Encephalitis and Antibodies to Dipeptidyl-Peptidase-Like Protein-6, a Subunit of Kv4.2 Potassium Channels
Por:
Boronat, A, Gelfand, JM, Gresa-Arribas, N, Jeong, HY, Walsh, M, Roberts, K, Martinez-Hernandez, E, Rosenfeld, MR, Balice-Gordon, R, Graus, F, Rudy, B, Dalmau, J
Publicada:
1 ene 2013
Resumen:
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. ANN NEUROL 2013;73:120-128
Filiaciones:
Boronat, A:
Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer, E-08036 Barcelona, Spain
Univ Barcelona, Hosp Clin, Serv Neurol, E-08036 Barcelona, Spain
Gelfand, JM:
Univ Calif San Francisco, Dept Neurol, Multiple Sclerosis Ctr, San Francisco, CA USA
Gresa-Arribas, N:
Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer, E-08036 Barcelona, Spain
Univ Barcelona, Hosp Clin, Serv Neurol, E-08036 Barcelona, Spain
Jeong, HY:
NYU, Sch Med, Dept Physiol & Neurosci, New York, NY USA
NYU, Sch Med, Dept Biochem, New York, NY 10016 USA
Walsh, M:
Princess Alexandra Hosp Brisbane, Dept Neurol, Woolloongabba, Qld, Australia
Univ Queensland, St Lucia, Qld, Australia
Roberts, K:
Columbia Univ, Coll Phys & Surg, Dept Neurol, New York Presbyterian Hosp, New York, NY USA
Martinez-Hernandez, E:
Autonomous Univ Barcelona, Dept Neurol, St Paul Hosp, Barcelona, Spain
Rosenfeld, MR:
Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer, E-08036 Barcelona, Spain
Univ Barcelona, Hosp Clin, Serv Neurol, E-08036 Barcelona, Spain
Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA
Balice-Gordon, R:
Univ Penn, Dept Neurosci, Philadelphia, PA 19104 USA
Graus, F:
Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer, E-08036 Barcelona, Spain
Univ Barcelona, Hosp Clin, Serv Neurol, E-08036 Barcelona, Spain
Rudy, B:
NYU, Sch Med, Dept Physiol & Neurosci, New York, NY USA
NYU, Sch Med, Dept Biochem, New York, NY 10016 USA
Dalmau, J:
Univ Barcelona, Hosp Clin, Inst Biomed Res August Pi & Sunyer, E-08036 Barcelona, Spain
Univ Barcelona, Hosp Clin, Serv Neurol, E-08036 Barcelona, Spain
Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA
Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain
Green Accepted
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