Epilepsy, migraine and related paroxysmal neurological disorders affect over 15% of the population, and account for an enormous burden to the individual and to society. Progress in managing these diseases is slow, with many patients failing to respond to available medication. Understanding the mechanisms will be an essential step not only towards improved diagnosis, but also towards the development of rational therapies.
Epilepsy and migraine both exhibit strong heritability. Mendelian inheritance is however very uncommon, and only a few genes have been identified in the rare families where monogenic inheritance can be demonstrated. These genes overwhelmingly point to disorders of synaptic transmission. Polygenic variability of synaptic genes is highly likely to contribute to common sporadic forms of these diseases.
This proposal brings together complementary expertise in (i) clinical genetics and deep phenotyping of people affected by epilepsy, migraine and paroxysmal movement disorders, (ii) biophysics of presynaptic vesicle trafficking and exocytosis, (iii) the interaction of postsynaptic receptors, ion channels and perisynaptic neurotransmitter transporters, and (iv) vertebrate, invertebrate and human-derived cellular models of synaptic disorders.
The Synaptopathies initiative is funded by a Strategic Award from the Wellcome Trust to a team of researchers at the UCL Institute of Neurology and King’s College London, led by Professor Dimitri M Kullmann. The grant was awarded in 2014 with a start date in April 2015.