Friday, March 31, 2017

It's time to end the autism epidemic (part 3)

Besides 5-MTHF, we need a sufficient supply of methylcobalamin (MeCbl), a form of cobalamin (vitamin B12), in order to support methionine synthase (MS) function. There are four kinds of vitamin B12 available as supplements: methylcobalamin, adenosylcobalamin, hydroxocobalamin, and cyanocobalamin (CnCbl). Only methylcobalamin and adenosylcobalamin occur naturally in our bodies, and we normally get them from animal products. Hydroxocobalamin is produced by bacteria and then is made stable synthetically by using cyanide to change it from hydroxocobalamin to cyanocobalamin. Cyanocobalamin is the form of B12 typically put into multivitamins and fortified foods.

What happens when we ingest methylcobalamin? Unfortunately, it doesn't seem to go straight to where it might be needed in the body. A complex processing of B12, which is still the subject of investigation, happens in the cells first. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692085/, https://www.ncbi.nlm.nih.gov/pubmed/27771510) Methylcobalamin, adenosylcobalamin, and cyanocobalamin all undergo separation of the non-cobalamin part from the cobalamin part by the protein MMACHC. MMACHC catalyzes the decyanation of cyanocobalamin and the dealkylation of methylcobalamin and adenosylcobalamin, after which the cobalamin is chaperoned (cobalamin is very volatile on its own) and changed to adenosylcobalamin and methylcobalamin. The transformation of cobalamin to methylcobalamin, based on recent findings, appears to be part of an interplay of several proteins, including both MMACHC and methionine synthase (MS). (https://www.ncbi.nlm.nih.gov/pubmed/27771510) In other words, a problem with MS could not only affect MS in its homocysteine-salvaging function but could also make MeCbl less available to due to MS interacting with MMACHC, which decyanizes cyanocobalamin.

If you've ever read about chaos theory, you probably saw a mention of feedback loops. Feedback loops are an important principle to understand when dealing with systems of complex interactions such as those involving MS and B12 transport, conversion, and use.
The term feedback refers to a situation in which two (or more) dynamical systems are connected together such that each system influences the other and their dynamics are thus strongly coupled. Simple causal reasoning about a feedback system is difficult because the first system influences the second and the second system influences the first, leading to a circular argument. This makes reasoning based on cause and effect tricky, and it is necessary to analyze the system as a whole. A consequence of this is that the behavior of feedback systems is often counterintuitive.

http://authors.library.caltech.edu/25062/1/Feedback08.pdf (Feedback Systems: An Introduction for Scientists and Engineers. Karl Johan Åström; Richard M. Murray (2010). "§1.1: What is feedback?" Princeton University Press, p. 1).

I'm not going to try to untangle exactly what is happening between cyanocobalamin, MMACHC, and MS in the human brain, for we lack the necessary knowledge to do so at present. But we have evidence from a paper published last year that the fetal brain, for whatever reason, doesn't break down cyanocobalamin as well as expected.
We found CNCbl to be 15-fold higher in fetal samples, as compared to 0–20 yr old subjects, suggesting unique Cbl metabolism during fetal development. However, the underlying cause of this higher CNCbl level remains unclear, as does the biological origin CNCbl. Maternal folate and vitamin B12 supplementation is a common recommendation during pregnancy, which could be a source of the elevated CNCbl we observed, although Cbl levels in placenta were comparatively low. Conversion of CNCbl to active cofactors MeCbl and AdoCbl requires NADPH- or GSH-dependent decyanation by MMACHC and it is possible that the developing fetal brain has diminished decyanation capacity. The markedly higher level of inactive CNCbl could potentially have functional consequences by competing with MeCbl and AdoCbl, restricting their cofactor activity.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797 (references omitted).

An excess of CnCbl in the developing fetal brain could be restricting MeCbl activity? Which would negatively affect MS activity? That's exactly what we don't want to have happen if MS dysfunction is behind autism spectrum disorders.

Too little B12 in the brain has been linked to autism. (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797) And so has an excess of B12, according to the Johns Hopkins findings last year that I mentioned in a previous blog post: "Very high vitamin B12 levels in new moms are also potentially harmful, tripling the risk that her offspring will develop an autism spectrum disorder." (http://www.jhsph.edu/news/news-releases/2016/too-much-folate-in-pregnant-women-increases-risk-for-autism-study-suggests.html) The high B12 levels in the Johns Hopkins study population were almost certainly a result of cyanocobalamin in prenatal vitamins and fortified foods, for naturally occurring B12 forms are unlikely to be consumed at sustained excessively high levels unless one frequently eats clams and liver. (https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/).

Here's the worst part of the finding from the Johns Hopkins study: "If both levels [folate and B12] are extremely high, the risk that a child develops the disorder increases 17.6 times." (http://www.jhsph.edu/news/news-releases/2016/too-much-folate-in-pregnant-women-increases-risk-for-autism-study-suggests.html)

Talk about synergy! Yes, that said 17.6 times the risk of an autism spectrum disorders for children of women who had blood containing too much folate and B12, which almost certainly came from folic acid and cyanocobalamin in their prenatal vitamins and their fortified foods. Both the conscientious mothers who take their prenatal vitamins dutifully and economically disadvantaged mothers who rely on WIC--which generally limits their cereal choices to those that are highly fortified with folic acid and cyanocobalamin--are at risk of having excessive folate and B12, so their children end up at much greater risk of autism spectrum disorders, which are disorders of development, meaning it will be difficult or impossible to fully repair the damage later in life.

The heavy use of folic acid and cyanocobalamin, especially in conjunction, appears to have helped cause the dramatic rise in autism spectrum disorders in the last three decades. Folic acid and cyanocobalamin should be replaced with other forms of folate and B12 that are bioidentical to naturally, commonly occurring forms in order to minimize the hazard of causing unintended problems as has apparently happened with autism spectrum disorders. (I think ADHD is related to this mess, too--https://www.ncbi.nlm.nih.gov/pubmed/27346490--but I'll stay focused on autism for now.)

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Thursday, March 30, 2017

It's time to end the autism epidemic (part 2)

In order to carry out the conversion of homocysteine back to methionine, the enzyme methione synthase (MS or MTR) is dependent on cobalamin (vitamin B12 or Cbl) and folate, specifically in the forms of methylcobalamin (CH3-Clb or MeCbl) and L-methylfolate (5-MTHF, 5-methyltetrahydrofolate, or levomefolic acid). Here's an illustration, showing how the 5-MTHF essentially gives up its methyl group and ends up as plain tetrahydrofolate (THF, another form of folate) while homocysteine is converted to methionine:
https://www.researchgate.net/figure/6580050_fig4_Figure-1-The-cobalamin-dependent-methionine-synthase-catalysed-reaction-CblI

We need sufficient 5-MTHF to keep methionine synthase operating. Where does 5-MTHF come from? It's a form of folate that is produced by the enzyme methylene tetrahydrofolate reductase (MTHFR), and the gene that produces MTHFR has the same name. The body cycles through different forms of folate. Here's an illustration of that "folate cycle":
Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.
Spellicy CJ, Northrup H, Fletcher JM, Cirino PT, Dennis M, Morrison AC, Martinez CA, Au KS - PLoS ONE (2012) https://openi.nlm.nih.gov/detailedresult.php?img=PMC3515551_pone.0051330.g001&req=4
A deficiency in 5-MTHF can apparently be caused by at least three things:

1 - A deficiency in total folate diminishes the amount of 5-MTHF that can be made from other forms of folate.
  • Defective folate transport can result in autism spectrum disorders and other developmental disorders, and treatment with folinic acid (a form of folate) has been effective in in many children to reverse some autism symptoms. (https://www.ncbi.nlm.nih.gov/pubmed/26924398)
2 - MTHFR gene polymorphisms can decrease the ability of the body to produce 5-MTHF, production of which is catalyzed by the MTHFR enzyme, because the variant genes result in MTHFR enzymes that are more prone to being inactivated by heat. (https://www.ncbi.nlm.nih.gov/pubmed/10201405)
3 - High folic acid consumption causes a pseudo-MTHFR deficiency in mice and so might do the same in humans. (http://ajcn.nutrition.org/content/early/2015/01/07/ajcn.114.086603) Folic acid thus appears highly likely to be a sub-optimal form of folate for preventing 5-MTHF deficiency.
The third point is still controversial because there is research that has found folic acid prenatal supplements help prevent autism specifically where the MTHFR polymorphism associated with autism is present. (https://www.ucdmc.ucdavis.edu/publish/news/newsroom/6677). How does this square with the research I cited that finds autism risk appears to go up when there is excess folic acid? The key word is "excess." Our bodies can handle a little folic acid, but too much can get in the way of making 5-MTHF. I suspect folic acid does this by partially inhibiting the enzyme dihydrofolate reductase (DHFR), leaving more dihydrofolic acid (DHF) to get in the way of the MTHFR enzyme and thus cause a pseudo-MTHFR deficiency. 

Are we getting too much folic acid in the USA? I've come across articles about north American study populations that found unmetabolized folic acid in 40-95% of fasting study participants. (http://ajcn.nutrition.org/content/92/2/383.longhttp://jn.nutrition.org/content/145/3/520.short) From that, I conclude that many in north America are definitely getting more folic acid than they need.

Am I anti-folate? Not at all. Every woman should take measures to ingest enough folate if she thinks she could become pregnant in order to lessen the risk of neural tube disorders such as spina bifida. But I think folic acid is a terrible form of folate to be putting in everyone's food and multivitamins. Folate is available in many foods naturally and in other supplement forms, including actual 5-MTHF.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Wednesday, March 29, 2017

It's time to end the autism epidemic (part 1)

Two weeks ago, a group of researchers published their findings about biological markers that can be used to a high degree of accuracy to predict the presence or absence of autism. In other words, they have deduced and tested a highly accurate "blood test" for autism. Here is the link to the entire report: http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1005385.

Here is the abstract:

The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.

Here is a pictorial summary of folate-dependent one-carbon metabolism:


http://journal.frontiersin.org/article/10.3389/fgene.2011.00036/full
And here is an illustration of the transsulfuration pathway:

https://www.researchgate.net/figure/261328951_fig2_The-methionine-cycle-and-transsulfuration-pathwayNotes-Glutathione-synthesis-begins
Do you see where the two connect? It's at the part where methionine is converted in steps to homocysteine and then the homocysteine is recycled to methionine. The major homocysteine-to-methionine pathway is via the enzyme methionine synthase (MS).

In 2013, preliminary findings (due to the small study size) were reported that clearly indicated prematurely low levels of methionine synthase mRNA in autistic subjects' brains during their early years. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577685/) I highly recommend viewing the findings as graphically represented (here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577685/figure/pone-0056927-g005/) as they make it clear just how dramatic the difference is during crucial years in child development.

Why is the methionine-homocysteine cycle important in autism? Autism spectrum disorders are pervasive developmental disorders that are characterized by delays in multiple areas of development, and candidate genes for autism seem to constitute an ever-lengthening list. An influential theory currently is that epigenetic mechanisms are involved, particularly DNA methylation (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955092/), which ties directly into the s-adenosylmethionine (AdoMet or SAMe) made from methionine (as illustrated above).

If a methionine synthase (MS) transcription deficiency can cause autism via epigenetic mechanisms, that suggests we need to efficiently and vigorously support the activity of whatever MS-associated activity is present. That is where getting the proper forms of folate and cobalamin (B12) comes in. I'll go more into detail on that tomorrow.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Tuesday, March 28, 2017

It's time to end the autism epidemic (Introduction)

The evidence in the past few years continues to accrue, pointing to a defect in the methionine synthase homocysteine-to-methionine pathway as being behind the development of autism. In the next few days, I will lay out the evidence for how we address that problem and probably end the human-caused autism "epidemic" of the past couple decades.

1) Proper support of the methione synthase pathway requires having the right kinds of folate and cobalamin. In the pursuit of cheap and stable vitamin supplements, we have made a mistake using cyanocobalamin and folic acid. Those should be phased out in multivitamins and fortified foods as soon as possible and replaced with other, more appropriate forms of B12 and folate.

2) Glycine betaine should be a standard part of multivitamin formulations. It supports the betaine-homocysteine S-methyltransferase (BHMT) minor homocysteine-to-methionine pathway. The best way to get glycine betaine in the diet appears to be via ingestion of the water used in boiling beetroot and spinach, which is supported by the low autism rates found in places where such liquid is commonly included in regional cuisines, such as Poland (barszcz czerwony) and the Punjabi region (saag or palak puree).

I cannot emphasize strongly enough how disappointed and heartsick I am that modern medicine and health initiatives have, due to cost considerations, led to heavy mass usage of inferior forms of B12 and folate and consequently inflicted pervasive developmental disorders on so many children, including one of my own relatives. I love science, medicine, public health initiatives, proper vitamin use, and capitalism. Something went seriously awry in public health policy in many countries, and it's time to fix it.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Saturday, March 25, 2017

Addressing one anti-vaccine alarmist

I have a family member I consider very intelligent, except on one point. She has bought into the "vaccines are a bigger risk than benefit" idea and promotes that persistently. She has two personal reasons for being set against vaccination, at least here in the USA where the risks are certainly lower for contracting polio than in, say, Syria. They are:

  1. Years ago, her neighbor lost a baby to sudden infant death syndrome (SIDS) right after the child was vaccinated.
  2. She did get a vaccination for her oldest child, and he had a febrile seizure afterward, which she blames on the vaccination.

I'll address each point.

1) Any SIDS death is tragic and too often unexplained. However, research statistics indicate that SIDS risk is neither increased nor decreased by vaccination. (https://www.ncbi.nlm.nih.gov/pubmed/22289512) SIDS appears correlated with breathing difficulties, particularly those related to mild upper respiratory infections and cigarette smoke (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1619535/?page=1https://www.nichd.nih.gov/sts/campaign/science/Pages/causes.aspx). Per the CDC, upper respiratory infections are not common side effects of any childhood vaccinations:
https://www.cdc.gov/vaccines/vac-gen/side-effects.htm.
Do you know what apparently can be a good source of upper respiratory infections? Going to the pediatrician's office, where there is a good chance of finding rhinovirus-shedding children. (http://www.today.com/moms/taking-your-healthy-kids-doctor-may-make-them-sick-2D12110565, https://www.ncbi.nlm.nih.gov/pubmed/20135827) Thus, regardless of vaccination, simply having gone to the pediatrician recently might conceivably have increased the chance of SIDS for my relative's neighbor's child.

2) A febrile seizure is associated with having a fever. ("Febrile" means having a fever.) Febrile seizures are relatively common, affecting up to 6.7% of children. (https://www.ncbi.nlm.nih.gov/pubmed/16510738) The fever after an immunization is a result of an immune response to the partial, weakened, or dead bacteria or viruses in the vaccine. Fever is a common side effect of nearly every available vaccine. (https://www.cdc.gov/vaccines/vac-gen/side-effects.htm). That is because fevers are part of a functioning immune system, and moderate fevers help save our lives when fighting infections. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786079/) Febrile seizures are more likely right after vaccinations (although not delaying vaccinations in toddlers results in a lower risk of febrile seizures: http://pediatrics.aappublications.org/content/pediatrics/early/2014/05/14/peds.2013-3429.full.pdf), but getting the vaccine-preventable illness is far more likely to result in febrile seizures if H1N1 is representative of what happens with infections generally. (https://www.ncbi.nlm.nih.gov/pubmed/26073015https://www.ncbi.nlm.nih.gov/pubmed/26553258) If one is certain that children will never encounter a vaccine-preventable illness, it is rational to not get the vaccine. But when is something like that certain? If one is wrong, and the child's immune system has to fight off the illness, there will likely be worse consequences--including febrile seizures--than the child would have suffered from the vaccine.

So is my relative right to treat vaccines as something she should avoid? Well, not with respect to the SIDS argument. But avoiding immunizations for her children probably has decreased the incidence of fevers and febrile seizures for her children, for she keeps a clean house and they haven't come down with measles, mumps, rubella, polio, etc. Their not having come down with vaccine-preventable diseases, however, is a result of her living in the USA, her own caution, and good luck. Next week a recently arrived traveler from Chicago could bring mumps to a school in her area, and her sons could end up with meningitis or decreased fertility as a result. I don't think her risk-benefit analysis has led her to the best decision for her family because she is unaware of how easily vaccine-preventable diseases can be brought to her orderly doorstep.

Wednesday, March 22, 2017

Silent, but not deadly

Today's topic is flatulence. Everyone passes gas. The trick is to have no one notice when it happens, which requires both silence and an absence of noticeable odor. Where does the offensive odor come from? Sulfur! Yes, brimstone (an archaic word for sulfur) really does deserve to be associated with imagined conceptions of hell. Specifically, hydrogen sulfide (H2S) correlates with the level of stinkiness of flatulence. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727181/)

Happily, we know how to bind H2S. Bismuth, zinc, iron, and nitrate are able to do so. (https://www.ncbi.nlm.nih.gov/pubmed/12927694) Nitrate is considered toxic, but the other three are commonly ingested by people. Bismuth is in Pepto-Bismol, and zinc and iron are in many foods and taken as vitamin supplements. Treatment with bismuth has been proven to bind fecal H2S in humans (http://www.gastrojournal.org/article/S0016-5085(98)70311-7/fulltext), but long-term supplementation with bismuth is possibly connected to encephalopathy; brain dysfunction is too high a price for me to pay to get rid of bad-smelling flatulence, so I won't run out and buy myself a bottle of Pepto-Bismol for that purpose. But zinc...that's in common use as a supplement, especially in connection with fighting colds, and appears relatively safe as long as one keeps zinc intake below 40 mg in a day. (https://umm.edu/health/medical/altmed/supplement/zinc) Moreover, the body has no specialized zinc storage system. People occasionally eat oysters, which are extremely high in zinc, and don't appear to be negatively affected by eating the oysters. Zinc is worth a try.

My husband's digestive system doesn't handle onions well. I was sad as a newlywed to realize that onions were going to have to be cut out of the household menu for his sake. And over time my gut bacteria seem to have altered so that I also have a hard time with onions now. This was a very unfortunate change to a woman who loves salsa. But then two days ago, I discovered from the studies cited above that H2S can be bound with easily obtained minerals, and so we experimented. Last night for dinner, we ate a packaged, reconstituted potato and onion soup that gave us both extraordinarily unpleasant gas about a year after our marriage. We adults took some chelated zinc right before eating the soup. We both had some gas today, but it didn't stink. Hurrah! We are fairly confident that the zinc helped us because our seven-year-old, who didn't get any zinc and did eat two bowls of the soup, had decidedly malodorous gas this morning.

Next step: Mexican food (well, American-style "Mexican" food, which really isn't the same thing as authentic Mexican food) with some zinc in our accompanying beverage. I really hope this works so that I can go back to cooking with onions.

Thursday, March 16, 2017

Natural remedies over the millennia

A promising trend I see on PubMed recently is a swelling of interest in and scientific research on natural compounds from herbs and foods that have been used by humans for thousands of years. There is relatively little profit motive for pharmaceutical companies to fund such research, so it has been neglected. There's certainly a need for new, patentable molecules designed to selectively inhibit certain processes in the body and to correct for genetic faults, but we have a lot of naturally occurring molecules to investigate, as well.

LDS people (Mormons) have scriptures that say

"And again, verily I say unto you, all wholesome herbs God hath ordained for the constitution, nature, and use of man— Every herb in the season thereof, and every fruit in the season thereof; all these to be used with prudence and thanksgiving.

But which herbs are wholesome? And for what conditions? Despite attempts to keep track of herbs and their effects for the past 5000 years, if Chinese oral tradition is accurate, humanity still has a long way to go in figuring them out.

Only 5000 years did I say? It looks like the Neanderthals might have been using natural remedies to treat their physical ailments well over 40,000 years ago:

"One of the most surprising finds, however, was in a Neanderthal from El Sidrón, who suffered from a dental abscess visible on the jawbone. The plaque showed that he also had an intestinal parasite that causes acute diarrhoea, so clearly he was quite sick. He was eating poplar, which contains the pain killer salicylic acid (the active ingredient of aspirin), and we could also detect a natural antibiotic mould (Penicillium) not seen in the other specimens.""Apparently, Neanderthals possessed a good knowledge of medicinal plants and their various anti-inflammatory and pain-relieving properties, and seem to be self-medicating. The use of antibiotics would be very surprising, as this is more than 40,000 years before we developed penicillin. Certainly our findings contrast markedly with the rather simplistic view of our ancient relatives in popular imagination."
http://popular-archaeology.com/issue/winter-2017/article/dental-plaque-dna-opens-new-window-on-neanderthal-life-ways

Reading that makes me think we should routinely reevaluate all the traditional remedies and "old wives' tales" to see whether new research has found out something indicating whether and how there might be something to those old uses of plants and other natural substances. (While we're at it, we should also probably stop maligning Neanderthals as stupid nonhumans if they were using penicillin intentionally that long ago.) Giving barley water a fresh look helped me see how molybdenum can help with migraines and nausea. Who knows what other real natural remedies we modern humans are missing?