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Epigenetic Modification of the FMR1 Gene in Fragile X Syndrome Is Associated with Differential Response to the mGluR5 Antagonist AFQ056
Open accessAbstract
An antagonist for the metabotropic glutamate receptor may improve symptoms in patients with fragile X syndrome whose FMR1 promoters are fully methylated.
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“Results from post-hoc analyses of a mavoglurant phase IIa trial71 showed improvement in patients with FXS and full methylation but were not replicated in the two phase IIb trials.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [71]
In the citing paper
“As a result, a broad range of secondary outcome measures were tested to search for a sensitive measure or subgroup of responders to inform the design of subsequent phase IIb and III trials68,71.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [71]
In the citing paper
“Intriguingly, in this small trial, improvements in inappropriate speech, stereotypic behavior, and hyperactivity and efficacy have been reported in adults with FXS who have a fully methylated FM allele but not in those with mosaicism (36).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [36]
In the citing paper
“Discovery of elevated metabotropic glutamate receptor subtype 5 (mGluR5)–mediated signaling and protein synthesis in fragile X knockout mice (53–56) provided the rationale for testing mGluR5 antagonists in ongoing fragile X clinical trials.”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [56]
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Metadata
- Authors
- Jacquemont, S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R. J., Ramos, F. J., Cornish, K., He, Y., Paulding, C., Neri, G., Chen, F., Hadjikhani, N., Martinet, D., Meyer, J., Beckmann, J. S., Delange, K., Brun, A., Bussy, G., Gasparini, F., Hilse, T., Floesser, A., Branson, J., Bilbe, G., Johns, D., & Gomez-Mancilla, B.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Centre National de la Recherche Scientifique (FR)
- National Reference Center for Fragile X and Other XLMR, Hospices Civils de Lyon, Université de Lyon and CNRS UMR 5230 (L2C2), F-69675 Bron, France.
- Università Cattolica del Sacro Cuore (IT)
- Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.
- University of California, Davis (US)
- Universidad de Zaragoza (ES)
- Monash University (AU)
- Biomarker Development, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
- Harvard University (US)
- Novartis (Switzerland) (CH)
- Neuroscience Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
- Corresponding author
- Jacquemont, Sébastien
- Curie, Aurore
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2011-01-05
- Volume
- 3
- Issue
- 64
- Pages
- 64ra1-64ra1
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2103709346
- Cited by
- 609
- References
- 22
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 10 · 2022: 7 · 2021: 29 · 2020: 27 · 2019: 17 · 2018: 26 · 2017: 53 · 2016: 51 · 2015: 56 · 2014: 76 · 2013: 104 · 2012: 89
- FWCI
- 64.25
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, FMR1 gene, mGluR5 antagonist, CGG repeat expansion, epigenetic silencing, aberrant behavior, Aberrant Behavior Checklist, metabotropic glutamate receptors, intellectual disability, treatment response
- MeSH terms
- Adult, Fragile X Syndrome, Humans, Male, Middle Aged, Promoter Regions, Genetic, Receptors, Metabotropic Glutamate, DNA Methylation, Epigenesis, Genetic, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Young Adult, Receptor, Metabotropic Glutamate 5
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