Approximately 30-40% of male and 8-16% of female carriers of the Fragile X premutation will develop a neurodegenerative
movement disorder characterized by intentional
tremor,
gait ataxia, autonomic
dysfunction, cognitive decline, and
Parkinsonism during their lifetime. At the molecular level, premutation carriers have increased expression levels of the FMR1 and the antisense FMR1 (ASFMR1) mRNAs. Both genes undergo alternative splicing giving rise to a number of different transcripts. Alteration in the alternative splicing process might be associated with
FXTAS. In this study, we have investigated the correlation between objective measures of movement (balance and
tremor using the CATSYS battery) and the expression of both the FMR1 and the ASFMR1 genes. In addition, we investigated whether their expression level and that of the ASFMR1 131 bp splice
isoform could distinguish between premutation carriers with
FXTAS and non-
FXTAS premutation carriers. Confirming previous findings, the expression levels of transcripts at the FMR1 locus positively correlated with the CGG repeat number and significantly differentiated the premutation carriers from the control groups. Furthermore, premutation carriers with and without
FXTAS, showed a significant difference in the expression level of the ASFMR1 131 bp splice
isoform when compared to age and gender matched controls. However, there was no significant difference in the ASFMR1 131 bp splice
isoform expression level when comparing premutation carriers with and without
FXTAS. Finally, our results indicate significant group differences in CATSYS dominant hand reaction time and postural sway with eyes closed in premutation carriers without
FXTAS compared to controls. In addition, a significant inverse association between the
tremor intensity and the expression level of ASFMR1 131 bp splice
isoform in premutation carriers compared to controls, was observed, suggesting a potential role in the pathogenesis of
FXTAS.