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.

 

Sulfarlem / Anethole trithione (AOL) for Autism secondary to Mitochondrial Dysfunction (AMD)? Not to mention Metastasis

Sulfarlem has been used to treat dry mouths for half a century

By www.scientificanimations.com - http://www.scientificanimations.com/wiki-images/, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=77499374

Sulfarlem is a drug containing a chemical called Anethole trithione. Anethole is an organic compound used as a flavouring, it contributes a large component of the odour and flavour of anise and fennel.

Anise seed, or aniseed, contains a large amount of Anethole. The popular Greek drink Ouzo turns cloudy when diluted with water because of the Anethole. For the French it is called Pastis.   

                                                                      

Ouzo has been used to treat dry Greek mouths for seven centuries, particularly after a good meal.

For Anethole without the alcohol, a good source would include aniseed or fennel.

Aniseed

Today's post was prompted by a comment made before Christmas by our reader Claudia; she highlighted some recent French research that repurposes a drug developed by Solvay half a century ago.  The drug is Sulfarlem / Anethole trithione and it is used to treat people with a dry mouth, mainly in French speaking countries (including Canada) and in China, particularly Taiwan.

Sulfarlem appears to have secondary effects that include inhibiting oxidative stress in mitochondria which might benefit a long list of diseases, though they do not mention autism secondary to mitochondrial disease.

The other effect is a reduction in metastasis in people with cancer. This effect was written about in 2002 in the mass media.

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity. 

Conclusion / Significance This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer’s diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.


Here is the associated patent:-

Compounds for the treatment of diseases linked to mitochondrial reactive oxygen species (rose) production

  

SUMMARY 

The present invention relates to an inhibitor of production of reactive oxygen species (ROS) for treating or for use in the treatment of free oxygen-radicals related diseases. In one embodiment, said inhibitor is anethole trithione (AOL). In one embodiment, said inhibitor inhibits mitochondrial production of ROS. In a preferred embodiment, said inhibitor inhibits mitochondrial production of ROS at site IQ of complex I of mitochondria. 

In one embodiment, said free oxygen-radicals related diseases are selected from the group comprising: age-related macular degeneration, Parkinson's disease, Alzheimer's disease, ischemic and reperfusion injury, pulmonary arterial hypertension, scleroderma, atherosclerosis, heart failure, myocardial infarction, arthritis, pulmonary toxicity, cardiopulmonary diseases, inflammatory diseases, cancer, metastasis, cardiac toxicity of anthracyclines, heart failure regardless of origin, ischemia, heart attack, stroke, thrombosis and embolism, asthma, allergic/inflammatory conditions, bronchial asthma, rheumatoid arthritis, Inflammatory Bowel Disease, Huntington's disease, cognitive disorders, Progeria, progeroid syndromes, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia, HIV-1-associated dementia, post-stroke dementia, Down's syndrome, motor neuron disease, amyloidosis, amyloid associated with type 11 diabetes, Creutzfelt-Jakob disease, necrotic cell death, Gerstmann-Straussler syndrome, kuru and animal scrapie, amyloid associated with longterm hemodialysis, senile cardiac amyloid and Familial Amyloidotic Polyneuropathy, cerebropathy, neurospanchnic disorders, memory loss, aluminum intoxication, reducing the level of iron in the cells of living subjects, reducing free transition metal ion levels in mammals, patients having toxic amounts of metal in the body or in certain body compartments, multiple sclerosis, amyotrophic lateral sclerosis, cataract, diabetes, cancer, liver diseases, skin ageing, transplantation, ototoxic secondary effects of aminoglycosides, neoplasms and toxicity of anti-neoplastic or immunosuppressive agents and chemicals, innate immune responses, and, Friedreich's Ataxia.

In one embodiment, said inhibitor is for preventing or for use in the prevention of metastasis.

                                                                                                   

From way back in 2002: -

Dry-Mouth Drug Joins Cancer Fight

Stephen Lam, director of the lung cancer prevention program at the British Columbia Cancer Research Center in Vancouver, British Columbia, found that one of Solvay's drugs, marketed as Sialor or Sulfarlem, also significantly reduces the spread of lung-cancer tumors.

Lam's study completed the second phase of trials necessary for the FDA's consideration. Over six months, 101 smokers and former smokers took the dry-mouth drug. It reduced the progression of their lung cancer tumors by an average of 22 percent.

To participate in the study, the smokers had to have smoked at least a pack a day for 30 years, or two packs a day for 15 years.

Those who took a placebo had 53 percent more new lesions or lesions that got worse than those who took the drug.

The billion-dollar question is, who will pay for more clinical trials? Lam's study was paid for with grants from the National Cancer Institute, and the money has run out. The final stage of clinical trials can cost hundreds of millions of dollars.

The French have recently followed up :-

Mitochondria ROS blocker OP2-113 downregulates the insulin receptor substrate-2 (IRS-2) and inhibits lung tumor growth

They go further in their patent and propose Sulfarlem as a blocker of metastasis.

A recent Chinese paper sets out the mechanism of action.

CXCR4 and PTEN are involved in the anti-metastatic regulation of anethole in DU145 prostate cancer cells

Taken together, anethole demonstrated to act as the CXCR4 antagonist and as the PTEN activator which resulted to PI3K/AKT-mediated inhibition of the metastatic prostate cancer progressions.

Regular readers will know that PTEN is both a cancer gene and an autism gene.

PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat.

Activating PTEN should also help some types of autism.

A recent Japanese study has a different take on the anti-metastatic mode of action.

Anethole Exerts Antimetastatic Activity via Inhibition of Matrix Metalloproteinase 2/9 and AKT/Mitogen-Activated Kinase/Nuclear Factor Kappa B Signaling Pathways

Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-kB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-kB signal transducers.

Metastasis

There is quite a lot in this blog about cancer, due to the overlapping signalling pathways with autism, so follows a little digression about metastasis.

Metastasis is a pathogenic agent's spread from an initial/primary site to a different/secondary site within the host's body.

Often it is the metastasis that ultimately kills people; indeed this just happened to the mother of one of Monty's friends with autism.

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension.

Source: Mikael Häggström 

If a cheap substance could reduce metastasis that would be a big deal.  Cancer is currently the second most common cause of death.  If you can take cheap/safe chemoprotective agents to reduce cancer’s occurrence and a cheap substance to reduce its spread/metastasis you would be pretty smart.

Cheap Cancer Drugs

Numerous cheap drugs have known anti-cancer properties (Metformin, Aspirin, Statins, plus many more) but absolutely no serious interest is shown to apply any of them.  Instead, some hugely expensive drugs have been developed that often extend life by a matter of months.

Sulfarlem certainly is cheap, costing 3 euros (USD 3.3) a pack in France, where it seems to be sold OTC.

It looks like the world of cancer research is as dysfunctional as the world of autism research, when it comes to translating existing knowledge into beneficial therapies.  Nobody wants a cheap cancer drug and I think nobody wants a cheap autism drug.  

Most people still believe autism cannot be treated and some even think it should not be treated. 

Conclusion

Sulfarlem has been around for 50 years and so there is plenty of safety data regarding its use.

It does look like a significant number of people with autism have a problem with Complex 1 in their mitochondria.  This subject has been covered extensively in this blog in regard to regressive autism and what Dr Kelley, from Johns Hopkins, termed autism secondary to mitochondrial disease (AMD).  Unfortunately for us, he has retired.

https://epiphanyasd.blogspot.com/p/regressive-autism.html

Dr Kelley’s mito-cocktail of antioxidants is used by many, but even he makes clear that it is far from perfect and it is not so cheap. 

Sulfarlem looks like an interesting potential add-on, or even a potential replacement.

The fact that Sulfarlem also activates PTEN means that an entirely different group with autism might see a benefit.

Who might carry out a trial of Sulfarlem in autism?  I think the one likely group are those irrepressible autism researchers in Iran, who have trialed so many off-label drugs.  Since Sulfarlem is already licensed in Canada, one of those more enlightened researchers in Toronto might like to investigate.

If you live in France you can skip your early morning expresso and go down to the pharmacy with your three euros and then make your own trial.

Sulfarlem, or just plain anethole, seems a cheap/safe way to potentially reduce metastasis once cancer has been identified. Probably not worth waiting another 20 years for any possible further clinical trials.

Treating Mitochondrial Disease/Dysfunction in Autism

In my book I will be covering the science behind hopefully almost all autism, which then naturally leads to translating it into therapy.  In the ideal world you would just skip straight to the therapy and the final section of the book will be just that.  Clearly it would make sense to read the science first, so that you know what are the dysfunctions that you might need to treat.

Hopefully there will also be some case studies from people who have applied a science-based approach to identify and implement effective therapies.

Roger would clearly make a very good example of a reversible in-born metabolic-caused type of autism.

I will be posting on my blog some drafts from the Part III - Translating Science to Treat Autism.  This is of course just one person's collection of other people's ideas and some of his one.  The reader and his/her medical medical team ultimately decide what to implement and must monitor its ongoing implementation.

 * * *

Mitochondrial disease is managed rather than cured. It seems to be present in autism in widely varying degrees of severity.  Extreme cases result in very severe regressive autism with MR/ID.

It is either diagnosed based on detailed analysis of numerous blood tests, or more recently via a sample taken from inside the cheek. These tests cannot be perfect, because mitochondrial disease can be organ-specific.

Someone with body-wide mitochondrial disease will have poor exercise endurance and this will be very noticeable compared to siblings and peers.

Dr Kelley, from Johns Hopkins, has published his therapy for autism secondary to mitochondrial disease (AMD):-

1.      Augment residual mitochondrial enzyme complex I activity

2.      Enhance natural systems for protection of mitochondria from reactive oxygen species

3.      Avoid conditions known to impair mitochondrial function or increase energy demands, such  as prolonged fasting, inflammation, and the use of drugs that inhibit complex I.

Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

L-Carnitine 50 mg/kg/d                Alpha Lipoic acid 10 mg/kg/d

Coenzyme Q10 10 mg/kg/d          Pantothenate 10 mg/kg/d

Vitamin C 30 mg/kg/d                  Nicotinamide 7.5 mg/kg/d (optional)

Vitamin E 25 IU/kg/d                   Thiamine 15 mg/kg/d (optional)

There are actually five stages in the OXPHOS process in mitochondria and there are five enzyme complexes. Dr Kelley's plan above is for the most common dysfunction, complex 1.

Different clinicians have different treatments.

Also appearing elsewhere are :-

Calcium folinate (2 x 25 mg), but not because of peroxynitrite

Biotin 5-10 mg/day

NAC

Methylcobalamin B12

Creatine

On the basis that peroxynitrite, from nitrosative stress, damages the mitochondria, you might consider:

·         Calcium folinate (leucoverin) in very high doses like 25mg twice a day.

·         Xanthine oxidase inhibitors, typically used to lower uric acid to treat gout. A good example is Allopurinol. It will both lower uric acid and peroxynitrite. Uric acid is itself a potent scavenger of peroxynitrite; this may look odd given the previous sentence. If someone has low uric acid and wants to reduce peroxynitrite then uric acid itself should be therapeutic. The purine metabolism may play a key role in some types of autism, as proposed by Professor Robert Naviaux.

·         Rosmarinic acid, a natural scavenger of peroxynitrite.

There are many anomalies in autism and one is uric acid.  Some people have low levels and some have high levels. Uric acid is itself a scavenger of peroxynitrite.  People with high levels of uric acid do get gout, but almost never MS (multiple sclerosis) and it has been suggested that scavenging peroxynitrite is neuroprotective.

Special, electrically charged, antioxidants have been developed to target the mitochondria.  MitoE is a charged version of vitamin E and MitoQ is a charged version of coenzyme Q10.

Based on the research, you might  also seek to activate PGC-1α, the master regulator of mitochondrial biogenesis. This can potentially be achieved via:-

·         Exercise  (gradual endurance training)

·         Activate PPARγ and perhaps  PPARα (e.g. Bezafibrate  and Rosiglitazone)

·         Activate AMPK (Metformin)

·         Activate Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Carnitine-like analogs may also help in theory.  The standard L-Carnitine, widely used as a supplement, is very poorly absorbed even at high doses. An analog is a modified version of a molecule that keeps the therapeutic beneficial effect, but overcomes a drawback, bioavailability in the case of carnitine. There is some basis in the literature to believe that the Latvian drug Mildronate might be useful to treat complex 1 mitochondrial dysfunction.



more detail at  https://epiphanyasd.blogspot.com/2017/02/mitochondrial-disease-and-autsim.html