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

01. Juli, 2017

Platzer K1, Yuan H2,3, Schütz H4, Winschel A4, Chen W2, Hu C2, Kusumoto H2, Heyne HO1, Helbig KL5, Tang S5, Willing MC6, Tinkle BT7, Adams DJ8, Depienne C9,10,11,12, Keren B9,10, Mignot C10, Frengen E13, Strømme P14, Biskup S15, Döcker D15, Strom TM16, Mefford HC17, Myers CT17, Muir AM17, LaCroix A17, Sadleir L18, Scheffer IE19, Brilstra E20, van Haelst MM20, van der Smagt JJ20, Bok LA21, Møller RS22,23, Jensen UB24, Millichap JJ25, Berg AT25, Goldberg EM26,27, De Bie I28, Fox S28, Major P29, Jones JR30, Zackai EH31, Abou Jamra R1,32, Rolfs A32, Leventer RJ33,34, Lawson JA35, Roscioli T36, Jansen FE37, Ranza E38, Korff CM39, Lehesjoki AE40,41, Courage C40,41, Linnankivi T42, Smith DR43, Stanley C43, Mintz M44, McKnight D45, Decker A45, Tan WH46, Tarnopolsky MA47, Brady LI47, Wolff M48, Dondit L49, Pedro HF50, Parisotto SE50, Jones KL51, Patel AD52,53, Franz DN54, Vanzo R55, Marco E56, Ranells JD57, Di Donato N58, Dobyns WB59,60,61, Laube B4, Traynelis SF2,3, Lemke JR1.



We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.


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.


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.


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.