Abstract
Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by −4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na+ current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.
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Acknowledgments
The authors thank all patients and their parents for participating in this study. We thank Markus Lommi, Ann-Liz Träskelin and Paula Hakala for technical assistance, Dr. Julian Schubert and Stefanie Garkisch for their help with analysis of genetic data. This work was supported by the German Research Foundation (DFG Le1030/10-2, Le1030/11-1 to HL, 416/5-1 to BAN) and the Folkhälsan Research Foundation (A-EL), partly in the frame of the EuroEPINOMICS programme of the European Science foundation.
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Informed consent was obtained from the parents of all four patients. All procedures were in accordance with the Declaration of Helsinki and were approved by the local ethical review boards.
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Schwarz, N., Hahn, A., Bast, T. et al. Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia. J Neurol 263, 334–343 (2016). https://doi.org/10.1007/s00415-015-7984-0
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DOI: https://doi.org/10.1007/s00415-015-7984-0