Precision Therapy for Epilepsy Related to Brain Malformations

Abstract

Malformations of cortical development (MCDs) represent a range of neurodevelopmental disorders that are collectively common causes of developmental delay and epilepsy, especially refractory childhood epilepsy. Initial treatment with antiseizure medications is empiric, and consideration of surgery is the standard of care for eligible patients with medically refractory epilepsy. In the past decade, advances in next generation sequencing technologies have accelerated progress in understanding the genetic etiologies of MCDs, and precision therapies for focal MCDs are emerging. Notably, mutations that lead to abnormal activation of the mammalian target of rapamycin (mTOR) pathway, which provides critical control of cell growth and proliferation, have emerged as a common cause of malformations. These include tuberous sclerosis complex (TSC), hemimegalencephaly (HME), and some types of focal cortical dysplasia (FCD). TSC currently represents the best example for the pathway from gene discovery to relatively safe and efficacious targeted therapy for epilepsy related to MCDs. Based on extensive pre-clinical and clinical data, the mTOR inhibitor everolimus is currently approved for the treatment of focal refractory seizures in patients with TSC. Although clinical studies are just emerging for FCD and HME, we believe the next decade will bring significant advancements in precision therapies for epilepsy related to these and other MCDs.

Keywords: Epilepsy; Malformations of cortical development (MCDs); Mammalian target of rapamycin (mTOR); Precision therapy; Somatic mosaicism.

Fig. 1

The mTOR pathway and associated MCDs. Schematic of the mammalian target of rapamycin (mTOR) pathway, with protein components annotated with the malformations of cortical development (MCDs) for which pathogenic mutations have been identified in the respective genes. Bold indicates pathogenic somatic mutations have been identified. FCD, focal cortical dysplasia; HME, hemimegalencephaly; MEG, megalencephaly; PMSE, polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; TSC, tuberous sclerosis complex

Fig. 2

mTORopathies timeline. Timeline of key events in the history of tuberous sclerosis complex (TSC) (left) and focal cortical dysplasia (FCD) II and hemimegalencephaly (HME) (right) from gene discovery to the development of precision therapies