Fragile X-associated tremor/ataxia syndrome - An aging face of the fragile X gene

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-adult-onset neurodegenerative disorder affecting primarily male (and occasionally female) carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). FXTAS is principally characterized as a movement disorder with progressive intention tremor and gait ataxia, with more variable associated features of parkinsonism, dysautonomia, peripheral neuropathy, and dementia. The pathogenic basis of FXTAS is overexpression of the toxic expanded CGG repeat FMR1 RNA, which leads to neural cell dysregulation, formation of intranuclear inclusions in neurons and astrocytes, and disruption of the nuclear lamin architecture. By contrast, larger CGG repeat expansions (> 200 CGG repeats, full mutation) generally result in FMR1 silencing and absence of FMR1 RNA and protein (FMRP). The lack of FMRP is the pathogenic basis of the developmental disorder fragile X syndrome, the leading heritable form of mental impairment. Thus, the same gene presents 2 opposing faces: a neurodegenerative syndrome (FXTAS) in older adults, caused by excess gene activity and production of a toxic RNA, and a childhood-onset disorder (fragile X syndrome), caused by absence of gene activity. This review will focus on FXTAS, the aging face of the fragile X gene.