Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056

Sébastien Jacquemont, Aurore Curie, Vincent Des Portes, Maria Giulia Torrioli, Elizabeth Berry-Kravis, Randi J Hagerman, Feliciano J. Ramos, Kim Cornish, Yunsheng He, Charles Paulding, Giovanni Neri, Fei Chen, Nouchine Hadjikhani, Danielle Martinet, Joanne Meyer, Jacques S. Beckmann, Karine Delange, Amandine Brun, Gerald Bussy, Fabrizio GaspariniTalita Hilse, Annette Floesser, Janice Branson, Graeme Bilbe, Donald Johns, Baltazar Gomez-Mancilla

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301 Scopus citations


Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It 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 resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation ofmetabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. 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, seven 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). We detected no response in 18 patients with partial promotermethylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. 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.

Original languageEnglish (US)
Article number64ra1
JournalScience Translational Medicine
Issue number64
StatePublished - Jan 5 2011

ASJC Scopus subject areas

  • Medicine(all)


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