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PPAR Gamma Agonists and Autism

One of my favorite bloggers (Peter Lloyd-Thomas) has been blogging about PPAR-Gamma Agonists and autism recently here http://epiphanyasd.blogspot.com/2015/05/tangeretin-vs-ibuprofen-as-ppar.html.

Among Peter’s observations:

1)  Actos improves behavior in autism, and Actos is a PPAR-gamma agonist. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781426/

2) PPAR-gamma agonists have antiepileptic properties in mice.  http://grantome.com/grant/NIH/R01-NS085389-01A1#panel-abstract-body

3) Peter’s son who has autism is doing better on PPAR-gamma agonists and no longer needs ibuprofen.

Some additional observations:

4)  Cntnap2 gene defect ameliorated with biochanin A in Zebrafish. https://imfar.confex.com/imfar/2015/webprogram/Paper20670.html  Biochanin A is a PPAR-gamma agonist.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212005/

5) Luteolin formulations have shown efficacy in autism in some open label trials: http://europepmc.org/abstract/med/22697063, http://www.clinicaltherapeutics.com/article/S0149-2918(13)00178-1/abstract  Luteolin is a partial PPAR-gamma agonist.  http://www.ncbi.nlm.nih.gov/pubmed/22391103.

6) IGF-1 seems to show some efficacy in Phellan McDermid syndrome: http://www.molecularautism.com/content/5/1/54.  An herb that upregulates IGF-1 also upregulates PPAR-gamma.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117754/  Is IGF-1 also a PPAR-gamma agonist?

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IMFAR 2015: Effectiveness of Over-the-counter therapies for autism

I am going to IMFAR 2015 in Salt Lake City and will be giving a poster presentation on “Effectiveness of Over-the-counter therapies for autism”.  The presentation is on Friday, May 15 between 11:30 AM and 1:30 PM.

Here is my main poster:

https://autismvitamind.files.wordpress.com/2015/05/imfar-may-17.pdf

Here are my two tables:

https://autismvitamind.files.wordpress.com/2015/05/table-1-may-17.pdf

https://autismvitamind.files.wordpress.com/2015/05/table-2-may-17.pdf

Here is a top 10 list of autism research ideas:

https://autismvitamind.files.wordpress.com/2015/05/top-10-ideas-for-autism-researchers-may-11.pdf

Milk as a risk factor for vascular dysfunction

One of my favorite bloggers, Paul Whiteley, has highlighted a paper that shows that significant milk consumption can have some major downsides for health.  See the paper here: http://www.bmj.com/content/349/bmj.g6015.  See Paul’s masterful discussion of it here: http://questioning-answers.blogspot.com/2014/11/milk-has-gotta-lotta-bottle.html.

The authors find a link between milk consumption and the elevations in markers for vascular damage, the elevation of cytokine IL-6, and the increases in mortality.  The propose that this is due to the D-galactose content of milk. An viable explanation is the vitamin D content of milk. I originally made a comment on this on Paul’s blog that he graciously posted.  I provide it here as well:

This is another fascinating paper that you have highlighted.  I completely agree with you that higher IL-6 is worthy of exploration.  It is interesting that the elevations were more common in males and that males were more likely to suffer increased mortality from milk intake.
I have an alternative interpretation of the authors’ findings which I think are more compelling.  I understand the subjects in the study were Swedish adults.  Sweden may have the highest level of oral vitamin D consumption of any European country.  See: http://journals.cambridge.org/download.php?file=%2FPNS%2FPNS62_04%2FS0029665103001071a.pdf&code=7875fc995d2e69bd559d97c60a9e146d.  A big part of this is the vitamin D in fortified milk and milk products.
At very high doses oral vitamin D is known to promote vascular calcification.  In addition there are hints of negative effects on serum lipids in some populations based on more modest supplementation.  See:http://www.ncbi.nlm.nih.gov/pubmed/9405029.  Interestingly it is more toxic in large doses to males than females (at least in rat studies):http://www.toxicologyinternational.com/article.asp?issn=0971-6580;year=2008;volume=15;issue=2;spage=143;epage=144;aulast=Kaur
Also oral vitamin D supplementation has been shown in some diseases to upregulate IL-6.  See: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2010.04463.x/pdf.  I should acknowledge that this was taken to be a positive effect by the authors of this study.
In any case what this data suggests to me is that Sweden has high levels of vitamin D supplementation already and raising them further by significant consumption of vitamin D fortified milk may be leading to dysfunctional upregulation of IL-6 production in some.  I suggest that this effect is most prominent in males as observed and this is a factor in the modest increases in markers for vascular damage and increased mortality that is most prominent among males.
Taking this a bit further what other populations receive large doses of supplemental vitamin D?  It turns out in most developed countries many infants and toddlers receive huge amounts of oral vitamin D relative to their weight and their size: much more than adults consume based on their weight and size.  Are there any conditions that feature elevations in IL-6, elevations in markers for vascular damage, and that affects male children disproportionately?  As you among others have pointed out autism is such a condition.  See here:http://www.ncbi.nlm.nih.gov/pubmed/23994594.
Going back to Sweden public health officials began recommending vitamin D supplementation in infancy for all infants using vitamin D drops starting in 1978:http://journals.co-action.net/index.php/fnr/article/viewArticle/1632.  And what was the effect of this on the autism incidence in Sweden?  I don’t think there is good data on Sweden as a whole for this time period but there is solid data on the Goteborg area in Sweden thanks to work by Gillberg et al.  They found that there was a 110% rise in autism diagnoses between birth years 1978 and 1979.  See:http://www.ncbi.nlm.nih.gov/pubmed/16568356.  Oral vitamin D supplementation among the young is a risk factor for autism.  Unfortunately most people don’t realize this yet.

Overgrowth, Autism, and Vitamin A and Vitamin D

Excessive infant supplementation of vitamin A and vitamin D: a risk factor for early overgrowth and autism?

Mr. Seth S. Bittker1*, Dr. Thomas E. Bittker, M.D.2

*Corresponding author: Seth S. Bittker

117 Edmond Street, Darien, Connecticut 06820

2Reno Psychiatric Associates, 80 Continental Drive, Reno, Nevada 89509

We commend the article by Campbell, et al. on “Early Generalized Overgrowth in Autism Spectrum Disorders” appearing in the October issue of the Journal of the American Academy of Child & Adolescent Psychiatry and appreciate their work showing that it is not just neurological overgrowth that is a risk factor for autism but also non-neurological overgrowth as well.  We also applaud Campbell, et al.’s suggestion that factors which may upregulate such growth in infants warrant examination.

With respect to such factors, while genetics and known environmental toxins should be considered, a policy of universal vitamin A and D supplementation among infants is a risk factor that compels closer examination.   Zhou et al. has suggested previously an association between excessive vitamin consumption in infancy and autism.i

Vitamin A and vitamin D in particular are fundamental to growth in infancy and deficiency can cause stunted growth.ii This suggests excessive consumption of these vitamins among infants could plausibly be a risk factor for the generalized overgrowth that Campbell, et al. describe.  In addition Tekes, et al. found when baby rats are given a single large dose of a combination of vitamin A and vitamin D, there are life-long effects in the brain including monoamine neurotransmitter dysregulation.iii  Zhou, et al. has observed that such neurotransmitter dysregulation is also characteristic of autism.i

But what happens when one takes human infants and gives them large doses of vitamin A and vitamin D?  Such experimentation would seem to be unethical.  However, as Tekes observed significant supplementation of these vitamins in infancy is common in most developed countries.iii   So it may be revealing to examine autism prevalence in years in which supplementation regimes were first implemented.  For example, in 1978 in an effort to combat rickets, Sweden’s National Board of Health and Welfare began recommending daily supplements of 3300 IU of vitamins A and 400 IU of vitamin D for all infants from ages 6 weeks to 6 years.iv  And what was the effect of this policy in Sweden?  Gillberg, et al. in their careful study of registered prevalence of autism in Goteborg, Sweden tracked autism by birth year.  For birth year 1978 there were 10 cases of autism in Goteborg.  For birth year 1979 there were 21 cases of autism in Goteborg.  This represents a 110% increase.  While there were variations in the number of cases of autism in nearby birth years, it is worth noting that in no future years did the number of cases ever approach the lower levels associated with birth years 1977 and 1978 and the percentage increase in cases was by far the greatest between 1978 and 1979.v  We find this evidence is troubling, and we believe that additional research in this area is warranted.

Acknowledgements

None.

Conflicts of Interest

The authors declare they have no conflict of interest regarding publication of this letter.

 

References

i Zhou SS, Zhou YM, Li D, Ma Q. Early infant exposure to excess multivitamin: a risk factor for autism? Autism Res Treat. 2013:963697.

ii Rolfes SR, Pinna K, Whitney E. Understanding Normal and Clinical Nutrition. 2011: 358,364.

iii Tekes K, Gyenge M, Folyovich A, Csaba G. Influence of neonatal vitamin A or vitamin D treatment on the concentration of biogenic amines and their metabolites in the adult rat brain. Horm Metab Res. 2009;41: 277-280.

iv Blomquist HK, Frangsmyr A, Hernell O, Stenberg B, Back O. Dietary intake of vitamin D during the second half of infancy in Swedish infants. Scandinavian Journal of Nutrition. 2004;48:173-177.

v Gillberg C, Cederlund M, Lamberg K, Zeijlon L. Brief Report: “The Autism Epidemic”. The Registered Prevalence of Autism in a Swedish Urban Area. Journal of Autism and Dev Disorders. 2006;36:429-435.

Methylation & Autism: a practical approach

methylators

Methylation is one of the biochemical processes that is fundamental to life.  About a decade ago a researcher named Jill James and her collaborators published a remarkable paper that established that autism often features a methylation deficit (http://ajcn.nutrition.org/content/80/6/1611.full.pdf+html).  Some therapies that have been tried to increase methylation include folinic acid and methylcobalamin.  While these therapies usually do not fully normalize biochemistry in autism they often bring the biochemistry closer to normal. See James’ work as well for some color on this (http://ajcn.nutrition.org/content/89/1/425.full).  In addition a number of parents including myself have noticed significant improvement with this therapy or variants of it.

Folinic acid is a form of folate that is methylated to form methylfolate in the body.  So when methylation is an issue, supplementation with methylfolate may be a more natural choice than folinic acid.  Based on my experience with my son, I feel methylfolate did in fact work better.  Many practitioners recommend methylcobalamin shots rather than oral methylcobalamin in autism.  In fact James’ studies were based on giving children shots of methylcobalamin rather than oral form.  However, methylcobalamin seems to be well-absorbed orally (http://informahealthcare.com/doi/abs/10.1517/14656560903456053).  So in my opinion shots are unnecessary.  Also many of the oral formulations suggest sucking on a tablet under the tongue for best absorption.  Don’t worry if your kid just eats it.  Mine does and my experience is that plenty of it will be absorbed.  In addition you can always give marginally more orally if you feel after trying it that not enough is absorbed well in your child.
To see if your child could be a candidate for methylfolate and methylcobalamin therapy you could ask your medical practitioner about ordering an organic acid test and/or a test to analyze oxidized and reduced glutathione.  If forminoglutamic acid is high, methylmalonic acid is high, or the ratio of oxidized to reduced glutathione is high, then your child may be a good candidate for this therapy.
With my son who is about 75 pounds we use about 5 milligrams of methylcobalamin per day and 1600 micrograms of methylfolate per day.  I think this improves his communications, his eye contact, and his socialability.  Of course your child could react differently than mine.  If you do choose to try this, it probably makes sense to give these methylators in the morning as high doses of methylcobalamin can cause insomnia and in fact with much higher doses I saw this in my son.  As with most therapies it makes sense to start at a very low dose and work up if you feel the therapy is working.
If you use this therapy or some variant of it already or you try it with or without success, please feel free to comment here.

Excessive vitamin D supplementation: a risk factor for autism

Some of the biochemistry that typically characterizes autism:
1) Th2 skew to the immune system. http://www.ncbi.nlm.nih.gov/pubmed/9627004
2) Overproduction of monoamine neurotransmitters. http://www.ncbi.nlm.nih.gov/pubmed/7914177
3) Oxidative stress. http://www.ncbi.nlm.nih.gov/pubmed/15585776
4) Vascular damage. http://www.ncbi.nlm.nih.gov/pubmed/16908745
5) Excessive neuronal connectivity. http://www.cell.com/cell-reports/fulltext/S2211-1247%2813%2900570-6
6) Extreme male brain. http://cogsci.bme.hu/~ivady/bscs/read/bc.pdf

Some of the effects of excessive supplementation with vitamin D in the young:
1) Th2 skew to the immune system. http://www.ncbi.nlm.nih.gov/pubmed/15564440
2) Overproduction of monoamine neurotransmitters. http://www.ncbi.nlm.nih.gov/pubmed/19053013
3) Oxidative stress. http://www.ncbi.nlm.nih.gov/pubmed/16620292
4) Vascular damage. http://www.ncbi.nlm.nih.gov/pubmed/227138
5) Excessive neuronal connectivity. http://www.sciencedirect.com/science/article/pii/S0304394003003033
6) High testosterone production. http://www.ncbi.nlm.nih.gov/pubmed/211541

My name is Seth Bittker and my son has been affected by ASD. After thinking about his development and carefully weighing the evidence I have come to the conclusion that oral vitamin D was a factor in inducing autism in him and I believe the same is true of a number of others.

If you are interested in hearing more, please feel free to peruse my paper on this topic here: http://omicsgroup.org/journals/infant-exposure-to-excessive-vitamin-d-a-risk-factor-for-autism-2165-7890.1000125.pdf.

If you wish to correspond with me about this, I would welcome it. My email address appears in the paper I published on this topic.