“X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia” (XMEN) disease is an inborn error of glycosylation and immunity caused by loss of function mutations in the magnesium transporter 1 (MAGT1) gene. It is a multisystem disease that strongly affects certain immune cells. MAGT1 is now confirmed as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates Asparagine (N)-linked glycosylation of specific substrates, making XMEN a congenital disorder of glycosylation manifesting as a combined immune deficiency. The clinical disease has variable expressivity, and impaired glycosylation of key MAGT1-dependent glycoproteins in addition to Mg²⁺ abnormalities can explain some of the immune manifestations. NKG2D, an activating receptor critical for cytotoxic function against EBV, is poorly glycosylated and invariably decreased on CD8⁺ T cells and natural killer (NK) cells from XMEN patients. It is the best biomarker of the disease. The characterization of EBV-naïve XMEN patients has clarified features of the genetic disease that were previously attributed to EBV infection. Extra-immune manifestations, including hepatic and neurological abnormalities, have recently been reported. EBV-associated lymphomas remain the main cause of severe morbidity. Unfortunately, treatment options to address the underlying mechanism of disease remain limited and Mg²⁺ supplementation has not proven successful. Here, we review the expanding clinical phenotype and recent advances in glycobiology that have increased our understanding of XMEN disease. We also propose updating XMEN to “X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect” in light of these novel findings.

“X 连锁免疫缺陷伴镁缺陷、爱泼斯坦-巴尔病毒 (EBV) 感染和瘤形成”(XMEN) 病是由镁转运蛋白 1 ( MAGT1 ) 基因功能丧失突变引起的糖基化和免疫的先天错误。它是一种多系统疾病，会强烈影响某些免疫细胞。MAGT1 现在被证实是寡糖基转移酶复合物的非催化亚基，并促进特定底物的天冬酰胺 (N) 连接的糖基化，使 XMEN 成为一种表现为联合免疫缺陷的先天性糖基化障碍。除了 Mg ²⁺之外，临床疾病具有可变的表达性，并且关键 MAGT1 依赖性糖蛋白的糖基化受损异常可以解释一些免疫表现。NKG2D 是一种对 EBV 细胞毒性功能至关重要的激活受体，其糖基化程度很低，并且在来自 XMEN 患者的CD8 ⁺ T 细胞和自然杀伤 (NK) 细胞上总是降低。它是该疾病的最佳生物标志物。EBV-naïve XMEN 患者的特征阐明了先前归因于 EBV 感染的遗传疾病的特征。最近报道了免疫外表现，包括肝脏和神经系统异常。EBV 相关淋巴瘤仍然是严重发病率的主要原因。不幸的是，解决疾病潜在机制的治疗选择仍然有限，而且 Mg ²⁺补充尚未被证明是成功的。在这里，我们回顾了扩展的临床表型和糖生物学的最新进展，这些进展增加了我们对 XMEN 疾病的理解。鉴于这些新发现，我们还建议将 XMEN 更新为“X 连锁 MAGT1 缺陷，对 EBV 感染和 N 连锁糖基化缺陷的易感性增加”。