Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany.
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Neuropediatrics. 2020 Oct;51(5):368-372. doi: 10.1055/s-0040-1710524. Epub 2020 May 11.
Patients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype-phenotype correlation between and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a variant in (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done.
患有神经纤维瘤病 1 型（NF1）的患者患 West 综合征（WS）的风险增加，但将 NF1 和 WS 联系起来的潜在机制尚不清楚。与其他神经皮肤综合征不同，解释婴儿痉挛（IS）病程的颅内异常常常不存在，并且癫痫发作的结局通常较好。有几项研究调查了 NF1 相关 WS（NF1-WS）与癫痫易感性之间的潜在基因型-表型相关性，但未发现关联。因此，我们在 51 名 NF1 患者的队列中鉴定了三名 NF1 相关 WS（NF1-WS）患者，并进行了全外显子组测序（WES）以鉴定遗传修饰因子。在两名 WS 且癫痫发作结局良好的 NF1 患者中，我们未发现与癫痫相关的基因中的变异。然而，在一名 NF1-WS 且转为耐药性癫痫的患者中，我们鉴定出 Kv3.2 中的 变异（c.G499T，p.D167Y），该变异以前未被描述为与癫痫相关的钾通道。鉴定出的 变异的电生理研究表明，对于电流幅度具有很强的失活作用，对于通道激活具有功能获得作用，建议存在复杂的网络作用。这些结果表明，应对 NF1 患者和严重癫痫发作表现进行系统的遗传分析，以确定潜在的继发遗传病因。
