title: Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.
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.
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Aurore
authors.initials: A
authors.lastname: Curie
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Torrioli
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.forename: Kim
authors.initials: K
authors.lastname: Cornish
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: He
authors.forename: Charles
authors.initials: C
authors.lastname: Paulding
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Nouchine
authors.initials: N
authors.lastname: Hadjikhani
authors.forename: Danielle
authors.initials: D
authors.lastname: Martinet
authors.forename: Joanne
authors.initials: J
authors.lastname: Meyer
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Karine
authors.initials: K
authors.lastname: Delange
authors.forename: Amandine
authors.initials: A
authors.lastname: Brun
authors.forename: Gerald
authors.initials: G
authors.lastname: Bussy
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Talita
authors.initials: T
authors.lastname: Hilse
authors.forename: Annette
authors.initials: A
authors.lastname: Floesser
authors.forename: Janice
authors.initials: J
authors.lastname: Branson
authors.forename: Graeme
authors.initials: G
authors.lastname: Bilbe
authors.forename: Donald
authors.initials: D
authors.lastname: Johns
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
mesh_terms: D000328:Adult; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497683:FMR1 protein, human; C578935:GRM5 protein, human