Background on Autism Spectrum Disorders (ASD)

Definition and prevalence of ASD

Autism Spectrum Disorder (ASD) is a neurological and developmental condition that affects communication, learning behaviour, and social interactions. It is classified as a “developmental disorder” since the symptoms typically manifest within the first two years of life even though diagnosis for this condition can be made at any age.¹ Globally, autism is estimated to affect approximately 1 in 100 individuals.² 

Overview of known genetic, environmental, and biological factors influencing ASD

Genetic factors 

• Heritability: Several studies suggest that autism has a high heritability rate, estimated to be between 50 to 90%. This implies that genetic factors are responsible for a substantial portion of the risk of developing autism. Autism is frequently observed in families. In comparison to the general population, siblings of individuals with autism are at a heightened risk of being diagnosed with ASD 
• Genetic Mutations: De novo Mutations are new genetic mutations that occur in a family member for the first time as a consequence of a mutation in the fertilised egg or sperm. De novo mutations have been identified in numerous genes that are linked to autism. Autism has been associated with specific inherited genetic variations, particularly rare mutations. These include both single nucleotide polymorphisms (SNPs) and copy number variations (CNVs)

Environmental factors

• Prenatal Factors: Infections during pregnancy, particularly viral infections like rubella, and influenza have been linked to an elevated risk of autism in the offspring. Valproate, an anti-epileptic drug has been associated with an elevated risk of autism when administered during pregnancy. Autism is more likely to occur in the infant of a mother who has conditions such as diabetes, obesity, and hypertension during pregnancy
• Perinatal Factors: Complications during birth, including preterm birth, low birth weight, and lack of oxygen have been associated with an increased risk of autism
• Postnatal Factors: Severe infections and abnormal immune response in early childhood are considered to be the potential risk factors for autism. The risk of autism may be increased during the critical developmental period by exposure to contaminants including heavy metals and air pollution³

Biological factors 

• Problems with the connections in/to the brain
• Problems with the development or proliferation of specific organs in the brain
• Problems with metabolism, the body’s mechanism for energy production
• Problems with the body’s immune system which protects against infections⁴

Introduction to Adenoviruses

Basic characteristics and common infections caused by adenoviruses

Adenoviruses are non-enveloped icosahedral viruses with double-stranded DNA that are medium-sized (90-100 nm). Infections in humans can be caused by over 50 varieties of immunologically distinct adenoviruses. Adenoviruses are relatively resistant to common disinfectants and can be detected on surfaces such as doorknobs, objects, and the water of swimming pools and small lakes. Respiratory distress is the most frequently caused by the adenoviruses. The range of diseases includes pneumonia, bronchitis, and the common cold. Adenoviruses can trigger a variety of conditions, including gastroenteritis, conjunctivitis, and less frequently neurological diseases. In some individuals, particularly those with compromised immune systems, adenovirus may persist in their tonsils, adenoids, and intestines without causing symptoms. They can transmit the virus for weeks or more.⁵ 

Brief history of adenovirus research about neurological impacts

Adenovirus was associated with central nervous system disease in children. Febrile seizures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis are the neurological complications associated with the adenovirus infection.⁶ 

Clarifying the need to explore the potential connection between adenovirus infections and ASD development

It is important to understand the potential impact of adenovirus infections on brain development or function in a way that could potentially contribute to ASD. This involves studying the possibility of adenoviruses disrupting normal neurodevelopmental processes by interacting with the immune system and central nervous system. It is necessary to examine whether there is a greater prevalence of adenovirus infections in populations diagnosed with ASD. This entails the examination of epidemiological data on a large scale to detect any statistically significant correlations. Several experiments are conducted on animal models to observe the effects of adenovirus infections on brain development and behaviour. It is also necessary to understand whether certain genetic profiles might make individuals more susceptible to both adenovirus infection and ASD. 

 Overview of Adenoviruses

 Structure and function

 The adenovirus particle is composed of a protein nucleus that contains a linear, double-stranded DNA genome and an icosahedral protein exterior. The shell is composed of 252 structural capsomeres and has a diameter ranging from 70 to 100 nm. The 12 vertices of the icosahedron are occupied by units known as pentons, each of which has slender projections known as a fibre. The 240 capsomeres that constitute the 20 faces and the margins of the icosahedron are referred to as hexons due to their hexagonal arrays. Some minor polypeptide elements are also present in the carapace. Two main proteins (polypeptide V and polypeptide VII) and a secondary arginine-rich protein (μ) comprise the central particle. The 5′ extremities of the DNA are covalently attached to a 55 kDa protein.⁷ The adenovirus capsid is responsible for finding the cell and delivering the viral genome inside.⁸ Adenoviruses are commonly used as vectors in gene therapy and also used in vaccine development. Adenoviruses are found to elicit strong immune responses.

Common infections 

• Acute Respiratory Disease
• Pneumonia
• Acute follicular conjunctivitis
• Epidemic keratoconjunctivitis
• Cystitis
• Gastroenteritis

Pathogenesis

Infection is typically transmitted through respiratory or ocular secretions in the form of droplets. 

How adenoviruses infect cells and cause disease. Persistent infections are developed in the tonsils. Certain adenovirus types are oncogenic in newborn rodents and can transform the cells. 

Mechanisms of immune response to adenovirus infections.⁷ 

Neurological implications

• Meningitis
• Encephalitis
• Acute Flaccid Paralysis
• Myelitis
• Cerebillitis 

Understanding autism spectrum disorders

Clinical features

• Avoids keeping eye contact
• Does not respond to the name of the individual by the age of nine months
• By nine months of age, does not exhibit facial expressions such as happiness, sorrow, anger, and surprise
• By the age of 12 months, the individual employs minimal or no gestures, such as not waving farewell
• Shows you an object that they like, but does not share interests with others by the age of 15 months
• Does not point to demonstrating something intriguing by the age of 18 months
• By the age of 24 months (2 years), the individual is unable to detect when others are distressed or injured
• By 36 months (3 years) of age, does not observe other children and participates in their activities
• Do not assume the role of another individual, such as a protagonist or teacher, during play by the age of 48 months (4 years)
• Must not be able to sing, dance, or act for you by the age of 60 months (5 years)⁹ 

Aetiology of ASD

• Genetics: Autism spectrum disorder is associated with a variety of genes. Autism spectrum disorder may be linked to a genetic disorder, such as Fragile X syndrome or Rett syndrome in certain individuals. Some genes may influence brain development, the communication between the brain cells, or the severity of the symptoms
• Environmental Factors: Currently, researchers are investigating the potential role of air pollution, medications or complications during pregnancy, or viral infection in the development of autism spectrum disorder¹⁰

Possible mechanisms linking adenoviruses to ASD

Maternal Immune Activation (MIA) mechanism: 

The production of pro-inflammatory cytokines can occur as a result of an infection in the mother during pregnancy. The developing foetal brain can be influenced by these cytokines, which can cross the placenta.

Impact: In animal models, this immune activation has been demonstrated to induce behavioural and cerebral developmental alterations that are indicative of ASD. Cytokines, including IL-6 and IL-17a, have been particularly implicated.

Direct viral effects on foetal brain development mechanism

Adenoviruses have the potential to directly infect the foetal brain by crossing the placental barrier, resulting in neuronal injury or disruption of normal brain development..

Impact: Neurodevelopmental abnormalities that manifest as ASD may result from direct infection of the developing brain by adenovirus.

Postnatal immune system dysregulation mechanism

 Chronic immune system dysregulation may result from adenovirus infection following birth. The development and function of the brain can be influenced by persistent immune activation.

Impact: The development of ASD in susceptible individuals may be influenced by chronic inflammation or an abnormal immune response to viral infections in early childhood.

Genetic susceptibility mechanism

 Certain individuals may be more susceptible to the effects of viral infections due to genetic factors. For instance, the risk of ASD may be elevated when adenovirus infection is combined with specific gene variants that are implicated in immune regulation or neural development.

Impact: Adenovirus infection may induce or worsen symptoms of ASD in children with a genetic predisposition to the condition. Children may exhibit an exaggerated or maladaptive response.

Disruption of the gut-brain axis mechanism

The gut microbiota can be altered by viral infections, such as adenovirus. The gut-brain axis is a bidirectional communication pathway that connects the intestines and the brain. Variations in the gut microbiota can have an impact on brain function and development.

Impact: The disruption of the gastrointestinal microbiota by adenovirus infection has the potential to impact brain development and function, potentially contributing to ASD.

FAQ’s

Can autism be triggered by a virus?

Several viruses have been identified to trigger autism including Rubella, Herpes Simplex virus, and Varicella Zoster Virus. 

What is the most common cause of autism spectrum disorder?

The exact cause of autism spectrum disorder is unknown but several studies have indicated that genetics and environmental factors might trigger ASD.

Summary 

Autism is classified as a neurological and developmental disorder that typically arises in the first two years after birth, despite being carrying the capability to be diagnosed later on in life. Its known characteristic is that it affects communication, learning and social behaviour. Adenoviruses are non-enveloped icosahedral viruses with double-stranded DNA that are medium-sized (90-100 nm). It is important to understand the potential impact of adenovirus infections on brain development or function in a way that could potentially contribute to ASD.