Models, Etiologies and Environmental Factors

Advances in Autism Research
April 2010

Models whereby autism is understood and researched have changed. Bettelheim espoused a "refrigerator mother" construct which gave way to models wherein virtually all cases of autism were primarily genetic in origin. More recently, an increasingly accepted autism model specifies an interaction between environmental exposures and gene alleles which predispose to adverse effects and atypical development and associated pathologies.

Importantly, causation models based upon mixtures of pollutants may be more accurate than are models seeking any one pollutant as “the cause” of autism and other autism spectrum disorders (ASDs). Indeed, a new European Union study by the EU's Directorate-General for the Environment is titled, "State of the Art Report on Mixture Toxicity". As a scientists' news announcement (here) summarized on March 29, 2010, "The study showed that all the relevant research is unambiguous: the combined "cocktail effect" of environmental chemicals is greater and more toxic than the effect of the chemicals individually." The study itself is available here.

On Dec 20, 2009, more than 1000 citations were generated by the Pubmed search:
autis* AND (environment[tw] OR environmental[tw])

Here is a small sampling of reviews and new findings which call attention to environmental factors that alter neurodevelopment in ways leading to autism and other autism-spectrum disorders, including the glutamate/autism papers of Russell Blaylock, M.D. (33-36) and a related new finding (37).

References:

1. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders
Herbert MR.
Curr Opin Neurol. 2010 Apr;23(2):103-10.
http://www.ncbi.nlm.nih.gov/pubmed/20087183

PURPOSE OF REVIEW: This review presents a rationale and evidence for contributions of environmental influences and environmentally vulnerable physiology to autism spectrum disorders (ASDs). RECENT FINDINGS: Recent studies suggest a substantial increase in ASD prevalence above earlier Centers for Disease Control figures of one in 150, only partly explicable by data artifacts, underscoring the possibility of environmental contributors to increased prevalence. Some gene variants in ASD confer altered vulnerability to environmental stressors and exposures. De-novo mutations and advanced parental age as a risk factor for ASD also suggest a role for environment. Systemic and central nervous system pathophysiology, including oxidative stress, neuroinflammation, and mitochondrial dysfunction can be consistent with a role for environmental influence (e.g. from air pollution, organophosphates, heavy metals) in ASD, and some of the underlying biochemical disturbances (such as abnormalities in glutathione, a critical antioxidant and detoxifier) can be reversed by targeted nutritional interventions. Dietary factors and food contaminants may contribute risk. Improvement and loss of diagnosis in some with ASD suggest brain circuitry amenable to environmental modulation. SUMMARY: Prevalence, genetic, exposure, and pathophysiological evidence all suggest a role for environmental factors in the inception and lifelong modulation of ASD. This supports the need for seeking targets for early and ongoing medical prevention and treatment of ASD

2. Mechanistic biomarkers for autism treatment
Hendren RL, Bertoglio K, Ashwood P, Sharp F.
Med Hypotheses. 2009 Dec;73(6):950-4.
$ http://tinyurl.com/y8g3n25

OBJECTIVE: Autism is a syndrome with a number of etiologies with differing mechanisms that lead to abnormal development. This review highlights the need to identify autism subgroups as they each might require unique approaches for prevention or treatment. METHODS: Targeting treatments to specific mechanisms and utilizing biomarkers can more rapidly advance our understanding of how to classify and treat autism subgroups based on translational mechanisms. We illustrate this approach using mechanisms that may influence the course of autism and provide rationale for selected biomarkers that could guide treatments targeted anywhere from DNA to symptom expression. CONCLUSIONS: The use of potential biomarkers that point to specific mechanisms of disordered neurodevelopment will help identify meaningful subtypes of autism and will help tailor treatment or prevention strategies for each mechanism rather than solely to a symptom category.

3. Understanding and Determining the Etiology of Autism
Currenti SA.
State University of New York (SUNY)
Cell Mol Neurobiol. 2009 Sep 23. [Epub ahead of print]
$ http://www.springerlink.com/content/e11208l0226n65t7/

Worldwide, the rate of autism has been steadily rising. There are several environmental factors in concert with genetic susceptibilities that are contributing to this rise. Impaired methylation and mutations of mecp2 have been associated with autistic spectrum disorders, and related Rett syndrome. Genetic polymorphisms of cytochrome P450 enzymes have also been linked to autism, specifically CYP27B1 that is essential for proper vitamin D metabolism. Vitamin D is important for neuronal growth and neurodevelopment, and defects in metabolism or deficiency have been implicated in autistic individuals. Other factors that have been considered include: maternally derived antibodies, maternal infection, heavy metal exposure, folic acid supplementation, epigenetics, measles, mumps, rubella vaccination, and even electromagnetic radiation. In each case, the consequences, whether direct or indirect, negatively affect the nervous system, neurodevelopment, and environmental responsive genes. The etiology of autism is a topic of controversial debate, while researchers strive to achieve a common objective. The goal is to identify the cause(s) of autism to understand the complex interplay between environment and gene regulation. There is optimism that specific causes and risk factors will be identified. The results of future investigations will facilitate enhanced screening, prevention, and therapy for "at risk" and autistic patients.

4. Advances in autism
Geschwind DH.
David Geffen School of Medicine
Annu Rev Med. 2009;60:367-80.
$ http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.med.60.053107.121225

Autism is a common childhood neurodevelopmental disorder with strong genetic liability. It is not a unitary entity but a clinical syndrome, with variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Recent advances in the genetics of autism emphasize its etiological heterogeneity, with each genetic susceptibility locus accounting for only a small fraction of cases or having a small effect. Therefore, it is not surprising that no unifying structural or neuropathological features have been conclusively identified. Given the heterogeneity of autism spectrum disorder (ASD), approaches based on studying heritable components of the disorder, or endophenotypes, such as language or social cognition, provide promising avenues for genetic and neurobiological investigations. Early intensive behavioral and cognitive interventions are efficacious in many cases, but autism does not remit in the majority of children. Therefore, development of targeted therapies based on pathophysiologically and etiologically defined subtypes of ASD remains an important and achievable goal of current research.

5. Bridging from Cells to Cognition in Autism Pathophysiology: Biological Pathways to Defective Brain Function and Plasticity
Anderson MP, Hooker BS, Herbert MR.
American Journal of Biochemistry and Biotechnology 4(2): 167-176 , 2008
http://www.scipub.org/fulltext/ajbb/ajbb42167-176.pdf

We review evidence to support a model where the disease process underlying autism may begin when an in utero or early postnatal environmental, infectious, seizure, or autoimmune insult triggers an immune response that increases reactive oxygen species (ROS) production in the brain that leads to DNA damage (nuclear and mitochondrial) and metabolic enzyme blockade and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with damaged DNA and impaired metabolic enzyme function may generate additional ROS which will cause persistent activation of the innate immune system leading to more ROS production. Such a mechanism would self-sustain and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Beyond the direct effects of ROS on neuronal function, receptors on neurons that bind the inflammatory mediators may serve to inhibit neuronal signaling to protect them from excitotoxic damage during various pathologic insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.

6. The Role of Neurodevelopmental Genes in Infectious Etiology of Autism
Fatemi SH.
American Journal of Biochemistry and Biotechnology 4(2): 177-182 , 2008
http://www.scipub.org/fulltext/ajbb/ajbb42177-182.pdf

7. Environmental Factors and Limbic Vulnerability in Childhood Autism
Lathe R.
American Journal of Biochemistry and Biotechnology 4(2): 183-197, 2008
http://www.scipub.org/fulltext/ajbb/ajbb42183-197.pdf

The rise in prevalence of autism spectrum disorders (ASD) is suggestive of a new etiology. Diagnostic substitution alone is unlikely to account for the increase, while genetic association with detoxification gene alleles points to an environmental contribution. Subtle structural anomalies in the ASD brain are widespread but limbic damage seems important for the development of behaviors diagnostic of ASD. The limbic brain is especially susceptible to environmental challenge: internal sensing, physiological feedback and neuroinflammatory processes may underlie this sensitivity to insult. Primary damage leading to ASD in later life is likely to take place in utero and/or in the immediate postnatal period. Despite evidence of heavy metal involvement, a causal connection may not yet be concluded because subjects exposed to metals tend to be exposed to other environmental agents. Because maternal minerals and lipids are supplied to the unborn child, historic toxic exposure of the mother may be pivotal. A two-hit combination of genetic susceptibility and environmental challenge is argued to underlie the rise in ASD.

8. Immunologic and neurodevelopmental susceptibilities of autism
Pessah IN et al.
University of California, Davis
Neurotoxicology. 2008 May;29(3):532-45. Epub 2008 Feb 23.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475601/pdf/nihms55471.pdf

Symposium 5 focused on research approaches that are aimed at understanding common patterns of immunological and neurological dysfunction contributing to neurodevelopmental disorders such as autism and ADHD. The session focused on genetic, epigenetic, and environmental factors that might act in concert to influence autism risk, severity and co-morbidities, and immunological and neurobiological targets as etiologic contributors. The immune system of children at risk of autism may be therefore especially susceptible to psychological stressors, exposure to chemical triggers, and infectious agents. Identifying early biomarkers of risk provides tangible approaches toward designing studies in animals and humans that yield a better understanding of environmental risk factors, and can help identify rational intervention strategies to mitigate these risks.

9. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis
Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M.
Northeastern University, Boston
Neurotoxicology. 2008 Jan;29(1):190-201. Epub 2007 Oct 13.

Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.

10. Autism and environmental genomics
Herbert MR et al.
Massachusetts General Hospital, Harvard Medical School
Neurotoxicology. 2006 Sep;27(5):671-84.
http://www.marthaherbert.com/Herbert%202006%20aut%20&%20env%20genomics%20finalpub.pdf

Autism spectrum disorders (ASD) are defined by behavior and diagnosed by clinical history and observation but have no biomarkers and are presumably, etiologically and biologically heterogeneous. Given brain abnormalities and high monozygotic concordance, ASDs have been framed as neurobiologically based and highly genetic, which has shaped the research agenda and in particular criteria for choosing candidate ASD genes. Genetic studies to date have not uncovered genes of strong effect, but a move toward "genetic complexity" at the neurobiological level may not suffice, as evidence of systemic abnormalities (e.g. gastrointestinal and immune), increasing rates and less than 100% monozygotic concordance support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors. We review this evidence and also use a bioinformatic approach to explore the possibility that "environmentally responsive genes" not specifically associated with the nervous system, but potentially associated with systemic changes in autism, have not hitherto received sufficient attention in autism genetics investigations. We overlapped genes from NIEHS Environmental Genome Project, the Comparative Toxicogenomics Database, and the SeattleSNPs database of genes relevant to the human immune and inflammatory response with linkage regions identified in published autism genome scans. We identified 135 genes in overlap regions, of which 56 had never previously been studied in relation to autism and 47 had functional SNPs (in coding regions). Both our review and the bioinformatics exercise support the expansion of criteria for evaluating the relevance of genes to autism risk to include genes related to systemic impact and environmental responsiveness. This review also suggests the utility of environmental genomic resources in highlighting the potential relevance of particular genes within linkage regions. Environmental responsiveness and systems impacts consistent with system-wide findings in autism are thus supported as important considerations in identifying the numerous and complex modes of gene-environment interaction in autism.

11. Determinants of serum concentrations of organochlorine compounds in Swedish pregnant women: a cross-sectional study
Glynn A, Aune M, Darnerud PO, Cnattingius S, Bjerselius R, Becker W, Lignell S.
Environ Health. 2007 Feb 1;6:2.
http://www.ehjournal.net/content/6/1/2

BACKGROUND: We performed a cross-sectional study of associations between personal characteristics and lipid-adjusted serum concentrations of certain PCB congeners and chlorinated pesticides/metabolites among 323 pregnant primiparous women from Uppsala County (age 18-41 years) sampled 1996-1999. METHODS: Extensive personal interviews and questionnaires about personal characteristics were performed both during and after pregnancy. Concentrations of organochlorine compounds in serum lipids in late pregnancy were analysed by gas chromatography. Associations between personal characteristics and serum levels of organochlorine compounds were analysed by multiple linear regression. RESULTS: Participation rate was 82% (325 of 395 women). Serum concentrations of PCB congeners IUPAC no. 28, 52, 101, 105 and 167, and o, p'-DDT and -DDE, p, p'-DDT and -DDD, oxychlordane, and gamma- and alpha-HCH were in many cases below the limit of quantification (LOQ). No statistical analysis of associations with personal characteristics could be performed for these substances. Concentrations of PCB congeners IUPAC no. 118, 138, 153, 156 and 180, HCB, beta-HCH, trans-nonachlor and p, p'-DDE increased with increased age and were highest in women sampled early during the 4 year study period. This shows that older women and women sampled early in the study had experienced the highest life-time exposure levels, probably mainly during childhood and adolescence. The importance of early exposures was supported by lower PCB concentrations and higher beta-HCH and p, p'-DDE concentrations among women born in non-Nordic countries. Moreover, serum concentrations of certain PCBs and pesticide/metabolites were positively associated with consumption of fatty fish during adolescence, and concentrations of CB 156, CB 180 and p, p'-DDE increased significantly with number of months women had been breast-fed during infancy. Short-term changes in bodily constitution may, however, also influence serum concentrations, as suggested by negative associations between concentrations of organochlorine compounds and BMI before pregnancy and weight change during pregnancy. CONCLUSION: Although some of the associations could be caused by unknown personal characteristics confounding the results, our findings suggest that exposures to organochlorine compounds during childhood and adolescence influence the body burdens of the compounds during pregnancy.

12. A possible central mechanism in autism spectrum disorders, part 1.
Blaylock RL.
Altern Ther Health Med. 2008 Nov-Dec;14(6):46-53.

The autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders that have been increasing in incidence since the 1980s. Despite a considerable amount of data being collected from cases, a central mechanism has not been offered. A careful review of ASD cases discloses a number of events that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link between excessive vaccination, use of aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis, and abnormal formation of the developing brain. It has now been shown that chronic microglial activation is present in autistic brains from age 5 years to age 44 years. A considerable amount of evidence, both experimental and clinical, indicates that repeated microglial activation can initiate priming of the microglia and that subsequent stimulation can produce an exaggerated microglial response that can be prolonged. It is also known that one phenotypic form of microglia activation can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate and quinolinic acid. Studies have shown that careful control of brain glutamate levels is essential to brain pathway development and that excesses can result in arrest of neural migration, as well as dendritic and synaptic loss. It has also been shown that certain cytokines, such as TNF-alpha, can, via its receptor, interact with glutamate receptors to enhance the neurotoxic reaction. To describe this interaction I have coined the term immunoexcitotoxicity, which is described in this article.

13. A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity
Blaylock RL.
Altern Ther Health Med. 2009 Jan-Feb;15(1):60-7.

In this section, I explore the effects of mercury and inflammation on transsulfuration reactions, which can lead to elevations in androgens, and how this might relate to the male preponderance of autism spectrum disorders (ASD). It is known that mercury interferes with these biochemical reactions and that chronically elevated androgen levels also enhance the neurodevelopmental effects of excitotoxins. Both androgens and glutamate alter neuronal and glial calcium oscillations, which are known to regulate cell migration, maturation, and final brain cytoarchitectural structure. Studies have also shown high levels of DHEA and low levels of DHEA-S in ASD, which can result from both mercury toxicity and chronic inflammation. Chronic microglial activation appears to be a hallmark of ASD. Peripheral immune stimulation, mercury, and elevated levels of androgens can all stimulate microglial activation. Linked to both transsulfuration problems and chronic mercury toxicity are elevations in homocysteine levels in ASD patients. Homocysteine and especially its metabolic products are powerful excitotoxins. Intimately linked to elevations in DHEA, excitotoxicity and mercury toxicity are abnormalities in mitochondrial function. A number of studies have shown that reduced energy production by mitochondria greatly enhances excitotoxicity. Finally, I discuss the effects of chronic inflammation and elevated mercury levels on glutathione and metallothionein.

14. A possible central mechanism in autism spectrum disorders, part 3: the role of excitotoxin food additives and the synergistic effects of other environmental toxins
Blaylock RL.
Altern Ther Health Med. 2009 Mar-Apr;15(2):56-60.

There is compelling evidence from a multitude of studies of various design indicating that foodborne excitotoxin additives can elevate blood and brain glutamate to levels known to cause neurodegeneration and in the developing brain, abnormal connectivity. Excitotoxins are also secreted by microglial activation when they are in an activated state. Recent studies, discussed in part 1 of this article, indicate that chronic microglial activation is common in the autistic brain. The interaction between excitotoxins, free radicals, lipid peroxidation products, inflammatory cytokines, and disruption of neuronal calcium homeostasis can result in brain changes suggestive of the pathological findings in cases of autism spectrum disorders. In addition, a number of environmental neurotoxins, such as fluoride, lead, cadmium, and aluminum, can result in these pathological and biochemical changes.

15. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders
Blaylock RL, Strunecka A.
Curr Med Chem. 2009;16(2):157-70.
http://www.generationrescue.org/blaylock/Immunoexcitotoxicity.pdf

Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.

16. Pathogenesis of autism: a patchwork of genetic causes
Grigorenko EL.
Child Study Center, Yale University
Future Neurol. 2009;4(5):591-599.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785085/pdf/nihms155248.pdf

Autism spectrum disorders (ASDs) are relatively infrequent but are devastating developmental conditions characterized by marked deficiencies in social, communicative and other behavioral domains. It has been known for a substantial period of time that these disorders are genetic in nature. However, elucidating the specific mechanisms of these disorders has been difficult. A major reason for such difficulty is the recognized genetic heterogeneity of ASDs. Specifically, many genetic mechanisms related to structural variations in the genome have been reported as possible genetic causes of these disorders. This review briefly exemplifies these genetic mechanisms, presents a concise overview of the evidence for the genetic basis of ASDs and provides an appraisal of the specific structural genetic variants thought to contribute to the pathogenesis of these complex disorders.

17. Prenatal influences on brain dopamine and their relevance to the rising incidence of autism
Previc FH.
Med Hypotheses. 2007;68(1):46-60. Epub 2006 Sep 7.
$ http://linkinghub.elsevier.com/retrieve/pii/S0306-9877%2806%2900497-X

The incidence of autism has risen 10-fold since the early 1980s, with most of this rise not explainable by changing diagnostic criteria. The rise in autism is paradoxical in that autism is considered to be one of the most genetically determined of the major neurodevelopmental disorders and should accordingly either be stable or even declining. Because a variety of epigenetic influences, particularly those occurring during the prenatal period, can override or masquerade as genetic influences, these should be considered as prime contributors to the recent increase of autism. Prenatal influences on dopamine activity are especially well-documented, including the effects of maternal psychosocial stress, maternal fever, maternal genetic and hormonal status, use of certain medications, urban birth, and fetal hypoxia. All of these factors have been implicated in the genesis of autism, which is characterized by a "hyperdopaminergic" state based on evidence from monkey and human behavioral studies, pharmacological studies in humans, and a left-hemispheric predominance of both dopamine and autistic-like symptoms. Chronically high maternal levels of dopamine caused by the pressures of increasingly urbanized societies and by changing maternal demographics such as increased workforce participation, educational achievement level, and age at first birth, may be especially significant epigenetic contributors to the recent autism rise.

18. Syndromic autism: causes and pathogenetic pathways
Benvenuto A, Moavero R, Alessandrelli R, Manzi B, Curatolo P.
World J Pediatr. 2009 Aug;5(3):169-76. Epub 2009 Aug 20.
$ http://www.springerlink.com/content/750436n438624758/

BACKGROUND: Autism is a severe neurodevelopmental disorder known to have many different etiologies. In the last few years, significant progresses have been made in comprehending the causes of autism and their multiple impacts on the developing brain. This article aims to review the current understanding of the etiologies and the multiple pathogenetic pathways that are likely to lead to the autistic phenotype. DATA SOURCES: The PubMed database was searched with the keywords "autism" and "chromosomal abnormalities", "metabolic diseases", "susceptibility loci". RESULTS: Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems. CONCLUSIONS: A wide variety of cytogenetic abnormalities have been recently described, particularly in the low functioning individuals with dysmorphic features. Routine metabolic screening studies should be performed in the presence of autistic regression or suggestive clinical findings. As etiologies of autism are progressively discovered, the number of individuals with idiopathic autism will progressively shrink. Studies of genetic and environmentally modulated epigenetic factors are beginning to provide some clues to clarify the complexities of autism pathogenesis. The role of the neuropediatrician will be to understand the neurological basis of autism, and to identify more homogenous subgroups with specific biologic markers.

19. The Association Between Autism and Errors in Early Embryogenesis: What Is the Causal Mechanism?
Ploeger A, Raijmakers ME, van der Maas HL, Galis F.
University of Amsterdam
Biol Psychiatry. 2009 Nov 20. [Epub ahead of print]

The association between embryonic errors and the development of autism has been recognized in the literature, but the mechanism underlying this association remains unknown. We propose that pleiotropic effects during a very early and specific stage of embryonic development-early organogenesis-can explain this association. In humans early organogenesis is an embryonic stage, spanning Day 20 to Day 40 after fertilization, which is characterized by intense interactivity among body parts of the embryo. This implies that a single mutation or environmental disturbance affecting development at this stage can have several phenotypic effects (i.e., pleiotropic effects). Disturbances during early organogenesis can lead to many different anomalies, including limb deformities, craniofacial malformations, brain pathology, and anomalies in other organs. We reviewed the literature and found ample evidence for the association between autism and different kinds of physical anomalies, which agrees with the hypothesis that pleiotropic effects are involved in the development of autism. The proposed mechanism integrates findings from a variety of studies on autism, including neurobiological studies and studies on physical anomalies and prenatal influences on neurodevelopmental outcomes. The implication is that the origin of autism can be much earlier in embryologic development than has been frequently reported.

20. Similarities in features of autism and asthma and a possible link to acetaminophen use
Becker KG, Schultz ST.
Med Hypotheses. 2010 Jan;74(1):7-11. Epub 2009 Sep 11.
$ http://www.medical-hypotheses.com/article/S0306-9877%2809%2900570-2/abstract

Autism and autism spectrum disorders are enigmatic conditions that have their origins in the interaction of genes and environmental factors. In this hypothesis, genes statistically associated with autism are emphasized to be important in inflammation and in innate immune pathways, including pathways for susceptibility to asthma. The role of acetaminophen (paracetamol) in an increased risk for asthma is described and a possible similar link to an increased risk for autism is suggested.

21. Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6-8 years of age
Larsson M, Weiss B, Janson S, Sundell J, Bornehag CG.
Karlstad University, Health and Environmental Sciences, Sweden.
Neurotoxicology. 2009 Sep;30(5):822-31. Epub 2009 Feb 10.
$ http://tinyurl.com/y8s8yxs

Potential contributions of environmental chemicals and conditions to the etiology of Autism Spectrum Disorders are the subject of considerable current research and speculation. The present paper describes the results of a study undertaken as part of a larger project devoted to the connection between properties of the indoor environment and asthma and allergy in young Swedish children. The larger project, The Dampness in Buildings and Health (DBH) Study, began in the year 2000 with a questionnaire distributed to parents of all children 1-6 years of age in one Swedish county (DBH-I). A second, follow-up questionnaire (DBH-III) was distributed in 2005. The original survey collected information about the child, the family situation, practices such as smoking, allergic symptoms, type of residence, moisture-related problems, and type of flooring material, which included polyvinyl chloride (PVC). The 2005 survey, based on the same children, now 6-8 years of age, also asked if, during the intervening period, the child had been diagnosed with Autism, Asperger's syndrome, or Tourette's syndrome. From a total of 4779 eligible children, 72 (60 boys, 12 girls) were identified with parentally reported autism spectrum disorder. A random sample of 10 such families confirmed that the diagnoses had been made by medical professionals, in accordance with the Swedish system for monitoring children's health. An analysis of the associations between indoor environmental variables in 2000 as well as other background factors and the ASD diagnosis indicated five statistically significant variables: (1) maternal smoking; (2) male sex; (3) economic problems in the family; (4) condensation on windows, a proxy for low ventilation rate in the home; (5) PVC flooring, especially in the parents' bedroom. In addition, airway symptoms of wheezing and physician-diagnosed asthma in the baseline investigation (2000) were associated with ASD 5 years later. Results from the second phase of the DBH-study (DBH-II) indicate PVC flooring to be one important source of airborne phthalates indoors, and that asthma and allergy prevalence are associated with phthalate concentrations in settled dust in the children's bedroom. Because these associations are among the few linking ASD with environmental variables, they warrant further and more extensive exploration.

22. Did acetaminophen provoke the autism epidemic?
Good P.
Altern Med Rev. 2009 Dec;14(4):364-72.

Schultz et al (2008) raised the question whether regression into autism is triggered, not by the measles-mumps-rubella (MMR) vaccine, but by acetaminophen (Tylenol) given for its fever and pain. Considerable evidence supports this contention, most notably the exponential rise in the incidence of autism since 1980, when acetaminophen began to replace aspirin for infants and young children. The impetus for this shift - a Centers for Disease Control and Prevention warning that aspirin was associated with Reye's syndrome - has since been compellingly debunked. If aspirin is not to be feared as a cause of Reyes syndrome, and acetaminophen is to be feared as a cause of autism, can the autism epidemic be reversed by replacing acetaminophen with aspirin or other remedies?

23. [Parker-Athill et al has significance for maternal vaccinations & maternal illness during pregnancy]

Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism
Parker-Athill E et al.
University of South Florida
J Neuroimmunol. 2009 Dec 10;217(1-2):20-7. Epub 2009 Sep 18.
$ http://www.jni-journal.com/article/S0165-5728%2809%2900316-6/abstract

Maternal immune activation (MIA) can affect fetal brain development and thus behavior of young and adult offspring. Reports have shown that increased Interleukin-6 (IL-6) in the maternal serum plays a key role in altering fetal brain development, and may impair social behaviors in the offspring. Interestingly, these effects could be attenuated by blocking IL-6. The current study investigated the effects of luteolin, a citrus bioflavonoid, and its structural analog, diosmin, on IL-6 induced JAK2/STAT3 (Janus tyrosine kinase-2/signal transducer and activator of transcription-3) phosphorylation and signaling as well as behavioral phenotypes of MIA offspring. Luteolin and diosmin inhibited neuronal JAK2/STAT3 phosphorylation both in vitro and in vivo following IL-6 challenge as well as significantly diminishing behavioral deficits in social interaction. Importantly, our results showed that diosmin (10mg/kgday) was able to block the STAT3 signal pathway; significantly opposing MIA-induced abnormal behavior and neuropathological abnormalities in MIA/adult offspring. Diosmin's molecular inhibition of JAK2/STAT3 pathway may underlie the attenuation of abnormal social interaction in IL-6/MIA adult offspring.

24. Autism: an emerging 'neuroimmune disorder' in search of therapy
Theoharides TC, Kempuraj D, Redwood L.
Tufts University School of Medicine
Expert Opin Pharmacother. 2009 Sep;10(13):2127-43.
$ http://informahealthcare.com/doi/pdf/10.1517/14656560903107789

BACKGROUND: Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by difficulties in communication and by repetitive and stereotypic behaviors, as well as by social impairment, attention, cognitive, and learning defects. ASDs present in early childhood and their prevalence has increased significantly to 1/150 children. Despite a number of theories, the actual reasons for this increase are still not clear. There is no reliable screening test, and no definite pathogenesis or curative therapy. Consequently, there is a major gap hampering development of effective treatments. OBJECTIVE: To review recent publications on ASDs pathogenesis and treatment with emphasis on neuroimmune processes and new therapeutic approaches. METHODS: Mostly original papers (450) on epidemiology, possible pathogenesis or treatment of ASDs in Medline from 1990 to May 2009 were reviewed. All authors contributed to this review. RESULTS/CONCLUSION: Increased oxidative stress and immune dysregulation are present in ASDs. Mast-cell activation may contribute to gut-blood-brain barrier disruption and brain inflammation. No effective treatments have emerged. Well-designed clinical trials with nonpsychotropic drugs were few and ASD characteristics varied considerably, making conclusions difficult. Psychotropic drugs are often used for stereotypic and aggressive behaviors. Unique combinations with antioxidant and anti-inflammatory flavonoids hold promise. New potential translational research areas and possible treatments are suggested.

25. Sensory Processing Subtypes in Autism: Association with Adaptive Behavior
Lane AE, Young RL, Baker AE, Angley MT.
The Ohio State University
J Autism Dev Disord. 2009 Jul 31. [Epub ahead of print]
$ http://www.springerlink.com/content/26u7j0420646g646/

Children with autism are frequently observed to experience difficulties in sensory processing. This study examined specific patterns of sensory processing in 54 children with autistic disorder and their association with adaptive behavior. Model-based cluster analysis revealed three distinct sensory processing subtypes in autism. These subtypes were differentiated by taste and smell sensitivity and movement-related sensory behavior. Further, sensory processing subtypes predicted communication competence and maladaptive behavior. The findings of this study lay the foundation for the generation of more specific hypotheses regarding the mechanisms of sensory processing dysfunction in autism, and support the continued use of sensory-based interventions in the remediation of communication and behavioral difficulties in autism.

26. The co-occurrence of autism and birth defects: prevalence and risk in a population-based cohort
Schendel DE, Autry A, Wines R, Moore C.
Dev Med Child Neurol. 2009 Oct;51(10):779-86. Epub 2009 Mar 30.
$ http://www3.interscience.wiley.com/journal/122295564/abstract

AIM :To estimate the prevalence of major birth defects among children with autism, the prevalence of autism in children with birth defects, and the risk for autism associated with having birth defects. METHOD: Retrospective cohort including all children born in Atlanta, GA, USA, 1986 to 1993, who survived to age 3 years and were identified through Georgia vital records. Children with autism and other developmental disabilities residing in Atlanta at ages 3 to 10 years in 1996 were identified through the Metropolitan Atlanta Developmental Disabilities Surveillance Program. Children with major birth defects through age 6 years were identified by the Metropolitan Atlanta Congenital Defects Program. RESULTS: Birth defects were found among 6% of children with autism (total n=617; 488 males, 129 females) and was associated with a near twofold increased risk for autism overall. However, the risk magnitude and statistical significance varied by type of birth defect. With any type of birth defect, the risk for autism accompanied by intellectual disability or other developmental disabilities was typically higher than the risk for autism alone. A 6:1 to 8:1 male bias was observed among children with autism and a birth defect. INTERPRETATION: Investigation of the association between autism and birth defects is warranted, especially for the role of birth defects in autism among sex-specific or autism subgroups.

27. Clinical Characteristics Associated with Language Regression for Children with Autism Spectrum Disorders
Jones LA, Campbell JM.
University of Georgia
J Autism Dev Disord. 2009 Jul 25. [Epub ahead of print]
$ http://www.springerlink.com/content/57271g6333300050/

We investigated correlates of language regression for children diagnosed with autism spectrum disorders (ASD). Using archival data, children diagnosed with ASD (N = 114, M age = 41.4 months) were divided into four groups based on language development (i.e., regression, plateau, general delay, no delay) and compared on developmental, adaptive behavior, symptom severity, and behavioral adjustment variables. Few overall differences emerged between groups, including similar non-language developmental history, equal risk for seizure disorder, and comparable behavioral adjustment. Groups did not differ with respect to autism symptomatology as measured by the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised. Language plateau was associated with better adaptive social skills as measured by the Vineland Adaptive Behavior Scales. Implications and study limitations are discussed.

28. Estimated autism risk and older reproductive age.
King MD, Fountain C, Dakhlallah D, Bearman PS.
Columbia University
Am J Public Health. 2009 Sep;99(9):1673-9. Epub 2009 Jul 16.
$ http://ajph.aphapublications.org/cgi/content/full/99/9/1673?view=long&pmid=19608957

OBJECTIVES: We sought to estimate the risk for autism associated with maternal and paternal age across successive birth cohorts. METHODS: We linked birth records and autism diagnostic records from the California Department of Developmental Services for children born in California between 1992 and 2000 to calculate the risk associated with maternal and paternal age for each birth cohort as well as for the pooled data. RESULTS: The categorical risks associated with maternal age over 40 years ranged from a high of 1.84 (95% confidence interval [CI] = 1.37, 2.47) to a low of 1.27 (95% CI = 0.95, 1.69). The risk associated with paternal age ranged from 1.29 (95% CI = 1.03, 1.6) to 1.71 (95% CI = 1.41, 2.08). CONCLUSIONS: Pooling data across multiple birth cohorts inflates the risk associated with paternal age. Analyses that do not suffer from problems produced by pooling across birth cohorts demonstrated that advanced maternal age, rather than paternal age, may pose greater risk. Future research examining parental age as a risk factor must be careful to avoid the paradoxes that can arise from pooling data, particularly during periods of social demographic change.

29. What are infant siblings teaching us about autism in infancy?
Rogers SJ.
University of California Davis
Autism Res. 2009 Jun;2(3):125-37.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791538/pdf/nihms149156.pdf

International research to understand infant patterns of development in autism spectrum disorders (ASDs) has recently focused on a research paradigm involving prospective longitudinal studies of infant siblings of children with autism. Such designs use a comparison group of infant siblings without any familial risks (the low-risk group) to gather longitudinal information about developmental skills across the first 3 years of life, followed by clinical diagnosis of ASD at 36 months. This review focuses on five topics: presence of ASD in the infant sibling groups, patterns and characteristics of motor development, patterns and characteristics of social and emotional development, patterns and characteristics of intentional communication, both verbal and nonverbal, and patterns that mark the onset of behaviors pathognomonic for ASD. Symptoms in all these areas typically begin to be detected during the age period of 12-24 months in infants who will develop autism. Onset of the symptoms occurs at varying ages and in varying patterns, but the pattern of frank loss of skills and marked regression reported from previous retrospective studies in 20-30% of children is seldom reported in these infant sibling prospective studies. Two surprises involve the very early onset of repetitive and unusual sensory behaviors, and the lack of predictive symptoms at the age of 6 months. Contrary to current views that autism is a disorder that profoundly affects social development from the earliest months of life, the data from these studies presents a picture of autism as a disorder involving symptoms across multiple domains with a gradual onset that changes both ongoing developmental rate and established behavioral patterns across the first 2-3 years of life.

30. Developmental regression in children with an autism spectrum disorder identified by a population-based surveillance system
Wiggins LD, Rice CE, Baio J.
Centers for Disease Control and Prevention, Atlanta, USA. lwiggins@cdc.gov
Autism. 2009 Jul;13(4):357-74.
$ http://aut.sagepub.com/cgi/reprint/13/4/357

This study evaluated the phenomenon of autistic regression using population-based data. The sample comprised 285 children who met the autism spectrum disorder (ASD) case definition within an ongoing surveillance program. Results indicated that children with a previously documented ASD diagnosis had higher rates of autistic regression than children who met the ASD surveillance definition but did not have a clearly documented ASD diagnosis in their records (17-26 percent of surveillance cases). Most children regressed around 24 months of age and boys were more likely to have documented regression than girls. Half of the children with regression had developmental concerns noted prior to the loss of skills. Moreover, children with autistic regression were more likely to show certain associated features, including cognitive impairment.These data indicate that some children with ASD experience a loss of skills in the first few years of life and may have a unique symptom profile.

31. Regression in autism: prevalence and associated factors in the CHARGE Study.
Hansen RL et al.
Ambul Pediatr. 2008 Jan-Feb;8(1):25-31.

OBJECTIVE: The aim of this study was to examine the prevalence of regressive autism and associated demographic, medical, and developmental factors by using 2 different definitions of regression based on the Autism Diagnostic Interview, Revised. METHODS: Subjects were aged 2 to 5 years, with autism (AU) or autism spectrum disorder (ASD) confirmed by standardized measures. Children with regression, defined as a) loss of both language and social skills or b) loss of either language or social skills, were compared with each other and to children with AU or ASD with no reported loss of skills on developmental and adaptive functioning. Parents reported on seizure, gastrointestinal, and sleep concerns. RESULTS: Fifteen percent (50/333) of the combined AU-ASD group lost both language and social skills; 41% (138/333) lost either language or social skills. No differences were found between the 2 samples of children with regression. Few developmental, demographic, or medical differences were found between the combined regression group and children without loss of skills, in both the larger AU-ASD sample and the more homogeneous AU-only sample. Children with regression had significantly lower communication scores than children without regression. CONCLUSIONS: The prevalence of regression in a large sample of young children with AU and ASD varies depending on the definition used; requiring loss of language significantly underestimates the frequency of developmental regression. Children with regression performed significantly less well than those without regression on 2 measures of communication, but the clinical meaningfulness of these differences is uncertain because of the small effect sizes.

32. A Prospective Study of the Emergence of Early Behavioral Signs of Autism
Ozonoff S et al.
J Am Acad Child Adol Psychiatry 2010 Mar;49(3):256-266.
http://www.jaacap.com/article/S0890-8567%2809%2900031-8/abstract

Objective: To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism.
Method: A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners.
Results: The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child's development.
Conclusions: These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.

33. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders.
Blaylock RL, Strunecka A.
Curr Med Chem. 2009;16(2):157-70. Review.

34. A possible central mechanism in autism spectrum disorders, part 1.
Blaylock RL.
Altern Ther Health Med. 2008 Nov-Dec;14(6):46-53. Review.

35. A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity.
Blaylock RL.
Altern Ther Health Med. 2009 Jan-Feb;15(1):60-7.


36. A possible central mechanism in autism spectrum disorders, part 3: the role of excitotoxin food additives and the synergistic effects of other environmental toxins.
Blaylock RL.
Altern Ther Health Med. 2009 Mar-Apr;15(2):56-60.

37. . Increased serum levels of high mobility group box 1 protein in patients with autistic disorder.
Emanuele E, Boso M, Brondino N, Pietra S, Barale F, di Nemi SU, Politi P.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Mar 16. [Epub ahead of print]

BACKGROUND: High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics. METHODS: We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6ng/mL versus 5.6+/-2.5ng/mL, respectively, P<0.001). After adjustment for potential confounders, serum HMGB1 levels were independently associated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. CONCLUSIONS: These results suggest that HMGB1 levels may be affected in autistic disorder. Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder.

{See a list of related articles and see also here}

This document prepared by
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 2010