Many RFSs, as exemplified by expansion of a CGG trinucleotide repeat sequence in the fragile X syndrome-associated FRAXA locus, exhibit fragility in response to folate deficiency or other forms of “folate stress.” We hypothesized that such folate stress, through disturbing the replication program within the pathologically expanded repeats within FRAXA, would lead to mitotic abnormalities that exacerbate locus instability. The gene discussed is FMR1; the disease is fragile X syndrome.