Abstract
Common variable immunodeficiency is the most prevalent of the primary immunodeficiency diseases, yet its pathogenesis is largely poorly understood. Of the cases that are monogenic, many arise due to pathogenic variants in NFKB1 and NFKB2. Here, we report enteroviral encephalomyelitis as the cause of a fatal neurodegenerative condition in a patient with a novel heterozygous mutation in NFKB2 (c.2543insG, p.P850Sfs36*) that disrupts non-canonical NF-κB signaling. Investigations of primary and secondary lymphoid tissue demonstrated a complete absence of B cells and germinal centers. Despite multiple negative viral PCR testing of cerebrospinal fluid during her disease progression, post-mortem analysis of cerebral tissue revealed a chronic lymphocytic meningoencephalitis, in the presence of Cocksackie A16 virus, as the cause of death. The clinical features, and progression of disease reported here, demonstrate divergent clinical and immunological phenotypes of individuals within a single family. This is the first reported case of fatal enteroviral encephalomyelitis in a patient with NF-κB2 deficiency and mandates a low threshold for early brain biopsy and the administration of increased immunoglobulin replacement in any patient with a defect in this pathway and deterioration of neurological status.
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Acknowledgements
We thank the patients and family for their participation in this study. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme Grant 361646. We also acknowledge the Australian National Health and Medical Research Council (NHMRC, Project Grant 1127198 for VLB; Postgraduate Scholarship 1075666 for CS).We thank Libby Kruse and Sebastian King for critical review of the manuscript.
Funding
VLB is supported by the Victorian State Government Operational Infrastructure Scheme, Holmes Grant Charitable Trust, Rae Grant, Bloody Long Way (BLW), and Walter and Eliza Hall Institute Innovation Grant.
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Patients and their healthy relatives were recruited from the Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Victoria, Australia. Informed consent was obtained from all individual participants included in the study for genomic analysis and functional immunologic studies prior to inclusion in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of Human Research Ethics Committees at Melbourne Health and The Walter and Eliza Hall Institute for Medical Research (Approved projects 2009.162, 10/02) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Slade, C.A., McLean, C., Scerri, T. et al. Fatal Enteroviral Encephalitis in a Patient with Common Variable Immunodeficiency Harbouring a Novel Mutation in NFKB2. J Clin Immunol 39, 324–335 (2019). https://doi.org/10.1007/s10875-019-00602-x
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DOI: https://doi.org/10.1007/s10875-019-00602-x