多巴胺转运体基因多态性与Tourette综合征疗效的相关性研究

目的 探讨不同疗效的Tourette综合征(TS)患者多巴胺转运体(DAT1)基因40 bp可变串联重复序列(VNTR)多态性分布频率是否存在差异.方法 应用聚合酶链反应-可变串联重复序列多态性分析技术,检测普通TS组(52例)、难治性TS组(63例)和正常对照组(57例)DAT1基因40 bp VNTR多态性;根据自制的临床资料调查表和耶鲁综合抽动严重程度量表(YGTSS)收集患者临床资料,使用美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)Tourette综合征诊断标准进行诊断.结果 正常对照组、普通TS组和难治性TS组DAT1基因40 bp VNTR基因型频率分布差异无统计学意义(χ2=12.638,P=0.125);难治性TS组等位基因440 bp频率为8,高于普通TS组及正常对照组(1、0),但差异无统计学意义(χ2=11.352,P=0.053).结论 难治性TS中DAT1基因40 bp VNTR 440 bp等位基因出现频率较高,普通TS与难治性TS遗传机制可能存在差异,但需扩大样本含量进一步验证.

Abstract：

Objective To study the difference of dopamine transporter ( DAT1 )gene 40 bp variable number of tandem repeat ( VNTR ) genotype and allele frequency in TS patients with different curative effect in Chinese Han population. Methods In this study, the 40 bp polymorphism in the DAT1 gene was analyzed by using polymerase chain reaction-variable number of tandem repeat and polymorphism. The clinical data and tic symptoms was assessed with the clinical data schedule table and the Yale Global Tic Severity Scale ( YGTSS ). TS was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders,the Forth Edition( DSM-Ⅳ )diagnostic criteria for Tourette syndrome. Results There was no significant differences in the frequencies of genotype for DAT1 gene 40 bp VNTR between normal controls ( 57 samples )and common TS children ( 52 samples ) and refractory TS children ( 63 samples ) (χ2 = 12. 638, P =0.125).The allele 440bp tended to be more in children with refractory TS(refractory TS:commmon TS:normal controls=8:1:0),but with no significat differences(χ2=11.352,P=0.053).Conclusions The DAT1 gene 40 bp VNTR 440 bp allele frequency seems to be higher in children with refractory TS,which suggests common TS and refractory TS have different genetic background. It should be verified by making larger samples in future study.     

影响利培酮治疗Tourette综合征疗效的多因素分析

目的 探讨影响利培酮治疗Tourette综合征（TS）疗效的关键因素。方法 对106例单用利培酮治疗（8周）的TS患者，采用标准评定工具的43个临床指标进行定量或半定量评估，应用单因素和多因素分析方法分析利培酮治疗TS疗效的影响因素。结果 经单因素分析，社会功能障碍[比值比（OR）值=1．340]、Achenbach儿童行为量表（CBCL）基线总分高（OR=1.477）、阳性家族史（主要指父母两系三代中TS或其他神经精神疾病史；OR=24．316）、家庭周边环境污染（OR=2．433）、起病年龄小（OR=1.594）、家庭教育类型为非民主型（OR=1．972）、阳性既往史（指病前有脑肿瘤等器质性病史、脑外伤、抽搐、高热惊厥、昏迷、一氧化碳中毒、夜惊症或遗尿症等病史；OR=11．468）、病程长（OR=3．491）导致利培酮疗效差；经多因素分析，社会功能障碍（OR=32．258）、阳性家族史（OR=12．804）、阳性既往史（OR=6．459）、CBCL基线总分（OR=1．093）4个指标选人回归方程。结论 中重度社会功能障碍、阳性家族史、阳性既往史、CBCL基线总分高是导致利培酮治疗，TS疗效差的关键因素。     

Tourette综合征与多巴胺

现在人们已认识到 Tourette综合征 ( Tourette's syndrome,TS)不是一种行为缺陷 ,而是一种遗传性神经系统疾病。据估计美国有 1 0万人患有典型的 TS,一百多万人被怀疑患有轻型 TS。最新研究正在探索这种以抽搐 ,尖叫和模仿言语为特征的疾病的化学起源。其成果可能引发既能抑制那些恼人症状却又无棘手副作用的更佳治疗方法。一个外科医生 ,一个杂货铺掌柜 ,一个专业运动员 ,一个建筑工人 ,一个作家 ,他们都有突发的反复抽搐、不随意运动和语言失控。六次鼻子抽动 ,三次顿足 ,一连串眨眼睛 ,同时有数次脖子拉紧 ,还发出猫头鹰叫声、狗叫声…     

精神分裂症患者多巴胺D2受体和多巴胺转运体基因表达水平与临床症状的关系

目的 探讨精神分裂症患者外周血淋巴细胞多巴胺D2受体(DRD2)和多巴胺转运体(DAT)的mRNA表达水平与精神分裂症临床症状的关系.方法 以实时荧光定量逆转录-聚合酶链反应技术检测治疗前精神分裂症组(25例)、长期服药(氯氮平)慢性精神分裂症组(27例)和对照组(30名)外周血淋巴细胞中DRD2和DAT的mRNA表达水平,同时对精神分裂症患者的阳性和阴性症状量表(PANSS)进行评定,并采用Spearman分析二者的相关性.结果 治疗前精神分裂症组、长期服药慢性精神分裂症组、对照组样本外周血淋巴细胞DRD2的基因表达水平分别为0.32±0.13、0.37±0.19、0.34±0.09,3组比较差异无统计学意义(F=0.510,P＞0.05);DAT的基因表达水平分别为0.48±0.24、0.58±0.21、0.39±0.24,3组比较差异有统计学意义(F=4.330,P＜0.05);长期服药慢性精神分裂症组DAT基因表达水平显著高于对照组(MS组内=0.194,P ＜0.01);治疗前精神分裂症组DRD2基因表达水平与PANSS阳性症状分呈显著正相关(r=0.443,P＜0.05),DAT基因表达水平与PANSS总分(r=-0.418,P=0.075)、一般病理症状分(r=-0.434,P=0.063)的相关性未达统计学意义.结论 精神分裂症患者外周血淋巴细胞DRD2的基因表达水平与PANSS量表的阳性症状分显著正相关,而精神分裂症患者外周血淋巴细胞DAT的基因表达水平可能受氯氮平影响上调.     

托吡酯与氟哌啶醇治疗Tourette综合征疗效的对照研究

目的 探讨托吡酯单一治疗Tourette综合征(TS)的疗效和安全性。方法 将53例TS患者按病例编号分为研究组(35例)和对照组(18例)。研究组予托吡酯(50-150 mg/d)治疗;对照组予氟哌啶醇(1.5-6 mg/d),共治疗24周。研究组3例脱落,对照组2例脱落。采用耶鲁抽动症整体严重度量表(YGTSS)、治疗中需处理的不良反应症状量表(TESS)于治疗前、治疗第8,24周末对两组进行评估。结果(1)治疗第8周末研究组有效率为72％,高于对照组(38％;Z=-3.284,P=0.001)。研究组YGTSS总分[(28.06±14.45)分]低于对照组[(40.00±20.90)分;P<0.05];减分率[(48.10±22.80)％]高于对照组[(33.17±31.90)％;但P>0.05]。治疗第24周末,研究组有效率为81％,高于对照组(56％;Z=-4.808,P<0.001)。研究组YGTSS总分[(24.96±16.28)分]低于对照组[(36.50±21.08)分;P<0.05];减分率[(52.90±24.49)％]高于对照组[(34.63±32.58)％;P<0.05]。(2)第8周末研究组TESS分[(2.69±3.02)分]低于对照组[(6.25±4.06)分;P<0.01];第24周末研究组TESS分[(1.69±1.79)分]低于对照组[(2.69±3.02)分;P<0.01]。结论 托吡酯能有效改善TS的运动、发声抽动和综合损伤效应,副作用相对较轻。     

多巴胺β羟化酶基因TaqⅠ酶切多态性与抽动秽语综合征:病例对照研究

目的 探讨多巴胺β羟化酶(DBH)基因第5内含子TaqⅠ酶切多态性在天津地区汉族人群抽动秽语综合征发病机制中的作用.方法 采用聚合酶链反应-限制性片断长度多态性方法对106例抽动秽语综合征患者和80例正常对照者进行DBH基因第5内含子TaqⅠ酶切多态性基因型分布和等位基因频率检测.结果 抽动秽语综合征患者与正常对照者DBH基因第5内含子TaqⅠ酶切多态性基因型分布和等位基因频率比较,差异无统计学意义(均P>0.05);抽动秽语综合征伴注意力缺陷多动症患者A2/A2基因型分布和A2型等位基因频率均高于不伴注意力缺陷多动症患者和正常对照者,差异具有统计学意义(均P<0.05),不伴注意力缺陷多动症患者与正常对照者比较差异无统计学意义(均P>0.05).关联分析显示,存在A2型等位基因的抽动秽语综合征患者伴发注意力缺陷多动症的风险增加2.91倍(OR=2.905,95%CI:1.313～6.929,P=0.009).结论 DBH基因第5内含子TaqⅠ酶切多态性可能与天津地区汉族人群抽动秽语综合征无相关性,但A2型等位基因可能会使抽动秽语综合征患者伴发注意力缺陷多动症的风险增加.     

Tourette综合征患儿三种肺炎支原体特异性抗体的检测

目的 探讨肺炎支原体(MP)感染与Tourette综合征(TS)的关系.方法 根据美国耶鲁综合抽动严重程度量表(YCTSS)评分,将4l例TS患儿(TS组)分为轻度组和中重度组,以同期健康儿童60例作为对照组,采用酶联免疫吸附法测定2组血清中MP特异性抗体免疫球蛋白A(MP-IgA)、免疫球蛋白G(MP-IgG)、免疫球蛋白M(MP-IgM)的水平;观察TS组与对照组是否存在血清MP-IgA、MP-IgG、MP-IgM的差别.结果 TS组MP-IgA阳性率(24.39%)和MP-IgG阳性率(53.66%)均高于对照组(6.67%,28.33%),差异均有统计学意义(P均＜0.05);TS组MP-IgM阳性率与对照组比较,差异无统计学意义(P＞0.05).结论 MP感染与TS发病可能存在一定的联系.

Abstract：

Objective To explore the association between mycoplasma pneumoniae infection and Tourette syndrome. Methods The serum mycoplasma pneumoniae-IgA, -IgG, -IgM in 41 children with Tourette syndrome and 60 healthy children were measured with ELISA method. Results The positive rate of mycoplasma pneumoniae IgA( 24. 39% )and IgG( 53.66% ) in Tourette syndrome group were higher than that of control group( 6. 67% and 28. 33%)( P ＜0. 05 ). The positive rate of mycoplasma pneumoniae-IgM was not different between patient and healthy children. Conclusion Mycoplasma pneumoniae infection may be associated with Tourette syndrome.     

110例Tourette综合征的临床与脑电图相关性分析

本文报告１１０例Ｔｏｕｒｅｔｔｅ综合的临床和脑电图资料，结果发现：多发性不自主抽动与不自主发声的严重程度之间无相关性；秽语的出现与抽动和发声的严重程度间有一定相关性，秽语与模仿言语的发生间联系较密切；ＥＥＧ异常率为４２．７３％，其异常程度与抽动和发声的严重程度间无相关性，但秽语的出现与ＥＥＧ异常相关。     

Tourette综合征患儿三种肺炎支原体特异性抗体的检测

Objective To explore the association between mycoplasma pneumoniae infection and Tourette syndrome. Methods The serum mycoplasma pneumoniae-IgA, -IgG, -IgM in 41 children with Tourette syndrome and 60 healthy children were measured with ELISA method. Results The positive rate of mycoplasma pneumoniae IgA( 24. 39% )and IgG( 53.66% ) in Tourette syndrome group were higher than that of control group( 6. 67% and 28. 33%)( P ＜0. 05 ). The positive rate of mycoplasma pneumoniae-IgM was not different between patient and healthy children. Conclusion Mycoplasma pneumoniae infection may be associated with Tourette syndrome.     

5-羟色胺转运体基因功能性多态与强迫症的关联研究

目的 探讨中国汉族人群中5-羟色胺转运体基因启动子区域多态(5-HTTLPR)功能性3等位基因L_A、L_G和S与强迫症(OCD)的关系.方法 采用聚合酶链反应-限制性片段长度多态技术测定138例OCD患者(OCD组)和199名健康人(对照组)的5-HTTLPR功能性3等位基因多态性.结果 OCD组5-HTTLPR功能性基因型及等位基因频率与对照组间的差异有统计学意义(χ~2=8.396,P＜0.05;χ~2=8.483,P＜0.01);L_A/L_A因型和L_A等位基因与OCD存在显著正关联[比值比分别为3.361(P＜0.05)和1.771(P＜0.01)].结论在中国汉族人群中5-HTTLPR功能性3等位基因可能与OCD存在遗传关联,L_A/L_A基因型和等位基因L_A可能是OCD的风险因子.     

Association between Tourette syndrome and comorbidities in Japan

The purpose of this study was (1) to document cases of Tourette syndrome (TS) with comorbidities such as obsessive–compulsive symptoms (OCS) and hyperkinetic disorder (HD), and (2) to examine differences in clinical characteristics between TS patients with OCS and HD and those without these comorbidities. The subjects in the study were 88 Japanese TS patients (67 males and 21 females; mean age: 15.2 years) who were treated by 31 clinicians including psychiatrists and pediatricians. Data on tic symptoms, comorbidities and severity were scrutinized. OCS were present in 42.0% of the subjects, while HD accounted for 28.4%. In the TS + OCS and/or HD group, coprophenomana, impulsiveness/aggression, school refusal, self-injurious behaviors (SIB), and clumsiness were significantly more frequent than in the TS-only group. Also, tic symptoms and impairment during the worst period was significantly severer in the TS + OCS and/or HD than in the TS-only group. When the age-matched TS + all OCS group (i.e., the young TS + OCS and TS + OCS + HD group) was compared with the TS-only group, it was found that the rates of impulsiveness/aggression, school refusal and SIB were significantly higher and the degree of global severity was significantly more intense in the young TS + all OCS group than in the TS-only group. The impact to clinical characteristics of TS from OCS was suggested to be slightly greater than that from HD. There was little ethnic difference in TS pathogenesis in terms of the impact of comorbidities. Further investigation is required to gain deeper insights into the relationships between TS, OCD or OCS and HD.     

感觉症状与Tourette综合征预后的关系

目的：分析Tourette综合征感觉症状对预后的影响.方法：随机选取Tourette综合征男性患儿120例,使用感觉性症状问卷进行评定,其中伴有感觉症状的患儿66例,不伴感觉症状的患儿54例,采用耶鲁抽动障碍严重程度量表（YGTSS）、抑郁自评量表（SDS）以及焦虑自评量表（SAS）评定,使用氟哌啶醇治疗4周后再次评定.结果：不伴有感觉症状的Tourette综合征患儿较伴有感觉症状的患儿抽动症状好转明显（P＜0.01）;抑郁自评、焦虑自评严重程度轻.结论：Tourette综合征常伴有各种感觉症状,重视感觉症状将对疗效可产生有利的影响.     

Gilles de la Tourette syndrome is associated with hypermethylation of the dopamine D2 receptor gene

Several lines of evidence support a “dopaminergic hypothesis” in the pathophysiology of Gilles de la Tourette syndrome (TS). The aim of this study was to investigate for the first time epigenetic changes in DNA methylation in different dopamine genes in adult patients with TS. We included 51 well characterized adult patients with TS (41 males, 10 females, mean age = 35 ± 12.6 years, range, 18–71 years) and compared results with data from a group of 51 sex- and age-matched healthy controls. Bisulfite sequencing was used to measure peripheral DNA methylation of the dopamine transporter (DAT), the dopamine D2 receptor (DRD2), and the catechol-O-methyltransferase (COMT) genes. Compared to healthy controls, patients with TS showed significantly elevated methylation level of the DRD2 gene that positively correlated with tic severity. In contrast, DAT methylation was lower in more severely affected patients. Our results provide evidence for a role of altered epigenetic regulation of dopaminergic genes in the pathophysiology of TS. While DRD2 hypermethylation seems to be directly related to the neurobiology of TS that may lead to dopaminergic dysfunction resulting in enhanced thalamo-cortical movement-stimulating activity, DAT hypomethylation might reflect a secondary mechanism in order to compensate for increased dopaminergic signal transduction due to DRD2 hypermethylation. In addition, it can be speculated that spontaneous fluctuations of tics may be caused by short-term alterations of methylation levels of dopaminergic genes resulting in dynamic changes of tonic/phasic dopaminergic signaling in the striatum and thalamo-cortical output pathways.     

Age-related gene expression in Tourette syndrome

Because infection and immune responses have been implicated in the pathogenesis of Tourette syndrome (TS), we hypothesized that children with TS would have altered gene expression in blood compared to controls. In addition, because TS symptoms in childhood vary with age, we tested whether gene expression changes that occur with age in TS differ from normal control children. Whole blood was obtained from 30 children and adolescents with TS and 28 healthy children and adolescents matched for age, race, and gender. Gene expression (RNA) was assessed using whole genome Affymetrix microarrays. Age was analyzed as a continuous covariate and also stratified into three groups: 5-9 (common age for tic onset), 10-12 (when tics often peak), and 13-16 (tics may begin to wane). No global differences were found between TS and controls. However, expression of many genes and multiple pathways differed between TS and controls within each age group (5-9, 10-12, and 13-16), including genes involved in the immune-synapse, and proteasome- and ubiquitin-mediated proteolysis pathways. Notably, across age strata, expression of interferon response, viral processing, natural killer and cytotoxic T-lymphocyte cell genes differed. Our findings suggest age-related interferon, immune and protein degradation gene expression differences between TS and controls.     

Dopamine receptor and dopamine transporter in obesity: A meta-analysis

The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and dopamine transporter (DAT) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords “dopamine receptor,” “dopamine transporter,” “obesity,” and “neuroimaging.” Body mass index (BMI) and the corresponding binding potential (BP_ND) were extracted from figures in each study using Engauge Digitizer, version 12.1, and plotted for radiopharmaceuticals and regions of interest (ROIs). Five studies involving 119 subjects with DR and five studies including 421 subjects with DAT were eligible for inclusion in this study. In overweight or obese subjects with BMI of 25 kg/m² or higher, DR availability from ¹¹C-Racloprie was negatively associated with BMI. However, DR availability from ¹¹C-PHNO was positively associated with BMI. DAT ratio was calculated after dividing DAT availabilities of overweight/obese BMI with mean DAT availabilities of normal BMI. The association between DAT ratio and BMI was not significant regardless of radiopharmaceuticals. In conclusion, dopamine plays a main role in the reward system with regard to obesity. Overweight and obese subjects had negative association between DR availability from ¹¹C-Raclopride and BMI. However, the association of DR availability with BMI was dependent on radiopharmaceuticals. DAT availability did not show the significant relationship with BMI regardless of radiopharmaceuticals.     

Association between the dopamine transporter gene and posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder that follows exposure to extreme events. A large twin study of Vietnam veterans had demonstrated a significant genetic contribution to chronic PTSD upon exposure to combat.(1,2) The underlying genes, however, have not been described. Given previous findings of abnormal dopamine (DA) function in PTSD, and given the putative effect of dopamine neurotransmission in shaping the responses to stress in animals, this study examined the association of the dopamine transporter (DAT) SLC6A3 3' variable number tandem repeat (VNTR) polymorphism with PTSD. The study evaluated 102 chronic PTSD patients and 104 carefully-documented trauma survivors (TS) who did not develop PTSD. Significant excess of 9 repeat allele was observed among PTSD patients (43% vs 30.5% in TS controls; chi(2) = 6.3, df = 1, P = 0.012). An excess of 9 repeat homozygous genotype was also observed in PTSD (20.43% in PTSD vs 9.47% in TS controls; chi(2) = 6.11, df = 2, P < 0.047). These findings suggest that genetically determined changes in dopaminergic reactivity may contribute to the occurrence of PTSD among trauma survivors.     

Tourette syndrome and neuropsychological performance

This study examined performance on a battery of neuropsychological tests in a sample of 28 patients with Tourette's syndrome (TS). Test scores were converted to age-corrected T-scores to control for the effect of age on test performance. The frequency of abnormal test performances was variable, but more frequent on motor and sensory tasks. Symptom severity as measured by the Tourette Syndrome Global Scale was inversely related to neuropsychological performance. In general, neuropsychological performance was mildly below average. The pattern of performance was similar to previous studies of TS patients.     

The prognosis of Tourette syndrome: implications for clinical practice

Tourette syndrome (TS) is a childhood-onset neuropsychiatric condition characterised by multiple motor and phonic tics. Comorbid behavioural problems are common, especially attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Little is known about the long-term prognosis of TS, despite the need to inform patients about their possible clinical course and advise health care providers on clinical resource allocation strategies. This paper reviews the scientific literature on the prognosis of TS spanning the period 1990-2010. After searching three scientific databases, we identified seven original studies investigating the prognosis of TS. It is suggested that tic frequency and severity decline with age in a large proportion of patients (59-85%). Predictors of increased tic severity in adulthood include higher childhood tic severity, smaller caudate volumes and poorer fine motor control. Furthermore, the presence of untreated comorbid psychopathology, such as ADHD and OCD, can adversely affect the long-term outcome of patients with TS. Future studies on the prognosis of TS should be conducted on larger samples, both in community and clinical settings.