Friday 10 August 2012

Folate and autism: more questions than answers

Athenian sunset @ Paul Whiteley
I don't know if you could tell but my previous few blog posts were a sort of stand-in whilst I took a few days off. Not exactly repeats of favourite soap operas or anything like that, but more like watching some pre-recorded non-league football (soccer) compared to the Premiership live. Suffice to say that I'm back now and ready to press on with some 'proper' posts.

Whilst away I've been thinking quite a bit about the paper from Rebecca Schmidt and colleagues* on maternal folic acid intake and offspring risk of autism spectrum conditions discussed in this post. Don't get me wrong I'm not disputing their findings of anything like that; recognising that is, the retrospective 'tell me what you did' methodology used and how studies of association are just that: studies of association.

The media attention following the Schmidt paper however painted an interesting picture of folic acid supplementation and autism. As perhaps expected, some outlets have taken up the 'preventative' side of folic acid supplements with headline such as this one: 'Consuming folic acid during early pregnancy cuts risk of an autistic child'. Maybe it's just me, but I don't believe that headlines like this paint as accurate a picture of the folic acid-autism link as perhaps the research literature suggests, as in this post I try and explain why.

There is no denying the important functions that folic acid supports not just to the developing foetus during early pregnancy but also in adult health, as for example seen in the growing literature on folic acid reducing the risk of stroke.

With autism in mind, the literature on folic acid is however a little more muddled in terms of the early days/months/years effects of supplementation and indeed the cycle of compounds in which folic acid finds itself in:

  • Eugene Rogers** published a speculative paper (in a speculative journal!) a few years back, asking whether supplementation with folic acid during pregnancy has influenced natural selection and further autism prevalence. The theory goes that children who carry previously discussed SNPs in genes like everyone's favourite Scrabble classic gene, MTHFR, which might influence the effectiveness of folate, are surviving in greater numbers as a result of mum's increased folate intake. After birth, kids with mutations in the MTHFR gene still need lots more folate but aren't getting enough; hence important processes like methylation aren't able to be carried out optimally and behavioural consequences are apparent (see here). Before you roll your eyes and click away, there is some evidence (albeit limited) to back up this hypothesis. So, SNPs in MTHFR in autism: check; elevations in homocysteine in kids with autism: check; suggestions of hypomethylation in cases of autism (and mums with children with autism): check. Some evidence at least, although as always I could be cherry-picking the data.
  • Beard and colleagues*** in a similar stance, also asked the question (in the same journal) as to whether excess folic acid supplementation might be a risk factor for autism. I'm slightly less convinced by their associations and presented data, but the question of whether "too much folic acid may result in nervous tissue damage associated with autism" is an interesting one particularly in light of research like this from Junaid and colleagues**** and over 1000 genes suspected to be 'dysregulated' by high folic acid supplementation.
  • The older literature on folic acid and autism also carries some interesting papers. So, this paper by Gillberg and colleagues***** reports results from a very small study on the supplementation of folic acid to boys diagnosed with autism and "the fragile X syndrome". Reviewing the evidence for a larger effect from folic acid supplementation for Fragile X syndrome, it has to be said however that it is not all that impressive (here).
  • I've talked before about an important piece of research which looked at folate receptor autoantibodies in cases of autism. In this scenario, folic acid is not necessarily the main issues but rather the fact that the folate receptors may not be functioning optimally, and so for example, are influencing the delivery of 5-MTHFR to cells. The suggestion from this (and another******) paper was that supplementation with folinic acid may be a better option. I shall at this point reiterate that medical advice is neither given nor intended in this or any post on this blog.

I hope I've made a preliminary case for some greater inspection of folic acid and its relations in cases of autism in light of how the recent Schmidt findings have been disseminated in some quarters. Recognising that vitamins and minerals are readily available to everyone combined with the possibility of a suggestion that increased folic acid intake during pregnancy might 'offset' the risk of offspring autism, to my mind makes for a strong requirement for some balanced advice on this matter.

The picture accompanying this post is a holiday snap from some family vacation time in Greece. Warm, very warm summer days and nights, cicada making their music and cycling seemingly becoming very popular in Greece (with the usual safety caveats suspended in quite a few cases). So to finish some Greek pop music from Mr Michalis Hatzigiannis. Ελλάδα γεια σου.


* Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. American Journal of Clinical Nutrition. May 2012.
DOI: 10.3945/​ajcn.110.004416

** Rogers EJ. Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link. Medical Hypotheses. 2008; 71: 406-410.

*** Beard CM. et al. Is excess folic acid supplementation a risk factor for autism? Medical Hypotheses. 2011; 77: 15-17.

**** Junaid MA. et al. Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochemical & Biophysical Research Communuications. 2011; 412: 688-692.

***** Gillberg C. et al. Folic acid as an adjunct in the treatment of children with the autism fragile-X syndrome (AFRAX). Developmental Medicine & Child Neurology. 1986; 28: 624-627.

****** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. American Journal of Clinical Nutrition. 2009; 89: 425-430.

---------- Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tassone F, & Hertz-Picciotto I (2012). Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. The American Journal of Clinical Nutrition, 96 (1), 80-9 PMID: 22648721


  1. I'm glad I found your blog. I've been diagnosed with MTHFR 677TT. As I learn more about methylation I'm starting to think about family members.
    Early death from cardiac disease in my father's family.
    My mother - early onset Parkinson's and a spinal cord condition (Syringomyelia) in her 60's that is normally associated with a brain malformation (Chari) that she lacked. My nephew's severe autism.

    My father's family probably has a prevalence of homozygous mthfr.
    I'm guessing that my mother and nephew are both compound heterozygous for 677T and A1298C.

    As a side note, I find it interesting(in a clinical sense), that both my mother and nephew are second-born children. I speculate about the folate status of my grandmother or sister-in-law. My mom was conceived immediately after my uncle's birth. With back-to-back pregnancies I'm guessing my grandmother was deficient in folate (of natural and/or folic acid) at the time. My sister-in-law, however, I'm sure was told to take folic acid and I'm sure she did but if she's got an MTHFR variant, well, who knows. With the emerging knowledge of methylation women should be encouraged to supplement with L-methylfolate in my opinion.

    Of course my family members would have to submit to genetic testing to know their genetic status. The purpose in knowing the answer is to make informed decisions on their health. For now, I'm finding out what I can and plan to encourage them to take L-methylfolate supplements (OTC, not Rx) with a B-multivitamin and perhaps in time they will begin to watch their intake of folic acid. In the meantime maybe the medical knowledge will advance to the point that the average physician can guide them toward better health with MTHFR/methylation issues.

  2. Many thanks for the comment and dropping by.

    An interesting family history indeed.

  3. One more twist: I started taking prenatals 5 years before I ever tried to conceive. That and my relatively healthy diet of lots of organic fruits & veggies may be the reason I never experienced pregnancy issues that I'm reading about from other MTHFR women.


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