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

Author:

Opie-Martin Sarah,Iacoangeli AlfredoORCID,Topp Simon D.ORCID,Abel Olubunmi,Mayl Keith,Mehta Puja R.ORCID,Shatunov Aleksey,Fogh Isabella,Bowles Harry,Limbachiya NaomiORCID,Spargo Thomas P.,Al-Khleifat AhmadORCID,Williams Kelly L.ORCID,Jockel-Balsarotti Jennifer,Bali Taha,Self WadeORCID,Henden LyndalORCID,Nicholson Garth A.ORCID,Ticozzi NicolaORCID,McKenna-Yasek Diane,Tang Lu,Shaw Pamela J.ORCID,Chio Adriano,Ludolph Albert,Weishaupt Jochen H.,Landers John E.ORCID,Glass Jonathan D.ORCID,Mora Jesus S.ORCID,Robberecht Wim,Damme Philip VanORCID,McLaughlin RussellORCID,Hardiman Orla,van den Berg Leonard,Veldink Jan H.ORCID,Corcia Phillippe,Stevic Zorica,Siddique Nailah,Silani Vincenzo,Blair Ian P.,Fan Dong-sheng,Esselin Florence,de la Cruz ElisaORCID,Camu WilliamORCID,Basak Nazli A.,Siddique TeepuORCID,Miller Timothy,Brown Robert H.ORCID,Al-Chalabi AmmarORCID,Shaw Christopher E.

Abstract

AbstractSuperoxide 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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