Long-Term Follow-up of Patients with Tourette's Syndrome.

BACKGROUND: Tourette's Syndrome (TS) is a childhood-onset movement disorder marked by the chronic presence of motor and vocal tics. Research shows that tics associated with TS tend to fade in severity for some (but not all) affected youth, though psychiatric comorbidities that commonly accompany TS may be more persistent. The long-term outcomes of individuals with TS have not been well characterized. OBJECTIVE: To characterize long-term clinical outcomes of individuals with TS. METHOD: We conducted a long-term (25-32 years) follow-up study of 45 patients with TS who presented to the Tourette's and Tic Disorders Clinic within the Department of Psychiatry at the University of California San Francisco Medical Center, which was staffed by the first author (Thomas L. Lowe, MD [T.L.L.]), between 1983 and 1990. Baseline data were obtained via chart review, and follow-up data were obtained by self-report surveys. RESULTS: Participants generally reported good psychosocial functioning, attainment of significant social milestones (academic attainment, gainful employment, marriage), and high subjective quality of life. The vast majority of participants (82%) reported improvement in their tics over time, though a significant minority continued to experience at least mild tic-related impairment (26%-40%, depending on metric). Lifetime rates of attention deficit hyperactivity disorder (ADHD) and anxiety disorders, including obsessive-compulsive disorder, were greater than in the general US population. Robust predictors of follow-up outcomes were not found. CONCLUSIONS: These findings reflect a positive overall long-term prognosis for individuals with TS. Providing information about this prognosis at the time of diagnosis may decrease distress in affected individuals and their families. Future studies using planned longitudinal designs that address potential confounds of survey nonresponse are needed to detail long-term outcomes of individuals with TS more precisely.

Tic symptom profiles in subjects with Tourette Syndrome from two genetically isolated populations.

BACKGROUND: Tourette Syndrome (TS) has a complex etiology and wide variability in phenotypic expression. Identifying underlying symptom patterns may be useful for etiological and outcome studies of TS. METHODS: Lifetime tic and related symptom data were collected between 1996 and 2001 in 121 TS subjects from the Central Valley of Costa Rica and 133 TS subjects from the Ashkenazi Jewish (AS) population in the US. Subjects were grouped by tic symptoms using an agglomerative hierarchical cluster analysis. Cluster membership was tested for association with available ancillary information (age of onset, tic severity, comorbid disorders, medication treatment and family history). RESULTS: Cluster analysis identified two distinct groups in each sample, those with predominantly simple tics (cluster 1), and those with multiple complex tics (cluster 2). Membership in cluster 2 was correlated with increased tic severity, global impairment, medication treatment, and presence of comorbid obsessive-compulsive symptoms in both samples, and with family history of tics, lower verbal IQ, earlier age of onset, and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in the AS sample. CONCLUSIONS: This study provides evidence for consistent and reproducible symptom profiles in two independent TS study samples. These findings have implications for etiological studies of TS.

Association between maternal smoking and increased symptom severity in Tourette's syndrome.

OBJECTIVE: Substantial evidence suggests that both environmental and genetic factors contribute to the development and clinical expression of Tourette's syndrome. Although genetic studies of Tourette's syndrome are common, studies of environmental factors are relatively few and have not identified consistent risk factors across studies. This study examines in a large cohort of subjects (N=180) the relationship between prenatal/perinatal adverse events with Tourette's syndrome severity as determined by tic severity and rates of commonly comorbid disorders such as obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and self-injurious behavior. METHOD: Tic severity, OCD, ADHD, self-injurious behavior, and exposure to a variety of prenatal/perinatal events were systematically assessed in all subjects enrolled in three genetic studies of Tourette's syndrome. Using linear and logistic regression, a best-fit model was determined for each outcome of interest. RESULTS: Prenatal maternal smoking was strongly correlated with increased tic severity and with the presence of comorbid OCD in these Tourette's syndrome subjects. Other variables, such as paternal age and subject's birth weight, were significantly but less strongly associated with increased symptom severity. The authors found no association between symptom severity and hypoxia, forceps delivery, or hyperemesis during pregnancy, which have been previously identified as risk factors. CONCLUSIONS: This study identifies prenatal maternal smoking as a strong risk factor for increased symptom severity in Tourette's syndrome.

Genetic studies of neuropsychiatric disorders in Costa Rica: a model for the use of isolated populations.

The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive-compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.

Prevalence and clinical correlates of explosive outbursts in Tourette syndrome.

The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified.

CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses.

Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.