Causes of autism

Autism and autism spectrum disorders are complex neurodevelopmental disorders. Many causes of autism have been proposed, but its theory of causation is still incomplete. Heritability contributes about 90% of the risk of a child developing autism, but the genetics of autism are complex and typically it is unclear which genes are responsible. In rare cases, autism is strongly associated with agents that cause birth defects. Many other causes have been proposed, such as exposure of children to vaccines; these proposals are controversial and the vaccine hypotheses have no convincing scientific evidence.

Autism and related disorders

Autism is a condition involving abnormalities of brain development and behavior which manifests itself before a child is three years old and has a steady course with no remission. It is characterized by impairments in social interaction and communication, as well as restricted and repetitive behavior. It is part of a larger family called the autism spectrum disorders (ASD) or pervasive developmental disorders (PDD), which include closely related syndromes such as Asperger syndrome and PDD-NOS. [cite book|title=Diagnostic and Statistical Manual of Mental Disorders|edition=4th ed., text revision (DSM-IV-TR)|author=American Psychiatric Association|year=2000|isbn=0890420254|chapter=Diagnostic criteria for 299.00 Autistic Disorder|chapterurl=http://www.behavenet.com/capsules/disorders/autistic.htm|accessdate=2007-06-25] [cite book|chapterurl=http://www.who.int/classifications/apps/icd/icd10online/?gf80.htm+f840|year=2006|accessdate=2007-06-25|title=International Statistical Classification of Diseases and Related Health Problems|edition=10th ed. (ICD-10)|author=World Health Organization|chapter=F84. Pervasive developmental disorders] This article uses "autism" to denote the classic autistic disorder and "ASD" to denote the wider family.

Autism's theory of causation is still incomplete. 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. Although these distinct causes have been hypothesized to often co-occur,cite journal |author= Happé F, Ronald A, Plomin R |title= Time to give up on a single explanation for autism |journal= Nat Neurosci |year=2006 |volume=9 |issue=10 |pages=1218–20 |pmid=17001340 |doi=10.1038/nn1770] it has also been suggested that the correlation between the causes has been exaggerated. [cite journal |journal= J Child Psychol Psychiatry |year=2008 |title= What is the association between the social-communication element of autism and repetitive interests, behaviours and activities? |author= Mandy WP, Skuse DH |doi=10.1111/j.1469-7610.2008.01911.x |pmid=18564070] 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.cite journal |author= Newschaffer CJ, Croen LA, Daniels J "et al." |title= The epidemiology of autism spectrum disorders |journal= Annu Rev Public Health |year=2007 |volume=28 |pages=235–58 |pmid=17367287 |doi=10.1146/annurev.publhealth.28.021406.144007] An increase in prevalence would suggest directing more attention and funding toward changing environmental factors instead of continuing to focus on genetics.

The consensus among mainstream autism researchers is that genetic factors predominate, but some are concerned, as one anonymous researcher put it, that "geneticists are running the show, and ignoring the environmental aspects." 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, 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. 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, as described in Mercury and MMR vaccine below, 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. [cite journal |journal= Child Care Health Dev |year=2006 |volume=32 |issue=5 |pages=511–9 |title= Vaccines and the changing epidemiology of autism |author= Taylor B |doi=10.1111/j.1365-2214.2006.00655.x |pmid=16919130]

In 2007 the National Institutes of Health announced an Autism Centers of Excellence (ACE) research program to find the causes of autism and identify new treatments for the disorder. Initial recipients are focusing on genetic factors, brain imaging, brain chemicals and functions including mirror neurons, effect on early parent-child behavior on autism, and learning in autistic children. [cite press release |title= NIH funds new program to investigate causes and treatment of autism |publisher= National Institutes of Health |date=2007-08-02 |url=http://www.nih.gov/news/pr/aug2007/nichd-02.htm |accessdate=2007-08-03]

Genetics

Genetic factors are the most significant cause for autism spectrum disorders. Early studies of twins estimated heritability to be over 90%, in other words, that genetics explains over 90% of whether a child will develop autism. This may be an overestimate; new twin data and models with structural genetic variation are needed. 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%. [cite journal|author=Folstein SE, Rosen-Sheidley B|title=Genetics of autism: complex aetiology for a heterogeneous disorder|journal=Nat Rev Genet|year=2001|volume=2|issue=12|pages=943–55|doi=10.1038/35103559|pmid=11733747]

The genetics of autism is complex.cite journal|author=Freitag CM|title=The genetics of autistic disorders and its clinical relevance: a review of the literature|journal=Mol Psychiatry|volume=12|issue=1|pages=2–22|year=2007|doi=10.1038/sj.mp.4001896|pmid=17033636|url=http://www.nature.com/mp/journal/v12/n1/full/4001896a.html] Linkage analysis has been inconclusive; many association analyses have had inadequate power.cite journal |journal= Expert Rev Mol Med |year=2007 |volume=9 |issue=24 |pages=1–15 |title= Autism: the quest for the genes |author= Sykes NH, Lamb JA |pmid=17764594 |doi=10.1017/S1462399407000452] 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, [cite journal|author=Persico AM, Bourgeron T|title=Searching for ways out of the autism maze: genetic, epigenetic and environmental clues|journal=Trends Neurosci|volume=29|issue=7|pages=349–58|year=2006|pmid=16808981|doi=10.1016/j.tins.2006.05.010] 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: that is, the mutation that causes the autism is not present in the parental genome. [cite journal |author= Beaudet AL |title= Autism: highly heritable but not inherited |journal= Nat Med |year=2007 |volume=13 |issue=5 |pages=534–6 |pmid=17479094 |doi=10.1038/nm0507-534] One hypothesis is that autism is in some sense diametrically opposite to schizophrenia, and that autism involves increased effects via genomic imprinting of paternally expressed genes that regulate overgrowth in the brain, whereas schizophrenia involves maternally expressed genes and undergrowth. [cite journal |journal= Behav Brain Sci |year=2008 |volume=31 |issue=3 |pages=241–61 |title= Psychosis and autism as diametrical disorders of the social brain |author= Crespi B, Badcock C |doi=10.1017/S0140525X08004214 |pmid=18578904]

Though autism's genetic factors explain most of autism risk, 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.cite journal|author=Trottier G, Srivastava L, Walker CD|title=Etiology of infantile autism: a review of recent advances in genetic and neurobiological research|journal=J Psychiatry Neurosci|year=1999|volume=24|issue=2|pages=103–115|pmid=10212552|url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?pubmedid=10212552|accessdate=2007-07-16] 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; others focus on the environment after birth, such as children's diets.

A 2007 review of risk factors found associated parental characteristics that included advanced maternal age, advanced paternal age, and maternal place of birth outside Europe or North America. It is not known whether these associations reflect genetic, epigenetic, or environmental factors.

Prenatal environment

The risk of autism is associated with several prenatal risk factors. Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare. Other potential prenatal environmental factors do not have convincing scientific evidence.

Teratogens

Teratogens are environmental agents that cause birth defects. Some agents that are known to cause other birth defects have also been found to be related to autism risk. These include exposure of the embryo to thalidomide, valproic acid, or misoprostol, or to rubella infection in the mother. These cases are rare;cite journal |journal= Environ Health Perspect |year=2006 |volume=114 |issue=7 |pages=A412–8 |title= Tracing the origins of autism: a spectrum of new studies |author= Szpir M |url=http://www.ehponline.org/members/2006/114-7/focus.html |pmid=16835042] congenital rubella syndrome is the most convincing. [cite journal |journal=Semin Pediatr Neurol |year=2008 |volume=15 |issue=1 |pages=27–31 |title= Genetic evaluation of autism |author= Mendelsohn NJ, Schaefer GB |doi=10.1016/j.spen.2008.01.005 |pmid=18342258] Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects, but current evidence is insufficient to determine whether autism risk is actually elevated with ethanol. [cite journal|journal=J Autism Dev Disord|year=2002|volume=32|issue=3|pages=243|title=Is exposure to alcohol during pregnancy a risk factor for autism?|author=Fombonne E|doi=10.1023/A:1015466100838|pmid=12108626] 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.cite journal|journal=Int J Dev Neurosci|year=2005|volume=23|issue=2–3|pages=189–99|title=The teratology of autism|author=Arndt TL, Stodgell CJ, Rodier PM|doi=10.1016/j.ijdevneu.2004.11.001|pmid=15749245] Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for other psychiatric disorders of presumed neurodevelopmental origin, notably schizophrenia. [cite journal|journal=Neuroscientist|year=2007|volume=13|issue=3|pages=241–56.|title=The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse?|author=Meyer U, Yee BK, Feldon J|pmid=17519367|doi=10.1177/1073858406296401]

Pesticides

A 2007 study by the California Department of Public Health found that women in the first eight weeks of pregnancy who live near farm fields sprayed with the organochlorine pesticides dicofol and endosulfan are several times more likely to give birth to children with autism. The association appeared to increase with dose and decrease with distance from field site to residence. The study's findings suggest that on the order of 7% of autism cases in the California Central Valley might have been connected to exposure to the insecticides drifting off fields into residential areas. These results are highly preliminary due to the small number of women and children involved and lack of evidence from other studies. [cite journal |journal=Environ Health Perspect |year=2007 |volume=115 |issue=10 |pages=1482–9 |author= Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C |title= Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley |doi=10.1289/ehp.10168 |pmid=17938740 |url=http://www.ehponline.org/members/2007/10168/10168.html |laysummary=http://www.ehponline.org/docs/2007/115-10/ss.html#auti |laysource=EHP |laydate=2007] It is not known whether these pesticides are human teratogens, though endosulfan has significant teratogenic effects in laboratory rats. [cite journal|journal=J Appl Toxicol|year=2007|volume=27|issue=2|pages=143–51|title=Citrinin and endosulfan induced teratogenic effects in Wistar rats|author=Singh ND, Sharma AK, Dwivedi P, Patil RD, Kumar M|doi=10.1002/jat.1185|pmid=17186572]

A 2005 study showed indirect evidence that prenatal exposure to organophosphate pesticides such as diazinon and chlorpyrifos may contribute to autism in genetically vulnerable children. [cite journal|journal=Mol Psychiatry|year=2005|volume=10|issue=11|pages=1006–16|title=Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions|author=D'Amelio M, Ricci I, Sacco R "et al."|doi=10.1038/sj.mp.4001714|pmid=16027737] Several other studies demonstrate the neurodevelopmental toxicity of these agents at relatively low exposure levels. [cite journal|journal=Pediatr Clin North Am|year=2007|volume=54|issue=1|pages=63–80|title=Health effects of common home, lawn, and garden pesticides|author=Karr CJ, Solomon GM, Brock-Utne AC|doi=10.1016/j.pcl.2006.11.005|pmid=17306684]

Folic acid

Folic acid taken during pregnancy might play an important role in causing autism by modulating gene expression through epigenetic mechanism. This hypothesis is untested. [Folic acid and autism:
*cite journal|journal=J Nutr Biochem|year=2006|volume=17|issue=11|pages=717–27|title=Folate and long-chain polyunsaturated fatty acids in psychiatric disease|author=Muskiet FA, Kemperman RF|doi=10.1016/j.jnutbio.2006.02.001|pmid=16650750
*cite journal |journal= Med Hypotheses |year=2008 |title= Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? a closer look at a possible link |author= Rogers EJ |doi=10.1016/j.mehy.2008.04.013 |pmid=18514430]

tress

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. [cite journal |journal= Neurosci Biobehav Rev |year=2008 |title= Prenatal stress and risk for autism |author= Kinney DK, Munir KM, Crowley DJ, Miller AM |doi=10.1016/j.neubiorev.2008.06.004 |pmid=18598714 |volume=32 |issue=8 |pages=1519–32]

Maternal antibodies

The maternal antibody theory hypothesizes that immunoglobulin G (IgG) in a mother's blood can cross the placenta, enter into the fetus's brain, react against fetal brain proteins, and cause autism. [cite journal |journal= Ann Neurol |year=2003 |volume=53 |issue=4 |pages=533–7 |title= Maternal neuronal antibodies associated with autism and a language disorder |author= Dalton P, Deacon R, Blamire A "et al." |doi=10.1002/ana.10557 |pmid=12666123] The theory is related to the autoimmune disease hypothesis, except it focuses on maternal antibodies rather than the child's. A 2007 study found that these antibodies bind to fetal brain cells, most commonly in mothers of children with regressive autism. [cite journal |journal= Neurotoxicology |year=2007 |title= Autism: maternally derived antibodies specific for fetal brain proteins |author= Braunschweig D, Ashwood P, Krakowiak P "et al." |doi=10.1016/j.neuro.2007.10.010 |pmid=18078998 |laysummary=http://www.sciencedaily.com/releases/2008/02/080211172535.htm |laysource= Science Daily |laydate=2008-02-12] A 2008 study found that rhesus monkeys exposed during gestation to IgG from mothers of children with ASD demonstrated stereotypies, one of the three main symptoms of autism. [cite journal |journal= Brain Behav Immun |year=2008 |title= Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism |author= Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG |doi=10.1016/j.bbi.2007.12.007 |pmid=18262386 |laysummary=http://www.sciencedaily.com/releases/2008/02/080211172526.htm |laysource= Science Daily |laydate=2008-02-12]

Fetal testosterone

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 EQ SQ Theory terminology, emphasizing "systemizing" over "empathizing". [cite book|author=Baron-Cohen S|title=The Essential Difference: Male and Female Brains and the Truth About Autism|publisher=Basic Books|year=2004|isbn=046500556X] One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism. [Fetal testosterone studies:
*cite journal |journal= Early Hum Dev |year=2006 |volume=82 |issue=12 |pages=755–60 |title= Fetal testosterone and sex differences |author= Knickmeyer RC, Baron-Cohen S |doi=10.1016/j.earlhumdev.2006.09.014 |pmid=17084045
*cite journal |journal= Br J Psychol |year=2008 |title= Fetal testosterone and autistic traits |author= Auyeung B, Baron-Cohen S, Ashwin E, Knickmeyer R, Taylor K, Hackett G |doi=10.1348/000712608X311731 |pmid=18547459 |laysource=BBC |laysummary=http://news.bbc.co.uk/1/hi/sci/tech/6989247.stm |laydate=2007-09-11] The theory and findings are controversial and many studies contradict the idea that baby boys and girls respond differently to people and objects. [cite web |author= Rivers C |url=http://www.alternet.org/story/42034 |title= Discrimination against the female brain |publisher=AlterNet |date=2006-09-28 |accessdate=2006-12-10]

Ultrasound

A 2006 study found that sustained exposure of mouse embryos to ultrasound waves caused a small but statistically significant number of neurons to fail to acquire their proper position during neuronal migration. [cite journal|author=Ang ES Jr, Gluncic V, Duque A, Schafer ME, Rakic P|title=Prenatal exposure to ultrasound waves impacts neuronal migration in mice|journal=Proc Natl Acad Sci U S A|volume=103|issue=34|pages=12903–10|year=2006|pmid=16901978|doi=10.1073/pnas.0605294103|url=http://www.pnas.org/cgi/content/full/103/34/12903] It is highly unlikely that this result speaks directly to risks of fetal ultrasound as practiced in competent and responsible medical centers. [cite journal|journal=Proc Natl Acad Sci U S A|volume=103|issue=34|pages=12661–2|year=2006|author=Caviness VS, Grant PE|title=Our unborn children at risk?|url=http://www.pnas.org/cgi/content/full/103/34/12661|doi=10.1073/pnas.0605505103] There is no scientific evidence of an association between prenatal ultrasound exposure and autism, but there are very little data on human fetal exposure during diagnostic ultrasound, and the lack of recent epidemiological research and human data in the field has been called "appalling". [cite journal|journal=Ultrasound Obstet Gynecol|year=2007|volume=29|issue=4|pages=363–7|title=Prenatal exposure to ultrasound waves: is there a risk?|author=Abramowicz JS|doi=10.1002/uog.3983|pmid=17352453]

Perinatal environment

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; an underlying cause could explain both autism and these associated conditions.cite journal |author= Kolevzon A, Gross R, Reichenberg A |title= Prenatal and perinatal risk factors for autism |journal= Arch Pediatr Adolesc Med |volume=161 |issue=4 |year=2007 |pages=326–33 |pmid=17404128 |doi= 10.1001/archpedi.161.4.326] 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. [cite journal |journal=Pediatrics |year=2007 |volume=120 |issue=3 |pages=584–93 |title= Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? |author= Limperopoulos C, Bassan H, Gauvreau K "et al." |doi=10.1542/peds.2007-1041 |pmid=17766532]

Postnatal environment

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.cite journal|author=Rutter M|title=Incidence of autism spectrum disorders: changes over time and their meaning|journal=Acta Paediatr|volume=94|issue=1|year=2005|pages=2–15|pmid=15858952|doi=10.1080/08035250410023124] The subject remains controversial and extensive further searches for environmental factors are underway.

Autoimmune disease

This theory hypothesizes that autoantibodies that target the brain may cause or exacerbate autism. It is related to the maternal antibodies 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. [cite journal |journal= Autoimmun Rev |year=2004 |volume=3 |issue=7–8 |pages=557–62 |title= Is autism an autoimmune disease? |author= Ashwood P, Van de Water J |doi=10.1016/j.autrev.2004.07.036 |pmid=15546805]

Interactions between the immune system and the nervous system begin early during embryogenesis, and successful neurodevelopment depends on a balanced immune response. Several symptoms consistent with a poorly regulated immune response have been reported in autistic children. It is possible that aberrant immune activity during critical periods of neurodevelopment is part of the mechanism of some forms of ASD. [cite journal |journal= J Leukoc Biol |year=2006 |volume=80 |issue=1 |pages=1–15 |title= The immune response in autism: a new frontier for autism research |author= Ashwood P, Wills S, Van de Water J |doi=10.1189/jlb.1205707 |pmid=16698940 |url=http://www.jleukbio.org/cgi/content/full/80/1/1] As autoantibodies have not been associated with pathology, are found in diseases other than ASD, and are not always present in ASD, [cite journal |journal= Ann N Y Acad Sci |year=2007 |volume=1107 |pages=79–91 |title= Autoantibodies in autism spectrum disorders (ASD) |author= Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J |doi=10.1196/annals.1381.009 |pmid=17804535] the relationship between immune disturbances and autism remains unclear and controversial. [cite journal |journal= Neuropathol Appl Neurobiol |year=2008 |volume=34 |issue=1 |pages=4–11 |title= The neuropathology of autism: where do we stand? |author= Schmitz C, Rezaie P |doi=10.1111/j.1365-2990.2007.00872.x |pmid=17971078]

Leaky gut syndrome

Parents have reported gastrointestinal (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut.cite journal|journal=Top Clin Nutr|volume=21|issue=3|pages=212–25|year=2006|author=Johnson TW|title=Dietary considerations in autism: identifying a reasonable approach] The controversial Wakefield "et al." vaccine paper discussed in "MMR vaccine" below also suggested that some bowel disorders may allow antigens to pass from food into the bloodstream and then to contribute to brain dysfunction. This produced several lines of investigation.

For example, employing secretin's effects on digestion, a 1998 study of three children with ASD treated with secretin infusion reported improved GI function and dramatic improvement in behavior, which suggested an association between GI and brain function in autistic children. [cite journal|author=Horvath K, Stefanatos G, Sokolski KN, Wachtel R, Nabors L, Tildon JT|title=Improved social and language skills after secretin administration in patients with autistic spectrum disorders|journal=J Assoc Acad Minor Phys|year=1998|volume=9|issue=1|pages=9–15|pmid=9585670] After this study, many parents sought secretin treatment and a black market for the hormone developed quickly. However, later studies found secretin ineffective in treating autism. [cite journal|author=Sturmey P|title=Secretin is an ineffective treatment for pervasive developmental disabilities: a review of 15 double-blind randomized controlled trials|journal=Res Dev Disabil|year=2005|volume=26|issue=1|pages=87–97|pmid=15590241|doi=10.1016/j.ridd.2004.09.002]

Leaky gut syndrome theories also inspired several dietary treatments, including gluten-free diets, casein-free diets, antifungal diets, low-sugar diets, as well as supplements that include nystatin, Bssub|12, and probiotics. Parents are more likely to get advice about these diets from other parents, the media, and the Internet than from medical experts. There is no solid research evidence that autistic children are more likely to have GI symptoms than typical children. In particular, design flaws in studies of elimination diets mean that the currently available data are inadequate to guide treatment recommendations.cite journal |journal= J Dev Behav Pediatr |year=2006 |volume=27 |issue= 2 Suppl 2 |pages=S162–71 |title= Elimination diets in autism spectrum disorders: any wheat amidst the chaff? |author= Christison GW, Ivany K |pmid=16685183 |doi= 10.1097/00004703-200604002-00015] A 2008 study found that children with autism had no more peptides in their urine than typical children, casting doubt on the proposed mechanism underlying the leaky-gut theory. [cite journal |journal= Arch Dis Child |year=2008 |title= Absence of urinary opioid peptides in children with autism |author= Cass H, Gringras P, March J "et al." |doi=10.1136/adc.2006.114389 |pmid=18337276 |laysummary=http://news.bbc.co.uk/1/hi/health/7300327.stm |laysource= BBC News |laydate=2008-03-17]

Viral infection

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. [cite journal|journal=J Neurovirol|year=2005|volume=11|issue=1|pages=1–10|title=Autistic disorder and viral infections|author=Libbey JE, Sweeten TL, McMahon WM, Fujinami RS|doi=10.1080/13550280590900553|pmid=15804954]

Excessive hygiene

The hygiene hypothesis is to some extent the inverse of the viral infection hypothesis: it states that a lack of early childhood exposure to microbes or parasites contributes to autism. This hypothesis relies on some similarities between autism and asthma and other autoimmune disorders which are already hypothesized to be affected by hygiene: for example, autism and asthma affect more boys than girls, affect more urban than rural children, and are associated with increased head circumference. This hypothesis has not been tested scientifically. [cite journal |journal= Med Hypotheses |year=2007 |volume=69 |issue=4 |pages=731–40 |title= Autism, asthma, inflammation, and the hygiene hypothesis |author= Becker KG |doi=10.1016/j.mehy.2007.02.019 |pmid=17412520 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17412520]

Oxidative stress

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. [cite journal |journal= Int J Neuropsychopharmacol |year=2008 |title= Oxidative stress in psychiatric disorders: evidence base and therapeutic implications |author= Ng F, Berk M, Dean O, Bush AI |doi=10.1017/S1461145707008401 |pmid=18205981] One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved. [cite journal|journal=J Toxicol Environ Health B Crit Rev|year=2006 |volume=9|issue=6|pages=485–99.|title=Evidence of toxicity, oxidative stress, and neuronal insult in autism|author=Kern JK, Jones AM|doi=10.1080/10937400600882079|pmid=17090484]

Amygdala neurons

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. [cite journal|journal=Int J Dev Neurosci|year=2005|volume=23|issue=2–3|pages=125–41|title=Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area|author=Schultz RT|doi=10.1016/j.ijdevneu.2004.12.012|pmid=15749240]

Vitamin D

This theory hypothesizes that autism is caused by vitamin D deficiency, and that recent increases in diagnosed cases of autism are due to medical advice to avoid the sun. The theory has not been studied scientifically. [cite journal |journal= Med Hypotheses |year=2007 |title= Autsim and vitamin D |author= Cannell JJ |pmid=17920208]

Lead

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. 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. [cite journal |journal= Brain Dev |year=2007 |volume=29 |issue=5 |pages=257–72 |title= Childhood autism and associated comorbidities |author= Zafeiriou DI, Ververi A, Vargiami E |doi=10.1016/j.braindev.2006.09.003 |pmid=17084999]

Mercury

This theory hypothesizes that autism is associated with mercury poisoning, based on perceived similarity of symptoms. [cite journal |journal= Med Hypotheses |year=2001 |volume=56 |issue=4 |pages=462–71 |title= Autism: a novel form of mercury poisoning |author= Bernard S, Enayati A, Redwood L, Roger H, Binstock T |doi=10.1054/mehy.2000.1281 |pmid=11339848 |url=http://safeminds.org/research/library/Bernard-et-al-2001.pdf |format=PDF |accessdate=2008-06-14] 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. [cite journal |journal=Pediatrics |year=2004 |volume=113 |issue=4 Suppl |pages=1023–9 |title= Mercury exposure and child development outcomes |author= Davidson PW, Myers GJ, Weiss B |pmid=15060195 |url=http://pediatrics.aappublications.org/cgi/content/full/113/4/S1/1023|doi=10.1542/peds.113.4.S1.1023]

A 2003 study reported that mercury measurements of hair samples from autistic children's first haircuts were significantly lower than a matched group of normal children, declining as measures of severity increased, [cite journal|author=Holmes AS, Blaxill MF, Haley BE|title=Reduced levels of mercury in first baby haircuts of autistic children|journal=Int J Toxicol|volume=22|issue=4|pages=277–85|year=2003|pmid=12933322|doi=10.1080/10915810305120] but a later meta-analysis based on two studies found that there was not enough evidence to conclude that hair mercury level is lower in autistic children. [cite journal|journal=Pediatr Int|year=2007|volume=49|issue=1|pages=80–7|title=Low-level chronic mercury exposure in children and adolescents: meta-analysis|author=Ng DK, Chan CH, Soo MT, Lee RS|doi=10.1111/j.1442-200X.2007.02303.x|pmid=17250511] A 2006 study found a slight association between autism and environmental releases of mercury, primarily from coal power plants; this study used Texas county-wide data and did not distinguish between prenatal and postnatal exposure. [cite journal|author=Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C|title=Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas|journal=Health Place|volume=12|issue=2|pages=203–9|year=2006|pmid=16338635|doi=10.1016/j.healthplace.2004.11.005] A 2008 followup study found a similar slight association between autism rates and distance to industrial and power plant mercury sources in Texas. [cite journal |journal= Health Place |year=2008 |title= Proximity to point sources of environmental mercury release as a predictor of autism prevalence |author= Palmer RF, Blanchard S, Wood R |doi=10.1016/j.healthplace.2008.02.001 |pmid=18353703 |laysummary=http://uthscsa.edu/hscnews/singleformat.asp?newID=2732 |laysource=UT HSC |laydate=2008-04-24]

Perhaps the best-known theory 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. Parents may first become aware of autistic symptoms in their child around the time of a routine vaccination. There is no convincing scientific evidence for a causal connection between thiomersal and autism, but parental concern about the thiomersal controversy has led to decreasing uptake of childhood immunizations and increasing likelihood of disease outbreaks.cite journal|journal=Can J Neurol Sci|year=2006|volume=33|issue=4|pages=341–6|title=Immunizations and autism: a review of the literature|author=Doja A, Roberts W|pmid=17168158]

MMR vaccine

The MMR vaccine theory of autism is one of the most extensively debated theories regarding the origins of autism. A controversial 1998 paper by Andrew Wakefield "et al." reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR. Though the paper concluded "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described,"cite journal |author= Wakefield A, Murch S, Anthony A "et al." |title= Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=351 |issue=9103 |pages=637–41 |year=1998 |doi=10.1016/S0140-6736(97)11096-0 |pmid=9500320 |url=http://briandeer.com/mmr/lancet-paper.htm |accessdate=2007-09-05] Wakefield nevertheless suggested during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single jab. This suggestion was again not supported by the paper, his co-authors or by any scientific evidencecite web|url=http://www.pm.gov.uk/output/page292.asp|title=MMR – the controversy|publisher=UK Prime Minister's Office|year=2005|accessdate=2007-07-29] and has been heavily criticized, both on scientific grounds and for triggering a decline in vaccination rates. Using separate, single vaccines in place of MMR is widely believed to put children at increased risk since the combined vaccine reduces the risk of them catching the diseases while they are waiting for full immunization cover. [cite web|url=http://www.mmrthefacts.nhs.uk/basics/truths.php|title=MMR the facts|publisher=NHS|accessdate=2007-07-29] Numerous peer-reviewed studies have also since failed to show any association between MMR vaccine and autism.

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors. [cite journal|author=Murch SH, Anthony A, Casson DH "et al."|title=Retraction of an interpretation|year=2004|journal=Lancet|volume=363|issue=9411|pages=750|doi=10.1016/S0140-6736(04)15715-2 |pmid=15016483] The retraction followed an investigation by The Sunday Times. [cite web|author=Deer B|url=http://briandeer.com/mmr/lancet-summary.htm|title=The MMR-autism scare – our story so far|year=2007|accessdate=2007-07-29] The Centers for Disease Control and Prevention, [cite web|url=http://www.cdc.gov/od/science/iso/concerns/mmr_autism.htm|accessdate=2007-07-29|title=Autism and vaccines theory|date=2007-07-05|publisher=Centers for Disease Control and Prevention] the Institute of Medicine of the National Academy of Sciences, [cite web|url=http://www.iom.edu/CMS/3793/4705/20155.aspx|title=Immunization safety review: vaccines and autism|publisher=Institute of Medicine, National Academy of Sciences|year=2004|accessdate=2007-06-13] and the U.K. National Health Service [cite web|url=http://www.mmrthefacts.nhs.uk/|accessdate=2007-06-13|title=MMR the facts|publisher=National Health Service] have all concluded that there is no evidence of a link between the MMR vaccine and autism.

In July 2007 Andrew Wakefield and coauthors John Walker-Smith and Simon Murch faced charges of serious professional misconduct at the General Medical Council. It is alleged that the trio acted unethically in preparing the research into safety of the MMR vaccine. Wakefield denies the charges. [cite news|url=http://news.bbc.co.uk/1/hi/health/6289166.stm|accessdate=2007-07-29|title=MMR scare doctor 'paid children'|date=2007-07-16|work=BBC News]

Paracetamol

A 2008 preliminary case-control study based on a parent survey presented evidence that paracetamol (acetaminophen) following MMR vaccine is apparently associated with development of autism in children aged 1–5 years. The effect seemed to appear only in children who show some post-vaccination regression together with other post-vaccination sequelae such as fever, and it was not seen with other painkillers such as ibuprofen. The effect has not been independently confirmed. [cite journal |journal=Autism |year=2008 |volume=12 |issue=3 |pages=293–307 |title= Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey |author= Schultz ST, Klonoff-Cohen HS, Wingard DL, Akshoomoff NA, Macera CA, Ji M |doi=10.1177/1362361307089518 |pmid=18445737]

Television watching

Three economists hypothesized that early childhood television viewing acts as an environmental trigger for an underlying genetic predisposition. They found that precipitation was associated with autism by examining county-level autism data for California, Oregon, and Washington. Precipitation is also associated with television watching, and their analysis concluded that just under 40% of autism diagnoses in the three states result from television watching due to precipitation. [cite paper|author= Waldman M, Nicholson S, Adliov N |title= Does television cause autism? |url=http://ssrn.com/abstract=989648 |year=2006 |version= Johnson School Research Paper Series No. 01-07 |accessdate=2007-07-27] This widely publicized study was not published in a refereed journal, [cite news |author=Wallis C |title= Does watching TV cause autism? |work=TIME |date=2006-10-20 |url=http://www.time.com/time/health/article/0,8599,1548682,00.html |accessdate=2007-07-28] and was strongly criticized on several grounds, including confusing association with causality: one environmental health researcher wrote, "Little details like the 'ecological fallacy,' confounding, and exposure assessment apparently do not apply in the world of economists, and all associations are causal in this parallel universe." [cite journal |journal= Arch Environ Occup Health |year=2005 |volume=60 |issue=6 |pages=283–4 |title= Evidence of causation |author= Guidotti T |doi=10.3200/AEOH.60.6.283-286 |pmid=17447569]

Refrigerator mother

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. [cite book |author= Bettelheim B |title= The Empty Fortress: Infantile Autism and the Birth of the Self |year=1967 |publisher= Free Press |isbn=0029031400] Leo Kanner, who first described autism, [cite journal |author= Kanner L |title= Autistic disturbances of affective contact |journal= Nerv Child |volume=2 |pages=217–50 |year=1943 cite journal |title=Reprint |quotes=no |year=1968 |journal= Acta Paedopsychiatr |volume=35 |issue=4 |pages=100–36 |pmid=4880460] suggested that parental coldness might contribute to autism. [cite journal |journal= Am J Orthopsychiatry |volume=19 |issue=3 |pages=416–26 |year=1949 |author=Kanner L |title= Problems of nosology and psychodynamics in early childhood autism |pmid=18146742] 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. [cite journal |journal= Skeptical Inquirer |volume=24 |issue=6 |pages=12–4 |year=2000 |title= The brutality of Dr. Bettelheim |author=Gardner M]

Other psychogenic theories

Psychogenic theories in general have become increasingly unpopular, particularly since twin studies have shown that autism is highly heritable. Nevertheless, some case reports have found that deep institutional privation can result in "quasi-autistic" features without the neuroanatomical differences. [cite journal|author=Rutter ML, Kreppner JM, O'Connor TG, English and Romanian Adoptees (ERA) study team|title=Specificity and heterogeneity in children's responses to profound institutional privation|journal=Br J Psychiatry|year=2001|volume=179|issue=2|pages=97–103|pmid=11483469|url=http://bjp.rcpsych.org/cgi/content/full/179/2/97|doi=10.1192/bjp.179.2.97] [cite journal|author=Hoksbergen R, ter Laak J, Rijk K, van Dijkum C, Stoutjesdijk F|title=Post-Institutional Autistic Syndrome in Romanian adoptees|journal=J Autism Dev Disord|year=2005|volume=35|issue=5|pages=615–23|doi=10.1007/s10803-005-0005-x|pmid=16167089] Other case reports have suggested that children predisposed genetically to autism can develop "autistic devices" in response to traumatic events such as the birth of a sibling. [cite journal|author=Gomberoff M, De Gomberoff LP|title=Autistic devices in small children in mourning|journal=Int J Psychoanal|year=2000|volume=81|issue=5|pages=907–20|pmid=11109576]

ocial construct

Like ADHD, which has a similar social construct theory, [cite journal|journal=Br J Psychiatry|year=2004|volume=184|pages=8–9|title=ADHD is best understood as a cultural construct|author=Timimi S, Taylor E|pmid=14702221|url=http://bjp.rcpsych.org/cgi/content/full/184/1/8|doi=10.1192/bjp.184.1.8] a spectral disorder such as autism may be understood as a cultural or social construct. [cite journal|author=Timimi S|title=Diagnosis of autism: current epidemic has social context|journal=BMJ|year=2004|volume=328|issue=7433|pages=226|doi=10.1136/bmj.328.7433.226-a|pmid=14739199|url=http://www.bmj.com/cgi/content/full/328/7433/226-a] The 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. [cite book|isbn=0674004124|author=Hacking I|title=The Social Construction of What?|publisher=Harvard University Press|year=1999|pages=114–23] This theory does not say that there are no neurological or quality-of-life differences between groups deemed "autistic" and "non-autistic". To falsify this theory it would need to be shown that an objective characteristic can clearly separate both groups. For example, a genetic test that can fully substitute for a psychiatric diagnosis would undermine this theory. [cite web|title=Does autism exist?|url=http://autismnaturalvariation.blogspot.com/2006/02/does-autism-exist.html|accessdate=2007-07-29|date=2006-02-24|work=Natural Variation – Autism Blog]

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. [cite book|chapter=The dialectics of autism: theorizing autism, performing autism, remediating autism, and resisting autism|title=Constructing Autism: Unravelling the 'Truth' and Understanding the Social|author=Nadesan MH|publisher=Routledge|isbn=0415321816|pages=179|year=2005]

References