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, 10 (3), e0120499
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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

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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

Harvey S Singer et al. PLoS One.

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.

Conflict of interest statement

Competing Interests: MWC is chief scientific officer of Molecular Labs, a company offering diagnosis testing for children with autoimmune movements and neuropsychiatric disorders. The authors alone are responsible for the content and writing of the article. This does not alter the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Diagram of sampling time points.
Number of days (mean ± SD) from the exacerbation point for serum samples evaluated in the ExWS (exacerbation with streptococcal infection) and ExWOS (exacerbation without streptococcal infection) groups. Time points: 1 (Pre-Exac 1), 2 (Pre-Exac 2), 3 (Exac), 4 (Post-Exac 1), and 5 (Post-Exac 2). Adapted from [14].
Fig 2
Fig 2. Anti-tubulin autoantibodies.
a) Longitudinal anti-tubulin serum IgG titer fold-change from baseline in PANDAS-chronic tics and OCD subjects having a clinical exacerbation associated with a streptococcal infection. Baseline (Pre-Exac 1) for each individual subject is set at “0”. Subsequent points indicate changes in titer level. A four-fold-rise (----) is equivalent to increase in titer level, e.g., 250 to 1000. Subject number is presented within each circle. b) Longitudinal anti-tubulin serum titers compared to controls. Control values for Groups 1–4 are shown (). The top and lower solid lines indicate the combined control group’s 95th percentile and median, respectively. Actual serial values are presented for subjects 1–6 (1 = red, 2 = black, 3 = blue, 4 = purple, 5 = orange, and 6 = green).
Fig 3
Fig 3. Anti-dopamine D2 autoantibodies.
a) Longitudinal anti-dopamine D2 receptor serum IgG titer fold-change from baseline in PANDAS-chronic tics and OCD subjects having a clinical exacerbation associated with a streptococcal infection. Baseline (Pre-Exac 1) for each individual subject is set at “0”. Subsequent points indicate changes in titer level. A four-fold-rise (----) is equivalent to increase in titer level, e.g., 250 to 1000. Subject number is presented within each circle. b) Longitudinal anti-dopamine D2 receptor serum titers compared to controls. Control values for Groups 1–4 are shown ().The top and lower solid lines indicate the combined control group’s 95th percentile and median, respectively. Actual serial values are presented for subjects 1–6. (1 = red, 2 = black, 3 = blue, 4 = purple, 5 = orange, and 6 = green).
Fig 4
Fig 4. Anti-dopamine D1 autoantibodies.
a) Longitudinal anti-dopamine D1 receptor serum IgG titer fold-change from baseline in PANDAS-chronic tics and OCD subjects having a clinical exacerbation associated with a streptococcal infection. Baseline (pre-Exac 1) for each individual subject is set at “0”. Subsequent points indicate changes in titer level. A four-fold-rise (----) is equivalent to increase in titer level, e.g., 250 to 1000. Subject number is presented within each circle. b) Longitudinal anti-dopamine D1 receptor serum titers compared to controls. Control values for Groups 1–4 are shown ().The top and lower solid lines indicate the combined control group’s 95th percentile and median, respectively. Actual serial values are presented for subjects 1–6. (1 = red, 2 = black, 3 = blue, 4 = purple, 5 = orange, and 6 = green).
Fig 5
Fig 5. Anti- lysoganglioside-GM1 autoantibodies.
a) Longitudinal anti-lysoganglioside-GM1 serum IgG titer fold-change from baseline in PANDAS-chronic tics and OCD subjects having a clinical exacerbation associated with a streptococcal infection. Baseline (pre-Exac 1) for each individual subject is set at “0”. Subsequent points indicate changes in titer level. A four-fold-rise (----) is equivalent to increase in titer level, e.g., 250 to 1000. Subject number is presented within each circle. b) Longitudinal anti- lysoganglioside-GM1 receptor serum titers compared to controls. Control values for Groups 1–4 are shown ().The top and lower solid lines indicate the combined control group’s 95th percentile and median, respectively. Actual serial values are presented for subjects 1–6. (1 = red, 2 = black, 3 = blue, 4 = purple, 5 = orange, and 6 = green).
Fig 6
Fig 6. Longitudinal CAMKII activity.
Longitudinal CAMKII activity in PANDAS-chronic tics and OCD compared to controls. Control values for Groups 1–4 are shown (). The top and lower solid lines indicate the combined control group’s 95th percentile and median, respectively. Actual serial values are presented for 7 subjects (1 = red, 2 = black, 3 = blue, 4 = purple, 6 = green, 7 = olive green, and 8 = dark red).

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