Fragile X Research and Treatment Center, UC Davis, MIND Institute, Sacramento, CA.
Fragile X syndrome (FXS) is the most prevalent and well-understood monogenetic cause of intellectual disability (ID) and autism spectrum disorder (ASD); its high penetrance and the seminal importance of FMRP in synaptic plasticity make FXS an ideal model for the study of neurodevelopmental disorders in general. In fact recent studies suggest that there is functional convergence of a number of genes that are implicated in ID and ASD, indicating that an understanding of the cellular and biochemical dysfunction that occurs in monogenic forms of ID are likely to reveal common targeted treatments.
Recent progress in understanding the biological mechanisms of FXS has provided information about how the loss of function of FMRP results in biochemical, anatomical and physiological dysfunction and how these abnormalities can be rescued in animal models with targeted treatments that reverse these neurobiological changes. Most promising are the targeted treatments of mGluR5 antagonists and GABAa agonists that are now in clinical trials in patients with FXS. The challenges faced in evaluating improvements and efficacy of targeted treatments will be reviewed. FXS has led to a new era in which targeted molecular treatments for a variety of neurodevelopmental disorders, including the RASopathies is becoming a reality.