Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy.
Action Potentials
/ drug effects
Anticonvulsants
/ pharmacology
Child, Preschool
Developmental Disabilities
/ diagnosis
Epilepsy
/ diagnosis
Female
Gain of Function Mutation
HEK293 Cells
Humans
Infant
Ion Channel Gating
Loss of Function Mutation
Male
NAV1.2 Voltage-Gated Sodium Channel
/ chemistry
Phenotype
Precision Medicine
Sodium Channel Blockers
/ pharmacology
SCN2A
developmental epileptic encephalopathy
patch-clamp
precise treatment
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
12
10
2019
revised:
01
03
2020
accepted:
05
03
2020
pubmed:
14
5
2020
medline:
1
5
2021
entrez:
14
5
2020
Statut:
ppublish
Résumé
To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE). We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole-cell patch-clamp recording. The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast-inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature. These findings provided the insights into the phenotype-genotype-funotype relationships of SCN2A-related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.
Sections du résumé
BACKGROUND
To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE).
METHODS
We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole-cell patch-clamp recording.
RESULTS
The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast-inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature.
CONCLUSION
These findings provided the insights into the phenotype-genotype-funotype relationships of SCN2A-related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.
Identifiants
pubmed: 32400968
doi: 10.1002/mgg3.1250
pmc: PMC7336724
doi:
Substances chimiques
Anticonvulsants
0
NAV1.2 Voltage-Gated Sodium Channel
0
SCN2A protein, human
0
Sodium Channel Blockers
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1250Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
Science. 2017 Mar 3;355(6328):
pubmed: 28183995
Annu Rev Physiol. 1984;46:455-72
pubmed: 6143532
Curr Opin Neurobiol. 2003 Jun;13(3):284-90
pubmed: 12850212
Trends Neurosci. 2018 Jul;41(7):442-456
pubmed: 29691040
F1000Res. 2019 Feb 6;8:
pubmed: 30800292
Ann Neurol. 2018 Apr;83(4):703-717
pubmed: 29466837
Mol Med. 2019 Feb 27;25(1):6
pubmed: 30813884
J Neurol. 2016 Feb;263(2):334-343
pubmed: 26645390
Physiol Rev. 2005 Oct;85(4):1271-301
pubmed: 16183913
Neurobiol Dis. 2012 Sep;47(3):378-84
pubmed: 22677033
Mol Genet Genomic Med. 2020 Jul;8(7):e1250
pubmed: 32400968
Clin Genet. 2016 Feb;89(2):198-204
pubmed: 26138355
Brain. 2012 Aug;135(Pt 8):2329-36
pubmed: 22719002
Science. 2019 Mar 22;363(6433):1309-1313
pubmed: 30765605
Hum Mol Genet. 2015 Mar 1;24(5):1457-68
pubmed: 25378553
Biol Psychiatry. 2017 Aug 1;82(3):224-232
pubmed: 28256214
Epilepsy Curr. 2019 Jan;19(1):51-53
pubmed: 30838929
J Physiol. 2003 Sep 15;551(Pt 3):741-50
pubmed: 12843211
Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10910-4
pubmed: 1332060
Brain. 2017 May 1;140(5):1316-1336
pubmed: 28379373
Eur J Clin Pharmacol. 2019 May;75(5):737-739
pubmed: 30643928
Brain. 2010 May;133(Pt 5):1403-14
pubmed: 20371507
J Physiol. 2005 May 1;564(Pt 3):803-15
pubmed: 15760941
Neurology. 2015 Sep 15;85(11):958-66
pubmed: 26291284
Hum Mutat. 2018 Dec;39(12):1942-1956
pubmed: 30144217
Proc Natl Acad Sci U S A. 1989 Oct;86(20):8147-51
pubmed: 2554301
Epilepsia. 2013 Sep;54(9):e117-21
pubmed: 23758435
Cell. 2017 Jul 27;170(3):470-482.e11
pubmed: 28735751
Epilepsy Behav. 2012 May;24(1):152
pubmed: 22481039
Epileptic Disord. 2014 Mar;16(1):13-8
pubmed: 24659627
Epilepsia. 2019 May;60(5):830-844
pubmed: 30968951
Neurology. 2009 Sep 29;73(13):1046-53
pubmed: 19786696
J Neurosci. 2004 Mar 17;24(11):2690-8
pubmed: 15028761
Epilepsia. 2002 Feb;43(2):201-4
pubmed: 11903470
Mol Cell Neurosci. 2009 Oct;42(2):90-101
pubmed: 19465131
Science. 2018 Oct 19;362(6412):
pubmed: 30190309
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5516-E5525
pubmed: 29844171
Eur J Hum Genet. 2019 Mar;27(3):408-421
pubmed: 30552426
Neurotherapeutics. 2016 Jan;13(1):192-7
pubmed: 26252990
Pharmacol Rev. 2018 Jan;70(1):142-173
pubmed: 29263209
Clin Genet. 2018 Dec;94(6):512-520
pubmed: 30182498
Ann Neurol. 2019 Apr;85(4):514-525
pubmed: 30779207