An update from Dr Natali Bozhilova on a recent study
Introduction: Fragile X syndrome (FXS) is caused by an excessive repetition of the CGG region of the FMR1 gene (>200 CGG repeats), also known as full mutation. 55 to 199 CGG repeats of the same gene are referred as premutation. Most men with the premutation have ≥70 CGG repeats. Some may also develop ataxia (i.e., balance and co-ordination difficulties), which could further develop into a neurodegenerative condition called Fragile X-associated tremor/ataxia syndrome (FXTAS).
In selected, clinical samples, the likelihood of developing FXTAS related to the size of the CGG repeats.
Methods: This study used registry data, which were more representative of the wider population to check whether the lifetime chance of developing FXTAS increased with the CGG repeat size. The analysis was done on 1320 males with undiagnosed ataxia, who were over 50 and tested for FXTAS.
Results: The likelihood of developing FXTAS for male premutation carriers with ≤70 CGG repeats was low, or less than 1% (0.03%), which is considerably lower than reported previously. The chance also increased together with size of the CGG repeats (i.e., 0.63% - 71-80 CGG repeats, 3.07% - 81-90 CGG repeats and 5.96% - ≥90 CGG repeats).
Limitations: This study may have underestimated the chance of developing FXTAS for several reasons: 1) ataxia develops ~10 years earlier compared to FXTAS, 2) scarce data on ataxia, 3) no females included in the analysis, 4) men with milder or slowly developing ataxia are less likely to be in the registries. Nevertheless, even if these figures were doubled, the chance would remain low (0.06%) for men with ≤70 CGG repeats. Future studies should however confirm this percentage in both sexes and bigger samples before definitive conclusion are made.
Original article: Martin, E. M., Zhu, Y., Kraan, C. M., Kumar, K. R., Godler, D. E., & Field, M. (2022). Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS). Journal of medical genetics, 59(7), 706-709.