The objective of this study was to determine whether there is a FMR1 premutation associated tremor in women who do not meet criteria for FXTAS.

Data from FMR1 premutation carrier women without FXTAS from two prior cross-sectional studies investigating clinical features and antisense FMR1 were included. Control women had normal FMR1 gene testing. Each woman had a FXTAS Rating Scale (FXTAS-RS) performed by a movement disorder neurologist, blinded to gene status.  Demographic features were analyzed using descriptive methods. The primary outcome measure was the total FXTAS rating scale score and secondary outcomes measures included adjustment for age, CGG size and molecular measures using linear regression. 

Data were included from 49 premutation and 22 control women: average age overall was 52±15 yrs (p=0.06), larger CGG1 repeat size in premutation carriers was 68.6±31 (p<0.001) and 68 women (68.57%, p<0.001) had a family history of fragile X syndrome. In the premutation women, FMR1 splice was increased at 5.6 (IQR=9.9, p<0.001), ASFMR1 increased at 2.8±2.1 (SD 2.1, p<0.001), and expression of FMR1 increased at 1.3±0.6 (p=0.001). There was a difference between premutation and control women in the total FXTAS-RS (7.3±5.1 vs. 4.1±2.; p=0.002).  Individual scores were increased in spiral drawing (p=0.01).

This study shows that there is an action tremor seen on spiral drawing in some FMR1 premutation women who do not meet criteria for FXTAS, which is associated with age. It is unclear if this phenotype is a forme fruste of FXTAS or whether this represents a separate tremor disorder that may or may not be neurodegenerative.