维生素D与孤独症谱系障碍的关系

孤独症谱系障碍（ASD）是一种复杂的与多个遗传和环境危险因素有关的神经发育障碍。过去几年遗传和环境因素间相互作用已成为研究的热点。最近提出了维生素D缺乏可能是ASD的一个环境危险因素。维生素D在维持大脑内稳态、促进胚胎和神经发育、免疫调节（包括大脑自身的免疫系统）、抗氧化、抗凋亡、影响神经分化及基因调控方面都有独特的作用。多项研究表明ASD患儿血清中维生素D浓度相比健康儿童存在显著降低。因此,母孕期和儿童早期缺乏维生素D可能是引起ASD的环境危险因素之一。     

孤独症谱系障碍易感基因相关研究进展

孤独症谱系障碍(ASD)是神经发育过程中的一种发育障碍性疾病,是多个易感基因参与发病的多基因疾病。目前已报道的易感基因有100 多个,相关研究包括易感基因的染色体位点研究、易感基因筛查研究和易感基因的表观遗传学异常。已报道的易感基因编码的蛋白质有:神经细胞粘着分子;离子通道蛋白;支架蛋白;蛋白激酶、受体、载体;信号通路调控蛋白以及昼夜节律相关蛋白。易感基因突变和表达调控机制的研究进展有助了解ASD 的遗传参与的发病机制,可望能给ASD 的诊断和治疗提供新的思路。该文对ASD 易感基因方面的研究现状进行了综述。     

先天性心脏病伴神经发育障碍的临床表现及遗传学研究进展

近年来研究发现先天性心脏病(CHD)患儿伴神经发育障碍(NDDs)的风险正逐年增加,包括认知、适应性、运动、语言、孤独症谱系障碍等。已通过结构及功能神经成像等影像学检查证实CHD患儿大脑发育存在异常,可能为宫内发育不良所致。拷贝数变异(CNVs)等基因异常对CHD伴NDDs具有重要影响。一些参与载脂蛋白E产生、Wnt信号传导通路和组蛋白修饰的基因变异以及1q21.1、16p13.1-11和8p23.1遗传位点变异均与CHD和NDDs相关。了解其中的相互联系对CHD患者的风险分层、疾病分类、筛查及药物治疗具有重要意义。     

维生素D在孤独症谱系障碍发病机制中的研究进展

孤独症谱系障碍(ASD)是一组神经发育障碍性疾病,虽然ASD患病率不断上升,但其发病机制至今未明。目前研究提示其可能与遗传因素、免疫因素和环境因素有关。有研究表明维生素D(Vit D)缺乏与ASD患病率存在负相关,补充Vit D可能降低ASD的发病风险。因为Vit D的广泛生理功能,Vit D可作为类固醇激素作用于遗传...     

孤独症谱系障碍特质研究进展

孤独症谱系障碍（ASD）特质主要包括社交互动障碍、言语交流困难、刻板重复行为等,不仅存在于ASD患者及其亲属,也存在于普通人群。近年来对ASD特质的研究越来越多,该文就ASD特质在ASD亲属和一般人群中的研究进展进行了综述。     

孤独症谱系障碍的免疫相关机制与治疗研究进展

孤独症谱系障碍(ASD)是以社交障碍和行为异常为特征的神经发育障碍性疾病。目前的诊疗手段主要基于行为学特征, 客观的诊断指标和疾病机制性治疗仍在研究中。越来越多的证据表明, 免疫、肠道菌群和神经系统异常相互联系, 共同参与ASD的发病过程。综述ASD的免疫相关机制、基因和表观遗传学改变以及免疫治疗进展, 可为ASD的早期诊断和治疗提供新思路。     

孤独症谱系障碍儿童智力发育与表情识别能力的关系

目的探讨孤独症谱系障碍(ASD)儿童的智力发育特点、表情识别能力及两者之间的关系。方法招募6~16岁的ASD儿童(ASD组,总智商均大于70)和年龄、性别匹配的正常发育儿童(对照组)各27例,使用韦氏儿童智力量表(第四版)和中国人物静态面部表情图片对两组儿童进行智力评估和表情识别测试。结果 ASD组总智商、言语理解、知觉推理、加工速度以及工作记忆指数得分均低于对照组(P0.05)。ASD组儿童的表情识别总正确率及高兴、生气、伤心、害怕表情识别的正确率均低于对照组儿童(P0.05)。ASD组表情识别总正确率、高兴及害怕表情识别的正确率与知觉推理呈正相关(r分别为0.415、0.455、0.393,P0.05),生气表情识别的正确率与工作记忆指数呈正相关(r=0.397,P0.05)。结论 ASD儿童在智力发育的多个领域落后于正常儿童,其表情识别能力受损。患儿智力中的知觉推理能力和工作记忆能力与表情识别能力存在正相关关系,推测知觉推理和工作记忆能力不足可能是影响ASD儿童表情认知的重要因素。     

孤独症谱系障碍儿童功能性近红外光谱成像拓扑结构44例病例系列报告

背景 青春期是大脑成熟和发育的重要时期.孤独症谱系障碍(ASD)青少年存在异常的前额叶和颞叶皮层激活和功能连通性,并可能与症状严重程度相关.目的 图论研究ASD个体的脑网络拓扑属性的发育轨迹与年龄、认知和症状严重程度的相关性.设计病例系列报告.方法 纳入符合DSM?Ⅳ?TR/DSM?Ⅴ/ICD?10/ICD?11诊断标...     

叶酸和维生素B12与孤独症谱系障碍儿童症状和发育水平相关性研究

目的 探讨孤独症谱系障碍(ASD)儿童与正常儿童之间叶酸及维生素B12(VB12)水平的差异,并分析叶酸和VB12水平与ASD儿童症状及发育水平的相关性.方法 对2016-2017年海南省妇幼保健院康复中心的244例ASD儿童采用孤独症行为量表(ABC)、社交反应量表(SRS)评估ASD儿童的症状,采用Gesell发育...     

孤独症谱系障碍遗传检测意义及方法选择专家建议

孤独症谱系障碍（autism spectrum disorder,ASD）是一组高异质性的神经发育障碍性疾病,目前有关ASD的发病机制尚未阐明,但研究证实遗传物质即基因突变是ASD和ASD样症状的重要病因。遗传检测技术的不断发展,为认识ASD和ASD样症状的遗传背景奠定了良好的基础,该文就相关问题及建议进行叙述。     

The genetics of autism

Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of approximately 3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is approximately 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.     

Behavioral interventions for children with autism spectrum disorders

Early intensive behavioral intervention is the only well-established treatment for young children with autism spectrum disorders (ASDs). Less intensive behavioral interventions are also effective for targeted concerns with older children and adolescents. This article describes the core features of behavioral treatments, summarizes the evidence base for effectiveness, and provides recommendations to facilitate family understanding of these interventions and identification of qualified providers. Recommendations are also provided for collaboration between pediatric providers and behavior analysts who are serving families of individuals with ASDs.     

Recommendations for early diagnosis and intervention in autism spectrum disorders: An Italian–Israeli consensus conference

On April 2013 experts in the field of autism from Italy and Israel convened in Jerusalem to discuss and finalize clinical recommendations for early diagnosis and intervention in Autism Spectrum Disorders (ASDs). In this paper, we summarize the results of this Italian–Israeli consensus conference.ASDs constitute a class of severe and heterogeneous neurodevelopmental conditions caused by atypical brain development beginning during early prenatal life, reflecting many genetic, neurobiological and environmental influences. The first clinical signs of ASDs begin to be evident in children between 12 and 18 months of age, often after a period of relatively typical postnatal development. Recent longitudinal studies reveal substantial diversity in developmental trajectories through childhood and adolescence. Some intervention approaches have been demonstrated to be effective in improving core symptoms of ASDs, even if the heterogeneity and developmental nature of the disorder make it implausible that only one specific treatment will be best for all children with ASDs. More randomized control trials (RCTs) on early intervention are needed to identify the most effective strategies and provide the most efficient allocation of resources during the critical early intervention time period. Future research should focus on linking biological phenotypes with specific genotypes, thus establishing a foundation for the development of diagnostic screening tools and individualization of treatments.     

Diagnosing autism

Awareness of autism within public and medical domains has continued to increase. Children and young people are being presented for earlier advice, assessment and diagnosis resulting in increasing demand on services. Recently published standards in the recognition, referral and diagnosis of autism mean it remains essential for paediatricians, child and adolescent psychiatrists, general practitioners and allied professionals with a role within developmental child health and child and adolescent mental health to have sound knowledge of the presentation and assessment of autism spectrum disorders (ASDs). Whilst routes of entry for referrals can vary due to diversity of presentation and local service provision, access to a local multidisciplinary team specialized in ASD assessment is recommended. Early identification of deviation away from the typical developmental trajectory in this group of patients is advantageous in order to maximize their potential, provide targeted intervention and minimize co-morbidities. This review addresses the diagnosis of ASD and provides an assessment framework for professionals who encounter a child with suspected autism.     

孤独症谱系障碍动物模型的研究进展

孤独症谱系障碍是一种神经发育障碍性疾病。其病因多样,多数认为是环境与遗传的共同结果。动物模型,作为孤独症谱系障碍疾病的研究工具,通过生化作用诱导与基因分子缺陷,从而获得不同的孤独症动物亚型,以研究孤独症的病因,行为学表型,探索药物及干预疗法的安全性和有效性,以期提高孤独症个体的生活质量。     

Efficacy of Risperidone in Managing Maladaptive Behaviors for Children With Autistic Spectrum Disorder: A Meta-Analysis

IntroductionAtypical antipsychotic agents are widely used psychopharmacological interventions for autism spectrum disorders (ASDs). Among the atypical antipsychotic agents, risperidone has demonstrated considerable benefits in reducing several behavioral symptoms associated with ASDs. This meta-analysis examined research regarding the effectiveness of risperidone use among children with ASD using articles published since the year 2000.MethodsThe database for the analyses comprised 22 studies including 16 open-label and six placebo-controlled studies. Based on the quality, sample size, and study design of studies prior to 2000, the database was then restricted to articles published after the year 2000. Effect sizes were calculated for each reported measure within a study to calculate an average effect size per study.ResultsThe mean effect size for the database was 1.047 and the sample weighted mean effect size was 1.108, with a variance of 0.18.ConclusionsOutcome measures demonstrated mean improvement in problematic behaviors equaling one standard deviation, and thus current evidence supports the effectiveness of risperidone in managing behavioral problems and symptoms for children with ASD. Although Risperdal has several adverse effects, most are manageable or extremely rare. An exception is rapid weight gain, which is common and can create significant health problems. Overall, for most children with autism and irritable and aggressive behavior, risperidone is an effective psychopharmacological treatment.     

Syndromic autism: causes and pathogenetic pathways

Background  Autism is a severe neurodevelopmental disorder known to have many different etiologies. In the last few years, significant progresses have been made in comprehending the causes of autism and their multiple impacts on the developing brain. This article aims to review the current understanding of the etiologies and the multiple pathogenetic pathways that are likely to lead to the autistic phenotype. Data sources  The PubMed database was searched with the keywords “autism” and “chromosomal abnormalities”, “metabolic diseases”, “susceptibility loci”. Results  Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons’ development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems. Conclusions  A wide variety of cytogenetic abnormalities have been recently described, particularly in the low functioning individuals with dysmorphic features. Routine metabolic screening studies should be performed in the presence of autistic regression or suggestive clinical findings. As etiologies of autism are progressively discovered, the number of individuals with idiopathic autism will progressively shrink. Studies of genetic and environmentally modulated epigenetic factors are beginning to provide some clues to clarify the complexities of autism pathogenesis. The role of the neuropediatrician will be to understand the neurological basis of autism, and to identify more homogenous subgroups with specific biologic markers.     

Diagnostic yield of genetic testing in children diagnosed with autism spectrum disorders at a regional referral center

The aim was to systematically review genetic testing guidelines in the evaluation of children with autism spectrum disorders (ASDs). The Clinical Report published by the American Academy of Pediatrics (AAP)(1) recommended individualizing the workup, including karyotype and specific DNA testing for fragile X syndrome. A recent publication reported higher rates of abnormalities on CGH microarray (CMA) testing on children with ASD.(2) The medical records of 507 children seen through the Kirch Developmental Services Center were abstracted for genetic testing and factors associated with this testing. Abnormalities were found on karyotype in 2.3% and in DNA for fragile X in 0.04%. The author concludes that the diagnostic yield of the genetic testing was low in this population. Furthermore, their findings support the theory that CMA can be considered as part of the initial genetic screening in children with ASD in most situations. Future studies will need to be done prospectively to evaluate children in a standard fashion.     

The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome)

The behavioral phenotype of 47,XXY (Klinefelter syndrome) includes increased risks for developmental delays, language-based learning disabilities, executive dysfunction/ADHD, and socialemotional difficulties. However there is significant variability between individuals with 47,XXY, and many children and adolescents have minimal or no behavioral features while others have quite significant involvement. This paper describes behavioral features in a cohort of 57 children and adolescents with 47,XXY, including results on standardized measures of behavior (BASC-2), attention (Conner's Rating Scales), and social skills (Social Responsiveness Scale). A subset was directly assessed for autism spectrum disorders using the ADOS and ADIR. We discuss our results within the context of previous literature, including implications for genetic counseling, recommendations for care, and areas for future research.