Definite Fatal Familial Insomnia (FFI) Disease with Voltage-Gated Potassium Channel (VGKC)-Complex Autoimmunity: A Rare Case of Molecular Mimicry or Incidental Finding? (P5.187)

Background: In the absence of a clear, positive family history, the diagnosis of fatal familial insomnia (FFI) can be difficult due to atypical clinical features for prion disease and low sensitivity with current diagnostic testing. Further complicating the diagnosis, its differential diagnosis includes a spectrum of autoimmune and neurodegenerative diseases, from potentially treatable paraneoplastic encephalitis to Creutzfeldt-Jakob disease (CJD). We report a case of autopsy-confirmed FFI that was initially treated as VGKC-complex antibody encephalitis. Case Presentation: A 45-year-old man presented with 6 months of progressive decline including insomnia, personality changes, hallucinations, startle myoclonus and memory disturbance as well as profound hyponatremia (122 millimoles/L). His initial work-up revealed a low positive VGKC-complex antibody titer (240 picomoles), prompting an aggressive course of immunotherapy, even including Rituximab. Of note, tau protein was low at 472 picogram/milliliter in CSF and the 14-3-3 protein was ambiguous. Despite treatment, he suffered progressive neurocognitive and respiratory decline for which his family elected tracheostomy and gastrostomy tube placement. His course was notable for marked physical wasting, extreme agitation and nearly constant hyperkinetic chorea-like movements. Given his poor prognosis, family pursued a palliative approach. Results: At autopsy, immunostaining of the brain revealed granular deposits of 3F4, a monoclonal antibody to prion protein, while the immunoblot disclosed abnormal scrapie protease-resistant prion protein (PrPSc) 27-30, and genetic testing noted a D178N129M mutation in the PrP gene, thus confirming the diagnosis of prion disease. Conclusions: To date, this is the first reported case of autopsy and genetically-confirmed FFI with a positive VGKC-complex autoantibody titer. Although low titers of VGKC-complex antibody may be an incidental finding, its coincidence in this case may have affected the phenotypic presentation of FFI. Global screening for paraneoplastic antibodies may provide important insight into understanding the complex pathophysiology, including the potential role of molecular mimicry, of prion diseases. Disclosure: Dr. Sanamandra has nothing to disclose. Dr. Youn has nothing to disclose. Dr. Maciel has nothing to disclose. Dr. Schrag has nothing to disclose. Dr. Machado has nothing to disclose. Dr. Gilmore has nothing to disclose.