Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3.

Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disorder and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al. 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation.     

Tourettesyndrome免疫病因学研究进展

多发性抽动症（Tourette syndrome）是一种慢性神经精神性疾病,好发于儿童和青少年,主要表现为一个或多个部位肌肉运动性或发声性抽动,发作期持续超过一年,间歇期不超过3个月。TS的病因和发病机制至今仍未明确,目前认为其发病与免疫因素,环境心理因素,遗传因素,生物化学因素等多种因素有关,目前,A族B溶血性链球菌与Ts的发生跟发展的关系已有所报道,较多研究是关于链球茵感染的,一些免疫相关研究发现与链球菌感染有关的小儿自身免疫性神经精神疾病会引发或加重抽动症状。另外,过敏性变态反应性疾病与Ts患儿的自身免疫应答活跃的关系也有所报道。神经．内分泌一免疫网络学说认为,外周免疫系统跟中枢神经系统之间,可通过直接接触或通过产生并释放出来的生物活性因子进行信息交流。细胞因子正是两大系统间相互作用的信使,不仅可以调节免疫,而且还可以调控神经元和神经胶质细胞的功能。细胞因子与神经介质、内分泌激素共同组成机体细胞间的信号分子,参与免疫系统并激活神经递质及激素间的信息传递,与精神障碍和心理机体反应密切相关。因此,有关免疫病因学异常可能是部分易感患儿发病的机制,文章从感染免疫学,过敏性变态反应性疾病,以及细胞因子调节网络等与免疫相关的几个方面加以综述。     

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.     

A controlled study of Tourette syndrome. VII. Summary: a common genetic disorder causing disinhibition of the limbic system.

Tourette syndrome (TS) is one of the most common genetic disorders affecting man. Approximately one in 100 individuals manifests one or more of the aspects of the TS gene. This series of papers has emphasized that although motor and vocal tics are the hallmark of TS, the complete range of behavioral problems is much broader. This spectrum of behavior can be explained on the basis of the TS gene causing an imbalance of the mesencephalic-mesolimbic dopamine pathways, resulting in disinhibition of the limbic system.     

A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems

Tourette syndrome (TS) is a common, hereditary, neurobehavioral disorder of childhood. To determine the frequency of various behavioral manifestations, we have compared 47 random normal controls to 246 patients with TS, 17 with attention-deficit disorder (ADD), and 15 with ADD secondary to a TS gene (ADD 2(0) TS). All subjects were examined prospectively with a 425-item questionnaire based on the Diagnostic Interview Schedule and the Diagnostic and Statistical Manual of Mental Disorders (DSM III). The TS patients were divided into grade 1 (too mild to treat [17.5%]), grade 2 (requiring treatment [58.9%]), and grade 3 (severe [23.6%]). Patients in all three grades of TS were significantly different from controls for DSM III symptoms of inattention, impulsivity, and hyperactivity. Sixty-two percent of TS patients had ADD, compared with 6.3% of controls; and 48.8% had ADD with hyperactivity (ADDH), compared with 4.2% of controls. In the majority of TS patients, the natural history of the disease was to start with ADDH and 2.4 years later develop motor and vocal tics. Among TS patients, 39% had previously received medication for ADDH or behavior problems, compared with 2% of the controls. Although stimulants can occasionally exacerbate tics, there was no evidence that stimulants cause TS and they are often a valuable adjunct to the treatment of TS. It is estimated that 10%-30% of ADDH is due to or associated with the presence of a TS gene. TS patients had a significantly increased frequency of (1) attending classes for the educationally handicapped, (2) placement in classes for the severely emotionally disturbed, (3) attending any special classes, (4) severe test anxiety, (5) stuttering, (6) letter, number, or word reversal, (7) reading very slowly, and (8) poor retention of material read. A reading-problem score (dyslexia) greater than or equal to 3 was present in 26.8% of TS patients, compared with 4.2% of controls. Number reversal, word reversal, and poor retention were significant even for the TS patients with tics too mild to treat. The multiple ways in which TS impacts school performance, as well as potential remedies, are discussed.     

The genetics of Tourette disorder

Tourette disorder (TD) is a childhood onset neuropsychiatric syndrome defined by persistent motor and vocal tics. Despite a long-standing consensus for a strong genetic contribution, the pace of discovery compared to other disorders of similar prevalence has been slow, due in part to a paucity of studies and both clinical heterogeneity and a complex genetic architecture. However, the potential for rapid progress is high. Recent rare variant findings have pointed to the importance of copy number variation, the overlap of risks among distinct diagnostic entities, the contribution of novel molecular mechanisms, and the value of family based studies. Finally, analysis of a cohort of sufficient size to identify common polymorphisms of plausible effect is underway, promising key information regarding the contribution of common alleles to TD.     

Genetic analysis of Tourette syndrome suggesting major gene effect.

Data on Gilles de la Tourette syndrome are analyzed by multiple threshold models in inheritance that incorporate sex effect. The polygenic-multifactorial model is rejected. Single major locus inheritance can account for the data, although many of the occurrences of Tourette are due to nongenetic phenocopies. In both models, males and females share a common genetic environmental liability, but the less prevalent sex, that is, females, has a higher genetic loading for the disorder. The predicted population prevalences in the single major locus model are 2.3% for males and 0.8% for females. The implications for genetic and biological research in Tourette syndrome are discussed.     

Dr Samuel Johnson's movement disorder.

Dr Samuel Johnson was noted by his friends to have almost constant tics and gesticulations, which startled those who met him for the first time. He also made noises and whistling sounds; he made repeated sounds and words and irregular or blowing respiratory noises. Further, he often carried out pronounced compulsive acts, such as touching posts, measuring his footsteps on leaving a room, and performing peculiar complex gestures and steps before crossing a threshold. His symptoms of (a) involuntary muscle jerking movements and complex motor acts, (b) involuntary vocalisation, and (c) compulsive actions constitute the symptom complex of Gilles de la Tourette syndrome (Tourette''s syndrome), from which Johnson suffered most of his life. This syndrome is of increasing interest recently because it responds to haloperidol, and because there are new insights into a possible biochemical basis for the tics, vocalisations, and compulsions.     

A controlled study of Tourette syndrome. V. Depression and mania.

To evaluate the role of depression and mania in Tourette syndrome (TS), we have examined 246 TS patients, 17 attention-deficit disorder (ADD) patients, 15 patients with ADD associated with TS, and 47 controls, using (1) the standardized National Institutes of Mental Health Diagnostic Interview Schedule questions for a life history of major depression and/or mania and (2) a modified Beck depression score for evaluation of depression at the time of the examination. The results were combined into depression, Beck, and mania scores. Among the controls, 2.1% had a depression score greater than 9, and none had a score greater than 10. Among the TS patients, 22.9% had a score greater than 9 and the scores ranged up to the maximum of 18 (P less than .0005). None of the pure ADD patients had a score greater than 6, whereas 20% of the ADD-secondary-to-TS (ADD 2(0) TS) patients had scores greater than or equal to 9. Among grade 3 TS patients, 46.6% had scores greater than or equal to 9. There were no differences in the frequency of depression in the TS patients with or without ADD. Comparable results were obtained for the Beck depression score, except that the percent with a score greater than or equal to 8 was higher for the TS patients with ADD (23.7%) than for those without ADD (9.3%). There was a good correlation between the depression score and the Beck score (r = .63), but no correlation between the ADD-with-hyperactivity (ADDH) score and either the depression score (r = .086) or the Beck score (r = .077). Among the controls, none had a mania score greater than or equal to 4, compared with 19.1% of the total TS patients (P = less than .0005), 11.8% of the ADD patients (P = .002), and 26.6% of the ADD 2(0) TS patients (P = .0005). Although some of the mania questions would be expected to be answered positively by ADDH patients, the correlation coefficient between the ADDH scores and the mania scores was only moderate (r = .29), whereas the correlation with the depression score was much higher (r = .63). There was minimal correlation between the number of tics and either the depression score (r = .267) or the Beck score (r = .193). We conclude that depression and manic-depressive symptoms are common in TS patients and are an integral part of the disorder rather than being secondary to motor or vocal tics.     

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.     

Neurofeedback Training for Tourette Syndrome: An Uncontrolled Single Case Study

Gilles de la Tourette syndrome (TS) is characterized by motor and vocal tic manifestations, often accompanied by behavioral, cognitive and affective dysfunctions. Electroencephalography of patients with TS has revealed reduced Sensorimotor Rhythm (SMR) and excessive fronto-central Theta activity, that presumably underlie motor and cognitive disturbances in TS. Some evidence exists that neurofeedback (NFB) training aimed at enhancing SMR amplitude is effective for reducing tics. The present report is an uncontrolled single case study where a NFB training protocol, involving combined SMR uptraining/Theta downtraining was delivered to a 17-year-old male with TS. After sixteen SMR-Theta sessions, six additional sessions were administered with SMR uptraining alone. SMR increase was better obtained when SMR uptraining was administered alone, whereas Theta decrease was observed after both trainings. The patient showed a reduction of tics and affective symptoms, and improvement of cognitive performance after both trainings. Overall, these findings suggest that Theta decrease might account for some clinical effects seen in conjunction with SMR uptraining. Future studies should clarify the feasibility of NFB protocols for patients with TS beyond SMR uptraining alone.     

Before your very eyes: illness, agency, and the management of Tourette Syndrome

In this article, I examine the ways that people with Tourette Syndrome (TS) manage the motor and vocal tics characteristic of this neurological disorder. To mitigate the powerful stigmas associated with TS, individuals must either remove tics from public view or strive to recast the way that they are perceived. Drawing on ethnographic research with TS sufferers in Indiana, I elaborate three strategies by which this is done, strategies referred to here as displacement, misattribution, and contextualization. These processes strongly affect both the symptoms themselves and the subjective experience of the illness. They also affect the perception of TS in the larger culture, associating the disease with florid symptoms like cursing--symptoms that, although not at all typical of TS, are the ones most resistant to these kinds of management. These patterns highlight how individual agency may actively shape the cultural construction of illness.     

A new gene for Tourette's syndrome: a window into causal mechanisms?

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by impairing motor-vocal tics. Locating genetic loci by associating the phenotype with DNA translocations, inversions, gain or losses, State et al. identified SLITRK1 as a candidate gene in an individual with GTS and inv(13) (q31.1; q33.1). This gene was also associated with abnormal axonal-dendritic development in embryonic mouse cells. Although SLITRK1 is not a major causal gene for GTS, it can shed light on our understanding of the gene-based neural correlates of this disease.     

Altered Synaptic Plasticity in Tourette's Syndrome and Its Relationship to Motor Skill Learning

Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics that can be considered motor responses to preceding inner urges. It has been shown that Tourette patients have inferior performance in some motor learning tasks and reduced synaptic plasticity induced by transcranial magnetic stimulation. However, it has not been investigated whether altered synaptic plasticity is directly linked to impaired motor skill acquisition in Tourette patients. In this study, cortical plasticity was assessed by measuring motor-evoked potentials before and after paired associative stimulation in 14 Tourette patients (13 male; age 18–39) and 15 healthy controls (12 male; age 18–33). Tic and urge severity were assessed using the Yale Global Tic Severity Scale and the Premonitory Urges for Tics Scale. Motor learning was assessed 45 minutes after inducing synaptic plasticity and 9 months later, using the rotary pursuit task. On average, long-term potentiation-like effects in response to the paired associative stimulation were present in healthy controls but not in patients. In Tourette patients, long-term potentiation-like effects were associated with more and long-term depression-like effects with less severe urges and tics. While motor learning did not differ between patients and healthy controls 45 minutes after inducing synaptic plasticity, the learning curve of the healthy controls started at a significantly higher level than the Tourette patients'' 9 months later. Induced synaptic plasticity correlated positively with motor skills in healthy controls 9 months later. The present study confirms previously found long-term improvement in motor performance after paired associative stimulation in healthy controls but not in Tourette patients. Tourette patients did not show long-term potentiation in response to PAS and also showed reduced levels of motor skill consolidation after 9 months compared to healthy controls. Moreover, synaptic plasticity appears to be related to symptom severity.     

A controlled study of Tourette syndrome. II. Conduct.

To assess conduct in Tourette syndrome (TS), 47 controls, 246 TS patients, 17 attention-deficit-disorder (ADD), and 15 ADD patients with minor tics or a family history of TS (ADD 2(0) TS) were compared for the following behaviors: running away from home, lying, stealing, starting fires, vandalism, being in trouble with the law, fighting, shouting at parents or peers, attacking others, lack of respect for adults, short temper, hurting animals, feeling full of hate, being unable to stop fighting, and problems with drugs and alcohol. With the exception of running away from home and being in trouble with the law, TS patients were significantly different from controls in all other behaviors. When the components were combined for a total conduct score, only one (2.1%) of the controls had a score greater than 13, and he had TS. By contrast, 35% of the TS patients had scores greater than 13 (P less than .0005). The correlation coefficient between the total conduct score and ADD score was .48. Although the presence of ADD was an important factor in determining conduct in TS, other factors such as depression and compulsive behavior also played a contributing role. There was little correlation between the total conduct score and the number of tics. It is estimated that among non-economically disadvantaged children, 10%-30% of conduct disorder may be due to the presence of a TS gene.     

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.     

ComorbiditéS associées au trouble déficit de l’attention avec hyperactivité : Données épidémiologiques et implications thérapeutiques

ADHD has become one of the most frequent cause of referrals for children’ behaviour disorders. ADHD is a prevalent psychiatric condition affecting 5% to 9% of school-age children with regards to DSM-IV R diagnostic criteria. In addition, according to the results of different epidemiological studies, patients with ADHD very often experience comorbid conditions in 50% to 90% of the cases. The most frequent comorbidities include externalised disorders, (oppositional defiant disorder, conduct disorders), learning disorders, internalised disorders (anxiety, depression) and tics (chronic motor tics, Tourette’s syndrome). Given their negative impact on the outcome of ADHD in terms of affective and social functioning, and of social and school adaptation, these comorbid conditions should be carefully and systematically searched, even without any actual complaint. Although management of comorbid psychiatric conditions is never simple nor straightforward, therapeutic option should be considered taking into consideration both management of ADHD and specificity of these comorbidities.     

A controlled study of Tourette syndrome. VI. Early development, sleep problems, allergies, and handedness.

Developmental milestones, problems with bladder and bowel control, sleep disturbances, allergies, and handedness were compared in 247 consecutive Tourette syndrome (TS) patients, 17 patients with attention-deficit disorder (ADD), 15 patients with ADD secondary to TS (ADD 2(0) TS), and 47 random controls. There were no significant differences in age of first talking or walking. By contrast, there were significant differences in problems with bladder and bowel control between TS patients and controls, as measured by age of first toilet training, age of last bed-wetting, frequency of enuresis, and age that bowel control was achieved. Sleep problems were pervasive in TS patients, with a significantly increased frequency of sleepwalking, night terrors, trouble getting to sleep, early awakening, and inability to take afternoon naps as a young child. In all diagnostic categories, including mild (grade 1) TS patients, a total sleep-problem score was significantly greater than that in controls. The sleep disorders and other TS symptoms are consistent with TS as a disorder of disinhibition of the limbic system. Allergies and left-handedness have been evoked as contributing to or being associated with ADD and learning disorders. There were no significant differences in the frequency of allergies or left-handedness in TS patients compared with that in controls. We conclude that when there is a clearly defined genetic cause of ADD and learning disorders, it is not associated with an increased frequency of allergies or left-handedness.     

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.     

Progress in the search for genetic linkage with Tourette syndrome: An exclusion map covering more than 50% of the autosomal genome

Gilles de la Tourette syndrome is a neuropsychiatric disorder with an autosomal dominant mode of inheritance and reduced penetrance at a single genetic locus. Several research groups have genetic linkage studies underway to detect the chromosomal location of the gene that predisposes for this disorder. Strong and clear evidence of linkage has not yet been produced for Tourette syndrome. This paper presents an overview of the methods and progress of the groups centered at Yale University and Erasmus University in excluding linkage from a large portion of the genome. Our labs have screened 228 genetic marker loci for linkage with a gene for this disorder in a series of affected families in the United States, Canada, The Netherlands, and Norway. More than 50% (and perhaps as much as 66%) of the autosomal genome has now been excluded on the assumption that genetic heterogeneity is not an important factor in the Tourette syndrome pedigrees pooled for this summary.