Impact of Neurodevelopment on Autism Spectrum Disorders

Autism, or autism spectrum disorders, also known as ASD (acronym in English Autism Spectrum Disorders) are neurodevelopmental disorders (ND) characterized by deficits or sustained difficulties in social exchange and communication, restricted interests, stereotyped behavior and resistance to change. But we can also observe the presence of Language Disorders, sensory dysfunctions, attention deficit disorder (ADD), bipolarity, intellectual disability and/or epilepsy.

The definition of ASD has been modified and adjusted over the last decades, based on the results of various investigations. These are complex and highly heterogeneous disorders, from their multidimensional etiology to their manifestation and evolution of symptoms in each of the different stages of development, in their expression and presentation according to sex, age or coexisting comorbidities.

Currently, ASDs are included in a new category called “neurodevelopmental disorders” (NDD). This category also includes, in addition to ASDs, intellectual development disorders, communication disorders, learning disorders, motor disorders and attention deficit hyperactivity disorder (ADHD). 

Children with ASD present a chronic evolution of their clinical symptoms, which begin in childhood and are present throughout life, going through different degrees of affectation, functional adaptation and development of the language and intellectual areas.

Studies on ASD have shown that there is a tendency for symptoms to improve and functional adaptation to improve with age, even when it is a chronic disorder. It has also been shown that a delay in the onset of language does not imply a significant difference in developmental functional adaptation in adulthood.

Over the last few decades, the study of the diagnostic criteria, risk factors, possible treatments and social implications of ASD has raised the concern of neuroscientists and clinicians. Early diagnosis is a huge challenge for specialists due to the complexity involved in ASD, the severity of its levels in the communication sphere, restricted and repetitive behaviors; and the overlapping of many symptoms in relation to other conditions of the autism spectrum.

Diagnosis is based on a thorough examination of the patient's clinical history, physical and neurological examinations, psychiatric examinations and a multitude of auxiliary tests related to the neurological, genetic, immunological, metabolic and gastrointestinal spheres.

The epidemiological and molecular data collected in the different investigations to date suggest that autism is the result of a complex interaction of genetic, immunological and environmental factors. Over the years, it has become a health problem of great impact due to its increase in prevalence worldwide in recent decades. In Spain, the rate of increase in the last decade was 310,36%, with children with ASD being the largest category among students with disabilities.

We must take into account the multifactorial origin, one of these origins being genetic, and the way it correlates with the whole for the patient. The molecules of the immune system and the glia are essential for normal development; translating into possible immunological problems with a genetic etiology in the background in patients with ASD. These patients have a high probability that, in viral co-infections, due to the existence of an immune system with a deregulated adaptive immune response, the immune response will not be optimal to confront said infection. 

Even the inheritance of these genetic variants is silenced and, due to these infections, environmental factors, oxidative stress, among others, this deregulated immune response or autoimmune diseases is triggered, thus presenting a clinical picture similar to that of Neurodevelopmental Disorders, so as it is a network of related symptoms we must be very thorough when evaluating patients. Follow the initial care protocol to rule out all possibilities that may generate these neurological symptoms related to ASD.

Several studies have identified variants in genes related to the immune system, such as those encoding cytokines and also those genes related to membrane receptors, and some studies suggest that they may be involved in the development of ASD.

In addition, some research suggests that alterations in genes of the complement system, which is a crucial part of the innate immune response, may be associated with ASD. Likewise, variations in HLA genes, which play an essential role in antigen presentation and the adaptive immune response, have also been associated with increased susceptibility to ASD.

Complement system

The complement system is a part of the immune system that plays a crucial role in defending against infections and in removing damaged or dead cells. Genetic variants affecting the complement system have been studied in relation to various neuropsychiatric disorders, including autism.

These alterations in complement not only involve a deregulated immune response, which makes the individual vulnerable, but also play a role in the regulation of inflammation and in the homeostasis of the nervous system. Alterations in complement activity could have repercussions on brain development and neuronal function. An imbalance between the delicate pro-inflammatory and anti-inflammatory line may actually damage different brain structures due to constant inflammation.

Some research has identified associations between genetic variants related to the complement system and the risk of developing ASD. For example, associations have been observed with the C4 gene, which is a part of the complement system. Variants in this gene may be involved in synapse elimination processes, where ineffective or harmful synapses are removed, a process that is vital for proper neuronal development.

It has been proposed that an increase in complement activation during brain development may contribute to inflammation and neuronal dysfunction. This could be related to the behavioral characteristics observed in people with autism. Variants that modulate the inflammatory response may influence the way children's brains develop and adapt. The balance of our body is so closely related that even alterations in the complement system can affect the intestinal microbiome.

The complex combination of rare deleterious variants with low-risk alleles has allowed the identification of approximately 600 to 1200 genes associated with ASD. Some have been detected in 5% of cases, and are caused by single point variations (SNPs) in genes such as NLGN3, NLGN4, NRXN1, MECP2, SHANK3, FMR1, TSC1/2 and UBE3A, while 10% of cases may be due to copy number variations (CNVs), including chromosomal duplications, macro and microdeletions, inversions or translocations of different chromosomal regions.

There are other variations in non-coding or intronic and intergenic regions that are considered a third type of variation associated with autism.

Transcription and Translation in Genetics

Transcription is the process by which information contained in DNA is copied into a messenger RNA (mRNA) molecule. This process is essential for gene expression and is regulated by a variety of factors, including:

• Transcription Factors: Proteins that bind to specific regions of DNA and regulate the rate of transcription of specific genes.
• Epigenetic Modifications: Changes in the structure of DNA or histones that affect the accessibility of DNA for transcription.
• Regulatory Elements: Promoters, enhancers and silencers that modulate gene activity.

Translation is the process of protein synthesis from mRNA on ribosomes. During this process:

• mRNA is read in triplets of nucleotides (codes) that correspond to specific amino acids.
• Ribosomes and transfer RNA (tRNA) play key roles in translation by incorporating amino acids into the specific protein sequence.

Research has identified several mutations and genetic variants associated with autism that can alter transcription and translation processes. Some of these include:

• Mutations in Transcription Factor Genes: Mutations in genes encoding transcription factors can lead to a change in the expression of genes critical for neuronal development.
• Alterations in Translation Initiation Genes: Mutations affecting the translation machinery can lead to abnormal production of proteins involved in synaptic function.

Epigenetic modifications, such as DNA methylation and histone modifications, can influence the transcription of genes relevant to autism. Studies have shown that:

• DNA methylation: Altered methylation patterns are often found in individuals with autism, which may lead to overexpression or underexpression of genes critical for neuroplasticity and synaptic formation.
• Histone Modification: Changes in histone marks can affect chromatin structure, altering DNA accessibility and therefore transcription.

Transcription and translation processes are crucial for neuronal development. Deregulations in these processes can lead to:

• Difficulties in Synaptogenesis: The production of proteins necessary for the formation and maintenance of synapses is affected, which can result in abnormal connectivity in the brain.
• Alterations in Neuronal Plasticity: Neuronal plasticity, the brain's ability to adapt and reorganize, can be compromised, contributing to autistic symptoms such as behavioral rigidity and difficulty adjusting to new situations.

Numerous studies have explored how transcription and translation dysregulation may contribute to autism, using diverse approaches: These studies have identified genetic variants that are associated with autism. Many of these variants affect genes involved in cell signaling processes, neuronal development, and synaptogenesis.

Gene expression analysis in autistic brains has revealed altered expression profiles. Changes in mRNA and protein levels of genes of interest, such as those related to synaptic development (e.g., SHANK3 and neurexins), suggest a fundamental role in the phenomena observed in autism.

Research on methylation and histone modifications in individuals with autism has identified altered patterns. For example, certain regions of DNA that regulate genes important in neuronal development have been found to be hypermethylated, which could reduce the expression of such genes.

Alterations in transcription and translation processes may lead to behavioral and cognitive phenotypes associated with autism. Some of the connections include:

• Repetitive and Restrictive Behaviors: Inadequate production of proteins necessary for synaptic function can lead to repetitive behavior, characteristic of autism.
• Communication difficulties: Dysfunction in genes involved in synaptic plasticity can affect the development of language and communication skills.
• Alterations in Social Interaction: Dysregulation in the expression of proteins that modulate neuronal interactions may contribute to difficulties in identifying and responding to social cues.

Understanding how transcription and translation dysregulation contributes to autism may open new opportunities for intervention:

• Therapies Based on the Modulation of Gene Expression: Strategies that restore normal expression of key genes may have therapeutic potential in the treatment of autism.
• Nutritional Interventions: Dietary modulation and supplementation can influence the gut microbiome and, in turn, gene expression at the neurological level.
• Pharmacological Treatments: Drugs that act on signaling pathways that regulate gene expression may be useful in improving symptoms associated with autism.

Dysregulation of gene transcription and translation has a significant impact on the etiology of autism. Genetic alterations, epigenetic changes, and modulation of gene expression also contribute to neuronal dysfunction and phenotypes associated with autism. Research also aims to not only mitigate symptoms but also address underlying causes.

Alterations in synaptic function

1. Synaptic Connectivity: In the brains of people with autism, it has been observed that synaptic connectivity can be altered. This can manifest as hyperconnectivity in certain regions of the brain and hypoconnectivity in others, which affects communication between neurons.
2. Synaptic Proteins: Many genes associated with autism encode proteins that are crucial for the formation and maintenance of synapses. For example, neuroligins and neurexins are synaptic adhesion proteins that are involved in synapse formation. Mutations or variations in these genes can lead to defective synaptic signaling.
3. Neuronal Excitability: Some research suggests that there is an imbalance in neuronal excitation and inhibition in people with autism. This may be related to alterations in neurotransmitter receptors, such as GABA and glutamate, which play crucial roles in regulating neuronal activity.
4. Inflammation and Oxidative Stress: Brain inflammation and oxidative stress have also been linked to autism. These factors may affect synaptic function and contribute to an environment that favors the development of autism traits.

Genetic and Epigenetic Factors

The interaction between genetic and epigenetic factors plays a crucial role in the development of autism spectrum disorder (ASD).

• Genetic Susceptibility: A number of genes associated with autism have been identified. Variability in these genes may increase susceptibility to developing ASD. Some of the genes implicated include:
  • SHANK3: Associated with synaptic functions and neuronal plasticity.
  • NLGN3 and NLGN4: Genes encoding synaptic adhesion proteins.
  • MECP2: Involved in the regulation of gene expression and related to disorders such as Rett syndrome.
• Inheritance: Studies have shown that autism tends to run in families, suggesting a hereditary component. Concordance in twins is high, highlighting the genetic influence in this disorder.
• Alterations in Gene Expression: Some genetic defects can result in abnormal expression of genes key to brain development, affecting the formation of neural circuits and, therefore, synaptic function.

Epigenetic factors refer to changes in gene expression that do not involve alterations in the DNA sequence. These changes can be influenced by environmental factors. Some relevant aspects are:

1. Epigenetic Modifications:
   • DNA methylation: The addition of methyl groups to cytosines in DNA can affect gene expression. Alterations in methylation patterns have been observed in individuals with autism, which may impact the functioning of genes involved in brain development.
   • Histone Modifications: These modifications can alter the way DNA is packaged in the cell nucleus, thus affecting the accessibility of specific regions of DNA and their expression.
2. Environmental Factors: Environmental factors, such as exposure to toxins, prenatal infections, and maternal stress during pregnancy, can induce epigenetic changes that, in turn, may influence the genetic predisposition to autism.
3. YoGene-Environment Interaction: The diatysis-stress model theory suggests that genetically predisposed individuals may be at risk of developing autism if they are exposed to certain environmental factors that induce epigenetic changes. This highlights the complex interaction between genetics and environment in the development of ASD. 

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Article written by Enevia Health Advisor and Collaborator: Dr. Julianny Albarran 

Medical surgeon, general medicine with more than 5 years of experience in the field.

https://eneviacare.com/tienda/consulta-medica-dra-julianny-albarran-enevia-care/

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