Autism spectrum disorder

Abstract

Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice.

Fig. 1 |. Theories and findings regarding autism mechanisms, outcomes and heterogeneity.

Original descriptions of the cardinal features of autism were attributed to a range of causes, including being raised by wolves (the Wild Boy of Aveyron), inborn limitations in affective contact and unfeeling parenting (such as ‘refrigerator mothers’), and holy people (such as Fools for Christ). Conceptualizations of autism as a common highly heritable neurodevelopmental disorder with underlying cognitive features began with the recognition of differences in brain function and cognition in the 1960s^– and the first twin study in the 1970s. Other proposed mechanisms include maturational lags in neurophysiology and cognitive mechanisms such as joint engagement^,. With the search for pathways to and sometimes out of autism on many levels, conceptualization of positive outcomes has been more recent but has also varied markedly. In the 1970s, autism societies and collaborative clinical programmes focused on community integration and de-institutionalization (such as National Autistic Society (NAS) and National Society for Autistic Children (NSAC)). Priorities shifted in the 1980s and 1990s, with still unreplicated claims of ‘recovery’ in children who participated in intensive behavioural interventions, new advocacy groups focusing on biomedical discoveries to yield potential biological treatments and even ‘cures’ (such as National Alliance for Autism Research (NAAR) and Cure Autism Now), and the neurodiversity movement, which rejected ‘cures’ and called for adaptation of environments to support autistic people, using terminology preferred by self-advocates and community participation. Recognition of the marked heterogeneity within autism began in the 1970s, with the triad of impairments in language, play and social interaction characterizing many children with intellectual disabilities (ID) or those with classical autism. The first twin study demonstrated that monozygotic twin pairs, although concordant for difficulties associated with autism, differed in specific characteristics and co-occurring conditions, including ID. More recently, phenotypic heterogeneity has been the rule in most, although not all, gene-first phenotypic studies. Thus, developmental aspects of differences in strengths, difficulties and trajectories as well as biological factors require highly personalized conceptualizations of the needs of autistic individuals and their families. ABA, applied behaviour analysis; AGRE, Autism Genetic Resource Exchange; ASD, autism spectrum disorder; DSM, Diagnostic and Statistical Manual of Mental Disorders; EEG, electroencephalography; GRASP, Global and Regional Asperger Syndrome Partnership; IDEA, Individuals with Disabilities Education Act; MECP2, the gene associated with Rett syndrome; PACT, Preschool Autism Communication Trial; PDD, pervasive developmental disorder; RCT, randomized controlled trial; SNAP, Special Needs and Autism Project; SPARK, Simons Foundation Powering Autism Research for Knowledge; TEACCH, Treatment and Education of Autistic and Related Communication-handicapped Children.

Fig. 2 |. Environmental risk factors for autism.

Data from studies aiming to identify risk factors for autism can be broadly split into three categories: those with evidence supporting an association (a), those with inconclusive evidence (b) and, importantly, those with no supporting evidence (c). Bars represent ranges. ^aRepresents recurrence risk. Figure adapted from REF. with added findings from select reviews and empirical papers: neonatal hypoxia estimate, childhood vaccines, valproate use during pregnancy, parent age estimates, preterm birth estimate^,, maternal obesity estimate, folic acid intake estimate, siblings estimate^,, interpregnancy interval estimate, assisted reproductive technologies estimate^,, pesticide and air pollution estimate, and caesarean section estimate. Adapted from REF., CC-BY-4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 3 |. Encoded proteins associated with autism risk.

Simplified schematic of the major cellular components of a neural circuit in the cerebral cortex, with a focus on pyramid-shaped glutamatergic excitatory projection neurons. Proteins encoded by selected high-confidence (false discovery rate < 0.1) autism risk genes and proteins encoded by selected syndromic autism genes have a role in these neurons during development. These proteins have a diverse intracellular distribution: those at the synapse have roles in cell adhesion, scaffolding and signalling. In addition, some of these proteins are localized to the nucleus and have been shown, broadly, to mediate chromatin modification and transcriptional control. Syndromic autism genes include FMR1 (encoding fragile X mental retardation protein; fragile X syndrome), UBE3A (encoding ubiquitin-protein ligase E3A; Angelman syndrome), TSC1 and TSC2 (encoding hamartin and tuberin; tuberous sclerosis complex), PTEN (encoding phosphatase and tensin homologue) and MECP2 (encoding methyl-CpG-binding protein 2; Rett syndrome). GABA, γ-aminobutyric acid; Ub; ubiquitin. Adapted with permission from REF., Elsevier.

Fig. 4 |. Longitudinal trajectories of total brain volume, surface area and cortical thickness in autism.

Brain trajectories from 6 to 24 months of age for total brain volume (a), total surface area (b) and total cortical thickness (c). Toddlers diagnosed with autism spectrum disorder (ASD) had significantly greater surface area growth from 6 to 12 months than infants who were high risk for ASD but did not receive a diagnosis as well as than typically developing infants. Differences in surface area growth became more pronounced from 12 to 24 months of age for toddlers who received an ASD diagnosis. Corrected age refers to the age corrected by length (body size). Adapted from REF., Springer Nature Limited.

Fig. 5 |. Co-occurring disorders.

Primary and secondary disorders and disadvantage can accumulate through development in people with autism. These disorders can form additional targets for treatment and policy. Prevalence estimates are preliminary, derived from QUEST, SNAP^, and EDX cohorts, but are limited by the fact that many are based on clinical populations or data that are inherently biased (such as US Medicaid data, in which billing for treatment is contingent on having a non-autism diagnosis) and few well-designed population studies exist. ADHD, attention-deficit/hyperactivity disorder; OCD, obsessive–compulsive disorder.

Fig. 6 |. Major parental milestones in advocating and supporting their child with autism.

Families of children and adults with autism have many decisions and expectations across the lifespan of their children, from seeking initial diagnostic evaluation and intervention to preparing for ageing-related services. These decisions vary across different cultures, regions and countries, and depend on many factors, including the resources and services available. However, several decisions are common across all regions, including low-income and middle-income countries, such as choices about who will care for their child if the parents are temporarily unable, the amount of time parents and other family members can spend with the child with autism versus meeting other needs, ways to modify their home environment to ensure the safety and independence of the individual with autism and the kinds of behavioural expectations that are most helpful for their child or adult. Of note, for many families, these choices and responsibilities are lifelong and are relevant for children, adolescents, adults and elders with autism.

Fig. 7 |. Changes in daily living scores as predicted by IQ scores and autistic symptoms.

Changes in independent daily living skills can be observed in people with autism over time. This sample consists of ~100 young adults with autism with a mean age of 26 years, who were evaluated at 2, 3 and 9 years of age and followed up to 26 years of age. Daily living scores are very diverse, ranging from age-appropriate levels of independence at adulthood (represented by a daily living score of 100, assessed using Vineland II) to very limited skills (represented by a score of <30). Increasing divergence shows where measurement after 2 years of age is additionally predictive, with the line thickness indicating the proportion of early referred children that followed each trajectory. Heterogeneity in intellectual functioning and severity of autistic symptoms (social communication and restricted, repetitive, sensory behaviours) can be observed. In addition, improvements and worsening of autistic symptoms and intellectual functioning can occur over time. a,b | Referred children had verbal IQs predominantly <50 (over 3 standard deviations below average) but could show improvement in daily living standard scores from 2 to 3 years of age that were indicative of eventual greater independence in adulthood. Relatively less early change in non-verbal IQ is seen but, like verbal IQ, by adulthood the association with eventual adult daily living skills is strong. c,d | Variation in autism symptom severity in social communication (CSS refers to the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) comparison scores) showed a stronger association with adult independence than restricted, repetitive behaviours and continued to change over the lifespan following more divergent pathways than intellectual functioning. Data from the EDX cohort compiled from REFS^,,.