Genomic and genetic aspects of autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.     

肠道微生物与自闭症谱系障碍

自闭症谱系障碍(autism spectrum disorder,ASD)是一种精神致残的重要疾病,严重影响儿童身心健康,给家庭和社会带来沉重的负担。患者常出现不同程度胃肠道症状和伴有肠道微生物组成的改变,以此为切入点,近年越来越多的研究聚焦于ASD和肠道微生物的关系上。本文介绍了肠道微生物组成、肠―脑轴及ASD患者肠道微生物的主要变化,并从多个方面阐述了ASD与肠道微生物的关系。     

Methyl‐CpG‐binding protein 2 polymorphisms and vulnerability to autism

The methyl‐binding protein gene, MECP2, is a candidate for involvement in autism through its implication as a major causative factor in Rett syndrome that has similarities to autism. Rare mutations in MECP2 have also been identified in autistic individuals. We have examined the possible broader involvement of MECP2 as a predisposing factor in the disorder. Analysis of polymorphic markers spanning the gene and comprising both microsatellites and single nucleotide polymorphisms (SNPs) by the transmission disequilibrium test in two collections of families (219 in total), one in the USA and one in the UK, has provided evidence for significant association (P = 0.009) for a three‐marker SNP haplotype of MECP2 with autism/autism spectrum disorders. This association is supported by association of both Single Sequence Repeat (SSR) and SNP single markers located at the 3′ end of the MECP2 locus and flanking sequence, the most significant being that of an indel marker located in intron 2 (P = 0.001 – Bonferroni corrected P = 0.006). This suggests that one or more functional variants of MECP2 existing at significant frequencies in the population may confer increased risk of autism/autism spectrum disorders and warrants further investigation in additional independent samples.     

Trace elements in children with autism spectrum disorder: A meta-analysis based on case-control studies

Autism spectrum disorder (ASD) is a common childhood neurodevelopmental disorder that may be related to trace elements. However, reports on the relationship between them are still inconsistent. In this article, we conducted a meta-analysis on this issue. We searched the PubMed, EMBASE, and Cochrane databases as of November 15, 2019. A random-effects model was used, and subgroups of studies were analyzed using samples of different measurements. Twenty-two original articles were identified (18 trace elements, including a total of 1014 children with ASD and 999 healthy controls). In autistic children, the overall levels of barium (Ba), mercury (Hg), lithium (Li), and lead (Pb) were higher. There were significant differences in the levels of copper (Cu) in the hair and serum between autistic children and the control group. The levels of Hg, Li, Pb and selenium (Se) in the hair of autistic children were higher than those of healthy children, while the levels of zinc (Zn) in the blood were lower. Excessive exposure to toxic heavy metals and inadequate intake of essential metal elements may be associated with ASD. Preventing excessive exposure to toxic metals and correcting poor dietary behaviors may be beneficial for the prevention and treatment of the disease.     

Radial cytoarchitecture and patterns of cortical connectivity in autism

To explain the pattern of preserved and superior abilities found in autism spectrum disorders, a hypothesis has emerged, which assumes that there is a developmental bias towards the formation of short-range connections. This would result in excessive activity and overconnectivity within susceptible local networks. These networks might become partially isolated and acquire novel functional properties. In turn, this would affect the formation of long-range circuits and systems governing top-down control and integration. Despite many tantalizing clues, mechanisms relating pathogenesis and altered cell function to the ‘disconnection’ of integrative and focal activity remain obscure. However, recent post-mortem studies of brains of individuals with autism have shown characteristic differences in the morphometry of radial cell minicolumns, which add credence to the connectivity hypothesis.     

Heavy metals and trace elements in scalp hair samples of children with severe autism spectrum disorder: A case-control study on Jordanian children

BackgroundElemental analysis has been increasingly used for biomonitoring heavy metals and trace elements.MethodsThis study monitored the levels of two heavy metals (Al and Pb), and seven trace elements (Macroelements Mg, K, P and Ca; Microelements Zn, Cu, Fe) in scalp hair of 57 children with severe autism spectrum disorder (ASD) and 50 age-matched controls, using Inductively Coupled Plasma Atomic Emission Spectrophotometry (ICP-AES).ResultsCompared to controls, significantly higher levels of Al (p = 0.001), Pb (p = 0.001) and K (p = 0.021), with lower levels of Mg and Zn (p = 0.038) were observed for the ASD group. ASD boys had higher levels of Al (p = 0.001), Pb (p = 0.001) and K (p = 0.017) than control boys, while ASD girls had higher Pb levels (p = 0.005) than control girls. The ASD subgroup exposed to passive smokers had higher levels of Al (p = 0.033) and Pb (p = 0.001, and the ASD subgroup not exposed to passive smoke had higher levels of Al (p = 0.011), Pb (p = 0.001), K (p = 0.003); and lower levels of Mg (p = 0.011) than their controls. Other confounding factors and the correlation between these elements were also investigated.ConclusionThis data suggests that exposure to Al and Pb, increase intake of K, and decreased intake of magnesium and zinc, may contribute to ASD etiology.     

The relationship between mercury and autism: A comprehensive review and discussion

The brain pathology in autism spectrum disorders (ASD) indicates marked and ongoing inflammatory reactivity with concomitant neuronal damage. These findings are suggestive of neuronal insult as a result of external factors, rather than some type of developmental mishap. Various xenobiotics have been suggested as possible causes of this pathology. In a recent review, the top ten environmental compounds suspected of causing autism and learning disabilities were listed and they included: lead, methyl-mercury, polychorinated biphenyls, organophosphate pesticides, organochlorine pesticides, endocrine disruptors, automotive exhaust, polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers, and perfluorinated compounds. This current review, however, will focus specifically on mercury exposure and ASD by conducting a comprehensive literature search of original studies in humans that examine the potential relationship between mercury and ASD, categorizing, summarizing, and discussing the published research that addresses this topic. This review found 91 studies that examine the potential relationship between mercury and ASD from 1999 to February 2016. Of these studies, the vast majority (74%) suggest that mercury is a risk factor for ASD, revealing both direct and indirect effects. The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD.     

Mutations in the gene encoding CADM1 are associated with autism spectrum disorder

The unified idea on the molecular pathogenesis of Autism Spectrum Disorder (ASD) is still unknown although mutations in genes encoding neuroligins and SHANK3 have been shown in a small part of the patients. RA175/SynCAM1/CADM1(CADM1), a member of immunoglobulin superfamily, is another synaptic cell adhesion molecule. To clarify the idea that impaired synaptogenesis underlies the pathogenesis of ASD, we examined the relationship between mutations in the CADM1 gene and ASD. We found two missense mutations, C739A(H246N) and A755C(Y251S), in the CADM1 gene of male Caucasian ASD patients and their family members. Both mutations were located in the third immunoglobulin domain, which is essential for trans-active interaction. The mutated CADM1 exhibited less amount of high molecular weight with the matured oligosaccharide, defective trafficking to the cell surface, and more susceptibility to the cleavage and or degradation. Our findings provide key support for the unified idea that impaired synaptogenesis underlies the pathogenesis of ASD.     

孤独症谱系障碍小鼠肠道屏障功能研究

研究孤独症谱系障碍（ASD）模型小鼠肠道屏障功能及肠道动力的改变情况,为微生物−肠−脑轴在ASD发病中的作用提供理论基础。

C57bl/6J雌鼠和雄鼠交配,丙戊酸钠（VPA）诱导的ASD模型及对照组小鼠分别于孕12.5天皮下注射VPA或生理盐水。BTBR模型组为BTBR T⁺Itpr3^tf/J小鼠交配所产幼雄鼠。各组小鼠出生3周后,每窝随机选择2只雄鼠,各组5窝,共计10只,纳入相应组别。各组小鼠6周开始按如下顺序进行行为学检测：旷场实验、埋珠实验、三室社交实验、发声检测和自我梳理实验,各检测间隔5 d。评估小鼠肠道动力（粪便含水量及小肠推进率）和小鼠肠道屏障功能：FITC-葡聚糖灌胃后光谱仪检测小鼠血清中FITC-葡聚糖水平;Western blot检测各组小鼠结肠TREK1,CLDN1,CLDN3,OCLN及ZO1蛋白的表达;qPCR检测各组小鼠结肠Il6,Tnf-α和Ifn-γ mRNA的表达情况。

行为学检测结果显示：与对照组相比,BTBR组和VPA组小鼠穿越旷场中间区次数和停留时间显著降低（P＜0.05）;于目标小鼠侧室的停留时间率显著降低（P＜0.05）;埋珠率和自我梳理时间均显著升高（P＜0.05）;在（20～50）kHz和（50～100）kHz频率范围的发声次数及持续时间均显著降低（P＜0.05）。与对照组相比,BTBR组小鼠粪便含水量显著降低（P＜0.05）,而VPA组小鼠的差异无统计学意义（P＞0.05）。BTBR组和VPA组小鼠小肠推进率与对照组相比无差异（P＞0.05）。此外,与对照组相比,BTBR组和VPA组小鼠血清FITC−葡聚糖水平均升高,结肠TREK1,CLDN1,CLDN3,OCLD蛋白的表达水平降低,结肠Il6,Tnf-α和Ifn-γ mRNA的表达显著升高,差异均具有统计学意义（P＜0.05）,而ZO1的表达差异无统计学意义（P＞0.05）。

鉴于BTBR及VPA模型小鼠均表现出与ASD患者类似的广泛行为障碍,上述模型可作为ASD研究的可靠参考。与此同时,两种ASD小鼠模型均出现肠道紧密连接蛋白表达下调,肠道屏障通透性和促炎细胞因子水平的增高,表明微生物−肠−脑轴在ASD发病中扮演重要角色,且对治疗ASD症状具有潜在临床价值。

     

不同碳水化合物对孤独症患儿肠道菌群 体外发酵产生短链脂肪酸的影响

目的探究孤独症谱系障碍(autism spectrum disorder,ASD)患儿与健康儿童的肠道菌群利用不同碳水化合物产生短链脂肪酸(short-chain fatty acids,SCFAs)的差异。方法前瞻性病例对照研究。选择2016年12月至2017年10月解放军总医院儿科门诊的15例ASD患儿为研究对象,并匹配15名健康儿童为对照组;收集研究对象粪便,稀释成10%悬浊液,然后分别接种到以乳果糖(LAU)、乳糖(LAT)、棉籽糖(RAF)、低聚半乳糖(GOS)、低聚异麦芽糖(IMO)和低聚甘露糖(MOS)为单碳源的肠道微生态小型模拟发酵系统中批量发酵24 h,检测SCFAs浓度、底物降解率和产气气压。结果 ASD组患儿粪便SCFAs浓度与对照组差异无统计学意义,在YCFA(无碳源对照培养基,蛋白发酵为主)培养基发酵后总SCFAs、乙酸和丙酸均低于对照组,差异有统计学意义(Z=-2.509、-2.509、-3.007,P=0.011、0.011、0.002);在添加LAT、RAF、GOS、IMO和MOS的培养基发酵后总SCFAs浓度显著高于对照组,差异有统计学意义(Z=2.385、2.344、2.675、2.344、2.302,P=0.016、0.019、0.007、0.019、0.021),而含LAU的培养基发酵后,两组研究对象总SCFAs浓度比较差异无统计学意义。结论 ASD患儿肠道菌群利用蛋白发酵产SCFAs能力显著低于健康对照,利用碳水化合物产SCFAs能力显著高于健康对照。6种发酵底物中,乳果糖是最适合ASD患儿的碳水化合物,有改善ASD患儿肠道菌群产SCFAs的潜力。     

Hair levels of heavy metals and essential elements in Chinese children with autism spectrum disorder

BackgroundDisproportional heavy metals and essential elements were reported in children with autism spectrum disorder (ASD) that is obscure in etiology. Inevitably, the association is biased by diet and environmental factors.MethodsFifty pairs, one with ASD and the other living together from the same special school with cerebral palsy (CP), were recruited in Hangzhou (China), aged from 2 to 11 years old (74.0 % male). All samples were divided into two subgroups: preschool-aged (2–5 years old) and school-aged (6–10 years old). Heavy metals (As, Hg, Pb) and essential elements (Al, Ca, Cu, Mg, Mn, Zn) in hair were quantified by inductively coupled plasma mass spectrometry analysis and flame atomic absorption spectroscopy.ResultsThe children with ASD generally had lower hair levels of Mn (ASD 0.124 μg/g, CP 0.332 μg/g, P = 0.001) compared to the children with CP. After stratification for age, there were no significant differences detected in preschool-aged group. In school-aged group, the results exhibited the children with ASD had higher hair Pb (1.485 μg/g, 0.690 μg/g, P = 0.007) and Cu/Zn ratio (0.092, 0.060, P = 0.003), while hair Hg (0.254 μg/g, 0.353 μg/g, P = 0.016)、Mn (0.089 μg/g, 0.385 μg/g, P = 0.002)、Mg (17.81 μg/g, 24.53 μg/g, P = 0.014) and Zn (100.15 μg/g, 135.83 μg/g, P = 0.007) showed an opposite pattern.ConclusionsThese results suggest an imbalance of Mn in Chinese children with ASD.     

Context sensitivity in action decreases along the autism spectrum: a predictive processing perspective

Recent predictive processing accounts of perception and action point towards a key challenge for the nervous system in dynamically optimizing the balance between incoming sensory information and existing expectations regarding the state of the environment. Here, we report differences in the influence of the preceding sensory context on motor function, varying with respect to both clinical and subclinical features of autism spectrum disorder (ASD). Reach-to-grasp movements were recorded subsequent to an inactive period in which illusory ownership of a prosthetic limb was induced. We analysed the sub-components of reach trajectories derived using a minimum-jerk fitting procedure. Non-clinical adults low in autistic features showed disrupted movement execution following the illusion compared to a control condition. By contrast, individuals higher in autistic features (both those with ASD and non-clinical individuals high in autistic traits) showed reduced sensitivity to the presence of the illusion in their reaching movements while still exhibiting the typical perceptual effects of the illusion. Clinical individuals were distinct from non-clinical individuals scoring high in autistic features, however, in the early stages of movement. These results suggest that the influence of high-level representations of the environment differs between individuals, contributing to clinical and subclinical differences in motor performance that manifest in a contextual manner. As high-level representations of context help to explain fluctuations in sensory input over relatively longer time scales, more circumscribed sensitivity to prior or contextual information in autistic sensory processing could contribute more generally to reduced social comprehension, sensory impairments and a stronger desire for predictability and routine.     

Analysis of serotonin receptor 2A gene (HTR2A): Association study with autism spectrum disorder in the Indian population and investigation of the gene expression in peripheral blood leukocytes

Several studies suggest involvement of serotoninergic system in the pathophysiology of Autism Spectrum Disorder (ASD). The 5-HT receptor binding studies using ³H-lysergic acid diethylamide (³H-LSD) and linkage analysis provided evidences to consider HTR2A as a potential candidate gene for ASD. The three SNPs, −1438A/G (rs6311), 102T/C (rs6313) and 1354C/T (rs6314) of HTR2A have been well studied in the etiology of various neuropsychiatric disorders. But studies on association of this gene with ASD are limited to two reports from American and Korean populations. Additionally there are reports, which demonstrated paternal imprinting of HTR2A with expression from only one allele. So far no reports are available on HTR2A and its association with any neuropsychiatric disorders from Indian population. Therefore, the present study investigates association of the above mentioned three markers of HTR2A with ASD in Indian population using population and family-based approaches. The study also deals with allelic expression pattern of HTR2A in Peripheral Blood Leukocytes (PBLs) to understand the parental imprinting status. The genotyping analyses were carried out for probands, parents and controls. The subsequent association analyses did not show association of these markers with ASD. So, HTR2A is unlikely to be a genetic marker for ASD in Indian population. The expression analyses showed absence of monoallelic expression, suggesting lack of parental imprinting of HTR2A gene. However, we noticed methylation of the CpG sites at −1438A/G and 102T/C loci of HTR2A gene. Further bioinformatics analysis revealed absence of CpG islands in the promoter of the gene supporting biallelic expression pattern of HTR2A in PBLs.     

Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways

Autism spectrum disorder (ASD) is a group of complex, neurological disorders that affect early cognitive, social, and verbal development. Our understanding of ASD has vastly improved with advances in genomic sequencing technology and genetic models that have identified >800 loci with variants that increase susceptibility to ASD. Although these findings have confirmed its high heritability, the underlying mechanisms by which these genes produce the ASD phenotypes have not been defined. Current efforts have begun to “functionalize” many of these variants and envisage how these susceptibility factors converge at key biochemical and biophysical pathways. In this review, we discuss recent work on intracellular calcium signaling in ASD, including our own work, which begins to suggest it as a compelling candidate mechanism in the pathophysiology of autism and a potential therapeutic target. We consider how known variants in the calcium signaling genomic architecture of ASD may exert their deleterious effects along pathways particularly involving organelle dysfunction including the endoplasmic reticulum (ER), a major calcium store, and the mitochondria, a major calcium ion buffer, and theorize how many of these pathways intersect.     

Biological implications of genetic variations in autism spectrum disorders from genomics studies

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental condition characterized by atypical social interaction and communication together with repetitive behaviors and restricted interests. The prevalence of ASD has been increased these years. Compelling evidence has shown that genetic factors contribute largely to the development of ASD. However, knowledge about its genetic etiology and pathogenesis is limited. Broad applications of genomics studies have revealed the importance of gene mutations at protein-coding regions as well as the interrupted non-coding regions in the development of ASD. In this review, we summarize the current evidence for the known molecular genetic basis and possible pathological mechanisms as well as the risk genes and loci of ASD. Functional studies for the underlying mechanisms are also implicated. The understanding of the genetics and genomics of ASD is important for the genetic diagnosis and intervention for this condition.     

High prevalence of serum folate receptor autoantibodies in children with autism spectrum disorders

Abstract

Background: Supplementation of folic acid by pregnant mothers is thought to lower the risk of autism spectrum disorders (ASDs) in the offspring. Folic acid is taken up by cells via receptors with high affinity for folate and reduced folic acid derivatives. However, this is blocked by the presence of folate receptor autoantibodies (FRAA). Cerebral FRAA have been detected with high frequency in children with ASDs, suggesting the existence of a link between folic acid uptake and disease aetiology.

Methods: We investigated the frequency of FRAA in serum samples from 40 children with ASDs and 42 gender- and age-matched children with typical development (TD). Serum FRAA concentrations were measured by enzyme-linked immunosorbent assay.

Results: We found a significant difference in the frequency of serum FRAA in the two study cohorts. Serum FRAA were present in 77.5% (31/40) of children with ASDs compared with 54.8% (23/42) of TD children (p?=?0.03746, Fischer’s exact test). Thus, serum FRAA are more prevalent in children with ASDs than in TD children.

Conclusions: Our data suggest that children with ASDs may have defects in folic acid absorption that play a role in the onset of ASDs.