Open AccessGRIN2A mutation and early‐onset epileptic encephalopathy: personalized therapy with memantine
Author(s) -
Pierson Tyler Mark,
Yuan Hongjie,
Marsh Eric D.,
FuentesFajardo Karin,
Adams David R.,
Markello Thomas,
Golas Gretchen,
Simeonov Dimitre R.,
Holloman Conisha,
Tankovic Anel,
Karamchandani Manish M.,
Schreiber John M.,
Mullikin James C.,
Tifft Cynthia J.,
Toro Camilo,
Boerkoel Cornelius F.,
Traynelis Stephen F.,
Gahl William A.
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.39
Subject(s) - memantine , medicine , proband , missense mutation , mutation , pharmacology , channelopathy , epilepsy , bioinformatics , disease , genetics , dementia , gene , biology , psychiatry
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 N‐methyl‐D‐aspartate receptors ( NMDA s) containing the mutant GluN2A‐L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A‐L812M‐containing NMDAR s 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.