Validation of the newly developed Sleep Screening Questionnaire Children and Adolescents (SSQ-CA) with objective sleep measures.

OBJECTIVES: Objectively validated pediatric sleep questionnaires covering a broader age range and different sleep disturbances are lacking, therefore we developed the Sleep Screening Questionnaire Children and Adolescents (SSQ-CA) and compared it with objective sleep parameters. METHODS: This child-reported questionnaire was developed by a multidisciplinary panel and face validated. In a cross-sectional prospective design, participants aged 6-17, answered the questionnaire twice with 21-28 days in between, wore actigraphy (AG) and kept a sleep diary for seven nights and home-polysomnography (PSG) for one of these nights. Exploratory factor analyses (EFA), reliability and validity assessments were performed. RESULTS: Of the 139 participants, 128 (F:47.7%, AG: n = 128, PSG: n = 59), were included in the analyses. Mean age: 11.3 years (SD: 2.9). EFA revealed 11 factors and 40 items loading above r = 0.4. Subscale internal consistency: 0.54-0.92. Subscale test-retest reliability: r = 0.71-0.87. Total sleep time (TST) from SSQ-CA on weekdays correlated with PSG (r = 0.48, p = 0.001) and with AG (r = 0.75, p < 0.001). The subscale total score for "Sleep duration and latency" correlated with TST from AG (r = -0.19, p = 0.03) and sleep latency (r = 0.31, p < 0.001), but not for PSG variables. The subscale "Awakenings" showed no correlation with objective measures whereas "Circadian rhythm" correlated to AG-derived mid-sleep time (r = 0.34, p < 0.001). CONCLUSIONS: The SSQ-CA shows adequate reliability for the 6-17-year-olds and acceptable criterion validity for two subscales. It appears to be a useful tool for screening for sleep disturbances in combination with objective tools as the subjective and objective parameters seem to uncover different aspects of sleep.

Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Is Tourette syndrome a rare condition?

Based on its prevalence, Tourette syndrome cannot be considered a rare disease. However, in this opinion article, we make the claim that it should nonetheless be considered as an orphan or neglected disease.

Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders: A Multinational Prospective Cohort Study.

OBJECTIVE: To examine prospectively the association between group A Streptococcus (GAS) pharyngeal exposures and exacerbations of tics in a large multicenter population of youth with chronic tic disorders (CTD) across Europe. METHODS: We followed up 715 children with CTD (age 10.7 ± 2.8 years, 76.8% boys), recruited by 16 specialist clinics from 9 countries, and followed up for 16 months on average. Tic, obsessive-compulsive symptom (OCS), and attention-deficit/hyperactivity disorder (ADHD) severity was assessed during 4-monthly study visits and telephone interviews. GAS exposures were analyzed using 4 possible combinations of measures based on pharyngeal swab and serologic testing. The associations between GAS exposures and tic exacerbations or changes of tic, OC, and ADHD symptom severity were measured, respectively, using multivariate logistic regression plus multiple failure time analyses and mixed effects linear regression. RESULTS: A total of 405 exacerbations occurred in 308 of 715 (43%) participants. The proportion of exacerbations temporally associated with GAS exposure ranged from 5.5% to 12.9%, depending on GAS exposure definition. We did not detect any significant association of any of the 4 GAS exposure definitions with tic exacerbations (odds ratios ranging between 1.006 and 1.235, all p values >0.3). GAS exposures were associated with longitudinal changes of hyperactivity-impulsivity symptom severity ranging from 17% to 21%, depending on GAS exposure definition. CONCLUSIONS: This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD. Specific workup or active management of GAS infections is unlikely to help modify the course of tics in CTD and is therefore not recommended.

Course of Tourette Syndrome and Comorbidities in a Large Prospective Clinical Study.

OBJECTIVE: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by tics and frequent comorbidities. Although tics often improve during adolescence, recent studies suggest that comorbid obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) tend to persist. This large prospective follow-up study describes the clinical course of tics and comorbidities during adolescence and the prevalence of coexisting psychopathologies. METHOD: The clinical cohort was recruited at the Danish National Tourette Clinic, and data were collected at baseline (n = 314, age range 5-19 years) and at follow-up 6 years later (n = 227) to establish the persistence and severity of tics and comorbidities. During follow-up, the Development and Well-Being Assessment (DAWBA) was used to diagnose coexisting psychopathologies. Repeated measures of severity scores were modeled using mixed effects models. RESULTS: Tic severity declined yearly (0.8 points, CI: 0.58-1.01, on the Yale Global Tic Severity Scale [YGTSS]) during adolescence; 17.7% of participants above age 16 years had no tics, whereas 59.5% had minimal or mild tics, and 22.8% had moderate or severe tics. Similarly, significant yearly declines in severity of both OCD (0.24, CI: 0.09-0.39, on the Yale-Brown Obsessive Compulsive Scale for Adults [Y-BOCS] and Yale-Brown Obsessive Compulsive Scale for Children [CY-BOCS]) and ADHD (0.42, CI: 0.32-0.52, DSM-IV) were recorded. At follow-up, 63.0% of participants had comorbidities or coexistent psychopathologies, whereas 37.0% had pure TS. CONCLUSION: Severity of tics, OCD, and ADHD were significantly associated with age and declined during adolescence. However, considerable comorbidities and coexisting psychopathologies persist throughout adolescence and require monitoring by clinicians.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Sequence analysis of SLITRK1 for var321 in Danish patients with Tourette syndrome and review of the literature.

Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by multiple motor and vocal tics and is often accompanied by comorbidities such as attention deficit hyperactivity disorder and obsessive-compulsive disorder. The complex etiology of TS and its co-occurrence with other disorders impedes linking genetic changes with disease segregation. One of the few genes that has been linked to TS is the SLITRK1 (Slit and Trk-like 1) gene, where four variations have been suggested as possible disease-associated changes. One of these variations, which has been reported in six unrelated TS patients, was a noncoding variant (var321) at the 3'-untranslated region of SLITRK1 within a conserved binding site for microRNA has-mir-189. To elucidate the potential role of var321 in disease pathogenesis, a cohort of 112 deeply phenotyped Danish TS patients was investigated for this variation. We could not detect var321 in the present cohort, suggesting that this is not a common variant among Danish TS patients.

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.

Validation of the presence of comorbidities in a Danish clinical cohort of children with Tourette syndrome.

Tourette syndrome (TS) is characterized by the presence of motor and vocal tics and is often accompanied by comorbid symptoms. We assessed the frequency of the comorbid symptoms obsessive-compulsive disorder obsessive-compulsive disorder, attention-deficit hyperactivity disorder (ADHD), rage attacks, sleeping disturbances, and depressive symptoms in a Danish clinical cohort of 314 children with TS using validated diagnostic instruments. For the assessment of symptoms of seasonal affective disorder and stuttering, we used a nonvalidated systematic interview. In total, only 10.2% of the children did not have any comorbid symptoms at all. If ADHD and/or obsessive-compulsive disorder were present, the rates of the comorbidities rage, symptoms of seasonal affective disorder, sleep disturbances, and depressive symptoms were significantly higher than if ADHD and/or obsessive-compulsive disorder were absent. The most severe tics were found in the group for which both ADHD and obsessive-compulsive disorder were present. Furthermore, there was a tendency toward more severe tics if other comorbid symptoms were present.