GABAA受体与脆性X综合征

脆性X综合征(fragile X syndrome,FXS)是引起先天性智力低下的常见疾病,GABAA受体是哺乳动物中枢神经系统内最主要的抑制性神经递质受体,与焦虑、抑郁、癫癎、睡眠、认知等相关.多项研究证明GABA能神经系统特别是GABAA受体的变化与FXS的遗传表型有关.GABAA受体某些亚基的表达变化是FXS患者神经行为学改变的原因之一,可为FXS的治疗提供一个新的方向.     

脆X综合征的分子基础及其认知研究进展

脆X综合征(FXS)由于存在X染色体CGG重复片段大量扩增,导致脆X智力低下基因异常甲基化,基因失活,脆X智力低下蛋白生成障碍,因嵌合体或X染色体活化率不同,引起不同程度的脆X智力低下蛋白降低和神经元与突触的生成与成熟障碍,导致学习与记忆功能异常.FXS的特殊认知表型与其分子基础有关,FXS具有不同程度认知功能的异常,主要有视觉空间能力、注意力、工作记忆及执行功能异常,而执行功能异常认为是其特殊的认知基础.     

γ-氨基丁酸A受体与早产儿脑损伤

缺氧缺血性脑损伤(HIBD)是早产儿脑损伤的主要原因,既往研究认为兴奋性谷氨酸受体(NMDA、海人藻酸受体)的过度激活导致细胞内钙超载是HIBD的主要发病机制,γ-氨基丁酸A受体(GABAA受体)可对抗其兴奋毒作用,在神经保护中占主要地位。但近年来研究发现GABAA受体在围生期脑损伤中的作用完全相反,是造成围生期脑损伤的主要因素,GABAA受体的过度激活还可诱发或加剧新生儿癫。本文就GABAA受体在早产儿脑损伤中的作用及其研究进展作一综述。     

脆X综合征的分子基础及其认知研究进展

脆X综合征 (FXS)由于存在X染色体CGG重复片段大量扩增 ,导致脆X智力低下基因异常甲基化 ,基因失活 ,脆X智力低下蛋白生成障碍 ,因嵌合体或X染色体活化率不同 ,引起不同程度的脆X智力低下蛋白降低和神经元与突触的生成与成熟障碍 ,导致学习与记忆功能异常。FXS的特殊认知表型与其分子基础有关 ,FXS具有不同程度认知功能的异常 ,主要有视觉空间能力、注意力、工作记忆及执行功能异常 ,而执行功能异常认为是其特殊的认知基础。     

脆性X染色体综合征癫(癎)发作机制研究进展

脆性X染色体综合征(fragile X syndrome, FXS)是一种X连锁不完全显性遗传病,男性发病率为1/4000,女性为1/6000[1],具有一种特殊的Sherman遗传现象,即FXS在家系内患病风险呈逐代递增趋势,而在兄弟姐妹中患病风险率较低的一种遗传现象.     

发根脆性X智力低下蛋白检测法诊断脆性X综合征

目的：至今已有多种筛查和诊断脆性X综合征(fragile X syndrome,FXS)的方法,以PCR法和Southern印迹方法应用最广,然而每种方法均存在各自的局限性。该研究探讨发根脆性X智力低下蛋白（fragile X mental retardation protein,FMRP）检测在诊断或筛查FXS中的可靠性,以建立一种快速、简便、价廉且可靠的诊断FXS的方法。方法：采用发根FMRP免疫组化的检测方法对80例健康儿童、40例不明原因智力低下儿童、已确诊FXS家系成员12例进行检查; 用7-deza-dGTP PCR 法进行对照,探讨其对诊断FXS的应用价值。结果：在80例健康儿童中,发根FMRP的表达率均在80%以上。40例不明原因智力低下患儿中,2例确诊为FXS患儿的发根FMRP表达率分别为10%和0,另38例非FXS患者发根FMRP的表达率均在80%以上。在FXS家系调查中,确诊的2例FXS患者的发根FMRP表达率均为0。结论：发根FMRP检测诊断FXS具有快速、简便、价廉、可靠等特点,值得进一步推广应用。［中国当代儿科杂志,2009,11（10）：817-820］     

全面性癫(癎)伴热性惊厥附加症及其相关基因γ-氨基丁酸A型受体γ2亚单位基因变异研究进展

全面性癫(癎)伴热性惊厥附加症(GEFS+)是常染色体显性遗传且具有遗传及表型异质性.近年来利用聚合酶链反应(PCR)、单链构型多态性分析(SSCP)等多种方法研究发现,其与γ-氨基丁酸A型(GABAA)受体γ2亚单位基因(GABRG2)变异密切相关,通过不同途径,最终导致癫(癎)的发生.     

肝X受体与代谢综合征代谢紊乱

肝X受体是与代谢综合征相关的核受体之一,对体内胆固醇的平衡和脂代谢的调控起重要作用.肝X受体能增加组织对葡萄糖的利用,延缓胰岛素抵抗,同时对胰岛β细胞有不利的作用.肝X受体影响脂肪细胞分化和下调肥胖基因的表达而引发肥胖,参与非酒精性脂肪肝的发生发展,同时具有控制动脉粥样硬化的作用,并参与巨噬细胞和淋巴细胞的炎症反应.作为代谢通路与炎症反应信号通路的结合点,肝X受体有望作为治疗代谢综合征的新靶点.     

γ-氨基丁酸A受体对新生大鼠基本节律性呼吸的调节作用

目的 探讨γ-氨基丁酸A(GABAA)受体对新生大鼠基本节律性呼吸的产生和调节作用.方法 制备新生大鼠离体延髓脑片标本,包括面神经后核内侧区(mNRF),并保留舌下神经根,予灌流改良Kreb's液(MKS),记录舌下神经根的呼吸相关节律性放电活动(RRDA).实验分为3组,每组分别使用6只脑片标本.GABA量效关系组:以10、20、40、60 μmol/L的GABA灌流脑片,加药前神经放电为对照组,观察RRDA的变化,描记量效曲线,选择最适质量浓度;荷包牡丹碱(bicuculline)组:以10 μmol/L bieuculline灌流脑片,观察RRDA的变化;GABA和bicuculline组:联合应用40 μmol/L GABA和10 μmol/L bicuculline灌流脑片,观察RRDA的变化.结果 GABA对延髓脑片RRDA有抑制作用,使用含GABA的MILS灌流脑片标本可使RRDA的吸气时程(TI)缩短、放电积分幅度(IA)下降、呼吸周期(RC)延长、呼气时程(TE)延长.40μmol/L的GABA对TI、LA、RC、TE等呼吸指标综合效果最显著.GABA可使RRDA的TI缩短、IA下降、RC和TE延长.bieuculline使TI延长、IA增加、RC和TE缩短,对RRDA有兴奋作用.联合使用GABA和bieuculline对RRDA无明显作用.结论 生理条件下内源性GABA通过GABAA受体对新生大鼠的基本呼吸节律的产生和调节发挥重要作用.     

全面性癫伴热性惊厥附加症及其相关基因γ-氨基丁酸A型受体γ_2亚单位基因变异研究进展

全面性癫伴热性惊厥附加症(GEFS )是常染色体显性遗传且具有遗传及表型异质性。近年来利用聚合酶链反应(PCR)、单链构型多态性分析(SSCP)等多种方法研究发现,其与γ-氨基丁酸A型(GABAA)受体γ2亚单位基因(GABRG2)变异密切相关,通过不同途径,最终导致癫的发生。     

Screening for fragile X syndrome: results from a school for mentally retarded children

Fragile X syndrome is the most common inherited form of familial mental retardation. The purpose of this study was to identify yet unrecognized fragile X individuals and to estimate the frequency of both the FRAXA and FRAXE forms of the disease in a population of mentally retarded children attending a special school in Croatia. The results are reported of molecular screening of 114 children with mild to severe mental retardation. Three individuals (2.6%) with the FRAXA form of the fragile X syndrome and one boy (0.9%) with FRAXE mental retardation were detected; a total of four newly diagnosed fragile X families were identified. Closer clinical examination revealed that behavioural and speech disturbances were clearly present among all fragile X cases (both FRAXA and FRAXE), indicating that these features could be additional diagnostic criteria for the preselection of individuals at risk.

Conclusion: Fragile X screening among mentally retarded children attending a special school should be highly encouraged to reveal the cause of mental retardation and to detect yet unrecognized fragile X individuals. The frequency of fragile X syndrome in a such population in Croatia was found to correlate with similar results from previous studies. However, since at the time of diagnosis all affected families had a second or even a third child born, earlier diagnosis should be considered to provide greater benefit to fragile X families.     

DNA testing for fragile X syndrome in schools for learning difficulties

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

DNA testing for fragile X syndrome in schools for learning difficulties.

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

脆性X综合征患儿细胞内环磷酸腺苷降低的机制

目的 探讨脆性X综合征细胞内环磷酸腺苷(cAMP)降低的机制。方法 通过基因封闭方法，建立Fra(X)细胞模型，研究cAMP代谢途径中的两个关键酶腺苷酸环化酶(AC)及磷酸二酯酶(PDE)的活性变化。结果 试验组AC的比活力明显低于对照组(P＝0．000)，而PDE比活力则无显著改变(P＝0．983)。结论 Fra—(X)细胞内cAMP水平的降低可能与AC活性的抑制有关，而与PDE活性无明显关系。     

Learning disabilities and attentional problems in boys with the fragile X syndrome

The fragile X syndrome is a relatively common form of mental retardation that tends to affect boys more severely than girls. The syndrome is associated with a fragile site at q27 on the X chromosome and with physical features including large or prominent ears and macro-orchidism. Four boys had physical and cytogenetic features of the fragile X syndrome. However, the IQ scores of these patients extended into the normal range. All four patients demonstrated similar learning difficulties that included hyperactivity, visuomotor incoordination, language deficits, and academic delays in mathematics. The fragile X syndrome should be considered in the differential diagnosis of learning disabled children.     

Language use in females with fragile X or Turner syndrome during brief initial social interactions

Fragile X and Turner syndromes are associated with risk of atypical social function. We examined language use, including normal and atypical speech, during initial social interactions among participants engaged in a brief social role play with an unfamiliar adult. There were 27 participants with Turner syndrome, 20 with fragile X syndrome and 28 in an age-matched comparison group. Females with fragile X did not exhibit more abnormal language, but exhibited less of what is typical during initial interactions. Overall rates of dysfluencies did not differ, although females with fragile X made more phrase repetitions. Females with Turner syndrome had no language use abnormalities. Our findings suggest that language use may influence social function in females with fragile X syndrome and that such language characteristics may be observed in the context of brief encounters with an unfamiliar adult.     

Nasopharyngeal carcinoma in a boy with fragile X syndrome

The authors report on what they believe to be the first case of nasopharyngeal carcinoma in a patient with fragile X syndrome. In the literature, a few cases of fragile X syndrome associated with malignancies are described. Although this association seems more than coincidental, the molecular correlation between this syndrome and cancer is yet unclear.     

NASOPHARYNGEAL CARCINOMA IN A BOY WITH FRAGILE X SYNDROME

The authors report on what they believe to be the first case of nasopharyngeal carcinoma in a patient with fragile X syndrome. In the literature, a few cases of fragile X syndrome associated with malignancies are described. Although this association seems more than coincidental, the molecular correlation between this syndrome and cancer is yet unclear.     

Family experiences and factors associated with the diagnosis of fragile X syndrome

The authors interviewed 41 mothers of young boys with fragile X syndrome to determine the process by which they learned their child had fragile X syndrome. The average family had concerns about the child's development at 9 months of age. Developmental delay was determined at an average age of 24 months, and fragile X syndrome was diagnosed at a mean age of 35 months. Considerable variability was found in age of first concern, determination of delay, and diagnosis of fragile X syndrome. Three child variables (severity of delay, autistic behavior, temperament style) and four family variables (mother's age, mother's education, sibling status, social support) did not account for this variability, although birth year did (children born more recently were somewhat more likely to be identified earlier). Families often encountered physicians who initially discounted concerns or said that it was too early to determine whether a problem did indeed exist. Given current knowledge and practice, improving the early identification (under 3 years of age) of children with fragile X syndrome is likely to remain difficult if based solely on behavioral and clinical observations.