RT Journal Article
SR Electronic
T1 C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis
JF Journal of Neurology, Neurosurgery & Psychiatry
JO J Neurol Neurosurg Psychiatry
FD BMJ Publishing Group Ltd
SP 281
OP 281
DO 10.1136/jnnp-2016-314093
VO 88
IS 4
A1 James Rooney
A1 Isabella Fogh
A1 Henk-Jan Westeneng
A1 Alice Vajda
A1 Russell McLaughlin
A1 Mark Heverin
A1 Ashley Jones
A1 Ruben van Eijk
A1 Andrea Calvo
A1 Letizia Mazzini
A1 Christopher Shaw
A1 Karen Morrison
A1 Pamela J Shaw
A1 Wim Robberecht
A1 Phillip Van Damme
A1 Ammar Al-Chalabi
A1 Leonard van den Berg
A1 Adriano Chiò
A1 Jan Veldink
A1 Orla Hardiman
YR 2017
UL http://jnnp.bmj.com/content/88/4/281.1.abstract
AB 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.