Etiology Of Tourette Syndrome Research Articles

Complex phenotype of Tourette syndrome in a ten-year-old boy (a clinical case)

Aim. The aim of the work is to draw attention to the symptoms associated with Tourette syndrome and to examine the association with comorbid diseases. Materials and methods. A review of the scientific literature on Tourette syndrome (TS) was conducted using the following Keywords “tics”, “Tourette syndrome”, “Tourette obsessive-compulsive disorder, TOCD”, “obsessive-compulsive disorder, OCD”, “attention deficit hyperactivity disorder, ADHD” using PubMed, MEDLINE, EMBASE as search engines. Taking into account studies conducted in the last 10 years, the abstracts of 275 articles were analyzed. Articles were selected for the study based on the criterion of their close relevance to the topic. The study results covered in 49 articles were examined in more detail. A description of a TOCD clinical case was prepared from primary medical documentation with parental informed consent. Results. The prevalence of TS is quite variable, depends on epidemiological research methods and ranges from 0.3 % to 1.0 % worldwide. Given the methodological limitations of most studies, the actual prevalence may be 10 times higher. TS is a progressive disease and is characterized by regular stages. Tourette syndrome-plus is distinguished, including autoaggressive actions besides the basic symptoms of OCD and ADHD. The etiology of TS is still being studied. In particular, the impact of environmental factors is considered: infection or inflammation, perinatal complications and chronic psychosocial stress in childhood. In 70–80 % of cases, TS is a hereditary disorder, making it one of the most heritable childhood-onset neuropsychiatric diseases. Various approaches have been applied to assess the genetic architecture of TS, including candidate gene studies, segregation analysis, linkage analysis, cytogenetics, copy number variants (CNV), rare variation studies, genome-wide association studies (GWAS), and whole exome sequencing (WES). Currently, there is no specific laboratory or genetic test for TS diagnosis. Pharmacological treatments are available but often ineffective; behavioral and surgical treatments are under development. The clinical case of TS in a 10-year-old boy is described with an onset at the age of 7 years following frequent infections, manifested as cephalocaudal motor tics and several vocal tics (coprolalia, echolalia) with a progression to obsessive-compulsive behavior (mysophobia, compulsive skin picking, self-hitting, self-biting, repetitive compulsions). The presented clinical case is of great interest from the viewpoint of somewhat belated diagnosis of TOCD syndrome, as well as indicates the need to continue the search for effective methods of diagnosis and treatment. Conclusions. The case of comorbid OCD and tic disorder is a unique endophenotype combining externalized disinhibited TS movements in parallel with internalized distress reminiscent of OCD. Clinicians should consider these features when choosing treatment methods.

Tourette syndrom - a review of current literature

Introduction Tourette syndrome is a disorder characterized by tics. It usually begins in childhood and often remains in adulthood. Tiki is best described as body movements performed automatically excluding the patient's will. It affects boys more often than girls and is associated with attention deficit hyperactivity disorder and obsessive-compulsive disorder. The etiology of Tourette syndrome has not yet been fully clarified. The aim of the study Review the latest literature on Tourette syndrome. Material and methods The research was conducted using Articles by PubMed and Google Scholar on Tourette syndrome. Description of the state of knowledge Tourette syndrome is a movement disorder most commonly found in schoolchildren. The occurrence peaks in the pre-puberty period, and half of the cases disappear in early adulthood and, while the severity of occurrence is higher than commonly assumed. It is often associated with mentally concomitant diseases, mainly attention deficit hyperactivity disorder and obsessive-compulsive disorder. Given the diverse presentation, Tourette's syndrome can mimic many hyperkinetic disorders, making it difficult or delaying correct diagnosis. Treatment can be behavioral, pharmacological or surgical and is dependent on the symptoms causing the greatest dysfunction. Summary Tourette syndrome can cause severe stress and worsen health-related quality of life. Often it is an embarrassing condition for patients. Treatment is multimodal, however, an important issue of treatment among patients is to undertake psychotherapy, so as not to perpetuate the tic reflex, as well as to cope with functioning in society.

Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

Background: Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression.Methods: We used an in silico approach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a sample composed of TS cases and controls (n = 290), as well as TS family trios (n = 148), we performed transmission disequilibrium test (TDT) and meta-analysis.Results: We found positive association of rs3750486 in the LIM homeobox 6 (LHX6) gene (p = 0.021) and rs7795011 in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene (p = 0.029) with TS in our meta-analysis. The TDT showed an over-transmission of the A allele of rs1042201 in the arylacetamide deacetylase (AADAC) gene in TS patients (p = 0.029).Conclusion: This preliminary study provides further support for the involvement of LHX6, IMMP2L, and AADAC genes, as well as epigenetic mechanisms, such as altered miRNA mediated gene expression regulation in the etiology of TS.

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

BackgroundGenes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches.MethodsWe first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish.ResultsThirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development.DiscussionThese results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

Dissecting The Etiology of Tourette Syndrome Through Large-Scale Genome, Epigenome And Transcriptome Studies and Cross-Disorder Analysis

Tourette Syndrome (TS) is a psychiatric disorder of childhood onset, marked by multiple motor and vocal tics and is caused by a complex and as of yet not fully understood genetic background interacting with environmental factors. Interestingly, there is a fluctuation in the severity of symptoms, with tics waxing and waning over time. Furthermore, the phenotype is extremely complex with 90% of patients presenting with additional neuropsychiatric symptomatology, and, notably, there is high comorbidity with other neurodevelopmental disorders such as Obsessive-Compulsive Disorder (OCD), Attention Deficit and Hyperactivity Disorder (ADHD), and Autism Spectrum Disorders leading to the hypothesis of a shared genetic basis. There are multiple large-scale efforts aiming to identify the genetic basis of TS and we are starting to reach an inflection point at which results are starting to become reproducible. Importantly, studies of the epigenome and genome-wide gene-expression patterns are allowing us to uncover additional missing pieces of the puzzle. Here, we present results from two of the largest collaborative efforts for TS: EMTICS (European Multicentre Tics in Children Study) and TS-EUROTRAIN (a Marie Curie Initial Training Network). Besides a genome-wide association study on 1500 patients with TS, we also present the first epigenomewide association study for TS supporting a role for aberrant DNA methylation levels in tic disorders as part of a broader neurodevelopmental dysregulation. We also present the first genome-wide gene expression study based on longitudinal follow-up of 700 TS patients for TS for two years and comparisons at points of tic exacerbation and remission in order to identify genes whose expression patterns correlate with tic fluctuation. The genes implicated by our analysis are enriched in cell-adhesion molecules and related to neurodevelopment but intriguingly, also cancer. Interestingly, several microRNAs and small nucleolar RNAs are found among our top hits. Meta-analysis of TS GWAS with GWAS for ADHD and ASD sheds light into the shared etiology identifying genes that play a role across the spectrum of neurodevelopmental disease. Leveraging power from large-scale collaborative efforts and participation from a multitude of clinical sites around the world we present here an integrative view of current studies aiming to understand the etiology of TS.

Genetics of Gilles De La Tourette Syndrome: Accelerating Discoveries Through Large-Scale Collaborative Efforts

Overall Abstract Gilles de la Tourette Syndrome (TS) is a common, albeit still under-diagnosed, neuropsychiatric disorder that is caused by a complex genetic basis, interacting with environmental factors. This symposium will showcase exciting findings from all current large-scale collaborative efforts aiming to elucidate the genetic background of TS, through diverse approaches and studies of several thousands of individuals with TS; genome-wide association studies (GWAS) aiming to identify common variants associated to the disorder, whole-exome sequencing approaches seeking rare variants, gene-expression studies aiming to identify the relative contribution of genetics versus environmental factors, and sophisticated approaches aiming to dissect complex and comorbid phenotypes. We will present novel TS susceptibility genes implicated on a genome-wide significance level either by GWAS, large-scale CNV scans or whole-exome sequencing and introduce heritable TS sub-phenotypes. We will also present large-scale GWAS meta-analysis of TS together with other, often comorbid neurodevelopmental disorders, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder and autism. Finally, after more than two decades of active research aiming to identify the genetic background of TS etiology, we are on the verge of a new era, yielding exciting and rapid discoveries in the field of TS genetics. Investigators from around the world, representing multiple disciplines and scientific approaches, are joining their efforts in large-scale initiatives supported both by the European Union and US National funding agencies. Propelled by the gradual availability of large scale TS cohorts, novel methodologies for the study of both common and rare genetic variants, and importantly, sheer enthusiasm by multiple researchers working together across different countries, the new era of TS genetics holds the promise to identify novel targets for improved therapies.

Altered dopaminergic regulation of the dorsal striatum is able to induce tic-like movements in juvenile rats.

Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette’s syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively. Different neurotransmitters can activate or repress striatal activity and among them, dopamine plays a major role. In this study we introduced a chronic dopaminergic alteration in juvenile rats, in order to modify the delicate balance between direct and indirect pathway. This manipulation was done in the dorsal striatum, that had been associated with tic-like movements generation in animal models. The results were movements resembling tics, which were categorized and scored according to a newly developed rating scale and were reduced by clonidine and riluzole treatment. Finally, post mortem analyses revealed altered RNA expression of dopaminergic receptors D1 and D2, suggesting an imbalanced dopaminergic regulation of medium spiny neuron activity as being causally related to the observed phenotype.

Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing.

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

T35 - Microrna Regulation Of Candidate Genes For Tourette Syndrome

Background Tourette Syndrome (TS) is a neurodevelopmental disorder that presents early in childhood and is marked by the appearance of multiple involuntary motor tics and at least one vocal tic. It presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Despite a strong genetic contribution, the molecular mechanisms behind TS are still uncertain, although multiple lines of evidence suggest involvement of specific candidate genes and corresponding epigenetic mechanisms via miRNA regulators. Methods To date only a few genetic findings have been replicated in TS. Among these the nicotinic acetylcholine receptor alpha 7 subunit (CHRNA7) gene has been recently suggested as candidate susceptibility gene. CHRNA7 is known to regulate a wide variety of developmental and secretory functions, however, the mechanism of its transcriptional regulation is still unclear [1]. Another recent promising finding in TS genetic research is Netrin 4 (NTN4), which belongs to a family of extracellular proteins that direct axon outgrowth and guidance [2]. Several microRNAs have already been associated with neuropsychiatric disorders, but most importantly a few miRNA have also been associated with Tourette Syndrome [3,4].Our goal was to investigate the role of selected candidate genes in a case-control setup along with functional validation involving miRNA regulation in the possible involvement in TS pathogenesis through analysis of 3’UTR regions. Results An OpenArray platform (TaqMan® OpenArray® Genotyping System) was used for the case-control analysis of TS patients (N=564) and healthy controls. Starting from a list of candidate genes previously indicated as possible risk factors for TS, we screened for presence of SNPs in the 3’UTR regulatory regions. This analysis (data retrieved by mirSNP and polymiRTS databases) led to the identification of 32 SNPs which were predicted to change the seed sequence of in silico proposed miRNAs. To proof this concept, we performed functional validation study using a luciferase assay reporter containing 3’ UTR regions of CHRNA7 and NTN4 transfected with their predicted miRNA. Specifically, miRNA-106b and miRNA-198b were identified as the most potent miRNA candidates for regulation of CHRNA7 and NTN4 gene expression. SKNF1 and HEK human cell lines were co-transfected using lipofectamine with the luciferase reporter-3’ UTR construct of CHRNA7 and NTN4 (SwitchGear Genomics) and the corresponding putative miRNAs (miR-106b, miR-198b) along with non-targeting control miRNAs (miR-196b, miR-641b) in the functional validation studies. Discussion In order to increase our understanding of the underlying genetic and epigenetic mechanisms of TS, we aimed to study the possible miRNA regulation processes in TS-related genes, which would help not only to better understand the full genetic architecture of this disorder but also to determine how miRNAs contribute to the complexity of gene regulation in the development of disease. OpenArray analysis identified significant differences among the selected candidates genes (LHX6, iMMP2L) confirming the implication of those genes in TS etiology. In the luciferase assays we characterized the regulatory effect of the predicted miRNAs on the expression candidate genes in a concentration-dependent manner, which showed up to 5-fold change in the relative gene expression levels in case of CHRNA7 and NTN4 thereby proving the concept of our study.

Targeted Re-Sequencing Approach of Candidate Genes Implicates Rare Potentially Functional Variants in Tourette Syndrome Etiology.

Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four candidate genes for TS (HDC, SLITRK1, BTBD9, and SLC6A4) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST. We prioritized variants using Variant ranker and validated five rare variants via Sanger sequencing in HDC and SLITRK1, all of which are predicted to be deleterious. Intriguingly, one of the identified variants is in linkage disequilibrium with a variant that is included among the top hits of a genome-wide association study for response to citalopram treatment, an antidepressant drug with off-label use also in obsessive compulsive disorder. Our findings provide additional evidence for the implication of these two genes in TS susceptibility and the possible role of these proteins in the pathobiology of TS should be revisited.

Investigation of a Possible Role for the Histidine Decarboxylase Gene in Tourette Syndrome in the Chinese Han Population: A Family-Based Study.

Tourette syndrome (TS) is a polygenic neuropsychiatric disease. Previous studies have indicated that dysregulation in the histaminergic system may play a crucial role in disease onset. In this study, we investigated the role of the histidine decarboxylase gene (HDC) in TS susceptibility in the Chinese Han population. After genotyping 241 TS nuclear families trios, we analyzed three tag HDC single nucleotide polymorphisms (rs854150, rs854151, and rs854157) in a family-based study using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT showed no over-transmission in these SNPs across the HDC region (for rs854150: χ2 = 0.472, P = 0.537, OR = 1.097, 95%CI = 0.738–1.630; for rs854151: χ2 = 0.043, P = 0.889, OR = 1.145, 95%CI = 0.767–1.709; for rs854157:χ2 = 0.984, P = 0.367, OR = 1.020, 95%CI = 0.508–2.049). HRR also showed the same tendency (for rs854150: χ2 = 0.211, P = 0.646, OR = 1.088, 95%CI = 0.759–1.559; for rs854151: χ2 = 0.134, P = 0.714, OR = 0.935, 95%CI = 0.653–1.339; for rs854157:χ2 = 0.841, P = 0.359, OR = 1.206, 95%CI = 0.808–1.799). Additionally, the haplotype-based haplotype relative risk showed a negative association. Although these findings indicate an unlikely association between HDC and TS in the Chinese Han population, a potential role for HDC cannot be ruled out in TS etiology. Future research should investigate this more thoroughly using different populations and larger samples.

The Genetic Etiology of Tourette Syndrome: Large-Scale Collaborative Efforts on the Precipice of Discovery.

Gilles de la Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder that is characterized by multiple motor and phonic tics. It has a complex etiology with multiple genes likely interacting with environmental factors to lead to the onset of symptoms. The genetic basis of the disorder remains elusive. However, multiple resources and large-scale projects are coming together, launching a new era in the field and bringing us on the verge of discovery. The large-scale efforts outlined in this report are complementary and represent a range of different approaches to the study of disorders with complex inheritance. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has focused on large families, parent-proband trios and cases for large case-control designs such as genomewide association studies (GWAS), copy number variation (CNV) scans, and exome/genome sequencing. TIC Genetics targets rare, large effect size mutations in simplex trios, and multigenerational families. The European Multicentre Tics in Children Study (EMTICS) seeks to elucidate gene-environment interactions including the involvement of infection and immune mechanisms in TS etiology. Finally, TS-EUROTRAIN, a Marie Curie Initial Training Network, aims to act as a platform to unify large-scale projects in the field and to educate the next generation of experts. Importantly, these complementary large-scale efforts are joining forces to uncover the full range of genetic variation and environmental risk factors for TS, holding great promise for identifying definitive TS susceptibility genes and shedding light into the complex pathophysiology of this disorder.

Addressing the Complexity of Tourette's Syndrome through the Use of Animal Models.

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority—up to 90%—of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed to elucidate TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions, and brain circuits in TS disease pathomechanisms is another focus area for preclinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single preclinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptomst hat have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms.

Neurobiology of Tourette Syndrome

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although it is a common disorder in childhood, the etiology of Tourette Syndrome has not been fully elucidated yet. Studies, -conducted so far- have revealed differences in neurobiological structures of individuals who suffer from Tourette Syndrome. The objective of this review is to assess etiological and pathophysiological studies in the Tourette Syndrome literature. An electronical search was conducted in PubMed database using the keywords tic disorders, Tourette Syndrome, neurobiology, genetics, neuroimaging and animal models. Research and review studies published between 1985 and 2015, with a selection preference towards recent publications, were reviewed. According to the studies, genetic predisposition hypothesis is considered as a priority. However, a precise genetic disorder associated with Tourette Syndrome has not been found. The evidence from postmortem and neuroimaging studies in heterogenous patient groups and animal studies supports the pathological involvement of cortico-striato-thalamo-cortical (CSTC) circuits in Tourette Syndrome. Consequently, the most emphasized hypothesis in the pathophysiology is the dopaminergic dysfunction in these circuits. Furthermore, these findings of the animal, postmortem and neuroimaging studies have confirmed the neurodevelopmental hypothesis of Tourette Syndrome. In conclusion, more studies are needed to understand the etiology of the disorder. The data obtained from neurobiological studies of the disorder will not only shed light on the way of Tourette Syndrome, but also guide studies on its treatment options.

Association of Glutathione S-Transferase P1 (GSTP1) Polymorphism with Tourette Syndrome in Taiwanese Patients

The etiology of Tourette syndrome (TS) is multifactorial. TS vulnerability may be associated with genetic and environmental factors. From the genetic point of view, TS is heterogeneous. Previous studies showed that some single-nucleotide polymorphisms (SNPs) of the glutathione-S-transferase P1 (GSTP1) gene can affect cellular proliferation and apoptotic activity and TS is a neurodevelopmental disorder. We guessed that there was a relationship between TS and genetic variants of the GSTP1 gene. Therefore, in this study, we aimed to test the hypothesis that GSTP1 SNPs were associated with TS. We performed a case-control study. One hundred twenty-one TS children and 105 normal children were included in the study. Polymerase chain reaction was used to identify the GSTP1 gene polymorphism at position rs6591256 (A/G, promoter polymorphism) in TS patients and normal children. The polymorphism at position rs6591256 in the GSTP1 gene revealed significant differences in the allele (p=0.0135) and genotype (p=0.0159) distributions between the TS patients and the control group. The A allele was present at a higher frequency than the G allele in the TS patients compared with the control group (odds ratio [OR]=1.91, 95% confidence interval [CI]: 1.14-3.21). The AA genotype was associated with susceptibility to TS with an OR of 2.38 for the AA versus AG genotype (95% CI: 1.29-4.41). These findings suggest that variants in the GSTP1 gene may play a role in susceptibility to TS.

Microduplication of 15q13.3 and Xq21.31 in a family with tourette syndrome and comorbidities

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology.

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.

Complementary and Alternative Medicine: Not Many Compliments but Lots of Alternatives

Complementary and Alternative Medicine: Not Many Compliments but Lots of Alternatives

Tourette's syndrome: from demonic possession and psychoanalysis to the discovery of gene

In this paper we make a brief historical review of the hypothesis concerning the etiology of Tourette's syndrome (TS), focusing on varying trends over time: at first, its presumed relation to witchcraft and demonic possessions, followed by the psychoanalytical theory, which attributed TS to a masturbatory equivalent. Then, progressing to modern time, to the immunological theory and finally the advent of genetics and their role in the etiology of TS.

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.