The Los Angeles Times produced a series of articles called “Discovering Autism”. The series is in four parts and represents was researched for years. The articles are:
Autism boom: an epidemic of disease or of discovery?
Autism rates have increased twentyfold in a generation, stirring parents’ deepest fears and prompting a search for answers. But what if the upsurge is not what it appears to be?
Warrior parents fare best in securing autism services
Public spending on children with autism in California varies greatly by race and class. A major reason: Not all families have the means to battle for coveted assistance.
Families cling to hope of autism ‘recovery’
An autism treatment called applied behavior analysis, or ABA, has wide support and has grown into a profitable business. It has its limits, though, and there are gaps in the science.
Autism hidden in plain sight
As more children are diagnosed with autism, researchers are trying to find unrecognized cases of the disorder in adults. The search for the missing millions is just beginning.
The first article brought a great deal of criticism, from many quarters. As you can imagine challenging the way the “autism epidemic” is viewed is not welcomed by those promoting vaccines as a primary cause of autism. This article also brought out at least one commenter who asserted that the rise in autism diagnoses is driven by people seeking social security payments (SSI), which goes to show that readers tend to bring their own preconceptions to what they read.
Interest in the online discussion of the series dropped off dramatically after day one.
Autism boom: an epidemic of disease or of discovery? looked at the rise in autism diagnoses observed in many places. Writer Alan Zarembo points out quite rightly that autism rates vary dramatically by school district in California, as well as state to state.
Such variability of autism rates across geography speak strongly against the idea of a single cause, such as vaccines. Autism Diva wrote about the strong variation by regional center district within California years ago (her piece is not up, but this article from LBRB discusses her article)
The variation by school district and by race/ethnicity was a major factor in helping me see that the vaccine-epidemic of autism did not make sense, back when I first started to read up on autism.
The LA Times quotes Prof. Peter Bearman of Columbia University, who studied the California Department of Developmental Services data closely and showed, amongst other things, that a large autism “cluster” existed in Southern California. The Times notes that similar clusters were found by U.C. Davis Professor Irva Hertz-Picciotto. (I was present when Autism Diva discussed the regional center graph with Prof. Hertz-Picciotto, by the way).
Prof. Bearman also showed that social forces were at work–awareness, if you will–which has aided the increase in autism diagnoses.
In other words, autism is not contagious, but the diagnosis is.
“`Is it real or not?’ is a meaningless question,” Bearman said of the surge in cases. “The sociological processes are as real as the biological processes.”
A diagnostician (neurologist) is quoted in the Times:
Dr. Nancy Niparko, a child neurologist in Beverly Hills, said that whether she identifies a child as autistic can come down to whether she believes it will do any good.
“If it’s going to improve the possibility of getting services that will be helpful, I will give the label,” she said.
“I don’t work for labels. Labels work for me.”
In Warrior parents fare best in securing autism services makes the point that it takes work, hard work, to get the services that a child may need. An autism diagnosis is not a ticket to services, it is a first step. Parents who fight harder and longer tend to get higher levels of services for their children.
The Times points out that within a single district (albeit one of the largest in the U.S., Los Angeles Unified), the fraction of students with 1:1 aides varies by geography and race/ethnicity:
District officials acknowledge that advocacy efforts make a big difference in who gets services, but see things differently than parents on the value of 1:1 aides:
L.A. Unified officials offered a similar explanation for the disparity. As parents successfully lobbied for outside aides, the idea spread, and in certain schools it became standard practice to offer them.
“Parents learned from each other,” said Nancy Franklin, a top special education administrator. “It became a cottage industry in LAUSD.”
The district is trying to break the pattern by persuading parents that its own staff can meet children’s needs in many cases.
“We’re paying lots of money for services that are of questionable value,” said Eileen Skone-Rees, who oversees the district’s contracts with companies that supply one-on-one aides.
In Families cling to hope of autism ‘recovery’, the Times focuses on ABA. Biomedical approaches are not really discussed.
The article talks about ABA from the early work of Ivar Lovaas to the present day, where it is common in some school districts and regional centers. The high costs and the level of research support are discussed along with examples of children who are success stories and those who are not.
In Autism hidden in plain sight, the Times looks at how autism is often missed in adults.
The Times presents an intriguing look at the past in medical records from a child diagnosed by Leo Kanner (whose work coined the term “autism”).
The times provided a number of slide show vignettes of people they interviewed.
I can’t link to them directly, but I’ve watched a few and enjoyed them. Jeane Duquet, autistic adult diagnosed at age 39 (right side, middle). Jesse Castillo, age 11 (bottom right corner)
The author of the series, as well as Catherine Lord were interviewed by NPR:
http://www.npr.org/v2/?i=144022386&m=144022377&t=audiowidth=”400″ height=”446″ />
I would certainly have done some things differently had I written the series. I would have chosen different wording, for example. Yes, the pieces brought out some less than pleasant perspectives. I’ve read a few complaints about the series, from not supporting vaccine causation or biomedical approaches to presenting autism as a costly burden. Ironically, these complaints come from the same people who repeatedly say that “autism costs society $3.5 million per individual”. A big piece of that $3.5M is ABA and if we as a community (or part of the community) are to defend the need for ABA, we have to accept that there is a cost. I believe, and I commented, that the choice of language at times put a negative slant where one was not needed. However, the series put some very good information out, including: 1) the “epidemic” has a large portion which is driven by social factors, with a much smaller part that may be a real change in the number of autistics, 2) services are not handed out on a silver platter. Parents and autistics have to fight for what supports the law says they should get, 3) 1:1 therapies such as ABA may be effective, but they are expensive and the research behind them is still incomplete and 4) adult autistics are out there in greater numbers than is currently reported.
The biggest complaint about the series is that it portrays parents as seeking diagnoses for their kids for some sort of financial gain. Dr. Jay Gordon (a major promoter of the vaccine-epidemic idea) has noted this where Mr. Zarembo has been interviewed (http://www.scpr.org/programs/patt-morrison/2011/12/22/21866/autism-diagnoses-spike-an-epidemic-in-the-making). Mr. Zarembo makes it clear in the interview that this is not his point. That the autism diagnosis “opens the door” and that parents are doing what they should for their children–including fighting hard to obtain appropriate services once the door is opened.
For those complaining that the LA Times series didn’t cover the vaccine-epidemic idea or biomedical approaches to autism: I’d recommend you be thankful. Quite frankly an evidence driven newspaper series on these issues will not go the way you want.
Left Brain Right Brain 
For those interested:
The $3.2 million figure is an estimate from this 2007 paper by Ganz
http://archpedi.ama-assn.org/cgi/reprint/161/4/343
Discussed at: Michelle Dawson,”Revisiting the Costs of Autism” “http://autismcrisis.blogspot.com/2009/02/revisiting-costs-of-autism.html
and
Joseph, Natural Variation: “Debunking the Costs of Autism” http://autismnaturalvariation.blogspot.com/2006/11/debunking-costs-of-autism.html.
In a comment at the former, Mike Stanton wrote:
CDC Source Source: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5532a5.htm.
To the best of my knowledge there have been no follow-up estimates or calculations.
While increased awareness of the condition, broadening diagnostic criteria and sociological factors all contribute to the 20 fold increase in autism incidence, there may also be an important environmental factor.
Two drugs taken in pregnancy are known to be associated with an increased incidence of autism in offspring. These are valproate and thalidomide http://www.ncbi.nlm.nih.gov/pubmed/21388746 The action of both drugs is at the GABA(A) receptor.
Environmental chemicals which have been similarly implicated include insecticides http://www.ncbi.nlm.nih.gov/pubmed/17938740 phthalates http://www.ncbi.nlm.nih.gov/pubmed/19822263 and mercury http://www.ncbi.nlm.nih.gov/pubmed/19106436 All of these chemicals inhibit GABA(A) receptor transmission.
Folic acid is also a GABA(A) receptor antagonist. Pregnant women are advised to take as much as 800ug daily of this unnatural chemical, which is converted to the natural vitamin, folate, in the body. The efficiency of the conversion process varies greatly between individuals, with a fivefold difference between the most and least efficient converters http://www.ncbi.nlm.nhi.gov/pubmed/19706381
In people with autism, there is evidence of folate receptor blocking antibodies http://www.ncbi.nlm.nih.gov/pubmed/18461502 and variants of enzymes involved in folic acid and folate metabolism http://www.ncbi.nlm.nih.gov/pubmed/19440165 There is also clear evidence of GABAergic Purkinje cell loss http://www.ncbi.nlm.nih.gov/pubmed/9593803 and reduced numbers of GABA(A) receptors http://www.ncbi.nlm.nih.gov/pubmed/18821008
I believe that folic acid and other chemicals which disrupt GABA(A) receptor function in the developing fetus are contributing to the increased incidence of autism. More information about how this causes autism can be found on my blog:
http://www.nfkbdiseases.wordpress.com
William Davidson:
I am curious why you begin your discussion of environmental factors in autism with thalidomide, a drug that was never approved for use by pregnant women in the USA, and has been contraindicated for pregnant women everywhere for over 50 years. How could that drug possibly have any effect on the increase in autism diagnoses of children born in the last two decades?
Frankly, your opening with that damages your credibility to the point that I’m not interested in checking out the rest of your links.
However, unfortunately I did read the rest of your comment, and tried to look at some of your links, including the one on folate. The link didn’t actually go anywhere. As a result, I cannot comprehend why you are making a big deal about the distinction between “folic acid” and “folate.” Do you have any idea how the two of those differ? It’s not as much as you’re trying to imply. The suffix “ate” in place of the suffix “ic” and the word “acid” is how we designate when an acid happens to be in salt form, with its acidic proton in solution, rather than bound to the rest of the molecule. This is what normally happens to acids in solution (including in blood and other bodily fluids. It’s what makes an acid an acid: the proton goes into the solution, and the rest of the molecule is an anion (negatively charged).
Physiological pH (what’s normal for blood) is 7.35 – just a hair more basic than neutral. At this pH, acidic protons are in solution, and the molecules which donated them to the solution exists as the salt form. Hence, folic acid becomes folate. It just happens – completely naturally.
But I did dig your reference out of PubMed, and read the abstract. From this, I gathered what was investigated was individual variability in reducing the heterocyclic portion of folic acid/folate to the active form of the coenzyme tetrahydrofolate, via the enzyme dihydrofolate reductase (DHFR). This enzyme has nothing to do with whether your initial intake of folate was as the acid or the salt form since it by the time the folic acid found the enzyme, the pH of the bloodsteam had long since converted it to salt form (folate).
And I’m honestly baffled why you might think that this has an effect on GABA receptors, since “GABA” is gamma butyric acid, a small molecule which has absolutely no structural relationship to the heterocycle that gets reduced to tetrahydrofolate discussed above. And I’m not inclined to follow any more of your links because nothing you’ve presented so far suggested you have any understanding of science at all.
And even if supplemental folic acid does contribute to an increased risk of autism, how does that risk weigh against the demonstrated decrease of neural tube defects and cleft palate?
In both my case,and in the studies by Jill James,you will find that both the mothers,and the autistic children,have problems with folate metabolism.Polymorphisms,or mutations of MTHFR,and MTRR,such as my mother and I both have,are common.
So it isn’t a case of the children getting too much folic acid,it’s a case of both the mother,and child being unable to utilize what they have,In such families,there is often a history of both cleft palate,and stllbirths on the mother’s side,as there is in my mother’s family.Both stillbirths and cleft palate,are due to both outright deficiencies,or inefficient metabolism of folate.
I am one of the few adults on the spectrum,who has spent a great deal of time learning about the medical problems I have,and their causes.I have serious problems with folate,and B12 metabolism.I have had severe anemia since I was in high school.I had problems with puberty,and muscle development,due in large part,to not getting enough folate during puberty.Once my problems were found,I was able to get treatment for my mother’s anemia as well.
Far too rarely is autism looked at in the context of the complete family medical history.
There is a subpopulation of autistics,like myself,who have both
MTHFR/MTRR polymorphisms or mutations,and COMT polymorphisms as well.COMT polymorphisms,are a key marker for 22q11.2 deletion,which I am trying to get tested for.Autism is now well documented in 22q.I believe their is a whole population of autistcs,who have an undiagnosed 22q deletion,where the genes for a cleft,has been expressed as folate metabolism defects instead.
Chemmomo,
It’s difficult to know where to start with a reply to all of that. You appear to misunderstand much of what I was saying.You wrongly assume I’m implying that thalidomide is contributing to the autism epidemic. I said no such thing. I said that autism was associated with thalidomide during pregnancy. Thalidomide’s therapeutic action is at the GABA(A) receptor. I am presenting a body of evidence to show that disruption of GABAergic transmission is key to what is going wrong in autism. Therefore, thalidomide is relevant. By the way, I stipulated GABA(A) throughout my post, but the (A) appears to have been deleted for some reason.
The significance of folic acid is that it binds to the GABA(A) receptor as an antagonist more strongly than folate http://www.ncbi.nlm.nih.gov/pubmed/2166659 However, I’m sure that if pregnant women were given 800ug daily of folate, this would also result in an increase in autism. I’m not sure what it is that you’re ‘absolutely baffled’ about, quite frankly. What part of ‘folic acid binds to the GABA(A) receptor as an antagonist’ is it that you don’t understand? Folic acid causes epilepsy in predisposed individuals in high doses, an effect mediated through the GABA(A) receptor.
You say folic acid converts naturally to folate and does not require an enzyme. My own understanding is that it requires the enzyme, dihydrofolate reductase, and that the efficiency of the conversion process varies greatly between individuals. However, this would merely be an additional predisposing factor. It is not key. Whether or not the conversion is enzymatic or non-enzymatic, there is still an abnormally large amount of folic acid and folate in circulatiom. That is key. Are you aware of the truism that ‘the poison is the dose’?
I’ll try again, this time with spaces. G A B A (A) receptor.
Here is a replacement for the broken link above http://www.ncbi.nlm.nih.gov/pubmed/19706381
From the abstract:
‘Folic acid is a synthetic oxidized form not significantly found in fresh natural foods; to be used it must be converted to tetrahydrofolate by dihydrofolate reductase’.
William Davidson:
Folate and folic acid interconvert in any aqueous solution through a process known as dissociation; with pKa’s of 4.7 and 6.8, folic acid would be predominately in the “folate” state at physiological pH. No enzyme is required.
Folic acid/folate (no matter the source) is not physiologically active – the active compounds are tetrahydrofolate (THF) and methyl-tetrahydrofolate (methyl-THF). The enzyme Mr. Davidson references – dihydrofolate reductase – converts dihydrofolate (DHF) to tetrahydrofolate (THF). The predominate form of folate inside the cell (a reducing environment except in the mitochondria) is THF/methyl-THF, but these compounds are not stable in air or even within the gut, so even when we eat fresh leafy greens, what we absorb in our guts is largely the oxidised folate.
While folic acid is, indeed, an “oxidised” form of THF and DHF, it is “synthetic” only in the sense that it is “synthesised” by bacteria. Humans (and most eukaryotes) cannot make folic acid; we get it either from bacteria or from plants and animals that have assimilated folate from bacteria. Storing THF or DHF for any length of time in air (or during the process of digestion) will oxidise them to folic acid, which is why we have the enzymes to reduce folic acid to DHF and THF.
Certain mutations of the gene for the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with autism, presumably due to defects in DNA methylation, but this has little to do with folate intake or whether the source is “natural” or “synthesised”.
I’d recommend that Mr. Davidson do some more careful reading and possible even enroll in some courses in biology and chemistry.
Prometheus
Well, thanks for that. If that’s the case (and I don’t doubt you), the scientists who submitted the PubMed article need to do more reading, too.
Anyway, this discussion about the relative properties of folate and folic acid is largely academic. BOTH are epileptogenic at high doses, but folic acid more so. That makes them both neurotoxins at high doses and the neurotoxicicity is mediated through GABA (A) receptor antagonism. A daily dose of 800ug of either is an unnaturally high dose. There are many indicators of dysregulated GABAergic functioning in autism, and the fact that thalidomide exerts its horrific developmental effects through the same GABA (A) receptor, and that taking thalidomide during pregnancy increases the risk of autism, I regard as significant.
I’ve a feeling that there are probably other, perhaps many other, environmental chemicals, which have a ‘modulating’ effect at the GABA (A)receptor. These include bisphenol A and metals such as zinc, which is increasingly being used to fortify foods, particularly breakfast cereals. Some perfumes are also known to be GABA(A) modulators.
So, it’s probably a ‘cocktail’ of chemicals, and although I believe that folic acid is the most important, it’s just one of many.
That Prometheus dude is wrong.
And I would also suggest that you look into the studies on FOLINIC acid and autism, and also the study of high-dose (very high dose) folinic acid and CFS. No reports of epileptic seizures. In fact, folinic seems to be calming in many…
I doubt that Prometheus is going to come back an do what you say after three years. Though if you were actually serious you would have actually included the PMIDs of those studies.
A good place to start with regards to autism,folate,and glutamate,is Joseph Galanko and Jill James’ 2004 study,that got me interested in it all in the first place.
http://www.jpands.org/vol9no4/boris.pdf
Dr. James’ 2006 lecture here
http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_special.html
Explains a lot,and explains it much better.Every lecture here is worth watching to anyone for anybody at all interested in develomental disabilities.
Mr. Kulp, the Journal of Physicians and Surgeons is not well respected around here, especially their papers addressing autism. With a bit of looking, we see that Dr. Boris uses discredited “treatments” for autism including chelation and HBOT, as do the rest of the authors.
In the future stick to actual peer reviewed studies indexed at PubMed that have been replicated, and not those who have “novel” ideas away from the consensus.
Mr. Davidson:
Again, folic acid and folate are the same thing – one is ionised and the other is not. Any study that claims to find folic acid more epileptogenic than folate is obviously erroneous, since the amount of one compared to the other is completely dependent on pH.
I’m not sure where Mr. Davidson got this rather unique view of folate “neurotoxicity”, but he might want to look at Tremblay et al (1984) “A multidisciplinary study of folic acid neurotoxicity: interactions with kainate binding sites and relevance to the aetiology of epilepsy.”. While injecting folate into the brain tissue can induce seizures, it didn’t cause neurotoxicity.
I don’t pretend to be up-to-date on the literature pertaining to folic acid and seizures, but the recent literature seems to indicate that seizures from orally administered folic acid are extremely rare and that there is no evidence of neurotoxicity. In fact, it was much easier to find articles about how folic acid prevents or stops seizures.
Mr. Davidson seems to think that 800 micrograms (mcg) of folic acid a day is an extreme dose – it is, in fact, one of the “upper limit” (UL) values for folic acid intake in teens (14 – 18 yrs). The recommended dose of folic acid is 400 mcg/day for adults, 600 mcg/day for pregnant women.
I can’t help thinking that Mr. Davidson misread the article he cited (Bailey and Ayling 2009); to my reading, they found that the conversion of folate to DHF is a rate-limiting step in humans and can lead to accumulation of folate. I should point out that their human tissue samples were from surgical specimens and organ donation and may not have been as “fresh” as the rat livers they were compared to. Also, the “toxicity” of folate that the authors refer to is primarily colon cancer. I’m not sure how this relates to autism.
Prometheus
Hello friends –
Wasn’t there a study on folic acid supplementation which found generally protective effects?
Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism
I felt this was particularly neat because they found greater risk from not taking folic acid in women with genetic markers associated with folate metabolism (and autism).
Ultimately, I believe that biomarker based studies will answer this question with better precision than a retrospective survey model. I’d be very surprised if such a study wasn’t already underway.
– pD
Hi Chris –
In the future stick to actual peer reviewed studies indexed at PubMed that have been replicated, and not those who have “novel” ideas away from the consensus.
But the ideas in Boris, changes in the MTHFR and associated risk of autism have been been replicated. A lot.
The study I mentioned above:
Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism.
Significant interaction effects were observed for maternal MTHFR 677 TT, CBS rs234715 GT + TT, and child COMT 472 AA genotypes, with greater risk for autism when mothers did not report taking prenatal vitamins periconceptionally (4.5 [1.4-14.6]; 2.6 [1.2-5.4]; and 7.2 [2.3-22.4], respectively).
Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families
The results associate the MTHFR gene with autism in SPX families only, suggesting that reduced MTHFR activity is a risk factor for autism in these families.
The MTHFR 677C–>T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations
Exploratory results indicated four behaviors from the ADI-R that were more common and problematic (95% CI) among those with at least one copy of the T allele as compared to homozygous wild-type individuals: direct gaze, current complex body movements, a history of self-injurious behavior, and current overactivity (ORs=2.72, 2.33, 2.12, 2.47, respectively). No differences existed among genotypes for level of functioning as measured with the Peabody Picture Vocabulary Test-Third Edition, Ravens Colored Progressive Matrices, or the Vineland Adaptive Behavior Scales. Findings call for further investigation of the relationship between folate metabolism and problem behaviors among children with autism.
Aberrations in folate metabolic pathway and altered susceptibility to autism
MTHFR C677T is a risk factor, whereas MTRR A66G and SHMT C1420T polymorphisms reduce risk for autism. MTHFR A1298C acts additively in increasing the risk for autism
Where, on Earth, did you come up with the idea that these ideas are ‘away from the consensus’? In the future, you might want to have an idea of what the existing data actually says on a subject before declaring it ‘away from the consensus’.
Note that these studies were from searching for autism and MTHFR. Other biomarkers studies provide the same view of folate metabolism that you would expect from these genetic findings, evidence of abnormal function in the autism group.
– pD
http://www.neurodiversity.com/weblog/article/91/
Sometimes it is the company you keep that matters. I not pleased that JPandS has published papers that attempt to exonerate those who abuse children (Buttram made a career out of getting those who shook children, sometimes to their death, out of jail as a professional “expert”). There is no excuse for that.
And I checked Boris’ website, he still had silly stupid “treatments” for autism. I don’t care what he wrote if he thinks that either HBOT or chelation is effective.
Essentially, Scopie’s Law applies to JPandS: In any discussion involving science or medicine, citing Whale.to (or the Journal of American Physicians and Surgeons, JAPS…oops, sorry, JPandS) as a credible source loses you the argument immediately …and gets you laughed out of the room
And really, you are still trying to find out “how” vaccines cause autism when the epidemiological evidence shows no correlation. That is just ridiculous. What do I care about what you think about vaccines? Don’t answer that. I don’t care, though I do appreciate many of your other contributions about family and life in autism… just not on biochemistry. In short, stick to the stuff you do know, and it is not from the University of Google. You are a compassionate parent, but not a scientist.
No loving parent nor scientist would ever take the writings of anyone associated with the American Association of Physicians and Surgeons seriously. They are the antithesis of compassion, understanding and real science.
(oh, and the whole bit is just one tiny fraction of the whole spectrum of what happens in the human genome… it is not a consensus but just a tiny bit)
Interesting paper here which confirms that a polymorphism of dihydrofolate reductase results in higher levels of circulating folic acid at both high and low supplement intakes:
http://www.ncbi.nlm.nih.gov/pubmed/19022952
“The biggest complaint about the series is that it portrays parents as seeking diagnoses for their kids for some sort of financial gain.”
Why do you think parents complained?
“Why do you think parents complained?”
Because they felt the story was slanted in a way which it wasn’t. Listen to the interviews the author has given since. That’s not his message at all.
William Davidson,
You missed my point entirely. Maybe the disruption of GABA receptors is factor in the development of autism; maybe it’s not. My point was that the way you presented your hypothesis did not lead me to believe you understand much about the subject matter. You’ve demonstrated that you made factual errors in your interpretation of the literature because you don’t know much about chemistry.
Prometheus did a better job of explaining the very first and simplest error. I suggest you re-read his comment, and think about his closing, with which I agree: “I’d recommend that Mr. Davidson do some more careful reading and possible even enroll in some courses in biology and chemistry.”
Chemmomo
I think It was you that missed my point, initially. I’ve already posted a PubMed link which contradicts the assertion by both yourself and Prometheus, that conversion of folic acid by dihydrofolate reductase in the liver is unimportant. This enzyme is essential to keep circulating levels of folic acid down and polymorphisms exhibit reduced efficiency. I could find more papers on PubMed to confirm this, if you like. The fact that I’m unfamiliar with the minutiae of PH dependent non-enzymatic interconversion of folic acid and folate is irrelevant. I’m sure you’re unfamiliar with the subject of the minutiae of GABA (A) and GABA (B) receptor subunit variations and their ligands. Doesn’t make you an ignoramus.
Although I’m a non-scientist, I’ve spent the last 30 years studying the etiology of non-communicable diseases and put the results online in March 2010 in a paper titled ‘Integrative Theory of the Causation of Non-Communicable diseases: Immune Mimicry Disease (IMD) Theory’. It can be seen at http://www.imdtheory.blogspot.com and I’ve had some very positive e-mails from medical researchers about it.
The first half of the paper is a general exposition of the pathogenesis of non-communicable diseases and contains several interrelated novel hypotheses which explain how the dysregulated immune system functioning seen in non-communicable diseases such as the autoimmune diseases, psychiatric disorders, neurological disorders, metabolic syndrome disorders, as well as cancer, porphyria and many other diseases is being caused by aberrant activation of the transcription factor, nuclear factor kappa beta (NF-kB). The second half of the paper deals with the specific etiologies of schizophrenia, multiple sclerosis, cardiovascular disease, types 1 and 2 diabetes, porphyria, obesity, Alzheimer’s disease, cancer, autism and ADHD
This aberrant activation is caused by a combination of genetic and environmental factors. Genetic factors include immune system, receptor, metalloenzyme and transporter polymorphisms, with variants of the cytochrome P450 enzyme superfamily and the intracellular aryl hydrocarbon receptor being particularly implicated.
Environmental factors include lack of immune challenge in infancy (hygiene hypothesis), lack of vitamin D, exposure to environmental chemicals and metals, pro-inflammatory diet, food/chemical intolerance/sensitivity, lack of physical exercise and psychological stress.
One of the roles of NF-kB is the control of intracellular pathogens which establish latency within cells. These include the herpes family, Hepatitis C, mycobacteria (TB, leprosy), Borna virus, enteroviruses, Borrelia (Lyme disease), Toxoplasma gondii, human endogenous retroviruses, mycoplasma pneumonia, Chlamydia pneumonia, Helicobacter pylori and the JC virus.
These pathogens enter cells through cell membrane receptors. In many of the diseases I’ve mentioned, there is evidence of decreased expression and decreased sensitivity of receptors, and sometimes receptor blockade by antibodies. The receptors involved are often the ones known to be used by microbes to enter cells.
Examples of this are decreased expression and sensitivity of insulin receptors, decreased expression of acetylcholine and noradrenaline receptors in Alzheimer’s disease, decreased expression of serotonin 5-HT2A receptors in schizophrenia, antibody blockade of acetylcholine NACH receptor in myasthenia gravis, antibody blockade of thyroid stimulating hormone receptors in Graves’ disease and reduced numbers of GABA (A) receptors in autism.
My research concludes that the reduced expression, sensitivity and blockade of receptors by antibodies in diseases where aberrant activation of the NF-kB immune response is seen is a stratagem of that immune response to prevent cellular infection by these pathogens. Moreover, the aberrant NF-kB driven immune reaction, in the absence of infection, is being caused by two main factors 1) excessive production of intracellular reactive oxygen species (ROS) by metalloenzymes 2) Hyperstimulation and hypostimulation of cell membrane receptors.
Both of these factors mimic the downstream effects of NF-kB activation. ROS are produced to kill microbes and hypo/hyperstimulation of membrane receptors is a response to infection. Although the NF-kB response is essentially antiapoptic, chronic activation results in the death of the cell. In the case of autism, it’s the GABA (A) receptor which is being closed down. This receptor has a crucial involvement in early brain development and there is also evidence of GABAergic Purkinje cell loss.
The study of autism is therefore only a small part of my research. However, the conclusion of this research is that it is being caused by an aberrant NF-kB driven immune response which decreases GABA (A) receptor expression and kills GABAergic neurons and that an important contribution to the disease process is aberrant suppression of GABA (A) receptor transmission by environmental chemicals, leading to aberrant activation of the NF-kB driven immune response.
A much shorter synopsis of my main blog, specific to autism and ADHD, can be seen at http://www.nfkbdiseases.wordpress.com
Thalidomide is one of the few teratogens that is known to cause autism. So is valproate. It is perfectly appropriate to bring up thalidomide and valproate in the context of autism causation. Most autism is not caused by thalidomide or valproate, but that they do cause autism indicates that thalidomide, valproate and the other cause(s) of autism very likely share common pathways.
The idea that extra folate could cause autism is (IMO), not supported by what is well known about folate and autism physiology. Folate during pregnancy is probably protective against autism (at some level).
In mice, extra folate rescues valproate caused neural tube defects.
http://www.ncbi.nlm.nih.gov/pubmed/12692401
Folate rescues other causes of neural tube defects, including high temperature
http://www.ncbi.nlm.nih.gov/pubmed/10539786
Folate also rescues neural tube defects caused by exogenous nitric oxide.
Nitric oxide synthase activity is necessary for neural tube closure. There is a lot of cross-talk between nitric oxide pathways and folate pathways.
One of the physiological states associated with autism is hyperhomocysteinemia. This state is also associated with higher levels of asymmetric dimethyl arginine which is an endogenous nitric oxide synthase inhibitor. Thalidomide is a nitric oxide synthase inhibitor. Valproate inhibits angiogenesis which is largely mediated through nitric oxide.
Folate is used to treat hyperhomocysteinemia and also other disorders associated with insufficient NO, such as atherosclerosis.
The role of dihydrofolate reductase polymorphisms in disorders is likely due to insufficient tetrahydrofolate inside cells (where it is important), and not due to too much dihydrofolate in the blood stream (where it is not so important).
The deletion dihydrofolate reductase polymorphism causes increased incidence of neural tube defects, and very high levels of folate don’t cause neural tube defects.
Folic acid is considered pretty non-toxic, with people having consumed hundreds of mg per day with seemingly no ill effects.
http://www.ajcn.org/content/50/2/353.short
Anti-folate medications (methotrexate) potentiate the incidence of neural tube defects with valproate.
I think the idea that autism is caused by too much folate is extremely unlikely.
Homocysteine is a minor cause of disease resulting from aberrant NF-kB activation. It appears to act as an immune system cytokine and it contributes to calcium induced intracellular excitotoxicity, leading to apoptosis, by binding to the glutamate NMDA receptor as an antagonist.
It’s been shown to be a factor in several diseases, the best researched being atherosclerosis. Folic acid supplementation does improve hyperhomocystinemia, as you say. So, it’s not all bad news.
The fact remains that folic acid and, to a lesser extent, folate, are epileptogenic neurotoxins at high doses, and some individuals with a genetic predisposition to epilepsy, possibly as a result of GABA (A) receptor polymorphisms, are likely to be more sensitive to this neurotoxic effect than others.
Epilepsy is the most common co-morbid condition seen in autism. It is caused by GABA (A) receptor inhibition, and reduced GABA (A) receptor expression in seen in autism, as are GABAergic Purkinje cell losses.
I can’t pretend to understand the complicated biology that I read daily in the peer reviewed journals such as molecular autism and autism but I am learning about my son’s puzzle and it does involve quite a bit of biological interventions. Whether or not his medical issues are comorbid, causational, or completely unrelated, there simply isn’t enough info at this point. The bottom line, however, is that it is commonly accepted that there are subsets of autism, regressive autism is more than casually linked to GI issues, these GI issues tentatively show a difference from typical GI issues, immune and metobolic issues also effect my son. The research, as we begin to separate out the subsets, is beginning to demonstrate this. Cure mark has just pasted Stage 3 of their FDA fast-tracked enzyme for autism treatment focusing on protein digestion, Seaside is also testing minocyclene and other GABA regulators. The time is coming when we will be treating the biology of certain subsets of autism. We have the MTHFR mutation, I didn’t take folate because I was sick, we also have fragile X premutation, which in the five years has been studied at the biological level.. Here in San Diego I work with UCSD and UC Davis to address my son’s biomedical treatment and the interesting thing is many of their recommendations are similar to the DAN protocol. We are on B6, B12, enzymes, etc… All based on testing… The truth is that for so long many people have shunned “biomedical” as witch doctoring but now that we are past the whole vaccine issue, we are beginning to take a look at what is happening biologically and the research is bearing out similar biomedical treatments as some doctors have been using for a while.
Oxygen is also an epileptogenic neurotoxin at high doses, and at relative doses that are much lower than the doses of folate that cause seizures. 2 atmospheres of O2 can cause seizures in two hours. That is only 10x the normal O2 in air.
The threshold for O2 toxicity is extremely variable, even in the same person, showing onset times under identical conditions that are different by a factor of 15.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2053400/
Thresholds for folate induced convulsions are pretty variable too. Are they as variable as the O2 thresholds? They do occur at much higher levels but there hasn’t been the research done on levels of folate that cause seizures because they are so high relative to typical levels.
Calling anything that can exhibit neurotoxic effects a “neurotoxin” is (in my opinion), disingenuous. The dose makes the poison. Folate is a necessary nutrient. So is O2. So is H2O. Calling them “toxins” because large amounts can be fatal isn’t helping understand what is happening at typical levels.
I DO think that the article had a ‘feeling’ of “You parents are pushing for services your children may or may not need and you are costing us all BILLIONS!” I got the feeling from that NPR interview, that the author was not on our side. Not against us, mind you, but more than happy to over exaggerate the Warrior Parent motivation and underplay the school districts’ almost criminal activity in denying services.
On the other hand, it was also refreshing to me to see a glaring light put on sociological factors and how they are THE major factor in increased reporting of autism. It’s almost hilarious to watch the vaccine epidemic-ologists completely ignore the factors surrounding the major changes in educational services as the overarching reason for increased diagnosis…
livsparents,
My experience–which is my experience and could be wrong–is that the autism communities are used to people taking one side or another. “not against us” but “not for us” is not what we expect.
I know when I write what I consider to be a rather dry article, presenting the information with as little commentary as I can, I can get spirited responses going either way.
That said, I’d have liked the writer to make it clear that for the vast majority, people are fighting to get “appropriate”. Not special. Not extra. Just what their kids are promised–just as any non-disabled kid is promised. Appropriate.
It’s hard to get concrete evidence of inappropriate placements by districts. They tend to settle if they will clearly lose.
I’ve had my district offer a program that was so inappropriate (and expensive, by the way) that a few years later a different staff from the same district were shocked that we even discussed the placement. Shocked that is until someone read the record and realized that placement was the district’s previous offer. Examples like that are rare–and only available in IEP recordings, not court records.
Also, the radio program where they field this question is on KPCC: http://www.scpr.org/programs/airtalk/2011/08/15/20288/autism-study.
I did hear all of the qualifiers in the stories, especially in the NPR audio (I think that Catherine Lord did a decent job bringing the author’s ideas back to reality). But I think sometimes we are so busy fighting amongst one another to listen to that 15 second soundbyte that people outside of the spectrum of disability awareness get from articles like these. The impression I get was that ‘we'(education for the disabled) are very expensive to the general population, that we may or may not be doing quantifiable good for our kids in the eyes of John Q Public. We need to have that word out that the accommodations being sought are often economically minimal and often tremendously advantageous to the student, the district and society. Even with the ‘hopeless causes’, students are learning, school systems AND society are benefiting having a child progress 10 ties farther than they would ever have thought possible 10-20 years ago.
Interesting that you mention the higher cost that the disticts offered you. I’m finding too that districts are more concerned with the singular child in front of them than building a cost effective infrastructure for servicing disabled students. If both ‘WE’ and ‘THEY’ are to survive these tight budgetary economic times, they are going to need to embrace the idea that there will ALWAYS be another child coming to replace the child they are currently servicing and that pooling resources/changing mindsets are a necessity, not just legally…but practically…
Heh. Inappropriate placements…
In a very small school district far far away, there were always 2 or 3 autistic kids put in the “behavior disorder” classroom. That got exciting.
(I loved all of the kids in that classroom. Just…”this kid behaves in a way the reg ed teachers don’t wish to deal with, but is academically able” isn’t how placements should happen!)