Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies

Human Mutation
Stephan LauxmannUlrike B S Hedrich

Abstract

Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p.(Lys908Glu)), a hyperpolarizing shift of the activation curve (p.(Val208Glu) and p.(Thr773Ile)), and an increased persistent current (p.(Thr773Ile)). To evaluate genotype-phenotype correlations, we next developed scoring systems for both the extent of the electrophysiological dysfunction and the severity of the clinical phenotype and applied those to 21 previously and newly functionally characterized SCN2A variants. All inherited variants were associated with a mild clinical phenotype and a lower electrophysiological score compared to those occurring de novo and causing severe phenotypes. Our results thus reveal...Continue Reading

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Citations

Jan 7, 2020·Epilepsia·Ulrike B S HedrichHolger Lerche
May 14, 2020·Molecular Genetics & Genomic Medicine·Pu MiaoJianhua Feng
Jun 28, 2019·Der Nervenarzt·Ulrike B S HedrichHolger Lerche
Apr 1, 2020·Developmental Medicine and Child Neurology·Andreas Brunklaus, Dennis Lal
Aug 18, 2020·Science Translational Medicine·Henrike O HeyneMark J Daly
Oct 21, 2020·Nature Reviews. Neurology·Rima Nabbout, Mathieu Kuchenbuch
Nov 26, 2020·Epilepsy Currents·Eric R Wengert, Manoj K Patel
Mar 19, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Katherine CrawfordIngo Helbig
Mar 27, 2021·Physiological Reviews·Massimo MantegazzaWilliam A Catterall
Dec 12, 2021·American Journal of Medical Genetics. Part a·Ruth RichardsonMeena Balasubramanian

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