Advances in next-generation sequencing technology and associated data analytics have accelerated genetic discovery in the epilepsies over the past two decades. Gene discovery in the developmental and epileptic encephalopathies (DEEs) has been particularly fruitful, with a specific genetic cause identified in up to 40% of cases. Evidence is now emerging for a significant monogenic contribution to the focal epilepsies. Genetic data increasingly inform clinical decision-making. Our enhanced understanding of the molecular mechanisms underpinning some monogenic epilepsies has prompted repurposing of existing drugs that target specific genetic mechanisms and development of novel precision therapies. Precision medicine aims to customise treatment to the personalized characteristics of individuals, including their genetic data. The majority of available treatments for epilepsy are imprecise symptomatic therapies, lacking true disease-modifying properties.
Epilepsy is fundamentally a disorder of neural networks, with seizures being the most visible manifestation and the target of the currently available symptomatic therapies. Disrupted brain networks may also account for the neuropsychiatric and neurodevelopmental comorbidities commonly seen in the genetic epilepsies. A broad range of disease mechanisms underlies the monogenic epilepsies including ion-channel dysfunction, dysregulation of synaptic processes, mechanistic target of rapamycin (mTOR) pathway hyperactivation and impaired chromatin remodelling and transcription regulation. For the purpose of this review, we will focus on the genetic epilepsies that result from dysregulation of the mTOR cascade, collectively referred to as mTORopathies.
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