Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021345 (infectious mononucleosis)
 3,358 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked lymphoproliferative (XLP) syndrome is a rare primary immune-deficiency disorder caused by mutations of the SH2D1A or XIAP genes. Males with the disorder are usually in good health until contracting Epstein-Barr virus (EBV) whereupon the majority of patients die from fulminant infectious mononucleosis, lymphoma or hypogammaglobulinaemia. This report describes a female carrier with an XLP phenotype who was retrospectively identified after her grandson died from the disorder. Subsequent genetic testing identified the patient's mother and affected maternal grandmother as XLP carriers. The family's medical records were significant. The proband had lymphoma at ages 2 and 8 and made a full recovery following treatment. Both the maternal grandmother and uncle died of non-Hodgkin's lymphoma. We were concerned that the XLP carrier mother may be predisposed to lymphoma if the normal X chromosome is skewed towards inactivation. The human androgen receptor assay detected random X chromosome inactivation in the carrier mother. EBV was not detected in the lymphoma tissues of the proband and his grandmother, confirming previous findings that EBV is not always associated with lymphoma in XLP. More significantly, our study highlights the importance of identifying XLP in families with a high incidence of lymphoma.
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PMID:Follicular lymphoma in a X-linked lymphoproliferative syndrome carrier female. 1870 45

Deletion or mutation of the SAP gene is associated with the X-linked lymphoproliferative disease (XLP) that is characterized by extreme sensitivity to Epstein-Barr virus (EBV). Primary infection of the affected individuals leads to serious, sometimes fatal infectious mononucleosis (IM) and proneness to lymphoma. Our present results revealed a proapoptotic function of SAP by which it contributes to the maintenance of T-cell homeostasis and to the elimination of potentially dangerous DNA-damaged cells. Therefore, the loss of this function could be responsible for the uncontrolled T-cell proliferation in fatal IM and for the generation of lymphomas. We show now the role of SAP in apoptosis in T and B lymphocyte-derived lines. Among the clones of T-ALL line, the ones with higher SAP levels succumbed more promptly to activation induced cell death (AICD). Importantly, introduction of SAP expression into lymphoblastoid cell lines (LCL) established from XLP patients led to elevated apoptotic response to DNA damage. Similar results were obtained in the osteosarcoma line, Saos-2. We have shown that the anti-apoptotic protein VCP (valosin-containing protein) binds to SAP, suggesting that it could be instrumental in the enhanced apoptotic response modulated by SAP.
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PMID:The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease. 1957 Sep 96

X-linked lymphoproliferative disease (XLP) is an immunodeficiency caused by defects in the adaptor molecule SAP. The manifestations of XLP generally occur following Epstein-Barr virus (EBV) infection and include fulminant mononucleosis, hypogammaglobulinemia and lymphoma. In this report, we describe two unrelated patients with fatal T-cell-mediated central nervous system vasculitis for whom repeated serologic and molecular testing for EBV was negative. In both patients, clonal T-cell populations were observed, but neither demonstrated evidence of lymphoma. Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection.
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PMID:Lymphocytic vasculitis involving the central nervous system occurs in patients with X-linked lymphoproliferative disease in the absence of Epstein-Barr virus infection. 1962 58

Deletion or mutation of the SH2D1A gene located at Xq25 is responsible for the development of the X-linked lymphoproliferative disease, XLP. Primary infection of the affected individuals with EBV leads to fulminant and often fatal infectious mononucleosis, FIM. Moreover, they run a 200 fold elevated risk for lymphoma development. Due to the critical role of the immune response for the outcome of EBV infection and the detection of EBV genomes in several malignancies, XLP studies have been mainly focused on the immunological aspects. The involvement of SAP in the apoptotic machinery provides a further aspect in the complex syndrome of XLP. Functional impairment of SAP leads to defective apoptotic responses. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in IM. This mechanism is inefficient in XLP patients. In addition, in the absence of SAP, lymphoma development may be promoted by the illegitimate survival of lymphocytes with damaged DNA that would be normally eliminated by apoptosis.
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PMID:The apoptosis modulating role of SAP (SLAM associated protein) contributes to the symptomatology of the X linked lymphoproliferative disease. 1973 28

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency affecting approximately 1 to 3 per million live male births. Patients are generally healthy until facing a viral infection such as Epstein-Barr Virus and then may develop fulminant infectious mononucleosis and die. XLP patients are also at increased risk of hemophagocytic lymphohistiocytosis (HLH), which may be triggered by assorted viruses. Here we report a novel case of HLH in a patient with XLP. Significant to his presentation is a paradoxical increase in natural killer (NK) cell activity. We hypothesize that this indicates that Parvovirus B19 activates NK cells via a signaling lymphocytic activation molecule-associated protein (SAP)-independent mechanism. Our case demonstrates an important etiology to consider in the differential diagnosis of XLP patients with nonfocal findings and febrile illnesses.
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PMID:Hemophagocytic lymphohistiocytosis in a patient with x-linked lymphoproliferative disease. 1977 67

The lack of functional SAP protein, a consequence of mutation or deletion of the SH2D1A gene is the cause of X-linked lymphoproliferative disease (XLP). Others and we have shown that SAP can be involved in apoptosis. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in infectious mononucleosis IM. This mechanism is inefficient in the XLP patients. Primary EBV infection of boys with XLP leads therefore to fulminant, often even fatal disease. In addition, the condition predisposes to considerably elevated incidence of lymphomas. Chromosomal translocation that juxtaposes one of the three immunoglobulin loci to the c-myc proto-oncogene is the hallmark of Burkitt lymphomas (BL), whether they carry the Epstein-Barr Virus (EBV) or not. Ig/myc translocations occur as rare accidents of normal B lymphocyte differentiation. The activated myc would drive the cells to proliferate, however unless protected, the cells become prone to apoptosis. Our results with BL derived cell lines suggest that the fate of the precursor cells is decided by the expression of the proapototic SAP and EBV infection. We found SAP expression in eight of ten EBV carrying, but none of nine EBV negative BL lines. Therefore it seems that the apoptosis prone Ig/myc translocation carrying EBV negative precursors of BL can grow into lymphomas only if they do not express the proapoptotic SAP while SAP expressor, but EBV positive cells can survive and proliferate. This is probably due to the antiapoptotic function of EBNA-1 and the proliferation induced by activated myc.
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PMID:Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development. 2008 Jan 27

X-linked lymphoproliferative disease (XLP) is a condition associated with mutations in the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP; SH2D1A). SAP functions as an adaptor, binding to and recruiting signaling molecules to SLAM family receptors expressed on T and natural killer cells. XLP is associated with extreme sensitivity to primary Epstein-Barr virus (EBV) infection, often leading to a lethal infectious mononucleosis. To investigate EBV-specific immunity in XLP patients, we studied 5 individuals who had survived EBV infection and found CD8(+) T-cell responses numerically comparable with healthy donors. However, further investigation of in vitro-derived CD8(+) T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand-negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand-positive, lymphoblastoid cell lines (LCLs). Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer-, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked. We propose that XLP patients' particular sensitivity to EBV, and not to other viruses, reflects at least in part EBV's strict tropism for B lymphocytes and the often inability of the CD8(+) T-cell response to contain the primary infection of SLAM ligand-expressing target cells.
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PMID:Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family-positive B-cell targets. 2103 May 66

X-linked lymphoproliferative disease is a rare congenital immunodeficiency that is most often caused by mutations in SH2D1A, the gene encoding signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). XLP caused by SAP deficiency is most often characterized by fulminant mononucleosis/EBV- associated hemophagocytic lymphohistiocytosis (HLH), lymphoma, and dysgammaglobulinemia. XLP has also been found to be caused by mutations in BIRC4, the gene encoding X-linked inhibitor of apoptosis (XIAP). Patients with XIAP deficiency often present with HLH or recurrent HLH, which may or may not be associated with EBV. XLP is prematurely lethal in the majority of cases. While genetic sequencing can provide a genetic diagnosis of XLP, a more rapid means of diagnosis of XLP is desirable. Rapid diagnosis is especially important in the setting of HLH, as this may hasten the initiation of life-saving medical treatments and expedite preparations for allogeneic hematopoietic cell transplantation (HCT). Flow cytometry offers a means to quickly screen patients for XLP. Flow cytometry can be used to measure lymphocyte SAP or XIAP protein expression, and can also be used to observe lymphocyte phenotypes and functional defects that are unique to XLP. This review will give a brief overview of the clinical manifestations and molecular basis of SAP deficiency and XIAP deficiency, and will focus on the use of flow cytometry for diagnosis of XLP.
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PMID:Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP deficiency. 2081 73

We report a 2.5-year-old boy with an X-linked lymphoproliferative disease (XLP) phenotype who presented with human herpes virus-8 (HHV-8)-related hemophagocytic lymphohistiocytosis (HLH). XLP is a rare primary immunodeficiency characterized by extreme susceptibility to herpes viruses, mainly Epstein-Barr virus (EBV). Approximately 60% of patients with XLP present with fulminant mononucleosis associated with HLH, whereas remaining patients present with hypogammaglobulinemia or lymphoproliferative disease. Most commonly, one of the XLP phenotypes appears after exposure to EBV, but at least 12% of affected individuals developed symptoms without an evidence of EBV infection. Rarely, patients with XLP may present with central nervous system vasculitis or aplastic anemia. HHV-8 is lymphotrophic and it is associated with lymphoproliferative disorders and Kaposi sarcoma in immunodeficient hosts. Kaposi sarcoma rarely occurs in children with well-defined primary immunodeficiency. Also, HHV-8-related HLH was previously reported in 2 siblings with a perforin gene deficiency. Recently, it became evident that besides EBV, other viruses may trigger the symptoms in XLP. We report for the first time HHV-8-related HLH in EBV-negative pediatric patient with an XLP phenotype.
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PMID:HHV-8-related hemophagocytic lymphohistiocytosis in a boy with XLP phenotype. 2225 54

Two related boys who died from fulminant infectious mononucleosis were diagnosed with X-linked lymphoproliferative disease type 1 (XLP-1). Family screening (n=17) identified 6 female mutation carriers and 2 more XLP-1 patients in whom, despite recurrent infections, agammaglobulinemia, and Hodgkin's Disease, the genetic basis had been unknown; demonstrating that awareness and early genetic testing are crucial to reveal underlying primary immunodeficiencies and improve outcome. Furthermore, XLP should be included routinely in the differential diagnosis of severe hypogammaglobulinemia and/or lymphoma in males.
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PMID:Fatal EBV infection and variable clinical manifestations in an XLP-1 pedigree - rapid diagnosis of primary immunodeficiencies may save lives. 2314 65


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