Focal epilepsies, where seizures initiate in spatially limited networks, are the most frequent epilepsy type, accounting for two-thirds of patients. Focal epilepsies have long been thought to be acquired disorders; several focal epilepsy syndromes are now proven to be (genetically heterogeneous) monogenic disorders. While earlier genetic studies have demonstrated a strong contribution of ion channel and neurotransmitter receptor genes, or synaptic secreted protein genes, later work has revealed a new class of genes encoding components of the mechanistic target of rapamycin (mTOR) signal transduction pathway. The mTOR pathway controls a myriad of biological processes among which cell growth and protein synthesis in response to several extracellular and intracellular. Recently, germline mutations have been found in genes encoding the components of the GATOR1 complex (DEPDC5, NPRL2, NPRL3), a repressor of mTORC1. These mutations are increasingly recognized as causing a wide and yet evolving spectrum of focal epilepsy syndromes, with and without cortical structural abnormalities (usually focal cortical dysplasia). Brain somatic mutations in the gene encoding mTOR (MTOR) have recently been linked to focal cortical dysplasia and other associated brain pathologies including hemimegalencephaly. This chapter reviews the genetics and neurobiology of DEPDC5, NPRL2, and NPRL3, and summarizes the clinical and molecular spectrum of GATOR1-related epilepsies.
Keywords: DEPDC5; GATOR1; Genetics; NPRL2; NPRL3; SUDEP; mTOR.
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