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)

• An MTHFR polymorphism is associated with autism spectrum disorders in countries that do not fortify with folic acid.(http://onlinelibrary.wiley.com/doi/10.1002/aur.1300/abstract) 

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.

• Dr. Subit Barua at Columbia University and his colleagues have repeatedly observed autism-like effects in the brains of young mice whose mothers were fed high levels of folic acid during gestation. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390789/, https://www.ncbi.nlm.nih.gov/pubmed/26547318, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854024/)
• In May of 2016, Johns Hopkins announced having found that "if a new mother has a very high level of folate right after giving birth--more than four times what is considered adequate--the risk that her child will develop an autism spectrum disorder doubles." (http://www.jhsph.edu/news/news-releases/2016/too-much-folate-in-pregnant-women-increases-risk-for-autism-study-suggests.html) Because it's difficult to ingest excessive folate from unfortified foods (https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/), I think that the sources of excessively high folate levels in a pregnant woman in the USA are prenatal vitamin supplements, which typically contain folic acid (a relatively inexpensive form of folate), and processed food (particularly breakfast cereal) that has been fortified with folic acid.

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.long, http://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