Objective: To report a case of a rare autoimmune disorder associated with dipeptidyl-peptidase-like protein- 6 (DPPX) antibodies, highlighting its classical features, diagnostic challenges, and therapeutic considerations. While typically presenting with myoclonus, tremor, hyperreflexia, or seizure, this case uniquely manifests with chorea.

Background: DPPX autoimmune encephalitis is a rare but treatable neurological disorder. It is characterized by antibodies against DPPX, a regulatory protein in the Kv4.2 potassium channel, which helps modulate neuronal excitability. DPPX is expressed throughout the nervous system, including the myenteric plexus, contributing to both neurological (e.g., cognitive dysfunction, abnormal movements) and gastrointestinal symptoms.

Method: A 64-year-old man presented to the movement disorders clinic with a 2-month history of abnormal movements, cognitive impairment, and a 20-pound weight loss due to nausea and decreased appetite. Neurological examination revealed chorea, hyperreflexia in the lower extremities, intention tremor, and ataxic gait. Extensive diagnostic workup was initiated.

Results: The serum autoimmune panel for movement disorders was positive for DPPX antibodies with a titer of <1:240. Cerebrospinal fluid (CSF) analysis showed 9 nucleated cells with 94% lymphocytic predominance. The CSF autoimmune/paraneoplastic panel was negative.

Infectious work up with the meningitis/encephalitis CSF panel, HIV, syphilis, herpes simplex virus screening, and anti-streptolysin O antibody was negative. CMP, CBC and serum copper were within normal limits. Malignancy screening with colonoscopy and chest CT was unrevealing. Brain MRI was unremarkable. The patient was treated with high-dose intravenous methylprednisolone (1 g daily for 3 days), followed by weekly intravenous methylprednisolone for 6 weeks, with plans to initiate rituximab. Methylprednisolone therapy has resulted in significant improvement in cognitive function and choreiform movements.

Conclusion: DPPX autoimmune encephalitis is a rare, immune-mediated condition that can present with nonspecific symptoms, making diagnosis challenging. The disease is characterized by hyperexcitability due to antibodies targeting the Kv4.2 potassium channel complex. Despite potential diagnostic delays, patients often respond well to immunotherapy. Given the relapsing nature of the disease, long-term immunosuppressive therapy, including steroid-sparing agents like rituximab, may be required.

References: Blackburn, K. M., Kubiliun, M., Harris, S., & Vernino, S. (2019). Neurological autoimmune disorders with prominent gastrointestinal manifestations: A review of presentation, evaluation, and treatment. Neurogastroenterology & Motility, 31(10). https://doi.org/10.1111/nmo.13611
Boronat, A., Gelfand, J. M., Gresa‐Arribas, N., Jeong, H., Walsh, M., Roberts, K., Martinez‐Hernandez, E., Rosenfeld, M. R., Balice‐Gordon, R., Graus, F., Rudy, B., & Dalmau, J. (2012). Encephalitis and antibodies to dipeptidyl‐peptidase–like protein‐6, a subunit of kv4.2 potassium channels. Annals of Neurology, 73(1), 120–128. https://doi.org/10.1002/ana.23756
Hara, M., Ariño, H., Petit-Pedrol, M., Sabater, L., Titulaer, M., Martinez-Hernandez, E., Schreurs, M., Graus, F., & Dalmau, J. (2017). DPPX-antibody associated encephalitis: Main syndrome and antibody effects (P2.106). Neurology, 88(16_supplement). https://doi.org/10.1212/wnl.88.16_supplement.p2.106
Mbonde, A. A., Gritsch, D., Arca, K., Blech, B., McKeon, A., & Carter, J. (2021). DPPX autoimmune encephalitis: A short report on two patients presenting with classic features of this rare but treatable disease. Multiple Sclerosis and Related Disorders, 52, 102934. https://doi.org/10.1016/j.msard.2021.102934
Li, E.-C., Zhang, T.-Y., Cai, M.-T., Su, S.-Y., Shen, C.-H., Lai, Q.-L., & Zhang, Y.-X. (2025). Clinical and paraclinical characterizations, management, and prognosis in DPPX antibody-associated encephalitis. Neurology Neuroimmunology & Neuroinflammation, 12(2). https://doi.org/10.1212/nxi.0000000000200350

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dppx-autoimmune-encephalitis-presenting-with-chorea/