Showing posts with label Asthma. Show all posts
Showing posts with label Asthma. Show all posts

Thursday, 2 August 2018

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.
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. 

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. 

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.


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 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.

Tuesday, 16 January 2018

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

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). 

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.  

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.  


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.  

Tuesday, 15 November 2016

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.

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.

“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


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


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 3wk, 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.


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.


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.


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. 

Thursday, 13 October 2016

Multigenerational Epigenetic Change Stimulating Inflammatory Disease

Multigenerational transmission of nicotine-induced effects. The diagram illustrates the experimental design and findings of Rehan et al. [4]. Pregnant dams (F0 generation) are injected with nicotine or nicotine + rosiglitazone. The lungs and gonads of both male and female offspring (F1 generation) of nicotine-treated dams exhibit epigenetic changes, and the lungs show an asthma-like functional phenotype (blue nicotine-induced changes). These nicotine effects are not seen in the offspring of animals treated with nicotine + rosiglitazone. Offspring of F1 mated pairs (F2 generation) exhibit the same nicotine-induced changes to lung function as their parents, even though they were not exposed to drug.

Today’s post is again filling in some gaps in this blog to date.

A big question in autism is whether the incidence is increasing or not.  According to the now best-selling autism author Silberman, incidence is not increasing at all; it is just that diagnosis is much better than it was half a century ago.  So it is not an “autism epidemic”, rather a “diagnosis epidemic”.

I did not buy Siberman’s book and while I would like to believe he has accurately assessed the facts, in this case he really has not.

Psychiatrists have done none of us any favours by constantly changing the definition of autism and clinicians have never adequately collated data on those who match those criteria.

It does actually matter whether or not incidence of autism is increasing, because this would then stimulate research as to why.  In time this better understanding would lead to therapeutic avenues.

Being neither a professional researcher, nor a best-selling author, my level of evidence can be a little lower.  In earlier posts we saw incidence of ASD (autism, Asperger’s and PDD-NOS) is around one percent of both the child and adult population.  Many adults with Asperger’s and milder dysfunctions were never diagnosed as children, because they did not have speech delay or great cognitive difficulties.

The autism figures are always of low quality, but there is an opinion that underlying them is a real increase in severe autism, as well as the increased diagnosis of milder autism due to lowering of the diagnostic threshold.

The data I would like to see is the incidence of severe autism over the last few decades, but it does not exist.  All we have is anecdotes.

I remember asking my retired doctor mother how many patients had autism in her medical practice of about 10,000, where she saw all the children.  They did not have any and apparently until the Wakefield autism-MMR business nobody even talked about autism.

Hidden away in a group of 10,000 there “should be” about 100 with some degree of autism.  About 30 might have quite severe autism, many with MR/ID and epilepsy. 30 sounds a lot, but it is only one or two births a year.  People with severe autism live half as long as typical people, so you would not see many past middle age. I suppose it was easy to just diagnose mental retardation and then put the child into “care” when the parents could not cope.  

When a friend of mine from graduate school asked our alumni group of 200 how many had a child with autism there were six responses.  None were Asperger’s, all were strictly defined autism (SDA).

Some disease surprisingly does correlate with educational level.  I recently read that IBS/IBD is much more common among more educated people.

So my take is that hidden in all those poor quality statistics is a rise in the incidence of strictly defined autism (SDA).  Just as it is known that there has been a rise in inflammatory disease like asthma.

Asthma and COPD are really well researched and we know at least some of the reason why they have become more common.  I think the same general mechanism is behind the increase in SDA.

By understanding this mechanism you can then try and reverse it.  This is already being done in COPD research and some of the single gene autisms like Pitt Hopkins.

The mechanism is epigenetics, where you can modify when genes turn on, or turn off.  COPD is a severe disease because an environmental factor (normally smoking) has caused the body's oxidative stress response genes to be turned off.  Pitt Hopkins is caused by an insufficient expression of the TCF4 gene.  This was unlikely to have been caused by epigenetic changes, but could potentially be treated by using epigenetics to turn on the TCF4 gene.

Today’s post highlights pretty convincing research that shows how an environmental factor, smoking in this case, can cause heritable epigenetic changes.  It shows how a Grandparent smoking increases asthma incidence in the grandchildren.

Other than sending the message that smoking can affect the health of your future grandchildren, it becomes clear that many other environmental insults could also be heritable.  The accumulation of these insults over generations affects the incidence of certain diseases, particularly those complex ones often caused by multiple hits (cancer, autism etc.).
This makes me recall how it is theorized that epilepsy can develop as an acquired channelopathy.  We saw how the threshold for a person’s first seizure is quite high, but after the first seizure the threshold falls.  The proposed mechanism is called an acquired channelopathy.  This means that one of the many ion channels whose dysfunction is known to lead to epilepsy has been permanently disturbed.  The ion channel can now behave aberrantly with little provocation,

Ion channel diseases are classified as ‘acquired’ or ‘genetic’. Genetic ion channel disorders of the brain generally manifest as epilepsy, migraine, paroxysmal dyskinesia or episodic ataxia.

Acquired channelopathies can be caused by antibodies which target specific ion channels or by toxins which block voltage-gated ion channels. Altered transcription of ion channels may contribute to many acquired neurological ion channel disorders.

Mutations in genes which encode subunits of CNS sodium, potassium, calcium channels, GABAA and nicotinic receptors have been reported in association with various epilepsy syndromes.

While genetic (inherited) ion channel disorders may be the cause of most people’s epilepsy, it is suggested that acquired channelopathies are also involved.  Perhaps both are present?

 the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy.

In summary, cell type-specific information on epilepsy-related ion channel modifications can explain and support AED strategies. Precisely those inhibitory ion channels which appear to be effective AED targets in preclinical tests are the ones upregulated in DG GCs during TLE. These data indicate that cell-endogenous ion channel homeostasis mechanisms could be used as “channelacoid” archetypes in the search of antiepileptic strategies. In particular, the enhancement of static shunt via combined K/Cl/cation leak channel support appears to be a promising strategy.

The science, though complex, is still in its infancy.  You do wonder if acquired channelopathy cannot be caused by epigenetic changes to the genes encoding the ion channel.

Nicotine, your genes and those of your heirs

Finally, the subject of today’s post, the research showing the epigenetic effects of nicotine. In place of nicotine you could likely substitute other environment damage such as intense air pollution in cities like Beijing.  Another example below is lead pollution. 

 First the easier to read article:-

"Our results therefore indicate that the increased disease risk associated with smoking is partly caused by epigenetic changes. A better understanding of the molecular mechanism behind diseases and reduced body function might lead to improved drugs and therapies in the future," 

Now the more interesting study that shows how the effect of nicotine is passed down the generations to non-smokers.

Multigenerational transmission of nicotine-induced effects. The diagram illustrates the experimental design and findings of Rehan et al. [4]. Pregnant dams (F0 generation) are injected with nicotine or nicotine + rosiglitazone. The lungs and gonads of both male and female offspring (F1 generation) of nicotine-treated dams exhibit epigenetic changes, and the lungs show an asthma-like functional phenotype (blue nicotine-induced changes). These nicotine effects are not seen in the offspring of animals treated with nicotine + rosiglitazone. Offspring of F1 mated pairs (F2 generation) exhibit the same nicotine-induced changes to lung function as their parents, even though they were not exposed to drug.

A recent preclinical study has shown that not only maternal smoking but also grandmaternal smoking is associated with elevated pediatric asthma risk. Using a well-established rat model of in utero nicotine exposure, Rehan et al. have now demonstrated multigenerational effects of nicotine that could explain this 'grandmother effect'. F1 offspring of nicotine-treated pregnant rats exhibited asthma-like changes to lung function and associated epigenetic changes to DNA and histones in both lungs and gonads. These alterations were blocked by co-administration of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, implicating downregulation of this receptor in the nicotine effects. F2 offspring of F1 mated animals exhibited similar changes in lung function to that of their parents, even though they had never been exposed to nicotine. Thus epigenetic mechanisms appear to underlie the multigenerational transmission of a nicotine-induced asthma-like phenotype. These findings emphasize the need for more effective smoking cessation strategies during pregnancy, and cast further doubt on the safety of using nicotine replacement therapy to reduce tobacco use in pregnant women.

More on epigenetic changes related to heart disease.

Finally the effect down the generations of lead, a known neurotoxin.

We report that the DNA methylation profile of a child’s neonatal whole blood can be significantly influenced by his or her mother’s neonatal blood lead levels (BLL). We recruited 35 mother-infant pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children’s neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren’s neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren.


As regards autism, heritable epigenetic changes could well explain the increase in strictly defined autism (SDA) that cannot be explained away in terms of widening diagnostic criteria and awareness.

With respect to many diseases it is hardly surprising that they are becoming more prevalent if we accumulate the environmental insults experienced by our ancestors, via heritable epigenetic changes.  Where this will lead in future generations?

There are further studies looking at the role of PPAR gamma agonists (the rosiglitazone given to protect the mouse from epigenetic change) and HDAC inhibitors, which together can do very clever things regarding epigenetics.

You may recall the broccoli sprout extract being given by John Hopkins researchers to protect Beijing residents from the effects of severe air pollution.  The sulforaphane produced is an HDAC inhibitor.  

The mouse studies showed how to protect a mouse from epigenetic change occurring, what would be more interesting would be studies looking at reversing that change, once it has already occurred.

The only bad thing in the Mediterranean diet/lifestyle is smoking; just imagine how healthy the Greeks would be without smoking 2,000 cigarettes per adult per year, compared to 1,000 in the US.