title: Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.
abstract: Double-seronegative myasthenia gravis (dSNMG) includes patients with myasthenia gravis (MG) without detectable antibodies to the nicotinic acetylcholine receptor (AChR) or to muscle-specific tyrosine kinase (MuSK). The lack of a biomarker hinders the diagnosis and clinical management in these patients. Cortactin, a protein acting downstream from agrin/low-density lipoprotein receptor-related protein 4 (LRP4)/MuSK, has been described as an antigen in dSNMG.
  
  
  
  To describe the frequency and clinical features of patients with dSNMG who have cortactin antibodies.
  
  
  
  A retrospective cross-sectional study was conducted at Hospital de la Santa Creu i Sant Pau, an institutional practice referral center in Barcelona, Spain, between May 1, 2015, and November 30, 2015. We included 250 patients with a definitive diagnosis of MG with available serum samples at the time of diagnosis. Descriptive and comparative data analyses were performed.
  
  
  
  Cortactin antibodies were measured by enzyme-linked immunosorbent assay and Western blot; AChR, MuSK, and anti-striated muscle antibodies were detected using a standard method; and LRP4 antibodies were tested using a cell-based assay.
  
  
  
  The primary outcome was the frequency of patients with dSNMG who have cortactin antibodies. Secondary outcomes were demographic, clinical, neurophysiological, and laboratory data.
  
  
  
  Of 250 patients (mean [SD] age at onset, 49.7 [21.2] years; 56% female), 38 (15.2%) had dSNMG, 201 (80.4%) had MG with AChR antibodies, and 11 (4.4%) had MG with MuSK antibodies. Cortactin antibodies were identified in 28 patients with MG: 9 of 38 (23.7%) who had dSNMG, 19 of 201 (9.5%) who had MG with AChR antibodies (significantly lower than those with dSNMG: 9.5% vs 23.7%; P = .02), and 0 of 11 who had MG with MuSK antibodies; 0 of 29 controls had cortactin antibodies. At onset, among the 9 patients with dSNMG and cortactin antibodies, 6 had ocular MG and 3 had Myasthenia Gravis Foundation of America clinical classification IIA. Two patients with ocular MG developed generalized MG. The group with dSNMG and cortactin antibodies, compared with those who had MG with AChR antibodies, more frequently had mild forms at onset (100.0% vs 62.7%; P = .03), had fewer bulbar signs at maximal worsening (0% vs 41.3%; P = .01), and were younger at onset (median [interquartile range], 34.9 [9.5] vs 53.9 [38.5] years; P = .03); the group with dSNMG and cortactin antibodies also more frequently had ocular MG at onset than those with MG and AChR antibodies, although the difference was not statistically significant (66.7% vs 40.8%; P = .17). Of 17 patients with ocular dSNMG, 4 (23.5%) had antibodies to cortactin.
  
  
  
  In this study, patients with cortactin antibodies and dSNMG had an ocular or mild generalized phenotype of MG. Including the detection of cortactin antibodies in the routine diagnosis of dSNMG may be helpful in ocular MG.
authors.affiliation: Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Cortés-Vicente
authors.affiliation: Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: Department of Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Martínez
authors.affiliation: Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Díaz-Manera
authors.affiliation: Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Querol
authors.affiliation: Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Rojas-García
authors.affiliation: Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Illa
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D051356:Cortactin / Q000276:immunology*; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000097:blood* / Q000453:epidemiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology; D011978:Receptors, Nicotinic / Q000276:immunology; D012189:Retrospective Studies; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
chemical_list: D001323:Autoantibodies; D051356:Cortactin; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases