Women carrying so-called premutations in FMR1, the gene associated with fragile X syndrome, are at risk of developing autistic traits and anxiety, according to a new study in the U.K.
Premutation carriers have an expansion of three nucleotides — the building blocks of DNA — in the FMR1 gene. This expansion lies somewhere between the normal number of repeats, up to about 40, and the excessive number that irreversibly disrupts the gene’s activity and leads to fragile X.
Notably, this higher risk was found to be specifically associated with the presence of FMR1 premutations, rather than with the stress of caring for a child with the developmental disorder.
These findings add to previous studies reporting that premutation carriers are more likely to have certain mental disorders than those carrying the normal version of the FMR1 gene.
Together, these data highlight the need for recognition of behavioral and cognitive problems in women with FMR1 premutations, according to investigators.
Such research also supports the newly proposed term fragile X-associated neuropsychiatric conditions, scientists say.
The normal FMR1 gene, involved in brain and reproductive organ development, has up to about 40 repeats of three nucleotides: CGG. The C stands for cytosine and G for guanine.
The presence of 55 to 200 CGG repeats is classified as a premutation, with more than 200 identified as a full mutation, leading to fragile X.
People carrying a FMR1 premutation do not develop the disease, but they may have fragile X-associated primary ovarian insufficiency or fragile X-associated tremor/ataxia syndrome. In addition, their children are at a higher risk of having the full mutation. All mothers of fragile X patients have the premutation, the researchers noted.
Increasing evidence suggests that premutation carriers have a higher risk of autistic traits and negative mental health outcomes. However, it remains unclear whether this risk is specifically associated with the premutation or with the known psychological effects of caring for a child with intellectual disability, including fragile X.
Now, researchers in the U.K. set out to evaluate whether the premutation increases the risk of autistic traits, depression, and anxiety in women, regardless of having a child with fragile X syndrome, or the maternal status.
First, the team compared the mental health and parental stress levels of 51 mothers of children with fragile-X syndrome — called the M-FX group — with those of 59 mothers of children with an unidentified genetic cause of autism, 27 mothers of children with Smith-Magenis syndrome, and 44 mothers of typically developing children (control group). Smith-Magenis syndrome is a rare developmental disorder that affects several organs in the body, including the brain.
Women were recruited through disease associations in the U.K. and through schools around London. Participants completed a battery of online tests that assessed autism traits, anxiety and depression (mental health symptoms), parental stress related to having a child with a disability, and positive mood.
The results showed that mothers of fragile X patients had significantly more autistic traits than those in the control group. In addition, a greater proportion of women in the M-FX group scored above a threshold indicative of significant autistic traits, compared with all other groups; a difference that reached statistical significance in all groups, except that of mothers of autistic children.
Significantly higher levels of anxiety, depression, and parental stress also were observed among mothers of children with neurodevelopmental disorders relative to those with typically developing children.
Given that high rates of mental health symptoms and parental stress were observed among all groups, but autistic traits were only higher among mothers of children with fragile X or autism, these traits may not be “entirely mediated by the stress of caring for a child with a significant level of need,” the researchers wrote.
To assess the influence of maternal status on autistic traits and mental health in women carrying the premutation, the researchers compared the scores of the M-FX group, the control group, 17 non-mothers carrying the premutation, and 31 non-mothers with typical development.
Data showed that women with the premutation, regardless of their maternal status, had significantly more autistic traits and higher levels of anxiety than those without the premutation.
This increased risk of autistic features and anxiety was “specific to the presence of the [premutation] and is not fully accounted for by maternal status or the stress of caring for children with neurodevelopmental disorders,” the researchers wrote.
Also, further analysis using the available genetic data of 24 of the premutation carriers (mothers and non-mothers) found no significant association between the number of CGG repeats in the FMR1 gene and both autistic traits and mental health symptoms.
“The findings have implications for decision-making pathways regarding testing and diagnosis of siblings and relatives of individuals with the full [mutation], who are at risk for the [premutation],” the researchers wrote.
“Early recognition and identification of these challenges may be important for providing preventative and early intervention and support for women with the [premutation] and their families,” they added.
Future studies with larger sample sizes and additional objective autistic and mental health measures are needed to confirm these findings.
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