Immunodeficiency, X-Linked, with Magnesium Defect, Epstein-Barr Virus Infection, and Neoplasia D81.8

Immunodeficiency X-linked with magnesium defect, Epstein-Barr virus infection, and neoplasia, also known by the acronym XMEN, is a recessive X-linked immunodeficiency, a multisystem disorder, with congenital disruption of glycosylation characterized by CD4 (186940) lymphopenia, severe chronic viral infections, and impaired T lymphocyte activation. The disease is caused by loss-of-function mutations in the magnesium transporter 1 gene(MAGT1 gene). Affected individuals have a chronic infection with Epstein-Barr virus(EBV) and are susceptible to the development of EBV-associated lymphoproliferative B-cell disorders.

MAGT1 functions as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates asparagine (N)-linked glycosylation of specific substrates. This results in XMEN congenital glycosylation disorder and combined immunodeficiency with EBV susceptibility.

The clinical phenotype is differentially expressed. Impaired glycosylation of key MAGT1-dependent glycoproteins and Mg2+ abnormalities explain some of the clinical immunodeficiencies.

Matsuda-Lennikov M et al (2019) demonstrated that EBV susceptibility in XMEN is associated with defective expression of the natural killer group 2 antiviral protein, member D (NKG2D), and abnormal Mg2+ transport. Poor glycosylation of NKG2D results in loss of function. Matsuda-Lennikov M et al (2019) found that MAGT1-dependent glycosylation is sensitive to Mg2+ content and that decreased Mg2+ impairs immune cell function through loss of specific glycoproteins. The receptor is decreased on CD8+ T cells and natural killer (NK) cells in this disease. It is the best biomarker for the disease. EBV-associated lymphoma is the major cause of severe morbidity in this immune disorder.

Treatment options to address the underlying disease mechanisms remain limited. Mg2+ supplementation is controversially discussed.

Disorders of magnesium homeostasis, often associated with altered magnesium channel expression and/or function, have been linked to a variety of diseases. Identification of genetic alterations and their functional consequences in patients with immunodeficiency has shown that magnesium and MAGT1 are key molecular determinants of T cell-mediated immune responses (Trapani Vet al. 2015)

Li et al (2011) studied two brothers aged 7 and 3 years with recurrent infections, including chronic Epstein-Barr virus infections, and low CD4 T-cell counts. Both patients had an inverted CD4:CD8 ratio and fewer CD31 (PECAM1; 173445)-positive cells in the naive CD4-positive T-cell population, suggesting decreased thymic production. However, both patients had pronounced defects in T-cell receptor (TCR; see 186880)-mediated activation events and impaired early TCR signaling events such as NF-kappa-B (see 164011) and NFAT (see 600490) nuclear translocation. Patients did not show defects in B cell stimulation by B cell receptors or Toll-like receptors (reviewed in 603030). Li et al (2011) identified another patient with a similar phenotype who had died of chronic Epstein-Barr virus-associated lymphoma 5 years earlier at age 45. This one also had a similar T-cell defect in NF-kappa B and NFAT nuclear translocation in response to TCR stimulation, but not in response to downstream T-cell activation inducers.

Li et al (2014) reported 4 other unrelated patients, aged 4 to 23 years, with XMEN. All patients had chronic EBV infection with persistent EBV detectable in the blood. Other features included splenomegaly and variable recurrent infections, mainly respiratory. Three patients developed EBV-associated B-cell lymphoproliferative disorders, including the 23-year-old patient who died after hematopoietic stem cell transplantation. One patient had autoimmune cytopenia.

1. Blommaert E et al. (2019) Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype. Proc Natl Acad Sci U S A 116: 9865-9870.
2. Li FY et al (2011) Second messenger role for Mg(2+) revealed by human T-cell immunodeficiency. Nature 475: 471-476.
3. Li FY et al. (2014) XMEN disease: a new primary immunodeficiency affecting Mg(2+) regulation of immunity against Epstein-Barr virus. Blood 123: 2148-2152.
4. Matsuda-Lennikov M et al (2019) Magnesium transporter 1 (MAGT1) deficiency causes selective defects in N-linked glycosylation and expression of immune-response genes. J Biol Chem 294:13638-13656.
5. Ravell JC et al (2020) An Update on XMEN Disease. J Clin Immunol 40: 671-681.
6. Trapani Vet al (2015) The role of MAGT1 in genetic syndromes. Magnes Res 28: 46-55.