This diagram shows the brain sections and how autism relates to them.
Many causes of autism have been proposed, but understanding of the theory of causation of autism and the other autism spectrum disorders (ASD) is incomplete. Research indicates that genetic factors predominate. The heritability of autism, however, is complex, and it is typically 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 childhood immunizations, but numerous epidemiological studies have shown no scientific evidence supporting any link between vaccinations and autism.
Related disorders
Autism involves atypical brain development
which often becomes apparent in behavior and social development before a
child is three years old. It can be characterized by impairments in
social interaction and communication, as well as restricted interests
and stereotyped behavior, and the characterization is independent of any
underlying neurological defects. Other characteristics include repetitive-like tasks seen in their behavior and sensory interests. This article uses the terms autism and ASD to denote classical autism and the wider dispersion of symptoms and manifestations of autism, respectively.
Autism's theory of causation is incomplete.
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.
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.
Different underlying brain dysfunctions have been hypothesized to
result in the common symptoms of autism, just as completely different
brain problems result in intellectual disability. The terms autism or ASDs capture the wide range of disease processes at work. Although these distinct causes have been hypothesized to often co-occur, it has also been suggested that the correlation between the causes has been exaggerated.
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.
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 that 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, there is overwhelming scientific evidence showing no causal association between the measles-mumps-rubella (MMR) vaccine and autism, and there is no scientific evidence that the vaccine preservative thiomersal causes autism.
Genetics
Genetic factors may be the most significant cause for autism spectrum disorders. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism. However, this may be an overestimation, as new twin studies estimate the heritability at between 60–90%.
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%.
However, in spite of the strong heritability, most cases of ASD
occur sporadically with no recent evidence of family history. It has
been hypothesized that spontaneous de novo mutations in the father's sperm or mother's egg contribute to the likelihood of developing autism.
There are two lines of evidence that support this hypothesis. First,
individuals with autism have significantly reduced fecundity, they are
20 times less likely to have children than average, thus curtailing the
persistence of mutations in ASD genes over multiple generations in a
family. Second, the likelihood of having a child develop autism increases with advancing paternal age, and mutations in sperm gradually accumulate throughout a man's life.
The first genes to be definitively shown to contribute to risk
for autism were found in the early 1990s by researchers looking at
gender-specific forms of autism caused by mutations on the X chromosome.
An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1 in boys causes fragile X syndrome, and at least 20% of boys with this mutation have behaviors consistent with autism spectrum disorder. Mutations that inactivate the gene MECP2 cause Rett syndrome, which is associated with autistic behaviors in girls, and in boys the mutation is embryonic lethal.
Besides these early examples, the role of de novo mutations in ASD first became evident when DNA microarray technologies reached sufficient resolution to allow the detection of copy number variation (CNV) in the human genome. CNVs are the most common type of structural variation in the genome, consisting of deletions and duplications of DNA that range in size from a kilobase to a few megabases. Microarray analysis has shown that de novo
CNVs occur at a significantly higher rate in sporadic cases of autism
as compared to the rate in their typically developing siblings and
unrelated controls. A series of studies have shown that gene disrupting de novo CNVs occur approximately four times more frequently in ASD than in controls and contribute to approximately 5–10% of cases. Based on these studies, there are predicted to be 130–234 ASD-related CNV loci. The first whole genome sequencing study to comprehensively catalog de novo structural variation
at a much higher resolution than DNA microarray studies has shown that
the mutation rate is approximately 20% and not elevated in autism
compared to sibling controls.
However, structural variants in individuals with autism are much larger
and four times more likely to disrupt genes, mirroring findings from
CNV studies.
CNV studies were closely followed by exome sequencing studies, which sequence the 1–2% of the genome that codes for proteins (the "exome"). These studies found that de novo
gene inactivating mutations were observed in approximately 20% of
individuals with autism, compared to 10% of unaffected siblings,
suggesting the etiology of ASD is driven by these mutations in around
10% of cases. There are predicted to be 350-450 genes that significantly increase susceptibility to ASDs when impacted by inactivating de novo mutations. A further 12% of cases are predicted to be caused by protein altering missense mutations that change an amino acid but do not inactivate a gene. Therefore approximately 30% of individuals with autism have a spontaneous de novo
large CNV that deletes or duplicates genes, or mutation that changes
the amino acid code of an individual gene. A further 5–10% of cases have
inherited structural variation at loci known to be associated with autism, and these known structural variants may arise de novo in the parents of affected children.
Tens of genes and CNVs have been definitively identified based on
the observation of recurrent mutations in different individuals, and
suggestive evidence has been found for over 100 others. The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic locus associated with autism.
These early gene and CNV findings have shown that the cognitive
and behavioral features associated with each of the underlying mutations
is variable. Each mutation is itself associated with a variety of
clinical diagnoses, and can also be found in a small percentage of
individuals with no clinical diagnosis.
Thus the genetic disorders that comprise autism are not
autism-specific. The mutations themselves are characterized by
considerable variability in clinical outcome and typically only a subset
of mutation carriers meet criteria for autism. This variable expressivity
results in different individuals with the same mutation varying
considerably in the severity of their observed particular trait.
The conclusion of these recent studies of de novo mutation is that the spectrum of autism is breaking up into quanta of individual disorders defined by genetics.
One gene that has been linked to autism is SHANK2. Mutations in this gene act in a dominant fashion. Mutations in this gene appear to cause hyperconnectivity between the neurons.
Epigenetics
Epigenetic
mechanisms may increase the risk of autism. Epigenetic changes occur as
a result not of DNA sequence changes but of chromosomal histone
modification or modification of the DNA bases. Such modifications are
known to be affected by environmental factors, including nutrition,
drugs, and mental stress. Interest has been expressed in imprinted regions on chromosomes 15q and 7q.
Prenatal environment
The risk of autism is associated with several prenatal
risk factors, including advanced age in either parent, diabetes,
bleeding, and use of psychiatric drugs in the mother during pregnancy. Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.
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 may greatly increase the risk for autism in mice. Congenital rubella syndrome is the most convincing environmental cause of autism.
Infection-associated immunological events in early pregnancy may affect
neural development more than infections in late pregnancy, not only for
autism, but also for psychiatric disorders of presumed
neurodevelopmental origin, notably schizophrenia.
Environmental agents
Teratogens are environmental agents that cause birth defects.
Some agents that are theorized to cause birth defects have also been
suggested as potential autism risk factors, although there is little to
no scientific evidence to back such claims. These include exposure of
the embryo to valproic acid, paracetamol, thalidomide or misoprostol. 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.
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.
Autoimmune and inflammatory diseases
Maternal inflammatory and autoimmune diseases can damage embryonic and fetal tissues, aggravating a genetic problem or damaging the nervous system.
Other maternal conditions
Thyroid problems that lead to thyroxine
deficiency in the mother in weeks 8–12 of pregnancy have been
postulated to produce changes in the fetal brain leading to autism.
Thyroxine deficiencies can be caused by inadequate iodine in the diet, and by environmental agents that interfere with iodine uptake or act against thyroid hormones. Possible environmental agents include flavonoids in food, tobacco smoke, and most herbicides. This hypothesis has not been tested.
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. A 2014 review also found
that maternal diabetes was significantly associated with an increased
risk of ASD. Although diabetes causes metabolic and hormonal abnormalities and oxidative stress, no biological mechanism is known for the association between gestational diabetes and autism risk.
Maternal obesity during pregnancy may also increase the risk of autism, although further study is needed.
Maternal malnutrition during preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is associated with ASD, in both term and preterm infants.
Other in utero
It has been hypothesized that folic acid taken during pregnancy could play a role in reducing cases of autism by modulating gene expression through an epigenetic mechanism. This hypothesis is supported by multiple studies.
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.
However, other studies have cast doubts on this association, notably
population based studies in England and Sweden finding no link between
stressful life events and ASD.
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.
Based in part on animal studies, diagnostic ultrasounds
administered during pregnancy have been hypothesized to increase the
child's risk of autism. This hypothesis is not supported by
independently published research, and examination of children whose
mothers received an ultrasound has failed to find evidence of harmful
effects.
Some research suggests that maternal exposure to selective serotonin reuptake inhibitors
during pregnancy is associated with an increased risk of autism, but it
remains unclear whether there is a causal link between the two. There is evidence, for example, that this association may be an artifact of confounding by maternal mental illness.
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. As a
result, an underlying cause could explain both autism and these
associated conditions. There is growing evidence that perinatal exposure to air pollution may be a risk factor for autism,
although this evidence suffers from methodological limitations,
including a small number of studies and failure to control for potential
confounding factors.
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.
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.
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.
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.
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. As autoantibodies are found in diseases other than ASD, and are not always present in ASD, the relationship between immune disturbances and autism remains unclear and controversial.
A 2015 systematic review and meta-analysis found that children with a
family history of autoimmune diseases were at a greater risk of autism
compared to children without such a history.
When an underlying maternal autoimmune disease is present,
antibodies circulating to the fetus could contribute to the development
of autism spectrum disorders.
Gastrointestinal connection
Gastrointestinal problems are one of the most commonly associated medical disorders in people with autism.
These are linked to greater social impairment, irritability, behavior
and sleep problems, language impairments and mood changes, so the theory
that they are an overlap syndrome has been postulated. Studies indicate that gastrointestinal inflammation, immunoglobulin E-mediated or cell-mediated food allergies, gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity, dysautonomia and gastroesophageal reflux are the mechanisms that possibly link both.
A 2016 review concludes that enteric nervous system
abnormalities might play a role in several neurological disorders,
including autism. Neural connections and the immune system are a
pathway that may allow diseases originated in the intestine to spread to
the brain. A 2018 review suggests that the frequent association of gastrointestinal disorders and autism is due to abnormalities of the gut–brain axis.
The "leaky gut" hypothesis is popular among parents of children with autism. It is based on the idea that defects in the intestinal barrier produce an excessive increase of the intestinal permeability, allowing substances present in the intestine, including bacteria, environmental toxins and food antigens,
to pass into the blood. The data supporting this theory are limited and
contradictory, since both increased intestinal permeability and normal
permeability have been documented in people with autism. Studies with
mice provide some support to this theory and suggest the importance of intestinal flora,
demonstrating that the normalization of the intestinal barrier was
associated with an improvement in some of the ASD-like behaviours. Studies on subgroups of people with ASD showed the presence of high plasma levels of zonulin, a protein that regulates permeability opening the "pores" of the intestinal wall, as well as intestinal dysbiosis (reduced levels of Bifidobacteria and increased abundance of Akkermansia muciniphila, Escherichia coli, Clostridia and Candida fungi) that promotes the production of proinflammatory cytokines, all of which produces excessive intestinal permeability. This allows passage of bacterial endotoxins from the gut into the bloodstream, stimulating liver cells to secrete tumor necrosis factor alpha (TNFα), which modulates blood–brain barrier
permeability. Studies on ASD people showed that TNFα cascades produce
proinflammatory cytokines, leading to peripheral inflammation and
activation of microglia in the brain, which indicates neuroinflammation. In addition, neuroactive opioid peptides
from digested foods have been shown to leak into the bloodstream and
permeate the blood–brain barrier, influencing neural cells and causing
autistic symptoms.
After a preliminary 1998 study of three children with ASD treated with secretin
infusion reported improved GI function and dramatic improvement in
behavior, many parents sought secretin treatment and a black market for
the hormone developed quickly. Later studies found secretin clearly ineffective in treating autism.
Endogenous opiate precursor theory
In 1979, Jaak Panksepp
proposed a connection between autism and opiates, noting that
injections of minute quantities of opiates in young laboratory animals
induce symptoms similar to those observed among autistic children. The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by Kalle Reichelt in 1991.
Opiate theory hypothesizes that autism is the result of a metabolic disorder in which opioid peptides gliadorphin (aka gluteomorphin) and casomorphin,
produced through metabolism of gluten (present in wheat and related
cereals) and casein (present in dairy products), pass through an
abnormally permeable intestinal wall and then proceed to exert an effect
on neurotransmission through binding with opioid receptors. It has been
postulated that the resulting excess of opioids affects brain
maturation, and causes autistic symptoms, including behavioural
difficulties, attention problems, and alterations in communicative
capacity and social and cognitive functioning.
Although high levels of these opioids are eliminated in the
urine, it has been suggested that a small part of them cross into the
brain causing interference of signal transmission and disruption of
normal activity. Three studies have reported that urine samples of
people with autism show an increased 24-hour peptide excretion.
A study with a control group found no appreciable differences in opioid
levels in urine samples of people with autism compared to controls. Two studies showed an increased opioid levels in cerebrospinal fluid of people with autism.
The theory further states that removing opiate precursors from a
child's diet may allow time for these behaviors to cease, and
neurological development in very young children to resume normally. As of 2014 there is no good evidence that a gluten-free diet is of benefit as a standard treatment for autism.
Problems observed in studies carried out include the suspicion that
there were transgressions of the diet because the participants asked for
food containing gluten or casein to siblings and peers; and the lack of
a washout period, that could diminish the effectiveness of the
treatment if gluten or casein peptides have a long term residual effect,
which is especially relevant in studies of short duration. In the subset of people who have gluten sensitivity there is limited evidence that suggests that a gluten-free diet may improve some autistic behaviors.
Lack of vitamin D
The hypothesis that vitamin D deficiency has a role in autism is biologically plausible, but not researched.
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.
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 coeruleus–noradrenergic
(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.
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. This view has gained little traction in the scientific community as the typical symptoms of mercury toxicity are significantly different from symptoms seen in autism. The principal source of human exposure to organic mercury is via fish consumption and for inorganic mercury is dental amalgams.
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 meta-analysis published in 2007 concluded that there was no link between mercury and autism.
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. One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved. Autistic children have lower levels of total glutathione, and higher levels of oxidized glutathione. Based on this theory, antioxidants may be a useful treatment for autism.
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.
Social construct
The social construct
theory says that the boundary between normal and abnormal is subjective
and arbitrary, so autism does not exist as an objective entity, but
only as a social construct. It further argues that autistic individuals
themselves have a way of being that is partly socially constructed.
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.
Discredited theories
Vaccines
Scientific studies have refuted a causal relationship between vaccinations and autism.
Despite this, some parents believe that vaccinations cause autism and
therefore delay or avoid immunizing their children, for example under
the "vaccine overload" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism, even though this hypothesis has no scientific evidence and is biologically implausible.
Because diseases such as measles can cause severe disabilities and
death, the risk of death or disability for an unvaccinated child is
higher than the risk for a child who has been vaccinated. Despite all this, antivaccine
activism continues. A developing tactic appears to be the "promotion of
irrelevant research [as] an active aggregation of several questionable
or peripherally related research studies in an attempt to justify the
science underlying a questionable claim."
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.
MMR vaccine
The MMR vaccine as a cause of autism is one of the most extensively debated hypotheses 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. Although the paper, which was later retracted by the journal, 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 dose.
In 2004, the interpretation of a causal link between MMR vaccine
and autism was formally retracted by ten of Wakefield's twelve
co-authors. The retraction followed an investigation by The Sunday Times, which stated that Wakefield "acted dishonestly and irresponsibly". 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 February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed. In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.
Thiomersal (thimerosal)
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 including US and the EU.
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 and increasing likelihood of disease outbreaks.
In 1999, due to concern about the dose of mercury infants were being
exposed to, the U.S. Public Health Service recommended that thiomersal
be removed from childhood vaccines, and by 2002 the flu vaccine was the
only childhood vaccine containing more than trace amounts of thimerosal.
Despite this, autism rates did not decrease after the removal of
thimerosal, in the US or other countries that also removed thimerosal
from their childhood vaccines.
A causal link between thimerosal and autism has been rejected by
international scientific and medical professional bodies including the American Medical Association, the American Academy of Pediatrics, the American College of Medical Toxicology, the Canadian Paediatric Society, the U.S. National Academy of Sciences, the Food and Drug Administration, Centers for Disease Control and Prevention, the World Health Organization, the Public Health Agency of Canada, and the European Medicines Agency.
