Understanding SCN8A and Voltage-Gated Sodium Channelopathies

Abstract

Epilepsy is one of the most common childhood neurologic conditions affecting roughly 1% of children younger than the age of 15 years. Epileptic events that occur early in a child’s life can range in severity from ‘benign’ cases, where a child ultimately outgrows their seizures, to more severe cases with children suffering from drug-resistant seizures. In fact, there are over 50 forms of early infantile epileptic encephalopathies (EIEE) caused by different genes, several of which are within voltage-gated sodium channels (VGSCs). The focus of this dissertation was to create a deeper understanding of the clinical and biological risk factors of developmental outcome in children affected by mutations within VGSCs. Closer examination of the similarities among VGSCs can reveal channel-specific sensitivities to mutations as well as common sensitivities that lead to childhood epilepsy. By analyzing patient and healthy variant distribution of three central nervous system VGSCs (NaV1.1, NaV1.2, and NaV1.6) I found that all three channels have a heightened sensitivity to variation from the voltage-sensing domain to the pore-forming domain. Channel-specific sensitivities were also found within the inactivation gate, responsible for fast inactivation of the channel, as well as the linker containing the selectivity filter, which is responsible for sodium ion permeation. These sensitivities are hypothesized to reflect the exact neuronal location of the channel and highlight key regions of interest for future studies. Once the pattern of variant distribution for SCN8A variants was established, I explored the phenotypic spectrum of patients. Like other childhood epilepsy disorders, the age at seizure onset, current seizure freedom, and febrile seizures were all found to be positively correlated with development in the SCN8A-cohort. Interestingly a clear distinction between children with a single SCN8A variant and those with an additional reported variant was found, suggesting a possible modifying effect. The establishment of these characteristics is the first of its kind for SCN8A-specific epilepsy and will be the basis of future longitudinal research. Finally, in order to better study SCN8A-related epilepsy, we utilized a previously established mouse model and by backcrossing the mouse onto 3 different genetic backgrounds, a mouse colony was created that resulted in the first ever adult SCN8AN1768D D/D mouse as well as a SCN8AN1768D D/+ line that has an average 6-month survival of >90%. These models present a before unavailable commodity which would allow for drug-testing on a SCN8AN1768D D/D mouse after it had been weaned; as well as become a model for studying genetic interactions or modifiers to SCN8A, which could result in new therapeutic avenues.