Chlorzoxazone for sound sensitivity (hyperacusis) and hyper-excitable neural circuits in Fragile X and broader autism – an alternative to Ponstan? Why is Gallic acid beneficial in Autism? Varenicline and other nicotinic therapies, revisited

  

 

Today’s post covers some practical interventions raised recently either in the research, or in the comments section.

 

·         Chlorzoxazone (via Potassium channels – BKCa, SKCa) an old muscle relaxant first approved in 1958

·         Varenicline a drug approved in 2006 that targets nicotinic receptors in the brain

·         Nicotine

·         Tropisetron, an anti-nausea drug that also targets nicotinic receptors in the brain; it was approved in 1992 in Switzerland and is available in the Europe but not the US.

·         Gallic acid, a component of numerous plants/foods (grapes, pomegranates, green tea, red wine etc) that have been used in traditional medicine across different cultures

 

The common link between the first four is the sensory problems usually found across all severities of autism, and some forms of ADHD/autism-lite. It can be either sound sensitivity (hyperacusis) or misophonia (impaired sensory gating), both of which often co-occur in the same person.

We will refer to some of the excellent research into Fragile X syndrome. This is the most common single gene type of autism; most autism is polygenic and some is not of genetic origin at all (hypoxia during birth, sepsis etc).

 

Let’s start with the easiest topic.

 

Gallic acid

I saw the recent study below and wondered what is gallic acid.

 

Vitamin C and Gallic Acid Ameliorate Motor Dysfunction, Cognitive Deficits, and Brain Oxidative Stress in a Valproic Acid‐Induced Model of Autism

Autism, a developmental‐neurodegenerative disorder, often manifests as social communication difficulties and has been correlated to oxidative stress in the brain. Vitamins C and gallic acid (GA) possess potent antioxidant properties, making them potential candidates for addressing autism‐related issues. This study examined the influence of vitamin C (Vit C) and GA on behavioral, motor, and cognitive performance, along with the assessment of brain oxidative markers, using an experimental model of autism.

Finding

The prenatal VPA‐induced autism model increased nociceptive threshold, heightened anxiety‐like behaviors, impaired balance power, delayed spatial learning, elevated malondialdehyde, and decreased glutathione and catalase levels in the brains of the male offspring. Administration of Vit C and GA effectively mitigated these anomalies.

Conclusions

Vit C and GA could potentially alleviate anxiety‐like behaviors, motor and cognitive deficits, and brain oxidative stress markers in a prenatal rat autism model. This underscores their viability as potential pharmacological interventions for treating autistic dysfunction.

 

Gallic acid is a naturally occurring organic acid widely found in various plants, fruits, and foods. It is notable for its antioxidant, anti-inflammatory, and antimicrobial properties, making it of interest in health and medicine.

For no obvious reason, gallic acid has never been commercialized as a supplement, but gallic acid is one of the reasons a glass of red wine a day may well be good for you.  It can give a you a 20 mg dose of gallic acid.

Red wines made from grape varieties with higher tannin content, such as Cabernet Sauvignon or Pinot Noir, tend to have higher levels of gallic acid because tannins contain gallic acid. Longer aging, especially in oak barrels, can increase gallic acid due to the extraction from the wood.

The new study suggests that gallic acid is a potential pharmacological intervention for treating autism.  It joins an already very long list! 

 

Varenicline and other nicotinic therapies

Our reader Dragos in Romania recently asked for help obtaining Varenicline, which is also sold as Chantix. This drug is similar to using a nicotine patch, but different in some important ways.

DAN doctors in the US used to prescribe nicotine patches to children with autism.

There is a lot of research to support the use  of therapies that target a specific nicotinic receptor in the brain called the alpha 7 nicotinic acetylcholine receptor (α7 nAChR).

Nicotine itself activates all nicotinic receptors, not just α7 nAChR.

Dragos want to trial the smoking cessation drug Varenicline, which targets α7 nAChRs and a little bit the one called α4β2 nAChR.

 

α7 nAChRs

These receptors are well known to be implicated in diseases such as Alzheimer's, schizophrenia, autism, and epilepsy.

They affect:

Cognition and memory

·        α7 nAChRs are involved in synaptic plasticity, learning, and memory formation due to their role in calcium signaling and modulation of neurotransmitter release.

·        Highly expressed in the hippocampus, which is critical for memory processing.

Neuroprotection

·        Calcium influx through α7 nAChRs activates signaling pathways that promote cell survival and neuroprotection.

·        Involved in reducing neuroinflammation and protecting against excitotoxicity.

Modulation of Neurotransmitter Release

·        Regulate the release of dopamine, glutamate, GABA, and serotonin, impacting mood, arousal, and reward mechanisms.

Inflammatory Regulation

·        Present on immune cells, where they regulate the release of pro-inflammatory cytokines like TNF-α via the cholinergic anti-inflammatory pathway.

Sensory Gating

·        α7 nAChRs are crucial for sensory filtering, preventing sensory overload. Dysfunction in these receptors is linked to conditions like autism and schizophrenia.

 

α4β2 nAChRs

These play a role in:

Cognitive function

·        Involved in attention, learning, and memory.

·        Enhances synaptic plasticity in brain regions like the hippocampus.

Dopamine release

Pain modulation

Mood regulation

 

Research has shown reduced expression of both α7 nAChRs and α4β2 nAChRs in the brains of people with autism.

Dragos has good reason to trial Varenicline; not only has another young adult in Romania with severe autism recently responded well, but there are published case reports to give further support.

 

Varenicline in Autism: Theory and Case Report of Clinical and Biochemical Changes

Objective: To explore the potential benefits of varenicline (CHANTIX^®), a highly specific partial agonist of neuronal α4β2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype.

Methods: The clinical and biochemical changes exhibited by a 19-year-old severely autistic man following the use of low-dose varenicline in an ABA experiment of nature, and his genotype, were extracted from chart review. Clinical outcome was measured by the Ohio Autism Clinical Impression Scale and 12 relevant urine and saliva metabolites were measured by Neuroscience Laboratory.

Results: With varenicline, this patient improved clinically and autonomic biochemical indicators in saliva and urine normalized, including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine, norepinephrine, taurine, and histamine levels. In addition, with varenicline, the dopamine D1 receptor (DRD1) antibody titer as well as the percent of baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped significantly. When varenicline stopped, he deteriorated; when it was resumed, he again improved. Doses of 0.5, 1, and 2 mg daily were tried before settling on a dose of 1.5 mg daily. He has remained on varenicline for over a year with no noticeable side effects.

Conclusion: This report is, to the best of our knowledge, only the second to demonstrate positive effects of varenicline in autism, the first to show it in a severe case, and the first to show normalization of biochemical parameters related to genotype. As with the previous report, these encouraging results warrant further controlled research before clinical recommendations can be made.

 

Varenicline vs Nicotine 

Let’s compare the mechanisms of action:

Varenicline

• Partial agonist at the α4β2 nicotinic acetylcholine receptor (nAChR) and a full agonist at α7 nAChRs.
• Modulates neurotransmitter release (e.g., dopamine, glutamate), which may improve cognitive function and reduce repetitive behaviors in ASD.
• FDA-approved for smoking cessation.

 

Nicotine Patches

• Deliver nicotine, a full agonist at nAChRs.
• Broadly activate multiple nAChR subtypes, leading to enhanced cholinergic signaling.
• Typically used for smoking cessation

 

Other Considerations

Varenicline

·         Offers more targeted modulation of nAChRs with less widespread cholinergic activation.

• Varenicline’s mechanism prevents full desensitization, maintaining its effects over time.

·         May be preferred if minimizing side effects like overstimulation is important.

 

Nicotine Patches:

• Easy to administer and widely available but less specific in its action, which may lead to more off-target effects.
• Nicotine can lead to rapid receptor desensitization and tolerance, especially with continuous delivery via patches.

 

Alternatives

There are some theoretical alternatives, such as:

 

ABT-126 (Pozanicline)

·         Type: Selective α7 nAChR agonist.

·         Status: Investigated for Alzheimer's disease and schizophrenia.

·         Cognitive enhancement and improved sensory gating.

 

RG3487 (MEM 3454)

·         Type: Partial α7 nAChR agonist and modulator of glutamate receptors.

·         Status: Investigated for schizophrenia and cognitive impairment.

·      Improves cognition and reduces symptoms like sensory gating deficits.

 

The one that caught my attention previously when writing about this subject was Tropisetron.

 

Tropisetron:

• Already approved as an antiemetic but also acts as a weak α7 nAChR agonist.
• Potential benefits in cognitive and inflammatory disorders.

 

Clinical Evidence with Tropisetron

Schizophrenia

Early studies show cognitive and sensory gating improvements in schizophrenia patients treated with tropisetron.

One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia

Not to forget Vagus Nerve Stimulation (VNS)

The vagus nerve activates α7 nAChRs on immune cells, reducing inflammation without immunosuppression.

The vagus nerve indirectly affects α7 and α4β2 nAChRs in the brain by modulating acetylcholine release.

Vagus nerve stimulation is already used in epilepsy, depression, and inflammatory disorders.

 

It is worthwhile highlighting the effect on people with some types of GI disorder. There is a known association between Asperger’s and ulcerative colitis.

 

Nicotine and Ulcerative Colitis (UC)

·         Smoking appears to have a protective effect on ulcerative colitis.

·         Smokers are less likely to develop UC, and those who quit smoking are at higher risk of developing the condition.

·         Current smokers with UC may experience milder disease with fewer flares and less severe symptoms.

The suggested mechanism

·         Dysregulated inflammation in the colonic mucosa leads to ulcerations, diarrhea, and abdominal pain.

·         α7 nAChR activation may reduce this inflammation, aiding in mucosal healing and symptom improvement.

·         Nicotine’s anti-inflammatory effects may play a role by modulating cytokine release (e.g., reduced IL-8 and TNF-α).

·         Nicotine also stimulates mucus production and increases colonic blood flow, potentially improving mucosal healing.

·         Smoking-induced changes in the microbiome may also reduce UC severity.

 

Note that for Crohn's Disease (CD) and Irritable Bowel Syndrome (IBS) smoking makes the symptoms worse.

 

So, it would make sense to use vagal nerve stimulation for inflammatory bowel disease?

 

Here are results from 2023

 

Vagus nerve stimulation reduces inflammation in children with inflammatory bowel disease

 

Bioelectronic medicine researchers at The Feinstein Institutes for Medical Research and Cohen Children’s Medical Center published results today, in the journal Bioelectronic Medicine, from a proof-of-concept clinical trial that showed non-invasive, non-pharmacological transcutaneous auricular vagus nerve stimulation (ta-VNS), or stimulating in the ear, significantly reduced inflammation in more than 64 percent of pediatric patients with IBD. 

Dr. Sahn and his team used a commercially available transcutaneous electrical nerve stimulator (TENS) unit (TENS 7000) and sensor probe for the trial. Two earbuds on the probes were placed on a small area of the external ear called the cymba conchae, where the vagus nerve is most accessible. For five-minute intervals, the patients received the stimulation for a total of 16 weeks.

 Finally to BKCa and SKCa channels in Fragile X syndrome (FXS) and broader autism !

 

Let’s have a quick recap on Fragile X.

 

Fragile-X

Fragile X (FXS) is the most common single gene cause of intellectual disability (IQ less than 70).

FXS affects approximately 1 in 4,000 males and 1 in 8,000 females.

The condition is very well studied and the Fragile X gene (FMR1) is considered an autism gene.

I am surprised how rarely (never?) FXS parents comment in this blog. They are actually the ones who stand to benefit the most, given how well-studied their syndrome is and how many treatment options exist. I was recently discussing this exact point with an autism therapist with an FXS patient – why do parents remain passive and not react?

 

More severe in males than females

Males have one copy of the FMR1 gene, while females have two.

In females with the full mutation, symptoms are generally less severe than in males due to what is called random X-inactivation. Since females have two X chromosomes, one of the X chromosomes in each cell is randomly inactivated. In cells where the X with the mutation is inactivated, FMRP is produced normally, and in cells where the normal X is inactivated, no FMRP is produced. The severity of symptoms often correlates with the proportion of cells in which the mutated X is active.

In a strange twist of fate females with the milder form of FXS, called premutation, have the greatest chance of being infertile. This is due to Fragile X-associated primary ovarian insufficiency (FXPOI).

 

Testing

The ability to conduct genetic testing began in the 1990s, became more widespread by the mid-1990s, and became integrated into routine clinical practice in the early 2000s. Today, genetic testing for Fragile X is a standard tool used to diagnose FXS, assess carrier status, and inform genetic counselling.

You can also identify Fragile X based on facial features and this is a common practice, especially in the early diagnosis of individuals with the syndrome.

BKCa and SKCa channels in autism and Fragile X

Ion channel dysfunctions play a key role in all neurological conditions. A great deal is known about them, making them an excellent target for intervention.

Fragile X is such a well-studied condition that you can access all the information very easily.

For other single gene autisms and the more common idiopathic (unknown cause) autism it is more a matter of guesswork. 

This recent paper is excellent: 

Channelopathies in fragile X syndrome

The paper lists all the proven ion channel dysfunctions and suggests how to treat some of them.

Potassium channels – BKCa, SKCa, Kv1.2, Kv3.1, Kv4.2,

Calcium channels – Cav1.3, Cav2.1, Cav2.3,

Misc – HCN, NKCC1, AMPAR, NMDAR, GABA_AR

 

Targeting BKCa, SKCa in Fragile X and for hyperacusis in broader autism

In FXS, hyperexcitability in brain circuits is thought to contribute to cognitive and behavioral symptoms.

Preclinical studies suggest that SKCa and BKCa channel activators may correct this hyperexcitability and improve neural network function.

The therapeutic effects of a cheap drug called chlorzoxazone in FXS models are believed to stem from its ability to enhance BKCa channel activity. These channels play a pivotal role in regulating neuronal firing rates and neurotransmitter release. By activating BKCa channels, chlorzoxazone may counteract the neuronal hyperexcitability observed in FXS, leading to improved behavioral and sensory outcomes.

BKCa channels are indispensable for hearing, as they regulate frequency tuning, temporal precision, and signal transmission in both cochlear hair cells and auditory neurons. Dysfunctions in these channels are linked to hearing impairments like frequency discrimination deficits, tinnitus, and hyperacusis (sound sensitivity). Modulating BKCa activity offers a promising avenue for treating auditory disorders.

 

Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener. Reduced BKCa channel functionality has been reported in FXS patients, suggesting that molecules activating these channels could serve as promising treatments for this syndrome. Here, we sought to characterize the therapeutic potential of chlorzoxazone using the Fmr1-KO mouse model of FXS which recapitulates the main phenotypes of FXS, including BKCa channel alterations. Chlorzoxazone, administered either acutely or chronically, rescued hyperactivity and acoustic hyper-responsiveness as well as impaired social interactions exhibited by Fmr1-KO mice. Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases.

  

·        Chlorzoxazone

In the FXS research they repurpose a drug called chlorzoxazone to activate BKCa channels, with positive results

 

·        Mefenamic acid (Ponstan)

In this blog Ponstan has shown promise to treat hyperacusis. Ponstan is a known activator of both BKCa and SKCa channels.

 

Which is “better” chlorzoxazone or Ponstan?

According to the science chlorzoxazone is more potent than Ponstan in affecting both BKCa and SKCa channels.

Ponstan has more effects on Kv channels like Kv7. Kv7 is implicated in autism and epilepsy.

In terms of gene expression Ponstan has more direct effects on gene expression due to its modulation of inflammatory pathways and inhibition of prostaglandin synthesis.

Chlorzoxazone primarily acts on ion channels, and its effects on gene expression are secondary and less pronounced.

In conclusion the two drugs are very different, both potentially useful, and some of their actions, such as on hyperacusis, are overlapping.

  

Conclusion

Chlorzoxazone an inexpensive drug used to treat muscle spasms is also known for its effects on calcium-activated potassium channels (BKCa and SKCa).

Some claim that Chlorzoxazone may affect GABAa and/or GABAb receptors, but that appears not to be the case.

The research suggests that Chlorzoxazone should have a beneficial effect in FXS and very likely would have a benefit in some broader autism and in hyperacusis specifically.

The effects of Chlorzoxazone are likely to overlap with the effects of Ponstan. Ponstan is quite possibly also going to be effective in FXS, as it is in broader autism.

There are many suggested therapies for FXS (Metformin, Lovastatin, Baclofen, Acamprosate, Gabapentin, Minocycline, Memantine, Rapamycin, L-carnitine, Omega 3 etc). None, when taken alone, are game-changers.

Every parent of a child with Fragile X should read the paper I have linked to in this post.

 

Channelopathies in fragile X syndrome

 

It is full of excellent ideas. If NKCC1 is overexpressed, as is suggested, trial bumetanide.

As in all autism, polytherapy is going to be key. No single therapy can be highly effective with so many dysfunctions present. To quote from the above paper:-

 “Ultimately, the most effective treatment strategies are likely to be multifactorial.”

This means do not be surprised if you need 5 different drugs, with 5 different targets to produce a game-changing effect. Better 5 cheap old re-purposed generic drugs than a single brand-new drug with little overall effect and that costs a king’s ransom, each and every year.

Unfortunately, a personalized approach will need to be used to find such a polytherapy. What works at one age may not be beneficial at another age. Even within single gene autisms, treatment response can vary widely from person to person.

At a conference, I did ask a clinician who is an “expert” in Fragile X, does she apply any of the existing therapies from the research, to her patients. She was rather taken aback by the idea and said “no, we have to follow the protocols.” So, an expert in exactly what then? An expert would make the protocols, if none existed.

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.