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.

 

The plural of anecdote is data – I vote for that

 

Most of my interactions in the world of treating autism are with people I have never met, but you cannot help keep learning new things.

I was recently contacted by a mother who is computer programmer and so used to dealing with “exact sciences.” She had read my book and noted from it that genetic testing in autism often misses important genes. Her child’s report stated that there were no mutated autism genes found. She asked if I know how to analyse the raw data from the testing. That is a bit too technical for me, though I discovered you can upload that file to ChatGPT for analysis. I said that all I do is take the 10-20 genes highlighted in the full report and look them all up, regardless of whether they are obvious autism genes or not. Back came the very short list and after a couple of minutes “Bingo” there was the gene. It was not on the lab’s “autism list,” but in the research one of the genes is described as having potential to cause autism.

In a perfect world the testing lab would have an updated list that includes all the genes known to cause autism, or indeed intellectual disability. It is not the exact science the mother is used to, it is sloppy science. You must dig deeper than you thought would be really necessary.

I did meet, in real life, the parents of a young child with severe autism a week or two ago. They had tried all sorts of expensive therapies, from stem cell therapy to GcMAF from Japan. There was a scandal in the US and Europe a decade ago when GcMAF was marketed to treat cancer, autism and other conditions. In Japan it is still used in alternative clinics, but it is not an approved therapy or a regulated drug anywhere.

I was told that in Japan GcMAF is now made from a patient’s own blood and saw that it is marketed as a "personalized" or "natural" therapy. The process typically involves isolating the Gc protein (a vitamin D-binding protein) from the patient’s blood, chemically modifying it to activate macrophages, and then injecting it back into the patient. I have no idea if it works.

I dared not ask how much it cost, but I did ask if it helped. I suggested that in autism the cheapest and safest therapies are often the most effective.

One reader of this blog remains a fan of the original GcMAF that was produced by David Noakes' company Immuno Biotech. He later went to jail in the UK and then in France for selling an unlicensed medical product. In June 2015 Dr Jeffrey Bradstreet, a well-known autism doctor who used GcMAF, was found dead the day after his office in Buford, Georgia was raided by the FDA, searching for evidence of illegal medical practices related to unapproved drugs.

Japan seems to be more “anything goes” when it comes to alternative medicine. This is probably not what you would have expected. GcMAF is still marketed there to treat cancer and autism.

Safety

Safety should be the prime concern when treating autism. I recall being told the key insight a mainstream doctor took away from attending the Brain Foundation’s autism conference in California a while back was that “you actually can safely treat autism.”

The GcMAF mother did ask me if it was safe.

Using common existing drugs that have been repurposed for autism is safe, as long as they are used responsibly and care is taken regarding interactions and the listed side effects.

Drugs taken orally are often considered inherently safer than those administered via injection or infusion for several reasons, perhaps the key one is the barrier of the digestive system.

When drugs are taken by mouth, they pass through the liver before entering systemic circulation. The liver metabolizes some of the drug, which can detoxify harmful substances or reduce their potency. This serves as a protective mechanism. The stomach and intestines have mechanisms to break down and filter harmful substances, adding another layer of safety.

Injectable drugs require sterile preparation and administration to avoid infections. Oral drugs are less prone to contamination since they do not bypass the body's natural barriers.

Gene therapy can be risky, as was shown recently in a trial for Rett syndrome: 

Patient Death in Rett Syndrome Trial Forces Neurogene to Drop High-Dose Arm

Despite the death, the FDA has allowed Neurogene to forge ahead with the Phase I/II Rett syndrome trial, but using only the lower 1E15 vg dose of its investigational gene therapy NGN-401.

Neurogene revealed in an SEC filing on Thursday that a patient has died in its Phase I/II Rett syndrome clinical trial after being dosed with its investigational gene therapy.

The patient had been treated with the higher, 3E15-vg dose of NGN-401 when they experienced what was initially described only as a treatment-related serious adverse event (SAE). In a follow-up announcement on Monday, Neurogene disclosed that the patient had developed systemic hyperinflammatory syndrome—a known but severe side effect of adeno-associated virus gene therapies—and was in critical condition.

 

The plural of anecdote is data vs The plural of anecdote is not data

"The plural of anecdote is not data" is a commonly used phrase in scientific and analytical discussions. It highlights the idea that individual anecdotes, no matter how numerous, do not constitute reliable evidence or robust data without proper scientific methods like controlled observation, experimentation, and statistical analysis.

The phrase the plural of anecdote is not data turns out to have been a misquote. The original observation, by the political scientist Ray Wolfinger, was just the opposite: The plural of anecdote is data.

Ray Wolfinger said this to emphasize that anecdotes, when systematically collected and analyzed, can form the foundation of meaningful data sets.

Wolfinger's point was not to dismiss the importance of rigorous scientific methods but rather to highlight that even seemingly small, subjective observations—when aggregated and scrutinized—can reveal broader patterns and insights.

This perspective challenges the overly dismissive view of anecdotes in research, acknowledging their potential as the seeds of inquiry and evidence in contexts where comprehensive data collection may not yet exist.

Human biology is not an exact science

The phrase "human biology is not an exact science" reflects the inherent complexity and variability of biological systems, particularly in humans. Unlike the physical sciences, which often operate under strict laws and predictable outcomes, human biology involves numerous interacting factors, such as genetics, environment, lifestyle, and individual variability. This makes it challenging to predict outcomes with precision.

Key reasons include:

• Genetic diversity: Each person has a unique genetic makeup, leading to different responses to stimuli, medications, and conditions.
• Environmental influences: Diet, climate, socioeconomic status, and exposure to toxins vary widely among individuals and populations.
• Biological variability: Even within the same individual, factors like age, hormonal changes, and microbiome composition can cause variations.
• Unpredictable interactions: Complex systems, such as the immune response or neural activity, often defy simple cause-and-effect explanations.

As a result, human biology relies on probabilities, trends, and patterns rather than absolutes, making it a science of approximations and context-dependent insights.

Again, bumetanide works for some

Our reader A.W. recently completed a trial of bumetanide and in parallel the pediatrician made a trial on her own 5-year-old granddaughter with severe autism. Bumetanide did not work for A.W. but it did for the 5-year-old granddaughter. Notably her speech increased from single words to multiple words. Continued use will now certainly bring profound benefits as she grows up.

We see that human biology is not an exact science, but the situation is made worse by diagnostic stupidity. We know that there are many hundreds of biological dysfunctions leading to the umbrella diagnosis of autism. All autism is still lumped in together in these supposedly gold-standard randomized clinical trials. In layman’s terms you have to compare apples with apples, not apples with kiwis.

As a result, all large randomized clinical trials for core autism symptoms have failed and will likely continue to do so.  Even the large bumetanide trial failed. 

Meanwhile some people, now including A.W.’s pediatrician, will continue effectively treating a small number of children and adults with autism.    

Conclusion

When I presented my take at the recent autism conference in Abu Dhabi I did have a confrontation with the moderator of my session.

I presented the scientific logic behind treating autism but what he saw was someone dealing with anecdotes. He said he only believes in randomized clinical trials. 15 years ago I would also have thought like him—then came my epiphany.

I then learnt the benefit of tinkering with things you supposedly cannot fix but cannot just throw away and replace.

I do fix many other things. I had Monty’s two electric scooters in pieces several times recently, the last job was fixing the battery pack that malfunctioned. I have no previous experience, you just start tinkering, apply common sense and solve the problem. Having a spare scooter is an advantage.  I can always buy a third one.

In years only recently gone by you did discard “malfunctioning” young children into institutions. The doctor would then suggest you try again for another child and wish you better luck next time. Like buying scooter number two and discarding the first one.

Nowadays you keep such children at home, leave them untreated, and only later on put them into mini-institutions (AKA group homes).

I think it pays to tinker (play around fixing things) and improve functioning as much as possible. There is no guarantee of success, but you do have a fighting chance.

Wonder cures promoted in catchy 60 second videos on TikTok, Facebook and Instagram may not be your best choice. 

Advances in personalized medicine to treat Autism/IDD – Rett syndrome as an example. Also, Piperine to upregulate KCC2, but what about its direct effect on GABAa receptors?

 

Source:  https://www.cell.com/neuron/pdf/S0896-6273(21)00466-9.pdf

Today’s post is drawn from a workshop I am invited to present at an autism conference in Abu Dhabi.

I decided to talk about advances in personalized medicine – no surprise there.  Since I have 2 ½ hours, I thought I will need some interesting examples to maintain the audiences interest.  One such topic is going to be Rett syndrome.

I regard Rett syndrome and all the other such syndromes in this blog as “single gene autisms” (monogenic autism).  If you apply the American DSM classification, from 2013 onwards Rett syndrome is no longer part of autism.  Hopefully there are no such purists attending in Abu Dhabi. 

Two gene therapies for Rett syndrome are currently undergoing human trials and one drug therapy has been FDA approved.  This looks very encouraging, so let’s dig a little deeper.

Rett syndrome can present with a wide range of disability ranging from mild to severe. 

Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.

Other symptoms may include:

•      Loss of speech

•      Loss of purposeful use of hands

•      Loss of mobility or gait disturbances

•      Loss of muscle tone

•      Seizures or Rett “episodes”

•      Scoliosis

•      Breathing issues

•      Sleep disturbances

•      Slowed rate of growth for head, feet and hands

Here are the new therapies: 

TSHA-102: This gene therapy, developed by Taysha Therapeutics, is a gene replacement therapy that aims to deliver a functional copy of the MECP2 gene to brain cells.  It utilizes an AAV-9 virus to carry the miniMECP2 gene product into cells for the body to produce more MeCP2 protein, which is deficient in Rett syndrome. As of February 2024, Taysha completed dosing for the first cohort (low dose) in their REVEAL Phase 1/2 adolescent and adult trial in Canada, with positive interim data on safety. They are also conducting trials in the US for both pediatric and adolescent/adult populations.

NGN-401: This gene therapy, by Neurogene Inc., employs a different approach. It uses an AAV9 vector to deliver a regulated version of the MECP2 gene called EXACT. This technology aims to control the amount of MECP2 protein produced by the gene, mitigating the risk of overproduction. NGN-401 is currently in a Phase 1/2 trial for girls with Rett syndrome aged 4 to 10 years old.

Daybue (trofinetide)

Daybue is the first and only FDA-approved treatment specifically for Rett syndrome in adults and children two years of age and older. It is not a gene therapy, but rather a medication taken orally.

The optimistic AI generated view:

Here's a breakdown of Daybue for Rett syndrome:

• Mechanism: The exact way Daybue works in Rett syndrome isn't fully understood, but it's believed to target neuroinflammation and support synaptic function.
• Dosage: The recommended dose is based on the patient's weight and is taken twice daily, morning and evening, with or without food.
• Administration: Daybue comes as an oral solution and can be taken directly or through a gastrostomy tube if swallowing is difficult.
• Efficacy: Studies have shown that Daybue can improve symptoms of Rett syndrome, including reducing scores on the Rett Syndrome Behavior Questionnaire (RSBQ) and showing improvement on the Clinical Global Impression-Improvement (CGI-I) scale.
• Side Effects: The most common side effects of Daybue are diarrhea and vomiting. Weight loss can also occur in some patients. It's important to consult with a healthcare professional for monitoring and managing any potential side effects.

Daybue is an expensive medication. Here's what we know about the cost:

• List Price: The list price of Daybue is around $21.10 per milliliter.
• Annual Cost: This translates to an estimated average annual cost of around $375,000 for patients.
• Dosage Variability: It's important to note that the dosage of Daybue is based on a patient's weight, so the annual cost can vary depending on the individual.

Insurance and Assistance Programs:

• The high cost of Daybue highlights the importance of insurance coverage. Whether insurance covers Daybue and to what extent will depend on your specific plan.
• The manufacturer, Acadia Pharmaceuticals, offers a copay program called Daybue Acadia Connect. This program may help eligible commercially insured patients pay $0 for their monthly prescription.

What are the parents' groups saying? 

Not as good as you might be expecting for $375,000 a year.

Affordable potential alternatives to Daybue/Trofinetide

Daybue/Trofinetide is the product of decades of research into a growth factor called IGF-1.

It is a complicated subject and as usual the abbreviations can be confusing.

As you will see below there already is an OTC product commercialized by one of the original researchers, Dr Jian Guan.

One Rett syndrome parent, who reads this blog, has trialed cGP and sees a benefit. You rather wonder why the Phelan-McDermid, Pitt Hopkins, Angelman and Prader-Willi parents don’t follow him and splash out 50 USD and make a trial.

 

 

Gene-therapy

Gene therapy is undoubtedly very clever and ultimately will likely be the best therapy.  It still may not be that silver bullet.

To be effective gene therapy needs to be given at a very young age, ideally as a fetal therapy prior to birth. Note that we saw that in the Rett mouse model they gave bumetanide to the pregnant mother just before birth.

Fetal therapy is not a crazy idea and much is already written about it; many pregnancies are terminated because genetic anomalies are detected prior to birth. Down syndrome is the best-known example. Fetal therapy is realistic for some disorders.

Girls with Rett syndrome are often diagnosed first with idiopathic autism and then years later with a more precise diagnosis of Rett syndrome. This is a common experience among readers of this blog.

Classic Rett syndrome 

The average age of diagnosis for this form is around 2.5 years old in the US and 5 years old in the UK.  Why do you think that is?

Research in mouse models has shown that the effect of gene therapy ranges from curative when given extremely young to more limited the later it is given.

Off-target effects

Gene therapy has the potential for off-target effects. This is a significant concern in the field and researchers are actively working on ways to minimize these risks. Here is a breakdown of what off-target effects are and why they matter:

During gene therapy, a modified gene is delivered to target cells with the aim of correcting a genetic defect.

Ideally, the modified gene integrates into the intended location in the genome.

However, there's a chance it might insert itself into unintended locations (off-target sites).

Potential Consequences of Off-Target Effects

Disrupting normal genes at off-target sites could lead to unpredictable and potentially harmful consequences. This could include triggering uncontrolled cell growth, which is a risk factor for cancer.

It can also cause unexpected side effects depending on which genes are accidentally disrupted.

Minimizing Off-Target Effects

Researchers are developing various strategies to improve the accuracy and specificity of gene therapy techniques.

This includes using more precise gene editing tools like CRISPR-Cas9 with optimized guide RNAs to reduce off-target edits.

Additionally, researchers are working on methods to detect and potentially repair any off-target modifications that might occur.

Over-expression of the target gene

Yes, there is a possibility that the replaced gene in gene therapy could overproduce the expressed protein. This can be a potential complication and researchers are working on ways to control the level of protein expression. Here's a breakdown of the concern:

• Gene Dosing: Ideally, gene therapy aims to deliver a functional copy of the gene at the right amount to compensate for the deficiency.
• Overproduction Risks: However, if the delivered gene is too active or multiple copies are inserted, it can lead to overproduction of the protein.

Consequences of Protein Overproduction:

• Overproduction of a protein can disrupt the delicate balance in the cell, potentially leading to cell dysfunction or even cell death.
• In some cases, the protein itself might have harmful effects if present in excessive amounts.

Controlling Protein Expression:

Researchers are developing several strategies to control protein expression in gene therapy:

• Promoter selection: Using promoters that have a weaker switch can help regulate protein production.
• Viral vectors: Engineering viral vectors to control the number of gene copies delivered to cells.
• Inducible systems: Developing gene therapy methods where the expression of the introduced gene can be turned on and off as needed.

The cost of gene therapy

•      Despite the high cost, gene therapy can be a cost-effective treatment for some diseases. This is because it can eliminate the need for lifelong treatment with other medications.

•      Here are some examples of the cost of currently available pediatric gene therapies:

•      Luxturna (gene therapy for Leber congenital amaurosis type 10): $425,000

•      Zolgensma (gene therapy for spinal muscular atrophy type 1): $2.1 million

•      Skysona (gene therapy for adrenoleukodystrophy): $3 million

Piperine to correct KCC2 expression in Rett syndrome?

One key feature of Rett syndrome is impaired cognition.

As regular readers are aware, there are many types of treatable intellectual disability (ID).

One type of treatable ID is caused when the GABA developmental switch fails to occur shortly after birth.  This creates an excitatory/inhibitory imbalance in neurons which impairs cognition and lowers IQ.

The faulty GABA switch is a feature of many types of autism, but far from all of them.

By using pharmaceuticals to lower chloride within neurons, you can compensate for the failure of the GABA switch.

This treatment can be achieved by:

1.     Blocking or down regulating NKCC1

2.     Up regulating KCC2

In the paper below they look at up regulating KCC2

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K⁺/Cl⁻ cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT.

Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.

Thus, our data demonstrate that activation of the SIRT1 pathway or the TRPV1 channel enhances KCC2 expression in RTT human neurons.

Treatment with piperine (10 μM), an activator of the TRPV1 channel (51), induced a significant rise in KCC2 expression in cultured human neurons 

We already knew this was likely from earlier research from Ben Ari, see below for a reminder.  Is Piperine an interesting option for those restricted to OTC interventions?

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2-/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

Treating the mother prior to delivery with bumetanide was a partially effective therapy in the mouse model of Rett syndrome.

Piperine

Bumetanide is cheap and very possibly effective in human Rett syndrome, but it is a prescription drug.

Piperine is an OTC supplement and a compound found in black pepper. By activating the TRPV1 channel it causes an increase in expression of the KCC2 transporter that allows flow of chloride out of neurons. So piperine should lower chloride inside neurons.  Piperine can cross the blood brain barrier, so when taken orally it should have some effect on intracellular chloride.

Piperine is also a positive allosteric modulator of GABA_A receptors

This means that piperine multiplies the effect of whatever GABA is around. This means that in typical people piperine should have anti-anxiety effects.

Piperine was recently found to interact with a previously unknown  benzodiazepine-independent binding site.

Researchers are currently toying with the piperine molecule to try and separate the effect on TRPV1 from the effects on  GABA_A.  They want to create 2 new drugs.

1.     a selective TRPV1 activator

2.     a selective GABA_A modulator (PAM)

Piperine as an alternative or complement to Bumetanide?

One effect of piperine would be great to have (TRPV1 activator) but the second effect would not be helpful (positive allosteric modulator of GABAA).

The question is what is the net effect. Nobody will be able to answer that without a human trial.

I was advised long ago by one drug developer than it is best to focus on reducing flow into neurons via NKCC1, rather than increase its exit by KCC2, because nobody had yet been successful with KCC2; many have tried.  KCC2 plays a key role in neuropathic pain and that is why it has been researched.

Conclusion

We did see years ago that taking coffee with your bumetanide made sense. Coffee contains compounds that are OAT3 inhibitors and slow down the excretion of bumetanide from the body; coffee increases the effect of bumetanide. You can achieve something very similar by just increasing the dose of bumetanide.

Taking black pepper (piperine) with your bumetanide might be good, or might not be. It certainly would be easy to find out. As with Daybue/Trofinetide, the result is likely to vary from person to person. If GABA function, post- bumetanide, is still a bit excitatory amplifying GABA signaling will make autism worse. If GABA function has been shifted to inhibitory then amplifying GABA signaling will be calming.

Gene therapy will require much earlier diagnosis of single gene autisms.

“Precision medicine” therapies like Daybue/Trofinetide may not be that precise after all and large variations exist in the response, even among children with the same affected gene.

The huge expense means that for most of the world they will see no benefit from gene therapy or indeed “precision medicine.”

The low hanging fruit is to repurpose affordable existing drugs and get the benefit from their secondary effects.  This is what I term personalized medicine.

The research clearly indicates that some girls with Rett syndrome likely will benefit from Bumetanide therapy. For a young child this therapy would cost 50 US dollars/euros a year, if you pay the actual price for generics.

Why are they trialing genetic therapies for Rett instead of first doing the obvious thing and trialing cheap bumetanide? They will likely be able to sell the gene therapy for $2 million a shot.  There is little interest in trialing a $50 a year therapy.

Our new reader from Turkey, MÜCADELECI ANNE DENIZ ( = FIGHTING MOTHER DENIZ), likely does not have $2 million to spend, but seems to be on the way to creating her own personalized medicine therapy for her son. Good luck to her.

As to the cGP Max supplement, it seems to work for some and have no effect in others. Nobody has reported any side effects. It looks worth a try for Rett syndrome.  As a supplement it is not cheap, that is until you see what they charge for Daybue.