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 journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)460-470
Number of pages11
JournalJournal of Medical Genetics
Volume54
Issue number7
DOIs
StatePublished - Jul 1 2017

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Brain Diseases
Cluster Analysis
Phenotype
Memantine
Malformations of Cortical Development
Vision Disorders
Movement Disorders
Epilepsy
Channelopathies
Therapeutics
Precision Medicine
Muscle Hypotonia
Autistic Disorder
Intellectual Disability
Patient Care
Binding Sites
Ligands
Research

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Platzer, Konrad ; Yuan, Hongjie ; Schütz, Hannah ; Winschel, Alexander ; Chen, Wenjuan ; Hu, Chun ; Kusumoto, Hirofumi ; Heyne, Henrike O. ; Helbig, Katherine L. ; Tang, Sha ; Willing, Marcia C. ; Tinkle, Brad T. ; Adams, Darius J. ; Depienne, Christel ; Keren, Boris ; Mignot, Cyril ; Frengen, Eirik ; Strømme, Petter ; Biskup, Saskia ; Döcker, Dennis ; Strom, Tim M. ; Mefford, Heather C. ; Myers, Candace T. ; Muir, Alison M. ; LaCroix, Amy ; Sadleir, Lynette ; Scheffer, Ingrid E. ; Brilstra, Eva ; van Haelst, Mieke M. ; van der Smagt, Jasper J. ; Bok, Levinus A. ; Møller, Rikke S. ; Jensen, Uffe B. ; Millichap, John J. ; Berg, Anne T. ; Goldberg, Ethan M. ; De Bie, Isabelle ; Fox, Stephanie ; Major, Philippe ; Jones, Julie R. ; Zackai, Elaine H. ; Abou Jamra, Rami ; Rolfs, Arndt ; Leventer, Richard J. ; Lawson, John A. ; Roscioli, Tony ; Jansen, Floor E. ; Ranza, Emmanuelle ; Korff, Christian M. ; Lehesjoki, Anna Elina ; Courage, Carolina ; Linnankivi, Tarja ; Smith, Douglas R. ; Stanley, Christine ; Mintz, Mark ; McKnight, Dianalee ; Decker, Amy ; Tan, Wen Hann ; Tarnopolsky, Mark A. ; Brady, Lauren I. ; Wolff, Markus ; Dondit, Lutz ; Pedro, Helio F. ; Parisotto, Sarah E. ; Jones, Kelly L. ; Patel, Anup D. ; Franz, David N. ; Vanzo, Rena ; Marco, Elysa ; Ranells, Judith D. ; Di Donato, Nataliya ; Dobyns, William B. ; Laube, Bodo ; Traynelis, Stephen F. ; Lemke, Johannes R. / GRIN2B encephalopathy : Novel findings on phenotype, variant clustering, functional consequences and treatment aspects. In: Journal of Medical Genetics. 2017 ; Vol. 54, No. 7. pp. 460-470.
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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.",
author = "Konrad Platzer and Hongjie Yuan and Hannah Sch{\"u}tz and Alexander Winschel and Wenjuan Chen and Chun Hu and Hirofumi Kusumoto and Heyne, {Henrike O.} and Helbig, {Katherine L.} and Sha Tang and Willing, {Marcia C.} and Tinkle, {Brad T.} and Adams, {Darius J.} and Christel Depienne and Boris Keren and Cyril Mignot and Eirik Frengen and Petter Str{\o}mme and Saskia Biskup and Dennis D{\"o}cker and Strom, {Tim M.} and Mefford, {Heather C.} and Myers, {Candace T.} and Muir, {Alison M.} and Amy LaCroix and Lynette Sadleir and Scheffer, {Ingrid E.} and Eva Brilstra and {van Haelst}, {Mieke M.} and {van der Smagt}, {Jasper J.} and Bok, {Levinus A.} and M{\o}ller, {Rikke S.} and Jensen, {Uffe B.} and Millichap, {John J.} and Berg, {Anne T.} and Goldberg, {Ethan M.} and {De Bie}, Isabelle and Stephanie Fox and Philippe Major and Jones, {Julie R.} and Zackai, {Elaine H.} and {Abou Jamra}, Rami and Arndt Rolfs and Leventer, {Richard J.} and Lawson, {John A.} and Tony Roscioli and Jansen, {Floor E.} and Emmanuelle Ranza and Korff, {Christian M.} and Lehesjoki, {Anna Elina} and Carolina Courage and Tarja Linnankivi and Smith, {Douglas R.} and Christine Stanley and Mark Mintz and Dianalee McKnight and Amy Decker and Tan, {Wen Hann} and Tarnopolsky, {Mark A.} and Brady, {Lauren I.} and Markus Wolff and Lutz Dondit and Pedro, {Helio F.} and Parisotto, {Sarah E.} and Jones, {Kelly L.} and Patel, {Anup D.} and Franz, {David N.} and Rena Vanzo and Elysa Marco and Ranells, {Judith D.} and {Di Donato}, Nataliya and Dobyns, {William B.} and Bodo Laube and Traynelis, {Stephen F.} and Lemke, {Johannes R.}",
year = "2017",
month = "7",
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language = "English (US)",
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pages = "460--470",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
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Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, HO, Helbig, KL, Tang, S, Willing, MC, Tinkle, BT, Adams, DJ, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, TM, Mefford, HC, Myers, CT, Muir, AM, LaCroix, A, Sadleir, L, Scheffer, IE, Brilstra, E, van Haelst, MM, van der Smagt, JJ, Bok, LA, Møller, RS, Jensen, UB, Millichap, JJ, Berg, AT, Goldberg, EM, De Bie, I, Fox, S, Major, P, Jones, JR, Zackai, EH, Abou Jamra, R, Rolfs, A, Leventer, RJ, Lawson, JA, Roscioli, T, Jansen, FE, Ranza, E, Korff, CM, Lehesjoki, AE, Courage, C, Linnankivi, T, Smith, DR, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, WH, Tarnopolsky, MA, Brady, LI, Wolff, M, Dondit, L, Pedro, HF, Parisotto, SE, Jones, KL, Patel, AD, Franz, DN, Vanzo, R, Marco, E, Ranells, JD, Di Donato, N, Dobyns, WB, Laube, B, Traynelis, SF & Lemke, JR 2017, 'GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects', Journal of Medical Genetics, vol. 54, no. 7, pp. 460-470. https://doi.org/10.1136/jmedgenet-2016-104509

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

In: Journal of Medical Genetics, Vol. 54, No. 7, 01.07.2017, p. 460-470.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GRIN2B encephalopathy

T2 - Novel findings on phenotype, variant clustering, functional consequences and treatment aspects

AU - Platzer, Konrad

AU - Yuan, Hongjie

AU - Schütz, Hannah

AU - Winschel, Alexander

AU - Chen, Wenjuan

AU - Hu, Chun

AU - Kusumoto, Hirofumi

AU - Heyne, Henrike O.

AU - Helbig, Katherine L.

AU - Tang, Sha

AU - Willing, Marcia C.

AU - Tinkle, Brad T.

AU - Adams, Darius J.

AU - Depienne, Christel

AU - Keren, Boris

AU - Mignot, Cyril

AU - Frengen, Eirik

AU - Strømme, Petter

AU - Biskup, Saskia

AU - Döcker, Dennis

AU - Strom, Tim M.

AU - Mefford, Heather C.

AU - Myers, Candace T.

AU - Muir, Alison M.

AU - LaCroix, Amy

AU - Sadleir, Lynette

AU - Scheffer, Ingrid E.

AU - Brilstra, Eva

AU - van Haelst, Mieke M.

AU - van der Smagt, Jasper J.

AU - Bok, Levinus A.

AU - Møller, Rikke S.

AU - Jensen, Uffe B.

AU - Millichap, John J.

AU - Berg, Anne T.

AU - Goldberg, Ethan M.

AU - De Bie, Isabelle

AU - Fox, Stephanie

AU - Major, Philippe

AU - Jones, Julie R.

AU - Zackai, Elaine H.

AU - Abou Jamra, Rami

AU - Rolfs, Arndt

AU - Leventer, Richard J.

AU - Lawson, John A.

AU - Roscioli, Tony

AU - Jansen, Floor E.

AU - Ranza, Emmanuelle

AU - Korff, Christian M.

AU - Lehesjoki, Anna Elina

AU - Courage, Carolina

AU - Linnankivi, Tarja

AU - Smith, Douglas R.

AU - Stanley, Christine

AU - Mintz, Mark

AU - McKnight, Dianalee

AU - Decker, Amy

AU - Tan, Wen Hann

AU - Tarnopolsky, Mark A.

AU - Brady, Lauren I.

AU - Wolff, Markus

AU - Dondit, Lutz

AU - Pedro, Helio F.

AU - Parisotto, Sarah E.

AU - Jones, Kelly L.

AU - Patel, Anup D.

AU - Franz, David N.

AU - Vanzo, Rena

AU - Marco, Elysa

AU - Ranells, Judith D.

AU - Di Donato, Nataliya

AU - Dobyns, William B.

AU - Laube, Bodo

AU - Traynelis, Stephen F.

AU - Lemke, Johannes R.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85021154784&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2016-104509

DO - 10.1136/jmedgenet-2016-104509

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JO - Journal of Medical Genetics

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