Researchers have shown that the negative prognos- tic characteristics of the C9orf72 repeat expansion
in amyotrophic lateral sclerosis (ALS) apply primarily to
males with spinal-onset disease, according to a report in
the April issue of the Journal of Neurology, Neurosurgery
and Psychiatry. This finding represents “a hitherto unrecognized gender-mediated effect of the genetic variant,” said
lead author James Rooney, MD, a research fellow in the
Academic Unit of Neurology at Trinity College Dublin.
The C9orf72 mutation represents the most common
genetic cause of ALS. It affects up to 50% of familial
cases and 20% of sporadic cases and is associated with
a distinctive clinical phenotype that sometimes includes
frontotemporal dementia. The C9orf72 repeat expansion
previously has been reported as a negative prognostic
factor in ALS, but studies have not been sufficiently
powered to determine how the expanded variant affects
subgroups of patients. To further explore the interaction
of the genetic variant with demographic features, Dr.
Rooney and colleagues examined the prognostic impact
of the C9orf72 repeat expansion in European subgroups
based on gender and site of onset.
C9orf72 status in combination with demographic and
clinical data was drawn from 4,925 patients with ALS in
three prospective national ALS registries (Ireland, Italy,
and the Netherlands) and clinical data sets in the Unit-
ed Kingdom and Belgium. Flexible parametric survival
models were built including known prognostic factors
(eg, age, diagnostic delay, and site of onset), gender, and
the presence of an expanded repeat in C9orf72. These
models were used to explore the effects of C9orf72 on
survival by gender and site of onset. Individual patient
data meta-analysis was used to estimate hazard ratios for
results of particular importance.
A total of 457 ( 8.95%) of the 4,925 patients carried the C9orf72 repeat expansion. A meta-analysis of
C9orf72 estimated a survival hazard ratio of 1. 36 (range,
1. 18 to 1.57) for those carrying the expansion. Models
evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival
due to C9orf72 expansion primarily occurred in males
with spinal-onset disease (hazard ratio, 1.56).
“Within this cohort, the median age of onset was
59.3, and the median survival was 2. 29 years,” Dr.
Rooney reported. These results compared with a median age of onset of 62.3 and median survival of 2.77
years in all other spinal-onset disease, with a median
age of onset of 65 and median survival of 2. 38 years
in all bulbar-onset disease. “Moreover, and contrary to
the usual pattern in young-onset disease, male spinal-onset C9orf72 expanded cases were also more likely to
have experienced a shorter diagnostic delay, suggesting
rapidly progressing disease,” he said.
“Dissecting prognostic factors associated with
C9orf72 remains essential and highly relevant for the
design of future therapeutic strategies,” said José Manuel
Matamala, MD, and colleagues in an accompanying editorial. Dr. Matamala is affiliated with the Brain and Mind
Centre at the University of Sydney. NR
—Glenn S. Williams
Rooney J, Fogh I, Westeneng HJ, et al. C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis. J Neurol Neurosurg
Psychiatry. 2017;88( 4):295-300.
Matamala JM, Dharmadasa T, Kiernan MC. Prognostic factors in C9orf72
amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2017;88( 4):281.
Genetic Insights Refine
Prognostic Information in ALS
New data suggest a gender effect on survival
mediated by C9orf72 in patients with ALS.
The reduced survival due to C9orf72
expansion primarily occurs in males
with spinal-onset disease. Median
survival among these patients may
be 2. 29 years.