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Research paper
Defining SOD1 ALS natural history to guide therapeutic clinical trial design
  1. Taha Bali1,
  2. Wade Self1,
  3. Jingxia Liu2,
  4. Teepu Siddique3,
  5. Leo H Wang4,
  6. Thomas D Bird4,5,
  7. Elena Ratti6,
  8. Nazem Atassi6,
  9. Kevin B Boylan7,
  10. Jonathan D Glass8,
  11. Nicholas J Maragakis9,
  12. James B Caress10,
  13. Leo F McCluskey11,
  14. Stanley H Appel12,
  15. James P Wymer13,
  16. Summer Gibson14,
  17. Lorne Zinman15,
  18. Tahseen Mozaffar16,
  19. Brian Callaghan17,
  20. April L McVey18,
  21. Jennifer Jockel-Balsarotti1,
  22. Peggy Allred19,
  23. Elena R Fisher1,
  24. Glenn Lopate1,
  25. Alan Pestronk1,
  26. Merit E Cudkowicz6,
  27. Timothy M Miller1
  1. 1Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA
  2. 2Division of Public Health Sciences, Washington University School of Medicine, St Louis, Missouri, USA
  3. 3Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  4. 4Department of Neurology at University of Washington Medical Center, University of Washington, Seattle, Washington, USA
  5. 5Geriatrics Research at Seattle Veterans Affairs Medical Center, Seattle, Washington, USA
  6. 6Massachusetts General Hospital, Neurology Clinical Research Institute, Boston, Massachusetts, USA
  7. 7Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA
  8. 8Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA
  9. 9Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
  10. 10Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  11. 11Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  12. 12Department of Neurology, Methodist Neurological Institute, The Methodist Hospital, Houston, Texas, USA
  13. 13The Neurosciences Institute, Albany Medical Center, Albany, New York, USA
  14. 14Department of Neurology, University of Utah, Salt Lake City, Utah, USA
  15. 15Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  16. 16Department of Neurology, University of California, Irvine, California, USA
  17. 17Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
  18. 18Department of Neurology, The University of Kansas Medical Center, Kansas City, Kansas, USA
  19. 19Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  1. Correspondence to Dr Timothy M Miller, Washington University in St. Louis, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO 63110, USA; millert{at}neuro.wustl.edu

Abstract

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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