Module 4: Autism Spectrum Disorder

ASD Defined

• A group of neurodevelopmental disorders that affect individual’s social interaction, communication skills, and behavioral patterns, with significant individual differences and complex etiology

• Its characteristics vary significantly between individuals, from mild social impairments to severe communication and behavioral problems, a diversity that reflects the use of the term “spectrum”

Characteristics of ASD

• Difficulties in social interaction

• Communication disorders

• Repetitive behaviors and interests

• Sensory sensitivity

Epidemiologic Profile of ASD

• According to the World Health Organization (WHO), the average prevalence of ASD among children globally is approximately 1%

Historical Background: Early History of Research and Diagnosis of ASD

• The concept of ASD was first clearly defined in the 1940s, when a group of children exhibiting extreme self-isolation and lack of responsiveness to the environment was first described by American psychiatrist Leo Kanner

Evolution of Research Paradigms

• In the early stages, ASD research focused on behavioral observations and psychoanalysis, when ASD was often mistaken for an emotional disorder due to an indifferent mother

  • During this period, understanding of ASD was relatively limited and treatments focused primarily on psychotherapy and behavior modification 

• Into the second half of the 20th century, with advances in genetics and neuroscience, researchers began to explore the biological basis of ASD

Etiologic Studies

• ASD has multifactorial etiology, involving complex interactions between genetic and environmental factors 

  • While most ASD cases involve polygenic interactions, a small subset is linked to single-gene variations, known as monogenic genetic cases

• These monogenic cases offer valuable insight into genetic mechanisms underlying ASD, despite representing only a small proportion of overall cases

• Several genetic syndromes caused by single-gene mutations are strongly associated with increased ASD risk

• These classical candidate genes and their ASD associations are commonly summarized in research tables (e.g., Table 1)

• Discovering monogenic ASD cases supports the development of targeted interventions and genetic-specific therapies

• Even monogenic cases show phenotypic heterogeneity, suggesting influence from other genetic modifiers and environmental factors

• Studying these conditions helps deepen understanding of ASD’s genetic basis and aids in developing personalized therapeutic strategies

Multigene Interactions

• ASD develops through interactions of genetic and environmental factors, with polygenic (multigene) interactions playing a central role 

• Unlike monogenic cases, polygenic interactions involve multiple gene variants or polymorphisms that individually have small effects but collectively increase ASD risk.

• No single gene accounts for all ASD cases; instead, hundreds of genetic loci contribute to susceptibility.

• Many ASD-associated genes are involved in brain development, neuronal signaling, and intercellular communication, indicating complex regulation of brain structure and function.

• Large-scale genomic data and advanced statistical methods are required to detect risk-associated variants due to the complexity of multigene interactions.

• Meta-analyses of GWAS consistently identify ASD risk loci in chromosomal regions such as 3p21, 5p14, 7q35, and 20p12.

• These regions contain important neurodevelopmental genes (e.g., CNTN4, CNTNAP2, NRXN1) linked to synaptic adhesion and neurotransmission.

• Integrating genetic findings with functional studies improves understanding of ASD’s genetic architecture and supports development of personalized diagnostic and therapeutic approaches.

• Understanding multigene interactions in ASD also contributes to potential preventive strategies aimed at reducing ASD incidence.

Single-Gene Mutations | Fragile X Syndrome

• Most common inherited intellectual disability 

• Strongest known single-gene association with ASD

• Caused by a repeat expansion in the FMR1 gene

Single-Gene Mutations | Tuberous Sclerosis Complex (TSC)

• Caused by mutations in TSC1 or TSC2 genes

• ASD prevalence is significantly higher in individuals with TSC

Single-Gene Mutations | 15q11-q13 Duplication Syndrome (Dup15q Syndrome)

• Involves duplication of a region on chromosome 15

• Associated with an elevated risk of ASD

Single-Gene Mutations | Rett Syndrome

• Primarily affects females

• Caused by mutations in the MECP2 gene

• Common ASD-like features include impaired social interaction 

Environmental Factors | Maternal Exposure

• Refers to environmental factors or substances encountered during pregnancy that may increase a child’s risk of ASD.

• Risk-increasing exposures include certain prescription medications (e.g., anti-seizure drugs, opioids), environmental pollutants (e.g., heavy metals, air pollution), infections (e.g., rubella, influenza), and nutritional deficiencies (e.g., folic acid).

• These exposures may disrupt fetal brain development and hinder normal nervous system maturation.

• Understanding prenatal exposure risks can guide preventive measures to reduce ASD incidence.

Environmental Factors | Effects of Early Developmental Stages

• Early ASD development is influenced by genetic factors, environmental exposures, and early life experiences.

• Rapid brain growth and neural network formation occur during early childhood, making this a critical developmental window.

• Disruptions during this period can interfere with the proper development of brain structure and function, contributing to ASD risk.

• Early warning signs may include limited social interaction, delayed language development, or abnormal sensory processing.

• These developmental irregularities reflect difficulties in information processing, neural connectivity, and adaptation to the environment.

• Early identification and intervention are essential to promote optimal development in children with ASD.

Social Communication | Level 3 “Requiring very substantial support”

Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others. 

For example, a person with few words or intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches

Restricted, Repetitive Behaviors | Level 3 “Requiring very substantial support”

Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. 

Great distress/difficulty changing focus or action.

Social Communication | Level 2 “Requiring substantial support”

• Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others. 

• For example, a person who speaks simple sentences, whose interaction is limited to narrow special interests, and who has markedly odd nonverbal communication.

Restricted, Repetitive Behaviors | Level 2 “Requiring substantial support”

• Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts. 

• Distress and/or difficulty changing focus or action.

Social Communication | Level 1 “Requiring support”

• Without supports in place, deficits in social communication cause noticeable impairments. 

• Difficulty initiating social interactions, and clear examples of atypical or unsuccessful responses to social overtures of others.

• May appear to have decreased interest in social interactions. 

• For example, a person who is able to speak in full sentences and engages in communication but whose to-and-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful.

Restricted, Repetitive Behaviors | Level 1 “Requiring support”

• Inflexibility of behavior causes significant interference with functioning in one or more contexts. 

• Difficulty switching between activities. 

• Problems of organization and planning hamper independence.