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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Brain and DevelopmentAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Letter: Fatal infectious mononucleosis in familial lymphohistiocytosis.N Engl J Med. 1974; 291: 736https://doi.org/10.1056/nejm197410032911415
- X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease).Lancet. 1975; 305: 935-941
- 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
- The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.Nature. 1998; 395: 462-469
- 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
- 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
- Diacylglycerol kinase alpha in X linked lymphoproliferative Disease Type 1.Int J Mol Sci. 2021; 22: 5816https://doi.org/10.3390/ijms22115816
- X-linked lymphoproliferative disease Type 1: A clinical and molecular perspective.Front Immunol. 2018; 9: 666https://doi.org/10.3389/fimmu.2018.00666
- CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis.Neurology. 2012; 78: 1150-1156
- Limbic encephalitis as presentation of a SAP deficiency.Neurology. 2007; 69: 218-219
- 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
- Antigenic and mechanistic characterization of anti-AMPA receptor encephalitis.Ann Clin Transl Neurol. 2014; 1: 180-189https://doi.org/10.1002/acn3.43
- 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
- Central nervous system opportunistic infections.Semin Neurol. 2019; 39: 383-390
- Diagnostic yield of next generation sequencing in genetically undiagnosed patients with primary immunodeficiencies: a systematic review.J Clin Immunol. 2019; 39: 577-591
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.
- Antibody-mediated encephalitis.N Engl J Med. 2018; 378: 840-851
Article info
Publication history
Published online: June 28, 2022
Accepted:
June 15,
2022
Received in revised form:
May 31,
2022
Received:
April 14,
2022
Identification
Copyright
© 2022 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.
