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Fatal X-linked lymphoproliferative disease type 1-associated limbic encephalitis with positive anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody

      Abstract

      Background

      X-linked lymphoproliferative disease type 1 (XLP1) is a rare monogenic immune dysregulation disorder caused by a deficiency of a signaling lymphocyte activation molecule-associated protein (SAP). While many patients with XLP1 present with fatal hemophagocytic lymphohistiocytosis upon Epstein Barr virus (EBV) infection, a small fraction present with limbic encephalitis in the absence of EBV infection. It is poorly understood why SAP deficiency may cause limbic encephalitis in XLP1.

      Case

      A 12-year-old boy presented with seizures, changes in personality, memory loss, and cognitive deficits during treatment for interstitial pneumonia. A diagnosis of limbic encephalitis was made. Despite treatment against CD8+ T cell-mediated autoimmunity with intravenous methylprednisolone, dexamethasone, intravenous immunoglobulin, plasma exchange, cyclosporine, weekly etoposide, mycophenolate mofetil, and adalimumab, encephalitis progressed until the patient died after one month of treatment intitiation. Post-mortem genetic testing revealed a de novo SH2D1A truncating mutation. Tests for EBV infection were negative. Initial spinal fluid revealed markedly elevated protein levels, mild pleocytosis, and elevation of two chemokines (C-X-C motif chemokine ligand [CXCL] 10 and CXCL 13). Moreover, initial spinal fluid was tested positive for anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) autoantibody.

      Discussion

      In XLP1-associated limbic encephalitis, anti-AMPAR autoantibody production by the dysregulated immune system due to SAP deficiency might be a pathogenic mechanism of central nervous system manifestations. In addition to the standard treatment for XLP1, targeted treatment against B-cell-mediated immunity might be indicated for patients with XLP1-associated limbic encephalitis.

      Keywords

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      References

        • Purtilo D.T.
        • Cassel C.
        • Yang J.P.
        Letter: Fatal infectious mononucleosis in familial lymphohistiocytosis.
        N Engl J Med. 1974; 291: 736https://doi.org/10.1056/nejm197410032911415
        • Purtilo D.T.
        • Yang J.S.
        • Cassel C.K.
        • Harper R.
        • Stephenson S.R.
        • Landing B.H.
        • et al.
        X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease).
        Lancet. 1975; 305: 935-941
        • Coffey A.J.
        • Brooksbank R.A.
        • Brandau O.
        • Oohashi T.
        • Howell G.R.
        • Bye J.M.
        • et al.
        Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
        Nat Genet. 1998; 20: 129-135
        • Sayos J.
        • Wu C.
        • Morra M.
        • Wang N.
        • Zhang X.
        • Allen D.
        • et al.
        The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.
        Nature. 1998; 395: 462-469
        • Nakahara E.
        • Sakuma H.
        • Kimura-Kuroda J.
        • Shimizu T.
        • Okumura A.
        • Hayashi M.
        A diagnostic approach for identifying anti-neuronal antibodies in children with suspected autoimmune encephalitis.
        J Neuroimmunol. 2015; 285: 150-155https://doi.org/10.1016/j.jneuroim.2015.06.005
        • Talaat K.R.
        • Rothman J.A.
        • Cohen J.I.
        • Santi M.
        • Choi J.K.
        • Guzman M.
        • et al.
        Lymphocytic vasculitis involving the central nervous system occurs in patients with X-linked lymphoproliferative disease in the absence of Epstein-Barr virus infection.
        Pediatr Blood Cancer. 2009; 53: 1120-1123
        • Velnati S.
        • Centonze S.
        • Girivetto F.
        • Baldanzi G.
        Diacylglycerol kinase alpha in X linked lymphoproliferative Disease Type 1.
        Int J Mol Sci. 2021; 22: 5816https://doi.org/10.3390/ijms22115816
        • Panchal N.
        • Booth C.
        • Cannons J.L.
        • Schwartzberg P.L.
        X-linked lymphoproliferative disease Type 1: A clinical and molecular perspective.
        Front Immunol. 2018; 9: 666https://doi.org/10.3389/fimmu.2018.00666
        • Deiva K.
        • Mahlaoui N.
        • Beaudonnet F.
        • de Saint Basile G.
        • Caridade G.
        • Moshous D.
        • et al.
        CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis.
        Neurology. 2012; 78: 1150-1156
        • Verhelst H.
        • Van Coster R.
        • Bockaert N.
        • Laureys G.
        • Latour S.
        • Fischer A.
        • et al.
        Limbic encephalitis as presentation of a SAP deficiency.
        Neurology. 2007; 69: 218-219
        • Zhang T.Y.
        • Cai M.T.
        • Zheng Y.
        • Lai Q.L.
        • Shen C.H.
        • Qiao S.
        • et al.
        Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis: A review.
        Front Immunol. 2021; 12652820https://doi.org/10.3389/fimmu.2021.652820
        • Gleichman A.J.
        • Panzer J.A.
        • Baumann B.H.
        • Dalmau J.
        • Lynch D.R.
        Antigenic and mechanistic characterization of anti-AMPA receptor encephalitis.
        Ann Clin Transl Neurol. 2014; 1: 180-189https://doi.org/10.1002/acn3.43
        • Okada T.
        • Fujita Y.
        • Imataka G.
        • Takase N.
        • Tada H.
        • Sakuma H.
        • et al.
        Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with acute focal bacterial nephritis.
        Brain Dev. 2022; 44: 30-35
        • Agnihotri S.P.
        Central nervous system opportunistic infections.
        Semin Neurol. 2019; 39: 383-390
        • Yska H.A.F.
        • Elsink K.
        • Kuijpers T.W.
        • Frederix G.W.J.
        • van Gijn M.E.
        • van Montfrans J.M.
        Diagnostic yield of next generation sequencing in genetically undiagnosed patients with primary immunodeficiencies: a systematic review.
        J Clin Immunol. 2019; 39: 577-591
      1. Raymond LS, Leiding J, Forbes-Satter LR. Diagnostic Modalities in Primary Immunodeficiency. Clin Rev Allergy Immunol 2022, in press. doi: 10.1007/s12016-022-08933-1.

        • Dalmau J.
        • Graus F.
        Antibody-mediated encephalitis.
        N Engl J Med. 2018; 378: 840-851