1. Ali G, Shin KC, Habbab W, Alkhadairi G, AbdelAleem A, AlShaban FA, Park Y, Stanton LW. Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines. Front Neurosci;2023;17:1302470.

We investigated whether a homozygous recessive genetic variant of NSF attachment protein beta (NAPB) gene inherited by monozygotic triplets contributed to their phenotype of early-onset epilepsy and autism. Induced pluripotent stem cell (iPSC) lines were generated from all three probands and both parents. The NAPB genetic variation was corrected in iPSC lines from two probands by CRISPR/Cas9 gene editing. Cortical neurons were produced by directed, in vitro differentiation from all iPSC lines. These cell line-derived neurons enabled us to determine that the genetic variation in the probands causes exon skipping and complete absence of NAPB protein. Electrophysiological and transcriptomic comparisons of cortical neurons derived from parents and probands cell lines indicate that loss of NAPB function contributes to alterations in neuronal functions and likely contributed to the impaired neurodevelopment of the triplets.

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2. Bar O, Vahey E, Mintz M, Frye RE, Boles RG. Reanalysis of Trio Whole-Genome Sequencing Data Doubles the Yield in Autism Spectrum Disorder: De Novo Variants Present in Half. Int J Mol Sci;2024 (Jan 18);25(2)

Autism spectrum disorder (ASD) is a common condition with lifelong implications. The last decade has seen dramatic improvements in DNA sequencing and related bioinformatics and databases. We analyzed the raw DNA sequencing files on the Variantyx(®) bioinformatics platform for the last 50 ASD patients evaluated with trio whole-genome sequencing (trio-WGS). « Qualified » variants were defined as coding, rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV), additionally, were present in genes directly linked to ASD and matched clinical correlation. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) cases with heterozygous de novo and 10 (20%) with inherited variants. De novo variants in genes directly associated with ASD were far more likely to be Qualifying than non-Qualifying versus a control group of genes (p = 0.0002), validating that most are indeed disease related. Sequence reanalysis increased diagnostic yield from 28% to 68%, mostly through inclusion of de novo PDVs in genes not yet reported as ASD associated. Thirty-three subjects (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate a high yield of trio-WGS for revealing molecular diagnoses in ASD, which is greatly enhanced by reanalyzing DNA sequencing files. In contrast to previous reports, de novo variants dominate the findings, mostly representing novel conditions. This has implications to the cause and rising prevalence of autism.

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3. Bleimeister I, Avni I, Granovetter M, Meiri G, Ilan M, Michaelovski A, Menashe I, Behrmann M, Dinstein I. Idiosyncratic pupil regulation in autistic children. bioRxiv;2024 (Jan 12)

Recent neuroimaging and eye tracking studies have suggested that children with autism spectrum disorder (ASD) may exhibit more variable and idiosyncratic brain responses and eye movements than typically developing (TD) children. Here we extended this research for the first time to pupillometry recordings. We successfully completed pupillometry recordings with 103 children (66 with ASD), 4.5-years-old on average, who viewed three 90 second movies, twice. We extracted their pupillary time-course for each movie, capturing their stimulus evoked pupillary responses. We then computed the correlation between the time-course of each child and those of all others in their group. This yielded an average inter-subject correlation value per child, representing how similar their pupillary responses were to all others in their group. ASD participants exhibited significantly weaker inter-subject correlations than TD participants, reliably across all three movies. Differences across groups were largest in responses to a naturalistic movie containing footage of a social interaction between two TD children. This measure enabled classification of ASD and TD children with a sensitivity of 0.82 and specificity of 0.73 when trained and tested on independent datasets. Using the largest ASD pupillometry dataset to date, we demonstrate the utility of a new technique for measuring the idiosyncrasy of pupil regulation, which can be completed even by young children with co-occurring intellectual disability. These findings reveal that a considerable subgroup of ASD children have significantly more unstable, idiosyncratic pupil regulation than TD children, indicative of more variable, weakly regulated, underlying neural activity.

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4. Canitano R, Bozzi Y. Autism Spectrum Disorder with Epilepsy: A Research Protocol for a Clinical and Genetic Study. Genes (Basel);2023 (Dec 31);15(1)

Autism spectrum disorder (ASD) is a common neurodevelopmental condition affecting ~1% of people worldwide. Core ASD features present with impaired social communication abilities, repetitive and stereotyped behaviors, and atypical sensory responses and are often associated with a series of comorbidities. Among these, epilepsy is frequently observed. The co-occurrence of ASD and epilepsy is currently thought to result from common abnormal neurodevelopmental pathways, including an imbalanced excitation/inhibition ratio. However, the pathological mechanisms involved in ASD-epilepsy co-morbidity are still largely unknown. Here, we propose a research protocol aiming to investigate electrophysiological and genetic features in subjects with ASD and epilepsy. This study will include a detailed electroencephalographic (EEG) and blood transcriptomic characterization of subjects with ASD with and without epilepsy. The combined approach of EEG and transcriptomic studies in the same subjects will contribute to a novel stratification paradigm of the heterogeneous ASD population based on quantitative gene expression and neurophysiological biomarkers. In addition, our protocol has the potential to indicate new therapeutic options, thus amending the current condition of absence of data and guidelines for the treatment of ASD with epilepsy.

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5. Chen L, Liu J, Kang JB, Rosenberg-Lee M, Abrams DA, Menon V. Atypical pattern separation memory and its association with restricted interests and repetitive behaviors in autistic children. Autism;2024 (Jan 23):13623613231223354.

Memory challenges remain understudied in childhood autism. Our study investigates one specific aspect of memory function, known as pattern separation memory, in autistic children. Pattern separation memory refers to the critical ability to store unique memories of similar stimuli; however, its role in childhood autism remains largely uncharted. Our study first uncovered that the pattern separation memory was significantly reduced in autistic children, and then showed that reduced memory performance was linked to their symptoms of repetitive, restricted interest and behavior. We also identified distinct subgroups with profiles of reduced and increased generalization for pattern separation memory. More than 72% of autistic children showed a tendency to reduce memory generalization, focusing heavily on unique details of objects for memorization. This focus made it challenging for them to identify commonalities across similar entities. Interestingly, a smaller proportion of autistic children displayed an opposite pattern of increased generalization, marked by challenges in differentiating between similar yet distinct objects. Our findings advance the understanding of memory function in autism and have practical implications for devising personalized learning strategies that align with the unique memory patterns exhibited by autistic children. This study will be of broad interest to researchers in psychology, psychiatry, and brain development as well as teachers, parents, clinicians, and the wider public.

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6. Choi H, Kim JH, Yang HS, Kim JY, Cortese S, Smith L, Koyanagi A, Dragioti E, Radua J, Fusar-Poli P, Shin JI, Cheon KA, Solmi M. Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the GRADE assessment. Mol Autism;2024 (Jan 23);15(1):7.

BACKGROUND: Numerous interventions for irritability in autism spectrum disorder (ASD) have been investigated. We aimed to appraise the magnitude of pharmacological and non-pharmacological interventions for irritability in ASD without any restrictions in terms of eligible interventions. METHODS: We systematically searched PubMed/MEDLINE, Scopus, and Web of Science until April 15, 2023. We included randomized controlled trials (RCTs) with a parallel design that examined the efficacy of interventions for the treatment of irritability in patients of any age with ASD without any restrictions in terms of eligible interventions. We performed a random-effects meta-analysis by pooling effect sizes as Hedges’ g. We classified assessed interventions as follows: pharmacological monotherapy, risperidone plus adjuvant therapy versus risperidone monotherapy, non-pharmacological intervention, and dietary intervention. We utilized the Cochrane tool to evaluate the risk of bias in each study and the GRADE approach to assess the certainty of evidence for each meta-analyzed intervention. RESULTS: Out of 5640 references, we identified 60 eligible articles with 45 different kinds of interventions, including 3531 participants, of which 80.9% were males (mean age [SD] = 8.79 [3.85]). For pharmacological monotherapy, risperidone (Hedges’ g - 0.857, 95% CI - 1.263 to - 0.451, certainty of evidence: high) and aripiprazole (Hedges’ g - 0.559, 95% CI - 0.767 to - 0.351, certainty of evidence: high) outperformed placebo. Among the non-pharmacological interventions, parent training (Hedges’ g - 0.893, 95% CI - 1.184 to - 0.602, certainty of evidence: moderate) showed a significant result. None of the meta-analyzed interventions yielded significant effects among risperidone + adjuvant therapy and dietary supplementation. However, several novel molecules in augmentation to risperidone outperformed risperidone monotherapy, yet from one RCT each. LIMITATIONS: First, various tools have been utilized to measure the irritability in ASD, which may contribute to the heterogeneity of the outcomes. Second, meta-analyses for each intervention included only a small number of studies and participants. CONCLUSIONS: Only risperidone, aripiprazole among pharmacological interventions, and parent training among non-pharmacological interventions can be recommended for irritability in ASD. As an augmentation to risperidone, several novel treatments show promising effects, but further RCTs are needed to replicate findings. Trial registration PROSPERO, CRD42021243965.

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7. Dakopolos A, Condy E, Smith E, Harvey D, Kaat AJ, Coleman J, Riley K, Berry-Kravis E, Hessl D. Developmental Associations between Cognition and Adaptive Behavior in Intellectual and Developmental Disability. Res Sq;2024 (Jan 8)

BACKGROUND: Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living (DSM-5). Individuals with IDD often present with an intellectual disability in addition to a developmental disability such as autism or Down syndrome. Those with IDD may present with deficits in intellectual functioning as well as adaptive functioning that interfere with independence and living skills. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two-year period. METHODS: Eligible participants for this multisite longitudinal study included those who were between 6 and 26 years at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID. Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid, Crystallized, Composite) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization). RESULTS: Over a two-year period, change in cognition (both Crystalized and Composite) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model. CONCLUSIONS: The present study demonstrated that developmental improvements in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in Daily Living Skills on the VABS-3 emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, « real life » meaningfulness of the NIHTB-CB in IDD, and important empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

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8. Dorsey SG, Mocci E, Lane MV, Krueger BK. Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism. Res Sq;2024 (Jan 10)

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 255 genes that have been reported to play fundamental roles in fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The set of genes meeting these criteria provides potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.

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9. Dunn JT, Guidotti A, Grayson DR. Behavioral and molecular characterization of prenatal stress effects on the C57BL/6J genetic background for the study of autism spectrum disorder. eNeuro;2024 (Jan 23)

Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic background. In the current manuscript, we stressed C57BL/6 dams during gestation and examined numerous behavioral and molecular endophenotypes in the adult male and female offspring to characterize the resultant phenotype as compared with offspring born from non-stressed dams. Adult mice born from prenatally restraint stressed (PRS) dams demonstrated reduced sociability and reciprocal social interaction along with increased marble burying behaviors relative to mice born from non-stressed (NS) control dams. Differential expression of genes related to excitatory and inhibitory neurotransmission was evaluated in the medial prefrontal cortex, amygdala, hippocampus, nucleus accumbens and caudate-putamen via qRT-PCR. The male PRS mouse behavioral phenotype coincided with aberrant expression of glutamate and GABA marker genes (e.g., Grin1, Grin2b, Gls, Gat1, Reln) in neural substrates of social behavior. Rescue of the male PRS sociability deficit by a known antipsychotic with epigenetic properties (i.e., clozapine (5 mg/kg) + 18-hr washout) indicated possible epigenetic regulation of genes that govern sociability. Clozapine treatment increased the expression levels of genes involved in DNA methylation, histone methylation, and histone acetylation in the nucleus accumbens. Identification of etiology-specific mechanisms underlying clinically relevant behavioral phenotypes may ultimately provide novel therapeutic interventions for the treatment of psychiatric disorders including ASD.Significance Statement The effects of prenatal stress on the C57BL/6J mouse genetic background are incompletely understood with regard to adverse psychiatric outcomes and respective underlying molecular mechanisms. Considering the prominent use of C57BL/6J mice for the generation of preclinical models for the study of autism spectrum disorder (ASD) and putative differences in stress resiliency across mouse strains, this gap in knowledge is an obstacle to contextualizing prenatal stress as an ASD etiological risk factor within the broader ASD preclinical literature. This study expands current knowledge of the relationship between prenatal stress exposure and the later presentation of representative behaviors for ASD symptom domains, underlying changes in gene expression, and insight into the potential of alleviating ASD-like behaviors through epigenetic mechanisms.

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10. Dunsky A, Barak S. Health Promotion with Long-Term Physical Activity Program for Adults with Autism Spectrum Disorder. Healthcare (Basel);2024 (Jan 18);12(2)

Individuals with autism spectrum disorder (ASD) are at higher risk for developing common chronic diseases. Engagement in physical activity (PA) can prevent health issues; however, people with ASD are known to engage in lower levels of PA in comparison to their peers. This study evaluated the effect of a long-term, 12-month PA intervention on the fitness and quality of life of adults with ASD. A quantitative approach was implemented to assess participants’ fitness, functional ability, quality of life, and participation in a range of PA classes at three different time points. Qualitative data were collected via in-depth, semi-structured interviews with three participants with ASD and three staff members. A total of 34 adults with ASD (mean age 39.76 + 7.27) participated in the quantitative part of the study. Approximately 53% of the participants exhibited perseverance and conducted adequate PA each month. Significant improvements were found in one fitness component and two quality-of-life components. Factors revealed for the program’s success were the individuals’ free choice of the PA classes and supporting people and a budget that tailored the project. Policymakers who plan health promotion programs for adults with ASD should consider long-term PA programs, with freedom of choice among PA modalities and schedules.

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11. Fernández-Batanero JM, Montenegro-Rueda M, Fernández-Cerero J, López-Meneses E. Fostering Motivation: Exploring the Impact of ICTs on the Learning of Students with Autism. Children (Basel);2024 (Jan 18);11(1)

Currently, the use of digital tools has led to significant changes in the educational system, favouring equity and the inclusion of students with educational needs. In this context, students with autism spectrum disorder (ASD) benefit from using these electronic devices to improve their learning experience. This study focuses on conducting a bibliometric analysis of the impact of information and communication technologies on the learning of students with ASD, with the aim of addressing two research questions. Through the analysis of three databases (Scopus, Dialnet, and Web of Science), a total of 24 articles related to the subject were collected. The results show that the use of different technological devices has numerous benefits for these students. Among the most prominent are the use of augmented reality and educational robotics, mainly providing improvements in academic performance, motivation and improved retention of knowledge acquired in the classroom. In conclusion, the clear need to train teachers in digital competencies and to intensify efforts in this line of research in order to improve the education of students, as well as to enrich the knowledge available to the scientific community, is highlighted.

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12. Ge C, Tian Y, Hu C, Mei L, Li D, Dong P, Zhang Y, Li H, Sun D, Peng W, Xu X, Jiang Y, Xu Q. Clinical impact and in vitro characterization of ADNP variants in pediatric patients. Mol Autism;2024 (Jan 22);15(1):5.

BACKGROUND: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare genetic disorder caused by variants in the activity-dependent neuroprotector homeobox (ADNP) gene; hence, it is also called ADNP syndrome. ADNP is a multitasking protein with the function as a transcription factor, playing a critical role in brain development. Furthermore, ADNP variants have been identified as one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability. METHODS: We assembled a cohort of 15 Chinese pediatric patients, identified 13 variants in the coding region of ADNP gene, and evaluated their clinical phenotypes. Additionally, we constructed the corresponding ADNP variants and performed western blotting and immunofluorescence analysis to examine their protein expression and subcellular localization in human HEK293T and SH-SY5Y cells. RESULTS: Our study conducted a thorough characterization of the clinical manifestations in 15 children with ADNP variants, and revealed a broad spectrum of symptoms including global developmental delay, intellectual disability, ASD, facial abnormalities, and other features. In vitro studies were carried out to check the expression of ADNP with identified variants. Two cases presented missense variants, while the remainder exhibited nonsense or frameshift variants, leading to truncated mutants in in vitro overexpression systems. Both overexpressed wildtype ADNP and all the different mutants were found to be confined to the nuclei in HEK293T cells; however, the distinctive pattern of nuclear bodies formed by the wildtype ADNP was either partially or entirely disrupted by the mutant proteins. Moreover, two variants of p.Y719* on the nuclear localization signal (NLS) of ADNP disrupted the nuclear expression pattern, predominantly manifesting in the cytoplasm in SH-SY5Y cells. LIMITATIONS: Our study was limited by a relatively small sample size and the absence of a longitudinal framework to monitor the progression of patient conditions over time. Additionally, we lacked in vivo evidence to further indicate the causal implications of the identified ADNP variants. CONCLUSIONS: Our study reported the first cohort of HVDAS patients in the Chinese population and provided systematic clinical presentations and laboratory examinations. Furthermore, we identified multiple genetic variants and validated them in vitro. Our findings offered valuable insights into the diverse genetic variants associated with HVDAS.

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13. Hosie S, Abo-Shaban T, Mou K, Balasuriya GK, Mohsenipour M, Alamoudi MU, Filippone RT, Belz GT, Franks AE, Bornstein JC, Nurgali K, Hill-Yardin EL. Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3(R451C) Mouse Model of Autism. Int J Mol Sci;2024 (Jan 9);25(2)

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3(R451C) mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3(R451C) mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3(R451C) mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3(R451C) mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3(R451C) mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABA(A) antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3(R451C) p = 0.002), but not the ileum, in both wild-type and Nlgn3(R451C) mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein.

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14. Hosozawa M, Cable N, Ikehara S, Aochi Y, Tanigawa K, Baba S, Hirokawa K, Kimura T, Sobue T, Iso H. Maternal Autistic Traits and Adverse Birth Outcomes. JAMA Netw Open;2024 (Jan 2);7(1):e2352809.

IMPORTANCE: Women with a high level of autistic traits in the general population may experience larger health disparities during pregnancy, particularly women diagnosed with autism spectrum disorder (ASD), which in turn may be associated with increased risk of adverse birth outcomes. OBJECTIVE: To investigate the association between maternal autistic traits and the risk of adverse birth outcomes in the general population. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included mothers of singletons from a nationwide, multicenter prospective birth cohort, the Japan Environmental Children’s Study. Expecting mothers were recruited between January 2011 and March 2014. Data were analyzed between June 2021 and November 2023. EXPOSURES: Autistic traits were self-reported during the second and third trimesters using the short form of the Autism-Spectrum Quotient Japanese version (AQ-J10) (score range, 0-10; clinical range, ≥7). MAIN OUTCOMES AND MEASURES: Data on preterm birth (<37 weeks' gestation) and neonates born small for gestational age (SGA) were transcribed from medical records. Additional analysis of gestational age groups (very preterm birth, <32 weeks' gestation; moderate-to-late preterm birth, 32-36 weeks' gestation) was also performed. RESULTS: Among 87 687 women (mean [SD] age, 31.2 [5.0] years) included in the study, 2350 (2.7%) had AQ-J10 scores within the clinical range yet only 18 (0.02%) were diagnosed with ASD. A higher AQ-J10 score was associated with an increased risk of all birth outcomes, including preterm births (relative risk [RR] per 1-SD increase, 1.06; 95% CI, 1.03-1.09), moderate-to-late preterm births (RR per 1-SD increase, 1.05; 95% CI, 1.01-1.08), very preterm births (RR per 1-SD increase, 1.16; 95% CI, 1.06-1.26), and child born SGA (RR per 1-SD increase, 1.04; 95% CI, 1.01-1.06) after adjusting for maternal and pregnancy-related factors. The risks of all outcomes increased with higher AQ-J10 scores; compared with women below the clinical range, women within the clinical range had greater risk of preterm births (RR, 1.16; 95% CI, 1.07-1.26), moderate-to-late preterm births (RR, 1.12; 95% CI, 1.03-1.22), very preterm births (RR, 1.49; 95% CI, 1.18-1.89), and a child born SGA (RR, 1.11; 95% CI, 1.04-1.19). CONCLUSIONS AND RELEVANCE: In this cohort study, higher level of maternal autistic traits was associated with increased risk of adverse birth outcomes, particularly very preterm birth. Acknowledging the risks and providing tailored and timely antenatal care support to women with a high level of autistic traits in the general population, particularly women with autistic traits within the clinical range, regardless of formal diagnosis, is warranted.

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15. Karimi P, Ghahfarroki MS, Lorigooini Z, Shahrani M, Amini-Khoei H. Umbelliprenin via increase in the MECP2 and attenuation of oxidative stress mitigates the autistic-like behaviors in mouse model of maternal separation stress. Front Pharmacol;2023;14:1300310.

Introduction: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition. Maternal separation (MS) stress is an early-life stress factor associated with behaviors resembling Autism. Both MECP2 and oxidative stress are implicated in the pathophysiology of Autism. Umbelliprenin (UMB) is a coumarin compound with various pharmacological properties. Our study aimed to investigate the potential effects of UMB in mitigating autistic-like behaviors in a mouse model subjected to MS stress, focusing on probable alterations in MECP2 gene expression in the hippocampus. Methods: MS paradigm was performed, and mice were treated with saline or UMB. Behavioral tests consisting of the three-chamber test (evaluating social interaction), shuttle box (assessing passive avoidance memory), elevated plus-maze (measuring anxiety-like behaviors), and marble-burying test (evaluating repetitive behaviors) were conducted. Gene expression of MECP2 and measurements of total antioxidant capacity (TAC), nitrite level, and malondialdehyde (MDA) level were assessed in the hippocampus. Results: The findings demonstrated that MS-induced behaviors resembling Autism, accompanied by decreased MECP2 gene expression, elevated nitrite, MDA levels, and reduced TAC in the hippocampus. UMB mitigated these autistic-like behaviors induced by MS and attenuated the adverse effects of MS on oxidative stress and MECP2 gene expression in the hippocampus. Conclusion: In conclusion, UMB likely attenuated autistic-like behaviors caused by MS stress, probably, through the reduction of oxidative stress and an increase in MECP2 gene expression.

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16. Li X, Jiang M, Zhao L, Yang K, Lu T, Zhang D, Li J, Wang L. Relationship between autism and brain cortex surface area: genetic correlation and a two-sample Mendelian randomization study. BMC Psychiatry;2024 (Jan 23);24(1):69.

BACKGROUND: Alterations in surface area (SA) in specific regions of the cortex have been reported in many individuals with autism spectrum disorder (ASD), however, the genetic background between ASD and SA is still unclear. This study estimated the genetic correlation and causal effect of ASD and cortical SA. METHODS: Summarized data of genome-wide association studies (GWAS) were separately downloaded from the Psychiatric Genomics Consortium (18,381 cases of ASD, and 27,969 controls) and the Enhancing Neuroimaging Genetics through Meta-Analysis Consortium (33,992 participants of Europeans). We used Linkage disequilibrium score regression (LDSC) and Heritability Estimation from Summary Statistics (HESS) to calculate the heritability of each trait. As for the genetic correlation between ASD and SA, LDSC was used for global correlation and HESS was used to examine the local genetic covariance further. We used three Mendelian randomization (MR) methods, Inverse-variance weighted, MR-Egger, and weighted median to estimate the causal relationship. RESULTS: LDSC observed a nominal significant genetic correlation (rg = 0.1229, P-value = 0.0346) between ASD and SA of the rostral anterior cingulate gyrus whereas analysis through HESS did not reveal any significant loci having genetic covariance. Based on MR results, statistically meaningful estimations were found in the following areas, postcentral cortex (β (SE) = 21.82 (7.84) mm, 95% CI: 6.46 to 37.19 mm, P(IVW) = 5.38 × 10(- 3), P(FDR) = 3.09 × 10(- 2)), posterior cingulate gyrus (β (SE) = 6.23 (2.69) mm, 95% CI: 0.96 to 11.49 mm, P(IVW) = 2.05 × 10(- 2), P(FDR) = 4.26 × 10(- 2)), supramarginal gyrus (β (SE) = 19.25 (8.43) mm, 95% CI: 29.29 to 35.77 mm, P(IVW) = 2.24 × 10(- 2), P(FDR) = 4.31 × 10(- 2)). CONCLUSION: Our results provided genetic evidence to support the opinion that individuals with ASD tend to develop differences in cortical SA of special areas. The findings contributed to understanding the genetic relationship between ASD and cortical SA.

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17. Luo Y, Wang Z. The Impact of Microglia on Neurodevelopment and Brain Function in Autism. Biomedicines;2024 (Jan 17);12(1)

Microglia, as one of the main types of glial cells in the central nervous system (CNS), are widely distributed throughout the brain and spinal cord. The normal number and function of microglia are very important for maintaining homeostasis in the CNS. In recent years, scientists have paid widespread attention to the role of microglia in the CNS. Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder, and patients with ASD have severe deficits in behavior, social skills, and communication. Most previous studies on ASD have focused on neuronal pathological changes, such as increased cell proliferation, accelerated neuronal differentiation, impaired synaptic development, and reduced neuronal spontaneous and synchronous activity. Currently, more and more research has found that microglia, as immune cells, can promote neurogenesis and synaptic pruning to maintain CNS homeostasis. They can usually reduce unnecessary synaptic connections early in life. Some researchers have proposed that many pathological phenotypes of ASD may be caused by microglial abnormalities. Based on this, we summarize recent research on microglia in ASD, focusing on the function of microglia and neurodevelopmental abnormalities. We aim to clarify the essential factors influenced by microglia in ASD and explore the possibility of microglia-related pathways as potential research targets for ASD.

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18. Miao Z, Chen L, Zhang Y, Zhang J, Zhang H. Bifidobacterium animalis subsp. lactis Probio-M8 alleviates abnormal behavior and regulates gut microbiota in a mouse model suffering from autism. mSystems;2024 (Jan 23);9(1):e0101323.

Probiotics can effectively improve a variety of neurological diseases, but there is little research on autism, and the specific mechanism is unclear. In this study, shotgun metagenomics analysis was used to investigate the preventive and therapeutic effects of Bifidobacterium animalis subsp. lactis Probio-M8 on autism. The results showed that Probio-M8 treatment significantly alleviated valproate (VPA)-induced autism in mice, with autistic symptoms characterized by increased stereotyped behaviors such as grooming, reduced learning ability, and decreased desire to socialize. Further studies have found that Probio-M8 can alleviate autism by optimizing gut microbiota diversity and regulating metabolic levels. Probio-M8 regulates gut microbiota structure by increasing the abundance of beneficial bacteria such as Bifidobacterium globosum and Akkermansia muciniphila. In addition, Probio-M8 regulates metabolic activity by increasing levels of choline, which corrects CAZy disorders. In conclusion, Probio-M8 is therapeutic in the VPA-induced autism mouse model by regulating the gut microbiome and metabolic levels.IMPORTANCEIndividuals with autism often exhibit symptoms of social invariance, obsessive-compulsive tendencies, and repetitive behaviors. However, early intervention and treatment can be effective in improving social skills and mitigating autism symptoms, including behaviors related to irritability. Although taking medication for autism may lead to side effects such as weight gain, probiotics can be an ideal intervention for alleviating these symptoms. In this study, we investigated the effects of Probio-M8 intervention on the behavior of autistic mice using an open-field test, a three-chamber sociability test, and a novel object recognition test. Metagenomic analysis revealed differences in gut microbiota diversity among groups, predicted changes in metabolite levels, and functionally annotated CAZy. Additionally, we analyzed serum neurotransmitter levels and found that probiotics were beneficial in mitigating neurotransmitter imbalances in mice with autism.

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19. Moser C, Campanelli A, Friedman L, Thurman AJ, Roberts JE, Abbeduto L, Klusek J. Characterising the social interaction style of autism in young adult males with fragile X syndrome. J Intellect Disabil Res;2024 (Jan 23)

BACKGROUND: The characterisation of autism in fragile X syndrome (FXS) has been a source of controversy due to the complexity of disentangling autism traits from common features of the FXS phenotype. Autism in FXS is significantly underdiagnosed in the community, which may be partly due to insufficient clinical description of the social interaction profile of autism within the FXS phenotype. In this study, we applied a classic framework for characterising social interaction styles in autism to a sample of young adult males with FXS and co-occurring autism to enhance understanding of how the social challenges associated with autism manifest within FXS. METHODS: Participants were 41 males (M age = 18 years) with FXS and co-occurring autism. Interaction samples were coded for expression of predominately ‘active’ (characterised by a desire to make social approaches) or ‘passive’ (characterised by lack of initiation of social approach towards others) interaction profiles. Differences in the expression of phenotypic features of FXS, including anxiety, attention-deficit/hyperactivity disorder, cognitive, adaptive and language impairments and autism symptom severity, were examined across those with passive and active interaction styles. RESULTS: Approximately half of the sample was classified as active and half as passive, demonstrating diversity in the social phenotype of autism associated with FXS. The two subtypes did not differ in autism severity, anxiety or attention-deficit/hyperactivity disorder symptoms or in cognitive, adaptive or language abilities. CONCLUSIONS: This study enhances understanding of FXS-associated autism by documenting phenotypic variability in the social interaction profile in this group, with active and passive social interaction styles represented. The two social interaction styles were not associated with differential expression of common phenotypic features of FXS, suggesting similar support needs.

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20. Mustafa AM, Grifa DS, Shebani A, Alharabi S, Alnajjar K. Knowledge and awareness of autism spectrum disorder among Libyans. J Public Health Afr;2023 (Dec 27);14(12):2762.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by the presence of delayed or defective development before the age of three years, as well as behavioral difficulties in social communication and interaction. To evaluate ASD knowledge and awareness, as well as ASD information sources in a sample of the Libyan general population, and to explore factors that could be associated with the knowledge and awareness. A cross-sectional study was carried out between 22 March and 13 August, 2022 using a self-administered questionnaire. The study included 2350 individual aged 18 and up from households living in different regions in Libya (eastern, southern, central, and western). Out of 2195 participants, 48.9% were females and 51.1% were males. Three-quarters of the participants (74.8%) presented a low level of knowledge about autism causes. Of those whose source of knowledge of autism was social media, 78.9% had a low level of knowledge. However, 57.9% of the participants showed a good level of awareness of autism symptoms and signs. The participants had a limited understanding of the causes and characteristics of ASD. Raising community awareness of the causes and characteristics of ASD is a priority.

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21. Nelson AD, Catalfio AM, Gupta JP, Min L, Caballero-Florán RN, Dean KP, Elvira CC, Derderian KD, Kyoung H, Sahagun A, Sanders SJ, Bender KJ, Jenkins PM. Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites. Neuron;2024 (Jan 23)

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel Na(V)1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how Na(V)1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding Na(V)1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a(+/-) conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

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22. Nisticò V, Ingrosso G, Lombardi F, Chiudinelli E, Bianchini G, Faggioli R, Bertani A, Gambini O, Demartini B. Autistic traits, sensory sensitivity and eating disturbances in a sample of young adults referring to a generalized mental health clinic. Eat Weight Disord;2024 (Jan 23);29(1):10.

PURPOSE: The relationship between autistic traits and eating disturbances has been given considerable attention over the last decades. The rise of a dimensional approach to psychopathology has expanded the way we think about autism, acknowledging that subthreshold autistic manifestations span across the general population and are more pronounced in psychiatric patients. Here we investigated the prevalence of eating disorders and its potential relationship with autistic traits and sensory sensitivity in a group of patients who were referred for the first time to a mental health outpatient clinic, without a formal diagnosis yet. METHODS: 259 young adults (between 18 and 24 years old) completed: the Eating Attitude Test (EAT-26), the Swedish Eating Assessment for Autism Spectrum Disorders (SWEAA), the Autism Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), and the Sensory Perception Quotient-Short Form 35 item (SPQ-SF35). RESULTS: 23.55% of participants scored above the cut-off at the EAT-26, suggesting that they presented a risk for eating disorders and should be assessed by a specialized clinician; associations emerged between hypersensitivity in the touch and vision domain and both the EAT-26 and the SWEAA; the presence of autistic traits was largely associated with eating disturbances. CONCLUSIONS: This study underlines the significance of the eating domain as a central psychopathological feature in the distress experienced by young adults with general psychiatric symptoms and psychological suffering; it adds evidence to the association between autistic traits and eating disorders and opens to new research questions about the role of subthreshold autistic traits in general psychopathology. LEVEL OF EVIDENCE: Level I: Evidence obtained from experimental studies.

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23. Pérez-Vigil A, Ilzarbe D, Garcia-Delgar B, Morer A, Pomares M, Puig O, Lera-Miguel S, Rosa M, Romero M, Calvo Escalona R, Lázaro L. Theory of mind in neurodevelopmental disorders: beyond autistic spectrum disorder. Neurologia (Engl Ed);2024 (Jan 23)

INTRODUCTION: Theory of mind (ToM) is the human ability to perceive, interpret, and attribute the mental states of other people, and the alteration of this cognitive function is a core symptom of autistic spectrum disorder (ASD). In such other neurodevelopmental disorders as childhood-onset obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) that can present with cognitive dysfunctions, ToM has been less extensively studied, especially in the young population. The aim of the study was to compare advanced ToM between groups of young people diagnosed with OCD, TS, or ASD and a control group. METHODS: Clinical interviews were conducted with male patients aged between 11 and 17 years with a main diagnosis of OCD (n = 19), TS (n = 14), or ASD (n = 18), and a control group (n = 20). We administered instruments for estimating intelligence quotient and severity of psychiatric symptoms, and tasks to evaluate ToM (the « Stories from everyday life » task and the « Reading the mind in the eyes » test). RESULTS: Young people with TS and with ASD present similar difficulties in solving advanced ToM tasks, whereas patients with childhood-onset OCD present similar results to controls. CONCLUSIONS: ToM is altered in other neurodevelopmental disorders beyond ASD, such as TS.

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24. Rezzani R, Gianò M, Pinto D, Rinaldi F, van Noorden CJF, Favero G. Hepatic Alterations in a BTBR T + Itpr3tf/J Mouse Model of Autism and Improvement Using Melatonin via Mitigation Oxidative Stress, Inflammation and Ferroptosis. Int J Mol Sci;2024 (Jan 16);25(2)

Autism spectrum disorder (ASD) is a complicated neurodevelopmental disorder, and its etiology is not well understood. It is known that genetic and nongenetic factors determine alterations in several organs, such as the liver, in individuals with this disorder. The aims of the present study were to analyze morphological and biological alterations in the liver of an autistic mouse model, BTBR T + Itpr3tf/J (BTBR) mice, and to identify therapeutic strategies for alleviating hepatic impairments using melatonin administration. We studied hepatic cytoarchitecture, oxidative stress, inflammation and ferroptosis in BTBR mice and used C57BL6/J mice as healthy control subjects. The mice were divided into four groups and then treated and not treated with melatonin, respectively. BTBR mice showed (a) a retarded development of livers and (b) iron accumulation and elevated oxidative stress and inflammation. We demonstrated that the expression of ferroptosis markers, the transcription factor nuclear factor erythroid-related factor 2 (NFR2), was upregulated, and the Kelch-like ECH-associated protein 1 (KEAP1) was downregulated in BTBR mice. Then, we evaluated the effects of melatonin on the hepatic alterations of BTBR mice; melatonin has a positive effect on liver cytoarchitecture and metabolic functions.

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25. Riebel M, Krasny-Pacini A, Manolov R, Rohmer O, Weiner L. Compassion focused therapy for self-stigma and shame in autism: a single case pre-experimental study. Front Psychiatry;2023;14:1281428.

INTRODUCTION: Exposure to public stigma can lead to the internalization of autism-related stigma (i.e., self-stigma), associated with negative health, occupational and social outcomes. Importantly, self-stigma is linked to shame and social isolation. Although elevated self-stigma has been reported in autistic adults, to the best of our knowledge, interventions designed to target this issue are lacking. Compassion is an effective way to reduce the emotional correlates of self-stigma (i.e., shame) and their impacts on mental health. However, no study has investigated whether compassion focused therapy (CFT) can effectively reduce self-stigma in autistic adults. The present study aims at investigating whether and how self-compassion improvement following CFT may reduce self-stigma and shame in an autistic individual. METHODS: A single case pre-experimental design (SCED) was used with weekly repeated measures during four phases: (i) pure baseline without any intervention (A), (ii) case conceptualization (A’), (iii) intervention (B) where CFT was delivered, (iv) follow-up without intervention (FU). The participant is a 46-year-old autistic man with high self-stigma and shame. Self-report measures of self-compassion and self-stigma and a daily idiographic measure of shame were used. RESULTS: There was a large increase in self-compassion between pure baseline (A) and the intervention phase (A’B) (Tau-U = 0.99), maintained at follow-up. Similarly, there was a moderate decrease of self-stigma (Tau-U = 0.32). In contrast, when we compared the whole baseline phase AA’ (i.e., considering the conceptualisation phase as baseline) to the intervention (B), there was no change in self-stigma (Tau-U = -0.09). There was no change in self-stigma between the intervention (B) and follow-up (Tau-U = -0.19). There was a moderate decrease in daily shame reports between the baseline (AA’) and the intervention (B) (Tau-U = 0.31) and a moderate decrease between the pure baseline (A) and intervention phase (A’B) (Tau-U = 0.51). CONCLUSION: CFT was feasible for this autistic client and our results show that CFT led to the improvement of self-compassion. Changes on self-stigma measures were moderate. Self-stigma may need more time to change. Because self-stigma is involved in poorer social functioning and mental health in autistic adults, our results are promising and suggesting conducting more large-scale studies on CFT in autistic adults.

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26. Rudrabhatla A, Hendrix N, Gillespie S, Ulven K, Jergel A, Greenfield E, Guerra K, Pickard K. A Mixed-methods Examination of Culturally Responsive Adaptation to an Evidence-based Parent-mediated Intervention Implemented for Autistic Children. Adm Policy Ment Health;2024 (Jan 23)

Parent-mediated interventions (PMIs) are considered an evidence-based practice for fostering social communication skills in young autistic children and for promoting parent responsivity and empowerment, yet barriers to caregiver engagement are evident when PMIs are implemented within historically underserved community settings. Issues of caregiver engagement can reflect a lack of fit between PMIs and the needs of diverse families. We used a mixed methods approach to examine barriers to participating in an evidence-based PMI, Project ImPACT (Ingersoll & Dvortcsak, 2019), within an outpatient setting, as well as strategies that clinicians reported using to deliver and adapt Project ImPACT for minoritized families. Participants included 134 caregivers of a child 13 to 48 months with autism or other social communication differences and six clinicians delivering Project ImPACT. Findings suggest that caregivers experience barriers to participating in Project ImPACT and that these barriers are associated with caregivers’ ability to complete the program. Although quantitative findings indicate that adaptation to Project ImPACT did not differ by caregiver and child background, qualitative findings highlighted that clinicians attempt to deliver Project ImPACT to respond to the needs of families from minoritized backgrounds by actively considering the family’s culture, psychosocial experiences, goals, and specific barriers. Further, both qualitative and quantitative findings suggest that culturally responsive care and adaptations may support caregiver engagement, including rapport, trust, buy-in, and attendance. Approaches to center cultural alongside contextual/psychosocial considerations within family-centered care in the implementation of PMIs are also highlighted.

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27. Sadhu C, Lyons C, Oh J, Jagadeeswaran I, Gray SJ, Sinnett SE. The Efficacy of a Human-Ready miniMECP2 Gene Therapy in a Pre-Clinical Model of Rett Syndrome. Genes (Basel);2023 (Dec 24);15(1)

Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and MECP2 duplication syndrome. These disorders underscore the conceptual dose-dependent risk posed by MECP2 gene therapy for mosaic RTT patients. Recently, a miRNA-Responsive Autoregulatory Element (miRARE) mitigated the dose-dependent toxicity posed by self-complementary adeno-associated viral vector serotype 9 (AAV9) miniMECP2 gene therapy (scAAV9/miniMECP2-myc) in mice. Here, we report an efficacy assessment for the human-ready version of this regulated gene therapy (TSHA-102) in male Mecp2(-/y) knockout (KO) mice after intracerebroventricular (ICV) administration at postnatal day 2 (P2) and after intrathecal (IT) administration at P7, P14 (±immunosuppression), and P28 (±immunosuppression). We also report qPCR studies on KO mice treated at P7-P35; protein analyses in KO mice treated at P38; and a survival safety study in female adult Mecp2(-/+) mice. In KO mice, TSHA-102 improved respiration, weight, and survival across multiple doses and treatment ages. TSHA-102 significantly improved the front average stance and swing times relative to the front average stride time after P14 administration of the highest dose for that treatment age. Viral genomic DNA and miniMECP2 mRNA were present in the CNS. MiniMeCP2 protein expression was higher in the KO spinal cord compared to the brain. In female mice, TSHA-102 permitted survivals that were similar to those of vehicle-treated controls. In all, these pivotal data helped to support the regulatory approval to initiate a clinical trial for TSHA-102 in RTT patients (clinical trial identifier number NCT05606614).

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28. Samoilova IG, Matveeva MV, Galyukova DE. [Biochemical markers of autism]. Zh Nevrol Psikhiatr Im S S Korsakova;2024;124(1):55-59.

Autism spectrum disorder (ASD) is becoming an increasingly common disorder of the development of the nervous system in the modern world. The diagnosis is made based on observation of the patient’s behavior, which significantly complicates the diagnosis and treatment of the disorder. The subjectivity of behavioral diagnostics dictates the need for the study of biomarkers of ASD. Over the past two decades, researchers have focused on identifying specific biological abnormalities in ASD that will help in the diagnosis of the disease. This review discusses the state of research on various biomarkers currently being developed for ASD.

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29. Sha M, Alqahtani A, Alsubai S, Dutta AK. Modified Meta Heuristic BAT with ML Classifiers for Detection of Autism Spectrum Disorder. Biomolecules;2023 (Dec 29);14(1)

ASD (autism spectrum disorder) is a complex developmental and neurological disorder that impacts the social life of the affected person by disturbing their capability for interaction and communication. As it is a behavioural disorder, early treatment will improve the quality of life of ASD patients. Traditional screening is carried out with behavioural assessment through trained physicians, which is expensive and time-consuming. To resolve the issue, several conventional methods strive to achieve an effective ASD identification system, but are limited by handling large data sets, accuracy, and speed. Therefore, the proposed identification system employed the MBA (modified bat) algorithm based on ANN (artificial neural networks), modified ANN (modified artificial neural networks), DT (decision tree), and KNN (k-nearest neighbours) for the classification of ASD in children and adolescents. A BA (bat algorithm) is utilised for the automatic zooming capability, which improves the system’s efficacy by excellently finding the solutions in the identification system. Conversely, BA is effective in the identification, it still has certain drawbacks like speed, accuracy, and falls into local extremum. Therefore, the proposed identification system modifies the BA optimisation with random perturbation of trends and optimal orientation. The dataset utilised in the respective model is the Q-chat-10 dataset. This dataset contains data of four stages of age groups such as toddlers, children, adolescents, and adults. To analyse the quality of the dataset, dataset evaluation mechanism, such as the Chi-Squared Statistic and p-value, are used in the respective research. The evaluation signifies the relation of the dataset with respect to the proposed model. Further, the performance of the proposed detection system is examined with certain performance metrics to calculate its efficiency. The outcome revealed that the modified ANN classifier model attained an accuracy of 1.00, ensuring improved performance when compared with other state-of-the-art methods. Thus, the proposed model was intended to assist physicians and researchers in enhancing the diagnosis of ASD to improve the standard of life of ASD patients.

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30. Song Y, Zhao Y, Baranova A, Cao H, Yue W, Zhang F. Causal association of attention-deficit/hyperactivity disorder and autism spectrum disorder with post-traumatic stress disorder. Psychiatr Genet;2024 (Jan 23)

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two neurodevelopmental disorders that often result in individuals experiencing traumatic events. However, little is known about the connection between ADHD/ASD and post-traumatic stress disorder (PTSD). This study aimed to investigate the genetic associations between these disorders. METHODS: Genetic correlation analysis was used to examine the genetic components shared between ADHD (38 691 cases and 275 986 controls), ASD (18 381 cases and 27 969 controls) and PTSD (23 212 cases and 151 447 controls). Two-sample Mendelian randomization analyses were employed to explore the bidirectional causal relationships between ADHD/ASD and PTSD. RESULTS: The results of the genetic correlation analysis revealed significant positive correlations of PTSD with ADHD(rg = 0.70) and ASD (rg = 0.34). Furthermore, the Mendelian randomization analysis revealed that genetic liabilities to ADHD [odds ratio (OR) = 1.14; 95% confidence interval (CI), 1.06-1.24; P = 7.88 × 10-4] and ASD (OR = 1.04; CI, 1.01-1.08; P = 0.014) were associated with an increased risk of developing PTSD later in life. However, no evidence supported that genetic liability to PTSD could elevate the risk of ADHD or ASD. CONCLUSION: The findings of this study supported that ADHD and ASD may increase the risk of PTSD, but not vice versa.

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31. Tadesse AW, Dachew BA, Ayano G, Betts K, Alati R. Prenatal cannabis use and the risk of attention deficit hyperactivity disorder and autism spectrum disorder in offspring: A systematic review and meta-analysis. J Psychiatr Res;2024 (Jan 23);171:142-151.

BACKGROUND: It is plausible that exposure to cannabis in-utero could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) during childhood and adolescence; however, mixed results have been reported. This study investigated whether there is an association between prenatal cannabis use and ADHD symptoms and ASD in offspring using a systematic review and meta-analysis methodology. METHODS: A systematic literature search was conducted in PubMed/Medline, Scopus, EMBASE, Web of Science, Psych-Info, and Google Scholar to identify relevant studies. The study protocol has been preregistered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42022345001), and the Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the methodological quality of included studies. An inverse variance weighted random effect meta-analysis was conducted to pool the overall effect estimates from the included studies. RESULTS: Fourteen primary studies, consisting of ten on ADHD and four on ASD, with a total of 203,783 participants, were included in this study. Our meta-analysis underscores an increased risk of ADHD symptoms and/or disorder [β = 0.39: 95 % CI (0.20-0.58), I(2) = 66.85 %, P = 0.001)] and ASD [RR = 1.30: 95 % CI (1.03-1.64), I(2) = 45.5 %, P = 0.14] associated with in-utero cannabis exposure in offspring compared to their non-exposed counterparts. Additionally, our stratified analysis highlighted an elevated risk of ADHD symptoms [β = 0.54: 95 % CI (0.26-0.82)] and a marginally significant increase in the risk of diagnostic ADHD among exposed offspring compared to non-exposed counterparts [RR = 1.13, 95 % CI (1.01, 1.26)]. CONCLUSION: This study indicated that maternal prenatal cannabis exposure is associated with a higher risk of ADHD symptoms and ASD in offspring.

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32. Tak Y, Tassone F, Hagerman RJ. Case Series: Vestibular Migraines in Fragile X Premutation Carriers. J Clin Med;2024 (Jan 16);13(2)

BACKGROUND: Vestibular migraine (VM) is one of the most common causes of recurrent vertigo and presents with a history of spontaneous or positional vertigo with a history of migraine headaches. While research has identified a high prevalence of migraine headaches and vestibular deficits among fragile X premutation carriers, there has been no discussion about VM within this population. OBJECTIVE: This case series and review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population. METHODS: A review of the literature regarding vestibular migraine and presentation of migraine headaches and vestibular deficits among premutation carriers was performed. A detailed clinical history of migraine headaches and vertigo was obtained from three patients with the fragile X premutation seen by the senior author (RJH). RESULTS: All three cases first developed symptoms of migraine headaches earlier in life, with the development of VM near menopause. Two of the three cases developed progressive balance issues following the development of VM. All three cases found that their VM episodes were improved or resolved with pharmacological and/or lifestyle interventions. CONCLUSIONS: It is important to recognize VM among premutation carriers because beneficial treatments are available. Future studies are needed regarding the prevalence of VM and the relationship to subsequent FXTAS. The pathophysiology of VM remains uncertain but possibilities include mitochondrial abnormalities, cranial nerve VIII toxicity secondary to neurotoxic protein accumulation, and calcitonin gene-related peptide (CGRP) signaling dysfunction due to altered levels of fragile X messenger ribonucleoprotein (FMRP).

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33. Talvio K, Castrén ML. Astrocytes in fragile X syndrome. Front Cell Neurosci;2023;17:1322541.

Astrocytes have an important role in neuronal maturation and synapse function in the brain. The interplay between astrocytes and neurons is found to be altered in many neurodevelopmental disorders, including fragile X syndrome (FXS) that is the most common inherited cause of intellectual disability and autism spectrum disorder. Transcriptional, functional, and metabolic alterations in Fmr1 knockout mouse astrocytes, human FXS stem cell-derived astrocytes as well as in in vivo models suggest autonomous effects of astrocytes in the neurobiology of FXS. Abnormalities associated with FXS astrocytes include differentiation of central nervous system cell populations, maturation and regulation of synapses, and synaptic glutamate balance. Recently, FXS-specific changes were found more widely in astrocyte functioning, such as regulation of inflammatory pathways and maintenance of lipid homeostasis. Changes of FXS astrocytes impact the brain homeostasis and function both during development and in the adult brain and offer opportunities for novel types of approaches for intervention.

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34. Viola TW, Danzer C, Mardini V, Szobot C, Chrusciel JH, Stertz L, Schmitz JM, Walss-Bass C, Fries GR, Grassi-Oliveira R. Prenatal cocaine exposure and its influence on pediatric epigenetic clocks and epigenetic scores in humans. Sci Rep;2024 (Jan 23);14(1):1946.

The investigation of the effects of prenatal cocaine exposure (PCE) on offspring has been inconsistent, with few studies investigating biological outcomes in humans. We profiled genome-wide DNA methylation (DNAm) of umbilical cord blood (UCB) from newborns with (n = 35) and without (n = 47) PCE. We used DNAm data to (1) assess pediatric epigenetic clocks at birth and (2) to estimate epigenetic scores (ES) for lifetime disorders. We generated gestational epigenetic age estimates (DNAmGA) based on Knight and Bohlin epigenetic clocks. We also investigated the association between DNAmGA and UCB serum brain-derived neurotrophic factor (BDNF) levels. Considering the large-scale DNAm data availability and existing evidence regarding PCE as a risk for health problems later in life, we generated ES for tobacco smoking, psychosis, autism, diabetes, and obesity. A gene ontology (GO) analysis on the CpGs included in the ES with group differences was performed. PCE was associated with lower DNAmGA in newborns, and this effect remained significant when controlling for potential confounders, such as blood cell type composition predicted by DNAm and obstetric data. DNAmGA was negatively correlated with BDNF levels in the serum of UCB. Higher tobacco smoking, psychosis, and diabetes ES were found in the PCE group. The GO analysis revealed GABAergic synapses as a potential pathway altered by PCE. Our findings of decelerated DNAmGA and ES for adverse phenotypes associated with PCE, suggest that the effects of gestational cocaine exposure on the epigenetic landscape of human newborns are detectable at birth.

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35. Westmark PR, Lyon G, Gutierrez A, Boeck B, Van Hammond O, Ripp N, Pagan-Torres NA, Brower J, Held PK, Scarlett C, Westmark CJ. Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice. Nutrients;2024 (Jan 18);16(2)

Obesity is a pediatric epidemic that is more prevalent in children with developmental disabilities. We hypothesize that soy protein-based diets increase weight gain and alter neurobehavioral outcomes. Our objective herein was to test matched casein- and soy protein-based purified ingredient diets in a mouse model of fragile X syndrome, Fmr1(KO) mice. The experimental methods included assessment of growth; 24-7 activity levels; motor coordination; learning and memory; blood-based amino acid, phytoestrogen and glucose levels; and organ weights. The primary outcome measure was body weight. We find increased body weight in male Fmr1(KO) from postnatal day 6 (P6) to P224, male wild type (WT) from P32-P39, female Fmr1(KO) from P6-P18 and P168-P224, and female Fmr1(HET) from P9-P18 as a function of soy. Activity at the beginning of the light and dark cycles increased in female Fmr1(HET) and Fmr1(KO) mice fed soy. We did not find significant differences in rotarod or passive avoidance behavior as a function of genotype or diet. Several blood-based amino acids and phytoestrogens were significantly altered in response to soy. Liver weight was increased in WT and adipose tissue in Fmr1(KO) mice fed soy. Activity levels at the beginning of the light cycle and testes weight were greater in Fmr1(KO) versus WT males irrespective of diet. DEXA analysis at 8-months-old indicated increased fat mass and total body area in Fmr1(KO) females and lean mass and bone mineral density in Fmr1(KO) males fed soy. Overall, dietary consumption of soy protein isolate by C57BL/6J mice caused increased growth, which could be attributed to increased lean mass in males and fat mass in females. There were sex-specific differences with more pronounced effects in Fmr1(KO) versus WT and in males versus females.

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36. Wilkes BJ, Archer DB, Farmer AL, Bass C, Korah H, Vaillancourt DE, Lewis MH. Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder. Mol Autism;2024 (Jan 23);15(1):6.

BACKGROUND: Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB. METHODS: We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB. RESULTS: Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FA(T)) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FA(T) and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes. LIMITATIONS: The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated. CONCLUSIONS: These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FA(T) was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.

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37. Yang J, He L, Dai S, Zheng H, Cui X, Ou J, Zhang X. Therapeutic efficacy of sulforaphane in autism spectrum disorders and its association with gut microbiota: animal model and human longitudinal studies. Front Nutr;2023;10:1294057.

INTRODUCTION: Sulforaphane (SFN) has been found to alleviate complications linked with several diseases by regulating gut microbiota (GM), while the effect of GM on SFN for autism spectrum disorders (ASD) has not been studied. Therefore, this study aimed to investigate the relationship between the effects of SFN on childhood ASD and GM through animal model and human studies. METHODS: We evaluated the therapeutic effects of SFN on maternal immune activation (MIA) induced ASD-like rat model and pediatric autism patients using three-chamber social test and OSU Autism Rating Scale-DSM-IV (OARS-4), respectively, with parallel GM analysis using 16SrRNA sequencing. RESULTS: SFN significantly improved the sniffing times of ASD-like rats in the three-chamber test. For human participants, the average verbal or non-verbal communication (OSU-CO) scores of SFN group had changed significantly at the 12-wk endpoint. SFN was safe and no serious side effects after taking. GM changes were similar for both ASD-like rats and ASD patients, such as consistent changes in order Bacillales, family Staphylococcaceae and genus Staphylococcus. Although the gut microbiota composition was significantly altered in SFN-treated ASD-like rats, the alteration of GM was not evident in ASD patients after 12 weeks of SFN treatment. However, in the network analysis, we found 25 taxa correlated with rats’ social behavior, 8 of which were associated with SFN treatment in ASD-like rats, For ASD patients, we found 35 GM abundance alterations correlated with improvements in ASD symptoms after SFN treatment. Moreover, family Pasteurellaceae and genus Haemophilus were found to be associated with SFN administration in the network analyses in both ASD-like rats and ASD patients. DISCUSSION: These findings suggest that SFN could provide a novel avenue for preventing and treating ASD, and its therapeutic effects might be related to gut microbiota.

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38. Yang W, Han Y, He C, Zhong S, Ren F, Chen Z, Mou Y, Sai K. Association between psychiatric disorders and glioma risk: evidence from Mendelian randomization analysis. BMC Cancer;2024 (Jan 23);24(1):118.

BACKGROUND: Observational studies have explored the association of psychiatric disorders and the risk of brain cancers. However, the causal effect of specific mental illness on glioma remains elusive due to the lack of solid evidence. METHODS: We performed a two-sample bidirectional Mendelian randomization (MR) analysis to explore the causal relationships between 5 common psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, and panic disorder) and glioma. Summary statistics for psychiatric disorders and glioma were extracted from Psychiatric Genomics Consortium (PGC) and 8 genome-wide association study (GWAS) datasets respectively. We calculated the MR estimates for odds ratio of glioma associated with each psychiatric disorder by using inverse-variance weighting (IVW) method. Sensitivity analyses such as weighted median estimator, MR-Egger and MR-PRESSO were leveraged to assess the strength of causal inference. RESULTS: A total of 30,657 participants of European ancestry were included in this study. After correction for multiple testing, we found that genetically predicted schizophrenia was associated with a statistically significant increase in odds of non-glioblastoma multiforme (non-GBM) (OR = 1.13, 95% CI: 1.03-1.23, P = 0.0096). There is little evidence for the causal relationships between the other 4 psychiatric disorders with the risk of glioma. CONCLUSIONS: In this MR analysis, we revealed an increased risk of non-GBM glioma in individuals with schizophrenia, which gives an insight into the etiology of glioma.

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39. Yousef BM, Bhaskar Raj N, Nadiah WA, Dhas BN, Mansour AM, Abd Alhadi SA, Rosal FV, Dizon MM. Integrated Life Skills Training and Executive Function Strategies in Children With Autism Spectrum Disorder in Qatar: A Pilot Study of a Randomized Controlled Trial. Cureus;2024 (Jan);16(1):e52809.

Background and aim Executive function (EF) impairment is common in children with autism spectrum disorder (ASD). EF strategies are considered effective in improving the therapeutic outcomes of children with ASD. This study primarily aimed to explore whether integrating EF strategies combined with regular occupational therapy intervention is more effective in improving daily life skills (DLS) and sensory integration/processing (SI/SP) skills than regular occupational therapy alone in children with ASD and secondarily aims to assess treatment outcomes on improving visual motor integration (VMI) skills. Methods A total of 17 participants (13 males, mean age 4.29 years, standard deviation 0.66) completed the study. Following the baseline assessments, the participants were randomly assigned to the treatment group (45-minute once-weekly individual occupational therapy plus EF strategies) or control group (45-minute once-weekly individual therapy sessions alone). All participants received one intervention per week for 14 weeks. All children were systematically evaluated using a pediatric functional independent measure (WeeFIM) and the Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) to assess DLS, the Short Sensory Profile 2 (SSP2) to assess SP/SI, and the Beery VMI test (Beery VMI) to assess VMI. Assessments were conducted at baseline, seven weeks, and 14 weeks of treatment. Results The analysis of the results between the treatment and control groups revealed that the treatment group had greater gains and significant differences in the mean values of both the WeeFIM and SSP2. In addition, notable distinctions were observed in the VB-MAPP transition subscale; although these differences did not reach statistical significance, they were clinically significant. Minimal differences were noted in the VMI between the two groups. Nevertheless, both groups showed statistically significant improvements across all outcome measures. Conclusions Our study provides preliminary evidence of the efficacy of EF strategies combined with regular occupational therapy for DLS, SP/SI, and VMI in children with ASD. The differences between the groups support further evaluation of the effectiveness of EF strategies for the next stage of a larger randomized clinical trial.

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40. Zhang Q, Li F, Li T, Lin J, Jian J, Zhang Y, Chen X, Liu T, Gou S, Zhang Y, Liu X, Ji Y, Wang X, Li Q. Nomo1 deficiency causes autism-like behavior in zebrafish. EMBO Rep;2024 (Jan 22)

Patients with neuropsychiatric disorders often exhibit a combination of clinical symptoms such as autism, epilepsy, or schizophrenia, complicating diagnosis and development of therapeutic strategies. Functional studies of novel genes associated with co-morbidities can provide clues to understand the pathogenic mechanisms and interventions. NOMO1 is one of the candidate genes located at 16p13.11, a hotspot of neuropsychiatric diseases. Here, we generate nomo1(-/-) zebrafish to get further insight into the function of NOMO1. Nomo1 mutants show abnormal brain and neuronal development and activation of apoptosis and inflammation-related pathways in the brain. Adult Nomo1-deficient zebrafish exhibit multiple neuropsychiatric behaviors such as hyperactive locomotor activity, social deficits, and repetitive stereotypic behaviors. The Habenular nucleus and the pineal gland in the telencephalon are affected, and the melatonin level of nomo1(-/-) is reduced. Melatonin treatment restores locomotor activity, reduces repetitive stereotypic behaviors, and rescues the noninfectious brain inflammatory responses caused by nomo1 deficiency. These results suggest melatonin supplementation as a potential therapeutic regimen for neuropsychiatric disorders caused by NOMO1 deficiency.

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