Childhood epilepsy is in many patients a long-term medical problem because idiopathic early onset seizures can have harmful developmental sequelae and substantially increase the occurrence of later-onset therapeutically resistant seizures. Indeed, up to 30% of epilepsy patients do not respond to currently available therapeutics despite the development in the last 15 years of more efficacious drugs with better bioavailability and reduced toxicity. Following this laboratory s discovery of the KCNQ2 and KCNQ3 early childhood epilepsy genes, Retigabine was investigated as a first-in-class anti-epileptic drug because it specifically targets these potassium channel protein subunits. Subsequent clinical trials demonstrated that Retigabine is effective as an adjunct treatment for partial onset seizures in adult patients with refractory epilepsy. This indicates the importance of the strategy of identifying monogenic susceptibility genes in families with idiopathic epilepsy. This proposal plans to continue to discover five novel childhood epilepsy genes segregating in large families using sequence capture and next generation sequencing methods. Seizures in two of these families are caused by mutations in genes located in regions of the genome not previously shown to harbor epilepsy genes. The protein products of novel mutated genes become important drug targets for adults as well as children. The second goal for this proposal is to identify new mutations in common, multifactorial epilepsies that are not amenable to traditional linkage studies and gene discovery because their complex etiology greatly reduces the statistical power to detect segregating alleles. These multifactorial epilepsies, such as temporal lobe epilepsy, may harbor molecular defects in genes known to cause clinically related Mendelian epilepsies, such as febrile seizures. These new epilepsy genetic discoveries will give biological insight into mechanisms underlying these complex phenotypes and pave the way for better diagnosis and treatment options.
The final aim i n this proposal is to create gene by environment (G x E) and digenic (G x G) mouse models that harbor the precise gene defects found in children with epilepsy. The G x E model is our already developed N10 congenic knockin Scn9a-N641Y mouse exposed to hyperthermia and infection to elicit the same events reported by severely affected family members with our recently discovered SCN9A-N641Y mutation. The second model is based on the identical digenic SCN1A and SCN9A missense mutations that we have discovered in one of our Dravet syndrome patients. These new mutant models will be characterized for EEG abnormalities, seizure thresholds and histological defects. Ultimately, to answer the question of how to block the development of epilepto-genesis in these models, the anticonvulsant profile will be investigated using a panel of therapeutically relevant drugs. If seizures in these new models are not blocked by existing anticonvulsant drugs, then these models will have high utility in the development of new antiepileptogenic agents.
This study involves geneticists, pediatric neurologists, and pharmacologists all working to translate basic science findings to individuals with common and severe epilepsy. The result of this proposed research plan will reveal novel therapeutic targets for drug development and will ultimately lead to better patient care for individuals with epilepsy.
