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Research paper
C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis
  1. James Rooney1,
  2. Isabella Fogh2,
  3. Henk-Jan Westeneng3,
  4. Alice Vajda1,
  5. Russell McLaughlin1,
  6. Mark Heverin1,
  7. Ashley Jones2,
  8. Ruben van Eijk3,
  9. Andrea Calvo4,
  10. Letizia Mazzini5,
  11. Christopher Shaw2,
  12. Karen Morrison6,
  13. Pamela J Shaw7,
  14. Wim Robberecht8,9,
  15. Phillip Van Damme8,10,
  16. Ammar Al-Chalabi2,
  17. Leonard van den Berg3,
  18. Adriano Chiò4,
  19. Jan Veldink3,
  20. Orla Hardiman1,11
  1. 1Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
  2. 2Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
  3. 3Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
  4. 4Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy
  5. 5Department of Neurology, ALS Center, Azienda Ospedaliera Universitaria Maggiore Della Carità, Novara, Italy
  6. 6Faculty of Medicine, University of Southampton, Southampton, UK
  7. 7Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
  8. 8Department of Neurosciences, Experimental Neurology—Laboratory of Neurobiology, KU Leuven—University of Leuven, Belgium
  9. 9Vlaams Instituut voor Biotechnologie (VIB), Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium
  10. 10Department of Neurology, University Hospital Leuven, Leuven, Belgium
  11. 11Department of Neurology, Beaumont Hospital, Dublin, Ireland
  1. Correspondence to Dr James Rooney, Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, 152-160 Pearse Street, Dublin 2, Dublin, D02 R590 Ireland; jrooney{at}


Introduction The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset.

Methods C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance.

Results 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96).

Conclusions This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration.

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