Among people with a so-called premutation in the FMR1 gene, the key gene in fragile X syndrome, males show a faster progression of motor impairments than do females, a study found.
The pattern and distribution of brain lesions was also seen to differ by sex, possibly explaining why female premutation carriers appear to have a milder disease course, its researchers noted. These women, however, were more likely than men to exhibit distress, anxiety, and compulsive behaviors.
Their study, “Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement,” was published in the journal Frontiers in Molecular Biosciences.
Fragile X syndrome is caused by the expansion of CGG repeats in the FMR1 gene, which provides instructions for making the fragile X mental retardation protein, or FMRP. (In these repeats, C stands for cytosine and G for guanine, which are two of the four building blocks of DNA.)
While “full mutation” carriers — those who develop fragile X — have more than 200 CGG repeats, premutation carriers have between 55 and 200 CGG repeats. Normally, the number of these repeats does not exceed 40.
Even though premutation carriers do not have fragile X, they at risk of other disorders, including fragile X-associated tremor/ataxia syndrome (FXTAS).
FXTAS, a neurodegenerative disorder, can cause a series of motor and cognitive difficulties. In premutation carriers older than 55, its incidence is thought to range between 8–16% in women and be up to 50% in men.
“Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented,” the researchers wrote.
Scientists in Australia, along with colleagues in the U.S., assessed and compared the progression of motor, cognitive, and mental impairments in FMR1 premutation carriers of each sex.
A group of 13 female carriers, ages 37–66, and nine male carriers, ages 50–72, was first studied to compare the progression of motor difficulties, including tremors, ataxia (lack of muscle control and coordination), and parkinsonism, which refers to slow movement, muscle stiffness and other movement abnormalities seen in Parkinson’s disease.
This group was also used to compare the progression of cognitive and mental difficulties, based on the scores of several cognitive and psychiatric tests.
A second group of 21 female carriers, ages 37–78, and 24 male carriers, ages 48–80, all with at least one typical FXTAS manifestation, was used to re-assess all score measures.
Initial analyses indicated that tremors and ataxia tended to progress faster in male premutation carriers compared with females, which was confirmed in a separate group.
In men, the rate of progression for ataxia and tremor — the two measured domains within ICARS, the International Cooperative Ataxia Rating Scale — were more than twice that of women. Progression rate measured using the Clinical Rating Scale for Tremor was also two times higher in male premutation carriers than female carriers.
Women, but not men, showed significant yearly progression in assessments of psychological distress, anxiety, and obsessive/compulsive behavior.
No major differences were found between premutation carriers of either sex regarding the progression rate of parkinsonism (Unified Parkinson’s Disease Rating Scale Part III-Motor scores) and all cognitive measures.
These findings were in agreement with data from brain MRI scans, which showed that all male premutation carriers had alterations in the cerebellum, a brain region responsible for movement control and balance. Female carriers had no such cerebellar lesions.
Apart from the cerebellum, no significant differences in the distribution or severity of lesions in other brain areas were found between men and women.
“Our study reveal[s] specific differences in the level and type of motor dysfunction between male and female carriers,” the investigators wrote.
“These data, being suggestive of the existence of some sex-limited neuroprotective factors linked to the diminished cerebellar involvement in female carriers of the FMR1 premutation allele [gene copy], may indicate an avenue for future … studies,” they added.
Limitations to this study’s findings included the small size of the groups, although “the moderate to large effect sizes regarding male-female differences in both progression rate and cross-sectional analysis of motor scores indicate that this risk is low for these comparisons,” the researchers noted.
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