The Atopic March - updated: Leading to Autism and ADHD in some children?

 

I was thinking yesterday about the link between eczema (atopic dermatitis) and autism following a comment regarding a therapy I must have mentioned long ago (l-histidine with zinc). The therapy did work well for this child.

This then brought me back to one of my pet subjects, which is the minimization of the risk of future autism. I did write a section in my book on this subject, but it remains a work-in-progress. My elder son wants to avoid autism in his future children. If there are simple, safe, inexpensive steps that can be taken, that also provide broader health benefits then it would be crazy not to take them.

This brings me to the subject of the so-called atopic march. I have updated it to include its effects on the brain, increasing the risk of autism and ADHD and also suggest that in fact there may be slightly different atopic journeys, rather than a singular march with the same start and end points.

 

The atopic march

The traditional "atopic march" describes the progression from atopic dermatitis (eczema) in infancy to food allergies, asthma and allergic rhinitis later in childhood. While this framework has been useful for decades, it may be too simplistic.

Perhaps there is not one atopic march, but several.

Recent years have seen an explosion of research into the gut microbiome, immune development, mast cells and neurodevelopment. Numerous studies continue to investigate probiotics as a treatment for eczema, allergies and even autism. However, there is a recurring problem: many of these studies are performed in children who may already be too old to receive the maximum benefit.

The first few months of life appear to be a critical developmental window. During this period, the gut microbiome, immune system and brain are all developing simultaneously. Alterations during this time may have lifelong consequences.

One particularly intriguing study from Finland was originally designed to investigate eczema prevention. What makes this study especially interesting is that the intervention began before many people would even think about treating the microbiome. Mothers received the probiotic Lactobacillus rhamnosus GG during the final 2–4 weeks of pregnancy. After birth, the infants received the probiotic for only the first six months of life.

A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial

Remarkably, this relatively brief intervention, lasting just a few months around the time of birth, was followed by measurable differences many years later.

In other words, the researchers were not treating eczema, ADHD or autism. They were attempting to influence the earliest stages of microbiome development. This timing is important because the infant microbiome is initially seeded by microbes acquired from the mother during birth, breastfeeding and close maternal contact. By giving the probiotic to both mother and infant, the researchers may have been influencing the microbial ecosystem at the very moment it was being established.

Years later, when the children were followed into adolescence, the researchers found not only a reduction in eczema but also a surprising reduction in diagnoses of ADHD and Asperger syndrome. If the finding proves to be real, it would suggest that a six-month intervention during infancy may have influenced developmental trajectories more than a decade later. The study was small and requires replication, but the findings were striking. 

Group	Children	ADHD or Asperger syndrome by age 13	Percentage
Probiotic (LGG)	40	0	0%
Placebo	35	6	17%

One reason the Finnish study has not been easily replicated is the sheer difficulty of performing such research. To repeat the study properly, researchers would need to recruit women during pregnancy, administer the intervention before birth, continue treatment during infancy, and then follow the children for 10–15 years while carefully tracking neurodevelopmental outcomes. Such studies are expensive, logistically challenging and suffer from inevitable participant drop-out over time. Furthermore, because probiotics are inexpensive and cannot easily be patented, there is limited commercial incentive to fund a trial that may take more than a decade to produce results. As a consequence, many probiotic studies focus on older children and adults where results can be obtained within months rather than years, even though the greatest biological impact may occur during the earliest stages of development.

At the same time, other observations point in a similar direction:

• Early pet exposure reduces the risk of eczema.
• Children raised on farms have lower rates of allergic disease.
• Early probiotic use can reduce the risk of atopic dermatitis.
• Food allergies are increasingly viewed as part of the atopic march.
• Autism and ADHD are associated with higher rates of allergic disease in many studies.

The common denominator may be early-life immune and microbiome development.

The protective effects of pets and farm exposure are often discussed in the context of the hygiene hypothesis, although the modern interpretation is really a microbial exposure hypothesis. Children growing up around animals are exposed to a much greater diversity of microorganisms. Rather than overwhelming the immune system, these microbial exposures appear to help educate and calibrate it. Studies of children raised on traditional farms consistently show lower rates of eczema, asthma and allergic disease. The immune system evolved in a world rich in microbial exposures, and it may require those signals to develop normally.

This brings us to an important point. The infant microbiome does not arise spontaneously. Much of it originates from the mother. During birth, breastfeeding and close maternal contact, microbes are transferred from mother to child. These pioneer organisms help establish the infant gut microbiome and play a critical role in training the developing immune system. In many ways, the microbiome acts as one of the earliest teachers of the immune system, helping it learn the difference between harmless substances and genuine threats.

This process of immune calibration appears to occur very early in life. Once established, the microbiome becomes increasingly stable and resistant to change. This may explain why probiotics often show their greatest effects when administered during pregnancy or infancy, while studies in older children and adults frequently produce much smaller results. By the time many interventions are attempted, the window during which the microbiome is shaping immune development may already be closing.

Perhaps the most remarkable aspect of the Finnish study is not the probiotic itself, but the timing. The intervention was completed by six months of age, yet the outcomes were measured at 13 years of age. This is precisely what one would expect if the microbiome plays a role in calibrating the developing immune system during a narrow critical window early in life.

Mast cells may also deserve greater attention. They play important roles in eczema, food allergies, asthma and anaphylaxis, but they are also found in the gut and nervous system. Some researchers have proposed that abnormal mast-cell activity could contribute to neurodevelopmental symptoms in susceptible individuals.

Another clue that early immune modulation may alter the trajectory of the atopic march comes from studies of ketotifen, an antihistamine and mast-cell stabilizer. In one notable study of infants with atopic dermatitis, children receiving ketotifen were significantly less likely to develop asthma during the follow-up period. The researchers also reported improvements in the severity of atopic dermatitis. These findings suggest that, at least in some children, modifying mast-cell activity and allergic inflammation early in life may alter the subsequent progression of allergic disease.

Prevention strategies for asthma — secondary prevention

If the classical atopic march can be interrupted before eczema progresses to asthma, it raises a broader question. Could other early interventions—such as probiotics, microbial exposure from pets and farm environments, or targeted immune modulation—also alter developmental trajectories extending beyond allergy and into neurodevelopment in susceptible children?

This raises an interesting possibility. For a subgroup of children, the atopic march may not end with asthma and hay fever. Instead, immune dysregulation, microbiome alterations and barrier dysfunction could also influence neurodevelopment, increasing the risk of ADHD or autism.

The proposed sequence might look something like this:

Microbiome disturbance / barrier dysfunction → Eczema → Food allergy → Mast-cell activation → ADHD / Autism susceptibility

or perhaps

Microbiome disturbance → Food allergy → Eczema → Neurodevelopmental effects

In other words, there may be multiple entry points and multiple destinations.

Importantly, this hypothesis does not suggest that eczema causes autism, nor that most children with eczema will develop autism. Rather, it suggests that some children may share an underlying biological pathway affecting the skin, gut, immune system and brain.

If this hypothesis contains even a grain of truth, it has profound implications. It would mean that interventions aimed at modifying the microbiome or immune system may be most effective during infancy, before symptoms of autism or ADHD are apparent. By the time a child is diagnosed at age 3, 5 or 10, the critical developmental window may already have passed.

The irony is that we continue to perform large numbers of probiotic studies in older children and adults, where effects are often modest. The greatest opportunity may lie much earlier, during the period when the microbiome and immune system are still being assembled.

The challenge for researchers is to identify which children belong to this subgroup before the window of opportunity closes.

The classical atopic march has evolved over time. Perhaps the next evolution will be to recognize that, in some children, the journey extends beyond allergies and into neurodevelopment.

  

Conclusion

 In the Finnish study, the intervention was actually in both the mother and the infant:

• Mothers took Lactobacillus rhamnosus GG during the final 2–4 weeks of pregnancy.
• After birth, the infants received the probiotic until 6 months of age.

It would be very easy to implement this.

Dog and farm animal exposure (pregnant mother and later the baby) might be more difficult for some, but easy for others.

NAC during pregnancy is another simple one. It was also show very effective in reducing miscarriages and increasing the “take-home baby rate.”

We also saw Prof Ramaekers using folinic acid during pregnancy where future parents test positive for folate receptor antibodies. This requires the future parents taking the FRAT test.

In older children and adults probiotics can have a benefit, but the dramatic effect only occurs when given prior to the immune system being (mis)calibrated. In the older age-group it appears that you need something more potent – FMT works in some cases. 

The Finnish study only refers to level 1 autism (then called Asperger's syndrome).

I imagine if you could repeat this study and also include all the common issues like

• Dyslexia
• Dyscalculia
• Developmental language disorder
• Dyspraxia (developmental coordination disorder)
• Learning disabilities generally
• Level 2 and 3 autism

you would see some shocking results. 

You would not have 0% incidence of each disorder in the probiotic group, but I bet you would see a substantial reduction.

Turmeric/Curcumin – clinically effective in humans after all? SLC6A15 Amino Acid Transporter

Turmeric powder, only in food, modified the SLC6A15 gene

I know that most readers of this blog want to treat autism with supplements and/or diet.

Many supplements and herbal medicines do show promise in the laboratory, when tests are conducted in vitro, but very often when tests are made in humans the results are much weaker, or just not present.  Turmeric/Curcumin is a perfect example; in the test tube it has a wide range of potent benefits, but due to low absorption into humans (bioavailability) it does not show such conclusive results in human studies.

One researcher a while back did send me a study that reviewed all the turmeric/curcumin trials and it concluded that curcumin has no beneficial effect in humans.

In modern medicine anecdotal evidence does not count. Some anecdotes are genuine, but some are coincidence and some are placebo. 

Mini trial of Turmeric at three UK Universities

There is a remarkably good medical program produced by the BBC in the UK, called Trust me I’m a Doctor, where the doctor presenters team up with universities to test practical medical hypotheses.

Does turmeric really help protect us from cancer?

In one study they took 100 people to assess whether turmeric has any measurable medical benefit. They teamed up with Newcastle University, Leeds University and a clever genetic researcher at University College London (UCL).

They showed that eating turmeric in your food modified a specific gene (SLC6A15) associated with certain cancers, asthma/eczema and depression.

Taking turmeric as a supplement pill or taking a placebo pill had no effect on the gene.

The researcher at UCL was measuring the epigenetic tags attached to the genes. He showed that methylation of this gene was increased by dietary turmeric. Changing the methylation of this gene will change when it turns on/off.

Anecdotally, we know that people who eat a lot of turmeric tend to have less cancer, less asthma and less eczema.

Given that this gene is also associated with depression, you might expect big eaters of turmeric to have either less, or more, depression. Probably nobody has researched this.  

SLC6 Gene Family

It is true that asthma and eczema (atopic dermatitis) are common in people with autism, but variations in the broader SLC6 family of genes are known to affect people with ADHD, Fragile X, Tourette’s and broad autism.

SLC transporters encompass approximately 350 transporters organized into 55 families. The SLC6 family is among the largest SLC families, containing 20 genes that encode a group of highly similar transporter proteins. These proteins perform transport of amino acids and amino acid derivatives into cells. 

SLC6 Transporters: Structure, Function, Regulation, Disease Association and Therapeutics

In humans, the SLC6 family of transporters defines one of the most clinically relevant protein groups with links to orthostatic intolerance, attention deficit hyperactivity disorder (ADHD), addiction, osmotic imbalance, X-linked mental retardation , Hartnup disorder, hyperekplexia, Tourette syndrome, schizophrenia, Parkinson disease (PD), autism  and mood disorders such as depression, anxiety, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

This review will focus on the structure-function aspects of the mammalian SLC6 transporters, their regulation by both classical as well as emerging epigenetic/transgenerational mechanisms and what impact these properties may have on disease and the use of biomarkers to detect these proteins in disease states  

The functional impact of SLC6 transporter genetic variation.

Solute carrier 6 (SLC6) is a gene family of ion-coupled plasma membrane cotransporters, including transporters of neurotransmitters, amino acids, and osmolytes that mediate the movement of their substrates into cells to facilitate or regulate synaptic transmission, neurotransmitter recycling, metabolic function, and fluid homeostasis. Polymorphisms in transporter genes may influence expression and activity of transporters and contribute to behavior, traits, and disease. Determining the relationship between the monoamine transporters and complex psychiatric disorders has been a particular challenge that is being met by evolving approaches. Elucidating the functional consequences of and interactions among polymorphic sites is advancing our understanding of this relationship. Examining the influence of environmental influences, especially early-life events, has helped bridge the gap between genotype and phenotype. Refining phenotypes, through assessment of endophenotypes, specific behavioral tasks, medication response, and brain network properties has also improved detection of the impact of genetic variation on complex behavior and disease. 

Amino acids are very important and it is not just that you need them, but you need them in the right place at the right time.

It appears that one of the many effects of defective amino acid/derivative transport into cells is on behaviour.

Improving amino acid transmission is therefore a potential therapy to correct aberrant behaviour, including depression but likely much more. 

Conclusion

Modern clinical trials are often hugely expensive, but as the BBC keeps showing with its TV series, you can carry out very meaningful research without breaking the bank.

You would think that cancer researchers would now look at the modified versions of turmeric that claim higher bioavailability and see if these pills can also modify this cancer gene, since they can easily repeat the UCL laboratory analysis. I doubt this will happen any time soon.

It has long been known that turmeric is not well absorbed, but just one teaspoon a day added to food was enough to modify the gene.

Indians have a low incidence of cancer and a high consumption of turmeric. Turmeric should particularly limit breast cancer.

Source: https://vizhub.healthdata.org/gbd-compare/

The above chart, where blue is best, shows India does well, as do some other turmeric eating countries (South Asia and the Middle East). Clearly longevity and quality of healthcare also matter, so beware Africa. Europe, Russia, Argentina, Uraguay, Oz, NZ and North American might want to up their turmeric intake.

We can say that turmeric is a potential epigenetic therapy for at least one important gene (SLC6A15) and possibly more, because turmeric does not just affect methylation. It has several other better documented epigenetic properties. 

Epigenetic changes induced by curcumin and other natural compounds

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.

Only a few reports have so far investigated the effect of curcumin on DNA methylation. Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of DNMT1 to exert its inhibitory effect on DNA methylation. However, a more recent study showed no curcumin-dependent demethylation, which suggested that curcumin has little or no pharmacologically relevant activity as a DNMT inhibitor. To clarify these contradictions, more research is urgently needed.

Given that 5-azacitidine and decitabine, two FDA-approved hypomethylating agents for treating myelodysplastic syndrome, have a demonstrated ability to sensitize cancer cells to chemotherapeutic agents, it would be worthwhile to explore whether the hypomethylation effect of curcumin can also induce cancer cell chemosensitization. Interestingly, a phase 1 trial with curcumin administered several days before docetaxel in patients with metastatic breast cancer resulted in 5 partial remissions and stable disease in 3 of 8 patients. This unexpected high response might have resulted from the clever sequential delivery of these two agents, which capitalized on and maximized curcumin’s epigenetic activity for cancer treatment.

Docetaxel is a 20 year old chemotherapy drug produced using extracts from the leaves of the European yew tree, perhaps best taken with root (rhizome) of the Asian Curcuma Longa plant. 

The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly. It exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.

How much Histidine? Dermatitis and FLG mutations

Today’s post is not about autism, it is about allergy and atopic dermatitis in particular.

Many people are affected by atopic dermatitis (AD), also known as eczema; it is particularly common in those with autism. Children who develop asthma have often first developed atopic dermatitis (AD).

Atopic Dermatitis is another of those auto-immune conditions and the sooner you stabilize such conditions the better the prognosis.

Skin therapies from a company

spun-off from Manchester University

Histidine

A while back on this blog I was looking at the various amino acids and came across the observation that histidine, a precursor of histamine, appears to be a mast cell stabilizer. Mast cells are the ones that release histamine and IL-6 into your blood. Histamine then does on the trigger yet more IL-6 to be produced.  IL-6 is a particularly troublesome pro-inflammatory cytokine.

At first sight giving a precursor of histamine to people who want less histamine seems a crazy thing to do, but plenty of people report their allergies improving after taking histidine. As we have discovered, feedback loops are very important in human biology and these can be used sometimes to trick the body into doing what you want it to do. Having a higher level of histidine in your blood might make histamine production easier but it might also be telling the body not to bother, or just to delay mast cells from degranulating.  Whatever the mechanism, it does seem to work for many people. 

How Much Histidine?

Most histidine pills are 0.5g and it appears people use about 1g to minimize their allergy. 1g is the dose Monty, aged 14 with ASD, has been using during the pollen allergy season.

My sister recently highlighted a new "high tech" OTC product for skin conditions, Curapella/Pellamex, its main ingredient is histidine and it is a lot of histidine, 4g.

The company that produces the supplement have teamed up with the Universities of Edinburgh and Manchester to make a clinical trial, which is featured below.

They are considering the interaction between histidine and filaggrine (produced by the FLG gene). 

            https://ghr.nlm.nih.gov/gene/FLG#conditions

Mutations in the FLG gene are associated with atopic dermatitis and indeed with asthma, hay fever, food allergies, and, rather bizarrely, skin sensitivity to nickel.

In effect it is suggested that histidine makes filaggrine work better and thus atopic dermatitis and some other skin conditions will improve.  

Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis 

Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0 .01="" respectively="" span="" style="background: yellow; margin: 0px;">Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0 .003="" 34="" 39="" 4="" ad="" after="" and="" assessment="" by="" disease="" eczema="" measure="" of="" oriented="" patient="" physician="" scoringad="" self-assessment="" severity="" span="" the="" tool="" treatment="" using="" weeks="">. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD. 

In this paper, we suggest that a simpler, nutritional supplementation of l-histidine may have a beneficial potential in AD.

l-histidine is a proteinogenic amino acid that is not synthesized by mammals. In human infants, it is considered “essential” due to low levels of histidine-synthesizing gut microflora and minimal carnosinase activity, which helps in releasing free l-histidine from carnosine.24 Our interest in the use of l-histidine in AD was stimulated by several observations. Firstly, in both infants and adults, a histidine-deficient diet results in an eczematous rash.25 In rodents, ³H-histidine is rapidly (1–2 hours) incorporated into profilaggrin within keratohyalin granules after intraperitoneal or intradermal injection14,26 and within 1–7 days is released as a free NMF amino acid in the upper stratum corneum.14 Furthermore, reduced stratum corneum levels of free NMF amino acids, including histidine and its acidifying metabolite urocanic acid (UCA), are associated with AD disease severity and FLG genotype.27,28

Given this evidence for the dependence of filaggrin processing and NMF formation on suitable levels of l-histidine, we hypothesized that l-histidine would both enhance filaggrin processing in an in vitro, organotypic, human skin model and have beneficial effects as a nutritional supplement in subjects with atopic dermatitis. 

After a 2-week wash-out period in which subjects were asked not to use any medicinal product for their AD, the same measures were repeated and patients were provided with identical sachets containing either 4 g l-histidine (Group A) or 4 g placebo (erythritol); Group B) which was taken once a day, dissolved in a morning fruit drink.  

The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort.

Conclusion

It looks like 4g of histidine has the same potency as mild topical steroid creams, when treating atopic dermatitis.

The big problem with topical steroids is that you can only use them for a week or two. It you use them for longer, you end up with a bigger problem than the one you were trying to treat.

The 4g a day of histidine is put forward as a safe long term therapy.

Is the mode of action related to mast cells or filaggrin (FLG)? Or perhaps both?

If 1g of histidine does improve your allergies, perhaps you should feel free to try a little more.

You can buy histidine as a bulk powder. Pellamex is quite expensive, particularly if more than one family member is affected, as you would expect to find in a genetic condition.  

Preventing Auto-Immune Disease and some Autism

Today’s post is another one filling in some gaps in this blog.

I think it is common sense to say that preventing a problem from developing is much wiser than trying to solve it later on.  This is a recurring issue in both life and medicine.

In the research we now see preventative measures developed to reduce the risk of cancer, we also see how some interventions are only effective when started very early.

In the case of autism we have seen than often it is caused by a myriad of factors that by themselves might have been harmless but when taken together are the multiples hits that caused the brain to develop differently.

Much research looks individually at these factors that increase the risk of autism.  In the wider media much disdain is directed to these findings as if each factor is THE cause of autism and how can so many things cause autism.  But by understanding these factors you can then set about countering them.

I did create my simplified schematic to explain classic autism a while back.  It is not perfect but it does illustrate much of what is going on.

I do get occasional questions about reducing the risk of autism.  For example, Monty now aged 13 with ASD, has a big brother and he wants to know.  Our reader, Kritika from India, has also raised this issue.  If you have autism in your family you may well decide you would like to minimize the risk of more cases.

In practical terms, you cannot change your genes or those inherited epigenetic markers.  Maybe this will change in future.  But there are things you can do.

We know that oxidative stress is a driver of much disease including autism.  This can be minimized by lifestyle changes and indeed with a little pharmacological help.

I was interested to see a study that used NAC to treat mothers who suffer unexplained pregnancy loss, the antioxidant showed a “significant increase in the take-home baby rate”.  I was really just looking for safety information.

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss 

Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL.

This then made be recall a US fertility clinic, that our reader Roger once mentioned in a comment.

http://www.preventmiscarriage.com/

http://www.preventautism.com/

“At Braverman Reproductive Immunology, we believe Autism Spectrum Disorder (ASD) and various pregnancy and infertility complications (listed below) appear to have the same cause. In fact, we have found that a large number of patients who present to our center with the below complications already have a child with ASD.

This discovery started us on the journey to see if ASD itself could be prevented while treating other associated conditions. We believe treatment for these common issues will not only prevent the pregnancy complications listed below, but may also prevent ASD in the group of patients that have already had a child with ASD.”

Dr Braverman does not mention oxidative stress, but perhaps he should.

So step one would be to reduce oxidative stress during pregnancy, via lifestyle changes and taking antioxidants.

Step two would be to avoid inflammation, Dr Braverman refers to the link to auto-immune disease and miscarriage/autism.

We know that maternal inflammation is one of the easiest ways to cause autism in mouse models (the MIA model - Maternal Immune Activation).

  

We have some research to show that the risk of auto-immune disease can indeed be reduced and indeed that the risk of progression from minor to more major auto-immune disease can also be minimized.

We even have a tiny study showing that immuno-modulatory therapy using a probiotic during pregnancy can reduce incidence of ADHD and autism. For me ADHD is just a case of autism-lite.

A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial

Background:

Recent experimental evidence suggests that gut microbiota may alter function within the nervous system providing new insight on the mechanism of neuropsychiatric disorders.

Methods:

Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria.

Results:

At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03.

Conclusion:

Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.

The issue, as with NAC during pregnancy, is whether immuno-modulatory therapy is safe.

The study on ADHD and autism was actually a study looking at whether a certain probiotic if given during pregnancy could reduce eczema later on in the child.

  

We also have the studied effect of having a pet dog at home.

House dust exposure mediates gut microbiome Lactobacillus enrichmentand airway immune defense against allergens and virus infection

 

Early-life exposure to dogs is protective against allergic disease development, and dog ownership is associated with a distinct milieu of house dust microbial exposures. Here, we show that mice exposed to dog-associated house dust are protected against airway allergen challenge. These animals exhibit reduced Th2 cytokine production, fewer activated T cells, and a distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii, which itself can confer airway protection when orally supplemented as a single species. This study supports the possibility that host–environment interactions that govern allergic or infectious airway disease may be mediated, at least in part, by the impact of environmental exposures on the gastrointestinal microbiome composition and, by extension, its impact on the host immune response.

One of my views is that by early treatment of autism you may indeed reduce the risk of epilepsy.  The key here is “reduce the risk”, it does not mean there is no risk.  There are likely hundreds of causes of epilepsy, but if you can reduce the incidence by 30+% that would look like a big success to me.

I recall another study that looked at treating people with eczema to see if you could reduce the chance of progression to asthma.  Using Ketotifen the trial showed that it was indeed possible.

Prevention of asthma by ketotifen in infants with atopic dermatitis. 

To evaluate the prophylactic effect of ketotifen against the onset of asthma we selected 121 infants with atopic dermatitis, without any history suggestive of asthma (cough and/or wheezing). Sixty-one children received ketotifen twice daily. Those who weighed less than 14 kg received 0.8 mg; 14 kg or more, 1.2 mg. Sixty children, a placebo syrup indistinguishable from the active syrup. Both groups were followed for 1 year, with bimonthly evaluations. The criteria for onset of asthma were two different episodes of wheezing treated with bronchodilator drugs. Both groups were comparable regarding age, sex, weight, onset, and duration of atopic dermatitis and age at the onset of asthma. During the 1 year study, asthma was observed in eight children of the ketotifen group (13.1%) and in 25 children of the placebo group (41.6%) (P less than .001). Side effects were negligible and routine laboratory tests disclosed no significant alterations. Ketotifen is a very useful drug for prevention of asthma in children with atopic dermatitis and total IgE more than 50 IU/mL.

Somali Autism Clusters

This then takes me back to that issue I looked at long ago, which was the reason for the Somali immigrants to Sweden and US having so many children with autism.  This even got termed the Swedish Disease by the migrants, they claimed to have never seen autism back home in Somalia.

Then we have the hygiene hypothesis which in effect says that, within limits, a little dirt is good for you.

Hormonal Dysfunction

We know that gestational diabetes increases the risk of autism and we also known that the mother being hypothyroid increases the risk.  In some cases the hormone dysfunction is a consequence of the auto-immune dysfunction.

We also know the female hormone progesterone is extremely neuro-protective.  The level of this hormone is supposed to rise during pregnancy.

  

In past times hormones were given to some pregnant mothers, but this went out of fashion.  Perhaps this should be revisited?

Then we have the surge of the hormone oxytocin that the baby is supposed to receive at birth.  This surge may be relevant to the GABA switch when shortly after birth this neurotransmitter is supposed to switch from excitatory to inhibitory as the neurons mature. If the baby is born by Caesarian there will be no oxytocin surge for the baby.   

Preventing Regressive Autism Secondary to Mitochondrial Disease (AMD)

It is on open secret that doctors at Johns Hopkins have identified a variant of regressive autism called Autism secondary to Mitochondrial Disease (AMD).

It remains unclear how rare this is and absolutely nobody serious is going to research this, if they ever want to receive a research grant in the future.

We saw that in people with a genetic predisposition to mitochondrial dysfunction, an immune over-reaction to an insult like multiple vaccinations can trigger mitochondrial disease.  This will present itself as autism and quite possibly severe autism in a previously unaffected child.

Those doctors treating AMD use mild immuno-suppressing drugs before any future vaccinations.

How do you minimize the chance of AMD? 

The first thing is to never use paracetamol/acetaminophen in a baby or child, particularly just after vaccination.  This drug may kill the pain but it depletes GSH the body’s main antioxidant, just when it needs it most.   Use something like Ibuprofen.

Vaccines are given in multiples so as to save time and money and I suppose improve compliance. You might expect giving them one-by-one would actually make them more effective as well minimizing any collateral damage to a small percentage of kids.

Conclusion

As I keep reminding readers, I am not a doctor, but it would be nice if a few more doctors other than Braverman took preventing autism seriously.

I would like to know if progesterone is an effective therapy in the MIA model of autism.  In this model they trigger the mother’s immune system during pregnancy which leads to offspring with autism.  What would be the effect of giving progesterone?  Would it protect the pups?

Are progesterone levels reduced in mice that will become autistic?

So I suppose I would trial NAC and progesterone in the mother mouse.

For everyone else it is case of choosing whether or not to make lifestyle changes to reduce oxidative stress.  Improving gut bacteria can be done via probiotics, eating more (slightly dirty) fruit and vegetables, having a pet dog, spending some time in the nature.  

As for vaccine risk, however small it might indeed be, there will never be a serious investigation of this, for understandable reasons.