GRIN2B Encephalopathy: Novel Findings
GRIN2B Encephalopathy: Novel Findings on Phenotype, Variant Clustering, Functional Consequences and Treatment Aspects
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.
Authors
- Konrad Platzer , MD
- Hongjie Yuan , PhD, MD
- Hannah Schütz
- Alexander Winschel
- Wenjuan Chen
- Chun Hu
- Hirofumi Kusumoto
- Henrike Heyne , MD
- Katherine Helbig
- Sha Tang , PhD
- Marcia Willing , PhD, MD
- Brad Tinkle , PhD, MD
- Darius Adams , MD
- Christel Depienne , PhD
- Boris Keren , PhD, MD
- Cyril Mignot , PhD, MD
- Prof. Eirik Frengen , PhD
- Prof. Petter Strømme , PhD
- Saskia Biskup , PhD, MD
- Dennis Döcker , MD
- Tim Strom , MD
- Heather Mefford , PhD, MD
- Candace Myers , PhD
- Alison Muir , PhD
- Amy LaCroix
- Lynette Sadleir , MD
- Ingrid Scheffer , PhD
- Eva Brilstra , PhD, MD
- Mieke van Haelst , MD
- Jasper van der Smagt , MD
- Levinus Bok , MD
- Rikke Møller
- Prof. Uffe Jensen , PhD, MD
- John Millichap , MD
- Anne Berg , PhD
- Ethan Goldberg , PhD, MD
- Isabelle De Bie , PhD, MD
- Stephanie Fox
- Philippe Major , MD
- Julie Jones , PhD
- Elaine Zackai , MD
- Rami Abou Jamra , MD
- Prof. Arndt Rolfs , MD
- Richard Leventer , PhD
- John Anthony Lawson , PhD
- Tony Roscioli , PhD
- Floor Jansen , PhD, MD
- Emmanuelle Ranza , MD
- Christian Korff , MD
- Anna-Elina Lehesjoki , PhD, MD
- Carolina Courage , MD
- Tarja Linnankivi , PhD, MD
- Douglas Smith , PhD
- Christine Stanley , PhD
- Mark Mintz , MD
- Dianalee McKnight , PhD
- Amy Decker
- Wen-Hann Tan , MD
- Mark Tarnopolsky , PhD, MD
- Lauren Brady
- Markus Wolff , MD
- Lutz Dondit , MD
- Helio Pedro , MD
- Sarah Parisotto
- Kelly Jones , MD
- Anup Patel , MD
- David Franz , MD
- Rena Vanzo
- Elysa Marco , MD
- Judith Ranells , MD
- Nataliya Di Donato , MD
- William Dobyns , MD
- Prof. Bodo Laube , PhD
- Stephen Traynelis , PhD
- Prof. Johannes Lemke , MD