Time for a disruptor in the world of Autism and Psychiatry?

Source: Thanks Gemini AI

It looks like half of America loves Donald Trump and the other half loathes him. Best not to even ask people in Canada and Mexico. 

One very good thing about the Don is that he is fully aware of the explosion in autism diagnosis since 1980 and he naturally asks why is it happening? Having figured that one out, you then move on to what to do about it: celebrate it, treat it, fix it, prevent it, ignore it, or just endlessly research it? 

We know that Elon Musk was diagnosed with Asperger’s syndrome and Bill Gates has announced that he likely had autism as a child. Kanye West has just announced that he was mistakenly diagnosed with bipolar disorder but now has an autism diagnosis.

Almost every time there is a mass shooting the perpetrator either has, or is seeking, an autism diagnosis.

At the other end of the spectrum, children with severe autism cannot get placements in special schools because there are no spaces. Mainstream schools now often have multiple kids with severe autism and their aides in regular classes, where previously there were none.

Rather than just accept this new normal, how about doing something about it? I have done my part and changed my world — it is possible.

Under Trump 2.0 it is very clear that many things are going to change.

It would be great if a genuine review was carried out into all pediatric psychiatric diagnoses and special educational needs in young people.

Throw away the rulebook and write a new one.

Create new diagnosis protocols that stratify the population correctly and in a way people can understand and that does not create infighting like we see today. Don’t lump Kanye in with people who cannot talk, take a shower independently or tie their Yeezy shoelaces.   

All common sense you would think, but in 12 years of writing this autism blog I very rarely encounter much common sense.

I certainly do not agree with everything the Don says or does, but to unleash RFK Jr on trying to make America healthy again looks a great idea.

As we have seen in this blog and in my book, it is wrong to say, “vaccines cause autism” but correct to say, “vaccines can cause autism.” This was proven by Dr Jon Poling and his Johns Hopkins colleagues in a case filed in 2008 against the National Vaccine Injury Compensation Program. Very many things can cause “autism:” it was mitochondrial dysfunction in the Poling case, but even a mosquito bite leading to cerebral malaria in a child can produce cognitive deficits, behavioral difficulties, and epilepsy, which I guess also counts as “autism” these days. There are many hundreds of documented factors that can lead to autism; some are random genetic mutations, but many can be controlled and minimized.

So, RFK, please go ahead and disrupt away. I am more than happy to have Amazon send you a free copy of my book! You may not agree with all of it, but then, you are not supposed to.

Go and ask all the questions you are not supposed to ask.

Challenge vested interests.

Forget political correctness and focus on the facts.

Tear up DSM5 (the Diagnositic and Statistical Manual of Mental Disorders) and make a new one. Save a decade and use some AI, check with Elon.

Don’t employ people with a psychiatric diagnosis or from persecuted minorities in your autism team; recruit from the vast pool of well-adjusted regular people out there — people without a built-in bias and their own agenda.

A hidden disability? - Automatic identification of autistic children based on appearance reaches 94% accuracy. Spectrum Needs assessed in a small trial. Bullying in ASD. TCF20 and GABAa receptors. Special educational needs – not so special any more.

 

Today’s post is a summary of a small part of the recent autism research. I am constantly amazed how much autism related research is churned out every day. To anyone who says more autism research is needed, just take a look at how much there already is !!  

 

Facial recognition of Autism?

Those working every day with special needs children have long known that you can pretty quickly spot a child with autism, without any lengthy diagnostic procedure.

Some advocates like to see autism as a hidden disability and believe you cannot “look autistic.” They had better not read this post.

I did write about facial recognition of single gene autisms and rare diseases where a commercialized product (Face2Gene) can now identify 200 conditions with 91% accuracy. This is from a single photo of the face. 

Now Chinese researchers have produce software that can predict autism in pre-schoolers with 94% accuracy based on automated analysis of a video.

Risk assessment and automatic identification of autistic children based on appearance

The diagnosis of Autism Spectrum Disorder (ASD) is mainly based on some diagnostic scales and evaluations by professional doctors, which may have limitations such as subjectivity, time, and cost. This research introduces a novel assessment and auto-identification approach for autistic children based on the appearance of children, which is a relatively objective, fast, and cost-effective approach. Initially, a custom social interaction scenario was developed, followed by a facial data set (ACFD) that contained 187 children, including 92 ASD and 95 children typically developing (TD). Using computer vision techniques, some appearance features of children including facial appearing time, eye concentration analysis, response time to name calls, and emotional expression ability were extracted. Subsequently, these features were combined and machine learning methods were used for the classification of children. Notably, the Bayes classifier achieved a remarkable accuracy of 94.1%. The experimental results show that the extracted visual appearance features can reflect the typical symptoms of children, and the automatic recognition method can provide an auxiliary diagnosis or data support for doctors.

The ASD group were all pre-school children, aged between 20 and 60 months, with an average age of 33.4 months for males and 31.5 months for females.

Like it or not, it seems that autistic toddlers do look different and so it is not a hidden disability. Nobody should be waiting years for a diagnosis.

Bullying

Most autism diagnosed today is mild, level 1 autism. Some of this group really do struggle and can genuinely benefit from pharmacologic therapies.

Bullying is one very common issue that is faced and does not need drug therapy, it needs a different kind of intervention.

A preliminary analysis of teaching children with autism spectrum disorder self-protection skills for bullying situations

Children diagnosed with autism spectrum disorder are at high risk of being bullied, but research on teaching children with autism self-protection skills for bullying situations is scant. We taught five children self-protection skills for two types of bullying (threats and unkind remarks) and consecutive bullying occurrences. We first evaluated behavioral skills training and a textual prompt to teach children to report threats of physical or material harm, provide a disapproving statement after a first unkind remark, and occupy themselves with an activity away from a bully after a second unkind remark. Additional tactics were necessary to aid in the discrimination of bullying situations for two children. There were increases in the self-protection skills with all children. Results further support that an active-learning approach is efficacious in teaching responses to bullying in simulated situations. Considerations for teaching these skills while maintaining trust and rapport with children and caregivers are discussed.

Having a sibling in the same school can be an effective defence against bullying. It might be an older brother, as was the case for Monty, but a younger sister can also be very effective. One episode, of many, I witnessed at school was a young Swedish girl intervening on behalf of her older Aspie-like brother. It really shocked the older boys and certainty impressed me.

I think most bullying affects those with level 1 autism. Those with severe autism would tend to have a 1:1 assistant and if he/she is doing their job there should not be the possibility bullying. I am told that out in the real world kids with level 3 autism do get bullied, which means the system has failed.

From the school’s perspective there is also the opposite issue of the pupil with autism/ADHD attacking other pupils or staff. This does happen and if the child is a large fully-grown male can lead to very serious injury. It is not just those with level 3 autism who can do this.

I think the best strategy to protect against bullying is to ensure your child is in a caring environment at school and is well integrated. This may be easier said than done, but it is possible for many people. Then the other pupils will look out for the one with special needs. This assumes you do not overdo it with who gets to be "special".

Special needs are not so special any more, as was highlighted recently in the UK. For the most privileged group of pupils, those going to private fee-paying schools, 41% are getting special treatment in their exams due to their various special needs. Even in the regular state schools, which for sure have a higher percentage of kids with actual special needs, 26% of pupils get extra time in exams.

Nearly one in three pupils in England given extra time in exams, says regulator

Nearly a third of pupils in England were given 25% extra time to complete their GCSEs and A-level exams following a surge in special exam access arrangements being granted, data from Ofqual has shown.

The figure is higher again among exam candidates in private schools where more than two in five received 25% extra time in the last academic year, according to England’s exams regulator.

The total number of approved special access arrangements for GCSE, AS and A-level exams rose by 12.3% in the 2023/24 school year compared to the year before, the data has revealed.

·         Independent centres 41.8%

·         Sixth form and FE colleges 35%

·         Non-selective state schools 26.5%

It comes as education leaders have suggested more pupils are seeking support after the pandemic due to a rise in young people with special educational needs and disabilities (Send) and mental health issues.

Requests for 25% extra time in exams was the most common approved access arrangement for pupils with learning difficulties or disabilities, followed by computer readers, scribes and speech recognition.

 

Folate supplementation in mothers prevent pesticides causing neurodevelopmental disorders in offspring

There is a lot of research about folate (vitamin B9), birth defects and autism. From the early 1990s women were encouraged to take folate supplements during pregnancy to avoid neural tube defects and other congenital abnormalities.

Some individuals have mutations in the MTHFR gene that impair their ability to convert folic acid into its active form, L-methylfolate. For such individuals, taking methylated folate supplements will be necessary.

More recently we have learned that some people with adequate folate intake can lack folate inside their brain. They have antibodies that block the transmission of folate across the blood brain barrier.

We saw how one clinician is prescribing high dose calcium folinate to couples wishing to reduce the risk of autism in their future offspring, if they test positive themselves for folate receptor auto-antibodies.

As we already know exposure to pesticides and some other unnatural chemicals during pregnancy can lead to neurodevelopmental disorders (NDDs) that include autism.

The paper below is interesting because it looks as how to minimize the potential damage caused by exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US.

Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles 

Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and NDDs. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams to vehicle or deltamethrin (3 mg/kg every 3 days) with or without folate supplementation (5 mg/kg methylfolate every 3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to NDDs; increased plasma folate concentrations; and increased neural expression of SHMT1, a cellular folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotype (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two other folate-related proteins. We conclude that DPE causes NDD-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.

 

A round-up of therapies to treat mouse autism

Treating human autism is not yet mainstream, but treating autism in mice has been going on for decades. Of course the idea is to use mouse models with a view to later treating humans.

The paper below is about mice, but it is actually a very good summary of the current status of treatment options more broadly.

It even covers the use of HDAC inhibitors to use epigenetics as a treatment tool. Click on the link to read the full text for free. 

The Use of Nutraceutical and Pharmacological Strategies in Murine Models of Autism Spectrum Disorder 

Autism spectrum disorder (ASD) is a common neurodevelopmental condition mainly characterized by both a scarce aptitude for social interactions or communication and engagement in repetitive behaviors. These primary symptoms can manifest with variable severity and are often paired with a heterogeneous plethora of secondary complications, among which include anxiety, ADHD (attention deficit hyperactivity disorder), cognitive impairment, sleep disorders, sensory alterations, and gastrointestinal issues. So far, no treatment for the core symptoms of ASD has yielded satisfactory results in a clinical setting. Consequently, medical and psychological support for ASD patients has focused on improving quality of life and treating secondary complications. Despite no single cause being identified for the onset and development of ASD, many genetic mutations and risk factors, such as maternal age, fetal exposure to certain drugs, or infections have been linked to the disorder. In preclinical contexts, these correlations have acted as a valuable basis for the development of various murine models that have successfully mimicked ASD-like symptoms and complications. This review aims to summarize the findings of the extensive literature regarding the pharmacological and nutraceutical interventions that have been tested in the main animal models for ASD, and their effects on core symptoms and the anatomical, physiological, or molecular markers of the disorder.

The body of research here summarized suggests that many therapeutic strategies have yielded positive results for ASD core symptoms and ASD-linked cellular, anatomical, and metabolic alterations at the preclinical level. These results ultimately confirm clinical and in vitro evidence regarding the main pathways involved in ASD pathogenesis and hint at the potential for the combination of different types of treatment. The studies reviewed here showed that a treatment’s success or failure in these models usually depends on administration timing. The best results are commonly achieved when protective treatment is given in the first weeks after birth or prenatally. Unfortunately, this is not easily translatable into clinical practice as ASD diagnosis, at the moment, postdates this time window. Moreover, it is notable that most of the treatments employed in these studies did not achieve significant improvements in all the behavioral tests or definitive success in clinical trials. Despite the exact causes for the disparity between promising preclinical results and modest or negative clinical outcomes remaining unknown, a few hypotheses can be formulated. The results of many tests commonly employed to measure sociability and repetitive behaviors in mice can be altered by other symptoms known to be observed in these murine models, such as altered motor coordination, cognitive impairment, and anxiety, which may lead scientists to overestimate the effect of certain treatments on social behavior. Moreover, poor translatability may also be ascribed to the heterogeneity in symptoms and genetic backgrounds found in ASD human patients which, conversely, is far more limited in these mice strains. Ultimately, other possible confounding factors such as interactions with concurrent medications, socio-economic elements, patient lifestyle, or concomitant diseases are significantly more frequent and variable in the human population. Poor translatability may be potentially alleviated by precision medicine approaches in clinical practice and by preclinical testing of single treatments in a variety of ASD murine models. Ultimately, the present literature shows that, despite the limited clinical translational success, murine models can be a valuable tool for testing a variety of treatments in ASD research.

 

Figure 2. Schematic representation of key elements of the mTOR pathway and of therapeutic interventions considered in murine models for ASD. Abbreviations: PIP2: phosphatidylinositol 4,5-bisphosphate PIP3: phosphatidylinositol 3,4,5-bisphosphate PI3K: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; Akt: protein kinase B; TSC1: tuberous sclerosis 1; TSC2: tuberous sclerosis 2; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; S6K: Ribosomal protein S6 kinase beta-1; eIF4E: eukaryotic Initiation Factor 4E; ULK complex: Unc-51-like kinase 1 complex; PKCa: protein kinase C alpha; P: phosphate group

You can see all the amino acids that have been trialed to modify mTOR (taurine, lysine, histidine and threonine) plus metformin and the potent rapamycin.

Also mentioned is the WHEN in what I call the what, when and where in autism treatment. This is the idea of treatment windows, when a specific therapy can potentially be beneficial.

This very concept was discussed in a recent paper on Rett syndrome.

Protein Loss Triggers Molecular Changes Linked to Rett Syndrome 

Key Facts

·         Early Gene Changes: Loss of MeCP2 leads to immediate gene expression dysregulation, affecting hundreds of genes.

·         Neuronal Impact: Dysregulated genes are linked to neuronal function, causing downstream circuit-level deficits.

·         Therapeutic Window: The study reveals a time frame between molecular changes and neurological symptoms, enabling early intervention opportunities.

Another transcription factor (TCF) that causes autism

There is a lot in this blog about TCF4 (transcription factor 4). Loss of this gene leads to Pitt Hopkins syndrome. Disruption of the gene is associated with schizophrenia and intellectual disability.

Mutations in TCF20 lead to a kind of autism plus intellectual disability called TCF20-Related Neurodevelopmental Disorder. Like Pitt Hopkins, this is a rare disorder, but milder misexpression of the gene is likely much more common. In the recent paper below we see which are the downstream effector genes.

Our old friends the sub-units of GABAa receptors are there. In this case it is GABRA1 and GABRA5 that are reduced.

Both GABRA1 and GABRA5 play essential but distinct roles in regulating neuronal inhibition. GABRA1 primarily contributes to synaptic inhibition and is critical in seizure and anxiety regulation, while GABRA5 is involved in tonic inhibition and cognitive processes.

Malfunctions in GABRA1 and GABRA5 can lead to autism, anxiety, schizophrenia, intellectual disability, epilepsy etc

Regulation of Dendrite and Dendritic Spine Formation by TCF20

Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20-associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre- and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function.

Based on these results, we analyzed the expression of neuronal proteins in TCF20-deficient neurons and found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates (Figure 5) and in synaptosomal preparations (Figure 5) of shTCF20 rat cortical cultures. Additionally, GluN2B and GABRA5 were significantly downregulated, and GluA2 was significantly upregulated in synaptosomal preparations of shTCF20 rat cortical cultures (Figure 5).

On the subject of GABA type A receptor, we have a very recent paper from Poland that delves into this subject in great detail. 

Molecular mechanisms of the GABA type A receptor function

The GABA type A receptor (GABA_AR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia.

And finally …

Dr Frye has published a study that assessed the effect of his friend Dr Boles’ mitochondrial cocktail.

I did meet Dr Boles a while back at a conference in London. He came with his wife and a stock of NeuroNeeds products for sale, including SpectrumNeeds which was the subject of today’s paper. He was telling me all about the great food just across the border in Mexico and how he learnt Spanish.

A Mitochondrial Supplement Improves Function and Mitochondrial Activity in Autism: A double-blind placebo-controlled cross-over trial

Autism spectrum disorder (ASD) is associated with mitochondrial dysfunction but studies demonstrating the efficacy of treatments are scarce. We sought to determine whether a mitochondrial-targeted dietary supplement designed for children with ASD improved mitochondrial function and ASD symptomatology using a double-blind placebo-controlled cross-over design. Sixteen children [Mean Age 9y 4m; 88% male] with non-syndromic ASD and mitochondrial enzyme abnormalities, as measured by MitoSwab, received weight-adjusted SpectrumNeeds and QNeeds  and placebos matched on taste, texture and appearance during two separate 12-week blocks. Which product received first was randomized. The treatment significantly normalized citrate synthase and complex IV activity as measured by the MitoSwab. Mitochondrial respiration of peripheral blood mononuclear cell respiration, as measured by the Seahorse XFe96  with the mitochondrial oxidative stress test, became more resilient to oxidative stress after the treatment, particularly in children with poor neurodevelopment. The mitochondrial supplement demonstrated significant improvement in standardized parent-rated scales in neurodevelopment, social withdrawal, hyperactivity and caregiver strain with large effect sizes (Cohen’s d’ = 0.77-1.25), while changes measured by the clinical and psychometric instruments were not significantly different. Adverse effects were minimal. This small study on children with ASD and mitochondrial abnormalities demonstrates that a simple, well-tolerated mitochondrial-targeted dietary supplement can improve mitochondrial physiology, ASD symptoms and caregiver wellbeing. Further larger controlled studies need to verify and extend these findings. These findings are significant as children with ASD have few other effective treatments.

Conclusion

Plus ça change, plus c'est la même chose.

The more things change, the more they stay the same.

There isn’t much new that we don’t already know. This is probably good news.

I think for Dr Boles and our Spanish speaking readers you would say "Cuanto más cambian las cosas, más siguen igual." Correct me if I am wrong.

Out with the old and in with the new? Maybe for iPhones but not for Autism therapies

 

It is important to move with the times, but it is equally important to realize that some old ideas remain better than some new ideas.

I was both pleased and surprised that my new car came with a full sized spare wheel in the boot/trunk. Where we live you can expect at least one puncture a year. In theory you do not need a spare wheel because cars rarely have punctures and you can carry an aerosol spray that will temporarily inflate the tire and fill a small hole. Some cars have skinny space-saver spare wheels. Neither of these is actually a good alternative.  

Old vs new autism therapies

People definitely are interested in new and “cutting edge” therapies for autism.

I was recently contacted again by a reader of this blog who has been struggling to control self injurious behaviors in her child for years. I have provided many ideas that have each worked a sub-group of those with SIB. One idea I had not yet suggested was Memantine/Namenda.

Memantine is a cheap, old, and not very effective Alzheimer’s drug.

It blocks NMDA receptors in the brain to prevent excessive stimulation by glutamate. It does actually have many other modes of action.

It has weak inhibitory effects on L-type calcium channels that add to its neuroprotective profile. This secondary mechanism helps regulate calcium influx, protect neurons from excitotoxicity, and mitigate oxidative stress, making it beneficial for managing various neurodegenerative and excitotoxic conditions.

Memantine has mild inhibitory effects on AMPA receptors, reducing overall excitotoxicity.

Memantine may block certain sodium ion channels, which can reduce neuronal excitability and help prevent excitotoxicity.

Memantine has been found to interact with serotonin (5-HT3) receptors, modulating their activity, which might contribute to cognitive and mood improvements.

Memantine reduces microglial activation, which is associated with neuroinflammation. This anti-inflammatory action can protect against secondary neuronal damage in neurodegenerative conditions.

By preventing excessive calcium influx through NMDA receptors, memantine reduces the production of reactive oxygen species (ROS), protecting neurons from oxidative damage.

Memantine's ability to stabilize calcium homeostasis helps maintain mitochondrial function, reducing energy deficits and apoptosis (programmed cell death).

Memantine may enhance synaptic plasticity by reducing pathological over activation of glutamate receptors. This improves synaptic connectivity and cognitive function.

Some studies suggest that memantine may partially activate or modulate nicotinic acetylcholine receptors, which are important for attention and memory.

Memantine may increase brain-derived neurotrophic factor (BDNF) levels, promoting neuronal survival and plasticity.

Memantine as a treatment for SIB in some, but a cause of it in others

It is clear from the above summary of Memantine’s modes of action that it should indeed be effective for some people’s SIB (self injurious behavior). Unfortunately, all these changes in the excitatory-inhibitory balance can cause problems in some other people where Memantine actually causes SIB.

Too much glutamate can be very damaging

Glutamate excitotoxicity refers to the pathological process in which excessive activation of glutamate receptors, particularly NMDA and AMPA receptors, leads to over-excitation of neurons. This over-excitation can result in cellular dysfunction, oxidative stress, and ultimately neuron death. It is a common mechanism underlying many neurological and neurodegenerative conditions.

NMDA and AMPA receptors, over activated by the high levels of glutamate, trigger a massive influx of calcium (Ca²⁺) ions into neurons.

High intracellular Ca²⁺ levels disrupt cellular homeostasis. It activates enzymes that damage cellular structures it causes oxidative stress, mitochondrial dysfunction and eventually cell death.

Elevated intracellular Ca²⁺ from allergy causing elevated glutamate and SIB

As we know from this blog, some SIB is triggered by allergy. You can halt it via treating the allergy, blocking the L-type calcium channels or targeting other inflammatory pathways.

In this allergy-driven self injurious behavior (SIB), glutamate is likely a significant downstream effector. Allergic reactions and inflammation can disrupt calcium homeostasis and activate pathways that increase glutamate signaling, leading to heightened excitotoxicity and contributing to behaviors such as SIB.

Allergic reactions significantly impact calcium homeostasis, primarily through the activation of immune cells, release of inflammatory mediators, and systemic effects on calcium metabolism. These disruptions contribute to the symptoms and complications of allergic diseases and highlight potential therapeutic targets to restore calcium balance.

When allergens bind to IgE on mast cells or basophils, they activate receptors that trigger intracellular calcium release from the endoplasmic reticulum (via IP3 signaling). Recall Prof Gargus proposed IP3 signaling as a nexus point in autism.

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

This calcium influx promotes the degranulation of histamine, serotonin, and other inflammatory mediators.

Abnormal calcium levels may trigger unregulated, spontaneous release of glutamate, even in the absence of an action potential.

Elevated calcium levels can impair the function of glutamate transporters (e.g., EAATs), responsible for clearing excess glutamate from the synaptic cleft.

Dysfunctional transporters exacerbate extracellular glutamate accumulation, amplifying excitotoxicity.

Memantine in broader autism

Memantine was extensively studied in a large clinical trial in autism that concluded that it was no better than a placebo.

You might well conclude that the matter should end there.

Memantine for Aspies

While looking for information about Memantine for SIB I came across some very positive reviews from Aspies.

If you believed social media you would think that people with level 1 autism are all anti-treatment and see autism as their superpower. In fact the majority of people contacting me about treating autism are actually those with level 1 autism and their parents.

I am really much more familiar with treatments for level 3 autism.

The symptoms may be slightly different, but the potential therapies are exactly the same.

 

https://www.drugs.com/comments/memantine/for-autism.html

"A life saver. I have autism. It is pretty bad autism. I saw help on day one. But it isn't a fix-it-all for me. Being able to understand nonverbal communication and verbal communication is huge improvements. This helps me with social interaction. This helps me with anxiety. Helps my expressive myself and respond better. Less meltdowns. Helps my cognitive functions. Helps me think. Helps my thought issue due to my autism and auditory processing disorder. Helps me slow down my mind to pay attention more and can respond to changes and sensory problems. Not a full fix for me but huge help. I am more polite. I can talk about others' interests not just my needs or wants or questions that I had trouble asking. Better behavior." 

"I was first prescribed this for Asperger's syndrome at the age of 24. I've been on numerous types of medications since I was a teenager, but this is the first one that I've been on that has significantly helped. My quality of life is much better. I don't have as many ruminating, obsessive thoughts that make me miserable." 

"I take 20 mg of memantine for my slight autism! And this has been a miracle drug! It helps me in social interactions, I can recognize social cues and skills that I couldn't before! It also helps with my obsessive and aggressive problems! Thank you to whoever made this drug." 

"I take 10 mg twice daily for autism spectrum disorder. It stops the intrusive thoughts, rumination, and repetitive thinking, which is a godsend. It also reduces repetitive behavior/stereotypes. I haven't noticed any side effects, maybe a little brain fog, but that has disappeared with continued use."

"Memantine has helped my social anxiety greatly, not through direct anxiolysis, but indirectly through dissociation from reality, albeit mild. It works perfectly for sensory overload as the autistic brain does not filter out unnecessary external stimuli due to NMDAR current blockade, similar to endogenous magnesium. Amazing, wonderful."

 

Conclusion

Don’t ignore all the therapies from the last 50 years and jump to the latest expensive therapy that is trending. You may after all find one of the oldies like Propranol, Pentoxifylline, Zoloft, Baclofen or Memantine is your Gamechanger. They each worked for some people.

Even though it failed in its phase 3 clinical trial, Memantine continues to have its believers. It is a cheap safe drug that clearly does provide a benefit to a sub group of autism that includes all levels of severity. It clearly does not work for all Aspies, but it certainly is worth trialing.

I think understanding glutamate excitotoxicity is very useful if you are trying to figure out a case of self injurious behavior.

In individuals where the GABA developmental switch has not occurred, oral GABA supplementation could potentially exacerbate glutamate excitotoxicity and trigger/worsen self injurious behavior. These are the people who react badly to benzodiazepine drugs and should respond very well to bumetanide.

No Wegovy/Mounjaro moment likely for autism – Lithium etc

 

Semaglutide, marketed under brand names like Wegovy, Mounjaro and Ozempic, is a GLP-1 receptor agonist originally approved for treating type 2 diabetes and more recently for obesity. The global semaglutide market is $27 billion in 2024. The broader market for GLP-1 receptor agonists, which includes semaglutide, is expected to experience significant growth. Analysts project that this market could reach between $150 billion and $200 billion by the early 2030s.

Semaglutide is a dream for pharmaceutical companies. The overweight can forget about diets and exercise; they just need a weekly self-administered dose and wait to lose 20% of their bodyweight in the first year. If they stop taking the drug all the weight will just come straight back, so the patient needs to take the drug for life.

Semaglutide is expensive, but nothing like the price hoped for by those developing elusive autism drugs.

Some obese people save so much money on food it covers the cost of their semaglutide.

Obesity is so damaging that semaglutide should have a transformative impact on healthcare.

On the other hand, the idea that society might increasingly rely on pharmaceutical solutions instead of encouraging lifestyle changes feels rather Orwellian, with a shift away from personal responsibility, fostering dependency on external control. In a society where health problems like obesity are "fixed" by a drug, self-regulation through lifestyle choices will be de-emphasized, giving the impression that human behavior is best managed through a weekly shot.

In the novel Brave New World by Aldous Huxley, published in 1932, people in a highly controlled society all take a drug called soma to feel good, maintain emotional stability, and suppress negative feelings.

 

No Wegovy/Mounjaro moment likely for autism

For people who get their information from social media it appears that such an effortless Wegovy/Mounjaro moment exists for autism. You just send a reply to Facebook post and get a message back telling you where to buy the miracle cure to autism.

Looking at the world of pharmaceuticals many parents hoped that Suramin would be the cure to autism.

Recently I saw yet another rather misleading headline:

Lithium restores brain function and behavior in Autism

Really, what it should say is:

Lithium may restore brain function and behavior in Autism caused by Dyrk1a mutation if given while a baby.

 

Here is the article.

Lithium Restores Brain Function and Behavior in Autism

Lithium, a drug widely used for bipolar disorder, may also treat autism spectrum disorder (ASD), according to new research. The study found that lithium restored brain function and reduced behavioral symptoms in mice with Dyrk1a gene mutations, a known ASD risk factor.

Administered during the juvenile period, lithium normalized brain size, improved neural connectivity, and eased anxiety and social deficits, with benefits persisting into adulthood.

This breakthrough highlights lithium’s potential to address core ASD mechanisms through its action on Kalirin-7, a molecule critical for synaptic function. The findings underscore the importance of early intervention and targeted treatments for ASD.

The team discovered that lithium’s therapeutic effects are partly mediated through its action on Kalirin-7, a molecule essential for synaptic structure and function.

By targeting this molecule, lithium helped to restore balance in the brain’s signaling networks, addressing one of the core mechanisms of ASD.

“This is an exciting breakthrough,” said Dr. Roh Junyeop, a senior researcher and co-first author of the study.

“Dyrk1a mutations disrupt neural connectivity, much like a traffic jam or roadblocks in a city. Lithium helps to clear the congestion, restoring smooth communication between neurons.”

Director Kim Eunjoon emphasized the potential impact of these findings, stating, “Our research shows that lithium, a widely used drug for bipolar disorder, could also serve as a treatment for ASD. The fact that its effects persist long after treatment ends underscores the importance of early intervention during critical developmental windows.”

This study, published in the journal Molecular Psychiatry on December 5, not only paves the way for new therapeutic approaches for ASD but also underscores the critical importance of early diagnosis and intervention.

It offers hope to families and individuals affected by ASD, suggesting that targeted treatments may one day reduce the burden of this complex disorder.

 

Too little Dyrk1a leads to small brains, autism and low IQ. In Down syndrome there is too much Dyrk1a expression and this is a contributing factor to low IQ. You need just the right amount of Dyrk1a for optimal brain development and then a higher IQ. Too much Dyrk1a also leads to Alzheimer’s which is why there can be early onset in those with Down syndrome.

Don’t give lithium to someone with Down syndrome.

 

GSK-3β and Dyrk1a

In previous posts we did look at something called GSK-3β, which plays a role in autism.

GSK-3β  and DYRK1A  are two enzymes that play significant roles in regulating cell signaling, neurodevelopment, and brain function. They also interact with each other. Both play a role in the Wnt signaling pathway, which is disturbed in much autism and some cancer.

 

Lithium in Autism

Lithium carbonate is a prescription drug used to treat bipolar.

Lithium orotate is an OTC product that some people do use to treat autism. The dosages are usually very low compared to what is used in bipolar.

It is not uncommon to be diagnosed with bipolar and autism.

 

Is Lithium a game changer for Autism?

While some people may well benefit, the usage to date shows that lithium is not a game changer for most autism.

 

Mebendazole for some Autism and indeed Down syndrome

I did propose years ago that Mebendazole/Vermox, the cheap drug used to treat pinworms in children, might have potential to treat some autism. Mebendazole is a Wnt inhibitor (the opposite of Lithium). I did receive a message recently that Mebendazole was beneficial in one reader’s son. Not much Mebendazole is absorbed into the bloodstream but you can maximize it by taking it with a fatty meal. It does cross the blood brain barrier.

Mebendazole has been shown to inhibit DYRK1A in laboratory settings, which could potentially address the effects of DYRK1A overexpression seen in conditions like Down syndrome. Since Down syndrome is diagnosed very early, treatment could start very early, which is critical to optimize the developing brain.

 

Mebendazole - Wnt Inhibition and other effects

Mebendazole is known to inhibit components of the Wnt signaling pathway. Inhibition of Wnt could potentially normalize overactive or dysregulated pathways, leading to more balanced dendritic spine dynamics in individuals with autism. In autism, there is often an imbalance in dendritic spine formation and pruning, leading to either excessive or insufficient connectivity. Modulating Wnt signaling could potentially restore this balance, improving synaptic function and related behaviors.

Mebendazole has been shown to have anti-inflammatory properties. Since neuroinflammation is often elevated in autism, this could indirectly improve symptoms.

Mebendazole also stabilizes microtubules, which are critical for intracellular transport and synaptic function. This might indirectly benefit neuronal communication in autism.

  

Conclusion

Autism is far more complicated and heterogeneous than obesity so sadly there can never be a simple Wegovy/Mounjaro moment.  Best not to listen to Autism Moms telling you otherwise on Facebook.

On the plus side there are numerous partially effective therapies, sitting on the shelf in the pharmacy that do benefit specific types of autism. You just have to find what works in your very specific case.

I was recently asked a German mother if I have a spreadsheet listing all the possible therapies, what the benefits are, and in what order to try them. It is a very rational request, but there is so much variation that this would not be a simple task.

 

 

Israel screening Ashkenazi Jews for the TBCB gene that can cause autism

 

Albert Einstein – perhaps an Aspie, but not a TBCB autistic

Today’s post was prompted by a very matter of fact approach proposed to deal with autism caused when both mother and father carry a single mutation in the TBCB gene. The unaffected parents produce a child with a 25% chance of having autism and a very specific movement disorder because the child has mutations in both of its copies of the gene.

The TBCB gene helps make something called tubulin, which is one of the three main components of the cytoskeleton.

The cytoskeleton plays a role in many well-known neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).

Disruptions in tubulin's normal function can impair cellular processes, including those involved in neuronal signaling and motor control, contributing to movement disorders. So we should not be surprised that one feature of TBCB autism is a difficulty in learning how to walk

 

Israeli researchers discover gene mutation in Ashkenazi Jews that can cause autism

In non-Jewish populations, the occurrence of the mutation in TBCB is 5 in 100,000.

In Ashkenazi Jews, the rate is 1 in 80.

The Israeli Health Ministry incorporated a screening test for the TBCB gene mutation as part of the national healthcare basket in November, making it accessible to all couples planning for pregnancy.

As reported in the Times of Israel, the parents’ options proposed are: 

“They can choose to have an abortion, she said, or to have in-vitro fertilization with genetic screening, in which only embryos without two abnormal copies of the TBCB gene are put into the uterus.

The third option is to keep the pregnancy, she said.

A year after the child is born, she said, parents will be able to see if their child has difficulty with motor development.

In that case, “they can give the child physiotherapy at an early age and help them develop,” Bratman-Morag said.

The illness “causes them difficulties with walking, but they can learn to live with that,” she said.

I don’t think you could be quite so blunt in other countries. The autism self-advocates would go bananas. Their worst dreams have actually materialized – "eugenics" has arrived and in Israel of all places.

The IVF therapy suggested is a very pragmatic approach. I am really surprised they propose it.

The arguments are similar to those that surround Down syndrome. In the world’s most advanced countries, like Denmark and Iceland, almost all DS fetuses are aborted.  In the US the number of live births actually went up, according to the chart below.

The difference with TBCB is that you can test the parents before conception and not just the fetus.

Source https://downsyndroom.nl/wp-content/uploads/2022/09/down-syndrome-population-usa-factsheet.pdf

The downside of Endogamy

Many genes are tagged as being associated with higher IQ, or higher educational attainment and some of these are also linked to autism.

Like it or not, some groups of people are cleverer than others, Albert Einstein might have been at the extreme for Ashkenazi Jews, but he comes from a clever genetic group. These discrete genetic groups are created by what is politely referred to as endogamy (marrying within the community), biologically it is interbreeding.

Unfortunately, there are also downsides caused by centuries of interbreeding particularly within a group that started out relatively small. European royal families famously suffered from it; in their quest for political alliances they created very unhealthy bloodlines.  The Habsburg dynasty took marrying their cousins to an extreme in their quest to keep territory and wealth in the family. This led to infertility, intellectual disability, physical disability, reduced lifespan and the famous Habsburg pronounced lower jaw. For American readers, this family were the royalty in Austria-Hungary, Spain, Holy Roman Empire (Germany etc), Belgium, Luxembourg, Netherlands etc. Very briefly a Habsburg, Maximilian I, was Emperor of Mexico - he was executed by firing squad in 1867.

Ashkenazi Jews are descended from communities that lived in Central and Eastern Europe in the middle ages. The majority now live in the United States. Of 11 million people, 6 million live in the United States. In the world there are another 5 million non-Ashkenazi Jews. In Israel there are 7 million Jewish people and the largest group is Mizrahi, who are descended from the Middle East and North Africa.

For Ashkenazi Jews the following medical conditions are known to be over represented:

• Bloom syndrome
• Canavan disease
• Cystic fibrosis
• Dihydrolipoamide dehydrogenase deficiency
• Familial dysautonomia
• Familial hyperinsulinism
• Fanconi anemia type C
• Gaucher disease
• Glycogen storage disease type 1A
• Joubert syndrome
• Maple syrup urine disease
• Mucolipidosis type IV
• Nemaline myopathy
• Niemann-Pick disease type A
• Spinal muscular atrophy
• Tay-Sachs disease
• Usher syndrome type 1F
• Usher syndrome type III
• Walker-Warburg syndrome

Four cancer genes are known to cause problems

• BRCA1 and BRCA2, linked to
• Breast cancer and ovarian cancer in women
• Breast cancer and prostate cancer in men
• Melanoma
• Pancreatic cancer
• About one in every 40 Ashkenazim has a BRCA mutation; in the general population, the rate is about one in every 400 people.
• GREM1, linked to colon cancer
• APC, linked to colon cancer

This is a wealthy group of people living in a country that looks after the health of rich people very well. That must be the reason why the group has been so well studied. I was a little surprised.

The recent research in Israel has identified the TBCB gene to be an autism gene and that mutations are substantially more come in Ashkenazi Jews.

The mutation is not more common in the other Jewish ethic groups (Sephardi, Mizrahi, Ethiopian, Yemenite, Bukharan, Indian, Kavkazi, Karaite, Cochin, Kaifeng).

Conclusion

I was a little surprised to learn recently from a chat with a kindergarten teacher who worked in Qatar that many of the kids already knew who they were going to marry. “He’s my cousin and I am going to marry him when I grow up,” said the little girl. This kind of arranged marriage is still common there. Well the Habsburgs also did it, so a European can hardly judge them.

Consanguineous marriage (cousin marriage) is alive and well.

Mixing up the gene pool looks to me like the best way to go.

In ancient times forced mixing was common. The Vikings used to abduct young women on the raiding trips across Europe, this continued until the Christianization of Scandinavia between the 9^th and 12^th centuries. In the wilder parts of the Balkans there was a practise called otmitza up until the 1800s, which can be best described as bride kidnapping, where the bride would be brought from a distant community over the mountains. In parts of Central Asia the practise of ala kachuu (to take and flee) continues to this day. In Kyrgyzstan 14% percent of married women say they were kidnapped. The UNDP have a special program to try and stop it.

When it comes to reducing neurodevelopmental disorders mixing up the gene pool looks the best option. Modern technology risks taking society in the opposite direction with online dating apps matching Aspie girl with Aspie boy to then potentially produce a more severe kind of autism, but then their bloodlines end. Mother Nature can indeed be harsh.

I wonder what will be the next genetic test for autism to join Israel’s “national healthcare basket.” Some people will like the idea and others will not, but it looks like the future is already here.

The plural of anecdote is data – I vote for that

 

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

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

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

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

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

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

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

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

Safety

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

The GcMAF mother did ask me if it was safe.

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

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

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

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

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

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

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

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

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

 

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

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

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

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

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

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

Human biology is not an exact science

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

Key reasons include:

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

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

Again, bumetanide works for some

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

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

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

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

Conclusion

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

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

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

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

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

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

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

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