1. Anacker L, Edwards M, Nonnemacher S, Pinals DA. Attending to Persons with Intellectual and/or Other Developmental Disorders in Crisis Settings. Psychiatr Clin North Am;2024 (Sep);47(3):563-576.

Crisis response is growing across the United States with increasingly broad phone, text, and chat response systems that lead to triaging callers who may be in need of further outreach. This might include deploying a mobile crisis response team and/or referring a caller to a crisis stabilization unit. The information set forth earlier aims to help advance the field and individual practices to ensure that persons with intellectual and/or other developmental disorders receive equivalent care and treatment with information that helps focus on this population’s unique features and needs.

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2. BF AL, Alrashdi BAT, Mallick A, Alruwaili TAM, Alanazi MF, Alruwaili HFS, Alanazi WF, Alanazi WM, Altaymani AFM. Knowledge, Attitude, and Perception towards Autism Spectrum Disorders among Parents in Sakaka, Al-Jouf Region, Saudi Arabia: A Cross-Sectional Study. Healthcare (Basel);2024 (Aug 10);12(16)

Parents are an essential element of family intervention for all children, including those with autism spectrum disorders (ASDs). We can better understand and address parents’ knowledge gaps about ASD through in-depth research and inquiry into parents’ current level of understanding, attitude, and perception. We aimed to assess the knowledge, attitude, and perception of ASD and influencing factors towards ASD among a group of parents with and without a child diagnosed with ASD in Sakaka, Al-Jouf Region, Saudi Arabia. Using the cross-sectional study design, information from the parents was gathered using a pretested questionnaire that included validated scales for measuring knowledge, attitudes, and perceptions related to ASD. The required number of participants was selected using the convenience sampling method. We used Spearman’s correlation test to determine the strength and direction of correlation between each domain. As a last step, we analyzed the influencing factors using binomial logistic regression. Among the 400 participants, 41.2% had high knowledge, 69.1% had a positive attitude, and 60.3% had a high perception of ASD. We found that knowledge was significantly higher among the parents with autistic individuals in the family (p = 038). The high and positive attitude was significantly greater among females (p = 0.010) and parents with high income (p = 0.007), and the perception was significantly associated with females (p = 0.037) and highly educated participants (p = 0.046). Furthermore, we found a positive correlation between knowledge, attitude, and perception. Overall, only less than half of the participants had a high knowledge of ASD. Hence, we recommend awareness-raising programs for the parents in this region. Furthermore, a prospective study involving parents from all provinces of Saudi Arabia is recommended.

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3. Cary E, Arnold E. Early intervention in autism: where do we go from here?. Evid Based Nurs;2024 (Aug 9)

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4. Chang S, Liu JJ, Zhao Y, Pang T, Zheng X, Song Z, Zhang A, Gao X, Luo L, Guo Y, Liu J, Yang L, Lu L. Whole-genome sequencing identifies novel genes for autism in Chinese trios. Sci China Life Sci;2024 (Aug 7)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (P<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (SCN2A, NF1, SHANK3, CHD8 etc.), several high confidence genes were highlighted by a series of functional analyses, including CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1, and MRPL12, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of de novo variants found in patient was significantly associated with the parents' ages at the birth of the child, and gender with trend. We also identified small de novo structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.

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5. Compañ-Gabucio L, Torres-Collado L, García-de-la-Hera M. Dietary Patterns in Children with Neurodevelopmental Disorders. Nutrients;2024 (Jul 29);16(15)

Neurodevelopmental disorders (NDDs), of which Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are two of the most common, are described as a group of conditions that begin in the developmental period and lead to deficits that impair functioning […].

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6. Dennison CA, Shakeshaft A, Eyre O, Tilling K, Rice F, Thapar A. Investigating the neurodevelopmental correlates of early adolescent-onset emotional problems. J Affect Disord;2024 (Nov 1);364:212-220.

BACKGROUND: Emotional problems (EPs) increase sharply after mid-adolescence. Earlier EPs are associated with poorer long-term outcomes, and their underlying mechanisms may differ to later-onset EPs. Given an established relationship between ADHD, autism, and later depression, we aimed to examine associations between neurodevelopmental conditions and correlates and early adolescent-onset EPs. METHODS: Adolescents in two UK population cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) and Millennium Cohort Study (MCS), were included. Individuals scoring >6 on the Strengths and Difficulties Questionnaire (SDQ) emotional problems subscale between ages 11-14 were defined as having early adolescent-onset EP, whilst those scoring >6 for the first time at 16-25 were defined as having later-onset EP. We tested associations between early adolescent-onset EP (total cases = 887, controls = 19,582) and ICD-10/DSM-5 neurodevelopmental conditions and known correlates, including: sex, birth complications, low cognitive ability, special educational needs (SEND), and epilepsy. Analyses were conducted separately in ALSPAC and MCS then meta-analysed. RESULTS: In the meta-analysis of both cohorts, early adolescent-onset EPs were associated with female sex and greater likelihood of low cognitive ability, SEND, autism, ADHD, and reading difficulties. Compared to later-onset EP, early adolescent-onset EPs were associated with male sex, low cognitive ability, SEND, epilepsy, ASD, ADHD, and reading difficulties. LIMITATIONS: A clinical definition of depression/anxiety was available only in ALSPAC, instead we primarily defined EP via questionnaires, which capture a broader phenotype. CONCLUSIONS: Individuals with early adolescent-onset EP are likely to have a co-occurring neurodevelopmental condition. Clinicians should consider assessing for neurodevelopmental conditions in young adolescents with EPs.

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7. Gao Y, Shonai D, Trn M, Zhao J, Soderblom EJ, Garcia-Moreno SA, Gersbach CA, Wetsel WC, Dawson G, Velmeshev D, Jiang YH, Sloofman LG, Buxbaum JD, Soderling SH. Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions. Nat Commun;2024 (Aug 9);15(1):6801.

One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.

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8. Gevezova M, Ivanov Z, Pacheva I, Timova E, Kazakova M, Kovacheva E, Ivanov I, Sarafian V. Bioenergetic and Inflammatory Alterations in Regressed and Non-Regressed Patients with Autism Spectrum Disorder. Int J Mol Sci;2024 (Jul 27);25(15)

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

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9. Jiang Y, Li R, Li X. [Report of a child with Bainbridge-Ropers syndrome due to a novel variant of ASXL3 gene and a literature review]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi;2024 (Aug 10);41(8):966-972.

OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Bainbridge-Ropers syndrome (BRPS). METHODS: A child with BRPS who had visited Nanjing Children’s Hospital on June 26, 2019 was selected as the study subject. Clinical data of the child was reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child was a 6-month-old girl with peculiar facial features, feeding difficulties, malnutrition, global developmental delay, hypotonia, mildly elevated aminotransferase and ulnar deviation. Results of WES showed that she has harbored a c.1533_1534del variant of the ASXL3 gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. No similar case had been retrieved from the HGMD and ClinVar databases. No frequency for this variant among Asian populations was available in the ExAC, 1000 Genomes, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1533_1534del variant of the ASXL3 gene was determined to be likely pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION: The ASXL3 gene c.1533_1534del variant probably underlay the BRPS in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling for children with similar disorders.

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10. Kereszturi É. Database-assisted screening of autism spectrum disorder related gene set. Mol Brain;2024 (Aug 9);17(1):55.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social and communication difficulties, along with repetitive behaviors. While genetic factors play a significant role in ASD, the precise genetic landscape remains complex and not fully understood, particularly in non-syndromic cases. The study performed an in silico comparison of three genetic databases. ClinVar, SFARI Gene, and AutDB were utilized to identify relevant gene subset and genetic variations associated with non-syndromic ASD. Gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network analysis were conducted to elucidate the biological significance of the identified genes. The integrity of ASD-related gene subset and the distribution of their variations were statistically assessed. A subset of twenty overlapping genes potentially specific for non-syndromic ASD was identified. GSEA revealed enrichment of biological processes related to neuronal development and differentiation, synaptic function, and social skills, highlighting their importance in ASD pathogenesis. PPI network analysis demonstrated functional relationships among the identified genes. Analysis of genetic variations showed predominance of rare variants and database-specific distribution patterns. The results provide valuable insights into the genetic landscape of ASD and outline the genes and biological processes involved in the condition, while taking into account that the study relied exclusively on in silico analyses, which may be subject to biases inherent to database methodologies. Further research incorporating multi-omics data and experimental validation is warranted to enhance our understanding of non-syndromic ASD genetics and facilitate the development of targeted research, interventions and therapies.

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11. Lagod PP, Abdelli LS, Naser SA. An In Vivo Model of Propionic Acid-Rich Diet-Induced Gliosis and Neuro-Inflammation in Mice (FVB/N-Tg(GFAPGFP)14Mes/J): A Potential Link to Autism Spectrum Disorder. Int J Mol Sci;2024 (Jul 25);25(15)

Evidence shows that Autism Spectrum Disorder (ASD) stems from an interplay of genetic and environmental factors, which may include propionic acid (PPA), a microbial byproduct and food preservative. We previously reported that in vitro treatment of neural stem cells with PPA leads to gliosis and neuroinflammation. In this study, mice were exposed ad libitum to a PPA-rich diet for four weeks before mating. The same diet was maintained through pregnancy and administered to the offspring after weaning. The brains of the offspring were studied at 1 and 5 months postpartum. Glial fibrillary acidic protein (astrocytic marker) was significantly increased (1.53 ± 0.56-fold at 1 M and 1.63 ± 0.49-fold at 5 M) in the PPA group brains. Tubulin IIIβ (neuronal marker) was significantly decreased in the 5 M group. IL-6 and TNF-α expression were increased in the brain of the PPA group (IL-6: 2.48 ± 1.25-fold at 5 M; TNF-α: 2.84 ± 1.16-fold at 1 M and 2.64 ± 1.42-fold, at 5 M), while IL-10 was decreased. GPR41 and p-Akt were increased, while PTEN (p-Akt inhibitor) was decreased in the PPA group. The data support the role of a PPA-rich diet in glia over-proliferation and neuro-inflammation mediated by the GPR41 receptor and PTEN/Akt pathway. These findings strongly support our earlier study on the role of PPA in ASD.

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12. Lampri S, Peristeri E, Marinis T, Andreou M. Metaphor comprehension and production in verbally able children with Autism Spectrum Disorder. Autism Res;2024 (Aug 9)

Research in the field of figurative language processing in Autism Spectrum Disorders (ASD) has demonstrated that autistic individuals experience systematic difficulties in the comprehension of different types of metaphors. However, there is scarce evidence regarding metaphor production skills in ASD. Importantly, the exact source of metaphor processing difficulties in ASD remains largely controversial. The debate has mainly focused on the mediating role of structural language skills (i.e., lexical knowledge) and cognitive abilities (i.e., Theory of Mind and executive functions) in ASD individuals’ ability to comprehend and generate metaphors. The present study examines metaphor comprehension and production in 18 Greek-speaking verbally able children with ASD and 31 typically-developing (TD) controls. Participants completed two tasks, namely, a low-verbal multiple-choice sentence-picture matching task that tested their ability to comprehend conventional predicate metaphors, and a sentence continuation task that assessed their ability to generate metaphors. The study also included measures of fluid intelligence, expressive vocabulary, and working memory within the sample. The results show that the ASD group had significantly lower performance than the TD group in both metaphor comprehension and production. The findings also reveal that expressive vocabulary skills were a key factor in the metaphor comprehension and production performance of the children with ASD. Working memory capacity was also found to correlate significantly with metaphor comprehension performance in the ASD group. Conversely, no correlations were found in the TD group with neither of the above factors. Of note, children with ASD generated significantly more inappropriate responses and no-responses to the metaphor production task compared with the control group. The overall results reveal that children with ASD had difficulty with both comprehending and using metaphorical language. The findings also indicate that TD children may employ diverse cognitive strategies or rely on different underlying skills when processing metaphors compared with children with ASD.

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13. Mitrakos AK, Kosma K, Makrythanasis P, Tzetis M. The Phenotypic Spectrum of 16p11.2 Recurrent Chromosomal Rearrangements. Genes (Basel);2024 (Aug 10);15(8)

The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2-BP3), and a proximal interval of ~593 Kb (BP4-BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4-BP5) and five included the distal 16p11.2 region (BP2-BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families.

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14. Mlinarič M, Jekovec Vrhovšek M, Neubauer D, France Štiglic A, Osredkar J. Association between Autism Spectrum Disorder, Trace Elements, and Intracranial Fluid Spaces. Int J Mol Sci;2024 (Jul 24);25(15)

(1) Autism spectrum disorder (ASD) belongs to the group of complex developmental disorders. Novel studies have suggested that genetic and environmental factors equally affect the risk of ASD. Identification of environmental factors involved in the development of ASD is therefore crucial for a better understanding of its etiology. Whether there is a causal link between trace elements, brain magnetic resonance imaging (MRI), and ASD remains a matter of debate and requires further studies. (2) In the prospective part of the study, we included 194 children, including an age-matched control group; in the retrospective study, 28 children with available MRI imaging were included. All children had urine analysis of trace elements performed. In those with available brain MRI, linear indexes for the ventricular volumes were measured and calculated. (3) We found the highest vanadium, rubidium, thallium, and silver levels in children with ASD. These elements also correlated with the estimated ventricular volume based on MRI indexes in children with ASD in the subanalysis. However, the severity of the deficits did not correlate with brain MRI indexes of our elements, except negatively with magnesium. (4) Trace elements have an impact on children with ASD, but further multi-centric studies are needed to explain the pathophysiological mechanisms.

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15. Nezamuldeen L, Jafri MS. Boolean Modeling of Biological Network Applied to Protein-Protein Interaction Network of Autism Patients. Biology (Basel);2024 (Aug 10);13(8)

Cellular molecules interact with one another in a structured manner, defining a regulatory network topology that describes cellular mechanisms. Genetic mutations alter these networks’ pathways, generating complex disorders such as autism spectrum disorder (ASD). Boolean models have assisted in understanding biological system dynamics since Kauffman’s 1969 discovery, and various analytical tools for regulatory networks have been developed. This study examined the protein-protein interaction network created in our previous publication of four ASD patients using the SPIDDOR R package, a Boolean model-based method. The aim is to examine how patients’ genetic variations in INTS6L, USP9X, RSK4, FGF5, FLNA, SUMF1, and IDS affect mTOR and Wnt cell signaling convergence. The Boolean network analysis revealed abnormal activation levels of essential proteins such as β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD. These proteins affect gene expression, translation, cell adhesion, shape, and migration. Patients 1 and 2 showed consistent patterns of increased β-catenin activity and decreased MTORC1, RPS6, and eIF4E activity. However, patient 2 had an independent decrease in Cadherin and SMAD activity due to the FLNA mutation. Patients 3 and 4 have an abnormal activation of the mTOR pathway, which includes the MTORC1, RPS6, and eIF4E genes. The shared mTOR pathway behavior in these patients is explained by a shared mutation in two closely related proteins (SUMF1 and IDS). Diverse activities in β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD contributed to the reported phenotype in these individuals. Furthermore, it unveiled the potential therapeutic options that could be suggested to these individuals.

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16. Nimbley E, Maloney E, Buchan K, Sader M, Gillespie-Smith K, Duffy F. Barriers and facilitators to ethical co-production with Autistic people with an eating disorder. J Eat Disord;2024 (Aug 9);12(1):113.

BACKGROUND: Co-production is the collaboration between researchers and the lived experience community in designing, conducting and sharing research. The importance of co-production is increasingly advocated in both the autism and eating disorder fields. Despite this, there remains a lack of clarity at how to define, apply and conduct ethical co-production. Understanding common challenges and what we can do to overcome these challenges are integral to ensuring ethical and meaningful research with Autistic people with an eating disorder. The current study therefore explored: What are the barriers and facilitators to ethical co-production with Autistic people with an ED? METHODS: Five workshops were conducted with 30 collaborators exploring barriers and facilitators to ethical co-production. Synchronous (online workshops) and asynchronous (offline discussion forum) data was analysed using thematic analysis. Themes were co-produced by a neurotypical and Autistic researcher with lived/living experience of an eating disorder. RESULTS: Four themes were identified that explored barriers to ethical co-production: unequal partnerships, the inaccessibility of research, excluded by diagnoses and communication differences. Three themes were identified with regards to facilitators of ethical co-production: shared power (with sub-themes relationships, not roles and creative compensation), clarity and transparency and autism-affirming approaches. DISCUSSION: Conducting ethical co-production with Autistic people with eating disorders has the potential to generate meaningful research that can be translated into improving the lives of the Autistic and eating disorder community. To achieve this, co-production teams should strive towards shared power and long-term relationships, adapting for communication differences and preferences and operating firmly within an autism-affirming framework. It is hoped that study findings will inspire collaboration, discussion and novel, translatable research. Co-production is the collaboration between researchers and the lived experience community in designing, conducting and sharing research. This study brought together Autistic people with lived/living experience of an eating disorder (ED), researchers, clinicians, third sector organisations and parents/carers to understand what the barriers (challenges) and facilitators (how to overcome these challenges) were to ethical co-production with Autistic people with an eating disorder. Common barriers were found to be unequal partnerships, difficulty accessing research, feeling or being excluded by a reliance on diagnoses and the impact of communication differences. Facilitators were felt to be a shared power dynamic, focusing on establishing relationships not just tokenistic roles and creating fair and person-centred compensation. Facilitators were also adapting for communication differences and moving away from harmful medicalised and ableists models, towards autism-affirming practice. It is hoped that the study will encourage discussion and positive co-production relationships between autism and ED researchers and the Autistic and ED community. It is also hoped that that this approach will lead to more meaningful research that will ultimately improve the lives of Autistic people with an ED. eng

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17. Osaki T, Delepine C, Osako Y, Kranz D, Levin A, Nelson C, Fagiolini M, Sur M. Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids. bioRxiv;2024 (Aug 10)

Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations – a missense mutation (R306C) and a truncating mutation (V247X) – using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutation. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABA(A) receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.

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18. Ouellette J, Lacoste B. Rock2 heterozygosity improves recognition memory and endothelial function in a mouse model of 16p11.2 deletion autism syndrome. Neurosci Lett;2024 (Aug 10);837:137904.

Rho-associated protein kinase-2 (ROCK2) is a critical player in many cellular processes and was incriminated in cardiovascular and neurological disorders. Recent evidence has shown that non-selective pharmacological blockage of ROCKs ameliorates behavioral alterations in a mouse model of 16p11.2 haploinsufficiency. We had revealed that 16p11.2-deficient mice also display cerebrovascular abnormalities, including endothelial dysfunction. To investigate whether genetic blockage of ROCK2 also exerts beneficial effects on cognition and angiogenesis, we generated mice with both 16p11.2 and Rock2 haploinsufficiency (16p11.2(df/+);Rock2(+/-)). We find that Rock2 heterozygosity on a 16p11.2(df/+) background significantly improved recognition memory. Furthermore, brain endothelial cells from 16p11.2(df/+);Rock2(+/-) mice display improved angiogenic capacity compared to cells from 16p11.2(df/+) littermates. Overall, this study implicates Rock2 gene as a modulator of 16p11.2-associated alterations, highlighting its potential as a target for treatment of autism spectrum disorders.

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19. Shinomiya S. The role of administrative categories in the globalisation of a psychiatric concept: Case studies of autism in Japan. Soc Sci Med;2024 (Aug 10);357:117223.

This paper explores how what I call ‘administrative categories’ have been adopted by the Japanese government and experts in autism support and what roles these categories have played in local settings. Since support practices for children and adults with autism began in the 1950s in Japan, the Japanese government and people engaging in autism support have used Japanese-specific administrative categories, instead of relying on a medical concept of autism, such as ‘severe moving disabilities’ (SMD), ’emotional disturbance’, and ‘extremely disruptive behavioural disorders’ (EDBD). To understand the emergence of these three autism-related administrative categories in Japan, historical materials published from the 1950s to the 1990s by Japanese authors (doctors, psychologists, teachers, educationalists, welfare workers, government officials, and parents) and interview data with 19 leading experts of autism in Japan were collected and analysed thematically. The analysis revealed that the governmental ministries aimed to focus on establishing administrative support by avoiding engaging in aetiological debates among doctors, and to describe the political agenda more vividly. Administrative categories filled the gap between local interests and international medical concepts, enabling the concept of autism to be rooted in Japan’s administrative systems. Three roles of administrative categories were identified: i) separation from medicine, ii) describing local problems, and iii) claimsmaking to wider actors and the public. I concluded that looking purely at medical and specifically diagnostic concepts limits our understanding of the formation of practices regarding disabilities, and thus more focus should be placed on categorisation practices outside of medicine. In addition, to the literature on the globalisation of Euro-American psychiatric concepts, this study contributes to our knowledge of a form of locality that has not been central in the exploration of the influence of globalisation on local settings and the relationships between the local and the global.

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20. Ujfalussy DJ, Gergely A, Petró E, Topál J. ASD-similar social behaviour scores affect stimulus generalization in family dogs. Sci Rep;2024 (Aug 10);14(1):18578.

Generalization, the tendency to respond in the same way to different but similar stimuli, is one of the main cognitive abilities that make category formation possible and thus is a prerequisite for efficiency in learning. Individuals with autism spectrum disorder (ASD) experience pervasive difficulty with producing generalized responses across materials, people, places, and contexts. Increasing evidence suggests that « ASD-like » social impairments appear endogenously and spontaneously in family dogs providing a high-validity model for understanding the phenotypic expression of human ASD. The present study aims to further investigate the dog model of ASD by the approach of searching for analogues in dogs showing « ASD-like » social impairments of cognitive phenomena in humans specific to ASD, specifically impairments of generalization abilities. We have tested 18 family dogs with formerly established « ASD-like » behaviour scores (F1, F2, F3) in a generalization task involving three conditions (size, colour and texture). We found a significant association between F1 scores and test performance as well as improvement during testing sessions. Our study provides further support for the notion that dogs with lower social competence-similarly to humans with ASD-exhibit attentional and perceptual abnormalities, such as being sensitive to minor changes to a non-adaptive extent.

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21. Winarni TI, Hwang YH, Rivera SM, Hessl D, Durbin-Johnson BP, Utari A, Hagerman R, Tassone F. Apolipoproteine and KLOTHO Gene Variants Do Not Affect the Penetrance of Fragile X-Associated Tremor/Ataxia Syndrome. Int J Mol Sci;2024 (Jul 25);25(15)

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

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22. Wu Y, Su Q. Harnessing the Gut Microbiome: To What Extent Can Pre-/Probiotics Alleviate Immune Activation in Autism Spectrum Disorder?. Nutrients;2024 (Jul 23);16(15)

Children diagnosed with autism spectrum disorder (ASD) are at an increased risk of experiencing gastrointestinal (GI) discomfort, which has been linked to dysfunctions in the microbiome-gut-brain axis. The bidirectional communication between gut and brain plays a crucial role in the overall health of individuals, and alterations in the gut microbiome can contribute to immune activation and gut-brain dysfunction in ASD. Despite the limited and controversial results of pre-/probiotic applications in ASD, this review comprehensively maps the association between ASD clinical symptoms and specific bacterial taxa and evaluates the efficacy of pre-/probiotics in modulating microbiota composition, reducing inflammatory biomarkers, alleviating difficulties in GI distress, sleep problems, core and other ASD-associated symptoms, as well as relieving parental concerns, separately, in individuals with ASD. Beyond simply targeting core ASD symptoms, this review highlights the potential of pre-/probiotic supplementations as a strategy to modulate gut homeostasis and immune response, and to delineate the potential mechanisms by which its direct or mediating effects can alleviate gut-brain dysfunction and poor nutritional status in ASD management. Further well-designed randomized controlled trials are needed to strengthen the existing evidence and establish optimal protocols for the use of pre-/probiotics in the context of ASD.

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