Etiology
The development of ASD is influenced by a number of genetic and nongenetic factors which interact over time, leading to heterogeneous outcomes across individuals.[39] It is well established that there are strong genetic influences in the development of ASD; a number of studies estimate its heritability to be between 50% and 80%.[40][41][42][43][44] However, it is important to recognize that most people with ASD do not have a relative with ASD. Sibling recurrence rates are in the region of 20%.[45][46] Twin studies have also indicated the importance of shared environment and other nonheritable genetic factors.[47] ASD is genetically heterogeneous, and the identification of susceptibility genes is further compounded by the fact that individuals with ASD also display phenotypic heterogeneity. A minority of people with ASD (approximately 10%) have cytogenetically detectable chromosomal abnormalities and recognized genetic syndromes, such as fragile X syndrome, neurofibromatosis type 1, tuberous sclerosis, and Down syndrome. Similarly, in a significant minority (approximately 10% to 30%) copy number variation (CNV) has also been observed at a submicroscopic level.[48][49] These CNV studies have mostly found "rare" variants, usually defined as those occurring in less than 1% of the population.[48] More recently, a number of exome and whole genome sequencing studies have been undertaken and identified a greater burden for nonsynonymous de novo genetic variants among ASD probands compared with sibling controls.[50][51][52] Single nucleotide variants are also associated with ASD.[53] Overall, a known genetic cause is identified in only a minority (around 20%-25%) of people with ASD in practice.[54] While ASD may run in families, other family members may have relatively mild, ASD-related social, communication, and repetitive domain difficulties, termed as the broader autism phenotype.[45][55][56][57][58]
Maternal health factors may play a role in the development of ASD, although in general the evidence on this is equivocal, with more research needed on a larger scale. Studies report a strong increased likelihood of ASD in the children of mothers who take sodium valproate during pregnancy, which, given the strength of the association and biologic plausibility, is considered likely to be causal.[59][60][61]
Pathophysiology
ASD is considered a lifelong neurodevelopmental disorder with a brain basis, as supported by its association with disordered development and, in some children, impaired cognitive skills (intellectual disability), epilepsy, and macrocephaly.
Modified brain development has been identified very early in life in children with ASD, which continues over time, resulting in the reorganisation of neural networks underlying cognition and behavior.[39] Studies looking at children at increased likelihood of ASD due to family history (who later received a diagnosis of ASD themselves) show atypical brain development at 6 months old, in particular affecting connections involved in low-level sensory processing.[62][63][64][65] It is hypothesized that these changes may have begun during the prenatal period, and that they could represent a lack of appropriate synaptic pruning or apoptosis.[62] Between the ages of 6 and 12 months, children with ASD may experience an expansion of cortical surface area, followed by exaggerated global overgrowth between the ages of 12 and 24 months, compared with their nonaffected peers.[65][66] Brain volume remains larger on average, compared with peers, until the age of 4; in particular, the amygdala, frontal cortex, and temporal cortex. However by school age, brain growth slows down in most children with ASD and by around 10 to 15 years, brain volume becomes similar to that of children without ASD.[67][68]
In parallel with the evolution of neuroanatomic models, three neurocognitive theories of ASD have also been described:[69][70][71]
Executive function (difficulties with problem solving and forward planning in order to achieve a goal)
Impaired central coherence (difficulties with integration of information into meaningful wholes)
The theory of mind hypothesis (difficulties in the consideration of how other people might think and react to a particular situation).
Classification
Diagnostic and statistical manual of mental disorders, 5th ed, text revision (DSM-5-TR)[1]
Most diagnoses are undertaken using DSM-5-TR criteria. See Criteria.
The clinician should specify if the patient has ASD:
With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known genetic or other medical condition, or environment factor
Associated with a neurodevelopmental, mental, or behavioral problem
With catatonia.
Note that autism, Asperger syndrome, and pervasive developmental disorder (not otherwise specified) are no longer differentiated; all children and adults with new diagnoses are now diagnosed with ASD.
World Health Organization International Classification of Diseases 11th edition (ICD-11)[2]
The clinician should specify if the patient has ASD:
With or without disorder of intellectual development
With mild or no impairment of functional language
With impaired functional language (i.e., not able to use more than single words or simple phrases)
With complete, or almost complete, absence of functional language
With or without loss of previously acquired skills.
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