Friday, May 27, 2011

New Studies: Nutritional and Pathologic Clues in Autism

I've devoted quite a few entires to autism (more properly called the autism spectrum disorders).  Perhaps because the illness can be so devastating, attacks so young, and is so mysterious in its origin.  I've migrated many of the autism entries over to Psychology Today, and the specifically nutritionally-related ones can be found here:

Diet and Autism
Diet and Autism - Newer Studies and Intriguing Links
Autism, Inflammation, Speculation, and Nutrition

The first new paper I want to present today is a Letter in Nature:  Transcriptomic analysis of autistic brain reveals convergent molecular pathology.  Like most Nature papers, the prose is dense with advanced molecular biology and neuroscience, but I think I can glean the meaning of it.  In this study, the researchers examined post-mortem brains from 19 autism cases and 17 controls.  They focused on three areas previously shown to be different in the autistic brain (specifically areas of the cerebral cortex and cerebellum), finding the most differences between autistic brains and controls in the cortex.

What is interesting about these sorts of studies is that they look at gene expression rather than just genetics, meaning they find out which genes are activated differently between cases and controls.  They found that many different genes were affected (consistent with the findings in autism in general - there is no single "autism gene" causing all cases, though 1% of cases have a 15q duplication, for example).  The interesting part is that the gene expression that was different between cases and controls clustered around specific areas, and were highly related to what is called "cortical patterning." These are some of the same gene areas that were already suspected to be causative for autism spectrum disorders,  and are also suspected to be causative in schizophrenia.  Other genes that were upregulated were functioning as part of the immune and inflammatory response.

What is intriguing about this study is that the researchers felt it showed convergence of the many different genetic causes in the area of transcription and splicing of certain genes as the underlying mechanism of the disorder.  They were also able to show that the inflammation was secondary rather than primary.

All right, we made it through the tough part.  Now on to the second paper, which is far more nutritionally related (possibly - it's just an observational study, but it is interesting).  Prenatal Vitamins, One-carbon Metabolism Gene Variants and Risk for Autism.

So, the intro - Prevalence in the US is about 1 in 110 children and may be rising (a recent Yale study in South Korea study suggests autism affects 1 in 38 children there).  It is widely accepted that genetic risk underlies the disorder, but there are also definitely interactions with environmental factors.  The recent study showing increased risk of autism in short intervals between pregnancies could implicate nutritional factors.  Valproic Acid (depakote) which disrupts folate metabolism is a known cause of autism and neural tube defects.

Other literature suggest that some children with autism have altered B vitamin metabolism and a reduced ability to methylate things.   So in this brand new study, the researchers specifically looked at vitamin supplement intake.  Children with autism in California were identified as part of large, population-based, case-control CHARGE study.  Their mothers were asked in telephone interviews whether they consumed prenatal vitamins, multivitamins, fortified cereals, and other supplements in the period 3 months before conception, and then during pregnancy and breastfeeding.  If they answered yes, they were asked specifically what vitamins and brands were consumed.

Interesting results ensued - 97% of mothers of the normal controls and 96% of mothers of the children with autism reported taking prenatal vitamins.  However, mothers who took the vitamins in the 3 months before conception and in the first month of pregnancy were significantly less likely to have autistic children than those who didn't.  There was no difference between vitamin and non-vitamin takers in months 2-9 of pregnancy or later.  The findings were controlled for various confounders, such as mom's education, race, whether conception was intentional or not, year of birth, etc.

Even more interesting - use of regular multivitamins in lieu of the prenatals was not associated with decreased risk of autism compared to taking no vitamins.  The major difference between most prenatal vitamins and regular multis is a doubling of folic acid.  The government says the synthetic folic acid is the same as the folate in food - Chris Kresser notes here that conversion from synthetic folic acid to the active tetrahydrofolate is poor in humans, and while synthetic folic acid pretty definitely reduces risk of neural tube defects, it also likely increases the risk of cancer - these kinds of population risks are a tough call.  If you are trying to get pregnant and you aren't always sure you are getting a lot of folate from foods, it may well be worth the risk to take synthetic folic acid for the periconception period.  Well, that's something to chew on.

The researchers in this study also checked genetics, finding that children with methylation issues (related to the folate cycle) were also more likely to have autism.  Maternal periconceptual folic acid seems to increase methylation in specific gene regions in the child (1), which can have epigenetic effects that can affect a child throughout life.

Get nutrients from food whenever possible, but there are certain circumstances in which wise supplementation may be very important.   And for public health recommendations (assuming the SAD) - supplementation for women trying to become pregnant seems wise, and when one reviews IOM and other reports, one often sees a fair accounting of the risks involved.  In fact, that is often why IOM or other recommendations seem quite conservative.   The questions continue!

14 comments:

  1. Take a look at leninger biomchemisty methyl transfer paths.......the answer to many hidden mysteries lie in that one liver detox path. I have spent years looking deeply at DNa methylation and hypermethylation and DNA/RNA interactions. The most common cause of death in psychiatric ilness is In anorexia nervosa.............and methylation is critical here as well. Most disease we treat we can prevent if we change the waymwe perceive the problem. Dr. K

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  2. Excellent overview of the current crop of autism related research literature. The MIND Institute paper on vits and SNPs, whilst not necessarily applicable to all cases, it perhaps the first study to show the 'gene-environment' interaction at work and provides a template for all. Perhaps also worth mentioning about the COMT findings in this paper and how an old friend, homocysteine (homocystine also) might show some involvement. Bravo!

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  3. Dr. K - Yes, that is a killer comment. Because when one looks at the genetics and mthylation, we really start lumping. Grossly speaking, genetics and some of this pathology bring together autism, schizophrenia, and possibly some kinds of dementia (and forms of bipolar disorder, which always has overlapped genetically and morphologically with schizophrenia) as a similar pathology striking at different ages, and due to the stage of brain development, having different symptoms. Then you have depression and anxiety, which have always overlapped with respect to genetics, presentation, and treatment. Then you have eating disorders and addictive disorders which also overlap with each other. There are some outliers and of course we are making some generalizations, but for the most part we have now swept up a lot of psychiatric disorders.

    Methylation - vital for making neurotransmitters, clearing homocysteine, vital for epigenetics, turning genes on and off. I hear this all the time - "autism is a disease of improper methylation."

    Paul - I was off to the playground before I could get very deep into the second part of that paper - I will revisit because it is important. Both pathologies are key - the methylation issues and the derangements in cortical patterning - and Dr. K suggests they are connected, the autism researchers, at least, know they are connected.

    Steve Parker made a comment on the blog after one of the homocysteine posts about connections between metabolic syndrome and bipolar disorder, schizophrenia.

    Folate cycle. Like Indiana Jones: "It had to be the folate cycle."

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  4. Great post Dr. Deans. The terminology for folate is really weird. In almost all of chemistry, the -ic acid and -ate can be used almost interchangeably, but in the case of folate, "folic acid" refers more specifically to the synthetic version that is not found in food.

    I saw a presentation once by grad student at Tufts who found that in the NHANES data, unmetabolized "folic acid" in human blood was very rare before they started mandating supplementation of bread flour with it, but after they mandated the supplementation, it became very common.

    So prenatal vitamins are indeed a source of "folic acid," but fortified refined bread is probably the major source right now.

    Chris

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  5. There appear to be many connections between gluten and schizophrenia and autism disorders. It would be interesting to see if there is a connection between gluten consumption and the methylation issues you spoke about in this post. I can only speak for myself, but every issue I have with gluten is neurological - migraines, brain fog, nerve pain, vision disturbances - all of which went away with removal of gluten from my diet three years ago. I would love to see you explore this area more and the connection, if any, to what you've posted. The work of Dr. Hadjivassiliou (lancet article) is especially interesting. http://www.ncbi.nlm.nih.gov/pubmed/16423158
    http://www.nutritionandmetabolism.com/content/6/1/10
    http://people.emich.edu/jtodd/whiteley_et_al_1999.pdf
    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)90540-1/abstract

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  6. Emily......the root cause of what you as a psychiatrist treat and what I as a neurosurgeon treat are one and the same. The only difference is the continuum in which we find our selves interacting with the patient. This is also is precisely what makes us different from Chris Masterjohn and Stephen Guyenet. I am also glad to see you jumping into epigenetics. I can not wait til you read my document. I think you and I think much a like but we tackle issues from different points of view. I really enjoy reading your stuff more than any other. I have been stimulated to look at things because of what you wrote and reconsider my thoughts on things. I thank you for making me a better thinker and better physician for it. Dr. K

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  7. Dr K - I listened to your podcast last night, and it contributed to my thinking on the next post. You are a couple of years ahead of me in your thinking and your insights are extraordinarily valuable. My only advantage is that the field of psychiatry requires such a holistic view to be effective that I've had to be trained to think this way from the beginning.

    Laurie D- thank you for the links! Wheat is my nemesis, in that it is suspected in so much and the direct evidence is so limited...

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  8. Just thought that this recent article might be a good read for the 'epigenetics' and methylation part of things: http://www.ncbi.nlm.nih.gov/pubmed/21617367
    Also, I would agree with Laurie D on Mario Hadjivassiliou and his partners (Dave Sanders et al) whose work starting at Sheffield Hallamshire hospital (love that place!) on the neurological presentation of gluten sensitivity has been unfortunately almost lost in the mist.

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  9. Thanks Paul! I've downloaded the article and will peruse it when I have some leisure...

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  10. Great article, Emily. If someone is trying to get pregnant or is already pregnant, I recommend supplementing with 5-methyltetrahydrofolate. There are multis now from companies like Pure Encapsulations (Nutrient 950), Thorne, Pro-Thera/Klaire and Designs for Health that use tetrahydrofolates instead of folic acid. They're usually not available in stores, but can be purchased online.

    Thanks for shedding more light on this important issue.

    As a side note, I'd say 40-50% of my patients have compromised methylation d/t B12 or folate deficiency or impaired liver detoxification pathways.

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  11. Today I found this ebook, it seems to be hanging on an ftp:
    Cellular and Mollecular Biology of Autism Spectrum Disorders

    Looks like a decent review of studies on the subject.

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  12. This is laughable
    Popular Autism Diet Does Not Demonstrate Behavioral Improvement

    First they exclude celiacs from the study, put the kids on a few weeks GFCF diet. After that they feed them gluten or casein and after that

    "Parents, teachers and a research assistant filled out standardized surveys about the child’s behavior the day before they received the snack, at two and 24 hours after the snack. (If the child’s behavior wasn’t usual at the scheduled snack time, the snack would be postponed until the child was back to baseline.) In addition, the parents kept a standard diary of food intake, sleep and bowel habits. Social interaction and language were evaluated through videotaped scoring of a standardized play session with a research assistant.

    Following the gluten and casein snacks, study participants had no change in attention, activity, sleep or frequency or quality of bowel habits."

    What did they expect? Gluten is not heroin, you will not turn 180 degrees afer you ingest it. Looks like totally wasted money.

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  13. ... this leaves me speechless. The wikipedia article on gluten exorphins states that

    clinical studies of autism patients who followed this diet /GFCF/ have found no evidence of benefit,[2][3] and the diet may even present a greater risk to brain development.[4]

    ... three studies, one of them the crap from my previous post here, [3] is a review stating that all studies thus far reported REDUCING in some autism symptoms and [4] reports "high rate of tryptophan and tyrosine deficiency" - how does this finding dovetails with the fact that both wheat and milk are quite mediocre sources of both amino acids?

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  14. Dr. K- I'm a post-doc trying to write a grant on this right now (methylation and rna in anorexia). Your ideas are brilliant. If you have time, I would love to chat. green_flash11@yahoo.com

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