GRIN2Amutation and early-onset epileptic encephalopathy: personalized therapy with memantine.
OBJECTIVE
Early-onset epileptic encephalopathies have been associated with denovomutations 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 novelde novomutation; 2)in vitroexpression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds.


RESULTS
Ade novo GRIN2Amissense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit.In vitroanalysis 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.


CONCLUSIONS
This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.
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.
Tyler Mark
TM
Pierson
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Hongjie
H
Yuan
Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Eric D
ED
Marsh
NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA.
Karin
K
Fuentes-Fajardo
NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA ; Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
David R
DR
Adams
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.
Thomas
T
Markello
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.
Gretchen
G
Golas
NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, MD, USA.
Dimitre R
DR
Simeonov
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.
Conisha
C
Holloman
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Anel
A
Tankovic
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Manish M
MM
Karamchandani
EEG Section, NINDS, NIH, Bethesda, MD, USA.
John M
JM
Schreiber
NIH Intramural Sequencing Center, NHGRI, NIH, Bethesda, MD, USA.
James C
JC
Mullikin
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.
Cynthia J
CJ
Tifft
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.
Camilo
C
Toro
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.
Cornelius F
CF
Boerkoel
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Stephen F
SF
Traynelis
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.
William A
WA
Gahl