title: Pathogenetic mechanisms of focal cortical dysplasia.
abstract: Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (mTOR) signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Encouraging progress has been achieved on the molecular and electrophysiologic basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches.
authors.affiliation: Department of Neurology and Neurotherapeutics, and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.
authors.forename: Isaac
authors.initials: I
authors.lastname: Marin-Valencia
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods; D004827:Epilepsy / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D054220:Malformations of Cortical Development / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000927:Anticonvulsants; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Focal cortical dysplasia; Giant cell; Mammalian target of rapamycin; PMSE syndrome; mTOR