Autism and the Environment Challenges and Opportunities for Research: Workshop Proceedings (2008) / Chapter Skim
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Day 1--April 18, 2007
Day 1--April 18, 2007
Pages 5-164
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From page 5... ...
The IOM's Forum on Neuroscience and Nervous System Disorders has the purpose of building partnerships and discussions to further understand the brain and the nervous system, to understand disorders and their structure and function, as well as clinical prevention and treatment strategies. What the forum does is to bring together leaders from the public and private sectors, including federal agencies, the pharmaceutical industry, advocacy organizations, and the academic community to have conversations about these general critical issues.
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From page 6... ...
Harvey Fineberg, president of the Institute of Medicine. I do want to specifically thank Kelli Ann Davis, Jim Moody, and Mark Blaxill -- Mark has also been a member on our planning committee -- who were instrumental members of the advocacy community in all of these discussions.
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From page 7... ...
It could not have been done without the joint activity of people from many different sectors with interest in this. One request of the speakers before we move on and that is -- and I apologize for doing this late, but we are a little bit concerned that with all the discussion and all the talk, it may be a bit difficult to capture each speaker's view of what a major opportunity or a major gap to be filled might be.
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From page 8... ...
The journey that brought us here began almost 2 years ago with a protest action directed against the Executive Branch. Parents of autistic children and other advocates were mindful of a reelection campaign promise to eliminate mercury-based compounds from vaccines.
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From page 9... ...
In other words, our research agenda should include studies of any and all environmental agents that plausibly might contribute to causing or exacerbating autism, irrespective of the medium of exposure. I am hopeful that the next 2 days will prove to be an important milestone for autism research -- not only because this workshop is addressing vitally important questions about the cause or causes of the disease, but also because the agenda is the product of collaboration between advocates for autistic children and their families and the scientific community.
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From page 10... ...
Let me not take more time, but rather turn to Laura Bono, who has been a member of our workshop planning committee, is a board member of the National Autism Association, and has agreed to bring to the group the perspectives of the advocacy community.
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From page 11... ...
Murder/suicides of parents and their autistic children are on the rise. I can't discuss the perspectives of the advocacy community without citing the failings of the CDC.
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From page 12... ...
They watch their children regress after being vaccinated. Their autistic children have been diagnosed with heavy metal poisoning and immune system dysfunction and when treated, get better.
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From page 13... ...
I hope that we will live up to the charge that you have just given us to look at the full array of environmental factors and the ways in which they can cause this disorder, affect its progression and then, of course, the variety of ways in which we can approach it. I think that your point about the need to both inform clinical practice, but also to listen to clinical practice is a very important charge and I assure you that we are planning to take advantage of that and listen to that carefully.
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From page 15... ...
Swedo's presentation, she may refer to slides that can be found online at http://www.iom.edu/?
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From page 16... ...
, which are now commonly called the autism spectrum disorders. I think that expanding the continuum to include all pervasive developmental disorders as "autism" is a bit confusing and dilutes the meaning of the term, so I am asking that we keep our focus today on those children who meet full criteria for autism.
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From page 17... ...
Here is an example of an autistic child's perseverative behaviors. You probably have heard about the autistic children who spin the wheels of the bus, rather than playing with the bus as it is intended.
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From page 18... ...
Potential environmental triggers that have been suggested are numerous. They include the toxicants, which will be discussed by Isaac Pessah; the infectious agents, which Ian Lipkin will be speaking to in a later session; and household exposures, such as household chemicals and cleaning products.
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From page 19... ...
At the NIH, we are attempting to do systematic studies of some of the more commonly used treatments, because open-label trials and anecdotal reports of benefit can be very difficult to assess because the child is developing naturally during that same period of time. The regressive subtype of autism is one of the most clinically compelling pieces of evidence for environmental triggers.
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From page 20... ...
Certainly in regressive autism, the hunt for the environmental trigger should take prominence, but how do we trace back from the clinical picture to that environmental trigger? As I said earlier, it is complex.
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From page 21... ...
It would be helpful to have incidence data from populations with disparate risk factors. If we could look at developing nations and their rates of autism, we might be able to find clues to environmental triggers here in the United States and elsewhere in the industrial world.
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From page 22... ...
The association between obsessive-compulsive disorder and Sydenham's chorea is what led us to suspect that strep bacteria might be the environmental trigger for the abrupt-onset form of obsessivecompulsive disorder. A decade of research suggested that the presence of untreated strep bacteria in a genetically susceptible host could cause an abnormal immune response and lead to clinical manifestations of obsessive-compulsive disorders and tics.
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From page 23... ...
The postulated abnormal immune response led to two lines of investigation. First, the search for a disease marker which would reliably distinguish children in the PANDAS subgroup from others with OCD, and the development of immunomodulatory treatments for severely affected children.
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From page 24... ...
Complex genetic disorders are complex and what we are trying to understand are the combination of risk alleles, variations in gene sequences or in copy number of specific genes which, in combination, end up underlying risk or, in fact, directly perturb brain development that ends up generating the three core symptoms that are diagnostic of autism spectrum disorders. You can see in the diagram that for any disorder, a combination of risk alleles may be correct, but there may be an intermediate phenotype rather than the features of the full disorder.
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From page 25... ...
You need to keep these in mind as you read genetic studies to determine the degree to which you can rely on the findings and conclusions. First, there may and are likely ascertainment biases.
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From page 26... ...
This is telling us something about the disorder, that there is locus heterogeneity. Thus, there are likely to be many different genes or combinations of risk alleles
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From page 27... ...
Keep in mind that genetically the causes are quite distinct from each other, but the high co-occurrence suggests that there may be many genetic routes to impact negatively the three core functions used to diagnose ASD. The literature is also replete with reports of association of common risk alleles with ASD; that is, gene variants have been identified from standard association studies that give us some clues regarding the impact of common variants on genetic risk.
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From page 28... ...
How much of genetic risk is due to direct impact of mutations on brain development?
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From page 29... ...
One approach is to focus on neurodevelopmental genes that have been characterized for altering the assembly of circuits that are likely to be disrupted in individuals who develop autism; it does allow investigators to move freely between animal models in which the biological functions of the genes are studied, and going back and working with human geneticists to try to determine whether there are meaningful relationships that would make sense in terms of variations of that gene that might underlie partial risk for ASD. One also can begin from human genetic research data and develop model systems that probe biological functions, trying to make sense in terms of what has been identified as a variant associated with the disorder that carries genetic risk.
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From page 30... ...
Met is involved in brain development, but we also thought more broadly about this when we were debating about doing the human genetics studies. Met is also involved in gastrointestinal repair, in immune response regulation, and some other peripheral functions that are consistent with the co-occurring medical issues that are described clinically for individuals with ASD.
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From page 31... ...
We need to increase subject ascertainment, character-izing populations in great detail, which will allow geneticists, psychologists, and neuroscientists to stratify groups more accurately to determine if certain phenotypes are associated with specific genetic variants, including SNPs, CNVs, and other genetic changes. Given that we all agree that we need to be very careful about how we phenotype in doing the genetic studies, it simply doesn't make sense to start out with a cohort of 1,000, because by the time you stratify based in different characteristics of ASD, or even life history, the study will be underpowered.
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From page 32... ...
Pessah: Thank you. Pat Levitt really summed up very nicely the complexity of the heritability of autism and autism spectrum disorder.
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From page 33... ...
At present, the cost and the causes of the majority of the developmental defects are not understood, but it is believed that about 3 percent of all developmental defects may be attributed to exposure to toxic chemicals and 25 percent of all developmental defects may be due to a combination of genetic and environmental factors, where the person's genome essentially confers increased susceptibility to the environmental hits that occur both during gestation and postnatally. Now, I wish I could tell you that the environmental issues, the chemicals, are simpler to address.
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From page 34... ...
Well, I would like to propose, and I think others have as well, that autism is really a multisystem disorder. We have focused on the developing nervous system, but because of the number of genes involved and the heritability pattern and the fact that greater than 90 percent are idiopathic, we have no clue how it is caused; we should assume that children who are susceptible to autism may actually be more adversely impacted by environmental exposures than the typical child.
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From page 35... ...
So, this becomes a very complicated problem. One way to approach a very complicated gene environment issue is to acknowledge that genetic susceptibility will play off of environmental exposure, and if the timing of those exposures are correct or critically timed, then the prevalence and severity of the developmental disorder will be influenced.
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From page 36... ...
Finally, polymorphisms between GABA receptor alpha 1 and GABA receptor beta 3 have also been suggested, as indicated by Pat Levitt. So, how might this imbalance in GABA-ergic transmission be influenced by pesticides?
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From page 37... ...
So, I want to finish, that a framework for future studies would be to accept the fact that there are several very complicated genetic susceptibilities in autism and the number and timing of environmental exposures need to be better defined and need to be relevant to the condition. We also need to pay attention to repair mechanisms that may be impaired, such as the DNA methylation.
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From page 38... ...
Dr. Pessah: I think there are several individuals, some I think will speak later, that one could use simple cell culture models to identify changes in signaling pathways.
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From page 39... ...
Herbert: I am happy to be here and I want to reiterate that our instructions have been to give a broad and general overview of what we 6 Throughout Dr. Herbert's presentation, she may refer to slides that can be found online at http://www.iom.edu/?
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From page 40... ...
Overall, we need to focus on biology and pathophysiology, and there are multiple levels of the biological hierarchy at which we need to measure, and we need to make a more concerted effort to coordinate measures across these levels of the biological hierarchy. I would like to propose from the point of view of learning more about autism pathophysiology, more than the thimble that Pat Levitt showed in his slide show, that we consider taking a middle-out approach.
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From page 41... ...
The serotonin is the only one, which was measured multiple times. I had the hypothesis that as genetics became more organized over the years, there would be fewer biomarker studies, and the graph on the bottom left shows the blue line is a decrease in the proportion of biomarker articles as a percentage of total articles that year, a modest increase in genetics, although it should be pointed out that people don't publish their genetic studies in this journal.
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From page 42... ...
Biomarker challenges in autism -- critical issues are involved in terms of recognizing what is going on with the phenotypes so that we understand and measure things that are appropriate to the challenge. Many autistic children -- not all, but many -- have striking variations in their severities, striking good hair days, bad hair days and I will get back to that in a minute.
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From page 43... ...
There are two reasons why measurements need to be coordinated across levels. It is not just that there is a great deal of variability among results of genetic studies.
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From page 44... ...
We need to learn about multisystem and multilevel impacts. Metabolism is a target for biomedical treatments and also metabolic changes are a final common pathway on which can converge multiple different genetic mutations.
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From page 45... ...
Dr. Levitt: I just wanted to comment that there are many patients with clear-cut primary genetic disorders like the Fragile X syndrome and Rett syndrome and many, many others, who have good hair days and bad hair days and you have a lot of this kind of variation, even though they have a primary underlying genetic condition.
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From page 46... ...
Dr. Insel: Martha, I really liked your presentation a lot, but could I get you to just expand a little bit for us so that we understand what you mean about some of the studies you would like to see done?
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From page 47... ...
That was on my first slide and I further would expand what I am saying -- what I said about that, which is that treatment response measured with biomarkers is an even further way of subtyping. Some of the nutritional treatments that are used in autism in certain settings are relatively low risk and a difference in response to those could be related to a genetically modulated environmentally sensitive set of differences in pathophysiology.
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From page 48... ...
Levitt's thimble in order to get going on this or can it be attacked in multiple levels? Can the geneticist be working on genetics and the metabolomics people working on metabolome?
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From page 49... ...
The autism centers of excellence RFA was actually written for an impressive number of common measures that will include medical history, environmental exposures, and other things. Every child evaluated within one of the new autism centers of excellence will have those common measures done and those data will be entered into the National Database for Autism Research, NDAR, in an effort to very rapidly get large enough populations to start doing the phenotyping.
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From page 50... ...
So, it is a problem in terms of division and definition because of the very components of brain function that we are focusing on, and you see these domains disrupted in the broad spectrum of psychiatric disorders and it is equally difficult to phenotype in those as it is in autism spectrum disorders.
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From page 51... ...
Some of them are, but a lot of them are actually conscientious, good clinicians, trying to treat sick kids and we ought to take that community more seriously than we do. They have a lot of data and they don't have any resources and if we spent some time, you know, learning from recovery, learning from treatment response, working with some hypotheses about inflammation and toxicology.
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From page 52... ...
Levitt can comment on this -- is the idea that we might also want to look a little bit at continuous outcomes related to the autism spectrum, the idea of endophenotypes or looking at continuous measures of social cognition in populations that perhaps include individuals affected with autism spectrum disorders, but also broader samples. Continuous endpoints are favorable to study in a number of different study designs, looking at -- that even include examinations of gene– environmental interaction.
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From page 53... ...
Have to look at those two subgroups very carefully and look at what is different about the autistic children who did respond and hopefully might find something there. Equally important, I think, are the negative responders because within the spectrum, you will have children who absolutely have clear responses and then others who go the other way, who regress.
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From page 54... ...
That is identical twins that were discordant for autism and we found differential expression. That means turning on or off of a number of genes, the majority of which or at least half of which had no neurological functions in lymphoblastoid cell lines from the AGRE repository.
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From page 55... ...
Participant: Lymphoblastoid cell lines. So, you have to consider the caveat in using those.
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From page 56... ...
I think that when we talk about complexity, what we are really trying to do is talk about it so that we could simplify things and, you know, one approach is MZ twins, so it simplifies one part of it. The other approach is to look for situations where people have common environmental exposure, which you implied in your comment, too.
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From page 57... ...
So, I go back to the need to really get at phenotyping and I am sort of struck as an outsider to this field by what sounds to me like a relative need for a bit of catch-up ball here in getting at the phenotype; understanding that clinical phenotype when you are dealing with cognitive and behavioral disorders is very challenging. It does seem like the biological phenotyping effort is really lagging behind that effort in several other fields.
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From page 59... ...
This session is set up as a way of taking some environmental diseases, diseases where we have uncovered causes in the environment that are related to complex diseases, identified the causes, and identifying the causes has led to a much richer understanding of the pathogenesis, genetics, and also ways to prevent the disease processes. So, to start this off, Phil Landrigan is going to give the first talk on environmental toxicants and neurodevelopment.
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From page 60... ...
7 Throughout Dr. Landrigan's presentation, he may refer to slides that can be found online at http://www.iom.edu/?
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From page 61... ...
The medical community came to learn additionally over succeeding decades that lead poisoning is a disease that can cause damage to children even in the absence of clinical symptoms. Prior to the 1940s, lead poisoning was thought to be a disease that either killed a child or from which the child recovered.
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From page 62... ...
In undertaking epidemiologic studies of environmental exposures, it is incredibly important to have stable biomarkers of exposure. Three further lessons emerge from the case study of lead.
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From page 63... ...
This decline has continued to the present day, so that the average blood-lead level now in the USA is less than 2 micrograms per deciliter. In other words, we have achieved a better than 90 percent reduction in blood-lead levels in this country as a consequence of our scientific discovery of the developmental neurotoxicity of lead.
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From page 64... ...
A specific consequence of this increased investment in children's environmental health is that in the study of organophosphate pesticides and their effects on the developing brain, we have made great progress, and we have done so at a far more rapid pace than in the case of lead. This rapid progress in understanding the developmental neurotoxicity of the OP insecticides began with Ted Slotkin's work at Duke in which he showed that exposure of newborn rodents to organophosphates could cause anatomical problems in the brain, reductions in the number of cells, and behavioral problems.
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From page 65... ...
• Chemically induced injury to the developing brain can be prevented by the application of scientific discovery. • The pace of scientific discovery can be dramatically accelerated by focused investment in research.
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From page 66... ...
Given the current prevalence of autism in the U.S., a study of 100,000 children will give us almost 1,000 children with autism and 99,000 controls. Moreover, because the study will collect data on hundreds of environmental exposures (to be measured by CDC)
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From page 67... ...
Mr. Blaxill: Phil, could you comment a little bit on the institutional response to the lead problems and some of the resistance that the science faced?
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From page 68... ...
Susser's presentation, he may refer to slides that can be found online at http://www.iom.edu/?
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From page 69... ...
These, in retrospect, are mostly neural tube defects and that is the black bar and you can see it peaks in the exposed group. We looked at schizoid personality disorder, measured at age 18 in military recruits -- all males -- that came from this population.
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From page 70... ...
They had much larger numbers than in the previous Dutch study, but they only had annual data, so in that sense the study was less precise. However, based on the previous Dutch study, they could specifically hypothesize that in years in which the birth rate dropped, the schizophrenia rate would go up, if periconceptual or early gestational exposure to famine was indeed linked to schizophrenia.
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From page 71... ...
A second hypothesis is "epigenetic." We know that the folate pathway is also important in DNA methylation, which is one of the key mechanisms for epigenetic effects. We know from animal studies, for example, that maternal folate supplements influence the methylation of the DNA of offspring in utero.
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From page 72... ...
Here we can use the example of neural tube defects as the classic model, the sort of hope or the Holy Grail, because we do know that periconceptual supplements of folate do reduce the incidence of neural tube defects. We know that from randomized clinical trials.
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From page 73... ...
So, there are two examples where I think we have studies that are going to yield some answers to these questions for autism. Finally, along the lines of the example that I showed and the comment that I made earlier, I think we should look for -- we call them natural experiments.
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From page 74... ...
Martinez: I hope that the examples that I will produce today are 9 Throughout Dr. Martinez's presentation, he may refer to slides that can be found online at http://www.iom.edu/?
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From page 75... ...
A researcher in Britain, David Strachan, working with one of the largest birth cohort studies as two of the previous speakers have talked about, the 1958 birth cohort in Britain, found a startling finding, which is that children who had older siblings at home were much less likely to have what could be
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From page 76... ...
This is true for pets, as it is true for day care and homes with heavy concentration of children. But perhaps the most interesting solid natural experiment is the one that you see here in this slide, which is a form of living, which still exists in Central Europe in which children and adults live in single-family farms as the ones you see here.
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From page 77... ...
I think the reason why the validity of asthma appears to be greater is simply because this was done earlier in life and the twin studies of autism were done later in life or perhaps because it is true since I know very little about autism, I don't know the answer. Something very interesting and paradoxical, however, is that these twin studies have both shown no shared environmental influences
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From page 78... ...
There was more atopy in our population among children who were CC and CT, who had low expression of CD14 and those who had TT. We thought we had to put ourselves in the hall of fame of geneticists, who had found something important until, of course, we fell into the same problem that every single other person working with complex diseases has fallen into, which is that three researchers were able to reproduce this and three researchers were unable to reproduce this result.
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From page 79... ...
What are my proposed conclusions? From our experience, natural experiments are very important and they may be true for both risk exposures and protective exposures.
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From page 80... ...
DISCUSSION Dr. Schwartz: Your talk, Fernando, brought up a really important point, which is that environment can be used to narrow the pathophysiologic phenotype in such a way that you can understand the genetics of and also potentially the biology that underlies a very complex disorder like asthma and consequently a complex disorder like autism.
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From page 81... ...
Can we follow as it relates to an autism endpoint or subclinical early condition that is along the pathogenic line or clinical line or development of autism? Phil Landrigan, you brought up and, Ezra Susser, you brought up the issue of the natural experiments.
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From page 82... ...
Furthermore, there is really no allocation as yet to do any sort of work to analyze environmental exposures or to look for biomarkers, anything of the like. Now, there are a number of people who are here who are working with that cohort.
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From page 83... ...
I think that there is a lot of evidence that genetic aspects of females and males with autism are very different and I will show a little bit of data and some speculation about this, but I think that the causes of autism in females and the causes of autism in males are very different, I believe.
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From page 84... ...
Autism is clearly one of the major outcomes that we are going to be looking at in the National Children's Study and as Phil Landrigan pointed out, it will take us about 4 years to recruit the hundred thousand sample as those kids age -- by age 3 we will have basically all the autism kids diagnosed and identified. So, we will be able to start looking at the analyses we intend to do with regard to autism for the whole cohort within 7 years.
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From page 85... ...
My understanding was that the number of children and wives was actually not as large and I don't know how much information. I know neurodevelopmental disorders at one point was on the panel of things we tried to look at.
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From page 86... ...
So, just to clear the record on that. With regard to the factors, I think the biggest factor that sped up the discovery of the developmental neurotoxicity of the organophosphate pesticides was the decision that a number of the federal agencies made beginning in the mid- to late 1990s to substantially increase the investment in studying the impact of chemical toxins on children's health, with a particular focus on brain development.
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From page 87... ...
It is my understanding that Tylenol reduces glutathione levels in our children and glutathione is responsible for pulling toxins, including heavy metals, out of the body. I think this is something we should seriously look at.
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From page 88... ...
88 AUTISM AND THE ENVIRONMENT are atypical trajectory of social, behavioral, development, and communication. I think the answer from several studies is, yes, there are and you can identify those; that is, skilled individuals doing research in that area can identify that there is a typical development and trajectory in those domains.
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From page 89... ...
Dr. Hertz-Picciotto: I guess I wanted to sort of link some of the discussions that we had earlier with the discussions just now and raise the question, so, we have these large birth cohorts, which have a lot of promise in terms of being able to go back because there will be stored specimens that we can do a lot of varieties of biomarker testing on.
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From page 90... ...
Deborah Fein's group at the University of Connecticut on children losing their diagnoses and it is informative potentially to look at what they lose -- what they have left after they lose their diagnosis. One group had specific language impairment, attention deficit.
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From page 91... ...
I am a neurochemist and I was very struck by Martha's talk earlier and also by listening to the other people talking. Many of the nutrient and alterations in metabolism that have been brought up, for instance, folate, B12, B6 are very important for brain development and it would seem to me that it would be extremely useful to come up with some sort of metabolic panel for testing for any kid suspected of autism, where you would look at all these vitamins that are possibly at risk, where you would look for heavy metals and you start screaming right when any sort of diagnosis is first suspected because you may come up with a lot of useful information if you start obtaining things like that.
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From page 92... ...
92 AUTISM AND THE ENVIRONMENT kids are non-excretors. So, you wouldn't find that in the blood when you first start testing them.
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From page 93... ...
Beaudet's presentation, he may refer to slides that can be found online at http://www.iom.edu/?
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From page 94... ...
I will just say that we have an ability to make a very good guess what the problem is with advanced paternal age. It is probably point mutations, so it is probably causing a de novo effect on a single gene.
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From page 95... ...
The reason the paternal age effect makes sense is that we know that paternal age effects will be relevant to this group of mutations up here. For almost all of these we have equal male–female distribution.
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From page 96... ...
Paternal age we have already talked about. I want to talk about folic acid a bit more.
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From page 97... ...
Why have we been very interested in it? My laboratory has been interested in epigenetics, and it is known that using folic acid intake in mice and in humans, you can alter gene expression because of the way it contributes to DNA methylation and histone methylation.
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From page 98... ...
The laboratory acid intake of the population at large, and particularly reproductive-age women, has dramatically increased over the last three decades. Your folate level and maybe imprinted gene expression are different today than they were 15 years ago, and we need to know more about whether folic acid intake is increasing or decreasing the intake of any diseases.
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From page 99... ...
Mark Nobel is our next speaker. He is going to talk about environmental factors impacting cell function.
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From page 100... ...
I am going to approach this talk from the perspective of our efforts to develop a comprehensive approach to the field of stem cell medicine. This work began with our initial isolation of CNS progenitor cells almost 25 years ago, and now extends to cover many components of stem cell medicine that are separate from the use of cell transplantation to repair damaged tissue.
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From page 101... ...
In the years of this work, we and others discovered that thyroid hormone promotes differentiation. We discovered that platelet-derived growth factor is a basal mitogen that is needed and is sufficient to promote division of oligodendrocyte progenitor cells and allows oligodendrocyte generation.
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From page 102... ...
Through our work on progenitor cells, we discovered a number of general principles. It now is clear that the redox state is a central regulator of precursor cell function, controlling whether a cell divides or differentiates as well as whether cells survive.
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From page 103... ...
What we found, which was recently published in PLoS Biology, is that environmentally relevant levels of toxicants make cells more oxidized precisely in the range of relevance to our work on development and on cell-extrinsic signaling molecules. And, just as we would predict, progenitor cells exposed to such pro-oxidants drop out of division and become more vulnerable to other physiological stressors.
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From page 104... ...
We next want to understand why do some people have an outcome that is bad and other people have no outcome at all that you can see when they are exposed to similar levels of environmental toxicants. So we got very interested in strain differences.
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From page 105... ...
We were hoping that maybe that wasn't the case, so we purified progenitor cells and asked at the single cell level what happens. It turns out that progenitor cells from the corpus callosum of SJL animals are much more vulnerable to anything that we throw at them.
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From page 106... ...
That is what would make thimerosal unique, rather than its chemistry. At a cellular level, it is important to stress that all the environmental toxicants that make cells more oxidized are something to be concerned about as potential disruptors of normal nervous system development.
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From page 107... ...
Slotkin: When we are dealing with autism, humans are the animal models of choice. If we could draw a connection between specific developmental neurotoxicants and ASD or autism per se, what we would like to be able to do is to use animals to define prototypes, that is, types of compounds that define entire families that attack the developing brain in the appropriate manner, that would then enable us to guide human investigations as to what we might look for in human populations with ASD as potential causative links.
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From page 108... ...
That raises some very serious questions that I think animal models help us address. That is, first of all, why is it that we adults are awash in them and our brains aren't permanently affected, whereas the developing organism is?
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From page 109... ...
So what that says is that if cells learn during a critical period, learn in the same way we learn language but at the cellular level, then when you provide an input during that period, you change the fate of the cell, and that changes what it is going to do permanently. Whereas, for our mature brains, input after the critical period just produces short-term responses, and if we continue to try to elicit the response, we become desensitized to that particular input -- it gets ignored in the same way that a continual sound eventually disappears from active perception.
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From page 110... ...
In other words, there is a critical period in which you must teach those cells what their fate is going to be -- this is learning at the cellular level. The same principles operate in the developing brain.
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From page 111... ...
It does involve things like oxidative stress and neuroinflammation. There is a critical period corresponding to the second trimester of brain development as it would be in the human fetus.
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From page 112... ...
I think there is an added value from examining an outcome where you can readily document the exposure. Terbutaline is different from most environmental exposures in that regard because the exposure is documented in an individual's medical records.
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From page 113... ...
As I pointed out, the peripheral surrogates that are predicted by common outcomes for autonomic input from the central nervous system to the periphery might then be an additional role for future use of studies. To sum up, the big impediment here is that there are too many candidate molecules to study, too little time, and too little money, and consequently designing high-throughput screens for developmental neurotoxicity is a mandatory first step to drawing connections between environmental chemical exposures and ASD as well as other neurodevelopmental disorders.
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From page 114... ...
To set the stage for consideration of how diagnostic and surveillance technologies can be implemented, I must first discuss the mechanisms by which infectious agents can cause disease. This introduction is critical because if infectious agents play a role in pathogenesis of autism spectrum disorders, common conceptions of mechanism may not apply.
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From page 115... ...
Finally, although I have been asked to focus on the role of pathogens, I want to emphasize that our working model is one with three dimensions where genetic susceptibility, environmental triggers, and temporal context act in concert to cause disease. Thus, a comprehensive investigation must address the intersection of all three components.
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From page 116... ...
In the context of a study of environmental triggers of type 1 diabetes mellitus in a Norwegian cohort, we recently examined stool samples from children using MassTag PCR and GreeneChips. To our surprise we found evidence of frequent infection with enterovirus subtype 71, a virus typically associated with paralytic illness in Asia.
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From page 117... ...
, a prospective birth cohort based in Norway of 100,000 children and their parents, that collects biological samples and clinical data beginning at the 17th week of gestation. ABC collections, joined with the diagnostic platforms for microbiology, toxicology, and genetics, will enable new strategies for examining gene–environment–timing interactions in health and disease.
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From page 118... ...
There are several people who are working with this cohort at present: Ezra Susser, Deborah Hertz, Mady Hornig, Alan Wilcox, and then we have counterparts in Norway as well. This was conceived to do the same sorts of things that all the other birth cohorts are conceived to do, but because we were later to get started, we were able to focus more on proteomics and transcriptomics and viromics and any other -omic you want to think of, so that we could try to address these kinds of questions.
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From page 119... ...
Participant: I had a question about the developmental disorders and children with autism. I think there is a deeper question here.
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From page 120... ...
They are also generated exogenously, and most relevant to our discussion today are pro-oxidant environmental exposures. Multiple or chronic exposures to pro-oxidant environmental toxicants can sustain redox imbalance and lead to oxidative damage and promote complex disease.
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From page 121... ...
Resistance or vulnerability to pro-oxidant environmental exposures depends largely on intracellular glutathione levels. Depleted glutathione reserves will increase sensitivity to pro-oxidant exposures.
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From page 122... ...
We find that the active reduced glutathione levels are decreased and the oxidized form, GSSG, is increased in many autistic children. The only reason that GSSG would be increased in the plasma is that it is being exported from cells under chronic oxidative stress as an attempt to normalize the intracellular redox environment inside the cell.
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From page 123... ...
Many of us have started looking beyond the brain. Martha Herbert has eloquently suggested this topic.
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From page 124... ...
For our recommendations, we would suggest focusing on candidate metabolic pathways to provide clues for environmentally relevant candidate genes, not only in the children -- and I think so many of the answers are in the children as well -- but we can look also into animal models and apply this to cell models to look for relevant signaling pathways or metabolic pathways, including redox, detox, immunologic, mitochondrial to name a few. We can also use metabolic biomarkers as targets for treatment strategies and treatment efficacy.
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From page 125... ...
Dr. James: The reason we picked those is because many autistic children have gut issues and immune issues.
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From page 126... ...
In the context of trying to understand this, we often don't reflect upon the impact that it has, not just on the individual biological system, whether it is a metabolic pathway or a cell, but on the individual child and the family as well. We talked about this this morning a little bit in the context that there is a lot to be learned and gained from listening to families and parents and listening to clinicians, at least from a basic scientist perspective, in terms of clues.
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From page 127... ...
That is not a very satisfactory answer, because you want to understand the mechanistic underpinning of why timing is important. What it appears to us, in the context of what we have been discussing today, is that for progenitor cells, and we are beginning to get data also for differentiated neurons, at times in their development when they are making decisions, am I going to differentiate or not, or am I supposed to have a lot of dendritic growth or not, they become extremely sensitive to these changes in redox state.
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From page 128... ...
Dr. Schwartz: A general comment that I have that I want to pose to the folks who gave these presentations in this last session, which I thought were really fantastic: It seems to me like we got a little bit off course, in the sense that part of the intent of this session was to figure out what we know about the biology of autism and what that tells us about
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From page 129... ...
Dr. Leshner: Can I just ask, are we moving out of this session a little bit?
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From page 130... ...
Dr. Herbert: I can clarify a little bit.
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From page 131... ...
It is a window that corresponds to the second trimester of human brain development.
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From page 132... ...
Maybe they are very relevant to aberrant brain development. I'm not sure we yet know why these things could result in the clinical picture of autism.
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From page 133... ...
PROCEEDINGS 133 mental disorders of mental retardation and motor disorders that are going to have very similar pathologies and very similar aberrations in redox and cell proliferation and differentiation, just to confuse this.
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From page 134... ...
What strikes me here is that the really urgent need for a biomarker that could be as Jill James was saying predictive, something that you could use at 1 week or 1 month or 6 months, well before you have to begin thinking about what the early detection behavioral paradigm might be. If there is an opportunity for that, I would think that would really drive a lot of the research, and it would be one of the most important things that could come out of trying to identify the pathophysiology.
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From page 135... ...
In my own clinical practice, I take this history on everybody who walks in the door, and I find this history -- and this again is not an epidemiological study, it is just my clinical experience with children with
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From page 136... ...
Dr. Levitt: Before you get to that, I was going to ask Art Beaudet, have studies been done in the syndrome disorders, independent of trying to link it to an association with the co-occurrence of autism diagnosis in those syndromes, in terms of metabolic studies and other things?
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From page 137... ...
Dr. Pessah: I think we also need to extend this to those genes or genetic markers that have strong evidence for linkage to autism, the Met gene, Cav1.2, and there are several others that were mentioned today, and construct the animal models and see if they have an inherent oxidative stress when it comes on board, does this influence their metabolic status, and then go back into the kids you have identified with the genetic problems who have the strongest linkage, and who are not as profoundly affected as Rett syndrome, and decide whether or not they are under oxidative stress.
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From page 138... ...
Robert Strausberg wasn't able to make it, and he was going to talk about environmental factors and mutations and draw upon his work in cancer, where it is clear that there are certain genes that are more susceptible to the environmental factors than others that cause de novo mutations. I wanted to put you on the spot to deal with this issue a little bit more.
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From page 139... ...
But I think we have to understand, particularly from the stuff that Jill James has presented, that a lot of the genetic mutations may actually be giving us these metabolic disorders that even though they are genetic are still going to be broadly treatable by metabolic modifications. So maybe the FDA is going to ask us for something that for here isn't exactly the right question.
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From page 140... ...
If autism is 1 among 50 and Fragile X permutation status is pretty common, it could have just been the two are unrelated. So I think we have to be careful that one of your gaps was assigning functional function to these polymorphisms, and I think we can't do that.
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From page 141... ...
If the incidence is not really changing, that is a very different situation. I think also, my impression is if the incidence is changing, the percentage of males relative to females should be rising with that, because that is the group that is going to be more likely to be involved in environmental interactions.
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From page 143... ...
You are all scientists and you are looking at it from the scientific perspective, and we need that. But there are thousands of parents out there who are heartbroken, and when they hear the descriptions of the brain and the white matter, it is almost too much to take.
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From page 144... ...
The constituency out there needs attention to treatment response. It may not be now, and it may not be specific.
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From page 145... ...
It seems to me that a large part of today, the discussion has been around mechanisms and pathways which could be impacted very significantly by environmental agents, but not nearly as much discussion about specific environmental agents. And of course, the pathways themselves may not be fully specific.
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From page 146... ...
Is it the case that the kids in whom that works, are those kids in whom we have higher levels of heavy metals? And is it the case that the parameters that Jill James's studies normalize, or that auditory brain stem response normalizes?
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From page 147... ...
He has looked at it in cell culture systems and also in clinical systems, and found that children with learning disorders and also sleep disorders often had tonsil problems, and when they were removed they actually improved considerably. So his repetitive hypoxia paradigm would also fit in with some of the redox type of studies people have been talking about, and I think should be thrown into the big picture.
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From page 148... ...
We thought it was such a great idea that we started 3 years ago to develop a national database for autism research, which allows clinicians in the field to become researchers by providing them with the clinical tools they need to do systematic assessment of their patients. Our group has been very impressed with the DAN practitioners and are grateful to them for what we are learning from them, are hoping to partner with them even more in the future.
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From page 149... ...
Dr. Insel: I think one of the great things about the National Database for Autism Research is, it does give you the standardized assessments.
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From page 150... ...
I don't know whether you quite said that, but maybe that is what I was thinking. You were implying I think that the specific environmental agents might be so numerous that.
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From page 151... ...
Then Tom Insel presented his two models exploring this, and bringing in the phenotype data as well as looking at it, which would be certainly meeting the scientific rigor that I think all of you want to meet. I wanted to propose -- and I think some of the people here, Nancy and others, have started to discuss this -- a third model that I think would fit well into that, and that is a treatment model.
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From page 152... ...
Sue Swedo, I have talked with you about this. I was saying to Pat Levitt, some of us, because we don't know what else to do, we can't wait for the clinical science to take 20 years to solve all these problems.
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From page 153... ...
There are 14 million kids in the United States with some kind of neurological disorder, and parents are trying everything. From the point of view of someone in stem cell medicine, I am desperately interested in keeping this stuff regulated, because there are so many cowboy clinics out there.
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From page 154... ...
154 AUTISM AND THE ENVIRONMENT do, anyway. I would propose from a sociological point of view that there could be usefully some support for the self-organization of the parents and some of the treating physicians, like the DAN docs, like Nancy and others, to have more support to build a platform of communicating what classes of data are available, a status report of what is being collected.
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From page 155... ...
One is an in-depth phenotyping effort, making use of the anecdotal literature and the clinical experience from clinicians across the country, but also the CHARGE, CADDRE, and other data that had been collected. It is everything from family history of medical illness and environmental exposures to neuroimaging, genetics, and other evaluations.
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From page 156... ...
I missed the very beginning, but I don't think until Sue Swedo just mentioned it that I have heard anything about the possibility of food allergies. I read a lot about and heard lectures on things like the gluten- and casein-free diet, the specific carbohydrate diet, and how for some children with autism, it has not only improved some, but even caused recovery in some.
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From page 157... ...
The D4 dopamine receptor is involved in methylating membranes of neurons. It uses methyl groups from the folate pathway through the enzyme methionine synthase.
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From page 158... ...
The third point is to talk about the National Children's Study a little bit more.
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From page 159... ...
So I just wanted to remind people that there are some studies in addition to the ones that Sue Swedo had mentioned within NIH. There are some studies underway that might be able to shed some light on some of these questions.
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From page 160... ...
I think it also allows us -- the tool also has the fingerprint for the individual child. So what Martha Herbert was talking about, as having a way to track our treatments, I think we should as physicians be allowed the freedom to do whatever we do, because each doctor may be fixing a certain subset of children, but if we don't know, that is the frustrating world of the clinician.
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From page 161... ...
PROCEEDINGS 161 particular hypothesis, absolutely, that can happen very quickly. The larger question is how physicians can be providing feedback and families can be providing information.
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From page 162... ...
Rhonegative mothers are subjected to a standard of care that calls for a RhoGAM injection at 5 months of gestation, so we give them a little extra environmental assault and a little extra mercury there. I understand that Rho-negative mothers have a higher percentage of autistic children than others, so what is the explanation for that?
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From page 163... ...
Participant: It will be including also immune dysfunction, which will address a lot of the other issues that have been raised today. Participant: There is someone in the United Kingdom whose name is Simon Cohen, who has been doing studies in relation to autistic symptoms or traits in the children who are born from these pregnancies.
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From page 164... ...
164 AUTISM AND THE ENVIRONMENT The most relevant question that has been asked today was asked by Dr.
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