1. Alasmari M, Alduais A, Qasem F, Almaghlouth S, AlAmri L. Examining Language, Speech and Behaviour Characteristics: A Cross-Sectional Study in Saudi Arabia Using the Arabic Version of Gilliam Autism Rating Scale-Third Edition. Children (Basel). 2024; 11(4).

Autism spectrum disorder (ASD) exhibits diverse manifestations influenced by demographic factors. This study evaluates these variations within Saudi Arabia, aiming to investigate language, speech and behaviour characteristics across different demographics in Saudi Arabia using the Arabic Version of the Gilliam Autism Rating Scale-Third Edition (A-GARS-3). Employing a cross-sectional design, 178 participants were stratified by developmental status (n = 124 school settings, n = 54 clinical setting), sex (Females = 77, Males =101), age (range = 3-22), and geographical region (different provinces in Saudi Arabia). The A-GARS-3 measured ASD manifestations across six subscales. The study identified significant differences in ASD manifestations by developmental status, with higher ASD likelihood and severity in clinical settings. Younger children showed more pronounced ASD characteristics, and males were slightly more likely to be diagnosed with ASD. Geographical analysis revealed regional differences in severity. The findings underline the importance of demographic considerations in ASD assessment and diagnosis, suggesting the need for age-specific and culturally sensitive approaches. The A-GARS-3 is a reliable tool for the Saudi context. Regional disparities in ASD prevalence and severity indicate a need for tailored health policies and resources across Saudi provinces.

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2. Arezoumand KS, Roberts CT, Rastegar M. Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact. Biomolecules. 2024; 14(4).

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target « BDNF » is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.

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3. Aymerich C, Pacho M, Catalan A, Yousaf N, Pérez-Rodríguez V, Hollocks MJ, Parellada M, Krebs G, Clark B, Salazar de Pablo G. Prevalence and Correlates of the Concurrence of Autism Spectrum Disorder and Obsessive Compulsive Disorder in Children and Adolescents: A Systematic Review and Meta-Analysis. Brain Sci. 2024; 14(4).

BACKGROUND: Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) are two common and impairing neurodevelopmental conditions with partial symptomatic overlap. The aim of this study is to systematically and meta-analytically examine the following: (i) the prevalence of an OCD diagnosis among young people with ASD, (ii) the prevalence of an ASD diagnosis among young people with OCD, and (iii) the clinical and therapeutic implications of such comorbidity. METHOD: A multistep literature search was performed from database inception until 17 November 2023. This PRISMA/MOOSE-compliant systematic review, registered in PROSPERO (CRD42023480543), identified studies reporting on the prevalence, sociodemographic, psychopathologic, prognostic, and therapeutic correlates of OCD and ASD concurrence in children and adolescents. A quantitative meta-analysis with random effects was conducted to analyse the pooled prevalence of OCD among samples with a mean age of < 18 years old with ASD and the prevalence of ASD among individuals under 18 with OCD. Sensitivity analyses were performed to investigate the effect of diagnostic criteria and different continents. Meta-regression analyses were conducted to examine the effect of gender, age, IQ, and OCD severity scores. A narrative review of the clinical and therapeutical implications of the comorbidity was provided. RESULTS: 42 studies were selected for the systematic review (SR), and 31 of them were also included in one of the meta-analyses. The pooled prevalence of OCD among ASD youth samples (n = 8916, mean age = 10.6 ± 1.6; 16.4% female) was 11.6% (95% confidence intervals [CI] = 6.9%; 18.8%), and the pooled prevalence of ASD among OCD children and adolescent samples (n = 6209, mean age = 14.1 ± 1.4; 45.7% female) was 9.5% (95% CI = 6.0%; 14.7%). Meta-regressions found a statistically higher prevalence of ASD among samples with a lower prevalence of females (β = -4.7; 95%CI = -8.6; -0.8). Children with both OCD and ASD present higher rates of functional impairment, psychopathology, and other comorbidities, compared to youth with either of the disorders alone. CONCLUSIONS: OCD and ASD are highly concurrent conditions in youth, with symptomatic, prognostic, severity, and therapeutic implications. Future research should focus on conducting longitudinal cohort studies prospectively to determine development trajectories, along with randomized controlled trials to assess the efficacy of specific therapeutic interventions.

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4. Bandara D, Riccardi K. Graph Node Classification to Predict Autism Risk in Genes. Genes (Basel). 2024; 15(4).

This study explores the genetic risk associations with autism spectrum disorder (ASD) using graph neural networks (GNNs), leveraging the Sfari dataset and protein interaction network (PIN) data. We built a gene network with genes as nodes, chromosome band location as node features, and gene interactions as edges. Graph models were employed to classify the autism risk associated with newly introduced genes (test set). Three classification tasks were undertaken to test the ability of our models: binary risk association, multi-class risk association, and syndromic gene association. We tested graph convolutional networks, Graph Sage, graph transformer, and Multi-Layer Perceptron (Baseline) architectures on this problem. The Graph Sage model consistently outperformed the other models, showcasing its utility in classifying ASD-related genes. Our ablation studies show that the chromosome band location and protein interactions contain useful information for this problem. The models achieved 85.80% accuracy on the binary risk classification, 81.68% accuracy on the multi-class risk classification, and 90.22% on the syndromic classification.

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5. Bataveljic D, Pivonkova H, de Concini V, Hébert B, Ezan P, Briault S, Bemelmans AP, Pichon J, Menuet A, Rouach N. Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model. Nat Commun. 2024; 15(1): 3583.

Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.1 expression and function in astrocytes. Further, we reveal that Kir4.1 mRNA is a binding target of FMRP. Finally, we show that the deficit in astroglial Kir4.1 underlies neuronal hyperexcitability and several behavioral defects in Fmr1 knockout mice. Viral delivery of Kir4.1 channels specifically to hippocampal astrocytes from Fmr1 knockout mice indeed rescues normal astrocyte potassium uptake, neuronal excitability, and cognitive and social performance. Our findings uncover an important role for astrocyte dysfunction in the pathophysiology of FXS, and identify Kir4.1 channel as a potential therapeutic target for FXS.

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6. Ben-Sasson A, Guedalia J, Nativ L, Ilan K, Shaham M, Gabis LV. A Prediction Model of Autism Spectrum Diagnosis from Well-Baby Electronic Data Using Machine Learning. Children (Basel). 2024; 11(4).

Early detection of autism spectrum disorder (ASD) is crucial for timely intervention, yet diagnosis typically occurs after age three. This study aimed to develop a machine learning model to predict ASD diagnosis using infants’ electronic health records obtained through a national screening program and evaluate its accuracy. A retrospective cohort study analyzed health records of 780,610 children, including 1163 with ASD diagnoses. Data encompassed birth parameters, growth metrics, developmental milestones, and familial and post-natal variables from routine wellness visits within the first two years. Using a gradient boosting model with 3-fold cross-validation, 100 parameters predicted ASD diagnosis with an average area under the ROC curve of 0.86 (SD < 0.002). Feature importance was quantified using the Shapley Additive explanation tool. The model identified a high-risk group with a 4.3-fold higher ASD incidence (0.006) compared to the cohort (0.001). Key predictors included failing six milestones in language, social, and fine motor domains during the second year, male gender, parental developmental concerns, non-nursing, older maternal age, lower gestational age, and atypical growth percentiles. Machine learning algorithms capitalizing on preventative care electronic health records can facilitate ASD screening considering complex relations between familial and birth factors, post-natal growth, developmental parameters, and parent concern.

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7. Benvenuto M, Cesarini S, Severi G, Ambrosini E, Russo A, Seri M, Palumbo P, Palumbo O, Castori M, Panza E, Carella M. Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene. Genes (Basel). 2024; 15(4).

O’Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the KMT2E gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient’s cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skipping. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in KMT2E.

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8. Blasco-Fontecilla H, Li C, Vizcaino M, Fernández-Fernández R, Royuela A, Bella-Fernández M. A Nomogram for Predicting ADHD and ASD in Child and Adolescent Mental Health Services (CAMHS). J Clin Med. 2024; 13(8).

Objectives: To enhance the early detection of Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) by leveraging clinical variables collected at child and adolescent mental health services (CAMHS). Methods: This study included children diagnosed with ADHD and/or ASD (n = 857). Three logistic regression models were developed to predict the presence of ADHD, its subtypes, and ASD. The analysis began with univariate logistic regression, followed by a multicollinearity diagnostic. A backward logistic regression selection strategy was then employed to retain variables with p < 0.05. Ethical approval was obtained from the local ethics committee. The models' internal validity was evaluated based on their calibration and discriminative abilities. Results: The study produced models that are well-calibrated and validated for predicting ADHD (incorporating variables such as physical activity, history of bone fractures, and admissions to pediatric/psychiatric services) and ASD (including disability, gender, special education needs, and Axis V diagnoses, among others). Conclusions: Clinical variables can play a significant role in enhancing the early identification of ADHD and ASD.

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9. Ceruti C, Mingozzi A, Scionti N, Marzocchi GM. Comparing Executive Functions in Children and Adolescents with Autism and ADHD-A Systematic Review and Meta-Analysis. Children (Basel). 2024; 11(4).

Two neurodevelopmental conditions, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), have been associated with executive function (EF) impairments but the specificity of their impairments is still controversial. The present meta-analysis aimed to identify the differences in EF profiles of ASD, ADHD, and ASD+ADHD in relation to a control group of individuals with typical development (TD) and to understand whether the EF performance could change depending upon the type of measure used to assess EF (performance tests vs. questionnaires). Results from 36 eligible studies revealed that ADHD and ASD showed more difficulties than the TD group in tests and, particularly, in questionnaires. No significant differences in the EF profile emerged between ASD and ADHD when assessed through neuropsychological tests (d = 0.02), while significant differences emerged when assessed through questionnaires, with ADHD having higher ratings than ASD (d = -0.34). EF questionnaires and neuropsychological tests may catch two different constructs of EF, with the former being more predictive of everyday life EF impairments. The comparison between the double diagnosis group (ADHD+ASD) and the clinical groups pointed out that the former has a more similar EF profile to the ADHD-alone one and that it shows more difficulties than ASD-alone.

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10. Congiu S, Doneddu G, Fadda R. Attention toward Social and Non-Social Stimuli in Preschool Children with Autism Spectrum Disorder: A Paired Preference Eye-Tracking Study. Int J Environ Res Public Health. 2024; 21(4).

Different dimensions of visual attention to social (human faces) and non-social stimuli (objects) were assessed in 19 preschool children with Autism Spectrum Disorder (ASD) and 19 typically developing (TD) age, gender, and IQ-matched controls through an original paired preference eye-tracking paradigm. The present study found a significantly reduced attentional bias toward human faces in children with ASD compared to TD controls. The analysis of the total fixation time showed a significantly reduced preference for faces in children with ASD compared to TD children. Moreover, while TD children showed a significant preference for the face over the object, children in the ASD group observed the two paired pictures for a similar amount of time, thus showing no preference. Besides, children with ASD paid significantly more sustained attention to the objects than TD children. Children in the TD group paid greater sustained attention to the faces over the objects, while children in the ASD group did not differentiate between objects and faces. Finally, an age effect was found in ASD, as younger children in the group tended to prefer objects and to show more sustained attention towards them. Overall, these findings add to the literature on anomalies in attention toward social and non-social stimuli in young children with ASD compared to their TD counterparts. These results are discussed in the light of previous studies and suggest possible directions for future research.

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11. Cordova I, Blesson A, Savatt JM, Sveden A, Mahida S, Hazlett H, Rooney Riggs E, Chopra M. Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental Disorder. Genes (Basel). 2024; 15(4).

Pathogenic ASH1L variants have been reported in probands with broad phenotypic presentations, including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, seizures, congenital anomalies, and other skeletal, muscular, and sleep differences. Here, we review previously published individuals with pathogenic ASH1L variants and report three further probands with novel ASH1L variants and previously unreported phenotypic features, including mixed receptive language disorder and gait disturbances. These novel data from the Brain Gene Registry, an accessible repository of clinically derived genotypic and phenotypic data, have allowed for the expansion of the phenotypic and genotypic spectrum of this condition.

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12. Csoka AB, El Kouhen N, Bennani S, Getachew B, Aschner M, Tizabi Y. Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder. Biomolecules. 2024; 14(4).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

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13. France K, Urquhart O, Ko E, Gomez J, Ryan M, Hernandez M, Gabinskiy M, Corby PM, Wolff MS. A Pilot Study Exploring Caregivers’ Experiences Related to the Use of a Smart Toothbrush by Children with Autism Spectrum Disorder. Children (Basel). 2024; 11(4).

BACKGROUND: Research on caregivers for children with intellectual disabilities, particularly those with autism spectrum disorder (ASD), has highlighted several obstacles to achieving better oral health. These include challenges with tolerating oral care, sensory processing differences, uncooperative behaviors, and communication impairments. There is limited understanding of what caregivers would consider « successful assistance » in improving oral health for these children. OBJECTIVES: This pilot study aimed to examine caregivers’ and user’s experiences with a Kids Smart Electric Toothbrush used by children with ASD. METHODS: It involved open-ended interviews and questionnaires with caregivers prior to utilization of the toothbrush and after 4 weeks of product use by the child. RESULTS: Seventeen children with ASD, aged 5-12, participated. A total of 58.8% of caregivers said their child brushed more often, and all reported brushing at least twice a day by week 4. Caregivers reported that children became more independent while brushing their teeth and achieved better quality brushing. Caregivers’ frustration with the brushing process, satisfaction with the device, and need to assist the child with brushing were improved. Caregivers did encounter some technical difficulties with the app. CONCLUSION: This study will assist in exploring « smart » toothbrush technologies for oral hygiene in children with ASD.

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14. Genovese AC, Butler MG. Behavioral and Psychiatric Disorders in Syndromic Autism. Brain Sci. 2024; 14(4).

Syndromic autism refers to autism spectrum disorder diagnosed in the context of a known genetic syndrome. The specific manifestations of any one of these syndromic autisms are related to a clinically defined genetic syndrome that can be traced to certain genes and variants, genetic deletions, or duplications at the chromosome level. The genetic mutations or defects in single genes associated with these genetic disorders result in a significant elevation of risk for developing autism relative to the general population and are related to recurrence with inheritance patterns. Additionally, these syndromes are associated with typical behavioral characteristics or phenotypes as well as an increased risk for specific behavioral or psychiatric disorders and clinical findings. Knowledge of these associations helps guide clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families.

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15. Gosse G, Kumar S, Banwell H, Moran A. Exploring Allied Health Models of Care for Children with Developmental Health Concerns, Delays, and Disabilities in Rural and Remote Areas: A Systematic Scoping Review. Int J Environ Res Public Health. 2024; 21(4).

BACKGROUND: Access to appropriate healthcare is essential for children’s healthy development. This is lacking in rural and remote areas, impacting health outcomes. Despite efforts to improve access for these communities, to date, no review has systematically mapped the literature on allied health models of care for children with developmental needs. This scoping review seeks to address this knowledge gap. METHODS: Adhering to the PRISMA-ScR and Joanna Briggs Institute guidelines, a systematic search was conducted. A total of 8 databases (from inception to May 2023) and 106 grey literature sources were searched. Two reviewers independently undertook a two-stage screening process. Data were extracted using customised tools and narratively synthesised utilising the Institute of Medicine’s quality domains. This review is registered a priori via Open Science Framework. RESULTS: Twenty-five citations were identified within the literature. Varied models of care were reported from five mostly Western countries. Models of care identified in these areas were classified as screening services, role substitution, consultative services, or online-based services. Positive impacts on quality of healthcare were reported across all quality domains (apart from safety) with the domain of effectiveness being the most commonly reported. CONCLUSIONS: Multiple models of care are currently in operation for children with developmental needs in rural and remote areas and appear to improve the quality of care. Due to complexities within, and limitations of, the evidence base, it is unclear if one model of care is superior to another. This review provides a basis for further research to explore why some models may be more effective than others.

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16. Gulsrud AC, Shih W, Paparella T, Kasari C. Comparative efficacy of an early intervention « parent and me » program for infants showing signs of autism: The Baby JASPER model. Infant Behav Dev. 2024; 76: 101952.

Despite important advancements into the early detection of autism, there are still few empirically supported interventions for children under the age of two years who are showing early signs. Caregiver-mediated interventions have gained in popularity as a method for delivering support to the child and family. The current study builds on current work by enrolling a comparatively large cohort of infants (ages 12-22 months of age) displaying early signs of autism into a randomized controlled intervention program. Infants and parents received a group-based program using a standard early childhood curriculum. In addition, all families were randomly assigned to receive parent training in the form of either parent-mediated Joint Attention Symbolic Play Engagement and Regulation (JASPER) training or psychoeducation. Infants in both classrooms made substantial gains in social-communication, play, and cognition during a brief, 8-week period. All infants gained over an average of 10 points in DQ and increased in standardized measures of social-communication and play, with these gains maintaining at a 2-month follow-up visit. The classroom that also received JASPER increased in child initiated joint engagement and play level during dyadic interactions with their parents, while the classroom that received psychoeducation increased in joint attention during a standardized assessment delivered by an independent assessor. Infant familial risk for autism (older sibling with autism) also moderated the effect of treatment on child initiated joint engagement where infants in the JASPER classroom without familial risk made the most gains from baseline to exit of the program. This study highlights the promise of intervening at the earliest stages to promote positive outcomes for children and families.

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17. Guzick AG, Schneider SC, Kook M, Rose Iacono J, Weinzimmer SA, Quast T, Olsen SM, Hughes KR, Jellinek-Russo E, Garcia AP, Candelari A, Berry LN, Goin-Kochel RP, Goodman WK, Storch EA. Parent-Led Cognitive Behavioral Teletherapy for Anxiety in Autistic Youth: A Randomized Trial Comparing Two Levels of Therapist Support. Behav Ther. 2024; 55(3): 499-512.

Parent-led cognitive behavioral therapy (CBT) is an efficient, promising form of therapy that may be well suited for autistic youth with anxiety disorders, though to date it has been minimally tested. In this study, 87 autistic youth (7 to 13 years old) with anxiety disorders and their parents were randomized to two forms of parent-led CBT in which parents led their child through a guided CBT workbook across 12 weeks: one with low therapist contact (four 30-minute telehealth calls), and one with standard therapist contact (ten 60-minute telehealth calls). Anxiety, functional impairment, and autism features significantly declined across therapy, without differences between groups. High satisfaction was reported in both groups, though significantly higher satisfaction ratings were reported in standard-contact CBT. Responder rates were 69% of completers at posttreatment (70% in standard contact, 68% in low contact) and 86% at 3-month follow-up (86% in standard contact, 87% in low contact). Low-contact CBT was estimated to incur an average cost of $755.70 per family compared with $1,978.34 in standard-contact CBT. Parent-led CBT with minimal or standard therapist contact both appear to be effective CBT delivery formats for autistic youth with anxiety disorders, with significant cost savings for low-contact CBT.

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18. Jayaprakash P, Isaev D, Yang KS, Beiram R, Oz M, Sadek B. Apigenin Alleviates Autistic-like Stereotyped Repetitive Behaviors and Mitigates Brain Oxidative Stress in Mice. Pharmaceuticals (Basel). 2024; 17(4).

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10-30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 mg/kg, i.p.). BTBR mice pretreated with APG (20 mg/kg) or ARP (1 mg/g, i.p.) displayed significant improvements in the marble-burying test (MBT), cotton-shredding test (CST), and self-grooming test (SGT) (all p < 0.05). However, a lower dose of APG (10 mg/kg, i.p.) failed to modulate behaviors in the MBT or SGT, but significantly attenuated the increased shredding behaviors in the CST of tested mice. Moreover, APG (10-30 mg/kg, i.p.) and ARP (1 mg/kg) moderated the disturbed levels of oxidative stress by mitigating the levels of catalase (CAT) and superoxide dismutase (SOD) in the hippocampus and cerebellum of treated BTBR mice. In patch clamp studies in hippocampal slices, the potency of choline (a selective agonist of α7-nAChRs) in activating fast inward currents was significantly potentiated following incubation with APG. Moreover, APG markedly potentiated the choline-induced enhancement of spontaneous inhibitory postsynaptic currents. The observed results propose the potential therapeutic use of APG in the management of ASD. However, further preclinical investigations in additional models and different rodent species are still needed to confirm the potential relevance of the therapeutic use of APG in ASD.

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19. Johnson CR, Barto L, Worley S, Rothstein R, Wenzell ML. Follow-up of telehealth parent training for sleep disturbances in young children with autism spectrum disorder. Sleep Med. 2024; 119: 114-7.

OBJECTIVE/BACKGROUND: Bedtime and sleep disturbances are ubiquitous in children with autism. The telehealth delivery of a behavior analytic parent training program was earlier reported to be efficacious in improving child sleep and parent sense of competency. Our aim in this brief report was to determine the durability of the telehealth delivered sleep parent training program (SPT) compared to the control condition in this randomized controlled trial. Telehealth delivery could be a means to expand access to such early treatment if efficacious. PARTICIPANTS/METHODS: Parents of young children, ages 2-7 years, with autism and co-occurring sleep disturbances were enrolled in this study. Participants were randomized to either SPT or a comparison arm that included non-sleep related parent education except for one session Sleep Parent Education; SPE). Each participant was individually administered a 5 session program delivered over 10 weeks. Outcome measures were collected at weeks 5 and 10 and at post-treatment follow-up at 16 weeks. RESULTS: Follow-up week 16 data were available for 30 participants randomized to SPT and 24 participants randomized to SPE. Demographics for this follow-up cohort were similar to the full sample. At week 16 follow-up, there was a significant group difference between SPT and SPE the Modified Simonds & Parraga Sleep Questionnaire-Composite Sleep Index (MSPSQ – CSI) (p = 0.011) with an effect size of 0.68. Further, 8 of the 10 children in SPT who were negative responders at the week 10 endpoint were rated as positive responders at week 16 by the treatment masked IE compared to 2 out of 12 in the SPE group (p = 0.008). CONCLUSIONS: Post-treatment follow-up data suggests SPT is durable over time compared to SPE, the active control group. Further, for some participants in SPT, a positive responsive emerged after the treatment endpoint. This brief report adds to the efficacy of SPT as a time-limited intervention for insomnia in young autistic children.

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20. La Valle C, Shen L, Shih W, Kasari C, Lord C, Tager-Flusberg H. Real-time coded measures in natural language samples capture change over time in minimally verbal autistic children. Autism Res. 2024.

Prior research supports the use of natural language sampling (NLS) to assess the rate of speech utterances (URate) and the rate of conversational turns (CTRate) in minimally verbal (MV) autistic children. Bypassing time-consuming transcription, previous work demonstrated the ability to derive URate and CTRate using real-time coding methods and provided support for their strong psychometric properties. (1) Unexplored is how URate and CTRate using real-time coding methods capture change over time and (2) whether specific child factors predict changes in URate and CTRate in 50 MV autistic children (40 males; M = 75.54, SD = 16.45 (age in months)). A NLS was collected at Time 1 (T1) and Time 2 (T2) (4.5 months between T1 and T2) and coding was conducted in ELAN Linguistic Annotator software using a real-time coding approach to derive URate and CTRate. Findings from paired samples Wilcoxon tests revealed a significant increase in child URate (not examiner URate) and child and examiner CTRate from T1 to T2. Child chronological age, Mullen expressive language age equivalent scores, and URate and CTRate at T1 were predictive of URate and CTRate at T2. Findings support using NLS-derived real-time coded measures of URate and CTRate to efficiently capture change over time in MV autistic children. Identifying child factors that predict changes in URate and CTRate can help in the tailoring of goals to children’s individual needs and strengths.

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21. Machado AS, Dias G, I PC. Disentangling the relationship between sensory processing, alexithymia and broad autism spectrum: A study in parents’ of children with autism spectrum disorders and sensory processing disorders. Res Dev Disabil. 2024; 149: 104742.

BACKGROUND: Autistic features and sensory processing difficulties and their phenotypic co-expression with alexithymia share a transdiagnostic vulnerability. In this work, we explored whether the current concept of broad autism phenotype rather translates altered sensory processing (non-specific to autism), meaning that the characteristics of altered sensory processing should be overexpressed among individuals with heightened vulnerability to sensory processing atypicalities (parents of children with sensorial processing disorder, or SPD parents) and individuals with heightened vulnerability to autistic traits (parents of children with autism spectrum disorders, or ASD parents). In addition, the association between altered sensory processing and alexithymia was inspected. METHOD: The Adolescent/Adult Sensory Profile, Autism Spectrum Quotient, and Toronto Alexithymia Scale were completed by 31 parents of children with ASD, 32 parents of children with SPD, and 52 parents of typically developed (TD) children. RESULTS: Extreme sensory patterns were overexpressed both in parents of children with SPD and parents of children with ASD when compared to parents of TD children. In addition, extreme sensory patterns were significantly associated with alexithymia scores. Specifically, sensory avoidance, low registration, and sensory sensitivity were positively correlated with alexithymia. No significant differences were found regarding the proportion of autistic traits and alexithymia between ASD and SPD groups of parents. CONCLUSIONS: These results challenge the specificity of broad autism phenotype and suggest a neurodevelopmental atypicity with roots in altered sensory and emotional processing.

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22. Margari A, De Agazio G, Marzulli L, Piarulli FM, Mandarelli G, Catanesi R, Carabellese FF, Cortese S. Autism spectrum disorder (ASD) and sexual offending: a systematic review. Neurosci Biobehav Rev. 2024: 105687.

The relationship between autism spectrum disorder (ASD) and sexual offending (SO) is an overlooked issue, both in clinical practice and in research. Based on a pre-specified protocol (PROSPERO: CRD42024501598), we systematically searched Pubmed and Scopus, between January 1(st), 1994 and January 12(th), 2024, for articles related to SO in ASD. Study quality was assessed with study design-specific tools (Study Quality Assessment Tools, NHLBI, NIH). We found 19 relevant publications (five cross-sectional studies, two case-control studies, and 12 case reports). Seven of the studies were deemed of « good » quality, the rest as « fair ». Included studies addressed three key aspects: 1) psychopathological characteristics of individuals with ASD that increase the risk of committing SO; 2) intervention strategies for individuals with ASD and SO; 3) involvement of individuals with ASD and SO in the justice system. Overall, while there is an increasing interest in this topic, more rigorous study designs, including randomised controlled trials, are needed to inform clinical practice and healthcare and social policies.

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23. Mavroeidi N, Sifnaios C, Ntinou A, Iatrou G, Konstantakopoulou O, Merino Martínez M, Nucifora M, Tanrikulu I, Vadolas A. Exploring the Potential Impact of Training on Short-Term Quality of Life and Stress of Parents of Children with Autism: The Integrative Parents’ Autism Training Module. Int J Environ Res Public Health. 2024; 21(4).

Parents of autistic children experience high levels of parental stress and low quality of life related to the demanding child caring burden they experience. Parent education and training programs are acknowledged to improve parental well-being and reduce parenting stress. In the framework of the Erasmus+ Integrative Autism Parents Training Project (IPAT), we developed the IPAT Training Module based on parents’ expressed needs, in order to improve parental quality of life (QoL) and decrease their perceived stress. Sixty-two parents from four countries participated in the IPAT Module Training activity. We used WHOQOL-BREF and Perceived Stress Scale (PSS-10 version) for QoL and stress, respectively, before and after training and a study-specific questionnaire to assess participants’ satisfaction. Parents’ QoL improved significantly in the environment domain and specific items, while stress levels remained unmodified. Training appeared more advantageous for parents with lower initial QoL and those whose child had been enrolled in a special education program for an extended duration. Parents were quite satisfied, in particular those with lower initial social relationships QoL. Larger studies including a control group are necessary to support preliminary evidence provided by this study, identify additional effect moderators, and disentangle the contribution of different components of the training.

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24. Meng H, Kim Y, Lee K. Impact of a Service-Learning Program Using Soccer Training on the Emotional and Behavioral Problems of Children with Developmental Disabilities. Children (Basel). 2024; 11(4).

Children with developmental disabilities may develop emotional and behavioral problems that arise from difficulties in social interaction, and therefore, a process of providing and testing intervention activities for emotional and behavioral issues in the early stages of development is required. This study evaluated the effects of a 12-week service-learning exercise program on children with developmental disabilities, contrasting it with a control group not engaged in specific physical activities. The participants included 18 children with developmental disabilities who participated in the service-learning exercise program (SLG) and 18 children with developmental disabilities (Non-SLG) who did not participate. The Korean Behavior Assessment System for Children-2 was used to evaluate children’s emotional and behavioral problems. A two-way repeated-measures ANOVA was conducted to verify the interaction effect between the group and period according to program participation. The results showed the positive internalization of problem behaviors in the emotional domain (F = 4.291, p = 0.011), attention deficit/hyperactivity (F = 4.761, p = 0.012), and personal adjustment (F = 4.116, p = 0.023) in the SLG group. These results suggest that participation in a service-learning exercise program positively affected emotional and behavioral problems in children with developmental disabilities. This could provide a basis for future research on service-learning exercise programs for children with developmental disabilities.

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25. Reilly C, Bjurulf B, Hallböök T. Autism and attention-deficit/hyperactivity disorder in children with Dravet syndrome: A population-based study. Dev Med Child Neurol. 2024.

AIM: To identify on a population basis the prevalence of autism and attention-deficit/hyperactivity disorder (ADHD) in children with Dravet syndrome and factors associated with symptoms of autism and ADHD. METHOD: Forty-one of 48 children with Dravet syndrome living in Sweden, born between 1st January 2000 and 31st December 2018 underwent assessment including measures of autism and ADHD. Diagnoses of autism and ADHD were made with respect to DSM-5 criteria. Factors associated with features of autism and ADHD were analysed via regression. RESULTS: Twenty-five of the 41 children fulfilled DSM-5 criteria for autism spectrum disorder and 12 of 37 children considered for an ADHD diagnosis fulfilled DSM-5 criteria for ADHD. Severe intellectual disability was significantly associated with a greater degree of autistic features (p < 0.001) and a DSM-5 diagnosis of autism spectrum disorder (p = 0.029). Younger children had significantly more features of ADHD (p = 0.004) and features of inattention were significantly more common than features of hyperactivity/impulsivity (p < 0.001). INTERPRETATION: Children with Dravet syndrome often have significant features of autism and ADHD, primarily inattentive type. Screening for autism and ADHD should be routine in children with Dravet syndrome.

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26. Sharifi G, Ansari M, Chalmiani EM, Javandoust Gharehbagh F, Darazam IA. An 11-month-old boy with tuberculous meningitis presenting as progressive limb weakness, fever, developmental retardation, and loss of consciousness: a case report. J Med Case Rep. 2024; 18(1): 210.

BACKGROUND: Tuberculous meningitis (TBM) accounts for about 1% of all tuberculosis cases and about 5% of extrapulmonary tuberculosis cases. However, it poses major importance because approximately half of those affected die or become severely disabled. Herein, the successful treatment of an 11-month-old boy with progressive limb weakness, fever, developmental retardation, and loss of consciousness due to tuberculosis, was reported. CASE PRESENTATION: An 11-month-old (Iranian Turk) boy was referred to Loghman Hakim hospital for progressive limb weakness and loss of previously attained developmental milestones for the past 2 months. He also had persistent fever and loss of consciousness for about 14 to 21 days. Before being referred to our center, the patient had been diagnosed with hydrocephalus at another center due to possible acute bacterial meningitis based on a CT scan and MRI imaging. On physical examination, anterior fontanel bulging and neck stiffness were observed on the admission. His body temperature and heart rate were 38.1 C and 86 beats per minute (bpm), respectively. He had left 6 cranial nerve palsy and spastic quadriparesis with a power of grade 3/5. Other systemic examinations were normal. Endoscopic third ventriculostomy (ETV) (and leptomeningeal biopsy) revealed diffuse thickening of the floor and lateral walls of the 3rd ventricle and also a cobblestone appearance in the form of multiple white patchy lesions was detected on the floor of the 3rd ventricle. CSF analysis and polymerase chain reaction confirmed the TB meningitis. During hospitalization, a temporary EVD (external ventricular drain) was initially inserted. Eventually, defervescence was denoted 5-6 days after initiation of anti-TB medications, and a permanent ventriculoperitoneal shunt was inserted due to hydrocephalus. Gradually his truncal and limb tone and motor function improved, as did his emotional responses to his parents and ability to eat. The patient can walk without help in the 15th month following the operation and resolved hydrocephalus demonstrated on follow-up imaging. CONCLUSION: Over half of treated TB meningitis patients die or suffer severe neurological sequelae, mainly due to late diagnosis. Hence, early diagnosis and prompt initiation of TB treatment offer the best chance of a good neurological outcome.

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27. Sobieski M, Grata-Borkowska U, Bujnowska-Fedak MM. Implementing an Early Detection Program for Autism Spectrum Disorders in the Polish Primary Healthcare Setting-Possible Obstacles and Experiences from Online ASD Screening. Brain Sci. 2024; 14(4).

A screening questionnaire for autism symptoms is not yet available in Poland, and there are no recommendations regarding screening for developmental disorders in Polish primary healthcare. The aim of this study was to assess the opinions of parents and physicians on the legitimacy and necessity of screening for autism spectrum disorders, potential barriers to the implementation of the screening program, and the evaluation and presentation of the process of online ASD screening, which was part of the validation program for the Polish version of one of the screening tools. This study involved 418 parents whose children were screened online and 95 primary care physicians who expressed their opinions in prepared surveys. The results indicate that both parents and doctors perceive the need to screen children for ASD in the general population without a clear preference as to the screening method (online or in person). Moreover, online screening is considered by respondents as a satisfactory diagnostic method. Therefore, online screening may prove to be at least a partial method of solving numerous obstacles indicated by participants’ systemic difficulties including time constraints, the lack of experienced specialists in the field of developmental disorders and organizational difficulties of healthcare systems.

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28. Taha MS, Ahmadian MR. Fragile X Messenger Ribonucleoprotein Protein and Its Multifunctionality: From Cytosol to Nucleolus and Back. Biomolecules. 2024; 14(4).

Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack of FMR protein (FMRP) synthesis are associated with fragile X syndrome, one of the most common inherited intellectual disabilities. FMRP is a multifunctional protein that is involved in many cellular functions in almost all subcellular compartments under both normal and cellular stress conditions in neuronal and non-neuronal cell types. This is achieved through its trafficking signals, nuclear localization signal (NLS), nuclear export signal (NES), and nucleolar localization signal (NoLS), as well as its RNA and protein binding domains, and it is modulated by various post-translational modifications such as phosphorylation, ubiquitination, sumoylation, and methylation. This review summarizes the recent advances in understanding the interaction networks of FMRP with a special focus on FMRP stress-related functions, including stress granule formation, mitochondrion and endoplasmic reticulum plasticity, ribosome biogenesis, cell cycle control, and DNA damage response.

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29. Thorell LB, Klint Carlander AK, Demetry Y, Marainen L, Nilsson S, Skoglund C. Parental Experiences of Distance Learning in Families with and without an Adolescent with ADHD/ASD: A Large Qualitative Survey Study. Int J Environ Res Public Health. 2024; 21(4).

One of the greatest COVID-19-related challenges for children and their families was managing distance learning due to school closures. We also know from previous research that families with a child with a neurodevelopmental disorder such as ADHD or ASD were struggling more than others but also experienced some positive effects. However, few qualitative studies have been conducted. The present study therefore aimed to investigate parental experiences of the negative and positive effects of distance learning during the COVID-19 pandemic in a large sample of families with an adolescent with ADHD and/or ASD and a matched comparison group (n = 682). Data were collected through open-ended questions as part of a larger survey study. Five main themes with different sub-themes were identified for both negative and positive effects: (1) Teaching, (2) Social, (3) Support, (4) Child factors, and (5) Home environment. In addition, the main theme « Technical problems » was identified for negative effects. Families with a child with ADHD/ASD reported negative effects related to « Child factors » and « Support » more frequently than the controls, as well as negative effects related to some aspects of « Teaching » and « Technical problems ». Regarding positive effects, significant group differences were primarily found for the theme « Child factors ». These findings are discussed both in terms of how to best prepare for possible future pandemics, but also of how to best provide educational support for children with ADHD and/or ASD when schools are open.

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30. Timm EC, Purcell NL, Ouyang B, Berry-Kravis E, Hall DA, O’Keefe JA. Potential Prodromal Digital Postural Sway Markers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Detected via Dual-Tasking and Sensory Manipulation. Sensors (Basel). 2024; 24(8).

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.

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31. Yuan X, Chen L, Saffen D. Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G). Genes (Basel). 2024; 15(4).

Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene that causes autistic phenotypes when deleted or duplicated. Observations from clinical cases and animal models also suggest that changes of RAI1 expression levels contribute to autism. Previously, we used a bioinformatic approach to identify several single nucleotide polymorphisms (SNPs) located within the 5′-region of RAI1 that correlate with RAI1 mRNA expression in the human brain. In particular, the SNP rs4925102 was identified as a candidate cis-acting regulatory variant, the genotype of which may affect the binding of transcription factors that influence RAI1 mRNA expression. In this study, we provide experimental evidence based on reporter gene, chromatin immunoprecipitation (ChIP), and chromatin conformation capture (3C) assays that rs4925102 regulates RAI1 mRNA expression in an allele-specific manner in human cell lines, including the neuroblastoma-derived cell line SH-SY5Y. We also describe a statistically significant association between rs4925102 genotype and autism spectrum disorder (ASD) diagnosis in a case-control study and near-statistically significant association in an Autism Genome Project (AGP) transmission disequilibrium (TDT) study using Caucasian subjects.

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