Dopaminergic Receptors in Sydenham's Chorea

Sydenham's Chorea: Is There a Link Between Neuropsychiatric Symptoms and Anti-dopamine Receptor Autoantibodies?

Sydenham's chorea (SC) is a post-streptococcal, neuropsychiatric disorder associated with anti-neuronal antibodies. The investigators demonstrated elevated anti-D1-receptor (D1R) and anti-D2-receptor (D2R) antibodies titers compared to controls using ELISA. Similarly, the investigators found antibodies to surface D2R in neuropsychiatric, autoimmune disorders, including SC using cell-based assays. The investigators hypothesize that these autoantibodies cause neuropsychiatric symptoms by inducing intracellular signaling changes resulting in altered dopaminergic neurotransmission. To check this, the investigators will test whether sera from patients with SC alter dopaminergic signaling pathways. The investigators will examine sera from 30 SC patients with active symptoms and 30 age-matched healthy controls. Patients with SC will be assessed for severity of neuropsychiatric symptoms using UFMG Sydenham's Chorea Rating Scale. Controls with evidence of streptococcal infections or autoimmune disorders will be excluded. Sera will be examined for anti-D1R and anti-D2R antibodies. Signaling studies will assess sera impact on 1) calcium/calmodulin-dependent protein kinase II activity in human neuronal cells. 2) dopamine D1/D2 receptors signaling using cAMP assays in transfected cell lines. The investigators will examine the correlation between modified signaling and clinical symptoms.

Study Overview

• Status: Unknown
• Conditions: Strep Throat; Sydenham Chorea
• Intervention / Treatment: Diagnostic test: Antibody detection

Detailed Description

Participants:

The investigators will enroll participants with acute Sydenham's chorea (aSC) and age-matched controls with streptococcal tonsillitis (ST) within the past 4 months and healthy children (HC) with no a history of a strep infection in the past 6 months and negative throat culture. Informed consent will be obtained from participants and/ or parents. Children with SC will be evaluated for SC severity using the USCRS. The investigators will record clinical data regarding gender, age, duration symptoms, and medical treatments. Controls will be examined by referring physician to rule out chorea. Sera samples from all participants will be stored at -70°C and shipped to the microbiology and immunology lab, University of Oklahoma Health Sciences Center (OHSC) on dry ice.

Laboratory testing:

Immunophenotyping for anti-D1R, anti-D2R, anti- LG and anti-tubulin titers and signaling studies will be performed at the OUHSC microbiology and immunology laboratory.

Autoantibody titers. Sera will be assayed for reactivity with the dopamine D1 and D2 receptors (Human dopamine D1 and D2 receptor membrane antigens, Perkin Elmer-Membrane Target Systems) in the direct ELISA and assays which include the ELISA competitive inhibition. Anti- LG and anti-tubulin titers will be tested as well.

Statistical Analysis:

Time will be categorized in order to model non-linear associations among the groups. Means will be compared among groups using an ANOVA model that included main effects for the time, participant diagnosis and the interaction between participant diagnosis and time. Modeling assumptions will be evaluated using residual plots. A natural log transformation of the antibody measure will be used when there was evidence of non-constant variance across the groups. If a significant interaction between time and participant group will be found, time trends will be summarized separately within each participant group. Post-hoc pair-wise comparisons will be made using Tukey's method to control the type I error rate. A two-sided 0.05 alpha level will be used to define statistical significance. Analyses will be performed using SAS (SAS Institute Inc., SAS v9.4, Cary, NC: SAS Institute Inc.).

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

Study Locations

• Israel
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

sydenhams chorea according to clinical parameters

Description

Inclusion Criteria:

• sydenham chora OR strep tonsilitiscontrol without strep tonsilitis OR

Exclusion Criteria:

• neurological disrder autoimmune disorder

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Retrospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sydenam Chorea (SC); individuals with SC	Diagnostic test: Antibody detection; detecting anti bodies against D1, D2 receptor, tubolin Lysoganglioside
tonsilitis; children with tonsilitis in the past 3 months	Diagnostic test: Antibody detection; detecting anti bodies against D1, D2 receptor, tubolin Lysoganglioside
control; children wit no tonsilitis	Diagnostic test: Antibody detection; detecting anti bodies against D1, D2 receptor, tubolin Lysoganglioside

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibody titers	titer levels of anti dopamine receptors (anti-D1 and anti-D2) using ELISA (titer levels are expresed as dilutions i.e. 1:400)	Once at time of initial visit within the first 4 months from onset
UFMG Sydenham's Chorea Rating Scale	the mean value of the 21 item of clinical chorea rating. Ranging from 0 (=none) to 4 (=severe) for each item	Upon presentation when symptomatic, usually within 4 months of onset

Collaborators and Investigators

• Sponsor: Shaare Zedek Medical Center
• Collaborators: University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Anticipated): December 30, 2019
• Study Completion (Anticipated): December 30, 2021

Study Registration Dates

• First Submitted: January 2, 2019
• First Submitted That Met QC Criteria: September 8, 2019
• First Posted (Actual): September 10, 2019

Study Record Updates

• Last Update Posted (Actual): September 10, 2019
• Last Update Submitted That Met QC Criteria: September 8, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias; Chorea; Physiological Effects of Drugs; Immunologic Factors; Antibodies
• Other Study ID Numbers: 139/14

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No