Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias
Alissa M. D’Gama,
Mollie B. Woodworth,
Amer A. Hossain,
Sara Bizzotto,
Nicole E. Hatem,
Christopher M. LaCoursiere,
Imad Najm,
Zhong Ying,
Edward Yang,
A. James Barkovich,
David J. Kwiatkowski,
Harry V. Vinters,
Joseph R. Madsen,
Gary W. Mathern,
Ingmar Blümcke,
Annapurna Poduri,
Christopher A. Walsh
Affiliations
Alissa M. D’Gama
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA
Mollie B. Woodworth
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA
Amer A. Hossain
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA
Sara Bizzotto
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA
Nicole E. Hatem
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA
Christopher M. LaCoursiere
Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Imad Najm
Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA
Zhong Ying
Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA
Edward Yang
Department of Radiology, Boston Children’s Hospital, Boston, MA 02115, USA
A. James Barkovich
Departments of Radiology and Diagnostic Imaging, Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA
David J. Kwiatkowski
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Harry V. Vinters
Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Joseph R. Madsen
Department of Neurosurgery, Boston Children’s Hospital, Boston, MA, USA
Gary W. Mathern
Departments of Neurosurgery and Psychiatry and Biobehavioral Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Ingmar Blümcke
Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA
Annapurna Poduri
Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Christopher A. Walsh
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.
