title: Focal brain malformations: seizures, signaling, sequencing.
abstract: Focal malformations of cortical development are highly associated with intractable epilepsy in children and adults. Most patients with focal cortical malformations and epilepsy will require epilepsy surgery. Recent studies have provided new insights into the developmental pathogenesis of cortical malformations specifically relating to alterations in cell signaling though the mammalian target of rapamycin (mTOR) pathway. Focal cortical dysplasias, hemimegalencephaly, and tubers in tuberous sclerosis complex all exhibit evidence for hyperactive mTOR signaling, suggesting that these disorders form a spectrum of malformations or "TORopathies" characterized by disorganized cortical lamination, cytomegaly, and intractable seizures. Alterations in mTOR activity in focal brain malformations provide a potential pathogenic pathway to investigate for gene mutations and to exploit for animal models. Most importantly, however, if select focal cortical malformations result from enhanced mTOR signaling, new therapeutic antiepileptic compounds, such as rapamycin, can be designed and tested that specifically target mTOR signaling.
authors.affiliation: Department of Neurology, PENN Epilepsy Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. peter.crino@uphs.upenn.edu
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
mesh_terms: D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D004828:Epilepsies, Partial / Q000235:genetics / Q000473:pathology / Q000601:surgery; D015870:Gene Expression; D006801:Humans; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D051379:Mice; D009154:Mutation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus