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Background: A subset of developmental disorders (DD) is characterized by disease-specific genome-wide methylation changes. These episignatures inform on the underlying pathogenic mechanisms and can be used to assess the pathogenicity of genomic variants as well as confirm clinical diagnoses. Currently, the detection of these episignature requires the use of indirect methylation profiling methodologies. We hypothesized that long-read whole genome sequencing would not only enable the detection of single nucleotide variants and structural variants but also episignatures. Methods: Genome-wide nanopore sequencing was performed in 40 controls and 20 patients with confirmed or suspected episignature-associated DD, representing 13 distinct diseases. Following genomic variant and methylome calling, hierarchical clustering and dimensional reduction were used to determine the compatibility with microarray-based episignatures. Subsequently, we developed a support vector machine (SVM) for the detection of each DD. Results: Nanopore sequencing-based methylome patterns were concordant with microarray-based episignatures. Our SVM-based classifier identified the episignatures in 17/19 patients with a (likely) pathogenic variant and none of the controls. The remaining patients in which no episignature was identified were also classified as controls by a commercial microarray assay. In addition, we identified all underlying pathogenic single nucleotide and structural variants and showed haplotype-aware skewed X-inactivation evaluation directs clinical interpretation. Conclusion: This proof-of-concept study demonstrates nanopore sequencing enables episignature detection. In addition, concurrent haplotyped genomic and epigenomic analyses leverage simultaneous detection of single nucleotide/structural variants, X-inactivation, and imprinting, consolidating a multi-step sequential process into a single diagnostic assay. [ABSTRACT FROM AUTHOR]

To investigate the impact of different types of exercise modalities on children and adolescents with developmental disorders. Data were obtained from randomized controlled trials retrieved from five databases. Following the PRISMA NMA guidelines, a Bayesian framework-based Markov chain Monte Carlo simulation was used for aggregation and analysis. The included studies were assessed for risk of bias and quality evaluation. A total of 68 studies were included. Moderate-quality evidence suggests that combative sports may be the best exercise for enhancing gross motor skills, ball sports are the most effective for improving executive function, neurodevelopmental motor training is the most effective for improving social skills, and aquatic exercise is the most effective for improving behavioral problems. Conclusions: Combat sports, ball sports, neurodevelopmental motor training, and aquatic exercise may be effective exercise modalities for improving symptoms in children and adolescents with developmental disorders. However, the degree of improvement can vary among individuals with specific developmental disorders. Therefore, precise assessment of the individual symptoms of children or adolescents is crucial before selecting specific exercise interventions. Trial registration: PROSPERO (CRD42024545673). What Is Known: • Many studies indicate that exercise as an intervention can have positive effects on individuals with developmental disorders, such as ADHD and autism. However, reported effects vary, and there is no clear consensus on the optimal exercise intervention method yet. What Is New: • Through a comprehensive network meta-analysis, various exercise interventions for children and adolescents with developmental disorders were compared to determine the optimal approach. The study found that combat sports, ball sports, neurodevelopmental motor training, and aquatic exercise could potentially be effective modalities for improving symptoms in this population. [ABSTRACT FROM AUTHOR]

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Integrator complex is a multisubunit complex that participates in the processing of small nuclear RNA molecules in eukaryotic cells by cleaving the 3’ end. In protein-coding genes, Integrator is a key regulator of promoter-proximal pausing, release, and recruitment of RNA polymerase II. Research on Integrator has revealed its critical role in the regulation of gene expression and RNA processing. Dysregulation of the Integrator complex has been implicated in a variety of human diseases including cancer and developmental disorders. Therefore, understanding the structure and function of the Integrator complex is critical to uncovering the mechanisms of gene expression and developing potential therapeutic strategies for related diseases. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Linguistic Research / Dilbilim Arastirmalari Dergisi is the property of Bogazici University Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties in social interaction and communication, repetitive behaviors, and restricted interests. Unfortunately, the underlying molecular mechanism behind ASD remains unknown. It has been reported that oxidative and nitrosative stress are strongly linked to ASD. We have recently found that nitric oxide (NO•) and its products play an important role in this disorder. One of the key proteins associated with NO• is thioredoxin (Trx). We hypothesize that the Trx system is altered in the Shank3 KO mouse model of autism, which may lead to a decreased activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in oxidative stress, and thus, contributing to ASD-related phenotypes. To test this hypothesis, we conducted in vivo behavioral studies and used primary cortical neurons derived from the Shank3 KO mice and human SH-SY5Y cells with SHANK3 mutation. We showed significant changes in the levels and activity of Trx redox proteins in the Shank3 KO mice. A Trx1 inhibitor PX-12 decreased Trx1 and Nrf2 expression in wild-type mice, causing abnormal alterations in the levels of synaptic proteins and neurotransmission markers, and an elevation of nitrosative stress. Trx inhibition resulted in an ASD-like behavioral phenotype, similar to that of Shank3 KO mice. Taken together, our findings confirm the strong link between the Trx system and ASD pathology, including the increased oxidative/nitrosative stress, and synaptic and behavioral deficits. The results of this study may pave the way for identifying novel drug targets for ASD. [ABSTRACT FROM AUTHOR]

During the process of language acquisition, sensitivity to statistical regularities within language contributes to children's learning of complex linguistic structures from an early age. This implicit learning mechanism, referred to as statistical learning, which does not require any instruction, reinforcement or feedback, is often associated with language disorders. In this review, the complex and multifaceted relationship between language disorders and statistical learning is discussed from the perspective of the Procedural Learning Deficit Hypothesis, which explains disruptions in linguistic and cognitive processes through difficulties in procedural learning skills. The similarities and differences between developmental language disorder, developmental dyslexia, and autism spectrum disorder are examined alongside the difficulties observed in statistical learning processes. Research indicates that children with developmental language disorder and developmental dyslexia generally perform poorly on statistical learning tasks compared to their typically developing peers. In contrast, children with autism spectrum disorder do not show any deficit in statistical learning tasks, but differences have been observed in the neural processes underlying statistical learning. Methodological differences, variations in paradigms, stimuli, and participant characteristics across studies result in inconsistent findings. Developing a more comprehensive and holistic theoretical framework, examining statistical learning abilities throughout typical and atypical developmental stages, and establishing standardized methodologies and robust assessment tools can enhance our understanding of the relationship between developmental disorders and statistical learning. This, in turn, can contribute to the development of more effective intervention and support strategies based on this knowledge.

Abstract Background Tourette syndrome (TS) is a neurodevelopmental disorder. The prevalence of TS in 2016–2017 has been reported; however, little is known about the current prevalence and trend in children and adolescents with TS. This study aimed to estimate the prevalence and trend of Tourette syndrome (TS) among US children and adolescents aged 0–17 years from 2016 to 2022. Methods We analyzed data from a nationally representative sample of 278,472 children and adolescents aged 0–17 years who participated in the 2016–2022 National Survey of Children’s Health (NSCH), a nationwide, population-based, cross-sectional survey of US children and adolescents. TS was defined as the affirmative response in the questionnaire completed by a parent or guardian. Results Among the 278,472 children and adolescents enrolled, 754 had been diagnosed with TS, with an overall prevalence of 0.23% in all children and adolescents aged 0-17 years. The weighted prevalence by age group was lower than 0.01% in children aged 0–2 years, 0.05% in children aged 3–5 years, 0.28% in children aged 6–11 years, and 0.38% in adolescents aged 12–17 years. There were significant sex and racial/ethnic differences in the overall prevalence of diagnosed TS (i.e., 0.35% in boys and 0.11% in girls, 0.22% in Hispanics, 0.28% in non-Hispanic whites and 0.16% in non-Hispanic blacks). There was no significant change in the estimated prevalence of TS from 2016 to 2022. Conclusion Based on nationally representative data, this study found that the national prevalence of TS among the US children and adolescents differed by sex and race/ethnicity but remained stable from 2016 to 2022.

Background: Tourette syndrome (TS) is a neurodevelopmental disorder. The prevalence of TS in 2016–2017 has been reported; however, little is known about the current prevalence and trend in children and adolescents with TS. This study aimed to estimate the prevalence and trend of Tourette syndrome (TS) among US children and adolescents aged 0–17 years from 2016 to 2022. Methods: We analyzed data from a nationally representative sample of 278,472 children and adolescents aged 0–17 years who participated in the 2016–2022 National Survey of Children's Health (NSCH), a nationwide, population-based, cross-sectional survey of US children and adolescents. TS was defined as the affirmative response in the questionnaire completed by a parent or guardian. Results: Among the 278,472 children and adolescents enrolled, 754 had been diagnosed with TS, with an overall prevalence of 0.23% in all children and adolescents aged 0-17 years. The weighted prevalence by age group was lower than 0.01% in children aged 0–2 years, 0.05% in children aged 3–5 years, 0.28% in children aged 6–11 years, and 0.38% in adolescents aged 12–17 years. There were significant sex and racial/ethnic differences in the overall prevalence of diagnosed TS (i.e., 0.35% in boys and 0.11% in girls, 0.22% in Hispanics, 0.28% in non-Hispanic whites and 0.16% in non-Hispanic blacks). There was no significant change in the estimated prevalence of TS from 2016 to 2022. Conclusion: Based on nationally representative data, this study found that the national prevalence of TS among the US children and adolescents differed by sex and race/ethnicity but remained stable from 2016 to 2022. [ABSTRACT FROM AUTHOR]

This study explored stress in Balkan parents of children with developmental disorders (DD), taking into account the type of child's DD, sociodemographic factors, and coping strategies. Sample comprised 139 mothers from Serbia (42%), Montenegro (27%), Bosnia and Herzegovina (14%), Croatia (16%), and Slovenia (2%), whose children were diagnosed with specific developmental disorders of speech and language (37%), autism spectrum disorders (39%) and mixed specific developmental disorders (24%). Mothers completed the Parenting Stress Index-SF and Brief COPE, and provided information on sociodemographic characteristics. The one-way ANOVA revealed that mothers of children with ASD reported the highest stress intensity. Linear regression suggests that having a child with autism spectrum disorder, lower education, and the use of Self-blame contribute to the prediction of stress. The results of several mediation analyses indicate that Religion and Behavioral disengagement mediate the relationship between parental stress and the child's age: parents of older children with DD show a greater tendency to use these coping strategies, which consequently leads to higher stress levels. [ABSTRACT FROM AUTHOR]

Introduction: To date, there are no caregiver-reported screening measures of oral behaviors related to feeding. The goal of this study was to develop such a measure. Method: Caregivers of 803 children referred to a feeding clinic and 188 comparison children reported their children's frequency of nine oral behaviors. These data were used to develop an Oral Behavior Screener (OBS). Both the psychometrics of the OBS and the relations between the OBS and child demographics were examined. Results: As expected, the clinical sample demonstrated more deficits in oral behaviors than the comparison sample. We also found special needs status and age were linked to the OBS summary score. Discussion: The OBS is a brief screener that can be used by clinicians to examine the need for further assessment, possible targets for intervention, oral behaviors often associated with feeding problems. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pulmonary sequestration is an uncommon congenital anomaly. It is usually diagnosed at a young age but can present in adults with recurrent episodes of pneumonia and cough. Isolated shortness of breath is an uncommon presentation of pulmonary sequestration and is rarely reported. We describe an adult male who presented with exertional dyspnea at a high altitude and was eventually diagnosed as a case of pulmonary sequestration. It is an uncommon developmental anomaly that can go undetected at a young age. In adults, it can present as isolated dyspnea, and a thorough work-up can lead to an accurate diagnosis.

Abstract Background Sharing and fairness are important prosocial behaviors that help us navigate the social world. However, little is known about how and whether individuals with Williams Syndrome (WS) engage in these behaviors. The unique phenotype of individuals with WS, consisting of high social motivation and limited social cognition, can also offer insight into the role of social motivation in sharing and fairness when compared to typically developing (TD) individuals. The current study used established experimental paradigms to examine sharing and fairness in individuals with WS and TD individuals. Methods We compared a sample of patients with WS to TD children (6-year-olds) matched by mental age (MA) on two experimental tasks: the Dictator Game (DG, Experiment 1, N = 17 WS, 20 TD) with adults modeling giving behaviors used to test sharing and the Inequity Game (IG, Experiment 2, N = 14 WS, 17 TD) used to test fairness. Results Results showed that the WS group behaved similarly to the TD group for baseline giving in the DG and in the IG, rejecting disadvantageous offers but accepting advantageous ones. However, after viewing an adult model giving behavior, the WS group gave more than their baseline, with many individuals giving more than half, while the TD group gave less. Combined these results suggest that social motivation is sufficient for sharing and, in particular, generous sharing, as well as the self-focused form of fairness. Further, individuals with WS appear capable of both learning to be more generous and preventing disadvantageous outcomes, a more complex profile than previously known. Conclusions In conclusion, the present study provides a snapshot into sharing and fairness-related behaviors in WS, contributing to our understanding of the intriguing social-behavioral phenotype associated with this developmental disorder.

Abstract Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

Abstract Background and objectives Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children’s Hospital, conducted a survey among Italian participants. Method Here, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities. Results Anxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM. Conclusion FXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches.

Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development. Methods We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis. Results Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways. Limitations Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain. Conclusions Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development.

Abstract Background HRASKO/NRASKO double knockout mice exhibit exceedingly high rates of perinatal lethality due to respiratory failure caused by a significant lung maturation delay. The few animals that reach adulthood have a normal lifespan, but present areas of atelectasis mixed with patches of emphysema and normal tissue in the lung. Methods Eight double knockout and eight control mice were analyzed using micro-X-ray computerized tomography and a Small Animal Physiological Monitoring system. Tissues and samples from these mice were analyzed using standard histological and Molecular Biology methods and the significance of the results analyzed using a Student´s T-test. Results The very few double knockout mice surviving up to adulthood display clear craniofacial abnormalities reminiscent of those seen in RASopathy mouse models, as well as thrombocytopenia, bleeding anomalies, and reduced platelet activation induced by thrombin. These surviving mice also present heart and spleen hyperplasia, and elevated numbers of myeloid-derived suppressor cells in the spleen. Mechanistically, we observed that these phenotypic alterations are accompanied by increased KRAS-GTP levels in heart, platelets and primary mouse embryonic fibroblasts from these animals. Conclusions Our data uncovers a new, previously unidentified mechanism capable of triggering a RASopathy phenotype in mice as a result of the combined removal of HRAS and NRAS.

Background: Sharing and fairness are important prosocial behaviors that help us navigate the social world. However, little is known about how and whether individuals with Williams Syndrome (WS) engage in these behaviors. The unique phenotype of individuals with WS, consisting of high social motivation and limited social cognition, can also offer insight into the role of social motivation in sharing and fairness when compared to typically developing (TD) individuals. The current study used established experimental paradigms to examine sharing and fairness in individuals with WS and TD individuals. Methods: We compared a sample of patients with WS to TD children (6-year-olds) matched by mental age (MA) on two experimental tasks: the Dictator Game (DG, Experiment 1, N = 17 WS, 20 TD) with adults modeling giving behaviors used to test sharing and the Inequity Game (IG, Experiment 2, N = 14 WS, 17 TD) used to test fairness. Results: Results showed that the WS group behaved similarly to the TD group for baseline giving in the DG and in the IG, rejecting disadvantageous offers but accepting advantageous ones. However, after viewing an adult model giving behavior, the WS group gave more than their baseline, with many individuals giving more than half, while the TD group gave less. Combined these results suggest that social motivation is sufficient for sharing and, in particular, generous sharing, as well as the self-focused form of fairness. Further, individuals with WS appear capable of both learning to be more generous and preventing disadvantageous outcomes, a more complex profile than previously known. Conclusions: In conclusion, the present study provides a snapshot into sharing and fairness-related behaviors in WS, contributing to our understanding of the intriguing social-behavioral phenotype associated with this developmental disorder. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate differences in maternal characteristics and obstetric and offspring childhood outcomes between births at and after 37 weeks of gestation (referred to as term and post-term births) according to the use of tocolytic treatment. Methods: Data for 63,409 women with singleton births at and after 37 weeks of gestation were analyzed using data from the Japan Environment and Children's Study (JECS). We compared maternal characteristics, obstetric outcomes, and offspring childhood outcomes between term and post-term births exposed and not exposed to tocolytic treatment. Additionally, multivariable logistic regression models were used to calculate adjusted odds ratios for offspring childhood outcomes with significant between-group differences in the univariable analysis, with term and post-term births without tocolytic agents as the reference group. Results: We observed differences in maternal characteristics and obstetric outcomes between term and post-term births exposed and not exposed to tocolytic treatment. The incidence of offspring childhood developmental disorders showed no significant between-group differences. However, participants exposed to tocolytic agents had higher incidence of offspring childhood allergic disorders. The adjusted odds ratio for any of the offspring childhood allergic disorders in term and post-term births with tocolytic agents was 1.08 (95% confidence interval, 1.03–1.13). Conclusion: This study found no significant difference in the incidence of offspring developmental disorders between term and post-term births exposed and not exposed to tocolytic treatment. However, tocolytic treatment was associated with differences in maternal characteristics and obstetric outcomes, along with a marginal increase in the incidence of childhood allergic disorders in offspring. [ABSTRACT FROM AUTHOR]

Background/Objectives: The relevance of psychomotor skills in children's growth is being increasingly recognized. The transversal role of psychomotor skills in learning performance is described through a link between cognitive and motor functioning, promoting socio-affective–expressive competencies, but there is a scarcity of evidence from the field. A two-fold goal was defined: to investigate the relationship between psychomotor functions and academic performance and to examine the factors affecting children's academic performance. Methods: The Portuguese versions of the Neuropsychomotor Functions Assessment Battery for Children (NPmot.pt), Preschool Diagnostic Tasks (PRE), and School Learning Skills Battery (SLSB) were applied to 350 children (85.72 ± 24.23 months) with and without disabilities attending mainstream schools. Results: Pearson correlations and regression analyses were used. NPmot.pt domains showed moderate to strong correlations with PRE domains (0.30 < r < 0.82) and weak ones with SLSB domains (r < 0.30). Psychomotor development is a stronger predictor (p < 0.001) of pre-academic performance outcomes: (βTonus = 0.67, βGross Motor Skills = 1.04, βSpatial Orientation = −1.44, βRhythm = −1.59 and βAuditory Attention = 3.68) than of academic performance above 7 years old (p > 0.05). Conclusions: Results strengthen the importance of psychomotor skills development from an early age, also at school, with implications for an early psychomotor assessment and intervention for children with and without disabilities. Tailor-fit interventions, including strategies to improve psychomotor skills, should be promoted during the school process of all children for a successful learning process. [ABSTRACT FROM AUTHOR]

Background: Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development. Methods: We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis. Results: Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways. Limitations: Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain. Conclusions: Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development. [ABSTRACT FROM AUTHOR]

Background and objectives: Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children's Hospital, conducted a survey among Italian participants. Method: Here, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities. Results: Anxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM. Conclusion: FXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Adolescence is a key period of vulnerability for poor mental health as the brain is still developing and may be more sensitive to the negative impacts of stress and adversity. Unfortunately, few measures comprehensively assess wellbeing in adolescents. Methods: The 26-item COMPAS-W Wellbeing Scale for adults was validated in a sample of 1,078 adolescents aged 13–17 years old (51.67% male, 79.13% nonclinical vs 20.87% psychiatric or developmental clinical cases). The six COMPASW sub-scales and total scale were examined in this sample using second-order confirmatory factor analysis, and psychometric testing. Results: The 23-item COMPAS-W demonstrated the best fit for this sample according to goodness-of-fit indices (c2 (220, 1078) = 1439.395, p < 0.001, CFI = 0.893, TLI = 0.877, RMSEA = 0.070, SRMR = 0.095). Internal reliability for the confirmed 23-item COMPAS-W model was run for the total scale (a = 0.912) and sub-scales (Composure, a = 0.735; Own-worth, a = 0.601; Mastery, a = 0.757; Positivity, a = 0.721; Achievement, a = 0.827; and Satisfaction, a = 0.867). Testretest reliability over 6 weeks was also good for the total scale at r = 0.845 and the sub-scales: Composure (r = 0.754), Own-worth (r = 0.743), Mastery (r = 0.715), Positivity (r = 0.750), Achievement (r = 0.750), and Satisfaction (r = 0.812). Compared with non-clinical participants’ wellbeing (M = 90.375, SE = 0.400), those with clinical diagnoses reported lower wellbeing, both for those with developmental diagnoses (M = 85.088, SE = 1.188), or psychiatric diagnoses (M = 78.189, SE = 1.758), or combined developmental and psychiatric diagnoses (M = 77.079, SE = 2.116). Yet, when wellbeing category scores were considered by diagnosis group, both non-clinical and clinical groups demonstrated incidence across all three categories of languishing, moderate and flourishing wellbeing, in support of the dual-continua model of mental health. On average, younger adolescents’ (13–14 years) wellbeing did not differ from older adolescents’ (15–17 years) wellbeing; however, for sex, males scored 1.731 points significantly higher in wellbeing compared with females (p = 0.028); and American participants scored 3.042 points significantly higher in wellbeing compared with Australian participants (p < 0.001). Discussion: In conclusion, the 23-item COMPAS-W is a reliable measure of wellbeing for adolescents, both for those with and without developmental and psychiatric diagnoses. [ABSTRACT FROM AUTHOR]

Background: One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as "genetic constraint". Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods: We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results: We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions: Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation. [ABSTRACT FROM AUTHOR]

Background: Zebrafish have emerged as an invaluable asset in biomedical research, particularly in comparison to other vertebrate models employed for studying human ailments. Their efficacy in large-scale studies of genetic variations and drug testing has been well-established. Recent advancements in CRISPR and next-generation sequencing have further boosted zebrafish-based disease modeling, enhancing our comprehension of the biological underpinnings of hereditary human diseases. Such efforts are critical for developing targeted therapies that offer innovative diagnostic and treatment options. Materials and Methods: We extensively examined original articles and papers from prominent databases such as PubMed, SCOPUS, Science Direct, and PubMed Central. This analysis included a comprehensive review of the articles, their citations, and cross-references. To identify relevant articles, we employed a variety of keywords, including but not limited to: Zebrafish applications, toxicity studies involving Zebrafish, CRISPR technology applications in Zebrafish research, substances utilized in developmental biology studies with Zebrafish, and various models employed in Zebrafish research. Results: In the medical field, zebrafish research has made strides in various areas, including developmental disorders, mental illnesses, and metabolic diseases. A growing trend involves studying an expanding spectrum of risk genes linked to neurological disorders using zebrafish as a model system. Zebrafish possess unique traits that make them an ideal choice for this purpose. For instance, their active partner growth of translucent embryos allows direct observation of the developing brain during early stages, providing valuable insights into developmental processes. Additionally, the large number of progenies zebrafish produce significantly enhances controllability, making them highly effective for therapeutic testing aimed at identifying specific molecular effectors of simple behavioral genetic traits. Conclusion:The exceptional attributes of zebrafish make them a potent and versatile tool for medical research. Their contributions have been instrumental in advancing our understanding of human diseases and developing potential treatments. As a result, zebrafish continue to play a pivotal role in biomedical research, propelling progress in personalized medicine and the pursuit of improved treatments for a wide range of health conditions. [ABSTRACT FROM AUTHOR]

Lymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne arenavirus, primarily spread by common house mouse species. Acquired human infections range from asymptomatic to mild flu-like symptoms and self-resolving neurological diseases. In contrast, intrauterine LCMV infection is associated with high mortality and morbidity. Infection of the fetus often leads to fetal death, and surviving fetuses may develop vision impairment and central nervous system developmental disorders. LCMV is mainly diagnosed by serological methods using in-house indirect immunofluorescence assays. LCMV nucleic acid is detected by the nested RT-PCR method and confirmed by Sanger sequencing. In Hungary, 23 acquired lymphocytic choriomeningitis cases were diagnosed between 2017 and 2023. Ten out of 23 confirmed patients proved to be positive by the PCR method. Two cases of intrauterine LCMV infections were detected in 2019 and 2021, respectively. The IgG antibody titers measured in the infant's serum samples were much higher than the IgG titers of the maternal serum samples. Both IgM and IgA antibodies were detectable in the infants' sera. As the microbiological diagnosis of LCMV is rather challenging and the symptoms are very similar to the clinical picture of other common teratogenic pathogens such as cytomegalovirus or Toxoplasma gondii, intrauterine LCMV infections might still be underdiagnosed. [ABSTRACT FROM AUTHOR]

The coronavirus pandemic (COVID-19) is one of the crises that had its drawbacks for all people and various aspects of their life activities. Especially, children with special needs and their caregivers who are in extreme need of attention in all health, psychological, and social fields. Therefore, this study explored the biopsychosocial profile of children with special needs and their caregivers during the COVID-19 pandemic. The biopsychosocial model determined the pandemic's effects regarding health follow-up, nutrition, learning, and psychological and social impacts. To screen the impact of the COVID-19 pandemic, 120 Egyptian caregivers of children with special needs responded to an online questionnaire distributed through social media. According to the findings, children with special needs suffered from negative effects in all health domains (physical, psychological, and social health) during the pandemic. The caregivers suffered from unavailability of health and rehabilitative services, disturbed social life, parental anxiety, and negative effects on income. The research findings showed that children with special needs and their caregivers did not escape from the drawbacks of the COVID-19 crisis. [ABSTRACT FROM AUTHOR]

Multilingualism has become the norm in families all over the world. These families need to juggle their children's linguistic identity and integration in their contexts. They may also need professional advice about which language(s) they should use at home, especially when children present with developmental disorders. There is a dearth of studies addressing the role parental views play in home-language maintenance with children with developmental disorders. This study is conducted in Spain, where Spanish is the national language, along with local languages in certain regions, as well as foreign languages. This qualitative study aimed to deepen our understanding of the views about language choice of multilingual families whose children have either typical language development or a developmental disorder in Spain. We recruited 26 parents of multilingual children aged between 5 and 10 years, from different linguistic backgrounds. Semi-structured online interviews were conducted. The data were analyzed through reflexive thematic analysis. The findings illustrate the complexity and nuance of parents' views and decisions regarding language choice in their contexts. The themes included identity and belonging, as well as the influences of external advice on parental decisions. It is important that professionals such as speech–language therapists understand these views to enable them to deliver family-centered care. [ABSTRACT FROM AUTHOR]

BACKGROUND: In the Republic of Serbia, to our knowledge, there has been no research dedicated to the professional stress faced by speech-language pathologists (SLPs). Since speech therapy belongs to the helping professions, SLPs might experience professional stress. OBJECTIVE: To examine the levels of professional stress in SLPs concerning sociodemographic characteristics and terms of the workplace. METHODS: The research was conducted online, using a questionnaire designed to determine professional stress in speech-language pathologists - Speech-Language Pathologist Stress Inventory. The voluntary sample consisted of 185 employed SLPs from the Republic of Serbia. The stress level was observed concerning marital status, years of working experience, age, educational degree, caseload size, job sector, job setting, type of patients' diagnosis, and type of service which SLPs provide. RESULTS: The results showed that SLPs experience mild to moderate levels of professional stress and that there is a statistically significant difference in the stress level concerning years of working experience, age, job sector, and job setting. Applying Generalized Linear Mixed Model revealed that two-way interaction (Years of working experience * Marital status) and three-way interaction (Age * Job Setting * Type of patients' diagnosis) dominated on the model. CONCLUSION: Since it is noted that SLPs are experiencing mild to moderate levels of professional stress, it is important to emphasize the need for adaptation of existing work terms as well as to provide additional support to speech therapists in order to improve their mental health. [ABSTRACT FROM AUTHOR]

Background: HRASKO/NRASKO double knockout mice exhibit exceedingly high rates of perinatal lethality due to respiratory failure caused by a significant lung maturation delay. The few animals that reach adulthood have a normal lifespan, but present areas of atelectasis mixed with patches of emphysema and normal tissue in the lung. Methods: Eight double knockout and eight control mice were analyzed using micro-X-ray computerized tomography and a Small Animal Physiological Monitoring system. Tissues and samples from these mice were analyzed using standard histological and Molecular Biology methods and the significance of the results analyzed using a Student´s T-test. Results: The very few double knockout mice surviving up to adulthood display clear craniofacial abnormalities reminiscent of those seen in RASopathy mouse models, as well as thrombocytopenia, bleeding anomalies, and reduced platelet activation induced by thrombin. These surviving mice also present heart and spleen hyperplasia, and elevated numbers of myeloid-derived suppressor cells in the spleen. Mechanistically, we observed that these phenotypic alterations are accompanied by increased KRAS-GTP levels in heart, platelets and primary mouse embryonic fibroblasts from these animals. Conclusions: Our data uncovers a new, previously unidentified mechanism capable of triggering a RASopathy phenotype in mice as a result of the combined removal of HRAS and NRAS. [ABSTRACT FROM AUTHOR]

EMI-ECO est une équipe mobile intervenant auprès des enfants âgés de moins de 12 ans confiés à l'aide sociale à l'enfance et qui a pour but un repérage/une évaluation des troubles du développement ou des troubles mentaux, une organisation des soins pour ces enfants mais aussi un travail partenarial avec l'ensemble des équipes prenant en charge ces jeunes (aide sociale a l'enfance, protection maternelle et infantile, Centre médico-psychologique/Centre médico-psycho-pédagogique). Les interventions sont intersectorielles dans une aire géographique correspondant aux intersecteurs de deux hôpitaux ayant créé l'équipe (AP–HM et CHS Valvert) soit le sud et l'est de Marseille, la Ciotat, Aubagne et Cassis. Ce territoire a été défini pour être cohérent et permettre une meilleure efficacité des interventions. Dans ce travail, nous présentons la mise en place et les premiers éléments d'activité d'un dispositif innovant, à savoir une équipe mobile intervenant au plus près du lieu de vie et dans l'écosystème des enfants confiés à l'aide sociale à l'enfance. Nous illustrerons également nos propos à travers deux cas cliniques d'enfants pris en charge par notre unité. La prise en charge de ces enfants implique un investissement réel du professionnel et un important travail de collaboration. Nous espérons que la présentation de notre dispositif permettra à d'autres équipes de s'en saisir et de l'adapter aux particularités de leur terrain d'intervention. EMI-ECO is a mobile team working with children under the age of 12 entrusted to the Children's Social Welfare Agency (Aide Sociale à l'Enfance). Its aim is to identify and assess developmental or mental disorders, organize care for these children and work in partnership with all the teams caring for these youngsters (Child Welfare Agency, Maternal and Child Protection, Centre médico-psychologique/Centre médico-psycho pédagogique). Intervention takes place across a geographical area corresponding to the intersectors of the two hospitals that created the team (AP–HM and CHS Valvert), i.e. the south and east of Marseille, La Ciotat, Aubagne and Cassis. This territory was defined to be coherent and to enable more effective interventions. In this work, we present the implementation and initial results of an innovative system, namely a mobile team working as close as possible to the living environment and ecosystem of children entrusted to the child welfare system. We will also illustrate our remarks with two clinical cases of children cared for by our unit. Caring for these children involves a real investment on the part of the professional and a major partnership effort. We hope that the presentation of our system will enable other teams to adopt it and adapt it to the particularities of their field of intervention. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. Methods We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. Results For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P < 2.2 × 10−6). We identified a number of genes, including ARID1B and GATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. Conclusions Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants.

Abstract Background Immersive and non-immersive VR technology has been increasingly employed in training. This has encouraged physicians working in skill development to try using it to improve the learning, emotional recognition, and social skills of various disorders. This study aimed to explore the controlled trials employing VR in autism, ADHD, and dyslexia. Methodology A literature review has been conducted, on PubMed, Scopus, and Web of Science. Any controlled trial in the pediatric age group, involving the comparison of VR training with other types of therapies in autism, ADHD, and dyslexia was included. Results Only 4 controlled trials were identified, comprising a total of 208 patients, with ages ranging from 6 to 16 years. Out of these studies, two involved patients with autism, one with ADHD, and one with dyslexia. VR was successful in improving emotional recognition but not social interaction in autism. All trials did not mention thoroughly possible complications of prolonged use of VR. Short conclusion Despite being a promising technology, there is still a long road to prove the validity of using VR in skills development. Few controlled trials have been tailored to explore VR advantages over conventional training and therapies, most of them have a limited sample size, a short training course, and no mention of possible setbacks, such as ocular effects and social isolation.

Background: Immersive and non-immersive VR technology has been increasingly employed in training. This has encouraged physicians working in skill development to try using it to improve the learning, emotional recognition, and social skills of various disorders. This study aimed to explore the controlled trials employing VR in autism, ADHD, and dyslexia. Methodology: A literature review has been conducted, on PubMed, Scopus, and Web of Science. Any controlled trial in the pediatric age group, involving the comparison of VR training with other types of therapies in autism, ADHD, and dyslexia was included. Results: Only 4 controlled trials were identified, comprising a total of 208 patients, with ages ranging from 6 to 16 years. Out of these studies, two involved patients with autism, one with ADHD, and one with dyslexia. VR was successful in improving emotional recognition but not social interaction in autism. All trials did not mention thoroughly possible complications of prolonged use of VR. Short conclusion: Despite being a promising technology, there is still a long road to prove the validity of using VR in skills development. Few controlled trials have been tailored to explore VR advantages over conventional training and therapies, most of them have a limited sample size, a short training course, and no mention of possible setbacks, such as ocular effects and social isolation. [ABSTRACT FROM AUTHOR]

Background: Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. Methods: We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. Results: For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P < 2.2 × 10−6). We identified a number of genes, including ARID1B and GATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. Conclusions: Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants. [ABSTRACT FROM AUTHOR]