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Ann Clin Transl Neurol. 2014 Mar 1;1(3):190-198.

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

Author information

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.

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.

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