Autism spectrum disorders (ASDs) represent a heterogeneous set of neurodevelopmental disorders characterized by deficits in social communication and reciprocal interactions as well as stereotypic behaviors. The prevalence of ASDs has been increasing over the past 2 decades. According to the latest review of medical records in 14 selected sites in the United States conducted by the CDC, 1 in 88 children (1 in 54 boys and 1 in 252 girls) aged 8 years were identified as having ASDs.1 The reason for this rise in prevalence is not fully understood, but this increase clearly shows that ASDs are a significant public health issue.
ASDs are often accompanied by significant lifelong impairments. Individuals with ASDs often require intensive parental, school, and other social support. In addition to intensive behavioral therapies, services at school ranging from individualized education plans with combinations of speech therapy, occupational therapy, social skills training and physical therapy, to individualized aides, specialized classrooms, and sometimes even specialized schools are required for most children with ASDs. While services vary by region and can be challenging to obtain for children, supports for adults are even more limited. For many adults with ASDs and significant intellectual disability, psychiatric comorbidity, and/or medical comorbidity, independence is often not achievable. Some may be able to participate in vocational training and hold basic jobs but still require assistance with daily living. Many adults live either with parents, with other family members, or in group homes or residential facilities. Most individuals with typical autism require lifelong assistance with basic living skills, as well as financial, medical, social, and psychiatric support.
In individuals with ASD and without significant intellectual disability, high-functioning autism is often diagnosed. In those without language development delays, a diagnosis of Asperger disorder is made. These individuals tend to have relatively good outcomes and are able to live independently, although challenges still exist. High-functioning individuals with normal, above-average, or even superior intelligence may be able to attend college and graduate school, but they often struggle significantly with social demands. These demands may be too challenging for many individuals with ASDs to complete higher education without substantial psychosocial supports. Similarly, high-functioning adults with ASDs may be intellectually quite capable of performing in a wide variety of jobs and pursuing careers, but navigating the unwritten social maps may be too complex and significantly limit their abilities to obtain and hold positions in the workforce. These individuals are not only at greater risk for social isolation, but they may also be at greater risk for depression and anxiety as they recognize their impairments and have enough insight to be all too aware of their differences.
As with other disorders in psychiatry, psychoeducation is critically important for patients and their families. This article aims to provide the general psychiatric community with an update on the major findings on the biology of ASDs as well as the advances in diagnostic and interventional strategies.
Update on biology of ASDs
The biology of ASDs has been investigated by state-of-the-art scientific methodologies in genetics, molecular biology, neurophysiology, neuroimaging, and neuropsychology. A consistent theme has been the heterogeneity of biological findings in the disorder. For example, to date, more than 100 disease genes and 44 genomic loci are reported in persons with ASD or autistic behavior.2 It is unlikely for a single anatomic abnormality or even a single physiologic process to explain the etiology of ASDs. Rather, it is more reasonable to anticipate discoveries of risk factors that when joined in various combinations result in ASDs. Nonetheless, careful investigations focusing on individual genes and protein products, anatomical structures and neurocircuits, endophenotypes, and the environment are important in identifying such risk factors. With this in mind, we focus on 3 categories of risk factors for ASDs: genetics, brain anatomy, and environment.
Genetics. One of the largest advancements in understanding the etiology of ASDs is the identification of a variety of genetic variations, and especially copy number variants, associated with ASDs. Copy number variants are segments of DNA that have been either deleted or duplicated from a person’s genome. Thus, while genes are typically inherited in pairs (one copy from the mother and one copy from the father), persons with copy number variants that consist of a deletion will only have a single copy of a gene(s), and those with a copy number variant consisting of a duplication will actually have 3 copies of the gene(s). Both deletions and duplications have been implicated in ASDs.
Copy number variants vary in size and may include several genes or only a few. They may be inherited, or they may arise spontaneously, in which case they are referred to as “de novo” mutations. Children with ASDs have been found to have higher rates of de novo copy number variants compared with siblings without ASD diagnoses.3
Table 1 lists some of the copy number variants that have been associated with ASDs and the respective genes thought to be involved. Several of these genes are involved with synaptic transmission and modulation of excitatory and inhibitory neurons. Of note, these variants are not unique to ASDs, and each may lead to diverse impairments, including other physical, cognitive, and/or psychiatric disorders. Similarly, the presence of a variant does not guarantee the development of ASDs. In addition to copy number variants, de novo single nucleotide variants have also been linked to autism through recent whole-exome sequencing studies and may help elucidate the protein networks involved in ASDs.4-6
Many genes associated with ASDs are involved in synaptic transmission.2,7-9 When the molecular and cellular machineries involved with neurotransmission become dysfunctional, neurological, psychiatric, and behavioral symptoms may occur. One proposed model for ASD suggests that the condition is a result of an imbalance of excitatory (E) and inhibitory (I) neurotransmission.10,11
Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters, respectively. Using optogenetic techniques, Yizhar and colleagues12 demonstrated that elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex caused profound impairment in cellular information processing, associated with behavioral impairments resembling social withdrawal. Furthermore, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation in these mice.
Consistent with the E/I hypothesis, another study on a key ASD-associated gene, CNTNAP2, has shown reduced number of GABAergic interneurons in CNTNAP2 knock-out mice.13 These results add to the accumulating evidence supporting the hypothesis of an elevated E:I ratio in ASD and other comorbid neuropsychiatric disease–related symptoms, such as seizures.
Brain anatomy. To date, E/I imbalance in the human brain is difficult to demonstrate directly. However, numerous neuroimaging studies have been conducted to define the ASD brain and elucidate how anatomic regions are connected functionally and structurally. Rapid advances in neuroimaging technology have been helpful for neuroscience in general, but they also present challenges in establishing consistent phenomenology regarding neuroanatomic changes in ASD.
Other challenges include the heterogeneity of the ASD population and the methodological limitations related to the deviation in developmental trajectory of the brain. One consistent finding is an increased rate of brain growth in individuals with ASDs that begins during the first year of life but slows throughout later childhood and/or adolescence.14 Longitudinal studies provide a better understanding of the underlying neurodevelopmental trajectories.
In the first longitudinal structural MRI studies of young children (2 to 5 years) with autistic disorder, the frontal, temporal, and cingulate cortices as well as the amygdala were found to be disproportionately larger than those in typically developing children at baseline.15,16 Repeated scans in the following 3 years showed that almost all regions in the gray and white matter in children with ASDs grew almost linearly instead of along a curve and lacked the more apparent deceleration seen in neurotypical children.15 Similarly, the amygdala’s growth in children with ASDs a year later showed an increased rate, compared with controls.16 The increased growth rate in the cortices appears to dissipate at a later age (8 to 12 years).17 In addition to longitudinal studies, functional MRI, diffusion tensor imaging, pharmacological MRI, and imaging-genetics continue to advance our understanding of ASDs.18-22
Environment. ASDs were once thought to be largely genetic; heritability was previously estimated to be as high as 90%. However, a twin study indicates that genetic components account for only approximately 30% to 35% of the factors involved in the etiology of ASDs. In other words, environmental factors likely account for 60% to 65%.23,24 Several environmental factors have been hypothesized to be involved in the development of ASDs. However, it remains largely unknown what the specific environmental factors are, their impact, and their contributing mechanics to the development of ASDs.
Environmental factors associated with ASDs include perinatal events, such as abnormal presentation at birth (ie, breech presentation), umbilical cord complications, fetal distress, birth injury or trauma, multiple birth (ie, twin or triplet birth), bleeding during pregnancy, low birth weight, small for gestational age, birth defects, low Apgar scores, feeding difficulties, meconium aspiration, neonatal anemia, ABO or Rh incompatibility, and jaundice.25
In addition, ASDs have been linked to maternal and, notably, paternal age (often defined as older than 35 or 40 or younger than 30), parity, preeclampsia, scheduled cesarean, and prematurity.26 The maternal immune system during pregnancy may also be involved in the development of ASDs as season of birth, maternal infection, and the presence of maternal antibodies/cytokines have also been associated with ASDs.27 Interestingly, E/I imbalance may be linked to some of the environmental factors potentially causing physiological abnormalities, such as oxidative stress28 and immune dysfunction29-31 that might be associated with ASDs.32