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. 相似文献
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. 相似文献
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. 相似文献
BackgroundPerchlorates ClO4(−) are known environmental and food contaminants that act as inhibitors of iodine uptake by the thyroid gland; however, information concerning their possible association with the development of autism spectrum disorder (ASD) is still missing. The current study is first presenting the alterations in perchlorate urine levels in euthyroid children with ASD.ObjectivesTo examine urinary perchlorates and iodides in euthyroid children diagnosed with ASD, compared to age-, and BMI-matched neurotypical controls, and to verify the association between these two ions in ASD.MethodsIons were determined in 24 h urine samples determined by ion chromatography–conductivity cell detection (IC-CD) and ion chromatography–pulsed amperometric detection (IC-PAD) techniques, respectively, in a total of 130 postpubertal euthyroid children with normal BMI (the mean age 14.46 years, SD = 1.32; the mean BMI 20.6, SD = 1.37), divided into age- and BMI-matched groups of ASD patients and neurotypical, healthy children (control).ResultsThe ASD group presented with significantly higher perchlorate urine levels than the controls (median = 1.05 μg/L, interquartile range(IQR) = 1.5 versus median = 0.09 μg/L, IQR = 0.097, respectively), as well as lower iodide urine levels (median = 100.2 μg/L, IQR = 37 versus median = 156.95 μg/L, IQR = 26.11, respectively). The ASD group presented significantly lower TSH and higher free thyroid hormone (fT4, fT3) levels than the controls. In regression analyses, perchlorate urine levels showed significant positive relationships with normal BMI values and serum TSH, and inverse relationships with serum fT4. Urinary iodide levels showed significant inverse relationships with BMI values. The absence of ASD was associated with decreased odds of perchlorate urine levels (OR = 0.012, 95 % confidence interval [CI] 0.0002−0.76), and increased odds of iodide urine levels (OR = 1.15, 95 %CI 1.05–1.27).ConclusionsASD may have an independent and significant impact on perchlorate as well as iodide levels in urine of euthyroid lean postpubertal children. Perchlorate levels do not appear to be directly associated with iodide levels in euthyroid children. 相似文献
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restrictive interests, and repetitive stereotypic behaviors. Among the various mechanisms underlying the pathogenesis of ASD, dysfunctions of dopaminergic signaling and mitochondria have been hypothesized to explain the core symptoms of children with ASD. However, only a few studies focusing on the pathological association between dopaminergic neurons (DN) and mitochondria in ASD have been performed using patient-derived stem cells and in vitro differentiated neurons. Stem cells from human exfoliated deciduous teeth (SHED) are neural crest-derived mesenchymal stem cells present in the dental pulp of exfoliated deciduous teeth; these cells can differentiate into dopaminergic neurons (DN) in vitro. This study aimed to investigate the pathological association between development of DN and mitochondria in ASD by using SHED as a disease- or patient-specific cellular model. The SHED obtained from three children with ASD and three typically developing children were differentiated into DN, and the neurobiology of these cells was examined. The DN derived from children with ASD showed impaired neurite outgrowth and branching, associated with decreased mitochondrial membrane potential, ATP production, number of mitochondria within the neurites, amount of mitochondria per cell area and intracellular calcium level. In addition, impaired neurite outgrowth and branching of ASD-derived DN were not improved by brain-derived neurotrophic factor (BDNF), suggesting impairment of the BDNF signaling pathway in ASD. These results imply that intracerebral dopamine production may have decreased in these children. The earliest age at which deciduous teeth spontaneously exfoliate in humans, and SHED can be noninvasively collected, is approximately 6 years. Our results suggest that in vitro analysis of SHED-derived DN obtained from children with ASD provides neurobiological information that may be useful in determining treatment strategies in the early stages of ASD. 相似文献
This study is the first to report the disturbance of contagious yawning in individuals with autism spectrum disorder (ASD). Twenty-four children with ASD as well as 25 age-matched typically developing (TD) children observed video clips of either yawning or control mouth movements. Yawning video clips elicited more yawns in TD children than in children with ASD, but the frequency of yawns did not differ between groups when they observed control video clips. Moreover, TD children yawned more during or after the yawn video clips than the control video clips, but the type of video clips did not affect the amount of yawning in children with ASD. Current results suggest that contagious yawning is impaired in ASD, which may relate to their impairment in empathy. It supports the claim that contagious yawning is based on the capacity for empathy. 相似文献
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. 相似文献
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. 相似文献
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. 相似文献
Autism spectrum disorder (ASD) is a group of developmental disabilities, the aetiology of which remains elusive. The endocannabinoid (eCB) system modulates neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. We investigated whether there is a disruption to the eCB system in ASD and whether pharmacological modulation of the eCB system might offer therapeutic potential. We examined three major components of the eCB system—endogenous cannabinoids, their receptors and associated enzymes—in ASD children as well as in the valproic acid (VPA) induced animal model in autism. Furthermore, we specifically increased 2-arachidonoylglycerol (2-AG) levels by administering JZL184, a selective inhibitor of monoacylglycerol lipase which is the hydrolytic enzyme for 2-AG, to examine ASD-like behaviours in VPA-induced rats. Results showed that autistic children and VPA-induced rats exhibited reduced eCB content, increased degradation of enzymes and upregulation of CBRs. We found that repetitive and stereotypical behaviours, hyperactivity, sociability, social preference and cognitive functioning improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed after administration of a dosage regimen of 3 mg kg−1, which affected both the eCB system and ASD-like behaviours. In conclusion, a reduced eCB signalling was observed in autistic children and in the ASD animal model, and boosting 2-AG could ameliorate ASD-like phenotypes in animals. Collectively, the results suggested a novel approach to ASD treatment. 相似文献
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. 相似文献
Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p?=?0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1. 相似文献