Gilles De La Tourette Syndrome

A number sign (#) is used with this entry because evidence suggests that mutations in one or more genes can cause Gilles de la Tourette syndrome (GTS). See MOLECULAR GENETICS and MAPPING.

Description

Tourette syndrome is a neurobehavioral disorder manifest particularly by motor and vocal tics and associated with behavioral abnormalities. Tics are sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics) or sounds (phonic or vocal tics). They typically consist of simple, coordinated, repetitive movements, gestures, or utterances that mimic fragments of normal behavior. Motor tics may range from simple blinking, nose twitching, and head jerking to more complex throwing, hitting, or making rude gestures. Phonic tics include sniffling, throat clearing, blowing, coughing, echolalia, or coprolalia. Males are affected about 3 times more often than females, and onset usually occurs between 3 and 8 years of age. By age 18 years, more than half of affected individuals are free of tics, but they may persist into adulthood (review by Jankovic, 2001).

Clinical Features

Gilles de la Tourette (1885) first described this disorder as a nervous affliction characterized by motor incoordination accompanied by echolalia and coprolalia (see HISTORY).

Kurlan et al. (1986) reported on a large Mennonite kindred from Alberta with chronic motor tics and vocal tics inherited in a probable autosomal dominant pattern. Studies led them to conclude that 10 persons had definite and 15 probable Tourette syndrome, and that 3 had definite and 1 probable chronic motor tics. In this kindred, Kurlan et al. (1987) later found that 30% of 54 persons thought to be affected were unaware of tics noted by the examiners and only 18.5% of the affected members had sought medical care. From these findings, the authors concluded that most cases are mild and do not come to medical attention; therefore, the disorder may be more prevalent than is generally appreciated.

Although one of the most notorious symptoms of the Tourette syndrome, coprolalia is rather infrequent. Goldenberg et al. (1994) found only 8% of their 112 patients exhibited coprolalia.

Fabbrini et al. (2007) reported a large Italian family with Tourette syndrome. Fifteen individuals had tics or other behavioral abnormalities: 5 had definite GTS, 5 had chronic motor tics, 2 had nonspecific tic disorder, and 3 had obsessive-compulsive disorder without motor or phonic tics. The disorder spanned 5 generations and appeared to show autosomal dominant inheritance. The mean age at onset was 9.9 years. Motor tics involved mainly the head and neck, and included head turning, eye blinking, facial grimacing, and shoulder shrugging. One individual each had pathologic gambling (606349), panic disorder (167870), generalized anxiety disorder (607834), and major depression (MDD; 608516). No patients had coprolalia. The findings confirmed Tourette syndrome as a neuropsychiatric disorder with a strong genetic background.

Ercan-Sencicek et al. (2010) reported a 2-generation family in which a father and all 8 of his children had Tourette syndrome. The father and 3 of the children also had OCD; 1 of the children with OCD also had Asperger (see 209850) and trichotillomania (TTM; 613229). The features of Tourette syndrome included eye rolling and blinking, throat clearing, limb moving, snorting, humming, swearing, jaw tightening or jutting, and shoulder shrugging, to name a few. Most family members also had evidence of a possible connective tissue disorder, with hypermobile joints and pectus excavatum, but only 1 individual was diagnosed with a variant of Ehlers-Danlos syndrome (130000). The mother, who did not have Tourette syndrome, had a history of Chiari malformation type I (118420) with tethered spinal cord, which was present in 5 of the affected children. In addition to 8 living children, the mother had had 7 miscarriages.

Other Features

In a series of 114 patients with Tourette syndrome, Van Woert et al. (1977) found that 43% had self-mutilating behavior.

In a family study of 86 probands, Pauls et al. (1988) found an increased frequency of Tourette syndrome, chronic tics, and obsessive-compulsive disorder (OCD; 164230) among first-degree relatives, but did not find an increased frequency of attention deficit disorder, conduct disorder, major depressive disorder, manic-depressive disorder, panic disorder, phobic disorders, schizoid disorders, sleep disorders, specific reading disability, or stuttering, as had been suggested by Comings and Comings (1987). Comings and Comings (1988) gave a lengthy rebuttal.

In a controversial presidential address to the American Society of Human Genetics, Comings (1989) extended the phenotypic range of expression of the GTS gene to include male type II alcoholism and the female type of familial obesity. He suggested that 'the primary problem is an appetitive compulsion that takes the form of alcoholism in men and of overeating in women.'

In a full report of their study of 338 biologic relatives of 86 GTS probands, 21 biologically unrelated relatives of adopted GTS probands, and 22 relatives of normal subjects, Pauls et al. (1991) found that the rates of GTS, chronic tics, and OCD in the total sample of biologic relatives of GTS probands were significantly greater than in the relatives of controls. In addition, the morbid risks of GTS, OCD, and chronic tics were not significantly different in families of probands with OCD when compared to relatives of probands without OCD. These findings were presented as further evidence that OCD is etiologically related to GTS.

Sverd (1991) and Comings and Comings (1991) reported families in which autism (see 209850) or pervasive developmental disorder (PDD) and Tourette syndrome coexisted, sometimes in the same individual. Comings and Comings (1991) described a PDD-to-GTS transition.

In reviews of Tourette syndrome, Jankovic (2001) and O'Rourke et al. (2009) stated that GTS is highly associated with attention deficit-hyperactivity disorder (ADHD; 143465) and OCD. Other behavioral problems can include poor impulse and anger control.

Biochemical Features

Because self-mutilation is so conspicuous a feature of the Lesch-Nyhan syndrome (see 308000), attention was directed to purine metabolism in GTS. The activity of HGPRT and APRT of red cell lysates was normal, but red cell HGPRT was less stable than normal, and abnormal enzyme peaks were detected after isoelectric focusing (Van Woert et al., 1977).

Comings (1990) found significant decreases in the serotonin/platelet ratio and in blood tryptophan level in unmedicated patients with GTS. A comparable significant decrease was found in parents of GTS patients, and there was no difference between parents with and those without symptoms. From these findings, Comings (1990) suggested tryptophan oxygenase (TDO2; 191070) as a possible candidate gene.

Pathogenesis

Comings (1987) suggested that the spectrum of behavior in Tourette syndrome can be explained on the basis of a gene causing an imbalance of the mesencephalic-mesolimbic dopamine pathways, resulting in disinhibition of the limbic system. Comings (1987) pointed out that the limbic system has been characterized as controlling the 4 F's--fight, flight, feeding, and sexual activity. He concluded: 'It has not escaped my attention that the reason many of the disorders described in the present series of papers (Comings and Comings, 1987) are so common is that they are (1) genetic, (2) dominant, and (3) result in disinhibition, especially of sexual activity.' Pauls et al. (1988) criticized the methods and conclusions of the studies of Comings and Comings (1987).

Involvement of dopaminergic systems in the basal ganglia have long been suspected to be of etiologic importance in this disorder because of the efficacy of dopamine D2 receptor antagonists in ameliorating some symptoms and the exacerbation of symptoms by dopamimetic agents. Singer et al. (1991) provided additional evidence for involvement of the basal ganglia by demonstrating a significant difference in measures of symmetry in the putamen and lenticular nucleus between Tourette patients and normal controls.

Wolf et al. (1996) reported increased binding of iodobenzamide to D2 receptors (see, e.g., DRD1; 126449) in the caudate nucleus but not the putamen in all 5 identical twins who were more affected than their similarly diagnosed twin sibs. Additional studies demonstrated no difference in regional cerebral blood flow. Wolf et al. (1996) discounted confounding by treatment with neuroleptic drugs because they had kept their study subjects free of neuroleptics for an extended period of time before the study by single photon emission computed tomography (SPECT). However, no information was provided on possible earlier discrepancies in medication history between severely and less severely affected twins.

Tobe et al. (2010) observed an association between abnormal cerebellar morphology and Tourette syndrome. Using high-resolution MRI in 163 patients with GTS and 147 controls, Tobe et al. (2010) found that GTS patients had volume reduction of the lateral cerebellar hemispheres compared to controls. The affected regions were localized to the gray matter portions of crus I and lobules VI, VIIB, and VIIIA. In both cases and controls, these volumes showed a significantly progressive decline with age in males, but not in females. Volume contraction in these cerebellar regions was associated with more severe tic symptoms and motoric disinhibition. Comorbid OCD was associated with relative enlargement of these regions in proportion to increasing severity of OCD symptoms. There was no apparent effect for comorbid ADHD.

Inheritance

The familial nature of this syndrome was noted by de la Tourette (1885) when he observed that mild cases occurred in the families of patients with the classic clinical picture. Eisenberg et al. (1959) confirmed the familial aggregation.

Parent-offspring involvement is known (Sanders, 1973; Friel, 1973). In 2 of 6 patients studied by Johnson et al. (1977), other members of the family (a father and a maternal uncle) were also affected.

Golden (1978) supported dominant inheritance. In a study of the families of 40 cases, he found 12 with 17 additional cases: 3 fathers, 4 mothers, 4 sibs, and 6 other relatives. An overrepresentation of persons of Ashkenazi or Mediterranean origin was noted.

Wilson et al. (1978) questioned the existence of any significant genetic component.

Nee et al. (1980) evaluated 50 cases. In 16 patients there was a family history of Gilles de la Tourette syndrome and in another 16 a family history of tics. No preponderance of Jewish background was encountered. Obsessive-compulsive behavior was displayed by 34 patients.

Comings et al. (1984) analyzed the families of 250 consecutive, unselected patients with Tourette syndrome and evaluated the inheritance of the combined tic-Tourette trait. They concluded that the most likely mode of inheritance is a major semidominant gene, Ts, with low heritability of multifactorial background variation. They rejected a pure recessive major gene effect and rejected the hypothesis of no major gene effect for any estimate of lifetime risk less than 1.2%. They estimated the frequency of the semidominant autosomal allele to be 0.4 to 0.9%. Assuming a frequency of 0.5%, penetrance of about 94% was estimated for Ts/Ts homozygotes, 50% for Ts/ts heterozygotes, and less than 0.3% for ts/ts homozygotes. More than 2 of every 3 cases are heterozygotes and most other cases are phenocopies or new mutations. Devor (1984) arrived at a similar conclusion by analyzing 35 published pedigrees.

Comings and Comings (1985) presented the findings in a series of 250 consecutive patients seen in a 3-year period. The sex ratio was 4 males to 1 female. Again the disorder was not more frequent in Jews (10% of the cases).

Pauls and Leckman (1986) concluded that obsessive-compulsive disorder is etiologically related to Tourette syndrome and chronic tics and that the Tourette syndrome is inherited as a highly penetrant, sex-influenced, autosomal dominant. They based these conclusions on segregation analyses in 30 nuclear families identified through 27 index cases. In the analyses of subjects with Tourette syndrome, chronic tics, or obsessive-compulsive disorder, the estimates of penetrance for the genotypes AA, Aa, and aa (A denoting the abnormal allele) were 1.000, 1.000, and 0.002, respectively, for males and 0.709, 0.709, and 0.000 for females. They estimated that approximately 10% of all patients are phenocopies.

Zausmer and Dewey (1987) found 46 persons who were 'tiqueurs' among the first- and second-degree relatives of 91 proband child tiqueurs.

On the basis of detailed pedigree data on more than 1,200 GTS families, Comings et al. (1989) concluded that the inheritance is 'semidominant, semirecessive.'

Kurlan et al. (1994) assessed the frequency of bilineal (i.e., from both maternal and paternal sides) transmission of GTS in 39 families in which 5 or more relatives were reported to be affected and 39 consecutively ascertained probands referred for evaluation of the disorder. In the first group of pedigrees, bilineal transmission was evident in 33% (considering tics) and 41% (considering tics or obsessive-compulsive behavior) of families. For the consecutive pedigrees, bilineal transmission was seen in 15% (tics) and 26% (tics or obsessive-compulsive behavior) of families. Both parents of the proband were affected in 38% of the first group of pedigrees and 10% of the consecutive pedigrees. In the first group of pedigrees, the frequency of bilineal transmission appeared to be related to the severity of the disorder in the proband; for both pedigree groups, the frequency of both parents' being affected was higher in families in which the proband's symptoms were severe. Kurlan et al. (1994) concluded that bilineal transmission and homozygosity are common in Tourette syndrome and may play a role in severity of illness as well as account for difficulties in localizing the gene defect by linkage analysis.

In a single large pedigree containing 182 members, Hasstedt et al. (1995) tested for major locus inheritance using segregation analysis incorporating assortative mating. The analysis provided evidence of a major locus with an intermediate inheritance pattern for which the penetrance was estimated from the data as 28% in heterozygotes and 98 to 99% in homozygotes. A significant assortative mating correlation was estimated from the data as 70 to 79%. In contrast, when assortative mating was not included in the model, intermediate inheritance was not inferred. If, in addition, constancy of the allele frequencies across generations was not assumed, mendelian transmission was rejected. When each subject, affected or unaffected, was assigned a score reflecting the presence and severity of symptoms, higher mean scores in affected homozygotes than in affected heterozygotes suggested greater severity in homozygotes. (Genotype information was obtained from genotype probabilities computed assuming intermediate inheritance.)

Walkup et al. (1996) performed complex segregation analysis on the data obtained from 53 independently ascertained children and adolescents with GTS and their 154 first-degree relatives. The results suggested that the susceptibility to GTS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitely rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the GTS susceptibility allele was estimated to be 0.01. The major locus accounted for over half of the phenotypic variance for GTS, whereas a multifactorial background accounted for approximately 40% of phenotypic variance. Penetrance estimates suggested that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with GTS, approximately 62% are heterozygous and approximately 38% are homozygous at the major locus. Walkup et al. (1996) noted that while none of the families had 2 parents affected with GTS, 19% of families had 2 parents affected with the broader GTS phenotype, which includes GTS, chronic tic disorder, or obsessive-compulsive disorder.

Patel (1996) reviewed the 'quest for the elusive genetic basis of Tourette syndrome.'

In a review of Tourette syndrome, Jankovic (2001) cited twin studies showing an 89 to 94% concordance for the disorder. One study involving 16 pairs of monozygotic twins showed that low birth weight was a strong predictor of more severe tics (Hyde et al., 1992). Transmission from both parents was found in 25 to 41% of families with Tourette syndrome (Hanna et al., 1999; Lichter et al., 1999).

Population Genetics

Kurlan et al. (1987) cited a prevalence of 28.7 per 100,000 in school children of Monroe County in New York. Kurlan (1994) estimated that 'developmental Tourette syndrome' occurred in at least 3% of all children and that up to 25% of children requiring special education may have mild to moderate Tourette syndrome. He proposed that these were the milder forms of the clinical spectrum that, at the extreme end, included the smallest group, patients with 'full-blown' Tourette syndrome.

Comings (1987) suggested that GTS is one of the most common genetic disorders affecting man, with a frequency of about 1 in 100, and that the complete range of behavioral problems is much broader than merely motor and vocal tics.

Mapping

Linkage to Chromosome 2p

The Tourette Syndrome Association International Consortium for Genetics (2007) reported the results of the largest genetic linkage study that had been undertaken for Tourette syndrome. The sample analyzed included 238 nuclear families yielding 304 'independent' sib pairs and 18 separate multigenerational families, for a total of 2,040 individuals. A whole genome screen using 390 microsatellite markers was completed. Analyses were completed using 2 diagnostic classifications: (1) only individuals with TS were included as affected, and (2) individuals with either TS or chronic tic (CT) disorder were included as affected. Strong evidence of linkage was observed for a region on chromosome 2p (p = 3.8 x 10(-5)). Results from several of the regions also provided moderate evidence of additional susceptibility loci for TS. No support was provided in this study for SLITRK1 (609678) on chromosome 13 as a susceptibility gene for TS.

Linkage to Chromosome 3

Brett et al. (1990) suggested possible linkage to markers located in the region 3p21-p14. Evidence of linkage was found to both THRB (190160) and RAF1 (164760), as well as to an anonymous marker, D3S11; a total maximum lod score of 2.998 was reported.

Linkage to Chromosome 4q

The Tourette Syndrome Association International Consortium for Genetics (1999) reported the results of a systematic genome screen of Tourette syndrome, using 76 families with a total of 110 sib pairs. While no results reached acceptable statistical significance, the multipoint maximum-likelihood scores (MLSs) for 2 regions, 4q and 8p, were suggested (MLS more than 2.0). Four additional genomic regions also gave multipoint MLSs between 1.0 and 2.0. Zhang et al. (2002) found linkage of hoarding, a Tourette syndrome subphenotype, to 4q34-q35 (p = 0.0007); the 4q site is in proximity to D4S1625.

Linkage to Chromosome 5

Zhang et al. (2002) found linkage of hoarding, a Tourette syndrome subphenotype, to 5q35.2-q35.3 (P = 0.000002).

Linkage to Chromosome 6p21

Riviere et al. (2009) genotyped 14 SNPs spanning 3 genomic loci (chromosomes 2p, 6p, and 15q) that had been found to be associated with restless legs syndrome (see RLS6; 611185), which shares some common movement features and perhaps involvement of the frontostriatal circuits. In a case-control study of 322 French Canadian patients with GTS and and 290 controls, Riviere et al. (2009) found an association between GTS and SNPs in intron 7 of the BTBD9 gene (611237) on chromosome 6p21. The major T risk allele of rs9357271 showed the most significant association with GTS (p = 0.005). Phenotypic stratification of the patients showed that the BTBD9 variants were most strongly associated with GTS without obsessive-compulsive disorder (OCD; 164230), and that allelic frequency of rs9357271 inversely correlated with severity of OCD. The findings did not reach significance in a family study of 298 French Canadian family trios with GTS, which included the patients in the case-control study.

Linkage to Chromosome 7

Because of cytogenetic studies implicating the 7q31 region in isolated cases of Tourette syndrome (Boghosian-Sell et al., 1996; Petek et al., 2001), Diaz-Anzaldua et al. (2004) undertook a family-based association study in a sample of French Canadian patients from Quebec using markers from that region. In the transmission disequilibrium test, they showed a biased transmission of alleles from heterozygote parents to their GTS offspring. When the analysis was restricted to patients without attention deficit hyperactivity disorder (ADHD; 143465) or OCD comorbidity, similar results were observed. A marker contained in the IMMP2L gene, which maps to the same region of 7q, also showed a tendency for association.

Linkage to Chromosome 11

To detect the underlying susceptibility gene(s) for GTS, Merette et al. (2000) performed linkage analysis in a large French Canadian family from the Charlevoix region of Quebec, in which 20 family members were definitely affected by GTS and 20 others showed related tic disorders. Using model-based linkage analysis, they observed a lod score of 3.24 at chromosome 11q23. This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with GTS had been detected in an Afrikaner population by Simonic et al. (1998).

To replicate reports of association and linkage between Tourette syndrome and markers at 11q24, Diaz-Anzaldua et al. (2005) undertook a family-based association study in 199 French Canadian TS nuclear families. The transmission disequilibrium test (TDT) analysis failed to detect an association between TS and 6 markers from 11q24. No haplotype combining alleles from the region was associated with the disorder. Linkage disequilibrium analysis showed evidence of historical recombination between every contiguous pair of markers, indicating that these genetic variants are probably in equilibrium in the French Canadian population.

Locus on Chromosome 13

See 'Variation in the SLITRK2 Gene' in Molecular Genetics Section.

Locus on Chromosome 15

See 'Mutation in the HDC Gene' in Molecular Genetics Section.

Linkage to Chromosome 17q25

Zhang et al. (2002) performed a genome scan of the hoarding phenotype (a component of OCD) on 77 sib pairs collected by the Tourette Syndrome Association International Consortium for Genetics. All sib pairs were concordant for a diagnosis of Gilles de la Tourette syndrome. Analyses reported by Zhang et al. (2002) were conducted for hoarding as both a dichotomous trait and a quantitative trait. Not all sib pairs in the sample were concordant for hoarding. Significant allele sharing was observed for both the dichotomous and the quantitative hoarding phenotypes for markers at 4q34-q35 (P = 0.0007), by use of GENEHUNTER, and at 5q35.2-q35.3 (P = 0.000002) and at 17q25 (P = 0.00002), by use of the Haseman-Elston method.

Because of the interest in a relationship between GTS and 17q25 raised by the study of Zhang et al. (2002) and others, Paschou et al. (2004) focused linkage studies on this area. An initial scan of chromosome 17 performed on 2 large pedigrees provided a nonparametric lod score of 2.41 near marker D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (p = 0.002). The original families, as well as 2 additional pedigrees, were genotyped for 25 SNPs, with a focus on 3 genes in the 17q25 region which, based on their function and expression profile, could play a role in the development of GTS: NPTX1 (602367), IRSP53 (605475), and TBCD (604649). The background linkage disequilibrium (LD) of the region was studied in 8 populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. Paschou et al. (2004) concluded that 17q25 was worthy of further investigation as a candidate susceptibility region for GTS.

Genomewide Association Studies

Barr et al. (1999) tested for linkage to Tourette syndrome in multigenerational families segregating for this condition using a panel of 386 markers with the largest interval between any 2 markers being 28 cM and an average distance between markers of 10 cM. No significant evidence for linkage was found with parametric analysis. For the nonparametric analysis, 8 markers were observed with a p value less than 0.00005 for significant evidence of linkage in at least 1 family. Barr et al. (1999) urged caution, however, in the interpretation of the nonparametric analyses, as this statistic (the affected-pedigree-member method) is known to have a high false-positive rate.

Exclusion Studies

On the basis of family linkage studies using DNA markers, Heutink et al. (1990) excluded all of chromosome 18 as well as the q21.3-qter region of chromosome 7 as the site for the GTS gene. By linkage studies, Pakstis et al. (1991) excluded more than 50% of the autosomal genome as the site of the Tourette syndrome (assuming that genetic heterogeneity is not an important factor).

The difficulties involved in linkage studies of GTS were reviewed by van de Wetering and Heutink (1993). They stated that an autosomal dominant pattern of inheritance with incomplete penetrance and variable expression was the most widely accepted model. Assuming that there is a single genetic vulnerability factor identical in all families, about 80% of the genome could be excluded as the site for the GTS gene by studies with over 600 DNA markers in an international collaborative effort.

Orth et al. (2007) reported a 3-generation family segregating both myoclonus dystonia (159900) and Gilles de la Tourette syndrome. There were 11 affected individuals: 3 had myoclonus dystonia, 2 had dystonia, 1 had GTS, 1 had tics, and 4 had various combinations of these with obsessive compulsive disorder. The phenotype of those with myoclonus dystonia was similar to that described for most families, with predominantly head, neck and arm myoclonus, mild cervical dystonia, and writer's cramp. Linkage analysis excluded association to the SGCE (604149), DYT15 (607488), DYT1 (128100), or DRD2 (126450) loci, and no pathogenic changes were identified in the SLITRK1 gene. Orth et al. (2007) suggested that there may be a novel susceptibility gene for both myoclonus dystonia and Tourette syndrome.

Cytogenetics

In linkage studies of 25 families, Comings et al. (1986) found no linkage but observed a family in which 6 members with various manifestations of Tourette syndrome carried a balanced translocation, t(7;18)(q22;q22.1). Linkage to COL1A2 (120160) on 7q22 was excluded, suggesting that the mutation is on chromosome 18. They noted with interest the assignment of the gene for gastrin-releasing peptide (bombesin; 137260) and pointed to this as a candidate for the site of the mutation in Tourette syndrome. They stated that injection of bombesin 'into the brains of mice reproduce many of the symptoms of Tourette syndrome.' Donnai (1987) presented further evidence for the location of the Tourette gene at 18q22.1; deletion at this site was found in a 23-year-old woman who 'had the behavioral characteristics described in members of Tourette families.' In the individual with the translocation between chromosomes 7 and 18 with Tourette syndrome reported by Comings et al. (1986), Boghosian-Sell et al. (1996) undertook physical mapping of the breakpoints on chromosomes 7 and 18 for identification of specific genes that might be involved in the Tourette syndrome phenotype. Using somatic cell hybrids retaining either the small der(7) or the der(18) chromosome, a more precise localization of the breakpoints was determined. Furthermore, physical mapping identified 2 YAC clones that span the translocation breakpoint on chromosome 18 as determined by fluorescence in situ hybridization.

Taylor et al. (1991) observed a de novo case of GTS in a boy who had deletion of the terminal portion of the short arm of chromosome 9, del(9)(qter-p2304:). The patient demonstrated only mild features of the 9p deletion syndrome, yet manifested all the features of GTS.

Petek et al. (2001) and Kroisel et al. (2001) identified a 13-year-old male with GTS and other anomalies who carried a de novo duplication of the long arm of chromosome 7 [46,XY,dup(7)(q22.1-q31.1)]. Further molecular analysis demonstrated that the duplication was inverted. The distal chromosomal breakpoint occurred between 2 genetic markers, D7S515 and D7S522, that define a region previously shown to be disrupted in a case of GTS (Boghosian-Sell et al., 1996). Additional anomalies in the patient reported by Petek et al. (2001) included reduced speech development, depression, strabismus convergens, a malformed left ear, stenosis of the meatus acusticus, slight microgenia, and gynecomastia. By further study, Petek et al. (2001) found that a novel gene, inner mitochondrial membrane peptidase-2-like (IMMP2L; 605977), was disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31.

In a review of all published cases of chromosomal translocations or inversions identified in patients with GTS, State et al. (2003) found that 3 segments of the genome had been reported to be rearranged in more than 1 unrelated individual: chromosomes 18q (Donnai, 1987; Boghosian-Sell et al., 1996), 7q (Petek et al., 2001), and 8q (Matsumoto et al., 2000).

State et al. (2003) reported a 12-year-old boy of Korean descent with chronic tics and OCD who was found to carry a paracentric inversion involving 18q22. They mapped the telomeric end of the inversion to a genomic location within 1 Mb of a previously described translocation that cosegregated in a family with a range of clinical phenomena encompassing GTS, chronic tics, and OCD (Boghosian-Sell et al., 1996). A detailed characterization of the rearrangement breakpoint revealed a relatively gene-poor region with 2 nearby transcripts, neither of which was structurally altered by the chromosomal abnormality. Many reports confirmed that balanced chromosomal abnormalities many hundreds of kilobases from disease-related genes may lead to the expected disease phenotypes (Kleinjan and van Heyningen, 1998). To explore the possibility that long-range position effects might be playing a role in their patient, State et al. (2003) undertook experiments assessing replication synchrony versus asynchrony in the patient and controls to evaluate this hypothesis and characterize the epigenetic phenomena in this genomic interval. They found a significant increase in replication asynchrony in the patient compared to controls, with the inverted chromosome showing delayed replication timing across an interval of at least 500 kb. The findings were consistent with long-range functional dysregulation of 1 or more genes in the region. The data supported a link between chromosomal aberrations and epigenetic mechanisms in GTS and suggested that the study of the functional consequences of balanced chromosomal rearrangements is warranted in patients with phenotypes of interest, irrespective of the findings regarding structurally disrupted transcripts.

Crawford et al. (2003) described 2 unrelated families wherein balanced t(6;8) chromosomal translocations occurred in individuals diagnosed with Tourette syndrome. In 1 of these families, the transmission of the translocation was associated with learning and behavioral difficulties. In the other family, 1 parent was unaffected and the other could not be traced; thus, transmission could not be demonstrated and it is possible the translocation may have occurred de novo. The breakpoint on chromosome 8 occurred within the q13 band in both families, suggesting that a gene or genes in this region may contribute to the Tourette syndrome phenotype. Linkage studies had previously suggested involvement of 8q and previously balanced translocations t(3;8) and t(1;8) had been reported by Brett et al. (1996) and Devor and Magee (1999), respectively. In their case, Crawford et al. (2003) identified a 200-kb BAC, which, by FISH, they demonstrated encompasses the chromosome 8 breakpoint in both families. They suggested that the fact that the chromosomal breaks in the TS cases from both families occur within such a small region of chromosome 8 supports the hypothesis that disruption of a specific gene or genes on 8q contributes to the clinical phenotype.

Verkerk et al. (2003) reported a family in which the father had OCD and both of his children, a girl and a boy, had GTS, OCD, mental retardation, speech abnormalities, and growth retardation. All 3 individuals had a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The father had inv(2)(p23q22),ins(7;2)(q35-q36;p21p23) and the 2 affected children inherited the abnormal chromosome 7, sharing the 2p21-p23 insertion on 7q35-q36. Both children had a normal chromosome 2; thus both children had 3 copies of this region on chromosome 2. Fine mapping of the involved regions using FISH and BAC clones showed that the insertion interrupted the contactin-associated protein-2 gene (CNTNAP2; 604569), which encodes a membrane protein located in axons at the nodes of Ranvier. Verkerk et al. (2003) hypothesized that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of potassium channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.

Belloso et al. (2007) reported a familial balanced reciprocal translocation t(7;15)(q35;q26.1) in phenotypically normal individuals, in which the 7q35 breakpoint disrupted the CNTNAP2 gene (604569). The authors concluded that truncation of CNTNAP2 does not necessarily result in the Gilles de la Tourette syndrome.

Diagnosis

The diagnostic criteria for Tourette syndrome recommended by the American Psychiatric Association include both multiple motor and vocal tics over a period of more than 1 year, voluntary suppression of symptoms, a waxing and waning course, and onset between ages 2 and 15 years. An organic basis is supported by the finding of neuropsychologic dysfunction in many patients and the frequent therapeutic response to haloperidol.

Clinical Management

The self-mutilation and biochemical findings prompted trial of L-5-hydroxytryptophan, the precursor of serotonin, reported to relieve self-mutilation in the Lesch-Nyhan syndrome. Van Woert et al. (1977) described a 15-year-old boy who improved with this medication and who returned to aggressive behavior, tics, biting and facial punching when given a placebo.

Molecular Genetics

Mutation in the HDC Gene

By genomewide linkage analysis followed by candidate gene sequencing in a large 2-generation family with Gilles de la Tourette syndrome, Ercan-Sencicek et al. (2010) identified a heterozygous nonsense mutation in the HDC gene (W317X; 142704.0001) in all 9 affected individuals. In vitro studies indicated that the mutation exerted a dominant-negative effect on the protein, resulting in lack of enzyme activity. Ercan-Sencicek et al. (2010) noted that animal studies had shown that lack of Hdc in mice results in increased locomotor and stereotypic behaviors, as well as increased anxiety. Overall, the findings suggested a role for histaminergic neurotransmission in neurobehavioral actions, such as tics.

Variation in the SLITRK1 Gene

Abelson et al. (2005) studied SLITRK1 as a candidate gene for GTS on chromosome 13q31.1 because of its proximity to a de novo chromosomal inversion in a child with the syndrome and no family history. Although they found no mutation in the child, they identified 2 different mutations in the SLITRK1 gene among 174 unrelated probands with GTS. The proband in 1 family, who had GTS and ADHD, had a single-base deletion in the coding region, leading to a frameshift mutation (609678.0001). The mutation was also found in the patient's mother, who had trichotillomania (613229). In 2 other probands, who had GTS and symptoms of OCD, they identified a single-base change (designated var321) in the 3-prime UTR of the gene (609678.0002). The base change corresponds to a highly conserved nucleotide within the predicted binding site for a microRNA, hsa-miR-189. The var321 mutations occurred on different haplotypes in the patients, indicating that they arose independently. Abelson et al. (2005) demonstrated that SLITRK1 mRNA and hsa-miR-189 have an overlapping expression pattern in brain regions previously implicated in Tourette syndrome. Wildtype SLITRK1, but not the frameshift mutant, enhanced dendritic growth in primary neuronal cultures. Abelson et al. (2005) concluded that their findings support the association of rare SLITRK1 sequence variants with Tourette syndrome.

There is controversial evidence about whether or not variation in the SLITRK1 gene plays a role in Tourette syndrome. Deng et al. (2006) and Chou et al. (2007) did not find the var321 change or any other potentially pathogenic changes in the SLITRK1 gene in 82 Caucasian and 160 Taiwanese patients with GTS, respectively. Fabbrini et al. (2007) also excluded the SLITRK1 as a basis for Tourette syndrome in a large Italian family. Although Fabbrini et al. (2007) did identify the var321 change in a few family members and 1 spouse, it did not segregate with the disorder. In addition, a genomewide linkage study by the Tourette Syndrome Association International Consortium for Genetics (2007) showed no support for a locus on chromosome 13 in Tourette syndrome.

Exome Sequencing Studies

By whole-exome sequencing of a 3-generation family in which 7 individuals had Tourette syndrome/chronic tic disorder, Sundaram et al. (2011) identified 4 novel nonsynonymous variants that segregated perfectly with the phenotype in all 7 affected family members. These variants included a pro45-to-ser (P45S) substitution in the PVRL3 gene (607147); a ser75-to-asn (S75N) substitution in the MRPL3 gene (607118); an ala2057-to-ser (A2057S) substitution in the DNAJC13 gene (614334); and an arg129-to-gly (R129G) substitution in the OFCC1 gene (614287). Three of the variants (in the MRPL3, DNAJC13, and OFCC1 genes) could be validated by Sanger sequencing; the PVRL3 variant could not be reliably verified. None of the variants were present in 100 controls or in the 1000 Genomes project. Comorbid disorders in affected individuals included obsessive-compulsive disorder (OCD; 164230) and attention deficit-hyperactivity disorder (ADHD; 143465). Subsequent analysis of 94 patients with GTS/chronic tics found that 2 carried a variant in the 5-prime untranslated region of the OFCC1 gene. Functional studies were not performed, and Sundaram et al. (2011) could not provide any insight into a potential disease mechanism based on the known functions of these genes. However, the authors postulated that the disorder may be caused by multiple rare variants in different genes.

History

Critchley (1986) gave a charming interpretation of the name of this disorder and of naming in general.

Pearce (1993) suggested that the well-known tics, mannerisms, postures, and verbal repetitions displayed by Samuel Johnson (1709-1784), the great scholar-lexicographer, were indications that he was a victim of Gilles de la Tourette syndrome.

Much of Gilles de la Tourette's description of the disorder that bears his name, the classic typology, was based on 'the case of the cursing marquise' (Itard, 1825). According to Kushner (1995), Gilles de la Tourette never examined or even met her. Moreover, Kushner (1995) insisted that, contrary to all the indications in the literature thereafter, Charcot (see Charcot, 1987) never diagnosed, treated, or even talked with the marquise. The Marquise de Dampierre was 26 years old when Itard (1825) reported her case; Georges Gilles de la Tourette was a 28-year-old neurologist at l'Hopital de la Salpetriere when he selected the marquise's life history as the first and prototypic example of the syndrome he set out to describe in an article published in 1885. Tourette's mentor, Jean-Martin Charcot, the director of l'Hopital de la Salpetriere and the foremost neurologist of late 19th century France, almost immediately renamed convulsive tic syndrome in honor of Gilles de la Tourette. By constructing a nosology that clearly distinguished convulsive motor and vocal tics from Sydenham's and other choreas, Gilles de la Tourette had provided another disorder for Charcot's journal project of classifying groups of neurologic symptoms into syndromes. Kushner (1995) observed that 'lecturers, as most of us know from personal experience, often repeat the same story slightly differently over time, and Charcot's explication of his encounter with the Marquise de Dampierre was no exception. What is unambiguous in four of these [his] lectures, however, is the fact that Charcot never had any direct contact with the marquise, let alone any contact with her as her physician.' (It is noteworthy that in 1881, Gilles de la Tourette published a translation of the 1880 article on 'jumping Frenchman of Maine' (244100) by American neurologist George Beard (1878).)

Animal Model