Autism: Exploring Its Complexity and Underlying Causes

March 15, 2025, By Dr. Daoud, MD

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairment in language development, social interactions, and restricted or repetitive behaviors. Individuals with ASD often present with comorbid psychiatric and medical conditions, including depression, anxiety, obsessive-compulsive disorder, aggression, self-injury, an increased risk of suicide, inattention, hyperactivity, impulsivity, sleep disorders, seizures, selective eating, gastrointestinal issues, and immune dysfunction1. When comorbidities are present, core autism symptoms are often more pronounced.

The severity of ASD varies widely, ranging from individuals who are non-speaking and highly dependent on others to those who may experience minimal symptoms and are considered “high-functioning.” This broad range of presentations is why ASD is referred to as “spectrum”. According to the CDC, approximately 1 in 36 children were diagnosed with ASD in 2020, a significant increase from 1 in 150 in 20002. This growing prevalence has created challenges for families, who often face barriers in accessing high-quality, affordable services and appropriate educational support. For example, children with complex ASD, such as those who are non-speaking or at risk of wandering, typically require one-on-one classroom assistance. However, resource limitations often result in children sharing support staff with one or more other special needs students. This contributes to not only burnout among educators, but also reduced care quality and missed learning opportunities.

The Genetic and Epigenetic Landscape of Autism

Understanding the genetic basis of autism spectrum disorder begins with the distinction between syndromic and non-syndromic forms. Syndromic ASD refers to cases in which autistic traits are one aspect of a broader neurological syndrome, such as Phelan-McDermid Syndrome, a rare genetic disorder, or Fragile X Syndrome. In these cases, autism may be accompanied by varying degrees of developmental delays, intellectual disabilities, low muscle tone, seizures, and/or distinctive facial features3. Syndromic ASD is often linked to inherited defects in single genes and chromosomes. For example, Phelan-McDermid Syndrome is caused by mutations in the SHANK3 gene. However, syndromic ASD accounts for only a small fraction of all ASD cases1,4.

Some studies have linked ASD to mutations that affect neurons and brain function. However, most of these mutations are rare de novo mutations, meaning they are genetic changes not inherited from either parent. This suggests that such mutations are acquired rather than inherited and likely resulted from errors in DNA maintenance and/or DNA damage caused by external or internal stressors4,5. Additionally, the current consensus is that autism does not follow mendelian inheritance patterns, meaning it typically does not arise from a single gene but typically results from interplay of multiple genetic variants (polygenic inheritance)6,7.

In addition to genetic factors, growing evidence points to the role of environmental and epigenetic influences in ASD. Epigenetics refers to how environmental factors can influence gene expression without altering the DNA sequence itself. Studies suggest that epigenetic dysregulation significantly contribute to ASD and that both genetic mutations and environmental factors disrupt epigenetic modifications, such as DNA methylation, histone methylation, and acetylation1, 7&8. These epigenetic disruptions affect critical biological pathways implicated in ASD, including:

  • Mitochondrial dysfunction: Impaired cellular energy production
  • Oxidative stress: Imbalance between free radicals and antioxidants leading to cellular damage
  • Immune dysfunction: Dysregulated immune system
  • Neuronal inflammation and microglial activation: Chronic brain inflammation affecting neural health
  • Synaptic connectivity and plasticity: Abnormal communication and adaptability between neurons.
  • Metabolic abnormalities: Imbalances in essential nutrients like folate and cobalamin
  • Neurotransmitter imbalances: Disruptions in brain chemicals that regulate mood, behaviour, and cognition1, 4, 7, 8, and 9

In conclusion, autism spectrum disorder is a multifaceted condition influenced by genetic, epigenetic, and environmental factors, alongside disruptions in key biological pathways. As research continues to shed light on its complexities, addressing the unique needs of individuals with ASD requires personalized, integrative approaches and comprehensive support systems.

References:

  1. Grabrucker, AM. “Autism Spectrum Disorders: Etiology and Pathology.” In Autism Spectrum Disorders, edited by AM Grabrucker. Brisbane: Exon Publications, 2021.
  2. Centers for Disease Control and Prevention (CDC). “Autism Data and Statistics.” CDC, 2024.
  3. Labkowsky, Alexander. “Understanding Pathophysiology of Nonsyndromic Autism by Examining and Extrapolating from Syndromic Variants.” The Science Journal of the Lander College of Arts and Sciences 15, no. 1 (2021): 39–43.
  4. Frye, Richard E., and Daniel A. Rossignol. “Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes.” Clinical Medicine Insights: Pediatrics 10 (2016): 43–56.
  5. Sanders, Stephan J., Michael T. Murtha, Abha R. Gupta, Jennifer D. Murdoch, Matthew J. Raubeson, Alexander J. Willsey, Ayça G. Ercan-Sencicek, et al. “De Novo Mutations Revealed by Whole-Exome Sequencing Are Strongly Associated with Autism.” Nature 485, no. 7397 (2012): 237–241.
  6. Geschwind, Daniel H. “Autism: Many Genes, Common Pathways.” Neuron 48, no. 3 (2005): 465–477.
  7.  Loke, Yuk Jing, Anthony John Hannan, and Jeffrey Mark Craig. “The Role of Epigenetic Change in Autism Spectrum Disorders.” Frontiers in Neurology 6 (2015): Article 107.
  8. Chaste, Pauline, and Marion Leboyer. “Autism Risk Factors: Genes, Environment, and Gene-Environment Interactions.” Dialogues in Clinical Neuroscience 14, no. 3 (2012): 281–292.
  9. Way, Heather, Grant Williams, Sharon Hausman-Cohen, and Jordan Reeder. “Genomics as a Clinical Decision Support Tool: Successful Proof of Concept for Improved ASD Outcomes.” Journal of Personalized Medicine 11, no. 7 (2021): 596.