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SCN3A-related neurodevelopmental disorder : A spectrum of epilepsy and brain malformation. / Zaman, Tariq; Helbig, Katherine L; Clatot, Jérôme; Thompson, Christopher H; Kang, Seok Kyu; Stouffs, Katrien; Jansen, Anna E; Verstraete, Lieve; Jacquinet, Adeline; Parrini, Elena; Guerrini, Renzo; Fujiwara, Yuh; Miyatake, Satoko; Ben-Zeev, Bruria; Bassan, Haim; Reish, Orit; Marom, Daphna; Hauser, Natalie; Vu, Thuy-Anh; Ackermann, Sally; Spencer, Careni E; Lippa, Natalie; Srinivasan, Shraddha; Charzewska, Agnieszka; Hoffman-Zacharska, Dorota; Fitzpatrick, David; Harrison, Victoria; Vasudevan, Pradeep; Joss, Shelagh; Pilz, Daniela T; Fawcett, Katherine A; Helbig, Ingo; Matsumoto, Naomichi; Kearney, Jennifer A; Fry, Andrew E; Goldberg, Ethan M.

In: Annals of Neurology, Vol. 88, No. 2, 01.08.2020, p. 348-362.

Research output: Contribution to journalArticle

Harvard

Zaman, T, Helbig, KL, Clatot, J, Thompson, CH, Kang, SK, Stouffs, K, Jansen, AE, Verstraete, L, Jacquinet, A, Parrini, E, Guerrini, R, Fujiwara, Y, Miyatake, S, Ben-Zeev, B, Bassan, H, Reish, O, Marom, D, Hauser, N, Vu, T-A, Ackermann, S, Spencer, CE, Lippa, N, Srinivasan, S, Charzewska, A, Hoffman-Zacharska, D, Fitzpatrick, D, Harrison, V, Vasudevan, P, Joss, S, Pilz, DT, Fawcett, KA, Helbig, I, Matsumoto, N, Kearney, JA, Fry, AE & Goldberg, EM 2020, 'SCN3A-related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation', Annals of Neurology, vol. 88, no. 2, pp. 348-362. https://doi.org/10.1002/ana.25809

APA

Zaman, T., Helbig, K. L., Clatot, J., Thompson, C. H., Kang, S. K., Stouffs, K., ... Goldberg, E. M. (2020). SCN3A-related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation. Annals of Neurology, 88(2), 348-362. https://doi.org/10.1002/ana.25809

Vancouver

Zaman T, Helbig KL, Clatot J, Thompson CH, Kang SK, Stouffs K et al. SCN3A-related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation. Annals of Neurology. 2020 Aug 1;88(2):348-362. https://doi.org/10.1002/ana.25809

Author

Zaman, Tariq ; Helbig, Katherine L ; Clatot, Jérôme ; Thompson, Christopher H ; Kang, Seok Kyu ; Stouffs, Katrien ; Jansen, Anna E ; Verstraete, Lieve ; Jacquinet, Adeline ; Parrini, Elena ; Guerrini, Renzo ; Fujiwara, Yuh ; Miyatake, Satoko ; Ben-Zeev, Bruria ; Bassan, Haim ; Reish, Orit ; Marom, Daphna ; Hauser, Natalie ; Vu, Thuy-Anh ; Ackermann, Sally ; Spencer, Careni E ; Lippa, Natalie ; Srinivasan, Shraddha ; Charzewska, Agnieszka ; Hoffman-Zacharska, Dorota ; Fitzpatrick, David ; Harrison, Victoria ; Vasudevan, Pradeep ; Joss, Shelagh ; Pilz, Daniela T ; Fawcett, Katherine A ; Helbig, Ingo ; Matsumoto, Naomichi ; Kearney, Jennifer A ; Fry, Andrew E ; Goldberg, Ethan M. / SCN3A-related neurodevelopmental disorder : A spectrum of epilepsy and brain malformation. In: Annals of Neurology. 2020 ; Vol. 88, No. 2. pp. 348-362.

BibTeX

@article{3a6f7379220a4b85888bc1e52a6361e0,
title = "SCN3A-related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation",
abstract = "OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood-onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type vs. variant Nav1.3 subunits co-expressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293 T cells).RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76{\%}; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75{\%}). Many, but not all (15/19; 79{\%}), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4-6 of domains II-IV. Most pathogenic missense variants tested (10/11; 91{\%}) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75{\%} of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis.",
author = "Tariq Zaman and Helbig, {Katherine L} and J{\'e}r{\^o}me Clatot and Thompson, {Christopher H} and Kang, {Seok Kyu} and Katrien Stouffs and Jansen, {Anna E} and Lieve Verstraete and Adeline Jacquinet and Elena Parrini and Renzo Guerrini and Yuh Fujiwara and Satoko Miyatake and Bruria Ben-Zeev and Haim Bassan and Orit Reish and Daphna Marom and Natalie Hauser and Thuy-Anh Vu and Sally Ackermann and Spencer, {Careni E} and Natalie Lippa and Shraddha Srinivasan and Agnieszka Charzewska and Dorota Hoffman-Zacharska and David Fitzpatrick and Victoria Harrison and Pradeep Vasudevan and Shelagh Joss and Pilz, {Daniela T} and Fawcett, {Katherine A} and Ingo Helbig and Naomichi Matsumoto and Kearney, {Jennifer A} and Fry, {Andrew E} and Goldberg, {Ethan M}",
note = "{\circledC} 2020 American Neurological Association.",
year = "2020",
month = "8",
day = "1",
doi = "10.1002/ana.25809",
language = "English",
volume = "88",
pages = "348--362",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - SCN3A-related neurodevelopmental disorder

T2 - A spectrum of epilepsy and brain malformation

AU - Zaman, Tariq

AU - Helbig, Katherine L

AU - Clatot, Jérôme

AU - Thompson, Christopher H

AU - Kang, Seok Kyu

AU - Stouffs, Katrien

AU - Jansen, Anna E

AU - Verstraete, Lieve

AU - Jacquinet, Adeline

AU - Parrini, Elena

AU - Guerrini, Renzo

AU - Fujiwara, Yuh

AU - Miyatake, Satoko

AU - Ben-Zeev, Bruria

AU - Bassan, Haim

AU - Reish, Orit

AU - Marom, Daphna

AU - Hauser, Natalie

AU - Vu, Thuy-Anh

AU - Ackermann, Sally

AU - Spencer, Careni E

AU - Lippa, Natalie

AU - Srinivasan, Shraddha

AU - Charzewska, Agnieszka

AU - Hoffman-Zacharska, Dorota

AU - Fitzpatrick, David

AU - Harrison, Victoria

AU - Vasudevan, Pradeep

AU - Joss, Shelagh

AU - Pilz, Daniela T

AU - Fawcett, Katherine A

AU - Helbig, Ingo

AU - Matsumoto, Naomichi

AU - Kearney, Jennifer A

AU - Fry, Andrew E

AU - Goldberg, Ethan M

N1 - © 2020 American Neurological Association.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood-onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type vs. variant Nav1.3 subunits co-expressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293 T cells).RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4-6 of domains II-IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis.

AB - OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood-onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type vs. variant Nav1.3 subunits co-expressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293 T cells).RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4-6 of domains II-IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=85087727204&partnerID=8YFLogxK

U2 - 10.1002/ana.25809

DO - 10.1002/ana.25809

M3 - Article

C2 - 32515017

VL - 88

SP - 348

EP - 362

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 2

ER -

ID: 52537207