GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Konrad Platzer, Hongjie Yuan, Hannah Schütz, Alexander Winschel, Wenjuan Chen, Chun Hu, Hirofumi Kusumoto, Henrike O. Heyne, Katherine L. Helbig, Sha Tang, Marcia C. Willing, Brad T. Tinkle, Darius J. Adams, Christel Depienne, Boris Keren, Cyril Mignot, Eirik Frengen, Petter Strømme, Saskia Biskup, Dennis DöckerTim M. Strom, Heather C. Mefford, Candace T. Myers, Alison M. Muir, Amy LaCroix, Lynette Sadleir, Ingrid E. Scheffer, Eva Brilstra, Mieke M. van Haelst, Jasper J. van der Smagt, Levinus A. Bok, Rikke S. Møller, Uffe B. Jensen, John J. Millichap, Anne T. Berg, Ethan M. Goldberg, Isabelle De Bie, Stephanie Fox, Philippe Major, Julie R. Jones, Elaine H. Zackai, Rami Abou Jamra, Arndt Rolfs, Richard J. Leventer, John A. Lawson, Tony Roscioli, Floor E. Jansen, Emmanuelle Ranza, Christian M. Korff, Anna Elina Lehesjoki, Carolina Courage, Tarja Linnankivi, Douglas R. Smith, Christine Stanley, Mark Mintz, Dianalee McKnight, Amy Decker, Wen Hann Tan, Mark A. Tarnopolsky, Lauren I. Brady, Markus Wolff, Lutz Dondit, Helio F. Pedro, Sarah E. Parisotto, Kelly L. Jones, Anup D. Patel, David N. Franz, Rena Vanzo, Elysa Marco, Judith D. Ranells, Nataliya Di Donato, William B. Dobyns, Bodo Laube, Stephen F. Traynelis, Johannes R. Lemke

Research output: Contribution to journalArticleAcademicpeer-review

168 Citations (Scopus)


Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Original languageEnglish
Pages (from-to)460-470
Number of pages11
JournalJournal of medical genetics
Issue number7
Publication statusPublished - 1 Jul 2017


  • Channelopathy
  • Clustering of missense variants
  • Epileptic encephalopathy
  • Pathogenic GRIN2B mutations
  • Precision medicine

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