C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis.
BACKGROUND
TheC9orf72repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of theC9orf72repeat expansion in European subgroups based on gender and site of onset.


METHODS
C9orf72status 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 inC9orf72.These were used to explore the effects ofC9orf72on 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 theC9orf72repeat expansion. A meta-analysis ofC9orf72estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender andC9orf72repeat expansions demonstrated that the reduced survival due toC9orf72expansion 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 theC9orf72expansion. 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.
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.
James
J
Rooney
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Isabella
I
Fogh
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Henk-Jan
HJ
Westeneng
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.
Alice
A
Vajda
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.
Russell
R
McLaughlin
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.
Mark
M
Heverin
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Ashley
A
Jones
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Ruben
R
van Eijk
Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Andrea
A
Calvo
Department of Neurology, ALS Center, Azienda Ospedaliera Universitaria Maggiore Della Carità, Novara, Italy.
Letizia
L
Mazzini
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Christopher
C
Shaw
Faculty of Medicine, University of Southampton, Southampton, UK.
Karen
K
Morrison
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Pamela J
PJ
Shaw
Department of Neurosciences, Experimental Neurology-Laboratory of Neurobiology, KU Leuven-University of Leuven, Belgium.|Vlaams Instituut voor Biotechnologie (VIB), Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium.
Wim
W
Robberecht
Department of Neurosciences, Experimental Neurology-Laboratory of Neurobiology, KU Leuven-University of Leuven, Belgium.|Department of Neurology, University Hospital Leuven, Leuven, Belgium.
Phillip
P
Van Damme
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Ammar
A
Al-Chalabi
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Leonard
L
van den Berg
Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Adriano
A
Chiò
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Jan
J
Veldink
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.|Department of Neurology, Beaumont Hospital, Dublin, Ireland.
Orla
O
Hardiman