DEVELOPMENTAL DISORDERS: Edited by Daniel GeschwindHemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disordersBaek, Seung Taea; Gibbs, Elizabeth M.a; Gleeson, Joseph G.a; Mathern, Gary W.b,cAuthor Information aDepartment of Neurosciences, Howard Hughes Medical Institute, University of California San Diego, La Jolla, California bDepartment of Neurosurgery cDepartment of Psychiatry and Biobehavioral Sciences, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, California, USA Correspondence to Gary W. Mathern, MD, Department of Neurosurgery, University of California, Los Angeles, CA 90095, USA. Tel: +1 310 825 7961; fax: +1 310 825 0922; e-mail: firstname.lastname@example.org Current Opinion in Neurology: April 2013 - Volume 26 - Issue 2 - p 122-127 doi: 10.1097/WCO.0b013e32835ef373 Buy Metrics Abstract Purpose of review Combining human genomics and molecular biology, recent studies have made pivotal progress toward understanding the cause of hemimegalencephaly (HME) and other cerebral megalencephaly syndromes. The present article highlights recent advances of the genetic cause of these conditions, and considers the role of somatic postzygotic genetic lesions in brain maldevelopment. Recent findings Studies over the past 12 months have identified de-novo somatic mutations as one possible cause in HME. The gene mutations involve components of the phosphatidylinositol 3-kinase (PI3K)–AKT (also known as protein kinase B)–mammalian target of rapamycin (mTOR) pathway and include PIK3CA, PIK3R2, AKT3, and MTOR. These mutations were identified by comparing genomic data obtained from surgically resected brain tissue with nondiseased tissue, and by single-neuron sequencing in combination with molecular biology techniques. The association between the somatic mutations and downstream activation of the PI3K–mTOR pathway suggests that HME is a neurodevelopmental disease caused by gain-of-function activation of the PI3K–AKT–mTOR pathway. Summary The studies reviewed suggest that somatic mutations of the PI3K–AKT–mTOR pathway limited to the brain may represent one cause of HME. Dysregulation of this pathway has possible therapeutic potential in the identification of HME. Somatic mutations may be an important yet underappreciated disease mechanism in developmental neurological diseases. © 2013 Lippincott Williams & Wilkins, Inc.