Genetics, white matter, and cognition

The fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked genetic disorder in which the premutation (55–200 CGG repeats) in fragile X mental retardation 1 ( FMR1 ) causes elevated levels of FMR1 mRNA, which in turn causes RNA toxicity through sequestration of critical proteins, dysregulated DNA repair processes, and production of FMRpolyG, a toxic protein produced from repeat-associated non-AUG (RAN) translation.1,2 FXTAS is associated with tremor and ataxia, and it presents in aging carriers of the premutation. However, there is evidence that the premutation causes changes in the brain far earlier than the onset of tremor and ataxia.3,4 The premutation is unmethylated, whereas those with fragile X syndrome have a full mutation (>200 CGG repeats), and the full mutation is methylated, leading to a lack of mRNA and a lack of fragile X mental retardation protein (FMRP).