Background:

- X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia syndrome is called XMEN syndrome. In this genetic condition, the cells have less magnesium than normal. This makes it hard for the body to fight infections. Researchers want to see if magnesium supplements can make it easier for the body to fight infection.

Objective:

- To see if magnesium supplements can strengthen the immune system and reduce the amount of Epstein-Barr virus in people with XMEN syndrome.

Eligibility:

- People ages 6 and older who have XMEN syndrome

Design:

• Participants will be screened with:
• Medical history
• Physical exam
• CT scan: Participants will drink a contrast and may get dye through an IV in the arm. They will lie in a machine that takes pictures of the body.
• EKG: Small sticky patches on the body will trace heart rhythm.
• Blood tests
• The study has 2 parts.
• Participants doing both parts will participate for 1 year and visit the clinic about 15 times. These visits will include a physical exam and blood and urine tests.
• Participants doing only the first part finish in 6 months and have fewer visits.
• For study part 1, participants will take magnesium pills for 3 months and placebo pills for another 3 months.
• At 3 and 6 months, they will have physical exam, medical history, blood and urine tests, and an EKG.
• If the magnesium pills are not helpful, participants will do study part 2.
• They will be admitted to the hospital for 4 5 days to get magnesium for 3 days through an arm vein.
• They will take magnesium pills for another 6 months.

X-linked immunodeficiency magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) syndrome is a primary immunodeficiency caused by the loss of expression of the magnesium transporter 1 (MAGT1). This syndrome is associated with cluster of differentiation 4 (CD4) lymphopenia, chronic EBV infection in most patients, and EBV-related lymphoproliferative disorders. The loss of MAGT1 leads to impaired T cell activation and decreased expression of the activator receptor, NKG2D on natural killer (NK) cells and CD8 T cells, leading to decreased EBV-specific cytolytic function of these cells. Results of previous studies suggest that magnesium supplementation may be a viable therapeutic option for patients with XMEN.

The proposed study has 2 parts, and patients will be divided into 2 cohorts. Patients in cohort 1 (high EBV group) will have baseline blood EBV viral load greater than or equal to 5,000 copies/mL or EBV log greater than or equal to 3.7 IU/mL. Patients in cohort 2 (low/no EBV group) will have baseline blood EBV viral load <5,000 copies/mL or EBV log <3.7 IU/mL. Part I is a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of oral magnesium L-threonate in patients with XMEN syndrome. Within each cohort, patients will be randomized to receive escalating doses of either placebo or oral magnesium L-threonate for 12 weeks. Patients will then receive the crossover treatment (magnesium or placebo) for an additional 12 weeks. For patients who experience a 0.5-log decrease in the number of EBV-infected B cells (cohort 1) or a greater than or equal to 2-fold increase in NKG2D receptor expression on cluster of differentiation 8 (CD8+) T cells (cohort 2) with oral magnesium as compared to placebo, the study will be complete. Patients who do not meet this efficacy outcome will undergo a 2-week washout period and proceed to Part II, an open-label, non-randomized evaluation of intravenous magnesium sulfate (MgSO4) followed by oral magnesium L-threonate. These patients will be hospitalized to receive 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day. They will then restart escalating doses of oral magnesium L-threonate and continue for the remaining 24 weeks of Part II. If conducted, Part II will allow for secondary analyses to compare different durations of magnesium supplementation.

• INCLUSION CRITERIA:

All of the following inclusion criteria must be met prior to enrollment:

1. Molecular diagnosis of the MAGT1 genetic defect
2. Greater than or equal to 6 years years of age
3. Willingness to stop magnesium supplements (other than the study agent) and any multivitamins or over-the counter-supplements that may contain magnesium for the duration of the study
4. Willingness to go without magnesium supplementation during a 12-week placebo period and during both 2-week washout periods (pre-study and mid-study)
5. Willingness to have samples stored for future research
6. Must have a physician at home for follow-up care

EXCLUSION CRITERIA:

1. Chemotherapy or radiotherapy for lymphoma within 12 months prior to enrollment
2. Rituximab exposure within 6 months prior to enrollment
3. Systemic symptoms suggestive of evolving lymphoma
4. History of clinically significant cardiac arrhythmias or cardiac defects
5. Renal insufficiency (calculated creatinine clearance <50 mL/min or insufficiency requiring dialysis)
6. Advanced heart block
7. Hypermagnesemia, defined as magnesium serum concentrations >2 mmol/L (>5 mg/dL)
8. Human immunodeficiency virus (HIV) seropositivity
9. Signs or symptoms of life-threatening active microbial infection
10. History of hypersensitivity to any of the study agents
11. Any condition that, in the investigator s opinion, may substantially increase the risk associated with study participation or compromise the study s scientific objectives
12. Participation in a clinical protocol which includes an intervention that, in the opinion of the investigator, may affect the results of the current study

1 year