Tourette Syndrome Phenotype Research Articles

Dimensional Assessment of Depression and Anxiety in a Clinical Sample of Adults With Chronic Tic Disorder.

Among adults with Tourette syndrome, depression and anxiety symptoms are widely prevalent and consistently associated with poor quality of life. Important knowledge gaps remain regarding mood and anxiety dimensions of the adult Tourette syndrome phenotype. Taking a dimensional approach, this study sought to determine the prevalence, severity, and clinical correlates of depression and anxiety symptoms in a clinical sample of adults with Tourette syndrome and other chronic tic disorders. A retrospective chart review was conducted of all adults with a chronic tic disorder presenting to a tertiary care Tourette syndrome clinic between December 2020 and July 2022. Information extracted during chart review included data from scales administered as part of routine care: Quality of Life in Neurological Disorders (Neuro-QoL) Depression Short Form, Neuro-QoL Anxiety Short Form, Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale, Dimensional Obsessive-Compulsive Scale, and Yale Global Tic Severity Scale. Relationships between variables were examined by conducting between-group, correlation, and multivariable regression analyses. Data from 120 adult patients with a chronic tic disorder (77 men and 43 women) were analyzed. Neuro-QoL Anxiety scores were elevated in 66% of the cohort; Neuro-QoL Depression scores were elevated in 26%. Neuro-QoL Anxiety scores were significantly higher than general population norms, whereas Neuro-QoL Depression scores were not. After adjustment for covariates, depressive and anxiety symptom severity scores were significantly associated with each other and with obsessive-compulsive disorder symptom severity but not with tic severity. Sex-based differences emerged in the analyses. Among adults with chronic tic disorder, anxiety symptoms were more prevalent and severe than depressive symptoms, co-occurring psychiatric symptoms were more tightly linked with each other than with tic severity, and sex-based differences were evident.

Phenotype Development in Adolescents With Tourette Syndrome: A Large Clinical Longitudinal Study.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by frequent comorbidities and a wide spectrum of phenotype presentations. This study aimed to describe the development of phenotypes in TS and tic-related impairment in a large longitudinal study of 226 children and adolescents followed up after 6 years. The participants were clinically examined to assess tic severity and impairment, obsessive compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). The development in phenotypes changed toward less comorbidity with 40% TS-only (no OCD or ADHD) (TS without OCD or ADHD) at baseline and 55% at follow-up.Tic-related impairment was expected to improve with an age-related tic decline, but surprisingly the impairment score did not reflect the tic decline. Sex, vocal and motor tics, and OCD and ADHD severity were highly significantly correlated to the impairment score. Knowledge of TS phenotype development is used in clinical settings to guide patients and for genetic, etiological, and clinical research purposes.

Tic symptom dimensions and their heritabilities in Tourette's syndrome.

Gilles de la Tourette's syndrome (TS) is both genotypically and phenotypically heterogeneous. Gene-finding strategies have had limited success, possibly because of symptom heterogeneity. This study aimed at specifically investigating heritabilities of tic symptom factors in a relatively large sample of TS patients and family members. Lifetime tic symptom data were collected in 494 diagnosed individuals in two cohorts of TS patients from the USA (n=273) and the Netherlands (n=221), and in 351 Dutch family members. Item-level factor analysis, using a tetrachoric correlation matrix in SAS (v9.2), was carried out on 23 tic symptoms from the Yale Global Tic Severity Scale. Three factors were identified explaining 49% of the total variance: factor 1, complex vocal tics and obscene behaviour; factor 2, body tics; and factor 3, head/neck tics. Using Sequential Oligogenic Linkage Analysis Routine, moderate heritabilities were found for factor 1 (h2r=0.21) and factor 3 (h2r=0.25). Lower heritability was found for overall tic severity (h2r=0.19). Bivariate analyses indicated no genetic associations between tic factors. These findings suggest that (i) three tic factors can be discerned with a distinct underlying genetic architecture and that (ii) considering the low tic heritabilities found, only focusing on the narrow-sense TS phenotype and leaving out comorbidities that are part of the broader sense tic phenotype may lead to missing heritability. Although these findings need replication in larger independent samples, they might have consequences for future genetic studies in TS.

Co-morbid disorders in Tourette syndrome.

Tourette syndrome (TS) is often accompanied by other symptoms and syndromes. The two best-known co-morbidities are Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD), but also other conditions like rage-attacks, depression, and sleeping disturbances are frequent in persons with TS. Both in clinical cohorts and in population-based cohorts the prevalence of co-morbidities is high. The presence of co-morbid ADHD and/or OCD has an impact on psychosocial, educational, and neuropsychological consequences of TS and it is associated with higher rates of other co-morbid disorders, like rage, anxiety, and conduct disorders. The symptoms of a co-morbid disorder might appear prior to the time that tics reach clinical attention. The TS phenotype probably changes during the course of the disease. The exact aetiology of the co-occurrence of co-morbid disorders and TS is not known, but they probably all are neurotransmitter disorders. European guidelines recommend first-choice pharmacological treatment, but randomised double-blinded trials are needed. Professionals need to be aware of the close relationship between TS and co-morbidities in order to give the patients the right treatment and support.

Co-Morbid Disorders in Tourette Syndrome

Tourette syndrome (TS) is often accompanied by other symptoms and syndromes. The two best-known co-morbidities are Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD), but also other conditions like rage-attacks, depression, and sleeping disturbances are frequent in persons with TS. Both in clinical cohorts and in population-based cohorts the prevalence of co-morbidities is high. The presence of co-morbid ADHD and/or OCD has an impact on psychosocial, educational, and neuropsychological consequences of TS and it is associated with higher rates of other co-morbid disorders, like rage, anxiety, and conduct disorders. The symptoms of a co-morbid disorder might appear prior to the time that tics reach clinical attention. The TS phenotype probably changes during the course of the disease. The exact aetiology of the co-occurrence of co-morbid disorders and TS is not known, but they probably all are neurotransmitter disorders. European guidelines recommend first-choice pharmacological treatment, but randomised double-blinded trials are needed. Professionals need to be aware of the close relationship between TS and co-morbidities in order to give the patients the right treatment and support.

Analysis of the BTBD9 and HTR2C variants in Chinese Han patients with Tourette syndrome

Variants of the BTB/POZ domain-containing protein 9 gene (BTBD9) (rs4714156, rs9357271, and rs9296249) and the serotonin 5-HT-2C receptor gene (HTR2C) (rs518147 and rs3813929) were reported to be associated with Tourette syndrome (TS) in White population recently. To examine the association between variants of the BTBD9 and the HTR2C genes and patients with TS among a Chinese Han population, 110 patients with TS and 440 sex-matched, age-matched, and ethnicity-matched healthy controls underwent sequencing and association analysis. There was a statistically significant association between the variant rs9296249 of the BTBD9 gene and the TS phenotype. However, no statistically significant associations were found between the other four variants (rs4714156, rs9357271, rs518147, and rs3813929) and the TS phenotype (P>0.05). Larger-scale studies are warranted to further define the relationship between variant rs9296249 of the BTBD9 gene and the risk of developing TS.

Reversible autism and intellectual disability in children

Studies on young children with reversible autism and intellectual disability are discussed. Present evidence suggests a clear cause in a minority of cases including early institutionalization, Landau and Kleffner syndrome, and other early onset epilepsies, intrauterine rubella, and blindness. The majority of cases have normal laboratory results and some have early onset Tourette syndrome. Preliminary data of a follow-up study of this last group are reported in 15 patients suggesting the possibility of two subgroups, one represented by early onset Tourette syndrome phenotype, characterized by a positive family history, and by its appearance at the same time as regression and persistence into adolescence while the other of a different nature. Genetic studies could be of help to clarify this issue and support a diagnosis of favorable outcome in young children.

Evaluation of the LIM homeobox genes LHX6 and LHX8 as candidates for Tourette syndrome

The etiology and pathophysiology of Tourette Syndrome (TS) remain poorly understood. Multiple lines of evidence suggest that a complex genetic background and the cortico-striato-thalamo-cortical circuit are involved. The role of Lhx6 and Lhx8 in the development of the striatal interneurons, prompted us to investigate them as novel candidate genes for TS. We performed a comparative study of the expression of Lhx6 and Lhx8 and investigated genetic association with TS using two samples of trios (TSGeneSEE and German sample - 222 families). We show that Lhx6 and Lhx8 expression in the forebrain is evolutionarily conserved, underlining their possible importance in TS-related pathophysiological pathways. Our tagging-single nucleotide polymorphism (tSNP)-based association analysis was negative for association with LHX8. However, we found positive association with LHX6 in the TSGeneSEE sample (corrected P-value = 0.006 for three-site haplotype around SNP rs3808901) but no association in the sample of German families. Interestingly, the SNP allele that was identified to be significantly associated in the TSGeneSEE dataset, showed an opposite trend of transmission in the German dataset. Our analysis of the correlation of the LHX6 region with individual ancestry within Europe, revealed the fact that this particular SNP demonstrates a high degree of population differentiation and is correlated with the North to South axis of European genetic variation. Our results indicate that further study of the LHX6 gene in relation to the TS phenotype is warranted and suggest the intriguing hypothesis that different genetic factors may contribute to the etiology of TS in different populations, even within Europe.

The genetics of Tourette syndrome

Tourette syndrome is a complex neurological disorder that usually becomes evident between 4 and 18 years of age. The disorder is characterized by chronic motor and phonic tics, often with a variety of behavioural comorbidities; in particular, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and impulse control disorder. The cause of Tourette syndrome is poorly understood. Although environmental factors are proposed to have a role, genetic factors are thought to be the primary contributors to the pathogenesis of this disorder. However, identification of the causative gene mutations or risk alleles has proved to be difficult. Early studies on the genetics of Tourette syndrome focused on multigenerational lineages and suggested Mendelian inheritance, but subsequent segregation analyses point to a more-complex inheritance pattern. A monogenic inheritance model has been proposed following the identification of rare genetic mutations associated with the Tourette syndrome phenotype. Although no specific mutations have found to directly cause Tourette syndrome, genetic findings may enable identification of the affected pathways, and could lead to the development of new treatment strategies. In this Review, we provide an overview of the genetics of Tourette syndrome and highlight how this knowledge has improved our understanding of the possible pathogenic mechanisms of this neurological disorder.

PA.02 Tourettism in adults

AimsWe investigated cases of Tourette syndrome (TS) with atypical chronology in terms of age of onset. According to DSM IV-TR onset of TS is by the age of 18. Most...

Tourette's syndrome in adults

Tourette's syndrome (TS) is defined as motor and phonic tics starting before age 18 years, and therefore most studies have focused on childhood TS, whereas the disorder in adults has not been well characterized. We reviewed medical records of all new TS patients referred to our Movement Disorders Clinic over the past 5 years, 19 years or older on initial evaluation and compared them with 100 TS patients 18 years or younger. The mean age at initial visit of 43 adult TS patients was 58.8 ± 6.7 years, whereas the mean age at initial visit of children with TS was 12.9 ± 2.0 years. Of the adult TS patients, 35 (81.4%) had a history of tics with onset before the age of 18 years (mean age at onset: 8.5 ± 3.4 years), with 8 (18.6%) reporting first occurrence of tics after the age of 18 years (mean age at onset: 37.8 ± 13.2 years). Only two (4.7%) patients reported tic onset after the age of 50 years. Adult patients with TS had significantly more facial and truncal tics, and a greater prevalence of substance abuse and mood disorders, but fewer phonic tics, and lower rates of attention-deficit hyperactivity disorder and oppositional behavior than children with TS. Adult TS largely represents reemergence or exacerbation of childhood-onset TS. During the course of TS, phonic and complex motor tics, self-injurious behaviors, and attention-deficit hyperactivity disorder tend to improve, but facial, neck, and trunk tics dominate the adult TS phenotype. In addition, adults with TS are more likely to exhibit substance abuse and mood disorders compared with children with TS.

Thinning of the Motor–Cingulate–Insular Cortices in Siblings Concordant for Tourette Syndrome

Fraternal twin studies on normal subjects have demonstrated low heritability (intra-class correlation coefficient) estimates for frontal brain regions (r = 0.43). Here we aimed to investigate the relatedness/similarity estimates of the frontal brain regions in fraternal subjects concordant for Tourette syndrome (TS). We sought to identify regional brain similarities between siblings concordant for TS as an exploratory step towards the identification of potential brain structures involved in the TS phenotype. The identified brain structures may then serve in subsequent molecular genetic and linkage studies. In addition, we regressed cortical thickness and TS clinical severity scores to assess the relation between TS clinical symptoms and cortical structures. Sixteen sibling pairs concordant for TS were scanned using a 1.5 T magnetic resonance imaging scanner (age range 10-25, mean 17.19 +/- 4.1). Brain morphology was assessed using the fully automated Civet pipeline at the Montreal Neurological Institute. TS was assessed using the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Yale Global Tic Severity Scale (YGTSS) and the Goetz Tic Scale. We report high relatedness/similarity estimates for fraternal siblings concordant for TS (r = 0.86-0.60) in the middle frontal-motor/cingulate/insular cortices. Regression analysis revealed significant negative correlations in the right insula with the YGTSS (r = -0.41, F = 6.09, P < 0.02) and the left cingulated cortex with the (CY-BOCS) (r = -0.35, F = 4.30, P < 0.05). Since previous findings have concluded that normal fraternal siblings are less alike in frontal cortices, the present findings may be attributed to TS. We speculate that the high ICC between siblings and the negative correlation between TS symptoms severity and cortical thickness measurements are related to the disturbances in the maturation of the motor-cingulate-insular cortical neural system that mediate self-regulatory processes. Such delayed maturation may consequently contribute to the development of TS by releasing motor and vocal tics from regulatory control. These findings may have important genetic implications.

The Gilles de la Tourette Syndrome: a principal component factor analytic study of a large pedigree

The genetics and phenotypes of Gilles de la Tourette syndrome are complicated. Once indicated to be inherited as a single major autosomal dominant condition, several areas of interest on many chromosomes and one gene have been identified for Gilles de la Tourette syndrome, but no results have been replicated. Factor analytic studies suggest that there are more than one Gilles de la Tourette syndrome phenotype and it is not a unitary condition. To characterize Gilles de la Tourette syndrome phenotypes in a group of individuals who underwent a complete genome scan. We studied 85 members of a multiply affected multigenerational kindred, of whom 69 displayed Gilles de la Tourette syndrome-related symptoms (tics, obsessive-compulsive behaviours, obsessive-compulsive symptoms, attention deficit hyperactivity symptoms), using first a hierarchical cluster analysis followed by a principal component factor analysis. Three significant factors resulted from our analysis, accounting for approximately 42% of the symptomatic variance: Factor 1 (predominantly 'pure tics'), Factor 2 (predominantly 'attention deficit hyperactivity disorder and aggressive behaviours') and Factor 3 (predominantly 'depression-anxiety-obsessional symptoms and self-injurious behaviours'). Different kinds of tics occurred in all three factors. Only frowning/raising eyebrows and sniffing/smelling loaded significantly on both Factors 1 and 3. Our results give further evidence that the genetics of Gilles de la Tourette syndrome is complex and suggest that Gilles de la Tourette syndrome is not a unitary condition, thus confirming the results of earlier studies which have described several Gilles de la Tourette syndrome phenotypes. Although a genome scan on the pedigree reported three areas of interest and the present study found three factors, further studies would have to be undertaken to elucidate whether the three factors 'mapped' with the genetic data. Possible reasons for our findings and suggestions for future research are discussed.

Genetics and Epidemiology of Tourette Syndrome

Although the genetic basis of Tourette syndrome is well established, uncertainty about how best to define and assess the Tourette syndrome phenotype has hampered efforts to identify the genes responsible for susceptibility to the disorder. In addition, such efforts have typically been underpowered or were undertaken before the technology was available to perform systematic genome-wide genetic investigations. The Tourette Syndrome Association International Consortium on Genetics was formed by more than a dozen research groups from around the world to develop common approaches to phenotyping Tourette syndrome and to pool samples for uniform, well-powered genetic investigations. Several recent advances, including the completion of genome-wide scans of affected sib-pairs and large families, show real promise for identifying Tourette syndrome susceptibility genes. In this review, we describe the key epidemiologic, linkage, and association studies in Tourette syndrome and illustrate the strategies currently being used to identify Tourette syndrome genes.

Complex segregation analysis for obsessive compulsive disorder and related disorders

Complex segregation analysis was applied to a sample of 107 Italian families with probands with obsessive compulsive disorder (OCD), using regressive logistic models to test for possible models of genetic transmission. We used two different phenotypic definitions of affection: 1) OCD; and 2) OCD plus Tourette's syndrome/chronic motor tics (CMT). Because of the potential relationship between OCD, Tourette's syndrome (TS), and other tic disorders, we considered these diagnoses to be determined by the same liability in subsequent steps of the analysis. For the 107 OCD families, the best fit was a dominant model of transmission (with a higher penetrance for females). When the phenotype boundaries were widened (OCD + CMT + TS), an unrestricted model of transmission became the best fit. We concluded that additional data are needed to support the hypothesis that Tourette's syndrome and OCD share a common etiology: on the basis of clinical and epidemiological considerations, the OCD phenotype probably presents a higher level of heterogeneity than the TS phenotype, and it could be regulated through different etiologic pathways.

Complex segregation analysis for obsessive compulsive disorder and related disorders.

Complex segregation analysis was applied to a sample of 107 Italian families with probands with obsessive compulsive disorder (OCD), using regressive logistic models to test for possible models of genetic transmission. We used two different phenotypic definitions of affection: 1) OCD; and 2) OCD plus Tourette's syndrome/chronic motor tics (CMT). Because of the potential relationship between OCD, Tourette's syndrome (TS), and other tic disorders, we considered these diagnoses to be determined by the same liability in subsequent steps of the analysis. For the 107 OCD families, the best fit was a dominant model of transmission (with a higher penetrance for females). When the phenotype boundaries were widened (OCD + CMT + TS), an unrestricted model of transmission became the best fit. We concluded that additional data are needed to support the hypothesis that Tourette's syndrome and OCD share a common etiology: on the basis of clinical and epidemiological considerations, the OCD phenotype probably presents a higher level of heterogeneity than the TS phenotype, and it could be regulated through different etiologic pathways.

Linkage study of the dopamine D5 receptor gene and Gilles de la Tourette syndrome

A defect in the dopamine system has been hypothesized as the etiological defect in Gilles de la Tourette syndrome (TS). In this report, we test the hypothesis that the dopamine D5 receptor locus (DRD5) is linked to the genetic susceptibility to TS in five families studied in Canada. We tested for linkage to the dopamine D5 receptor gene using a microsatellite polymorphism located in the same cosmid clone. Using an autosomal dominant model with reduced penetrance, we were able to exclude linkage in four of the five families for the TS and chronic multiple tics (CMT) phenotype. Also, no evidence for linkage was found using nonparametric methods in all five families.

Clinical evidence of genomic imprinting in Tourette's syndrome

Recent genetic studies of Tourette's syndrome (TS) have suggested a sex-specific expression of TS behaviors but not a sex-associated difference in their transmission. In a retrospective study designed to assess the influence of gender of the affected parent on childhood TS phenotype, we compared unmedicated TS subjects with patrilineal (n = 25) or matrilineal (n = 25) inheritance of TS, as determined by family history methodology, with respect to demographic variables, temporal profile of tic evolution, and clinical ratings of tics and associated behaviors, particularly obsessive-compulsive symptoms and attention deficit hyperactivity disorder (ADHD). Maternal transmission of TS was characterized by trends toward greater motor tic complexity and more frequent noninterfering rituals (p < 0.05); paternal transmission was associated with increased vocal tic frequency (p = 0.01), an earlier onset of vocal tics relative to motor tics (p < 0.01), and more prominent ADHD behaviors, including motor restlessness (p < 0.01). These findings are consistent with genomic imprinting in TS. Confirmation of this phenomenon promises not only to advance understanding concerning the genetic link between TS and ADHD but may also help to explain the apparent fit of competing models of genetic transmission in TS.

Bilineal transmission in Tourette's syndrome families

We assessed the frequency of bilineal (from maternal and paternal sides) transmission of Tourette's syndrome (TS) in two groups of pedigrees: (1) 39 high-density families in which five or more relatives were reported to have TS, and (2) the families of 39 consecutively ascertained probands referred for evaluation of TS. We used two designations for the TS phenotype (tics, tics or obsessive-compulsive behavior [OCB]), and we attempted to verify bilineal transmission with direct examinations. For the high-density pedigrees, bilineal transmission was evident in 33% (considering tics) and 41% (considering tics or OCB) of families, which was confirmed by examination in 77% of the kindreds. For the consecutive pedigrees, bilineal transmission was seen in 15% (tics) and 26% (tics or OCB) of families, which was verified by examination in 66% of the kindreds. Both parents of the proband were affected (tics or OCB) in 38% of the high-density pedigrees and 10% of the consecutive pedigrees. For the high-density families only, the frequency of bilineal transmission appeared to be related to the proband's severity of TS, and for both pedigree groups, the frequency of both parents being affected was higher in families in which the proband's symptoms were most severe. Our findings support the contention that bilineal transmission and homozygosity are common in TS. These genetic phenomena might play a role in determining severity of illness and may explain current difficulties in localizing the gene defect by linkage analysis.