1. Arenella M, Mota NR, Teunissen MWA, Brunner HG, Bralten J. Autism spectrum disorder and brain volume link through a set of mTOR-related genes. Journal of child psychology and psychiatry, and allied disciplines. 2023.

BACKGROUND: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. METHODS: We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher’s exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. RESULTS: Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). CONCLUSIONS: This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.

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2. Bai C, Zheng Y, Tian L, Lin J, Song Y, Huang C, Dong Q, Chen J. Structure-based developmental toxicity and ASD-phenotypes of bisphenol A analogues in embryonic zebrafish. Ecotoxicology and environmental safety. 2023; 253: 114643.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has become more prevalent in recent years. Environmental endocrine disruptor bisphenol A (BPA) has been linked to ASD. BPA analogues (BPs) are structure-modified substitutes widely used as safer alternatives in consumer products, yet few studies have explored the developmental neurotoxicity (DNT) of BPA analogues. In the present study, we used the larval zebrafish model to assess the DNT effects of BPA and its analogues. Our results showed that many BPA analogues are more toxic than BPA in the embryonic zebrafish assay regarding teratogenic effect and mortality, which may partially due to differences in lipophilicity and/or different substitutes of structural function groups such as CF3, benzene, or cyclohexane. At sublethal concentrations, zebrafish embryos exposed to BPA or BPs also displayed reduced prosocial behavior in later larval development, evidenced by increased nearest neighbor distance (NND) and the interindividual distance (IID) in shoaling, which appears to be structurally independent. An in-depth analysis of BPA, bisphenol F (BPF), and bisphenol S (BPS) revealed macrocephaly and ASD-like behavioral deficits resulting from exposures to sublethal concentrations of these chemicals. The ASD-like behavioral deficits were characterized by hyperactivity, increased anxiety-like behavior, and decreased social contact. Mechanistically, accelerated neurogenesis that manifested by increased cell proliferation, the proportion of newborn mature neurons, and the number of neural stem cells in proliferation, as well as upregulated genes related to the K(+) channels, may have contributed to the observed ASD-like morphological and behavioral alterations. Our findings indicate that BPF and BPS may also pose significant risks to ASD development in humans and highlight the importance of a comprehensive assessment of DNT effects for all BPA analogues in the future.

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3. Bharat R, Uzaina, Yadav T, Niranjan S, Kurade P. mHealth Apps Delivering Early Intervention to Support Parents of Children With Autism Spectrum Disorder: A Scoping Review. Indian pediatrics. 2023; 60(3): 224-30.

CONTEXT: Early intervention, and parent-mediated intervention are effective in achieving early childhood development goals for children with autism spectrum disorder. There is a surge in mHealth technologies delivering such interventions. This review aims to explore the concept, context and methodology of implementation of such mHealth apps. EVIDENCE ACQUISITION: A search was conducted using NICE (National Institute of Clinical Excellence) healthcare database, including keyword ‘early intervention,’ ‘mHealth,’ ‘parent support,’ ‘apps,’ and ‘autism.’ The quantitative, qualitative, mixed-methods, case reports, grey literature, systematic reviews, clinical trials, and feasibility studies of children between 2 to 6 years with ASD were included from inception of database to December, 2021. Web/Internet-based or computer-dependent programs were excluded. The initial search yielded 3786 studies; 17 were finally included based on the inclusion and exclusion criteria. RESULT: Studies on a total of mhealth apps were reviewed. Nine apps, apart from TOBY (Therapy outcome by you), lacked a holistic approach and instead targeted a specific difficulty in autism. The provision of support to parents using apps was equally beneficial as in-person support, reduced costs, and improved outcomes in children. CONCLUSIONS: The review revealed limited evidence-based mHealth apps available currently in a community setting. This also underscores an opportunity for clinicians to re-direct parents towards evidence-based information and interventions.

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4. Clark KA, Konrad M, Test DW. The effects of UPGRADE your performance on employment soft skills of students with intellectual and developmental disabilities: A pilot study of generalization. Journal of intellectual disabilities : JOID. 2023: 17446295231163263.

Previous research has identified UPGRADE Your Performance as a method for teaching employment soft skills to students with disabilities. UPGRADE Your Performance instruction is a multicomponent intervention including self-evaluation, self-graphing, goal setting, and technology-aided instruction. This pilot study investigated the generalized effects of UPGRADE Your Performance on soft skills of secondary students with intellectual and other developmental disabilities participating in an 18-21 transition program located on a university campus. Results indicated that when students improved in two targeted soft skill areas, generalization occurred to three non-targeted soft skill areas. Implications for practice and suggestions for future research are included.

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5. Cole RH, Elmalem MS, Petrochilos P. Prevalence of autistic traits in functional neurological disorder and relationship to alexithymia and psychiatric comorbidity. Journal of the neurological sciences. 2023; 446: 120585.

INTRODUCTION: In a cohort of adults with Functional Neurological Disorder (FND), we aim to: METHODS: 91 patients participating in a FND 5-week outpatient program completed baseline self-report questionnaires for total phobia, somatic symptom severity, attention deficit hyperactivity disorder (ADHD) and dyslexia. Patients were grouped by Autism Spectrum Quotient (AQ-10) score of <6 or ≥ 6 and compared for significant differences in tested variables. This analysis was repeated with patients grouped by alexithymia status. Simple effects were tested using pairwise comparisons. Multistep regression models tested direct relationships between autistic traits and psychiatric comorbidity scores, and mediation by alexithymia. RESULTS: 36 patients (40%) were AQ-10 positive (scoring ≥6 on AQ-10). A further 36 patients (across AQ-10 positive and AQ-10 negative groups) (40%) screened positive for alexithymia. AQ-10 positive patients scored significantly higher for alexithymia, depression, generalised anxiety, social phobia, ADHD, and dyslexia. Alexithymia positive patients scored significantly higher for generalised anxiety, depression, somatic symptoms severity, social phobia, and dyslexia. Alexithymia score was found to mediate the relationship between autistic trait and depression scores. CONCLUSION: We demonstrate a high proportion of autistic and alexithymic traits, in adults with FND. A higher prevalence of autistic traits may highlight a need for specialised communication approaches in FND management. Mechanistic conclusions are limited. Future research could explore links with interoceptive data.

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6. Correia BSB, de Moraes Pontes JG, Nani JVS, Villalta F, Mor NC, Bordini D, Brunoni D, Brentani H, Mari JJ, Hayashi MAF, Tasic L. (1)H NMR Metabolomics and Lipidomics To Monitor Positive Responses in Children with Autism Spectrum Disorder Following a Guided Parental Intervention: A Pilot Study. ACS chemical neuroscience. 2023; 14(6): 1137-45.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by patients displaying at least two out of the classical symptoms, such as impaired social communication, impaired interactions, and restricted repetitive behavior. Early parent-mediated interventions, such as video modeling for parental training, were demonstrated to be a successful low-cost way to deliver care for children with ASD. Nuclear magnetic resonance (NMR)-based metabolomics/lipidomics has been successfully employed in several mental disorder studies. Metabolomics and lipidomics of 37 ASD patients (children, aged 3-8 years), who were divided into two groups, one control group with no parental-training intervention (N = 18) and the other in which the parents were trained by a video modeling intervention (ASD parental training, N = 19), were analyzed by proton NMR spectroscopy. Patients in the ASD parental-training group sera were seen to have increased glucose, myo-inositol, malonate, proline, phenylalanine, and gangliosides in their blood serum, while cholesterol, choline, and lipids were decreased, compared to the control group, who received no parental-training. Taken together, we demonstrated here significant changes in serum metabolites and lipids in ASD children, previously demonstrated to show clinical positive effects following a parental training intervention based on video modeling, delivered over 22 weeks. We demonstrate the value of applying metabolomics and lipidomics to identify potential biomarkers for clinical interventions follow-up in ASD.

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7. Curie A, Oberlander TF, Jensen KB. Placebo effects in children with autism spectrum disorder. Developmental medicine and child neurology. 2023.

Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with neurodevelopmental disorders. Here, we review the placebo effect in autism spectrum disorder (ASD). Placebo responses are widely evident in ASD clinical trials and could partly operate via so-called placebo-by-proxy, whereby caregivers or clinicians indirectly shape patient outcomes. Understanding the role of placebo effects in ASD may help discern genuine treatment effects from contextual factors in clinical trials. The much less studied nocebo effect, or negative placebo, might contribute to the experience of side effects in ASD treatments but empirical data is missing. Better knowledge about placebo and nocebo mechanisms may contribute to the development of more effective research designs, such as three-armed designs that account for natural history, and improved treatments for ASD symptoms. At a clinical level, deeper knowledge about placebo and nocebo effects may optimize the delivery of care for individuals with ASD in the future.

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8. Dardani C, Schalbroeck R, Madley-Dowd P, Jones HJ, Strelchuk D, Hammerton G, Croft J, Sullivan SA, Zammit S, Selten JP, Rai D. Childhood Trauma As a Mediator of the Association Between Autistic Traits and Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children Cohort. Schizophrenia bulletin. 2023; 49(2): 364-74.

BACKGROUND: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. STUDY DESIGN: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. STUDY RESULTS: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. CONCLUSIONS: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

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9. Deng W, Marmelat V, Vanderbilt DL, Gennaro F, Smith BA. Barcoding, linear and nonlinear analysis of full-day leg movements in infants with typical development and infants at risk of developmental disabilities: Cross-sectional study. Infancy : the official journal of the International Society on Infant Studies. 2023.

Traditional methods do not capture the multidimensional domains and dynamic nature of infant behavioral patterns. We aim to compare full-day, in-home leg movement data between infants with typical development (TD) and infants at risk of developmental disabilities (AR) using barcoding and nonlinear analysis. Eleven infants with TD (2-10 months) and nine infants AR (adjusted age: 2-14 months) wore a sensor on each ankle for 7 days. We calculated the standard deviation for linear variability and sample entropy (SampEn) of leg acceleration and angular velocity for nonlinear variability. Movements were also categorized into 16 barcoding states, and we calculated the SampEn and proportions of the barcoding. All variables were compared between the two groups using independent-samples t-test or Mann-Whitney U test. The AR group had larger linear variability compared to the TD group. SampEn was lower in the AR group compared to TD group for both acceleration and angular velocity. Two barcoding states’ proportions were significantly different between the two groups. The results showed that nonlinear analysis and barcoding could be used to identify the difference of dynamic multidimensional movement patterns between infants AR and infants with TD. This information may help early diagnosis of developmental disabilities in the future.

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10. D’Mello AM, Frosch IR, Meisler SL, Grotzinger H, Perrachione TK, Gabrieli JDE. Diminished Repetition Suppression Reveals Selective and Systems-Level Face Processing Differences in ASD. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023; 43(11): 1952-62.

Repeated exposure to a stimulus results in reduced neural response, or repetition suppression, in brain regions responsible for processing that stimulus. This rapid accommodation to repetition is thought to underlie learning, stimulus selectivity, and strengthening of perceptual expectations. Importantly, reduced sensitivity to repetition has been identified in several neurodevelopmental, learning, and psychiatric disorders, including autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by challenges in social communication and repetitive behaviors and restricted interests. Reduced ability to exploit or learn from repetition in ASD is hypothesized to contribute to sensory hypersensitivities, and parallels several theoretical frameworks claiming that ASD individuals show difficulty using regularities in the environment to facilitate behavior. Using fMRI in autistic and neurotypical human adults (females and males), we assessed the status of repetition suppression across two modalities (vision, audition) and with four stimulus categories (faces, objects, printed words, and spoken words). ASD individuals showed domain-specific reductions in repetition suppression for face stimuli only, but not for objects, printed words, or spoken words. Reduced repetition suppression for faces was associated with greater challenges in social communication in ASD. We also found altered functional connectivity between atypically adapting cortical regions and higher-order face recognition regions, and microstructural differences in related white matter tracts in ASD. These results suggest that fundamental neural mechanisms and system-wide circuits are selectively altered for face processing in ASD and enhance our understanding of how disruptions in the formation of stable face representations may relate to higher-order social communication processes.SIGNIFICANCE STATEMENT A common finding in neuroscience is that repetition results in plasticity in stimulus-specific processing regions, reflecting selectivity and adaptation (repetition suppression [RS]). RS is reduced in several neurodevelopmental and psychiatric conditions including autism spectrum disorder (ASD). Theoretical frameworks of ASD posit that reduced adaptation may contribute to associated challenges in social communication and sensory processing. However, the scope of RS differences in ASD is unknown. We examined RS for multiple categories across visual and auditory domains (faces, objects, printed words, spoken words) in autistic and neurotypical individuals. We found reduced RS in ASD for face stimuli only and altered functional connectivity and white matter microstructure between cortical face-recognition areas. RS magnitude correlated with social communication challenges among autistic individuals.

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11. Gallardo Montes CDP, Rodríguez Fuentes A, Caurcel Cara MJ. ICT training for educators of Granada for working with people with autism. Heliyon. 2023; 9(3): e13924.

BACKGROUND: Innovative methodologies based on Information and Communication Technology (ICT) are a tested and motivating option for working with people with autism. Their use, however, should not be indiscriminatory and arbitrary, but didactic and appropriate. OBJECTIVE: We aimed to discover the training in ICT they had, its frequency of use, and the types of digital resources that they used. METHODS: We administered the questionnaire, « Demands and Potentials of ICT and Apps for Assisting People with Autism » to 310 educators in the city of Granada (Spain). The participants belonged to schools and associations that worked with people with autism. Adopting a quantitative-type study, we carried out descriptive analyses (frequencies, mean, mode, and standard deviation). Having confirmed that the data did not follow a normal distribution (Kolmogorov-Smirnov test for samples of >50 participants), we carried out non-parametric inferential and intrafactorial correlation analyses. We also calculated the effect size. RESULTS: The educators revealed that they had ICT training for working with people with autism, but not enough. This suggests that there is still a need to improve the digital competence of these professionals. Strong, direct and significant correlations were found between ICT training and the frequency with which they were used. There were also statistically significant differences according to sex, gender, age, type of institution, and type of educator. The educators who worked as Therapeutic Pedagogy teachers and those who worked in Special Education schools were shown to be more competent than the rest in educational technology applied to people with autism. CONCLUSIONS: The results, which were not wholly positive since ICT training should be better and have achieved higher scores, revealed that there is a foundation in ICT education but it needs to be heightened and improved with greater knowledge and more practical experience.

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12. Gao MM, Shi H, Yan HJ, Long YS. Proteome profiling of the prefrontal cortex of Fmr1 knockout mouse reveals enhancement of complement and coagulation cascades. Journal of proteomics. 2023; 274: 104822.

Fragile X mental retardation protein (FMRP) deficit resulted from mutations in its encoded fragile X mental retardation 1 (Fmr1) gene is a common inherited cause of Fragile X syndrome (FXS) characterized by intellectual disability and autism spectrum disorder (ASD). The FMRP absence-induced altered gene expression in prefrontal cortex (PFC) are associated with autistic behaviors. However, there lacks a large-scale protein profiling in the PFC upon loss of FMRP. This study used a TMT-labeled proteomic analysis to identify a protein profile of the PFC in the Fmr1 knockout mouse. A total of 5886 proteins were identified in the PFC with 100 differentially abundant proteins (DAPs) in response to FMRP deficiency. Bioinformatical analyses showed that these DAPs were mostly enriched in immune system, extracellular part and complement and coagulation cascades. The complement and coagulation cascades include 6 upregulated proteins (SERPING1, C1QA, C3, FGA, FGB and FGG), which are associated with fibrin degradation, cell lysis, degranulation chemotaxis and phagocytosis linked to activation of immune and inflammatory responses. Thus, our data provide an altered protein profile upon loss of FMRP in the PFC, and suggest that the enhancement of complement and coagulation cascades might contribute to etiological and pathogenic roles of ASD in FXS. SIGNIFICANCE: The etiology of autism spectrum disorder (ASD), a group of neurobiological disorders characterized by deficits in social interaction barriers and other abnormal behaviors, is still elusive. Autistic-like phenotypes are present in both Fragile X syndrome (FXS) patients and FMRP-deficiency FXS models. Given that prefrontal cortex is a critical brain area for social interaction, the FMRP absence induced-changes of a subset of proteins might contribute to ASD in FXS. Using a comprehensive proteomic analysis, this study provides a prefrontal protein profile of the FMRP-absent mouse with a total of 100 differentially abundant proteins (DAPs). Bioinformatic analyses suggest that these DAPs are mainly involved in the regulations of immune system and complement and coagulation cascades. We also show that 6 upregulated proteins (SERPING1, C1QA, C3, FGA, FGB and FGG) in the complement and coagulation cascades are associated with fibrin degradation, cell lysis, degranulation chemotaxis and phagocytosis regarding dysregulation of immune and inflammatory responses in the prefrontal cortex. Therefore, this study suggests that these FMRP-deficient DAPs in the prefrontal cortex might contribute to the etiology and pathogenesis of ASD in FXS.

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13. Gonçalves AM, Monteiro P. Autism Spectrum Disorder and auditory sensory alterations: a systematic review on the integrity of cognitive and neuronal functions related to auditory processing. Journal of neural transmission (Vienna, Austria : 1996). 2023.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a wide spectrum of symptoms, mainly characterized by social, communication, and cognitive impairments. Latest diagnostic criteria according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013) now include sensory issues among the four restricted/repetitive behavior features defined as « hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment ». Here, we review auditory sensory alterations in patients with ASD. Considering the updated diagnostic criteria for ASD, we examined research evidence (2015-2022) of the integrity of the cognitive function in auditory-related tasks, the integrity of the peripheral auditory system, and the integrity of the central nervous system in patients diagnosed with ASD. Taking into account the different approaches and experimental study designs, we reappraise the knowledge on auditory sensory alterations and reflect on how these might be linked with behavior symptomatology in ASD.

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14. Guthrie W, Wetherby AM, Woods J, Schatschneider C, Holland RD, Morgan L, Lord CE. The earlier the better: An RCT of treatment timing effects for toddlers on the autism spectrum. Autism : the international journal of research and practice. 2023: 13623613231159153.

Behavioral interventions that incorporate naturalistic, developmental strategies have been shown to improve outcomes for young children who receive an autism spectrum disorder (ASD) diagnosis. Although there is broad consensus that children on the spectrum should begin supports as soon as possible, the empirical evidence for this is relatively limited and little is known about the optimal age to start autism-specific interventions. Our team conducted a randomized controlled trial (RCT) to test the effects of starting intervention at different ages, using the Early Social Interaction (ESI) model, a parent-implemented intervention for toddlers on the spectrum. Participants included 82 autistic toddlers and their caregiver(s) who received 9 months of Individual-ESI and 9 months of Group-ESI, with the timing/order of these two treatment conditions randomized. Thus, families received the more intensive and individualized Individual-ESI at either 18 or 27 months of age. Results revealed that children who received Individual-ESI earlier showed greater treatment gains than those who received this intervention later. Gains were demonstrated in several areas, which included the use and understanding of language, social use of communication skills, and self-help skills. Importantly, these findings were specific to the intensive and individualized parent coaching model compared to group-based treatment, allowing us to rule out the possibility that these timing effects were due to children getting older rather than the treatment itself. Our results suggest that even a narrow window of 18 versus 27 months may have an impact on outcomes and underscore the importance of screening and evaluation as young as possible.

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15. Haratizadeh S, Ranjbar M, Basiri M, Nozari M. Astrocyte responses to postnatal erythropoietin and nano-erythropoietin treatments in a valproic acid-induced animal model of autism. Journal of chemical neuroanatomy. 2023: 102257.

BACKGROUND: Despite ample evidence of the potential protective effects of erythropoietin (EPO) on the developing brain, no study has addressed the effects of postnatal EPO on behaviors and brain tissue of animal models of autism. In the present study, we examined the therapeutic effects of postnatal erythropoietin on stereotypic behaviors and astrocyte responses via glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) immunohistochemistry in a valproic acid (VPA) animal model of autism. Also, we compared the effects of EPO with EPO-loaded solid lipid nanoparticles (NEPO) because the blood-brain barrier has limited permeability to EPO. METHODS: Pregnant rats received a single dose of VPA (600mg/kg) at gestational day 12.5. EPO (2000U/kg) and EPO-loaded solid lipid nanoparticles (NEPO1000 and 2000U/kg) were injected intraperitoneally from postnatal days 1-5. Repetitive behaviors in male offspring were assessed by a marble burying test. The immune-staining method was performed to evaluate S100B and GFAP-positive cells in the prefrontal cortex and hippocampal CA1 region. RESULTS: VPA animal models revealed more repetitive behavior and displayed higher astrogliosis in the prefrontal cortex (PFC) and hippocampus (CA1) regions. The repetitive behaviors were ameliorated relatively in VPA groups with NEPO2000 treatment, and astrogliosis was reduced even when VPA rats were treated with a lower dosage of NEPO. CONCLUSION: Our results indicate beneficial effects of postnatal NEPO exposure in the VPA animal model of autism, which proposes it as an early treatment in infants with, or at risk of, autism.

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16. Harris E. Inflammation Genes Show Age-Dependent Link With Autism. Jama. 2023.

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17. Hassan ZR, Zekry KM, Heikal EA, Ibrahim HF, Khirala SK, Abd El-Hamid SM, Amin DR, Seliem N, El-Aal GNA, Alkherkhisy MM, Elhamid SAA, Mahgoub EA, Hefny MEN, El Nady GH, Badr MS. Toxoplasmosis and cytomegalovirus infection and their role in Egyptian autistic children. Parasitology research. 2023.

Autism is a neurodevelopmental disorder with a significantly increased incidence rate across the world over the past few years. Toxoplasmosis and cytomegalovirus (CMV) infection are globally prevalent and have been associated with diverse neurological and psychiatric disorders. A few studies have demonstrated the role of toxoplasmosis and CMV as potential etiological factors for autism. Accordingly, this study was performed to estimate the relationship between toxoplasmosis and CMV infection in children with autism as well as to assess their impact on the Childhood Autism Rating Scale (CARS) score. A total of 45 autistic children (6 girls, 39 boys) and 45 (21 girls, 24 boys) healthy control children were enrolled in our study. Their blood samples were collected and tested for the presence of Toxoplasma and CMV (IgG and IgM) antibodies and DNA by ELISA and real-time PCR (RT-PCR), respectively. Toxoplasmosis was detected in 11 (24.4%) autistic children through the ELISA [10 (22.2%) IgG + /IgM - and 1 (2.2%) IgG + /IgM +]; however, RT-PCR assay recorded only 1 positive case (2.2%), while it was detected in 10 (22.2%) control children through ELISA [9 (20%) IgG + /IgM - and 1 (2.2%) IgG + /IgM +] and 1 (2.2%) by RT-PCR. On the other hand, CMV infection was detected in all autistic children with 44 (97.8%) testing positive by ELISA [24 (53.3%) IgG + /IgM - , 18 (40%) IgG + /IgM + and 2 (4.4%) IgG - /IgM +] and 25 (55.6%) testing positive by RT-PCR assay. In addition, ELISA assay recorded 43 (95.6%) [19 (42.2%) IgG + /IgM + and 22 (48.9%) IgG + /IgM - and 2 (4.4%) IgG-/IgM +] and RT-PCR recorded 21 (46.7%) positive samples in control children with CMV. No significant difference was noted between autistic and control children for the overall prevalence of Toxoplasma or/and CMV infection. Similarly, the CARS score indicated a non-significant difference with Toxoplasma or/and CMV infection. Our data does not show an association between autism and toxoplasmosis or/and CMV infection. Nevertheless, considering that autistic children are at a high risk of contracting these infections, further studies with a larger sample size are recommended.

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18. Leslie AC, O’Sullivan M. The Triad of Childhood-Onset Schizophrenia, Autism Spectrum Disorder, and Catatonia: A Case Report. Schizophrenia bulletin. 2023; 49(2): 239-43.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia with an estimated prevalence of 1/10,000. Schizophrenia and Autism spectrum disorder (ASD) have shared phenotypic features and shared genetic etiology. There is growing research surrounding the co-occurrence of psychomotor syndromes like catatonia with neurodevelopmental disorders like ASD or psychiatric disorders like schizophrenia. In 2013, Shorter and Wachtel described a phenomenon of the ‘Iron Triangle’ where COS, ASD, and catatonia often co-occur. The Iron Triangle theory is based on observation of historical case literature, which showed that all three diagnoses in the Iron Triangle were routinely assigned to children and adolescents. The pattern of this « Iron Triangle » suggests there may be a single underlying pathology resulting in a unique mixed form of catatonia, autism, and psychosis. We describe the case of a boy with sequential development of COS, ASD, and catatonia who also has syndromic facial and musculoskeletal features. This case highlights overlapping diagnostic features of these three disorders and can help us better understand how « hidden » features of catatonia may occur in patients with COS or ASD but go unrecognized, because they are grouped as features under autism/schizophrenia rather than a distinct diagnosis of catatonia. Further study is warranted to elucidate if this phenotypic pattern constitutes a new single diagnosis that is not well understood, an endophenotype of schizophrenia, or if this is the result of phenomenological overlap between catatonia, ASD, and COS.

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19. Liu D, Meyer D, Fennessy B, Feng C, Cheng E, Johnson JS, Park YJ, Rieder MK, Ascolillo S, de Pins A, Dobbyn A, Lebovitch D, Moya E, Nguyen TH, Wilkins L, Hassan A, Burdick KE, Buxbaum JD, Domenici E, Frangou S, Hartmann AM, Laurent-Levinson C, Malhotra D, Pato CN, Pato MT, Ressler K, Roussos P, Rujescu D, Arango C, Bertolino A, Blasi G, Bocchio-Chiavetto L, Campion D, Carr V, Fullerton JM, Gennarelli M, González-Peñas J, Levinson DF, Mowry B, Nimgaokar VL, Pergola G, Rampino A, Cervilla JA, Rivera M, Schwab SG, Wildenauer DB, Daly M, Neale B, Singh T, O’Donovan MC, Owen MJ, Walters JT, Ayub M, Malhotra AK, Lencz T, Sullivan PF, Sklar P, Stahl EA, Huckins LM, Charney AW. Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations. Nature genetics. 2023; 55(3): 369-76.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes(1). This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10(-6)). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

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20. Maillard C, Roux CJ, Charbit-Henrion F, Steffann J, Laquerriere A, Quazza F, Buisson NB. Tubulin mutations in human neurodevelopmental disorders. Seminars in cell & developmental biology. 2023; 137: 87-95.

Mutations causing dysfunction of tubulins and microtubule-associated proteins, also known as tubulinopathies, are a group of recently described entities that lead to complex brain malformations. Anatomical and functional consequences of the disruption of tubulins include microcephaly, combined with abnormal corticogenesis due to impaired migration or lamination and abnormal growth cone dynamics of projecting and callosal axons. Key imaging features of tubulinopathies are characterized by three major patterns of malformations of cortical development (MCD): lissencephaly, microlissencephaly, and dysgyria. Additional distinctive MRI features include dysmorphism of the basal ganglia, midline commissural structure hypoplasia or agenesis, and cerebellar and brainstem hypoplasia. Tubulinopathies can be diagnosed as early as 21-24 gestational weeks using imaging and neuropathology, with possible extreme microlissencephaly with an extremely thin cortex, lissencephaly with either thick or thin/intermediate cortex, and dysgyria combined with cerebellar hypoplasia, pons hypoplasia and corpus callosum dysgenesis. More than 100 MCD-associated mutations have been reported in TUBA1A, TUBB2B, or TUBB3 genes, whereas fewer than ten are known in other genes such TUBB2A, TUBB or TUBG1. Although these mutations are scattered along the α- and β-tubulin sequences, recurrent mutations are consistently associated with almost identical cortical dysgenesis. Much of the evidence supports that these mutations alter the dynamic properties and functions of microtubules in several fashions. These include diminishing the abundance of functional tubulin heterodimers, altering GTP binding, altering longitudinal and lateral protofilament interactions, and impairing microtubule interactions with kinesin and/or dynein motors or with MAPs. In this review we discuss the recent advances in our understanding of the effects of mutations of tubulins and microtubule-associated proteins on human brain development and the pathogenesis of malformations of cortical development.

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21. Majhi S, Kumar S, Singh L. A Review on Autism Spectrum Disorder: Pathogenesis, Biomarkers, Pharmacological and Non-Pharmacological Interventions. CNS & neurological disorders drug targets. 2023; 22(5): 659-77.

Autistic spectrum disorder (ASD) is a complicated developmental disease characterized by persistent difficulties in social interaction, speech and nonverbal communication, and restricted/ repetitive activities. Our goal is to deliver a step ahead awareness on neurodevelopment in ASD through early behavioral screenings, genetic testing, and detection of various environmental triggers. This would significantly reduce the tally of people with autistic characteristics. As of now, much work is to be done in understanding and treating ASD. Firstly, awareness campaigns must be organized and maintained so that ASD children can be identified and treated feasibly. Secondly, prenatal and prepregnancy environmental risk awareness, including advice against consanguineous marriages, information on optimum mother nutrition, and minimizing pollutants exposure, can be focused. Finally, the extension of genetic screening along with early postnatal monitoring of newborn feeding, nutrition, and eye contact will help in early therapy. People with ASD have strict dietary habits, but they are also more prone to gastrointestinal problems, including diarrhoea, constipation, and sometimes irritable bowel syndrome. Despite significant studies on the symptoms and possible causes of ASD, GI dysfunction is becoming a hot issue of discussion. Dietary strategies can partially help to alleviate both GI and behavioural issues due to the link between gut-microbiota and brain activity. Dietary treatments may be less expensive, easier to administer and have fewer adverse effects than pharmacological interventions. Hence, there is an increasing interest in autistic children’s customized diets and supplements. Future studies should look at whether these diets are applicable to diverse people and whether they are practical in various circumstances (areas with fewer resources, lower socioeconomic areas, countries with different dietary restrictions, etc.). The dietary phytochemicals, including curcumin, resveratrol, naringenin, and sulforaphane, have a substantial role as neurotherapeutic agents. These agents can act as an antioxidant, immunomodulator, gut microbiota modulator and Nrf2 activator to provide benefits to ASD patients. Hence an urgent need is to create brain-targeted delivery methods for these dietary phytochemicals and to investigate their therapeutic value in ASD.

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22. Moravej H, Inaloo S, Nahid S, Mazloumi S, Nemati H, Moosavian T, Nasiri J, Ghasemi F, Alaei MR, Dalili S, Aminzadeh M, Katibeh P, Amirhakimi A, Yazdani N, Ilkhanipoor H, Afshar Z, Hadipour F, Hadipour Z. Inborn Errors of Metabolism Associated With Autism Among Children: A Multicenter Study from Iran. Indian pediatrics. 2023; 60(3): 193-6.

OBJECTIVE: This study aimed to find the common inborn errors of metabolism in Iranian patients with autism spectrum disorder. METHODS: In this cross-sectional multicenter study, 105 children and adolescents with autism spectrum disorder from six centers in different cities of Iran were enrolled between August, 2019 and October, 2020. Metabolic screening, including measuring plasma levels of amino acids, acylcarnitines, creatine, and guani-dinoacetate, and urinary levels of organic acids, purines, and pyrimidines was performed. Other data, including age, parental consanguinity, history of seizure, developmental mile-stones, and physical examination, were also recorded. RESULTS: An inborn error of metabolism was found in 13 (12.4%) patients. Five patients (4.8%) had cerebral creatine deficiency syndrome, 4 (3.8%) had arginine succinate aciduria, 2- methylbutyryl glycinuria, short-chain acyl-CoA dehydrogenase deficiency, and combined methylmalonic aciduria/malonic aciduria. There was a strong association between positive meta-bolic evaluation and parental consanguinity, history of seizures, microcephaly, and delayed development. CONCLUSIONS: Our results suggest that metabolic screening should be performed in the cases of autism associated with parental consanguinity, developmental delay, and a history of seizures. The assays to be considered as a screening panel include plasma or blood amino acids, acylcarnitines, creatine and guanidinoacetate, and urinary levels of organic acids.

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23. Mukherjee S, Beresford B. Factors influencing the mental health of autistic children and teenagers: Parents’ observations and experiences. Autism : the international journal of research and practice. 2023: 13623613231158959.

Autistic people are more likely to experience mental health difficulties compared to neurotypical people. It is very important that we understand what increases the risk for mental health difficulties, and what helps to protect against them. So far, research on this for children and young people has only investigated a small number of factors and these have been chosen by researchers and clinicians. This study took a different approach in which parents’ expertise in their children was recognised. Parents were asked to tell the story of their autistic teenagers’ mental health from diagnosis in early childhood through to the present, and to explain the ‘theories’ they developed about what affected their child’s mental health – positively and negatively – and how. Parents believed a wide range of factors played a role. These include: (1) aspects of their child (e.g. their autistic traits, intelligence); (2) aspects of their surroundings (e.g. the efforts parents make to prevent and respond to their child’s difficulties, features of the school they attend, availability of social activities); (3) changes their child experienced growing up (e.g. puberty, awareness of being autistic); and (4) life events involving loss and separation. Many of the factors parents identified as important have received little or no research attention to date. The findings suggest issues that should be considered in future research and reveal ways that support for parents and autistic children and teenagers can be improved.

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24. Newell V, Phillips L, Jones C, Townsend E, Richards C, Cassidy S. A systematic review and meta-analysis of suicidality in autistic and possibly autistic people without co-occurring intellectual disability. Molecular autism. 2023; 14(1): 12.

BACKGROUND: Suicidality is highly prevalent in autistic people without co-occurring intellectual disabilities, and high autistic traits are found in adults who have attempted suicide. However, prevalence rates for both autistic and possibly autistic people have not been synthesised meta-analytically. AIMS: To (1) calculate pooled prevalence estimates of suicidality in autistic people and possibly autistic people without co-occurring intellectual disability; (2) evaluate the influence of participant and study level characteristics on heterogeneity; and (3) determine the quality of evidence. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. PsycINFO, Embase, MEDLINE and Web of Science were systematically searched from 1992 to January 25, 2022. Empirical quantitative studies reporting prevalence of suicidal ideation, suicide plans, or suicide attempts and behaviours were considered for inclusion. Random effects models were used to estimate pooled prevalence of each suicidality outcome with 95% confidence intervals. Heterogeneity was explored using sensitivity and moderator analyses. RESULTS: Data from 48,186 autistic and possibly autistic participants in 36 primary studies were meta-analysed. Pooled prevalence of suicidal ideation was 34.2% (95% CI 27.9-40.5), suicide plans 21.9% (13.4-30.4), and suicidal attempts and behaviours 24.3% (18.9-29.6). High levels of heterogeneity (I(2) > 75) were observed in all three analyses. Estimates did not differ between autistic or possibly autistic samples. Geographical location (p = 0.005), transgender or gender non-conforming samples (p < 0.001) and type of report (p < 0.001) significantly moderated suicidal ideation, whereas age group (p = 0.001) and measure of suicidality (p = 0.001) significantly moderated suicide plans. There was a significant association between the proportion of male participants and prevalence of suicide plans, with a decrease in the proportion of males for every unit change of suicide plan prevalence (p = 0.013). No variables were found to moderate estimates of suicide attempts and behaviours. CONCLUSIONS: The results confirm suicidality is highly prevalent in both autistic and possibly autistic people without co-occurring intellectual disability and highlights potential moderators. Possibly autistic individuals require more attention in clinical and research considerations going forward to further understand and prevent suicide in both groups.

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25. Pye K, Jackson H, Iacono T, Shiell A. Economic Evaluation of Early Interventions for Autistic Children: A Scoping Review. Journal of autism and developmental disorders. 2023.

Many autistic children access some form of early intervention, but little is known about the value for money of different programs. We completed a scoping review of full economic evaluations of early interventions for autistic children and/or their families. We identified nine studies and reviewed their methods and quality. Most studies involved behavioral interventions. Two were trial-based, and the others used various modelling methods. Clinical measures were often used to infer dependency levels and quality-adjusted life-years. No family-based or negative outcomes were included. Authors acknowledged uncertain treatment effects. We conclude that economic evaluations in this field are sparse, methods vary, and quality is sometimes poor. Economic research is needed alongside longer-term clinical trials, and outcome measurement in this population requires further exploration.

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26. Ranganath P, Dalal A. Does Every Child With Autism Need Investigations for Inborn Errors of Metabolism?. Indian pediatrics. 2023; 60(3): 177-8.

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27. Sabzevari F, Amelirad O, Moradi Z, Habibi M. Artificial intelligence evaluation of COVID-19 restrictions and speech therapy effects on the autistic children’s behavior. Scientific reports. 2023; 13(1): 4312.

In the present study, we aimed to quantify the effects of COVID-19 restrictions and speech treatment approaches during lockdowns on autistic children using CBCL and neuro-fuzzy artificial intelligence method. In this regard, a survey including CBCL questionnaire is prepared using online forms. In total, 87 children with diagnosed Autism spectrum disorders (ASD) participated in the survey. The influences of three treatment approaches of in-person, telehealth and public services along with no-treatment condition during lockdown were the main factors of the investigation. The main output factors were internalized and externalized problems in general and their eight subcategory syndromes. We examined the reports by parents/caregivers to find correlation between treatments and CBCL listed problems. Moreover, comparison of the eight syndromes rating scores from pre-lockdown to post-lockdown periods were performed. In addition, artificial intelligence method were engaged to find the influence of speech treatment during restrictions on the level of internalizing and externalizing problems. In this regard, a fully connected adaptive neuro fuzzy inference system is employed with type and duration of treatments as input and T-scores of the syndromes are the output of the network. The results indicate that restrictions alleviate externalizing problems while intensifying internalizing problems. In addition, it is concluded that in-person speech therapy is the most effective and satisfactory approach to deal with ASD children during stay-at-home periods.

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28. Song C, Broadie K. Fragile X mental retardation protein coordinates neuron-to-glia communication for clearance of developmentally transient brain neurons. Proceedings of the National Academy of Sciences of the United States of America. 2023; 120(12): e2216887120.

In the developmental remodeling of brain circuits, neurons are removed by glial phagocytosis to optimize adult behavior. Fragile X mental retardation protein (FMRP) regulates neuron-to-glia signaling to drive glial phagocytosis for targeted neuron pruning. We find that FMRP acts in a mothers against decapentaplegic (Mad)-insulin receptor (InR)-protein kinase B (Akt) pathway to regulate pretaporter (Prtp) and amyloid precursor protein-like (APPL) signals directing this glial clearance. Neuronal RNAi of Drosophila fragile X mental retardation 1 (dfmr1) elevates mad transcript levels and increases pMad signaling. Neuronal dfmr1 and mad RNAi both elevate phospho-protein kinase B (pAkt) and delay neuron removal but cause opposite effects on InR expression. Genetically correcting pAkt levels in the mad RNAi background restores normal remodeling. Consistently, neuronal dfmr1 and mad RNAi both decrease Prtp levels, whereas neuronal InR and akt RNAi increase Prtp levels, indicating FMRP works with pMad and insulin signaling to tightly regulate Prtp signaling and thus control glial phagocytosis for correct circuit remodeling. Neuronal dfmr1 and mad and akt RNAi all decrease APPL levels, with the pathway signaling higher glial endolysosome activity for phagocytosis. These findings reveal a FMRP-dependent control pathway for neuron-to-glia communication in neuronal pruning, identifying potential molecular mechanisms for devising fragile X syndrome treatments.

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29. Stogios N, Hahn MK, Lunsky Y, Desarkar P, Agarwal SM. Metformin for the treatment of antipsychotic-induced metabolic disturbances in people with intellectual and developmental disabilities. Journal of psychiatry & neuroscience : JPN. 2023; 48(2): E99-e101.

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30. Thom RP, McDougle CJ. Repetitive Thoughts and Behaviors in Autism Spectrum Disorder: A Symptom-Based Framework for Novel Therapeutics. ACS chemical neuroscience. 2023; 14(6): 1007-16.

While the core symptoms of autism spectrum disorder include repetitive thoughts and repetitive behaviors, repetitive phenomena also occur in many other psychiatric disorders. Types of repetitive thoughts include preoccupations, ruminations, obsessions, overvalued ideas, and delusions. Types of repetitive behaviors include tics, stereotypies, compulsions, extrapyramidal symptoms, and automatisms. We provide a description of how to recognize and classify different types of repetitive thoughts and behaviors in autism spectrum disorder, providing clarity on which phenomena should be considered a core feature of autism spectrum disorder and which phenomena are indicative of a comorbid psychiatric disorder. Clinical features that can be used to differentiate types of repetitive thoughts include whether they are distressing and the degree of insight the individual has, while repetitive behaviors can be classified based on whether they are voluntary, goal-directed/purposeful, and rhythmic. We present the psychiatric differential diagnosis of repetitive phenomena within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) framework. Careful clinical consideration of these transdiagnostic features of repetitive thoughts and behaviors can improve diagnostic accuracy and treatment outcomes, and influence future research.

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31. Turner KM, Weiss JA, Howe SJ, Sanguino H, Kerns CM, Ames ME, McMorris CA. Autistic characteristics and mental health symptoms in autistic youth during the first COVID-19 wave in Canada. Autism research : official journal of the International Society for Autism Research. 2023.

Autistic youth are at heightened risk for mental health issues, and pandemic-related stressors may exacerbate this risk. This study (1) described caregiver-reported youth mental health prior to and during the pandemic; and (2) explored individual, caregiver, and environmental factors associated with changes in autistic characteristics, social-emotional symptoms, and overall mental health. 582 caregivers of autistic children (2-18 years old) completed an online survey between June and July 2020 in which they provided demographic information, their child’s pre-COVID and current mental health, autistic characteristics, and social-emotional symptoms. Caregivers also rated their own perceived stress, and COVID-related household and service disruption. According to caregivers, youth experienced more autistic characteristics and social-emotional concerns during the pandemic. Autistic youth were also reported to experience poorer overall mental health during the pandemic than before the pandemic. Older youth whose caregiver’s indicated higher perceived stress and greater household disruption were reported to experience more autistic traits during pandemic. Caregiver-reported increases in youth social-emotional symptoms (i.e., behavior problems, anxiety, and low mood) was associated with being older, the presence of a pre-existing mental health condition, higher caregiver stress, and greater household and service disruption. Finally, experiencing less household financial hardship prior to COVID-19, absence of a pre-existing psychiatric condition, less caregiver stress, and less service disruption were associated with better youth pandemic mental health. Strategies to support the autistic community during and following the pandemic need to be developed. The developmental-ecological factors identified in this study could help target support strategies to those autistic youth who are most vulnerable to mental health problems.

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32. Wang B, Li YD, Wang ZY, Zhao JQ, Zhang GQ, Man MQ. Alterations in Epidermal Biophysical Properties in Autistic Children. Skin pharmacology and physiology. 2023.

Autism is a neurodevelopmental disorder. Individuals with autism can exhibit multiple neurological symptoms such as deficit in social communication, restricted interests and repetitive behaviors. Recent study showed that murine model of autism displays an increased transepidermal water loss (TEWL) and dry skin. But whether epidermal functions are also altered in children with autism is unknown. In the present study, TEWL, stratum corneum hydration and skin surface pH were compared between children with autism (N=56) and normal controls (N=48). Our results showed that children with autism exhibited lower stratum corneum hydration levels, higher TEWL and elevated skin surface pH in comparison to normal controls (p<0.0001 for all). These results demonstrate that children with autism exhibit epidermal dysfunction.

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33. Zhang X, Liu S, Liu X, Wang J. Inhibiting silence information regulator 2 and glutaminase in the amygdala can improve social behavior in autistic rats. Zhejiang da xue xue bao Yi xue ban = Journal of Zhejiang University Medical sciences. 2022; 51(6): 707-15.

OBJECTIVE: To investigate the underlying molecular mechanisms by which silence information regulator (SIRT) 2 and glutaminase (GLS) in the amygdala regulate social behaviors in autistic rats. METHODS: Rat models of autism were established by maternal sodium valproic acid (VPA) exposure in wild-type rats and SIRT2-knockout ( SIRT2 (-/-)) rats. Glutamate (Glu) content, brain weight, and expression levels of SIRT2, GLS proteins and apoptosis-associated proteins in rat amygdala at different developmental stages were examined, and the social behaviors of VPA rats were assessed by a three-chamber test. Then, lentiviral overexpression or interference vectors of GLS were injected into the amygdala of VPA rats. Brain weight, Glu content and expression level of GLS protein were measured, and the social behaviors assessed. RESULTS: Brain weight, amygdala Glu content and the levels of SIRT2, GLS protein and pro-apoptotic protein caspase-3 in the amygdala were increased in VPA rats, while the level of anti-apoptotic protein Bcl-2 was decreased (all P<0.01). Compared with the wild-type rats, SIRT2 (-/-) rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala, reduced Glu content, and improved social dysfunction (all P<0.01). Overexpression of GLS increased brain weight and Glu content, and aggravated social dysfunction in VPA rats (all P<0.01). Knockdown of GLS decreased brain weight and Glu content, and improved social dysfunction in VPA rats (all P<0.01). CONCLUSIONS: The glutamate circulatory system in the amygdala of VPA induced autistic rats is abnormal. This is associated with the upregulation of SIRT2 expression and its induced increase of GLS production; knocking out SIRT2 gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.

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34. Zlatnik K, Milliken A, Weaver M, Sideridis G, Harris H, Harstad E. Gastrointestinal and Sleep Issues in Toddlers With Autism Versus Other Neurodevelopmental Disorders. Clinical pediatrics. 2023: 99228231156774.

Neurodevelopmental disorders (NDDs) are frequently associated with gastrointestinal symptoms (GIS) and sleep issues, but there are insufficient data on the occurrence of these symptoms in young children with autism spectrum disorder (ASD) compared with other NDDs. We abstracted data on 500 children aged 18 to 36 months with ASD and 146 children aged 18 to 47 months with non-ASD NDDs to compare the frequency of these symptoms. In the overall sample, there was a high rate of GIS (46.0%) and sleep difficulties (22.6%). In age-adjusted analyses, children with non-ASD NDDs were more likely to have GIS (61.0% vs 41.6%; adjusted odds ratio [OR] = 2.35; 95% confidence interval = 1.56-3.56) and sleep difficulties (34.9% vs 19.0%; adjusted OR = 2.08; 95% confidence interval = 1.33-3.26) compared with those with ASD. These findings demonstrate the need to assess these symptoms in all young children with developmental concerns to provide appropriate guidance to their families.

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