Current Gaps in Understanding the Molecular Basis of FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with defining clinical features that include kinetic tremor, gait ataxia, and parkinsonism, with associated features spanning medical, cognitive, and psychiatric clinical domains. The emerging model for the pathogenesis of FXTAS is that of RNA toxicity as a consequence of the sequestration of RNA binding proteins by the expanded CGG-repeat element within the FMR1 message, thus compromising the normal functions of those proteins. A principal challenge at this point is to determine precisely which proteins are involved in FXTAS pathogenesis and how to prevent or reverse this process. A second challenge is to determine why there is incomplete penetrance of FXTAS among premutation carriers with identical CGG-repeat lengths, and what the protective factors are in some carriers. Finally, the discovery in premutation mice of early neurodevelopmental abnormalities, some occurring even during late embryogenesis, raises the question of whether FXTAS is the end-stage of a life-long process of neuronal dysregulation. If an extended pre-clinical phase precedes the development of FXTAS, there is great potential for therapeutic intervention, years or even decades before its clinical features are manifest.