Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome.

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.

Genomic variants and inferred biological processes in multiplex families with Tourette syndrome.

BACKGROUND: Tourette syndrome is a developmental neuropsychiatric disorder. Its etiology is complex and elusive, although an important role of genetic factors has been established. The aim of the present study was to identify the genomic basis of Tourette syndrome in a group of families with affected members in 2 or 3 generations. METHODS: Whole-genome sequencing was performed followed by co-segregation and bioinformatic analyses. Identified variants were used to select candidate genes, which were then subjected to gene ontology and pathway enrichment analysis. RESULTS: The study group included 17 families comprising 80 patients with Tourette syndrome and 44 healthy family members. Co-segregation analysis and subsequent prioritization of variants pinpointed 37 rare and possibly pathogenic variants shared among affected individuals within a single family. Three such variants, in the ALDH2, DLD and ALDH1B1 genes, could influence oxidoreductase activity in the brain. Two variants, in SLC17A8 and BSN genes, were involved in sensory processing of sound by inner hair cells of the cochlea. Enrichment analysis of genes whose rare variants were present in all patients from at least 2 families identified significant gene sets implicated in cell-cell adhesion, cell junction assembly and organization, processing of sound, synapse assembly, and synaptic signalling processes. LIMITATIONS: We did not examine intergenic variants, but they still could influence clinical phenotype. CONCLUSION: Our results provide a further argument for a role of adhesion molecules and synaptic transmission in neuropsychiatric diseases. Moreover, an involvement of processes related to oxidative stress response and sound-sensing in the pathology of Tourette syndrome seems likely.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

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.

Is deep brain stimulation effective in Huntington's Disease? - a systematic literature review.

INTRODUCTION: Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Substantial for a diagnosis of the disease are motor disorders, with chorea as a hallmark symptom. Other disease manifestations include cognitive dysfunction and psychiatric disorders. Currently, pharmacological treatment plays the most important role in the therapy of HD patients. However, deep brain stimulation (DBS) is considered a potential therapeutic option. AIM OF THE STUDY: Systematic review of current literature on DBS efficacy and safety in the management of motor, behavioural and cognitive functions in patients with HD. MATERIAL AND METHODS: A systematic review was conducted with the use of the Scopus database and the following search criteria: TITLE (huntington*) AND TITLE-ABS-KEY ('deep brain stimulation' OR 'neuromodulation'). Our search criteria included original studies with at least five patients, reporting any motor, cognitive and/or behavioural, and functional assessment data with at least a 6-month follow-up. Finally, four selected publications were analysed. RESULTS: In all analysed publications, we found a statistically significant improvement of Unified Huntington's Disease Rating Scale (UHDRS) chorea subscore by an average of 40, to over 60% after DBS implantation. Heterogeneous results were obtained for UHDRS total motor score. DBS did not improve functional capacity of HD patients in the analysed studies. We found no systematic assessment concerning the effect of DBS in HD on behaviour, cognition or speech. CONCLUSIONS: DBS implantation could be considered as a therapeutic option for patients with severe, drug-resistant chorea. However, the evidence for this is limited. To date, no high-quality data based on randomised controlled trials supports the long-term safety and efficacy of DBS in HD. This treatment option should therefore currently be considered as investigational.

Tonic Tics in Gilles de la Tourette Syndrome.

AIM: Tonic tics (TTs) are a part of a clinical picture of Gilles de la Tourette syndrome (GTS) and manifest themselves as sustained and isometric contraction of a muscle group devoid of the movement effect or accompanied by only slight visible motion. The aim of this study was to evaluate the prevalence and phenomenology of TTs, and to assess the clinical associations of TTs with tic severity and comorbidities in patients with GTS. METHODS: We performed a one-time registration study in a cohort of 241 consecutive outpatients with GTS aged 5 to 50 years (188 males, 153 patients under the age of 18 years). All patients were personally interviewed and examined. RESULTS: TTs occurred in 85.2% of adults and 63.9% of children and adolescents. Most frequently reported types of TTs were tensing of the abdomen (58.7%), neck (52.7%), and upper limbs (50.3%). Multivariate statistical analysis showed a significant correlation between TTs and the total number of simple tics, total number of complex tics, and age at evaluation. In the group of children and adolescents, an additional significant variable was the duration of GTS. In the group of adults, significant parameters were total number of simple tics, total number of complex tics, peak tic severity ever experienced, premonitory urges, and the presence of dystonic tics. CONCLUSION: TTs belong to the tic spectrum, common and early symptoms of GTS, are associated with overall a greater number of tics which are more severe, and with more comorbidities.

Clinical phenotype heterogeneity in a family with ε-sarcoglycan gene mutation.

AIM OF THE STUDY: This paper describes six cases of patients with myoclonus-dystonia syndrome who are members of a family in which an SGCE gene mutation has been confirmed. CLINICAL RATIONALE FOR THE STUDY: Myoclonus-dystonia syndrome is a very rare disease, with an incidence in Europe of about 2 in every million. Due to the fact that only a few case reports of this illness are accessible in the literature, the material we collected seems to be valuable for clinical practice. MATERIALS AND METHODS: A history was taken, and physical and genetic examinations of the patients were performed. Furthermore, the clinical examination of three patients was video-recorded. RESULTS: The clinical picture of the disease varied significantly between the described individuals, from a healthy carrier of the SGCE mutation to patients presenting mild to moderate symptoms. The differences concerned the age at onset of the disease, the initial symptoms, the intensity of involuntary movements, and the predominant symptoms. In addition to the typical movement disorders which are myoclonus and dystonia, in the described family there was also the coexistence of epilepsy, obsessive-compulsive behaviour, dyslexia, dysgraphia, non-harmonious development of cognitive processes, as well as mild phenotypic features of muscular dystrophy. The mutation (NM_001099401.2:c.806-809delACTG) found in the presented family has not been described elsewhere. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our description of six cases of patients demonstrates the heterogeneity of the natural course of the disease, even in patients with the same mutation. It seems reasonable to regularly examine relatives of patients with myoclonus-dystonia syndrome, who should be observed for involuntary movements as well as non-motor symptoms.

Female Sexual Function and Sexual Well-being Before and After Breast Reduction: A Pilot Cross-sectional Study and Review of Literature.

BACKGROUND: Breast reduction is one of the most frequently performed procedures in plastic surgery practice. Patients often undergo this procedure for not only aesthetic but also functional reasons because breast hypertrophy may hinder daily activities because of chronic spinal pain. Breast reduction has a documented impact on quality of life. However, there are only a few reports on the influence of breast reduction on sexuality. OBJECTIVE: The aim of the study was to analyze the impact of breast reduction on female sexual dysfunction and on sexual well-being. METHODS: Ours was a pilot cross-sectional 2-cohort study, including 75 females who had undergone breast reduction (post-BRG) and a preoperative group of 27 females with breast hypertrophy awaiting surgery (pre-BRG). Female Sexual Function Index (FSFI), Sexual Quality of Life-Female, and BREAST-Q Reduction/Mastopexy module were assessed within 12 to 36 months postoperatively via e-mail. A review of literature was performed. RESULTS: The mean total Sexual Quality of Life-Female score was significantly higher in the post-BRG than in the pre-BRG (76.7 ± 11.6 vs 64.4 ± 13.7; P < 0.01). The mean total FSFI score in the pre-BRG was 21 ± 11.4. It was below the FSFI cutoff score for female sexual dysfunction (≤26). In the post-BRG, the total FSFI score was significantly higher (27.4 ± 9.1; P < 0.01). The outcome of the sexual well-being domain of BREAST-Q was significantly higher in the post-BRG (72 ± 14 vs 39.3 ± 14.5; P < 0.01). CONCLUSIONS: Breast reduction procedure has a positive impact on female sexual function, sexual quality of life, and sexual well-being.

Dystonic tics in patients with Gilles de la Tourette syndrome.

CLINICAL RATIONALE FOR THE STUDY: Gilles de la Tourette syndrome (GTS) is a childhood onset disorder characterised by motor and vocal tics. Different types of motor tics may occur in GTS, including dystonic tics (DTs). Although DTs have been recognised as part of GTS symptomatology, little is known about their risk factors or about how often and at what age they appear in affected individuals. AIM OF THE STUDY: The aim of our study was to investigate lifetime prevalence and clinical correlations of DTs in a Polish cohort of GTS patients. MATERIAL AND METHODS: We performed a prospective, one-registration study in a cohort of 207 consecutive ambulatory patients (mean age: 16.5 ± 9.4 years, 131 children, 162 males) with GTS. Duration of GTS was 9.0 ± 8.0 years (range: 1-39 years). DTs were diagnosed during the interview. DTs were defined as slower and lasting longer than typical clonic tics, abnormal dystonia-like movements that led to a sustained, but not fixed, posture. RESULTS: DTs occurred at some point in the lifetime of 73.9% (n = 153) of patients. The prevalence of DTs in adults and children was almost the same (p = 0.963). Age at onset of DTs was 9.9 ± 5.2 years with the most frequent onset in children (7-11 years, 74.4%, n = 64), followed by adolescence (12-18 years; 17.4%, n = 15) and adulthood (≥ 18 years, 8.1%, n = 7). DTs occurred 3.7 ± 4.2 years after tic onset. On average, patients suffered from 1.8 ± 1.7 types of DTs. The most frequent manifestations of DTs were: eyes (tightening resembling blepharospasm 84.3%, n = 129 and oculogyric crisis 45.8%, n = 70), trunk (dystonic postures 59.5%, n = 91), jaw (bruxism 34.6%, n = 53), neck (30.7%, n = 47), upper limb (26.1%, n = 40), and foot (20.9%, n = 32). Multivariate logistic regression analysis showed significant associations of DTs with the total number of simple, and the total number of complex, tics. CONCLUSIONS AND CLINICAL IMPLICATIONS: DTs are early and frequent symptoms of GTS. They tend to localise in the facial area. DTs occur more frequently in individuals with a higher number of tics and probably add to the global impairment caused by tics.

Electrophysiological and clinical assessment of dysautonomia in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP): a comparative study.

CLINICAL RATIONALE FOR THE STUDY: Autonomic nervous system (ANS) involvement in different parkinsonian syndromes has been frequently discussed. It is well established in multiple system atrophy (MSA), whereas it is less evident in progressive supranuclear palsy (PSP). AIMS OF THE STUDY: The aims were to assess the presence and pattern of ANS involvement in MSA and PSP using noninvasive tests i.e. the sympathetic skin response (SSR) test and the R-R interval variation (RRIV) test; to analyse the relationship between clinical and electrophysiological abnormalities in both disorders; and to assess whether an autonomic profile might help to differentiate them. MATERIALS AND METHODS: Clinical and electrophysiological assessments of dysautonomia were performed in 59 patients with MSA (24 cases of MSA-C and 35 cases of MSA-P), these 59 cases including 31 females, mean disease duration 4.2 ± 2.7 years, mean age 60.3 ± 8.4 years, and in 37 patients with PSP (12 females, mean disease duration 4.6 ± 3.6 years, mean age 67.5 ± 6.1 years) and the results were compared to the results obtained from 23 healthy controls matched for age and sex. RESULTS: Clinical dysautonomia assessed by an Autonomic Symptoms Questionnaire was observed in 97% of the MSA patients and in 84% of the PSP patients. SSR was abnormal in 64% and RRIV was abnormal in 73% of MSA cases. In PSP cases, these figures were 78% and 81% respectively. Dysautonomia was clinically more pronounced in MSA compared to PSP (p < 0.05), whereas electrophysiological testing revealed frequently subclinical ANS damage in PSP patients. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our results point to the complementary role of electrophysiological tests in the diagnostic work-up of dysautonomia in parkinsonian syndromes.

Aripiprazole in treatment of Gilles de la Tourette syndrome - New therapeutic option.

Aripiprazole is a dopamine D2- and serotonin 5-hydroxytryptamine (5-HT)1A receptor partial agonist and 5-HT2A receptor antagonist primarily used for the treatment of schizophrenia, bipolar disorder or depression with psychotic ideation. However, recently a number of new possible indications have been suggested, among them Gilles de la Tourette syndrome (GTS). In two randomized, double-blind, placebo-controlled studies in children and adolescents with GTS has been confirmed the efficacy of aripiprazole in tic reduction. In comparison to other neuroleptics, aripiprazole seems to be similarly effective. What is more, the number and profile of possible adverse effects is also favorable. As a consequence, aripiprazole had been registered by Food and Drug Administration (FDA) for the treatment of tics and represents new therapeutic option in treatment of GTS.

Characteristics and clinical correlates of white matter changes in brain magnetic resonance of migraine females.

OBJECTIVE: White matter hyperintensities (WMHs) were often found in migraine patients. The aim of study was to characterize WMHs, assess their prevalence, determine relationship to clinical symptoms and homocysteine levels in migraine females. METHODS: 69 women 38 with migraine without aura (MO), 31 with migraine with aura (MA) who underwent brain MRI with 1.5T scanner were enrolled. The WMHs number, location and size in FLAIR sequence were evaluated. Migraine severity was measured by pain intensity, number of attacks per month and MIDAS scale. RESULTS: WMHs were found in 39.1% females. There was no WMHs and migraine type correlation. The total WMHs number was higher in MO (p=0.027). Patients with WMHs were older (p=0.025), have higher BMI (p=0.042), suffered longer (p=0.001), more often had positive pregnancy history (p=0.010) and less frequent prodromal symptoms. The age of onset, migraine's severity and homocysteine did not correlate with WMHs. No effect of antimigraine medication and oral contraceptive pills (OCP) was found. Both in MO and MA groups WMHs were located only supratentorially. In MO females WMHs were mainly located in one cerebral hemisphere (p=0.024) whereas in MA were found bilaterally. WMHs were most commonly located in the frontal lobes. In MO lesions were small ≤3mm and present in almost all MO patients (p=0.027). CONCLUSION: WMHs are present in more than one third of migraine females, regardless of aura. WHMs are located supratentorially, subcortically and in the frontal lobes. Older age, longer disease's duration, obesity and positive history of pregnancy are main risk factors for WMHs. Symptomatology and migraine severity, hyperhomocysteinemia, OCP and anti-migraine medications do not increase WMHs.

Expression of RNAs Coding for Metal Transporters in Blood of Patients with Huntington's Disease.

Recent studies have demonstrated elevated levels of iron (Fe) in brains of patients with Huntington's disease (HD). Striatal cells carrying mutated Huntingtin presented increased sensitivity to cadmium (Cd) toxicity, decreased sensitivity to manganese (Mn) toxicity and deficits in Mn uptake. The hypothesis arose that the observed alterations result from the altered expression and/or activity of proteins engaged in the transport of these metals, that is: transferrin (TF), transferrin receptor (TFR), divalent metal transporter 1 (DMT1) and ZIP8 protein. Here we examined the expression levels of genes encoding these proteins in blood of HD patients and control subjects. A decreasing tendency in the level of TF transcript and increasing tendency of SLC11A2 mRNA encoding DMT1 was observed in the blood of HD patients compared to the control subjects, but neither attained statistical significance. No changes were found in the levels of TFRC coding for TFR and SLC39A8 coding for ZIP8 between HD patients and controls. The results indicate that HD-associated changes in metal homeostasis occur are not related to mechanisms other than the expression level of the here analyzed metal transporters.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) - a case report and review of literature.

CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome) is a rare neurological syndrome of unknown etiology. The main clinical features include bilateral vestibulopathy, cerebellar ataxia and sensory neuropathy. An abnormal visually enhanced vestibulo-ocular reflex is the hallmark of the disease. We present a case of 58-year-old male patient who has demonstrated gait disturbance, imbalance and paresthesia of feet for 2 years. On examination ataxia of gait, diminished knee and ankle reflexes, absence of plantar reflexes, fasciculations of thigh muscles, gaze-evoked downbeat nystagmus and abnormal visually enhanced vestibulo-ocular reflex were found. Brain magnetic resonance imaging revealed cerebellar atrophy. Vestibular function testing showed severely reduced horizontal nystagmus in response to bithermal caloric stimulation. Nerve conduction study revealed loss of upper and lower limb sensory nerve action potentials. The course of illness was progressive with ataxic gait and unsteadiness as the most disabling symptoms. We report 4-year follow-up of the patient since the beginning of the disease.

Coprolalia and copropraxia in patients with Gilles de la Tourette syndrome.

BACKGROUND AND PURPOSE: Involuntary expression of socially unacceptable words (coprolalia) or gestures (copropraxia) is the best-known symptom of Gilles de Tourette syndrome (GTS) that contributes to the social impairment. The aim of the study was to assess the prevalence, age at onset and co-occurring symptoms of coprophenomena. MATERIALS AND METHODS: One hundred and sixty-eight consecutive subjects with GTS including 94 adults and 74 children and aged between 4 and 54 years (mean: 18.0±8.3) were studied. Demographic and clinical data were obtained from medical history and neurological examination. RESULTS: Coprolalia or copropraxia appeared in 44 patients. Both coprophenomena were present in 9 patients. Coprolalia occurred in 25.0% (n=42) and copropraxia in 6.5% (n=11) of patients. Mean age at onset was 12.2±5.7 years (range: 4-33) for coprolalia and 12.4±4.9 years (range: 7-24) for copropraxia. Coprolalia started 4.4±3.7 years (range: 0-16) after the onset of disease; copropraxia started 6.1±4.0 years (range: 1-12) after the onset of the disease. Coprolalia began in adulthood in six patients only, and copropraxia in one person. In six patients, coprolalia appeared in the first year of the disease. Copropraxia was never seen in the first year of the disease. Coprophenomena were more frequent in patients with comorbid mental disorders, behavioral problems and severe tics. Three quarters of patients reported significant influence of coprophenomena on daily living. CONCLUSIONS: Coprophenomena affect one quarter of GTS patients, appear in the time when tics are most severe, and are positively associated with comorbidity and more severe form of disease. Coprophenomena may reflect more widespread dysfunction of brain in GTS.

[Psychogenic tics: clinical characteristics and prevalence]. / Tiki psychogenne: charakterystyka kliniczna i czestosc wystepowania.

AIM: Clinical characteristics and the prevalence of psychogenic tics (PT) METHODS: 268 consecutively examined patients aged 4 to 54 years (221 men, 47 females; 134 children, 134 adults) with tic phenotype: Gilles de la Tourette syndrome (GTS, n = 255), chronic motor tics (n = 6), chronic vocal tics (n= 1), transient tics (n = 1), tics unclassified (n = 2), PT (n= 5) were analyzed. The diagnosis of tic disorders was made on the DSM-IV-TR criteria and mental disorders by psychiatrists. RESULTS: PT were found in 5 patients (1.9%), aged 17 to 51 years, four men and one woman. The phenotype included vocalizations and complex movements. In none of the patients simple motor facial tics, inability to tic suppress, unchanging clinical pattern, peak severity from the beginning of the disease, lack of concern about the disease were present. The absence of premonitory urges, regression in unexpected positions, and the presence of atypical for GTS mental disorders were found in two persons. PT occurred in three persons in whom organic tics were present in childhood. Pharmacological treatment and psychotherapy were unsuccessful. In two persons spontaneous resolution occurred, in two patients the tics persist, in one person the course of PT is unknown. CONCLUSIONS: PT are rare and may occur in patients with organic tics. The most typical features of PT are: early onset in adulthood, lack of simple motor tics, inability to tic suppress. The diagnosis is established if a few atypical symptoms for organic tics occur.

Polish Translation and Linguistic Validation of the SCAR-Q.

Introduction Patient-reported outcome measurements (PROMs) are gaining considerable popularity as tools to assess the effectiveness of the treatment in plastic surgery, being a complement to surgical outcomes. The SCAR-Q questionnaire has been recently developed for patients with surgical, traumatic, and burn scars. Aim The study aims to describe the process of translation and linguistic validation of the scar questionnaire (SCAR-Q) for use in Polish patients undergoing scar treatment. Material and methods An official Polish translation and language validation of the SCAR-Q were done in adherence to International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. The process consisted of four steps: two independent forward translations, a back translation, a review of the back translation, and cognitive participant interviews. Results The field-tested version of the SCAR-Q consisted of 29 items across three scales measuring appearance concerns, symptoms, and the psychosocial impact of the scar. The forward translation was done by two independent translators and revealed specific difficulties in translation to the Polish language (4/29 items). The back translation showed no significant differences compared to the original English version. Cognitive debriefing interviews involved nine Polish patients with postraumatic scars, burn scars, and scars after skin tumor resection. Participants have not reported any major difficulties in understanding the content of the questionnaire. Conclusions The ISPOR provides a straightforward and thorough guideline for the PROMs translation process. The new SCAR-Q is an accessible and efficient PROM that can be implemented in Polish patients to assess the effectiveness of scar treatment.

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.

[Searching for Tourette's syndrome gene. Part 1. Heterogeneity of clinical phenotypes]. / W poszukiwaniu genu zespolu Gilles de la Tourette'a. Czesc 1. Róznorodnosc fenotypów klinicznych.

The French neuropsychiatrist Georges Gilles de la Tourette described in 1885 the "Maladie des Tics" which later was named after him, as Gilles de la Tourette syndrome (GTS). Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by simple and complex motor and vocal tics with multiple neuropsychiatric comorbidities. GTS is often concurrent with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). There are several clinical GTS subtypes: GTS only, GTS+OCD, and GTS+OCD+ADHD. Additional clinical aspects of the disorder include occurrence of anger episodes, anxiety and mood disorders, and learning and sleeping disturbances. The genetics of GTS is complex and remains unclear. So far, no causative candidate genes have been identified. However, segregation studies in families and twins with GTS provide strong evidence for the existence of a genetic background associated with a multifactorial mode of inheritance. Progress in studies on genome variability among patients with GTS is necessary to improve pharmacotherapeutic strategies of the disorder.

[Searching for Tourette's syndrome gene. Part 2. Patient's genome variability]. / W poszukiwaniu genu zespolu Tourette'a. Czesc 2. Zmiennosc genomu chorych.

Gilles de la Tourette syndrome (GTS) is a complex, heterozygous genetic disorder. Twenty chromosomal rearrangements (7q22-q31, 8q13-q22, and 18q22) indicating genomic regions which may be involved in the etiology of the disorder have been reported in families with GTS. Moreover, pathogenic mutations responsible for GTS were found in the SLITRK1 and the L-histidine decarboxylase (HDC) genes. The W317X mutation in the HDC gene points to a possible role for histaminergic neurotransmission in the mechanism and modulation of tic disorder. The distribution of single nucleotide polymorphisms (SNPs) was examined in at least 14 candidate genes (DRD1, DRD2, DRD3, DRD4, DAT1, MAOA, 5HTR2A, 5HTR3A, TDO2, CNR1, HLA-DRB, IL1RA, MOG, and SGCE) using a case-control genetic association analysis. Still, a lack of replicated and consistent results was observed. Recently, rare structural variants of different genes involved in neurodevelopment determined by recurrent exonic copy number variations (CNVs) have been found in a subset of patients suffering from GTS.

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.