title: Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection.
abstract: Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham's chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A β-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control's 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group's 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform movements and elevated antibodies against D2R; 2) the originally reported group with choreiform movements and elevated anti-D2R antibodies, similar to SC. Increased antibody mediated CaMKII activation was found in both groups and requires further study as a potential biomarker.
authors: Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Harvey S
authors: HS
authors: Singer
authors: Departments of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors: Adda
authors: A
authors: Mascaro-Blanco
authors: Departments of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors: Kathy
authors: K
authors: Alvarez
authors: Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Christina
authors: C
authors: Morris-Berry
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors: Ivana
authors: I
authors: Kawikova
authors: Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
authors: Hilla
authors: H
authors: Ben-Pazi
authors: Biostatistics Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors: Carol B
authors: CB
authors: Thompson
authors: Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Syed F
authors: SF
authors: Ali
authors: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors: Edward L
authors: EL
authors: Kaplan
authors: Departments of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors: Madeleine W
authors: MW
authors: Cunningham
mesh_terms: D000293:Adolescent; D000906:Antibodies / Q000378:metabolism*; D000989:Antistreptolysin / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002819:Chorea / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D002908:Chronic Disease; D003851:Deoxyribonucleases / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D009474:Neurons / Q000378:metabolism*; D009771:Obsessive-Compulsive Disorder / Q000209:etiology*; D012008:Recurrence; D013290:Streptococcal Infections / Q000150:complications*; D020323:Tics / Q000209:etiology*
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D015415:Biomarkers; D007074:Immunoglobulin G; D000989:Antistreptolysin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003851:Deoxyribonucleases; C020069:deoxyribonuclease B