title: Focal malformations of cortical development: new vistas for molecular pathogenesis.
abstract: Focal malformations of cortical development (FMCD) are highly associated with several neurological disorders including intractable epilepsy and neurocognitive disabilities. Over the past decade, several FMCD subtypes have been linked to hyperactivation of the mammalian target of rapamycin (mTOR) signaling cascade. In view of the roles that mTOR plays in cell proliferation, size, motility, and stem cell phenotype, many of the features of FMCD such as cytomegaly, disorganized lamination, and expression of stem cell markers can be explained by enhanced mTOR signaling. FMCD result from several distinct and fascinating molecular mechanisms including biallelic gene inactivation, somatic mutation, and potentially, viral infection. These mechanisms have been directly linked to mTOR activation. Perhaps most compelling, pharmacological inhibition of mTOR has been implemented successfully in clinical trials for select FMCD and provides a new vista for treatment.
authors.affiliation: Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, United States.
authors.forename: K-C
authors.initials: KC
authors.lastname: Lim
authors.forename: P B
authors.initials: PB
authors.lastname: Crino
mesh_terms: D000818:Animals; D006801:Humans; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: ATGC; BC; DN; FCD; FMCD; GC; GFAP; GG; HME; HPV16; MCAP; MCD; ME/ID; MPPH; MRI; PDK1; PI3K; PMSE; PTEN; Ras homolog enriched in brain; Rheb; TBC1 domain family member 7; TBC1D7; TSC; VEGF; atypical ganglion cell; autism; balloon cell; dysmorphic neuron; epilepsy; focal cortical dysplasias; focal malformations of cortical development; ganglioglioma; giant cell; glial fibrillary acidic protein; hemimegalencephaly; human papillomavirus type 16; mTOR; mTOR complex 1; mTOR complex 2; mTORC1; mTORC2; magnetic resonance imaging; malformations of cortical development; mammalian target of rapamycin; megalencephaly and intellectual disability; megalencephaly-capillary malformation; megalencephaly-polymicrogyria-polydactyly-hydrocephalus; p70S6K; p70S6Kinase; phosphatase and tensin homolog deleted in chromosome ten; phosphatidylinositol 3-kinase; phosphoinositide-dependent kinase-1; polyhydramnios-megalencephaly-symptomatic-epilepsy syndrome; rapamycin; tuberous sclerosis complex; vascular endothelial growth factor