Autism Spectrum Disorder Risk Research Articles

Influences of RASopathies on Neuroanatomical Variation in Children

BackgroundRASopathies are a group of disorders characterized by pathogenic mutations in the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder and attention-deficit/hyperactivity disorder. MethodsThis study examined the effect of RASopathies (NS and NF1) on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. Using vertex-based analysis for cortical measures and Desikan region of interest parcellation for subcortical volumes, we compared structural T1-weighted images of children with RASopathies (n = 91, mean age = 8.81 years, SD = 2.12) to those of sex- and age-matched typically developing children (n = 74, mean age = 9.07 years, SD = 1.77). ResultsCompared with typically developing children, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibited divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall, children with NS showed decreased volumes in striatal and thalamic structures, and children with NF1 displayed increased volumes in the hippocampus, amygdala, and thalamus. ConclusionsOur study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

Suicide risk in adults with autism spectrum disorder: prevalence, assessment, and possible therapeutic interventions

Suicide risk in autism spectrum disorder (ASD) has emerged as a long-neglected issue. This revision aims to explore the prevalence, methods of assessment, and available treatments for suicide risk in this population. A narrative review was carried out on three aspects related to the risk of suicide in the adult population with ASD: prevalence, evaluation and available evidence-based interventions. The bibliographic search was carried out using the Pubmed, Scielo, Dialnet and Psychinfo search engines, limited to articles published from 2010 onwards. In order to identify relevant literature, various combinations of keywords were used, such as “suicide risk,” “autism spectrum disorder,” and “suicide in autism,” in both Spanish and English. The main findings suggest a high prevalence of suicide risk, highlighting the need of developing standardized protocols to assess such risk in the autistic population. Moreover, Dialectical Behavioral Therapy has shown promise as a therapeutic option to decrease suicidality, but further research is needed to establish its effectiveness and standardization as a treatment.

Multigenerational association between smoking and autism spectrum disorder: findings from a nationwide prospective cohort study.

Animal studies have shown that exposure to cigarette smoke during pregnancy can induce neurobehavioral anomalies in multiple subsequent generations. However, little work has examined such effects in humans. We examined the risk of grandchild autism spectrum disorder (ASD) in association with grandmother's smoking during pregnancy, using data from 53 562 mothers and grandmothers and 120 267 grandchildren in Nurses' Health Study II. In 1999, Nurses' Health Study II participants with children reported on their mothers' smoking. Grandchildren's ASD diagnoses were reported by the mothers in 2005 and 2009. Among grandmothers, 13 383 (25.0%) smoked during pregnancy, and 509 (0.4%) grandchildren were diagnosed with ASD. The adjusted odds ratio for ASD for grandmother smoking during pregnancy was 1.52 (95% CI, 1.06-2.20). Results were similar with direct grandmother reporting in 2001 of her smoking during pregnancy from the Nurses' Mothers Cohort Study subgroup (n = 22 167 grandmothers, n = 49 917 grandchildren) and were stronger among grandmothers who smoked ≥15 cigarettes per day during pregnancy (adjusted odds ratio = 1.93 [95% CI, 1.10-3.40]; n = 1895 grandmothers, n = 4212 grandchildren). Results were similar when we adjusted for mother's smoking during pregnancy. There was no association with grandfather's smoking as reported by the grandmother. Our results suggest a potential persistent impact of gestational exposure to environmental insults across 3 generations.

Associations of neighborhood greenspace, and active living environments with autism spectrum disorders: A matched case-control study in Ontario, Canada

BackgroundIncreasing evidence links early life residential exposure to natural urban environmental attributes and positive health outcomes in children. However, few studies have focused on their protective effects on the risk of autism spectrum disorder (ASD). The aim of this study was to investigate the associations of neighborhood greenspace, and active living environments during pregnancy with ASD in young children (≤6 years). MethodsWe conducted a population-based matched case-control study of singleton term births in Ontario, Canada for 2012–2016. The ASD and environmental data was generated using the Ontario Autism Spectrum Profile, the Better Outcomes Registry & Network Ontario, and Canadian Urban Environmental Health Research Consortium. We employed conditional logistic regressions to estimate the odds ratio (OR) between ASD and environmental factors characterizing selected greenspace metrics and neighborhoods conducive to active living (i.e., green view index (GVI), normalized difference vegetation index (NDVI), tree canopy, park proximity and active living environments index (ALE)). ResultsWe linked 8643 mother-child pairs, including 1554 cases (18%). NDVI (OR 1.034, 0.944–1.024, per Inter Quartile Range [IQR] = 0.08), GVI (OR 1.025, 95% CI 0.953–1.087, per IQR = 9.45%), tree canopy (OR 0.992, 95% CI 0.903–1.089, per IQR = 6.24%) and the different categories of ALE were not associated with ASD in adjusted models for air pollution. In contrast, living closer to a park was protective (OR 0.888, 0.833–0.948, per 0.06 increase in park proximity index), when adjusted for air pollution. ConclusionsThis study reported mixed findings showing both null and beneficial effects of green spaces and active living environments on ASD. Further investigations are warranted to elucidate the role of exposure to greenspaces and active living environments on the development of ASD.

The PRECISE-DYAD protocol: linking maternal and infant health trajectories in sub-Saharan Africa.

PRECISE-DYAD is an observational cohort study of mother-child dyads running in urban and rural communities in The Gambia and Kenya. The cohort is being followed for two years and includes uncomplicated pregnancies and those that suffered pregnancy hypertension, fetal growth restriction, preterm birth, and/or stillbirth. The PRECISE-DYAD study will follow up ~4200 women and their children recruited into the original PRECISE study. The study will add to the detailed pregnancy information and samples in PRECISE, collecting additional biological samples and clinical information on both the maternal and child health.Women will be asked about both their and their child's health, their diets as well as undertaking a basic cardiology assessment. Using a case-control approach, some mothers will be asked about their mental health, their experiences of care during labour in the healthcare facility. In a sub-group, data on financial expenditure during antenatal, intrapartum, and postnatal periods will also be collected. Child development will be assessed using a range of tools, including neurodevelopment assessments, and evaluating their home environment and quality of life. In the event developmental milestones are not met, additional assessments to assess vision and their risk of autism spectrum disorders will be conducted. Finally, a personal environmental exposure model for the full cohort will be created based on air and water quality data, combined with geographical, demographic, and behavioural variables. The PRECISE-DYAD study will provide a greater epidemiological and mechanistic understanding of health and disease pathways in two sub-Saharan African countries, following healthy and complicated pregnancies. We are seeking additional funding to maintain this cohort and to gain an understanding of the effects of pregnancies outcome on longer-term health trajectories in mothers and their children.

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder.

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

A systematic review of maternal exposures and the risk of autism spectrum disorders in their infants

Background Maternal exposures associated with autism spectrum disorder remain poorly understood. Objective The purpose of this systematic review was to assess the current understanding of maternal exposures and their associations with increased or decreased risk of infant autism. Study Design We searched Ovid MEDLINE databases and reference lists in 2021 for studies looking at maternal factors analyzed for an association with ASD. The primary outcome was autism or autism spectrum disorder diagnosis. Exposures were grouped as biomarkers, environmental, occupational, medication, genetic variability, and maternal illnesses and conditions. PRISMA guidelines were followed. Descriptive summary statistics were evaluated. Results Of 433 reports identified, 47 studies published between 2006 and 2021 fulfilled the inclusion criteria. Exposures consistently associated with a significant increased risk of autism spectrum disorder outcomes included: benzoate, 10-hydroxydecanoate, methyl jasmonate, 1-methylhistidine, nonanoic acid, organohalogens, ornithine, polyunsaturated fatty acids, agricultural pesticides, heavy metals (arsenic, cadmium, chromium, lead, low levels of manganese, tin), cigarette smoking, hypotaurine, indoor household pesticides, methanol, newborn complications at delivery, occupational exposures, solvents, strontium, urate, antibiotics, placental differently methylated regions, diabetes, maternal fever, maternal depression, androgen-associated conditions and psychiatric disorders. Factors consistently associated with a significant decreased risk included: quinoline, air conditioning, cesium, copper, 3-hydroxybutanic acid, maternal fruit consumption, mercury, and phenylalanine. Conclusions This review provides evidence that there are several potential pregnancy exposures and biomarkers associated with an autism spectrum disorder diagnosis in children. Genetic mutations may play role in impact of exposures’ risks. Continued work on identifying potential exposures and biomarkers is needed to better counsel pregnant individuals.

Prenatal Cannabis Use Disorder and Risk of Neurodevelopmental Disorders in Offspring: A Linked Data Cohort

IntroductionCannabis use has been increasing among women of reproductive age in the last few decades. In-utero cannabis exposure could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID) during childhood and adolescence; however, existing evidence was generated based on maternal self-report of cannabis use in pregnancy. We conducted a large-scale with data linkage cohort study, in which both exposure and outcome of interests were confirmed using diagnostic tools, ICD-10-AM.ObjectivesThis study aimed to examine the association between prenatal cannabis use disorder (CUD) and neurodevelopmental disorders in offspring using a large-scale cohort study.MethodsWe conducted an administrative health data-based cohort study of 222,569 mother-offspring pairs using linked data obtained from health registries in New South Wales (NSW), Australia. Data were drawn from the NSW Perinatal Data Collection (PDC), which included all live births in the Australian state of NSW between January 2003 and December 2005. These were linked with the NSW in-patient and ambulatory data collections for mothers and offspring. The prenatal cannabis use disorder (exposure) and neurodevelopmental disorders in offspring (outcomes of interest) were measured by using ICD-10-AM. Generalized linear regression with a binomial family model was used to explore the association. We also carried out a modification/interaction effect of low birth weight (LBW), smoking and premature births (PTB), which enhanced the methodological robustness of the study.ResultsThis study found that offspring from mothers with prenatal CUwD had a 98%, 94% and 46% increased risk of ADHD [aRR = 1.98: 95 % CI 1.36 – 2.88], ASD [aRR = 1.94: 95 % CI 1.34 – 2.82], and ID [aRR = 1.46: 95 % CI 1.01 – 2.63] compared to those non-exposed offspring, respectively. We observed a significant interaction effect between CUD during pregnancy and maternal smoking on the risk of childhood ADHD, ASD and ID [CUD*smoking: RR = 5.62: 95 % CI 3.77 – 8.39, RR = 2.72: 95 % CI 1.78 – 4.18, and RR = 2.84: 95 % CI 1.54 – 5.22, respectively]. Furthermore, we also found significant associations between PCUD and ADHD, ASD and ID when interacting with LBW, and PTB.ConclusionsMaternal prenatal CUD is associated with a higher risk of ADHD, ASD, and ID in offspring. The effect of maternal CUD on neurodevelopmental disorders was also found to be stronger when mothers also reported smoking during pregnancy, compared to the individual effects of cannabis use or smoking alone. The findings highlight the importance of implementing preventive strategies to reduce cannabis use in pregnancy.Disclosure of InterestNone Declared

FAMILY HISTORY OF PSYCHOLOGICAL DISORDERS MODERATES THE ASSOCIATION BETWEEN PRENATAL MATERNAL STRESS AND RISK OF AUTISM

The increase in number of cases with autism spectrum disorder (ASD) requires further investigation to the etiology of it, which is not fully understood. It is suggested that children who are vulnerable to psychological disorders more likely to develop ASD when experience prenatally stress than children who do not. The researcher sought to conduct a natural experiment by collecting data from a sample derived from population lived in a region that experienced number of the worst civil wars in Libya. The sample consisted of 38 parents of children with ASD and 40 parents of typical children living in south Tripoli. These children were in utero during the civil wars that happened in 2011, 2014, and 2019. A case-control study was carried out comparing the two groups in terms of family history of psychological disorders. The child’s sex, parents’ age, and birth complications were controlled. Conditional logistic regression models were utilized to examine whether family history of psychological disorders predicted ASD. Findings from this study indicated that: children with ASD were more likely to have relatives with psychological disorders than those without ASD; the proportion of relatives with psychological disorders was significantly higher among children with ASD than those without ASD; there was significant associations between ASD and parents’, grandparents’, uncles’, aunts’ psychological disorders, having a first-degree relative suffers from a psychological disorder was associated with increase in odds of ASD. ,having second-degree relatives with a psychological disorder was significantly associated with increase odds of ASD, psychological disorders in first degree relatives and second degree relatives had comparable effect on the risk of ASD, when first degree relatives and second degree relatives affected the risk of ASD did not increase compared to the presence of a psychological disorder in either relatives

Gestational age and sex interaction and risk for autism spectrum disorder in extremely preterm newborns: an 18‑month follow‑up study

IntroductionExtremely preterm newborns - EPTN (born ≤28 weeks gestational age) are at increased risk of developing autism spectrum disorders (ASD). Demographic and perinatal risk factors associated with ASD risk in EPTN are understudied.Objectives(i) In EPTN and born at full-term healthy controls (HC), to characterize the emergence of ASD traits and autistic symptom load at age 18 months; (ii) in EPTN, to identify the influence of perinatal characteristics such as sex and gestational age on autistic symptom load at corrected-age 18 months.MethodsObservational, longitudinal, prospective, 18-month follow-up study. We recruited a cohort of n=113 EPTN and n=47 HC (the PremTEA cohort); n=57 EPTN and n=42 HC successfully completed the 18-month follow-up visit. We assessed autistic symptom load & risk at 18 months using the M-CHAT-R/F questionnaire. For all EPTN and HC, we collected demographic and perinatal data. Using GLMs, we assessed, in EPTN, the association between demographic/perinatal variables and 18-month autistic symptom levels.ResultsAt 18 months, EPTN children showed higher autistic symptom levels than HC (M-CHAT-R/F score, mean (SD) [range] = 2.21 (3.23) [0-12] in EPTN vs. 0.33 (0.57) [0-2] in HC; d=.873, p=.001. In EPTN, we identified differences by gestational age and sex in autistic symptom levels at 18 months (aR2=0.517, p=.006). In particular, female EPTNs born with lower gestational age showed higher autistic symptom load at age 18 months.ConclusionsOur findings support the need for early screening of ASD symptomatology in EPTN infants, particularly in higher-risk subgroups, such as female patients born with lower gestational ages.Disclosure of InterestNone Declared

Autism spectrum disorder profiles in RASopathies: Asystematic review.

RASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually. We conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers. We included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies. Our systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated.

IJCM_333A: Household Air Pollution Exposure and Autism Spectrum Disorder Outcomes in Children: Insights from the HAPIN India Study

Background: The global public health challenge of household air pollution, stemming from conventional cooking practices and the widespread use of solid fuels, is a critical concern. Exposure to indoor air pollutants has been associated with adverse health outcomes, particularly affecting vulnerable populations like pregnant women and young children. The Household Air Pollution and Neurodevelopment (HAPIN) study addresses this issue through a multicentric randomized controlled trial spanning four diverse countries: Guatemala, India, Peru, and Rwanda. Objectives: The study aims to evaluate the prevalence of autistic spectrum disorder among children residing in HAPIN study site of India. Methodology: A cross-sectional assessment for autism spectrum disorders within the HAPIN cohort was done.365 children aged 2 to 3 years were studied to explore the potential link between household air pollution and autism spectrum disorder (ASD). Household air quality, measuring PM2.5, CO, and black carbon, was assessed using established protocols. Neurodevelopmental outcomes, particularly ASD, was screened using the Modified Checklist for Autism in Toddlers (M-CHAT) in children aged 2 to 3 years, and screened positive children were evaluated by a psychiatrist to diagnose autism spectrum disorder using DSM-5 criteria. Results: There is significant association between exposure to air pollutants (PM2.5, CO, and black carbon) and the diagnosis of autism spectrum disorder (ASD), with a prevalence rate of 5.48%. Conclusion: ASD prevalence rate of 5.48%, underscore the global relevance of the impact of household air pollution on neurodevelopment. Urgent interventions are warranted to mitigate the risk of ASD, particularly for vulnerable populations like pregnant women and young children, emphasizing the imperative for cleaner cooking practices and improved indoor air quality.

Association of cerebral palsy with autism spectrum disorder and attention-deficit/hyperactivity disorder in children: a large-scale nationwide population-based study

ObjectiveTo examine the association of cerebral palsy with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), providing evidence for interdisciplinary medical service for children with cerebral palsy.DesignA large-scale nationwide population-based...

Exploring the association between early-life air pollution exposure and autism spectrum disorders in children: A systematic review and meta-analysis

The objective of this meta-analysis is to investigate the association between air pollution and the vulnerability of children to autism spectrum disorders (ASD). A thorough examination and analysis of data obtained from a compilation of 14 studies was undertaken, with a particular emphasis on investigating the effects of nitrogen dioxide (NO2), oxide of nitrogen (NOx), ozone (O3), and particulate matter (PM10 and PM2.5) on individuals diagnosed with ASD. The findings demonstrate a moderate association between exposure to nitrogen dioxide (NO2) and ASD, as indicated by a combined odds ratio (OR) of 1.13 and a 95% confidence interval (CI) spanning from 0.77 to 1.549. O3 shows a combined odds ratio (OR) of 0.82, along with a 95% confidence interval (CI) ranging from 0.49 to 1.14. NOx shows a moderate level of heterogeneity (I² = 75.9%, p = 0.002), suggesting that the impact of NOx on the risk of ASD. There is a statistically significant relationship between exposure to O3 and ASD, although the strength of this relationship is diminished. The findings demonstrated a noteworthy correlation between exposure to PM10 and PM2.5 and the occurrence of ASD. The study found a significant correlation, in relation to PM2.5, with a combined odds ratio (OR) of 1.22 and a 95% confidence interval (CI) ranging from 1.11 to 1.34. The findings have significant implications for the formulation of programs aimed at reducing exposure to harmful chemicals, especially among vulnerable groups such as children.

Stimulant exposure in utero not linked to child neurodevelopmental disorders

A cohort study involving both publicly and commercially insured patients has found in adjusted analyses that exposure to stimulant medications during pregnancy did not significantly increase risk of childhood neurodevelopmental disorders. The investigators focused largely on children's risk of autism spectrum disorder (ASD) and attention‐deficit hyperactivity disorder (ADHD). Study results were published online Jan. 24, 2024, in JAMA Psychiatry.

Mendelian randomization analysis using GWAS and eQTL data to investigate the relationship between chronotype and neuropsychiatric disorders and their molecular basis.

Chronotype is a proxy sleep measure that has been associated with neuropsychiatric disorders. By investigating how chronotype influences risk for neuropsychiatric disorders and vice versa, we may identify modifiable risk factors for each phenotype. Here we used Mendelian randomization (MR), to explore causal effects by (1) studying the causal relationships between neuropsychiatric disorders and chronotype and (2) characterizing the genetic components of these phenotypes. Firstly, we investigated if a causal role exists between five neuropsychiatric disorders and chronotype using the largest genome-wide association studies (GWAS) available. Secondly, we integrated data from expression quantitative trait loci (eQTLs) to investigate the role of gene expression alterations on these phenotypes. Evening chronotype was causal for increased risk of schizophrenia and autism spectrum disorder and schizophrenia was causal for a tendency toward evening chronotype. We identified 12 eQTLs where gene expression changes in brain or blood were causal for one of the phenotypes, including two eQTLs for SNX19 in hippocampus and hypothalamus that were causal for schizophrenia. These findings provide important evidence for the complex, bidirectional relationship that exists between a sleep-based phenotype and neuropsychiatric disorders, and use gene expression data to identify causal roles for genes at associated loci.

Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor.

Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of Kmt2c (Kmt2c+/fs mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of Kmt2c haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult Kmt2c+/fs mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, P < 2.2 × 10-16, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to Kmt2c haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure

BackgroundMaternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use.MethodsWe identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control.ResultsThe estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score–adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine.ConclusionsThe incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.)

Assessment of Psychotic Risk in a Sample of Children and Adolescents with Autism Spectrum Disorder Compared to a Group of "Clinical High Risk" Patients: A Preliminary Study.

Autism spectrum disorder and psychotic risk show several overlapping symptoms, so differential diagnosis is often difficult. In addition, there is a high rate of comorbidity between the two conditions, which further complicates the work of clinicians. We evaluated the presence of subthreshold psychotic symptoms and/or defined psychotic risk syndromes in autistic children and adolescents; we compared the prevalence, type, and severity of psychotic risk symptoms with those of a group of non-autistic patients at clinical high risk for psychosis (CHR-P). 2. In total, 23 autistic patients and 14 CHR-P patients without autism (aged 8-17) were enrolled in the study. The main assessment was made through clinical interviews for autism (Autism Diagnostic Observation Schedule, Second Edition-ADOS-2, Autism Diagnostic Interview, Revised-ADI-R) and psychotic risk (Schizophrenia Proneness Instrument, Child and Youth version-SPI-CY, Structured Interview for Psychosis Risk Syndromes-SIPS). 3. No above-threshold psychotic risk symptoms were detected in our autistic patients, but subthreshold psychotic symptoms were identified in all areas. Specific items from all four dimensions of SIPS appear to be more specific for psychotic risk than autism without comorbidity. 4. An a priori screening of psychotic risk in neurodiverse populations is fundamental to prevent more severe conditions. Research should clarify the effective specificity of the available tools to modify them to improve their detection capability.

Prenatal, perinatal and parental risk factors for autism spectrum disorder in China: a case- control study.

Autism spectrum disorder (ASD) is heritable neurodevelopmental disorders (NDDs), but environmental risk factors have also been suggested to a play a role in its development. Prenatal, perinatal and parental factors have been associated with an increased risk of ASD in children. The aim of the present study was to explore the prenatal, perinatal, and parenting risk factors in children with autism spectrum disorder (ASD) from Beijing, China by comparing them with typically developing (TD) children. A sample of 151 ASD children's parents who from rehabilitation institutions in Beijing were enrolled in this study, and an additional 151 children from kindergartens in Beijing were recruited as a control group (child age: mean = 4.4 years). TD children were matched according to age, sex and maternal education. We explored the maternal AQ (Autism Spectrum Quotient) scores (mean:19.40-19.71, no significant difference between two groups) to referring the genetic baseline. This study evaluated 17 factors with unadjusted and adjusted analyses. Birth asphyxia was associated with a more than a thirteen-fold higher risk of ASD (adjusted odds ratio (AOR) = 13.42). Breastfeeding difficulties were associated with a higher risk of ASD(AOR = 3.46). Parenting influenced the risk of ASD, with low responding (LR) and harsh or neglectful parenting associated with a higher risk of ASD in offspring (AOR = 2.37 for LR, AOR = 3.42 for harsh parenting and AOR = 3.01 for neglectful parenting). Maternal fever during pregnancy was associated with a higher risk of ASD in offspring (AOR = 3.81). Many factors were associated with ASD in offspring. Further assessment is needed to elucidate the role of modifiable environmental factors to inform prevention strategies.