1. Anbar J, Matthews N, James S, Ariff A, Pierce K, Smith CJ. Examination of Clinical and Assessment Type Differences Between Toddlers with ASD from Multiplex and Simplex Families. Journal of autism and developmental disorders. 2023.

Few studies have examined differences in autism spectrum disorder (ASD) phenotype between children from multiplex and simplex families at the time of diagnosis. The present study used an age- and gender-matched, community-based sample (n = 105) from the southwestern United States to examine differences in ASD symptom severity, cognitive development, and adaptive functioning. No significant differences between children from multiplex and simplex families were observed. Exploratory analysis revealed that parents underreported receptive and expressive language and fine motor skills compared to professional observation, especially among children from multiplex families. These findings suggest that diagnosticians may need to consider family structure when choosing and interpreting assessments of receptive language, expressive language, and fine motor skills.

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2. Badia M, Pérez B, Orgaz BM, Gómez-Vela M. Leisure education in youth with developmental disabilities: Effects on individual quality of life, adaptive behavior, and family quality of life. Journal of intellectual disabilities : JOID. 2023: 17446295231168442.

Leisure participation enhances the learning of adaptive skills and the quality of life in youth with developmental disabilities. The goal of this study was to evaluate the effects of a leisure education program in individuals with developmental disabilities in terms of adaptive behavior and quality of life. Nine participants divided into two small groups and their families were included. A quasi-experimental design was employed to determine whether there was a program effect. The Adaptive Behavior Assessment System, the KIDSCREEN-27, and the Family Quality of Life Scale were administered before and after the intervention. There was a significant increase in social, home, and school skills as well as a better perception of quality of life in relationships with parents, social support, and school. In addition, the program affected the family’s perception of practical and emotional support. Findings provide support for the application of this leisure program to enhance quality of life outcomes.

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3. Cao X, Tang X, Feng C, Lin J, Zhang H, Liu Q, Zheng Q, Zhuang H, Liu X, Li H, Khan NU, Shen L. A Systematic Investigation of Complement and Coagulation-Related Protein in Autism Spectrum Disorder Using Multiple Reaction Monitoring Technology. Neuroscience bulletin. 2023.

Autism spectrum disorder (ASD) is one of the common neurodevelopmental disorders in children. Its etiology and pathogenesis are poorly understood. Previous studies have suggested potential changes in the complement and coagulation pathways in individuals with ASD. In this study, using multiple reactions monitoring proteomic technology, 16 of the 33 proteins involved in this pathway were identified as differentially-expressed proteins in plasma between children with ASD and controls. Among them, CFHR3, C4BPB, C4BPA, CFH, C9, SERPIND1, C8A, F9, and F11 were found to be altered in the plasma of children with ASD for the first time. SERPIND1 expression was positively correlated with the CARS score. Using the machine learning method, we obtained a panel composed of 12 differentially-expressed proteins with diagnostic potential for ASD. We also reviewed the proteins changed in this pathway in the brain and blood of patients with ASD. The complement and coagulation pathways may be activated in the peripheral blood of children with ASD and play a key role in the pathogenesis of ASD.

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4. Che X, Roy A, Bresnahan M, Mjaaland S, Reichborn-Kjennerud T, Magnus P, Stoltenberg C, Shang Y, Zhang K, Susser E, Fiehn O, Lipkin WI. Metabolomic analysis of maternal mid-gestation plasma and cord blood in autism spectrum disorders. Molecular psychiatry. 2023.

The discovery of prenatal and neonatal molecular biomarkers has the potential to yield insights into autism spectrum disorder (ASD) and facilitate early diagnosis. We characterized metabolomic profiles in ASD using plasma samples collected in the Norwegian Autism Birth Cohort from mothers at weeks 17-21 gestation (maternal mid-gestation, MMG, n = 408) and from children on the day of birth (cord blood, CB, n = 418). We analyzed associations using sex-stratified adjusted logistic regression models with Bayesian analyses. Chemical enrichment analyses (ChemRICH) were performed to determine altered chemical clusters. We also employed machine learning algorithms to assess the utility of metabolomics as ASD biomarkers. We identified ASD associations with a variety of chemical compounds including arachidonic acid, glutamate, and glutamine, and metabolite clusters including hydroxy eicospentaenoic acids, phosphatidylcholines, and ceramides in MMG and CB plasma that are consistent with inflammation, disruption of membrane integrity, and impaired neurotransmission and neurotoxicity. Girls with ASD have disruption of ether/non-ether phospholipid balance in the MMG plasma that is similar to that found in other neurodevelopmental disorders. ASD boys in the CB analyses had the highest number of dysregulated chemical clusters. Machine learning classifiers distinguished ASD cases from controls with area under the receiver operating characteristic (AUROC) values ranging from 0.710 to 0.853. Predictive performance was better in CB analyses than in MMG. These findings may provide new insights into the sex-specific differences in ASD and have implications for discovery of biomarkers that may enable early detection and intervention.

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5. Geng J, Khaket TP, Pan J, Li W, Zhang Y, Ping Y, Cobos Sillero MI, Lu B. Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome. Developmental cell. 2023; 58(7): 597-615.e10.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca(2+)) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca(2+) transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca(2+) homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca(2+) homeostasis as contributors to FXS and offer potential therapeutic targets.

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6. Guan L, Li J, Zhang Z, Huang A, Ke X. Neurofibromatosis Type I and autism spectrum disorder caused by deletion of the NF1 gene: A case report. Asian journal of psychiatry. 2023; 84: 103544.

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7. Hsu TW, Liang CS, Tsai SJ, Bai YM, Su TP, Chen TJ, Chen MH. Risk of Major Psychiatric Disorders Among Children and Adolescents Surviving Malignancies: A Nationwide Longitudinal Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023; 41(11): 2054-66.

PURPOSE: Evidence suggests an increased long-term risk of major psychiatric disorders (MPDs) in childhood and adolescent cancer survivors (CACSs). However, definitive conclusions regarding such associations and whether such associations vary for different types of cancers remain unclear. METHODS: Using a nationwide data set from 2001 to 2011, we enrolled CACSs and likewise randomly selected individuals without cancer from the general population (1:10 ratio) who were matched to the CACSs with regard to demographic data. We investigated eight organ system-related cancers. The primary outcomes were the risks of seven MPD diagnoses: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder. RESULTS: CACSs (n = 5,121; mean age = 9.08 years) showed increased risks of six MPD diagnoses than controls (n = 51,210), with results as follows (in descending order): ASD (hazard ratio [HR], 10.42; associated 95% CI, 4.58 to 23.69), ADHD (HR, 6.59; 95% CI, 4.91 to 8.86), BD (HR, 2.93; 95% CI, 1.26 to 6.80), MDD (HR, 1.88; 95% CI, 1.26 to 2.79), OCD (HR, 3.37; 95% CI, 1.33 to 8.52), and post-traumatic stress disorder (HR, 6.10; 95% CI, 1.46 to 25.54). CACSs also showed earlier ages at diagnoses of ADHD, schizophrenia, MDD, and OCD than controls. The risks of MPD diagnoses vary according to specific cancer types/categories. Brain cancer and lymphatic/hematopoietic tissue cancer were associated with the greatest number of MPD diagnoses (ie, each was associated with six diagnoses). In addition, ASD and ADHD were associated with most organ system-related cancers (ie, each was associated with five categories). CONCLUSION: We found that CACSs were at higher risks of MPD diagnoses than controls. Follow-up care should include psychosocial interventions focusing on early signs of mental health problems and early interventions in this high-risk group.

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8. Ma Y, Lee LY, Zhang X. Affiliate stigma and related factors among parents of autism spectrum condition: A pilot study from mainland China. Autism & developmental language impairments. 2023; 8: 23969415231168567.

BACKGROUND: Autistic individuals show differences in social and behavioral performances. Autism-related stigma affects autistic children as well as their caregivers (e.g., parents). Research has shown that stigmatizing reactions from others toward caregivers of autistic children are common and that these caregivers suffer from affiliate stigma. AIMS: To examine the level of affiliate stigma among parents of autistic children and its predictive factors in mainland China. METHODS: This was a cross-sectional study involving parents of autistic children from mainland China. The sample consisted of 183 parents (mean age  =  36.5 years). The measures assessed included demographic characteristics, and parents completed two questionnaires. The Social Responsiveness Scale (SRS) was used to evaluate the characteristics of children by their parent’s subjective assessments, and the Affiliate Stigma Scale (ASS) was used to investigate the affiliate stigma level of parents. RESULTS: The affiliate stigma levels of parents of autistic children were high, and the mean score of the affect subscale was higher than those of the other subscales. The mean ASS score differed significantly between employed and unemployed parents, those aged under 40 and over 40, and high- and low-income parents. The hierarchical regression analysis showed that parents’ age, monthly household income, and mean SRS score were significant predictors of the mean ASS score. The results indicated that parents of autistic children and their children need more social support and inclusion in mainland China. CONCLUSION: The present study confirms the importance of studying primary caregivers (i.e., parents) in the context of traditional mainland Chinese culture. Although preliminarily, findings showed that the affiliate stigma levels of parents are high in mainland China, probably due to the influence of traditional cultural values. Moreover, considering the importance of autistic child characteristics, our results suggest that we should increase public knowledge of autism, enrich the general understanding of autism, and reduce the autism-related stigma of parents in mainland Chinese societies.

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9. Madigand J, Rio M, Vandevelde A. Equine assisted services impact on social skills in autism spectrum disorder: A meta-analysis. Progress in neuro-psychopharmacology & biological psychiatry. 2023; 125: 110765.

Many studies focus on the impact of equine assisted services (EAS) on social skills in autism spectrum disorder (ASD) but existing data are not consensual and the only available meta-analysis included only three studies and did not consider the social responsiveness scale (SRS). This meta-analysis aims to measure the impact of EAS on social skills in ASD. Using Pubmed, Embase, Web of Science and the Cochrane Library, the means and standard deviations of every available SRS post-intervention scores in each participant group were collected from the five selected randomised controlled trials with 240 participants. An EAS significant beneficial impact was found for the total SRS score, social communication and social cognition. A tendency to a significant impact was found for social awareness and social motivation. No significant difference was shown for autistic mannerisms. This meta-analysis shows a significant beneficial impact of EAS for several social skills in ASD. Further randomised controlled trials are required to complement these results and expand the knowledge on the field of possibilities of this care in ASD.

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10. McGlade A, Whittingham K, Barfoot J, Taylor L, Boyd RN. Efficacy of very early interventions on neurodevelopmental outcomes for infants and toddlers at increased likelihood of or diagnosed with autism: A systematic review and meta-analysis. Autism research : official journal of the International Society for Autism Research. 2023.

The aim of this systematic review was to determine the efficacy of very early interventions for infants and toddlers at increased likelihood of or diagnosed with autism for autism symptomatology, developmental outcomes and/or neurocognitive markers. Eight databases were searched (14 April 2022) with inclusion criteria: (i) RCTs with care as usual (CAU) comparison group, (ii) participants at increased likelihood of or diagnosed with autism and aged <24 months corrected age (CA), (iii) parent-mediated and/or clinician directed interventions, and (iv) outcome measures were autism symptomatology, cognition, language, adaptive skills, or neurocognitive assessments (EEG and eye tracking). Quality was assessed using Risk of Bias 2 and GRADE. Nineteen publications from 12 studies reported on 715 infants and toddlers. There was low to moderate certainty evidence that clinician-assessed outcomes did not show significant treatment effects for: autism symptomatology (ADOS CSS: MD -0.08, 95% CI -0.61, 0.44, p = 0.75), cognitive outcome (Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC): SMD 0.05, 95% CI -0.19, 0.29, p = 0.67), receptive language (MSEL-Receptive Language: SMD 0.04, 95% CI -0.21, 0.3, p = 0.74) or expressive language (MSEL-Expressive Language: SMD 0.06, 95% CI -0.1, 0.23, p = 0.45). Neurocognitive outcomes (EEG and eye tracking) were heterogeneous, with inconsistent findings. There is low to moderate certainty evidence that very early interventions have limited impact on neurodevelopmental outcomes by age 3 years.

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11. Meng F, Xuan B. Reliability and validity of the Chinese version of the Comprehensive Autistic Trait Inventory-short form (CATI-SF-C) in the general population. Asian journal of psychiatry. 2023; 84: 103580.

The current study aims to provide psychometric analyses of a shortened version of the Comprehensive Autistic Trait Inventory (CATI) from three different samples administered to 4910 Chinese populations (56.864 % females, mean age 19.857 ± 4.083) aged 14-56. The factor structure of CATI in Chinese was examined by confirmatory factor analysis and exploratory structural equation modeling, and a 24-item Chinese version short form of CATI (CATI-SF-C) was developed. The validity (structure validity, convergent validity, and discriminant validity) and reliability (internal consistency and test-retest reliability) were evaluated, and the predictive ability for classifying autism was examined (Youden’s Index = 0.690). According to these findings, the CATI-SF-C is a reliable and valid autistic traits assessment tool for the general population.

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12. Qi N, Yang K, Lei X, Wang F, Wu D, Gao Y, Zhang Y, Liao S. [Clinical and genetic analysis of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2023; 40(4): 408-12.

OBJECTIVE: To explore the clinical features and genetic etiology of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Two children with MICPCH who were presented at the Henan Provincial People’s Hospital between April 2019 and December 2021 were selected as the study subjects. Clinical data of the two children were collected, along with peripheral venous blood samples of them and their parents, and amniotic fluid sample of the mother of child 1. Whole exome sequencing (WES), array-comparative genomic hybridization (aCGH) and real-time quantitative PCR (qPCR) were carried out for the children, their parents and the fetus. The pathogenicity of candidate variants were evaluated. RESULTS: Child 1 was a 6-year-old girl featuring motor and language delay, whilst child 2 was a 4.5-year-old girl mainly featuring microcephaly and mental retardation. WES revealed that child 2 has harbored a 158.7 kb duplication in Xp11.4 (chrX: 41446160_41604854), which has encompassed exons 4~14 of the CASK gene. The same duplication was not found in either of her parents. aCGH revealed that child 1 has harbored a 29 kb deletion at Xp11.4 (chrX: 41637892_41666665), which encompassed exon 3 of the CASK gene. The same deletion was not found in either of her parents and the fetus. The above results were confirmed by qPCR assay. Above deletion and duplication were not found in the ExAC, 1000 Genomes and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PS2+PM2_Supporting). CONCLUSION: The deletion of exon 3 and duplication of exons 4~14 of the CASK gene probably underlay the pathogenesis of MICPCH in these two children, respectively.

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13. Quetsch LB, Brown C, Onovbiona H, Bradley R, Aloia L, Kanne S. Understanding aggression in autism across childhood: Comparisons with a non-autistic sample. Autism research : official journal of the International Society for Autism Research. 2023.

As many as half of all autistic youth face challenges with aggression. And while research in this area is growing, the prevalence and characterization of aggressive behaviors across autistic development remains poorly understood. This lack of knowledge on the autistic experience is further clouded as aggression is rarely compared against non-autistic youth samples. To address this gap in the literature, the present study compared autistic children (N = 450) to non-autistic children (N = 432) on multiple caregiver-report measures of aggressive behavior and associated constructs (i.e., anger, disruptive behavior) across key developmental periods (<6, 6-12, 13-17 years) via a cross-sectional design. Outcomes indicated higher levels of verbal aggression and behavioral intensity for autistic youth across development. Further, autistic children under age 6 had more significant levels of physical aggression than non-autistic peers; however, these levels became equal to non-autistic peers as the youths aged. Implications for differences in the presence of aggressive behavior as well as possible treatment options for aggression are discussed.

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14. Xi A, Cai SQ, Yan HF, Tian Y, Cai J, Yang XM, Wang JM, Xing GG. CSMD3 deficiency leads to motor impairments and autism-like behaviors via dysfunction of cerebellar Purkinje cells in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 (CSMD3) gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using male CSMD3-knock out (CSMD3(-/-) ) mice, we found that genetic deletion of CSMD3 produced core autistic-like symptoms (social interaction deficits, restricted interests, repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that CSMD3 gene can be considered as a candidate for ASD. Moreover, we discovered that ablation of CSMD3 in mice led to abnormal cerebellar Purkinje cells (PCs) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combining in vivo fiber photometry calcium imaging and ex vivo electrophysiological recordings, we showed that the CSMD3 (-/-) mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression (LTD) at the parallel fibers (PF)-PC synapse. These results suggest that CSMD3 plays an important role in cerebellar PCs development. Loss of CSMD3 causes abnormal PCs morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms in CSMD3 (-/-) mice. Our findings provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.Significance Statement:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains (CSMD) has been identified as a candidate gene for ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain largely unknown. Here, we unravel that loss of CSMD3 results in abnormal morphology, increased intrinsic excitabilities and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.

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