Showing posts with label Autism. Show all posts
Showing posts with label Autism. Show all posts

Monday, 4 September 2023

The therapeutic effects of apigenin are pleiotropic. Is its effect on sound sensitivity mediated via potassium channels?

Chamomile, a good source of Apigenin


Today we return to flavonoids, those healthy chemicals found in fruits, vegetables, flowers etc.

In particular, the focus is on apigenin, found in things like chamomile, parsley, oregano and in medicinal herbs like Bacopa monnieri.


Why the interest in Apigenin?

I did discover a while back that sound sensitivity in some autism responds almost immediately to low dose Ponstan (Mefenamic acid), which is a widely used as a pain reliever.

I was recently informed by a reader who responds well to Ponstan (250mg once a day) that he gets exactly the same relief from sound sensitivity from taking the flavonoid Apigenin (500mg a day). 

Both Ponstan and Apigenin are OTC in many countries. In countries like Greece Ponstan is extremely cheap.  In the US Ponstan is very expensive and supplements tend to be cheap. 

For adults with sound sensitivity drinking chamomile tea might be a good source of 50 mg of Apigenin (you would need about 20g of chamomile flowers). Using the dried flowers likely gives better results than ready-made tea bags.


Pleiotropic effects

Both Ponstan and apigenin have numerous beneficial effects.  I noted in my earlier posts on Ponstan that it seems to offer protection from Alzheimer’s. Perhaps surprisingly, people who take Ponstan are much less likely to develop Alzheimer’s. Nobody has studied apigenin in human Alzheimer’s, but in animal studies, apigenin has been shown to improve cognitive function, reduce amyloid plaques, and protect neurons from damage.


Other Flavonoids used in Autism

Dr Theoharides wrote a lot about flavonoids to treat autism and mast cell disorders.  His product Neuroprotek is a combination of three flavonoids: luteolin, quercetin, and rutin, which are found in plants such as celery, onions, and citrus fruits.

Epigallocatechin gallate (EGCG) is a flavonoid found in green tea. The Spanish like doing research on EGCG and they believe it has promise as an autism therapy. One of the effects is to modify the gut microbiome. EGCG has also been shown to accumulates in mitochondria making it an interesting therapeutic candidate for neurodegenerative diseases involving neuronal apoptosis triggered by mitochondrial oxidative stress. It has been studied in Down syndrome, Rett syndrome and some other models of autism.


A very detailed overview is available in the paper below:-

The Emerging Role of Flavonoids in Autism Spectrum Disorder: A Systematic Review

Although autism spectrum disorder (ASD) is a multifaceted neurodevelopmental syndrome, accumulating evidence indicates that oxidative stress and inflammation are common features of ASD. Flavonoids, one of the largest and best-investigated classes of plant-derived compounds, are known to exert antioxidant, anti-inflammatory, and neuroprotective effects. This review used a systematic search process to assess the available evidence on the effect of flavonoids on ASD. A comprehensive literature search was carried out in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. A total of 17 preclinical studies and 4 clinical investigations met our inclusion criteria and were included in the final review. Most findings from animal studies suggest that treatment with flavonoids improves oxidative stress parameters, reduces inflammatory mediators, and promotes pro-neurogenic effects. These studies also showed that flavonoids ameliorate the core symptoms of ASD, such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination. However, there are no randomized placebo-controlled trials that support the clinical efficacy of flavonoids in ASD. We only found open-label studies and case reports/series, using only two flavonoids such as luteolin and quercetin. These preliminary clinical studies indicate that flavonoid administration may improve specific behavioral symptoms of ASD. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of flavonoids on features of ASD. These promising preliminary results may provide the rationale for future randomized controlled trials aimed at confirming these outcomes.


It seems that the many flavonoids have numerous beneficial effects - this is why it is important to include them in your diet.



Years ago, I wrote about Sytrinol, a dietary supplement that is made from citrus peel extract. It contains polymethoxylated flavones (PMFs), which are a type of flavonoid. It mainly contains nobiletin and tangeritin, flavones that are found in citrus fruits, such as lemons, oranges, and grapefruits. They have been shown to have a number of health benefits, including lowering cholesterol, reducing inflammation, and protecting cells from damage.

The idea was of interest because these flavones are known to activate PPAR-gamma, which seemed potentially beneficial in autism.  Readers did confirm Sytrinol provided a cognitive benefit, but it only lasts a few days and is then lost.


Sources of Apigenin

Apigenin is sold as a supplement.

Chamomile is one of the oldest, most widely used and well documented medicinal plants in the world and has been recommended for a variety of healing applications for centuries. Apigenin is thought to be one of the most potent substances found within it.

Bacopa monnieri is another rich source of flavonoids being a good source of luteolin and apigenin. An extract of Bacopa monnieri, a nootropic herb, has been used to evaluate its neuroprotective effect in a valproic acid (VPA) model of ASD. The results showed that B. monnieri extract may attenuate VPA-induced damage by restoring antioxidant enzymes and reducing inflammatory cytokines in the hippocampus and prefrontal cortex.


The biological effects of Apigenin

 What does the Google AI (artificial intelligence) program Bard have to say:-


Apigenin is a flavonoid that is found in a variety of plants, including chamomile, parsley, celery, and citrus fruits. It has several potential health benefits, including:

Antioxidant. Apigenin is an antioxidant, which means it can help protect cells from damage caused by free radicals. Free radicals are unstable molecules that can damage DNA, proteins, and other cellular structures.

Anti-inflammatory. Apigenin has anti-inflammatory properties, which can help reduce inflammation in the body. Inflammation is a contributing factor to many diseases, including heart disease, cancer, and arthritis.

Cancer prevention. Apigenin has been shown to have cancer-fighting properties in both animal and human studies. It may help prevent cancer by blocking the growth and spread of cancer cells.

Brain health. Apigenin may be beneficial for brain health. It has been shown to improve cognitive function in animal studies, and it may also help protect against Alzheimer's disease and other neurodegenerative diseases.

Heart health. Apigenin may help improve heart health. It has been shown to lower blood pressure and cholesterol levels, and it may also help protect against heart arrhythmias.

Hormone modulation. Apigenin may modulate the production of hormones, such as estrogen and testosterone. This could have benefits for women's health, such as reducing the risk of breast cancer and improving menopausal symptoms.

Immune health. Apigenin may boost the immune system. It has been shown to increase the production of white blood cells, which help fight infection.

Other benefits. Apigenin may also have other health benefits, such as relieving anxiety, promoting sleep, and strengthening bones.

When you push Bard a little bit you get more:

Apigenin and ion channels, Bard?

Apigenin is a flavonoid that has been shown to interact with a variety of ion channels in the body. These include:

Voltage-gated calcium channels. Apigenin has been shown to inhibit the activity of voltage-gated calcium channels, which are involved in the regulation of many cellular processes, including muscle contraction, cell growth, and cell death.

Transient receptor potential vanilloid 4 (TRPV4) channels. TRPV4 channels are activated by heat and inflammation, and they play a role in pain perception, thermoregulation, and inflammation. Apigenin has been shown to activate TRPV4 channels, which could have potential implications for the treatment of pain and inflammation.

Nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels that are activated by acetylcholine. They are involved in a variety of functions, including learning, memory, and muscle contraction. Apigenin has been shown to potentiate the activity of nAChRs, which could have potential implications for the treatment of Alzheimer's disease and other neurodegenerative diseases.

Potassium channels: Potassium channels are responsible for the efflux of potassium ions from cells. Apigenin has been shown to activate some types of potassium channels, which can have cardioprotective effects.

Gamma-aminobutyric acid (GABA)A receptors. GABAA receptors are ligand-gated ion channels that are activated by GABA. They are involved in the regulation of anxiety, sleep, and epilepsy. Apigenin has been shown to modulate the activity of GABAA receptors, which could have potential implications for the treatment of anxiety and epilepsy.


Which potassium channels, Bard? 

Apigenin has been shown to activate some types of potassium channels, including:

Small conductance calcium-activated potassium channels (SK channels): SK channels are activated by calcium ions and play a role in regulating cell excitability. Apigenin has been shown to activate SK channels in a number of cell types, including neurons, smooth muscle cells, and cardiac cells.

Large conductance calcium-activated potassium channels (BK channels): BK channels are also activated by calcium ions and play a role in regulating cell excitability and blood pressure. Apigenin has been shown to activate BK channels in some cell types, but the effects are less well-studied than the effects on SK channels.

Transient receptor potential vanilloid 4 (TRPV4) channels: TRPV4 channels are activated by a variety of stimuli, including heat, inflammation, and mechanical stress. Apigenin has been shown to activate TRPV4 channels in some cell types, but the effects are less well-studied than the effects on SK and BK channels.


The effect of mefenamic acid on potassium channels, Bard? 

Mefenamic acid has been shown to have effects on a variety of ion channels, including potassium channels.

In vitro studies have shown that mefenamic acid can activate certain types of potassium channels, such as small conductance calcium-activated potassium channels (SK channels) and large conductance calcium-activated potassium channels (BK channels). This activation of potassium channels can lead to a decrease in the excitability of cells, which can be beneficial in conditions where excessive cell excitability is a problem, such as epilepsy and arrhythmias.

 However, mefenamic acid can also inhibit certain types of potassium channels, such as ATP-sensitive potassium channels (KATP channels). This inhibition of KATP channels can lead to an increase in the excitability of cells, which can be harmful in conditions where excessive cell excitability is a problem, such as heart arrhythmias.

The effects of mefenamic acid on potassium channels are complex and depend on the type of channel, the concentration of mefenamic acid, and the cell type. More research is needed to fully understand the mechanisms by which mefenamic acid interacts with potassium channels and the implications for its potential therapeutic applications.


Apigenin in Down syndrome


Plant Compound Apigenin Reduces Cognitive Deficits in Mouse Model of Down Syndrome

Mice treated with apigenin had better memory and developmental milestone scores.

The plant compound apigenin improved the cognitive and memory deficits usually seen in a mouse model of Down syndrome, according to a study by researchers at the National Institutes of Health and other institutions.

Apigenin is found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. The researchers fed the compound to pregnant mice carrying fetuses with Down syndrome characteristics and then to the animals after they were born and as they matured.

The findings raise the possibility that a treatment to lessen the cognitive deficits seen in Down syndrome could one day be offered to pregnant women whose fetuses have been diagnosed with Down syndrome through prenatal testing. The study appears in the American Journal of Human Genetics.

Down syndrome is a set of symptoms resulting from an extra copy or piece of chromosome 21. The intellectual and developmental disabilities accompanying the condition are believed to result from decreased brain growth caused by increased inflammation in the fetal brain.

Apigenin is not known to have any toxic effects, and previous studies have indicated that it is an antioxidant that reduces inflammation. Unlike many compounds, it is absorbed through the placenta and the blood brain barrier, the cellular layer that prevents potentially harmful substances from entering the brain.

Compared to mice with Down symptoms whose mothers were not fed apigenin, those exposed to the compound showed improvements in tests of developmental milestones and had improvements in spatial and olfactory memory. Tests of gene activity and protein levels showed the apigenin-treated mice had less inflammation and increased blood vessel and nervous system growth.


Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.



I am still delighted to have found a treatment for my son’s sound sensitivity, which got much more extreme almost overnight a couple of years ago.

I had already established long ago that he got short term sound sensitivity relief from taking a potassium supplement.  Some readers found a potassium supplement provided long term relief.

I thought that Ponstan might provide a good longer term solution and indeed it worked from the first pill.  This low dose therapy also works for other people with sound sensitivity, even one adult who has no autism.  The effective adult dose is 250 mg once a day.

Unlike other fenamate class drugs, like Diclofenac, Ponstan seems to be free from GI side effects at this low dose in most people.

Apigenin is an interesting alternative for those who do not tolerate Ponstan well, or who cannot access it.

A common link between what seems to improve sound sensitivity:

                    Oral potassium

                    Ponstan (Mefenamic acid)


is potassium ion channels. 

If you ask Google’s AI program Bard, he will tell you:

“It is possible that all 3 substances could affect the same potassium ion channel in some cell types, but this has not been definitively shown. More research is needed to fully understand the effects of these substances on potassium ion channels.”

Technically Bard is genderless, but he is a reflection of the programmers behind the software. In our house he is called Bart anyway.

Bart does make mistakes, contradicts himself in the same answer and he gives you different answers if you ask the same question more than once. He is also prone to mixing things up, just like humans do.

Monday, 7 August 2023

Differential Diagnosis and Treatment in Autism – Verapamil & Curcumin for Williams Syndrome?


The face of Williams syndrome kids. Source: Figure 2.  GeneReviews® - NCBI Bookshelf

Continuing from the last post, today we look again at differential diagnosis and treatment, which I prefer to just call personalized medicine.

This is the subject of a conference for parents in the UK, that I agreed to draw to the attention of readers.


Click on the picture above to read about the upcoming event in London.



Williams syndrome

Williams syndrome: MedlinePlus Genetics (click for info)

Williams syndrome occurs when someone is missing a small piece of chromosome 7, resulting in them lacking 25 to 27 genes. Most people with Williams syndrome have not inherited the condition from a parent.

Williams syndrome can delay a child’s milestones including:

·         Learning (mild to moderate intellectual challenges)

·         Saying their first words and talking

·         Sitting and walking

Socializing is unusual – there is excessive empathy. A child will be outgoing and very friendly, but has difficulty identifying strangers. There may be attention problems, phobias, or anxiety.

Williams is another syndrome with distinct facial features that can help with diagnosis.

·         Large ears

·         Full cheeks

·         Small jaw

·         Wide mouth

·         Small teeth

·         Upturned nose

Williams syndrome is still viewed as untreatable.

In this blog we always start from the basis that all severe autism is potentially treatable.  Often some of the downstream effects of genetic mutations overlap with other types of autism and some of these effects actually are treatable.

There is a great deal in this blog about targeting both calcium channels and potassium channels to treat autism. Verapamil and Ponstan are the two drugs I have written most about.

Curcumin is an OTC therapy for autism that has been widely covered in this blog and people do regularly write to me to tell me that it is beneficial.  Just last week a reader told me that both Ponstan and Curcumin are beneficial in his specific case.

I was intrigued to read the paper from Spain below where the researchers found the combination of Verapamil + Curcumin to improve behaviors in Williams syndrome.  The mechanism was found to be by regulation of MAPK pathway and microglia overexpression.


Verapamil + Curcumin to treat the behavioral issues in Williams syndrome

One key takeaway is that in the model of Williams syndrome you need both verapamil (VER) and curcumin (CUR). Either intervention on its own provided no benefit – you need the combination (VERCUR). 

Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

Accumulated evidence has described that curcumin, the major constituent of turmeric (Curcuma longa), exerts a variety of pharmacological effects due to its antioxidant, anti-inflammatory, and neuroprotective properties. Recent studies have reported positive effects of curcumin over different cognitive aspects such as anxiety-like behaviors, memory deficits, and motor impairments of different murine models Many studies have described that its effects on the behavioral phenotype of mice models are mediated by upregulation of BDNF (brain-derived neurotrophic factor) expression BDNF has been described as a crucial molecule for neural development and plasticity processes and its mechanism of action is highly dependent on a proper maintenance of intracellular ionic homeostasis Moreover, it has also been described to prevent neuroinflammation by modulating pathways related to NRF2 and MAPK signaling.

Verapamil is a widely used medication, and its mechanism of action involves mainly the blocking of voltage-dependent calcium channels, but it has also been proven to directly bind and block voltage-gated potassium channels  and to inhibit drug efflux pump proteins like P-glycoprotein. Although it has been mainly studied for cardiovascular applications, it has also been associated with positive effects on anxiety and memory processing in murine models.

Given the properties of both compounds, we decided to explore the effects of each compound and a combinatorial treatment on the behavioral phenotype of CD mice. The results show that only the combined treatment with curcumin and verapamil improved the deficits. This improvement can be correlated with the normalization of the MAPK and inflammasome signaling pathways and with the concomitant reduction of activated microglia. 

·   The Increased Microglia Activation in Motor Cortex and Hippocampus Presented by CD Mice Is Prevented by VERCUR Co-Treatment

·    Combinatorial Treatment Prevents Hypersociability of CD Mice

·    Only VERCUR Co-Treatment Improves Motor Coordination in CD Mice

·    VERCUR Co-Treatment Prevents Gene Expression Changes in Cortex of CD Animals

·    Neuroanatomical Features of CD Mice Do Not Change After VERCUR Co-Treatment

In conclusion, we suggest that the hemizygous loss of WBSCR in the cerebral cortex of CD mice has a direct effect on the neuroinflammatory state of the brain, as well as on the expression of some genes related to synaptic signaling or extracellular matrix structure, which are crucial for a proper neural function. This may at least be partly responsible for the behavioral phenotype observed in CD animals. A treatment combining verapamil and curcumin is able to address different molecular targets and rescue some of those pathways, being a promising therapeutic approach for the cognitive phenotype of WBS patients.



Today’s study was in a mouse model of William’s syndrome; clearly it would be more informative if the researchers had tried it on humans.  It does though raise the question as to what other treatments from idiopathic autism might be effective in this supposedly untreatable genetic condition.

The other perspective of course is to wonder what other types of autism might benefit from Verapamil plus curcumin (VERCUR). It was interesting to note that in the model neither Verapamil nor curcumin was effective by itself, they needed the combined therapy (VERCUR).

If you read the experiences that have been shared over the years in this blog you can see that some parents spend a lot of money on genetic testing, hoping to improve their child’s outcome.  It is only very rarely that you see any great success resulting.

The alternative approach is understand the commonly shared biological features of autism and try and treat those, to see whether the individual shows a benefit.  Where there is a positive response, it is a “keeper,” if there is no response, or a negative response, the therapy is dropped.  Essentially it is a process of trial and error.  Not as fancy as genetic testing, but it works.

Clearly if your child has Williams syndrome you would be well advised to look up the function of each of the 26 missing genes, to see if there are any obvious steps to take. One good tool to use is  

Old posts that refer to cucumin:

Epiphany: Curcumin (


Old posts that refer to verapamil

Epiphany: Verapamil (

Thursday, 20 July 2023

Genetic testing results

Click on the picture above to read about the upcoming event in London. There are familiar faces appearing, like Agnieszka, Dr Boles and indeed me.


I am quite often sent genetic testing results. There are many types of tests ranging from inexpensive tests looking at SNPs to the expensive WES or WGS tests.

SNP = Snip = Single Nucleotide Polymorphism = a tiny genetic spelling mistake

WES = Whole Exome Sequencing

WGS = Whole Genome Sequencing

There is a small industry based around selling expensive supplements for SNPs.

We all carry thousands of SNPs and I think these tests may often raise issues that are not causal.  The results from WGS or WES can be much more insightful.  A good example being in the comment recently posted on this blog.


I've been following your blog for many years, it's a real blessing and the perfect place to come and read for us, parents of ASD kids. My boy, 9, has non-regressive autism, is largely non verbal (one word sentence) and has pronounced OCD symptoms (similar to excoriating disorder, but aimed at the environment), hyperactivity and severe gut problems, recurrent vomitting, gastroparesis, etc. The only thing that visibly stopped the hyperactivity and inappropriate laughing and helped him sit for longer periods of time and read his books or watch whole movies was 0.5/kg mg Naltrexone daily, as advised by this paper Lower doses saw the OCD creep back. As for his WGS test results, I've found relevant the fact that he has four pathogenic mutations in the EIF4EBP1, also a de novo mutation in the PIK3R1 gene and multiple other mutations in the STAT3, HTR3a, MAPT and also HLA-DRB1, HLA-DQA1, HLA-A, HLA-B, HLA-C, NRG1, NRG2, SCN4a, CACNA1S genes, amongst many others. We recently tried a course of Azythromycin for immuno-modulation, which saw his OCD reduced further, also his academic interest and focus increased visibly. He responds very well to Ibuprofen, AlkaSeltzer gold, Propranolol, Sytrinol and Cromolyn, but a quite long trial of Bumetanide two years ago did nothing for him. After all trials of various protocols and individual drugs, his gut is still bad, very often food seems to have major difficulty to pass though his digestive tract, no matter how finely tuned his diet is or how many prokinetics he takes. Given your extensive knowledge, I've always wondered what your take on the underlying problem/genetic pathway might be in his case (microglial activation, MTOR activation, perhaps?) and what drugs/cocktail of drugs might work best for his specific genetics and symptoms. He is a smart boy, has self-taught reading, loves music and masters his iPAD like a pro and, unlike what we know about autism, loves being around people. I cannot give up on him. We live in the UK, not the best place to even talk about treatments for autism. Please, if it's not too much to ask, tell me what other medications you thing it might boost his cognition further and help him start talking and develop more skills. Sorry for the long post. And thank you for any advice and ideas you might have to offer.


It would be useful to know which of the above mutations are present in at least one of the parents.  There so many possibly causal mutations here; I expect some are actually not relevant. In other words, it is not as scary at it may appear to be.

I do like to start with the easy part, which will be the ion channels.  Dysfunctions in ion channels (channelopathies) are often treatable with existing drugs and there is a great deal of information on each one.



This gene encodes the calcium channel Cav1.1.

This is known as an L type calcium channel, the other ones being Cav1.2 and Cav1,3 and Cav1.4.

These ion channels are extremely important to how your brain works.  Because they also play a role in how your heart works, numerous drugs have been developed, some are more specific to one type of channel (Amlodipine for Cav1.3, Verapamil for Cav1.2).

The individual channels interact with other sub-types, so a mutation in one sub-type can affect other subtypes.

Very interesting in this case are the GI problems. There were efforts made a few years ago to develop R-verapamil as a drug to treat IBS/IBD under the name of Rezular. Some readers of this blog have reported that the only thing that resolves their child’s GI problems is an L-type calcium channel blocker.

Note Memantine, which is an Alzheimer’s drug that was subject to a very large autism clinical trial in the US.  The trial was deemed a failure, but one reader told me that Memantine is the only drug she had found that solved her child’s GI problems.  Memantine has several different modes of action, and a little reported one is blocking L-type calcium channels.

Conclusions. Our results suggest that the neuroprotective effect of memantine could arise not only through the inhibition of the NMDA receptor current but also through the suppression of the L-type Ca2+ current.   


You might expect/hope a geneticist would suggest treatment with a drug like Verapamil.



This gene encodes the sodium ion channel Nav1.4.

This is one of the genes associated with Hypokalemic Periodic Paralysis (HPP), that was covered extensively in this blog. Interestingly the above Cav1.1 is also associated with Hypokalemic Periodic Paralysis (HPP).

The other genetic cause of HPP is KCNJ2 (an inward-rectifier potassium channel Kir2.1).

The immediate recovery therapy is drinking a potassium supplement.

A common preventative measure is acetazolamide (Diamox). This drug has also been covered in previous posts. The proposed mechanism is that it “increases the flow of potassium” – not sure what that is supposed to mean.

Some common anti-epilepsy drugs block Nav1.4 (Lamotrigine, Phenytoin etc).

All of the above-mentioned drugs have been used in autism. In specific cases they have shown a benefit.

You could ask your doctor to cautiously try them one by one.

Interestingly, the drug that seems to help many with sound sensitivity is Ponstan.  This cheap drug that affects the flow of potassium ions was proposed by Knut Witkowski as a therapy for 2-3 year olds to prevent non-verbal severe autism. 



Here you mention there are 4 pathogenic mutations.

This gene is a real mouthful, but regular reader might recall the odd looking eIF4E part appearing in some previous posts

“This gene encodes one member of a family of translation repressor proteins. The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is a limiting component of the multi subunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. Interaction of this protein with eIF4E inhibits complex assembly and represses translation. This protein is phosphorylated in response to various signals including UV irradiation and insulin signaling, resulting in its dissociation from eIF4E and activation of cap-dependent mRNA translation.”

eIF4E inhibitors for Autism – Why not Ribavirin?


As you can see in the above post there are numerous ways to block elF4E. It is possible that the 4 mutations in your gene EIF4EBP1 could have the reverse effect in which case you would want to activate elF4E, not block it.

On the list, in my post above, is quercetin which is OTC and simple to try.



A mutation in this gene can alter the PI3K/AKT/mTOR signaling pathway.

If this gene is causing a problem you might see some facial features a triangular face, a prominent forehead, small chin with a dimple, a loss of fat under the skin, prominent ears, hearing loss and delayed speech.

A mutation in this gene can lead to SHORT syndrome, which hopefully your pediatrician will have heard of.



STAT3 plays a key role in the immune system and elsewhere.

You can either have too much or too little STAT3.

In lay terms the immune system might end up either over-activated (hence benefiting from Ibuprofen and Cromolyn sodium) or under activated.

The immunomodulatory probiotics prescribed by gastroenterologists might be worth a try.

Lactobacillus rhamnosus GG

Lactobacillus plantarum 299v 


This might well reduce GI problems as well.



This gene encodes subunit A of the type 3 serotonin receptor. It has lots of effects, but it may contribute to the vomiting.

It is associated with:

  • Motion sickness
  • Irritable bowel syndrome
  • Social phobia
  • Serotonin syndrome

For gastroparesis (impaired stomach's motility) the good drug seems to be Domperidone, which you should be able to get for free from your NHS doctor.

Another very popular therapy for gut dysbiosis of all kinds in some countries, but not the UK, is sodium butyrate. This has been mentioned in previous posts. It is an OTC supplement that will produce butyric acid in the gut and it helps restore a healthy mucosa. If you eat lots of fiber and have a healthy microbiome you would produce butyric acid naturally. The cheapest place in Europe to buy it is Poland, where they sell a product called Intesta Max (a weaker version is Intesta).  In the UK it is 3 times more expensive. Making friends with a Pole will save you money.



The MAPT gene makes tau proteins.  There is a class of disease called tauopathy.

Tau Reduction Prevents Key Features of Autism in Mouse Models


Tau: A Novel Entry Point for mTOR-Based Treatments in Autism Spectrum Disorder?


As with the PIK3R1 mutation this will lead you to the idea of targeting mTOR signalling. You can inhibit this with Rapamycin, which has been used in autism.


Rapamycin/Sirolimus Improves the Behavior of an 8-Year-Old Boy With Nonsyndromic Autism Spectrum Disorder


One UK reader did get Everolimus prescribed on the NHS, but that was because the child was diagnosed with a genetic disorder called TSC. Several readers of this blog have tried Rapamycin as used in the Chinese case study.

If you do not have an over activated immune system, Rapamycin will cause the problem of an underactive immune system.



 These genes all play a role in the immune system.

The human leukocyte antigen (HLA) system is a complex of genes in humans which encode cell-surface proteins responsible for regulation of the immune system.

The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and is therefore not an invader.


HLA Immune Function Genes in Autism

The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.

One specific HLA gene has been studied in autism.

 Inheritance of HLA-Cw7 Associated With Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a behaviorally defined disorder that is now thought to affect approximately 1 in 69 children in the United States. In most cases, the etiology is unknown, but several studies point to the interaction of genetic predisposition with environmental factors. The immune system is thought to have a causative role in ASD, and specific studies have implicated T lymphocytes, monocytes, natural killer (NK) cells, and certain cytokines. The human leukocyte antigen (HLA) system is involved in the underlying process for shaping an individual’s immune system, and specific HLA alleles are associated with specific diseases as risk factors. In this study, we determine whether a specific HLA allele was associated with ASD in a large cohort of patients with ASD. Identifying such an association could help in the identification of immune system components which may have a causative role in specific cohorts of patients with ASD who share similar specific clinical features. Specimens from 143 patients with ASD were analyzed with respect to race and ethnicity. Overall, HLA-Cw7 was present in a much greater frequency than expected in individuals with ASD as compared to the general population. Further, the cohort of patients who express HLA-Cw7 shares specific immune system/inflammatory clinical features including being more likely to have allergies, food intolerances, and chronic sinusitis as compared to those with ASD who did not express HLA-Cw7. HLA-Cw7 has a role in stimulating NK cells. Thus, this finding may indicate that chronic over-activation of NK cells may have a role in the manifestation of ASD in a cohort of patients with increased immune system/inflammatory features.


The therapeutic implication would be to look at immunomodulatory therapy.

At the simple level you have NSAIDs like Ibuprofen, but then you have the more potent drugs used to treat psoriasis, arthritis, IBD etc.

If you saw Dr Arthur Krigsman, the autism gastroenterologist, I guess he would prescribe Humira.  This is an injection you take every few weeks.  That very well might help your son in many ways. He does also come to Europe for consultations. You would need a colonoscopy.

Some British parents take their autistic kids with GI problems to Italy for treatment. You could ask the Thinking Autism charity who they go to see. One of these doctors presented at their conference in London in 2019.  He used some of Krigsman’s slides in his presentation.



Neuregulin 1 and 2 are implicated in brain disorders. NRG1 is well known as a schizophrenia gene, but it has been shown to be miss-expressed in autism as well.

NRG2 also plays a role in many neurological conditions.  

Neuregulins in Neurodegenerative Diseases 

The downstream effect of NRG1 is on epidermal growth factor (EGF). There are expensive cancer drugs like Lapatinib that are inhibitors of EGFR. 

As I have written in my blog, disturbed growth factors is a recurring feature of autism. This is why son many autism genes are also cancer genes. Don’t worry, this does not mean everyone with autism is going to get cancer.



Try and find a doctor who is interested to treat your son.

I think you will make great strides by treating the GI problems that you see every day.

I did meet an UK autism mother at that conference in London in 2019 who was told by her doctor that her son’s GI problems would not be treated in the UK and she should look abroad. She went to Italy and solved his problems.  It sounds so bizarre, I would not have believed it to be possible, had I not been talking directly to the mother.  I did talk to the Italian gastroenterologist at that same event.  Contact Thinking Autism and ask who was the Italian who presented in 2019.