Decoding the developmental and pathologic mechanisms of intractable seizure

Abstract

Combining human genomics and molecular biology, recent studies have made pivotal progress toward understanding the cause of neurodevelopmental diseases. Genetic abnormalities in somatic cells are emerging as a novel mechanism in neurodevelopmental diseases with previously unknown causes, such as focal malformation of cortical development (FMCD). FMCDs are the leading cause of pediatric epilepsies, especially medically intractable ‘catastrophic’ epilepsy. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3-E17K mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non–cell autonomous migration defect in neighboring cells. A potential future therapy may include pharmacologically targeting defective gene regulatory networks. The unique animal and stem cell models can further the molecular mechanisms of FMCD-associated seizures and the fundamental processes governing normal brain development and function.