Autism Spectrum Disorders Part 2 – Causes and Diagnosis

We are back this week to look at part 2 of our most recent OTFC journal club paper on Autism Spectrum Disorders. The below is a summary of the second part of the paper by Mark Fakhoury, from the Department of Neuroscience at the University of Montreal, and covers causes and diagnosis of ASD.

Fakoury, M (2015), ‘Autistic spectrum disorders: A review of clinical features, theories and diagnosis’, International Journal of Developmental Neuroscience, vol. 43, pp 70–77

Causes of ASD

Environmental factors

Evidence is building to show the contribution of environmental factors in  ASD. Environmental exposure has shown to alter brain development and influence neurological processes (e.g. It has been shown that maternal lifestyle, diet and overall nutrition can impact foetal brain development). Moreover, several studies have identified that smoking, alcohol recreational drugs and antidepressant use during pregnancy could increase the risk of brain anomalies observed in children with ASD. Furthermore, potential factors that can influence the predisposition to ASD include exposure to air pollutants, nutritional disorders infection occurring to the mother during pregnancy, poor socioeconomic status, and low maternal educational level. However, while the role of environmental factors in causing ASD has been examined in more detail in recent yeas and, there is still no conclusion that a single environmental factor is sufficient to significantly influence a predisposition to ASD. As such, more needs to be done to understand the role of environmental factors as a cause of Autism.


ASD has been found to be a highly heritable disorder associated with complex cognitive
changes that lead to impairments in social interaction and language development (Klauck, 2006). Twin and family studies show a clear contribution of genetic factors to ASD, and a heritability of more than 80%.

There are a few genetic syndromes associated with ASD: Fragile X syndrome (FXS) and tuberous sclerosis (TS), both share abnormal genetic mechanisms similar to those observed in ASD. FXS is characterised by distinguishing facial features, and cognitive impairments of variable severity and TS (an autosomal dominant disease) has clinical manifestations including epilepsy, learning difficulties, and behavioural problems, with more than 40% of individuals with TS also having an ASD diagnosis.

Genetic testing procedures; whole exome sequencing (WES), microarray analysis and selective candidate gene analysis are the most commonly employed techniques to detect ASD susceptible genes. Through the above genetic procedures, it has been identified that in ASD: there are links with Fragile X, synaptic abnormalities exist, there are inhibitory receptor abnormalities, there are mutations in serotonergic genes and neuroligins (which have implications in synapse development), and the presence of abnormalities in serotonin transporter genes have been associated with clinical presentations of anxiety, attention, and behavioural symptoms related to ASD. The above findings support the fact that there are a number of gene mutations associated with cognitive disorders, and give evidence to suggest a role of genetics in ASD.

Gene-environment interaction

Epigenetics is an area that is becoming increasingly prominent, and this is certainly the case for studies in ASD. Studies have shown that environmental factors can directly affect
genes, which can in turn lead to changes in gene expression that
increase the risk to ASD. These Epigenetic changes impact the DNA and protein synthesis, and can prevent the normal development of neurons and their structure. A study in 2014, by Zhu et al., found that ASD is associated with abnormalities in synapse formation, important in brain development. In 2014, Volk et al. showed that after exposure to high air pollutants, those with genetic variants had an increased risk of ASD. Other environmental factors identified as influencing the development of
ASD include maternal infection during pregnancy, malnutrition, stress, poor maternal
care, and exposure to toxins. In animal models, there has been similar evidence for gene-environment interaction (e.g. diets low in choline, altered brain development of fetal mice). The effect of the interaction of environmental factors with certain gene variants on ASD was also examined in humans (Volk et al., 2014).

Despite all this, there is still variation amongst studies about the impact of genetic and environmental factors in the development of ASD, and no single or major environmental factor has been identified as yet. Further research is required in animal models
of ASD and in examining a genetic and environmental interactions.

Diagnosis of ASD

For diagnosis of ASD, several rating-scale instruments exist. These focus on the behavioural characteristics of children with ASD and include: The autism diagnostic observation schedule (ADOS) and the autism diagnostic interview-revised (ADI-R).

The ADOS is a standardized diagnostic observation tool that helps evaluate the social and communication deficits associated with ASD-related behaviours. It involves the observation of a subject performing a variety of imaginative activities and socials tasks that normally illicit spontaneous behaviour. The ADOS is commonly used in conjunction with ADI-R, which uses a stye of interview process with the parents in order to detect abnormalities that are consistent with deficits seen in children with Autism.

The strengths of the ADOS and ADI-R are that they are designed to differentiate children with autism from those with other neurodevelopmental disorders. As such, they are often seen in clinical use. To accompany these, is the childhood autism rating scale (CARS), which uses a numbered score to determine the severity of the disorder based on specific criteria for clinical observations. Similarly, the CARS differentiates ASD from other developmental disorders such as Intellectual Disability and PDD-NOS.


In 2013, the old diagnostic system DSM-IV was replaced with the revised DSM-5, which removed specific diagnostic subcategories for Aspergers and PDD–NOS. As such, those with these diagnoses requires a different evaluation, to reassess. In addition, revision have been made to the criteria for a diagnosis of ASD, to make it more precise and reliable.

For example, impaired social interaction and reduced communication (e.g. social-emotional reciprocity, difficulties developing friendships) are now one  one category, and restricted and repetitive behaviours (e.g. stereotyped movements, fixated interests and altered sensory input) were retained as the second category required for diagnosis of ASD (Fakoury, 2015).

In order to receive a diagnosis for an ASD, the DSM-5 requires that individuals meet all three of the criteria in the category of social-communication impairments, and two of four criteria in the category of restricted and repetitive behaviours. Moreover, the DSM-5 specifies the severity levels of ASD as follow:

  • ‘Level 1’ when support is required,
  • ‘Level 2’ when substantial support is required,
  • ‘Level 3’ when very substantial support is required

These changes are already having an impact on the individuals currently diagnosed with ASD, especially those with characteristics of Aspergers or PDD–NOS.

Diagnostic markers of ASD

There is now more research discovering and developing new markers designed to better diagnose ASD. By definiiton, a marker is ‘a variable implicated in the symptomatology of the disease of interest across and within individuals, which can be measured directly from a given patient using sensitive and reliable quantitative approaches’ (Fakoury, 2015).

The above table gives an overview of the quantitative approaches used for the measurement of ASD markers. There are a number of neurotransmitters that have been identified as possible ASD markers (e.g. GABA, glutamate and Serotonin). For example, the neurotransmitter Serotonin plays an important role in behavioural regulation, autonomic and cognitive functions. In more than 25% of patients with ASD, Serotonin blood levels are found to be elevated, supporting links to altered levels in patients with ASD. As such Serotonin is an important biomarker in ASD. Other biochemical markers known are within urinary solutes (e.g. tryptophan and nicotinic metabolites). Hormonal and immunological biomarkers have also proven efficient in the detection of ASD (e.g. dopaminergic pathways – associated with reward and motivation – are altered in the brains of ASD children and oxytocin levels – important for regulation – is altered in ASD). In addition, the presence of immunological markers, such as inflammatory cytokines and autoantibodies, also correlate with the underlying features of ASD.

Advances in neuroimaging have shown that reduced brain connectivity is an underlying characteristic of ASD symptoms, with fMRI showing that those with ASD have deficits in brain structures and connectivity involved in attention, regulation and cognitive processes. Morphologically, as brain development and facial features are closely linked, some evidence has shown that there are physical features of those with ASD, including prominent foreheads, facial asymmetry – which have been linked to abnormal brain growth. This has led to some research into identifying facial phenotypes of those with ASD. The above markers have proven to show some clinical success for the diagnosis of ASD, but also for the identification of appropriate support to those with ASD, to improve social and cognitive skills.

So, we have come to the end of our discussion about Autism Spectrum Disorder and its causes, diagnostic factors, theories and characteristics. As we a re drawing close to the end of April and in turn Autism Awareness month, we hope this article provides further insight into where the research stands on Autism Spectrum Disorders. We hope to have more from the OTFC Journal Club hit our blog soon!


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