Summary of RFI Responses: Risk Factors

Genetics:

Since the vast majority of research on ASDs has been conducted in Caucasian populations, genetic research should be conducted in genetically diverse and non-Western populations. Genetic heterogeneity in the current genetic databases used in research on ASDs, including locus and allelic heterogeneity, will facilitate increased knowledge of the pathophysiology of both ASDs and potentially other complex genetic diseases (e.g., breast cancer, in which genetic mutations and variations linked to breast cancer vary among ethnic groups).

The primary etiologic factor in autism is genetic. Far too much money is being spent on trying to identify purely environmental etiologies or gene-environment interactions. When the heritability estimates for the autisms are >.90, spending money and effort on identifying the small portion of remaining variance will not be fruitful until the other causes that account for the majority of variance are understood. The majority of effort in this area needs to be on identifying the number and composition of genetic changes that lead to autism. Heavy emphasis should be given to analyses that focus on identifying finer-grained copy number variations/spontaneous mutations, even point mutations, which result in loss or gain of function. Large scale association studies have been unproductive and given recent data from Cold Spring Harbor Laboratory, are unlikely to be productive given the large number of single gene/copy number variations observed.

Further look at the genetically based syndromes like Cornelia de Lange Syndrome may help to inform your work on autism generally (including cases of autism that have not been linked -- at least yet -- to genetic disorders).

Overexpression of maternally imprinted genes in the Prader-Willi syndrome (PWS) region may confer susceptibility to autism. Additional studies suggest that functional alterations of specific genes in this region are associated with social deficits found in autism as well as other neurodevelopmental disorders. Collectively, these findings suggest that studies focused on understanding autistic symptomatology in PWS will provide an excellent opportunity to better understand the etiology, neurobiology, and pathophysiology of ASD. Finally, therapeutic interventions effective in PWS may similarly be applicable to the broader population with ASD.

High-resolution comparative genomic hybridization should look for systematic gains/losses in DNA content of ASD vs. controls.

Make a concerted effort to fund creation of novel genetic animal models of autism (Shank3, Ca channels, etc) and to fund multidisciplinary characterization of these models.

Although candidate genes are a useful route to explore, they shouldn't be pursued to the exclusion of complementary strategies at biochemical, physiological, anatomical, and behavioral levels of analysis, or to the exclusion of links to each other in networks of genes and proteins. The currently developing emphasis on big science applied within a genetics-only perspective will, if pursued single-mindedly and with the degree of monomania that it seems to have attracted of late, displace other productive approaches. Single-gene studies are an important component of biological investigations of autism, but must be addressed within a broad context of systems and integrative neurobiology.

Does the apparent high incidence of autism in children of academically high achieving parents provide a clue to genetic predispositions?

Are male twins at greater risk for ASD?

Most parents I have met, though highly productive members of society, have “a touch of autism” (mild autistic traits). Therefore, statistical methods that count these parents (and many siblings) as unaffected will fail to identify autism genes. Understanding what modulates the degree of penetrance, whether genetic or environmental, will immediately suggest effective therapeutic targets.

Identify genetic vulnerabilities to environmental exposures -- for example, from the environmental genome project -- that would be of particular relevance to autism.

Genetic epidemiology (GE) can give more clues about the effect in autistic people of some particular polymorphisms (such as BDNF, CPOX, MTHFR, COMT, GSMT, MET with GI issues, ALAD, MTF-1, etc) and the impact of combination of polymorphisms. The careful selection of controls and randomization should be addressed properly to make the studies significant.

Medical Issues:

Immune System

The risk of autism spectrum disorder is increased in offspring of women with a history of allergic disease (asthma and allergic rhinitis) during pregnancy. Replication of this observation in a well designed prospective study would be a key since this appears to suggest maternal fetal immune interactions may affect developing fetal neural tissues.

Can autoimmune models of dysfunction (e.g. Crohn’s Disease, Juvenile Onset Diabetes) provide clues to the development of autism?

Many moms in our support group have hypothyroidism, rheumatoid arthritis, MS, lupus, CFS (I have RSD). We have relatives with ADD and bipolar disorder. What are the commonalities?

Is a family history of irritable bowel syndrome a risk factor or suggestive of some autoimmune disorder that may be associated with ASD?

Small surveys I have seen suggest that children on the spectrum are much more likely to have allergies than NT children. Is there a correlation?

Research is needed on these underlying causes of our unhealthy kids and the medicines to cure them. High viral titers, low ferritin, antifungal issues, chronic infection, etc., so prevalent in ASD kids, are all signs of a dysfunctional immune system. The brain cannot develop properly if the body is ill. There are immune modulating agents in existence right now that would help these sick immune systems.

Investigate gut-immune system-brain axis signaling systems (neuropeptides, growth factors, etc).

Look at the possibility of RNA viral mutation in vivo and at the exchange of RNA material in persistent (co)infections due to abnormal immune answers (from wild and non-wild origin) in ASD, related to nutritional status (Se deficiency; vitamin A deficiency).

Develop more specific and high-technology techniques to detect evasive, hidden, or tricky abnormalities in the immune system in autistic people (even subclinical abnormalities such as atypical CVID).

Study the effects of autoimmunity in families with autism, why this is relative to how infections are cleared or not affectively in autistic children, looking at C4B anulle, HLA-DR4, etc.

Study immune dysregulation problems in autism, and brain inflammation signs (hypoperfusion, chiaria, encephalitis).

Since a number of gene profiling approaches point to changes in gene expression profiler of immune cells, research on the role of dysfunctional immune system in autism should be undertaken with the following components: (1) effect of altered immune system on brain dysfunction in autism (2) role of microbial agents in alteration of immune system in autism.

Study the genetic history of immune disorders such as multiple sclerosis and of food and other allergies.

Infection

Study whether alpha and gamma strep in the GI track can affect the brain and cause OCD in children with autism.

Analyze the role of streptococcus infection, Lyme disease, and neurothropic (co)infectious agents in ASD.

Gastrointestinal

Study gastro-esophageal reflux (and/or formula intolerance) in infancy. ASD is associated with ear infections in infants/children. GER is a cause of ear infections in some infants/children. (Allergic rhinitis is also a cause of ear infections in some infants/children and some food allergies/sensitivities cause rhinitis and/or GER.) ASD children often have feeding issues (texture/taste/etc.). The "leaky gut theory" is becoming more popular among parents, as is celiac disease, milk allergy, etc.

I know that Indiana University Medical Center, home to Riley Children's Hospital, is a leader in medical informatics. I had mentioned the GERD to one of the researchers there, as they have the ability to track hundreds of newborns in the Indianapolis area and could do scan sheets (color in the circles) to follow the growth and development of patients through the pediatrics and family practice residency clinics as well as possibly through local physician offices as a prospective study, tracking complaints of spitting up/feeding problems, growth parameters, sleep issues, ear infections, etc.

Research the role of gastrointestinal conditions (enzymes deficiencies, organic dysfunctions, reflux, food intolerances) and immune abnormalities (hyper-answers, such as autoimmunity, and hypo-answers, such as immune depression/deficiency) to viruses/bacteria/xenobiotics.

Many people with autism suffer from gastrointestinal symptoms - symptoms that cause pain and discomfort and which can be addressed if only they can be communicated, and if only professionals would not shrug off the patient's attempts at such communication as "part of the autism." What are the profiles of gastrointestinal symptoms in autism spectrum conditions, and how can these symptoms be addressed?

Perform further research into gastrointestinal flora, both beneficial and pathogenic, to determine phenotypes associated with certain profiles.

Investigate the gluten-free casein-free soy-free (GFCFSF) diet as an approach to treat gluten/casein intolerances; immune factors from celiac disease to milk allergy; toxic elements (Pb/Cd/As/Hg/Al/others) and essential elements (Zn/Ca/Mg/Fe/others) in blood, hair, urine, fecal stool during a diet GFCFSF without Se or amino acids supplementation; and transport systems of toxic/essential elements.

Why do so many seem to improve with the GFCF diet, probiotics, B6, B12, and magnesium? Why do so many need melatonin supplements to sleep?

Study the role of nutritional deficiencies in terms of vitamins, amino acids and minerals -- mainly essential elements.

Please research the effect on the newborn brain (in mice) to being exposed to a sugar substitute instead of feeding the newborn brain with real sugars and carbohydrates. Please see if this affects brain development. Also please survey families and see if this was the case in any other cases of autism, that the baby was breastfed while the mother was eating Nutrasweet to lose weight.

Does drinking diet soda while pregnant lead to a higher risk of an autism spectrum disorder? I've read that diet soda is really toxic. Does the use of aluminum (cooking goods/cans) lead to toxicity and finally to autism?

There has been some biomedical research done on secluded areas (like mountainous areas where "outsiders" and imported goods can't get to easily) whose data reflect the nutritional quality of a grandparent having direct effect on the health and development of their grandchildren. The consensus is that the crop cycles are directly influencing the genetics of the groups. More research should be done on parents and grandparents to delineate individual biological differences - including nutrition - that might contribute to offspring having ASD.

There are some very specific gastroenterologic questions which do seem to be important to answer. There is a cohort in Finland with celiac disease who have an abnormality on their chromosome 15 (Wooley Human Genetics 2002 111:40-45) at a site near the Angelman/ Prader-Willi site, and some children with autism spectrum syndrome have been reported to have [this] specific chromosomal abnormality. I have not found any literature to support an increase of celiac disease in children with autism, nor have I found an increase in autism in people with celiac disease. Given the emphasis that many parents and alternative interventionists give to a gluten-free diet, I would be interested in specific research to either her refute or support a claim that the biology of autism is somewhat related to the biology of celiac disease. Similarly, issues of constipation, diarrhea, lactose intolerance, GERD have also been reported to be of higher incidence in children with autism, and many are suggesting that all children with autism be referred for gastroenterologic evaluation. It has been my experience that all of these common childhood disorders of digestion can be approached from the pediatric and developmental pediatric perspective without increasing costs for referral for common GI complaints.

Prenatal and Maternal Factors:

Factors that should be studied are age of mother (ovums), drug use or diet in father's sperm or mother during pregnancy, environmental toxins and all the latex and plastic that babies suck on or come in contact with constantly, thorough diet research--candida, allergies, wheat/gluten free diets, etc.

Please confirm or refute the results of the ultrasound study suggesting that frequent ultrasounds may correlate somehow to ASD in the child.

The time is ripe to explore in much greater depth the connection between fetal alcohol exposure and autism. In addition to highlighting a possible ASD risk factor, this could serve to better illuminate the biology and origins of ASD.

I only have anecdotal info, but my nephew was conceived with "washed sperm," and other people I know with autism were conceived with infertility treatments as well. I hope to see more research into this possible correlation.

Investigate prenatal developmental windows for environmental exposures impact.

Study vitamin D deficiency in pregnant mothers of children with autism spectrum disorders.

Does maternal stress prenatally effect the expression of ASD?

Investigate the role of maternal viral/bacterial infections (herpes, strep, flu) plus environmental exposures (including medication and vaccines) in the risk of autism.

Compare incidence of ASD populations correlating maternal prenatal exposure to Rhogam with unexposed mothers.

Search for commonalities in the pregnancy experience of mothers whose children ultimately develop ASD disorders. This would include medical issues, exposure to potential toxins, and exposure to potential viruses or bacteria.

Capture pre-natal exposures - prospectively or retrospectively – via medical records, maternal surveys, and cord blood examinations.

Study how multiple infections in utero could cause autism -- e.g., syphilis, lyme, disease, Toxoplasmosis, Borna, Herpes 6, or other well known, less well known infections.

Study the effects of genetic predisposition to prenatal injury -- e.g., low metallothionein, low sulphation, low glutathione, low selenium, low zinc, high copper, and high iron.

Study immediate cord clamping in autism, ie, hypoxia events. (ACOG now says thirty seconds, previously, minutes, are we asphyxiating our babies with our current recommendations?)

Study effects of pitocin/chlorbutunol on infants.

Pre- and post natal exposure history should be assessed as part of the autism diagnosis and evaluation process. Exposure and body burden assessments should form a key component of subtyping and phenotyping efforts.

Other issues involve testing at birth: How many children have a traumatic birth? What was the protein level in the placenta? Was it high or low? What were the Apgar scores at birth? Was the cord wrapped around the baby’s neck? Was the baby in proper position? Did the child swallow any fluid? Did the child have jaundice at birth? Did the child go into the incubator? Was a light used on the child? Did the child have any spots or birth marks? The chemistry in the umbilical cord could be evaluated. What kind of birth was it? Did the mom have anesthesia? Was the baby delivered with forceps or vacuumed out of the womb?

Is hypothyroidism of the mother during pregnancy or postpartum a risk factor for ASD?

Compare incidence of ASD population born to mothers diagnosed with hypothyroidism within five years before or after childbirth to incidence among children of healthy birth mothers.

Toxicology:

Look at the role of transporters of toxic elements (Hg/Cd/Pb, etc) and nontoxic elements (Mg/Ca/Zn) of +2 oxidation state (including the EAAT and the ABC- Pg glycoprotein-) and +3 oxidation state (Al/As/Fe/others) and the amino acids transporters.

Study the role of certain polymorphisms in the management of xenobiotics in ASD, related to the cycle of glutathione conjugation (coenzymes and cofactors) and phase I and phase II in the liver in autistic people, including food additives, pesticides/organophosphorates/PCBs and antibiotics at chronic/acute/low doses.

Study the impact of neonatal immaturities in the management of xenobiotics and viral/bacterial infections in autistic children (mucosal immunity, neuropeptides, growth factors-BDNF, GI maturation). Do developmental studies of the xenobiotics, including the adverse effects of drugs.

Study the combined impact of medical pediatrics management in the GI/immune system of autistic children (from antibiotics to vaccines, including the overall schedule and overall composition, plus chronic exposure to xenobiotics from food, water and air (heavy metals/Al, PCBs, PAHs, pesticides, organophosphates) and allergic reactions plus common bacterial/viral childhood conditions NOT possible to prevent, such as otitis, pharyngitis, laryngitis, colds, etc) vs. non-autistic children. Consider the possibility of molecular mimicry in the management of xenobiotics.

Research use of flame retardants in pajamas and bedding with the correlation of heavy metal toxicity of children with ASD

Investigate alternative methods (rather than blood tests, which tell only of recent exposures) of detecting lead/mercury levels in the tissues of autistic children. Is there really lead/mercury in the tissues?

Conduct studies of the rate and severity of ASDs by geography, and link these geographic areas to databases of pollutants.

Identify differences in exposure between siblings developing autism and those developing normally, and identify any differences in autism subtype based on differences in exposures.

Investigate exposure histories among disconcordant MZ twins; establish a twin registry.

Study the effect of chronic low-dose xenobiotics from all sources, including antibiotics and other medicines used in childhood, as endocrinological, gastrointestinal, and immune disruptors in autistic vs. non-autistic children. Do adequate testing to detect these disruptions.

Is early use of antibiotics (during pregnancy for treatment of preterm labor, during breastfeeding for mastitis, for an infant's ear infection) a risk factor for ASD? Is magnesium sulfate a risk? Is progesterone during first trimester, as common in infertility treatment, a risk?

Investigate the effects of both ingested and injected excitatory free amino acids (glutamic acid and aspartic acid) on children with these "autism genes."

Investigate how other foods a mother is eating (such as fish which may contain mercury and other contaminates) may affect children who are breastfeeding. Investigate how the upswing in autism correlates with the timing of the upswing in mothers returning to breastfeeding and how what the mother's are ingesting could affect the baby. Of course breast feeding is good, but people in the U.S. eat a lot of non-nutritious processed food with additives, hormones (i.e. in dairy products), excess salt, trans-fats, MSG, artificial colors and flavors, pesticides, etc. that could go through breast milk to the baby.

Aggressively pursue environmental causes/contributions since this is the one area we can actually alter. We can't do anything about genetics.

Study populations within 60 miles of coal powered processing plants starting with low emissions up to high emission plants to determine prevalence of childhood developmental disorders.

Identify the environmental factors that increase risk for PDD and might give rise to subtypes within the PDDs, depending on the exposure, exposure interactions, timing, and individual genetics. Special attention to detoxification pathways, including glutathione and cysteine levels, is warranted.

Please launch a nationwide Internet survey of families with autism to the environmental exposures their ASD kids had, that their "normal" kids were not exposed to, and in the survey include an open essay question for any exposures the families can think of that are not included in the multiple choice questions.

Study the ability of patients with autism to excrete toxic metals as compared to non-ASD patients, and effective ways to treat heavy metal toxicity in patients with ASD.

Review toxicological literature and databases for susceptibility gene candidates and potential biomarkers.

Toxicologically-relevant susceptibility genes should be screened among ASD subgroups.

Exposure/body burden can be extended to post-mortem brain studies and other biosamples, for example, determining the levels of mercury in autism brains and other organs.

Research is showing that cumulative and synergistic effects of multiple exposures, whether of toxicants or microbes, can have a far greater impact than a single exposure. Exposure and body burden assessments should factor in "multiple hits".

Exposures may be directly measured or indirectly through intermediate biomarkers. Techniques should be developed to identify these biomarkers and their validity to autism. An example is altered porphyrin profiles and mercury exposure. Many markers already exist in microbiology and immunology but need to be applied to autism. Transcriptomics, proteomics, and animal models should be used to discover markers for exposure to heavy metals, PCBs, PBDEs, and other plausible candidates identified biologically or epidemiologically.

Add exposure history and body burden components to the baby sibling longitudinal study; add extensive autism components to large environmental epidemiology studies like the National Children's Study or the Norway Longitudinal Study.

The fumes from glycol ether in a floor sealant used in our home when our son was two set off his life-changing fever. In the Chinese manufactured toothpaste, recently in the news, is a poison called dietholene glycol -- the same chemical as glycol ether. How old are children when they are encouraged to brush their teeth? Krylon craft spray had glycol ether in it as a solvent until recently. I guess my question is: how do we identify clearly some realistic common denominators that might set off a process that leads to the ASD?

Research needs to be directed toward identification of the most common xenotoxic agents. Analysis of their levels in biological samples (serum, urine) from autistic children is an obvious starting point. Evaluation of brain toxicity at environmental exposure levels in rodents is reasonable, but there is good reason to believe that human neuronal cells operate under a different redox status. For example, levels of brain cystathionine (a key transsulfuration metabolite) in humans is 40-fold lower than rat or mouse. Thus rat or mouse studies may grossly underestimate the oxidative stress sensitivity of human brain.

The practice of adding MSG to foods and vaccines needs to undergo serious scrutiny.

Study environmental toxins on the development of autism, including (1) assay development for heavy metal in people (user-friendly kits such as pregnancy test kits) (2) multicenter studies with a required statistical team support to study the possible elevation of heavy metals or other toxins in autism.

Look into ingredients for fertilizers. In 1980 the EPA established a rule that allows hazardous waste materials to be used in zinc fertilizers (and this does not need to be labeled). These ingredients can include lead, mercury, arsenic, cadmium, chromium, and dioxin. Lead has been known to cause behavioral problems, learning disabilities, seizures and even death. Mercury may cause neurological abnormalities, including cerebral palsy in children and severe deformations in animals. Arsenic and cadmium may damage internal organs, skin, and nerve function. There is also a past history of these types of materials being used for de-icing on roads. Both fertilizers and road de-icers eventually run off and end up in our water tables and food supply. It would be interesting to see how the timelines of these chemicals intersect with the rise in autistic cases.

Are there disparities with respect to exposure to environmental risks, as has been documented in the environmental justice movement?

Do research on the detection of children prone to adverse reactions to medications (including vaccines) and bioaccumulation of toxic elements.

Study multiple chemical sensitivities in ASD.

Compare incidence and severity of ASD in children correlating with number of dental amalgams in mothers.

Vaccines

Concern about simultaneous administration of three live viruses at an age when the neural underpinnings of speech are developing is not at all inappropriate, particularly in light of new understanding of the synergy and biochemistry of neuroinflammation, its role in normal brain development, and the ability of many viral envelop proteins to activate inflammation or suppress immunity. Recently, chemokines and chemokine receptors have been shown not only to direct the migration of subsets of T cells, B cells, and monocytes to sites of injury and tissue repair, but also to orchestrate early brain regional development via modulation of neuronal numbers and migration.

The area of neurovirology should be a priority for funding: live virus vaccines contain “attenuated” viruses that take up residence in gut immune tissue and can thus be transferred throughout the body and into brain microglial cells. AIDS research has revealed that via this process almost undetectable levels of virus can give rise to brain disease via the highly receptor active viral envelop (gp120). In vitro experiments studying brain cultures and viral proteins from live viruses given as vaccines to young children and women of child-bearing age should be a priority, along with the effects of chemokines --which are released during inflammation -- on mammialian brain development and behavior.

Do research on the potential cognitive and physical side effects of repeated multiple vaccinations on children under the age of 4, both from a biological and an epidemiological perspective.

Since we have significantly decreased the thimerosol in vaccines, are we seeing a decrease in the incidence of autism?

Investigate the benefits of spacing out vaccines so multiple vaccines are not given at the same time, putting less strain on the baby's immune system. I have seen a lot of babies who were just miserable after receiving vaccines, including one who had seizures after receiving the MMR. Also, investigate the benefits of delaying vaccines until a child is older and more able to handle the effects of the vaccine instead of giving vaccines to day-old infants.

Investigate the possibility that the chickenpox and/or MMR live virus vaccination of the older sibling during the pregnancy of the affected child resulted in some form of in-utero immune status change or infection. When the affected child is subsequently given their immunization, their body responds in an atypical way, perhaps even “inviting” the virus to colonize in the gut.

Can MMR vaccine, or DPT cause autism in monkeys, animals?

Continued investigation of vaccines suggests to the public that the question remains open and feed parents’ fears about vaccination. I therefore suggest that the IACC recognize the work that has already been done in this area and focus its recommendations on strategies that have the potential to yield public benefit.

Don’t spend any more federal money on the question of whether vaccines cause autism.

Pro-actively encourage vaccine research. The legislative history of the CAA specifically calls upon NIH to perform research related to vaccines and their preservatives as a potential cause of ASD. This research is essential because it will either rule out vaccines as a cause or implicate them so that immediate corrective measures can be taken. To our knowledge, no research presently being undertaken by CDC or NIH fulfills this mandate. Indeed, CDC (perhaps predictably) seems to have designed all its presently sponsored data gathering. Apparently, the newly undertaken comprehensive child health study will not include a comparison of the health outcomes of vaccinated versus unvaccinated children. Such a comparison must be undertaken immediately to assess the effect of vaccines on ASD and other related disorders.

Implement a study of the rate and severity of ASD outcomes in vaccinated compared to unvaccinated populations or to alternatively vaccinated (later and fewer vaccines) populations.

Ensure that vaccination history is included as part of any exposure assessment.

Other Factors

Wireless signals (cellular, GPS, wireless baby monitor intercoms) continue to be high on many parents’ suspect list. Further research in this area would be greatly appreciated./li>
Please consider the pervasive issue of parasites in autism. This is not something that can be treated with one round of antibiotics. Parasites adapt to their environment, develop biofilm enclosures in the gut, and grow uninhibited in immunocompromised individuals.

Cross-National Studies

Do a comparative study of autism manifestation between individuals in Western (Industrialized) and nonindustrialized nations. The goal would be to see whether the anatomical, physiological, and the genetic basis as well as social and behavioral aspects of autism manifest itself differently between people across different culture and more importantly people who have been exposed to different stringency vaccination programs and industrial wastes.

Miscellaneous Comments

I would like to have another child. What is the likelihood we will give birth to another child on the autism spectrum?

I love my daughter, I am her only voice. And like any other mother of an ASD child out there, I beat myself up wondering what I did that may have caused this. We have also stopped having children in fear of having another with this disorder. This disorder has a devastating impact on families both emotionally and financially.

I am not so interested in spending resources on genetic research. It hasn’t yielded much in the way of helpful information for therapy, and it has eugenic implications that I don’t think are healthy.

Shift the focus of autism research away from an exclusively heritability model to one that investigates the role of environmental factors combined with a genetic vulnerability as a potential culprit behind this otherwise unexplained epidemic.