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 Döcker; Tim 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

doi:10.1136/jmedgenet-2016-104509

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

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 language	English (US)
Pages (from-to)	460-470
Number of pages	11
Journal	Journal of medical genetics
Volume	54
Issue number	7
DOIs	https://doi.org/10.1136/jmedgenet-2016-104509
State	Published - Jul 1 2017

Funding

We thank the patients and their families for their participation and support of this study. We thank Lisa Ewans, Michael F Buckley, Asbjørn Holmgren and Doriana Misceo for technical support. Funding for the project was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD082373 to HY), by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 (to HY), and by the National Institute of Neurological Disorders and Stroke (NS036654, R01NS065371 and R24NS092989 to SFT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Additional funding was received from the Australian NHMRC (512123 to TR), NIH NINDS training grant (K12 NS049453 to EMG), Cure Kids NZ to LS and the SNSF Early Postdoc fellowship (P2SKP3_164945 to CC). Funding for the DECIPHER project was provided by the Wellcome Trust.

Keywords

Channelopathy
Clustering of missense variants
Epileptic encephalopathy
Pathogenic GRIN2B mutations
Precision medicine

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1136/jmedgenet-2016-104509

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Platzer, K., Yuan, H., Schütz, H., Winschel, A., Chen, W., Hu, C., Kusumoto, H., Heyne, H. O., Helbig, K. L., Tang, S., Willing, M. C., Tinkle, B. T., Adams, D. J., Depienne, C., Keren, B., Mignot, C., Frengen, E., Strømme, P., Biskup, S., ... Lemke, J. R. (2017). GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects. Journal of medical genetics, 54(7), 460-470. https://doi.org/10.1136/jmedgenet-2016-104509

@article{8ab74d6ee4344522a55950931b9785d5,

title = "GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects",

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.",

keywords = "Channelopathy, Clustering of missense variants, Epileptic encephalopathy, Pathogenic GRIN2B mutations, Precision medicine",

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.}",

note = "Funding Information: We thank the patients and their families for their participation and support of this study. We thank Lisa Ewans, Michael F Buckley, Asbj{\o}rn Holmgren and Doriana Misceo for technical support. Funding for the project was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD082373 to HY), by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 (to HY), and by the National Institute of Neurological Disorders and Stroke (NS036654, R01NS065371 and R24NS092989 to SFT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Additional funding was received from the Australian NHMRC (512123 to TR), NIH NINDS training grant (K12 NS049453 to EMG), Cure Kids NZ to LS and the SNSF Early Postdoc fellowship (P2SKP3_164945 to CC). Funding for the DECIPHER project was provided by the Wellcome Trust.",

year = "2017",

month = jul,

day = "1",

doi = "10.1136/jmedgenet-2016-104509",

language = "English (US)",

volume = "54",

pages = "460--470",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "7",

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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

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.

N1 - Funding Information: We thank the patients and their families for their participation and support of this study. We thank Lisa Ewans, Michael F Buckley, Asbjørn Holmgren and Doriana Misceo for technical support. Funding for the project was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD082373 to HY), by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 (to HY), and by the National Institute of Neurological Disorders and Stroke (NS036654, R01NS065371 and R24NS092989 to SFT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Additional funding was received from the Australian NHMRC (512123 to TR), NIH NINDS training grant (K12 NS049453 to EMG), Cure Kids NZ to LS and the SNSF Early Postdoc fellowship (P2SKP3_164945 to CC). Funding for the DECIPHER project was provided by the Wellcome Trust.

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.

KW - Channelopathy

KW - Clustering of missense variants

KW - Epileptic encephalopathy

KW - Pathogenic GRIN2B mutations

KW - Precision medicine

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

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

U2 - 10.1136/jmedgenet-2016-104509

DO - 10.1136/jmedgenet-2016-104509

M3 - Article

C2 - 28377535

AN - SCOPUS:85021154784

SN - 0022-2593

VL - 54

SP - 460

EP - 470

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 7

ER -

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

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