Causes of autism

# Overview
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. 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 triad of core aspects (social impairment, communication difficulties, and repetitive behaviors) that have distinct causes but often co-occur. 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. 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."
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.

# 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 of having one or more features of the broader autism phenotype might be as high as 30%.
The genetics of autism is complex. Linkage analysis has been inconclusive; many association analyses have had inadequate power. 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, but the mutations that increase risks of autism have not been identified for most candidate genes.
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. 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, while 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. 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. 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. 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.

## 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. It is not known whether these pesticides are human teratogens, though endosulfan has significant teratogenic effects in laboratory rats.
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. Several other studies demonstrate the neurodevelopmental toxicity of these agents at relatively low exposure levels.

## 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.

## 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". One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism. The theory and findings are controversial and many studies contradict the idea that baby boys and girls respond differently to people and objects.

## 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.  It is highly unlikely that this result speaks directly to risks of fetal ultrasound as practiced in competent and responsible medical centers. 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".

# 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. 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.

# 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. The subject remains controversial and extensive further searches for environmental factors are underway.

## Leaky gut syndrome
Parents have reported gastrointestinal (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut. 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. 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.
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, ], 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.

## 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.

## Oxidative stress
This theory hypothesizes that toxicity and oxidative stress may cause autism in some cases by damaging Purkinje cells in the cerebellum after birth. One possibility is that glutathione is involved.

## 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.

## 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.

## 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.

## Mercury
This theory hypothesizes that autism is associated with mercury poisoning, based on perceived similarity of symptoms. 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.
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, 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. A 2006 study found an 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.
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.

## 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," 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 evidence 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. 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. The retraction followed an investigation by The Sunday Times. The Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, and the U.K. 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.

## 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. This study has not been published in a refereed journal and its results have not been confirmed by others.

## 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. Leo Kanner, who first described autism, suggested that parental coldness might contribute to autism. 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.

## 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. 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.

# Social construct
Like ADHD, which has a similar social construct theory, a spectral disorder such as autism may be understood as a cultural or social construct. 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. 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. One such example would be a genetic test that can fully substitute for a psychiatric diagnosis.
Asperger syndrome and high-functioning autism are particular targets of the social construct theory. 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.