EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

中文翻译：

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从头EIF2AK1和EIF2AK2变体与发育延迟，白质脑病和神经系统失代偿有关。

EIF2AK1和EIF2AK2编码的真核翻译起始因子2α激酶（EIF2AK）家族的成员抑制蛋白质合成响应生理压力条件。EIF2AK2还参与先天免疫应答以及信号转导，凋亡，细胞增殖和分化的调节。尽管有这些发现，但尚未报道与EIF2AK1和EIF2AK2有害变异有关的人类疾病。在这里，我们描述了在EIF2AK1（1/9）或EIF2AK2（8/9）中具有杂合的从头错义突变的9个无关个体的鉴定。在这9个人中看到的特征包括白质改变（9/9），发育迟缓（9/9），语言障碍（9/9），认知障碍（8/9），共济失调（6/9），先知性构音障碍语言能力（6/9），肌张力低下（7/9），高渗（6/9）和不自主运动（3/9）。具有EIF2AK2变体的个体在高热疾病或感染的情况下也表现出神经系统退化。我们使用哺乳动物细胞系和先证者成纤维细胞来进一步证实这些基因中变体的致病性，并发现激酶活性降低。EIF2AKs磷酸化真核翻译起始因子2亚基1（EIF2S1，也称为EIF2α），然后抑制EIF2B活性。编码EIF2B蛋白的基因中的有害变体导致儿童期共济失调，并伴有中枢神经系统髓鞘过少/白质消失（CACH / VWM），这是一种白细胞营养不良，其特征是在高热疾病和其他应激源的情况下发生神经系统退化。