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

  • Sci Transl Med. 2011 Jan 5;3(64):64ra1. doi: 10.1126/scitranslmed.3001708.
Sébastien Jacquemont  1 ,  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 Gasparini ,  Talita Hilse ,  Annette Floesser ,  Janice Branson ,  Graeme Bilbe ,  Donald Johns ,  Baltazar Gomez-Mancilla
Affiliations
  • 1. Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
PMID: 21209411 DOI: 10.1126/scitranslmed.3001708
Abstract

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 of metabotropic 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 promoter methylation. 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.

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