Encephalitis and antibodies to dipeptidyl-peptidase–like protein-6, a subunit of Kv4.2 potassium channels

Boronat, Anna, Gelfand, Jeffrey M., Gresa-Arribas, Nuria, Jeong, Hyo-Young, Walsh, Michael, Roberts, Kirk, Martinez-Hernandez, Eugenia, Rosenfeld, Myrna R., Balice-Gordon, Rita, Graus, Francesc, Rudy, Bernardo and Dalmau, Josep (2013) Encephalitis and antibodies to dipeptidyl-peptidase–like protein-6, a subunit of Kv4.2 potassium channels. Annals of Neurology, 73 1: 120-128. doi:10.1002/ana.23756

Author Boronat, Anna
Gelfand, Jeffrey M.
Gresa-Arribas, Nuria
Jeong, Hyo-Young
Walsh, Michael
Roberts, Kirk
Martinez-Hernandez, Eugenia
Rosenfeld, Myrna R.
Balice-Gordon, Rita
Graus, Francesc
Rudy, Bernardo
Dalmau, Josep
Title Encephalitis and antibodies to dipeptidyl-peptidase–like protein-6, a subunit of Kv4.2 potassium channels
Journal name Annals of Neurology   Check publisher's open access policy
ISSN 0364-5134
Publication date 2013-01
Year available 2012
Sub-type Article (original research)
DOI 10.1002/ana.23756
Volume 73
Issue 1
Start page 120
End page 128
Total pages 9
Place of publication Hoboken, United States
Publisher John Wiley & Sons
Collection year 2013
Language eng
Formatted abstract
Objective: To report a novel cell surface autoantigen of encephalitis that is a critical regulatory subunit of the Kv4.2 potassium channels.

Methods: Four patients with encephalitis of unclear etiology and antibodies with a similar pattern of neuropil brain immunostaining were selected for autoantigen characterization. Techniques included immunoprecipitation, mass spectrometry, cell-base experiments with Kv4.2 and several dipeptidyl-peptidase–like protein-6 (DPPX) plasmid constructs, and comparative brain immunostaining of wild-type and DPPX-null mice.

Results: Immunoprecipitation studies identified DPPX as the target autoantigen. A cell-based assay confirmed that all 4 patients, but not 210 controls, had DPPX antibodies. Symptoms included agitation, confusion, myoclonus, tremor, and seizures (1 case with prominent startle response). All patients had pleocytosis, and 3 had severe prodromal diarrhea of unknown etiology. Given that DPPX tunes up the Kv4.2 potassium channels (involved in somatodendritic signal integration and attenuation of dendritic back-propagation of action potentials), we determined the epitope distribution in DPPX, DPP10 (a protein homologous to DPPX), and Kv4.2. Patients' antibodies were found to be specific for DPPX, without reacting with DPP10 or Kv4.2. The unexplained diarrhea led to a demonstration of a robust expression of DPPX in the myenteric plexus, which strongly reacted with patients' antibodies. The course of neuropsychiatric symptoms was prolonged and often associated with relapses during decreasing immunotherapy. Long-term follow-up showed substantial improvement in 3 patients (1 was lost to follow-up).

Interpretation: Antibodies to DPPX are associated with a protracted encephalitis characterized by central nervous system hyperexcitability (agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy
Keyword Nmda-receptor encephalitis
Limbic encephalitis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 7 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
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