The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Sarah Opie-Martin, Alfredo Iacoangeli, Simon D. Topp, Olubunmi Abel, Keith Mayl, Puja R. Mehta, Aleksey Shatunov, Isabella Fogh, Harry Bowles, Naomi Limbachiya, Thomas P. Spargo, Ahmad Al-Khleifat, Kelly L. Williams, Jennifer Jockel-Balsarotti, Taha Bali, Wade Self, Lyndal Henden, Garth A. Nicholson, Nicola Ticozzi, Diane McKenna-Yasek, Lu Tang, Pamela J. Shaw, Adriano Chio, Albert Ludolph, Jochen H. Weishaupt, John E. Landers, Jonathan D. Glass, Jesus S. Mora, Wim Robberecht, Philip Van Damme, Russell McLaughlin, Orla Hardiman, Leonard Berg, Jan H. Veldink, Phillippe Corcia, Zorica Stevic, Nailah Siddique, Vincenzo Silani, Ian P. Blair, Dong-sheng Fan, Florence Esselin, Elisa Cruz, William Camu, Nazli A. Basak, Teepu Siddique, Timothy Miller, Robert H. Brown, Ammar Al-Chalabi and Christopher E. Shaw ()
Additional contact information
Sarah Opie-Martin: Psychology and Neuroscience, King’s College London
Alfredo Iacoangeli: Psychology and Neuroscience, King’s College London
Simon D. Topp: Psychology and Neuroscience, King’s College London
Olubunmi Abel: Homerton University Hospital
Keith Mayl: Psychology and Neuroscience, King’s College London
Puja R. Mehta: Psychology and Neuroscience, King’s College London
Aleksey Shatunov: Psychology and Neuroscience, King’s College London
Isabella Fogh: Psychology and Neuroscience, King’s College London
Harry Bowles: Psychology and Neuroscience, King’s College London
Naomi Limbachiya: Psychology and Neuroscience, King’s College London
Thomas P. Spargo: Psychology and Neuroscience, King’s College London
Ahmad Al-Khleifat: Psychology and Neuroscience, King’s College London
Kelly L. Williams: Macquarie University
Jennifer Jockel-Balsarotti: Washington University School of Medicine
Taha Bali: Washington University School of Medicine
Wade Self: Washington University School of Medicine
Lyndal Henden: Macquarie University
Garth A. Nicholson: Macquarie University
Nicola Ticozzi: IRCCS Istituto Auxologico Italiano
Diane McKenna-Yasek: University of Massachusetts Medical School
Lu Tang: Peking University Third Hospital
Pamela J. Shaw: University of Sheffield
Adriano Chio: University of Turin
Albert Ludolph: Ulm University
Jochen H. Weishaupt: University of Ulm
John E. Landers: University of Massachusetts Medical School
Jonathan D. Glass: Emory University School of Medicine
Jesus S. Mora: Hospital San Rafael
Wim Robberecht: Univeristy Hospitals Leuven
Philip Van Damme: Univeristy Hospitals Leuven
Russell McLaughlin: Trinity College Dublin
Orla Hardiman: Trinity Biomedical Sciences Institute, Trinity College Dublin
Leonard Berg: University Medical Center Utrecht
Jan H. Veldink: University Medical Center Utrecht
Phillippe Corcia: Centre de Référence pour la SLA et les Autres Maladies du Motoneurone (FILSLAN)
Zorica Stevic: University of Belgrade
Nailah Siddique: Feinberg School of Medicine
Vincenzo Silani: IRCCS Istituto Auxologico Italiano
Ian P. Blair: Macquarie University
Dong-sheng Fan: Peking University Third Hospital
Florence Esselin: University Hospital Gui de Chauliac
Elisa Cruz: University Hospital Gui de Chauliac
William Camu: University Hospital Gui de Chauliac
Nazli A. Basak: School of Medicine Translational Medicine Research Center KUTTAM-NDAL
Teepu Siddique: Feinberg School of Medicine
Timothy Miller: Washington University School of Medicine
Robert H. Brown: University of Massachusetts Medical School
Ammar Al-Chalabi: Psychology and Neuroscience, King’s College London
Christopher E. Shaw: School of Neuroscience, King’s College London

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.

Date: 2022
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DOI: 10.1038/s41467-022-34620-y

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