title: Neuronal Na+/K+ ATPase is an autoantibody target in paraneoplastic neurologic syndrome.
abstract: OBJECTIVE
  To identify an autoreactivity in a 66-year-old woman who presented with combined brainstem and cerebellar syndrome including vertical gaze palsy, severe progressive ataxia, and spastic tetraparesis, an acute deterioration of vision, dysarthria, and dysphagia with concurrent diagnosis of a colon adenocarcinoma.
  
  
  METHODS
  Patient's serum and CSF underwent comprehensive autoantibody screening by indirect immunofluorescence assay and immunoblot. For autoantigen purification, a histo-immunoprecipitation technique was developed followed by mass spectrometrical analysis. Recombinant candidate antigens were expressed in HEK293 and used to verify the identification.
  
  
  RESULTS
  Indirect immunofluorescence assay screening revealed strong immunoglobulin G reactivity with neural tissues in serum and CSF, but not with a panel of 28 recombinantly expressed established neural autoantigens. The hitherto unknown target antigen was identified as the neuronal Na(+)/K(+) ATPase. Epitope mapping and competitive inhibition experiments showed that the autoantibodies were directed against the membrane-spanning alpha 3 subunit (ATP1A3) of the enzyme but did not bind to extracellular epitopes. Immunohistochemical analysis revealed overexpression of this subunit in the patient's tumor.
  
  
  CONCLUSIONS
  We describe a case of an anti-ATP1A3-associated neurologic disorder. Mutations in the gene encoding this neuronal surface protein have already been recognized as the cause of infantile alternating hemiplegia, rapid-onset dystonia parkinsonism, and CAPOS syndrome. Although the autoantibodies are unlikely to be pathogenic, they are likely to be rare biomarkers for the apparently paraneoplastic neurologic syndrome or for the tumor itself.
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Madeleine
authors: M
authors: Scharf
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Ramona
authors: R
authors: Miske
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Fedor
authors: F
authors: Heidenreich
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Ralf
authors: R
authors: Giess
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Peter
authors: P
authors: Landwehr
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Inga-Madeleine
authors: IM
authors: Blöcker
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Nora
authors: N
authors: Begemann
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Yvonne
authors: Y
authors: Denno
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Stephan
authors: S
authors: Tiede
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Cornelia
authors: C
authors: Dähnrich
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Wolfgang
authors: W
authors: Schlumberger
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Mandy
authors: M
authors: Unger
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Bianca
authors: B
authors: Teegen
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Winfried
authors: W
authors: Stöcker
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany.
authors: Christian
authors: C
authors: Probst
authors: From the Institute of Experimental Immunology (M.S., R.M., I.-M.B., N.B., Y.D., S.T., C.D., W. Schlumberger, M.U., B.T., W. Stöcker, C.P., L.K.), EUROIMMUN AG, Lübeck; and Departments of Neurology and Clinical Neurophysiology (F.H., R.G.) and Diagnostic and Interventional Radiology (P.L.), Hospital of the Henriettenstiftung, Hannover, Germany. l.komorowski@euroimmun.de.
authors: Lars
authors: L
authors: Komorowski
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology*; D000368:Aged; D001259:Ataxia / Q000503:physiopathology*; D001323:Autoantibodies / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D009474:Neurons / Q000276:immunology*; D020361:Paraneoplastic Syndromes, Nervous System / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000276:immunology*
chemical_list: C488756:ATP1A3 protein, human; D001323:Autoantibodies; D007074:Immunoglobulin G; D000254:Sodium-Potassium-Exchanging ATPase