1. Akol I, Gather F, Vogel T. Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective. International journal of molecular sciences. 2022; 23(2).

Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions.

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2. Alfieri P, Scibelli F, Casula L, Piga S, Napoli E, Valeri G, Vicari S. Cooperative Parent-Mediated Therapy in Children with Fragile X Syndrome and Williams Beuren Syndrome: A Pilot RCT Study of a Transdiagnostic Intervention-Preliminary Data. Brain sciences. 2021; 12(1).

Children with fragile X syndrome and William Beuren syndrome share several socio-communicative deficits. In both populations, around 30/35% of individuals meets criteria for autism spectrum disorder on gold standard instruments. Notwithstanding, few studies have explored feasibility and validity of therapy for socio-communicative deficits in individuals with these genetic conditions. In this study, we present preliminary data on a pilot RCT aimed to verify the effectiveness of cooperative parent-mediated therapy for socio-communicative deficits in a transdiagnostic perspective in a small sample of 12 participants. Our preliminary data showed that the experimental group had significant improvement in one socio-communicative skill (responsivity) and in clinical global impression, while the control group in an adaptive measure of socialization and word production. Implications of these results are then discussed.

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3. Ali MT, ElNakieb Y, Elnakib A, Shalaby A, Mahmoud A, Ghazal M, Yousaf J, Abu Khalifeh H, Casanova M, Barnes G, El-Baz A. The Role of Structure MRI in Diagnosing Autism. Diagnostics (Basel, Switzerland). 2022; 12(1).

This study proposes a Computer-Aided Diagnostic (CAD) system to diagnose subjects with autism spectrum disorder (ASD). The CAD system identifies morphological anomalies within the brain regions of ASD subjects. Cortical features are scored according to their contribution in diagnosing a subject to be ASD or typically developed (TD) based on a trained machine-learning (ML) model. This approach opens the hope for developing a new CAD system for early personalized diagnosis of ASD. We propose a framework to extract the cerebral cortex from structural MRI as well as identifying the altered areas in the cerebral cortex. This framework consists of the following five main steps: (i) extraction of cerebral cortex from structural MRI; (ii) cortical parcellation to a standard atlas; (iii) identifying ASD associated cortical markers; (iv) adjusting feature values according to sex and age; (v) building tailored neuro-atlases to identify ASD; and (vi) artificial neural networks (NN) are trained to classify ASD. The system is tested on the Autism Brain Imaging Data Exchange (ABIDE I) sites achieving an average balanced accuracy score of 97±2%. This paper demonstrates the ability to develop an objective CAD system using structure MRI and tailored neuro-atlases describing specific developmental patterns of the brain in autism.

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4. Avraham O, Deng PY, Maschi D, Klyachko VA, Cavalli V. Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model. Frontiers in molecular neuroscience. 2021; 14: 796070.

Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated transcriptional changes in both neurons and SGCs, indicative of defects in neuronal maturation and altered SGC vesicular secretion. We validated these changes using fluorescence microscopy, qPCR, and high-resolution transmission electron microscopy (TEM) in combination with computational analyses using deep learning networks. These results revealed a disrupted neuron-glia association at the structural and functional levels. Given the well-established role for SGCs in regulating sensory neuron function, altered neuron-glia association may contribute to sensory deficits in FXS.

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5. Champigny C, Morin-Parent F, Bellehumeur-Lefebvre L, Çaku A, Lepage JF, Corbin F. Combining Lovastatin and Minocycline for the Treatment of Fragile X Syndrome: Results From the LovaMiX Clinical Trial. Frontiers in psychiatry. 2021; 12: 762967.

Background: Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). Here, we report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently. Aim: The main goals of the study were to assess the safety and efficacy of a treatment combining lovastatin and minocycline for patients with FXS. Design: Pilot Phase II open-label clinical trial. Patients with a molecular diagnostic of FXS were first randomized to receive, in two-step titration either lovastatin or minocycline for 8 weeks, followed by dual treatment with lovastatin 40 mg and minocycline 100 mg for 2 weeks. Clinical assessments were performed at the beginning, after 8 weeks of monotherapy, and at week 20 (12 weeks of combined therapy). Outcome Measures: The primary outcome measure was the Aberrant Behavior Checklist-Community (ABC-C) global score. Secondary outcome measures included subscales of the FXS specific ABC-C (ABC-C(FX)), the Anxiety, Depression, and Mood Scale (ADAMS), the Social Responsiveness Scale (SRS), the Behavior Rating Inventory of Executive Functions (BRIEF), and the Vineland Adaptive Behavior Scale second edition (VABS-II). Results: Twenty-one individuals out of 22 completed the trial. There were no serious adverse events related to the use of either drugs alone or in combination, suggesting good tolerability and safety profile of the combined therapy. Significant improvement was noted on the primary outcome measure with a 40% decrease on ABC-C global score with the combined therapy. Several outcome measures also showed significance. Conclusion: The combination of lovastatin and minocycline is safe in patients for FXS individuals and appears to improve several elements of the behavior. These results set the stage for a larger, placebo-controlled double-blind clinical trial to confirm the beneficial effects of the combined therapy.

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6. Cheng YL, Chu CL, Wu CC. How Do Children with Autism Spectrum Disorder and Children with Developmental Delays Differ on the Child Behavior Checklist 1.5-5 DSM-Oriented Scales?. Children (Basel, Switzerland). 2022; 9(1).

The Child Behavior Checklist 1.5-5 (CBCL 1.5-5) is applied to identify emotional and behavioral problems on children with developmental disabilities (e.g., autism spectrum disorder [ASD] and developmental delays [DD]). To understand whether there are variations between these two groups on CBCL DSM-oriented scales, we took two invariance analyses on 443 children (228 children with ASD). The first analysis used measurement invariance and multiple-group factor analysis on the test structure. The second analysis used item-level analysis, i.e., differential item functioning (DIF), to discover whether group memberships responded differently on some items even though underlying trait levels were the same. It was discovered that, on the test structure, the Anxiety Problems scale did not achieve metric invariance. The other scales achieved metric invariance; DIF analyses further revealed that there were items that functioned differently across subscales. These DIF items were mostly about children’s reactions to the surrounding environment. Our findings provide implications for clinicians to use CBCL DSM-oriented scales on differentiating children with ASD and children with DD. In addition, researchers need to be mindful about how items were responded differently, even though there were no mean differences on the surface.

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7. Clarke RA, Eapen V. LRRTM4 Terminal Exon Duplicated in Family with Tourette Syndrome, Autism and ADHD. Genes. 2021; 13(1).

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by motor and vocal tics and strong association with autistic deficits, obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). The genetic overlap between TS and autism spectrum disorder (ASD) includes those genes that encode the neurexin trans-synaptic connexus (NTSC) inclusive of the presynaptic neurexins (NRXNs) and postsynaptic neuroligins (NLGNs), cerebellin precursors (CBLNs in complex with the glutamate ionotropic receptor deltas (GRIDs)) and the leucine-rich repeat transmembrane proteins (LRRTMs). In this study, we report the first evidence of a TS and ASD association with yet another NTSC gene family member, namely LRRTM4. Duplication of the terminal exon of LRRTM4 was found in two females with TS from the same family (mother and daughter) in association with autistic traits and ASD.

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8. Fusar-Poli L, Martinez M, Surace T, Meo V, Patania F, Avanzato C, Signorelli MS, Aguglia E. The Psychological Impact of the COVID-19 Lockdown: A Comparison between Caregivers of Autistic and Non-Autistic Individuals in Italy. Brain sciences. 2022; 12(1).

The COVID-19 outbreak has disrupted the daily routine of the population worldwide, including autistic people and their caregivers, with severe consequences on mental health. On one hand, the reduced social contacts and the interruption of outpatient and daycare services during the lockdown have represented a real challenge for autistic people and their caregivers. On the other hand, confinement has allowed individuals to spend more time pursuing their interests and stay home with their family members without feeling the pressure of social expectations. The present study aimed to compare the levels of personal wellbeing, family distress, insomnia, and resilience between caregivers of autistic people and caregivers of people with other neurodevelopmental, psychiatric, or relational disabilities. A web survey was completed by 383 participants, of which 141 were primary caregivers of autistic people. We did not find any significant difference between caregivers of autistic and non-autistic people in any of the considered psychological variables. Lower age of the autistic family member and lower resilience levels were significantly associated with higher individual distress in the group of caregivers of autistic people. Our findings do not corroborate the hypothesis that caregivers of autistic individuals have had more severe consequences than other caregivers during the lockdown. However, they confirm the importance of promoting resilient coping strategies in autistic people and their caregivers.

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9. Gordillo ML, Chu A, Long K. Differences in Processes Underlying Autism Service Engagement Among Latina and Non-Latina Mothers. Journal of autism and developmental disorders. 2022.

Latino children on the autism spectrum experience less access to autism services and more barriers to service-use than non-Latino White children. Yet, existing research leaves unanswered questions about how cultural, family, and service system-level processes contribute to autism service-use disparities. This study aimed to qualitatively explore how Latina and non-Latina mothers experience similar encounters with autism services. Twenty Latina and non-Latina mothers completed semi-structured interviews regarding their experiences accessing services. Data were analyzed using applied thematic analysis. Ethnicity-based differences emerged in mothers’ service-use motivations (i.e., desiring ongoing support vs. eventual departure), service evaluations (i.e., dissatisfaction vs. satisfaction), and service-seeking approaches (i.e., proactive vs. reactive). Findings illustrate how these processes underlying service engagement may contribute to service disparities for Latino children.

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10. Gouda B, Sinha SN, Chalamaiah M, Vakdevi V, Shashikala P, Veeresh B, Surekha VM, Kasturi V, Boiroju NK. Sex Differences in Animal Models of Sodium-Valproate-Induced Autism in Postnatal BALB/c Mice: Whole-Brain Histoarchitecture and 5-HT2A Receptor Biomarker Evidence. Biology. 2022; 11(1).

Autism spectrum disorder (ASD) is characterised by problems with social interaction, verbal and nonverbal communication and repetitive behaviour. In mice, the 14th postnatal day is believed to correspond to the third trimester of human embryonic development and is considered a vital period for central nervous system development. It has been shown that ASD affects 2 to 3 times more male than female individuals. In the present study, ASD was induced in 14 postnatal day (PND) BALB/c mice using valproic acid (VPA). VPA administration brought about substantial differences in the histoarchitecture of the brain in both male and female mice, linked to behavioural deficits. We observed that both male and female mice showed similar morphological changes in the prefrontal cortex, hippocampus and Purkinje cells. We also observed hair loss from PND 17 to 25, which was again similar between male and female mice. However, there were higher rates of change in the cerebral cortex, frontal cortex and temporal lobe and hippocampus in VPA-treated male animals. With respect to the cerebellum, we did not observe any alterations by haematoxylin and eosin (H&E) staining, but detailed morphological observation using scanning electron microscopy (SEM) showed a higher rate of phenotype changes in VPA-treated male animals. Moreover, 5-HT2A receptor protein levels were upregulated in the cerebral cortex, hippocampus and Purkinje cells in VPA-treated male mice compared with control animals and VPA-treated female mice, as shown by immunohistochemical analysis. Based on all these findings, we conclude that male animals are more susceptible to VPA-induced ASD than females.

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11. Herman A, Herman AP. Could Candida Overgrowth Be Involved in the Pathophysiology of Autism?. Journal of clinical medicine. 2022; 11(2).

The purpose of this review is to summarize the current acquiredknowledge of Candida overgrowth in the intestine as a possible etiology of autism spectrum disorder (ASD). The influence of Candida sp. on the immune system, brain, and behavior of children with ASD isdescribed. The benefits of interventions such as a carbohydrates-exclusion diet, probiotic supplementation, antifungal agents, fecal microbiota transplantation (FMT), and microbiota transfer therapy (MTT) will be also discussed. Our literature query showed that the results of most studies do not fully support the hypothesis that Candida overgrowth is correlated with gastrointestinal (GI) problems and contributes to autism behavioral symptoms occurrence. On the one hand, it was reported that the modulation of microbiota composition in the gut may decrease Candida overgrowth, help reduce GI problems and autism symptoms. On the other hand, studies on humans suggesting the beneficial effects of a sugar-free diet, probiotic supplementation, FMT and MTT treatment in ASD are limited and inconclusive. Due to the increasing prevalence of ASD, studies on the etiology of this disorder are extremely needed and valuable. However, to elucidate the possible involvement of Candida in the pathophysiology of ASD, more reliable and well-designed research is certainly required.

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12. Hume K, Steinbrenner JR, Odom SL, Morin KL, Nowell SW, Tomaszewski B, Szendrey S, McIntyre NS, Yücesoy-Özkan S, Savage MN. Correction to: Evidence-Based Practices for Children, Youth, and Young Adults with Autism: Third Generation. Journal of autism and developmental disorders. 2022.

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13. Ji C, Yang J. Effects of Physical Exercise and Virtual Training on Visual Attention Levels in Children with Autism Spectrum Disorders. Brain sciences. 2021; 12(1).

This study compared the effects of physical exercise (PE) and virtual training (VT) on the improvement of the visual attention mechanism in children with autism spectrum disorders (ASD). One hundred eighty-nine children with ASD were recruited from Orphan School in Liaoning Province, China. After screening, 100 children ultimately participated in the experiment. Children with ASD were randomly assigned to VT (VT, n = 34), PE (PE, n = 33) and control group (CG, n = 33). The VT group experiment was performed in a virtual environment through the game FIFA21 three times per week for 6 weeks. The PE group played physical football matches three times per week for 6 weeks. Children with ASD in the CG group did not receive VT or PE but only received psychological counseling. Visual attention of children with ASD is evaluated by using the multiple object tracking paradigm (MOT). After 6 weeks of observation, although none of the three groups saw improvements in the correct rate of ring tracking, the observations of the VT and PE groups were significant (p < 0.05) compared to the CG group in finding detection rate of probe stimulus. Through MOT tests, VT and PE improved the detection rate of probe stimulus in children with ASD. Therefore, this paper indicates that VT and PE can improve the visual attention ability of children with ASD.

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14. Lamash L, Little L, Hen-Herbst L. Telehealth Interventions to Promote Health and Behavior-Related Outcomes in Adolescents with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022: 1-19.

This systematic review examined the effectiveness in a hybrid telehealth model for adolescents with autism spectrum disorder (ASD), exploring the evidence base, methodology, and outcomes of health and behavior-related interventions for adolescents with ASD. The 11 included studies (a) were quantitative, (b) evaluated interventions delivered through a hybrid telehealth model (i.e., combined remote intervention with minimal in-person procedures), (c) measured health and behavior-related outcomes, and (d) considered adolescence as ages 12 through 25 years. The studies were a mixture of designs, methods, and outcome measures, and participant numbers were extremely low. Results demonstrated an overall lack of empirical evidence on the efficacy of hybrid-delivered interventions for adolescents with ASD, and more studies are needed to explore their effectiveness.

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15. Larraceleta A, Castejón L, Iglesias-García MT, Núñez JC. Assessment of Public Special Education Teachers Training Needs on Evidence-Based Practice for Students with Autism Spectrum Disorders in Spain. Children (Basel, Switzerland). 2022; 9(1).

Over decades, the concern for the quality of psychoeducational practices for students with autism spectrum disorders has led to study to what extent are evidence-based educational methods disseminated among teachers. The purpose of this cross-sectional study, taking as reference Hsiao and Sorensen’s previous research, was to identify through a survey to what extent social-communication evidence-based practices for these students were provided in teacher education and in-service training programs, in a sample of 108 special education teachers from Spain, and to compare these results with Hsiao and Sorensen’s. Overall, more than 70% of the teachers reported that evidence-based practices in their teacher education programs (87.6%) and in-service training programs (73.6%) were never taught or mentioned incidentally. Finally, a higher percentage of addressing on each practice (i.e., mentioned and discussed or mentioned and taught through direct instruction) is shown in the sample of American teachers compared to the Spaniards, in both training paths.

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16. Lee CL, Chuang CK, Tu RY, Chiu HC, Lo YT, Chang YH, Chen YJ, Chou CL, Wu PS, Chen CP, Lin HY, Lin SP. Increased Diagnostic Yield of Array Comparative Genomic Hybridization for Autism Spectrum Disorder in One Institution in Taiwan. Medicina (Kaunas, Lithuania). 2021; 58(1).

Background and Objectives: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNVs) and is recommended for the initial genetic testing of patients with autism spectrum disorder (ASD). This study aims to determine the diagnostic yield of array comparative genomic hybridization (array-CGH) in ASD patients from a cohort of Chinese patients in Taiwan. Materials and Methods: Enrolled in this study were 80 ASD children (49 males and 31 females; 2-16 years old) followed up at Taipei MacKay Memorial Hospital between January 2010 and December 2020. The genomic DNA extracted from blood samples was analyzed by array-CGH via the Affymetrix GeneChip Genome-Wide Human single nucleotide polymorphism (SNP) and NimbleGen International Standards for Cytogenomic Arrays (ISCA) Plus Cytogenetic Arrays. The CNVs were classified into five groups: pathogenic (pathologic variant), likely pathogenic (potential pathologic variant), likely benign (potential normal genomic variant), benign (normal genomic variant), and uncertain clinical significance (variance of uncertain significance), according to the American College of Medical Genetics (ACMG) guidelines. Results: We identified 47 CNVs, 31 of which in 27 patients were clinically significant. The overall diagnostic yield was 33.8%. The most frequently clinically significant CNV was 15q11.2 deletion, which was present in 4 (5.0%) patients. Conclusions: In this study, a satisfactory diagnostic yield of array-CGH was demonstrated in a Taiwanese ASD patient cohort, supporting the clinical usefulness of array-CGH as the first-line testing of ASD in Taiwan.

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17. Lu W, Xu C, Hu X, Liu J, Zhang Q, Peng L, Li M, Li W. The Relationship Between Resilience and Posttraumatic Growth Among the Primary Caregivers of Children With Developmental Disabilities: The Mediating Role of Positive Coping Style and Self-Efficacy. Frontiers in psychology. 2021; 12: 765530.

This study was conducted to investigate the relationship between posttraumatic growth (PTG), resilience, positive coping style, and self-efficacy among the primary caregivers of children with developmental disorders in Chongqing, China. A total of 198 primary caregivers (parents and grandparents) aged from 22 to 66 years old (M = 35.55, SD = 9.16), including 155 females (78.3%) and 43 males (21.7%), were enrolled. The Posttraumatic Growth Inventory, Connor-Davidson Resilience Scale-10, Simplified Coping Style Questionnaire, and General Self-Efficacy Scale were used for data collection. The results found that PTG could be positively predicted by resilience. Positive coping style and self-efficacy mediated the relationship between resilience and PTG. The different levels of PTG were determined by the resident location, monthly income and education of the primary caregivers. The results suggest that it is critical to improve the mental health of the primary caregivers (parents and grandparents) of children with developmental disabilities. Our results also provide a scientific basis for future research.

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18. Lung FW, Shu BC. The synergistic interaction between urbanicity and maternal education affecting childcare pressure related to autism spectrum disorder in two national birth cohort studies. European child & adolescent psychiatry. 2022.

To gain a holistic approach for parental help-seeking behavior and ASD diagnosis, this study aimed to use two national birth cohort study datasets to investigate the pathway relationship between personal and social/environmental factors, including maternal perceived childcare pressure, maternal level of education, urbanization at age 3, and the chance of receiving a autism spectrum disorder (ASD) diagnosis at when children are aged 5.5 years (2.5 years later). The 2003 Taiwan Birth Cohort Pilot Study (TBCS-p; N = 1618) and 2005 Taiwan Birth Cohort Study (TBCS; N = 19,183) datasets were used. The TBCS-p and TBCS both showed similar prevalence of ASD (0.3-0.4%). Children with ASD characteristics, as measured using the Modified Checklist of Autism in Toddlers, had 8.27-18.20 times increased likelihood of receiving ASD diagnosis [TBCS confidence interval (CF) of 5.32-12.86; TBCS-p CF of 2.03-163.46]. Pathway analysis showed that, although having a mother with higher education or who lived in a city decreased the chance for ASD diagnosis, the interactive effect of a maternal higher level of education and living in a city led to an increased likelihood for ASD diagnosis. Additionally, mothers who perceived a higher level of childcare pressure were also more likely to seek medical assistance and diagnosis. Access to healthcare (living in the city), maternal level of awareness (level of education), and perceived childcare pressure are all factors that influence help-seeking behavior and diagnosis. Therefore, medical professionals should pay special attention to the developmental condition of children in underserved backgrounds and rural areas to prevent delayed diagnosis.

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19. Masedu F, Vagnetti R, Pino MC, Valenti M, Mazza M. Comparison of Visual Fixation Trajectories in Toddlers with Autism Spectrum Disorder and Typical Development: A Markov Chain Model. Brain sciences. 2021; 12(1).

Autism spectrum disorder (ASD) is a neurodevelopmental condition in which visual attention and visual search strategies are altered. Eye-tracking paradigms have been used to detect these changes. In our study, 18 toddlers with ASD and 18 toddlers with typical development (TD; age range 12-36 months) underwent an eye-tracking paradigm where a face was shown together with a series of objects. Eye gaze was coded according to three areas of interest (AOIs) indicating where the toddlers’ gaze was directed: ‘Face’, ‘Object’, and ‘No-stimulus fixation’. The fixation sequence for the ASD and TD groups was modelled with a Markov chain model, obtaining transition probabilities between AOIs. Our results indicate that the transition between AOIs could differentiate between toddlers with ASD or TD, highlighting different visual exploration patterns between the groups. The sequence of exploration is strictly conditioned based on previous fixations, among which ‘No-stimulus fixation’ has a critical role in differentiating the two groups. Furthermore, our analyses underline difficulties of individuals with ASD to engage in stimulus exploration. These results could improve clinical and interventional practice by considering this dimension among the evaluation process.

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20. Mujeeb Rahman KK, Subashini MM. Identification of Autism in Children Using Static Facial Features and Deep Neural Networks. Brain sciences. 2022; 12(1).

Autism spectrum disorder (ASD) is a complicated neurological developmental disorder that manifests itself in a variety of ways. The child diagnosed with ASD and their parents’ daily lives can be dramatically improved with early diagnosis and appropriate medical intervention. The applicability of static features extracted from autistic children’s face photographs as a biomarker to distinguish them from typically developing children is investigated in this study paper. We used five pre-trained CNN models: MobileNet, Xception, EfficientNetB0, EfficientNetB1, and EfficientNetB2 as feature extractors and a DNN model as a binary classifier to identify autism in children accurately. We used a publicly available dataset to train the suggested models, which consisted of face pictures of children diagnosed with autism and controls classed as autistic and non-autistic. The Xception model outperformed the others, with an AUC of 96.63%, a sensitivity of 88.46%, and an NPV of 88%. EfficientNetB0 produced a consistent prediction score of 59% for autistic and non-autistic groups with a 95% confidence level.

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21. Ni’matuzahroh, Suen MW, Ningrum V, Widayat, Yuniardi MS, Hasanati N, Wang JH. The Association between Parenting Stress, Positive Reappraisal Coping, and Quality of Life in Parents with Autism Spectrum Disorder (ASD) Children: A Systematic Review. Healthcare (Basel, Switzerland). 2021; 10(1).

Parents with autism spectrum disorder (ASD) children generally suffer from poor coping and an impaired quality of life (QoL). This systematic review investigates parenting stress, positive reappraisal coping, and QoL in parents with ASD children. A literature search was carried out for publications written in English on the selected investigation topics using five databases, namely, Scopus, PubMed, Wiley, ScienceDirect Online, and EBSCO. Only studies investigating or measuring parenting stress, positive reappraisal coping, and QoL in ASD were included. Our results indicate that parents with ASD children have high stress levels. This is associated with the ineffective use of coping strategies and a low QoL. Adaptive coping strategies are related to a higher QoL, whereas maladaptive coping techniques are related to a worse QoL. Positive reappraisal coping is negatively correlated to meaningfulness, and it is used by parents to change their daily routines in order to motivate themselves towards new and evolving goals in life. Finally, we found a significant negative correlation between parenting stress, positive reappraisal coping, and the QoL of parents with ASD children. Positive reappraisal coping as a strategy helps parents adapt to stress and was found to be a potential mediatory function between parental stress and QoL.

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22. Niu Y, Qian Q, Li J, Gong P, Jiao X, Mao X, Xiao B, Long L, Yang Z. De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype. Clinical genetics. 2022; 101(4): 459-65.

AGO1, as one of the rare genes in neurodevelopmental disorders, is involved in the microRNA-induced silencing complex. Here, we describe the clinical and genetic features of 18 individuals with de novo AGO1 variants: four new and 14 previously reported. Three variants are identified: two in-frame deletion variants and one missense variant. The spectrum of AGO1-related disorders included global development delay (GDD), intellectual disability (ID) with or without epilepsy, autism spectrum disorder, hypotonia and dysmorphisms. Focal seizures are the most common type of seizure, occasionally with atypical absence. Mild deafness may be a new phenotype of AGO1-releated disease. Gly199Ser may be a hot-spot variant of AGO1 with the same phenotype: GDD/ID, intractable epilepsy, remarkably with Rolandic discharges, and even reaching electrical status epilepticus during sleep.

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23. O’Leary K. Understanding microbiome alterations in autism. Nature medicine. 2022.

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24. Padrón I, García-Marco E, Moreno I, Birba A, Silvestri V, León I, Álvarez C, López J, de Vega M. Multisession Anodal tDCS on the Right Temporo-Parietal Junction Improves Mentalizing Processes in Adults with Autistic Traits. Brain sciences. 2021; 12(1).

Persons with autism spectrum disorder (ASD) have impaired mentalizing skills. In this study, a group of persons with ASD traits (high-AQ scores) initially received sham tDCS before completing a pre-test in two mentalizing tasks: false belief and self-other judgments. Over the next week, on four consecutive days, they received sessions of anodal electrical stimulation (a-tDCS) over the right temporo-parietal junction (rTPJ), a region frequently associated with the theory of mind. On the last day, after the stimulation session, they completed a new set of mentalizing tasks. A control group (with low-AQ scores) matched in age, education and intelligence received just sham stimulation and completed the same pre-test and post-test. The results showed that the high-AQ group improved their performance (faster responses), after a-tDCS, in the false belief and in the self-other judgments of mental features, whereas they did not change performance in the false photographs or the self-other judgments of physical features. These selective improvements cannot be attributed to increased familiarity with the tasks, because the performance of the low-AQ control group remained stable about one week later. Therefore, our study provides initial proof that tDCS could be used to improve mentalizing skills in persons with ASD traits.

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25. Pillay S, Duncan M, de Vries PJ. Who’s waiting for a school? Rates, socio-demographics, disability and referral profile of children with autism spectrum disorder awaiting school placement in the Western Cape Province of South Africa. Autism : the international journal of research and practice. 2022: 13623613211067324.

In South Africa, there are limited educational opportunities for children with autism spectrum disorder and many children with autism spectrum disorder have to wait for school placement. This study examined the education waiting list for children with autism spectrum disorder in the Western Cape Province of South Africa and reported on the demographic, disability, referral and service provision characteristics of these children. In June 2016, there were 744 children with definite autism spectrum disorder or possible autism spectrum disorder between the ages of 1 and 17 years waiting for school placement. There were children of compulsory school-going age who were reported to be at home and not receiving any intervention while they waited. More than half the children on the waiting list had been waiting for more than a year. We then combined the findings of this study with the findings of a previous study on children with autism spectrum disorder already attending schools in the province over the same period of time. We found a total of 1684 children known to have autism spectrum disorder – this was less than 0.1% of all young people in the province at the time. Between 2012 and 2016, there was a 276% increase in the number of children with autism spectrum disorder waiting for schools in the Western Cape. The results show that education systems in the Western Cape need to be strengthened to accommodate all children with autism spectrum disorder in appropriate education settings from as early as possible. We recommend engaging with different stakeholders to develop policies, best practice guidelines and actions for autism spectrum disorder education in South Africa.

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26. Ramachandran S, Kalra S, Shaw SC. Fordyce Spots in a Neonate. Indian pediatrics. 2022; 59(1): 91.

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27. Riemersma IW, Havekes R, Kas MJH. Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder. Genes. 2021; 13(1).

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.

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28. Sheikh TI, Harripaul R, Vasli N, Ghadami M, Santangelo SL, Ayub M, Sasanfar R, Vincent JB. Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization. Genes. 2021; 13(1).

Nucleolin (NCL/C23; OMIM: 164035) is a major nucleolar protein that plays a critical role in multiple processes, including ribosome assembly and maturation, chromatin decondensation, and pre-rRNA transcription. Due to its diverse functions, nucleolin has frequently been implicated in pathological processes, including cancer and viral infection. We recently identified a de novo frameshifting indel mutation of NCL, p.Gly664Glufs*70, through whole-exome sequencing of autism spectrum disorder trios. Through the transfection of constructs encoding either a wild-type human nucleolin or a mutant nucleolin with the same C-terminal sequence predicted for the autism proband, and by using co-localization with the nucleophosmin (NPM; B23) protein, we have shown that the nucleolin mutation leads to mislocalization of the NCL protein from the nucleolus to the nucleoplasm. Moreover, a construct with a nonsense mutation at the same residue, p.Gly664*, shows a very similar effect on the location of the NCL protein, thus confirming the presence of a predicted nucleolar location signal in this region of the NCL protein. Real-time fluorescence recovery experiments show significant changes in the kinetics and mobility of mutant NCL protein in the nucleoplasm of HEK293Tcells. Several other studies also report de novoNCL mutations in ASD or neurodevelopmental disorders. The altered mislocalization and dynamics of mutant NCL (p.G664Glufs*70/p.G664*) may have relevance to the etiopathlogy of NCL-related ASD and other neurodevelopmental phenotypes.

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29. Shimomura H, Hasunuma H, Tokunaga S, Taniguchi Y, Taniguchi N, Fujino T, Utsunomiya T, Tanaka Y, Tokuda N, Okuda M, Shima M, Takeshima Y, The Japan E, Children’s Study Jecs G. Early Developmental Signs in Children with Autism Spectrum Disorder: Results from the Japan Environment and Children’s Study. Children (Basel, Switzerland). 2022; 9(1).

Autism spectrum disorder (ASD) is a developmental disability in early childhood. Early identification and intervention in children with ASD are essential for children and their families. This study aimed to identify the earliest signs of ASD. Using a large cohort including data from 104,062 fetal records in the Japan Environment and Children’s Study, we examined the Ages and Stages Questionnaires(®) (ASQ-3(TM)) scores of children with and without ASD. The ASQ-3 comprises five domains: communication, gross motor, fine motor, problem solving, and personal-social. The ASQ-3 scores were obtained at ages 6 months, 1 year, and 3 years. There were 64,501 children with available ASQ-3 data. The number of children diagnosed with ASD was 188 (0.29%) at 3 years of age. The highest relative risk (RR) for any domain below the monitoring score at 6 months was in the communication (RR 1.90, 95% CI 1.29-2.78, p = 0.0041), followed by fine motor (RR 1.50, 95% CI 1.28-1.76, p < 0.0001) domain. A low ASQ-3 score in the communication domain at 6 months was related to an ASD diagnosis at 3 years of age. The ASQ-3 score at 6 months can contribute to the early identification of and intervention for ASD.

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30. Tal-Ben Ishay R, Shil A, Solomon S, Sadigurschi N, Abu-Kaf H, Meiri G, Flusser H, Michaelovski A, Dinstein I, Golan H, Davidovitch N, Menashe I. Diagnostic Yield and Economic Implications of Whole-Exome Sequencing for ASD Diagnosis in Israel. Genes. 2021; 13(1).

Whole-exome sequencing (WES) is an effective approach to identify the susceptibility of genetic variants of autism spectrum disorder (ASD). The Israel Ministry of Health supports WES as an adjunct tool for ASD diagnosis, despite its unclear diagnostic yield and cost effectiveness. To address this knowledge gap, we applied WES to a population-based sample of 182 Bedouin and Jewish children with ASD from southern Israel, and assessed its yield in a gene panel of 205 genes robustly associated with ASD. We then compared the incremental cost-effectiveness ratios (ICERs) for an ASD diagnosis by WES, chromosomal microarray analysis (CMA), and CMA + WES. Overall, 32 ASD candidate variants were detected in 28 children, corresponding to an overall WES diagnostic yield of 15.4%. Interestingly, the diagnostic yield was significantly higher for the Bedouin children than for the Jewish children, i.e., 27.6% vs. 11.1% (p = 0.036). The most cost-effective means for genetic testing was the CMA alone, followed closely by the CMA + WES strategy (ICER = USD 117 and USD 124.8 per child). Yet, WES alone could become more cost effective than the other two approaches if there was to be a 25% increase in its yield or a 50% decrease in its cost. These findings suggest that WES should be recommended to facilitate ASD diagnosis in Israel, especially for highly consanguineous populations, such as the Bedouin.

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31. Trifonova EA, Mustafin ZS, Lashin SA, Kochetov AV. Abnormal mTOR Activity in Pediatric Autoimmune Neuropsychiatric and MIA-Associated Autism Spectrum Disorders. International journal of molecular sciences. 2022; 23(2).

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the early onset of communication and behavioral problems. ASD is highly heritable; however, environmental factors also play a considerable role in this disorder. A significant part of both syndromic and idiopathic autism cases could be attributed to disorders caused by mammalian target of rapamycin (mTOR)-dependent translation deregulation. This narrative review analyzes both bioinformatic and experimental evidence that connects mTOR signaling to the maternal autoantibody-related (MAR) autism spectrum and autoimmune neuropsychiatric disorders simultaneously. In addition, we reconstruct a network presenting the interactions between the mTOR signaling and eight MAR ASD genes coding for ASD-specific maternal autoantibody target proteins. The research discussed in this review demonstrates novel perspectives and validates the need for a subtyping of ASD on the grounds of pathogenic mechanisms. The utter necessity of designing ELISA-based test panels to identify all antibodies related to autism-like behavior is also considered.

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32. Yan H, Elkaim LM, Venetucci Gouveia F, Huber JF, Germann J, Loh A, Benedetti-Isaac JC, Doshi PK, Torres CV, Segar DJ, Elias GJB, Boutet A, Cosgrove GR, Fasano A, Lozano AM, Kulkarni AV, Ibrahim GM. Deep brain stimulation for extreme behaviors associated with autism spectrum disorder converges on a common pathway: a systematic review and connectomic analysis. Journal of neurosurgery. 2022: 1-10.

OBJECTIVE: Individuals with autism spectrum disorder (ASD) may display extreme behaviors such as self-injury or aggression that often become refractory to psychopharmacology or behavioral intervention. Deep brain stimulation (DBS) is a surgical alternative that modulates brain circuits that have yet to be clearly elucidated. In the current study the authors performed a connectomic analysis to identify brain circuitry engaged by DBS for extreme behaviors associated with ASD. METHODS: A systematic review was performed to identify prior reports of DBS as a treatment for extreme behaviors in patients with ASD. Individual patients’ perioperative imaging was collected from corresponding authors. DBS electrode localization and volume of tissue activated modeling were performed. Volumes of tissue activated were used as seed points in high-resolution normative functional and structural imaging templates. The resulting individual functional and structural connectivity maps were pooled to identify networks and pathways that are commonly engaged by all targets. RESULTS: Nine patients with ASD who were receiving DBS for symptoms of aggression or self-injurious behavior were identified. All patients had some clinical improvement with DBS. Connectomic analysis of 8 patients (from the systematic review and unpublished clinical data) demonstrated a common anatomical area of shared circuitry within the anterior limb of the internal capsule. Functional analysis of 4 patients identified a common network of distant brain areas including the amygdala, insula, and anterior cingulate engaged by DBS. CONCLUSIONS: This study presents a comprehensive synopsis of the evidence for DBS in the treatment of extreme behaviors associated with ASD. Using network mapping, the authors identified key circuitry common to DBS targets.

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33. Yin S, Hong SJ, Di Martino A, Milham MP, Park BY, Benkarim O, Bethlehem RAI, Bernhardt BC, Paquola C. Shared and Distinct Patterns of Atypical Cortical Morphometry in Children with Autism and Anxiety. Cerebral cortex (New York, NY : 1991). 2022.

Autism spectrum disorder (ASD) and anxiety disorders (ANX) are common neurodevelopmental conditions with several overlapping symptoms. Notably, many children and adolescents with ASD also have an ANX diagnosis, suggesting shared pathological mechanisms. Here, we leveraged structural imaging and phenotypic data from 112 youth (33 ASD, 37 ANX, 42 typically developing controls) to assess shared and distinct cortical thickness patterns of the disorders. ANX was associated with widespread increases in cortical thickness, while ASD related to a mixed pattern of subtle increases and decreases across the cortical mantle. Despite the qualitative difference in the case-control contrasts, the statistical maps from the ANX-vs-controls and ASD-vs-controls analyses were significantly correlated when correcting for spatial autocorrelation. Dimensional analysis, regressing trait anxiety and social responsiveness against cortical thickness measures, partially recapitulated diagnosis-based findings. Collectively, our findings provide evidence for a common axis of neurodevelopmental disturbances as well as distinct effects of ASD and ANX on cortical thickness.

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