Environmental risk factors for autism: Do they help cause de novo genetic mutations that contribute to the disorder?

[ema-adama]

: Med Hypotheses. (javascript:AL_get(this,%20'jour',%20'Med%20Hypoth eses.');) 2009 Aug 20. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048&itool=AbstractPlus-def&uid=19699591&nlmid=7505668&db=pubmed&url=http://linkinghub.elsevier.com/retrieve/pii/S0306-9877%2809%2900530-1) Links (javascript:PopUpMenu2_Set(Menu19699591);)
Environmental risk factors for autism: Do they help cause de novo genetic mutations that contribute to the disorder?

Kinney DK (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kinney%20DK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Barch DH (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Barch%20DH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Chayka B (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chayka%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Napoleon S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Napoleon%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Munir KM (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Munir%20KM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Genetics Laboratory, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors - mercury, cadmium, nickel, trichloroethylene, and vinyl chloride - are established mutagens. Another four - including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation - are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress - a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism - and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches - which we suggest - to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.
PMID: 19699591 [PubMed - as supplied by publisher


So how best to avoid mercury, cadmium, nickel, trichloroethylene, and vinyl chloride?

[Momtezuma Tuatara]

Is this not blindingly obvious? After all, LACK of folic acid, causes de novo genetic mutations in utero, which lead to neural tube defects, which obviously cause flow down effects for the rest of life. A baby is simply continuing that process quickly to begin with, until late puberty. Adults more moderately so until, one way or another, dying at the age of 90 or earlier.

I would suggest that the vitamin D deficiency, and the other macro and micronutrients come first in terms of research, because it's upon that platform, or the lack of, that known mutagens are either least effective or most effective at "causing" damage.

Some could argue that one of the most important minerals in utero to look at, is actually zinc, since it's fundamental to so many processes... but then, others could argue the same with magnesium, calcium, phosphorus balance,,... copper... and so it goes on.

Until all the fundamentals are know, the peripherals will never be understood.

IMO, it's the fundamental integrity or lack of, which explain why not everyone keels over from exposure to known mutagens.

[ema-adama]

(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Med%20Hypot heses.%27%29;)Med Hypotheses. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Med%20Hypot heses.%27%29;) 2008 Sep;71(3):406-10. Epub 2008 Jun 2. Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu18514430%29;)
Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.

Rogers EJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rogers%20EJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
University of Massachusetts Lowell, Clinical Laboratory and Nutritional Sciences, Lowell, MA 01854, United States. Eugene_Rogers@uml.edu
The inverse association between maternal folate status and incidence of infants born with neural tube defects (NTD's) was recognized over twenty years ago and led the US health agencies in the early 1990s to recommend that women of childbearing age consume 400 microg of folic acid each day. The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's. However, this same time period directly coincides with what many feel is the apparent beginning and continuous increase in the prevalence of Autism and related Autism Spectrum Disorders (ASD's) in the US. Are these similar time frames of changes in maternal folate status and possible Autism prevalence a random event or has improved maternal (and fetal) folate status during pregnancy played a role? It is not only plausible but highly likely. A particular polymorphic form to a key enzyme required to activate folate for methylation in neurodevelopment, 5-methylenetetrahydrofolate reductase (MTHFR), demonstrates reduced activity under low or normal folate levels but normal activity under conditions of higher folate nutritional status. A consequence of the presence of the polymorphic form of this enzyme during normal or reduced folate status are higher plasma homocysteine levels than noncarriers and the combination of these factors have been shown in several studies to result in an increase rate of miscarriage via thrombotic events. However, the incidence of hyperhomocysteinemia in the presence of the polymorphism is reduced under the common condition of enhanced folate status and thereby masks the latent adverse effects of the presence of this enzyme form during pregnancy. Of great importance is that this polymorphism, although common in the normal population, is found in significantly higher frequency in Autisic individuals. It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates. This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period. If these numbers have increased then so have the absolute number of infants that after birth fail to maintain the higher folate status experienced in utero thus leading to an increased number of cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well as other methionine cycle enzymes related to folate metabolism and methylation at birth as part of newborn screening programs could determine which newborns need be monitored and maintained on diets or supplements that ensure adequate folate status during this critical postnatal neurodevelopment period.


Your mentioning of folic acid made me think of this article..... and interesting potential problem as a result of across the board folic acid supplementation.

I wonder about vit D as well. I would be surprised if the vit D drops prescribed in the ped's office, laced with sweetners, is the answer to meeting baby and children's vit D needs. I am sure vit D from the sun is superior - I just don't know how superior yet. Or is it just that the body can modulate how much it actually needs?

[Momtezuma Tuatara]

There is a critical key here, though, that they are missing. They say:
The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's.

When you look at neural tube defects they occur in about one in how many thousand? Before fortification?

Folic acid is hard to get high levels of in "natural" eating, because in nature, folic acid comes hand in hand with other nutrients, which balance out, and adjust what is necessary at the time.

folic acid supplements, for instance, in white denatured bread, simply exacerbate the problem in my opinion.

How can any thinking scientist say that increasing one substance without taking into account, the natural balancing, the co-enzymes required, and everything else, would possible be all roses? I took folic acid in both my pregnancies, at higher rates than probably was advised. But I knew my own nutritional background, and had a very wide variety of foods.

Today, I watch pregnant women pigging out of junk and popping the supplement, because... that's all they need to do, isn't it?

It is logical to me, that something done in isolation in the wrong way, in the absense of natural partners, has as much chance to backfire than anything else.

HOWEVER, most of the people I know with autistic children never took folic acid, and many of them wouldn't know it existed.

So instead of talking about this in a time relation issue, you'd have to look at the actual children

the hypothesis above is akin to saying that the fact that TV became a regular feature in household, at the same time as polio, is a very plausible and highly likely cause of the decline in polio.

He could be right, but he could be wrong. What is needed to prove that isn't conjecture, but scientifically accurate proof. That is done IMO by large studies of autistic children, not a seeming temporal time coincidence.

with vitamin D, the body modulates how much it actually needs. for me, sun is superior, but if you just can't get out in the sun for a while, cholecalciferol sure is a better option than a deficiency.

[TanyaL]

So how best to avoid mercury, cadmium, nickel, trichloroethylene, and vinyl chloride?

Don't get amalgam fillings in your teeth to start with, and good nutrition to detoxify the metals and chemicals that you _do_ come in contact with. Although that's not a full explanation, because some people, even with sub-optimal nutrition, cope with their amalgams just fine, and some of us don't. But once you have some sort of exposure that you can't deal with, at whatever level it takes, detoxification problems cascade and those other chemicals build up.

I like this site as a good read of how detox pathways work, and the various nutrients involved...
http://www.tuberose.com/Liver_Detoxification.html

It's not short, I've had to go back and re-read many times.

As for vitamin D, healthy people can maybe manage with sun and food, depending on skin tone and locale, but once you start down the unhealthy path, getting back to right is difficult. Vitamin D deficiency seems to cause problems in and of itself, but I wonder if in some circumstances it's more an indicator that something more global is amiss. I mean--if you live in New York in the US, fairly far north, it wouldn't be as useful, but educated guesswork says I was pretty low before I started supplementing this year, and I'm white, fairly pale, and I live in Texas, a sunny environment.

[TanyaL]

Of great importance is that this polymorphism, although common in the normal population, is found in significantly higher frequency in Autisic individuals. It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates. This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period.

I missed this part earlier. To me, it looks like they're asking the wrong question and looking at the folic acid / folate issue poorly.

The C677T polymorphism is involved in converting folic acid to active folate (5mthf), or rather, it does a a poorer job than the most common form of the gene. Food has real folate, some as 5mthf and some as folinic acid, but it's not folic acid, and some of the people who most need more folate aren't benefitting from the food fortification program. Adding folic acid to the food supply isn't helping these people, and arguably having extra folic acid (not active folate) floating around in their bodies has negative effects.


It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates.

This sentence, in particular, boggles my mind. I can't even write a coherent sentence to evaluate it.

Consumption of folate in the US is particularly low, and any reasonable comparison to long-term historical consumption would imply that, at best, for people that convert folic acid well, it's just bumping folate status back to something historically more appropriate. Best I remember, average folate intake in the US is around 250mcg vs an estimated 400mcg needed. But before the massive variety of processed foods and pounds of sugar were available, when people were eating fewer processed foods and more vegetables (and chicken liver :cool:), it wouldn't be that hard to get 400mcg. Getting 800mcg, the estimate I've seen for people who are homozygous for either of the two polymorphisms would be harder, and take planning, but it still seems possible.

Somehow the C677T polymorphism exists at a reasonable level in the population (I've seen estimates in the range of 30-50% of people having one copy of either C677T or A1298), and it's only now, with horrible eating habits and supplemental folic acid that we're creating autistic kids instead of them dying in miscarriage (and thus not being around to reproduce)?

[ema-adama]

Tanya, thanks so much for your post

This was such an important study for me to find - as it gave me the impetus to look at all the various ways our immediate environment and our bodies are being polluted. It was such an eye opener just how toxic everything around me is. I knew it was a good idea to stay away from packaged foods, plastics, regular cosmetics, cleaning products, medications etc. I guess this just cemented my conviction that this is true for chidbearing women and their families.

I also found the whole folate tounge tie connection, which is also grabbed my attention.

I am working with the idea that I can manage living in a toxic environment to a certain extent through diet and choices I make in our home about cleaning products and furniture/utensils/kicthen tools etc. And I am hoping that nutrition will be the key to managing it - I am guessing yes, in a TF sense.

I do have amalgams. Although, for now they are there to stay. No new ones will be added.

Again, thanks for posting. I have also learnt a lot from your posts at MDC This is a most facinating journey to be on.

[Momtezuma Tuatara]

this is an interesting read.