深圳市育龄女性FMR1基因CGG重复序列的多态性分析

目的 通过对深圳市育龄女性进行脆性X智力低下1(FMR1)基因筛查,了解本市育龄女性FMR1基因(CGG)重复序列分布特征。方法 采集100名育龄女性的外周血,提取基因组DNA,应用三引物PCR及毛细管电泳技术检测全血样本中FMR1基因CGG重复序列,并对检测结果进行统计分析。结果 在78名具有自然流产史(15名)、复发性流产史(42名)和其他不良生育史(21名)的育龄女性中,FMR1等位基因1及等位基因2 CGG重复序列分布情况均无差异(P>0.05)。100名育龄女性FMR1基因CGG重复数范围为21～44,最常见CGG重复数为30和29,未检出突变基因携带者。结论 不同地区、种族女性FMR1前突变基因携带率存在一定差异,但同一种族在不同地区携带率无差异。     

外周血淋巴细胞FMRP检测在脆性X综合征中的应用

目的 探讨外周血脆性X智力低下蛋白(fragile X mental retardation protein,FMRP)表达对脆性X综合征(fragile X syndrome,FXS)的诊断价值.方法 运用免疫细胞化学方法对38例不明原因的智力低下男性患儿的FMRP进行外周血淋巴细胞FMRP表达检测,并与38例年龄相近、智商或发育商均大于85的正常男性患儿比较,同时对FXS儿童FMRP表达水平与智力水平进行相关分析.结果 通过FMRP检测,智力低下组符合FXS诊断标准者5例,正常对照组外周血淋巴细胞FMRP表达均未达到诊断标准(P=0.022);FXS患儿FMRP表达率与发育商或智商间的相关性没有统计学意义(r=-0.610,P=0.275).结论 外周血淋巴细胞FMRP免疫细胞化学检测方法是一种具有快速、简便、价廉等优点的FXS实验诊断方法,可以用作FXS的诊断和筛查.     

不明原因智力低下和孤独症谱系障碍儿童脆性X综合征的筛查结果分析

目的 不明原因智力低下和孤独症谱系障碍儿童脆性X综合征FMR1基因筛查结果分析.方法 选择不明原因智力低下和孤独症谱系障碍患儿35例,采用常规G显带染色体核型分析患儿染色体畸变情况,CNV-seq技术分析染色体拷贝数变异,PCR结合毛细管电泳法分析FMR1基因5'非编码区的CGG重复序列数目.结果 35例患儿中核型异常...     

白化病与脆性X染色体综合征同患一个体的分析

目的白化病与脆性X染色体综合征同患一个体的分析。方法用低叶酸培养基Te-199和双诱导检出fra（x）。结果 6例患者共观查细胞总数435个,检出fra（x）阳性细胞145个,fra（x）平均检出率为：33.3%,最高出现频率为50%。结论白化病与脆性X染色体综合征同患一个体与近亲结婚有关。     

一种经济的脆性X综合征的PCR检测法

目的建立一种经济的用于脆性x综合征临床大面积筛查的简便的检测方法。方法同时用加入betaine作为PCR增强剂的扩增体系和用PfxAmpTaq酶Enhance扩增体系检测脆性x综合征（FraX）FMR-1基因，检N（CGG）n重复数的多少，对脆性x综合征可疑病人进行筛查。结果扩增目的片段为237—372bp，样本未见扩增片段的为脆性x综合征患者。样本可见明显扩增片段的为正常人。在不明原因的智力低下的儿童中筛查出3例脆性x综合征患者。两种方法对FMR-1基因的CGG重复序列扩增效果均较好。结论用加入betaine扩增体系更经济可应用于临床大批量的标本筛查。     

脆性X综合征三例家系分析

脆性X综合征（fragile X chromosome，FraX）是由于X染色体畸变导致的以智能低下为主要表现的染色体病。本文就脆性X综合征的临床特点、细胞遗传学特征以及遗传规律进行分析，以期为临床上早期诊断、遗传咨询和生殖干预提供参考依据。     

智低人群中脆性X综合征的细胞,分子遗传学研究

采用ＰＣＲ、ＳｏｕｔｈｅｒｎＢｌｏｔ印迹杂交及细胞遗传学方法，对２３３名原性智力低下患儿进行了ＦＭＲ－１基因的突变分析和Ｘｑ２７．３脆性位点检查。结果：确诊９名脆性Ｘ综合征患者，占３．８６％，并在部分家庭成员中检出了女性前突变和全突变携带者，排除细胞学方法假阳性１例。     

脆性X综合征诊断及出生前诊断

目的探讨脆性X综合征诊断及出生前诊断方法。方法建立低叶酸双诱导双定位方法和基因诊断方法对弱智、癫痫加弱智、智力低下及其亲属及产前诊断共1326例。结果发现外周血1318例,脆性X染色体阳性148例,经过家系调查9个大的家系(超过3个患者/家系);基因产前诊断4例阳性,脆性X染色体阳性共152例,检出率占11.46%。结论低叶酸双诱导双定位方法结合基因诊断方法脆性X综合征和产前诊断,提高诊断率。     

The challenges of clinical trials in fragile X syndrome

Rationale

Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.

Objectives

We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.

Results

Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABA_B agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.

Conclusion

Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.     

The quest for targeted therapy in fragile X syndrome

Fragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotypes were improved in preclinical studies with drugs targeting these pathways in the FXS mouse model, attempts to translate these animal-model success stories into treatment of patients in clinical trials have been extremely disappointing. Complicating factors, particularly in animal studies, include mouse inbred strains, variability in functional studies between laboratories, publication bias and lack of reliable and objective primary outcome measures in both mice and patients. Possibly most important, however, is one factor that has been little explored: the complexity of the molecular imbalance in FXS and the need to simultaneously target several different disturbed pathways and different cellular compartments. New, well-conceived animal studies should generate more productive approaches in the quest for targeted therapy for FXS.     

A prospective open-label study of aripiprazole in fragile X syndrome

Rationale  

Fragile X syndrome (FXS) is the most common inherited form of developmental disability and most common single gene cause of autism. Persons with FXS frequently exhibit irritable behavior marked by aggression, self-injury, and severe tantrums. Despite frequent clinical use of atypical antipsychotic drugs to target this behavioral cluster, no systematic trials to date have assessed the efficacy and safety of these drugs in persons with FXS.     

Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy

Fragile X syndrome is the leading inherited form of mental retardation, and second only to Down's syndrome as a cause of mental retardation attributable to an identifiable genetic abnormality. Fragile X syndrome is caused by a defect in the fragile X mental retardation 1 gene (FMR1), located near the end of the long arm of the X chromosome. FMR1 normally synthesises the fragile X protein (FMRP), but mutations in FMR1 lead to a lack of FMRP synthesis, resulting in fragile X syndrome. While the specific function of FMRP is not yet fully understood, the protein is known to be important for normal brain development. The physical, cognitive and behavioural features of individuals with fragile X syndrome depend on gender (females have two X chromosomes, one active and one inactive) and the molecular status of the mutation (premutation, full mutation or mosaic). Features of the behavioural profile of individuals with fragile X syndrome include hypersensitivity to stimuli, overarousability, inattention, hyperactivity and (mostly in men) explosive and aggressive behaviour to others or self. Social anxiety, other anxiety disorders, depression, impulse control disorder and mood disorders are the most common psychiatric disorders diagnosed in individuals with fragile X syndrome, although no formal studies have been undertaken. There have been very few psychopharmacological studies of the treatment of behaviours associated with fragile X syndrome. These limited studies and surveys of psychotropic drugs used in individuals with fragile X syndrome suggest that stimulants are helpful for hyperactivity, that alpha(2)-adrenoceptor agonists and beta-adrenoceptor antagonists help to control overarousability, impulsivity and aggressiveness, and that SSRIs can control anxiety, impulsivity and irritability, alleviate depressive symptoms and decrease aggressive and self-injurious behaviour. Typical and atypical antipsychotics in combination with other psychotropics have been used for control of psychotic disorders and severe aggressive behaviours. Mood stabilisers have been found to be useful when mood dysregulation or mood disorders are present with or without aggressive behaviour. Folic acid and L-acetylcarnitine (levacecarnine) have not been found to improve deficits or behaviours. As there is no specific psychotropic drug for any of the deficits or behaviours associated with fragile X syndrome, clinicians are advised to diagnose any psychiatric syndromes or disorders present and treat them with the appropriate psychotropic drug. If no psychiatric disorder can be diagnosed and the patient's challenging behaviours cannot be controlled with environmental manipulation or behaviour modification techniques, the most benign psychotropic drug should be used. Antipsychotics should be reserved for psychotic disorders, for impulse control disorders (used in combination with other psychotropics), or when challenging behaviours constitute an emergency. In the future, new medications targeting molecules implicated in the modulation of anxiety, fear and fear responding will be useful for treating the social anxiety and overarousability exhibited by individuals with fragile X syndrome.     

Reducing histone acetylation rescues cognitive deficits in mouse model of fragile X syndrome

Fragile X syndrome(FXS) is the most prevalent inherited intellectual disability, resulting from a loss of fragile X mental retardation protein(FMRP). Patients with FXS suffer lifelong cognitive disabilities, but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood. Here, we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs). Consequently, FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion, leading to cognitive impairment in mature adult mice. Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice. Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel therapeutic strategy for treating adult FXS patients.     

河源市新生儿疾病筛查结果的分析

目的 回顾性地分析2003-2010年的筛查结果,了解我市新生儿中的PKU、CH和G6PD缺乏症的发病率及治疗效果.方法 运用芬兰Labsystem公司提供的筛查试剂盒对在本市33间医院采集的36 119份标本进行PKU、CH和G6PD缺乏症实验检测.结果 筛查新生儿36 119例,确诊TSH 9例,发病率为1/4013;苯丙酮尿症（PKU）筛查阳性2例,1例被确诊为轻型PKU,另1例确诊为其他代谢病,PKU发病率为1/36119;确诊G6PDD 2636例,发病率为7.33%.结论 新生儿疾病筛查是现代预防医学的一项重要内容,可以早期检出患儿,并早期治疗患儿,避免发生体格和智能发育障碍,对优生优育和提高我国人口素质具有深远意义.     

新生儿高胆红素血症听力筛查结果分析

目的探讨高胆红素血症对新生儿听力的影响。方法对焦作市妇幼保健院2009年8月至2011年8月NICU收住的高胆红素血症新生儿528例进行初筛和复筛,初筛用畸变产物耳声发射(DPOAE)模式,对初筛未通过者再行复筛,复筛用DPOAE联合听性脑干反应(ABR)的方法,而对于复筛未通过者进行听力学评估及确诊;另选取产科出生,正常足月新生儿400例作为对照组。结果黄疸患儿组畸变产物耳声发射(DPOAE)初筛未通过130例(24.6%),42d自动听性脑干反应(ABR)复筛未通过25例(19.2%);对照组DPOAE初筛未通过40例(10%),42dABR复筛全部通过。高胆新生儿的听力筛查未通过率明显多于正常新生儿。结论高胆红素血症是导致新生儿听力障碍的高危因素,新生儿胆红素水平与听力损失程度成正相关。     

Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome

Rationale  

Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice.     

Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome

Rationale  

Muscarinic acetylcholine receptors (mAChR) are G protein-coupled receptors, widely expressed in the CNS. Electrophysiological and molecular studies have provided evidence for overactive M1 receptor signaling in the fragile X knockout (Fmr1 KO) mouse model, suggesting the involvement of the M1 receptors in fragile X syndrome. Overactive signaling through the M1 receptor has been hypothesized to contribute to the phenotypes seen in fragile X mice.