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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that impairs communication, socialization, and behavior. The association of ASD with folic acid has been investigated due to the importance of this vitamin for neurological health. This study is an update of the publication 'Folic acid and autism: What do we know?' and aims to systematically review studies examining the relationship between folic acid and ASD. The search resulted in 2,389 studies on folic acid and ASD, which were selected by two reviewers based on their titles and abstracts. Studies meeting the inclusion criteria were fully read. The 52 included studies involved 10,429 individuals diagnosed with ASD and assessed the intake of vitamin B6, folic acid, and vitamin B12; serum levels of these vitamins, homocysteine, and methionine; therapeutic interventions using folic acid; and the association between maternal exposure to this vitamin and the risk of ASD. The evidence of insufficient folic acid intake in most individuals with ASD remains consistent in this update. No association was found between maternal exposure to folic acid and the risk of ASD in their children. Despite observed improvements in communication, socialization, and behavior in individuals with ASD following folic acid interventions, it is crucial to consider the individuality and complexity of ASD. Given the relevance of the topic, there remains a need for more high-quality research and clinical trials characterized by rigorous methodological designs. more...

ASD is a complex condition defined by many causes, one of them being excessive concentrations of necessary and harmful chemicals in children. The serum, hair, and nails of children with ASD have lower levels of critical trace elements, according to studies. It is quite obvious that bio elements are involved in physiology and pathophysiology. Thus, this study examined trace element contents in serum samples from children with autism spectrum disorder (ASD), specifically zinc (Zn), aluminum (Al), and selenium (Se). The study also looked for links between trace element levels and autistic severity. The study included 47 children with autism spectrum disorder, and the Gilliam's Scale was used for severity. The study also included 53 healthy kids with age and gender-matched with those of ASD. For serum trace element analysis, graphite furnace atomic absorption spectrophotometry was used. The study found significant decreases in selenium and zinc concentration (OR, 5.25; CI, 1.96 ~ 14.08; p < 0.001) and increases in aluminum level (OR, 39.34; CI, 8.20 ~ 89.45; p < 0.001) in children with ASD compared to the control group. The area under the curve (AUC) values of 0.85 for Se, 0.98 for Al, and 0.7 for Zn showed high sensitivity and specificity for all parameters. Results indicate a strong positive connection between ASD and their levels of selenium (Se) and zinc (Zn) (β, 0.48; CI, 0.280 ~ 0.679; p < 0.001 and β, 0.31; CI, 0.10 ~ 0.52; p = 0.005). There is a negative correlation between ASD and aluminum (Al) (β 0.83; CI, 0.71 ~ 0.95; p < 0.001). This element may be a biomarker for autism in youngsters. High odds ratio (OR) values indicate trace element risk in autistic children., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

The clinical identification of regression phenomena in ASD lacks specific biological or laboratory criteria and is often based on family history and highly subjective observations by clinicians. The present study aimed to investigate the potential role of plasma clusterin (CLU), very long-chain fatty acids (VLCFA), and carnitine as biomarkers of neurodegeneration in children with autism spectrum disorder (ASD) with and without regression. By exploring these biomarkers, we sought to provide insights into mitochondrial dysfunction, glial activation, and lipid metabolism, which may contribute to the pathophysiology of ASD and aid in the early diagnosis and intervention of regression phenomena in ASD. Ninety children aged 2-6 years were included: 30 with autism spectrum disorder (ASD), 30 with regressive ASD, and 30 healthy controls. Psychiatric assessments were conducted using DSM-5 criteria, CARS, ABC, RBS-R, and ASSQ scales. Regression in ASD was evaluated retrospectively using a modified ADI-R questionnaire. Fasting blood samples were collected, and plasma clusterin (CLU), VLCFA, and carnitine levels were measured. Statistical analyses were performed using MANOVA to assess the effect of group differences on dependent biochemical variables. Serum clusterin and carnitine levels showed no significant differences between groups. However, C22 VLCFA levels were significantly higher in both autism groups compared to controls (p = 0.04), with post hoc analysis indicating the difference between the non-regressive and control groups (p = 0.02). Serum carnitine was positively correlated with stereotypic behaviors subscale scores (r = 0.37, p = 0.004) and total scores (r = 0.35, p = 0.006) of RBS-R. Our study provides insights into the complexities of biomarker research in autism spectrum disorder (ASD), highlighting the challenges in identifying consistent biological markers for regression and non-regression phenotypes. Although no significant findings were observed, further biomarker studies are essential to distinguish possible endophenotypes, improve early diagnosis, and uncover potential therapeutic targets in ASD., Competing Interests: Declarations. Ethical Approval: Ethics approval was obtained from the Human Research Ethics Committee of Ankara University Faculty of Medicine (approval number: i05-294–23). Informed Consent: Verbal and written informed consent was obtained from all children and their parents. This study complies with the Declaration of Helsinki. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an increasing prevalence worldwide, including in Saudi Arabia. Emerging evidence suggests that biochemical markers, such as oxidative stress indicators, neurotransmitter levels, and lipid profiles, play a significant role in ASD's pathology and may also elevate cardiovascular and metabolic risks in affected individuals. This systematic review and meta-analysis synthesize current findings on these biomarkers, with a particular focus on the Saudi population, to elucidate their relationship with ASD pathology and associated health outcomes. Following the PRISMA guidelines, data from 41 studies on oxidative stress markers, neurotransmitters, lipid profiles, and immune markers were analyzed. Searches were conducted across major databases, including PubMed, Scopus, Web of Science, and Embase, and effect sizes were calculated using standardized mean differences with a 95% confidence interval. To further interpret the data, bioinformatics tools such as Reactome, Panther, and STRING were employed to analyze biomarker pathways. The results highlight a significant association between elevated oxidative stress and mitochondrial dysfunction in individuals with ASD, with profound effects on gastrointestinal and mitochondrial health. These biochemical abnormalities disrupt synaptic plasticity and drive chronic neuroinflammation, which impairs neurodevelopmental processes, contributing to the pathology of ASD. The meta-analysis reveals minimal heterogeneity (I 2  = 0.02%) and limited publication bias, supporting the reliability of these associations. The findings underscore the need for a multidisciplinary approach to ASD management in Saudi Arabia, emphasizing biomarker-based diagnostics and personalized treatment strategies. Future research directions include developing individualized diagnostic and therapeutic frameworks utilizing these biomarkers to enhance ASD-related health outcomes., Competing Interests: Declarations. Ethical Approval: Ethical approval was deemed unnecessary for this study. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental condition that now impacts 1 in 36 children in the United States and is characterized by deficits in social communication, repetitive behaviors, and restricted interests. Children with ASD also frequently experience co-morbidities including anxiety and ADHD, and up to 80% experience gastrointestinal (GI) symptoms such as constipation, diarrhea, and/or abdominal pain. Systemic immune activation and dysregulation, including increased pro-inflammatory cytokines, are frequently observed in ASD. Evidence has shown that the innate immune system may be impacted in ASD, as altered monocyte gene expression profiles and cytokine responses to pattern recognition ligands have been observed compared to typically developing (TD) children. In humans, circulating monocytes are often categorized into three subpopulations-classical, transitional (or "intermediate"), and nonclassical monocytes, which can vary in functions, including archetypal inflammatory and/or reparative functions, as well as their effector locations. The potential for monocytes to contribute to immune dysregulation in ASD and its comorbidities has so far not been extensively studied. This study aims to determine whether these monocyte subsets differ in frequency in children with ASD and if the presence of GI symptoms alters subset distribution, as has been seen for T cell subsets. Whole blood from ASD children with (ASD + GI + ) and without gastrointestinal symptoms (ASD + GI - ) and their TD counterparts was collected from children enrolled in the Childhood Autism Risk from Genetics and Environment (CHARGE) study. Peripheral blood mononuclear cells were isolated and stained for commonly used subset identifiers CD14 and CD16 as well as activation state markers CCR2, HLA-DR, PD-1, and PD-L1 for flow cytometry analysis. We identified changes in monocyte subpopulations and their expression of surface markers in children with ASD compared to TD children. These differences in ASD appear to be dependent on the presence or absence of GI symptoms. We found that the ASD + GI + group have a different monocyte composition, evident in their classical, transitional, and nonclassical populations, compared to the ASD + GI - and TD groups. Both the ASD + GI + and ASD + GI - groups exhibited greater frequencies of classical monocytes compared to the TD group. However, the ASD + GI + group demonstrated lower frequencies of transitional and nonclassical monocytes than their ASD + GI - and TD counterparts. CCR2 + classical monocyte frequencies were highest in the ASD + GI - group. HLA-DR + classical, transitional, and nonclassical monocytes were statistically comparable between groups, however, HLA-DR - nonclassical monocyte frequencies were lower in both ASD groups compared to TD. The frequency of classical monocytes displaying exhaustion markers PD-1 and PD-L1 were increased in the ASD + GI + group compared to ASD + GI - and TD, suggesting potentially impaired ability for clearance of foreign pathogens or debris, typically associated with worsened inflammation. Taken together, the findings of differential proportions of the monocyte subpopulations and altered surface markers may explain some of the characteristics of immune dysregulation, such as in the gastrointestinal tract, observed in ASD. more...

Objective: This study compared serum levels of S100B, GFAP, UCHL-1, NF-H and MMP-9 between children with Autism Spectrum Disorder (ASD) and controls, focusing on their association with regression in ASD. We hypothesized that neuroinflammation and neuronal/astroglial damage markers would be higher in the ASD group than in controls and even more elevated in the regressive ASD subgroup compared to the non-regressive subgroup., Methods: The study included 50 children with ASD (ages 4-10) and 30 healthy children. Participants underwent the K-SADS-PL diagnostic interview, CARS, a semi-structured interview for regression, ABC, AuBC, CPRS-RS and SRS assessments. Serum levels of S100B, GFAP, UCHL-1, NF-H and MMP-9 were measured using flow cytometry and ELISA., Results: Serum levels of S100B, GFAP, UCHL-1, NF-H and MMP-9 showed no significant differences between the ASD and control groups. Within the ASD group, no notable differences were found in sociodemographic, clinical characteristics, or serum marker levels between those with and without regression., Conclusion: The findings obtained in this study suggested that it is necessary to question whether the peripheral circulation can represent changes in central nervous system and to review the existence of autistic regression as a separate entity in ASD in terms of clinical features and etiopathogenesis., (© 2025 International Society for Developmental Neuroscience.) more...

Background: Mitochondrial DNA (mtDNA) rearrangements are recognised factors in mitochondrial disorders and ageing, but their involvement in neurodevelopmental disorders, particularly intellectual disability (ID) and autism spectrum disorder (ASD), remains poorly understood. Previous studies have reported mitochondrial dysfunction in individuals with both ID and ASD. The aim of this study was to investigate the prevalence of large-scale mtDNA rearrangements in ID and ID with comorbid ASD (ID-ASD)., Method: We used mtDNA-targeted next-generation sequencing and the MitoSAlt high-throughput computational pipeline in peripheral blood samples from 76 patients with ID (mean age 52.5 years, 37% female), 59 patients with ID-ASD (mean age 41.3 years, 46% female) and 32 healthy controls (mean age 42.4 years, 47% female) from Catalonia., Results: The study revealed a high frequency of mtDNA rearrangements in patients with ID, with 10/76 (13.2%) affected individuals. However, the prevalence was significantly lower in patients with ID-ASD 1/59 (1.7%) and in HC 1/32 (3.1%). Among the mtDNA rearrangements, six were identified as deletions (median size 6937 bp and median heteroplasmy level 2.3%) and six as duplications (median size 10 455 bp and median heteroplasmy level 1.9%). One of the duplications, MT-ATP6 m.8765-8793dup (29 bp), was present in four individuals with ID with a median heteroplasmy level of 3.9%., Conclusions: Our results show that mtDNA rearrangements are frequent in patients with ID, but not in those with ID-ASD, when compared to HC. Additionally, MitoSAlt has demonstrated high sensitivity and accuracy in detecting mtDNA rearrangements, even at very low heteroplasmy levels in blood samples. While the high frequency of mtDNA rearrangements in ID is noteworthy, the role of these rearrangements is currently unclear and needs to be confirmed with further data, particularly in post-mitotic tissues and through age-matched control studies., (© 2024 The Author(s). Journal of Intellectual Disability Research published by John Wiley & Sons and MENCAP.) more...

Imbalances in several trace elements related to antioxidant function may lead to autism spectrum disorder (ASD)-related physiological dysfunction. Nonetheless, contradictory results have been found on the connection between these elements and ASD, and studies of their joint effects and interactions have been insufficient. We therefore designed a case-control study of 152 ASD children and 152 age- and sex-matched typically developing (TD) children to explore the individual and combined associations of manganese (Mn), zinc (Zn), copper (Cu), and selenium (Se) with ASD. Compared with TD, ASD has lower Zn and Se levels and higher Cu levels. The restricted cubic spline model showed J-shaped non-linearity, L-shaped non-linearity, and positive linearity correlations between Mn, Zn, Cu, and ASD. Zn and Cu were negatively and positively correlated with ASD symptoms, respectively. The superoxide dismutase (SOD) mediated 50.53% and 39.07% of the association between Zn, Se, and ASD, respectively. Bayesian kernel machine regression (BKMR) confirmed a U-shaped correlation between the element mixtures and ASD. Interactions of Mn with the other three elements and Cu with Zn were also observed. Our results confirm that the independent and combined exposure to the four trace elements was associated with ASD, with oxidative stress being an important mechanism. Due to the potential interactions between the elements, further research is needed to explore their involvement in the pathogenesis and progression of ASD from a combined perspective, as well as the beneficial and harmful concentration ranges., (© 2024 International Society for Autism Research and Wiley Periodicals LLC.) more...

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Environmental pollutants may contribute to the etiology of ASD, but studies of perfluoroalkyl substances (PFAS) have shown conflicting results., Objectives: We assessed associations between cord blood concentrations of PFAS with autistic traits at age seven years in a Singaporean birth cohort., Methods: We measured cord blood concentrations of eight PFAS in a sample of 430 mother-child pairs from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort. We assessed autistic traits using the Social Responsiveness Scale Second Edition (SRS-2) and its sub-scores, in which higher scores indicate more autistic traits. We estimated covariate-adjusted associations between the PFAS and SRS-2 scores using Bayesian weighted quantile sum (BWQS) regression models for the PFAS mixtures and multivariable regressions for single PFAS. We additionally evaluated effect modification by biological sex., Results: We observed a positive association between the PFAS mixture and SRS-2 cognition sub-scores (β per SD increase = 1.25 points, 95% CI -0.03, 2.40). Perfluorononanoic acid (PFNA) was the strongest contributor to the mixture effect. In single PFAS models, exposure to PFNA was associated with a higher SRS-2 total score (β = 0.93 points, 95% CI 0.29, 1.58), cognition sub-score (β = 1.26 points, 95% CI 0.55, 1.97), communication sub-score (β = 0.88 points, 95% CI 0.20, 1.56), and restrictive and repetitive behaviors sub-score (β = 0.93 points, 95% CI 0.23, 1.63). We also observed evidence of effect modification by sex for perfluoroundecanoic acid (PFUnDA) for the total score (p-effect modification [EM] = 0.03), cognition sub-score (p-EM = 0.03), and communication sub-score (p-EM = 0.04), with negative associations seen in females and null associations in males., Discussion: Cord blood PFAS concentrations were positively associated with autistic traits measured by SRS-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.) more...

The purpose of this study was to investigate the expression of miR-499a-5p in children with autism spectrum disorders (ASD) and its value in early diagnosis of ASD. This is a retrospective case-control study that included 40 children with ASD as a case group and 43 healthy children as a control group. Magnetic resonance imaging (MRI) was performed on all subjects, and the children were scored with childhood autism rating scale (CARS) and autism behavior checklist (ABC). The expression of miR-499a-5p in serum was detected by RT-qPCR, and the diagnostic value of miR-499a-5p in ASD was evaluated by ROC curve. Pearson correlation coefficient was used to evaluate the correlation between miR-499a-5p levels and scores. Compared with healthy children, the expression level of serum miR-499a-5p was significantly reduced in children with ASD. ROC curve showed that miR-499a-5p is of high diagnostic value for ASD. The results of MRI suggested that the volume of the amygdala in ASD children was significantly larger than that in healthy children, while the volume of the caudate nucleus was significantly reduced. Correlation results showed that the scores of CARS and ABC in the ASD group were significantly negatively correlated with the levels of miR-499a-5p. In the ASD group, the volume of the amygdala was negatively correlated with the level of miR-499a-5p, while the volume of the caudate nucleus was positively correlated with the level of miR-499a-5p. The decreased expression of miR-499a-5p in the serum of children with ASD was significantly related to the changes in brain volume of children with ASD, and the miRNA showed good diagnostic accuracy in children with ASD., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The study protocol was approved by The Ethics Committee of Xingtai People’s Hospital and followed the principles outlined in the Declaration of Helsinki. In addition, informed consent has been obtained from the participants involved. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

Background and Aims: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder in children. Early intervention is effective. Investigation of novel blood biomarkers of ASD facilitates early detection and intervention., Materials and Methods: Sequential window acquisition of all theoretical spectra-mass spectrometry (SWATH-MS)-based proteomics technology and 30 DSM-V defined ASD cases versus age- and sex-matched controls were initially evaluated, and candidate biomarkers were screened using machine learning methods. Candidate biomarkers were validated by targeted proteomics multiple reaction monitoring (MRM) analysis using an independent group of 30 ASD cases vs. controls., Results: Fifty-one differentially expressed proteins (DEPs) were identified by SWATH analysis. They were associated with the immune response, complements and coagulation cascade pathways, and apolipoprotein-related metabolic pathways. Machine learning analysis screened 10 proteins as biomarker combinations (TFRC, PPBP, APCS, ALDH1A1, CD5L, SPARC, FGG, SHBG, S100A9, and PF4V1). In the MRM analysis, four proteins (PPBP, APCS, FGG, and PF4V1) were significantly different between the groups, and their combination as a screening indicator showed high potential (AUC = 0.8087, 95 % confidence interval 0.6904-0.9252, p < 0.0001)., Conclusions: Our study provides data that suggests that a few plasma proteins have potential use in screening for ASD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

Background: The metabolism of plasma amino acid (AA) in children with autism spectrum disorder (ASD) has been extensively investigated, yielding inconclusive results. This study aims to characterize the metabolic alterations in AA profiles among early-diagnosed children with ASD and compare the findings with those from non-ASD children., Methods: We analyzed plasma AA profiles, measured by ion exchange chromatography, from 1242 ASD children (median age = 4 years; 81% male). Additionally, we studied AA profiles from 488 children, matched for age and free of ASD (control group). Principal component and cluster analysis were employed to explore potential associations within the ASD group and to identify subgroups., Results: We observed lower plasma levels of glutamine in children with ASD compared to non-ASD children ( p < 0.001). Six essential, two conditionally essential, and four non-essential AA were found to be increased in children with ASD. The clustering analysis revealed two groups, labeled Neurological (NEU) and Nutritional (NUT), which included a majority of ASD children (94% and 78%, respectively). The NEU group exhibited high levels of taurine, aspartate, glutamic acid, and ornithine, while the NUT group showed elevated levels of branched-chain AA., Conclusions: In children with ASD, we identified some heterogeneous AA patterns that may serve as biochemical signatures of neurological impairment in some individuals, while in others they may indicate nutritional dysregulation. more...

Objective: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication differences and restricted interests. One proposed biologic mechanism underlying ASD is oxidative stress, leading to the clinical use of glutathione based on anecdotal reports of improved behavior in autistic children. In this pilot study, we tested this observation using a randomized clinical trial format to collect preliminary data on glutathione safety and efficacy., Methods: Glutathione and glutathione in combination with vitamin C and N-acetylcysteine (Trio) were tested. Both treatments were administered in double-blind placebo-controlled randomized crossover studies. In total, 24 children between the ages of 5 and 16 years with ASD and severe behavior disorders were randomized to receive weekly intravenous injections of either placebo or 1 of the 2 interventions (glutathione or Trio) for 8 weeks. After a 1-week washout period, participants were crossed over for the subsequent 8 weeks. Behavioral measures and plasma levels of glutathione were obtained at baseline, during the washout period, and at the end of the study., Results: No differences between treatment groups in behavioral or biologic measures were found. No significant adverse side effects attributable to the treatments were observed. Small improvements in specific glutathione and behavioral measures occurred over the study period for all groups., Conclusion: Treatment with glutathione or glutathione in combination with vitamin C and N-acetylcysteine did not result in improvements in behavior or biologic measures. The positive trends over the course of the study were likely due to the placebo effect or decreased anxiety associated with the study routine., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.) more...

Background: Autism spectrum disorder (ASD) is a persistent neurodevelopmental disorder affecting brains of children. Mounting evidences support the associations between gut microbial dysbiosis and ASD, whereas detailed mechanisms are still obscure., Methods: Here we probed the potential roles of gut microbiome in ASD using fecal metagenomics and metabolomics., Results: Children with ASD were found to be associated with augmented serum cytokines milieu, especially TNFα. Metagenomic analysis generated 29 differential species and 18 dysregulated functional pathways such as Bifidobacterium bifidum, Segatella copri, and upregulated 'Sphingolipid metabolism' in children with ASD. Metabolomics revealed steroid hormone dysgenesis in children with ASD with lower abundances of metabolites such as estriol, estradiol and deoxycorticosterone. A three-way association analysis showed positive correlations between TNFα and microbial function potentials such as 'Bacterial toxins' and 'Lysosome', indicating the contribution of microbial dysbiosis to neuroinflammation. TNFα also correlated positively with 'Sphingolipid metabolism', which further showed negative correlations with metabolites estriol and deoxycorticosterone. Such results, in consistent with current findings, revealed the contribution of increased TNFα to upregulated sphingolipid metabolism, which further impaired steroid hormone biosynthesis., Conclusion: Our study proposed the gut microbial 'TNFα-sphingolipids-steroid hormones' axis in children with ASD, which may provide new perspectives for developing gut microbiome-based treatments in the future., Competing Interests: Declarations. Ethics approval and consent to participate: All research was approved by the Ethics Committee of the Lishui Second People’s Hospital, Zhejiang, Chia. Informed written consent was obtained from each of the participants before enrollment. Consent for publication: All the authors approve the publication of this article and this version of the manuscript. Competing interests: The authors declare no conflicts of interest., (© 2024. The Author(s).) more...

Developmental delays have been associated with metabolic disturbances in children. Previous research in the childhood autism risk from genetics and the environment (CHARGE) case-control study identified neurodevelopment-related plasma metabolites in children, suggesting disturbances in the energy-related tricarboxylic acid (TCA) cycle and 1-carbon metabolism (1CM). Here, we investigated associations between children's neurodevelopmental outcomes and their mothers' plasma metabolite profiles in a subset of mother-child dyads from CHARGE, including those with autism spectrum disorder (ASD, n = 209), Down syndrome (DS, n = 76), idiopathic developmental delay (iDD, n = 64), and typically developed (TD, n = 185) controls. Multiple linear regression revealed associations between child neurodevelopmental outcomes and maternal plasma metabolites related to the TCA cycle, 1CM, and lipid metabolism. Despite profound metabolic disturbances in children with DS reported previously, few of these differences were observed in the mothers, which might reflect differences in gene dosage between children with DS and their euploid mothers. Notably differences in maternal metabolism related to ASD and iDD followed similar patterns of disturbance in previously reported metabolic signatures in children but were generally smaller in magnitude. Similar patterns of metabolic disturbances observed in mothers and their children with ASD or iDD could reflect shared genetic, mitochondrial, and/or environmental risk factors., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).) more...

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and restricted, repetitive patterns of behavior, interests, or activities. Given the lack of specific pharmacological therapy for ASD and the clinical heterogeneity of the disorder, current biomarker research efforts are geared mainly toward identifying markers for determining ASD risk or for assisting with a diagnosis. A wide range of putative biological markers for ASD are currently being investigated. Proteomic analyses indicate that the levels of many proteins in plasma/serum are altered in ASD, suggesting that a panel of proteins may provide a blood biomarker for ASD. Serum samples from 76 boys with ASD and 78 typically developing (TD) boys, 2-10 years of age, were analyzed to identify possible early biological markers for ASD. Proteomic analysis of serum was performed using SomaLogic's SOMAScanTM assay 1.3K platform. A total of 1,125 proteins were analyzed. There were 86 downregulated proteins and 52 upregulated proteins in ASD (FDR < 0.05). Combining three different algorithms, we found a panel of 12 proteins that identified ASD with an area under the curve (AUC) = 0.8790±0.0572, with specificity and sensitivity of 0.8530±0.1076 and 0.8324±0.1137, respectively. All 12 proteins were significantly different in ASD compared with TD boys, and 4 were significantly correlated with ASD severity as measured by ADOS total scores. Using machine learning methods, a panel of serum proteins was identified that may be useful as a blood biomarker for ASD in boys. Further verification of the protein biomarker panel with independent test sets is warranted., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hewitson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.) more...

Objective. Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction and communication, restrictive and repetitive patterns of behavior, interests and activities. The aim of this study was to determine the postnatal levels of thyroid hor-mones and investigate their association with the severity of ASD symptoms. Methods. The study included 56 children (46 boys and 10 girls) with ASD aged 24-42 months. For ASD diagnostics the Autism Diagnostic Observation Schedule - second version (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) - interview with the child's parents or guard-ians were used. Venous blood was drawn right after the diagnostic procedures to analyze serum thyroid-stimulating hormone (s-TSH), free triiodothyronine (s-fT3), and free thyroxine (s-fT4) levels. Linear regression analysis was conducted to assess the relationship between the concentra-tions of thyroid hormones and ASD symptoms severity. Results. Serum concentrations of measured hormones were within normal reference ranges in almost all children. Decline of s-TSH was significantly associated with an increase in the severity of impaired social interaction and impaired communication as rated by parents (ADI-R) and with a higher prevalence of stereotyped behavior as observed in the diagnostic examination (ADOS-2). A decrease in s-fT3 was associated with higher frequency of stereotyped behavior as assessed by parents (ADI-R). Neither sex nor age were significant predictors. Conclusion. Although thyroid hormone levels were normal, we demonstrated an association of thyroid hormones with ASD symptoms., (© 2024 Maria Kopcikova et al., published by Sciendo.) more...

Abnormal feeding behaviors and inadequate nutrient intake of children with autism spectrum disorder (ASD) have been reported. This study aimed to examine the plasma vitamin status of boys with autism spectrum disorder (ASD) and to analyze the association between vitamin status and symptoms of ASD. A total of 45 boys with ASD (age = 3.25 ± 0.68 years) and 45 typically developing (TD) boys (age = 3.33 ± 0.66 years) were enrolled. The developmental levels were evaluated using the Gesell Developmental Schedules (GDS), the severity of ASD was evaluated using the Childhood Autism Rating Scale (CARS). The plasma vitamin levels were determined using metabolomics method. The Vitamin B1, nicotinamide, pyridoxamine dihydrochloride and Vitamin E were found to be significantly higher in the boys with ASD compared with those without ASD. In addition, no significant differences in vitamin metabolic pathways were found between the ASD group and the TD group.The nicotinamide and pyridoxamine dihydrochloride concentration were found to be negatively correlated with GDS score. In comparison with TD boys, the plasma vitamin concentration of ASD boys was not insufficient. Further studies are required to investigate whether it is necessary to use vitamin nutritional supplements in children with ASD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This work has been carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association. This study was approved by the Ethics Committee of Affiliated Children’s Hospital of Jiangnan University [WXCH2019-05-001]. Due to the retrospective analysis, the Ethics Committee of Affiliated Children’s Hospital of Jiangnan University waived the need for individual informed consent. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication: Not applicable., (© 2024. The Author(s).) more...

Objective: This study aimed to ascertain the serum levels of selectins (E, L, P) and platelet-endothelial adhesion molecule-1 (PECAM-1) in preschool children with autism spectrum disorder (ASD) and to establish a comparison with the levels observed in healthy controls., Methods: The study included 34 children aged 2-7 years diagnosed with ASD (ASD group) and 34 randomly selected healthy children matched for age and sex to the ASD group. The children were free of any genetic or physical disease, clinically active infection, or medication use. The sociodemographic data form was completed by all parents. The Childhood Autism Rating Scale (CARS) and the Autism Behavior Checklist (ABC) were administered to the patient group, and the Aberrant Behavior Checklist (AbBC) was completed by the families of all children. Serum selectin (E, L, P) and PECAM-1 levels were measured using enzyme-linked immunosorbent assay (ELISA) kits., Results: The results showed that the levels of both L-selectin (p = 0.007) and PECAM-1 (p = 0.019) were significantly lower in the ASD group than in the control group. No significant difference was observed between the groups concerning E-selectin and P-selectin levels (p > 0.05). It was observed that P-selectin variables were statistically significant in predicting the presence of ASD (p = 0.019). A remarkable inverse correlation was found between the AbBC irritability subscale score and L-selectin (r = -0.296, p = 0.014) and PECAM-1 (r = -0.276, p = 0. 023); the AbBC Lethargy-Social Withdrawal subscale score and E-Selectin (r = -0.239, p = 0.049), L-Selectin (r = -0.297, p = 0.014) and PECAM-1 (r = -0.264, p = 0.029); L-Selectin levels and the AbBC stereotypic behavior subscale (r = -0.248, p = 0.042). No statistically significant relationship was observed between selectins (E, L, P) and PECAM-1 levels and CARS scale, ABC subscale or total scores and age variables (p > 0.05)., Conclusions: These study results suggest that L-selectin, P-selectin and PECAM-1 may play a role in the pathophysiology of ASD., (© 2024 International Society for Developmental Neuroscience.) more...

Background: Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified., Methods: We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods., Results: We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro., Conclusion: Our results suggest a role for inflammasome dysregulation in ASD pathophysiology., Competing Interests: Declaration of competing interest OAA is a consultant to Cortechs.ai and has received speakers honorarium from Lundbeck, Janssen and Sunovion. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.) more...

Ascorbic acid (Vitamin C) is crucial for bodily functions, including collagen synthesis, immune system support and antioxidant defense. Despite autism spectrum disorder's multifactorial nature involving genetic, environmental and neurological factors, robust evidence exploring the association between ascorbic acid and this disorder is notably lacking. This study introduces an innovative spectrofluorometric method to quantify ascorbic acid in the plasma of healthy children and those with autism spectrum disorder. The method relies on the interaction of ascorbic acid with the fluorescent dye propidium iodide. In acidic conditions, propidium iodide undergoes protonation and selectively binds to the negatively charged ascorbic acid forming an ion-pair complex. This complex alters the molecular structure of propidium iodide inducing chemical fluorescence quenching, that can be utilized for ascorbic acid quantification. The developed method undergoes rigorous validation following ICH guidelines, demonstrating a linear relationship within a concentration range of 4-40 μg/mL, with high precision and accuracy metrics. Analysis of real plasma samples from autistic and healthy children reveals clinically and statistically elevated levels of ascorbic acid in those with autism spectrum disorder., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Background: Driven by the complex multifactorial etiopathogenesis of autism spectrum disorder (ASD), a growing interest surrounds the disturbance in folate-dependent one-carbon metabolism (OCM) in the pathology of ASD, whereas the evidence remained inconclusive., Objectives: The study aims to investigate the association of OCM metabolism and ASD and characterize differential OCM metabolites among children with ASD., Methods: Plasma OCM metabolites were investigated in 59 children with ASD and 40 neurotypical children using ultra-performance liquid chromatography tandem mass spectrometry technology. Differences (significance level < 0.001) were tested in each OCM metabolite between cases and controls. Multivariable models were also performed after adjusting for covariates., Results: Ten out of 22 examined OCM metabolites were significantly different in children with ASD, compared with neurotypical controls. Specifically, S-adenosylmethionine (SAM), oxidized glutathione (GSSG), and glutathione (GSH) levels were increased, whereas S-adenosylhomocysteine (SAH), choline, glycine, L-serine, cystathionine, L-cysteine, and taurine levels were significantly decreased. Children with ASD showed significantly higher SAM/SAH ratio (3.87 ± 0.93 compared with 2.00 ± 0.76, P = 0.0001) and lower GSH/GSSG ratio [0.58 (0.46, 0.81) compared with 1.71 (0.93, 2.99)] compared with the neurotypical controls. Potential interactive effects between SAM/SAH ratio, taurine, L-serine, and gastrointestinal syndromes were further observed., Conclusions: OCM disturbance was observed among children with ASD, particularly in methionine methylation and trans-sulfuration pathways. The findings add valuable insights into the mechanisms underlying ASD and the potential of ameliorating OCM as a promising therapeutic of ASD, which warrant further validation., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.) more...

In studies investigating the etiology and pathophysiology of autism spectrum disorder (ASD), immune dysregulation is commonly observed, with elevated levels of inflammatory cytokines frequently found in gestational tissues. However, studies investigating the relationship between early immune dysregulation within the umbilical cord blood (CB) compartment and neurodevelopmental outcomes remains limited. In this exploratory study, we utilized data from the prospective Markers for Autism Risk in Babies - Learning Early Signs (MARBLES) study to examine cytokine levels in the plasma fraction of CB in infants later diagnosed with ASD (n = 38) compared to infants typically developing (TD) at age 3 years (n = 103), using multiplex cytokine assays. Our findings reveal altered levels of several inflammatory cytokines in children later diagnosed with ASD, including increased granulocyte colony-stimulating factor (G-CSF) and decreased interleukin-1α (IL-1α), IL-1β, and IL-4 in CB. Furthermore, we identified several associations between behaviors and levels of cytokines, chemokines and growth factors. IL-1α, IL-17A, interferon γ-induced protein 10 (IP-10), and epidermal growth factor (EGF) were associated with worse scores on Autism Diagnostic Observation Schedule (ADOS) and the Mullen Scales of Early Learning (MSEL) assessments. In summary, our study demonstrates dysregulated levels of inflammatory cytokine mediators in the CB of children later diagnosed with ASD and that inflammatory mediators were associated with ASD severity, comorbid behaviors, and neurodevelopmental measures. These findings have important implications for the possible predictive value of early cytokine measures in neurodevelopmental outcomes and subsequent behavioral manifestations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Introduction: Autism Spectrum Disorder (ASD) is a disorder that severely affects neurodevelopment, and its underlying causes are not yet entirely understood. Research suggests that there may be a connection between the occurrence of ASD and changes in immune responses. This study aims to know if some biochemical and inflammatory cytokines are promising biomarkers for ASD and whether they are involved in the pathogenesis of ASD., Methods: The serum levels of CRP, TNF-α, TGF-β, IL-1β, IL-10, 1 L-8, and IL-6 were measured in all of the patients (n = 22) and in the healthy (n = 12) children using ELISA method., Results: The serum concentrations of IL-10 and IL-8 were significantly lower in the ASD patients compared to the control group (p < 0.05) and there were not significant differences between CRP, TNF-α, TGF-β, IL-6 and IL-1β levels in two groups. There were positive correlations between CRP and IL-10, also CRP and IL-8, in ASD group. In contrast to the ASD patients, the correlations of IL-8, IL-10, and CRP were not significant in the control group., Conclusion: In conclusion, this study highlights the potential role of certain biochemical markers and inflammatory cytokines in ASD. Specifically, the lower levels of IL-10 and IL-8 in ASD patients, along with the significant correlations between CRP and these cytokines, suggest an altered immune response in individuals with ASD. These findings support the hypothesis that immune dysregulation may be involved in ASD pathogenesis. Further research is needed to explore these biomarkers and their mechanistic links to ASD, which could lead to improved diagnostics or therapeutic strategies., (© 2024. The Author(s).) more...

Objective: Neurodevelopmental disorders (NDDs) are the most common psychiatric disorders in childhood, and there are many factors in their etiology. In recent years, many biomarkers have been studied to elucidate the etiology of these disorders. In this study, it was aimed to investigate the levels of nerve growth factor (NGF) and angiotensin converting enzyme 2 (ACE2) in attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID)., Methods: The study included 74 children with NDDs (the number of patients in ADHD, ASD and ID groups were 24, 25 and 25 respectively) and 30 healthy controls (HCs). Serum NGF and ACE2 levels were studied with ELISA kits, also complete blood count (CBC), levels of fasting glucose and serum lipids were assessed., Results: ACE2 levels were found to be lower in NDD group than HCs in girls. In boys with ASD, triglyceride levels were significantly higher than other groups. Also a positive correlation was found between ACE2 and NGF levels when all sample assessed together., Conclusions: This study is a premise for investigating ACE2 and NGF in NDDs. The role of these markers in ADHD, ASD, ID and other NDDs and their associations with gender should be assessed by studies in which both larger sample groups and more disorders. more...

Background: Literature indicates that L-carnosine may be deficient in autism spectrum disorder (ASD) children. The aim of the present study was to estimate the level of L-carnosine in plasma and correlate it with the Autism Treatment Evaluation Checklist (ATEC) and Childhood Autism Rating Scale 2nd Edition, Standard Version (CARS2-ST) scores. To measure L-carnosine level, a bio-analytical method was developed using reverse phase high- liquid chromatography and validated as per International Conference on Harmonization guidelines., Method: Children were supplemented with L-carnosine (10-15 mg/kg) along with standard care therapies for 2 months. Before and after supplementation, scores on the ATEC, CARS2-ST, BEARS sleep screening tool, 6-item Gastrointestinal Severity Index, and Parental Stress Scale were evaluated, and L-carnosine was measured at the end of the trial., Results: The calibration curve was linear in the range of 100-600 ng/mL (R 2 = 0.998). The level of L-carnosine quantified was 33.7 ± 0.2 ng/mL. There was no significant difference found in any of the outcome measures ( p > 0.05)., Conclusions: Despite the fact that L-carnosine is detectable in the blood, it was found to be ineffective in the management of ASD in children., Clinical Trial Registration: The study was registered in the Clinical Trial Registry-India, registration number: CTRI/2019/07/020102., (© 2024 The Author(s). Published by IMR Press.) more...

Background: Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD)., Objectives: To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels., Methods: 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC., Results: Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001)., Conclusions: We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way., (© 2024. The Author(s).) more...

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well-defined cohort of young children with ASD (n = 100) and their matched controls (n = 60) utilizing a high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in-depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC-AUC) of 0.937 (95% CI = 0.890, 0.983; p < 0.001), which demonstrated the diagnostic accuracy of the eight-marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight-autoantibody panel for ASD severity classification., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.) more...

Purpose: To investigate serum levels of VEGF, IGF-1 and FGF-2, and relationships with several clinical characteristics in children and adolescents with autism spectrum disorder (ASD) with and without bipolar disorder (BD)., Method: 40 subjects with ASD + BD as study group, and 40 subjects with ASD as control group were included. Serum levels of VEGF, IGF-1, and FGF-2 were measured using commercial enzyme-linked immunosorbent assay kits., Results: The study group was significantly higher than the control group in terms of ASD severity, self-harming behavior and sleep disturbance. Serum VEGF and FGF-2 levels were significantly higher in the ASD + BD group than in the control group. There was no significant difference in serum IGF-1 levels between the two groups. There was no correlation between VEGF, IGF-1 and FGF-2 serum levels and ASD severity in the study group. However there was a negative correlation between VEGF levels and age at first diagnosis of BD, and a positive correlation between IGF-1 levels and the number of bipolar episodes in the study group., Conclusion: Growth factors like VEGF and FGF-2 may be potential biomarkers of bipolar disorder in young subjects with ASD. Given the difficulty of clinical management of BD in young subjects with ASD, potential biomarkers would help clinicians in the diagnosis and follow up of BD in this special population. Further research is needed whether VEGF and FGF-2 can be potential biomarkers in the clinical management of young subjects with ASD and BD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

This study aims to identify potential correlations of the severity of symptoms of children with autism spectrum disorder (ASD) with serum nutritional levels, body composition indicators, diet partiality, and sleep disturbances. The cohort of this cross-sectional study included 120 children with ASD and 110 typically developing (TD) children to assess symptoms of ASD, and to measure serum levels of vitamins and minerals and the body composition values. Diet partiality and sleep disturbances were assessed by administering questionnaires. The serum levels of folic acid, copper, and vitamin B were lower in children with ASD than in TD children, while magnesium and homocysteine were higher ( p < 0.05). Children with ASD had greater chest circumference, abdominal skinfold thickness, and body mass index (BMI) than TD children ( p < 0.05), and higher prevalences of diet partiality and sleep disturbances ( p < 0.001). Lower vitamin A levels and higher vitamin D levels were related to social impairment in children with ASD. Moreover, there were significantly positive correlations of BMI, chest circumference, diet partiality, and sleep disturbances with severity of ASD symptoms ( p < 0.05). Collectively, rational nutritional supplementation, dietary management, and behavioral interventions are essential for children with ASD. more...

Aim: Autism spectrum disorder (ASD) is associated with abnormal lipid metabolism, such as a high total ratio of omega-6 to omega-3 in polyunsaturated fatty acids (PUFAs). PUFAs are metabolized to epoxy fatty acids by cytochrome P450 (CYP); then, dihydroxy fatty acid is produced by soluble epoxide hydrolase. This study examined the association between PUFA metabolites in the cord blood and ASD symptoms and adaptive functioning in children., Methods: This prospective cohort study utilized cord blood to quantify PUFA metabolites of the CYP pathway. The Autism Diagnostic Observation Schedule (ADOS-2) and Vineland Adaptive Behaviors Scales, Second Edition (VABS-II) were used to assess subsequent ASD symptoms and adaptive functioning in children at 6 years. The analysis included 200 children and their mothers., Results: Arachidonic acid-derived diols, 11,12-diHETrE was found to impact ASD symptom severity on the ADOS-2-calibrated severity scores and impairment in the socialization domain as assessed by the VABS-II (P = 0.0003; P = 0.004, respectively). High levels of 11,12-diHETrE impact social affect in ASD symptoms (P = 0.002), while low levels of 8,9-diHETrE impact repetitive/restrictive behavior (P = 0.003). Notably, there was specificity in the association between diHETrE and ASD symptoms, especially in girls., Conclusion: These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth. Given that the role of diol metabolites in neurodevelopment in vivo is completely uncharacterized, the results of this study provide important insight into the role of diHETrE and ASD pathophysiology., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.) more...

&lt;b&gt;Background and Objective:&lt;/b&gt; Autism Spectrum Disorder (ASD) is a range of neurodevelopmental disabilities that lack a clear etiology. To date, studies investigating the role of immune reactivity to gluten in ASD have been inconsistent. This study aimed to compare levels of gluten reactivity markers in 319 ASD patients to 172 of their unaffected siblings and 322 of unrelated healthy controls (UHC). &lt;b&gt;Materials and Methods:&lt;/b&gt; Patients younger than 12 years old diagnosed with ASD via experienced child psychiatrists and neuro-pediatricians were recruited and gluten reactivity markers and gastrointestinal (GI) complaints commonly found in children with ASD were also investigated. Serum levels of anti-gluten and anti-tissue transglutaminase IgA (anti-TTG IgA) were measured via ELISA. &lt;b&gt;Results:&lt;/b&gt; No significant differences were detected in IgA levels and IgG levels for anti-TTG among all groups (p<0.05). The anti-gliadin IgG levels were significantly higher in ASD patients and their siblings compared to the UHC group (p<0.05). Also, those IgG levels were not associated with any GI complaints or Electroencephalogram (EEG) abnormalities (p>0.05). &lt;b&gt;Conclusion:&lt;/b&gt; The data suggested gluten sensitivity has no role in ASD pathophysiology or its comorbid symptoms. more...

The severity of autism spectrum disorder (ASD) shows wide variations, though the reason remains unclear. Vitamin D (VitD) deficiency is considered a risk factor for ASD and its supplementation was reported to reduce symptom severity. Since VitD, either synthesized in the skin or absorbed from the food, is transported to the liver by the vitamin D binding protein (DBP), we have analyzed DBP genetic polymorphisms [rs7041 (A/C), rs4588 (G/T), and rs3755967 (C/T)] affecting DBP function [Case = 411; Control = 397], levels of plasma 25(OH)D and DBP [Case = 25; Control = 26], and DBP mRNA expression [Case = 74; Control = 44] in a group of Indo-Caucasoid ASD probands and neurotypical subjects. ASD probands with rs7041'CC', rs4588 'TT', and rs3755967 'TT' genotypes exhibited higher scores for a few traits. Scores for Imitation and Listening response were also higher in the presence of the "A-T" haplotype (rs7041-rs4588). Plasma 25(OH)D and DBP levels as well as DBP mRNA expressions were significantly lower in the ASD probands as compared to the neurotypical subjects. We infer that DBP deficiency, in the presence of risk genetic variants, could be one of the reasons for the reported 25(OH)D deficiency of the ASD probands., (© 2024. The Author(s).) more...

Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.) more...

Several studies have linked branched-chain amino acid (BCAA) metabolism disorders with autism spectrum disorder (ASD), but the results have been inconsistent. The purpose of this study was to explore the association between BCAA concentrations and the risk of ASD. A total of 313 participants were recruited from two tertiary referral hospitals from May 2018 to July 2021. Concentrations of BCAAs in dried blood spots were analyzed using liquid chromatography-tandem mass spectrometry-based analysis. Multivariate analyses and restricted cubic spline models were used to identify the association between BCAAs and the risk of ASD, and a nomogram was developed by using multivariate logistic regression and the risk was determined by receiver operating characteristic curve analysis and calibration curve analysis. Concentrations of total BCAA, valine, and leucine/isoleucine were higher in the ASD group, and all of them were positively and non-linearly associated with the risk of ASD even after adjusting for potential confounding factors such as age, gender, body mass index, and concentrations of BCAAs (P < 0.05). The nomogram integrating total BCAA and valine showed a good discriminant AUC value of 0.756 (95% CI 0.676-0.835). The model could yield net benefits across a reasonable range of risk thresholds. In the stratified analysis, the diagnostic ability of the model was more pronounced in children older than 3 years. We provide evidence that increased levels of BCAAs are associated with the risk of ASD, and the nomogram model of BCAAs presented here can serve as a marker for the early diagnosis of ASD., (© 2024. The Author(s).) more...

Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and inflammation-related molecules such as Cyclooxygenase-2 (COX-2), chitinase 3-like protein 1 (YKL-40), Interleukin-1 beta (IL-1β), Interleukin-9 (IL-9) in ASD children with and without regression compared to healthy controls. Children with ASD (n = 56) and typically developing children (TDC, n = 12) aged 1.11 to 11 years were studied. Mitochondrial activity was examined in peripheral blood mononuclear cells (PBMCs) isolated from children with ASD and from the control group, using a metabolic analyzer. Gene and protein levels of IL-1β, IL-9, COX-2, and YKL-40 were investigated in parallel. Our results showed that PBMCs of the ASD subgroup of regressed patients (ASD R(+), n = 21) had a specific pattern of mitochondrial activity with significantly increased maximal respiration, respiratory spare capacity, and proton leak compared to the non-regressed group (ASD R(-), n = 35) and TDC. Furthermore, we found an imbalance in the studied proinflammatory molecules and increased levels in ASD R(-) proving the involvement of inflammatory changes. The results of this study provide new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD. For the first time, data on a unique metabolic profile in ASD R(+) and its comparison with a random group of children of similar age and sex are provided. Our data show that mitochondrial dysfunction is more significant in ASD R(+), while in ASD R(-) inflammation is more pronounced. Probably, in the group without regression, immune mechanisms (immune dysregulation, leading to inflammation) begin initially, and at a later stage mitochondrial activity is also affected under exogenous factors. On the other hand, in the regressed group, the initial damage is in the mitochondria, and perhaps at a later stage immune dysfunction is involved. more...

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly., (© 2024. The Author(s).) more...

Background: Increasing evidence suggests that leptin is involved in the pathology of autism spectrum disorder (ASD). In this study, our objective was to investigate the levels of leptin in the blood of children with ASD and to examine the overall profile of adipokine markers in ASD through meta-analysis., Methods: Leptin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while adipokine profiling, including leptin, was performed via meta-analysis. Original reports that included measurements of peripheral adipokines in ASD patients and healthy controls (HCs) were collected from databases such as Web of Science, PubMed, and Cochrane Library. These studies were collected from September 2022 to September 2023 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Standardized mean differences were calculated using a random effects model for the meta-analysis. Additionally, we performed meta-regression and explored heterogeneity among studies., Results: Our findings revealed a significant increase in leptin levels in children with ASD compared to HCs (p = 0.0319). This result was consistent with the findings obtained from the meta-analysis (p < 0.001). Furthermore, progranulin concentrations were significantly reduced in children with ASD. However, for the other five adipokines analyzed, there were no significant differences observed between the children with ASD and HCs children. Heterogeneity was found among the studies, and the meta-regression analysis indicated that publication year and latitude might influence the results of the meta-analysis., Conclusions: These findings provide compelling evidence that leptin levels are increased in children with ASD compared to healthy controls, suggesting a potential mechanism involving adipokines, particularly leptin, in the pathogenesis of ASD. These results contribute to a better understanding of the pathology of ASD and provide new insights for future investigations., (© 2024. The Author(s).) more...

Background: Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined., Methods: We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes., Results: Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08)., Conclusion: Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.) more...

Background: Accumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the regulation of androgens, such as testosterone and dehydroepiandrosterone (DHEA), in relation to sex differences in individuals with ASD are limited and inconsistent. We conducted the systematic review with meta-analysis to quantitatively summarise the blood, urine, or saliva androgen data between individuals with ASD and controls., Methods: A systematic search was conducted for eligible studies published before 16 January 2023 in six international and two Chinese databases. We computed summary statistics with a random-effects model. Publication bias was assessed using funnel plots and heterogeneity using I 2 statistics. Subgroup analysis was performed by age, sex, sample source, and measurement method to explain the heterogeneity., Results: 17 case-control studies (individuals with ASD, 825; controls, 669) were assessed. Androgen levels were significantly higher in individuals with ASD than that in controls (SMD: 0.27, 95% CI: 0.06-0.48, P =0.01). Subgroup analysis showed significantly elevated levels of urinary total testosterone, urinary DHEA, and free testosterone in individuals with ASD. DHEA level was also significantly elevated in males with ASD., Conclusion: Androgen levels, especially free testosterone, may be elevated in individuals with ASD and DHEA levels may be specifically elevated in males., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Mu, Qiao, Chen, Zhao, Cui, Zhang and Li.) more...

Importance: Disturbances in maternal, placental, and fetal metabolism are associated with developmental outcomes. Associations of maternal, placental, and fetal metabolism with subsequent neurodevelopmental outcomes in the child are understudied., Objective: To investigate the metabolic associations within the maternal-placental-fetal unit and subsequent neurodevelopmental outcomes in younger siblings of children with autism spectrum disorder (ASD)., Design, Setting, and Participants: This cohort study was conducted within a subset of the Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) cohort. MARBLES is a prospective birth cohort of younger siblings of children with ASD assessed for neurodevelopmental outcomes at approximately age 36 months. Participants in MARBLES were recruited through the UC Davis MIND Institute. This subset of the MARBLES cohort included younger siblings born between 2009 and 2015. Maternal third trimester serum, placental tissue, and umbilical cord serum samples were collected from participants. Only pregnancies with at least 2 of these sample types were included in this analysis. Data analysis was conducted from March 1, 2023, to March 15, 2024., Exposures: Quantitative metabolomics analysis was conducted on maternal third trimester serum, as well as placental tissue and umbilical cord serum collected at delivery., Main Outcomes and Measures: Using the Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning, outcomes were classified as ASD, other nontypical development (non-TD), and typical development (TD)., Results: This analysis included 100 maternal serum samples, 141 placental samples, and 124 umbilical cord serum samples from 152 pregnancies (median [IQR] maternal age, 34.6 [30.8-38.3] years; median [IQR] gestational age, 39.0 [38.6-39.7] weeks; 87 [57.2%] male infants). There was no evidence that the maternal third trimester serum metabolome was significantly associated with the other metabolomes. The placental and cord serum metabolomes were highly correlated (first latent variate pair: R2 = 0.75; P < .001) and the variate scores for each tissue were significantly associated with reduced risk of non-TD (placenta: relative risk [RR], 0.13; 95% CI, 0.02-0.71; cord: RR, 0.13; 95% CI, 0.03-0.70) but not ASD (placenta: RR, 1.09; 95% CI, 0.42-2.81; cord: RR, 0.63; 95% CI, 0.23-1.73) compared with the TD reference group., Conclusions and Relevance: In this cohort study of children with high familial risk of ASD, placental and cord serum metabolism at delivery were highly correlated. Furthermore, placental and cord serum metabolic profiles were associated with risk of non-TD. more...

Background: Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD., Methods: Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship., Results: The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD., Conclusion: This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Long, Dang, Su, Moneruzzaman and Zhang.) more...

Objectives: To investigate the levels of serum folate and vitamin B 12 (VB 12 ) and their association with the level of neurodevelopment in preschool children with autism spectrum disorder (ASD)., Methods: A total of 324 ASD children aged 2-6 years and 318 healthy children aged 2-6 years were recruited. Serum levels of folate and VB 12 were measured using chemiluminescent immunoassay. The Social Responsiveness Scale and the Childhood Autism Rating Scale were used to assess the core symptoms of ASD children, and the Gesell Developmental Schedule was employed to evaluate the level of neurodevelopment., Results: The levels of serum folate and VB 12 in ASD children were significantly lower than those in healthy children ( P <0.05). Serum folate levels in ASD children were positively correlated with gross and fine motor developmental quotients ( P <0.05), and serum VB 12 levels were positively correlated with adaptive behavior, fine motor, and language developmental quotients ( P <0.05). In ASD children aged 2 to <4 years, serum folate levels were positively correlated with developmental quotients in all domains ( P <0.05), and serum VB 12 levels were positively correlated with language developmental quotient ( P <0.05). In male ASD children, serum VB 12 levels were positively correlated with language and personal-social developmental quotients ( P <0.05)., Conclusions: Serum folate and VB 12 levels in preschool ASD children are lower than those in healthy children and are associated with neurodevelopmental levels, especially in ASD children under 4 years of age. Therefore, maintaining normal serum folate and VB 12 levels may be beneficial for the neurodevelopment of ASD children, especially in ASD children under 4 years of age. more...

Mitochondrial dysfunction in autism leads to impair the mitochondria's ability to synthesis adenosine triphosphate (ATP) by impairment citric acid cycle as well as increase anaerobic glycolysis. Aim - measuring and evaluating the levels of mitochondrial markers; including glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), malate dehydrogenase, and pyruvate kinase) in the autistic group and knowing the possibility of using these markers to diagnose children with autism spectrum disorder. A case-control study was done in the Al-Zahraa Teaching Hospital (Kut City, Iraq) on 100 Iraqi children (male and female), between (April 2023 and January 2024). Their ages ranged between 3 and 9 years. Among them were 50 patients enrolled as autistic group and 50 healthy enrolled as control group. Blood samples were collected and bioassays for GOT, GPT, pyruvate kinase, and malate dehydrogenase were measured by ELISA technique. The autistic group showed that the urine GOT, urine GPT, serum malate, and serum pyruvate levels in the ASD group was significantly higher (P<0.001) than the control group. The ROC analysis showed that urine GOT, urine GOT, serum malate and serum pyruvate had an accuracy level of (81%,71%,77%, and 80 %) and the area under the curve (AUC) was > 0.7 (0.8),0.7, 0.7(0.76), and 0.7(0.8) thus urine GOT, urine GPT, serum, malate, and serum pyruvate are a valid diagnostic marker. There was a significant difference in the mean urine and serum concentrations of mitochondrial markers (GOT, GPT, malate dehydrogenase, and pyruvate kinase) between autistic children and the control group due to mitochondrial dysfunction. more...

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children. It is currently diagnosed by behaviour-based assessments made by observation and interview. In 2018 we reported a discovery study of a blood biomarker diagnostic test for ASD based on a combination of four plasma protein glycation and oxidation adducts. The test had 88% accuracy in children 5-12 years old. Herein, we present an international multicenter clinical validation study (N = 478) with application of similar biomarkers to a wider age range of 1.5-12 years old children. Three hundred and eleven children with ASD (247 male, 64 female; age 5.2 ± 3.0 years) and 167 children with typical development (94 male, 73 female; 4.9 ± 2.4 years) were recruited for this study at Sidra Medicine and Hamad Medical Corporation hospitals, Qatar, and Hospital Regional Universitario de Málaga, Spain. For subjects 5-12 years old, the diagnostic algorithm with features, advanced glycation endproducts (AGEs)-N ε -carboxymethyl-lysine (CML), N ω -carboxymethylarginine (CMA) and 3-deoxyglucosone-derived hydroimidazolone (3DG-H), and oxidative damage marker, o,o'-dityrosine (DT), age and gender had accuracy 83% (CI 79 - 89%), sensitivity 94% (CI 90-98%), specificity 67% (CI 57-76%) and area-under-the-curve of receiver operating characteristic plot (AUROC) 0.87 (CI 0.84-0.90). Inclusion of additional plasma protein glycation and oxidation adducts increased the specificity to 74%. An algorithm with 12 plasma protein glycation and oxidation adduct features was optimum for children of 1.5-12 years old: accuracy 74% (CI 70-79%), sensitivity 75% (CI 63-87%), specificity 74% (CI 58-90%) and AUROC 0.79 (CI 0.74-0.84). We conclude that ASD diagnosis may be supported using an algorithm with features of plasma protein CML, CMA, 3DG-H and DT in 5-12 years-old children, and an algorithm with additional features applicable for ASD screening in younger children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and N ε (1-carboxyethyl)lysine (CEL). The successful validation herein may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress., (© 2023. The Author(s).) more...

Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members., Methods: We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE., Findings: Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P < 5.27 × 10 - 11 ), 44 of which were not observed in the PLHD group. Plasma glutamine levels were found to be associated with variants in the NLGN1 gene, a gene that encodes post-synaptic cell-adhesion molecules in excitatory neurons. This association was not detected in the PLHD group. Notably, a significant negative correlation between plasma glutamine and glutamate levels was observed in the AGRE group, but not in the PLHD group. Furthermore, plasma glutamine levels showed a negative correlation with the severity of restrictive and repetitive behaviours (RRB) in ASD, although no direct association was observed between RRB severity and the NLGN1 genotype., Interpretation: Our findings suggest that plasma glutamine levels could potentially serve as an endophenotype, thus establishing a link between the genetic risk associated with NLGN1 and the severity of RRB in ASD. This identified association could facilitate the development of novel therapeutic targets, assist in selecting specific cohorts for clinical trials, and provide insights into target symptoms for future ASD treatment strategies., Funding: This work was supported by the National Institute of Health (grant numbers: R01MH107205, U01TR002623, R24OD024622, OT2OD032720, and R01NS129188) and the PrecisionLink Biobank for Health Discovery at Boston Children's Hospital., Competing Interests: Declaration of interests All authors have no potential conflicts of interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.) more...

Aim: Increased intestinal and blood-brain barriers (BBB) permeability has been suggested to have a role in autism spectrum disorder (ASD). Claudin-5, claudin-11, occludin, β-catenin, vinculin, and paxillin are crucial components of these barriers. This study assessed concentrations of these molecules in preschool children with ASD., Methods: A total of 80 children with ASD and 40 controls aged 18-60 months were enrolled in this study. Serum levels of biochemical variables were determined using commercial enzyme-linked immunosorbent assay kits., Results: Serum claudin-11, occludin, and β-catenin levels were significantly higher in the ASD group than in the control group. However, no significant difference for serum claudin-5, vinculin, and paxillin levels was detected between the groups., Conclusion: These findings suggest that claudin-11, occludin, and β-catenin may be involved in the pathogenesis of ASD. These proteins may affect the brain by causing dysregulation in intestinal or blood-brain barrier permeability or with other unknown mechanisms. more...

To distinguish between children with autism spectrum disorder (ASD) and typically developing (TD) children, we have uncovered a new discriminative feature, hemoglobin coupling. Functional near-infrared spectroscopy (fNIRS) was used to record resting-state hemodynamic fluctuations in the bilateral temporal lobes in 25 children with ASD and 22 TD children, in which the coupling between low frequency oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb) fluctuations was evaluated by Pearson correlation coefficient. The results showed significantly weak coupling in children with ASD in both the left and right, and throughout the whole temporal cortex. To explain this observation, a simulation study was performed using a balloon model, in which we found four related parameters could impact the coupling. This study suggested that hemoglobin coupling might be applied as a new cerebral hemodynamic characteristic for ASD screening or diagnostics., (© 2022 Wiley-VCH GmbH.) more...

Objectives: 1) To explore the associations between autistic traits and sex hormone changes in patients with polycystic ovary syndrome (PCOS); 2) To explore the influence of PCOS parental autistic traits and related sex hormone changes on autistic traits in their offspring., Method: This is a case-control study that recruited two groups: polycystic ovarian syndrome-induced infertile subjects as the observation group and fallopian tube factor-induced infertility subjects as the control group. Both cohorts were patients undergoing infertility treatment in the Productive Medicine Center, Peking University People's Hospital. Two types of questionnaires were completed by patients between May 1 st , 2015, and May 1 st , 2016: 1. The autism-spectrum quotient (AQ) 2. Repetitive behavior scale-revised (RBS-r). Levels of sex hormones in serum were measured in patients. The correlations between the levels of these biochemical factors and scores of the autistic traits were analysed. From July 1 st , 2020 to September 1 st , 2021, these patients were followed up by telephone and asked to fill out a questionnaire online. The questionnaire included date of delivery, complications, medicine used and negative events during pregnancy (e.g., death of relatives, divorce, etc.), delivery condition, breastfeeding, AQ scale and Autism Behavior Checklist (ABC) of their children., Results: The patients in the PCOS group had significantly higher AQ scores than those in the control group. Levels of luteinizing hormone and testosterone were also higher in the PCOS group. No significant differences were found between the two groups in RBS-r levels, follicle-stimulating hormone, estradiol or progesterone. In the two combined groups, there were significantly positive correlations between the AQ scores and the luteinizing hormone concentration, as well as between scores of RBS-r and testosterone concentration. Moreover, there was a significantly negative correlation between the level of progesterone and the RBS-r score. According to the follow-up data, the AQ scores of offspring were positively correlated with the RBS-r scores of their mothers. The ABC scores of offspring were positively correlated with the RBS-r scores and the childbearing age of their mothers. No significant difference was found between the two groups in age of delivery, complications, special medication used, negative events during pregnancy, delivery situation, postpartum breastfeeding, age of children, or AQ scores or ABC scores of children. There were no significant correlations between the scale scores of children and the related sex hormone levels of mothers. This could indicate that the higher levels of luteinizing hormone and testosterone and the lower level of progesterone accompanied more pronounced autistic traits in PCOS. Furthermore, the higher delivery age and RBS-r score in mothers accompanied the higher AQ and ABC scores in children., Conclusion: Compared with the control group, PCOS patients had more autistic traits (especially social dysfunction). The autistic traits in PCOS patients might be related to the elevation in testosterone concentration and luteinizing hormone levels and the decline in progesterone level. Moreover, the autistic traits in the offspring of PCOS patients might be related to the parental high delivery age and high tendency to autism traits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Tian, Yuan, Xu, Qu, Zhang and Wang.) more...

Environmental factors have been associated with the etiology of autism spectrum disorder ASD in recent times. The involvement of toxic metals in the generation of reactive oxygen species and their epigenetics effects have been implicated in ASD. This systemic review examines the association of toxic metals with autism in children. A systematic literature search was performed in scientific databases such as PubMed, Google scholar, and Scopus. Case-control studies evaluating toxic metal levels in different tissues of ASD children and comparing them to healthy children (control group) were identified. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of the included studies. Six case-control studies with 425 study subjects met our inclusion criteria. A total of four studies indicated higher levels of As, Pb, Hg, Cd, Al, Sn, Sb, Ba, TI, W, and Zr in whole blood, RBC, in whole blood, RBC, and hair samples of children with autism compared with control suggestive of a greater toxic metal exposure (immediate and long-term). Three studies identified significantly higher concentrations of Cd, Pb and Hg in urine and hair samples of autistic children compared to control suggesting decreased excretion and possible high body burden of these metals. The findings from this review demonstrate that high levels of toxic metals are associated with ASD, therefore, critical care is necessary to reduce body burden of these metals in children with ASD as a major therapeutic strategy., (Copyright © 2021. Published by Elsevier Inc.) more...