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

Tyler Mark Pierson; Hongjie Yuan; Eric D Marsh; Karin Fuentes-Fajardo; David R Adams; Thomas Markello; Gretchen Golas; Dimitre R Simeonov; Conisha Holloman; Anel Tankovic; Manish M Karamchandani; John M Schreiber; James C Mullikin; PhD for the NISC Comparative Sequencing Program; Cynthia J Tifft; Camilo Toro; Cornelius F Boerkoel; Stephen F Traynelis; William A Gahl

doi:10.1002/acn3.39

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

Ann Clin Transl Neurol. 2014 Mar 1;1(3):190-198. doi: 10.1002/acn3.39.

Authors

Tyler Mark Pierson¹, Hongjie Yuan², Eric D Marsh³, Karin Fuentes-Fajardo⁴, David R Adams⁵, Thomas Markello⁶, Gretchen Golas⁶, Dimitre R Simeonov⁴, Conisha Holloman⁶, Anel Tankovic², Manish M Karamchandani², John M Schreiber⁷, James C Mullikin⁸; PhD for the NISC Comparative Sequencing Program; Cynthia J Tifft⁹, Camilo Toro⁹, Cornelius F Boerkoel⁹, Stephen F Traynelis², William A Gahl⁹

Affiliations

¹ NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA ; Neurogenetics Branch, NINDS, NIH, Bethesda, MD, USA ; Department of Pediatrics and Neurology, and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
³ Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁴ NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA.
⁵ NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA ; Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
⁶ NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA ; Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA.
⁷ EEG Section, NINDS, NIH, Bethesda, MD, USA.
⁸ NIH Intramural Sequencing Center, NHGRI, NIH, Bethesda, MD, USA.
⁹ NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA ; Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

PMID: 24839611
PMCID: PMC4019449
DOI: 10.1002/acn3.39

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 NMDA receptors 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.

Abstract

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