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.

Cilantro (Coriander leaves) for sound sensitivity? cGPMax for some Pitt Hopkins and Rett syndrome. Plus, microdeletion of 2P16.3 NRXN1 and mutations in GPC5

 

Today’s post combines a very simple therapy for sound sensitivity that landed in my inbox from New Zealand with two more genes that I was recently asked about.

Before I get started I would like to thank our reader Daniel who is trying to spread that word that the IGF-1 targeting therapy cGPMax works in some Rett syndrome (half a capsule daily). I did go into the science of IGF-1 related therapies at the recent conference in Abu Dhabi. In that presentation I pointed out that the cGPMax therapy might well be helpful in Pitt Hopkins syndrome. I saw today that Soko, an 8 year old girl with Pitt Hopkins, had already made a trial and her parents are impressed:-

“Equally significant has been the positive shift in Soko's emotional well-being. Her struggles with irritability and mood fluctuations feel like are not as frequent and we feel like there is more often a sense of calm and emotional regulation. This has had a profound ripple effect on our little family and our stress levels.

Perhaps most striking has been the accelerated rate at which Soko acquires new skills. CGP Max has seemingly unlocked hidden potentials within her. This rapid skill acquisition has been very exciting for us. In the last year she has gone from being unable to walk to walking unassisted and even tackling steps no handed!”

I did some checking and some other parents have tried cGPMax for Pitt Hopkins. For Rett syndrome Daniel found that a lower dose was more beneficial than a higher dose. It is always best to start with low doses and gradually increase them.

This does link to today’s post because a  microdeletion of NRXN1 can cause Pitt Hopkins Like Syndrome 2 (PHLS2). In theory all these syndromes are untreatable, but try telling that to Soko’s parents.

 

Back to sound sensitivity

Today’s sound sensitivity is the type that is moderated by Ponstan (mefenamic acid) and indeed Diclofenac. It might well include those whose sound sensitivity responds to a simple potassium supplement.

If you want to look into the details, you can see from previous posts how potassium and potassium ion channels play a fundamental role in both hearing and its sensory processing. They also play a key role in excitability of neurons and so can play a key role in some epilepsy and some intellectual disability.

It turns out that Cilantro/Coriander leaves contains a chemical that activates the ion channels  KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3). This effect is shared by Ponstan and Diclofenac.

In the case of Andy from New Zealand the effect of a 425mg Cilantro supplement lasts very much longer than taking a low dose of Ponstan or Diclofenac.

So, if your child responds well to Ponstan and can then happily take off his/her ear defenders, but you do not want to medicate every day, then a trial of Cilantro could be interesting.

I was curious as to why the effect would last so much longer than Ponstan/Diclofenac.  All of these drugs lower potassium levels within neurons.  Is the beneficial effect coming from lowering potassium levels and so reducing neuronal excitability?  Or, is the effect coming directly from a specific ion channel?

Nobody can tell you the half-life of the active component of cilantro,  (E)-2-dodecenal, in humans.  Andy thinks it must have a long half-life.

 

Cilantro (Coriander leaves)

If you live in North America you will know what cilantro is, for everyone else it means coriander leaves. Coriander seeds are the dried fruit of the coriander plant and, confusingly, in American English coriander means coriander seeds.

The medicinal properties of the leaves and seeds are not the same.

Cilantro leaves contain a compound called (E)-2-dodecenal, which has been shown to activate a specific family of potassium ion channel called KCNQ, otherwise known as Kv7 . These channels are found in neurons, and they play an important role in regulating the electrical activity of the brain.

When (E)-2-dodecenal binds to KCNQ/Kv7 channels, it causes them to open, which allows potassium ions to flow out of the neuron. This outflow of potassium ions helps to stabilize the neuron's membrane potential and makes it less likely to fire an action potential.

The level of potassium inside neurons is much higher than the level outside. Having it too high, or indeed too low, would affect the excitability of the neuron.

I am wondering if the problem with potassium is mirroring the problem we have with chloride; perhaps both are elevated inside neurons. That would be nice and simple.

The discovery that cilantro can activate KCNQ channels helps to explain its potential anticonvulsant properties.  KCNQ channel dysfunction has been linked to certain types of epilepsy, and drugs that activate these channels are being investigated as potential treatments for these conditions.

Research suggests cilantro's active compound, (E)-2-dodecenal, targets multiple KCNQ channels, particularly:

• KCNQ2/KCNQ3: This is the most common type of KCNQ channel found in neurons.
• KCNQ1 in complex with KCNE1: This form is mainly present in the heart. KCNE1 acts as a regulatory subunit that influences KCNQ1 channel function.

 

Cilantro leaf harbors a potent potassium channel-activating anticonvulsant

Herbs have a long history of use as folk medicine anticonvulsants, yet the underlying mechanisms often remain unknown. Neuronal voltage-gated potassium channel subfamily Q (KCNQ) dysfunction can cause severe epileptic encephalopathies that are resistant to modern anticonvulsants. Here we report that cilantro (Coriandrum sativum), a widely used culinary herb that also exhibits antiepileptic and other therapeutic activities, is a highly potent KCNQ channel activator. Screening of cilantro leaf metabolites revealed that one, the long-chain fatty aldehyde (E)-2-dodecenal, activates multiple KCNQs, including the predominant neuronal isoform, KCNQ2/KCNQ3 [half maximal effective concentration (EC50), 60 ± 20 nM], and the predominant cardiac isoform, KCNQ1 in complexes with the type I transmembrane ancillary subunit (KCNE1) (EC50, 260 ± 100 nM). (E)-2-dodecenal also recapitulated the anticonvulsant action of cilantro, delaying pentylene tetrazole-induced seizures. In silico docking and mutagenesis studies identified the (E)-2-dodecenal binding site, juxtaposed between residues on the KCNQ S5 transmembrane segment and S4-5 linker. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important KCNQ channels

Activation of KCNQ5 by cilantro could also contribute to its gut stimulatory properties, as KCNQ5 is also expressed in gastrointestinal smooth muscle, and its activation might therefore relax muscle, potentially being therapeutic in gastric motility disorders such as diabetic gastroparesis.

The KCNQ activation profile of (E)-2-dodecenal bears both similarities and differences to that of other KCNQ openers. We recently found that mallotoxin, from the shrub Mallotus oppositifolius that is used in African folk medicine, also activates KCNQ1-5 homomers, prefers KCNQ2 over KCNQ3, and in docking simulations binds in a pose reminiscent to that predicted for (E)-2-dodecenal, between (KCNQ2 numbering) R213 and W236 In addition to the widespread use of cilantro in cooking and as an herbal medicine, (E)-2-dodecenal itself is in broad use as a food flavoring and to provide citrus notes to cosmetics, perfumes, soaps, detergents, shampoos, and candles (59).

Our mouse seizure studies suggest it readily accesses the brain, and it is likely that its consumption as a food or herbal medicine (in cilantro) or as an added food flavoring would result in KCNQ-active levels in the human body; we found the 1% cilantro extract an efficacious KCNQ activator, and (E)-2-dodecenal itself showed greater than half-maximal opening effects on KCNQ2/3 at 100 nM (.10 mV shift at this concentration) (EC50, 60 6 20 nM). We anticipate that its activity on KCNQ channels contributes significantly to the broad therapeutic spectrum attributed to cilantro, which has persisted as a folk medicine for thousands of years throughout and perhaps predating human recorded history.

 

From the University of California: 

How cilantro works as a secret weapon against seizures

In a new study, researchers uncovered the molecular action that enables cilantro to effectively delay certain seizures common in epilepsy and other diseases.

The study, published in FASEB Journal, explains the molecular action of cilantro (Coriandrum sativum) as a highly potent KCNQ channel activator. This new understanding may lead to improvements in therapeutics and the development of more efficacious drugs.

“We discovered that cilantro, which has been used as a traditional anticonvulsant medicine, activates a class of potassium channels in the brain to reduce seizure activity,” said Geoff Abbott, Ph.D., professor of physiology and biophysics at the UC Irvine School of Medicine and principal investigator on the study.

“Specifically, we found one component of cilantro, called dodecenal, binds to a specific part of the potassium channels to open them, reducing cellular excitability.”

 

KCNQ channels and autism

There is a growing body of research suggesting a connection between KCNQ channels and autism.

·        KCNQ channel mutations: Genetic studies have identified mutations in several KCNQ channel genes (including KCNQ2, KCNQ3) in individuals with ASD. These mutations might disrupt the normal function of KCNQ channels, leading to abnormal brain activity.

• Neuronal excitability: KCNQ channels help regulate the electrical activity of neurons by controlling the flow of potassium ions. Mutations or dysfunction in KCNQ channels could lead to increased neuronal excitability, which has been implicated in ASD. 

• Shared features: Epilepsy is a common comorbidity with autism. Interestingly, KCNQ channel dysfunction is also linked to certain types of epilepsy. This suggests some shared mechanisms between these conditions.

 

KCNQ Dysfunction and Intellectual Disability

Mutations in certain KCNQ genes can lead to malfunctions in the corresponding potassium channels. These malfunctions can disrupt normal neuronal activity and contribute to intellectual disability.

• KCNQ2/3 Mutations: Research suggests increased activity in KCNQ2 and KCNQ3 channels, due to mutations in their genes, might be associated with a subset of patients with intellectual disability alongside autism spectrum disorder. 

• KCNQ5 Mutations: Studies have identified mutations in the KCNQ5 gene, leading to both loss-of-function and gain-of-function effects on the channel. These changes in KCNQ5 channel activity can contribute to intellectual disability, sometimes accompanied by epilepsy.

 

The other naming system

KCNQ channels belong to a larger potassium channel family called Kv7. So, you might see them referred to as Kv7.1 (KCNQ1), Kv7.2 (KCNQ2), and so on, based on their specific gene and protein sequence.

 

Mefenamic acid and Kir channels (inwards rectifying potassium ion channels)

Ponstan (mefenamic acid) affects Kir channels and KCNQ channels.

Different Kir channel subtypes contribute to various brain functions, including:

• Neuronal excitability: Kir channels help regulate the resting membrane potential of neurons, influencing their firing activity.
• Potassium homeostasis: They play a role in maintaining the proper balance of potassium ions within and outside neurons, crucial for normal electrical signaling.
• Synaptic inhibition: Some Kir channels contribute to inhibitory neurotransmission, which helps balance excitatory signals in the brain.

Kir Channels are primarily inward rectifiers, meaning they allow potassium ions to flow more easily into the cell than out. They play a role in setting the resting membrane potential of cells, influencing their excitability.

KCNQ Channels can be voltage-gated or regulated by other factors. They contribute to various functions like regulating neuronal firing in the brain,

 

Other effects of Cilantro

It is certainly could be just a coincidence that Cilantro and Ponstan affect KCNQ channels. Cilantro has many other effects.

Coriandrum sativum and Its Utility in Psychiatric Disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10385770/

Recent research has shown that Coriandrum sativum offers a rich source of metabolites, mainly terpenes and flavonoids, as useful agents against central nervous system disorders, with remarkable in vitro and in vivo activities on models related to these pathologies. Furthermore, studies have revealed that some compounds exhibit a chemical interaction with γ-aminobutyric acid, 5-hydroxytryptamine, and N-methyl-D-aspartate receptors, which are key components in the pathophysiology associated with psychiatric and neurological diseases. 

 

Bioactivities of isolated compounds from Coriandrum sativum by interaction with some neurotransmission systems involved in psychiatric and neurological disorders.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10385770/table/molecules-28-05314-t002/?report=objectonly

 

 

Understanding 2p16.3 (NRXN1) deletions

One parent contacted me to ask about the genetic test results they had received for their child.

To understand what happens when parts of the NRXN1 gene are missing you need to read up on neurexins and neuroligins.

 

Neurexins and Neuroligins

Neurexins ensure the formation of proper synaptic connections, fine-tune their strength, and contribute to the brain's adaptability. Understanding their role is crucial for understanding brain development, function, and various neurological disorders.

Neurexins and neuroligins are cell adhesion molecules that work together to ensure proper synapse formation, function, and ultimately, a healthy and functioning brain.

Neuroligins are located on the postsynaptic membrane (receiving neuron) of a synapse.

Neurexins are located on the presynaptic membrane (sending neuron) of a synapse.

Mutations in either neurexin or neuroligin genes have been linked to various neurodevelopmental disorders, including autism.

A comprehensive presentation for families is below:

 

Understanding 2p16.3 (NRXN1) deletions

https://www.rarechromo.org/media/information/Chromosome%20%202/2p16.3%20(NRXN1)%20deletions%20FTNW.pdf

 

A microdeletion in the NRXN1 gene on chromosome 2p16.3 can cause a condition similar to Pitt-Hopkins syndrome, but referred to as Pitt-Hopkins like syndrome 2 (PHLS2).

 

NRXN1 Gene:

• NRXN1 codes for a protein called neurexin 1 alpha, which plays a critical role in the development and function of synapses, the junctions between neurons in the brain.
• Neurexin 1 alpha helps neurons connect with each other and transmit signals.

Microdeletion:

• A microdeletion is a small deletion of genetic material from a chromosome.
• In PHLS2, a microdeletion occurs in the NRXN1 gene, removing some of the genetic instructions needed to produce functional neurexin 1 alpha protein.

Pitt-Hopkins Like Syndrome 2 (PHLS2):

• PHLS2 is a genetic disorder characterized by intellectual disability, developmental delays, and various neurodevelopmental features.
• Symptoms can vary depending on the size and specific location of the NRXN1 microdeletion.
• Common features include:
• Intellectual disability (ranging from mild to severe)
• Speech and language impairments
• Developmental delays in motor skills
• Stereotypies (repetitive movements)
• Seizures
• Behavioral problems (e.g., hyperactivity, anxiety)
• Distinctive facial features (not always present)

 

What has this got to do with Pitt Hopkins syndrome (loss of TCF4)?

“TCF4 may be transcribed into at least 18 different isoforms with varying N-termini, which impact subcellular localization and function. Functional analyses and mapping of missense variants reveal that different functional domains exist within the TCF4 gene and can alter transcriptional activation of downstream genes, including NRXN1 and CNTNAP2, which cause Pitt-Hopkins-like syndromes 1 and 2.”

 

NRXN1 interactions with other genes/proteins

Given the function of neurexins and neuroligins, you would expect that the common interactions of NRXN1 are with neuroligins. We see below the NLGNs (neuroligin genes/proteins)

Our more avid readers may recall that neuroligins are one mechanism for regulating the GABA switch. This is the developmental switch that should occur in all humans about two weeks after birth.  If it does not occur, the brain cannot develop and function normally. Autism and intellectual disability are the visible symptoms.

 

An unexpected role of neuroligin-2 in regulating KCC2 and GABA functional switch

https://molecularbrain.biomedcentral.com/articles/10.1186/1756-6606-6-23#:~:text=Novel%20function%20of%20neuroligin%2D2,expression%20level%20was%20significantly%20decreased.

 

We report here that KCC2 is unexpectedly regulated by neuroligin-2 (NL2), a cell adhesion molecule specifically localized at GABAergic synapses. The expression of NL2 precedes that of KCC2 in early postnatal development. Upon knockdown of NL2, the expression level of KCC2 is significantly decreased, and GABA functional switch is significantly delayed during early development. Overexpression of shRNA-proof NL2 rescues both KCC2 reduction and delayed GABA functional switch induced by NL2 shRNAs. Moreover, NL2 appears to be required to maintain GABA inhibitory function even in mature neurons, because knockdown NL2 reverses GABA action to excitatory. 

Our data suggest that in addition to its conventional role as a cell adhesion molecule to regulate GABAergic synaptogenesis, NL2 also regulates KCC2 to modulate GABA functional switch and even glutamatergic synapses. Therefore, NL2 may serve as a master regulator in balancing excitation and inhibition in the brain.

 

It would seem plausible that in the case of microdeletions of the NRXN1 gene there will be a direct impact on the expression of NLGN2 gene that encodes neuroligin 2.

So plausible therapies to trial for microdeletions of the NRXN1 gene would include bumetanide, as well as cGPMax, due to the link with Pitt Hopkins.

 

GPC5 gene 

Finally, we move on to our last gene which is GPC5.

The protein Glpycan 5/GPC5 plays a role in the control of cell division and growth regulation.

Not surprising, GPC5 acts a tumor suppressor, making it a cancer gene. Because of this it is also an autism gene. It also plays a role in Alzheimer’s disease.

I was not sure I would be able to say anything about how you might treat autism caused by a mutation in GPC5.

 

Glycan susceptibility factors in autism spectrum disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556687/

 

I am assuming the mutation causes a loss of function, meaning there is a reduced level of the protein Glpycan 5.

Since one role of this gene is to suppress Wnt/beta-catenin signaling, you might want to replace this action.

This is actually covered in my blog in various places. One way is via a GSK-3β inhibitor.

GSK-3β inhibitor include drugs designed to block GSK-3β activity, examples include lithium (used for bipolar disorder), kenpaullone, and tideglusib. Certain natural compounds like curcumin and quercetin have been shown to possess GSK-3β inhibitory effects.

Atorvastatin, which my son has taken for 10 years, is indirectly a GSK-3β inhibitor

Some natural compounds like fisetin (found in fruits and vegetables) have been shown to promote beta-catenin phosphorylation, leading to its degradation.

In previous posts I pointed out that the cheap kids’ anthelmintic medication Mebendazole is indirectly another Wnt inhibitor. This is because it reduces TNIK. TNIK promotes Wnt signaling by stabilizing beta-catenin, a key player in the pathway. By reducing TNIK levels, mebendazole indirectly disrupts Wnt signaling. Mebendazole is therefore a novel cancer therapy and is being investigated to treat brain cancers, colon cancer, breast cancers etc.

Unlike what is says in the literature about GPC5, there actually are many options that can be safely trialed.

Note that you may not know for sure that any mutation is actually causal/pathogenic. Some people have several “likely pathogenic” mutations, some likely are not.

 

Conclusion

We have covered the potassium ion channel Kv7.1 previously. In Pitt Hopkins syndrome this ion channel is over expressed and so you would want to inhibit it. Do not take Cilantro, it would have the opposite effect to what you want.

It looks like cGPMAX is one thing you need to trial for Pitt Hopkins syndrome and Rett syndrome. For idiopathic autism it may, or may not help. Try a low dose first, observe the effect, then try a higher dose.

In Rett syndrome we know that people with have as much NKCC1 RNA — a molecule that carries the instructions to make the protein — as healthy individuals. However, their levels of KCC2 RNA are much lower, potentially disrupting the excitation/inhibition balance of nerve cell signaling. This will result in elevated chloride in neurons. This is correctable today using bumetanide.

People with NRXN1 microdeletions do seem to have treatment options, as do people with GPC5 mutations.

Note that out reader Janu, treating a mutation in GABRB2, reports success with a combination of the SSRI drug Lexapro and sodium valproate.

I am a fan of low dose Ponstan for sound sensitivity, it has numerous potentially beneficial mechanisms. It has been even shown to protect against Alzheimer’s disease.  There is no reason not to give cilantro a try as an alternative or complement to improve sound sensitivity.

Dried coriander is normally made from the seeds and is not what you need. In your supermarket you can buy fresh coriander leaves (Cilantro). The fresh herb is about 90% water, but when you dry the herb you will lose at lot of the active substance because it is volatile and will evaporate. My guess is that you will need 2-3 g of the fresh herb to equal Andy’s 425mg supplement.  You can eat the stalks as well as the leaves, it all has the same pungent taste.