Objective: To determine whether there is a FMR1 premutation associated tremor in women who do not meet criteria for Fragile X-associated tremor ataxia syndrome (FXTAS)

Background: FXTAS is a progressive neurodegenerative disorder characterized by tremor, cerebellar gait ataxia, parkinsonism, and executive dysfunction.  It occurs in premutation carriers women of 55-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene usually over the age of 60. Many FMR1 premutation carrier women who do not meet criteria for FXTAS report hand tremor, most noticeable with actions of the hands.

Method: Data from FMR1 premutation carrier women from two prior cross-sectional studies were included. Women who met criteria for FXTAS were excluded and control women had normal FMR1 gene testing. A FXTAS Rating Scale (FXTAS-RS) performed by a movement disorder neurologist (DH), who was blinded to gene status.  The primary outcome measure was the total FXTAS rating scale score compared between premutation carriers and controls. Demographic features were analyzed using descriptive methods. Secondary analysis included adjustment for age, CGG size and molecular measures using linear regression and comparison of scores on individual tremor items using chi-square or Fisher’s exact.

Results: Data were included from 49 premutation and 22 normal women: age 50±15 vs. 57±14 years (p=0.06), larger CGG1 repeat size of 85±22 vs. 32± 5 (p<0.001) and 48 (90% vs. 23%, p<0.001) with a family history of fragile X syndrome. In the premutation women, FMR1 splice, ASFMR1, and expression of FMR1 were increased (p<0.001). There was a significant difference between premutation and control women in the total FXTAS-RS (7.31±5.13 vs. 4.14±2.; p=0.002). After correcting for age, the difference remained significant (p=0.003). Individual scores were increased in spiral drawing (p=0.01), but not other individual tremor items.

Conclusion: 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. The presence of tremor 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. The limitations of this study are the sample size, the lack of longitudinal follow up, and the incomplete blinding of the rater.  Additional datasets or prospective studies are needed to further define this phenotype.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fragile-x-related-tremor-in-fmr1-premutation-women-without-fxtas/