A TBK1 N455S variant in a woman with refractory psychosis and catatonia

Authors

• JJ Wlaschin
• P Lee
• S Seddighi
• M Alkaslasi
• H Sliberberg
• CE Le Pichon

Abstract

Systemic autoimmunity and severe infections are associated with an increased risk of developing a psychotic spectrum disorder.

We present a young woman who, three weeks after a high school wilderness retreat, developed subacute psychosis characterized by behavioral disorganization, memory loss, nonsensical speech, mood lability, ritualistic behaviors, and features of catatonia. Three months later, she was diagnosed with Lyme disease (B. burgdorferi) by immunoblot. She was unable to take oral antibiotics due to paranoia and behavioral disorganization. Two months later, a lumbar puncture revealed neuroinflammation indicated by a mild pleocytosis, 16 oligoclonal bands, and an elevated IgG index. Her cerebrospinal fluid (CSF) was negative for infectious encephalitis and paraneoplastic and anti-neural autoantibodies. Blood labs revealed thyroglobulin autoantibodies and subclinical hyperthyroidism. She returned to baseline after intravenous immunoglobulin but relapsed nine months later. She was referred to NIMH where whole genome sequencing identified a heterozygous variant in TANK-binding kinase 1, TBK1 N455S.

TBK1 mediates type I interferon production in response to microbial double-stranded RNA and DNA, including B. burgdorferi, and is implicated in autoimmunity. Heterozygous TBK1 variants predispose to herpes simplex encephalitis, frontotemporal dementia, and amyotrophic lateral sclerosis via impairment of kinase activity, homodimerization, protein-protein interactions, TBK1 stability, or autophagy—however TBK1 N455S has not been characterized.

Western blotting revealed unaffected TBK1 N455S autophosphorylation but modestly lower expression than wild type TBK1. Additionally, rodent brain tissue staining with her CSF revealed an unclassified anti-glial autoantibody. Studies to assess additional functional consequences of TBK1 N455S and to identify the glial antigen are ongoing.

Scientific Focus Area: Immunology

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