Keeping ahead of the curve in Autism (and Pitt Hopkins syndrome) treatment - the placebo effect, clinical trials, and a promising case study

Since AI is a trending tool in this blog, I decided to let ChatGPT rewrite today's post. It did rather strip out the science bits.  It added the "don't wait for permission at the end"—a little cheeky, I think. It does like to use dashes.

 

Keeping out in front of the pack is not always easy

Today’s post highlights a compelling new case study—one that turns theoretical research into a real therapy.

About time too! That was my reaction when a reader sent me the paper.

This case study reports on the repurposing of a cheap, well-known drug—Nicardipine—to treat Pitt Hopkins syndrome (PTHS). The drug had already shown promise in earlier mouse models.

So why aren’t we doing this more often? Because the system misunderstands risk.

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What About the Risk?

When it comes to trying new treatments, people often fixate on the risk of the therapy itself. But that’s only half the equation. The risk of doing nothing is often much greater—especially in autism.

Most conventional drug repurposing therapies pose minimal long-term risk. Things change only when you start injecting compounds or using untested chemicals. But even then, there’s surprisingly little harm on record.

Only one death has ever been clearly attributed to a therapy for autism:

A 5-year-old autistic boy from the UK died in the US while undergoing chelation therapy. The wrong form of EDTA—disodium EDTA instead of calcium EDTA—was used. The result was fatal hypocalcemia-induced cardiac arrest. The doctor administering the therapy didn’t understand the pharmacology.

Lesson: Always read the label.

Meanwhile, the risk of death from untreated autism is well established:

• In severe autism, common causes include drowning, accidents, and seizures.
• In milder cases, the biggest risk is suicide.

Another overlooked danger, mentioned previously in this blog, is polydipsia—excessive water drinking—which can cause hyponatremia (low blood sodium), leading to seizures, coma, and even death.

Bottom line?

The risks from untreated autism far exceed the risks from science-based, carefully applied therapies.

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The Nicardipine Case Study

A newly published study builds on promising mouse results and shows real benefit in a young child with PTHS. The drug used—Nicardipine—has been around since 1988 and is commonly prescribed to older adults for high blood pressure or angina.

🔗 Read the case study

Highlights:

• Pitt Hopkins syndrome involves loss of function in the TCF4 gene, leading to overactivity of Nav1.8 sodium channels in neurons.
• Nicardipine inhibits Nav1.8, making it a logical therapy.
• In this case study, the child received oral nicardipine for 7 months (0.2–1.7 mg/kg/day).
• Result: Mild to moderate improvement in all developmental areas, and reduced restlessness.
• No significant side effects reported.

It’s not a magic bullet—but it’s a start.
Used as part of polytherapy, this could become a powerful tool for treating PTHS.

And there’s more coming: Vorinostat, another potential therapy, is entering human trials.

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Why Don’t More Therapies Get Adopted?

A recent paper by Antonio Hardan sheds light on this. He’s the researcher who showed that the OTC antioxidant NAC benefits many with autism, and later explored the hormone vasopressin.

This time, he tackled the placebo effect—a real barrier in autism research.

🔗 Placebo Effect in Clinical Trials in Autism: Experience from a Pregnenolone Treatment Study

What They Did:

• A two-week placebo lead-in before the main trial.
• The drug tested was pregnenolone, a neurosteroid.
• They used parent-reported ABC-I scores to measure irritability.

What They Found:

• A 30% reduction in irritability—just from placebo.
• Also improvements in lethargy, hyperactivity, and repetitive speech.
• The placebo effect was strongest in the first two weeks, then plateaued.
• Clinician-rated scores (CGI) did not show this placebo response.

The Takeaway:

Parent expectations strongly shape trial results—at least in the early stages.
A placebo lead-in is a clever way to measure and filter out this noise.

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Early Adopters, Take Note

It pays to be ahead of the curve.

Some Pitt Hopkins parents are already trying nicardipine at home based on this case study. Good luck to them—I hope they find the right specialists and support.

Let’s not forget: the big autism trials of recent years—Bumetanide, Memantine, Balovaptan, Oxytocin, Arbaclofen—all officially “failed.”

But the drugs didn’t fail—the trial designs did.

Each of these drugs helped some individuals. The problem?
The trials weren’t structured to identify responder subgroups. We wasted time, money, and hope by not tailoring inclusion criteria more carefully.

Consider Trofinetide, the first FDA-approved drug for Rett syndrome (2023). It helps only 20% of patients, but was still approved.

I’d argue that Bumetanide has an even higher response rate in severe autism, particularly with intellectual disability—and that the best outcome measure is IQ, not a generalized autism scale.

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My Own Example: No Placebo Here

How do I know I wasn’t misled by the parental placebo effect?

Simple. No one knew I was trialing treatments—not even the teachers or therapists. That meant their feedback was objective and uninfluenced by my hopes.

My son Monty went from being unable to do basic subtraction at age 9, to later passing his externally graded IGCSE high school math exam.

Not bad for a therapy that mainstream medicine still ignores.

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Final Thoughts

• Drug repurposing is safe, smart, and often effective.
• The placebo effect is real—but it’s measurable and manageable.
• If we want progress in autism treatment, we need smarter trial designs, not just more of them.
• Being ahead of the curve isn’t risky—it’s essential.

💡 Stay informed, stay curious, and don’t wait for permission.

Thanks for the guest post, ChatGPT !!

One point to add to the risk assessment: by my estimation, each year in the US, around 200 to 300 people die from drowning, seizures, accidents, and suicides related to autism. In living memory, only one person has died as a result of visiting an autism doctor in the US and that death was entirely preventable.

Vorinostat, a potent HDAC inhibitor trialed in several autism models, was mentioned in the above post. Interestingly, there is a recent comment from a reader who finds it resolves 80% of his autism but only for about 2 hours. The half-life of this drug is about 2 hours. There are discussions on Reddit by people using it for autism, anxiety, PTSD etc. It is about 1,000 times more potent than HDAC inhibitors people typically might try at home. Perhaps there should be trials of micro-dosing Vorinostat? I think daily use of high-dose Vorinostat may not work well, due to side effects.  Human trials will soon inform us better. It is often older people who struggle with drug side effects, not children.  

Vorinostat may not only correct Differentially Expressed Genes (DEGs) but also:

• Increase synaptic plasticity
• Improve synaptic morphology (the shape and function of neuronal connections)
• Improve memory and cognition 

The main research interest is in single gene autisms, where one specific gene is under-expressed (eg Pitt Hopkins, Rett, Fragile-X etc) but the general ideas are equally applicable to broader autism. 

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.

 

Time for T? Targeting language-associated gene Cntnap2 with a T-type calcium channel blocker corrects hyperexcitability driving sensory abnormalities, repetitive behaviors, and other ASD symptoms, but will it improve language? Will it also benefit Pitt Hopkins syndrome (PTHS) and broader autism?

 

  

 

There are at least 2 Natasas I can think of who will like this post.

Today’s post revisits the subject of calcium channels in autism.  Ion channel dysfunctions are a favourite area of mine because many should be treatable by repurposing safe, existing drugs. I do take note that many readers of this blog have reported success by targeting L-type calcium channels.

Many years ago, at the start of this blog, I recall reading about Timothy syndrome and a researcher at Stanford, Ricardo Dolmetsch, who was exploring treatment using a T-type calcium channel blocker.  It turned out that he had a son with severe autism, which was driving his interest at that time. He won all kinds of awards, but I always wondered why he did not treat his own son.

It is quite strange because Timothy syndrome is caused by a gain of function of an L-type channel. This mutation causes the Cav1.2 channel to fail to inactivate properly after opening. As a result, there is prolonged calcium influx into cells.

Instead of blocking Cav1.2, the researchers blocked the T-channels Cav3.2 and 3.3.

I did my homework on idiopathic autism a dozen years ago and concluded I needed to block Cav1.2. I went ahead and did it – it works like a charm.

It was a real drama back in those days, with self-injury and aggression, so Timothy syndrome and T channels remains stuck in my mind a decade later.

 

Language Genes

Even before parents worry about self-injurious behavior (SIB), they go through the phase of worrying about if their child will ever speak. Some do and some do not.  What really matters is communication, rather than speech.

 

FOXP2 - The language Gene

FOXP2 is a transcription factor involved in the development of neural circuits related to speech and language production, particularly in areas such as the basal ganglia and cerebellum. Mutations in FOXP2 can lead to speech and language deficits.

FOXP2 influences motor control and vocalization processes that are critical for speech, and it is thought to have evolved specifically in humans to support complex language abilities.

 

CNTNAP2 - The language-associated gene

CNTNAP2 (Contactin-associated protein-like 2) is a gene that encodes a cell adhesion protein. It plays a critical role in the development of neural connectivity and the formation of synapses in areas of the brain involved in language, such as the broca’s area and temporal lobes. CNTNAP2 is also involved in the regulation of neuronal excitability and is crucial for the development of white matter tracts that connect language-related brain regions.

Mutations in CNTNAP2 have been implicated in neurodevelopmental disorders such as specific language impairment (SLI), autism, and developmental language disorders.

 

FOXP2 and CNTNAP2 Interaction

FOXP2 and CNTNAP2 work together in the development of the neural circuits that are crucial for language and speech. They are both involved in the formation and maintenance of synaptic connections in key brain regions like the cortex, basal ganglia, and cerebellum, which are critical for motor control, vocalization, and language processing.

There is evidence to suggest that FOXP2 may regulate the expression of CNTNAP2 as part of a broader gene network that governs language development. FOXP2 may influence CNTNAP2 gene expression, which in turn impacts neural connectivity and synaptic function in brain regions responsible for speech and language.

 

CNTNAP2 sounds familiar?

We have come across this gene before.

At least one reader has a child with a mutation in this gene.

We also discovered that the Pitt Hopkins gene TCF4 regulates CNTNAP2 and that

“PTHS (Pitt Hopkins syndrome) is characterised by severe intellectual disability, absent or severely impaired speech, characteristic facial features and epilepsy. Many of these features are shared with patients carrying CNTNAP2 mutations, leading researchers to test patients with PTHS-like features for CNTNAP2 mutations”

Several readers have children with PTHS (Pitt Hopkins syndrome).

It is not inconceivable that what works for CNTNAP2 will also work for at least some PTHS (Pitt Hopkins syndrome).

The question is whether what works for CNTNAP2 will work much more broadly and could it even improve language development?

Here is the recent research from Stanford:

 

Reticular Thalamic Hyperexcitability Drives Autism Spectrum Disorder Behaviors in the Cntnap2 Model of Autism

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by social communication deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Dysregulation of thalamocortical circuits has been implicated in these comorbid features, yet their precise roles in ASD pathophysiology remain elusive. This study focuses on the reticular thalamic nucleus (RT), a key regulator of thalamocortical interactions, to elucidate its contribution to ASD-related behavioral deficits using a Cntnap2 knockout (KO) mouse model. Our behavioral and EEG analyses comparing Cntnap2^+/+ and Cntnap2^-/- mice demonstrated that Cntnap2 knockout heightened seizure susceptibility, elevated locomotor activity, and produced hallmark ASD phenotypes, including social deficits, and repetitive behaviors. Electrophysiological recordings from thalamic brain slices revealed increased spontaneous and evoked network oscillations with increased RT excitability due to enhanced T-type calcium currents and burst firing. We observed behavior related heightened RT population activity in vivo with fiber photometry. Notably, suppressing RT activity via Z944, a T-type calcium channel blocker, and via C21 and the inhibitory DREADD hM4Di, improved ASD-related behavioral deficits. These findings identify RT hyperexcitability as a mechanistic driver of ASD behaviors and underscore RT as a potential therapeutic target for modulating thalamocortical circuit dysfunction in ASD.

Teaser RT hyperexcitability drives ASD behaviors in Cntnap2-/- mice, highlighting RT as a therapeutic target for circuit dysfunction.

 

Overall, this study identifies elevated RT burst firing and aberrant thalamic oscillatory dynamics in Cntnap2^−/− mice as a key driver of ASD-related behavioral deficits. If this is a common mechanism of ASD-circuit pathology arising from a variety of genetic causes, then compounds such as Z944, or subtype specific T-type calcium channel antagonists that would target the Cav3.2 and Cav3.3 expressed in RT neurons, might be an effective therapeutic strategy. Furthermore, future research should focus on elucidating RT’s roles in sensory, emotional, and sleep regulation to optimize therapeutic strategies in the context of ASD.

 

Existing T-type calcium channel blockers for humans

Mibefradil is one of the most well-known T-type calcium channel blockers. It was initially developed for hypertension and angina because of its ability to block T-type channels. However, mibefradil was withdrawn from the market in 1998 due to serious drug interactions with other medications, particularly those that inhibit liver enzymes involved in drug metabolism, like statins.

Despite its withdrawal, mibefradil has been studied for other potential uses, including in epilepsy and chronic pain, due to its effects on neuronal excitability.

Zonisamide is an anticonvulsant medication that has some T-type calcium channel blocking properties. It is approved for epilepsy and partial seizures, but it is not typically used specifically for Timothy syndrome or conditions involving T-type channel dysfunction.

Zonisamide is also used to treat seizures in pet dogs and cats.  

Zonisamide: chemistry, mechanism of action, and pharmacokinetics

Zonisamide is a novel antiepileptic drug (AED) that was developed in search of a less toxic, more effective anticonvulsant. The drug has been used in Japan since 1989, and is effective for simple and complex partial seizures, generalized tonic-clonic seizures, myoclonic epilepsies, Lennox–Gastaut syndrome, and infantile spasms. In Japan, zonisamide is currently indicated for monotherapy and adjunctive therapy for partial onset and generalized onset seizures in adults and children. In the United States, zonisamide was approved by the Food and Drug Administration (FDA) in 2000 as an adjunctive treatment for partial seizures.

The drug’s broad spectrum of activity and favorable pharmacokinetic profile offer certain advantages in the epilepsy treatment armamentarium. Chemically distinct from other AEDs, zonisamide has been shown to be effective in patients whose seizures are resistant to other AEDs. Zonisamide’s long plasma elimination half-life has allowed it to be used in a once-daily or twice-daily treatment regimen in Japan.

It is believed that zonisamide’s effect on the propagation of seizure discharges involves blocking the repetitive firing of voltage-sensitive sodium channels, and reducing voltage-sensitive T-type calcium currents without affecting L-type calcium currents. These mechanisms stabilize neuronal membranes and suppress neuronal hypersynchronization, leading to the suppression of partial seizures and generalized tonic–clonic seizures in humans.

Zonisamide possesses mechanisms of action that are similar to those of sodium valproate, e.g., suppression of epileptogenic activity and depression of neuronal responses. These mechanisms are thought to contribute to the suppression of absence and myoclonic seizures.

  

Conclusion

It would seem that zonisamide should be trialed in:

·        CNTNAP2-related neurodevelopmental disorder

·        Pitt Hopkins syndrome (PTHS)

·        Timothy syndrome

·        Idiopathic/polygenic autism

(But, don’t hold your breath!)

Due to the nature of CNTNAP2 disorder and PTHS, I think the greatest impact will be if given from a very young age. However, we do see improvements with many autism interventions regardless of age.

It is certainly conceivable that even mild autism can benefit from damping down reticular thalamic (RT) hyperexcitability.

If shown effective, zonisamide would join the long list of anti-epileptic drugs (AEDs) “repurposable” to treat certain subtypes of autism.