GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine
Article first published online: 3 MAR 2014
© 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 article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Annals of Clinical and Translational Neurology
Volume 1, Issue 3, pages 190–198, March 2014
How to Cite
Pierson, T. M., Yuan, H., Marsh, E. D., Fuentes-Fajardo, K., Adams, D. R., Markello, T., Golas, G., Simeonov, D. R., Holloman, C., Tankovic, A., Karamchandani, M. M., Schreiber, J. M., Mullikin, J. C., Tifft, C. J., Toro, C., Boerkoel, C. F., Traynelis, S. F. and Gahl, W. A. (2014), GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Annals of Clinical and Translational Neurology, 1: 190–198. doi: 10.1002/acn3.39
- Issue published online: 14 MAR 2014
- Article first published online: 3 MAR 2014
- Manuscript Accepted: 14 JAN 2014
- Manuscript Received: 3 DEC 2013
- National Institutes of Health. Grant Number: HSN268201300162P
- NIH-NINDS. Grant Number: NS036654
- Cedars-Sinai Diana and Steve Marienhoff Fashion Industries
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.
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.
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.
This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.