Causes of autism

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Many causes of autism have been proposed, but understanding of the theory of causation of autism and the other autism spectrum disorders is incomplete.[1] Research indicates that genetic factors predominate. The heritability of autism, however, is complex, and it is typically unclear which genes are responsible.[2] In rare cases, autism is strongly associated with agents that cause birth defects.[3] Many other causes have been proposed, such as childhood immunizations, but numerous clinical studies have shown no scientific evidence supporting any link between vaccinations and autism.[4]

Autism and related disorders[edit]

Autism involves abnormalities of brain development and behavior which become apparent before a child is three years old and have a steady course with no remission. It is characterized by impairments in social interaction and communication, as well as restricted interests and stereotyped behavior, and the characterization is independent of any underlying neurological defects.[5][6] This article uses autism to denote the classical autism and ASD (autism spectrum disorders) to denote the wider family.

Autism's theory of causation is incomplete.[1] It has long been presumed that there is a common cause at the genetic, cognitive, and neural levels for autism's characteristic triad of symptoms.[7] However, there is increasing suspicion among researchers that autism does not have a single cause, but is instead a complex disorder with a set of core aspects that have distinct causes.[7][8] Different underlying brain dysfunctions have been hypothesized to result in the common symptoms of autism, just as completely different brain problems result in intellectual disability. The terms autisms or ASDs capture the wide range of disease processes at work.[9] Although these distinct causes have been hypothesized to often co-occur,[8] it has also been suggested that the correlation between the causes has been exaggerated.[10] The number of people known to have autism has increased dramatically since the 1980s, at least partly due to changes in diagnostic practice. It is unknown whether prevalence has increased as well.[11]

The consensus among mainstream autism researchers is that genetic factors predominate. Environmental factors that have been claimed to contribute to autism or exacerbate its symptoms, or may be important to consider in future research, include certain foods,[12] infectious disease, heavy metals, solvents, diesel exhaust, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, and vaccines.[11] Among these factors, vaccines have attracted much attention, as parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks. However, there is overwhelming scientific evidence showing no causal association between the measles-mumps-rubella vaccine and autism, and there is no scientific evidence that the vaccine preservative thiomersal helps cause autism.[4][13]

Genetics[edit]

Genetic factors may be the most significant cause for autism spectrum disorders. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism.[2] However, this may be an overestimate, as new twin data and models with structural genetic variation are needed.[14] Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%.[15]

The genetics of autism are complex.[2] Linkage analysis has been inconclusive; many association analyses have had inadequate power.[14] More than one gene may be implicated, different genes may be involved in different individuals, and the genes may interact with each other or with environmental factors. Several candidate genes have been located,[16] but the mutations that increase autism risk have not been identified for most candidate genes. A substantial fraction of autism may be highly heritable but not inherited because the mutation that causes the autism is not present in the parental genome.[17]

Though autism's genetic factors explain most of the risk of developing autism, they do not explain all of it. A common hypothesis is that autism is caused by the interaction of a genetic predisposition and an early environmental insult.[1] Several theories based on environmental factors have been proposed to address the remaining risk. Some of these theories focus on prenatal environmental factors, such as agents that cause birth defects, and others focus on the environment after birth, such as children's diets.

Risk factors for autism include parental characteristics such as advanced maternal age and advanced paternal age.[18] The risk is greater for advanced paternal age. One hypothesis is that this is caused by older sperm that have greater mutation burden, and another is that men who carry more genetic liability have some features of autism and therefore marry and have children later. These two hypotheses are not mutually exclusive.[9]

Epigenetics[edit]

Epigenetic mechanisms may increase the risk of autism. Epigenetic changes occur as a result not of DNA sequence changes but of chromosomal histone modification or modification of the DNA bases. Such modifications are known to be affected by environmental factors, including nutrition, drugs, and mental stress.[19] Interest has been expressed in imprinted regions on chromosomes 15q and 7q.[20]

Prenatal environment[edit]

The risk of autism is associated with several prenatal risk factors, including advanced age in either parent, diabetes, bleeding, and use of psychiatric drugs in the mother during pregnancy.[18] Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.[21]

Infectious processes[edit]

Prenatal viral infection has been called the principal non-genetic cause of autism. Prenatal exposure to rubella or cytomegalovirus activates the mother's immune response and greatly increases the risk for autism.[22] Some cases of autism may have infectious or immunological origins.[23] Congenital rubella syndrome is the most convincing environmental cause.[24] Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for psychiatric disorders of presumed neurodevelopmental origin, notably schizophrenia.[25]

Environmental agents[edit]

Teratogens are environmental agents that cause birth defects. Some agents that are theorized to cause birth defects have also been suggested as potential autism risk factors, although there is little to no scientific evidence to back such claims. These include exposure of the embryo to valproic acid,[26] thalidomide or misoprostol.[27] These cases are rare.[28] Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects.[27] All known teratogens appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, it is strong evidence that autism arises very early in development.[3]

Other maternal conditions[edit]

Thyroid problems that lead to thyroxine deficiency in the mother in weeks 8–12 of pregnancy have been postulated to produce changes in the fetal brain leading to autism. Thyroxine deficiencies can be caused by inadequate iodine in the diet, and by environmental agents that interfere with iodine uptake or act against thyroid hormones. Possible environmental agents include flavonoids in food, tobacco smoke, and most herbicides. This hypothesis has not been tested.[29]

Diabetes in the mother during pregnancy is a significant risk factor for autism; a 2009 meta-analysis found that gestational diabetes was associated with a twofold increased risk. Although diabetes causes metabolic and hormonal abnormalities and oxidative stress, no biological mechanism is known for the association between gestational diabetes and autism risk.[18]

Other in utero[edit]

It has been hypothesized that folic acid taken during pregnancy could play a role in causing autism by modulating gene expression through an epigenetic mechanism. This hypothesis is untested.[30]

Prenatal stress, consisting of exposure to life events or environmental factors that distress an expectant mother, has been hypothesized to contribute to autism, possibly as part of a gene-environment interaction. Autism has been reported to be associated with prenatal stress both with retrospective studies that examined stressors such as job loss and family discord, and with natural experiments involving prenatal exposure to storms; animal studies have reported that prenatal stress can disrupt brain development and produce behaviors resembling symptoms of autism.[31]

The fetal testosterone theory hypothesizes that higher levels of testosterone in the amniotic fluid of mothers pushes brain development towards improved ability to see patterns and analyze complex systems while diminishing communication and empathy, emphasizing "male" traits over "female", or in E-S theory terminology, emphasizing "systemizing" over "empathizing". One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism.[32]

Based in part on animal studies, diagnostic ultrasounds administered during pregnancy have been hypothesized to increase the child's risk of autism. This hypothesis is not supported by independently published research, and examination of children whose mothers received an ultrasound has failed to find evidence of harmful effects.[33]

Perinatal environment[edit]

Autism is associated with some perinatal and obstetric conditions. A 2007 review of risk factors found associated obstetric conditions that included low birth weight and gestation duration, and hypoxia during childbirth. This association does not demonstrate a causal relationship. As a result, an underlying cause could explain both autism and these associated conditions.[34] A 2007 study of premature infants found that those who survived cerebellar hemorrhagic injury (bleeding in the brain that injures the cerebellum) were significantly more likely to show symptoms of autism than controls without the injury.[non-primary source needed][35]

Postnatal environment[edit]

A wide variety of postnatal contributors to autism have been proposed, including gastrointestinal or immune system abnormalities, allergies, and exposure of children to drugs, vaccines, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies.[36]

Amygdala neurons[edit]

This theory hypothesizes that an early developmental failure involving the amygdala cascades on the development of cortical areas that mediate social perception in the visual domain. The fusiform face area of the ventral stream is implicated. The idea is that it is involved in social knowledge and social cognition, and that the deficits in this network are instrumental in causing autism.[37]

Opiate excess[edit]

In 1979, Jaak Panksepp proposed a connection between autism and opiates, noting that injections of minute quantities of opiates in young laboratory animals induce symptoms similar to those observed among autistic children.[38] Opiate theory hypothesizes that autism is caused by a digestive disorder present from birth which causes gluten (present in wheat-derived foods) and casein (present in dairy products) to be converted to the opioid peptides gliadorphin (aka gluteomorphin), and casomorphin.

According to the theory, exposure to these opiate compounds in young children interferes with normal neurological development by dulling sensory input. Lacking sufficient sensory input, the developing brain attempts to artificially generate the auditory, vestibular, visual, and tactile input on its own. This attempt at generating input manifests itself as behaviors common to autism, such as grunting or screaming (auditory), spinning or rocking back and forth (vestibular), preoccupation with spinning objects or waving of the fingers in front of the eyes (visual), and hand flapping or self-injury (tactile).

The theory further states that removing opiate precursors from a child's diet may allow time for these behaviors to cease, and neurological development in very young children to resume normally.[39] The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by Kalle Reichelt in 1991.[40] The scientific evidence is not yet adequate to make treatment recommendations regarding diets, such as the GFCF diet, which exclude these substances.[41]

Autoimmune disease[edit]

This theory hypothesizes that autoantibodies that target the brain or elements of brain metabolism may cause or exacerbate autism. It is related to the maternal infection theory, except that it postulates that the effect is caused by the individual's own antibodies, possibly due to an environmental trigger after birth. It is also related to several other hypothesized causes; for example, viral infection has been hypothesized to cause autism via an autoimmune mechanism.[42]

Interactions between the immune system and the nervous system begin early during embryogenesis, and successful neurodevelopment depends on a balanced immune response. It is possible that aberrant immune activity during critical periods of neurodevelopment is part of the mechanism of some forms of ASD.[43] A small percentage of autism cases are associated with infection, usually before birth. Results from immune studies have been contradictory. Some abnormalities have been found in specific subgroups, and some of these have been replicated. It is not known whether these abnormalities are relevant to the pathology of autism, for example, by infection or autoimmunity, or whether they are secondary to the disease processes.[44] As autoantibodies are found in diseases other than ASD, and are not always present in ASD,[45] the relationship between immune disturbances and autism remains unclear and controversial.[46]

When an underlying maternal autoimmune disease is present, antibodies circulating to the fetus could contribute to the development of autism spectrum disorders.[47]

Gastrointestinal connection[edit]

Parents have reported gastrointestinal (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut,[48] but the results so far are inconclusive.

The now-retracted Wakefield et al. paper also suggested that some bowel disorders may allow antigens to pass from food into the bloodstream and then to contribute to brain dysfunction.[49] Although Wakefield later proposed the term autistic enterocolitis, his methodology has been criticized and results have not been replicated by other groups.[50]

There is no research evidence that autistic children are more likely to have GI symptoms than typical children.[48] In particular, design flaws in studies of elimination diets mean that the data are inadequate to guide treatment recommendations.[12]

After a preliminary 1998 study of three children with ASD treated with secretin infusion reported improved GI function and dramatic improvement in behavior, many parents sought secretin treatment and a black market for the hormone developed quickly.[48] Later studies found secretin clearly ineffective in treating autism.[51]

Lack of vitamin D[edit]

There is limited evidence for the hypothesis that vitamin D deficiency has a role in autism, and it may be biologically plausible,[52] but more research is needed.[53]

Lead[edit]

Lead poisoning has been suggested as a possible risk factor for autism, as the lead blood levels of autistic children has been reported to be significantly higher than typical.[54] The atypical eating behaviors of autistic children, along with habitual mouthing and pica, make it hard to determine whether increased lead levels are a cause or a consequence of autism.[54]

Locus coeruleus–noradrenergic system[edit]

This theory hypothesizes that autistic behaviors depend at least in part on a developmental dysregulation that results in impaired function of the locus coeruleusnoradrenergic (LC-NA) system. The LC-NA system is heavily involved in arousal and attention; for example, it is related to the brain's acquisition and use of environmental cues.[55]

Mercury[edit]

This theory hypothesizes that autism is associated with mercury poisoning, based on perceived similarity of symptoms and reports of mercury or its biomarkers in some autistic children.[56] This view has gained little traction in the scientific community as the typical symptoms of mercury toxicity are significantly different from symptoms seen in autism.[57] The principal source of human exposure to organic mercury is via fish consumption and for inorganic mercury is dental amalgams. Other forms of exposure, such as in cosmetics and vaccines, also occur. The evidence so far is indirect for the association between autism and mercury exposure after birth, as no direct test has been reported, and there is no evidence of an association between autism and postnatal exposure to any neurotoxicant.[58] A meta-analysis published in 2007 concluded that there was no link between mercury and autism.[59]

Oxidative stress[edit]

This theory hypothesizes that toxicity and oxidative stress may cause autism in some cases. Evidence includes genetic effects on metabolic pathways, reduced antioxidant capacity, enzyme changes, and enhanced biomarkers for oxidative stress; however, the overall evidence is weaker than it is for involvement oxidative stress with disorders such as schizophrenia.[60] One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved.[61] Autistic children have lower levels of total glutathione, and higher levels of oxidized glutathione.[62] Based on this theory, antioxidants may be a useful treatment for autism.[63]

Paracetamol (acetaminophen)[edit]

A 2008 preliminary case-control study based on a parent survey presented evidence that paracetamol (acetaminophen, Tylenol) following MMR vaccine may be associated with development of autism in children aged 1–5 years.[64] Evidence for the hypothesis is that in the U.S. paracetamol began to replace aspirin for infants and young children in the 1980s, about the same time that the number of known autism cases began to rise. However, a similar rise in autism occurred in France, where children continued to receive aspirin.[64] A 2009 review said that the synchronous surge in autism and use of parcetamol was unlikely to be coincidence.[64] and that there was more autism in children given paracetamol rather than ibuprofen following vaccination.[64]

The strongest support for this hypothesis is a 2013 prospective cohort study which shows that children who had been exposed to paracetamol for more than 28 days of pregnancy had poorer gross motor skills, poor communication skills and more behavioral problems compared with unexposed siblings. The same trend was seen with paracetamol taken for less than 28 days, but this was weaker. The researchers did not find any similar long-term effects after use of ibuprofen.[non-primary source needed][65] Additional support for the paracetamol hypothesis and a plausible hypothesis to explain the male sex bias of autism comes from a 2013 ecologic study. In the mid-1990s, circumcision pain management guidelines began recommending paracetamol. A 98% correlation was found between country level autism prevalence rates and male circumcision rates for CDC reported studies including boys born after 1995. A similar pattern was seen among U.S. states and when comparing the three main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision. This study also found an 80% correlation between country-level prenatal use of paracetamol and autism prevalence.[non-primary source needed][66]

Refrigerator mother[edit]

Child psychologist Bruno Bettelheim believed that autism was linked to early childhood trauma, and his work was highly influential for decades both in the medical and popular spheres. Parents, especially mothers, of individuals with autism were blamed for having caused their child's condition through the withholding of affection.[67] Leo Kanner, who first described autism,[68] suggested that parental coldness might contribute to autism.[69] Although Kanner eventually renounced the theory, Bettelheim put an almost exclusive emphasis on it in both his medical and his popular books. Treatments based on these theories failed to help children with autism, and after Bettelheim's death, it came out that his reported rates of cure (around 85%) were found to be fraudulent.[70]

Vaccines[edit]

There is no evidence of a causal relationship between vaccinations and autism.[71][72] Despite this, many parents believe that vaccinations cause autism and therefore delay or avoid immunizing their children under the "vaccine overload" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism[73] even though this hypothesis has no scientific evidence and is biologically implausible.[74] As diseases like measles can cause severe disabilities and death, the risk of a child's death or disability due to not vaccinating a child is significantly larger than any minuscule risks due to vaccinating.[75]

MMR vaccine[edit]

The MMR vaccine theory of autism is one of the most extensively debated theories regarding the origins of autism. Andrew Wakefield et al. reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR.[76] Although the paper, which was later retracted by the journal,[76] concluded "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described,"[49] Wakefield nevertheless suggested during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose.

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors.[77] The retraction followed an investigation by The Sunday Times, which stated that Wakefield "acted dishonestly and irresponsibly".[78] The Centers for Disease Control and Prevention,[79] the Institute of Medicine of the National Academy of Sciences,[80] and the U.K. National Health Service[81] have all concluded that there is no evidence of a link between the MMR vaccine and autism.

In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed.[76] In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.[82][83][84][85]

Thiomersal (thimerosal)[edit]

Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound thiomersal, a preservative that has been phased out from most childhood vaccinations in developed countries such as the USA.[86] Parents may first become aware of autistic symptoms in their child around the time of a routine vaccination. There is no scientific evidence for a causal connection between thiomersal and autism, but parental concern about the thiomersal controversy has led to decreasing rates of childhood immunizations[4] and increasing likelihood of disease outbreaks.[87][88] Because of public concerns, thiomersal content was completely removed or dramatically reduced from childhood vaccines that contained it in the 1990s; despite this, autism rates continued to climb well into the late 2000s.

A causal link between thimerosal and autism has been rejected by international scientific and medical professional bodies including the American Medical Association,[89] the American Academy of Pediatrics,[90] the American College of Medical Toxicology,[91] the Canadian Paediatric Society,[92] the U.S. National Academy of Sciences,[80] the Food and Drug Administration,[93] Centers for Disease Control and Prevention,[79] the World Health Organization,[94] the Public Health Agency of Canada,[95] and the European Medicines Agency.[96]

Viral infection[edit]

Many studies have presented evidence for and against association of autism with viral infection after birth. Laboratory rats infected with Borna disease virus show some symptoms similar to those of autism but blood studies of autistic children show no evidence of infection by this virus. Members of the herpes virus family may have a role in autism, but the evidence so far is anecdotal. Viruses have long been suspected as triggers for immune-mediated diseases such as multiple sclerosis but showing a direct role for viral causation is difficult in those diseases, and mechanisms whereby viral infections could lead to autism are speculative.[22]

Social construct[edit]

The social construct theory says that the boundary between normal and abnormal is subjective and arbitrary, so autism does not exist as an objective entity, but only as a social construct. It further argues that autistic individuals themselves have a way of being that is partly socially constructed.[97]

Asperger syndrome and high-functioning autism are particular targets of the theory that social factors determine what it means to be autistic. The theory hypothesizes that individuals with these diagnoses inhabit the identities that have been ascribed to them, and promote their sense of well-being by resisting or appropriating autistic ascriptions.[98]

References[edit]

  1. ^ a b c Trottier G, Srivastava L, Walker CD. Etiology of infantile autism: a review of recent advances in genetic and neurobiological research. J Psychiatry Neurosci. 1999;24(2):103–115. PMID 10212552.
  2. ^ a b c Freitag CM. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry. 2007;12(1):2–22. doi:10.1038/sj.mp.4001896. PMID 17033636.
  3. ^ a b Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism. Int J Dev Neurosci. 2005;23(2–3):189–99. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245.
  4. ^ a b c Doja A, Roberts W. Immunizations and autism: a review of the literature. Can J Neurol Sci. 2006;33(4):341–6. PMID 17168158.
  5. ^ American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th, text revision (DSM-IV-TR) ed. 2000 [Retrieved 2009-02-17]. ISBN 0-89042-025-4. Diagnostic criteria for 299.00 Autistic Disorder.
  6. ^ World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th (ICD-10) ed. 2006 [Retrieved 2007-06-25]. F84. Pervasive developmental disorders.
  7. ^ a b Happé F, Ronald A. The 'fractionable autism triad': a review of evidence from behavioural, genetic, cognitive and neural research. Neuropsychol Rev. 2008;18(4):287–304. doi:10.1007/s11065-008-9076-8. PMID 18956240.
  8. ^ a b Happé F, Ronald A, Plomin R. Time to give up on a single explanation for autism. Nat Neurosci. 2006;9(10):1218–20. doi:10.1038/nn1770. PMID 17001340.
  9. ^ a b Geschwind DH. Advances in autism. Annu Rev Med. 2009;60:367–80. doi:10.1146/annurev.med.60.053107.121225. PMID 19630577.
  10. ^ Mandy WP, Skuse DH. What is the association between the social-communication element of autism and repetitive interests, behaviours and activities? J Child Psychol Psychiatry. 2008;49(8):795–808. doi:10.1111/j.1469-7610.2008.01911.x. PMID 18564070.
  11. ^ a b Newschaffer CJ, Croen LA, Daniels J et al.. The epidemiology of autism spectrum disorders [PDF]. Annu Rev Public Health. 2007 [Retrieved 2009-10-10];28:235–58. doi:10.1146/annurev.publhealth.28.021406.144007. PMID 17367287.
  12. ^ a b Christison GW, Ivany K. Elimination diets in autism spectrum disorders: any wheat amidst the chaff? J Dev Behav Pediatr. 2006;27(2 Suppl 2):S162–71. doi:10.1097/00004703-200604002-00015. PMID 16685183.
  13. ^ Taylor B. Vaccines and the changing epidemiology of autism. Child Care Health Dev. 2006;32(5):511–9. doi:10.1111/j.1365-2214.2006.00655.x. PMID 16919130.
  14. ^ a b Sykes NH, Lamb JA. Autism: the quest for the genes. Expert Rev Mol Med. 2007;9(24):1–15. doi:10.1017/S1462399407000452. PMID 17764594.
  15. ^ Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet. 2001;2(12):943–55. doi:10.1038/35103559. PMID 11733747.
  16. ^ Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29(7):349–58. doi:10.1016/j.tins.2006.05.010. PMID 16808981.
  17. ^ Beaudet AL. Autism: highly heritable but not inherited. Nat Med. 2007;13(5):534–6. doi:10.1038/nm0507-534. PMID 17479094.
  18. ^ a b c Gardener H, Spiegelman D, Buka SL. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009;195(1):7–14. doi:10.1192/bjp.bp.108.051672. PMID 19567888.
  19. ^ Miyake K, Hirasawa T, Koide T, Kubota T (2012). "Epigenetics in autism and other neurodevelopmental diseases". Adv. Exp. Med. Biol. (Review) 724: 91–8. doi:10.1007/978-1-4614-0653-2_7. PMID 22411236. 
  20. ^ Schanen NC (October 2006). "Epigenetics of autism spectrum disorders". Hum. Mol. Genet. (Review). 15 Spec No 2: R138–50. doi:10.1093/hmg/ddl213. PMID 16987877. 
  21. ^ Roullet FI, Lai JK, Foster JA. In utero exposure to valproic acid and autism--a current review of clinical and animal studies. Neurotoxicol Teratol. 2013;36:47–56. doi:10.1016/j.ntt.2013.01.004. PMID 23395807.
  22. ^ a b Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005;11(1):1–10. doi:10.1080/13550280590900553. PMID 15804954.
  23. ^ [unreliable source?] Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev Neurobiol. 2012;72(10):1272–6. doi:10.1002/dneu.22024. PMID 22488761.
  24. ^ Mendelsohn NJ, Schaefer GB. Genetic evaluation of autism. Semin Pediatr Neurol. 2008;15(1):27–31. doi:10.1016/j.spen.2008.01.005. PMID 18342258.
  25. ^ Meyer U, Yee BK, Feldon J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse?. Neuroscientist. 2007;13(3):241–56. doi:10.1177/1073858406296401. PMID 17519367.
  26. ^ Chomiak T, Turner N, Hu B. What We Have Learned about Autism Spectrum Disorder from Valproic Acid. Patholog Res Int. 2013;2013:712758. doi:10.1155/2013/712758. PMID 24381784.
  27. ^ a b Dufour-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, Andres CR. Fetal exposure to teratogens: evidence of genes involved in autism. Neurosci Biobehav Rev. 2011;35(5):1254–65. doi:10.1016/j.neubiorev.2010.12.013. PMID 21195109.
  28. ^ Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int. J. Dev. Neurosci.. 2005;23(2-3):201–19. doi:10.1016/j.ijdevneu.2004.06.007. PMID 15749246.
  29. ^ Román GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci. 2007;262(1–2):15–26. doi:10.1016/j.jns.2007.06.023. PMID 17651757.
  30. ^ Muskiet FA, Kemperman RF. Folate and long-chain polyunsaturated fatty acids in psychiatric disease. J Nutr Biochem. 2006;17(11):717–27. doi:10.1016/j.jnutbio.2006.02.001. PMID 16650750.
  31. ^ Kinney DK, Munir KM, Crowley DJ, Miller AM. Prenatal stress and risk for autism. Neurosci Biobehav Rev. 2008;32(8):1519–32. doi:10.1016/j.neubiorev.2008.06.004. PMID 18598714.
  32. ^ Fetal testosterone and autistic traits:
  33. ^ Abramowicz JS. Ultrasound and autism: association, link, or coincidence?. J Ultrasound Med. 2012;31(8):1261–9. PMID 22837291.
  34. ^ Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism. Arch Pediatr Adolesc Med. 2007;161(4):326–33. doi:10.1001/archpedi.161.4.326. PMID 17404128.
  35. ^ Limperopoulos C, Bassan H, Gauvreau K et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics. 2007;120(3):584–93. doi:10.1542/peds.2007-1041. PMID 17766532.
  36. ^ Rutter M. Incidence of autism spectrum disorders: changes over time and their meaning. Acta Paediatr. 2005;94(1):2–15. doi:10.1111/j.1651-2227.2005.tb01779.x. PMID 15858952.
  37. ^ Schultz RT. Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int J Dev Neurosci. 2005;23(2–3):125–41. doi:10.1016/j.ijdevneu.2004.12.012. PMID 15749240.
  38. ^ Panksepp, J. (1979) A neurochemical theory of autism. Trends in Neurosciences, 2, 174-177
  39. ^ Christison GW, Ivany K (2006). "Elimination diets in autism spectrum disorders: any wheat amidst the chaff?". J Dev Behav Pediatr 27 (2 Suppl 2): S162–71. doi:10.1097/00004703-200604002-00015. PMID 16685183. 
  40. ^ Reichelt KL, Knivsberg A-M, Lind G, Nødland M. Probable etiology and possible treatment of childhood autism. Brain Dysfunct 1991; 4: 308-19
  41. ^ Shattock P, Whiteley P. (2002) "Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention" "Autism Research Unit, University of Sunderland, UK.
  42. ^ Ashwood P, Van de Water J. Is autism an autoimmune disease? Autoimmun Rev. 2004;3(7–8):557–62. doi:10.1016/j.autrev.2004.07.036. PMID 15546805.
  43. ^ Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006;80(1):1–15. doi:10.1189/jlb.1205707. PMID 16698940.
  44. ^ Stigler KA, Sweeten TL, Posey DJ, McDougle CJ. Autism and immune factors: a comprehensive review. Res Autism Spectr Disord. 2009;3(4):840–60. doi:10.1016/j.rasd.2009.01.007.
  45. ^ Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J. Autoantibodies in autism spectrum disorders (ASD). Ann N Y Acad Sci. 2007;1107:79–91. doi:10.1196/annals.1381.009. PMID 17804535.
  46. ^ Schmitz C, Rezaie P. The neuropathology of autism: where do we stand? Neuropathol Appl Neurobiol. 2008;34(1):4–11. doi:10.1111/j.1365-2990.2007.00872.x. PMID 17971078.
  47. ^ Fox E, Amaral D, Van de Water J. Maternal and fetal antibrain antibodies in development and disease. Dev Neurobiol. 2012;72(10):1327–34. doi:10.1002/dneu.22052. PMID 22911883.
  48. ^ a b c Johnson TW. Dietary considerations in autism: identifying a reasonable approach. Top Clin Nutr. 2006;21(3):212–25.
  49. ^ a b Wakefield A, Murch S, Anthony A et al.. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998;351(9103):637–41. doi:10.1016/S0140-6736(97)11096-0. PMID 9500320. (Retracted, see doi:10.1016/S0140-6736(10)60175-7)
  50. ^ MacDonald TT, Domizio P. Autistic enterocolitis; is it a histopathological entity? Histopathology. 2007;50(3):371–9. doi:10.1111/j.1365-2559.2007.02606.x. PMID 17257133.
  51. ^ Krishnaswami S, McPheeters ML, Veenstra-Vanderweele J. A systematic review of secretin for children with autism spectrum disorders. Pediatrics. 2011;127(5):e1322–5. doi:10.1542/peds.2011-0428. PMID 21464196.
  52. ^ Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013;34(1):47–64. doi:10.1016/j.yfrne.2012.07.001. PMID 22796576.
  53. ^ Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012;33(5):1541–50. doi:10.1016/j.ridd.2012.02.015. PMID 22522213.
  54. ^ a b Zafeiriou DI, Ververi A, Vargiami E. Childhood autism and associated comorbidities. Brain Dev. 2007;29(5):257–72. doi:10.1016/j.braindev.2006.09.003. PMID 17084999.
  55. ^ Mehler MF, Purpura DP. Autism, fever, epigenetics and the locus coeruleus. Brain Res Rev. 2009;59(2):388–92. doi:10.1016/j.brainresrev.2008.11.001. PMID 19059284. Lay summary: TIME, 2009-04-07.
  56. ^ Austin D. An epidemiological analysis of the 'autism as mercury poisoning' hypothesis. Int J Risk Saf Med. 2008;20(3):135–42. doi:10.3233/JRS-2008-0436.
  57. ^ Nelson KB, Bauman ML. Thimerosal and autism?. Pediatrics. 2003;111(3):674–9. doi:10.1542/peds.111.3.674. PMID 12612255.
  58. ^ Davidson PW, Myers GJ, Weiss B. Mercury exposure and child development outcomes. Pediatrics. 2004;113(4 Suppl):1023–9. doi:10.1542/peds.113.4.S1.1023. PMID 15060195.
  59. ^ Ng DK, Chan CH, Soo MT, Lee RS. Low-level chronic mercury exposure in children and adolescents: meta-analysis. Pediatr Int. 2007;49(1):80–7. doi:10.1111/j.1442-200X.2007.02303.x. PMID 17250511.
  60. ^ Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008;11(6):851–76. doi:10.1017/S1461145707008401. PMID 18205981.
  61. ^ Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9(6):485–99. doi:10.1080/10937400600882079. PMID 17090484.
  62. ^ Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A. Glutathione-related factors and oxidative stress in autism, a review. Curr. Med. Chem.. 2012;19(23):4000–5. doi:10.2174/092986712802002572. PMID 22708999.
  63. ^ Villagonzalo KA, Dodd S, Dean O, Gray K, Tonge B, Berk M. Oxidative pathways as a drug target for the treatment of autism. Expert Opin. Ther. Targets. 2010;14(12):1301–10. doi:10.1517/14728222.2010.528394. PMID 20954799.
  64. ^ a b c d Good P. Did acetaminophen provoke the autism epidemic? [PDF]. Altern Med Rev. 2009;14(4):364–72. PMID 20030462.
  65. ^ Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013. doi:10.1093/ije/dyt183. PMID 24163279.
  66. ^ Prenatal and perinatal analgesic exposure and autism: an ecologic link. Environmental Health. May 9, 2013. doi:10.1186/1476-069X-12-41.. PMID 23656698.
  67. ^ Bettelheim B. The Empty Fortress: Infantile Autism and the Birth of the Self. Free Press; 1967. ISBN 0-02-903140-0.
  68. ^ Kanner L. Autistic disturbances of affective contact. Nerv Child. 1943;2:217–50. Reprinted in Acta Paedopsychiatr. 1968;35(4):100–36. PMID 4880460.
  69. ^ Kanner L. Problems of nosology and psychodynamics in early childhood autism. Am J Orthopsychiatry. 1949;19(3):416–26. doi:10.1111/j.1939-0025.1949.tb05441.x. PMID 18146742.
  70. ^ Gardner M. The brutality of Dr. Bettelheim. Skeptical Inquirer. 2000;24(6):12–4.
  71. ^ Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics. 2006;118(1):e139–50. doi:10.1542/peds.2005-2993. PMID 16818529.
  72. ^ Gross L. A broken trust: lessons from the vaccine–autism wars. PLoS Biol. 2009;7(5):e1000114. doi:10.1371/journal.pbio.1000114. PMID 19478850.
  73. ^ Hilton S, Petticrew M, Hunt K. 'Combined vaccines are like a sudden onslaught to the body's immune system': parental concerns about vaccine 'overload' and 'immune-vulnerability'. Vaccine. 2006;24(20):4321–7. doi:10.1016/j.vaccine.2006.03.003. PMID 16581162.
  74. ^ Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. Clin Infect Dis. 2009;48(4):456–61. doi:10.1086/596476. PMID 19128068. Lay summary: IDSA, 2009-01-30.
  75. ^ Paul R. Parents ask: am I risking autism if I vaccinate my children? J Autism Dev Disord. 2009;39(6):962–3. doi:10.1007/s10803-009-0739-y. PMID 19363650.
  76. ^ a b c Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 2010-02-06;375(9713):445. doi:10.1016/S0140-6736(10)60175-4. PMID 20137807. Lay summary: BBC News, 2010-02-02.
  77. ^ Murch SH, Anthony A, Casson DH et al. Retraction of an interpretation. Lancet. 2004;363(9411):750. doi:10.1016/S0140-6736(04)15715-2. PMID 15016483.
  78. ^ Deer B. The MMR-autism crisis - our story so far; 2008-11-02 [Retrieved 2008-12-06].
  79. ^ a b Centers for Disease Control and Prevention. Measles, mumps, and rubella (MMR) vaccine; 2008-12-23 [Retrieved 2009-02-14].
  80. ^ a b Institute of Medicine, National Academy of Sciences. Immunization safety review: vaccines and autism; 2004 [Retrieved 2007-06-13].
  81. ^ National Health Service. MMR the facts [Retrieved 2007-06-13].
  82. ^ Godlee F, Smith J, Marcovitch H. Wakefield's article linking MMR vaccine and autism was fraudulent. BMJ. 2011;342:c7452. doi:10.1136/bmj.c7452. PMID 21209060.
  83. ^ Deer B. How the case against the MMR vaccine was fixed. BMJ. 2011;342:c5347. doi:10.1136/bmj.c5347. PMID 21209059.
  84. ^ Study linking vaccine to autism was fraud. 2011-01-05 [Retrieved 2011-01-06]. Associated Press. NPR.
  85. ^ Retracted autism study an 'elaborate fraud,' British journal finds. (Atlanta) 2011-01-06 [Retrieved 2011-01-06].
  86. ^ "Vaccines, blood and biologics: thimerosal in vaccines". US Food and Drug Administration. 2012. Retrieved October 24, 2013. 
  87. ^ Eaton L. Measles cases in England and Wales rise sharply in 2008. BMJ. 2009;338:b533. doi:10.1136/bmj.b533. PMID 19208716.
  88. ^ Choi YH, Gay N, Fraser G, Ramsay M. The potential for measles transmission in England. BMC Public Health. 2008;8:338. doi:10.1186/1471-2458-8-338. PMID 18822142.
  89. ^ American Medical Association. AMA Welcomes New IOM Report Rejecting Link Between Vaccines and Autism; 2004-05-18 [Retrieved 2007-07-23].
  90. ^ American Academy of Pediatrics. What Parents Should Know About Thimerosal; 2004-05-18 [Retrieved 2007-07-23].
  91. ^ Kurt TL. ACMT position statement: the Iom report on thimerosal and autism [PDF]. J Med Toxicol. 2006;2(4):170–1. doi:10.1007/BF03161188. PMID 18072140.
  92. ^ Infectious Diseases and Immunization Committee, Canadian Paediatric Society. Autistic spectrum disorder: No causal relationship with vaccines. Paediatr Child Health. 2007 [Retrieved 2008-10-17];12(5):393–5. Also published (2007) in Can J Infect Dis Med Microbiol 18 (3): 177–9. PMID 18923720.
  93. ^ "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-09-06. Retrieved 2007-10-01. 
  94. ^ World Health Organization (2006). "Thiomersal and vaccines: questions and answers". Retrieved 2009-05-19. 
  95. ^ National Advisory Committee on Immunization. Thimerosal: updated statement. An Advisory Committee Statement. Can Commun Dis Rep. 2007;33(ACS-6):1–13. PMID 17663033.
  96. ^ European Medicines Agency. EMEA Public Statement on Thiomersal in Vaccines for Human Use; 2004-03-24 [Retrieved 2007-07-22].
  97. ^ Hacking I. The Social Construction of What? Harvard University Press; 1999. ISBN 0-674-00412-4. p. 114–23.
  98. ^ Nadesan MH. Constructing Autism: Unravelling the 'Truth' and Understanding the Social. Routledge; 2005. ISBN 0-415-32181-6. The dialectics of autism: theorizing autism, performing autism, remediating autism, and resisting autism. p. 179–213.