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 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, lacebocontrolled, 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 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 openlabel,
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