Cause Of Autism Spectrum Disorder Research Articles

Background: Fragile X Syndrome (FXS) is the most common monogenic cause of autism spectrum disorders, and is characterized by the excessive immature excitatory synapses in cortical neurons, leading to excitatory/inhibitory imbalance and core autistic behaviors. This synaptic pathology has been attributed to dysregulated levels of synaptic proteins, including CYFIP2: a key regulator of synaptic structure and plasticity. However, the mechanism underlying the increased CYFIP2 protein level in FXS neurons remains unclear. Neurons abundantly secrete extracellular vesicles (EVs) enriched with bioactive cargos (proteins and miRNAs). Objectives: the goal of this research is to identify whether EV-dependent secretion plays important roles in regulating the intracellular CYFIP2 protein level in WT and FXS neurons. Methods and Results: our proteomic analysis reveals that CYFIP2 protein is packaged in EVs released by mouse cortical neurons. Pharmacological and genetic blockades of neuronal EV release significantly elevated intracellular CYFIP2 levels by 78 ± 14% and 168 ± 39%, respectively. Glutamate-evoked EV release significantly reduced the CYFIP2 level by 24 ± 2%. Neurons from Fmr1 KO mice, an FXS model, secreted significantly less EVs (46 ± 5%) than the wild type, and showed significantly elevated CYFIP2 (by 155 ± 31%). Evoking EV release in FXS neurons significantly lowered the intracellular CYFIP2 (by 53 ± 6%). Conclusions: these findings identify an EV-secretion-dependent mechanism that controls neuronal CYFIP2 level, implicating EV-mediated export in the regulation of synaptic protein homeostasis, synaptic remodeling, and FXS-associated synaptic deficits.

Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability (ID) and the primary monogenic cause of autism spectrum disorder (ASD) worldwide. The disorder arises from a CGG trinucleotide expansion of more than 200 repeats, known as a full mutation (FM) that occurs in the fragile X messenger ribonucleoprotein 1 (FMR1) gene locus at Xq27.3. This expansion induces hypermethylation of the gene's promoter region, leading to epigenetic silencing and a consequent reduction in the expression of the FMR1 (FMRP)-a protein critical for synaptic plasticity and maturation. While the genetic basis of FXS is well established, further clarification is needed to understand how variations in the FMR1 gene lead to divergent clinical outcomes. This systematic review explores the differences in clinical features, genetic variations and molecular mechanisms between individuals with a FM, clinically diagnosed with FXS and premutation (PM) carriers with fragile X premutation-associated conditions (FXPAC), with a focus on implications for improving support for individuals with ID and their families. Three databases (PubMed, Web of Science and Scopus) were systematically searched, guided by a variety of keywords, to identify qualitative, empirical research about clinical, genetic and molecular differences between FM and PM carriers. A total of 62 articles were examined, and 44 were included in the review. The information is presented in the following categories: clinical features, genetic variations, molecular mechanisms, diagnostics and treatments. Three primary themes are discussed: (1) variability in clinical manifestations, (2) genetic insights and diagnostic advancements and (3) current and emerging management strategies. Research gaps are also highlighted along with perspectives and implications for further research. The identification and treatment of FXS and FXPAC remains a major public health and clinical concern. This systematic literature review provides a more robust understanding of FXS and the clinical, genetic and molecular distinctions between FM and PM carriers. Despite growing knowledge of the condition, significant efforts are still required to refine diagnostic tools, develop targeted interventions and support individuals and families affected by FXS.

FMR1 mutant marmosets show fragile X syndrome phenotypes.

Background:The cause of autism spectrum disorder (ASD) is currently still unclear. Research on the etiology and biomolecular aspects of autism is needed to develop further prevention and therapy strategies. Animal models of autism are needed for further research.Aim:This study aimed to investigate the effect of valproic acid administration on motor coordination and sensory function in Mus musculus as an animal model of autism.Methods:This study used M. musculus that were ready to be mated and waited until they were pregnant. Randomization was carried out using the website random.org, and the participants were divided into two groups: the control and experimental groups. On embryo day 12.5, the control group was injected intraperitoneally with normal saline, and the experimental group was injected intraperitoneally with 600 mg/kg body weight of valproic acid. The offspring of the mice underwent autism symptom behavior test, motor coordination, and pain response.Results:There were significant differences in the negative geotropism test and hot plate test between the control and experimental groups (p < 0.05). The experimental group that was intraperitoneally injected with valproic acid takes longer to reorient on an inclined plane as part of motor coordination skills. The experimental group also provided a longer response time to heat stimuli on a hot plate, indicating an abnormal response to pain stimuli.Conclusion:Intraperitoneally injected M. musculus with valproic acid showed symptoms of autism, especially disorders in motor coordination and response to pain stimuli.

Fragile X Syndrome and multidisciplinary strategy: a clinical case

Cortical layer-specific abnormalities in auditory responses in a mouse model of Fragile X Syndrome.

Gut microbiota mediated regulation of vitamin B homeostasis in autism spectrum disorders.

Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related mechanisms. Using single-cell and single-nucleus RNA sequencing of cortical organoids from dup15q patient-derived iPSCs and post-mortem brain samples, we identify increased glycolysis, disrupted layer-specific marker expression, and aberrant morphology in deep-layer neurons during fetal-stage organoid development. In adolescent-adult postmortem brains, upper-layer neurons exhibit heightened transcriptional burden related to synaptic signaling, a pattern shared with idiopathic autism. Using spatial transcriptomics, we confirm these cell-type-specific disruptions in brain tissue. By gene co-expression network analysis, we reveal disease-associated modules that are well preserved between postmortem and organoid samples, suggesting metabolic dysregulation that may lead to altered neuron projection, synaptic dysfunction, and neuron hyperexcitability in dup15q syndrome.

IntroductionPrenatal exposure to valproic acid (VPA) is a common environmental cause of autism spectrum disorder (ASD) and often leads to expressive and receptive language impairments. Similar communication difficulties among individuals with ASD are often linked to abnormal subcortical and cortical sound processing. Rodents prenatally exposed to VPA exhibit degraded cortical responses to speech and an impaired ability to behaviorally discriminate speech sounds.MethodsWe sought to determine whether sound processing could be restored with paired vagus nerve stimulation (VNS). In a first experiment, we evaluated whether sound-paired VNS would alter in vivo extracellular multi-unit responses to tones, noise burst trains, and speech sounds from the anterior auditory field. We next sought to evaluate whether improvements to neural sound processing led to improvements in sound discrimination ability. In a second experiment, rats underwent go/no-go sound discrimination testing where VNS was paired with successful trials.ResultsWe found that VPA-exposed rats had degraded spectral, temporal, and speech sound processing compared to saline-exposed control rats. VPA-exposed rats which received sound-paired VNS exhibited a partial or full restoration of processing across sound types. However, across several sound discrimination tasks, we did not observe changes in behavioral performance in response to prenatal exposure to VPA or VNS.DiscussionOur study is the first to show that speech-paired VNS leads to a generalized improvement in cortical sound processing across sound types, rescuing neural processing among VPA-exposed rats. These results provide a framework for future studies to develop VNS-based interventions for communication disorders.

Fragile X syndrome (FXS), a leading inherited cause of autism spectrum disorder and intellectual disability, has been studied extensively using rodent models. More recently, human stem cell-derived model systems have also been used to gain mechanistic insights into the pathophysiology of FXS. However, these studies have focused almost exclusively on neurons. Further, despite growing evidence for a key role of glia in neuronal function in health and disease, little is known about how human astrocytes are affected by FXS. Therefore, in this study, we successfully developed a protocol that captures key spatiotemporal milestones of brain development and aligns with the process of gliogenesis as well. Together this offers a useful framework for studying neurodevelopmental disorders. First, we patterned the human induced pluripotent stem cells into the neuroectodermal lineage with dual Suppressor of Mothersagainst Decapentaplegic (SMAD) inhibition and small molecules. Subsequently, we utilized specific growth factors and cytokines to generate control (CTRL) and FXS patient-derived astrocytic progenitor cells (APCs). Treatment of APCs with ciliary neurotrophic factor, a differentiating cytokine, regulated and drove the progenitor cells towards astrocytic maturation, yielding forebrain-specific glial fibrillary acidic protein-expressing astrocytes. We found that these astrocytes are functional, as evidenced by their calcium responses to ATP application, and they exhibit dysregulated glycolytic and mitochondrial metabolism in FXS. Taken together, these findings provide a useful experimental platform of human origin for the investigation of cell-autonomous and non-cell-autonomous consequences of alterations in astrocytic function caused by neurodevelopmental disorders.

Aim: This study addresses the parental perspective on the causes of Autism Spectrum Disorder (ASD) and the concerns of those who are severely stressed about their offspring with it. The study looks at parental views regarding the reasons behind ASD, some early symptom detection, and demographic characteristics in order to better understand the difficulties families encounter, the length of suffering from this disorder, and to generate some recommendations when necessary. Methodology: In the Sylhet Division, 126 parents of autistic children who were chosen from 9 special schools participated in a cross-sectional study. Using the lottery method, 14 parents were selected from each school out of a sample frame of 200. Data was gathered through personal interviews with a semi-structured questionnaire. Key variables were analyzed using descriptive statistics, and Microsoft Excel 2013 and SPSS Version 22 were utilized for data analysis. Results: Most parents had at least a secondary level of education, and most participants came from nuclear families. With symptoms often found between the ages of 0 and 5, autism was more commonly diagnosed in male children (74%). The average age at diagnosis was 2.5 years. 48% of the autistic children had been receiving medication for 0–5 years. Parents blamed autism on a variety of causes, including hereditary, environmental, and spiritual elements. Those who had less access to official support services had much greater levels of parental stress. On the other hand, psychological stress levels were lower among parents who received community-based support, counseling, or early intervention. Conclusion: Lack of knowledge about autism, inadequate support networks, and delayed diagnosis are all strongly associated with parental stress. The well-being of autistic children and their parents may be greatly enhanced by enabling early identification initiatives and increasing financial, educational, and psychological assistance.

JOURNAL/atin/04.03/02274269-202506000-00002/figure1/v/2025-09-16T151948Z/r/image-tiff Autism spectrum disorder is a neurodevelopmental disorder characterized by differences in social behaviors, intellectual disabilities, and various mental health conditions. It is often undiagnosed due to overlapping symptoms with other disorders and the challenging, subjective nature of behavioral analysis. However, recent studies have identified dysregulated microRNAs as potential biomarkers for autism spectrum disorder, which could enable more accurate quantitative diagnoses. This study aimed to develop a machine learning model to predict whether dysregulation of a specific miRNA is associated with autism spectrum disorder. We selected an even number of autism spectrum disorder-associated miRNAs and randomly chosen miRNAs for analysis. Data was collected on amino acid sequences, gene targets, and predicted pathway attributes to classify each microRNA. Feature selection was then performed to identify the optimal number of features for achieving the highest accuracy. Only statistically significant predictions (P &lt; 0.05) were included in the training dataset. The sequential model with two hidden layers emerged as the best classifier, achieving an accuracy of 95.24% for microRNA biomarkers. This model was further validated with an independent, unseen dataset, which achieved 81.67% accuracy. The study also explored the genes and pathways of significance to understand better potential causes of autism spectrum disorder, particularly those involved in regulating the pluripotency of stem cells. This study presents a rapid and efficient method for classifying microRNAs as potential biomarkers for autism spectrum disorder based on their biological characteristics. By screening for dysregulated microRNAs in patients’ blood or serum samples, this approach can enhance early diagnosis and timely intervention.

Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function.

The exact cause of Autism spectrum disorder (ASD) remains unclear. The accumulation of heavy metals and the imbalance of trace elements are believed to play a key role in the pathogenesis of ASD. This study aimed to compare the levels of trace elements and heavy metals in the hair of 1-16-year-old children with varying ASD severity. We included a control group of 57 children, as well as 124 children with autism, consisting of 53 with mild to moderate autism and 71 with severe autism. Questionnaires and hair samples were collected, and 21 chemical elements were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). Children with severe autism showed significantly higher levels of the trace elements copper (Cu) and heavy metals vanadium (V), cobalt (Co), nickel (Ni), arsenic (As), cadmium (Cd), and lead (Pb) in their bodies compared to the control group. Boys with severe autism showed significantly higher levels of Cu, As, Cd, and Pb compared to the control group, while girls with severe autism exhibited significantly lower levels of potassium (K) and increased levels of Pb. Severely autistic children under 7years old had significantly increased levels of Mn, Cu, V, Co, Ni, As, Cd, and Pb. Children with severe autism aged 7-16years typically showed significantly higher levels of Cu and As. These findings underscore the importance of heavy metals and essential minerals as environmental factors in the severity of ASD disease.

ADNP-Related Disorder [previously known as Helsmoortel-Van der Aa syndrome (HVDAS)] is a rare genetic condition resulting from mutations in the activity-dependent neuroprotector homeobox (ADNP) gene. The ADNP protein has multiple functions, including serving as an essential transcription factor for brain development. In addition, pathogenic variants in ADNP have been recognized as one of the most frequent monogenic causes of autism spectrum disorder (ASD) and intellectual disability. Clinical features include craniofacial dysmorphisms, congenital heart defects, gastrointestinal problems such as feeding difficulties, gastroesophageal reflux and frequent vomiting, vision problems, recurrent infections and seizures. Here we describe the novel case of a girl who came to our attention in infancy because of poor and stereotyped motor repertoire, repetitive purposeless movements, and intellectual disability. Whole exome sequencing revealed a de novo heterozygous variant in the ADNP gene, leading to the diagnosis of HVDAS at age 5 years. At the age of 12, nerve conduction velocity testing showed severe four-limb axonal motor polyneuropathy. In this article, we would like to focus on the presence of peripheral nervous system involvement associated with the pathogenic ADNP de novo variant, which may contribute to the clinical characterization of ADNP-Related Disorder.

Loss-of-function mutations in tuberous sclerosis 1 (TSC1) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific Tsc1 deletion (Tsc1mut/mut) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in Tsc1mut/mut Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Interestingly, anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of Tsc1mut/mut Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of Tsc1mut/mut Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous Tsc1 deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to Tsc1 haploinsufficiency are delayed compared to age-matched Tsc1mut/mut Purkinje neurons. Together, these data reveal the loss of Tsc1 impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins necessary for AIS organization and function.

Objective: To find out the causes of autism spectrum disorder therefore some biochemical parameters were measured include serum lactate, pyruvate, lactate to pyruvate ratio, lactate dehydrogenase, ferritin and glutamate. Study Design: Case-control study Place and Duration of Study: This study was conducted at the Thi-Qar Autistic Center, Nasiriya City, Iraq from 1st September 2022 to 28th February 2023. Methods: This study contained 192 children among which 96 patients were diagnosed as cases of ASD and age range was 3 to 13 years. The control group contained 96 children with ages range was 3-13 years. The Enzyme Linked Immunosorbent Assay method is applied in detection of parameters. Results: there were significant statistical association between biochemical parameters and autism spectrum disorder in compare with control group except serum pyruvate in which there was no significant association Conclusion: The cause of autisms spectrum disorder may be a defect in mitochondrial functions where there was elevation in serum lactate and lactate to pyruvate ratio.

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography-tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.

Role of peroxisome proliferator-activated receptors α and γ in mediating the beneficial effects of β-caryophyllene in a rat model of fragile X syndrome.

Anecdotal reports link a distinct, bilateral, parieto-temporally generated 4.5-Hz rhythm on an electroencephalogram to a methylenetetrahydrofolate reductase gene variant co-occurring in autism spectrum disorder, but the validation of its precision is needed. The electroencephalograms of children with autism spectrum disorder showing the distinct bilateral parieto-temporally generated 4.5-Hz rhythm and their clinical chart report on polymerase chain reaction screening for methylenetetrahydrofolate reductase gene variants, 677C>T and 1298A>C, were retrieved from an outpatient clinic between February 2019 and April 2024. Twenty-five cases were identified. Patients were between 2 and 12 (7 ± 3) years old from Asian (n = 16, 64%), European (n = 5, 20%), African (n = 1, 4%) and mixed (n = 3, 12%) ethnicities. Twenty patients (80%) were positive for 677 C>Theterozygous (n = 3, 15%), 1298A>Cheterozygous (n = 8, 40%) or both (n = 9, 45%). The polymerase chain reaction testing detected neither variant in 5 (20%) patients. Therefore, the electroencephalogram-endophenotype showed 80% precision in identifying methylenetetrahydrofolate reductase gene variant within the sample. This preliminary data support the precision of the proposed distinct, bilateral, parieto-temporally generated 4.5-Hz rhythm in identifying methylenetetrahydrofolate reductase gene variants and its potential clinical applications as a valuable, non-invasive and objective measure within the population.Lay abstractMethylenetetrahydrofolate reductase mutations refer to genetic variations in the methylenetetrahydrofolate reductase enzyme, which plays an important role in folate metabolism. Folate is essential for neural development and signalling. Children with autism spectrum disorder have atypical neural signals compared with control. This study used a non-invasive method to identify a distinct neural signal that may be useful in future screening for methylenetetrahydrofolate reductase mutation in children with autism spectrum disorder. Given that the underlying causes of autism spectrum disorder have multiple genetic factors and often require subjective assessment, this study introduces a potential non-invasive screening method for methylenetetrahydrofolate reductase gene mutation. This method could provide valuable biomarkers for screening and personalised treatments, offering hope for improved risk stratification and bespoke nutritional support and supplements to mitigate the impact on affected individuals and their descendants.