Background
Although autism spectrum condition (ASC) is strongly genetic in origin, accumulating evidence points to the critical roles of various environmental influences on its emergence and ...subsequent developmental course.
Methods
A developmental psychopathology framework was used to synthesise literature on environmental factors associated with the onset and course of ASC (based on a systematic search of the literature using PubMed, PsychInfo and Google Scholar databases). Particular emphasis was placed on gene–environment interplay, including gene–environment interaction (G × E) and gene–environment correlation (rGE).
Results
Before conception, advanced paternal and maternal ages may independently enhance offspring risk for ASC. Exogenous prenatal risks are evident (e.g. valproate and toxic chemicals) or possible (e.g. selective serotonin reuptake inhibitors), and processes endogenous to the materno‐foeto‐placental unit (e.g. maternal diabetes, enhanced steroidogenic activities and maternal immune activation) likely heighten offspring vulnerability to ASC. Folate intake is a prenatal protective factor, with a particular window of action around 4 weeks preconception and during the first trimester. These prenatal risks and protective mechanisms appear to involve G × E and potentially rGE. A variety of perinatal risks are related to offspring ASC risk, possibly reflecting rGE. Postnatal social factors (e.g. caregiver–infant interaction, severe early deprivation) during the first years of life may operate through rGE to influence the likelihood of manifesting a full ASC phenotype from a ‘prodromal’ phase (a proposal distinct to the discredited and harmful ‘refrigerator mother hypothesis’); and later postnatal risks, after the full manifestation of ASC, shape life span development through transactions mediated by rGE. There is no evidence that vaccination is a postnatal risk for ASC.
Conclusions
Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene–environment interplay, large‐sample genome–envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed.
Although autism spectrum condition (ASC) is highly genetic, environmental factors play a role in its emergence and development across the life span. Susceptibility to some environmental risks for ASC (e.g. traffic‐related air pollution), may be moderated by genotype. Other environmental risks, (e.g. perinatal complications associated with hypoxia) may be part of gene–environment correlations, whereby genetic risk increases the probability of environmental exposure, which in turn shapes the emergence of the ASC phenotype. Based on a developmental psychopathology synthesis of the research literature, this review shows that although genes are highly influential on the aetiology and development of ASC, environmental interventions have the potential to reduce susceptibility to the condition, alleviate symptoms and modify the developmental course. The clinical and public health implications of the findings are discussed, but one clear finding is that there is no evidence that vaccination is a postnatal risk for ASC. Further work on the study of environmental risk and protection will help elucidate aetiological and phenotypic heterogeneity, and will promote the discovery of mechanisms underpinning the emergence and development of ASC, and the recommendations for various study designs are outlined.
Read the Commentary on this article at doi: 10.1111/jcpp.12527
Autism is a diagnostic label based on behavior. While the diagnostic criteria attempt to maximize clinical consensus, it also masks a wide degree of heterogeneity between and within individuals at ...multiple levels of analysis. Understanding this multi-level heterogeneity is of high clinical and translational importance. Here we present organizing principles to frame research examining multi-level heterogeneity in autism. Theoretical concepts such as 'spectrum' or 'autisms' reflect non-mutually exclusive explanations regarding continuous/dimensional or categorical/qualitative variation between and within individuals. However, common practices of small sample size studies and case-control models are suboptimal for tackling heterogeneity. Big data are an important ingredient for furthering our understanding of heterogeneity in autism. In addition to being 'feature-rich', big data should be both 'broad' (i.e., large sample size) and 'deep' (i.e., multiple levels of data collected on the same individuals). These characteristics increase the likelihood that the study results are more generalizable and facilitate evaluation of the utility of different models of heterogeneity. A model's utility can be measured by its ability to explain clinically or mechanistically important phenomena, and also by explaining how variability manifests across different levels of analysis. The directionality for explaining variability across levels can be bottom-up or top-down, and should include the importance of development for characterizing changes within individuals. While progress can be made with 'supervised' models built upon a priori or theoretically predicted distinctions or dimensions of importance, it will become increasingly important to complement such work with unsupervised data-driven discoveries that leverage unknown and multivariate distinctions within big data. A better understanding of how to model heterogeneity between autistic people will facilitate progress towards precision medicine for symptoms that cause suffering, and person-centered support.
It is unclear whether transgender and gender-diverse individuals have elevated rates of autism diagnosis or traits related to autism compared to cisgender individuals in large non-clinic-based ...cohorts. To investigate this, we use five independently recruited cross-sectional datasets consisting of 641,860 individuals who completed information on gender, neurodevelopmental and psychiatric diagnoses including autism, and measures of traits related to autism (self-report measures of autistic traits, empathy, systemizing, and sensory sensitivity). Compared to cisgender individuals, transgender and gender-diverse individuals have, on average, higher rates of autism, other neurodevelopmental and psychiatric diagnoses. For both autistic and non-autistic individuals, transgender and gender-diverse individuals score, on average, higher on self-report measures of autistic traits, systemizing, and sensory sensitivity, and, on average, lower on self-report measures of empathy. The results may have clinical implications for improving access to mental health care and tailoring adequate support for transgender and gender-diverse individuals.
Autism is both a medical condition that gives rise to disability and an example of human variation that is characterised by neurological and cognitive differences. The goal of evidence-based ...intervention and support is to alleviate distress, improve adaptation, and promote wellbeing. Support should be collaborative, with autistic individuals, families, and service providers taking a shared decision-making approach to maximise the individual's potential, minimise barriers, and optimise the person–environment fit. Comprehensive, naturalistic early intervention with active caregiver involvement can facilitate early social communication, adaptive functioning, and cognitive development; targeted intervention can help to enhance social skills and aspects of cognition. Augmentative and alternative communication interventions show preliminary evidence of benefit in minimising communication barriers. Co-occurring health issues, such as epilepsy and other neurodevelopmental disorders, sleep problems, and mental health challenges, should be treated in a timely fashion. The creation of autism-friendly contexts is best achieved by supporting families, reducing stigma, enhancing peer understanding, promoting inclusion in education, the community, and at work, and through advocacy.
Summary Autism is a set of heterogeneous neurodevelopmental conditions, characterised by early-onset difficulties in social communication and unusually restricted, repetitive behaviour and interests. ...The worldwide population prevalence is about 1%. Autism affects more male than female individuals, and comorbidity is common (>70% have concurrent conditions). Individuals with autism have atypical cognitive profiles, such as impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. These profiles are underpinned by atypical neural development at the systems level. Genetics has a key role in the aetiology of autism, in conjunction with developmentally early environmental factors. Large-effect rare mutations and small-effect common variants contribute to risk. Assessment needs to be multidisciplinary and developmental, and early detection is essential for early intervention. Early comprehensive and targeted behavioural interventions can improve social communication and reduce anxiety and aggression. Drugs can reduce comorbid symptoms, but do not directly improve social communication. Creation of a supportive environment that accepts and respects that the individual is different is crucial.
With increasing awareness of potential differences of autism presentation in nonmale versus male individuals, this review summarizes the rapidly evolving literature on sex and gender impacts on ...autism across nosology, behavioural presentation, developmental change and contextual recognition biases.
Most studies have not differentiated sex versus gender impacts. Regarding behavioural presentation, measurement invariance across sex/gender was found in several standard measures. On this basis, diagnosed females overall showed lower restricted/repetitive behaviour/interests/activities (RRBI) than males, with small and variable effects depending on age, developmental level and kinds of RRBI. Differences insufficiently captured by standard measures may include autistic females displaying female-gender-typical narrow interests, higher social attention, linguistic abilities, motivation for friendship and more camouflaging than autistic males. Regarding developmental change, diagnosed young girls were more likely to have better cognitive development, less intense autistic symptoms and reduction of symptoms over time. Difficulties in adaptive functioning and social challenges, however, may emerge more for females in adolescence. Regarding diagnosis, general expectancy biases and gender-stereotypes may impede timely recognition of autism in females.
Appreciating the multilevel sex and gender impacts on presentation, development, and diagnosis is key to sex-equitable and gender-equitable care for autistic individuals. A holistic approach to understanding the person in the contexts of sex and gender is essential for timely and accurate diagnosis and support.
Social camouflaging describes the use of strategies to compensate for and mask autistic characteristics during social interactions. A newly developed self-reported measure of camouflaging ...(Camouflaging Autistic Traits Questionnaire) was used in an online survey to measure gender differences in autistic (n = 306) and non-autistic adults (n = 472) without intellectual disability for the first time. Controlling for age and autistic-like traits, an interaction between gender and diagnostic status was found: autistic females demonstrated higher total camouflaging scores than autistic males (partial η2 = 0.08), but there was no camouflaging gender difference for non-autistic people. Autistic females scored higher than males on two of three Camouflaging Autistic Traits Questionnaire subscales: Masking (partial η2 = 0.05) and Assimilation (partial η2 = 0.06), but not on the Compensation subscale. No differences were found between non-autistic males and females on any subscale. No differences were found between non-binary individuals and other genders in either autistic or non-autistic groups, although samples were underpowered. These findings support previous observations of greater camouflaging in autistic females than males and demonstrate for the first time no self-reported gender difference in non-autistic adults.
Autism spectrum conditions comprise a set of early-onset neurodevelopmental syndromes with a prevalence of 1% across all ages. First diagnosis in adulthood has finally become recognised as an ...important clinical issue due to the increasing awareness of autism, broadening of diagnostic criteria, and the introduction of the spectrum concept. Thus, the idea of a lost generation of people who were previously excluded from a diagnosis of classic autism has arisen. Making a first diagnosis of autism spectrum conditions in adults can be challenging for practical reasons (eg, no person to provide a developmental history), developmental reasons (eg, the acquisition of learnt or camouflaging strategies), and clinical reasons (eg, high frequency of co-occurring disorders). The diagnostic process includes referral, screening, interviews with informants and patients, and functional assessments. In delineating differential diagnoses, true comorbidities, and overlapping behaviour with other psychiatric diagnoses, particular attention should be paid to anxiety, depression, obsessive-compulsive disorder, psychosis, personality disorders, and other neurodevelopmental disorders. Possible misdiagnosis, especially in women, should be explored. The creation of supportive, accepting, and autism-friendly social and physical environments is important and requires a coordinated effort across agencies and needs support from government policies.
The relationship between sex/gender differences and autism has attracted a variety of research ranging from clinical and neurobiological to etiological, stimulated by the male bias in autism ...prevalence. Findings are complex and do not always relate to each other in a straightforward manner. Distinct but interlinked questions on the relationship between sex/gender differences and autism remain underaddressed. To better understand the implications from existing research and to help design future studies, we propose a 4-level conceptual framework to clarify the embedded themes.
We searched PubMed for publications before September 2014 using search terms “‘sex OR gender OR females’ AND autism.” A total of 1,906 articles were screened for relevance, along with publications identified via additional literature reviews, resulting in 329 articles that were reviewed.
Level 1, “Nosological and diagnostic challenges,” concerns the question, “How should autism be defined and diagnosed in males and females?” Level 2, “Sex/gender-independent and sex/gender-dependent characteristics,” addresses the question, “What are the similarities and differences between males and females with autism?” Level 3, “General models of etiology: liability and threshold,” asks the question, “How is the liability for developing autism linked to sex/gender?” Level 4, “Specific etiological–developmental mechanisms,” focuses on the question, “What etiological–developmental mechanisms of autism are implicated by sex/gender and/or sexual/gender differentiation?”
Using this conceptual framework, findings can be more clearly summarized, and the implications of the links between findings from different levels can become clearer. Based on this 4-level framework, we suggest future research directions, methodology, and specific topics in sex/gender differences and autism.
Background
Clinically significant attention‐deficit/hyperactivity disorder (ADHD) symptoms are common and impairing in children and youth with autism spectrum disorder(ASD). The aim of this ...systematic review and meta‐analysis was to (a) evaluate the efficacy and safety of pharmacotherapy for the treatment of ADHD symptoms in ASD and (b) distil findings for clinical translation.
Methods
We searched electronic databases and clinical trial registries (1992 onwards). We selected randomized controlled trials conducted in participants <25 years of age, diagnosed with ASD that evaluated ADHD outcomes (hyperactivity/impulsivity and inattention) following treatment with stimulants (methylphenidate or amphetamines), atomoxetine, alpha‐2 adrenergic receptor agonists, antipsychotics, tricyclic antidepressants, bupropion, modafinil, venlafaxine, or a combination, in comparison with placebo, any of the listed medications, or behavioral therapies. Data were pooled using a random‐effects model.
Results
Twenty‐five studies (4 methylphenidate, 4 atomoxetine, 1 guanfacine, 14 antipsychotic, 1 venlafaxine, and 1 tianeptine) were included. Methylphenidate reduced hyperactivity (parent‐rated: standardized mean difference SMD = −.63, 95%CI = −.95,−.30; teacher‐rated: SMD = −.81, 95%CI = −1.43,−.19) and inattention (parent‐rated: SMD = −.36, 95%CI = −.64,−.07; teacher‐rated: SMD = −.30, 95%CI = −.49,−.11). Atomoxetine reduced inattention (parent‐rated: SMD = −.54, 95%CI = −.98,−.09; teacher/investigator‐rated: SMD = −0.38, 95%CI = −0.75, −0.01) and parent‐rated hyperactivity (parent‐rated: SMD = −.49, 95%CI = −.76,−.23; teacher‐rated: SMD = −.43, 95%CI = −.92, .06). Indirect evidence for significant reductions in hyperactivity with second‐generation antipsychotics was also found. Quality of evidence for all interventions was low/very low. Methylphenidate was associated with a nonsignificant elevated risk of dropout due to adverse events.
Conclusions
Direct pooled evidence supports the efficacy and tolerability of methylphenidate or atomoxetine for treatment of ADHD symptoms in children and youth with ASD. The current review highlights the efficacy of standard ADHD pharmacotherapy for treatment of ADHD symptoms in children and youth with ASD. Consideration of the benefits weighed against the limitations of safety/efficacy data and lack of data evaluating long‐term continuation is undertaken to help guide clinical decision‐making regarding treatment of co‐occurring ADHD symptoms in children and youth with ASD.
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