Division of Neurology Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104.
Division of Genomic Diagnostics, Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104.
Ann Clin Transl Neurol. 2019 Aug;6(8):1445-1455. doi: 10.1002/acn3.50839. Epub 2019 Jul 23.
Pathogenic variants in SCN8A, encoding the voltage-gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single-tertiary care center, with biophysical data on identified Nav1.6 variants and pharmacological response to selected Na+ channel blockers.
SCN8A variants were identified via an exome-based panel of epilepsy-associated genes for next generation sequencing (NGS), or via exome sequencing. Biophysical characterization was performed using voltage-clamp recordings of ionic currents in heterologous cells.
We observed a range in age of onset and severity of epilepsy and associated developmental delay/intellectual disability. Na+ channel blockers were highly or partially effective in most patients. Nav1.6 variants exhibited one or more biophysical defects largely consistent with gain of channel function. We found that clinical severity was correlated with the presence of multiple observed biophysical defects and the extent to which pathological Na+ channel activity could be normalized pharmacologically. For variants not previously reported, functional studies enhanced the evidence of pathogenicity.
We present a comprehensive single-center dataset for SCN8A epilepsy that includes clinical, genetic, electrophysiologic, and pharmacologic data. We confirm a spectrum of severity and a variety of biophysical defects of Nav1.6 variants consistent with gain of channel function. Na+ channel blockers in the treatment of SCN8A epilepsy may correlate with the effect of such agents on pathological Na+ current observed in heterologous systems.
SCN8A 基因编码电压门控钠离子（Na+）通道 α 亚基 Nav1.6，其致病性变异是癫痫的已知病因。在此，我们描述了在单一三级护理中心评估的所有 SCN8A 癫痫患者的临床和遗传特征，包括鉴定出的 Nav1.6 变异的生物物理数据和对选定的 Na+通道阻滞剂的药理反应。
通过针对癫痫相关基因的外显子组 NGS 或外显子组测序，鉴定 SCN8A 变异。使用异源细胞中的离子电流电压钳记录进行生物物理特性分析。
我们观察到癫痫发作和相关发育迟缓/智力残疾的发病年龄和严重程度的差异。大多数患者对 Na+通道阻滞剂高度或部分有效。Nav1.6 变异表现出一种或多种生物物理缺陷，这些缺陷在很大程度上与通道功能的获得一致。我们发现临床严重程度与存在多个观察到的生物物理缺陷以及病理性 Na+通道活性在多大程度上可以通过药理学正常化相关。对于以前未报道过的变体，功能研究增强了其致病性的证据。
我们呈现了 SCN8A 癫痫的一个全面的单中心数据集，包括临床、遗传、电生理和药理学数据。我们证实了 Nav1.6 变异的严重程度范围和多种生物物理缺陷与通道功能的获得一致。在 SCN8A 癫痫的治疗中，Na+通道阻滞剂可能与这些药物在异源系统中观察到的病理性 Na+电流的作用相关。
