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Monday, 20 June 2016

Autism – Getting Lost in the Translation

I think most lay people would be surprised to know that literally tens of thousands of scientific papers have been published on autism and yet not a single drug has been approved to treat core autism.

Surely there must be some value in all this research, that can be extracted today?

A reader recently sent me a link to an excellent lecture about propionic acid in autism.  The first part of the lecture was much more general and concisely summarizes what we know about autism.  We know a vast amount; it just has not been translated (applied).  Click below for the video.









Translation

Alli from Switzerland, a medical reader of this blog did raise this issue a while back.  Why has the vast knowledge about autism not been translated across into medical therapies?

Her conclusion was the same as mine; don’t wait, do the translation yourself.  This is of course easier said than done, because there are wide variations in what causes autism.  Not surprisingly, her effective therapy is very different to mine.  In fact almost nothing that helps my son helps hers; but that is of course the point, there isn’t one autism.  There are thousands of variations, within which fortunately there are some clusters.

These are the elements of that therapy:-

·        PAK1/WNT inhibitor
·        Longvida Curcumin / J147  as cognitive enhancer via mtor inhibition
·        Ibudilast, a Pde4 inhibitor, as a modulator of microglia
·        Sodium Butyrate 500mg
·        Propranolol 30mg as PI3K/Akt/enos/vegf inhibitor
·        Garlic, to moderate Cytokine related autism flare ups
·        L-Theanine to regulates hyperactive behavior
·        Syntocinon (oxytocin) to improve social awareness
·        Biogaia gastrus probiotic (which down regulates TH1 and upregulates IL-10)

As in my case, there are flare-ups in symptoms and they are accompanied by loss in cognitive function.

Alli points out that dosage is key (paradoxical effects can occur at lower or higher dosages) and that some components of the treatment should be taken alternatively.

We also have the UK paediatrician who stumbled upon the fact that moderate dosage of baclofen is a remarkably effective therapy for the majority of people with Asperger's and shared that on this blog.  This does not appear anywhere in the literature and that doctor did not want to publish a trial, so it will remain hidden, except to readers of this blog. The more potent R-baclofen is being studied for more severe autism, but it is a research drug.

For various reasons mainstream clinicians do not publish their autism therapies, this was also the case with autism secondary to mitochondrial disease (AMD) where the detailed knowledge from Johns Hopkins does not appear in any medical journal.

In my post on the history of autism we saw that way back in 1877 there was an effective autism therapy (then being used as an epilepsy therapy) by a Dr Dickinson at London's Great Ormond Street Hospital.  He used potassium bromide which modifies the effect of GABA in a broadly similar way to Ben-Ari's use of Bumetanide today, that I promote on this blog. 

Likely other discoveries have also been lost.



Cancer Research

Cancer research is being translated into clinical use and so numerous new drugs are being developed.  As I have pointed out before, many of the affected pathways in some autism are shown to be affected in some cancer.  This means some new drugs can potentially be used to treat both conditions.

The idea of sub-types in cancer is now widely accepted.  Therapies can only be effective if used in the specific sub-type of the cancer.  The same applies to autism. The same applies to epilepsy.

The overlap between cancer genes and autism genes is very clearly shown in a recent graphic on Spectrum News (Simons Foundation). More food for thought.

Note WNT. mTOR, AKT, P53 etc.

  














Conclusion

It would be very helpful to gather together the combination therapies of other parents who have followed the science and applied it to an unrestricted palette of drugs/supplements that exist today.  There must be other people who have successfully done this.

Some OTC therapies are indeed very helpful, but full access to pharmacotherapy is needed to effectively translate science into therapy.  

There are of course DAN/MAPS type doctors in North America.  Some of them have some clever therapies, but there is also a great deal of nonsense and the priority appears to be making money rather than translating science.

I do get people writing to me with various theories and it is always important to keep an open mind. It looks like all truly effective therapies are reversible, they are not curative or disease changing.  If you stop the therapy you gradually lose the benefit. 

Only radical therapies, like the one below, are likely to be curative and only partially so in autism.  I do not see anyone giving high doses of chemotherapy drugs to two and three year olds any time soon.







19 comments:

  1. I find it interesting at 26:27 Dr. MacFabe talks about PANDAS as a distinct disorder,that is now broken away from autism the way Rett Syndrome is.It has been very interesting to follow Susan Swedo's work in doing this in recent years.I think you are going to see more and more disorders becoming their own distinct entities in the future.A good candidate for this,would be the syndrome caused by PTEN mutations.You might want to look at this site.

    http://ptenlife.com/

    There are other cancer gene syndromes that are associated with autism,beyond the ones in this graphic.Some are very rare,and have been discovered very recently.I think we will see more and more of these become distinct clinical entities in the years to come.

    I do wonder if I have one of these cancer gene syndromes,but an even rarer one than listed here.I hope to have more tests.A lot of these cancer gene syndromes,seem to have mixed inborn metabolic and immune elements.I can see this both in my own test results,in talking with families online,and in the research.

    You will notice at 30:42 Dr. McFabe mentions other organic acidemias,that can cause features of autism,including methylmalonic acidemia,which I have if I go off my meds.Methylmalonic acidemia is feature of severe folate deficiency,and of cerebral folate deficiency.

    Yet another subtype.

    The gene mutations I have,besides the folate stuff,seem to be linked to an extremely rare neuromobility disease,which I may not have,colorectal cancer,ovarian tumors,and disorders of Interferon Regulatory Factors,which,for me,would make more sense.

    https://www.researchgate.net/profile/Shunbin_Ning/publication/265768399_Interferon_Regulatory_Factors_and_Autoimmune_Diseases/links/541ad3380cf25ebee988c52c.pdf

    Interferon Regulatory Factors,of a different type,have also linked to autism.

    http://www.nature.com/ejhg/journal/v17/n6/full/ejhg2008215a.html

    So many different pathways,but all roads lead to autism.

    https://www.youtube.com/watch?v=Q--Dg2fZvtA

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  2. I will share the combination therapies I use for my son when I have more time.

    In the meantime, this study is not specific to autism but when you remember the binocular rivalry study a few months back that showed reduced GABAergic function in the brain of those with autism, you will see the parallels here:

    https://www.sciencedaily.com/releases/2016/06/160621155010.htm

    This compared young people to old people and surprise surprise older people had worse inhibition in the visual areas of their brain, leading to a decreased ability to filter out competing representations of what the visual cortex selects as a representation of reality via competitive inhibition (just like binocular rivalry though this study dealt with higher level percepts).

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  3. Hi Peter, I told you before that a probiotic completely stops my son's stereotypy. Instead testosterone/cortisol(?) hormones levels raise and he is in a really bad mood with minor aggresive episodes.
    These episodes are not like having an uncontrollable meltdown, they are more like an expression of his frustration.
    Not being on stereotypy he is much more expressive and seeks help. He says there are both external and internal factors that prevent him from thrieving. The problem is that he is too self conscious when it comes to external factors.
    He describes internal factors as if there is "something" that constantly controls both his brain and body, making him freeze.
    I am thinking of putting him on Agomelatin for depession and Clonazepam for anxiety and OCD.
    This presentation supporting the hypothesis of propionic acid toxicity looks very convincing. I think both my son and nephew may fit this profile.
    My son has seious problems digest carbohydrates, straches in particular, and they come back as opioids in his brain.
    He also has oily scalp and lots of dead cells in his skin.
    Propionate toxicity goes to the liver and also affects cholesterol synthesis, similarly to my son's metabolism.
    Is the release of testosterone/cortisol hormones a good thing to happen?
    Do you think Agomelatine with Clonazepam would be a good option?
    If it is a case of propionate, are there any effective applications to keep it under control?

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    Replies
    1. NAC was shown to be protective in rats injected with propionic acid.

      http://www.sciencedirect.com/science/article/pii/S1018364713000542

      Too much propionic acid certainly makes rats behave autistic and it may do in some humans.

      Did you try atorvastatin? Your son's freezing sounds like my son's "getting stuck". I would try that ahead of your melatonin agonist.

      Normal dose clonazepam is likely not a good idea, since people become dependent on it.

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    2. Thank you Peter. As soon as I sent my comment it also struck me to use atorvastatin before trying Agomelatine.

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    3. Which probiotic? I have tried a variety of approaches with no effect on behavior though several different forms of soluble fiber (prebiotics) seem to help a lot with digestion issues as well as hunger issues. Right now he will raid the refrigerator and drink insane amounts of milk whenever I am distracted with his siblings. This is a new behavior as a result of his increased confidence and maybe something else (he at least pours the gallon of milk into a cup without making a mess which is really good in terms of motor control for his age and condition).

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    4. Hi Tyler, thanks for asking.
      I use Vivomixx probiotic and yes, there are behavioural changes at present. Doctor also advised me to use elementary zinc 22mg which I haven't added yet.
      This craving for milk, how can you account for it biologically? Both my son and nephew have shown weird attitude towards milk. I think it says something, there must be an explanation. Is his belly a little swollen?
      I have never used prebiotic, which one do you use?

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    5. Interesting about Zinc. I have posted before here about Aspartic Acid having benefits in my son, just the method I had of mixing it with baking soda yielding monosodium aspartate so that it would be soluble in water made the drink I give him considerably less palatable. So, recently I moved to ZMA (Zinc, Magnesium Aspartate) which is by weight about 80% aspartate with the remaining weight being magnesium, zinc, and b6. So a male adult serving which is typically taken once a day before bedtime (3 capsules) I give twice a day as two capsules which gets a little less aspartate than I was supplementing for good results in modulating aggressive behaviors and stereotypies (likely via the opioid system). Things seem basically the same as before just compliance is improved because the drink I give him tastes better (I was not worried about his magnesium intake, though I didn't do supplemental zinc before). The monosodium aspartate solution I was using was straight from the 30+ year old study showing improvement in attenuating withdrawal symptoms in opioid addicts upon abstinence from heroin.

      Also, about the Vivomixx, I looked at it and only know a few of those strains so I can't make an informed opinion about it. I was curious if it had a species called Lactobacillus Reuteri of which a strain cultured from human breast milk and grown as a prebiotic was shown in a paper released in the last week to reduce autistic behaviors in a couple mouse models of autism, likely via upregulating oxytocin signaling. Here is the press release with the link to the paper below:

      https://www.sciencedaily.com/releases/2016/06/160616140723.htm

      There are Lactobacillus Reuteri probiotic supplements, but this experiment used a specific strain cultured from HUMAN breast milk and then fed it to mice, so I am not sure at this point if this strain would help or not, but it is almost definitely safe to trial (so I am going to do that and see what happens unless something I come across dissuades me from doing so).

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    6. Tyler. I think that Biogaia Gastrus is the one that Alli uses and it contains two types of L. Reuteri bacteria. They have patents on many such bacteria.

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    7. Wow thanks a lot. One of the strains in Biogaia Gastrus is labeled as ATCC-PTA-6475 and in the paper, the strain they used was Lactobacillus reuteri MM4-1A (ATCC-PTA-6475).

      I assume MMR-1A has something special about that (like maternal mammary something), but this is a lot closer than to the other L-Reuteri products I was looking at.

      Thanks alot!

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    8. Dear all,
      Lactobacillus Reuteri ATCC 55730
      was initially discovered and sourced from women from Peru who carried this strain in their breast milk.
      "The first strain of Lactobacillus reuteri for human use was isolated in 1990 from the breast milk of a Peruvian mother living in the Andes. This strain was deposited at the American Type Culture Collection (ATCC) as Lactobacillus reuteri SD 2112 (SD = safety deposit), and was later given the number ATCC 55730.
      In 2007 Lactobacillus reuteri ATCC 55730 was replaced by the “daughter strain” Lactobacillus reuteri DSM 17938. The only difference between the strains is the loss of two plasmids of ATCC 55730 that carried resistance to tetracycline and lincomycin, respectively."http://www.biogaia.com/history-lactobacillus-reuteri

      Through my personal review of immunology literature and ASD/immunity related literature and documenting crossroads between immune pathways and Mtor pathways, I came to the conclusion more than one year ago that this was a very interesting strain to try on my son with ASD and a TH1 profile. Biogaia Gastrus was only available in Korea and Italy at the time so I ordered it from an Italian pharmacy online.
      It has helped my son significantly in combination with other interventions.
      The mechanism at stake is probably the following:
      - downregulation of TH1 through upregulation of IL-10 and downregulation of IL-17
      This prevents autoimmune phenomenas and cytokine flares which affect cognition in certain subtypes of ASD. However, the downside is that long term intake also impairs one's immune system's capacity to fight off infections...
      We use Biogaia on and off for 3 week periods- at a dosage of 5 tablets a day (less is useless in terms of potency).
      Use must be stopped if a child shoes any sign of infection.
      I have shared this over the past year with several parents around me who have children with similar subtypes and they report similar results.

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    9. This should be a real topic here as even though the study cited about which got a bit of press has been bantered around a bit, for parents looking to trial this strain, most will probably go with standard L-Reuteri probiotics based on the press which may or may not get the intended results (which was what I was going to do until Peter mentioned you and Biogaia Gastrus).

      Before I say anything else, thank you very much for this clarification on the dosage you found effective (I ordered some last night). This probiotic isn't cheap but neither is Niagen which I use for my son.

      Also that is some very interesting stuff on your believed mechanism of action. An IL-17 dominant immune system in the mother of course is also associated with obesity as well as Rheumatoid Arthritis, Gout, and Psoriasis. I wonder how many obese mothers of children with autism have these comorbid conditions as well.

      As far as cycling goes, do you think this particular probiotic has any evidence of long-term colonization in your child (since you have used it for so long now)? In the aforementioned study, there was some evidence (or at least the researchers believed there was some evidence) of the L-Reuteri strain not just transiently passing through the digestive tract as most probiotics do.

      Lastly, is the cycling regimen you use just a theoretical precaution or else have you done blood work showing certain immune markers in your child going too low.

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    10. Alli, thank you for this information. I’ve ordered Biogaia Gastrus as soon as I read your previous comments, but did not know the dose.

      It is all very interesting. May I ask you how did you establish a Th1 profile in your son?
      Does he or other children who responded to B.G. fit into the description of an inflammatory subtype of ASD by Jyonouchi et al.: “characterized by fluctuating behavioral symptoms following immune insults, persistent gastrointestinal (GI) symptoms, and a lack of response to the first-line intervention measures” - associated with reduced IL-10 expression capability?
      http://www.ncbi.nlm.nih.gov/pubmed/25344730

      As far as I followed it, preliminary IL-10 targeted therapies for other conditions are considered relatively safe in terms of clinical impact on infections - I have no personal experience though.

      Vitamin D has been reported to induce IL-10 receptor expression and suggested to improve the results of IL-10 therapy response:
      http://www.ncbi.nlm.nih.gov/pubmed/12773629
      What do you think?

      Again, thank you very much for sharing!

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    11. Here is an interesting discussion thread in Biogaia Gastrus from a website I peruse and farm for information from time to time:

      http://www.longecity.org/forum/topic/70456-lactobacillus-reuteri-atcc-pta-6475-most-potent-thing-ever/

      Apparently, to save money some people are culturing the capsules milk and making yogurt. I am a little skeptical of this (we make our own kefir so I have some experience here) and then there is the dosage aspect. Nevertheless, an interesting idea.

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    12. Alli, can you please share your son's th1 dominance symptoms? I have wondered if some of the nutrients I have been giving my son to lower a th2 dominance I have unwittingly pushed him in to th1 overdrive?? it is hard for me to know for sure as so many of his reactions overlap
      ~Tanya

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  4. Peter, here is a study on broccoli sprout extract helping to prevent oral cancer via carcinogens (tobacco, etc.) via sulphuraphane upregulating NRF2 which you have discussed in length in previous posts:

    http://cancerpreventionresearch.aacrjournals.org/content/early/2016/04/30/1940-6207.CAPR-15-0290

    Just thought you might want to read it.

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  5. Peter, Statins seem to help get my son "unstuck".
    How are statins connected with my son's NAFLD, liver hemangioma, low LDL?
    I have 30 mg Q10, shall I give it with atorvastatin?

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    Replies
    1. Petra, do give the Q10 to minimize any possible side effects. I do not think there is a direct connection to those other conditions. We have used atorvastatin for three years with no side effects.

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  6. A very good overview article has just been published, by Frye and Rossignol. Free access if anyone is interested

    Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes

    http://www.la-press.com/identification-and-treatment-of-pathophysiological-comorbidities-of-au-article-a5697

    (with a video abstract, how cool is that! :)

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