Fragile X syndrome, which is caused by mutation in a single gene, on the X chromosome.
The most common causes of intellectual disability.
Many Fragile X patients also present with the symptoms of autism, and Fragile X mutations account for 3 to 4 percent of autism cases.
This syndrome was described in 1943, but the mutated gene was not molecularly identified until 1991.
Based on findings in cellular and animal models, interpreted in the context of a vast literature from basic neuroscience studies, the function of the mutated protein called FMRP was elucidated.
Works at neuronal synapses to put the brakes on a biochemical process that generates new proteins and mediates synaptic plasticity changing the strengths of connections between neurons; when the gene encoding FMRP is mutated in mice, the process of synaptic plasticity is misregulated, excitatory neurons become hyperconnected, at the cellular level, and the cortex becomes hyperexcitable, with altered patterns of rhythmic activity.
These changes are associated with cognitive defects, impaired social interaction, hyperactivity, auditory hypersensitivity, and audiogenic seizures, mimicking many aspects of Fragile X syndrome in humans.
The detailed knowledge of how FMRP functions suggested a therapeutic approach:
1. If the brakes on the process of synaptic plasticity were not working so well.
2. FMRP normally antagonizes a pathway that is activated by a protein that senses the level of activity between neurons a metabotropic glutamate receptor and in the absence of FMRP, that pathway is overactive.
3. Lowering the amount of the metabotropic glutamate receptor, or blocking its function with drugs, proved remarkably successful in reversing many of the effects of mutation of the Fragile X gene in mice, from the cellular level to the physiological and behavioral levels.
4. Drugs that block this metabotropic glutamate receptor are now in clinical trials for Fragile X syndrome. Although still at an early stage, these efforts illustrate the core concept in medicine of developing therapeutics based on detailed biological knowledge, as opposed to serendipity or random screening of chemical compounds.
For a field where no drugs with new mechanisms of action have been developed for over sixty years, the seismic nature of this paradigm shift cannot be overstated. This example also highlights the importance of individual genetic diagnoses and personalized treatment.
Even if such drugs can prevent or reverse some of the symptoms in Fragile X patients, they may not be effective in other cases of intellectual disability or autism and they may, in fact, be contraindicated for some patients.