Autism Spectrum Disorder Factors Research Articles

A Systematic Review of the Risk Factors for Autism Spectrum Disorder in Children Born Preterm.

Preterm birth is associated with an increased risk for autism spectrum disorder, with various factors proposed to underlie this relationship. The aim of this systematic review was to provide a narrative synthesis of the literature regarding the prenatal, perinatal and postnatal factors associated with autism spectrum disorder in children born preterm. Medline, Embase and PsycINFO databases were searched via Ovid to identify studies published from January 1990 to December 2019. Original studies in which a standardized diagnostic tool and/or clinical assessment was used to diagnose autism, along with a risk factor analysis to identify associated predictors, were included. A total of 11 eligible studies were identified. Male sex, being born small for gestational age and general cognitive impairment were the most robust findings, with each reported as a significant factor in at least two studies. Comparisons across studies were limited by variation in risk factor measurement and gestational age ranges investigated.

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders defined clinically by core deficits in social reciprocity and communication, restrictive interests and repetitive behaviors. ASD affects one in 54 children in the United States, one in 89 children in Europe, and one in 277 children in Asia, with an estimated worldwide prevalence of 1–2%. While there is increasing consensus that ASD results from complex gene x environment interactions, the identity of specific environmental risk factors and the mechanisms by which environmental and genetic factors interact to determine individual risk remain critical gaps in our understanding of ASD etiology. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been linked to altered neurodevelopment in humans. Preclinical studies demonstrate that PCBs modulate signaling pathways implicated in ASD and phenocopy the effects of ASD risk genes on critical morphometric determinants of neuronal connectivity, such as dendritic arborization. Here, we review human and experimental evidence identifying PCBs as potential risk factors for ASD and discuss the potential for PCBs to influence not only core symptoms of ASD, but also comorbidities commonly associated with ASD, via effects on the central and peripheral nervous systems, and/or peripheral target tissues, using bladder dysfunction as an example. We also discuss critical data gaps in the literature implicating PCBs as ASD risk factors. Unlike genetic factors, which are currently irreversible, environmental factors are modifiable risks. Therefore, data confirming PCBs as risk factors for ASD may suggest rational approaches for the primary prevention of ASD in genetically susceptible individuals.

Risk and Protective Factors in Autism Spectrum Disorders: A Case Control Study in the Lebanese Population.

Autism spectrum disorders (ASD) are among the most common childhood neurodevelopmental disorders. Identification of risk and protective factors are necessary to improve the guidance of prevention and intervention strategies. Our study aims to determine the potential risk and protective factors in ASD in the Lebanese population. Our case-control study included 100 ASD patients and 100 healthy matched controls recruited from all the Lebanese districts. The data collected from the questionnaires was analyzed using SPSS 23.0. Independent Student T-test and Chi-Square test were carried out for the bivariate analysis of the data. In addition, the variables revealing a p-value < 0.05 were used for the multivariate logistic regression analysis. Multivitamins intake, especially omega 3 and vitamin B (Odds Ratio (OR) = 0.257; 95% Confidence Interval (CI) [0.115–0.579]), rich cereal diet (OR = 0.212; 95% CI [0.089–0.510]), and supplementation in iron during pregnancy (OR = 0.229; 95% CI [0.083–0.627]) were identified as protective factors against ASD. On the other hand, stress during pregnancy (OR = 6.339; 95% CI [2.845–14.125]), the presence of ASD patients in the family (OR = 7.878; 95% CI [1.877–33.065]) and the presence of attention deficit hyperactivity disorder (ADHD) patients in the family (OR = 6.981; 95% CI [1.362–35.789]) were associated with ASD. This study shed light on risk and protective factors associated with ASD in the Lebanese population. Further rigorous research, taking into consideration these factors, is needed to assist in early detection, prevention and subsequent intervention targeting ASD and its associated comorbidities, given that our study is not experimental and does not prove causality.

Autism risk linked to prematurity is more accentuated in girls.

Prematurity has been identified as a risk factor for Autism Spectrum Disorder (ASD). The link between Autism Spectrum Disorder (ASD) and birth-week has not been strongly evidenced. We evaluated the correlation between the degree of prematurity and the incidence of autism in a cohort of 871 children born prematurely and followed from birth. The cohort was reduced to 416 premature infants born between 2011-2017 who were followed for 2-14 years, and analyzed according to birth week (degree of prematurity), and according to gender. 43 children (10.3%) received a definite diagnosis of ASD. There was a significant correlation between birth week and the risk of ASD, with 22.6% of children diagnosed with ASD when born at 25 weeks, versus 6% of ASD diagnoses at 31 weeks of prematurity. For children born after 32 weeks, the incidence decreased to 8-12.5%. A strong link was found between earlier birth week and increased autism risk; the risk remained elevated during near-term prematurity in boys. A correlation between early birth week and an elevated risk for ASD was seen in all children, but accentuated in females, gradually decreasing as birth week progresses; in males the risk for ASD remains elevated for any birth week. A statistically significant increase in rates of autism was found with each additional week of prematurity. Females drove this direct risk related to degree of prematurity, while males had an elevated risk throughout prematurity weeks, even at near-term. We recommend including ASD screening in follow up of infants born prematurely, at all levels of prematurity.

Kirrel3-Mediated Synapse Formation Is Attenuated by Disease-Associated Missense Variants.

Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability, but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss of function using KO mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo Here, we developed an in vitro, gain-of-function assay for Kirrel3 using neuron cultures prepared from male and female mice and rats. We find that WT Kirrel3 induces synapse formation selectively between Kirrel3-expressing neurons via homophilic, transcellular binding. We tested six disease-associated Kirrel3 missense variants and found that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to WT Kirrel3. Two tested variants lack homophilic transcellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating that Kirrel3 transcellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to the mechanism of Kirrel3 function and the consequences of missense variants associated with autism and intellectual disability.SIGNIFICANCE STATEMENT Here, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 transcellular interactions mediate target recognition and signaling to promote synapse development. Moreover, this study tests the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, increases understanding of the complex etiology of neurodevelopmental disorders arising from rare missense variants in synaptic genes.

Time Trends in Diagnostics and Clinical Features of Young Children Referred on Suspicion of Autism: A Population-Based Clinical Cohort Study, 2000-2010.

The present study aimed to explore clinical trends in the period 2000-2010, along with discriminating clinical factors for autism spectrum disorder (ASD), in young children suspected of ASD. The following trends were observed: (1) a rise in referrals including an increase in referrals among language-abled children, (2) an increase in children assigned an ASD diagnosis after assessment, and (3) a decrease in Autism Diagnostic Observation Schedule total score. The distribution of ASD subtypes and IQ level did not change. Results suggest that a higher proportion of children with less severe autism symptoms were referred and diagnosed. Further, restricted and repetitive behaviors seemed to be a key discriminating factor when distinguishing between ASD and no-ASD children with a discordant symptom profile.

Maternal Immune Activation in Mice Only Partially Recapitulates the Autism Spectrum Disorders Symptomatology

Prenatal viral/bacterial infections are considered risk factors for autism spectrum disorders (ASD) and rodent models of maternal immune activation (MIA) have been developed and extensively used in preclinical studies. Poly inosinic-cytidylic acid (Poly I:C) was injected in C57BL6/J dams to mimic a viral infection on gestational day 12.5; the experimental design includes 10/12 litters in each treatment group and data were analysed always considering the litter-effect; neonatal (spontaneous motor behaviour and ultrasonic vocalizations) and adult [open field, marble burying, social approach, fear conditioning, prepulse inhibition (PPI)] offspring of both sexes were tested. In vivo magnetic resonance imaging/spectroscopy (MRI-MRS) and high-performance liquid chromatography (HPLC) to quantify both aminoacid and/or neurotransmitter concentration in cortical and striatal regions were also carried out. In both sexes high levels of repetitive motor responses and sensory gating deficits in PPI were the more striking effects of Poly I:C, whereas no alteration of social responses were evidenced. Poly I:C treatment did not affect mean values, but, intriguingly, increased variability in the levels of four aminoacids (aspartate glycine and GABA) selectively in males. As a whole prenatal Poly I:C induced relevant long-term alterations in explorative-stereotyped motor responses and in sensory gating, sparing cognitive and social competences. When systematically assessing differences between male and female siblings within each litter, no significant sex differences were evident except for increased variability of four aminoacid levels in male brains. As a whole, prenatal Poly I:C paradigms appear to be a useful tool to investigate the profound and translationally-relevant effects of developmental immune activation on brain and behavioural development, not necessarily recapitulating the full ASD symptomatology.

Sensory processing profiles and autistic symptoms as predictive factors in autism spectrum disorder and Williams syndrome.

Unusual sensory responses were included in the diagnostic criteria for autism spectrum disorder (ASD), yet they are also common among individuals with other neurodevelopmental disorders, including Williams syndrome (WS). Cross-syndrome comparisons of sensory atypicalities and the evaluation of their syndrome specificity however have rarely been undertaken. We aimed to (1) examine and compare the sensory profiles in ASD and WS groups and (2) investigate whether autistic symptoms, including sensory processing scores, can predict a group membership. Parents of 26 children with ASD and intellectual disability, 30 parents of children with ASD (no intellectual disability) and 26 with WS aged between 4 and 16years were recruited. Parents completed the Sensory Profile to provide information about their children's sensory experiences and the Social Responsiveness Scale - Second Edition (SRS-2) to assess the degree of social impairment in their children. No significant differences were found in sensory processing scores between the three groups. Binary logistic regression analyses were undertaken with sensory quadrants and SRS-2 total score as factors. Models significantly predicted group membership, with Low Registration, Sensory Sensitivity and SRS-2 total score being significant predictors. The findings suggest that high rates of sensory atypicalities are a common neurodevelopmental characteristic that do not reliably distinguish between WS and ASD groups. Low Registration and Sensory Sensitivity-related behaviours might, however, be more specific to ASD. Further work is needed to explore what behaviours within sensory profiles can discriminate between neurodevelopmental disorders and should be included in diagnostic classifications.

Advanced paternal age as a risk factor for autism spectrum disorder in a Mexican population

Introduction. Risk factors for autism spectrum disorders (ASD) have been identified, as is the case of advanced parental age. Advanced parental age as an ASD risk factor has been studied in Scandinavian populations; there are no reports for Mexican children. Objective. The present work aim is to analyze if advanced parental age is a risk factor for ASD in a Mexican children sample. Method. Mexican children (N = 1 068) participated in a case-control study, 162 had an ASD diagnosis. Multivariate logistic regression adjusted by cofounders was performed to explore the effect of paternal age on ASD risk. Results. Advanced paternal age in Mexican children increases the risk for ASD, and also, a difference of 10 years between parental ages have a higher risk. Discussion and conclusion. The effect of advanced paternal age in Mexican children was lower than those reported previously for other populations. Advanced paternal age and difference between parental ages could be a risk factor for ASD in Mexican population. Nevertheless, the analysis of larger sample sizes is required.

Functional Connectivity Analyses Suggest Shared Molecular Mechanisms Across 12 Neuropsychiatric Mutations, Autism and Schizophrenia

Copy number variants (CNVs) are among the most highly penetrant risk factors for autism spectrum disorder (ASD) and schizophrenia (SZ). Almost nothing is known about their impact on functional connectivity (FC). As several CNVs confer risk for both ASD and SZ, we hypothesized that CNVs and idiopathic conditions may converge on a smaller set of FC alteration patterns. We aimed to characterize FC dimensions altered across CNVs and idiopathic psychiatric conditions.

The Association Between Parental Age and Autism-Related Outcomes in Children at High Familial Risk for Autism.

Advanced parental age is a well-replicated risk factor for autism spectrum disorder (ASD), a neurodevelopmental condition with a complex and not well-defined etiology. We sought to determine parental age associations with ASD-related outcomes in subjects at high familial risk for ASD. A total of 397 younger siblings of a child with ASD, drawn from existing prospective high familial risk cohorts, were included in these analyses. Overall, we did not observe significant associations of advanced parental age with clinical ASD diagnosis, Social Responsiveness Scale, or Vineland Adaptive Behavior Scales scores. Instead, increased odds of ASD were found with paternal age < 30 years (adjusted odds ratio [AOR] = 2.83 and 95% confidence intervals [CI] = 1.14-7.02). Likewise, younger age (<30 years) for both parents was associated with decreases in Mullen Scales of Early Learning early learning composite (MSEL-ELC) scores (adjusted β = -9.62, 95% CI = -17.1 to -2.15). We also found significant increases in cognitive functioning based on MSEL-ELC scores with increasing paternal age (adjusted β associated with a 10-year increase in paternal age = 5.51, 95% CI = 0.70-10.3). Results suggest the potential for a different relationship between parental age and ASD-related outcomes in families with elevated ASD risk than has been observed in general population samples. Autism Res 2020, 13: 998-1010. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Previous work suggests that older parents have a greater likelihood of having a child with autism. We investigated this relationship in the younger siblings of families who already had a child with autism. In this setting, we found a higher likelihood of autism, as well as poorer cognitive scores, in the siblings with younger fathers, and higher cognitive scores in the siblings with older parents. These results suggest that parental age associations may differ based on children's familial risk for autism.

Association study between genetic variants in vitamin D metabolism related genes and childhood autism spectrum disorder.

Vitamin D deficiency has been implicated as a risk factor for autism spectrum disorder (ASD). This case-controlled study was to determine the association between single nucleotide polymorphisms (SNPs) in genes encoding vitamin D metabolism related enzymes and childhood ASD in a Chinese Han population. Both autistic children and age-and gender-matched healthy controls were recruited from September 2012-November 2017. The severity of ASD was evaluated by the childhood autism rating scale (CARS). Taqman probe based real-time PCR was applied to examine genotypes. The association between SNPs and the risk of ASD or the disease severity was examined through the logistic regression. This study recruited 249 children with ASD and 353 healthy controls. The G/A genotype (P = 0.0112) or the G allele (P = 0.0117) of CYP24A1 rs17219315, and the G/A genotype of CYP27B1 rs4646536 (P = 0.0341) were significantly associated with an increased risk of ASD. In addition, multivariate analysis found that A allele of both CYP2R1 rs12794714 (P = 0.0159) and CYP27B1 rs4646536 (P = 0.0268) were significantly associated with the severity of ASD. Genetic polymorphisms in vitamin D metabolism related enzymes are associated with the risk of childhood ASD and the severity of the disease.

Maternal sleep disordered breathing during pregnancy as a cause of autism relevant neuronal and behavioral aberrations in the offspring.

Sleep disordered breathing (SDB) is characterized by recurring breathing cessations during sleep, causing intermittent hypoxia (oxygen deprivation) often several hundred times per night. SDB is present in ~15% of pregnant women as compared to ~2–4% of non‐pregnant women of childbearing age. Risk factors for gestational SDB development bear striking similarities to the collection of maternal risk factors for autism spectrum disorders (ASD), including advanced maternal age and maternal obesity. Maternal immune activation/inflammation is both a consequence of SDB, and an independent risk factor for, ASD. We posit that an overlooked, yet increasingly common inflammatory stimulus, maternal SDB, contributes to ASD etiology. We recently developed a rat model in which to study the consequences of maternal SDB on the offspring by exposing pregnant rats to nightly intermittent hypoxia from gestational days 10–21. Our findings indicate that offspring of mothers subjected to intermittent hypoxia during pregnancy exhibit deficits in several autism‐relevant behaviors, including a constellation of cognitive impairments, reduced interest in social interaction, and heightened anxiety. In most instances, the magnitude of behavioral disruption was more severe in male than female offspring. To begin to understand the mechanisms contributing to these behavioral aberrations, we examined the density of dendritic spines in the prefrontal cortex (PFC) and CA3 region of the hippocampus. Our data suggest that the offspring of mothers subjected to nightly intermittent hypoxia exhibited a striking increase in dendritic spine density in the PFC when compared to control offspring. However, the dendritic spine density in the CA3 region showed no significant differences between groups. Similar to our behavioral observations, dendritic spine aberrations were more prominent in male vs. female offspring. Additionally, these male offspring showed significant differences in spine morphology when compared to control offspring. Taken together, these findings indicate that maternal sleep disordered breathing not only induces autism‐relevant behavioral impairments, but also mimics the heightened cortical synaptic connectivity phenotypes recently uncovered in autism. Future studies are aimed at identifying a role for microglial inflammation and concomitant reduction in microglial‐mediated synaptic pruning in the behavioral and synaptic structural alterations that we have revealed in this model.Support or Funding InformationR25 Team‐ScienceUW2020 Pilot Award

Genetic Variation across Phenotypic Severity of Autism

It is still unclear how genetic factors of autism spectrum disorder (ASD) are implicated in the significant clinical heterogeneity ranging from intellectual disability (ID) to high-functioning profiles. Here, evidence from recent genetic studies encompassing common and rare variants are combined to suggest a genetic model that may explain the broad gradient of phenotypic severity observed in ASD.

Incomplete Gestation has an Impact on Cognitive Abilities in Autism Spectrum Disorder.

Extreme prematurity is known as a risk factor for autism spectrum disorder (ASD). However, the association between prematurity and ASD, for children born moderately and late preterm (MLPT) and those born early term (ET), is less established. This retrospective study aimed to characterize the phenotypic characteristics (i.e. behavioral profile and cognitive abilities) of 254 children with ASD, between 3 and 15years of age, born MLPT (19 children), ET (60 children) and full term (175 children). MLPT and ET births do not modify ASD symptomatology, but modify cognitive development. The results highlight that incomplete gestation, i.e., MLPT or ET, has a negative impact on both verbal and nonverbal cognitive abilities, in children with neurodevelopmental vulnerability.

Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task.

The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon existing assays to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD-relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within-group comparisons only, and then interpret a difference in significance levels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs: Erroneous Within-group Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach could produce misleading inferences. Our review of Social Approach studies of high-confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often does not correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models. Autism Res 2019, 12: 1171-1183. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret these data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies.

Atypical behaviour and connectivity in SHANK3-mutant macaques.

Mutation or disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of Phelan-McDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPR-Cas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3 gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and Phelan-McDermid syndrome.

Autism Spectrum Disorder Screening and Early Action

Since its diagnostic inception, autism has garnered stigma and fear, often to the exclusion of action. Early detection and treatment of autism spectrum disorders have become crucial priorities of the National Institutes of Health. The primary care provider is the point of entry to the health care system for infants/children showing risk factors for autism spectrum disorders and/or symptoms of the disorder. Despite the existence of low-cost, well-tested developmental screening tools, many primary care providers rely solely on clinical judgment to ascertain developmental status. Current best screening practices were determined by a review of the literature. Key recommendations are highlighted.

Birth seasonality and risk of autism spectrum disorder

Season of birth has been hypothesized to be a risk factor for autism spectrum disorder (ASD). However, the evidence has been mixed and limited due to methodological challenges. We examine ASD birth trends for 5,464,628 births across 5 countries. ASD birth prevalence data were obtained from the International Collaboration for Autism Registry Epidemiology database, including children born in Denmark, Finland, Norway, Sweden, and Western Australia. Empirical mode decomposition and cosinor modeling were used to assess seasonality. We show seasonal variation in ASD births for the countries of Finland and Sweden. There was a modest increase in risk for children born in the fall and a modest decrease in risk for children born in the spring. Solar radiation levels around conception and the postnatal period were inversely correlated with seasonal trends in ASD risk. In the first multinational study of birth seasonality of ASD, there was evidence supporting the presence of seasonal trends in Finland and Sweden. The observations that risk was highest for fall births (i.e., conceived in the winter) and lowest for spring births (i.e., conceived in the summer), and sunlight levels during critical neurodevelopmental periods explained much of the seasonal trends, are consistent with the hypothesis that a seasonally fluctuating risk factor may influence risk of ASD.

Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies.

One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. The protein–protein interactions between the products of NLGN, SHANK, and NRXN synaptic genes indicate that the dysfunction in synaptic plasticity could be one reason for the development of ASD. Designing more accurate diagnostic tests for the early diagnosis of ASD would improve treatment strategies and could enhance the appropriate monitoring of prognosis. This comprehensive review describes the psychotropic and antiepileptic drugs that are currently available as effective pharmacological treatments and provides in-depth knowledge on the concepts related to clinical, diagnostic, therapeutic, and genetic perspectives of ASD. An increase in the prevalence of ASD in Gulf Cooperation Council countries is also addressed in the review. Further, the review emphasizes the need for international networking and multidimensional studies to design novel and effective treatment strategies.