Translational endpoints in fragile X syndrome

Neurosci Biobehav Rev. 2014 Oct:46 Pt 2:256-69. doi: 10.1016/j.neubiorev.2013.10.012. Epub 2013 Oct 30.

Abstract

Fragile X syndrome (FXS) occurs in less than 10% of the intellectually disabled (ID) population. The cause of FXS is a CGG trinucleotide repeat longer than 200 CGG units within the first exon of the FMR1 gene, which leads to hypermethylation and consequently silencing of the FMR1 gene. The lack of FMR1's gene product, the fragile X mental retardation protein (FMRP) in neurons is the cause of the ID in patients with FXS. FMRP plays an important role in local protein synthesis at the synapse including modulation of synaptic plasticity. The advancing knowledge about the cellular function of FMRP has led to the identification of translational endpoints for future therapeutic intervention strategies. This review highlights the challenging routes to the identification of reliable outcome measures in preclinical studies using both cellular models and Fmr1 knockout mice. Finally, clinical studies carried out to correct intellectual and behavioral deficits in patients with FXS, using a variety of existing and new drugs, are discussed.

Keywords: FMR1; Fmr1 KO mouse; Fragile X syndrome; Outcome measures; Therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / diagnosis
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / metabolism*
  • Humans
  • Mice, Knockout
  • Models, Neurological
  • Molecular Targeted Therapy*
  • Neuronal Plasticity / genetics*
  • Neurons / metabolism
  • Nootropic Agents / therapeutic use
  • Outcome Assessment, Health Care

Substances

  • Biomarkers
  • Nootropic Agents
  • Fragile X Mental Retardation Protein