Magnesium Supplementation in People With XMEN Syndrome

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.

Sex

Male

Minimum age

6 Years

* 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

• BACKGROUNDLi FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G, Su HC, Lenardo MJ. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011 Jul 27;475(7357):471-6. doi: 10.1038/nature10246. PMID 21796205
• BACKGROUNDChaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, Uzel G, Lenardo MJ. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science. 2013 Jul 12;341(6142):186-91. doi: 10.1126/science.1240094. PMID 23846901
• BACKGROUNDLi FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014 Apr 3;123(14):2148-52. doi: 10.1182/blood-2013-11-538686. Epub 2014 Feb 18. PMID 24550228
• RESULTChauvin SD, Price S, Zou J, Hunsberger S, Brofferio A, Matthews H, Similuk M, Rosenzweig SD, Su HC, Cohen JI, Lenardo MJ, Ravell JC. A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease. J Clin Immunol. 2022 Jan;42(1):108-118. doi: 10.1007/s10875-021-01137-w. Epub 2021 Oct 16. PMID 34655400