, FXTAS, CANVAS and SCA27B.

Results

A genetic diagnosis was reached in 62 of 206 cases (30.1 %). Mean age was 60.1 ± 11.2 (35–87) years and mean age at onset (AAO) 52.5 ± 11.4 (30–80) years. SCA27B accounted for 9.7 % of LOCA cases, CANVAS for 7.8 % and FRDA for 4.4 %. The overall frequency of SCA1, SCA2 and SCA7 was 6.8 %. No cases of SCA3 and SCA6 were identified. FXTAS contributed 1.5 % of cases. In sporadic cases, the diagnostic yield was 22.8 % (34 of 149; SCA27B: 8.7 %, CANVAS: 8.1 %, FRDA: 2.7 %, SCA2: 1.3 %, FXTAS: 1.3 % and SCA7: 0.7 %). In familial cases, the diagnostic yield was 49.1 % (28 of 57). Two cases with CANVAS had pseudodominant inheritance. Patients with SCA27B, CANVAS and FXTAS had mean AAO > 50 years, whereas patients with FRDA, SCA1, SCA2 and SCA7 had mean AAO < 50 years.

Conclusion

Recently-discovered TREs causing SCA27B and CANVAS represent the commonest known genetic causes of LOCA. Prioritizing testing for FGF14 and RFC1 expansions in the diagnostic algorithm of LOCA is recommended.