Importance Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.
Objective To establish an updated natural history of ALSSOD1.
Design, setting and participants Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.
Main outcomes and measures Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.
Results Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02).
Conclusions and relevance SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.
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TB and WS contributed equally.
Contributors TMM, AP, JJ-B, PA, MEC, TB designed the study. TMM, TB, WS, JJ-B, JL, ERF analysed data. TMM, TB, WS, JJ-B, JL, ERF wrote the manuscript. TS, LHW, TDB, ER, NA, KBB, JDG, NJM, JBC, LFM, SHA, JPW, SG, LZ, TM, BC, ALM, PA, GL, AP, MEC, TMM contributed clinical data to the study. TMM had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Funding provided by Seattle VA Medical Center, Department of Veterans Affairs research funds (TDB) for collection of SOD1 data at University of Washington; Amyotrophic Lateral Sclerosis Association (ER) for collection of SOD1 clinical information at MGH; Harvard NeuroDiscovery Center (ER) for collection of SOD1 clinical information at Massachusetts General Hospital; the Dr Anne B. Young Neuroscience Translational Medicine Fellowship (Massachusetts General Hospital Neurology and Biogen Idec; ER) for collection of SOD1 clinical information at Massachusetts General Hospital; Muscular Dystrophy Association (TMM) for design and conduct of the study, collection of clinical information, data management and analysis, interpretation of the data, and preparation and review of the manuscript; NIH/NINDS R25NS065743 (ER) for collection of SOD1 clinical information at Massachusetts General Hospital, R01NS078398 (TMM) for salary support to TMM during the conduct of the study, U01NS084970 (TMM) for salary support to TMM during the conduct of the study.
Competing interests TB, WS, JL, TS, LHW, ER, NA, KBB, JDG, NJM, JBC, LFM, SHA, JPW, SG, LZ, ALM, JJ-B, PA, ERF, GL, AP report no disclosures. TDB receives licensing fees from Athena Diagnostics, Inc. TM served on a medical advisory board for Biogen Idec. BC receives research support from Impeto Medical Inc and performs medical consultations for Advance Medical and consults for a PCORI grant. MEC is a consultant for Denali Inc, Cytokinetics Inc, AstraZeneca, Biogen Idec, and Voyager Therapeutics. TMM receives research support from Biogen Idec, Ionis Pharmaceuticals and research reagents from Regulus Therapeutics. Washington University, with TMM as a co-inventor, has submitted the US non-provisional patent application ‘Metabolism of SOD1 in CSF’ (Docket #011873-PCT1/1). C2N Diagnostics has licensed IP associated with this patent. TMM served on a medical advisory board for Biogen Idec, and for Ionis Pharmaceuticals.
Ethics approval Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.