Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls.

PANDAS and some cases of Tourette syndrome (TS) have been proposed to be post-streptococcal movement disorders in which antibodies produced against group A beta-hemolytic streptococcus cross react against brain epitopes. Attempts to identify disease specific anti-striatal antibodies in the serum of affected patients have focused on the use of Western immunoblotting and ELISA methodologies. In this study, immunohistochemical techniques were used to identify serum anti-striatal antibody reactivity. In positive samples, double staining with anti-GFAP (glial) and anti-MAP2 (neuronal) was used to establish localization of the immunofluorescence. No significant differences in immunofluorescence or localization were identified in patients with PANDAS (n=30) and TS (n=30) as compared to controls (n=30). IF reactivity did not correlate with tic severity or elevated titers of antistreptococcal antibodies. Further comparisons showed no correlation between autoreactivity determined by immunofluorescence and the presence of previously measured immunoblot reactivity against human caudate or putative antigens (pyruvate kinase M1 and aldolase C). These results confirm an inability to distinguish patient populations by antibody measurements and raise further concerns about the presence of an autoimmune mechanism in PANDAS and TS.

Antibodies against fetal brain in sera of mothers with autistic children.

Serum antibodies in 100 mothers of children with autistic disorder (MCAD) were compared to 100 age-matched mothers with unaffected children (MUC) using as antigenic substrates human and rodent fetal and adult brain tissues, GFAP, and MBP. MCAD had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue. The density of bands was greater in fetal brain at 61 kDa. MCAD plus developmental regression had greater reactivity against human fetal brain at 36 and 39 kDa. Data support a possible complex association between genetic/metabolic/environmental factors and the placental transfer of maternal antibodies in autism.

Antibrain antibodies in children with autism and their unaffected siblings.

Serum autoantibodies to human brain, identified by ELISA and Western immunoblotting, were evaluated in 29 children with autism spectrum disorder (22 with autistic disorder), 9 non-autistic siblings and 13 controls. More autistic subjects than controls had bands at 100 kDa in caudate, putamen and prefrontal cortex (p<0.01) as well as larger peak heights of bands at 73 kDa in the cerebellum and cingulate gyrus. Both autistic disorder subjects and their matched non-autistic siblings had denser bands (peak height and/or area under the curve) at 73 kDa in the cerebellum and cingulate gyrus than did controls (p<0.01). Results suggest that children with autistic disorder and their siblings exhibit differences compared to controls in autoimmune reactivity to specific epitopes located in distinct brain regions.

Double-blind, crossover study of clonidine and levetiracetam in Tourette syndrome.

We compared the efficacy of clonidine and levetiracetam for treating tics in Tourette syndrome. Twelve subjects were enrolled; 10 (ages 8-27 years) with moderate to moderately severe tics completed a 15-week randomized, double-blind, flexible-dose crossover protocol. Initial medication doses were clonidine (0.05 mg, twice daily) or levetiracetam (10 mg/kg/day, divided twice daily). Doses were adjusted weekly, based on telephone assessment. The primary outcome measure was baseline-to-posttreatment (6-week) change in Total Tic Score of the Yale Global Tic Severity Scale. Secondary outcome measures included total Yale Global Tic Severity Scale and Clinical Global Impression scores and behavioral measures. The mean Total Tic Score improved significantly from baseline to posttreatment with clonidine (25.2 versus 21.8) compared with levetiracetam (22.7 versus 23.6) (P = 0.013). The mean total Yale Global Tic Severity Scale and Clinical Global Impression score did not change. For levetiracetam, no changes occurred in any scales. No significant change occurred in any secondary behavioral outcome measures for either group. The most commonly reported side effects were, for clonidine, sedation (n = 5), and for levetiracetam, irritability (n = 4). Treatment with clonidine, but not levetiracetam, resulted in a small reduction in Total Tic Score, with an effect size of 0.57.

Childhood serum anti-fetal brain antibodies do not predict autism.

Autoimmune hypotheses for autism include in utero transplacental exposure to maternal antibodies and acquired postnatal insults. Previous work demonstrated that some mothers of children with autistic disorder have specific antibodies against human fetal brain that differentiate them from mothers with typical children. In the present study, Western immunoblotting was used to determine whether children with autistic spectrum disorders (n = 29) have serum reactivity against human fetal brain that differs from that of controls (n = 14). There was no significant difference in reactivity, corrected for serum immunoglobulin G content and brain actin content and with special attention to reactive bands at 36, 39, 61, and 73 kDa, between autistic children and normal control subjects. Thus, in contrast to mothers, antibody reactivity against human fetal brain as measured in children ages 3-12 years does not appear to be a useful biomarker for autism.

Dopaminergic polymorphisms in Tourette syndrome: association with the DAT gene (SLC6A3).

Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by involuntary motor and phonic tics. The pattern of inheritance and associated genetic abnormality has yet to be fully characterized. A dopaminergic abnormality in this disorder is supported by response to specific therapies, nuclear imaging, and postmortem studies. In this protocol, dopaminergic polymorphisms were examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). Polymorphisms investigated included the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine beta-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene. DNA was obtained from 266 TS individuals +/- ADHD and 236 controls that were ethnicity-matched. A significant association, using a genotype-based association analysis, was identified for the TS-total and TS-only versus control groups for the DAT1 DdeI polymorphism (AG vs. AA, P = 0.004 and P = 0.01, respectively). Population structure, estimated by the genotyping of 27 informative SNP markers, identified 3 subgroups. A statistical re-evaluation of the DAT1 DdeI polymorphism following population stratification confirmed the association for the TS-total and TS-only groups, but the degree of significance was reduced (P = 0.017 and P = 0.016, respectively). This study has identified a significant association between the presence of TS and a DAT polymorphism. Since abnormalities of the dopamine transporter have been hypothesized in the pathophysiology of TS, it is possible that this could be a functional allele associated with clinical expression.