Researchers have shown that the negative prognostic 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 United 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.
—Glenn S. Williams
Suggested Reading
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.