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

Platzer, Konrad and Yuan, Hongjie and Schütz, Hannah and Winschel, Alexander and Chen, Wenjuan and Hu, Chun and Kusumoto, Hirofumi and Heyne, Henrike O. and Helbig, Katherine L. and Tang, Sha and Willing, Marcia C. and Tinkle, Brad T. and Adams, Darius J. and Depienne, Christel and Keren, Boris and Mignot, Cyril and Frengen, Eirik and Strømme, Petter and Biskup, Saskia and Döcker, Dennis and Strom, Tim M. and Mefford, Heather C. and Myers, Candace T. and Muir, Alison M. and LaCroix, Amy and Sadleir, Lynette and Scheffer, Ingrid E. and Brilstra, Eva and van Haelst, Mieke M. and van der Smagt, Jasper J. and Bok, Levinus A. and Møller, Rikke S. and Jensen, Uffe B. and Millichap, John J. and Berg, Anne T. and Goldberg, Ethan M. and De Bie, Isabelle and Fox, Stephanie and Major, Philippe and Jones, Julie R. and Zackai, Elaine H. and Abou Jamra, Rami and Rolfs, Arndt and Leventer, Richard J. and Lawson, John A. and Roscioli, Tony and Jansen, Floor E. and Ranza, Emmanuelle and Korff, Christian M. and Lehesjoki, Anna-Elina and Courage, Carolina and Linnankivi, Tarja and Smith, Douglas R. and Stanley, Christine and Mintz, Mark and McKnight, Dianalee and Decker, Amy and Tan, Wen-Hann and Tarnopolsky, Mark A. and Brady, Lauren I. and Wolff, Markus and Dondit, Lutz and Pedro, Helio F. and Parisotto, Sarah E. and Jones, Kelly L. and Patel, Anup D. and Franz, David N. and Vanzo, Rena and Marco, Elysa and Ranells, Judith D. and Di Donato, Nataliya and Dobyns, William B. and Laube, Bodo and Traynelis, Stephen F. and Lemke, Johannes R. (2017):
GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.
In: Journal of medical genetics, pp. 460-470, 54, (7), ISSN 1468-6244,
[Article]

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 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.

Item Type: Article
Erschienen: 2017
Creators: Platzer, Konrad and Yuan, Hongjie and Schütz, Hannah and Winschel, Alexander and Chen, Wenjuan and Hu, Chun and Kusumoto, Hirofumi and Heyne, Henrike O. and Helbig, Katherine L. and Tang, Sha and Willing, Marcia C. and Tinkle, Brad T. and Adams, Darius J. and Depienne, Christel and Keren, Boris and Mignot, Cyril and Frengen, Eirik and Strømme, Petter and Biskup, Saskia and Döcker, Dennis and Strom, Tim M. and Mefford, Heather C. and Myers, Candace T. and Muir, Alison M. and LaCroix, Amy and Sadleir, Lynette and Scheffer, Ingrid E. and Brilstra, Eva and van Haelst, Mieke M. and van der Smagt, Jasper J. and Bok, Levinus A. and Møller, Rikke S. and Jensen, Uffe B. and Millichap, John J. and Berg, Anne T. and Goldberg, Ethan M. and De Bie, Isabelle and Fox, Stephanie and Major, Philippe and Jones, Julie R. and Zackai, Elaine H. and Abou Jamra, Rami and Rolfs, Arndt and Leventer, Richard J. and Lawson, John A. and Roscioli, Tony and Jansen, Floor E. and Ranza, Emmanuelle and Korff, Christian M. and Lehesjoki, Anna-Elina and Courage, Carolina and Linnankivi, Tarja and Smith, Douglas R. and Stanley, Christine and Mintz, Mark and McKnight, Dianalee and Decker, Amy and Tan, Wen-Hann and Tarnopolsky, Mark A. and Brady, Lauren I. and Wolff, Markus and Dondit, Lutz and Pedro, Helio F. and Parisotto, Sarah E. and Jones, Kelly L. and Patel, Anup D. and Franz, David N. and Vanzo, Rena and Marco, Elysa and Ranells, Judith D. and Di Donato, Nataliya and Dobyns, William B. and Laube, Bodo and Traynelis, Stephen F. and Lemke, Johannes R.
Title: GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.
Language: English
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 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.

Journal or Publication Title: Journal of medical genetics
Volume: 54
Number: 7
Divisions: 10 Department of Biology
10 Department of Biology > Neurophysiology and Neurosensory Systems
Date Deposited: 11 Apr 2017 09:58
Identification Number: pmid:28377535
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