Two autopsy cases of sudden unexpected death from Dravet syndrome with novel de novo SCN1A variants
Two autopsy cases of sudden unexpected death from Dravet syndrome with novel de novo SCN1A variants
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DOI：
10.1016/j.braindev.2019.10.005
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发表时间：
2020-02-01
影响因子：
1.7
通讯作者：
Nishida, Naoki
中科院分区：
文献类型：
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作者：
Hata, Yukiko;Oku, Yuko;Nishida, Naoki
目的：Dravet综合征（DS）的特点是与癫痫相关的过早死亡率较高，且死亡年龄明显较年轻，但DS猝死的尸检报告却少于预期。 方法：我们报道了2例DS猝死的尸检病例。病例1是一名13岁男性，在浴缸中溺水身亡；病例2是一名3岁女性，在睡觉时死亡。在病例 1 中，抗惊厥药丙戊酸的血液浓度低于推荐的治疗范围。通过二代测序对 402 个心血管疾病相关基因和 146 个癫痫相关基因进行神经病理学研究和遗传分析。结果：在两名患者的大脑中均未观察到明显的神经元丢失和神经胶质增生。尽管两者都可能存在轻度皮质发育畸形，但其程度与年龄匹配的对照相似。遗传分析在病例 1 中发现了 SCN1A 内含子 23 (c.4477-3T > C) 中的一个新变异，该变异位于次要剪接共有序列之外。使用小基因构建体进行的体外剪接功能测定表明，这种内含子变体导致紧邻外显子 24 之前插入 2 bp，从而导致蛋白质截短。同样，在病例 2 中发现了一种意义不明的新的从头错义突变 SCN1A Arg 1 87Pro。在这两种情况下，我们还发现了与心肌病相关的变异，被归类为可能致病；结论：目前的病例强调需要对DS病例进行多方面的检查，以获得明确的尸检诊断并探索意外猝死的机制。 (C) 2019 年日本儿童神经病学学会。由 Elsevier B.V. 出版。保留所有权利。
Aim: Dravet syndrome (DS) is characterized by high epilepsy-related premature mortality with a markedly young age at death, however, autopsy report of sudden unexpected death with DS has been fewer than expected.Methods: We report two autopsy cases with sudden unexpected death from DS. Case 1 was a 13-year-old male who drowned in a bathtub, and Case 2 was a 3-year-old female who died while sleeping. In Case 1, the blood concentration of the anticonvulsant, valproic acid, was below the recommended therapeutic range. Neuropathological investigation and genetic analysis of 402 cardiovascular disease-related and 146 epilepsy-related genes by next generation sequencing were applied.Results: No significant neuronal loss with gliosis was observed in the brain of either patient. Although possible mild malformations of cortical development were found in both, the degree thereof was similar to that of age-matched controls. Genetic analysis identified a novel variant in SCN1A intron 23 (c.4477-3T > C) in Case 1 that falls outside of the minor splicing consensus sequence. In vitro splicing functional assays with minigene constructs revealed that this intronic variant leads to a 2-bp insertion immediately before exon 24 that results in protein truncation. Similarly, a novel de novo missense mutation of unknown significance, SCN1A Arg 1 87Pro, was identified in Case 2. In both cases, we also identified cardiomyopathy-related variants classified as likely pathogenic; however, the effect of these variants at death was minimal because there was an absence of pathological change indicating inherited cardiomyopathy.Conclusion: The present cases emphasize the need for multifaceted examination of DS cases so as to obtain a definitive autopsy diagnosis and to explore the mechanism of sudden unexpected death. (C) 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.