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Author Notes:

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

We are grateful to Shannon McNeil, Chevalia Robinson, Jose Salas, and Cheryl Hipple for excellent administrative assistance; Mary Andriola, Eva Baker, Craig Blackstone, Joy Bryant, Barrington Burnett, Roxanne Fischer, Phuong Le, Kasper Hansen, Edwin Kolodny, Greg Pastores, Swati Sathe, David Sleat, Chigolum Umeonyido, Lissenka Vissers, Lynne Wolfe, and Jing Zhang for clinical and technical assistance and critical analysis.

We especially thank the family of our patient for the loving care for their child and cooperation with our work.

Conflict of Interest: None declared.

Subjects:

Research Funding:

During this study T. M. P., D. A., T. M., K. F. F., D. R. S., C. F. B., and C. T. were supported by the National Institutes of Health (NIH) Undiagnosed Diseases Program; T. M., G. G., C. H., C. T., J. C. M., andW. A. G. were supported by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health.

H. Y. was supported by NIH HSN268201300162P.

S. T. was supported by NIH-NINDS NS036654.

T. M. P. was also supported by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Neurosciences & Neurology

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

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Journal Title:

Annals of Clinical and Translational Neurology

Volume:

Volume 1, Number 3

Publisher:

, Pages 190-198

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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