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

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

doi:10.1007/s10875-021-01137-w

Cited by 17 publications

(9 citation statements)

References 22 publications

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“…Recently, the results of a double-blind, placebo-controlled, crossover study of Mg-L-threonate or high-dose intravenous MgSO4 supplementation in XMEN patients were published. Similar to our results obtained in P1, no changes in EBV nor NKG2D levels were observed in these patients, upon which was concluded that Mg 2+ supplementation is unlikely to have an effect (Chauvin et al 2021). Altogether, this data raises questions as to the effectiveness of Mg 2+ treatment to restore NKG2D steady state expression.…”

Section: )supporting

confidence: 90%

“…Additional biochemical workup of P1 showed no differences before or after treatment (Table S1). In line with our results, a randomized, double-blind, placebo-controlled, crossover study of magnesium supplementation in XMEN patients indicated that there is no effect of the treatment on NKG2D or EBV levels (Chauvin et al 2021). However, subjectively the patient reported improved general health and reduced frequency of minor infectious episodes under supplementation, which was continued.…”

Section: Magnesium Supplementation Does Not Rescue Nkg2d Expressionsupporting

confidence: 89%

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Lack of NKG2D in MAGT1-deficient patients is caused by hypoglycosylation

et al. 2022

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Mutations in the X-linked gene MAGT1 cause a Congenital Disorder of Glycosylation (CDG), with two distinct clinical phenotypes: a primary immunodeficiency (XMEN disorder) versus intellectual and developmental disability. It was previously established that MAGT1 deficiency abolishes steady state expression of the immune response protein NKG2D (encoded by KLRK1) in lymphocytes. Here, we show that the reduced steady state levels of NKG2D are caused by hypoglycosylation of the protein and we pinpoint the exact site that is underglycosylated in MAGT1-deficient patients. Furthermore, we challenge the possibility that supplementation with magnesium restores NKG2D levels and show that addition of this ion does not significantly improve NKG2D steady state expression nor does it rescue the hypoglycosylation defect in CRISPR engineered human cell lines. Moreover, magnesium supplementation of an XMEN patient did not result in restoration of NKG2D expression on the cell surface of lymphocytes. In summary, we demonstrate that in MAGT1-deficient patients the lack of NKG2D is caused by hypoglycosylation, further elucidating the pathophysiology of XMEN/MAGT1-CDG.

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Section: )supporting

confidence: 90%

Section: Magnesium Supplementation Does Not Rescue Nkg2d Expressionsupporting

confidence: 89%

Lack of NKG2D in MAGT1-deficient patients is caused by hypoglycosylation

et al. 2022

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“…Recently, a double-blind, placebo-controlled, crossover study of magnesium supplementation in patients with XMEN disease was published. 6 It showed no benefit from Mg supplementation and concluded that supplementation is unlikely to be effective, but the conclusion was based on outcomes in only three out of the initial eight patients included in the study though, similar to our study they too noticed a mild increase in the MFI of NKG2D on CTLs. The study also concluded after 24 weeks of magnesium supplementation, which was when we had just seen the significant improvement in NKG2D expression.…”

Section: E T T E R T O T H E E D I T O R Xmen Saved By Magnesiumsupporting

confidence: 70%

XMEN saved by magnesium

et al. 2022

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“…In vitro studies have revealed that MAGT1 deficiency abrogates magnesium influx into T cells. However, oral magnesium supplementation has not proven successful improvement in patients (Chaigne-Delalande et al, 2013;Li et al, 2014;Klinken et al, 2020;Chauvin et al, 2021). Allogeneic HSCT has also been applied to treat XMEN; the disease phenotype reversed in two out of five patients, and three died of transplant-related complications (Li et al, 2014;Dimitrova et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Further Delineation of the Spectrum of XMEN Disease in Six Chinese Pediatric Patients

Peng

Wang

et al. 2022

Front. Genet.

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X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect (XMEN) disease is a primary immunodeficiency caused by loss-of-function variants in the MAGT1 gene. Only two patients from one family have been diagnosed with XMEN in China. In this study, we retrospectively analyzed the genetic, clinical, and immunological characteristics of six pediatric patients in a Chinese cohort. Medical records were retrieved, immunological phenotypes were assessed, and infectious microbes in patients were detected. Six male patients (mean age, 6.3 years) from five unrelated families were genetically diagnosed as XMEN. Five patients presented with a major complaint of elevated liver enzymes, while one patient was referred for recurrent fever, cough and skin rash. Five patients developed EBV viremia, and one patient developed non-Hodgkin’s lymphoma. Histopathological findings from liver biopsy tissues showed variable hepatic steatosis, fibrosis, inflammatory infiltration, and glycogenosis. Immune phenotypes included CD4 T-cell lymphopenia, elevated B cells, inverted CD4/CD8 ratios, and elevated αβDNTs. No pathogenic microbes other than EBV were identified in these patients. This study reports the clinical and molecular features of Chinese patients with XMEN. For patients with transaminase elevation, chronic EBV infection and EBV-associated lymphoproliferative disease, the possibility of XMEN should be considered in addition to isolated liver diseases.

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

Cited by 17 publications

References 22 publications

Lack of NKG2D in MAGT1-deficient patients is caused by hypoglycosylation

Lack of NKG2D in MAGT1-deficient patients is caused by hypoglycosylation

XMEN saved by magnesium

Further Delineation of the Spectrum of XMEN Disease in Six Chinese Pediatric Patients

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