Background: ATP1A1 encodes an α1 isoform of Na+/K+-ATPase, which is expressed abundantly in kidneys and central nervous system. ATP1A1 variants may cause Na+/K+-ATPase loss of function and lead to a wide spectrum of phenotypes. This study aims to summarize the clinical and genetic features of ATP1A1 de novo mutation-related disorders and explore the potential correlations between phenotypes and genotypes. Methods: We analyzed two new cases harboring novel de novo ATP1A1 variants and reviewed all reported cases. Results: Both our probands had developmental delay, patient 1 accompanied with sleep disorders, irritability , and patient 2 with refractory seizures. They each had a novel de novo heterozygous missense variant, c.2797G>A[p.Asp933Asn] (NM_000701) and c.2590G>A[p.Gly864Arg] (NM_000701) respectively. Four patients with de novo ATP1A1 variants have been reported in two previous papers. Among them, three patients had refractory seizures and one patient had complex hereditary spastic paraplegia (HSP) . Therefore, all six patients had developmental delay, and four of them had epilepsy. All variants located in the transmembrane regions M3, M4, M7, and M8 of ATP1A1 protein. Four patients with mutations in M3 and M7 had more severe phenotypes, including developmental delay and epileptic encephalopathy, three of them with hypomagnesemia, whereas two patients with mutations in M4 and M8 had milder phenotypes, only with mild developmental delay, without seizures or hypomagnesemia. Correcting hypomagnesemia had not controlled those seizures. Conclusions: Two novel de novo ATP1A1 variants identified in two patients here enriched the genotypic and phenotypic spectrum of ATP1A1 mutation -related disorder. Our findings suggest that hypomagnesemia in this disorder might relate to more severe phenotype and indicate more severe Na+/K+-ATPase dysfunction. Variations in M3 and M7 transmembrane regions were related to more severe phenotype than those in M4 and M8, which suggested that variations in M3 and M7 might cause more severe ATP1A1 functional defect.

中文翻译：

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ATP1A1从头突变相关疾病：临床和遗传特征

背景：ATP1A1编码Na + / K + -ATPase的α1亚型，在肾脏和中枢神经系统中大量表达。ATP1A1变异可能会导致Na + / K + -ATPase功能丧失并导致广泛的表型。这项研究旨在总结ATP1A1从头突变相关疾病的临床和遗传特征，并探讨表型和基因型之间的潜在相关性。方法：我们分析了两个带有新型从头ATP1A1变异的新病例，并复查了所有报道的病例。结果：我们的两个先证者都有发育迟缓，患者1伴有睡眠障碍，烦躁不安，患者2伴有难治性癫痫发作。他们每个人都有一个新的从头杂合错义变异体，分别是c.2797G> A [p.Asp933Asn]（NM_000701）和c.2590G> A [p.Gly864Arg]（NM_000701）。在先前的两篇论文中已经报道了四名患有从头ATP1A1变异的患者。其中，3例患者患有难治性癫痫发作，1例患者患有复杂的遗传性痉挛性截瘫（HSP）。因此，所有6例患者都有发育迟缓，其中4例患有癫痫病。所有变体都位于ATP1A1蛋白的跨膜区域M3，M4，M7和M8中。4例M3和M7突变的患者具有更严重的表型，包括发育迟缓和癫痫性脑病，其中3例患有低镁血症，而2例M4和M8突变的患者具有较轻的表型，仅具有轻度的发育延迟，没有癫痫或低镁血症。纠正低镁血症并不能控制那些癫痫发作。结论：在两名患者中鉴定出的两个新的从头ATP1A1变异体丰富了ATP1A1突变相关疾病的基因型和表型谱。我们的发现表明，该疾病的低镁血症可能与更严重的表型有关，并表明更严重的Na + / K + -ATPase功能障碍。M3和M7跨膜区域的变异比M4和M8的变异与更严重的表型有关，这表明M3和M7的变异可能导致更严重的ATP1A1功能缺陷。