Magnesium Supplementation in People With XMEN Syndrome

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:

• Molecular diagnosis of the MAGT1 genetic defect
• Greater than or equal to 6 years years of age
• 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
• Willingness to go without magnesium supplementation during a 12-week placebo period and during both 2-week washout periods (pre-study and mid-study)
• Willingness to have samples stored for future research
• Must have a physician at home for follow-up care

Exclusion criteria

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