Identification of a novel mutation in MAGT1 and progressive multifocal leucoencephalopathy in a 58-year-old man with XMEN disease

Abstract

XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.

Fig. 1. Lymph node histology and imaging

a Lymph node histology showing EBV-driven lymphoproliferative disease with atypical Reed-Sternberg-like cells (arrow, top image), staining for CD20 (middle image) and EBV LMP1 (bottom image). b MRI brain showing high T-2 signal in right occipital lobe (top image), which persisted and was associated with underlying atrophy 4 years later (bottom images). c Lymph node histology showing diffuse large B-cell lymphoma with extensive necrosis and fibrosis (top image) and ghostly outlines of very large CD20+ cells (bottom image). d PET-CT images showing widespread adenopathy with avid FDG uptake, hepatosplenomegaly and bony uptake in the pelvis and spine (top images) with regression of nodal and bony disease post-chemotherapy (bottom images). e MRI brain showing multifocal white matter changes in the occipital and parietal lobes

Fig. 2. Validation of novel mutation in MAGT1

a RT-PCR showing the level of MagT1 mRNA normalized to GAPDH in PBMCs from the nephew compared to three controls. All samples were assayed on at least two different days and each time in duplicate or triplicate.Asterisks indicate P<0.02. b Flow cytometry of NKG2D surface expression on CD8 cells from the nephew and normal controls. c Intracellular magnesium level from then nephew and normal controls. Flow cytometry shows the ratio of the mean fluorescent intensity (MFI) of a Mg2+-specific fluorescent probe (MagFluo4) to the MFI of a Ca2+-sensitive probe (FuraRed) as (MF4/FR) in PBMCs. The ratio is set at 1 for the normal controls. Isotype control antibody staining indicates background fluorescence in both panels. All plots are representative of at least 2 independent experiments.

Fig. 3. EBV-specific T-cell responses in XMEN patient compared with a healthy control and a patient with a hypomorphic mutation in XIAP resulting in the expression of a truncated protein

a CFSE proliferation assay of PBMCs using medium (nil), PHA, and EBV lysate. b OX-40 assay using medium (nil), PHA, VZV and EBV lysates. Cells are gated to acquire 30, 000 CD3+ events, a negative gate is applied to exclude monocytes and apoptotic cells that may aberrantly express activation markers, then dual expression of activation markers CD25 and CD134 (OX-40) is measured amongst the CD4+ population; the gate coordinates are fixed to give 0.1% double positive events in the nil tube (supplementary methods section)