Causes of autism

Source: Wikipedia, the free encyclopedia.
This diagram shows the brain sections and how autism relates to them.

Many causes of

autism, including environmental and genetic factors, have been recognized or proposed, but understanding of the theory of causation of autism is incomplete.[1] Attempts have been made to incorporate the known genetic and environmental causes into a comprehensive causative framework.[2] ASD (autism spectrum disorder) is a neurodevelopmental disorder marked by impairments in communicative ability and social interaction, as well as restricted and repetitive behaviors, interests, or activities not suitable for the individual's developmental stage. The severity of symptoms and functional impairment vary between individuals.[3]

There are many known environmental, genetic, and biological causes of autism. Research indicates that genetic factors are predominate in the appearance of autism; however, the heritability of autism is complex, and many of the genetic interactions involved are unknown.[1] In rare cases, autism has been associated with agents that cause birth defects.[4] Many other causes have been proposed.

Different underlying brain dysfunctions have been hypothesized to result in the common symptoms of autism, just as completely different brain types result in intellectual disability.[1][5] In recent years, the prevalence and number of people diagnosed with the disorder have increased dramatically. There are many potential reasons for this occurrence, particularly the changes in the diagnostic criteria for autism.[6]

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,

thimerosal causes autism, studies have indicated a possible link between thimerosal and autism in individuals with a hereditary predisposition for autoimmune disorders.[10][11] In 2007, the Center for Disease Control stated there was no support for a link between thimerosal and autism, citing evidence from several studies, as well as a continued increase in autism cases following the removal of thimerosal from childhood vaccines. [12]

Genetics

Main article: Heritability of autism
See also: Missing heritability problem

Genetic factors may be the most significant cause of autism. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism.[1] This may be an overestimation, as later twin studies estimate the heritability at between 60 and 90%.[1][13] Evidence so far still suggests a strong genetic component, with one of the largest and most recent studies estimating the heritability at 83%.[14] Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%.[15]

In spite of the strong heritability, most cases of autism occur sporadically with no recent evidence of family history. It has been hypothesized that spontaneous de novo mutations in the sperm or egg contribute to the likelihood of developing autism.[16][1] 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.[1][5] Second, the likelihood of having a child develop autism increases with advancing parental age, and mutations in sperm gradually accumulate throughout a man's life.[1][17]

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.[18][19] 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.[20]

Besides these early examples, the role of de novo mutations in autism first became evident when

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 autism than in controls and contribute to approximately 5–10% of cases.[16][23][24][25] Based on these studies, there are predicted to be 130–234 autism-related CNV loci.[25] 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.[26] However, structural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies.[26]

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 autism is driven by these mutations in around 10% of cases.[27][28][29][30][31][32] There are predicted to be 350-450 genes that significantly increase susceptibility to autism when impacted by inactivating de novo mutations.[33] 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.[29] 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.[26]

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.[34] The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic locus associated with autism.[35]

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.[36][37] 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.[38]

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.[38]

One gene that has been linked to autism is SHANK2.[39] Mutations in this gene act in a dominant fashion. Mutations in this gene appear to cause hyperconnectivity between the neurons.

A study conducted on 42,607 autism cases has identified 60 new genes, five of which had a more moderate impact on autistic symptoms. The related gene variants were often inherited from the participant's parents.[40]

Metabolic disorders

Selected metabolic conditions which may (rarely) be associated with an ASD appearance are:[41]

Disorders of amino acid metabolism

Disorders of γ-aminobutyric acid metabolism

Disorders of cholesterol metabolism

  • Smith-Lemli-Opitz syndrome

Disorders associated with cerebral folate deficiency

Disorders of creatine transport or metabolism

Disorders of carnitine biosynthesis

  • 6-N-trimethyllysine dioxygenase deficiency

Disorders of purine and pyrimidine metabolism

Lysosomal storage disorders

Mitochondrial disorders

Others

Epigenetics

Main article:
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.[42] Interest has been expressed in imprinted regions on chromosomes 15q and 7q.[43]

Most data supports a

epistatic model, meaning that the disorder is caused by two or more genes and that those genes are interacting in a complex manner. Several genes, between two and fifteen in number, have been identified and could potentially contribute to disease susceptibility.[44][45] However, an exact determination of the cause of ASD has yet to be discovered and there probably is not one single genetic cause of any particular set of disorders, leading many researchers to believe that epigenetic mechanisms, such as genomic imprinting or epimutations, may play a major role.[46][47]

DNA cytosine methylation and post-translational modifications to histones. These mechanisms contribute to regulating gene expression without changing the sequence of the DNA and may be influenced by exposure to environmental factors and may be heritable from parents.[43] Rett syndrome and Fragile X syndrome (FXS) are single gene disorders related to autism with overlapping symptoms that include deficient neurological development, impaired language and communication, difficulties in social interactions, and stereotyped hand gestures. It is not uncommon for a patient to be diagnosed with both autism and Rett syndrome and/or FXS. Epigenetic regulatory mechanisms play the central role in pathogenesis of these two disorders.[46][48][49]

Genomic imprinting may also contribute to the development of autism. Genomic imprinting is another example of epigenetic regulation of gene expression. In this instance, the epigenetic modification(s) causes the offspring to express the maternal copy of a gene or the paternal copy of a gene, but not both. The imprinted gene is silenced through epigenetic mechanisms. Candidate genes and susceptibility alleles for autism are identified using a combination of techniques, including genome-wide and targeted analyses of allele sharing in sib-pairs, using association studies and transmission disequilibrium testing (TDT) of functional and/or positional candidate genes and examination of novel and recurrent cytogenetic aberrations. Results from numerous studies have identified several genomic regions known to be subject to imprinting, candidate genes, and gene-environment interactions. Particularly, chromosomes 15q and 7q appear to be epigenetic hotspots in contributing to autism. Also, genes on the X chromosome may play an important role, as in Rett Syndrome.[43]

An important basis for autism causation is also the over- or underproduction of brain permanent cells (neurons, oligodendrocytes, and astrocytes) by the neural precursor cells during fetal development.[50]

Prenatal environment

The development of autism is associated with several

prenatal risk factors, including advanced age in either parent, diabetes, bleeding, and maternal use of antibiotics and psychiatric drugs during pregnancy.[1][51][52] Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.[53] If the mother of the child is dealing with autoimmune conditions or disorders while pregnant, it may have an effect on the child's development of autism.[54] All of these factors can cause inflammation or impair immune signaling in one way or another.[54]

Obstructive sleep apnea in pregnancy

hypoxia and has been increasing in prevalence due in part to the obesity epidemic. The known maternal risk factors for autism diagnosis in her offspring are similar to the risk factors for sleep apnea. For example, advanced maternal age, maternal obesity, maternal type 2 diabetes and maternal hypertension all increase the risk of autism in her offspring.[55][56][57][58] Likewise, these are all known risk factors for sleep apnea.[59][60][61]

One study found that gestational sleep apnea was associated with low reading test scores in children and that this effect may be mediated by an increased risk of the child having sleep apnea themselves.[62] Another study reported low social development scores in 64% of infants born to mothers with sleep apnea compared to 25% of infants born to controls, suggesting sleep apnea in pregnancy may have an effect on offspring neurodevelopment.[63] There was also an increase in the amount of snoring the mothers with sleep apnea reported in their infants when compared to controls.[63] Children with sleep apnea have "hyperactivity, attention problems, aggressivity, lower social competency, poorer communication, and/or diminished adaptive skills".[64] One study found significant improvements in ADHD-like symptoms, aggression, social problems and thought problems in autistic children who underwent adenotonsillectomy for sleep apnea.[65] Sleep problems in autism have been linked in a study to brain changes, particularly in the hippocampus, though this study does not prove causation.[66] A common presentation of sleep apnea in children with autism is insomnia.[67]

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.[68] Congenital rubella syndrome is the most convincing environmental cause of autism.[69] 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.[70]

Environmental agents

fetal alcohol syndrome or alcohol-related birth defects.[72] 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.[4]

A small but significant link has been shown to exist between prenatal exposure to airborne pollutants and autism risk. However, this finding was not consistent across studies, and exposure to pollutants was measured indirectly.[74]

Autoimmune and inflammatory diseases

Maternal inflammatory and autoimmune diseases can damage embryonic and fetal tissues, aggravating a genetic problem or damaging the nervous system.[75]

Other maternal conditions

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.[76]

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 autism.[77] Although diabetes causes metabolic and hormonal abnormalities and oxidative stress, no biological mechanism is known for the association between gestational diabetes and autism risk.[78]

Maternal diagnoses of polycystic ovary syndrome was found to associated with higher risk of autism.[79]

Maternal obesity during pregnancy may also increase the risk of autism, although further study is needed.[80]

Maternal malnutrition during preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is associated with autism, in both term and preterm infants.[81]

Other in utero

It has been hypothesized that

epigenetic mechanism. This hypothesis is supported by multiple studies.[82]

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.[83] 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 autism.[84]

The fetal testosterone theory hypothesizes that higher levels of

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.[85]

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.[86]

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.[87] There is evidence, for example, that this association may be an artifact of confounding by maternal mental illness.[88]

Perinatal environment

Autism is associated with some

jaundice/hyperbilirubinemia. These associations do not denote a causal relationship for any individual factor.[90] There is growing evidence that perinatal exposure to air pollution may be a risk factor for autism, although this evidence has methodological limitations, including a small number of studies and failure to control for potential confounding factors.[91][92] A few studies have found an association between autism and frequent use of acetaminophen (e.g. Tylenol, Paracetamol) by the mother during pregnancy.[93][94]
This association does not necessarily demonstrate a causal relationship.

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, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies.[95]

Paracetamol

Paracetamol has been suggested as a possible risk factor for autism and other neurodevelopmental disorders.[96][97] A study has found that male children exposed to Paracetamol before the age of 2 years old are associated with being at risk for being diagnosed with autism.[98]

Amygdala neurons

This theory hypothesizes that an early developmental failure involving 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.[99]

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

broken anchor] 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.[100]

Interactions between the

autoantibodies are found in diseases other than autism, and are not always present in autism,[103] the relationship between immune disturbances and autism remains unclear and controversial.[104] 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.[105]

When an underlying maternal autoimmune disease is present, antibodies circulating to the fetus could contribute to the development of autism spectrum disorders.[106]

Gastrointestinal connection

gastroesophageal reflux are the mechanisms that possibly link both.[108]

A 2016 review concludes that

gastrointestinal disorders and autism is due to abnormalities of the gut–brain axis.[107]

The "

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.[113] 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.[113] (See Endogenous opiate precursor theory
)

After a preliminary 1998 study of three children with autism 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.[114] Later studies found secretin clearly ineffective in treating autism.[115]

Endogenous opiate precursor theory

Main article: Opioid excess theory

In 1979, a possible association between autism and opiate was proposed, it was noted that injecting small amounts of opiates into young laboratory animals resulted in symptoms similar to those seen in autistic children.[116] The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by Kalle Reichelt in 1991.[117]

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: behavioral difficulties, attention problems, and alterations in communicative capacity and social and cognitive functioning.[117][118]

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.[117] A study with a control group found no appreciable differences in opioid levels in urine samples of people with autism compared to controls.[113] Two studies showed an increased opioid levels in cerebrospinal fluid of people with autism.[117]

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.[119] As of 2021, reliable studies have not demonstrated the benefit of gluten-free diets in the treatment of autism.[120][7] 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.[120][7]

Nutrition-related Factors

There have been multiple attempts to uncover a link between various nutritional deficiencies such as vitamin D and folate and autism risk.[121] Although there have been many studies on the role of vitamin D in the development of autism, the majority of them are limited by their inability to assess the deficiency prior to an autism diagnosis.[121] A meta-analysis on the association between vitamin D and autism found that individuals with autism had significantly low levels of serum 25-hydroxy vitamin D than those without autism.[121] Another analysis showed significant differences in levels of zinc between individuals with and without autism. Although studies showed significant differences protein intake and calcium in individuals with autism, the results were limited by their imprecision, inconsistency, and indirect nature.[121] Additionally, low levels of 5-methyltetrahydrofolate (5-MTHF) in the brain can result in cerebral folate deficiency (CFD) which has been shown to be associated with autism.[121][122]

Toxic Exposure

Multiple studies have made attempts to study the relationship between toxic exposure and autism. However, these studies often met with limitations related to the measurement of toxic exposure the methods for which were often indirect and cross-sectional. Systematic reviews have been conducted for numerous toxins including air pollution, thimerosal, inorganic mercury, and levels of heavy metals in hair, nails, and bodily fluids.[121]

Although no link was found to exist between the vaccine additive thiomersal and autism risk, this association may hold true for individuals with a hereditary predisposition for autoimmune disorders.[123][121]

Environmental exposure to inorganic mercury may be associated with higher autism risk, with high levels of mercury in the body being a valid

disease-causing agent for autism.[121][124]

Significant evidence has not been found of an association between autism and the concentration of mercury, copper, cadmium, selenium, and chromium in the hair, nails, and bodily fluids.[121][125][124] Levels of lead were found to be significantly higher in individuals with autism.[121][124] The precision and consistency of results were not maintained across studies and were influenced by an outlier study.[121] 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.[126]

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

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.[127]

Oxidative stress

Oxidative stress, oxidative DNA damage and disruptions of DNA repair have been postulated to play a role in the etiopathology of both ASD and schizophrenia.[128] Physiological factors and mechanisms influence by oxidative stress are believed to be highly influential to autism risk. Interactions between environmental and genetic factors may increase oxidative stress in children with autism.[129] 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.[129] One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved.[130] Polymorphism of genes involved metabolization of glutathione is evidenced by lower levels of total glutathione, and higher levels of oxidized glutathione in autistic children.[129][131] Based on this theory, antioxidants may be a useful treatment for autism.[132] Environmental factors can influence oxidative stress pre, peri, and postnatally and include heavy metals, infection, certain drugs, and toxic exposure from various sources including cigarette smoke, air pollutants, and organophosphate pesticides.[129]

Social construct

Beyond the genetic, epigenetic, and biological factors that can contribute to an autism diagnosis are theories related to the "autistic identity."[133] It has been theorized that perceptions towards the characteristics of autistic individuals have been heavily influenced by neurotypical ideologies and social norms.[133]

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.[134]

Mild and moderate variations of 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.[135]

Lynn Waterhouse suggests that autism has been reified, in that social processes have endowed it with more reality than is justified by the scientific evidence.[136]

Although social construction of the autistic identity can have a positive impact on the well-being and treatment of autistic individuals.[133] That is not always the case when the individuals in question belong to historically marginalized populations.[133]

When it comes to social constructs, people are often marginalized on the basis of race, sex, and LGBTQ+ identities. [133][137][138] Autism and autistic traits are typically associated with the masculine identity. This association severely limits autistic women's ability to benefit from the freedom men might attain through the appropriation of the social constructed autistic identity.[133][137] Autism-related neurological and social impairments have also been used to disregard the identities and healthcare needs of non-heterosexual and gender non-conforming individuals with autism on the basis that their impairments had caused their perceptions toward gender and sexual identity to deviate from social norms.[133][139] Autism diagnoses are typically associated with individuals who identify as 'White.' Because of this, individual from other racial and ethnic backgrounds are often overlooked, misdiagnosed, and underrepresented in relevant studies.[137][138]

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.[68]

Evolutionary explanations

Research exploring the

balanced polymorphism.[142]

A 2011 study proposed the "Solitary Forager Hypothesis" in which autistic traits, including increased abilities for spatial intelligence, concentration and memory, could have been

hunter-gathering. The authors further suggest that "mutual interdependence of different social strategies" may have "contributed to the rise of innovation and large scale social networks".[146]

Neanderthal theory

Main article:
Archaic human admixture with modern humans
Further information: Neanderthal genetics
Oase 2 with around 7.3% Neanderthal DNA (from an ancestor 4–6 generations back)[147]

One theory on the evolutionary and biological origins of autism traits in

Homo sapiens that has gained recent attention in the 2010s and 2020s is that some genes linked to autism may have originated from early humans crossbreeding with Neanderthals, an extinct group of archaic humans (generally regarded as a distinct species, Homo neanderthalensis, though some regard it as a subspecies of Homo sapiens, referred to as H. sapiens neanderthalensis) who lived in Eurasia
until about 40,000 years ago.

A possible link between

autism spectrum disorders (ASDs) and Neanderthal DNA was identified in 2009, pending genome sequencing.[148]

The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans.[149][150][151][152] The genomes of all studied modern populations contain Neanderthal DNA.[149][153][154][155][156] Various estimates exist for the proportion, such as 1–4%[149] or 3.4–7.9% in modern Eurasians,[157] or 1.8–2.4% in modern Europeans and 2.3–2.6% in modern East Asians.[158] Pre-agricultural Europeans appear to have had similar, or slightly higher,[156] percentages to modern East Asians, and the numbers may have decreased in the former due to dilution with a group of people which had split off before Neanderthal introgression.[159]

Typically, studies have reported finding no significant levels of Neanderthal DNA in Sub-Saharan Africans, but a 2020 study detected 0.3-0.5% in the genomes of five African sample populations, likely the result of Eurasians back-migrating and interbreeding with Africans, as well as human-to-neanderthal gene flow from dispersals of Homo sapiens preceding the larger Out-of-Africa migration, and also showed more equal Neanderthal DNA percentages for European and Asian populations.[156] Such low percentages of Neanderthal DNA in all present day populations indicate infrequent past interbreeding,[160] unless interbreeding was more common with a different population of modern humans which did not contribute to the present day gene pool.[159] Of the inherited Neanderthal genome, 25% in modern Europeans and 32% in modern East Asians may be related to viral immunity.[161] In all, approximately 20% of the Neanderthal genome appears to have survived in the modern human gene pool.[162]

However, due to their small population and resulting reduced effectivity of natural selection, Neanderthals accumulated several weakly harmful mutations, which were introduced to and slowly selected out of the much larger modern human population; the initial hybridised population may have experienced up to a 94% reduction in fitness compared to contemporary humans. By this measure, Neanderthals may have substantially increased in fitness.[163] A 2017 study focusing on archaic genes in Turkey found associations with coeliac disease, malaria severity and Costello syndrome.[164]

Nonetheless, some genes may have helped modern East Asians adapt to the environment; the putatively Neanderthal Val92Met variant of the MC1R gene, which may be weakly associated with red hair and UV radiation sensitivity,

sugar metabolism, muscle contraction, body fat distribution, enamel thickness and oocyte meiosis.[173] Nonetheless, a large portion of surviving introgression appears to be non-coding ("junk") DNA with few biological functions.[159]

A 2016 study indicated that human-Neanderthal gene variance may be involved in autism, with chromosome 16 section 16p11.2 deletions playing a large role.[174][175]

A 2017 study reported finding that the more Neanderthal DNA a person has in their genome, the more closely the brain of the individual would resemble that of a Neanderthal. The study also found that parts of the Neanderthal brain related to tool use and visual discrimination may have also experienced evolutionary or adaptational 'trade-offs' with the 'social brain', as also found in scientific studies on autism.

neurotypicals."[citation needed
]

Another 2017 study that analyzed 68 genes associated with

single nucleotide polymorphisms (SNPs) and neurodevelopmental disorders, including autism, in modern-day humans.[177]

A 2021 study confirmed these findings, noting that "the protective allele of rs7170637(A)

autism spectrum disorder (ASD)], was present in primates to Neanderthals, and reemerged in modern humans, while absent in early modern humans"; "identified significant positive selection signals in 18 ASD risk SNPs"; that "ancient genome analysis identified de novo mutations...representing genes involved in cognitive function...and conserved evolutionary selection clusters"; and that "relative enrichment of the ASD risk SNPs from the respective evolutionary cluster or biological interaction networks may help in addressing the phenotypic diversity in ASD", with "cognitive genomic tradeoff signatures impacting the biological networks [explaining] the paradoxical phenotypes in ASD".[178]

Discredited theories

Refrigerator mother

Main article:
Refrigerator mother

Psychologist Bruno Bettelheim believed that autism was linked to early childhood trauma, and his work was highly influential for decades both in the medical and popular spheres. In his discredited theory, he blamed the mothers of individuals with autism for having caused their child's condition through the withholding of affection.[179] Leo Kanner, who first described autism,[180] suggested that parental coldness might contribute to autism.[181] 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, his reported rates of cure (around 85%) were found to be fraudulent.[182]

Vaccines

The most recent scientific research has determined that changes to brain structures correlated with the development of autism can already be detected while the child is still in the womb, well before any vaccines are administered.[183] Furthermore, scientific studies have consistently refuted a causal relationship between vaccinations and autism.[184][185][186]

Despite this, some parents believe that vaccinations cause autism; they therefore delay or avoid immunizing their children (for example, under the "

antivaccine activism continues. A developing tactic is the "promotion of irrelevant research to justify the science underlying a questionable claim."[190]

MMR vaccine

Main article: MMR vaccine and autism

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.[191] Although the paper, which was later retracted by the journal, concluded that there was no association between the MMR vaccine and autism, Wakefield nevertheless suggested a false notion during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose.[191][192] Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first.[193][10]

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors.

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.[196][197][198]

In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed.[191] In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.[199][200][201][202]

Thiomersal (thimerosal)

Main article: Thiomersal and vaccines

Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound

childhood immunizations and increasing likelihood of disease outbreaks.[204][205][10] 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.[206]

A causal link between thimerosal and autism has been rejected by international scientific and medical professional bodies including the

U.S. National Academy of Sciences,[197] the Food and Drug Administration,[211] Centers for Disease Control and Prevention,[196] the World Health Organization,[212] the Public Health Agency of Canada,[213] and the European Medicines Agency.[214]

See also

Notes

  1. ^ OAS1[168] and STAT2[169] both are associated with fighting viral inflections (interferons), and the listed toll-like receptors (TLRs)[170] allow cells to identify bacterial, fungal, or parasitic pathogens. African origin is also correlated with a stronger inflammatory response.[171]
  2. ^ Higher levels of Neanderthal-derived genes are associated with an occipital and parietal bone shape reminiscent to that of Neanderthals, as well as modifications to the visual cortex and the intraparietal sulcus (associated with visual processing).[172]

References

  1. ^
    S2CID 206257210
    .
  2. S2CID 244119594
    .
  3. S2CID 249488050
    .
  4. ^
    S2CID 17797266
    .
  5. ^
    PMID 32206584
    .
  6. ^
    PMID 35804408
    .
  7. ^
    PMC 6512700
    .
  8. PMID 32175710
    .
  9. PMID 31562000
    .
  10. ^
    PMID 34806766
    .
  11. S2CID 219468115
    .
  12. ^ "Timeline: Thimerosal in Vaccines (1999-2010)". CDC. Retrieved 2024-04-24.
  13. PMID 32703331
    .
  14. PMID 28973605
    .
  15. S2CID 9331084
    .
  16. ^
    PMID 17363630
    .
  17. PMID 22914163
    .
  18. PMID 28955201
    .
  19. S2CID 11017841
    .
  20. S2CID 3350350
    .
  21. S2CID 20357402
    .
  22. S2CID 1433674
    .
  23. PMID 24768552
    .
  24. S2CID 11132936
    .
  25. ^
    PMID 21658581
    .
  26. ^
    PMID 27018473
    .
  27. PMID 22542183
    .
  28. PMID 25363760
    .
  29. ^
    PMID 25363768
    .
  30. PMID 22495311
    .
  31. PMID 22495306
    .
  32. PMID 22495309
    .
  33. S2CID 9073763
    .
  34. S2CID 41429306
    .
  35. ^ "SFARI Gene". SFARI gene. Archived from the original on 2016-04-01. Retrieved 2016-04-13.
  36. S2CID 3842341
    .
  37. PMID 19914906
    .
  38. ^
    PMID 25587659
    .
  39. PMID 30911184
    .
  40. PMID 35982159
    . Retrieved September 7, 2022.
  41. S2CID 209390456
    .
  42. PMID 22411236
    .
  43. ^
    PMID 16987877
    .
  44. PMID 7668301
    .
  45. PMID 10417292
    .
  46. ^
    PMID 15615769
    .
  47. S2CID 9570482
    .
  48. S2CID 85160435
    .
  49. S2CID 33650811
    .
  50. ^ Rutgers University (August 21, 2022). "Scientists Discover That Irregular Production of Brain Cells Could Cause Autism". SciTech Daily.
  51. PMID 31652518
    .
  52. PMID 29332605
    .
  53. PMID 23395807
    .
  54. ^
    PMID 33479207
    .
  55. PMID 24057131
    .
  56. PMID 29874359
    .
  57. PMID 22525954
    .
  58. PMID 27687989
    .
  59. PMID 10770144
    .
  60. S2CID 4871197
    .
  61. PMID 18250205
    .
  62. PMID 29029347
    .
  63. ^
    PMID 25576821
    .
  64. PMID 23543901
    .
  65. PMID 28514706
    .
  66. PMID 32375538
    .
  67. S2CID 249085906
    .
  68. ^
    S2CID 9962647
    .
  69. PMID 18342258
    .
  70. S2CID 26096561
    .
  71. PMID 27353198
    .
  72. ^
    S2CID 5180756
    .
  73. S2CID 14248227
    .
  74. PMID 28331572
    .
  75. PMID 25110424
    .
  76. S2CID 31805494
    .
  77. PMID 24057131
    .
  78. PMID 19567888
    .
  79. S2CID 76660638
    .
  80. S2CID 26406333
    .
  81. S2CID 28637473
    .
  82. PMID 24518932
    .
  83. PMID 18598714
    .
  84. PMID 22719977
    .
  85. ^ Fetal testosterone and autistic traits:
  86. S2CID 36234852
    .
  87. S2CID 8862487
    .
  88. PMID 28129495
    .
  89. ^
    PMID 30541449
    .
  90. PMID 21746727
    .
  91. PMID 26399256
    .
  92. PMID 27609410
    .
  93. PMID 28415925
    .
  94. PMID 24710095
    .
  95. S2CID 79259285
    .
  96. PMID 31906400
    .
  97. PMID 35175416
    .
  98. PMID 31906400
    .
  99. S2CID 17078137
    .
  100. PMID 15546805
    .
  101. S2CID 17531542
    .
  102. doi:10.1016/j.rasd.2009.01.007
    .
  103. S2CID 24708891
    .
  104. S2CID 23551620
    .
  105. S2CID 42029820
    .
  106. PMID 22911883
    .
  107. ^
    PMID 29614380
    .
  108. ^
    PMID 29388597
    .
  109. ^
    PMID 27435372
    .
  110. S2CID 26364726
    .
  111. S2CID 210922352
    .
  112. PMID 33299942
    .
  113. ^
    S2CID 54523742
    .
  114. S2CID 76326593
    .
  115. PMID 21464196
    .
  116. S2CID 54373822
    .
  117. ^
    PMID 18425890
    .
  118. S2CID 40904799
    .
  119. PMID 16685183
    .
  120. ^
    PMID 34072914
    .
  121. ^
    PMID 28331572
    .
  122. PMID 34834493
    .
  123. S2CID 219468115
    .
  124. ^
    PMID 33061742
    .
  125. PMID 34813844
    .
  126. S2CID 16386209
    .
  127. PMID 19059284. For a lay summary, see Kluger J (2009-04-07). "Why Fever Helps Autism: A New Theory". Time. Archived from the original
    on 2013-03-28.
  128. PMID 27258260
    .
  129. ^
    S2CID 255484540
    .
  130. S2CID 1096750
    .
  131. PMID 22708999
    .
  132. S2CID 44864562
    .
  133. ^
    S2CID 246893906
    .
  134. ISBN 0-674-00412-4
    .
  135. ISBN 0-415-32181-6
    .
  136. ISBN 978-0-12-415961-7
    . Although autism spectrum disorder has not been proven to exist either as a set of meaningful subgroups, or as the expression of a unifying deficit or causal pattern, nonetheless, autism appears to have been unified as a real entity in public opinion... Some researchers have argued that, over time, autism has been transformed from a hypothesis to an assumed reality. This transformation is called reification. Reification is the conversion of a theorized entity into something assumed and believed to be real... the intense public discussion of autism, the long history of autism in the diagnostic manuals of the American Psychiatric Association, and the long history of autism research are in full view, and they all have made autism seem more concrete and less hypothetical.
  137. ^
    PMID 35471566
    .
  138. ^
    PMID 36161181
    .
  139. S2CID 257768606
    .
  140. ^ Spikins P (March 27, 2017). "How our autistic ancestors played an important role in human evolution". The Conversation.
  141. ^ Spikins P (March 6, 2013). "The Stone Age Origins of Autism". In Fitzgerald M (ed.). Recent Advances in Autism Spectrum Disorders - Volume II.
  142. ^ Lomelin DE (2010). "An Examination of Autism Spectrum Disorders in Relation to Human Evolution and Life History Theory". Nebraska Anthropologist. 57.
  143. S2CID 25378900
    .
  144. ^ "Autism may have had advantages in humans' hunter-gatherer past, researcher believes". ScienceDaily. June 3, 2011.
  145. ^ Rudacille D (8 July 2011). "Lonely hunters". Spectrum.
  146. S2CID 151820168
    .
  147. PMID 26098372
    .
  148. ^ Rehnström, Karola. "Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate" (PDF). Julkari. National Institute for Health and Welfare (Finland). Retrieved 24 March 2024.
  149. ^
    PMID 20448178
    .
  150. PMID 23055938
    .
  151. PMID 22513287
    .
  152. PMID 23082212
    .
  153. PMID 24476815
    .
  154. PMID 21266489
    .
  155. PMID 25341783
    .
  156. ^
    S2CID 210955842
    .
  157. Bibcode:2013arXiv1307.8263L
    .
  158. PMID 28982794
    .
  159. ^ a b c Reich 2018.
  160. S2CID 5628263
    .
  161. PMID 30290142
    .
  162. S2CID 23003860
    .
  163. PMID 27824859
    .
  164. PMID 29040546
    .
  165. PMID 30657907
    .
  166. PMID 24916031
    . "We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (~5%), moderate in continental East Asians (~30%), and high in Taiwanese aborigines (60–70%)."
  167. PMID 25190608
    .
  168. ^
    S2CID 2839679. Archived from the original
    (PDF) on 2019-02-23.
  169. ^
    PMID 22883142
    .
  170. ^
    PMID 26748514
    .
  171. ^
    PMID 27768889
    .
  172. PMID 28740249
    .
  173. PMID 30022013
    .
  174. ^ "Human-Neanderthal Gene Variance is Involved in Autism". Neuroscience News. 4 August 2016. Retrieved 24 March 2024.
  175. ^ McCarthy, Michael (4 August 2016). "Human-Neanderthal gene variance is involved in autism". Medical Express. Retrieved 24 March 2024.
  176. PMC 5524936
    . Retrieved 23 March 2024.
  177. hdl:2434/554557
    . Retrieved 23 March 2024.
  178. PMID 33986442
    . Retrieved 23 March 2024.
  179. ISBN 0-02-903140-0
    .
  180. PMID 4880460
    .
  181. PMID 18146742
    .
  182. ^ Gardner M (2000). "The brutality of Dr. Bettelheim". Skeptical Inquirer. 24 (6): 12–14.
  183. SciTechDaily
    .
  184. S2CID 17981294.Closed access icon
  185. PMID 19478850.Open access icon
  186. PMID 24814559.Open access icon
  187. PMID 16581162.Open access icon
  188. PMID 19128068
    . For a lay summary,
  189. S2CID 34467853.Closed access icon
  190. ^ Foster CA, Ortiz SM (2017). "Vaccines, Autism, and the Promotion of Irrelevant Research: A Science-Pseudoscience Analysis". Skeptical Inquirer. 41 (3): 44–48. Archived from the original on 2018-10-06. Retrieved 6 October 2018.
  191. ^
    S2CID 26364726. For a lay summary, see Triggle N (2010-02-02). "Lancet accepts MMR study 'false'"
    . BBC News.
  192. doi:10.1016/S0140-6736(10)60175-7
    )
  193. PMID 32175710
    .
  194. S2CID 5128036
    .
  195. ^ Deer B (2008-11-02). "The MMR-autism crisis – our story so far". Retrieved 2008-12-06.
  196. ^ a b "Measles, mumps, and rubella (MMR) vaccine". Centers for Disease Control and Prevention. 2008-12-23. Retrieved 2009-02-14.
  197. ^ a b "Immunization safety review: vaccines and autism". Institute of Medicine, National Academy of Sciences. 2004. Archived from the original on 2007-06-23. Retrieved 2007-06-13.
  198. ^ "MMR the facts". National Health Service. Archived from the original on 2007-06-15. Retrieved 2007-06-13.
  199. S2CID 43640126
    .
  200. S2CID 46683674
    .
  201. ^ "Study linking vaccine to autism was fraud". NPR. Associated Press. 2011-01-05. Archived from the original on 2011-01-07. Retrieved 2011-01-06.
  202. ^ "Retracted autism study an 'elaborate fraud,' British journal finds". Atlanta. 2011-01-06. Retrieved 2011-01-06.
  203. ^ "Vaccines, blood and biologics: thimerosal in vaccines". US Food and Drug Administration. 2012. Retrieved October 24, 2013.
  204. PMID 32175710
    .
  205. PMID 31562000
    .
  206. ^ Gorski D (7 January 2008). "Mercury in vaccines as a cause of autism and autism spectrum disorders (ASDs): A failed hypothesis". Science-Based Medicine.
  207. ^ American Medical Association (2004-05-18). "AMA Welcomes New IOM Report Rejecting Link Between Vaccines and Autism". Archived from the original on 2012-10-06. Retrieved 2007-07-23.
  208. ^ American Academy of Pediatrics (2004-05-18). "What Parents Should Know About Thimerosal". Archived from the original on 2007-07-08. Retrieved 2007-07-23.
  209. PMID 18072140. Archived from the original
    (PDF) on 2008-02-29.
  210. PMID 18923720
    ..
  211. ^ "Thimerosal in vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2007-09-06. Retrieved 2007-10-01.
  212. ^ World Health Organization (2006). "Questions and answers about autism spectrum disorders (ASD)". Retrieved 2014-11-02.
  213. PMID 17663033
    .
  214. ^ European Medicines Agency (2004-03-24). "EMEA Public Statement on Thiomersal in Vaccines for Human Use" (PDF). Archived from the original (PDF) on 2007-06-10. Retrieved 2007-07-22.

Bibliography
Retrieved from "https://en.wikipedia.org/w/index.php?title=Causes_of_autism&oldid=1220620423"