The Molecular Biology of FXTAS

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult onset neurodegenerative disorder that affects many individuals, mostly males, carriers of a premutation CGG repeat expansion in the FMR1 gene (55–200 CGG repeats). FXTAS symptoms include progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, cognitive decline, and autonomic dysfunctions. The disorder is due to an RNA gain-of-function mechanism, which has also been implicated in other non-coding repeat expansion diseases, as elevated FMR1 mRNA expression levels have been observed in premutation carriers. The mechanism is very distinct from the complete transcriptional silencing of the FMR1 gene that causes fragile X syndrome. The severity of both clinical and neuropathological phenotypes, including intranuclear inclusions throughout the brain, the neuropathological hallmark of FXTAS, appears to be positively correlated with the size of the CGG repeat expansion. Disruption of the lamin A/C nuclear architecture, seen in other neuromuscular disorders, has also been reported in FXTAS and could be linked to clinical features of FXTAS, particularly peripheral neuropathy.