When sex and genes interact: sex-related risk factors for ALS and dementia
Women with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have a higher prevalence of carrying two of the most common gene mutations that cause the genetically inherited forms of the diseases, suggests a new study.
Genetic mutations account for up to 10 per cent of ALS and 10 to 20 per cent of FTD cases.
“Because of where these mutations are located on the genes, one would expect them to be inherited similarly by men and women,” says Dr. Mary Tierney, senior author of the study and Professor and Clinician Scientist Family & Community Medicine, University of Toronto and Sunnybrook Health Sciences Centre.
“But when sex differences like this are found in the prevalence of these mutations, this suggests there may be sex-specific environmental risk factors (such as neurotoxic exposure) or biological factors (such as hormonal changes and sex-mediated brain development) that are impacting the gene.”
Another consideration, say the authors, is that women live on average longer than men and therefore are more likely to reach the age for this genetic mutation to occur.
In a large meta-analysis published in the October 2017 issue of the journal Neurology, the researchers aimed to examine differences between men and women in the prevalence of the genetic mutations that are the most common known genetic cause of both ALS and FTD. The analysis included studies that comprised a pooled sample size of 21,028 patients, and found 32 articles of 12,784 ALS patients that revealed a higher prevalence of females with the C9orf72-related ALS, and 36 articles of 3857 patients with FTD revealing a higher prevalence of females with the GRN-related FTD.
“We observed a 16 per cent higher prevalence of female C9orf72–related ALS and a 33 per cent higher female prevalence of those with FTD carrying GRN mutations,” says Dr. Ashley Curtis, lead author of the study and a postdoctoral fellow under the supervision of Dr. Tierney.
“Our findings support the consideration of sex in the understanding of gene-related ALS and FTD,” says Dr. Tierney, a neuropsychologist and Director of the Primary Care Research Unit at Sunnybrook Health Sciences Centre. “This information could increase our understanding of the causes of ALS and FTD, which could be important for treatment and management of the disorders, and could also be factored into genetic counseling recommendations.”
FTD is the second leading cause of early onset dementia, characterized by severe behaviour and language disturbances due to neuronal death in the frontal and temporal parts of the brain. ALS has similar pathological processes as it causes severe motor impairment due to neuronal loss in the spinal cord and motor cortex part of the brain. These incurable disorders have progressive, short disease courses, spanning approximately three years for ALS, and three to ten years for FTD. Men are known to have a higher prevalence of ALS overall (combination of sporadic and mutation carriers).
The researchers stress the need for more research to explore: potential sex differences in the C9orf72 and GRN gene mechanisms, and how sex-related risk factors might moderate mutation specific mechanisms such as disruption of neuroprotection and anti-inflammatory responses. They suggest longitudinal incidence studies are the only manner in which sex differences in survival and disease course can be accounted for when examining sex differences in genetically-related ALS and FTD.
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Nadia Norcia Radovini
Sunnybrook Health Sciences Centre
nadia.radovini@sunnybrook.ca
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