• J. Neurol. Neurosurg. Psychiatr. · Apr 2017

    C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis.

    • James Rooney, Isabella Fogh, Henk-Jan Westeneng, Alice Vajda, Russell McLaughlin, Mark Heverin, Ashley Jones, Ruben van Eijk, Andrea Calvo, Letizia Mazzini, Christopher Shaw, Karen Morrison, Pamela J Shaw, Wim Robberecht, Phillip Van Damme, Ammar Al-Chalabi, Leonard van den Berg, Adriano Chiò, Jan Veldink, and Orla Hardiman.
    • Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.
    • J. Neurol. Neurosurg. Psychiatr. 2017 Apr 1; 88 (4): 281281.

    IntroductionThe 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.MethodsC9orf72 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.Results457 (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).ConclusionsThis 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.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

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