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.     

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.     

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.     

Potentiation of haloperidol catalepsy by microinjections of nicotine into the striatum or pons in rats

It was reported that systemic administration of nicotine in rats potentiated the cataleptogenic effect of haloperidol. Moreover, addition of nicotine to the treatment with haloperidol in patients suffering from the Gilles de la Tourette's syndrome resulted in reduction in frequency and severity of tics. In the present article we report results of experiments aimed at investigating the role of striatum and pontine reticular formation in the synergistic relations between the two drugs. Nicotine was microinjected directly into the striatum or pontine reticular formation of rats and its cataleptogenic effects were studied when given alone or in combination with systemical injections of haloperidol. It was found that nicotine has cataleptogenic effects when microinjected both into the striatum and pontine reticular formation. The synergism between the two drugs occurred both after microinjections into the striatum and pontine reticular formation.     

Differential modulation of mouse brain biogenic amines by haloperidol and pimozide: implications in Tourette's syndrome

1. A comparison between the effect of equal dose regimens of Tourette's medications on mouse motor activity and regional brain monoamines suggests differential responses which may underlie drug-induced side-effects. 2. Haloperidol was more potent than pimozide in altering striatal dopamine concentration which may account for the greater incidence of haloperidol-induced extrapyramidal disorders compared to pimozide. 3. Pimozide, but not the haloperidol treatment, altered brain serotonin concentrations to suggest a decrease in turnover rate which may underlie pimozide-caused sedation in Tourette's syndrome. 4. Pimozide was more potent than haloperidol in duration of behavioral depression which suggests differential dopamine receptor subtypes blockade. 5. Pimozide was more potent than haloperidol in altering 3 of the 6 brain regions content of norepinephrine-derived normetanephrine which may be responsible for the increase in blood pressure reported during pimozide treatment.     

Enhanced cognitive control in young people with Tourette's syndrome

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.     

Whole blood serotonin and tryptophan levels in Tourette's disorder: effects of acute and chronic clonidine treatment

Whole blood serotonin (WB5HT) and tryptophan (WBTRP) levels were studied in 20 patients (aged 8 to 45 years) with Tourette's disorder under medication-free baseline conditions and following acute and chronic clonidine treatment. Compared to 87 normal controls, Tourette's disorder patients had lower mean baseline WBTRP levels (mean +/- SEM: Tourette's, 5993 +/- 304 ng/ml vs. 6822 +/- 169 ng/ml; p less than .03). No significant differences in mean baseline WB5HT levels were found. Three hours after an acute dose of clonidine (2.5 - 5.1 micrograms/kg, p.o. at 9:00 A.M.), no mean differences were observed (baseline vs. post 3 hours) in WB5HT or WBTRP levels. However, following chronic treatment (greater than 3 weeks) with clonidine (3-8 micrograms/kg/day, p.o.), WB5HT levels were increased in 9 of 14 Tourette's disorder patients. The mean increases in WB5HT levels following chronic clonidine treatment were significant when WB5HT levels were expressed per 10(9) platelets. (mean +/- SEM: baseline, 471 +/- 45 ng/10(9) platelets vs. chronic, 697 +/- 82 ng/10(9) platelets, p = .02). No mean differences in WBTRP levels were observed after chronic clonidine treatment. These findings are discussed in light of a proposed intermediary role of 5HT systems in the mode of action of clonidine in the treatment of Tourette's disorder.     

Elevated CSF dynorphin A [1-8] in Tourette's syndrome

A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. We report on the presence of elevated concentrations of dynorphin A [1-8] in the CSF of 7 TS patients, aged 20 to 45 years. The increase in CSF dynorphin was found to be associated with the severity of the obsessive compulsive symptoms but not with tic severity in these patients. Although CSF studies lack the precision necessary to address questions of selective involvement of neuronal system in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiology of TS and related disorders. Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) (1). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case per 10,000 girls, and milder variants of the syndrome are likely to occur in a sizeable percentage of the population (2). Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consistent with an autosomal dominant form of inheritance (3,4). Neurobiologic and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and basal ganglia structures remain the prime candidates as the neuroanatomical origin for TS and related conditions (1). Endogenous opioids, including dynorphin and met-enkephalin are concentrated in structures of the basal ganglia (5), are known to interact with central dopaminergic neurons (6, 7), and may play an important role in the control of motor functions (8). Post-mortem brain studies have directly implicated opioids in the pathophysiology of Parkinson's disease (9), Huntington's disease (10), and most recently in TS (11). The neuropathological study of Haber et al. (11) reported decreased levels of dynorphin A [1-17] immunoreactivity in striatal fibers projecting to the globus pallidus in the brain of a patient with severe TS. This ovservation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS.(ABSTRACT TRUNCATED AT 400 WORDS)     

Tourette's syndrome: update.

Tourette''s syndrome is a widely misunderstood chronic disorder that develops in childhood and is usually lifelong. It is characterized by waxing and waning of involuntary motor and phonic tics. The features and differential diagnosis are discussed in this paper. The estimated prevalence rate of Tourette''s syndrome, 0.05%, implies that this disorder is not rare. The reasons for diagnostic confusion are outlined, and the genetic and neurotransmitter features discussed. The management of Tourette''s syndrome has become more effective with the availability of at least two psychoactive drugs, haloperidol and pimozide. Although the cause of this syndrome is thought to be organic, these drugs and their adverse effects are best known to psychiatrists. Psychiatric and multidisciplinary intervention is often necessary because of the frequent association of psychosocial problems, cognitive and learning difficulties, and aggravation of the symptoms by stress. The understanding of Tourette''s syndrome will probably increase significantly with the advent of the newer imaging techniques and the rapid progress of research in the neurosciences.     

Interactions between estradiol and haloperidol on perseveration and reversal learning in amphetamine-sensitized female rats

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25 mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25 mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13 mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25 mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13 mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.     

The effect of lithium on chronic haloperidol enhanced apomorphine aggression in rats

The effect of chronic haloperidol or haloperidol plus lithium on apomorphine-induced aggressive and stereotyped behaviors was assessed. Rats withdrawn from chronic haloperidol treatment showed increased aggressiveness and had an increased duration of stereotyped behavior. Rats treated chronically with haloperidol in combination with lithium did not display a supersensitive response. These findings are discussed in relation to the results of other investigators.     

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.     

Tourette syndrome: clinical and psychological aspects of 250 cases.

Tourette syndrome is a common hereditary neuropsychiatric disorder consisting of multiple tics and vocal noises. We summarize here clinical aspects of 250 consecutive cases seen over a period of 3 years. The sex ratio was four males to one female, and the mean age of onset was 6.9 years. Only 10% were Jewish, indicating that it is not more prevalent in Ashkenazi Jews. Only 33% had compulsive swearing (coprolalia), indicating that this is not necessary for the diagnosis. The most frequent initial symptoms were rapid eye-blinking, facial grimacing, and throat-clearing. In this series, it was clear that Tourette syndrome is a psychiatric as well as a neurological disorder. Significant discipline problems and/or problems with anger and violence occurred in 61%, and 54% had attention-deficit disorder with hyperactivity. Some degree of exhibitionism was present in 15.9% of males and 6.1% of females. Obsessive-compulsive behavior was seen in 32%. Other than tics and vocal noises, the most common parental complaints were of short temper and everything being a confrontation. There were no significant clinical differences between familial and sporadic cases. Whenever a child presents with a learning disorder, attention-deficit disorder, or significant discipline or emotional problems, the parents should be questioned about the presence of tics or vocal noises in the patient and other family members.     

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.     

Serotonin transporter: gene, genetic disorders, and pharmacogenetics

The highly evolutionarily conserved serotonin transporter (SERT) regulates the entire serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations. Differences in SERT expression and function produced by three SERT genes and their variants show associations with multiple human disorders. Screens of DNA from patients with autism, ADHD, bipolar disorder, and Tourette's syndrome have detected signals in the chromosome 17q region where SERT is located. Parallel investigations of SERT knockout mice have uncovered multiple phenotypes that identify SERT as a candidate gene for additional human disorders ranging from irritable bowel syndrome to obesity. Replicated studies have demonstrated that the SERT 5'-flanking region polymorphism SS genotype is associated with poorer therapeutic responses and more frequent serious side effects during treatment with antidepressant SERT antagonists, namely, the serotonin reuptake inhibitors (SRIs).     

Effects of melatonin on behavioral dopaminergic supersensitivity

This study examines the effects of melatonin on dopaminergic supersensitivity induced by long-term treatment with haloperidol in rats. Enhancements of spontaneous general activity in an open-field and of stereotyped behavior induced by apomorphine after abrupt withdrawal from long-term treatment with haloperidol were used as experimental parameters for dopaminergic supersensitivity. Experiment 1 was conducted to investigate the effects of melatonin on the development of dopaminergic supersensitivity, and experiment 2 was conducted to investigate the effects of melatonin on the development as well as on expression of dopaminergic supersensitivity. Rats of both experiments were long-term treated with saline or haloperidol concomitant to saline or melatonin. In experiment 1 behavioral observations were performed after abrupt withdrawal from long-term treatment. In experiment 2 behavioral observations were performed 1 hour after an acute injection of saline or melatonin, administered after the abrupt withdrawal from long-term treatment. Both behavioral parameters used showed the development of central dopaminergic supersensitivity in rats treated with haloperidol since 24 hours after abrupt withdrawal. Concomitant treatment with melatonin intensified haloperidol-induced dopaminergic supersensitivity, observed 72 hours after withdrawal. Melatonin treatment per se also induced behavioral supersensitivity evaluated by both open-field and stereotyped behaviors, although it was more fugacious than that presented by haloperidol. Acute treatment with melatonin reverted the enhancement of the haloperidol-induced dopaminergic supersensitivity produced by concomitant long-term treatment with melatonin, as well as melatonin-induced dopaminergic supersensitivity per se. Our results support previous evidence of antidopaminergic effects of melatonin and demonstrate that repeated administration of this hormone modifies the plasticity of behaviors mediated by central dopaminergic systems.     

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.     

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 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.     

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。