Etiology Of Autism Spectrum Disorder Research Articles

Unravelling the Cerebellar Involvement in Autism Spectrum Disorders: Insights into Genetic Mechanisms and Developmental Pathways

Autism spectrum disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction and communication, as well as repetitive behaviors. Although the etiology of ASD is multifactorial, with both genetic and environmental factors contributing to its development, a strong genetic basis is widely recognized. Recent research has identified numerous genetic mutations and genomic rearrangements associated with ASD-characterizing genes involved in brain development. Alterations in developmental programs are particularly harmful during critical periods of brain development. Notably, studies have indicated that genetic disruptions occurring during the second trimester of pregnancy affect cortical development, while disturbances in the perinatal and early postnatal period affect cerebellar development. The developmental defects must be viewed in the context of the role of the cerebellum in cognitive processes, which is now well established. The present review emphasizes the genetic complexity and neuropathological mechanisms underlying ASD and aims to provide insights into the cerebellar involvement in the disorder, focusing on recent advances in the molecular landscape governing its development in humans. Furthermore, we highlight when and in which cerebellar neurons the ASD-associated genes may play a role in the development of cortico–cerebellar circuits. Finally, we discuss improvements in protocols for generating cerebellar organoids to recapitulate the long period of development and maturation of this organ. These models, if generated from patient-induced pluripotent stem cells (iPSC), could provide a valuable approach to elucidate the contribution of defective genes to ASD pathology and inform diagnostic and therapeutic strategies.

Assessment of 8-Hydroxy-2’-Deoxyguanosine (8-OH-dG) Level in Urine as a Urinary Marker of Oxidative Stress in Children with Autism Spectrum Disorder

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder characterized by deficits in social interaction, restricted interest and repetitive behavior. Oxidative stress in response to environmental exposure plays a role in virtually every human disease and represents a significant avenue of research into the etiology of ASD. Objective The aim of this study was to asses 8-hydroxy-2’-deoxyguanosine (8-OH-dG) level in urine as a urinary marker of oxidative stress in children with autism spectrum disorder in comparison to sex and age matched healthy control group. Patients and Methods We included 51 children with autism (43 males and 8 females whose age ranged from 2 to 16 years). They were compared to 51 children of the same age as a control group. The diagnosis of autism was made based on the criteria of autistic disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSMV). In the patients group, detailed medical history included sociodemographic form and family history was taken for autistic group also Intelligence Quotient test IQ test and Childhood Autism Rating Scale (CARS) used to measure the severity of autism. In the study, 8-OHdG values in urine were investigated using the enzyme-linked immunosorbent assay (ELISA) method and Urinary creatinine was determined with the Beckham Coulter analyzer and was used to normalize all biochemical measurements then the urinary 8-OHdG/creatinine levels were corrected to the urinary concentration of creatinine. Results The median age was 9.9 in the ASD group and 9.1 in the control group (P = 0.256). In the ASD group, (8-OH-dG)/creatinine ratio values were found to be significantly higher than those of the controls (P < 0.001). but also No statistically significant correlation between (8-OH- dG)/creatinie ratio and CARS score or IQ score (P = 0,7). Conclusion The data from this study supported the hypothesis of the oxidant/antioxidant balance as a key piece that may contribute to the autistic pathology

Genetic causal relationship between placental weight and autism spectrum disorder: A two-sample Mendelian randomization study

ObjectPrevious research has suggested an association between placental tissue abnormalities and the diagnosis of autism spectrum disorder. This study aims to explore the causal relationship between placental weight and autism spectrum disorder. MethodsThis study employed Mendelian randomization analysis to investigate the potential causal relationship between placental weight and autism spectrum disorder. The study design involved two sample populations, with data for the exposed population sourced from previous studies focusing on PW, and data for the outcome population obtained from the Integrative Psychiatric Research and the Psychiatric Genomics Consortium study. To ensure the robustness of the results, three sensitivity analyses were performed, including heterogeneity testing, pleiotropy testing, and a leave-one-out analysis. The inverse variance weighted method served as the gold standard for the Mendelian randomization analysis. ResultsThe results of the first analysis revealed a significant correlation between an increase in placental weight and an elevated risk of autism spectrum disorder (p = 0.02). Sensitivity analysis detected heterogeneity and outliers. After removing two outlier SNPs in the second round of analysis, the results still supported a genetic causal relationship between placental weight and autism spectrum disorder (p = 0.01). The second-round sensitivity analysis did not reveal any heterogeneity or outliers. ConclusionOur study provides compelling evidence supporting a causal relationship between elevated placental weight and increased risk of autism spectrum disorder. These findings underscore the significance of placental development in the etiology of autism spectrum disorder and propose a potential early predictive indicator for autism spectrum disorder.

Autism Spectrum Disorders: Etiology, Epidemiology, and Challenges for Public Health.

Autism spectrum disorder (ASD) is a growing public health problem. American psychiatrist Leo Kanner is considered the "father of autism." ASD encompasses a range of neurodevelopmental disorders that last throughout life. Symptoms of ASD include impairments in social skills, including specific repetitive behaviors, as well as abnormal sensory responses. The clinical symptoms of ASD vary among patients. Their severity also differs, both in the area of social communication and cognitive functioning. The etiology of ASD is still unclear, although a role is attributed to both genetic and environmental factors. According to the World Health Organization, 1/100 children have ASD, but these estimates vary depending on the methodology used. Nevertheless, early detection of ASD and initiation of appropriate therapy may be essential in the continued functioning of patients and their families. The purpose of this article is to provide an overview of current knowledge about autism spectrum disorders. We discuss factors associated with autism and the prevalence of ASD in various parts of the world, and identify the most common diseases comorbid with ASD, pointing to limitations in the quality of life of patients with ASD and their families.

Prenatal & Perinatal Risk Factors of Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is lifelong neurodevelopmental disorder characterized by impairments in social function, communication, and certain behaviors. The etiology of ASD is unclear & it is believed to be multi-factorial, among those several prenatal & perinatal factors are found to be significant. So, the necessity of this study is to detect the presence of known risk factors of ASD which in turn may help in the early diagnosis and intervention for better long-term outcomes. Objective: To find out prenatal and perinatal risk factors of ASD. Method: A case control study was conducted with 112 cases of ASD and 201 controls of 2-6 years of age. The study was carried out in Center for Neurodevelopment and Autism in Children (CNAC), in the department of Paediatrics, Bangabandhu Sheikh Mujib Medical University and Autism Welfare Foundation (AWF). ASD was diagnosed by DSM-IV TR criteria. Mothers were interviewed and data were collected by semistructured questionnaires. Results: Total 5 risk factors were identified as the risk factors of ASD. They were: advanced paternal age (OR=2.84) and maternal age (OR=1.87); male baby (OR=2.01); environmental stress during pregnancy (OR=1.61) and preterm delivery (OR=1.80). Conclusions: It is concluded that advanced paternal age, maternal age, male baby, environmental stress during pregnancy and preterm delivery are associated with increased risk of ASD. BANGLADESH J CHILD HEALTH 2022; VOL 46 (3) : 115-121

Microglial Dysfunction in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with onset in childhood. The molecular mechanisms underlying ASD have not yet been elucidated completely. Evidence has emerged to support a link between microglial dysfunction and the etiology of ASD. This review summarizes current research on microglial dysfunction in neuroinflammation and synaptic pruning, which are associated with altered transcriptomes and autophagy in ASD. Dysbiosis of gut microbiota in ASD and its correlation with microglial dysfunction are also addressed.

Management of Autism Spectrum Disorder Through Ayurvedic Intervention and Diet Modifications

Autism spectrum disorder includes a group of neurodevelopmental disorders, which disrupts normal functioning of the brain and impairs communication, social interaction, emotional balance with the presence of repetitive stereotypic mannerisms. Underlying etiology of autism spectrum disorder is still unknown. Studies on genetic causes, immune system dysregulation, inflammation, exposure to environmental toxicants, defective gut microbiome are still continuing. In ayurveda, most psycho social abnormalities are included in the category of Unmada. Along with other etiological factors, impaired digestive and metabolic functions are postulated as the root cause of Unmada. And in accord with the gut brain axis, systemic accumulation of metabolic wastes also disrupts the functional integrity of the brain. The present study describes the case of a child with ASD with hyperactivity, who has been clinically diagnosed and treated with Ayurvedic medications, Sneha sweda therapies and diet modifications, which helps in maintaining the healthy functioning of the brain. Within 3 months of intervention, the child became symptomatically better. Case study briefs Ayurvedic concepts and Ayurvedic treatment protocols regarding ASD.

Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review.

Existing evidence indicates that environmental factors might contribute up to 50% of the variance in autism spectrum disorder (ASD) risk. This structured narrative review offers a comprehensive synthesis of current knowledge on environmental risk factors in ASD, including evaluation of conflicting evidence, exploration of underlying mechanisms, and suggestions for future research directions. Analysis of diverse epidemiological investigations indicates that certain environmental factors, including advanced parental age, preterm birth, delivery complications, and exposure to toxic metals, drugs, air pollutants, and endocrine-disrupting chemicals, are linked to an increased ASD risk through various mechanisms such as oxidative stress, inflammation, hypoxia, and its consequences, changes in neurotransmitters, disruption of signaling pathways and some others. On the other hand, pregnancy-related factors such as maternal diabetes, maternal obesity, and caesarian section show a weaker association with ASD risk. At the same time, other environmental factors, such as vaccination, maternal smoking, or alcohol consumption, are not linked to the risk of ASD. Regarding nutritional elements data are inconclusive. These findings highlight the significance of environmental factors in ASD etiology and emphasize that more focused research is needed to target the risk factors of ASD. Environmental interventions targeting modifiable risk factors might offer promising avenues for ASD prevention and treatment.

Study of the genetic association between selected 3q29 region genes and schizophrenia and autism spectrum disorder in the Japanese population.

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

Classification of Autism Spectrum Disorder using Resting State-Functional Magnetic Resonance Imaging and Artificial Neural Network

Autism Spectrum Disorder (ASD) represents a growing challenge in public health, characterized by irreversible neurodevelopmental abnormalities. Despite a rising prevalence, the underlying aetiology and neural substrates of ASD remain incompletely understood. Resting state-functional Magnetic Resonance Imaging (rs-fMRI) has emerged as a valuable non-invasive tool for probing the organization and cognitive functions of the brain by capturing hemodynamic changes. This study explores the relationship between Functional Connectivity (FC) alterations, measured by rs-fMRI, and the manifestation of ASD-related brain disorders. In this paper, we propose a hybrid approach employing an InfoMax Independent Component Analysis (ICA) algorithm and Artificial Neural Network to distinguish between the ASD subjects and Healthy Controls (HCs). Initially, rs-fMRI datasets are preprocessed using Statistical Parametric Mapping (SPM). Further, these datasets are processed using InfoMax ICA to extract the distinct features such as fractional Amplitude of Low-Frequency Fluctuations (fALFF) and Dynamic Range and visualize the FC alterations by region mapping. In addition to this, the number of activated voxels for each brain regions are estimated to observe the neural abnormalities. Finally, the extracted features are fed as input to train, test and validate the ANN classifier. The efficacy of the proposed network is evaluated using the Autism Brain Imaging Data Exchange (ABIDE) dataset and an accuracy of 75.3 percentage is achieved.

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

The etiology of autism spectrum disorder (ASD) has been linked to both genetic and epigenetic factors. Among the epigenetic factors, exposure to valproic acid (VPA), an antiepileptic and mood-modulating drug, has been shown to induce characteristic traits of ASD when exposed to during embryogenesis. Conversely, in animal models, enriched environment (EE) has demonstrated positive behavioral and neural effects, suggesting its potential as a complementary treatment to pharmacological approaches in central nervous system disorders. In this study, we utilized zebrafish to model ASD characteristics induced by VPA and hypothesized that sensory stimulation through EE could ameliorate the behavioral and neuroanatomical features associated with ASD. To test this hypothesis, we assessed social behavior, cerebellar volume, and Purkinje cell populations via histology and immunohistochemistry after exposing the fish to EE. The results revealed that zebrafish exposed to VPA exhibited social deficits, reduced cerebellar cortex volume, and a decrease in c-Fos-positive cells in the Purkinje layer. In contrast, VPA-exposed fish treated with EE showed increased socialization, augmented cerebellar cortex volume, and an elevation in c-Fos-positive Purkinje cells. These findings suggest that alterations induced by VPA may be ameliorated through EE treatment, highlighting the potential therapeutic impact of sensory stimulation in conditions related to ASD.

Conduction velocity, G-ratio, and extracellular water as microstructural characteristics of autism spectrum disorder.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a new approach to calculating axonal conduction velocity termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel formulation for calculating aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD.

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

Innate Immune Dysfunction and Neuroinflammation in Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation. Appeared originally in Brain Behav Immun 2023; 108:245-254.

The genetic landscape of autism spectrum disorder in the Middle Eastern population.

Introduction: Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong clinical heterogeneity. Genetic factors play an important role in ASD, but about 75% of ASD cases have an undetermined genetic risk. Methods: We extensively investigated an ASD cohort made of 102 families from the Middle Eastern population of Qatar. First, we investigated the copy number variations (CNV) contribution using genome-wide SNP arrays. Next, we employed Next Generation Sequencing (NGS) to identify de novo or inherited variants contributing to the ASD etiology and its associated comorbid conditions in families with complete trios (affected child and the parents). Results: Our analysis revealed 16 CNV regions located in genomic regions implicated in ASD. The analysis of the 88 ASD cases identified 41 genes in 39 ASD subjects with de novo (n = 24) or inherited variants (n = 22). We identified three novel de novo variants in new candidate genes for ASD (DTX4, ARMC6, and B3GNT3). Also, we have identified 15 de novo variants in genes that were previously implicated in ASD or related neurodevelopmental disorders (PHF21A, WASF1, TCF20, DEAF1, MED13, CREBBP, KDM6B, SMURF1, ADNP, CACNA1G, MYT1L, KIF13B, GRIA2, CHM, and KCNK9). Additionally, we defined eight novel recessive variants (RYR2, DNAH3, TSPYL2, UPF3B KDM5C, LYST, and WNK3), four of which were X-linked. Conclusion: Despite the ASD multifactorial etiology that hinders ASD genetic risk discovery, the number of identified novel or known putative ASD genetic variants was appreciable. Nevertheless, this study represents the first comprehensive characterization of ASD genetic risk in Qatar's Middle Eastern population.

The Use of CGH Arrays for Identifying Copy Number Variations in Children with Autism Spectrum Disorder.

Autism spectrum disorders (ASDs) encompass a broad group of neurodevelopmental disorders with varied clinical symptoms, all being characterized by deficits in social communication and repetitive behavior. Although the etiology of ASD is heterogeneous, with many genes involved, a crucial role is believed to be played by copy number variants (CNVs). The present study examines the role of copy number variation in the development of isolated ASD, or ASD with additional clinical features, among a group of 180 patients ranging in age from two years and four months to 17 years and nine months. Samples were taken and subjected to array-based comparative genomic hybridization (aCGH), the gold standard in detecting gains or losses in the genome, using a 4 × 180 CytoSure Autism Research Array, with a resolution of around 75 kb. The results indicated the presence of nine pathogenic and six likely pathogenic imbalances, and 20 variants of uncertain significance (VUSs) among the group. Relevant variants were more prevalent in patients with ASD and additional clinical features. Twelve of the detected variants, four of which were probably pathogenic, would not have been identified using the routine 8 × 60 k microarray. These results confirm the value of microarrays in ASD diagnostics and highlight the need for dedicated tools.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways

BackgroundEpigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic...

The complex etiology of autism spectrum disorder due to missense mutations of CHD8.

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.

The Autism Spectrum Disorder and Its Possible Origins in Pregnancy.

Autism Spectrum Disorder (ASD) belongs to the group of neurodevelopmental disorders, and has a high prevalence, affecting 1 in 100 children according to data from the World Health Organization (WHO). To be diagnosed with ASD, the child must have persistent deficits in communication and social interactions, and restricted and repetitive patterns of behavior, interests, or activities. Despite its prevalence, the etiology of ASD is still uncertain, with multifactorial characteristics, including those associated with the gestational period, where maternal exposure to biological, chemical, or physical hazards occurs, some of which have already been proposed as causes of ASD outcomes. Since pregnancy requires a balance between the maternal-fetal binomial, the breakdown of this balance caused by such environmental hazards can lead to altered fetal neurodevelopment, including ASD. With this firmly in mind, this review aims to compile the most recent data on the gestational causes that may be associated with the development of ASD to help health professionals identify risk factors and act for the prevention and management of ASD.

Correlation analysis of maternal condition during pregnancy with head circumference and autism spectrum disorder: A propensity score-matched study.

To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children's Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case-control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended.