title: A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis.
abstract: Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Zisimopoulou
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece; University of Patras, Patras, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Evangelakou
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece.
authors.forename: J
authors.initials: J
authors.lastname: Tzartos
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Lazaridis
authors.affiliation: Neurology Department, Aeginition Hospital, Athens, Greece.
authors.forename: V
authors.initials: V
authors.lastname: Zouvelou
authors.affiliation: Neurological Institute "C. Besta", Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Mantegazza
authors.affiliation: Neurological Institute "C. Besta", Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Antozzi
authors.affiliation: Neurological Institute "C. Besta", Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Andreetta
authors.affiliation: Institute of Neurology, Catholic University, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Evoli
authors.affiliation: Istanbul University, Istanbul, Turkey.
authors.forename: F
authors.initials: F
authors.lastname: Deymeer
authors.affiliation: Istanbul University, Istanbul, Turkey.
authors.forename: G
authors.initials: G
authors.lastname: Saruhan-Direskeneli
authors.affiliation: Istanbul University, Istanbul, Turkey.
authors.forename: H
authors.initials: H
authors.lastname: Durmus
authors.affiliation: Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Vaknin
authors.affiliation: UPMC and INSERM, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Berrih-Aknin
authors.affiliation: UPMC and INSERM, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Frenkian Cuvelier
authors.affiliation: UPMC and INSERM, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Stojkovic
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: DeBaets
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Losen
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Martinez-Martinez
authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: K A
authors.initials: KA
authors.lastname: Kleopa
authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: E
authors.initials: E
authors.lastname: Zamba-Papanicolaou
authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: T
authors.initials: T
authors.lastname: Kyriakides
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Kostera-Pruszczyk
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Szczudlik
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Szyluk
authors.affiliation: Serbia, Clinic of Neurology, Clinical Center of Serbia, Serbia.
authors.forename: D
authors.initials: D
authors.lastname: Lavrnic
authors.affiliation: Serbia, Clinic of Neurology, Clinical Center of Serbia, Serbia.
authors.forename: I
authors.initials: I
authors.lastname: Basta
authors.affiliation: Serbia, Clinic of Neurology, Clinical Center of Serbia, Serbia.
authors.forename: S
authors.initials: S
authors.lastname: Peric
authors.affiliation: Norway Department of Neurology, Ullevaal University Hospital, Oslo, Norway.
authors.forename: C
authors.initials: C
authors.lastname: Tallaksen
authors.affiliation: Norway Department of Neurology, Ullevaal University Hospital, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Maniaol
authors.affiliation: Hellenic Pasteur Institute, Athens, Greece; University of Patras, Patras, Greece. Electronic address: tzartos@pasteur.gr.
authors.forename: S J
authors.initials: SJ
authors.lastname: Tzartos
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D007074:Immunoglobulin G / Q000097:blood; D007223:Infant; D007231:Infant, Newborn; D007391:International Cooperation; D026502:LDL-Receptor Related Proteins / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000175:diagnosis / Q000453:epidemiology* / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology; D012698:Serologic Tests / Q000379:methods*; D012737:Sex Factors; D013950:Thymus Gland / Q000473:pathology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: Autoantibodies; Cell based assay; Diagnosis; LRP4; Myasthenia gravis; Therapy