Defining SOD1 ALS natural history to guide therapeutic clinical trial design

• Type of Material: Article
• Authors: Taha Bali, Washington University; Wade Self, Washington University; Jingxia Liu, Washington University; Teepu Siddique, Northwestern University; Leo H Wang, University of Washington; Thomas D Bird, University of Washington; Elena Ratti, Massachusetts General Hospital; Nazem Atassi, Massachusetts General Hospital; Kevin B Boylan, Mayo Clinic Florida; Jonathan D Glass, Emory University; Nicholas J Maragakis, Johns Hopkins University; James B Caress, Wake Forest School of Medicine; Leo F McCluskey, University of Pennsylvania; Stanley H Appel, The Methodist Hospital; James P Wymer, Albany Medical Center; Summer Gibson, University of Utah; Lorne Zinman, Sunnybrook Health Sciences Centre
• Language: English
• Date: 2017-02-01
• Publisher: BMJ Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017, British Medical Journal
• Final Published Version (URL): http://dx.doi.org/10.1136/jnnp-2016-313521
• Title of Journal or Parent Work: Journal of Neurology, Neurosurgery and Psychiatry
• ISSN: 0022-3050
• Volume: 88
• Issue: 2
• Start Page: 99
• End Page: 105
• Grant/Funding Information: 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.
• Keywords: MUTATIONS; Clinical Neurology; SUPEROXIDE-DISMUTASE GENE; FLUID; MOUSE MODEL; MUTANT SOD1; Life Sciences & Biomedicine; Psychiatry; DISEASE PROGRESSION; ANTISENSE OLIGONUCLEOTIDE THERAPY; ANTIBODY; SURVIVAL; Science & Technology; AMYOTROPHIC-LATERAL-SCLEROSIS; Surgery; Neurosciences & Neurology
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology

Abstract

Importance Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS SOD1) will provide key information for optimising clinical trials in this patient population. Objective To establish an updated natural history of ALS SOD1. 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 (SOD1 A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1 non-A4V) for analysis. Results Mean age of disease onset was 49.7±12.3years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1 A4V and SOD1 non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7years for SOD1 A4V. SOD1 A4V survival probability (median survival 1.2years) was significantly decreased compared with SOD1 non-A4V (median survival 6.8years; p < 0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1 A4V compared with SOD1 non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1 A4V compared with SOD1 non-A4V (p=0.02). Conclusions and relevance SOD1 A4V 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 ALS SOD1 patient population.