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Saturday, 24 June 2017

Modulating Wnt Signaling in Autism and Cancer








In earlier posts I have covered various signaling pathways such as Wnt, mTOR and the unusually sounding Hedgehog.
You can go into huge detail if you want to understand these pathways, or just take a more superficial view. In most cases, things only start to go wrong if you are hypo/hyper (too little/too much) in these pathways.
We saw with mTOR that most people with autism are likely to have too much activity and so might benefit from mTOR inhibition, but a minority will have the opposite status and stand to benefit from more mTOR activity.
When it comes to Wnt signaling the research suggests the same situation. Wnt signaling is likely to be aberrant, but both extremes exist.

Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.
While the human genetic data is an important supporting factor, it is not the only one. There are a number of mouse genetic knockout (KO) models targeting Wnt signaling molecules, describing molecular, cellular, electrophysiological, and behavioral deficits that are consistent with ASD and ID. Furthermore, the genes involved in Wnt signaling are of significant clinical interest because there are a variety of approved drugs that either inhibit or stimulate this pathway.
There are many drugs developed and tested as modulators of Wnt signaling in the cancer field that could potentially be repurposed for developmental cognitive disorders. In cases where a reduction in Wnt signaling is thought to underlie the pathology of the disorder, usage of compounds that elevated canonical Wnt signaling could be applied. An example of this is GSK-3β inhibitors that have failed in cancer trials but may be effective for ASDs and ID (e.g., Tideglusig, ClinicalTrials.gov identifier: NCT02586935). In cases where elevated Wnt signaling is thought to contribute to disease pathology, there are many potential options to inhibit canonical Wnt signaling using chemicals (Fig. 1) that inhibit the interaction between β-catenin and its targets (e.g., inhibiting β-catenin interaction with the TCF factors), disheveled inhibitors (through targeting of the PDZ domain which generally inhibit the Frizzled–PDZ interaction), and tankyrase inhibitors (e.g., XAV939, which induces the stabilization of axin by inhibiting the poly (ADP)-ribosylating enzymes tankyrase 1 and tankyrase 2)

In recent years, strong autism ties have cropped up for one group of genes in particular: those that make up a well-known signaling pathway called WNT, which also has strong links to cancer. This pathway is especially compelling because some people with autism carry mutations in various members of it, including one of its central players: beta-catenin1. What’s more, studies from the past year indicate that several of the strongest autism candidate genes, including CHD8 and PTEN, interact with this pathway.
“There might be a particular subgroup of genes associated with autism that could all be feeding into or be regulating this pathway,” says Albert Basson, reader in developmental and stem cell biology at King’s College London, who studies CHD8 and WNT. “That clearly has emerged as a relatively major theme over the last few years.”

The connection between cancer and some autism is over-activated pro-growth signaling pathways. Many signaling pathways have growth at one extreme and cell death at the other. In cancer you actually want cell death to suppress tumor growth; in much autism there is also too much growth.  
Many cancers are associated with elevated signaling of mTOR, Wnt and indeed Hedgehog.  These are targets for cancer drug therapy and so there is already a great deal known.
A complication is that in a developmental neurological condition, like autism, it also matters when these signaling pathways were/are disturbed. For example Wnt signaling is known to play a role in dendritic spines and synaptic pruning, some of this is an ongoing process but other parts are competed at an early age, so it would matter when you intervene to modulate these pathways.
Historically cancer therapies involve potent drugs, often with potent side effects, however in recent years there has been growing awareness that some safe existing drugs can have equally potent anti-cancer effects. Many of these drugs are anti-parasite drugs, but even the very widely used diabetes drug Metformin has been shown to have significant anti-cancer effects, not to forget Simvastatin.
Many autism pathways/genes play a role in cancer (RAS, PTEN) and the upstream targets considered in cancer research are also autism targets.  For example many human cancers are RAS dependent and in theory could be treated by a RAS inhibitor, but after decades of looking nobody has found one. So instead scientists go upstream to find another target that will indirectly reduce RAS. This led to the development of PAK1 inhibitors that will reduce RAS.
RAS plays a role in some types of intellectual disability and indeed autism. The collective term is RASopathy.  Logically, drugs that modulate RAS to treat cancer might be helpful in modulating RAS for some autism.
Most types of cancers are complex and so there are multiple potential targets to attack them, but also the same target can have multiple possible approaches. RAS dependent cancers can be targeted via Wnt and even Hedgehog signaling.
This may sound all very complicated but does it have any relevance to autism?
It apparently does because almost all these pathways are known to be disturbed hypo/hyper in autism.  This means that clever insights developed for cancer can be repurposed for autism.


Anti-parasite drugs and Cancer
It is indeed remarkable how many anti-parasite drugs have an anticancer effect and indeed there is a much maligned theory to justify this.



Quite possibly it is just a coincidence.
There are many ways to kill parasites, one of which involves starving them of ATP. ATP is the fuel that is produced in your mitochondria.
Cancer cells and many parasites use a very inefficient way to produce ATP that does not require oxygen. In normal human cells the process followed is known as OXPHOS, by which glucose and oxygen from the blood is converted into ATP (energy) is very efficient. Only when you run low on oxygen, like a marathon runner at the end of the race, can you run into trouble because there is not enough oxygen for OXPHOS.  What happens next is anaerobic respiration, when a different process takes over to make ATP. It is much less efficient and causes lactic acidosis which makes marathon runners' muscles hurt.
A cheap anti-parasite drug Pyrvinium targets anaerobic respiration and starves the parasite of ATP and thus kills it. Another common children’s anti-parasite drug albendazole also works by starving the parasite of ATP.
Other anti-parasite drugs work in different ways.
We already know from the autism trials of Suramin, another anti-parasite drug,  that it works via P2X and P2Y purinergic channels.
Ivermectin  binds to glutamate-gated chloride channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased permeability to chloride ions, resulting in cellular hyper-polarization, followed by paralysis and death.  Fortunately in mammals ivermectin does not cross the BBB.
Ivermectin is also a PAK1 inhibitor and a positive allosteric modulator of P2X7.
Both PAK1 and P2X7 are relevant to many cancers and so not surprisingly research shows that Ivermectin has an anti-cancer effect.
Ivermectin appears to have a positive effect in some autism, but strangely it does not cross the BBB.
Mebendazole is another extremely cheap children’s anti-parasite drug which has remarkable potential anti-cancer properties. It inhibits hedgehog signaling and, via the inhibition of TNIK, it is a Wnt inhibitor.
Unfortunately in the US the private sector has also noticed the anticancer effects of Mebendazole and albendazole and they have recently become astronomically expensive. Mebendazole (MBZ), which costs almost nothing in many countries, now costs hundreds of dollar per dose in the US under the name Emverm. Outside of the US, Mebendazole is OTC in many developed countries. In poor countries it is donated free by big pharma.
In the cancer research they consider taking advantage of the fact that cimetidine (a cheap H2 antihistamine) interacts with Mebendazole to increase its bioavailability. Cimetidine is by chance another generic drug also being considered to be repurposed for cancer.
While some anti-parasite drugs like Suramin have side effects or cannot be taken regularly like Ivermectin, others are seen as safe for continued use even at high doses (e.g. Mebendazole and albendazole).  

Anti-parasite drugs and Autism
Just as many anti-parasite drugs seem to have a positive effect on some cancers it looks likely that the same may be true for autism.  This does not mean that parasites cause either cancer or autism.
We know from Professor Naviaux that some people respond to Suramin.
Two people who comment on this blog have found their child responds to PAK1 inhibitors, one of which is the drug Ivermectin.
There are groups of people on the internet who think parasites cause autism and you will find some of them if you google “autism mebendazole”, but there are some very valid reasons why some people’s autism may respond to mebendazole, but nothing to do with little worms.

Potency of Anticancer drugs
Failed anticancer drugs are already considered as possible drugs to treat neurological conditions.
The same pathways do seem to be involved in some cancer and some neurological conditions, but the severity by which that pathway is affected may be very different, so a new drug may lack potency to treat a type of cancer but be potent enough to benefit others.
In the case of the anti-parasite drugs Ivermectin and indeed mebendazole the dosage being used in current cancer studies are very much higher than normally used.
Very little mebendazole makes its way out of your intestines and so researchers counter this by using a dose 15 times higher and even taking advantage of the interaction with the H2 antagonist cimetidine to boost bioavailability.
The standard human dose of Ivermectin is 3mg, but in the cancer trials (IVINCA trial - IVermectin IN CAncer) in Switzerland and Spain the trial dose is 12, 30 and 60 mg.
So when it comes to autism and the possible repurposing of these drugs, the cancer studies will give valuable safety information, but the likely dose required to fine-tune these signaling pathways will likely be a tiny fraction of the cancer dose.
The newly developed cancer drugs that fail in clinical trials, may have potential in autism but it is unlikely that anyone will develop them, test them and bring them to the market.
The clever thing for autism seems to be to keep an eye on the existing generic drugs considered to benefit the overlapping cancer pathways.

Conclusion
Aberrant Wnt signaling has been identified by researchers as playing a key role in autism; the Simons Foundation is among those now funding further research.

In practical terms you can be either hypo or hyper, but hyper seems more likely. It may be a case of shutting the stable door after the horse has bolted, because the ideal time to modulate Wnt signaling is probably as a baby, or before. Nonetheless some older people may indeed benefit from modulating Wnt; the Simons Foundation must also believe so.
In the case of people with hyperactive Wnt signaling, there is a case to make for the potential use of the cheap anti-parasite drug Mebendazole.
The drug Mebendazole (MBZ) can found in three states/polymorphs called Polymorph A, B or C. This is relevant because they do not cross the blood brain barrier to the same extent.


To treat brain tumors, or indeed potentially some autism, you need MBZ-B or MBZ-C, it looks like MBZ-A does not cross the blood brain barrier.
Fortunately, MBZ-C is  the polymorph found most commonly in generic mebendazole tablets.  
Ivermectin is known not to cross the blood brain barrier but yet has been shown to show anti-tumor activity in brain cancer. The anti-cancer effect is thought to be as a PAK1 inhibitor, but this effect must be occurring outside the brain. Some people do use Ivermectin for autism.
The people using Ivermectin for autism are told they cannot use it continuously. Perhaps as the high dose cancer trials evolve the safety advice may change.





51 comments:

  1. Well I have had some amazing results with Agmatine in the last week after rereading a bunch of research on it and concluding that the anxiety side effects I had before were because agmatine at low doses seems to paradoxically agonize NMDA receptors (probably bad for autism) while at higher doses it antagonizes them (probably good for autism).

    So I carefully reread the study I linked to a few posts down and then followed these guidelines for a new dose:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

    So the study that peaked my interest is here:

    http://www.sciencedirect.com/science/article/pii/S0028390816303987

    In this study the best results were 100mg/kg in rats. Using the calculations in converting from animals to humans, or more specifically from rats to humans I get this:

    HED (Human Equivalent Dose = 100mg/kg x (6 / 37) = 16.22 mg/kg

    My son is pretty much exactly 50kg (110 pounds) so that comes out to 810.811 mg per dose. The agmatine was delivered by injection, whereas for oral dosage it is estimated that 64% is absorbed in a typical human being which comes out to 1266.89 mg. This comes out to almost exactly 1 teaspoon of agmatine sulphate.

    So at first I did half a teaspoon because I erroneously was basing my calculations off of mice and not rats which gave me half the dose of rats (which were used in this study).

    Interestingly, in another agmatine study on mice for OCD, the best dose was 80mg:

    https://www.jgtps.com/admin/uploads/2j0FpS.pdf

    which comes out to roughly 40% of a teaspoon based on my calculations (for mice to humans).

    Now in these experiments, the dose was administered shortly before experimental trials, probably because agmatine has a very short half-life in the peripheral blood supply, however, for reasons not quite well understood it seems to accumulate in the brain and the half life in the brain is more like 12 hours which I have found out the hard way seems to also lead to some insomnia if the dose is given in the evening. However, if the dose is given in the morning, the positive effects seem to last all day.

    And the positive effects are much more spontaneous speech, more reasoning, little to no stereotypies or hyperactivity after the first half hour or so. Lower doses seem to produce hyperactivity and stereotypies and even aggression and SIB sometimes. The 1.2 gram dose seems to lead to none of these problem behaviors with a significant cognitive boost (I have not measured it formally yet).

    As for safety of agmatine, I suppose there is some debate here, but here is one study showing a self-administered study on agmatine over 5 years (in adult humans) with no adverse effects:

    http://online.liebertpub.com/doi/abs/10.1089/jmf.2014.0026

    This dosage is more than twice what I give my son (in adults of course).

    I also found that agmatine also induces NRF2:

    https://www.ncbi.nlm.nih.gov/pubmed/25084759

    In this paper it also shows agmatine binding to 5-HT2A receptors (implicated in autism in various ways but also the serotonin receptor which effectively gets glued in by LSD which is why the psychedelic effects last so long). Not sure if this is good for bad because I have read mixed opinions on 5-HT2A and autism, though blocking the 5-HT2A receptors seems to reduce repetitive behaviors in some animal models.

    Obviously, a lot is going on here with agmatine but in my experience it seems like a big plus at the moment. He is out of school right now for the summer so I don't have any objective input on his behaviors and cognition at the moment, but my observations are very positive to the point I can almost have a very primitive conversation with him which is not something I can do often when not using agmatine (he is mostly non-verbal but can request things).

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    1. Tyler, very interesting. Hopefully the good effect will be maintained over the summer.

      Agmatine see seems to have other potentially beneficial effects. Its effect on polyamine metabolism may even help induce autophagy. It affects many ion channels and even affect Nitric Oxide.

      It is logical that the effect is very dose dependent.

      It is a cheap supplement and, at least in the US, is readily available. It clearly pays to follow the research in mouse models of autism.

      Keep us all posted as to the longer term effect.

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    2. Hi Peter and Tyler,

      Thanks to Tyler's original suggestion (and the rationale he had provided), I started Agmatine and interestingly enough, soon after we did notice what were minor improvements but clearly something had changed albeit in a minor way.

      Now, the capsules I got have 650mg per capsule, and to compensate for my daughter's size, I have been giving her half a capsule per day split into 2, so 1/4 capsule every 12 hours. This is 162mg per dose.

      So if I do the calculation Tyler has shown above, the right dose would be 15kg X 16.22 = 243.3, then adjusted for oral dosing would be 243.3 / .64 = 380mg which is more than twice the dose I had been giving her. This is actually exciting to ne as this means that the minor benefits we have been seeing may be improved upon by increasing the dosage.

      I do have a question for Tyler - Tyler in my calculation, would that be the daily total dosage of 380mg (i.e. 190mgs X 2) or is it 380mgs per dose (i.e. 760mgs per day). I'm assuming its 380mgs per dose but would like to get your input on this.

      Tyler, if this leads to a big cognitive improvement and improvements in speech, it would be huge for us.

      Thanks for your input on the above, and for sharing this most interesting info!

      AJ

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    3. If you read the study, they did one dose shortly before behavioral trials, but did not mention daily usage from my reading of it. Who knows what the upper bounds happen to be. I also gave it to him with milk, unsweetened cocoa powder and sucrose and the amino acids in milk will no doubt impede absorbtion somewhat (agmatine uses the same enzyme as arginine for transport into from the intestines).

      I have no idea what the optimum dose happens to be but I imagine best usage follows a dose response curve.

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    4. Spell checker autocorrected where I said "sucrose" when I meant to say "sucralose".

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    5. Hello Tyler,

      Would you be kind enough to recommend a brand wrt agmatine sulfate? What would a safe and effective dose for a 25 kg boy be which is unlikely to cause 'nmdar agonism' and could intermittent dosing work with this compound?

      Regards

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  2. Peter and Tyler, my son´s tics are becoming more complex and persistent, today were uncontrollable. Excess dopamine, neuronal hyperextibality, electrical activity, and possibly may be adding up allergy and chronic infection of some kind, don´t know if parasites could be an issue, if I had to tell what is the result of all these I would say Tourette is here. I am with Bcaas, NR, Valproate 250mg, suspended Diamox.
    Valentina

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    1. Here is a study done on DBS for treating tardive dyskinesia using stimulation of the medial globus pallidus:

      http://www.sciencedirect.com/science/article/pii/S1353802012003653

      The medial globus pallidus is the final output of the indirect pathway of the basal ganglia for motor movements. The more it fires, the more other motor commands are suppressed. If it is stimulated from another pathway via the cortex (the hyperdirect pathway), it essentially acts as a stop signal for all motor movement. With respect to the more commonly researched indirect pathway, the parts of the ventral lateral thalamus (which acts as a motor relay station from the cerebellum to the premotor cortex) are only suppressed with GABAergic inhibition if they are not involved in a particular motor action. The motor actions initiated by the direct pathway are supposed to suppress the medial global pallidus which in effect causes motor programs relayed by the ventral thalamus to engage. The main problem area for tics is probably another part of the basal ganglia which act as an intermediary between all of this called the lateral global pallidus, but it is too complex in its circuitry to target with a relatively dumb method of neuronal stimulation like DBS.

      Medial global pallidus neurons are GABAergic so if there are dysfunctions here, then unnecessary firing of motor commands (tics) will ensue. There are many possible routes of modulating basal ganglia output here, but the most practical route is the medial pallidum. Another interesting thing about the medial pallidum is that the amount of total motor inhibition spreads based upon the rate of firing from an individual neuron. In other words, if a single medial pallidum neuron is stimulated at a very fast rate, then it will cause nearby GABAergic neurons to also fire, thereby inhibiting the ventral lateral thalamus more broadly.

      So this is why you should be looking at GABAergic interventions because it looks like you are already doing your best at keeping dopamine in check without using dopaminergic antagonists like risperidone that have terrible long-term side effects.

      Peter's two best GABAergic interventions are obviously Bumetanide and Clonazepam. If those are unavailable to you, then I would even try straight GABA which recent research suggests some of it does make it past the blood-brain barrier as stop-signal tests on research subjects were enhanced (a sign of proper basal ganglia function) with supplementation. It is worth a try and pretty cheap compared to most interventions. There are also many other GABAergic interventions, but I would try straight GABA before progressing to harder stuff which often does more harm than good long-term.

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    2. Valentina, Have you ever used nicotine patches? This may also help with Gaba issues.
      Nicotine for the treatment of Tourette's syndrome. - NCBI
      https://www.ncbi.nlm.nih.gov/pubmed/9336013 -

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    3. Thankyou Petra, it seems that my son is following your son´s steps,as he grows up, I will consider this possibility too, in fact, I remember that nicotine patches were the first thing that Peter suggested to me, 3 or 4 years ago, when I told him about my son´s profile.Petra, did you try them in your son?Another intervention that has helped him?
      Valentina

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    4. Tyler, valproate works on Gaba, that is not new, but also inhibits excess dopamine release, look at this link:

      https://www.ncbi.nlm.nih.gov/pubmed/24583338

      I will try with plain Gaba also,hope to find it,my son´s godfather just left, he brought me Alpha R Lipoic Acid, but he returns in August.
      Valentina

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    5. The striatum has strong affinity for acetylcholine receptors but the pallidum much less so, so I am not so sure nicotine would be a good idea as I would think it would drive striatal function over pallidum function. A very recent study suggested a sizable percentage of those with diagnosed Tourettes also display strong autism symptoms as well, so maybe I will have to see what is going on there with thus nicotine/Tourettes research before commenting any further.

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    6. Valentina, Tyler, I think cod liver oil with vitamins A&D, EPA and DHA has helped my son regain skills he had lost, maybe due to adrenal fatigue and severe anxiety and OCD.
      I don't want to risk so I started low, for example 500mg CLO, with vitamins A and D almost at average daily level of intake. Then I doubled the dose and if I don't see side effects I could go to safe upper limit intake according to research.
      I started with CLO because my son is definitely vitamin D deficient and thought this might be a safer method.
      This is what I am doing at present and although I noticed improvement don't know yet if it's going to last for long.
      Tyler, I'd like your opinion on cod liver oil.

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    7. Well cod liver oil like many fish oils are high in Omega-3's as well as Vitamin A and D, and cod liver oil I think has been touted as a cure for many ailments for literally hundreds of years.

      I don't know about it being good for autism, other than a few studies I have seen suggesting Omega-3's and Vitamin D have effects on serotonin genes in that they downregulate peripheral serotonin (good for autism) while upregulating cerebral serotonin levels (good for autism as well).

      I don't know of anything bad about cod liver oil, and like I said it has been supplemented by people for 100's of years so as far as I know there are no toxicity concerns other than the usual ones with fish and heavy metals.

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    8. Thank you very much and good luck with agmatine, which is very interesting for anxiety like behaviours.

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  3. Article:The puzzling question of inhibitory control in Tourette syndrome: A meta-analysis.
    Conclusion:Therefore, deficits in inhibitory control seem to be an inherent component of TS, and are exacerbated when ADHD is concomitant.
    Article:Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.
    Conclusion:This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction.
    Nowadays, even in Greece, doctors instead of prescribing antidepressants, they recommend to start with omega 3 fatty acids or a combination of both to minimise the dose and side effects.

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    1. Petra,I am afraid that with fish oil supplements tics get worse. I remember we tried krill years ago and did well. Returned to valproic acid 3 days ago and was like a balm for him, tics dropped 80% and he returned to sleep. But it is in a very low dose and plan to keep it.
      Valentina

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  4. Tyler, there is some interesting documentation in schizophrenia about VPA, dopamine and Gaba acting like a thermostast, when VPA is withdrawn and reinitiated. What happened with my son latley was the clear example. It seems that withdrawal and reinitiation of VPA produces reversable dopamine enhancement and reduction in different brain areas. A differential Gaba effect occures in cortical and subcortical dopamine.Gaba modulation of dopamine depends on gabaergic stimulation intensity and pre existing dopaminergic activity. VPA withdrawal eliminated the facilitatory Gaba effect on dopamine in nigrostriatal circuits.
    It also increased dopamine release in the highly activated mesolimbic system, exacerbating psychosis.
    Valentina

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    1. Can you link to a study on this as I am not entirely clear what you are saying here.

      You are right about dopamine doing very different things in the cortex as opposed to some of the more primitive areas of the brain involved in action selection and reward circuitry.

      Since GABA and dopamine are so broad in their functions in the brain and the body looking at some of the more obscure pre-synaptic neurotransmitters that are co-released for various compromised pathways I think would be better for our efforts since they often have more limited effects in the body and brain. For example with the striatum looking at dynorphins and enkephalins rather than just dopamine and gaba.

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    2. Tyler, here is the link:

      http://www.nature.com/npp/journal/v29/n6/full/1300461a.html

      Valentina

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  5. Off topic for this post but hoping to get some ideas from others:
    any thoughts on cycles of excessive water drinking and then of course the excessive urination that comes with it? Not a constant but comes in cycles. Over the years I have considered a variety of explanations for this from diabetes to infection triggered to histamine to adrenal fatigue. Thoughts??

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    1. Tanya,

      Same here. I was narrowing it down to histamine and adrenal fatigue...in fact adrenal fatigue seems to offer explanation for lots his issues as well as mine. Our minds seem to be working in sync here...yours and mine.

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    2. Hi Tanya, amazing timing for your post. We have just started seeing this for the first time over the last week and a half and can't figure it out. We were going to keep an eye on it, but had no idea this was even an ASD issue. I thought maybe one of the new supplements I am giving is a mild diuretic or maybe the warmer summer air is making her thirstier, but the increase in water drinking over the last week or so has been very dramatic. Please share anything you know.

      Thanks,

      AJ

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    3. Tanya, it is quite common in autism and has the name polydipsia. I think it is a kind of self-rewarding stimming behavior. You have to be careful not to let it get excessive, because it can ultimately have serious consequences.

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    4. Peter,

      In my son's case these frequent urination periods are not really accompanied by excessive water intake... And it almost always happens at night, after dinner and when he is preparing to go to sleep. I had the same issues as a child and it happens to me even now sometimes. Could this have a hormonal basis?

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    5. It could be a lot of things, but considering my son has gone through phases like this before (not including use of Bumetanide), my best guess at this time is circadian abnormalities in the hypothalamus. Vasopressin which is a peptide very close in molecular terms to oxytocin is actively being studied with respect to autism. Vasopressin in the brain is released from three parts of the hypothalamus. Two are similar in that they both have oxytocin and vasopressin releasing neurons right next to each other and that is the paraventricular nucleus and the preoptic area. How stimulation of these areas of the hypothalamus selectively release more oxytocin or vasopressin is a big mystery right now, but generally when one peptide is released, the other is as well. However, in the superchiasmatic nucleus, in addition to other neurotransmitters being released synaptically, vasopressin is also released in significant quantities which in a properly functioning animal will cause it to become a little thirsty before bedtime so that they will ingest liquids. This behavior is not designed to drive parents of autistic children crazy because they have to change their bedsheets every night, rather it is very bad for the brain to become dehydrated while asleep.

      Now, the superchiasmatic nucleus has an inhibitory function in that the actual circuitry it connects to, also in the parventricular nucleus, traverses a long course down to the brainstem, the lower back of your neck, and then finally back up into your brain where the pineal gland rests in order to drive melatonin release. This circuit is facilitory so the more this circuit beginning in the PVN fires, the more melatonin release you will get.

      This means that the more the superchiasmatic nucleus fires, the less the PVN will fire so in humans the SCN fires more during the day and less during the night. And the more it fires, the more vasopressin is released.

      Vasopressin of course is also known as anti-diuretic hormone (ADH) and causes you to retain water. It is also produced in the kidneys (not just the brain), but the hypothalamus nevertheless has a very strong influence on water retention.

      So one could posit a situation where local circuitry in the SCN is hyperexcitatory leading to both excess inhibition on the PVN (leading to less melatonin output), while at the same time co-releasing too much vasopressin. This is going to cause the animal (or person) to have melatonin producing problems as well as perhaps high blood pressure problems from excess vasopressin. Of course, the SCN functions like a clock so you can imagine that if it is compromised in some way where it is running faster some parts of the day and slower during other parts of the day, then you may also have wild swings in fluid retention as well.

      I must reiterate, much of what I am saying is not proven, just it is my best guess on the subject based upon how the neural circuitry works as I have thought about it quite a bit as I likely am in the same boat as you are in dealing with these problems.

      Oh last but not least, longer summer days may cause some circadian issues relative to other times of the year. If your child is more sensitive to light (as many with autism are) it could be that in addition to perhaps supplementing melatonin it might help if you lightproof his/her room at night in the hopes of getting that circadian clock working as best as possible.

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    6. Kritika, I think there are multiple issues here. In some cases drinking all the time is like breath holding, it is just a kind of stimming. Frequent visits to the WC can be for all kinds of reasons: anxiety, attention seeking, escape from another activity ...

      Hormonal changes often coincide with behavioral changes. Autism can get better or worse around puberty. The case of polydipsia I recalled was a well known English philanthropist who wrote about her daughter with autism and in her case it was menopause that triggered behavioral change including excess drinking of water, that resulted in cardiac arrest (from lack of sodium). This is why polydipsia is potentiallly dangerous.

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    7. Extreme drinking and urination is a feature of mast cell related flare-ups in my son, but only those most severe. It comes in cycles and urinary histamine metabolites were found elevated in him then.

      Tanya and all, is it the only symptom that you see in your children when it happens? Why do you think it's histamine related?
      In my son at times of these flare-ups he has increased flushing, night sweats, headaches and GI symtpoms. He suffers much then. I thought that polydipsia can be a form of OCD, one of many he has during such periods. He also has the need to touch objects etc. When asked once about why he behaves in that way he told me: "Because I'm in pain" :-(

      Anyway it can be more then just OCD and diabetes insipidus comes to my mind. This is not about glucose and "normal" diabetes was ruled out in my son.

      In another discussion one parent highlighted this study about rats and DI/histamine:
      https://www.ncbi.nlm.nih.gov/pubmed/6627008

      "Our results suggest a physiological interaction between vasopressin and histamine systems in specific hypothalamic areas of the rat and support the hypothesis of a role of brain histamine on the central control of water balance."

      I would be happy to know what is really going on then, but I am not sure...

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    8. Peter,

      I think I belong to Adam's family. My neurotypical paternal aunt suffered serious neurological damage leading to hospitalization for six months at AIMS following obsessive comsumption of water leading to near fatal fall in electrolyte levels. She too was approaching menopause and was left with serious tremors and slurred speech following recovery.

      But in our case, my sons and mine, I know its linked to endocrine imbalance and my observations on fluid retention, circadian rhythms and even metabolism completely tally with Tylers explanation. Not trying to sound frivolous here but I always avoided going on dates in the first half of the day as I looked my grumpy worst in the pre evening hours. But these aberrations can only be inconvenient for a neurotypical while spelling disaster for a child with autism.

      What about solutions other than melatonin...it made my son very agitated though sleepy. Would assessment of endocrine profile be helpful....leading to practical solutions I mean?

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    9. Thanks everyone for the input. In my son's case it does seem there is more to it than just a behavior. Agnieszka, that is interesting you see this too during mast cell flare ups. It could very well be that is what is behind this for my son too - because usually what I see when he has these cycles, is morning fatigue also. The kind of fatigue so many of the mast cell folks talk about. My son's excessive drink and urnation mostly happens in the morning through mid day. But at night he will wake up several times to run to the toilet. Peter, of course you are right to mention this excessive drinking of water is dangerous - this is why through the years I have frequently brought it up to his doctors and even a visit with an endocrinologist. Diabetes mellitus is always ruled out - glucose levels are fine. But diabetes insipidus I am curious about too, Agnieszka. I have read that infections can trigger d.i. episodes so that makes me think of PANDAS-type flare ups causing this also. When my son has the xcessive water drinking flares, he always craves salt - I'm sure following his body's innate desire for balance. In the past I have always made an electrolyte drink for him - would just give intermittently, then sometimes forget about it. Yesterday I talked to,his doctor and we thought to test it out givng him the electrolyte drink first thing in the morning and through morning hours and see if things improve. I can let you all know how that goes if anyone is interested. Tyler, thanks so much for that detailed explanation. I have giving melatonin for years, and I actually started wonderinf if somehow someway all of that melatonin dosing was creating some kind of rebound effect and indirectly effecting the pituitary gland and messing up the vasopressin balance. Can you see any way this would be possible? There really isn't any information on what long term melatonin use in children through adolescence can do - or is there? I haven't found anything.

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    10. Tanya,

      I agree there is more to these episodes than just behaviour. My sons excessive urination episodes are usually accompanied by increased cognition...histamines role in neurotransmission? But the entire last month was a dark period...first rage, defiance, then painful urination, then acute fatigue in the mornings and bucketfull of no-1. I felt that my supplementation trials have just unleashed all kinds of issues...excitotoxicity, liver issues, sleeplessness and adrenal fatigue,oxalate, histamine..endless list of endless possibilities.

      Now he is down with a viral and back to his relaxed, happy self, moulding letters out of play dough. Apart from the vasopressin and cortisol aberrrations, which may be chronic in nature, I do think keeping a tab on his virals and strep infections and his behaviours just before it is important. I have been noticing that days before he ultimately displays explicit symptoms of a cold, he has behavioural deterioration which improves following the actual onset of illness What could be the reason behind this...its so puzzling.

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    11. Agnieszka, something I just remembered - Dr Theo's papers on chondroiton sulfate as an effective mast cell stabilizer - and I read about it being effective for bladder issues. Have you tried it? Kritika, maybe this is something tat might help your son?

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    12. Melatonin may help with sleep issues, but as best I know it won't help with the vasopressin issues. Ironically, synthetic vasopressin is given to some people (children sometimes) for the purposes of preventing bedwetting. Nevertheless, if there is too much then you might have situations where the child overdrinks due to excess vasopressin telling him that he is thirsty when water levels are actually normal, then when vasopressin levels subside or else blood pressure rises too much (from all the fluid ingestion), then the dam bursts so to speak and you have lots of trips to the bathroom (or in the pants) if the child cannot get to a bathroom.

      Strangely, I have read separate studies on autism where vasopressin inhalation (just like with oxytocin) improved socialability in males with autism, while another study showed that blocking the vasopressin type 1A receptor with an antagonist improved socialability and general behavior issues as well. On top of that, even though vasopressin is not supposed to cross the blood-brain barrier, peripheral vasopressin could be leaking into the brain as well, causing wild swings in hypothalamic function.

      Also, BTW the recommendation I had for helping get his circadian rhythms on track were on the theoretical grounds of reducing the excessive firing rate of the SCN which may be releasing excess vasopressin. Last but not least, the SCN firing rate is also driven by intracellular chloride levels in some of the neurons whereas hypothetically Bumetanide could cause a shift in the clock forward (longer day) if it was given too late in the day (this was animal research). In other words, if intracellular chloride levels decrease, then the SCN fires more, whereas if intracellular chloride levels increase the SCN fires less and inhibition on the PVN is relaxed leading to more melatonin production and less vasopressin production.

      So you don't want to think of this in the sense of vasopressin being good or bad or the SCN releasing vasopressin as being good or bad, rather you want to normalize things so that these push/pull mechanisms function properly.

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    13. Hello Peter,

      I used melatonin, 1.5 mg, twice with my son and on both occasions he got upset and agitated and though it made him go off to sleep, the quality of sleep was poor unlike the deep sleep he usually enjoys. As per your suggestion, I trialled 3 mg melatonin on myself and it was pure horrible. I felt like kill bill's Uma Thurman inside that coffin. Not a wink till eight in the morning and an upset tummy in the morning. I have had similar aberrant reactions to alprazole (spl?). A few days back a reader on your blog commented how she had an atypical response to benzodiazapine and the likelihood of gaba being excitory in her case as well as her daughter.

      Do you see some indication of abnormal biochemistry in me and my son ...late onset of sleep is a big issue for us right now and it impinges on an entire range of quality of health, learning and behavioural issues, especially for my son.

      Please enlighten

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    14. Kritika, unusual reactions to drugs and also unusual things in the wider family history (aunts, uncles, cousins etc) do provide clues as to what is going on. It is not easy to figure out.

      Sleep is a big issue with many people with autism. Melatonin is just one possible issue. An unusual reaction to extra melatonin is something you could look into.

      It really is a case for personalized medicine, meaning you may benefit from looking into each of the issues that define your son's autism. The issues may well be different to those affecting other commenters here. It is not an easy process.

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    15. Dear Peter,

      I have really started getting convinced that my and sons constitution, which may have much similarities including blood group may well benefit from a gentle treatment type like homeopathy. I remember how my son slept breathing deeply after starting homeopathy. With the harsh supplement and drug protocols, I have observed disruptions with the fundamental health indicators...sleep, digestion, energy levels, mood. I think with my son, it would be wise to back off at the first sign of trouble...no matter what big shots like dr. Neurbander, for example say about side effects like sleeplessness part of healing process with mb 12. Or is it a case of Indian autism being different from your white western one.

      Biomedical forums are full of terms like healing crisis, die offs, detox reactions, but mums intuition should be the guiding factor here. Its easy to get carried away when everyone is giving testimonials on effective therapies. Just now, on an indian parents forum, I have recieved an autism treatment plan, summarised by some dr. Sunil gupta, dha, epa, antifungal, zinc and stuff, which probably I could have done better. A cut and paste job, it makes everything seem like a cakewalk.

      Really wanting to help my son as he is a clever child (all of them are) but as the song goes 'when the suummer beats down you pray for the rain, hope for the harvest through the long cold winters and then you plant your seeds again'.

      Thanks and regards








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    16. You will need the EPA and DHA and Phosyphatidylserine because of the pollution. The zinc you will need for the wide variety of functions zinc is responsible for and this will also help you in polluted areas. These are great across the board recommendations.

      I want to do a study and take a bunch of kids and pull them out of the urban areas, into areas of less environmental manipulation, and pollution and see what happens after a year. Better yet, lets all go ask the Amish if we could somehow pay to live with them for a while and see if it improves our kids. Then some of us could set up shot with other cultures of environmental balance and see how our kids do.......If anyone does this come back and share.......

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    17. Well, these great across the board recommendations do not really show benefits a across the board. On this blog itself one can find cases of kids doing badly on all the great four you have listed.

      As Richard Feynman ( I think) said 'it doesnt matter how beautiful your theory is or how smart you are. If it does not agree with experiment (or my experience...), its wrong.




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    18. Anonymous from Anonymous- I realize that others do not do well on all. It is interesting you wrote about Feynman I was just listening to him..........

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    19. Kritika- Check out what electrosmog can do to VDR

      https://link.springer.com/article/10.1007%2Fs12026-016-8825-7

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  6. Hi Peter,

    I know you have tackled hypothyroidism on the blog in the past, so I thought you would find the following paper of interest:

    http://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0888-4

    It appears that TSH is indeed lower than normal in the blood of ASD kids (at least boys as this study focused on boys), and the following analytes were found to be higher in the blood of ASD kids, with both low TSH and high analytes noted identified as relevant in potentially diagnosing ASD kids.

    Any thoughts you or the community has on any of the analytes further to this study would be much appreciated. I will also post anything of interest I dig up on the relevant analytes.

    Thanks everyone and have a Happy Canada Day (July 1) to our Canadian friends and 4th of July to our American friends!

    AJ

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    1. Hi everyone,

      Just a small addition - above I had noted that certain analytes were found to be higher in ASD kids than controls and their names would follow, but I didn't name them in my post - they are:

      - stem cell factor
      - monocyte chemotactic protein 4
      - ferritin
      - IL-8

      It's in the study but I had intended to name them specifically in my post.

      Have a wonderful day!

      AJ

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    2. If I understand correctly what they did, they would have the same results if they started with (110) random numbers as markers (except maybe correlation of TSH with ADOS). I believe statistics used in this paper is very wrong.

      Journal of Neuroinflammation should be reliable source, right?

      Delete
    3. AJ- Speaking of Ferritin. Beet juice has iron. I wondered why it seems my son was secreting the Beet juice through urine and bowel and mom and dad where not. I wonder if there is a protective mechanism of the liver. If the liver secrets or maybe another mechanism secrets a protective enzyme to prevent iron absorption for use due to the potential for increased inflammation. How do we measure iron absorption, iron metabolism, and interference in its use. This would mean that it is a possibility that inflammation contributes to a systemic type of feedback mechanism that alters our ability to fully heal if we are in constant states of inflammation. Iron can help us get oxygen where we need it. Thank you AJ for that source InfinityBeyondLove

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  7. Hi Peter and community,

    I've found an interesting recent paper that connects GABA B Receptors with KCC2 in a way that had not been known before. The paper is called "Neuronal Chloride Regulation via KCC2 Is Modulated through a GABAB Receptor Protein Complex":

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452337/

    Have a great night!

    AJ

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  8. The Successful use of Pregabalin in the Management of Autism ...
    https://www.researchgate.net/.../264422542_The_Succe...

    Peter, Could you have a look at this paper about pregabalin for autism anxiety?

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  9. Here is a very interesting paper released today that posits one significant cause of obesity may be as a side-effect of gliosis and more specifically excessive microglial activation in the medialbasal hypothalamus (usually also referred to as the arcuate nucleus):

    Press Release:

    https://www.sciencedaily.com/releases/2017/07/170705123138.htm

    Paper:

    http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30339-X?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS155041311730339X%3Fshowall%3Dtrue

    Now they don't mention the word "autism" anywhere in the paper or press release, but what is important here is that they show that a high-fat diet can induce activated microglia which can further lead to more overeating. Not to beat a dead horse, but obesity and excessive weight grain during pregnancy in the mother is one of the strongest linked if not the strongest linked environmental components of autism to date. It is also interesting that the levels of obesity are very high in the autistic population, even after taking into consideration knee-jerk observations such as people with autism not engaging in sports or doing outdoor activities because it may be unsafe for them (especially if they are ID impaired). According to this research, chronically activated microglia may be (my speculation only) the driving force for increased rates of obesity in autism as well.

    Another exciting as well as frustrating bit of information from this research is that they used an experimental drug called PLX5622 (the press release says PLX522 which must be a typo since the paper says PLX5622) to rescue the mice from gliosis in the hypothalamus. A similar drug the same company is trialing right now which is "currently in clinical trials for hard-to-treat leukemias, solid tumors, and rare forms of arthritis" called PLX3977 sounds like a potential game changer for autism from the looks of things. It may turn out to be a strong drug with side-effects, but I am wondering why this company would not even consider trialing this for autism unless they just don't see the money being there or else the high risk of failure for autism drugs since every commercial drug attempt at dealing with autism has more or less failed to date since the definition of failure seems to be if 80% of people with autism are not helped, but 20% are helped, well then how do you market a pill claiming only a 20% success rate (yes this is the frustrating part).

    This type of drug sounds like it could be a potential game-changer for many people with autism, but I suppose visual health problems like obesity are a bigger deal than invisible ones like autism.

    Considering the drug is for "hard-to-treat leukemias, solid tumors, and rare forms of arthritis", it sounds like it is being marketed for niche purposes at the moment, but perhaps in addition to its initial success in the obesity realm, perhaps the research group could be pushed in the direction of at least taking a few minutes to ponder the use of this drug for autism if they have not done so already.

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  10. Peter, I use cod liver oil 460 mg, vitamin a and d supplement daily one, which means that my son gets 1250IU vitamin a (47% RDA) and 135IU vitamin d (68% RDA), EPA 137mg and DHA 125mg only.
    I believe this supplement very much improved his quality of life, especially motor skills, reflexes, expressive language and motivation. His cognition seems fine.
    As I said before I chose it because my son is vitamin d deficient and had rejected the idea of giving him high dose vitamin d which might have caused problems to his long time compromised neurological system.
    I remember your post about vitamin a and oxytocin upregulation but would like a very simple explanation about retinoids and Gaba.
    I found a paper that says retinoid-regulated neuronal genes, among many interesting others, are GabaA receptor γ2 subunit (Reynolds et. al. 1996).Developmental expression of functional GABAA receptors containing the gamma 2 subunit in neurons derived from embryonal carcinoma (P19) cells.
    and also found this:
    The gamma 2 subunit of GABA(A) receptors is required for maintenance of receptors at mature synapses.

    Schweizer C1, Balsiger S, Bluethmann H, Mansuy IM, Fritschy JM, Mohler H, Lüscher B.
    It says something about the gaba benzodiazepine binding site but cannot understand if this is relevant in my case.
    I've seen my son many times responding badly to benzodiazepines, aprazolam for example, which 0,25 mg for me is a wonderful drug and treat it with respect.
    Saffron binds to benzodiazepine binding site and although for me is really beneficial, my son gets overload with just a small quantity and maybe it was fortunate that I didn't use the 30mg pills.
    Still I think for people who don't have this kind of reaction saffron may help with cognition and asthma.
    My sister in low, who has chronic asthma, after her daughter's regression became really sick. Meanwhile it was the time that I was interested in saffron and told her to use it and finally helped her enormously.

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    1. Petra, I am glad the cod liver oil + vit A & D works well. Many people seem to find this helps.

      Saffron has numerous effects and a Greek researcher is proposing its use in schizophrenia. It seems to help in anxiety, depresion and even Alzheimers. But if just one of its modes of action is negative then it can cause an effect like in your son. So care needs to be taken.

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  11. Some interesting research that may apply to some autism cases came out just recently:

    Press Release:

    https://www.sciencedaily.com/releases/2017/07/170706143105.htm

    Paper:

    http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2001246

    This research shows that early life exposure to isoflurane (an anesthetic) causes mTOR hyperactivity in the brain, more specifically the hippocampus. While it is likely very few children with autism are exposed to isoflurane, what is interesting here is its interaction with mTOR and autism like symptoms as well as the fact it shows that it is possible certain environmental chemicals can alone cause this shift.

    When my first son was gestating (the one with the most severe symptoms) we lived in an area half a mile away from a big diesel truck yard and a road right next to our development where big diesel trucks would go up and down all hours of the day. Pollution levels in previous studies have been shown to track with autism levels as well. This is correlative here, but this research here shows very important metabolic pathways that are also very important for neural development can be perturbed by a single exposure to the wrong kind of chemical during sensitive times in development. Also, I would take him on walks in the neighborhood as an infant before we moved where he presumably would suck up all that invisible poison in the air. During that time he seemed like the happiest little boy in the world and then between 18 months and 2 years of age, well you all how the story goes.

    Now there was also another big twin study done that seemed to suggest autism symptoms are 80% heritable, but just because you have a genetic profile which is common in an autism population, does not necessarily mean you will develop autism symptoms. The big gap in autism science is finding people with a significant number of autism gene variants who do not have an autism diagnosis and then researchers asking themselves why do these people not have autism? All the environmental studies seem to ask the question of what went wrong in utero and thereafter, but what about people who should have autism but do not? In that regard why not ask the question as to what went right, if not for the simple purpose of giving high risk autism gene families information on possible interventions that may spare their children and the entire family an entire lifetime of pain.

    On another note, many cities in China have some of the worst air pollution if not the worst air pollution in the world and autism rates for whatever reason don't seem to be exploding in number as you would expect them to, so why is this the case even though air pollution is strongly linked to autism symptoms? Is it just undereporting or testing in China or something else? There are many Chinese families from wealthy industrialists who have resettled in Vancouver and now Seattle in the last several decades, so is it a fair question to ask if the autism rates are different between Chinese immigrants to North America and Chinese citizens living in Beijing?

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  12. Do they have mechanisms of protection in place, how aware are its citizens? Do they take precautions?

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