title: Brain overgrowth in disorders of RTK-PI3K-AKT signaling: a mosaic of malformations.
abstract: Disorders of brain overgrowth are significant causes of intractable epilepsy, intellectual disability, autism, and other complex neurological problems. The pathology of these disorders is sometimes striking and characteristic, as in hemimegalencephaly, but can also be subtle, as in autism. Recent genetic studies have shown that many diverse forms of brain overgrowth are caused by de novo mutations that increase activity in the receptor tyrosine kinase (RTK)-phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway, a key mediator of signaling by growth factors in the developing brain, such as fibroblast growth factors. In cases where mutations arise in postzygotic embryos, brain regions exhibit mosaic pathology that reflects the distribution of mutant cells, ranging from focal cortical dysplasia to lobar or hemispheric overgrowth. In turn, the histopathology of these disorders is also remarkably varied. The common underlying mechanisms of RTK-PI3K-AKT overactivation suggest new possibilities for drugs that inhibit this pathway.
authors.affiliation: Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA; Department of Pathology, University of Washington School of Medicine, Seattle, WA; Center for Integrative Brain Research, Seattle Children׳s Research Institute, 1900 Ninth Ave, Seattle, WA 98101. Electronic address: rhevner@uw.edu.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hevner
mesh_terms: D001921:Brain / Q000254:growth & development / Q000473:pathology*; D006801:Humans; D054220:Malformations of Cortical Development / Q000235:genetics / Q000473:pathology*; D058627:Megalencephaly / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D059906:Neuroimaging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Apert syndrome; Balloon cells; Dysplastic neurons; Heterotopia; Megalencephaly; Pachygyria; Polymicrogyria; Thanatophoric dysplasia; Tuberous sclerosis