Abstract
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 CGGrepeat 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.
Highlights
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects, with age- and gender-specific penetrance, carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene
It was found that premutation alleles of the FMR1 gene are transcriptionally up-regulated (Figure 1), with some individuals producing more than eight times the normal levels of FMR1 mRNA.[3,4]
Because cases of FXTAS are largely limited to the premutation range (FMRP levels at or near normal levels), and are generally not found among those with full mutation alleles (FMRP substantially diminished), the mechanisms of FXTAS and the neurodevelopmental disorder, fragile X syndrome, must be entirely distinct—one involving elevated mRNA and the other involving a protein deficit.[7]
Summary
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects, with age- and gender-specific penetrance, carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is principally a premutation disorder, the RNA-toxicity mechanism predicts that occasional individuals with alleles producing excess FMR1 mRNA that are outside of the premutation range may, manifest some characteristics of FXTAS Consistent with this prediction, Hall et al.[58] reported a case of an older adult male with fragile X syndrome who developed a progressive neurodegenerative syndrome. It should be noted that the majority of studies have not found increased premutation or gray zone alleles in patients with parkinsonism.[64,65,66,67,68,69,70] there remains a fundamental uncertainty with respect to the involvement of gray-zone alleles in the neurodegenerative phenotypes (e.g., FXTAS, PD) that will require either much larger studies or a clear mechanistic understanding of how such alleles might contribute to disease pathogenesis
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