Phenotype Description and Lower Pathogenicity Threshold in a Large Cohort of SCA27B
Pablo Iruzubieta1, Catherine Ashton2, David Pellerin3, Felipe Villa1, Matt Danzi3, Marie-Josee Dicaire1, Mayra Aldecoa1, Mathilde Renaud4, Jean Mathieu5, Rami Massie1, Colin Chalk6, Anne-Louise Lafontaine1, François Evoy5, Marie-France Rioux7, Jean Denis Brisson5, Kim Boycott8, Stephan Zuchner9, Roberta La Piana1, Antoine Duquette10, Bernard Brais1
1Montreal Neurological Hospital and Institute, 2Hospital in Perth, Western Australia, 3Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 4Centre Hospitalier Universitaire de Nancy, 5Université de Sherbrooke, 6Montreal General Hospital, 7CHUS Fleurimont, 8CHEO Research Institute, 9University of Miami School of Medicine, 10Centre hospitalier de l'Université de Montréal
Objective:
To describe a large cohort of patients with pathogenic expansions in FGF14 from Quebec, Canada.
Background:
Spinocerebellar ataxia 27B (SCA27B) is an autosomal dominant ataxia caused by an intronic GAA repeat expansion in FGF14. The pathogenic threshold is considered above 250 GAA repeats with incomplete penetrance and above 300 GAA repeats with full penetrance. Scarce reports suggest a lower pathogenic threshold.
Design/Methods:
We clinically evaluated and performed in-depth phenotyping of individuals followed in our clinic carrying an FGF14 (GAA)≥250 allele and we conducted segregation studies in large families.
Results:
We identified 136 affected individuals from 64 families who carried an FGF14 (GAA)≥250 allele, with a mean of 381 repeats (range, 250–716). 117 were French Canadian. 111 of the patients with updated data were symptomatic (111/122, 91%). Thirteen of them had only episodic symptoms at last examination (13/111, 12%), although 77% (86/111) had episodic symptoms at disease onset. Episodic symptoms included ataxia (52/86, 60%), diplopia (40/86, 47%), dysarthria (34/86, 40%), and vertigo (24/86, 28%), frequently combined. Mean age at onset of episodic symptoms was 52.6 (range, 27-87) and it correlated inversely with the repeat size (Pearson -0.367, p = 0.001). Mean age of permanent symptoms was 58.7 and also correlated inversely with repeat size (Pearson -0.5084, p <0.0001). Interestingly, we also identified 20 affected patients with an expansion between 200-249. Although its pathogenicity is difficult to determine, some of them show a compatible phenotype, ie. episodic onset in 13 or downbeat nystagmus in six. Five of them had a positive family history of SCA27B.
Conclusions:
SCA27B is commonly associated with a episodic onset before the permanent ataxia. Our results show a correlation between repeat size and age of onset. This series provide evidence that even lower threshold may be pathogenic, although further research and precised criteria are needed.
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