There is a proverb, said by the famous British historical literary critic, who published the first English Dictionary. “The road to hell is paved with good intentions.” – Samuel Johnson (1709-1784)
Today is the last day of April, which has been autism awareness month. I think it’s fitting to point out a provocative hypothesis of autism causation. Studies of folic acid metabolism and autism have been published over the past several years, by various authors. This recent paper King CR. A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription. A possible link between twelve autism risk factors and the autism ‘epidemic’ Med hypotheses (2011) is interesting, since it presents a hypotheses that autism is an epigenetics disorder.
Is it possible that excessive folic acid is a teratogenic environmental factor for susceptible populations? Is epigenetics the basis of autism? Here are a few of the tidbits which the author ties together as evidence for a Retinoic Acid/Estradiol Causation model.
- Folic acid is converted to 5′-methyltetrahydrofolate, (5′-MTHF) in the folate cycle. 5′-MTHF is a methyl donor to homocysteine, creating methionine. Methionine activates to S-adenosylmethionine (SAM), which has a significant role in de novo methylation/imprinting.
- Since the late 1980s, expectant mothers are advised to take 600mcg of folic acid per day, as a harmless way to prevent birth defects and prevent miscarriages. Also, folic acid supplementation of enriched grain products, has been required in the USA since 1988. This time line fits with the uptick in Autism spectrum diagnoses.
- Autistic brain stems are shortened, due to the lack of a transient embryological structure which has shown to be dependent in mice, on one of the Hox gene transcription factors.
- Retinoic acid signaling initiates expression of the developmental master regulator Hox genes – mutations in Hoxa-1 cause autism.
- Excess folic acid might temporarily compensate in utero, for genetic mutations to methylation cycle related proteins, which would normally be terminally disruptive to early central nervous system development.
- Higher functioning autism may be caused by folic acid promoting estrogen sensitive growth responses.
- Testosterone is converted in the brain to estadiol. Male embryos could be overexposed to maternal estradiol during sexual differentiation, hence the high male to female ratio in high functioning autism.
- Aspergers may be caused by overexposure to self produced testosterone. Most of the affected areas of the brain would be converting that testosterone to estradiol. However, the brain region for speech development might lack the enzyme to catalyze that conversion, and be developmentally unaffected.
- Autism symptoms which have also been shown to be functions affected by estrogen, include motor coordination, epilepsy, attentiveness, pain regulation, memory, spatial ability, etc.
Now, I hate to distract from this author’s critical scientific thinking applied to the controversial problem of increasing incidences of autism. However, if this hypothesis gets proven with data – prenatal folic acid supplementation will end up being an outrageous example of how broad medical recommendations, can fail us! I prefer to view this hypotheses as an opportunity to concretely apply epigenetics to prove or disprove a simple solution for combating the rising incidence of autism spectrum disorders.
I think the idea that autism is due to epigenetic programming due to excess folate is very unlikely. I think it is more likely that folate prevents autism.
http://www.ncbi.nlm.nih.gov/pubmed/21610500
There is disruption of folate pathways in people with autism, but seems to be a disruption in the low direction.
http://www.ajcn.org/content/91/6/1598.full
Low folate does cause neural tube defects, and teratogens that cause neural tube defects (valproate and thalidomide) also cause autism.
Folate protects against the neural tube defects associated with valproate (in mice).
http://www.ncbi.nlm.nih.gov/pubmed/12692401
Rett Syndrome is an ASD, and is caused by deletion of the MeCP2 gene. MeCP2 regulates epigenetic readout of methylated DNA and in mouse models, reactivation of MeCP2 eliminates the RS symptoms. Implying that proper readout of methylated DNA is sufficient to resolve RS symptoms.
See Arthur Beaudet (Baylor Medicine) research investigating these ideas for over five years.
First of all, Happy 4th of July!
Thanks for your comments, and especially, the link to the July 2011 paper, Dave.
Bill, I would love to know more about what Arthur Beaudet’s lab has found. Is there a publication you would suggest, out of this lab? Or please feel free to post a comment on any of his upcoming talks, that you may know of, so that other readers will know how to learn more. Thanks! Best, -Nicole
Folic acid is an antagonist of the GABA(A) receptor. It’s actually a fairly ‘unnatural’ substance. The natural vitamin, found in food, is folate. Folic acid needs to be converted to folate in the body by the enzyme, dihydrofolate reductase. The efficiency of the conversion process is highly variable between individuals, with a fivefold difference between the most and least efficient converters.
http://www.ncbi.nih.gov/pubmed/19706381
Folate also acts as an antagonist at the GABA(A) receptor, but folic acid has a more powerful antagonistic action.
http://www.ncbi.nih.gov/pubmed/2166659.
Other chemicals which have been associated with autism are insecticides http://www.ncbi.nih.gov/pubmed/17938740 phthalates http://www.ncbi.nih.gov/pubmed/19822263 and methyl mercury http://www.ncbi.nih.gov/pubmed/16914205 . All are GABA(A) receptor antagonists. This is unlikely to be coincidence, therefore it is likely to be causal.
If GABA transmission in the developing brain is hindered by GABA(A) receptor antagonists, it is reasonable to assume that those receptors may become more sensitive and/or numerous to compensate for this. Babies will therefore be born with GABAergic neurons which are hyperfunctional.
I believe this is responsible for the modern ‘epidemics’ of autism, ADHD, asthma and type 1 diabetes, although the mechanisms which are responsible are complex, involving chronic, aberrant sctivation of the immune system. I have written about this on my blog at -
http://nfkbdiseases.wordpress.com
Hi William, Thank you for your comment. Have you seen any research concerning providing people, especially young children, diagnosed with autism spectrum disorders with folic acid supplements?
Hi, Nicole
I’ve had a quick look on PubMed for an answer to your question. There doesn’t appear to be much research advocating folic acid supplementation, but I found the following two papers interesting. The first is a Polish study which found high levels of homocysteine in the blood of autistic patients. Homocysteine induces excitotoxicity and high levels are associated with several diseases. Supplemental folic acid apparently helped to reduce the high homocysteine levels;
http:www.ncbi.nih.gov/pubmed/21530806
This other paper, from Belgium, found low levels of 5MTHF (methyltetrahydrofolate) in two autistic sub-groups, Rett syndrome and infantile low functioning autism with neurological abnormalities. It claims ‘oral folinic acid supplements led to normal CSF 5MTHF and partial or complete recovery after 12 months’! As far as I can make out, this was 19 patients. I assume that what they mean is that there was a recovery to normal levels of 5MTHF, rather than recovery from autism, although I could be wrong about that!
http:www.ncbi.nih.gov/pubmed/18461502
Maybe these links will work
http://www.ncbi.nih.gov/pubmed/21530806
http://www.ncbi.nih.gov/pubmed/18461502
I’ve been updating my blog this morning, adding references to support my belief that environmental chemicals which are associated with a higher incidence of autism are antagonists at the GABA(A) receptor.
I’ve now come to the conclusion that it might be more prudent to say that the chemicals ‘either act as antagonists, or otherwise inhibit GABA(A) receptor functioning’.
Here are the refs:
folic acid (http://www.ncbi.nih.gov/pubmed/1327745), phthalates (http://www.ncbi.nih.gov/pubmed/17646496) , methyl mercury (http://www.ncbi.nih.gov/pubmed/20060493) and a variety of insecticides, including organophosphates (http://www.ncbi.nih.gov/pubmed/10591520) , organochlorines (http://www.ncbi.nih.gov/pubmed/21278053) and pyrethroids (http://www.ncbi.nih.gov/pubmed/2562766)