Sleep research article
Functional and pharmacological characterization of the <i>SCN2A</i> variant p.C258R with mixed gain and loss of function causing developmental and epileptic encephalopathy type 11.
Authors: Köppel A , de Vries H , Jamili M , Stanke C , Brandl U , Leipold E , Heinemann SH
One-line summary
A sleep science research article on Functional and pharmacological characterization of the <i>SCN2A</i> variant p.C258R with mixed gain and loss of function causing developmental and epileptic encephalopathy type 11..
Sleep health notes
Sleep health notes will be added by the Sleepatch editorial team.
中文解读
中文解读待补充：本站会优先为失眠研究、睡眠质量改善、昼夜节律等高价值睡眠研究添加中文说明。
Original abstract
Pathogenic variants in <i>SCN2A</i> cause dysfunction of the Na<sub>V</sub>1.2 voltage-gated sodium channel and are associated with neurodevelopmental disorders with or without epilepsy. Treatment of epilepsy in these patients is challenging and depends on whether the variant results in a gain (GoF) or loss of function (LoF). We describe a patient with the <i>de novo SCN2A</i> variant p.C258R presenting with therapy-resistant developmental and epileptic encephalopathy type 11 (DEE type 11). We aimed to electrophysiologically analyze the functional consequences of this mutation and to examine the <i>in vitro</i> properties of phenytoin, lamotrigine, and topiramate, which resulted in clinical improvement. Depending on the specific functional readout after transient expression in HEK293T cells, mutation C258R of Na<sub>V</sub>1.2 channels resulted in a mixed LoF and GoF phenotype. Na<sub>V</sub>1.2-C258R channels exhibited slower inactivation kinetics and a left-shifted voltage dependence of steady-state inactivation. Current density was reduced when expressed in HEK293T cells although single-channel conductance and maximal channel open probability were only marginally affected. During repetitive stimulation, mutated channels showed stronger cumulative inactivation, consistent with LoF. Phenytoin and lamotrigine caused use-dependent block, but lamotrigine was less effective for C258R compared with the wild type. Topiramate diminished the current density in both variants with less use-dependence. The C258R mutation impairs Na<sub>V</sub>1.2 function through both LoF and GoF mechanisms. Sodium channel blockers with a strong use-dependence, such as phenytoin, may be preferential for seizure control in such cases.
Links and sources
This content is provided for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Sleep disorders, chronic insomnia, sleep apnea, and other conditions must be evaluated and treated by a qualified healthcare professional. If you experience persistent or severe sleep problems, consult a licensed physician or sleep specialist. Research cited refers to peer-reviewed studies; individual results may vary. Sleepatch does not endorse any specific medication, supplement, or therapy.
Want a personalized sleep improvement plan?
Sleepatch can prepare a customized sleep wellness program, insomnia relief guide, and evidence-based sleep coaching based on your needs.
Explore sleep services
Comments