Piotr Janik

Background/Objectives: Behavioral disturbances are common in Gilles de la Tourette syndrome (GTS) and can include risky impulsive behaviors (RIBs), but RIB classification remains unclear. This study aims to define the epidemiology of RIB in GTS and to assess its relationship with tic severity and the prevalence of comorbid psychiatric disorders. Methods: The study was structured as a cross-sectional registration study, with each patient enrolled into the database during a single clinical visit. The study included 365 participants with GTS (272 males, 74.5%), of whom 278 (76.2%) were children and adolescents. The mean age at evaluation was 14.4 ± 9.8 years (range 4–64). Clinical data on RIB were obtained during routine outpatient visits using semi-structured questionnaires developed by the authors. Results: RIB was reported in 64 (17.6%) patients with GTS, a group composed of 19 (29.7%) adults and 45 (70.3%) minors. RIB commenced at a mean age of 8.1 ± 5.4 years (range 2–30). The mean age at onset of RIB was 2.6 ± 4.9 years after the onset of tics. Of the patients with RIB, 84.4% had at least one comorbid psychiatric disorder, whereas 15.6% of RIB patients had no psychiatric comorbidity. Multivariable logistic regression showed significant associations between RIB and YGTSS (p = 0.02, OR = 1.02), ADHD (p < 0.01, OR = 2.91), and ODD (p = 0.01, OR = 3.02). Conclusions: RIB may occur early in the course of GTS, typically beginning during childhood, and was identified in 17.6% of patients. Its occurrence was associated with the presence of comorbid psychiatric disorders, particularly ADHD and ODD. Greater tic severity was also statistically associated with RIB, although the effect was small and of limited clinical significance.

Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3, and CELSR3. Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

Neurologia i Neurochirurgia Polska

Background/Objectives: Behavioral disturbances are a common phenomenon associated with Gilles de la Tourette syndrome (GTS), which can manifest as non-obscene socially inappropriate behaviors (NOSIBs). The classification of NOSIB has not yet been clearly established. The objective of this study was to determine the frequency, age of onset, and clinical correlation of NOSIB with tic severity and the prevalence of comorbid psychiatric disorders in individuals with GTS. Methods: A total of 365 participants (272 male, 74.5%) with GTS were included in the study. Of these, 278 (76.2%) were children and adolescents. The mean age of the participants at evaluation was 14.4 ± 9.8 years, with a range of 4 to 64 years. The clinical data of NOSIB were collected during a routine, ambulatory examination using half-structured questionnaires developed by the authors. Results: NOSIB was observed in 86 patients with GTS, representing a prevalence of 23.6%. NOSIB commenced at a mean age of 6.6 ± 4.1 years (range 2–19). The mean age at onset of NOSIB was 1.4 ± 3.7 years after the onset of tics, with 18 cases (26.1%) preceding tics and 13 cases (18.8%) starting at the same age as tics. The results of the multivariate analysis confirmed the associations between NOSIB and YGTSS (p = 0.02) and coprophenomena (p < 0.01), as well as ADHD (p < 0.01), ODD (p = 0.01), ASD (p < 0.01), and anxiety disorders (p = 0.02). Conclusions: NOSIB is an early symptom of GTS that typically manifests in childhood and occurs in approximately a quarter of patients. Tic severity and the presence of psychiatric comorbidities, which indicate a more severe disease course, may serve as risk factors for NOSIB.

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental psychiatric disorder with complex and elusive etiology with a significant role of genetic factors. The aim of this study was to identify structural variants that could be associated with familial GTS. The study group comprised 17 multiplex families with 80 patients. Structural variants were identified from whole-genome sequencing data and followed by co-segregation and bioinformatic analyses. The localization of these variants was used to select candidate genes and create gene sets, which were subsequently processed in gene ontology and pathway enrichment analysis. Seventy putative pathogenic variants shared among affected individuals within one family but not present in the control group were identified. Only four private or rare deletions were exonic in LDLRAD4, B2M, USH2A, and ZNF765 genes. Notably, the USH2A gene is involved in cochlear development and sensory perception of sound, a process that was associated previously with familial GTS. In addition, two rare variants and three not present in the control group were co-segregating with the disease in two families, and uncommon insertions in GOLM1 and DISC1 were co-segregating in three families each. Enrichment analysis showed that identified structural variants affected synaptic vesicle endocytosis, cell leading-edge organization, and signaling for neurite outgrowth. The results further support the involvement of the regulation of neurotransmission, neuronal migration, and sound-sensing in GTS.

Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Gilles de la Tourette syndrome (GTS) and other Tic Disorders (TDs) have a substantial genetic component with their heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients, their families, and control samples (n = 278). The model is based on the overrepresentation of coding and non-coding genetic variants in and in the vicinity of genes selected from a set of 84 genes previously indicated as putatively associated with GTS. In the discovery phase, based on a variant burden test between unrelated GTS cases (n = 37) and a database of local allele frequencies 10 genes were selected for the model ( CHADL , DRD2 , MAOA , PCDH10 , HTR2A , SLITRK5 , SORCS3 , KCNQ5 , CDH9, and CHD8 ). Variants in these genes (n = 7654) with a median minor allele frequency in the non-Finnish European population of 0.02 were integrated into an additive classifier. This risk model was then applied to healthy and GTS-affected individuals from 23 families and 100 unrelated healthy samples from the Polish population (AUC-ROC=0.62, p=0.02). Application of the oligogenic model to a group of patients with other tic disorders revealed a continuous increase of the oligogenic score with healthy individuals with the lowest mean, then patients with other tic disorders, then GTS patients, and finally with severe GTS cases with the highest oligogenic score. Results were also overlapped with Psychiatric Genomics Consortium (PGC) GWAS data and we found no significant overlap between the common variant signal and our oligogenic model (p=0.21). Therefore obtained results were compared with the polygenic risk score built from the PGC GWAS data, which revealed a significant contribution of common variant background in severe GTS cases. Overall, we leveraged WGS data to construct a GTS/TDs risk model based on variants that may cooperatively contribute to the etiology of these disorders. This study provides evidence that typical and severe adult GTS as well as other tic disorders may exist on a single spectrum in terms of their genetic background.

Coprolalia and echophenomena repeated in the patients’ mind (CTPh—cognitive tic-like phenomena) have been rarely recognized as part of Gilles de la Tourette syndrome (GTS) symptomatology and their assignment to tics, OCD or other psychopathologies has not been settled. The aim of the paper was to assess the incidence and clinical associations of CTPh in GTS, and to establish if CTPh belong to the tic spectrum. We performed a prospective, one-registration study on a cohort of 227 consecutive patients with GTS. CTPh were diagnosed during the interview and defined as brief, sudden, involuntary thoughts that had corresponding complex vocal tics. CTPh occurred at some point in the lives of 34 (15.0%) patients. The median age at onset of CTPh was 14.5 years (IQR: 10.5–17.5). CTPh were found more frequently in adults, with the most frequent onset in adolescence (44.1%). Four mental phenomena resembling tics were recognized: echolalia (n = 17), coprolalia (n = 16), palilalia (n = 13) and repeating of words in the mind (n = 7). The older the age of patients, the more severe tics, and anxiety disorder significantly correlated with CTPh. CTPh may be considered as a part of tic spectrum with a substantial impact of anxiety disorder. CTPh are a late and age-related symptom of GTS.

Introduction: Patients with Gilles de la Tourette syndrome (GTS) may experience blocking tics (BTs) defined as recurrent, brief cessations of motor acts. The aim of this study was to assess the prevalence, age of onset, and clinical correlates of BTs in GTS patients.Materials and Methods: We performed a one-time registration study in a cohort of 195 consecutive GTS patients aged 5–66 years (mean age: 15.0 ± 9.2; 47 females, 24.1%). All patients were personally interviewed and examined.Results: At least one BT occurred at some point in the lifetime of 73 patients (37.4%) with a mean age of onset of 10.4 ± 5.9 years. BTs occurred an average of 4.8 ± 5.3 years after tic onset. The most common BT was cessation of walking (n = 59, 80.8%), followed by speech (n = 19, 26.0%), running (n = 18, 24.7%), and writing (n = 9, 12.3%). Most of the patients (n = 52, 71.2%) reported cessation of only one activity. Clinical associations of BTs included more severe tics, overall greater number of tics, and, to a lesser extent, higher age at evaluation and comorbid obsessive-compulsive disorder.Conclusions: BTs represent complex tics, early and common symptoms of GTS, and are associated with a more severe form of GTS.