From Basic Neuroscience to Improved Clinical Care

Fragile X syndrome (FXS) is the most common form of inherited intellectual deficiency and the most common identifiable single gene cause of autism, affecting 1 in 5,000 males and a lesser number of females. Autism spectrum disorders (ASD) occur in up to 2/3 of males and 1/3 of females with FXS. The Fragile X gene (FMR1) was cloned in 1991 and since then a large field has grown with roughly one hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMR1 gene homologs have been found in Drosophila and mice, and useful null mutant models generated in both. FMRP has been found to be involved in the regulation of specific messenger RNA transport, localization and expression in neurons. Briefly put, FMRP is thought to bind and help transport a crucial subset of messages to the sites of neural action (the synapses). At those synapses, FMRP is a critical switch that mediates changes in local protein expression in response to neural activity - in effect causing the synapses to strengthen or weaken as required in response to experience. When FMRP is reduced or missing in an affected person, the synapses are much less able to change with experience and learning is greatly reduced. More recently, specific signaling mechanisms have been proposed to mediate this control at the synapse, via a specific set of Gq-linked (neurotransmitter) receptors, including group I mGluRs (metabotropic glutamate receptors). It has become clear that in addition to clinical overlap between FXS and ASD, there is likely substantial overlap in the molecular pathology of the two disorders. As such, molecular defects known to cause ASD may involve other proteins in the signaling pathways that are regulated by or regulate FMRP activity, may involve proteins for which synaptic translation is regulated by FMRP, or may involve defects in neurotransmitter systems shown to be dysregulated in FXS models. Molecules aimed at targets in pathways that are dysregulated in the absence of FMRP are now being developed and tested in academic laboratories and through the pharmaceutical industry, in order to offer effective drug therapies for affected patients with FXS. It is expected that many of these targeted treatments will have therapeutic overlap in subsets of individuals with ASD.

This conference will bring together leading scientists and clinicians in the Fragile X and ASD fields. Topics will include molecular genetics, model system characterizations, synaptic signaling and function studies, small molecule trials and clinical reports.