Targeted Treatments in Fragile X Syndrome

Fragile X syndrome (FXS) is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and subsequent transcriptional silencing. The absence of FMRP (FMR1 protein) at the synapse has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. It has been postulated that this increased mGluR5 signal may be responsible for many of the clinical manifestations observed in fragile X syndrome. mGluR5 receptor antagonists have repeatedly been shown to rescue many phenotypes and endophenotypes in animal models of the fragile X syndrome. Comprehensive phenotype correction also occurs when treatment is administered later in the adult KO mice. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however the patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.