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A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease

Abstract

X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection and N-linked glycosylation defect (XMEN) disease is an inborn error of immunity caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. The original studies of XMEN patients focused on impaired magnesium regulation, leading to decreased EBV-cytotoxicity and the loss of surface expression of the activating receptor “natural killer group 2D” (NKG2D) on CD8+ T cells and NK cells. In vitro studies showed that supraphysiological supplementation of magnesium rescued these defects. Observational studies in 2 patients suggested oral magnesium supplementation could decrease EBV viremia. Hence, we performed a randomized, double-blind, placebo-controlled, crossover study in 2 parts. In part 1, patients received either oral magnesium l-threonate (MLT) or placebo for 12 weeks followed by 12 weeks of the other treatment. Part 2 began with 3 days of high-dose intravenous (IV) magnesium sulfate (MgSO4) followed by open-label MLT for 24 weeks. One EBV-infected and 3 EBV-naïve patients completed part 1. One EBV-naïve patient was removed from part 2 of the study due to asymptomatic elevation of liver enzymes during IV MgSO4. No change in EBV or NKG2D status was observed. In vitro magnesium supplementation experiments in cells from 14 XMEN patients failed to significantly rescue NKG2D expression and the clinical trial was stopped. Although small, this study indicates magnesium supplementation is unlikely to be an effective therapeutic option in XMEN disease.

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Data Availability

Data are available on written request to the corresponding authors.

Code Availability

Code for statistical analysis is available in the Online Supplement.

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Acknowledgements

The authors thank the patients and their families. The authors also thank Elaine Kulm (NIAID/NIH) and V. Koneti Rao (NIAID/NIH) for trial support, Ryan Kissinger for diagram design, and Kimiyo Raymond (Mayo Laboratories) for laboratory support.

Funding

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. S.D.C. was supported in part by NIH Medical Scientist Training Program T32 GM007170.

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Correspondence to Michael J. Lenardo or Juan C. Ravell.

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Ethics Approval

This study followed the principles of the Declaration of Helsinki, the International Conference on Harmonization (ICH)-Good Clinical Practice (GCP) guidelines, and the National Institute of Allergy and Infectious Diseases (NIAID) guidelines. This trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02496676.

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All patients or their legal representatives provided written informed consent.

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Not applicable.

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The authors declare no competing interests.

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Chauvin, S.D., Price, S., Zou, J. et al. A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease. J Clin Immunol (2021). https://doi.org/10.1007/s10875-021-01137-w

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Keywords

  • Immunodeficiency
  • XMEN disease
  • MAGT1
  • magnesium
  • NKG2D
  • congenital disorder of glycosylation