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

Samuel D Chauvin, Susan Price, Juan Zou, Sally Hunsberger, Alessandra Brofferio, Helen Matthews, Morgan Similuk, Sergio D Rosenzweig, Helen C Su, Jeffrey I Cohen, Michael J Lenardo, Juan C Ravell

Journal: Journal of clinical immunology 2022;42(1):108-118

PMID: 34655400

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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 (MgSO) 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 MgSO. 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.

Address: Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N311, 10 Center Drive, MSC 1892, Bethesda, MD, 20892-1892, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.; Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.; Cardiovascular and Pulmonary Branch, National Heart Lung and Blood Institute, Bethesda, MD, USA.; Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, USA.; Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, USA.; Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N311, 10 Center Drive, MSC 1892, Bethesda, MD, 20892-1892, USA. [email protected].; Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N311, 10 Center Drive, MSC 1892, Bethesda, MD, 20892-1892, USA. [email protected].; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA. [email protected].; Division of Allergy and Immunology, Department of Internal Medicine, Hackensack University Medical Center, 360 Essex Street, Suite 302, Hackensack, NJ, 07601, USA. [email protected].; Department of Internal Medicine, Hackensack Meridian School of Medicine, Nutley, NJ, USA. [email protected].

DOI: 10.1007/s10875-021-01137-w

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MeSH Terms: CD8-Positive T-Lymphocytes, Cation Transport Proteins, Cross-Over Studies, Dietary Supplements, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Humans, Magnesium, Neoplasms, X-Linked Combined Immunodeficiency Diseases