title: Titin antibodies in "seronegative" myasthenia gravis--A new role for an old antigen.
abstract: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece; Tzartos NeuroDiagnostics, Athens, Greece.
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authors.lastname: Stergiou
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece.
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authors.lastname: Lazaridis
authors.affiliation: Neurology Department, Aeginition Hospital, Athens, Greece.
authors.forename: V
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authors.affiliation: Hellenic Pasteur Institute, Athens, Greece; Tzartos NeuroDiagnostics, Athens, Greece.
authors.forename: J
authors.initials: J
authors.lastname: Tzartos
authors.affiliation: Neurological Institute "C. Besta", Milano, Italy.
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authors.affiliation: Neurological Institute "C. Besta", Milano, Italy.
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authors.affiliation: Neurological Institute "C. Besta", Milano, Italy.
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authors.affiliation: Institute of Neurology, Catholic University, Rome, Italy.
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authors.affiliation: Istanbul University, Istanbul, Turkey.
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authors.affiliation: Istanbul University, Istanbul, Turkey.
authors.forename: G
authors.initials: G
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authors.affiliation: Istanbul University, Istanbul, Turkey.
authors.forename: H
authors.initials: H
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authors.affiliation: Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: T
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authors.lastname: Brenner
authors.affiliation: Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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authors.affiliation: UPMC and INSERM, Paris, France.
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authors.affiliation: UPMC and INSERM, Paris, France.
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authors.affiliation: Raymond Poincaré Hospital, Garches, France.
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authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
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authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
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authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
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authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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authors.initials: KA
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authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: E
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authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: A
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authors.lastname: Kostera-Pruszczyk
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: P
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authors.lastname: Szczudlik
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
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authors.affiliation: Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: D
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authors.affiliation: Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: I
authors.initials: I
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authors.affiliation: Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: S
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authors.affiliation: Norway Department of Neurology, Ullevaal University Hospital, Oslo, Norway; Faculty of Medicine, Olso University, Norway.
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authors.lastname: Tallaksen
authors.affiliation: Norway Department of Neurology, Ullevaal University Hospital, Oslo, Norway.
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authors.lastname: Maniaol
authors.affiliation: Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: N E
authors.initials: NE
authors.lastname: Gilhus
authors.affiliation: Bellvitge University Hospital, Barcelona, Spain.
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authors.affiliation: Department of Neurology and Clinical Neuroscience Center, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Prague, Czech Republic.
authors.forename: J
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authors.lastname: Pitha
authors.affiliation: Department of Neurology and Clinical Neuroscience Center, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Prague, Czech Republic.
authors.forename: M
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authors.lastname: Jakubíkova
authors.affiliation: Universitätsklinikum Halle, Halle, Germany.
authors.forename: F
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authors.affiliation: Faculty of Clinical Medicine Manheim, University of Heidelberg, Germany.
authors.forename: J
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authors.lastname: Bogomolovas
authors.affiliation: Faculty of Clinical Medicine Manheim, University of Heidelberg, Germany; Myomedix GmbH, 69151 Neckargemuend, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Labeit
authors.affiliation: Faculty of Clinical Medicine Manheim, University of Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Labeit
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece; Tzartos NeuroDiagnostics, Athens, Greece. Electronic address: stzartos@gmail.com.
authors.forename: S J
authors.initials: SJ
authors.lastname: Tzartos
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D064211:Connectin / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007391:International Cooperation; D026502:LDL-Receptor Related Proteins / Q000276:immunology; D008297:Male; D009157:Myasthenia Gravis / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D015531:Radioimmunoprecipitation Assay; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology
chemical_list: D001323:Autoantibodies; D064211:Connectin; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: Autoantibodies; Diagnosis; Myasthenia gravis; Radioimmunoprecipitation assay; Seronegative; Titin