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

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

Konrad Platzer, MD 1 Hongjie Yuan, PhD, MD 2 Hannah Schütz 3 Alexander Winschel 3 Wenjuan Chen 2 Chun Hu 2 Hirofumi Kusumoto 2 Henrike Heyne, MD 1 Katherine Helbig 4 Sha Tang, PhD 4 Marcia Willing, PhD, MD 5 Brad Tinkle, PhD, MD 6 Darius Adams, MD 7 Christel Depienne, PhD 8, 9, 10 Boris Keren, PhD, MD 8, 9 Cyril Mignot, PhD, MD 9 Prof. Eirik Frengen, PhD 11 Prof. Petter Strømme, PhD 11 Saskia Biskup, PhD, MD 12 Dennis Döcker, MD 12 Tim Strom, MD 13 Heather Mefford, PhD, MD 14 Candace Myers, PhD 14 Alison Muir, PhD 14 Amy LaCroix 14 Lynette Sadleir, MD 15 Ingrid Scheffer, PhD 16 Eva Brilstra, PhD, MD 17 Mieke van Haelst, MD 17 Jasper van der Smagt, MD 17 Levinus Bok, MD 18 Rikke Møller 19, 20 Prof. Uffe Jensen, PhD, MD 21 John Millichap, MD 22 Anne Berg, PhD 22 Ethan Goldberg, PhD, MD 23 Isabelle De Bie, PhD, MD 24 Stephanie Fox 24 Philippe Major, MD 25 Julie Jones, PhD 26 Elaine Zackai, MD 27 Rami Abou Jamra, MD 1, 28 Prof. Arndt Rolfs, MD 28 Richard Leventer, PhD 29, 16 John Anthony Lawson, PhD 30 Tony Roscioli, PhD 31 Floor Jansen, PhD, MD 17 Emmanuelle Ranza, MD 32 Christian Korff, MD 32 Anna-Elina Lehesjoki, PhD, MD 33 Carolina Courage, MD 33 Tarja Linnankivi, PhD, MD 33 Douglas Smith, PhD 34 Christine Stanley, PhD 34 Mark Mintz, MD 35 Dianalee McKnight, PhD 36 Amy Decker 36 Wen-Hann Tan, MD 37 Mark Tarnopolsky, PhD, MD 38 Lauren Brady 38 Markus Wolff, MD 39 Lutz Dondit, MD 40 Helio Pedro, MD 41 Sarah Parisotto 41 Kelly Jones, MD 42 Anup Patel, MD 43, 44 David Franz, MD 45 Rena Vanzo 46 Elysa Marco, MD 47 Judith Ranells, MD 48 Nataliya Di Donato, MD 49 William Dobyns, MD 14, 50 Prof. Bodo Laube, PhD 3 Stephen Traynelis, PhD 2 Prof. Johannes Lemke, MD 1
1 University of Leipzig 2 Emory University School of Medicine Atlanta 3 Technical University Darmstadt 4 Ambry Genetics 5 Washington University School of Medicine, St. Louis 6 Advocate Children’s Hospital Park Ridge 7 Goryeb Children's Hospital Morristown 8 Sorbonne University Paris 9 Pitié-Salpêtrière Hospital Paris 10 University of Strasbourg 11 University of Oslo 12 CeGaT 13 Helmholtz Centre Munich 14 University of Washington Seattle 15 University of Otago 16 University of Melbourne 17 Utrecht University Medical Center 18 Màxima Medical Centre Veldhoven 19 The Danish Epilepsy Centre Filadelfia Dianalund 20 University of Southern Denmark Odense 21 Aarhus University Hospital 22 Northwestern University Feinberg School of Medicine Chicago 23 University of Pennsylvania Philadelphia 24 McGill University Health Center Montreal 25 CHU Sainte-Justine Montreal 26 Greenwood Genetic Center 27 Children's Hospital of Philadelphia 28 CENTOGENE AG 29 Royal Children’s Hospital Melbourne 30 Sydney Children's Hospital 31 Genome.One 32 University Hospitals of Geneva 33 University of Helsinki 34 Courtagen Life Sciences 35 The Center for Neurological and Neurodevelopmental Health and the Clinical Research Center of New Jersey 36 GeneDx 37 Boston Children's Hospital 38 McMaster University Children's Hospital Hamilton 39 University Hospital of Tübingen 40 Olgahospital Stuttgart 41 Hackensack University Medical Center 42 University of Mississippi Medical Center Jackson 43 Nationwide Children's Hospital Columbus 44 The Ohio State University College of Medicine Columbus 45 Cincinnati Children's Hospital Medical Center 46 Lineagen 47 University of San Francisco School of Medicine 48 University of South Florida Tampa 49 University of Technology Dresden 50 Seattle Children's Research Institute
June 23, 2017

J Med Genet. 2017 Apr 4. pii: jmedgenet-2016-104509. doi: 10.1136/jmedgenet-2016-104509

Abstract:

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 lossof- 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.