【作者】 季卫东；

【导师】 郭兰婷； 黄颐； 刘协和； 孙学礼； 杨彦春；

【作者基本信息】 四川大学 ， 精神病学与精神卫生学， 2005， 博士

【摘要】 目的:抽动秽语综合症(Gilles de la Tourette syndrome,GTS)是一种起病于儿童期、复杂的、慢性神经精神障碍,以多种运动和发声抽动为主要临床表现,是抽动障碍中症状最重、预后不佳的一种,其患病率男性大于女性,常伴有强迫、多动等行为和情绪障碍,新的流行病学资料认为抽动秽语综合症的患病率在1.0%～3.8%之间,家系、分离研究发现遗传因素在其发病过程中起着重要作用,候选基因研究尽管发现了一些基因位点和抽动秽语综合症存在不同程度的关联,但迄今为止仍没有发现肯定的致病基因,多巴胺功能失调被认为是抽动秽语综合症发病机制最为重要的假说。近年来链球菌感染相关儿童自动免疫性神经精神障碍(Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection,PANDAS)概念的提出为研究抽动秽语综合症的发病机制提供了新的思路,自身免疫机制可能参与部分抽动秽语综合症的发病过程。前额叶—纹状体有关的认知损害可能和抽动秽语综合症临床症状相关,认知损害以及和注意缺陷多动综合症、强迫症等较高的共病率严重影响儿童的学业、同伴关系、社会适应能力和生活质量,妨碍儿童个性心理品质的健康发展。为了探讨多巴胺D4受体第3外显子48bp重复多态性、多巴胺转运蛋白1非编码区40bp多态性、儿茶酚胺—氧位—甲基转移酶met/val基因多态性、白介素-1受体拮抗剂第2内含子86bp重复多态性、白介素-1β基因外显子5多态性和抽动秽语综合症以及认更多还原

【Abstract】 [Objective] Gilles de la Tourette’s syndrome (GTS) is a childhood-onset neuro- psychiatric disorder characterised by multiple motor and vocal tics lasting more than one year. The new prevalence of this syndrome is estimated to be between 1 and 3.8 per 1000 children and adolescents and the outcome is generally favourable. Affected individuals are at increased risk of various comorbid neurobehavioural problems, the negative effects of which commonly exceed those of tics. Despite evidence that TS is an inherited disorder, the exact genetic abnormality is unknown. Dopaminergic hypotheses have included abnormalities of both pre- and postsynaptic function in GTS. Family and twin studies provide substantial evidence for genetic factors being implicated in the occurrence of GTS. Recent evidence, however, suggests a prefrontal dopaminergic abnormality in children with GTS. An immune-mediated mechanism involving molecular mimicry has been proposed for PANDAS (Paediatric autoimmune neuropsychiatricdisorders associated with streptococcal infection). PANDAS may offer a new way to explore the pathogens of GTS. Significant data, however, support the concept that TS is a neurological disorder associated with frontal-subcortical pathways. In this paper, DRD4exonⅢ48bp VNTR,DAT1, COMTmet/val, IL-1Ra86bp,IL-1βexon5 gene Polymorphism and Cognitive Function are studied in Children with Tourette’s Syndrome.[Method] 1. In the present study, we genotyped a large multiplex sample of GTS affected children for polymorphisms in DRD4exonⅢ48bp VNTR, DAT1, COMT met/val, IL-1Ra86bp,IL-1βexon5 genes. Associations were tested by the transmission disequilibrium test (TDT). 2. 86 Han Chinese children with GTS were tested using a set of neuropsychological test(Stroop test, trail making test, verbal fluency test, modified Wisconsin Card sorting test) and compared with 51 healthy control group to understand the relationship between cognitive deficits and genetics. 3. To investigate psychological problems in GTS, Conners Scale was applied in children with GTS and normal children. 4. Psychological tests above-mentioned were used to study the cognitive function in GTS parents.[Result] 1. No evidence for transmission disequilibrium was found for polymorphisms of DRD4exonⅢ48bp VNTR,DAT1,COMTmet/val, IL-1 Ra86bp,IL-1 βexon5 gene in this GTS sample. 2. DRD4exonⅢ48bp VNTR was significantly associated with GTS plus attention-deficit/hyperactivity disorder (+ADHD). The frequency of 410bp/240bp genotype and 240bp allele in combined ADHD were significantly different from GTS alone. 3. Compared with normal children, The GTS group showed impairment on almost all psychological measures. In some stroop test, combined ADHDgroup differed from the GTS-alone group. 4. Subjects with the met/met COMT genotype made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val/val genotype. The individual carried COMT met allele differed from individuals carried COMT val allele in delayed memory, WCST errors and perseverative errors. No evidence show significantly difference among DRD4exonIII48bp VNTR, DAT1, IL-lRa86bp, IL-ipexon5 gene Polymorphism and Cognitive Function. 5. Apart from anxiety, those factor score of Corners Parent Rating Scales in children with GTS were significantly different from that in healthy control group. 6. There was a significantly different effect for the number of word fluency, errors of WCST test, categories control and perseverative errors of WCST test compared with normal controls. 7. For the GTS group, Yale Tic Severity scores correlated significantly with some psychological test. [Conclusion] 1. The long repeat allele of the DRD4 48-bp repeat polymorphism was significantly associated with ADHD. This linkage showed the long repeat allele may be a risk factor for GTS+ADHD subjects. For the GTS+ADHD group, the 240bp allele of IL-IRa gene Polymorphism perhaps is another risk factor. 2. These data are consistent with the results of other studies examining the role of COMT in cognitive function. GTS subjects with the met allele produced fewer perseverative errors on the Wisconsin Card Sorting Test than subjects with the val allele, suggesting that a functional genetic polymorphism may influence prefrontal cognition.. No evidence showed the association among DRD4exonIII48bp VNTR,DAT1, IL-IRa 86bp, IL-l[3exon5 gene Polymorphism and cognitive function in children with GTS. 3. GTS patient has memory, attention and executivefunction defect, these defects may have something to do with the prefrontal dopamine disfunction. For comorbid, there is a certain influence in the cognition function. 4. GTS parents carry out function defects as the risky colony, this kind of defect may be involved in many attitudes of COMTmet/val gene polymorphism. The impact of COMTmet/val gene polymorphism on mankind’s cognitive function may be commom. 5. The symptom severity of GTS may correlate with cognitive function.更多还原