GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine

Authors

  • Tyler Mark Pierson,

    Corresponding author
    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Neurogenetics Branch, NINDS, NIH, Bethesda, Maryland
    3. Department of Pediatrics and Neurology, and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • Correspondence

      Tyler Mark Pierson, Department of Pediatrics and Neurology, and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, AHSP 8401, Los Angeles, CA 90048. Tel: 310-248-8558; Fax: 310-248-8066; E-mail: tyler.pierson@cshs.org

    Search for more papers by this author
  • Hongjie Yuan,

    1. Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
    Search for more papers by this author
  • Eric D. Marsh,

    1. Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Karin Fuentes-Fajardo,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    Search for more papers by this author
  • David R. Adams,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Medical Genetics Branch, NHGRI, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Thomas Markello,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Office of the Clinical Director, NHGRI, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Gretchen Golas,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Office of the Clinical Director, NHGRI, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Dimitre R. Simeonov,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    Search for more papers by this author
  • Conisha Holloman,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Office of the Clinical Director, NHGRI, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Anel Tankovic,

    1. Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
    Search for more papers by this author
  • Manish M. Karamchandani,

    1. Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
    Search for more papers by this author
  • John M. Schreiber,

    1. EEG Section, NINDS, NIH, Bethesda, Maryland
    Search for more papers by this author
  • James C. Mullikin,

    1. NIH Intramural Sequencing Center, NHGRI, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Cynthia J. Tifft,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Camilo Toro,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Cornelius F. Boerkoel,

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Stephen F. Traynelis,

    1. Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
    Search for more papers by this author
  • William A. Gahl

    1. NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland
    2. Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author

Abstract

Objective

Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.

Methods

Three modern translational medicine tools were utilized: (1) high-throughput sequencing technology to identify a novel de novo mutation; (2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and (3) screening of existing drug libraries to identify potential therapeutic compounds.

Results

A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by N-methyl-D-aspartate receptors (NMDAs) containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden.

Interpretation

This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.

Ancillary