Detection of major gene for Gilles de la Tourette syndrome

The families of 250 consecutive, unselected patients with Tourette syndrome (TS) were analyzed. If the parents had either motor or vocal tics, but not both, there was an increased risk of both TS and tics in the offspring. The mode of inheritance of the combined tic-Tourette trait was evaluated in both nuclear families and extended pedigrees. Complex segregation analysis was carried out allowing for possible contributions from both a major autosomal locus and multifactorial inheritance of variation in the background of each genotype. The most likely mode of inheritance was a major semidominant gene, Ts, with low heritability of the multifactorial background variation. This was true regardless of assumptions about the prevalence of the disorder. The hypothesis of strict multifactorial inheritance could not be rejected with nuclear family data alone. However, the hypothesis of no major gene effect was rejected using data on 3 generations for any estimate of lifetime risk less than 12 per 1,000 in the general population. A pure recessive major gene effect was also rejected. With a gene frequency of approximately .5%, the penetrance was estimated to be about 94% in abnormal Ts/Ts homozygotes, 50% in Ts/ts heterozygotes, and less than 0.3% in normal ts/ts homozygotes. More than two of every three cases are heterozygotes, and nearly all other cases are phenocopies or new mutations. This is the first demonstration by segregation analysis of a major gene in a human neuropsychiatric disorder with a frequency approaching 1% of the population.     

A family study of Gilles de la Tourette syndrome.

Previous studies have demonstrated that Gilles de la Tourette syndrome (TS) is a familial disorder and that chronic tics (CT) and obsessive compulsive disorder (OCD) appear to be etiologically related to the syndrome. In the present study we report the results from a study of 338 biological relatives of 86 TS probands, 21 biologically unrelated relatives of adopted TS probands, and 22 relatives of normal subjects. The 43 first-degree relatives of the adopted TS and normal probands constituted a control sample. The rates of TS, CT, and OCD in the total sample of biological relatives of TS probands were significantly greater than in the relatives of controls. In addition, the morbid risks of TS, OCD, and CT were not significantly different in families of probands with OCD when compared to relatives of probands without OCD. These findings provide further evidence that OCD is etiologically related to TS.     

Genomewide scan of hoarding in sib pairs in which both sibs have Gilles de la Tourette syndrome

A genome scan of the hoarding phenotype (a component of obsessive-compulsive disorder) was conducted on 77 sib pairs collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). All sib pairs were concordant for a diagnosis of Gilles de la Tourette syndrome (GTS). However, the analyses reported here were conducted for hoarding as both a dichotomous trait and a quantitative trait. Not all sib pairs in the sample were concordant for hoarding. Standard linkage analyses were performed using GENEHUNTER and Haseman-Elston methods. In addition, novel analyses with a recursive-partitioning technique were employed. Significant allele sharing was observed for both the dichotomous and the quantitative hoarding phenotypes for markers at 4q34-35 (P=.0007), by use of GENEHUNTER, and at 5q35.2-35.3 (P=.000002) and 17q25 (P=.00002), by use of the revisited Haseman-Elston method. The 4q site is in proximity to D4S1625, which was identified by the TSAICG as a region linked to the GTS phenotype. The recursive-partitioning technique examined multiple markers simultaneously. Results suggest joint effects of specific loci on 5q and 4q, with an overall P value of.000003. Although P values were not adjusted for multiple comparison, nearly all were much smaller than the customary significance level of.0001 for genomewide scans.     

CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder

Gilles de la Tourette syndrome (GTS) is a sporadic or inherited complex neuropsychiatric disorder characterized by involuntary motor and vocal tics. There is comorbidity with disorders like obsessive compulsive disorder and attention deficit hyperactivity disorder. Until now linkage analysis has pointed to a number of chromosomal locations, but has failed to identify a clear candidate gene(s). We have investigated a GTS family with a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The affected father [46,XY,inv(2) (p23q22),ins(7;2) (q35-q36;p21p23)] and two affected children [46,XX,der(7)ins(7;2)(q35-q36;p21p23) and 46,XY,der(7)ins(7;2)(q35-q36;p213p23)] share a chromosome 2p21-p23 insertion on chromosome 7q35-q36, thereby interrupting the contactin-associated protein 2 gene (CNTNAP2). This gene encodes a membrane protein located in a specific compartment at the nodes of Ranvier of axons. We hypothesize that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of the K(+) channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.     

Stress management and Gilles de la Tourette's syndrome

Tourette's syndrome is a lifelong disorder characterized by multiple motor and verbal tics. The present study examined relaxation training and desensitization training as a method of reducing the frequency and intensity of tics and the distress they caused in a young adult diagnosed with Tourette's syndrome. After a period of symptom monitoring the subject underwent 3 weeks of intensive training in relaxation skills and 5 weeks of desensitization training with situational cues previously identified as eliciting Tourette's symptoms. According to self-report monitoring, the experience of symptoms was decreased across 3 global dimensions: distress (48%), frequency (48%), and intensity (50%), and an hourly symptom count (50%). Collateral parental symptom report agreed with an observed decreased across distress (40%), frequency (41%), and intensity (40%). Inspection of data suggests that both components of stress management added to total treatment efficacy.     

Stress management and Gilles de la Tourette's syndrome

Tourette's syndrome is a lifelong disorder characterized by multiple motor and verbal tics. The present study examined relaxation training and desensitization training as a method of reducing the frequency and intensity of tics and the distress they caused in a young adult diagnosed with Tourette's syndrome. After a period of symptom monitoring the subject underwent 3 weeks of intensive training in relaxation skills and 5 weeks of desensitization training with situational cues previously identified as eliciting Tourette's symptoms. According to self-report monitoring, the experience of symptoms was decreased across 3 global dimensions: distress (48%), frequency (48%), and intensity (50%), and an hourly symptom count (50%). Collateral parental symptom report agreed with an observed decrease across distress (40%), frequency (41%), and intensity (40%). Inspection of data suggests that both components of stress management added to total treatment efficacy.     

Complex segregation analysis of Gilles de la Tourette syndrome: further evidence for a major locus mode of transmission

A sample of 35 published pedigrees of Gilles de la Tourette syndrome is studied using complex segregation analysis with pointers. Results indicate the presence of a rare, semidominant, incompletely penetrant allele leading to affection. This result is consistent with that previously reported by Comings et al. on a larger, independent sample.     

抽动秽语综合征遗传学研究

抽动秽语综合症(Gilles de la Tourette’s syndrome,GTS,TS)是一种慢性复杂性神经精神障碍,多起病于儿童期,以多发性运动性抽动伴不自主发声为主要临床表现,并伴多种并发症及神经行为障碍.目前已有大量关于TS遗传学研究报道,但其主要遗传学基础尚未鉴定.在此就抽动秽语综合征的遗传学研究做一介绍.     

Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS.     

Auditory event-related potentials in adult patients with Gilles de la Tourette's syndrome in the oddball paradigm

In 20 Tourette patients and 20 control subjects auditory event-related potentials evoked in an oddball paradigm were studied in 2 conditions: a non-motor condition (NMC) in which subjects had to attend tones, and a motor condition (MC) in which they had to press a microswitch to deviant tones. In the NMC patients had a reduced P2 in response to the standards. The deviant-standard subtraction wave forms of the NMC showed a discernible MMN-P165-N2b-P3 complex in the controls, whereas in the patients only the P3 was well developed. In the MC patients had a reduced N1 to the standards. Both groups showed in the deviant-standard subtraction wave forms a clear MMN-P165-N2b-P3 complex, N2b being reduced in the patients. In the patients the P2 amplitude and latency to the standards and in the controls the N2b amplitude in the deviant-standard subtraction wave form were larger in the MC than in the NMC. Both groups also showed a larger P3 and a larger parietal slow positive wave in the MC than in the NMC.The results are discussed in relation to behavioural and neuropsychological disturbances found in Gilles de la Tourette's syndrome.     

Association of ADORA1 rs2228079 and ADORA2A rs5751876 Polymorphisms with Gilles de la Tourette Syndrome in the Polish Population

Background

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. Hyperactivity of dopaminergic transmission is considered a prime abnormality in the pathophysiology of tics. There are reciprocal antagonistic interactions between adenosine and dopamine transmission. The aim of the study was to analyze the association of two polymorphisms, rs2228079 in ADORA1 and rs5751876 in ADORA2A, with the risk of GTS and co-morbid disorders.

Material and Methods

A total of 162 Polish GTS patients and 270 healthy persons were enrolled in the study. Two polymorphisms were selected on the basis of knowledge of SNPs frequencies in ADORA1 and ADORA2A. Chi-square test was used for allelic and genotypic association studies. Association of genotypes with age of tic onset was analyzed with Mann-Whitney test. Multivariate logistic regression was used to find independent predictors of GTS risk.

Results

We found that the risk of GTS was associated with rs2228079 and rs5751876 polymorphisms. The GG+GT genotypes of rs2228079 in ADORA1 were underrepresented in GTS patients (p = 0.011), whereas T allele of rs5751876 in ADORA2A was overrepresented (p = 0.017). The GG genotype of rs2228079 was associated with earlier age of tic onset (p = 0.046). We found also that the minor allele G of rs2228079 was more frequent in GTS patients with depression as compared to the patients without depression (p = 0.015). Also the genotype GG was significantly more frequent in patients with obsessive compulsive disorder/behavior (OCD/OCB, p = 0.021) and depression (p = 0.032), as compared to the patients without these co-morbidities. The minor allele T frequency of rs5751876 was lower in GTS patients with co-morbid attention deficit hyperactivity disorder (p = 0.022), and TT+TC genotypes were less frequent in the non-OCD anxiety disorder group (p = 0.045).

Conclusion

ADORA1 and ADORA2A variants are associated with the risk of GTS, co-morbid disorders, and may affect the age of tic onset.     

Current theories on the etiology and treatment of Gilles de la Tourette's disease]

Gilles de la Tourette syndrome is a condition marked by: (1) onset usually in childhood and adolescence, i.e. between 2 and 15 years of life; (2) violent facial tics and echolalia; (3) increased excitability and apathy; (4) progressive increase in symptoms intensity; (5) chronic course. This syndrome is threefold more frequent in men than in women. None hypothesis concerning its etiopathogenesis (genetic, organic, organic-functional, psychomotor, and mixed) does explain its origin. Many cases respond with some degree of relief to neuroleptics, carbamazepine, clonidine, and glucocorticosteroids. Neurosurgery and psychotherapy are also of value. Haloperidol is commonly considered the most effective in this syndrome.     

Compensatory neural reorganization in Tourette syndrome

Children with neurological disorders may follow unique developmental trajectories whereby they undergo compensatory neuroplastic changes in brain structure and function that help them gain control over their symptoms. We used behavioral and brain imaging techniques to investigate this conjecture in children with Tourette syndrome (TS). Using a behavioral task that induces high levels of intermanual conflict, we show that individuals with TS exhibit enhanced control of motor output. Then, using structural (diffusion-weighted imaging) brain imaging techniques, we demonstrate widespread differences in the white matter (WM) microstructure of the TS brain that include alterations in the corpus callosum and forceps minor (FM) WM that significantly predict tic severity in TS. Most importantly, we show that task performance for the TS group (but not for controls) is strongly predicted by the WM microstructure of the FM pathways that lead to the prefrontal cortex and by the functional magnetic resonance imaging blood oxygen level-dependent response in prefrontal areas connected by these tracts. These results provide evidence for compensatory brain reorganization that may underlie the increased self-regulation mechanisms that have been hypothesized to bring about the control of tics during adolescence.