Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia

A number sign (#) is used with this entry because X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) is caused by hemizygous mutation in the gene encoding magnesium transporter-1 (MAGT1; 300715) on chromosome Xq13.

Hemizygous mutation in the MAGT1 gene can also cause congenital disorder of glycosylation type Icc (CDG1CC; 301031). Patients with XMEN are usually not assessed for abnormal glycosylation of serum transferrin, but at least 1 patient with a primary diagnosis of XMEN was demonstrated to have the laboratory features of CDG1CC (Blommaert et al., 2019).

Description

XMEN is an X-linked recessive immunodeficiency characterized by CD4 (186940) lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation (Li et al., 2011). Affected individuals have chronic EBV infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders. Magnesium supplementation may be therapeutic (summary by Li et al., 2014).

Clinical Features

Li et al. (2011) examined 2 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 (see 186910) ratio and reduced CD31 (PECAM1; 173445)-positive cells in the naive CD4-positive T-cell population, suggesting diminished thymic output. However, both patients exhibited 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. In contrast, the patients' T cells were fully activated by downstream inducers. The patients showed no defects in B-cell receptor or Toll-like receptor (see 603030) stimulation of B cells. Li et al. (2011) detected skewed lyonization, the process of X chromosome inactivation by methylation, in the boys' mother, with only the X chromosome inherited by her 2 sons inactivated in her T cells. Li et al. (2011) identified an additional patient with a similar phenotype who had died 5 years earlier, at the age of 45 years, from chronic Epstein-Barr virus-associated lymphoma. Like the affected boys, he exhibited 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. (2011) termed the immunodeficiency in these patients 'X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia,' or XMEN. Li et al. (2014) noted that the 45-year-old patient reported by Li et al. (2011) died from complications after hematopoietic stem cell transplantation.

Li et al. (2014) reported 4 additional unrelated patients, ranging in age from 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 of the respiratory tract. 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 an autoimmune cytopenia. None had failure to thrive or developmental problems. Laboratory studies showed decreased CD4+ T cells, suggesting reduced thymic output, and moderately high B cells, likely due to chronic EBV infection. Some patients had variable deficiencies in immunoglobulin levels and vaccine responses, which were thought to be attributable to a deficiency in T follicular helper cells or an underlying B-cell dysfunction. T-cell proliferative responses were inconsistently defective.

Dhalla et al. (2015) reported a 58-year-old man with XMEN who was followed for over 20 years. He first presented at age 36 with a long history of sinopulmonary infections since early childhood. Laboratory studies showed a reversed CD4/CD8 T-cell ratio, poor response to pneumococcal polysaccharide vaccine, and mild intermittent thrombocytopenia. At age 52, he developed worsening infections, lymphadenopathy, and hepatosplenomegaly; he was found to have EBV viremia and an EBV-driven lymphoproliferative disorder. He was treated with chemotherapy, but the disease recurred at age 57. At that time, he had intermittent thrombocytopenia, neutropenia, CD4 and B-cell lymphopenia, increased EBV viral load, and diffuse B-cell lymphoma. He also showed neurologic decompensation associated with multifocal white matter changes on brain imaging and JC virus in the CSF, consistent with progressive multifocal leukoencephalopathy; this ultimately resulted in death. Patient cells showed absent proliferative response specifically to EBV. Family history revealed a nephew with a similar phenotype who developed an EBV-driven lymphoproliferative disorder at age 13.

Patiroglu et al. (2015) reported a 17-year-old boy with a complex presentation of XMEN. He had a history of recurrent respiratory infections since childhood and developed Hodgkin lymphoma at age 15. After treatment, he developed Guillain-Barre syndrome and was later diagnosed with immune thrombocytopenia, autoimmune hepatitis with elevated liver function tests, and autoimmune anemia. Laboratory studies showed chronic CMV infection, and later EBV infection. Immunologic workup showed selective CD4 lymphopenia, an inverted CD4/CD8 ratio, and low levels of class-switched B cells.

Blommaert et al. (2019) reported a 17-year-old boy (patient 3) with XMEN. He had recurrent infections, chronic active EBV infection, and decreased CD4+ T cells, but a normal CD4:CD8 ratio. He also had a type 1 pattern of abnormal glycosylation of serum transferrin, consistent with CDG1CC, but he did not have other features of that disorder, including developmental delay. Blommaert et al. (2019) noted that patients with XMEN are usually not assessed for the laboratory abnormalities of CDG.

Clinical Management

MAGT1 is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. Chaigne-Delalande et al. (2013) showed that decreased intracellular free Mg(2+) causes defective expression of the natural killer (NK)-activating receptor NKG2D (611817) in NK and CD8+ T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restored intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, the authors concluded that their findings revealed a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.

Inheritance

The transmission pattern of XMEN in the families reported by Li et al. (2014) was consistent with X-linked recessive inheritance.

Mapping

XMEN results from mutations in the MAGT1 gene, which Goytain and Quamme (2005) mapped to chromosome Xq13.1-q13.2.

Molecular Genetics

In the 2 brothers with XMEN that they reported, Li et al. (2011) identified a 10-bp deletion in the MAGT1 gene (300715.0002) that removed a splice donor site located in the 3-prime exon-intron junction of exon 7. The boys' mutant MAGT1 splice variant was missing exons 7 and 8, resulting in a premature stop codon after val286. In the unrelated male patient with XMEN who had died at age 45 years, Li et al. (2011) identified an arg137-to-ter (R137X; 300715.0003) mutation in MAGT1. Studies with XMEN patient cells showed that MAGT1 deficiency abrogated Mg(2+) influx, leading to impaired responses to antigen receptor engagement, including defective activation of PLCG1 (172420) and a markedly impaired Ca(2+) influx in T lymphocytes, but not B lymphocytes.

In 4 unrelated males with XMEN, Li et al. (2014) identified hemizygous loss-of-function mutations in the MAGT1 gene (see, e.g., 300715.0003-300715.0005). The patients' mothers, who appeared to be asymptomatic, had preferential X chromosome inactivation of the chromosome harboring the mutant allele. Functional studies of the variants were not performed, but combined with the findings in their previous reports (Li et al., 2011; Chaigne-Delalande et al., 2013), Li et al. (2014) proposed a pathogenic mechanism. Loss of MAGT1 decreases the flux of free intracellular Mg(2+) flux, which is required to coordinate T-cell signaling during T-cell activation, and also leads to loss of NKG2D expression, which is involved in antiviral and antitumor cytotoxicity of NK and cytotoxic T lymphocytes, particularly affecting the control of EBV infection.

In a man and his nephew with XMEN, Dhalla et al. (2015) identified a hemizygous nonsense mutation in the MAGT1 gene (R238X; 300715.0006). Analysis of the nephew's blood showed a 5- to 10-fold reduction in MAGT1 mRNA, decreased NKG2D expression on CD8+ T cells, and decreased basal intracellular free magnesium compared to controls.

In a 17-year-old boy with XMEN, Patiroglu et al. (2015) identified a hemizygous frameshift mutation in the MAGT1 gene (300715.0007). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. NKG2D expression on NK and CD8+ T cells was decreased, although cytotoxic degranulation of both cell types was normal.

In a 17-year-old boy (patient 3) with XMEN, Blommaert et al. (2019) identified a hemizygous nonsense mutation in the MAGT1 gene (L313X; 300715.0010). Patient-derived fibroblasts showed only 6% residual MAGT1 transcript, whereas a lymphocyte cell line from the patient showed 50% residual MAGT1 transcript levels. There was almost complete absence of the protein, consistent with a loss of function. The patient also had abnormal serum transferrin glycosylation, consistent with a defect in glycosylation (see CDG1CC, 301031). Patient fibroblasts and lymphocytes showed an N-glycosylation defect, with hypoglycosylation of STT3B (608605)-dependent substrates, including SHBG (182205), CTSC (602365), and GLUT1 (138140). Expression of the mutation into MAGT1-null HEK293 cells was unable to rescue the glycosylation defect. The patient had no intellectual disability or other features of CDG1CC.