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

Authors

  • Anna Boronat BS,

    1. Institute of Biomedical Research August Pi i Sunyer and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
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  • Jeffrey M. Gelfand MD,

    1. Department of Neurology, Multiple Sclerosis Center, University of California at San Francisco, San Francisco, CA
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  • Nuria Gresa-Arribas PhD,

    1. Institute of Biomedical Research August Pi i Sunyer and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
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  • Hyo-Young Jeong PhD,

    1. Department of Physiology and Neuroscience and Department of Biochemistry, New York University School of Medicine, New York, NY
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  • Michael Walsh MD,

    1. Department of Neurology, Princess Alexandra Hospital Brisbane, Woolloongabba, and University of Queensland, St Lucia, Australia
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  • Kirk Roberts MD,

    1. Department of Neurology, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY
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  • Eugenia Martinez-Hernandez MD,

    1. Department of Neurology, Saint Paul Hospital, Autonomous University of Barcelona, Barcelona, Spain
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  • Myrna R. Rosenfeld MD, PhD,

    1. Institute of Biomedical Research August Pi i Sunyer and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
    2. Department of Neurology, University of Pennsylvania, Philadelphia, PA
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  • Rita Balice-Gordon PhD,

    1. Department of Neuroscience, University of Pennsylvania, Philadelphia, PA
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  • Francesc Graus MD,

    1. Institute of Biomedical Research August Pi i Sunyer and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
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  • Bernardo Rudy PhD,

    1. Department of Physiology and Neuroscience and Department of Biochemistry, New York University School of Medicine, New York, NY
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  • Josep Dalmau MD, PhD

    Corresponding author
    1. Institute of Biomedical Research August Pi i Sunyer and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain
    2. Department of Neurology, University of Pennsylvania, Philadelphia, PA
    3. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
    • ICREA-IDIBAPS, Hospital Clinic, University of Barcelona, Department of Neurology, c/ Villarroel 170, Barcelona, 08036, Spain
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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. ANN NEUROL 2013.

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