Authors: Jessica Famula, Emilio Ferrer, Randi J. Hagerman, Flora Tassone, Andrea Schneider, Susan M. Rivera and David Hessl

Summary

Fragile X premutation carriers are at increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset progressive neurodegenerative disease characterized by intention tremor (involuntary shaking during a purposeful movement), gait ataxia (abnormal, uncoordinated movements while walking), and cognitive decline.

To date, there is no clear picture of how FXTAS develops over time and no agreed upon markers that indicate risk. While some studies have provided indications that certain features may precede a FXTAS diagnosis, including changes in executive functioning (cognitive skills that direct things like working memory, flexible thinking, and self-control) and motor skills, the prior work had focused on comparing different people at different ages (cross-sectional research). To really understand the emergence of a disease or syndrome, it is essential to follow the same individuals over time. Drs. David Hessl and Susan Rivera of the UC Davis MIND Insititute have conducted such a study: a longitudinal (long-term) investigation, to learn more about premutation carrier aging and FXTAS progression.

The study team followed 64 men who carry the fragile X premutation and 30 men without the premutation (control participants) between the ages of 40-80 years old, many of whom have been followed for 15 years. Fifty of the premutation carriers and 22 of the control participants were re-assessed after an average of 2.33 years, and 37 of the premutation carriers and 20 control participants were re-assessed a third time after an average of another 2.15 years.

The study team conducted various tests at each timepoint in order to assess if participants were showing early signs of FXTAS and when. The study team was also looking for biomarkers – certain markers in the blood or indicators within brain images- that could help clinicians identify and treat premutation carriers at high risk for FXTAS as early as possible.

Eighteen of the 64 carriers (28%) developed or converted to FXTAS during the study to date. During their progression, the study team identified early indicators of FXTAS such as loss of visual working memory, manual dexterity, and movement speed.

Why This Matters

This is the first time that fragile X premutation carriers have been tracked in a longitudinal study. This study provides evidence for early markers of FXTAS that may be helpful to eventually identify the best candidates for early, preventive intervention. These markers should also be helpful in treatment development for FXTAS, as researchers now are better informed about which tests to assess change in the condition (or stability – suggesting protection from decline) due to treatment.

Next Steps

Members of the study team, along with other researchers, are working to develop a validated tool that can be used to track progression in premutation carriers, including those with FXTAS. The study team cites resources like the International Fragile X Premutation Registry and collaborations across the field as important ways to move this science forward.

Acknowledgements

The study team thanks the participants and their families for their effort and dedication to this research.

Famula, J., Ferrer, E., Hagerman, R.J. et al. Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome. J Neurodevelop Disord 14, 23 (2022). https://doi.org/10.1186/s11689-022-09436-y

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