Effects of controlled discontinuation of long-term used antipsychotics for behavioural symptoms in individuals with intellectual disability.

BACKGROUND: Antipsychotics are frequently and often long-term used for challenging behaviour in persons with intellectual disability (ID), but the evidence base for this is meagre. As these agents may cause harmful side effects, discontinuation should be considered. Previous studies regarding discontinuation of long-term used antipsychotics mostly were uncontrolled and involved small numbers. The primary objective was to investigate the effects of controlled discontinuation of antipsychotics prescribed for challenging behaviour. Secondary objectives were to compare the results of two discontinuation time schedules, to compare groups of participants who had and had not achieved complete discontinuation, and to identify patient and medication characteristics that might predict the outcomes. Our hypothesis was that discontinuation of antipsychotics used for behavioural symptoms would not lead to worsening in behaviour. METHODS: This was a multi-centre parallel-group study comparing two discontinuation schedules of 14 and 28 weeks. Allocation to the two discontinuation schedules took place in a 1:1 ratio. Antipsychotics were tapered off every 2 or 4 weeks with approximately 12.5% of the initial dosage. Follow-up was 12 weeks after the scheduled complete discontinuation, that is, 26 or 40 weeks after the first dose reduction, respectively. Discontinuation was stopped in case of significant behavioural worsening. Participants were 98 residents with ID of three care providing organisations in the Netherlands, aged 15-66 year, who had used for more than 1 year one or more of the six most frequently prescribed antipsychotics for challenging behaviour. Main outcome measure was the total score of the Aberrant Behaviour Checklist (ABC); also ABC sub-scales were used. RESULTS: Of 98 participants, 43 achieved complete discontinuation; at follow-up 7 had resumed use of antipsychotics. Mean ABC ratings improved significantly for those who achieved complete discontinuation (directly after discontinuation, P < 0.01 and at follow-up, P = 0.03), and at follow-up (P = 0.03) for those who had not achieved complete discontinuation. Similar results were found with respect to most ABC sub-scales, including the 'irritability' sub-scale. There were no significant differences in improvement of ABC ratings between both discontinuation schedules. Higher ratings of extrapyramidal and autonomic symptoms at baseline were associated with less improvement of behavioural symptoms after discontinuation; higher baseline ABC rating predicted higher odds of incomplete discontinuation. CONCLUSIONS: Discontinuation of antipsychotics prescribed for challenging behaviour in patients with ID is associated with improved behavioural functioning. There is no need to taper off in a time frame longer than 14 weeks.

High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

PDD symptoms in ADHD, an independent familial trait?

The aims of this study were to investigate whether subtle PDD symptoms in the context of ADHD are transmitted in families independent of ADHD, and whether PDD symptom familiality is influenced by gender and age. The sample consisted of 256 sibling pairs with at least one child with ADHD and 147 healthy controls, aged 5-19 years. Children who fulfilled criteria for autistic disorder were excluded. The Children's Social Behavior Questionnaire (CSBQ) was used to assess PDD symptoms. Probands, siblings, and controls were compared using analyses of variance. Sibling correlations were calculated for CSBQ scores after controlling for IQ, ADHD, and comorbid anxiety. In addition, we calculated cross-sibling cross-trait correlations. Both children with ADHD and their siblings had higher PDD levels than healthy controls. The sibling correlation was 0.28 for the CSBQ total scale, with the CSBQ stereotyped behavior subscale showing the strongest sibling correlation (r = 0.35). Sibling correlations remained similar in strength after controlling for IQ and ADHD, and were not confounded by comorbid anxiety. Sibling correlations were higher in female than in male probands. The social subscale showed stronger sibling correlations in elder than in younger sibling pairs. Cross-sibling cross-trait correlations for PDD and ADHD were weak and not-significant. The results confirm that children with ADHD have high levels of PDD symptoms, and further suggest that the familiality of subtle PDD symptoms in the context of ADHD is largely independent from ADHD familiality.

Measuring theory of mind in children. Psychometric properties of the ToM Storybooks.

Although research on Theory-of-Mind (ToM) is often based on single task measurements, more comprehensive instruments result in a better understanding of ToM development. The ToM Storybooks is a new instrument measuring basic ToM-functioning and associated aspects. There are 34 tasks, tapping various emotions, beliefs, desires and mental-physical distinctions. Four studies on the validity and reliability of the test are presented, in typically developing children (n = 324, 3-12 years) and children with PDD-NOS (n = 30). The ToM Storybooks have good psychometric qualities. A component analysis reveals five components corresponding with the underlying theoretical constructs. The internal consistency, test-retest reliability, inter-rater reliability, construct validity and convergent validity are good. The ToM Storybooks can be used in research as well as in clinical settings.

A new symptom model for autism cross-validated in an independent sample.

BACKGROUND: Results from several studies indicated that a symptom model other than the DSM triad might better describe symptom domains of autism. The present study focused on a) investigating the stability of a new symptom model for autism by cross-validating it in an independent sample and b) examining the invariance of the model regarding three covariates: symptom severity, intelligence, and age. METHOD: The validity of the symptom model was examined in an independent sample of N = 263 children and adolescents with autism spectrum disorders, and model invariance was studied in a larger sample of N = 356 children and adolescents with autism spectrum disorders. The fit of the symptom model to the sample data was compared to that of alternative models (including the DSM triad), and the invariance of the new model was investigated for each covariate by multiple-group comparisons. RESULTS: The fit of the new symptom model was better than that of two alternative models. It could not be compared to that of the DSM triad, because the latter encountered empirical identification problems. There were no significant or substantive differences between the estimated model in each of the dichotomised groups for any of the three covariates, which indicated factorial invariance of both structural form and factor loadings. CONCLUSIONS: The symptom model appeared to be relatively stable: It could be cross-validated in the independent sample and factorial invariance was shown between the dichotomised groups for each covariate. Further model validation with instruments other than the Autism Diagnostic Interview-Revised (ADI-R) is recommended.

Differential family and peer environmental factors are related to severity and comorbidity in children with ADHD.

Behavioral genetic studies imply that salient environmental influences operate within families, making siblings in a family different rather than similar. This study is the first one to examine differential sibling experiences (as measured with the Sibling Inventory of Differential Experience) and its effect on behavioral outcomes within ADHD families. Subjects were 45 Dutch ADHD probands and their unaffected siblings (n = 45) aged 10-18 years. ADHD probands and their unaffected siblings reported differences in sibling interaction, parental treatment, and peer characteristics. These nonshared environmental influences were related to both the severity of ADHD symptoms as well as to comorbid problem behaviors. These findings suggest that environmental influences that operate within ADHD families appear relevant to the severity of problem behaviors of ADHD children and their siblings.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA.

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Internalizing and externalizing problems in adolescence: general and dimension-specific effects of familial loadings and preadolescent temperament traits.

BACKGROUND: We investigated the links between familial loading, preadolescent temperament, and internalizing and externalizing problems in adolescence, hereby distinguishing effects on maladjustment in general versus dimension-specific effects on either internalizing or externalizing problems. METHOD: In a population-based sample of 2230 preadolescents (10-11 years) familial loading (parental lifetime psychopathology) and offspring temperament were assessed at baseline by parent report, and offspring psychopathology at 2.5-years follow-up by self-report, teacher report and parent report. We used purified measures of temperament and psychopathology and partialled out shared variance between internalizing and externalizing problems. RESULTS: Familial loading of internalizing psychopathology predicted offspring internalizing but not externalizing problems, whereas familial loading of externalizing psychopathology predicted offspring externalizing but not internalizing problems. Both familial loadings were associated with Frustration, low Effortful Control, and Fear. Frustration acted as a general risk factor predicting severity of maladjustment; low Effortful Control and Fear acted as dimension-specific risk factors that predicted a particular type of psychopathology; whereas Shyness, High-Intensity Pleasure, and Affiliation acted as direction markers that steered the conditional probability of internalizing versus externalizing problems, in the event of maladjustment. Temperament traits mediated one-third of the association between familial loading and psychopathology. Findings were robust across different composite measures of psychopathology, and applied to girls as well as boys. CONCLUSIONS: With regard to familial loading and temperament, it is important to distinguish general risk factors (Frustration) from dimension-specific risk factors (familial loadings, Effortful Control, Fear), and direction markers that act as pathoplastic factors (Shyness, High-Intensity Pleasure, Affiliation) from both types of risk factors. About one-third of familial loading effects on psychopathology in early adolescence are mediated by temperament.

Adaptive functioning and behaviour problems in relation to level of education in children and adolescents with intellectual disability.

BACKGROUND: The interrelationship between adaptive functioning, behaviour problems and level of special education was studied in 186 children with IQs ranging from 61 to 70. The objective was to increase the insight into the contribution of adaptive functioning and general and autistic behaviour problems to the level of education in children with intellectual disability (ID). METHODS: Children from two levels of special education in the Netherlands were compared with respect to adaptive functioning [Vineland Adaptive Behavior Scales (VABS)], general behaviour problems [Child Behavior Checklist (CBCL)] and autistic behaviour problems [Autism Behavior Checklist (ABC)]. The effect of behaviour problems on adaptive functioning, and the causal relationships between behaviour problems, adaptive functioning and level of education were investigated. RESULTS: Children in schools for mild learning problems had higher VABS scores, and lower CBCL and ABC scores. The ABC had a significant effect on the total age equivalent of the VABS in schools for severe learning problems, the CBCL in schools for mild learning problems. A direct effect of the ABC and CBCL total scores on the VABS age equivalent was found, together with a direct effect of the VABS age equivalent on level of education and therefore an indirect effect of ABC and CBCL on level of education. CONCLUSIONS: In the children with the highest level of mild ID, adaptive functioning seems to be the most important factor that directly influences the level of education that a child attends. Autistic and general behaviour problems directly influence the level of adaptive functioning. Especially, autistic problems seem to have such a restrictive effect on the level of adaptive functioning that children do not reach the level of education that would be expected based on IQ. Clinical implications are discussed.

Drug utilisation by children and adolescents with mental retardation: a population study.

OBJECTIVE: Little is known about the utilisation of drugs by mentally retarded children; population studies are even more sparse. In this study the chronic drug utilisation in children aged 4-18 years with mental retardation in a large population in the Netherlands was investigated. METHODS: Throughout all special schools and (day) care facilities for children with mental retardation in Friesland, parents/representatives were approached requesting participation of their children. Participants were interviewed about a number of aspects including medication use. For 921 of the 1,057 participants, information was available on medication use for those physical and psychiatric illnesses that bothered them or was expected to bother them for at least 3 months per year; 912 of the participants were within the age category under study: 4-18 years. RESULTS: About 22% of the 912 participants used chronic medication, 47% of whom used two or more drugs. The prevalence of drug use increased with severity of mental retardation from about 17% to 49%. The exception was the 6% of children with borderline intellectual functioning: their medication prevalence was 27%. Overall, 17% of the study population used a nervous system drug, 4% used a respiratory system drug and 3% used an alimentary tract drug. Of the drugs for the nervous system, alimentary tract and respiratory tract, 32% was prescribed off-label. For 3%, we were unable to establish on/off-label use. CONCLUSIONS: Chronic drug utilisation patterns in children and adolescents with mental retardation are different from those in the general paediatric population. These different patterns suggest the need for additional research.

Social skills in children with intellectual disabilities with and without autism.

BACKGROUND: Social skills were studied in 363 children with mild intellectual disabilities (ID) and 147 with moderate ID with and without autism (age 4 through 18). The objective was to investigate the value of the Children's Social Behaviour Questionnaire (CSBQ), as a measure of subtle social skills, added to a measure of basic social skills with the Vineland Adaptive Behaviour Scales (VABS), in identifying children with ID with or without autism. METHOD: Children with mild and moderate ID, with and without autistic symptomatology were compared on basic social skills, measured with the Communication and Socialization domains of the VABS, and subtle social skills, measured with the CSBQ. RESULTS: Measuring basic social skills is not sufficient in differentiating between levels of ID. Communicative skills and subtle social skills, that concern overlooking activities or situations and fear of changes in the existing situation, seem to play a far greater role. Additionally, with respect to identifying autistic symptomatology, basic social skills do not contribute, as opposed to communicative skills and the tendency to withdraw from others. CONCLUSIONS: The results implicate that the CSBQ not only has specific value as a measure of subtle social skills to identify pervasive developmental disorders, but that the instrument also has a specific contribution to differentiating between the two levels of ID. Furthermore, our outcomes imply a slight difference between limitations in subtle social skills as mentioned by the AAMR (American Association on Mental Retardation 2002) and limitations in subtle social skills as seen in milder forms of pervasive developmental disorders. Clinical and theoretical implications will be discussed.

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls.

Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior.

Neurobiology and neuroimmunology of Tourette's syndrome: an update.

Tourette's syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics. While the pathogenesis at a molecular and cellular level remains unknown, structural and functional neuroimaging studies point to the involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits as the neuroanatomical site for Tourette's syndrome. Moreover, Tourette's syndrome has a strong genetic component, and considerable progress has been made in understanding the mode of transmission and in identifying potential genomic loci. Summaries of recent findings in these areas will be reviewed, followed by a critical overview of findings both supporting and challenging the proposed autoimmune hypothesis of Tourette's syndrome. We conclude that Tourette's syndrome is a heterogeneous disorder, and that immune factors may indeed be involved in some patients.

Face recognition in children with a pervasive developmental disorder not otherwise specified.

This study investigates the accuracy and speed of face recognition in children with a Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS; DSM-IV, American Psychiatric Association [APA], 1994). The study includes a clinical group of 26 nonretarded 7- to 10-year-old children with PDDNOS and a control group of 65 normally developing children of the same age. Two computerized reaction time tasks were administered: a face recognition task and a control task designed to measure the recognition of abstract visuospatial patterns. The latter were either easy or difficult to distinguish from a set of alternative patterns. The normally developing children recognized the faces much faster than the hardly distinguishable abstract patterns. The children in the PDDNOS group needed an amount of time to recognize the faces that almost equalled the time they needed to recognize the abstract patterns that were difficult to distinguish. The results suggest that, when processing faces, children with PDDNOS use a strategy that is more attention-demanding and, hence, less automatic or "Gestalt-like" than the one used by the control children. The results are discussed in the light of a theory that explains the development of coherent mental representations.

A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q.

A genome scan was performed on 164 Dutch affected sib pairs (ASPs) with attention-deficit/hyperactivity disorder (ADHD). All subjects were white and of Dutch descent and were phenotyped according to criteria set out in the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition. Initially, a narrow phenotype was defined, in which all the sib pairs met the full ADHD criteria (117 ASPs). In a broad phenotype, additional sib pairs were included, in which one child had an autistic-spectrum disorder but also met the full ADHD criteria (164 ASPs). A set of 402 polymorphic microsatellite markers with an average intermarker distance of 10 cM was genotyped and analyzed using the Mapmaker/sibs program. Regions with multipoint maximum likelihood scores (MLSs) >1.5 in both phenotypes were fine mapped with additional markers. This genome scan indicated several regions of interest, two of which showed suggestive evidence for linkage. The most promising chromosome region was located at 15q, with an MLS of 3.54 under the broad phenotype definition. This region was previously implicated in reading disability and autism. In addition, MLSs of 3.04 and 2.05 were found for chromosome regions 7p and 9q in the narrow phenotype. Except for a region on chromosome 5, no overlap was found with regions mentioned in the only other independent genome scan in ADHD reported to date.

Theory of mind in children with 'lesser variants' of autism: a longitudinal study.

BACKGROUND: The study investigated the development of theory-of-mind (ToM) knowledge in children with lesser variants' of autism (PDD-NOS) over a period thought to be critical for ToM development (i.e., 3 to 5 years of age). METHOD: The sample included 11 children with PDD-NOS; 23 normally developing children were included for cross-sectional comparison and 13 normally developing children for longitudinal comparison. The groups were comparable in verbal and non-verbal mental age. Two storybooks were used for repeated assessment of various aspects of the children's theory of mind: emotion recognition, the distinction between physical and mental entities, prediction of behaviour and emotions on the basis of desires and prediction of behaviour and emotions on the basis of beliefs. RESULTS: The results showed that the children with PDD-NOS had specific difficulties in understanding and predicting other people's emotions on the basis of situational cues, desires and beliefs. However, their ability to predict actions from beliefs and desires were relatively intact. Compared to the normally developing children, these children achieved lower levels of theory-of-mind knowledge, both at time of initial assessment and approximately 6 months later. CONCLUSIONS: The data suggest that the theory-of-mind development of children with PDD-NOS is both delayed and deviant. The growth pattem of theory-of-mind skills in children with PDD-NOS seemed to be qualitatively different from the growth pattern found in the group of normally developing children.

Is Tourette's syndrome an autoimmune disease?

We provide a review of recent research findings which support the involvement of autoimmunity in childhood-onset tic disorders, in particular the presence of antineuronal autoantibodies, D8/17 B lymphocyte overexpression, a marker of chorea associated with streptococcal infection, and possible beneficial effects of immunomodulatory intervention. One of the most controversial areas in this field is the validity of the proposed PANDAS concept. Some researchers have delineated a putatively unique subgroup of patients, from the spectrum of illness encompassing Tourette's syndrome and obsessive-compulsive disorder (OCD), whose tics and obsessive-compulsive symptoms are shown to arise in response to beta-hemolytic streptococcal infections. They designated it by the term pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Herein we additionally present pros and cons concerning the concept of PANDAS. Finally, recommendations for future research directions are given.

Elevated D8/17 expression on B lymphocytes, a marker of rheumatic fever, measured with flow cytometry in tic disorder patients.

OBJECTIVE: Elevated D8/17 expression on B lymphocytes is a known susceptibility marker of rheumatic fever. Previous studies have reported higher than usual D8/17 expression on B lymphocytes of patients with tic disorders. The purpose of this study was to assess D8/17 expression on B lymphocytes of tic disorder patients by using an objective method in which no operator variability was involved. METHOD: D8/17 expression on B lymphocytes was assessed with flow cytometry by using an immunoglobulin M (IgM) monoclonal D8/17-specific antibody in an unselected group of Dutch patients with tic disorders (N=33) and healthy volunteers (N=20). Binding of this monoclonal antibody was compared with binding of an irrelevant IgM monoclonal antibody, and the shift in mean fluorescence intensity of the D8/17-specific antibody compared to that of the irrelevant IgM monoclonal antibody was used as a measure of D8/17 overexpression. For the patients, Yale Global Tic Severity Scale scores were used to assess disease severity. RESULTS: D8/17 overexpression in the patient group (mean=16.8 arbitrary units, SD=30.5) was significantly higher than in the comparison group (mean=3.2, SD=3.0). A significant minority of the patients (N=13, 39.4%), however, had levels of D8/17 overexpression within the range of that of the healthy comparison subjects. Flow cytometric analysis did not indicate a separate subpopulation of D8/17-positive B cells. CONCLUSIONS: These data confirm the utility of D8/17 B cell overexpression as a peripheral blood marker in patients with tic disorders and are compatible with a streptococcus-related pathogenesis for at least a subgroup of patients with tic disorders.