Including Autism Spectrum Disorder Research Articles

Identification of novel driver risk genes in CNV loci associated with neurodevelopmental disorders

Copy number variants (CNVs) are genome-wide structural variations involving the duplication or deletion of large nucleotide sequences. While these types of variations can be commonly found in humans, large and rare CNVs are known to contribute to the development of various neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Nevertheless, given that these NDD-risk CNVs cover broad regions of the genome, it is particularly challenging to pinpoint the critical gene(s) responsible for the manifestation of the phenotype. In this study, we performed a meta-analysis of CNV data from 11,614 patients with NDDs and 4,031 controls from SFARI database to identify 41 NDD-risk CNV loci, including 24 novel regions. We also found evidence for dosage-sensitive genes within these regions being significantly enriched for known NDD-risk genes and pathways. In addition, a significant proportion of these genes was found to i) converge in protein-protein interaction networks; ii) be among most expressed genes in the brain across all developmental stages; and iii) be hit by deletions that are significantly over-transmitted to individuals with ASD within multiplex ASD families from the iHART cohort. Finally, we conducted a burden analysis using 4,281 NDD cases from Decipher and iHART cohorts, and 2,504 neurotypical controls from 1,000 Genomes and iHART, that resulted in the validation of the association of 162 dosage sensitive genes driving risk for NDDs, including 22 novel NDD-risk genes. Importantly, most NDD-risk CNV loci entail multiple NDD-risk genes in agreement with a polygenic model associated with the majority of NDD cases.

Valproate Use During Spermatogenesis and Risk to Offspring

Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis. To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders. This nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024. Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception). Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders. Among 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points. In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.

CELF2 Deficiency Demonstrates Autism-Like Behaviors and Interferes with Late Development of Cortical Neurons in Mice.

CELF2 variants have been linked to neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). However, the molecular mechanisms remain unclear. We generated Celf2 Nestin-Cre knockout mice.Our findings revealed that Celf2 Nestin-Cre heterozygous knockout mice exhibited social impairment and anxiety, an autism-like behavior, though no manifestations of repetitive stereotyped behavior, learning cognitive impairment, or depression were observed. Immunofluorescence assay showed an underdeveloped cerebral cortex with significantly reduced cortical thickness, albeit without abnormal cell density. Further in vitro neuronal culture demonstrated a significant reduction in dendritic spine density and affected synaptic maturation in Celf2 deficient mice, with no notable abnormalities in total neurite and axon length. RNA-seq and RIP-seq analysis of the cerebral cortex revealed differentially expressed genes post Celf2 gene knockout compared with the control group. Enrichment analysis highlighted significant enrichment in dendrite and synapse-related biological processes and pathways. Our study delineated the behavioral and neurodevelopmental phenotypes of Celf2, suggesting its potential involvement in autism through the regulation of target genes associated with dendritic spines and synapse development. Further research is needed to elucidate the specific mechanisms involved.

Sex Differences in Morphine Sensitivity of Neuroligin-3 Knockout Mice.

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.

Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM.

This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.

Posterior default mode network is associated with the social performance in male children with autism spectrum disorder: A dynamic causal modeling analysis based on triple-network model.

The triple-network model has been widely applied in neuropsychiatric disorders including autism spectrum disorder (ASD). However, the mechanism of causal regulations within the triple-network and their relations with symptoms of ASD remains unclear. 81 male ASD and 80 well matched typically developing control (TDC) were included in this study, recruited from Autism Brain Image Data Exchange-I datasets. Spatial reference-based independent component analysis was used to identify the anterior and posterior part of default-mode network (aDMN and pDMN), salience network (SN), and bilateral executive-control network (ECN) from resting-state functional magnetic resonance imaging data. Spectral dynamic causal model and parametric empirical Bayes with Bayesian model reduction/average were adopted to explore the effective connectivity (EC) within triple-network and the relationship between EC and autism diagnostic observation schedule (ADOS) scores. After adjusting for age and site effect, ASD and TDC groups both showed inhibition patterns. Compared with TDC, ASD group showed weaker self-inhibition in aDMN and pDMN, stronger inhibition in pDMN→aDMN, weaker inhibition in aDMN→LECN, pDMN→SN, LECN→SN, and LECN→RECN. Furthermore, negative relationships between ADOS scores and pDMN self-inhibition strength, as well as with the EC of pDMN→aDMN were observed in ASD group. The present study reveals imbalanced effective connections within triple-networks in ASD children. More attentions should be focused at the pDMN, which modulates the core symptoms of ASD and may serve as an important region for ASD diagnosis and the target region for ASD treatments.

Computerized Cognitive Retraining Program for Home Training of Children with Disabilities

Cognitive impairments in children with disabilities can significantly impact their learning and daily functioning. Computerized cognitive retraining programs offer a promising solution for enhancing cognitive skills in a home-based setting. This research paper explores the development and effectiveness of a computerized cognitive retraining program designed specifically for children with disabilities. The program includes a series of interactive exercises aimed at improving attention, memory, problem- solving, and executive functioning skills. The study involved a cohort of children with various disabilities, including autism spectrum disorder and attention- deficit/hyperactivity disorder. Participants engaged in the retraining program at home under the guidance of caregivers, with progress monitored over a period of several weeks. The results showed a marked improvement in cognitive performance across multiple domains, as measured by standardized assessment tools. Caregivers also reported increased engagement and motivation among the children. This paper concludes that computerized cognitive retraining can be a valuable tool for supporting children with disabilities. It provides a flexible and accessible approach to cognitive development, allowing for consistent practice in a familiar environment. Further research is recommended to explore the long-term effects of the program and to identify specific elements that contribute to its success.

MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Cell-type-specific effects of autism-associated chromosome 15q11.2-13.1 duplications in human brain.

Recurrent copy number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder (ASD). Duplication of 15q11.2-13.1 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of ASD by over 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex we conducted single-nucleus RNA-sequencing and multi-omic sequencing on dup15q cases (n=6) as well as non-dup15q ASD (n=7) and neurotypical controls (n=7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene expression changes. Neuronal subtypes, showed greater upregulation of gene expression across a critical region within the duplication as compared to other cell types. Genes within the duplicated region that had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and ASD had largely distinct signatures of chromatin accessibility, but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding factor motifs implicated in each condition implicated distinct biological mechanisms; neuronal JUN/FOS networks in ASD vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain and finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects CNVs more broadly in neurodevelopmental disorders.

Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing

BackgroundTrio-based whole-exome sequencing (trio-WES) enables identification of pathogenic variants, including copy-number variants (CNVs), in children with unexplained neurodevelopmental delay (NDD) and neurodevelopmental comorbidities (NDCs), including autism spectrum disorder (ASD), epilepsy, and attention deficit hyperactivity disorder. Further phenotypic and genetic analysis on trio-WES-tested NDD-NDCs cases may help to identify key phenotypic factors related to higher diagnostic yield of using trio-WES and novel risk genes associated with NDCs in clinical settings.MethodsIn this study, we retrospectively performed phenotypic analysis on 163 trio-WES-tested NDD-NDCs children to determine the phenotypic differences between genetically diagnosed and non-genetically diagnosed groups. Additionally, we conducted genetic analysis of ASD genes with the help of Simons Foundation for Autism Research Institute (SFARI) Gene database to identify novel possible ASD-risk genes underlying genetic NDD conditions.ResultsAmong these 163 patients, pathogenic variants were identified in 82 cases (82/163, 50.3%), including 20 cases with CNVs. By comparing phenotypic variables between genetically diagnosed group (82 cases) and non-genetically diagnosed group (81 cases) with multivariate binary logistic regression analysis, we revealed that NDD-NDCs cases presenting with severe-profound NDD [53/82 vs 17/81, adjusted-OR (95%CI): 4.865 (2.213 – 10.694), adjusted-P < 0.001] or having multiple NDCs [26/82 vs 8/81, adjusted-OR (95%CI): 3.731 (1.399 – 9.950), adjusted-P = 0.009] or accompanying ASD [64/82 vs 35/81, adjusted-OR (95%CI): 3.256 (1.479 – 7.168), adjusted-P = 0.003] and head circumference abnormality [33/82 vs 11/81, adjusted-OR (95%CI): 2.788 (1.148 – 6.774), adjusted-P = 0.024] were more likely to have a genetic diagnosis using trio-WES. Moreover, 37 genes with monogenetic variants were identified in 48 patients genetically diagnosed with NDD-ASD, and 15 dosage-sensitive genes were identified in 16 individuals with NDD-ASD carrying CNVs. Most of those genes had been proven to be ASD-related genes. However, some of them (9 genes) were not proven sufficiently to correlate with ASD. By literature review and constructing protein-protein interaction networks among these 9 candidate ASD-risk genes and 102 established ASD genes obtained from the SFARI Gene database, we identified CUL4B, KCNH1, and PLA2G6 as novel possible ASD-risk genes underlying genetic NDD conditions.ConclusionsTrio-WES testing is recommended for patients with unexplained NDD-NDCs that have severe-profound NDD or multiple NDCs, particularly those with accompanying ASD and head circumference abnormality, as these independent factors may increase the likelihood of genetic diagnosis using trio-WES. Moreover, NDD patients with pathogenic variants in CUL4B, KCNH1 and PLA2G6 should be aware of potential risks of developing ASD during their disease courses.

Predictors of parental attitudes towards sexual health education for persons with special needs

ABSTRACT International guidelines on sexual health education suggest that parents should be the primary educators in their children’s sexuality education, considering that sexuality education is a lifelong process that begins in early childhood and continues into adulthood. The study aimed to investigate the relationships among parental self-efficacy, parental knowledge about sexuality, attitudes towards sexuality of people with disabilities, and parental stress. A total of 58 parents of children with various disabilities, including Autism Spectrum Disorders, ADHD, and physical disabilities, participated in the study. The findings indicate that knowledge about sexuality is an important predictor of the parental attitudes towards sexuality of people with disabilities.

Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.

Autism's Impact on Cochlear Implantation Surgery Outcomes in Deaf Children.

Cochlear implants (CI) provide a hearing sense for severe to profound hearing-impaired patients, both adults and children, and they are a broadly effective and accepted therapeutic method for those patients. Also, Deaf children with comorbidities, including autism spectrum disorders (ASDs), undergo cochlear implantation. ASDs are a group of developing disorders characterized by abnormalities in social interaction and communication with limited repetitive patterns of behavior. This study aimed to assess the effect of Autism on CI surgery outcomes in Deaf Children. We followed 12 autistic patients with cochlear implantation and 12 non-autistic cochlear-implanted patients for two years. The Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores were used to assess 6, 12, and 24 months after cochlear implantation surgery. During the 24-month follow-up, the CAP means scores increased in both groups, and SIR and CAP progresses were considerably greater in non-ASD children (P<0.001). However, in ASD children, the progress of CAP and SIR variables were significant, with 99% and 95% confidence, respectively, at 24 months after surgery. Although the CIs could improve hearing performance in autistic patients, speech development after CIs in autistic children could affected by several factors, including the severity of autism, and this can be effective in providing pre-implant counseling to parents. The application of the alternative communication methods could be taken into account as a potential rehab technique.

Clinical and neurobehavioral phenotype in children with autism and intragenic copy number duplications in CNTN4: Case series report

Copy Number Variation (CNV) of contactin genes (CNTNs) - CNTN3, CNTN4, CNTN5, and CNTN6 - have been associated with various neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). However, the literature on the associated phenotypes to specific copy number variants of these genes is still scarce. Therefore, limiting clinicians' and researchers' understanding of the impact of these CNVs makes genetic counselling regarding recurrence risks more challenging. In this study, we report on five patients with rare CNVs involving the CNTN4 gene and the associated clinical and neurobehavioral phenotype. Overall, the patients exhibited stereotypic motor symptoms, including finger and hand mannerisms (4/5), and repetitive use of objects (4/5), as well as sensory symptoms, including unusual sensory interests or hypersensitivity (4/5). One child of the cohort had epilepsy, and (4/5) had Intellectual Disability. All cases fulfilled DSM-5 criteria for diagnosis of Autism Spectrum Disorder (ASD). However, larger cohorts are needed for unbiased characterization of the phenotypic features associated with the genetic variations in CNTN4.

A new era of ICTs for combating symptoms of neurodevelopmental disorders

Information Communication Technology (ICT) is an umbrella definition, where the purpose of its creation and use is to facilitate communication, storage, and transfer of big data and the development and use of the technology that supports it. In contemporary research, several studies have observed attempts to incorporate them in populations with neurodevelopmental disorders (NDDs) to detect/assess, intervene, and improve deficits for the inclusion of these individuals in education and society. This review attempts to explore new universal and mainstream technology and to broaden and provide data for employing it in future research or intervention in the school setting as a complementary addition to education combating core symptoms of the three most recurring NDDs including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and developmental coordination disorder (DCD).

Challenges of Sexuality Expression in Individuals with Autism Spectrum Disorder

IntroductionSexuality, although an essential component of human health, remains a controversial topic shrouded in stigma, particularly in the context of neurodiversity, which includes autism spectrum disorder (ASD), where the expression of sexuality presents unique challenges. Autism and sexuality is a complex and multifaceted topic that involves understanding the unique ways in which individuals on the autism spectrum experience and express their sexuality.ObjectivesThe purpose of this work is to address the complexity of the biopsychosocial sexuality components of people with autism, promoting a shift in the medical perspective, societal attitudes, and supporting greater inclusion of these individuals in current discussions regarding this area of human behavior and experience.MethodsEvidence-based review, through research conducted on PubMed and selection of the most relevant studies on this topic, published in the last decade.ResultsSexuality in autism is now recognized as a normative and integral aspect of development and functioning. Existing research suggests that most individuals with ASD display a clear interest in sexuality and relationships, with a study reviling that 96% of the ASD sample expressed an interest in sexuality. Individuals with high autistic traits tended to identify themselves more times as bisexual or presented a sexuality not definable within the categories of heterosexual. The relationship between autism and gender dysphoria is an area of ongoing research and discussion. Studies have suggested a higher prevalence of gender diverse identities and experiences within the autism community compared to the general population. Various hypotheses have been proposed to explain the increased gender and sexual diversity among individuals with autism. People with ASD may face unique challenges when it comes to their sexuality. The impairments in social skills and communication central to ASD potentially impact an autistic individual’s expression and experience of sexuality by affecting their abilities to understand and interpret social cues, emotions, and nonverbal behaviors of others. Importantly, such individuals may be more vulnerable, as they may have different or even limited understanding of boundaries and consent. To address these challenges, it is important to acknowledge and respect the diversity of sexual experiences and desires among individuals with neuro(bio)logical differences. This can be done by providing accurate and inclusive sex education, creating safe spaces for such individuals to explore and express their sexuality, and working to address discrimination and abuse in intimate contexts.ConclusionsRecognizing and respecting this diversity and fostering inclusive and accepting environments, we can help individuals with neurological differences to fully express and explore their sexuality and have satisfying sexual lives.Disclosure of InterestNone Declared

Unravelling Neurodevelopment: A Comprehensive Neuroimaging Exploration of Paediatric Disorders in a Tertiary Care Setting

Background: Paediatric neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability (ID), and specific learning disabilities (SLD), present a growing healthcare challenge globally. This study, conducted at a tertiary care hospital in India, aims to explore the utility of neuroimaging techniques in understanding the structural and functional abnormalities associated with these disorders, considering the unique demographic and healthcare landscape of India. Methods: A multidisciplinary team collaborated in a cross-sectional observational study involving paediatric patients diagnosed with neurodevelopmental disorders. State-of-the-art magnetic resonance imaging (MRI) and functional MRI (fMRI) were employed. Participants underwent clinical assessments, and neuroimaging data were analyzed for structural and functional abnormalities. Advanced techniques such as diffusion tensor imaging (DTI) were utilized to explore microstructural changes in white matter tracts. Results: Distinct neuroimaging patterns were observed in different neurodevelopmental disorders. Structural abnormalities were prominent in ASD and ID, with nuanced variations in gray and white matter volumes. Functional connectivity abnormalities in ADHD were highlighted, emphasizing the involvement of attention and executive function networks. DTI revealed microstructural changes in white matter tracts, particularly in the prefrontal-striatal circuitry in ADHD and disruptions in interhemispheric communication in ASD. Conclusion: Our study contributes valuable insights into the neurobiological underpinnings of paediatric neurodevelopmental disorders, emphasizing the importance of neuroimaging for tailored diagnostic and therapeutic approaches.

184 PTEN Mutations Portend Cerebral Ventriculomegaly With Autism-Like Deficits in Cortical Circuitry

INTRODUCTION: Fetal ventriculomegaly, the most common antenatally-diagnosed brain abnormality, is the defining feature of congenital hydrocephalus (CH). Fetal ventriculomegaly is also an overlooked associated finding in neuropsychiatric disorders, including autism spectrum disorder (ASD), which is diagnosed at a 10-fold higher rate in CH patients than in the general population. METHODS: We subjected 2,978 parent-trio probands with primary ventriculomegaly, including shunted, sporadic CH, to whole exome sequencing (WES). Using mouse molecular genetics, we generated a novel CH mutant mouse model via prenatal, genetic deletion of a WES-identified CH gene. MRI, measurement of CSF secretion, and cortex-wide, mesoscopic Ca2+ imaging were performed in mice. RESULTS: We identify phosphatase and tensin homolog (PTEN) to be the most frequently mutated gene in primary human ventriculomegaly. Integrative analysis of the human fetal brain revealed PTEN was most highly expressed in NKX2.1+ neuroprogenitor cells (NPCs) and their post-natal interneuron descendants. Pten mutant mice with Nkx2.1-specific Pten deletion exhibited neonatal-onset obstructive hydrocephalus, resulting from aqueductal stenosis due to mTor-activated hyperproliferation of NPCs, and CSF hypersecretion due to inflammation-driven choroid plexus hyperplasia. Hydrocephalic Pten mutants also exhibit autism-like hypersynchronization of the somatosensory cortices due to impaired activity of interneurons. Strikingly, genetic or pharmacologic mTORC1 inhibition (everolimus) corrects ventriculomegaly and rescues cortical pathology of Pten mutants. CONCLUSIONS: Our data demonstrate that PTEN, a commonly mutated ASD gene, is also the most frequently mutated gene in primary ventriculomegaly. To attenuate the pathologically entangled enlargement of the ventricular system and intrinsic neuronal deficits within the surrounding cortical mantle, the use of rapamycin analogs has high translational potential as an adjunct therapy to neurosurgical CSF diversion in ventriculomegalic patients harboring PTEN mutations. Ventriculomegaly may also be a useful radiographic biomarker for early referral for exome sequencing and formal neurodevelopmental assessments.

Clinico-Demographic Profile of Children and Adolescents with Attention Deficit Hyperactivity Disorder Presenting to a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children. ADHD leads to significant impairment in overall functioning of the child. There is limited information concerning the clinical scenario of ADHD within Nepal. The study aims to determine the clinico-demographic profile and pattern of medication use in the treatment of ADHD. This study retrospectively examines the records of children diagnosed with ADHD at the Child and Adolescent Psychiatry (CAP) Unit, Kanti Children's Hospital (KCH), Nepal. Approval for the study was granted by KCH's Institutional Review Board. The analysis focused on data extracted from hospital records of ADHD patients spanning from 1 January 2021 to 30 June 2023 encompassing two and a half years. A total of 585 children were diagnosed with ADHD, with a mean age 7±3.04 years. The majority 501 (85.64%) were male, and 377 (64.44%) were from the school going age group (6 to 11 years). The prevalent psychiatric comorbidities included Autism Spectrum Disorder (ASD) at 102 (17.43%), Intellectual Disability (ID) at 93(15.89%), and Oppositional Defiant Disorder (ODD) at 36 (6.15%). The commonly used medication was Clonidine 165 (28.20%) followed by Atomoxetine 154 (26.32%) and Risperidone 65 (11.11%). The study indicates that ADHD is highly prevalent in Nepal. Comorbidities like ASD and ID are frequently seen which further necessitates the need for structured assessments and multidisciplinary approaches to address ADHD. In our context with limited treatment options, the management of ADHD is extremely challenging.

Colitis reduces active social engagement in mice and is ameliorated by supplementation with human microbiota members

Multiple neurological disorders are associated with gastrointestinal (GI) symptoms, including autism spectrum disorder (ASD). However, it is unclear whether GI distress itself can modify aspects of behavior. Here, we show that mice that experience repeated colitis have impaired active social engagement, as measured by interactions with a foreign mouse, even though signs of colitis were no longer present. We then tested the hypothesis that individuals with ASD harbor a microbiota that might differentially influence GI health by performing microbiota transplantation studies into male germfree animals, followed by induction of colitis. Animals that harbor a microbiota from ASD individuals have worsened gut phenotypes when compared to animals colonized with microbiotas from familial neurotypical (NT) controls. We identify the enrichment of Blautia species in all familial NT controls and observe an association between elevated abundance of Bacteroides uniformis and reductions in intestinal injury. Oral treatment with either of these microbes reduces colon injury in mice. Finally, provision of a Blautia isolate from a NT control ameliorates gut injury-associated active social engagement in mice. Collectively, our data demonstrate that past intestinal distress is associated with changes in active social behavior in mice that can be ameliorated by supplementation of members of the human microbiota.