Defining SOD1 ALS natural history to guide therapeutic clinical trial design.
OBJECTIVE
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.


METHODS
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.


METHODS
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 SOD1A4Vand 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. SOD1A4Vsurvival 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 SOD1A4Vcompared with SOD1non-A4Vparticipants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4Vcompared with SOD1non-A4V(p=0.02).


CONCLUSIONS
SOD1A4Vis 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 ALSSOD1patient population.
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Taha
T
Bali
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Wade
W
Self
Division of Public Health Sciences, Washington University School of Medicine, St Louis, Missouri, USA.
Jingxia
J
Liu
Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Teepu
T
Siddique
Department of Neurology at University of Washington Medical Center, University of Washington, Seattle, Washington, USA.
Leo H
LH
Wang
Department of Neurology at University of Washington Medical Center, University of Washington, Seattle, Washington, USA.|Geriatrics Research at Seattle Veterans Affairs Medical Center, Seattle, Washington, USA.
Thomas D
TD
Bird
Massachusetts General Hospital, Neurology Clinical Research Institute, Boston, Massachusetts, USA.
Elena
http://orcid.org/0000-0002-9321-7908
E
Ratti
Massachusetts General Hospital, Neurology Clinical Research Institute, Boston, Massachusetts, USA.
Nazem
N
Atassi
Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
Kevin B
KB
Boylan
Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
Jonathan D
JD
Glass
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
Nicholas J
NJ
Maragakis
Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
James B
JB
Caress
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Leo F
LF
McCluskey
Department of Neurology, Methodist Neurological Institute, The Methodist Hospital, Houston, Texas, USA.
Stanley H
SH
Appel
The Neurosciences Institute, Albany Medical Center, Albany, New York, USA.
James P
JP
Wymer
Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
Summer
S
Gibson
Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Lorne
L
Zinman
Department of Neurology, University of California, Irvine, California, USA.
Tahseen
T
Mozaffar
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Brian
B
Callaghan
Department of Neurology, The University of Kansas Medical Center, Kansas City, Kansas, USA.
April L
AL
McVey
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Jennifer
J
Jockel-Balsarotti
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Peggy
P
Allred
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Elena R
ER
Fisher
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Glenn
G
Lopate
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Alan
A
Pestronk
Massachusetts General Hospital, Neurology Clinical Research Institute, Boston, Massachusetts, USA.
Merit E
ME
Cudkowicz
Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
Timothy M
TM
Miller
D000328:Adult; D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002986:Clinical Trials as Topic; D018450:Disease Progression; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D012107:Research Design; D012189:Retrospective Studies; D013482:Superoxide Dismutase / Q000235:genetics*; D014797:Vital Capacity / Q000502:physiology
D013482:Superoxide Dismutase