Abstract
Background
Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual
disability and autistic spectrum disorders. Recent major advances have been made in
the understanding of the neurobiology and functions of fragile X mental retardation
protein, the FMR1 gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated
with abnormalities of long-term depression and long-term potentiation and immature
dendritic spine architecture, related to dysregulation of dendritic translation typically
activated by group I mGluR and other receptors. This work has led to efforts to develop
treatments for FXS with neuroactive molecules targeted to pathways dysregulated in
the absence of fragile X mental retardation protein.
Conclusion
These agents have been shown to rescue molecular, spine, and behavioral phenotypes
in the FXS mouse model, and clinical trials are underway to translate findings in
animal models of FXS to humans, raising complex issues about trial design and outcome
measures to assess disease-modifying changes that might be associated with treatment.
Genes known to be causes of autistic spectrum disorders interact with the translational
pathway defective in FXS and it is likely that there will be substantial overlap in
molecular pathways and mechanisms of synaptic dysfunction. Thus targeted treatment
and clinical trial strategies in FXS may serve as a model for ASD and other cognitive
disorders.
Keywords
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Article info
Publication history
Published online: December 06, 2013
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© 2014 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
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