X-linked lymphoproliferative syndrome presenting as adult-onset multi-infarct dementia

Patrick R. Blackburn, Wen Lang Lin, David A. Miller, Oswaldo Lorenzo-Betancor, Emily S. Edwards, Michael T. Zimmermann, Luca P. Farrugia, William D. Freeman, Alexandra I. Soto, Ronald L. Walton, Eric W. Klee, Paldeep S. Atwal, Roshini S. Abraham, Daniel D. Billadeau, Owen A. Ross, Dennis W. Dickson, James F. Meschia

Research output: Contribution to journalArticle

Abstract

Pathogenic hemizygous variants in the SH2D1A gene cause X-linked lymphoproliferative (XLP) syndrome, a rare primary immunodeficiency usually associated with fatal Epstein-Barr virus infection. Disease onset is typically in early childhood, and the average life expectancy of affected males is 11 years. We describe clinical, radiographic, neuropathologic, and genetic features of a 49-year-old man presenting with central nervous system vasculitis that was reminiscent of adult primary angiitis but which was unresponsive to treatment. The patient had 2 brothers; 1 died of aplastic anemia at age 13 and another died of diffuse large B-cell lymphoma in his sixties. Exome sequencing of the patient and his older brother identified a novel hemizygous variant in SH2D1A (c.35G>T, p.Ser12Ile), which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Molecular modeling and functional analysis showed that this variant had decreased protein stability, similar to other pathogenic missense variants in SH2D1A. The family described in this report highlights the broadly heterogeneous clinical presentations of XLP and the accompanying diagnostic challenges in individuals presenting in adulthood. In addition, this report raises the possibility of a biphasic distribution of XLP cases, some of which may be mistaken for age-related malignancies and autoimmune conditions.

Original languageEnglish (US)
Pages (from-to)460-466
Number of pages7
JournalJournal of Neuropathology and Experimental Neurology
Volume78
Issue number5
DOIs
StatePublished - 2019

Keywords

  • CNS vasculitis
  • Diffuse large B-cell lymphoma
  • Exome sequencing
  • SH2D1A
  • X-linked lymphoproliferative syndrome

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Blackburn, P. R., Lin, W. L., Miller, D. A., Lorenzo-Betancor, O., Edwards, E. S., Zimmermann, M. T., Farrugia, L. P., Freeman, W. D., Soto, A. I., Walton, R. L., Klee, E. W., Atwal, P. S., Abraham, R. S., Billadeau, D. D., Ross, O. A., Dickson, D. W., & Meschia, J. F. (2019). X-linked lymphoproliferative syndrome presenting as adult-onset multi-infarct dementia. Journal of Neuropathology and Experimental Neurology, 78(5), 460-466. https://doi.org/10.1093/jnen/nlz018