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

J Neurol Sci. 2024 Dec 15:467:123309. doi: 10.1016/j.jns.2024.123309. Epub 2024 Nov 15.

Authors

Georgios Koutsis¹, Chrisoula Kartanou², Zoi Kontogeorgiou², Chrysoula Koniari², Alexandros Mitrousias², David Pellerin³, Marie-Jose Dicaire⁴, Pablo Iruzubieta⁵, Matt C Danzi⁶, Konstantinos Athanassopoulos², Nikolaos Ragazos², Maria Stamelou⁷, Michail Rentzos⁸, Evangelos Anagnostou⁸, Stephan Zuchner⁶, Bernard Brais⁹, Henry Houlden¹⁰, Marios Panas², Leonidas Stefanis⁸, Georgia Karadima¹¹

Affiliations

¹ Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginitio Hospital, Athens, Greece. Electronic address: gkoutsis@med.uoa.gr.
² Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginitio Hospital, Athens, Greece.
³ Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, Québec, Canada; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology London and The National Hospital for Neurology and Neurosurgery, University College London, London, UK.
⁴ Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, Québec, Canada.
⁵ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology London and The National Hospital for Neurology and Neurosurgery, University College London, London, UK; Department of Neurology, Donostia University Hospital, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain; CIBERNED Centro de Investigacion Biomédica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), Madrid, Spain.
⁶ Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁷ Parkinson's disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece; School of Medicine, European University of Cyprus, Nicosia, Cyprus.
⁸ 1st Department of Neurology, National and Kapodistrian University of Athens, Eginitio Hospital, Athens, Greece.
⁹ Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, Québec, Canada; Department of Human Genetics, McGill University, Montreal, Québec, Canada.
¹⁰ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology London and The National Hospital for Neurology and Neurosurgery, University College London, London, UK.
¹¹ Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginitio Hospital, Athens, Greece. Electronic address: gkaradim@med.uoa.gr.

PMID: 39571249
DOI: 10.1016/j.jns.2024.123309

Abstract

Objective: Late-onset cerebellar ataxia (LOCA) is a slowly progressive cerebellar disorder with symptom onset ≥30years 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.

Keywords: FGF14; Greek population; Late-onset cerebellar ataxia; RFC1; Tandem repeat expansions; ataxia.

MeSH terms

Adult
Age of Onset
Aged
Aged, 80 and over
Algorithms
Cerebellar Ataxia* / diagnosis
Cerebellar Ataxia* / epidemiology
Cerebellar Ataxia* / genetics
DNA Repeat Expansion / genetics
Female
Fibroblast Growth Factors / genetics
Genetic Testing / methods
Greece / epidemiology
Humans
Male
Middle Aged
Replication Protein C / genetics
Spinocerebellar Ataxias / diagnosis
Spinocerebellar Ataxias / epidemiology
Spinocerebellar Ataxias / genetics
Spinocerebellar Degenerations

Substances

RFC1 protein, human
Replication Protein C
fibroblast growth factor 14
Fibroblast Growth Factors

Supplementary concepts

Spinocerebellar ataxia 27