1. An KM, Ikeda T, Hirosawa T, Yaoi K, Yoshimura Y, Hasegawa C, Tanaka S, Saito DN, Kikuchi M. Decreased grey matter volumes in unaffected mothers of individuals with autism spectrum disorder reflect the broader autism endophenotype. Scientific reports. 2021; 11(1): 10001.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an early onset and a strong genetic origin. Unaffected relatives may present similar but subthreshold characteristics of ASD. This broader autism phenotype is especially prevalent in the parents of individuals with ASD, suggesting that it has heritable factors. Although previous studies have demonstrated brain morphometry differences in ASD, they are poorly understood in parents of individuals with ASD. Here, we estimated grey matter volume in 45 mothers of children with ASD (mASD) and 46 age-, sex-, and handedness-matched controls using whole-brain voxel-based morphometry analysis. The mASD group had smaller grey matter volume in the right middle temporal gyrus, temporoparietal junction, cerebellum, and parahippocampal gyrus compared with the control group. Furthermore, we analysed the correlations of these brain volumes with ASD behavioural characteristics using autism spectrum quotient (AQ) and systemizing quotient (SQ) scores, which measure general autistic traits and the drive to systemize. Smaller volumes in the middle temporal gyrus and temporoparietal junction correlated with higher SQ scores, and smaller volumes in the cerebellum and parahippocampal gyrus correlated with higher AQ scores. Our findings suggest that atypical grey matter volumes in mASD may represent one of the neurostructural endophenotypes of ASD.

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2. Hansén-Larson J, Bejnö H, Jägerskogh E, Eikeseth S, Klintwall L. TRAS: Validity and sensitivity of a language assessment tool for children with ASD. Scandinavian journal of psychology. 2021; 62(4): 522-8.

Interventions for preschool children with autism typically require professionals and parents to identify which social and language skills the individual child shows deficits in. Many assessment tools aimed at identifying such deficits exist, but they often require extensive training to use. The present study investigated the potential usefulness for said assessment purposes of the Norwegian assessment tool, TRAS – « Tidig Registrering Av Språkutveckling » (i.e. Nordic acronym for assessment of early language development), which can be used by preschool teachers without any specific training. Participants were 54 children with ASD, aged 2-5 years, enrolled in a behavioral intervention program. Participants were scored using TRAS at three time points during treatment to investigate TRAS’ sensitivity for detecting change. Only participants who had TRAS scores registered at all three time points were used for this analysis (n = 27). At intake, children were also scored using the Vineland Adaptive Behavior Scales, the results of which was then compared to TRAS scores. Results showed that TRAS scores increased significantly across time points, indicating that the tool is sensitive to treatment effects. TRAS scores also correlated significantly with Vineland communication subscale (n = 50), indicating that the measure can be used to measure language abilities in children with ASD. We conclude that TRAS is a potential alternative to more comprehensive language assessment tools for children with ASD.

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3. Jellett R, Muggleton J. Correction to: Implications of Applying « Clinically Significant Impairment » to Autism Assessment: Commentary on Six Problems Encountered in Clinical Practice. Journal of autism and developmental disorders. 2022; 52(3): 1422.

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4. Kojic M, Gawda T, Gaik M, Begg A, Salerno-Kochan A, Kurniawan ND, Jones A, Drożdżyk K, Kościelniak A, Chramiec-Głąbik A, Hediyeh-Zadeh S, Kasherman M, Shim WJ, Sinniah E, Genovesi LA, Abrahamsen RK, Fenger CD, Madsen CG, Cohen JS, Fatemi A, Stark Z, Lunke S, Lee J, Hansen JK, Boxill MF, Keren B, Marey I, Saenz MS, Brown K, Alexander SA, Mureev S, Batzilla A, Davis MJ, Piper M, Bodén M, Burne THJ, Palpant NJ, Møller RS, Glatt S, Wainwright BJ. Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype. Nature communications. 2021; 12(1): 2678.

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

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5. Longo F, Klann E. Reciprocal control of translation and transcription in autism spectrum disorder. EMBO reports. 2021; 22(6): e52110.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted patterns of interest and repetitive behaviors. ASD is genetically heterogeneous and is believed to be caused by both inheritable and de novo gene variations. Studies have revealed an extremely complex genetic landscape of ASD, favoring the idea that mutations in different clusters of genes interfere with interconnected downstream signaling pathways and circuitry, resulting in aberrant behavior. In this review, we describe a select group of candidate genes that represent both syndromic and non-syndromic forms of ASD and encode proteins that are important in transcriptional and translational regulation. We focus on the interplay between dysregulated translation and transcription in ASD with the hypothesis that dysregulation of each synthetic process triggers a feedback loop to act on the other, which ultimately exacerbates ASD pathophysiology. Finally, we summarize findings from interdisciplinary studies that pave the way for the investigation of the cooperative impact of different genes and pathways underlying the development of ASD.

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6. Noel JP, Zhang LQ, Stocker AA, Angelaki DE. Individuals with autism spectrum disorder have altered visual encoding capacity. PLoS biology. 2021; 19(5): e3001215.

Perceptual anomalies in individuals with autism spectrum disorder (ASD) have been attributed to an imbalance in weighting incoming sensory evidence with prior knowledge when interpreting sensory information. Here, we show that sensory encoding and how it adapts to changing stimulus statistics during feedback also characteristically differs between neurotypical and ASD groups. In a visual orientation estimation task, we extracted the accuracy of sensory encoding from psychophysical data by using an information theoretic measure. Initially, sensory representations in both groups reflected the statistics of visual orientations in natural scenes, but encoding capacity was overall lower in the ASD group. Exposure to an artificial (i.e., uniform) distribution of visual orientations coupled with performance feedback altered the sensory representations of the neurotypical group toward the novel experimental statistics, while also increasing their total encoding capacity. In contrast, neither total encoding capacity nor its allocation significantly changed in the ASD group. Across both groups, the degree of adaptation was correlated with participants’ initial encoding capacity. These findings highlight substantial deficits in sensory encoding-independent from and potentially in addition to deficits in decoding-in individuals with ASD.

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7. Pan W, Xu X, Zhang M, Song X. Human urine-derived stem cell-derived exosomal miR-21-5p promotes neurogenesis to attenuate Rett syndrome via the EPha4/TEK axis. Laboratory investigation; a journal of technical methods and pathology. 2021; 101(7): 824-36.

Rett syndrome (RTT) is a rare neurodevelopmental disorder that results in multiple disabilities. Exosomal microRNA (miRs) from urine-derived stem cells (USCs) have been shown to induce neurogenesis and aid in functional recovery from brain ischemia. In the present study, we sought to determine whether that exosomal miR-21-5p from USCs could promote early neural formation in a model of RTT. USCs were isolated and evaluated by flow cytometry. Exosomes were analyzed by transmission electron microscopy, tunable resistive pulse sensing (TRPS), and western blotting. PKH26 fluorescent dyes were used to observe intake of exosomes in vivo and in vitro. An RTT mouse model was treated with exosomes for behavioral studies. Dual-luciferase report gene assays were conducted to evaluate the relationship between miR-21-5p and Eph receptor A4 (EphA4). In vitro, treatment with exosomes from human urine-derived stem cells (USC-Exos) increased the percentage of neuron-specific class III beta-tubulin (Tuj1)(+) nerve cells as well as the transcription levels of β-III tubulin and doublecortin (DCX). A higher level of miR-21-5p was observed in USC-Exos, which promoted differentiation in NSCs by targeting the EPha4/TEK axis. In vivo, exosomal miR-21-5p improved the behavior, motor coordination, and cognitive ability of mice, facilitated the differentiation of NSCs in the subventricular zone of the lateral ventricle and promoted a marked rise in the number of DCX(+) cells. Our data provide evidence that exosomal miR-21-5p from human USCs facilitate early nerve formation by regulating the EPha4/TEK axis.

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8. Prior I. Ras Variant Biology and Contributions to Human Disease. Methods in molecular biology (Clifton, NJ). 2021; 2262: 3-18.

Analysis of cancer and RASopathy genetic databases reveals that ~19% of all cancer cases and ~4% of developmental disorders contain Ras mutations. Ras isoform and mutation variants differentially contribute to these diseases and provide an opportunity for deeper understanding of Ras function. The putative mechanisms underpinning these differences, new approaches that are being applied, and some of the key questions and challenges that remain are discussed.

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9. Santos PA, Bordini D, Scattolin M, Asevedo G, Caetano SC, Paula CS, Perissinoto J, Tamanaha AC. The Impact of the Implementation of the Picture Exchange Communication System – PECS on Understanding Instructions in Children with Autism Spectrum Disorders. CoDAS. 2021; 33(2): e20200041.

PURPOSE: The purpose of this study was to analyze the impact of the implementation of the Picture Exchange Communication System (PECS) on the comprehension of instructions by children with Autism Spectrum Disorder (ASD). METHODS: This is a longitudinal study (N° 0809/2018). The sample consisted of 20 children with nonverbal ASDs, 15 boys and 5 girls, aged 6 to 12 years, evaluated and diagnosed by a multidisciplinary team according to the DSM-5. For assessment of the comprehension of instructions, we used eight visual instructions and eight oral instructions, which were applied at two points in the PECS Implementation Program: early phases II and IV. The program consisted of 24 individual speech therapy sessions with the presence of a family member and followed the six phases originally proposed by the PECS Training Manual. RESULTS: There was an expressive increase in the comprehension of all instructions, in the comparison between the two moments of the study; and this increase was statistically significant in six of the oral instructions (p=0.001) and five of the visual ones (p=0.002). CONCLUSION: It was possible to observe the positive impact of the use of PECS in the comprehension of both visual and oral instructions, showing that this system not only provides an augmentative or alternative communication tool for the children to express themselves but also promotes significant improvement in the understanding of contextual information.

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10. Sheehan R, Dalton-Locke C, Ali A, Vera San Juan N, Totsika V, Hassiotis A. Effects of the COVID-19 pandemic on mental healthcare and services: results of a UK survey of front-line staff working with people with intellectual disability and/or autism. BJPsych bulletin. 2021: 1-7.

AIMS AND METHOD: Mental health services have changed the way they operate during the COVID-19 pandemic. We investigated the challenges and innovations reported by staff working in services for people with intellectual disability and/or autism in National Health Service (NHS) and non-NHS sectors, and in in-patient and community settings. RESULTS: Data were drawn from 648 staff who participated in a UK-wide online survey. Issues around infection risk and mitigation were more important to those working in the NHS and in-patient settings. Community staff were more likely to express concern about the practicalities of a rapid shift to remote working and engaging patients remotely. Qualitative data revealed support for maintaining remote staff working and remote service provision post-pandemic. CLINICAL IMPLICATIONS: Given the current emphasis on community support for people with intellectual disability and/or autism, the focus of research and clinical practice should be the development of accessible and effective models of remote service provision.

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11. Wang L, Tang S, Wu S, Yao L, Su D, Wang Y. Maternal Exposure to Pesticides and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis. Journal of autism and developmental disorders. 2022; 52(4): 1640-51.

This meta-analysis was conducted to estimate the overall association between maternal exposure to pesticides and risk of ASD in offspring. PubMed, EMBASE, Web of Science, and the PsycINFO were searched until December 30, 2020 to include eligible studies. Eight studies with 50,426 participants, 5810 of whom had ASD, were involved in the study. Overall, the summary OR (95% confidence interval) of ASDs in offspring for maternal exposure to pesticide estimated by residential proximity measures and self-report was 1.88 (1.10-3.20). However, maternal exposure to pesticide measured by biomarkers was not associated with an increased risk of ASDs (pooled OR 1.13; 95% CI 0.83-1.54). Further well-designed studies are needed to confirm our findings.

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