Understanding the Brain

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] Heritability contributes about 90% of the risk of a child developing autism, but the heritability of autism is complex and typically it is 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

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 repetitive behavior; the characterization is independent of any underlying neurological defects. 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.[5][6] 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.[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] In other words, completely different underlying brain dysfunctions have been hypothesized to result in the common symptoms of autism, just as completely different brain problems result in mental retardation. The term "the autisms" or "the ASDs" captures 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] 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. 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, 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.[13][14]

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.[2] This may be an overestimate; new twin data and models with structural genetic variation are needed.[15] 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%.[16]

The genetics of autism is complex.[2] Linkage analysis has been inconclusive; many association analyses have had inadequate power.[15] 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,[17] 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.[18][19] 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.[20]

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.[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; 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.[21] The risk is greater for advanced paternal age. One hypothesis is that this is caused by older sperm that have greater mutation burden; 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]

Prenatal environment

The risk of autism is associated with several prenatal risk factors, including advanced age in either parent, and diabetes, bleeding, and use of psychiatric drugs in the mother during pregnancy.[21] Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.[22]

A child's risk of developing autism is associated with the age of its mother and father at birth.[21][23][24] The biological reasons for this are unknown: possible explanations include increased risk of pregnancy complications;[21] maternal autoimmunity;[24] increased risk of chromosomal abnormalities or unstable trinucleotide repeats in the egg; and imprinted genes, spontaneous mutations, and confounding sociocultural factors in the sperm. Since ages of the father and mother are correlated, it is possible that only the mother's age, or only the father's age, or both, contribute to the risk.[21]

A study of California children born between 1992 and 2002 suggested that second children born at shorter intervals after the first pregnancy were at increased risk of developing autism.[25]

Infectious processes

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.[26] Congenital rubella syndrome is the most convincing environmental cause.[27] 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.[28]

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.[29] The theory is related to the autoimmune disease hypothesis, except it focuses on maternal antibodies rather than the child's. A 2008 study found that these antibodies bind to fetal brain cells, most commonly in mothers of children with regressive autism.[30] If confirmed, these findings will account for about 12% of autism cases, and, since certain maternal antibody patterns are not found in mothers of typically developing children, it may be possible for mothers to take the antibody test before conception to avoid having an autistic child. 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.[31]

Environmental agents

Teratogens are environmental agents that cause birth defects. Some agents that are theorized to cause other 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 thalidomide, valproic acid, or misoprostol. These cases are rare.[22] Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects, but evidence is insufficient to determine whether autism risk is actually elevated with ethanol.[32] 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]

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.[33] It is not known whether these pesticides are human teratogens, though endosulfan has significant teratogenic effects in laboratory rats.[34]

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.[35] Several other studies demonstrate the neurodevelopmental toxicity of these agents at relatively low exposure levels.[36]

It has been suggested that exposure during pregnancy to pyrethrin, a common ingredient in antiflea and antitick pet shampoos, can cause autism in the child. One retrospective study suggesting an association has been conducted, but has not been published.[37]

Other maternal conditions

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.[21]

Thyroid problems that lead to thyroxine deficiency in the mother in weeks 8–12 of pregnancy has 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.[38] A related untested hypothesis is that exposure to pesticides could combine with suboptimal iodine nutrition in a pregnant mother and lead to autism in the child.[39]

Research at UC Davis Medical School has found a link between certain maternal antibodies to fetal brain and autism. One particular pattern of maternal antibodies has only been found in the mothers of autistics, and never in the mothers of typically developing children. [40]

Other in utero

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.[41]

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.[42]

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.[43] The theory and findings are controversial and many studies contradict the idea that baby boys and girls respond differently to people and objects.[44]

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.[45] It is highly unlikely that this result speaks directly to risks of fetal ultrasound as practiced in competent and responsible medical centers.[46] 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".[47]

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.[48] 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.[49]

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.[4] The subject remains controversial and extensive further searches for environmental factors are underway.[22]

Mercury

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.[50] This view has gained little traction in the scientific community as the typical symptoms of mercury toxicity are significantly different than symptoms seen in autism.[51] 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.[52] A meta-analysis published in 2007 concluded that there was no link between mercury and autism (based on a literature search by two independent reviewers who did a med-line search from 1980 to 2003).[53]

Vaccines

The scientific consensus is that there is no evidence of a causal relationship between vaccinations and autism.[54] 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.[55] even though this hypothesis has no scientific evidence and is biologically implausible.[56] 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.[57]

Thiomersal

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.[58] 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[13] and increasing likelihood of disease outbreaks.[59][60] 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,[61] the American Academy of Pediatrics,[62] the American College of Medical Toxicology,[63] the Canadian Paediatric Society,[64] the U.S. National Academy of Sciences,[65] the Food and Drug Administration,[66] Centers for Disease Control and Prevention,[67] the World Health Organization,[68] the Public Health Agency of Canada,[69] and the European Medicines Agency.[70]

MMR vaccine

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.[71] Although the paper, which was later retracted by the journal,[71] concluded "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described,"[72] Wakefield nevertheless suggested during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose. This suggestion has been heavily criticized, both on scientific grounds and for triggering a decline in vaccination rates.[13] 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.[73] Numerous peer-reviewed studies have also since failed to show any association between MMR vaccine and autism.[13]

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors.[74] The retraction followed an investigation by The Sunday Times, which stated that Wakefield "acted dishonestly and irresponsibly".[75] The Centers for Disease Control and Prevention,[67] the Institute of Medicine of the National Academy of Sciences,[65] and the U.K. National Health Service[76] 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.[77] In February 2009 The Sunday Times reported that Wakefield had manipulated patient data and misreported results in his 1998 paper, creating the appearance of a link with autism.[78]

In 2009, the US Federal Vaccine Court rejected "speculative and unpersuasive" claims that the MMR vaccine caused autism.[79]

In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed.[71] In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.[80][81][82][83]

Autoimmune disease

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.[84]

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.[85] 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.[86] As autoantibodies are found in diseases other than ASD, and are not always present in ASD,[87] the relationship between immune disturbances and autism remains unclear and controversial.[88]

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.[89]

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.[90]

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.[91] One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved.[92]

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.[93]

Locus coeruleus–noradrenergic system

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.[94]

Lack of 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.[95]

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.[96]

Leaky gut syndrome

Parents have reported gastrointestinal (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut.[97] The disputed 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.[72] Although Wakefield later proposed the term autistic enterocolitis, his studies' methodology has been criticized, their results have not been replicated by other groups,[98] and Wakefield has been accused of manipulating patient data and misreporting results.[78]

There is no research evidence that autistic children are more likely to have GI symptoms than typical children.[97] In particular, design flaws in studies of elimination diets mean that the data are inadequate to guide treatment recommendations.[12] 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.[99]

In another example, 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, although the low number of patients is statistically insignificant.[100] After this study, many parents sought secretin treatment and a black market for the hormone developed quickly.[97] However, later studies found secretin ineffective in treating autism.[101]

Paracetamol

A 2008 preliminary case-control study based on a parent survey presented evidence that paracetamol (acetaminophen, Tylenol) following MMR vaccine is apparently associated with development of autism in children aged 1–5 years. The effect has not been independently confirmed.[102] More 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.[103]

Rain

It has been hypothesized that rain, or some environmental trigger positively associated with rain, acts together with an underlying genetic predisposition to cause autism. A 2008 study found that precipitation was associated with autism by examining county-level autism data for California, Oregon, and Washington.[104] Noel S. Weiss was highly critical of the publication of this work in an editorial published in the same journal, and argued that it is possible that nonprofessionals will misinterpret this result, and that it may not lead to insights about the causes of autism.[105]

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.[106] Leo Kanner, who first described autism,[107] suggested that parental coldness might contribute to autism.[108] 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.[109]

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.[110][111] 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.[112]

Social construct

Like ADHD, which has a similar social construct theory,[113] a spectral disorder such as autism may be understood as a cultural or social construct.[114] 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.[115] 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.[116]

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.[117]

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