Faculty Collaboration Database

X-Linked Lymphoproliferative Syndrome Presenting as Adult-Onset Multi-Infarct Dementia. J Neuropathol Exp Neurol 2019 May 01;78(5):460-466

Date

04/17/2019

Pubmed ID

30990878

Pubmed Central ID

PMC6467195

DOI

10.1093/jnen/nlz018

Scopus ID

2-s2.0-85064977307 (requires institutional sign-in at Scopus site)   7 Citations

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.

Author List

Blackburn PR, Lin WL, Miller DA, Lorenzo-Betancor O, Edwards ES, Zimmermann MT, Farrugia LP, Freeman WD, Soto AI, Walton RL, Klee EW, Atwal PS, Abraham RS, Billadeau DD, Ross OA, Dickson DW, Meschia JF

Author

Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Dementia, Multi-Infarct
Diagnosis, Differential
Humans
Lymphoproliferative Disorders
Male
Middle Aged
Pedigree
Protein Structure, Secondary
Signaling Lymphocytic Activation Molecule Associated Protein