Chronic Multiple Tics Research Articles

Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as ‘cases’ (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and 5 with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

Centrality of prefrontal and motor preparation cortices to Tourette Syndrome revealed by meta-analysis of task-based neuroimaging studies.

Tourette Syndrome (TS) is a neurodevelopmental condition characterized by chronic multiple tics, which are experienced as compulsive and ‘unwilled’. Patients with TS can differ markedly in the frequency, severity, and bodily distribution of tics. Moreover, there are high comorbidity rates with attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), anxiety disorders, and depression. This complex clinical profile may account for apparent variability of findings across neuroimaging studies that connect neural function to cognitive and motor behavior in TS.Here we crystalized information from neuroimaging regarding the functional circuitry of TS, and furthermore, tested specifically for neural determinants of tic severity, by applying activation likelihood estimation (ALE) meta-analyses to neuroimaging (activation) studies of TS. Fourteen task-based studies (13 fMRI and one H2O-PET) met rigorous inclusion criteria. These studies, encompassing 25 experiments and 651 participants, tested for differences between TS participants and healthy controls across cognitive, motor, perceptual and somatosensory domains.Relative to controls, TS participants showed distributed differences in the activation of prefrontal (inferior, middle, and superior frontal gyri), anterior cingulate, and motor preparation cortices (lateral premotor cortex and supplementary motor area; SMA). Differences also extended into sensory (somatosensory cortex and the lingual gyrus; V4); and temporo-parietal association cortices (posterior superior temporal sulcus, supramarginal gyrus, and retrosplenial cortex).Within TS participants, tic severity (reported using the Yale Global Tic Severity Scale; YGTSS) selectively correlated with engagement of SMA, precentral gyrus, and middle frontal gyrus across tasks.The dispersed involvement of multiple cortical regions with differences in functional reactivity may account for heterogeneity in the symptomatic expression of TS and its comorbidities. More specifically for tics and tic severity, the findings reinforce previously proposed contributions of premotor and lateral prefrontal cortices to tic expression.

Chromosome 5 and Gilles de la Tourette syndrome: Linkage in a large pedigree and association study of six candidates in the region

Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. In our previous genome scan for TS we identified evidence for linkage to the centromeric region of chromosome 5 in a single large family of 32 individuals with 10 family members with TS or chronic multiple tics (CMT). In this paper we report further analyses of the 5p-centromeric region in this pedigree. An additional 11 family members were identified and screened for TS. Using a set of 14 microsatellite markers we refined the linked region to a approximately 28 Mb interval between the markers D5S1506 and D5S76. A set of six candidate genes located in this region were selected to be tested for genetic association with TS. These genes were GDNF, ITGA1, ISL1, FGF10, HCN1 and SLC1A3. The TDT statistic was used for the association tests in a sample of 171 independent nuclear families with 241 affected children with TS. We found no evidence for an association between TS and markers in these genes in this sample of families. This study represents the first efforts to narrow the linkage region in the extended pedigree and the first tests of candidate genes in the chromosome 5 region linked to TS.

Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5, 10 and 13.

To localize genes influencing the susceptibility to Gilles de la Tourette syndrome (GTS) and associated chronic multiple tics (CMT). A single, large, multiple affected pedigree containing 35 subjects diagnosed with GTS and a further 14 with CMT was genotyped for markers spanning the autosomes. Linkage analysis was carried out using classical lod score analysis and model-free lod score analysis. All markers were subjected to two-point analysis, and markers producing a two-point result significant at P<0.005 were subjected to three-point analysis using adjacent markers. The following markers produced at least one result significant at 0.005 using two-point analysis: D5S1981, D5S2050, D10S591, D10S189, D13S217, and D14S288. Three-point analysis with D5S2050 and D5S400 produced a lod of 2.9 with CMT. Three-point analysis of D10S591 and D10S189 produced lods of 1.9 with GTS and CMT. Three-point analysis of D13S217 and D13S171 produced a lod of 2.7 with GTS. No single haplotype appeared to account for the majority of cases within the pedigree. It seems likely that more than one susceptibility allele is present in the pedigree. Although none of the three positive regions is conclusively implicated, it seems probable that at least one contains a susceptibility locus. We recommend that association-based studies be carried out in these three regions to produce further evidence for a localization and to carry out fine-mapping.

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

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

Linkage analysis and exclusion of regions of chromosomes 3 and 8 in Gilles de la Tourette syndrome following the identification of a balanced reciprocal translocation 46 XY, t(3:8)(p21.3 q24.1) in a case of Tourette syndrome.

Gilles de la Tourette syndrome (GTS) and related disorders such as chronic multiple tics and obsessive compulsive behaviour are likely to be genetically transmitted with a Mendelian autosomal dominant mode of transmission. Following our discovery of a patient with GTS who also carried a balanced translocation 46 XY, t(3:8) (p21.3 q24.1), a linkage study of several families was performed covering the areas on chromosomes 3 and 8 implicated by the cytogenetic abnormality in this unique GTS patient. A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB and D3S11. Subsequently, the genetic map of this region was improved and new polymorphic markers close to our original three markers were identified. With the new map the maximum two-point lod with any marker was reduced to 1.77 at RAF1, and the FASTMAP approximate multipoint lod excluded the likely region of the breakpoint. After constructing a somatic cell hybrid, the original three markers were mapped relative to the break point of the translocation and to other new markers. It was confirmed that the original markers were at least 20 cM away from the position of the break point. In addition, we traced further family members of our translocation GTS proband, and identified affected individuals who did not possess the translocation. We concluded that the translocation was not responsible for the GTS symptoms in our affected proband.

Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior

Previous studies have demonstrated a relationship between obsessive-compulsive disorder or behavior and Gilles de la Tourette syndrome. It has been hypothesized that the serotonergic system is implicated in the etiology of obsessive-compulsive disorder. Therefore, the authors investigated whether genetic variation in a serotonergic receptor and a modifying enzyme were associated with Tourette's syndrome. A linkage analysis using DNA and blood group markers was carried out in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior. There was no evidence to support the hypothesis that genetic variation in the serotonin 5-HT1A receptor and tryptophan oxygenase genes causes susceptibility to Tourette's syndrome and chronic multiple tics. The results eliminate two possible candidate genes from having a role in the pathophysiology of Tourette's syndrome.

D2 dopamine receptor alleles do not influence severity of Tourette's syndrome. Results from four large kindreds.

We investigated the recently proposed hypothesis that the A1 allele of the Taq I polymorphic system at the D2 dopamine receptor gene (DRD2) influences the severity of Tourette's syndrome (TS). We have previously demonstrated that DRD2 is not linked to TS, establishing that it cannot be the major locus determining the susceptibility to develop TS. We studied alleles at the DRD2 A system in patients with TS or chronic multiple tics in four extended kindreds segregating TS. If this allelic system at DRD2 is associated with severity of TS, then among affected family members, those with the A1 allele should have more severe disease than those without it. Severity of disease was compared in affected members of the kindreds with A1 alleles and in those without A1 alleles. We evaluated disease severity in two ways. First, we evaluated 17 individuals from two families using a derivative of the Yale Global Tic Severity Scale composed of subscales concerning number, frequency, and severity of motor and phonic tics, rated separately. We divided this sample (n = 17, nine with TS and eight with chronic multiple tics) by genotype at the A1/A2 system. The heterozygotes (n = 7) had an average severity score of 11.3; the A2 homozygotes had an average severity score of 14.2. (There were no A1 homozygotes.) Second, we evaluated 47 individuals from two different families (all with TS) using the TS symptomatology evaluation. We compared severity scores for these individuals by genotype at the A1/A2 system. The heterozygotes (n = 24) had a mean severity score of 3.0, and the A2 homozygotes (N = 21) had a mean severity score of 3.7. Our data do not support alleles at the A system of DRD2 as a factor associated with severity of TS.

Exclusion of close linkage of Tourette's syndrome to D1 dopamine receptor.

The authors' goal was to establish if a mutation in D1 dopamine receptor locus (DRD1), or one genetically close to it, could cause Gilles de la Tourette's syndrome. DRD1 and linked markers (D5S36, D5S61, and D5S62) were studied in a large Mennonite Tourette's syndrome kindred. Only individuals with the full Tourette's syndrome were considered to be affected in one series of analyses; in another series the diagnostic spectrum was broadened to include chronic multiple tics. Liability classes were defined to take into account age at onset and sex differences; dominant inheritance was assumed. The authors' version of the LINKMAP program of the LINKAGE package modified to run under distributed parallel processing (Linda LINKMAP) was used for the multipoint linkage analysis. Complete (theta = 0.0) linkage of Tourette's syndrome with DRD1 was ruled out (lod score of -10.1) when the disease was defined narrowly. The area of exclusion of linkage (lod score between -2 and -10.5) extended from map position -0.10 to map position 0.50. The authors conducted an additional (centromeric) multipoint analysis with D5S36 as well as glucocorticoid receptor (GRL) and D5S22, resulting in an overlapping area of exclusion to map position -0.30 when the disease was defined narrowly. This result provides strong evidence against linkage of the DRD1 D1 dopamine receptor locus with Tourette's syndrome. This exclusion extends the authors' earlier work with the dopamine system in Tourette's syndrome to exclude the two best characterized dopamine receptors from linkage with Tourette's syndrome.

An epidemiological study of obsessive-compulsive disorder and related disorders in Israeli adolescents.

Five hundred and sixty-two, 16- to 17-year-old consecutive inductees into the Israeli Army, constituting a random sample of their cohort, were screened for obsessive-compulsive disorder (OCD), Tourette's syndrome, transient tics (TT), chronic multiple tics (CMT), and attention-deficit hyperactive disorder (ADHD). Two child psychiatrists interviewed the subjects, using screening items from structured interviews that implement DSM-III-R diagnostic criteria. For OCD, a point prevalence of 3.6% was found, 3.9% for ADHD, 1.8% for CMT, and 1.6% for TT. For ADHD, TT, and CMT, but not for OCD, there was a significantly higher prevalence for males than for females. Among the OCD individuals, there was an elevation of TT, CMT, and Tourette's syndrome relative to the population rates.

Familial Tourette's Syndrome in a Large British Pedigree

A British pedigree multiply affected by the Gilles de la Tourette syndrome and spanning six generations is described. Of 122 members identified, 85 were individually interviewed, and 50 were diagnosed as 'cases'. 'Cases' consisted of 29 with definite or probable Gilles de la Tourette syndrome, 17 with definite or probable chronic multiple tics, and four with definite or probable obsessive-compulsive behaviour. Only eight of the 50 'cases' had consulted a doctor for their symptoms. 'Cases' and 'non-cases' could be distinguished on the basis of echo-phenomena, obsessive-compulsive features, self-injurious behaviour, and the trait score of the Leyton Obsessional Inventory, but did not differ significantly on any other psychopathological variables. The pattern of inheritance of the Gilles de la Tourette syndrome in this pedigree is consistent with autosomal dominant transmission.

Gilles de la Tourette's syndrome and obsessive-compulsive disorder. Evidence supporting a genetic relationship.

Previous studies have suggested that obsessive-compulsive symptoms frequently occur among patients with Gilles de la Tourette's syndrome (TS). To examine the relationship between TS and obsessive-compulsive disorder (OCD), data from all first-degree relatives of TS probands were obtained with a semistructured interview designed to collect information on the presence of TS, other tic disorders, and neuropsychiatric illnesses during the lifetime of the individual. The rate of OCD among first-degree relatives was significantly increased over estimates from the general population and a control sample of adoptive relatives. The rates of TS, OCD, and chronic multiple tics (CMT) were virtually the same in families of probands with OCD (TS +/- OCD) when compared with families of probands without OCD (TS - OCD). Finally, the frequency of OCD without TS or CMT among first-degree relatives was significantly elevated in families of both TS + OCD and TS - OCD probands, suggesting that some forms of OCD may represent an alternative expression of the factors responsible for TS and/or CMT.

The Risk of Tourette's Syndrome and Chronic Multiple Tics among Relatives of Tourette's Syndrome Patients Obtained by Direct Interview

Direct interview information was collected using a structured interview from first degree relatives of 27 Tourette's syndrome (TS) patients. The morbid risks obtained are considerably higher for both TS and chronic multiple tics when compared to risks calculated from family history studies. Although this is a small sample of families, the results suggest that the risks for TS and chronic multiple tics in families of TS probands are higher than originally believed and that analyses based on those earlier data need to be reexamined.

NEUROPSYCHIATRIC DISORDERS

Eighty-five patients with childhood-onset pervasive neuropsychiatric disorders (infantile autism, pervasive developmental disorders, developmental language disorders, severe attentional deficit disorders with learning difficulties, and Tourette's syndrome of chronic multiple tics) underwent computed tomographic scanning of the brain. Clinical assessments of each image of the patients' scans by a diagnostic radiologist, who was "blind" to the neuropsychiatric diagnosis, were used in the first phase of the study, which is reported here. Twenty-four percent of the scan series revealed clear abnormalities and 13% showed mild asymmetries in ventricular and/or hemispheric size. Of the children with pervasive developmental disorders, 59% had abnormal scans, as did 44% of those who were language impaired and 38% of those with Tourette's syndrome. No distinct abnormality was isolated by which diagnostic categories could be separated, nor was an increased prevalence of scan abnormalities associated with overall severity of symptoms. Mild asymmetries, involving increased size of the left hemisphere and/or left ventricular system, were found in all diagnostic groups, and may be associated with one or more behavioral or cognitive disturbances found in the five syndromes. No systematic relationship was found between computed tomography (CT) scan abnormalities and EEG abnormalities. Critical methodologic issues involving diagnostic formulation and assessment of brain status through computed tomographic scanning are discussed.

Computed Tomographic Brain Scanning in Children with Developmental Neuropsychiatric Disorders

Eighty-five patients with childhood-onset pervasive neuropsychiatric disorders (infantile autism, pervasive developmental disorders, developmental language disorders, severe attentional deficit disorders with learning difficulties, and Tourette's syndrome of chronic multiple tics) underwent computed tomographic scanning of the brain. Clinical assessments of each image of the patients' scans by a diagnostic radiologist, who was “blind” to the neuropsychiatric diagnosis, were used in the first phase of the study, which is reported here. Twenty-four percent of the scan series revealed clear abnormalities and 13% showed mild asymmetrics in ventricular and/or hemispheric size. Of the children with pervasive developmental disorder, 59% had abnormal scans, as did 44% of the language impaired and 38% of the Tourette's syndrome groups. No distinct abnormality was isolated by which diagnostic categories could be separated, nor was an increased prevalence of scan abnormalities associated with overall severity of symptoms. Mild asymmetries, involving increased size of the left hemisphere and/or the left ventricular system, were found in all diagnostic groups.

Gilles de la tourette syndrome in oriental children

Seventy-four cases of tic syndromes were classified into four groups: chronic multiple tics, subacute multiple tics, chronic simple tics and transient simple tics, and 37 cases of chronic multiple tics (Tourette syndrome) were investigated. Clinical evaluation suggested that a transition existed between the four groups. Posture abnormalities were found in 27% of Tourette syndrome and a relation to dystonia was implied. Clinical evaluation and studies of catecholamine blockers' effectiveness suggested the validity of subtyping Tourette syndrome into four groups whose topographical or biochemical abnormalities differ. It was argued that the neurochemical basis of Tourette syndrome might lie in a multiplicity of biochemical abnormalities including disturbances of dopaminergic and noradrenergic pathways.

EEG Profiles of Neuropsychiatrically Disturbed Children

The use of the electroencephalogram (EEG) in clinical research and as a diagnostic tool requires operationally defined diagnostic criteria and objective EEG reporting. We studied the EEGs of 119 children with neuropsychiatric disorders, including childhood autism, aphasia, schizophrenia, and chronic multiple tics (Tourette syndrome). It was possible to discriminate between select populations on the basis of clusters of EEG findings, despite overall similarity on the normal-abnormal dimension. Examination of individual EEG parameters and sex differences suggests different pathways to similar behavioral phenotypes. EEG profiles may be related to differential patterns of disorganization of cerebral functioning in child psychiatric population.

Tics and tourette's: A continuum of symptoms?

Analysis of the families of 39 unselected children with Tourette syndrome revealed other members with tic disorders in twenty kindreds. In eight families there were 13 individuals with chronic multiple tics, usually motor, not vocal. Twelve different families contained 18 subjects with Tourette syndrome other than the index patient. In three of these families there were 6 additional individuals with chronic motor tics, forming a bridge to the first group. An autosomal dominant mode of inheritance was suggested in all cases. Tourette syndrome and chronic motor tics appear to represent conditions along a continuum and have, in many instances, a hereditary basis.

Animal Models and Childhood Behavioral Disturbances: Dopamine Depletion in the Newborn Rat Pup

Abstract Abnormalities in catecholamine metabolism have been implicated in the pathogenesis of various psychiatric disturbances of childhood, including minimal brain or cerebral dysfunction (MBD), childhood psychosis, affective disturbances, and the syndrome of chronic multiple tics. Developmental research on the relationship between brain function and behavior can be facilitated by appropriate animal models, interpreted conservatively. When rat pups are selectively depleted of brain dopamine by treatment with 6-hydroxydopamine in the newborn period, they display a constellation of behaviors similar to those seen in childhood MBD: hyperactivity, disturbed habituation, cognitive deficits, and “normalization” with stimulant medication. As adults, dopamine-depleted rats exhibit aberrations in mothering. This and similar models may help clarify certain aspects of the developmental associations between alterations in brain physiology, abnormal psychological mechanisms, and the emergence of behavioral deviance.

Chronic, Multiple Tics of Gilles de la Tourette's Disease

Central nervous system metabolism in six children and one adult with the syndrome of chronic multiple tics was studied by measuring the accumulation of acid metabolites of dopamine and serotonin (homovanillic acid [HVA] and 5-hydroxyindole-acetic acid [5-HIAA], respectively) in the CSF following probenecid administration. The accumulation of 5-HIAA was reduced in patients with multiple tics in contrast with other pediatric patients (N = 27). The degree of reduction in 5-HIAA relative to HVA appeared to be associated with the severity of the tic disorder. With dextroamphetamine, tic symptoms worsened, CSF HVA level decreased, and CSF 5-HIAA concentration increased. These findings suggest an association in Gilles de la Tourette's disease of reduced functioning of inhibitory serotonergic mechanisms and functional dopaminergic overactivity.