Autism Spectrum Disorder: A Precision Medicine Approach

“If you’ve met one person with autism, you have met one person with autism“. As stated by Dr Shore, a professor of special education with autism spectrum disorder (ASD), although ASD people share common traits, each is a unique individual personality that experiences and percepts their disability differently. But how does an individual with autism differ from the healthy population?

Diversity of ASD

Autism is a neurodevelopmental disorder that affects approximately 1% of the world’s population. Particularly, it is estimated that 1 in 100 children were diagnosed with ASD in 2021 and the most affected patients were males (WHO, 2021). ASD is typically identified in the first three years of life and is a lifelong condition. ASD affects the developing brain and shows three core symptoms; impaired social interaction, compromised language and communication and repetitive pattern of behaviours and interests (Faras et al., 2010). In contrast with other neurodevelopmental disorders, such as Fragile X or Down syndrome, the autistic population usually maintains similar physical attributes to healthy individuals (Mefford et al., 2012). In the Caucasian population, morphological abnormalities including asymmetry of the face, multiple hair whorls, and predominant forehead are usually present (Ozgen et al., 2010). However, it is difficult to identify an autistic person only by his appearance. Some indicators of the disorder include specific behavioural patterns, such as repetitive behaviour and impairment in reciprocal social interaction and communication (World Health Organization: WHO, 2023). Other ASD-related characteristics include delayed language, cognitive, and fundamental movement skills and unusual emotional reactions (CDC, 2022).

Figure 1: The view from the Shard, drawing by Stephen Wiltshire (Choo Yut Shing, 2014).

In addition, epidemiological data from Denisova et al. (2023) have indicated a high prevalence of low intelligence quotient (IQ) scores in children with ASD. However, autistic people demonstrate high variability in intellectual functioning. For instance, there are autistic individuals with savant skills in different fields and advanced logical thinking. A renowned example of this is Stephen Wiltshire, a British architect with autism that draws panoramic landscapes from memory based on a single look at the scene. Wiltshire has drawn cities from all over the world and has received various awards. Individuals with these capabilities are often characterized as “high-functioning”. However, this term has initiated an ongoing debate in the scientific community. High-functioning autism refers to autistic people with strong language skills and high intelligence quotients (IQs) based on diagnostic tests (De Giambattista et al., 2019). However, this outcome does not necessarily indicate that autistic people in this group have sufficient adaptive skills for their age. Particularly, a study by Alvares et al. (2020) evaluated the cognitive level and functional abilities of 2.225 patients (1-18 years of age) diagnosed with autism and different levels of intellectual disability. The results demonstrated that the participants who were characterised as “high functioning” according to their cognitive levels (IQ), had lower adaptive abilities than anticipated. This confirms the hypothesis that even “high-functioning” autistic individuals encounter difficulties in their functioning skills in everyday life. They might struggle with executive functioning, social interaction, and self-care, although they perform remarkably in other areas.

Therefore, providing these individuals equal opportunities in healthcare, education, and additional support is crucial to improve their quality of life. Moreover, the incorporation of complex diagnostic tests including functional assessments is essential to better understand the needs of this distinct population.

Causes of ASD

Autism is a multifactorial condition caused by genetic, environmental, and immunological factors. Although scientific research has made remarkable discoveries, the “roots” of the condition have not been fully identified. Factors that affect the development of the disorder include inherited and spontaneous genetic mutations, prenatal neurologic insults, and premature birth (Mefford et al., 2012). Recent studies identified hundreds of genes linked to the pathogenesis of ASD, and family studies estimate the heritability of ASD to range from 50 to 90% (Stafford et al., 2022). In addition, genetic syndromes or chromosomal abnormalities are present in up to 40% of individuals with ASD. Other influences include toxic exposures, smoking, and advanced parent age (Mefford et al., 2012). Therefore, autism is potentially the outcome of genetic defects and/or brain inflammation.

In addition to those factors, there was a controversial theory that supported the contribution of childhood vaccines to the development of autism. This hypothesis referred to the toxicity of the preservative thimerosal (mercury) found in the measles, mumps, and rubella (MMR) vaccine that was administered to children up to the age of six (Ratajczak, 2011). Furthermore, the MMR II vaccine (without Thimerosal), and the pertussis toxin found in diphtheria, pertussis, and tetanus (DPT) vaccine were also suggested as potential contributors to the development of autism (Ratajczak, 2011). However, subsequent studies from the American Academy of Pediatrics did not identify any correlation between the development of ASD and the administration of these vaccines (Taylor et al., 2014). It is worth mentioning that the association between those vaccines and autism still persists in the public’s mind despite the scientific evidence that confirms otherwise.

Figure 2: Edward Jenner vaccinating a young child, held by its mother, with a man behind taking cowpox from a cow (Unknown, n.d.).

Diagnosis of ASD

In terms of ASD diagnosis, there are currently no biomarkers or diagnostic tests for the condition. The diagnosis is solely based on the fulfilment of descriptive criteria. The screening process includes ongoing developmental monitoring by trained healthcare providers including developmental paediatricians, child psychologists, and occupational specialists and, when necessary, referral for comprehensive neuropsychological assessments that fulfil the optimal specificity criteria for ASD (Human et al., 2020). In certain cases, the contribution of a genetic counsellor might be recommended, particularly in cases with a family history of ASD. Genetic testing includes whole genome and/or exome sequencing, chromosomal microarray, regular karyotyping, and fragile X testing in males (Faras et al., 2010).

Precision Medicine in ASD

Although there is a high prevalence of ASD, the heterogeneous phenotypic nature of the affected population and the limited understanding of ASD pathogenesis requires alternative medical interventions including the implementation of genomic medicine. Following the completion of the human genome project more than a decade ago the use of genomic information has significantly contributed to new treatment approaches for several diseases, including cystic fibrosis and Duchenne muscular dystrophy (Roth et al., 2019). As defined by Roth et al. (2019) genomic medicine is an interdisciplinary medical specialty that involves the use of a person's genomic information as part of their clinical care. This approach aims to provide insights related to the diagnosis of a disease and the anticipated outcomes and suggests potential alternatives for effective treatment. The most considerable achievements in genomic medicine are precision medicine, CRISPR, omics, genetic testing, and gene therapy.

In ASD, precision medicine aims to identify more homogenous subgroups of patients by understanding the underlying pathophysiology and combining the drug with a stratification biomarker to optimize treatment selection for the affected patient (Loth et al., 2016). To achieve this, ASD should be first clinically classified into syndromic and non-syndromic (or idiopathic). In syndromic ASD, the condition is associated with a known genetic syndrome usually caused by mutations in a single gene and chromosomal abnormalities (Fernandez et al., 2017). Therefore, ASD is presented in conjunction with other clinical features and conditions. On the other hand, in idiopathic ASD, the aetiology is unknown and there is no correlation with other genetic conditions. Hence, the applications of genomic medicine are crucial to detect the different forms of ASD. Whole genome sequencing (WGS) and exome sequencing (ES) can identify mutations in genes that regulate pathways involved in ASD. The non-profit autism awareness organisation Autism Speaks in collaboration with other organizations has initiated the world’s largest autism genome sequencing program MSSNG (pronounced “missing”) that is freely accessible to researchers in an online database (AutismSpeaks, 2022). The MSSNG database includes the whole genome sequencing of blood DNA derived from 11,500+ ASD individuals from the Autism Genetic Research Exchange repository. The aim of this initiative is to enable the identification and analysis of the entire genome of ASD individuals, which can significantly contribute to personalised and more effective treatments for the various subtypes of the condition (AutismSpeaks, 2022).

Figure 3: Leveraging existing genomic data to stratify the broad Autism Spectrum (Torres, 2021).

Apart from the non-profit organisations, there are biotechnology companies developing precision therapeutics for neurodevelopmental disorders including autism. The Swiss clinical-stage biotech Stalicla with the help of its AI-driven discovery platform analyses genetic data to identify the genes and molecular pathways involved in ASD (Pharmavoice, 2022). The main objective is to stratify ASD patients into subtypes and progress with the development of therapeutic drugs tailored to each group. Stalicla has developed combination drug treatments that target two different ASD phenotype subgroups. These ASD phenotypes account for approximately 20% of ASD cases, while additional drugs were developing for other phenotypes as well. Both therapies are being tested in phase I and II clinical trials and target

specific areas of the brain related to social interaction and executive function (Pharmavoice, 2022).

Conclusion

ASD is a high-prevalence neurodevelopmental disorder that is caused by genetic and environmental factors and is characterised by repetitive behaviours and deficits in social communication. Individuals with ASD demonstrate high variability and diversity and require different diagnostic strategies. Therefore, genomic medicine and especially the applications of precision medicine can provide a better understanding of the pathophysiological mechanisms of the condition. In addition, subsequent pharmacological interventions can achieve disease-modifying effects and implement personalised approaches to treatments. The ultimate goal is the improvement in the quality of life of the ASD population, the effective management of the condition, and the prevention of other comorbidities. Although there are still several aspects to explore in ASD, there are significant scientific advancements in the early detection and management of the condition. In addition, there are constant efforts to increase public health awareness in order to achieve equal access to resources and to promote the inclusion of autistic individuals in society.

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