Epstein Barr virus (EBV) is a cause of infectious mononucleosis and is associated with a number of cancers including Burkitt lymphoma and lymphoma in transplant recipients. Severe chronic active Epstein-Barr virus (CAEBV) disease is defined as a severe progressive illness lasting 6 months or longer with infiltration of tissues with EBV-positive lymphocytes, markedly elevated levels of EBV DNA in the blood, and no known immunodeficiency such as HIV. These patients usually have fever, splenomegaly, lymphadenopathy, and may have markedly elevated EBV antibody titers to viral capsid antigen. Although the cause of most cases of severe CAEBV is unknown, one well-documented case was associated with compound heterozygous mutations in PRF1 (perforin 1). This year we reported a patient with prolonged severe CAEBV who underwent bone marrow transplant for his disease and subsequently was found to have compound heterozygous mutations in STXBP2 (MUNC18-2) as well as a heterozygous mutation in PRF1 (perforin 1). These two genes are among several that have previously been associated with familial hemophagocytic lymphohistiocytosis (FHL). These findings suggest that other mutations in genes associated with FHL may be responsible for other cases of CAEBV. 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. Last year in collaboration with Dr. Michael Lenardo, we showed that patients with mutations in MagT1 have reduced expression of a protein (NKG2D) present on natural killer (NK) and cytotoxic (CD8) T cells that is important for activation of the cells and their ability to kill target cells. Cells from patients that have mutations in MagT1 are impaired for killing Epstein-Barr virus-infected cells and these patients have a high rate of Epstein-Barr virus B cell lymphomas. Addition of magnesium to the patient's cells in culture increased the level of the NKG2D protein on the surface of the cells and improved killing of Epstein-Barr virus-infected cells. Intravenous or oral magnesium supplements given to patients with mutations in MagT1 increased expression of the NKG2D on the surface of their cells, and reduced the number of copies of EBV DNA in their cells. This year we reported a 58-year-old man with a novel mutation in MAGT1 who developed an EBV lymphoma, was treated with chemotherapy, and died of progressive multifocal leukoencephalopathy. This is the first patient with XMEN who has developed this fatal complication. We also reported his nephew who has the same mutation and had a history of EBV lymphoproliferative disease. These findings expand the phenotype of diseases associated with XMEN and emphasize the need for better treatments for this disease.
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