Understanding how and why regression occurs in young children with either polygenic or single gene autism

 

Just ask Peter

I see that in the US, RFK Jr has told the President that he will figure out the cause of the autism epidemic by September 2025. Well, some people are saying that will be impossible. The facts are actually already there in the research, if you care to look for them. It might have been better to give the task to Elon Musk and give him 6 days, rather than RFK 6 months.

Today, I thought it would be interesting to address the issue of how apparently typically developing young toddlers can regress into autism. This post was written at Musk++ speed.

 

What is autism?

Autism is a complex neurodevelopmental condition that can manifest in diverse ways. One particularly perplexing phenomenon is regression—the loss of previously acquired skills such as speech, social interaction, or motor abilities. Regression typically occurs between 18 months and 5 years of age and can be observed in both polygenic (several genes affected) and monogenic (single gene) forms of autism. Understanding why and how this occurs requires examining the interplay between genetic, metabolic, and environmental factors during critical periods of early brain development.

 

Key Processes in Early Brain Development

Synaptic Pruning and Plasticity

During early childhood, the brain refines its neural connections through a process known as synaptic pruning, where unused or weaker synapses are eliminated, and stronger ones are reinforced. This process is essential for optimizing neural circuits but is highly vulnerable to dysregulation. In conditions like Rett syndrome, caused by mutations in the MECP2 gene, or in polygenic autism, excessive or insufficient pruning can disrupt circuits necessary for maintaining skills. 

Myelination

Myelination—the coating of axons with myelin to improve signal transmission—occurs rapidly during this period. Disruptions in myelination due to metabolic dysfunctions or mitochondrial impairments can impair communication between brain regions, potentially contributing to skill regression. 

Critical Periods of Neuroplasticity

Early childhood represents a window of heightened neuroplasticity, where the brain’s capacity to adapt and rewire is greatest. This sensitivity allows for rapid learning but also renders the brain more susceptible to adverse influences, such as inflammation, energy deficits, or genetic mutations. Dysregulation of plasticity mechanisms can lead to maladaptive changes, erasing previously acquired skills. 

Mitochondrial Dysfunction: A Key Factor

Mitochondrial dysfunction has been increasingly implicated in autism regression. The brain’s energy demands are extraordinarily high during early childhood, consuming up to 50% of the body’s total energy to support growth and neural connectivity. Mitochondrial deficits, whether due to genetic mutations or environmental stressors, can cause energy crises that disrupt critical developmental processes. Dr. Richard Kelley from Johns Hopkins has highlighted mitochondrial dysfunction as a near-universal factor in cases of regression.

Kelley proposed the diagnosis AMD, autism secondary to mitochondrial disease.

Evaluation and Treatment of Patients with Autism and Mitochondrial Disease 

Unfortunately, there are many factors other than mitochondrial dysfunction that cause regression into autism. This point has been highlighted by many readers of this blog, based on their own experiences.

 

Age-Specific Vulnerability

 

Why Regression Occurs Between 18 Months and 5 Years

This period is marked by rapid acquisition of key developmental milestones, including speech, language, and social skills. These abilities rely on the integrity of neural circuits that are still maturing. Regression is more apparent when these nascent circuits are disrupted, as the skills they support are not yet deeply embedded.

• Before 18 Months: Skills like speech or social interaction are not fully developed, making regression less visible.
• After 5 Years: Neural circuits and skills stabilize, and the brain becomes less susceptible to environmental and metabolic disruptions.

 

The Role of Synaptic and Circuit Stability

Regression is less likely in older children or adults because the brain has completed most of its synaptic pruning and has established more stable circuits. By this time, skills are less reliant on vulnerable developmental processes.

 

Environmental and Epigenetic Triggers

During early childhood, environmental factors such as infections, stress, or dietary deficiencies can significantly influence gene expression and neurodevelopment. In genetically predisposed children, these triggers can lead to neuroinflammation or exacerbate mitochondrial dysfunction, further increasing the risk of regression.

 

Polygenic vs. Monogenic Autism Regression

• Monogenic Autism: In single-gene disorders like Rett syndrome or Fragile X syndrome, genetic mutations directly impair brain development and function. Regression in these cases is often linked to disruptions in genes crucial for synaptic maintenance and neuroplasticity.

• Polygenic Autism: Regression in polygenic autism likely results from a combination of genetic predispositions interacting with environmental and metabolic stressors. The cumulative effect of multiple risk genes can dysregulate processes like synaptic pruning, energy metabolism, or immune responses.

 

Regression up the age of 10 is rare, but possible

Childhood Disintegrative Disorder (CDD), also known as Heller's syndrome, is a rare condition characterized by significant regression in developmental skills after at least two years of apparently typical development. It is classified as a part of the autism spectrum disorders,  but is distinct due to its dramatic loss of previously acquired skills, typically between the ages of 3 and 10 years.

CDD is often considered a more severe form of regressive autism because of the profound and widespread nature of the regression:

• Loss of language, social skills, motor skills, and adaptive behaviors (e.g., toileting).
• Behavioral changes often include anxiety, irritability, and stereotypic behaviors resembling autism.

However, its exact cause remains poorly understood, with current hypotheses focusing on both polygenic inheritance and mitochondrial dysfunction.

CDD is a spectrum with a wide range of outcomes. While it is often associated with severe and permanent disability, some children can regain partial skills with appropriate interventions. Recovery varies greatly, and prognosis depends on factors such as the timing and extent of regression, the underlying cause, and the availability of tailored therapeutic approaches.

Simple conclusion

Regression in autism is a multifaceted phenomenon that occurs during a critical window of early childhood when the brain is rapidly developing and highly sensitive to disruption. Key processes such as synaptic pruning, myelination, and neuroplasticity are particularly vulnerable to genetic, metabolic, and environmental influences. Mitochondrial dysfunction emerges as a central factor in many cases, highlighting the need for a deeper understanding of energy metabolism in neurodevelopmental disorders. While the mechanisms differ between polygenic and monogenic autism, both forms underscore the importance of this critical developmental window and the need for timely interventions to support skill retention and neurodevelopment.

 

How Mitochondrial Dysfunction Causes Regression

1. Energy Crisis in the Brain
• The brain is highly energy-dependent, consuming a significant portion of the body’s ATP (adenosine triphosphate), produced by mitochondria.
• Skills like speech and motor function rely on the continuous and efficient operation of neural networks. If mitochondria cannot meet the energy demands, these networks may fail to maintain function, leading to regression.
2. Critical Periods of High Energy Demand
• Developmental regression often occurs during phases of rapid brain growth and synaptic pruning (e.g., 18 months to 3 years in children with autism).
• During these periods, mitochondrial dysfunction can result in:
• Depletion of neural energy reserves
• Impaired synaptic plasticity and signaling
• Loss of functional neural networks
3. Vulnerability to Stressors
• Children with mitochondrial dysfunction are more susceptible to stressors such as infections, fevers, or environmental toxins, which can further impair mitochondrial function and precipitate regression.
4. Oxidative Stress and Neuroinflammation
• Dysfunctional mitochondria generate excessive reactive oxygen species (ROS), leading to oxidative stress and damage to cellular components, including neurons.
• This can exacerbate inflammation in the brain and contribute to neural circuit disruptions.

 

Example of single gene autisms featuring regression 

Rett Syndrome Overview

• Rett syndrome is caused by mutations in the MECP2 gene, which encodes the methyl-CpG-binding protein 2. This protein is critical for regulating gene expression, particularly in neurons.
• MECP2 acts as a transcriptional regulator, ensuring that certain genes are activated or repressed as needed during development.

Why Development Seems Normal Initially

1. Early Brain Development
• During early development, processes like neuronal proliferation (growth in the number of neurons) and initial migration of neurons to their proper locations occur.
• These stages of brain development are not as heavily dependent on MECP2 function, which primarily regulates post-mitotic (non-dividing) neurons.
• Other compensatory mechanisms in early life might temporarily mask the effects of MECP2 dysfunction.
2. Low Demand for Synaptic Plasticity
• In the first year of life, the brain focuses on basic structural growth rather than complex synaptic connections.
• The regulatory role of MECP2 in maintaining synaptic plasticity becomes more critical as the child begins to acquire higher cognitive and motor functions.

 

Why Regression Occurs

1. Synaptic Maturation and Plasticity
• Around 18 months, the brain enters a critical phase of synaptic pruning and circuit refinement, where unnecessary connections are removed, and essential ones are strengthened.
• MECP2 dysfunction leads to impaired synaptic maturation, resulting in disrupted communication between neurons.
• This manifests as the loss of previously acquired skills, such as speech, purposeful hand use, and motor coordination.
2. Epigenetic Dysregulation
• MECP2 is a key player in epigenetic regulation, meaning it modifies how genes are expressed without changing the DNA sequence.
• During this developmental window, MECP2 is critical for the fine-tuning of neural circuits through epigenetic mechanisms. A defective MECP2 protein disrupts these processes, leading to neurodevelopmental regression.
3. Imbalance in Excitation and Inhibition
• MECP2 mutations often result in an imbalance between excitatory and inhibitory signaling in the brain, leading to abnormal neural activity patterns.
• This imbalance might not become evident until the neural network demands increase during the toddler years.

 

Why the Timing?

• Critical Periods: Brain development occurs in stages with "critical periods" where specific genes and proteins are essential. MECP2 dysfunction becomes evident when the brain transitions from basic growth to complex functional organization.
• Developmental Threshold: The early compensatory mechanisms or residual MECP2 activity may be sufficient for initial growth but fail as demands on the neural system intensify.

 

Implications for Treatment

• Early Interventions: Therapies like MECP2 gene therapy, neuroplasticity-enhancing interventions, and symptom management strategies aim to prevent or reduce the impact of regression.
• Critical Timing: Intervening before or during the regression window may maximize the potential for preserving neural function.

This pattern of normal early development followed by regression highlights the dynamic and stage-specific roles that single-gene mutations can play in neurodevelopment.

  

Contrast Pitt-Hopkins syndrome vs Rett syndrome

Pitt-Hopkins syndrome and Rett syndrome are both monogenic disorders associated with autism-like features, but they differ significantly in their developmental trajectories and underlying mechanisms.

Newborns with Pitt-Hopkins syndrome often appear physically normal, with no distinct features at birth to suggest a genetic syndrome. Birth weight and head circumference may fall within normal ranges. Developmental delays, especially in motor skills, usually become noticeable during the first year of life. Hypotonia (low muscle tone) may be evident early, affecting feeding and physical development. Pitt-Hopkins syndrome typically does not feature a dramatic loss of previously acquired skills (regression) as seen in conditions like Rett syndrome. Instead, Pitt-Hopkins is more characterized by delayed acquisition of developmental milestones rather than a significant loss of skills once they are gained.

 

Pitt-Hopkins Syndrome (TCF4 Mutation)

• Developmental Course: Children with Pitt-Hopkins syndrome typically show early developmental delays, particularly in motor and cognitive domains. While there may be some regression, it is less abrupt and pronounced compared to Rett syndrome.
• Mechanism: Mutations in the TCF4 gene disrupt transcriptional regulation critical for neuronal differentiation and synaptic formation. This leads to global developmental delays from early infancy, with limitations in skill acquisition rather than significant loss of previously acquired abilities.
• Features: Severe intellectual disability, absent or minimal speech, and distinctive facial features are characteristic. Respiratory irregularities and motor impairments are common.

Rett Syndrome (MECP2 Mutation)

• Developmental Course: Girls with Rett syndrome often develop typically for the first 6 to 18 months before experiencing a dramatic regression. Skills such as speech, purposeful hand use, and social engagement are lost, often accompanied by the onset of stereotypic hand movements.
• Mechanism: MECP2 mutations impair the regulation of gene expression involved in synaptic maintenance and neuroplasticity. This results in the progressive loss of neuronal function and connectivity, particularly during the sensitive period of early childhood.
• Features: Rett syndrome includes severe intellectual disability, motor impairments, seizures, and breathing abnormalities, along with hallmark hand-wringing behaviors.

 

Polygenic regressive autism

In polygenic regressive autism, the regression is believed to result from a complex interplay of multiple genetic, environmental, and metabolic factors. Unlike monogenic autism, where a single gene mutation explains most of the phenotype (e.g., Rett syndrome), polygenic regressive autism arises from the combined effects of multiple genetic variants, each contributing a small risk, along with external triggers

 

1. Key Features of Regression in Polygenic Autism

• Loss of previously acquired skills (e.g., speech, social interaction, motor abilities) after a period of typical development.
• Often occurs between 18 and 36 months, a critical period for brain development.
• Associated with a subset of autism cases, possibly more linked to environmental sensitivity or metabolic vulnerabilities.

 

2. Contributing Factors

 

Genetic Susceptibility

• Multiple Genes Involved: Variants in genes related to synaptic function, neural plasticity, and energy metabolism (e.g., SHANK3, SLC6A4, SCN2A) may predispose the brain to functional impairments.
• Epistasis: Interactions between these genes amplify the risk of neural circuit disruptions.

Epistasis is a Greek word for stoppage and in science when you want to sound clever, you often pick a Greek word, so only Greeks will understand it.

Our Greek reader Konstantinos is currently dealing with the implications of epistasis.

Epistasis is a precise term used in genetics. It refers to specific interactions between genes where one gene modifies, suppresses, or enhances the effect of another gene. This is a technical concept that has well-defined implications in studies of inheritance and molecular biology. For example:

• Gene A masks the effect of Gene B.

• Gene C enhances the effect of Gene D.

Mitochondrial Dysfunction

• Energy Deficits: The developing brain has high energy demands, especially during synaptic pruning and circuit refinement. If mitochondria are inefficient, neural circuits may fail.
• Triggered by Stress: Stressors like fever, infections, or environmental toxins may overwhelm already fragile mitochondrial function, causing regression.

Excitatory-Inhibitory Imbalance

• Synaptic Dysregulation: Variants in genes affecting GABAergic (inhibitory) or glutamatergic (excitatory) signaling can lead to circuit over or under-activation, resulting in regression.
• Neuroinflammation: Chronic inflammation may exacerbate synaptic dysfunction, further disrupting brain networks.

Immune and Neuroinflammatory Factors

• Maternal Immune Activation (MIA): In utero exposure to maternal immune challenges may predispose the child to neuroinflammation, which could be triggered later in life.
• Postnatal Immune Dysregulation: Autoimmune or inflammatory responses (e.g., microglial activation) may interfere with neural connectivity.

Epigenetic and Environmental Triggers

• Epigenetic Modifications: Environmental factors, such as nutrition, infections, or toxins, can influence the expression of autism-related genes.
• Gut-Brain Axis: Dysbiosis or gut inflammation may exacerbate systemic inflammation, impacting brain function.

 

3. What Happens Neurologically?

Synaptic Dysfunction

• Dendritic Spine Abnormalities: Regression is often associated with a loss of dendritic spines, impairing synaptic connections.
• Neuronal Circuitry Breakdown: Brain regions critical for speech, social cognition, and motor skills may lose functional connectivity.

Myelination and Axonal Integrity

• While widespread demyelination is not typical, localized impairments in white matter connectivity may slow information processing in key circuits.

Neuronal Stress and Oxidative Damage

• Reactive Oxygen Species (ROS): Mitochondrial inefficiency leads to oxidative stress, damaging neurons and synapses.
• Excitotoxicity: Overactivation of neurons due to excitatory-inhibitory imbalances can lead to synaptic burnout.

Neuroinflammation

• Microglial Activation: Overactive microglia can prune healthy synapses, leading to regression.
• Cytokine Dysregulation: Elevated inflammatory markers (e.g., IL-6, TNF-alpha) are frequently observed in regressive autism.

4.   Why Are Skills Lost?

• Functional Overload: Circuits supporting skills like speech or motor coordination are highly energy-dependent. Mitochondrial dysfunction or inflammation can make these circuits fail under stress.
• Synaptic Pruning: Abnormal or excessive pruning during development can eliminate neural pathways necessary for previously learned skills.
• Metabolic Crisis: Temporary or chronic deficits in energy production impair the maintenance of neural plasticity required for skill retention.

 

5. Potential Triggers for Regression

• Fever or Infections: Increase metabolic demand and inflammatory markers, overwhelming the child's already vulnerable systems.
• Vaccines or Illnesses: Vaccines do not directly cause autism, but in rare cases of mitochondrial dysfunction, the immune activation they trigger may become excessive and act as a major stressor and cause a "power outage." Regressive autism is the consequence.
• Environmental Toxins: Pesticides, heavy metals, and air pollution can exacerbate oxidative stress and mitochondrial inefficiency.
• Nutritional Deficits: Inadequate intake of key nutrients (eg CoQ10, carnitine, B vitamins) may worsen mitochondrial dysfunction.

 

What about early-onset polygenic autism (the main type)?

Well, this post was to explain regressive autism.

Nonetheless, here is the difference between early-onset polygenic autism and regressive polygenic autism.

The specific genetic makeup in polygenic autism likely plays a critical role in determining whether autism manifests as early-onset or regressive autism. The timing and nature of symptoms can depend on the functions of the genes involved, their interactions, and the biological systems they affect.

Early-Onset Autism

• Key Features:

• Symptoms are evident from infancy.
• Includes difficulties with social engagement, communication, and restricted interests or repetitive behaviors from an early age.

• Genetic Contributions:

• Synaptic genes: Mutations or variations in genes like SHANK3, SYNGAP1, and NRXN1 disrupt synaptic formation and function during early brain development. This can lead to abnormalities in the foundational wiring of the brain, manifesting as early-onset autism.
• Genes affecting neurodevelopment: Genes regulating early neuronal proliferation, migration, or differentiation may predispose to early structural or functional deficits.
• Reduced redundancy: Early-onset cases might involve high-impact mutations in critical pathways, such as those regulating synaptic plasticity, which leave little compensatory capacity for normal development.
•  

Regressive Autism

• Key Features:

• Normal or near-normal development during infancy.
• Loss of previously acquired skills, typically occurring between 18 months and 5 years of age.

• Genetic Contributions:

• Mitochondrial dysfunction-related genes: Variants in genes involved in mitochondrial energy metabolism (e.g. NDUFS4, SLC25A12) may impair the brain's ability to meet energy demands during rapid synaptic pruning and development, triggering regression.
• Immune or inflammatory response genes: Variations in genes affecting immune regulation (e.g. HLA genes, cytokine signaling genes) could result in neuroinflammation during critical developmental windows, leading to regression.
• Activity-dependent plasticity genes: Genes like MEF2C or UBE3A are involved in maintaining synaptic connections based on neuronal activity. Disruptions could lead to the loss of skills as synaptic pruning occurs.
• Environmental sensitivity: Some polygenic profiles might predispose individuals to environmental triggers (e.g. infections, stress, or dietary changes), unmasking vulnerabilities during critical developmental phases.

 

Gene combinations and their timing effects

• The interaction of multiple genes likely determines whether autism manifests as early-onset or regressive:

• High-impact mutations in multiple pathways (e.g. synaptic formation and plasticity) might produce early-onset autism.
• Combinations of moderate-risk variants that interact with environmental or biological stressors (e.g., immune challenges or mitochondrial stress) may predispose to regression.
• Timing of gene expression: Genes active during infancy might contribute to early-onset autism, while those playing roles during later synaptic refinement may contribute to regression.