Causes of autism: Difference between revisions
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[[File:Autismbrain.jpg|thumb|This diagram shows the brain sections and how autism relates to them.]] |
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Many '''causes of autism''' have been proposed, but understanding of the [[Etiology|theory of causation]] of [[autism]] and the other [[autism spectrum]] disorders (ASD) is incomplete.<ref name="Trottier">{{vcite journal |author= Trottier G, Srivastava L, Walker CD |title= Etiology of infantile autism: a review of recent advances in genetic and neurobiological research |journal= J Psychiatry Neurosci |year=1999 |volume=24 |issue=2 |pages=103–115 |pmid=10212552 |pmc=1188990|type=Review}}</ref> Research indicates that genetic factors predominate. The [[heritability of autism]], however, is complex, and it is typically unclear which genes are responsible.<ref name="Freitag">{{vcite journal|author=Freitag CM|title=The genetics of autistic disorders and its clinical relevance: a review of the literature|journal=Mol Psychiatry|volume=12|issue=1|pages=2–22|year=2007|doi=10.1038/sj.mp.4001896|pmid=17033636|url=http://www.nature.com/mp/journal/v12/n1/full/4001896a.html|type=Review}}</ref> In rare cases, autism is strongly associated with [[Teratology|agents that cause birth defects]].<ref name="Arndt" /> Many other causes have been proposed, such as [[vaccination schedule|childhood immunizations]], but numerous [[epidemiological studies]] have shown no [[Evidence-based medicine|scientific evidence]] supporting any link between vaccinations and autism.<ref name="Doja" /> |
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==Related disorders== |
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{{main|Autism}} |
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[[Autism]] involves [[Neurodevelopmental disorder|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.<ref>{{vcite book |title= Diagnostic and Statistical Manual of Mental Disorders |edition=4th, text revision ([[DSM-IV-TR]]) |author= American Psychiatric Association |year=2000 |isbn=0-89042-025-4 |chapter= Diagnostic criteria for 299.00 Autistic Disorder |chapterurl=http://cdc.gov/ncbddd/autism/overview_diagnostic_criteria.htm#Autistic |accessdate=2009-02-17 |publisher=<!--comment to foil Citation bot-->|location= <!--comment to foil Citation bot-->}}</ref><ref>{{vcite book |chapterurl=http://www.who.int/classifications/apps/icd/icd10online/?gf80.htm+f840 |year=2006 |accessdate=2007-06-25 |title= International Statistical Classification of Diseases and Related Health Problems |edition=10th ([[ICD-10]]) |author= [[World Health Organization]] |chapter= F84. Pervasive developmental disorders}}</ref> Other characteristics include repetitive-like tasks seen in their behavior and sensory interests.<ref>{{cite journal |last1=McPartland |first1=James C. |last2=Law |first2=Karen |last3=Dawson |first3=Geraldine |title=Autism Spectrum Disorder |journal=Encyclopedia of Mental Health (Second Edition) |date=August 26, 2015 |pages=124–130 |doi=10.1016/B978-0-12-397045-9.00230-5}}</ref> This article uses the terms ''autism'' and ''ASD'' to denote classical autism and the wider dispersion of symptoms and manifestations of autism, respectively. |
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Autism's [[Etiology|theory of causation]] is incomplete.<ref name="Trottier" /> 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.<ref name="Fractionable" /> 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.<ref name="Fractionable">{{vcite journal |author= Happé F, Ronald A |title= The 'fractionable autism triad': a review of evidence from behavioural, genetic, cognitive and neural research |journal= Neuropsychol Rev |volume=18 |issue=4 |pages=287–304 |year=2008 |pmid=18956240 |doi=10.1007/s11065-008-9076-8|type=Review}}</ref><ref name="Happe" /> 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.<ref name="Geschwind2009">{{vcite journal |author=Geschwind DH |title=Advances in autism |journal=Annu Rev Med |volume=60 |pages=367–80 |year=2009 |pmid=19630577 |doi=10.1146/annurev.med.60.053107.121225 |pmc=3645857|type=Review}}</ref> Although these distinct causes have been hypothesized to often co-occur,<ref name="Happe">{{vcite journal |author= Happé F, Ronald A, [[Robert Plomin|Plomin R]] |title= Time to give up on a single explanation for autism |journal= Nat Neurosci |year=2006 |volume=9 |issue=10 |pages=1218–20 |pmid=17001340 |doi=10.1038/nn1770|type=Review}}</ref> it has also been suggested that the correlation between the causes has been exaggerated.<ref>{{vcite journal |journal= J Child Psychol Psychiatry |year=2008 |title= What is the association between the social-communication element of autism and repetitive interests, behaviours and activities? |title.= |author= Mandy WP, Skuse DH |doi=10.1111/j.1469-7610.2008.01911.x |pmid=18564070 |volume=49 |issue=8 |pages=795–808|type=Review}}</ref> 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.<ref name="Newschaffer">{{vcite journal |author=Newschaffer CJ, Croen LA, Daniels J ''et al.''|title=The epidemiology of autism spectrum disorders |journal=Annu Rev Public Health |year=2007 |volume=28 |pages=235–58 |pmid=17367287 |doi=10.1146/annurev.publhealth.28.021406.144007 |format=PDF |accessdate=2009-10-10 |type=Review}}</ref> |
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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,<ref name="Christison" /> [[infectious disease]], [[heavy metals]], [[solvent]]s, [[diesel exhaust]], [[Polychlorinated biphenyl|PCBs]], [[phthalates]] and [[phenol]]s used in [[plastic]] products, [[pesticide]]s, [[brominated flame retardant]]s, [[Ethanol|alcohol]], [[smoking]], [[illicit drug]]s, and [[vaccine]]s.<ref name="Newschaffer" /> 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#Public health|measles outbreaks]]. However, there is overwhelming scientific evidence showing no causal association between the [[MMR vaccine controversy|measles-mumps-rubella (MMR) vaccine and autism]], and there is no scientific evidence that the vaccine preservative [[Thiomersal controversy|thiomersal]] causes autism.<ref name="Doja">{{vcite journal|journal=Can J Neurol Sci|year=2006|volume=33|issue=4|pages=341–6|title=Immunizations and autism: a review of the literature|author=Doja A, Roberts W|pmid=17168158|type=Review|doi=10.1017/s031716710000528x}}</ref><ref>{{vcite journal |journal= Child Care Health Dev |year=2006 |volume=32 |issue=5 |pages=511–9 |title= Vaccines and the changing epidemiology of autism |author= Taylor B |doi=10.1111/j.1365-2214.2006.00655.x |pmid=16919130|type=Review}}</ref> |
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==Genetics== |
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{{main|Heritability of autism}} |
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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.<ref>{{cite journal|last1=Freitag|first1=C M|title=The genetics of autistic disorders and its clinical relevance: a review of the literature|journal=Molecular Psychiatry|date=10 October 2006|volume=12|issue=1|pages=2–22|doi=10.1038/sj.mp.4001896}}</ref> However, this may be an overestimation, as new twin studies estimate the heritability at between 60-90%.<ref>{{cite journal|last1=Hallmayer|first1=Joachim|title=Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism|journal=Archives of General Psychiatry|date=1 November 2011|volume=68|issue=11|pages=1095|doi=10.1001/archgenpsychiatry.2011.76}}</ref><ref>{{cite journal|last1=Ronald|first1=Angelica|last2=Hoekstra|first2=Rosa A.|title=Autism spectrum disorders and autistic traits: A decade of new twin studies|journal=American Journal of Medical Genetics Part B: Neuropsychiatric Genetics|date=April 2011|volume=156|issue=3|pages=255–274|doi=10.1002/ajmg.b.31159}}</ref> 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%.<ref>{{vcite journal|author=Folstein SE, Rosen-Sheidley B|title=Genetics of autism: complex aetiology for a heterogeneous disorder|journal=Nat Rev Genet|year=2001|volume=2|issue=12|pages=943–55|doi=10.1038/35103559|pmid=11733747|type=Review}}</ref> |
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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.<ref name="ReferenceA">{{cite journal|last1=Sebat|first1=J.|last2=Lakshmi|first2=B.|last3=Malhotra|first3=D.|last4=Troge|first4=J.|last5=Lese-Martin|first5=C.|last6=Walsh|first6=T.|last7=Yamrom|first7=B.|last8=Yoon|first8=S.|last9=Krasnitz|first9=A.|last10=Kendall|first10=J.|last11=Leotta|first11=A.|last12=Pai|first12=D.|last13=Zhang|first13=R.|last14=Lee|first14=Y.-H.|last15=Hicks|first15=J.|last16=Spence|first16=S. J.|last17=Lee|first17=A. T.|last18=Puura|first18=K.|last19=Lehtimaki|first19=T.|last20=Ledbetter|first20=D.|last21=Gregersen|first21=P. K.|last22=Bregman|first22=J.|last23=Sutcliffe|first23=J. S.|last24=Jobanputra|first24=V.|last25=Chung|first25=W.|last26=Warburton|first26=D.|last27=King|first27=M.-C.|last28=Skuse|first28=D.|last29=Geschwind|first29=D. H.|last30=Gilliam|first30=T. C.|last31=Ye|first31=K.|last32=Wigler|first32=M.|title=Strong Association of De Novo Copy Number Mutations with Autism|journal=Science|date=20 April 2007|volume=316|issue=5823|pages=445–449|doi=10.1126/science.1138659}}</ref> There are two lines of evidence that support this hypothesis. Firstly, 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.<ref>{{cite journal|last1=Uher|first1=R|title=The role of genetic variation in the causation of mental illness: an evolution-informed framework|journal=Molecular Psychiatry|date=25 August 2009|volume=14|issue=12|pages=1072–1082|doi=10.1038/mp.2009.85}}</ref> Secondly, the likelihood of having a child develop autism increases with advancing paternal age,<ref>{{cite journal|last1=Reichenberg|first1=Abraham|last2=Gross|first2=Raz|last3=Weiser|first3=Mark|last4=Bresnahan|first4=Michealine|last5=Silverman|first5=Jeremy|last6=Harlap|first6=Susan|last7=Rabinowitz|first7=Jonathan|last8=Shulman|first8=Cory|last9=Malaspina|first9=Dolores|last10=Lubin|first10=Gad|last11=Knobler|first11=Haim Y.|last12=Davidson|first12=Michael|last13=Susser|first13=Ezra|title=Advancing Paternal Age and Autism|journal=Archives of General Psychiatry|date=1 September 2006|volume=63|issue=9|pages=1026|doi=10.1001/archpsyc.63.9.1026}}</ref> and mutations in sperm gradually accumulate throughout a man's life.<ref>{{cite journal|last1=Kong|first1=Augustine|last2=Frigge|first2=Michael L.|last3=Masson|first3=Gisli|last4=Besenbacher|first4=Soren|last5=Sulem|first5=Patrick|last6=Magnusson|first6=Gisli|last7=Gudjonsson|first7=Sigurjon A.|last8=Sigurdsson|first8=Asgeir|last9=Jonasdottir|first9=Aslaug|last10=Jonasdottir|first10=Adalbjorg|last11=Wong|first11=Wendy S. W.|last12=Sigurdsson|first12=Gunnar|last13=Walters|first13=G. Bragi|last14=Steinberg|first14=Stacy|last15=Helgason|first15=Hannes|last16=Thorleifsson|first16=Gudmar|last17=Gudbjartsson|first17=Daniel F.|last18=Helgason|first18=Agnar|last19=Magnusson|first19=Olafur Th.|last20=Thorsteinsdottir|first20=Unnur|last21=Stefansson|first21=Kari|title=Rate of de novo mutations and the importance of father’s age to disease risk|journal=Nature|date=22 August 2012|volume=488|issue=7412|pages=471–475|doi=10.1038/nature11396}}</ref> |
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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. |
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An expansion of the CGG trinucleotide repeat in the [[Promoter (biology)|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.<ref>{{cite journal|last1=Hatton|first1=Deborah D.|last2=Sideris|first2=John|last3=Skinner|first3=Martie|last4=Mankowski|first4=Jean|last5=Bailey|first5=Donald B.|last6=Roberts|first6=Jane|last7=Mirrett|first7=Penny|title=Autistic behavior in children with fragile X syndrome: Prevalence, stability, and the impact of FMRP|journal=American Journal of Medical Genetics Part A|date=1 September 2006|volume=140A|issue=17|pages=1804–1813|doi=10.1002/ajmg.a.31286}}</ref> 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.<ref>{{cite journal|last1=Zoghbi|first1=Huda Y.|last2=Amir|first2=Ruthie E.|last3=Van den Veyver|first3=Ignatia B.|last4=Wan|first4=Mimi|last5=Tran|first5=Charles Q.|last6=Francke|first6=Uta|journal=Nature Genetics|date=1 October 1999|volume=23|issue=2|pages=185–188|doi=10.1038/13810}}</ref> |
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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.<ref>{{cite journal|last1=Sebat|first1=J.|title=Large-Scale Copy Number Polymorphism in the Human Genome|journal=Science|date=23 July 2004|volume=305|issue=5683|pages=525–528|doi=10.1126/science.1098918}}</ref><ref>{{cite journal|last1=Iafrate|first1=A John|last2=Feuk|first2=Lars|last3=Rivera|first3=Miguel N|last4=Listewnik|first4=Marc L|last5=Donahoe|first5=Patricia K|last6=Qi|first6=Ying|last7=Scherer|first7=Stephen W|last8=Lee|first8=Charles|title=Detection of large-scale variation in the human genome|journal=Nature Genetics|date=1 August 2004|volume=36|issue=9|pages=949–951|doi=10.1038/ng1416}}</ref> 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 [[megabase]]s. 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.<ref name="ReferenceA"/><ref>{{cite journal|last1=Pinto|first1=Dalila|last2=Delaby|first2=Elsa|last3=Merico|first3=Daniele|last4=Barbosa|first4=Mafalda|last5=Merikangas|first5=Alison|last6=Klei|first6=Lambertus|last7=Thiruvahindrapuram|first7=Bhooma|last8=Xu|first8=Xiao|last9=Ziman|first9=Robert|last10=Wang|first10=Zhuozhi|last11=Vorstman|first11=Jacob A.S.|last12=Thompson|first12=Ann|last13=Regan|first13=Regina|last14=Pilorge|first14=Marion|last15=Pellecchia|first15=Giovanna|last16=Pagnamenta|first16=Alistair T.|last17=Oliveira|first17=Bárbara|last18=Marshall|first18=Christian R.|last19=Magalhaes|first19=Tiago R.|last20=Lowe|first20=Jennifer K.|last21=Howe|first21=Jennifer L.|last22=Griswold|first22=Anthony J.|last23=Gilbert|first23=John|last24=Duketis|first24=Eftichia|last25=Dombroski|first25=Beth A.|last26=De Jonge|first26=Maretha V.|last27=Cuccaro|first27=Michael|last28=Crawford|first28=Emily L.|last29=Correia|first29=Catarina T.|last30=Conroy|first30=Judith|last31=Conceição|first31=Inês C.|last32=Chiocchetti|first32=Andreas G.|last33=Casey|first33=Jillian P.|last34=Cai|first34=Guiqing|last35=Cabrol|first35=Christelle|last36=Bolshakova|first36=Nadia|last37=Bacchelli|first37=Elena|last38=Anney|first38=Richard|last39=Gallinger|first39=Steven|last40=Cotterchio|first40=Michelle|last41=Casey|first41=Graham|last42=Zwaigenbaum|first42=Lonnie|last43=Wittemeyer|first43=Kerstin|last44=Wing|first44=Kirsty|last45=Wallace|first45=Simon|last46=van Engeland|first46=Herman|last47=Tryfon|first47=Ana|last48=Thomson|first48=Susanne|last49=Soorya|first49=Latha|last50=Rogé|first50=Bernadette|last51=Roberts|first51=Wendy|last52=Poustka|first52=Fritz|last53=Mouga|first53=Susana|last54=Minshew|first54=Nancy|last55=McInnes|first55=L. 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Gulhan|last3=Hus|first3=Vanessa|last4=Luo|first4=Rui|last5=Murtha|first5=Michael T.|last6=Moreno-De-Luca|first6=Daniel|last7=Chu|first7=Su H.|last8=Moreau|first8=Michael P.|last9=Gupta|first9=Abha R.|last10=Thomson|first10=Susanne A.|last11=Mason|first11=Christopher E.|last12=Bilguvar|first12=Kaya|last13=Celestino-Soper|first13=Patricia B.S.|last14=Choi|first14=Murim|last15=Crawford|first15=Emily L.|last16=Davis|first16=Lea|last17=Davis Wright|first17=Nicole R.|last18=Dhodapkar|first18=Rahul M.|last19=DiCola|first19=Michael|last20=DiLullo|first20=Nicholas M.|last21=Fernandez|first21=Thomas V.|last22=Fielding-Singh|first22=Vikram|last23=Fishman|first23=Daniel O.|last24=Frahm|first24=Stephanie|last25=Garagaloyan|first25=Rouben|last26=Goh|first26=Gerald S.|last27=Kammela|first27=Sindhuja|last28=Klei|first28=Lambertus|last29=Lowe|first29=Jennifer K.|last30=Lund|first30=Sabata C.|last31=McGrew|first31=Anna D.|last32=Meyer|first32=Kyle A.|last33=Moffat|first33=William J.|last34=Murdoch|first34=John D.|last35=O'Roak|first35=Brian J.|last36=Ober|first36=Gordon T.|last37=Pottenger|first37=Rebecca S.|last38=Raubeson|first38=Melanie J.|last39=Song|first39=Youeun|last40=Wang|first40=Qi|last41=Yaspan|first41=Brian L.|last42=Yu|first42=Timothy W.|last43=Yurkiewicz|first43=Ilana R.|last44=Beaudet|first44=Arthur L.|last45=Cantor|first45=Rita M.|last46=Curland|first46=Martin|last47=Grice|first47=Dorothy E.|last48=Günel|first48=Murat|last49=Lifton|first49=Richard P.|last50=Mane|first50=Shrikant M.|last51=Martin|first51=Donna M.|last52=Shaw|first52=Chad A.|last53=Sheldon|first53=Michael|last54=Tischfield|first54=Jay A.|last55=Walsh|first55=Christopher A.|last56=Morrow|first56=Eric M.|last57=Ledbetter|first57=David H.|last58=Fombonne|first58=Eric|last59=Lord|first59=Catherine|last60=Martin|first60=Christa Lese|last61=Brooks|first61=Andrew I.|last62=Sutcliffe|first62=James S.|last63=Cook|first63=Edwin H.|last64=Geschwind|first64=Daniel|last65=Roeder|first65=Kathryn|last66=Devlin|first66=Bernie|last67=State|first67=Matthew W.|title=Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism|journal=Neuron|date=June 2011|volume=70|issue=5|pages=863–885|doi=10.1016/j.neuron.2011.05.002}}</ref> Based on these studies, there are predicted to be 130-234 ASD-related CNV loci.<ref name="Stephan J 2011"/> 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.<ref name="Brandler2016">{{cite journal|last1=Brandler|first1=William M.|last2=Antaki|first2=Danny|last3=Gujral|first3=Madhusudan|last4=Noor|first4=Amina|last5=Rosanio|first5=Gabriel|last6=Chapman|first6=Timothy R.|last7=Barrera|first7=Daniel J.|last8=Lin|first8=Guan Ning|last9=Malhotra|first9=Dheeraj|last10=Watts|first10=Amanda C.|last11=Wong|first11=Lawrence C.|last12=Estabillo|first12=Jasper A.|last13=Gadomski|first13=Therese E.|last14=Hong|first14=Oanh|last15=Fajardo|first15=Karin V. Fuentes|last16=Bhandari|first16=Abhishek|last17=Owen|first17=Renius|last18=Baughn|first18=Michael|last19=Yuan|first19=Jeffrey|last20=Solomon|first20=Terry|last21=Moyzis|first21=Alexandra G.|last22=Maile|first22=Michelle S.|last23=Sanders|first23=Stephan J.|last24=Reiner|first24=Gail E.|last25=Vaux|first25=Keith K.|last26=Strom|first26=Charles M.|last27=Zhang|first27=Kang|last28=Muotri|first28=Alysson R.|last29=Akshoomoff|first29=Natacha|last30=Leal|first30=Suzanne M.|last31=Pierce|first31=Karen|last32=Courchesne|first32=Eric|last33=Iakoucheva|first33=Lilia M.|last34=Corsello|first34=Christina|last35=Sebat|first35=Jonathan|title=Frequency and Complexity of De Novo Structural Mutation in Autism|journal=The American Journal of Human Genetics|date=March 2016|volume=98|issue=4|pages=1–13|doi=10.1016/j.ajhg.2016.02.018}}</ref> However, structural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies.<ref name="Brandler2016" /> |
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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.<ref>{{cite journal|last1=Iossifov|first1=Ivan|last2=Ronemus|first2=Michael|last3=Levy|first3=Dan|last4=Wang|first4=Zihua|last5=Hakker|first5=Inessa|last6=Rosenbaum|first6=Julie|last7=Yamrom|first7=Boris|last8=Lee|first8=Yoon-ha|last9=Narzisi|first9=Giuseppe|last10=Leotta|first10=Anthony|last11=Kendall|first11=Jude|last12=Grabowska|first12=Ewa|last13=Ma|first13=Beicong|last14=Marks|first14=Steven|last15=Rodgers|first15=Linda|last16=Stepansky|first16=Asya|last17=Troge|first17=Jennifer|last18=Andrews|first18=Peter|last19=Bekritsky|first19=Mitchell|last20=Pradhan|first20=Kith|last21=Ghiban|first21=Elena|last22=Kramer|first22=Melissa|last23=Parla|first23=Jennifer|last24=Demeter|first24=Ryan|last25=Fulton|first25=Lucinda L.|last26=Fulton|first26=Robert S.|last27=Magrini|first27=Vincent J.|last28=Ye|first28=Kenny|last29=Darnell|first29=Jennifer C.|last30=Darnell|first30=Robert B.|last31=Mardis|first31=Elaine R.|last32=Wilson|first32=Richard K.|last33=Schatz|first33=Michael C.|last34=McCombie|first34=W. 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A further 5-10% of cases have inherited [[structural variation]] at [[locus (genetics)|loci]] known to be associated with autism, and these known structural variants may arise ''de novo'' in the parents of affected children.<ref name="Brandler2016" /> |
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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.<ref>{{cite journal|last1=Betancur|first1=Catalina|title=Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting|journal=Brain Research|date=March 2011|volume=1380|pages=42–77|doi=10.1016/j.brainres.2010.11.078}}</ref> The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic [[locus (genetics)|locus]] associated with autism.<ref>{{cite web|url=https://gene.sfari.org/autdb/Welcome.do|website=SFARI gene}}</ref> |
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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.<ref>{{cite journal|last1=Stefansson|first1=Hreinn|last2=Meyer-Lindenberg|first2=Andreas|last3=Steinberg|first3=Stacy|last4=Magnusdottir|first4=Brynja|last5=Morgen|first5=Katrin|last6=Arnarsdottir|first6=Sunna|last7=Bjornsdottir|first7=Gyda|last8=Walters|first8=G. Bragi|last9=Jonsdottir|first9=Gudrun A.|last10=Doyle|first10=Orla M.|last11=Tost|first11=Heike|last12=Grimm|first12=Oliver|last13=Kristjansdottir|first13=Solveig|last14=Snorrason|first14=Heimir|last15=Davidsdottir|first15=Solveig R.|last16=Gudmundsson|first16=Larus J.|last17=Jonsson|first17=Gudbjorn F.|last18=Stefansdottir|first18=Berglind|last19=Helgadottir|first19=Isafold|last20=Haraldsson|first20=Magnus|last21=Jonsdottir|first21=Birna|last22=Thygesen|first22=Johan H.|last23=Schwarz|first23=Adam J.|last24=Didriksen|first24=Michael|last25=Stensbøl|first25=Tine B.|last26=Brammer|first26=Michael|last27=Kapur|first27=Shitij|last28=Halldorsson|first28=Jonas G.|last29=Hreidarsson|first29=Stefan|last30=Saemundsen|first30=Evald|last31=Sigurdsson|first31=Engilbert|last32=Stefansson|first32=Kari|title=CNVs conferring risk of autism or schizophrenia affect cognition in controls|journal=Nature|date=18 December 2013|volume=505|issue=7483|pages=361–366|doi=10.1038/nature12818}}</ref><ref>{{cite journal|last1=Shinawi|first1=M.|last2=Liu|first2=P.|last3=Kang|first3=S. H. L.|last4=Shen|first4=J.|last5=Belmont|first5=J. W.|last6=Scott|first6=D. A.|last7=Probst|first7=F. J.|last8=Craigen|first8=W. J.|last9=Graham|first9=B. H.|last10=Pursley|first10=A.|last11=Clark|first11=G.|last12=Lee|first12=J.|last13=Proud|first13=M.|last14=Stocco|first14=A.|last15=Rodriguez|first15=D. L.|last16=Kozel|first16=B. A.|last17=Sparagana|first17=S.|last18=Roeder|first18=E. R.|last19=McGrew|first19=S. G.|last20=Kurczynski|first20=T. W.|last21=Allison|first21=L. J.|last22=Amato|first22=S.|last23=Savage|first23=S.|last24=Patel|first24=A.|last25=Stankiewicz|first25=P.|last26=Beaudet|first26=A. L.|last27=Cheung|first27=S. W.|last28=Lupski|first28=J. R.|title=Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size|journal=Journal of Medical Genetics|date=12 November 2009|volume=47|issue=5|pages=332–341|doi=10.1136/jmg.2009.073015}}</ref> 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 (genetics)|expressivity]] results in different individuals with the same mutation varying considerably in the severity of their observed particular trait.<ref name="ReferenceC">{{cite journal|last1=Brandler|first1=William M.|last2=Sebat|first2=Jonathan|title=From De Novo Mutations to Personalized Therapeutic Interventions in Autism|journal=Annual Review of Medicine|date=14 January 2015|volume=66|issue=1|pages=487–507|doi=10.1146/annurev-med-091113-024550}}</ref> |
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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.<ref name="ReferenceC"/> |
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==Epigenetics== |
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{{Main|Epigenetics of autism}} |
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[[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.<ref>{{vcite journal |author=Miyake K, Hirasawa T, Koide T, Kubota T |title=Epigenetics in autism and other neurodevelopmental diseases |journal=Adv. Exp. Med. Biol. |volume=724 |issue= |pages=91–8 |year=2012 |pmid=22411236 |doi=10.1007/978-1-4614-0653-2_7 |type=Review}}</ref> Interest has been expressed in imprinted regions on chromosomes 15q and 7q.<ref>{{vcite journal |author=Schanen NC |title=Epigenetics of autism spectrum disorders |journal=Hum. Mol. Genet. |volume=15 Spec No 2 |issue= |pages=R138–50 |date=October 2006 |pmid=16987877 |doi=10.1093/hmg/ddl213 |url=http://hmg.oxfordjournals.org/content/15/suppl_2/R138.long |type=Review}}</ref> |
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==Prenatal environment== |
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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.<ref name="Gardener">{{vcite journal |author=Gardener H, Spiegelman D, Buka SL |title=Prenatal risk factors for autism: comprehensive meta-analysis |journal=Br J Psychiatry |volume=195 |issue=1 |pages=7–14 |year=2009 |pmid=19567888 |doi=10.1192/bjp.bp.108.051672 |pmc=3712619 |type=Review, meta-analysis}}</ref> Autism has been linked to birth defect agents acting during the first eight weeks from [[Human fertilization|conception]], though these cases are rare.<ref>{{vcite journal |author=Roullet FI, Lai JK, Foster JA |title=In utero exposure to valproic acid and autism--a current review of clinical and animal studies |journal=Neurotoxicol Teratol |volume=36 |issue= |pages=47–56 |year=2013 |pmid=23395807 |doi=10.1016/j.ntt.2013.01.004 |type=Review}}</ref> |
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===Infectious processes=== |
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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.<ref name="Libbey" /> [[Congenital rubella syndrome]] is the most convincing environmental cause of autism.<ref>{{vcite journal |journal= Semin Pediatr Neurol |year=2008 |volume=15 |issue=1 |pages=27–31 |title= Genetic evaluation of autism |author= Mendelsohn NJ, Schaefer GB |doi=10.1016/j.spen.2008.01.005 |pmid=18342258|type=Review}}</ref> 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]].<ref>{{vcite journal |journal=Neuroscientist |year=2007 |volume=13 |issue=3 |pages=241–56|title= The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? |author= Meyer U, Yee BK, Feldon J |pmid=17519367 |doi=10.1177/1073858406296401|type=Review}}</ref> |
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===Environmental agents=== |
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[[Teratogen]]s are environmental agents that cause [[birth defect]]s. 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]],<ref>{{vcite journal |author=Chomiak T, Turner N, Hu B |title=What We Have Learned about Autism Spectrum Disorder from Valproic Acid |journal=Patholog Res Int |volume=2013 |issue= |pages=712758 |year=2013 |pmid=24381784 |pmc=3871912 |doi=10.1155/2013/712758 |type=Review}}</ref> [[thalidomide]] or [[misoprostol]].<ref name="Dufour2011" /> These cases are rare.<ref>{{vcite journal |author=Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C |title=Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review |journal=Int. J. Dev. Neurosci. |volume=23 |issue=2-3 |pages=201–19 |year=2005 |pmid=15749246 |doi=10.1016/j.ijdevneu.2004.06.007 |url=}}</ref> Questions have also been raised whether [[ethanol]] (grain alcohol) increases autism risk, as part of [[fetal alcohol syndrome]] or alcohol-related birth defects.<ref name="Dufour2011">{{vcite journal |author=Dufour-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, Andres CR |title=Fetal exposure to teratogens: evidence of genes involved in autism |journal=Neurosci Biobehav Rev |volume=35 |issue=5 |pages=1254–65 |year=2011 |month=April |pmid=21195109 |doi=10.1016/j.neubiorev.2010.12.013|type=Review}}</ref> 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.<ref name="Arndt">{{vcite journal|journal=Int J Dev Neurosci|year=2005|volume=23|issue=2–3|pages=189–99|title=The teratology of autism|author=Arndt TL, Stodgell CJ, Rodier PM|doi=10.1016/j.ijdevneu.2004.11.001|pmid=15749245|type=Review}}</ref> |
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===Other maternal conditions=== |
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[[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 [[Goitrogen|interfere with iodine uptake]] or [[Antithyroid agent|act against thyroid hormones]]. Possible environmental agents include [[flavonoid]]s in food, [[tobacco smoke]], and most [[herbicide]]s. This hypothesis has not been tested.<ref>{{vcite journal |author= Román GC |title=Autism: transient ''in utero'' hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents |journal= J Neurol Sci |volume=262 |issue=1–2 |pages=15–26 |year=2007 |pmid=17651757 |doi=10.1016/j.jns.2007.06.023|type=Review}}</ref> |
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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.<ref>{{vcite journal|author=Xu, Guifeng|title=Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis|journal=Journal of Autism and Developmental Disorders|date=22 September 2013|volume=44|issue=4|pages=766–775|doi=10.1007/s10803-013-1928-2|pmid=24057131|pmc=4181720}}</ref> Although diabetes causes metabolic and hormonal abnormalities and [[oxidative stress]], no biological mechanism is known for the association between gestational diabetes and autism risk.<ref name="Gardener" /> |
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Maternal obesity during pregnancy may also increase the risk of autism, although further study is needed.<ref>{{vcite journal|author=Li YM et al.|title=Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis|journal=J Autism Dev Disord|year=2015|doi=10.1007/s10803-015-2549-8|pmid=26254893}}</ref> |
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===Other ''in utero''=== |
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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.<ref>{{vcite journal|author=Lyall K, Schimdt RJ, Hertz-Picciotto I|title=Maternal lifestyle and environmental risk factors for autism spectrum disorders|journal=International Journal of Epidemiology|date=11 February 2014|volume=43|issue=2|pages=443–464|doi=10.1093/ije/dyt282}}</ref> |
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[[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.<ref>{{vcite journal |journal= Neurosci Biobehav Rev |year=2008 |title= Prenatal stress and risk for autism |author= Kinney DK, Munir KM, Crowley DJ, Miller AM |doi=10.1016/j.neubiorev.2008.06.004 |pmid=18598714 |volume=32 |issue=8 |pages=1519–32 |pmc= 2632594|type=Review}}</ref> |
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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.<ref>Fetal testosterone and autistic traits: |
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*{{vcite book |title= Autism: Current Theories and Evidence |editor= Zimmerman AW |author= Auyeung B, Baron-Cohen S |chapter= A role for fetal testosterone in human sex differences |doi=10.1007/978-1-60327-489-0_8 |isbn=978-1-60327-488-3 |pages=185–208 |publisher=Humana |year=2009}} |
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*{{vcite journal |author= Manson JE |title= Prenatal exposure to sex steroid hormones and behavioral/cognitive outcomes |journal=Metabolism |volume=57 |issue= Suppl 2 |pages=S16–21 |year=2008 |pmid=18803959 |doi=10.1016/j.metabol.2008.07.010|type=Review}}</ref> |
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Based in part on animal studies, diagnostic [[ultrasound]]s 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.<ref>{{vcite journal |author=Abramowicz JS |title=Ultrasound and autism: association, link, or coincidence? |journal=J Ultrasound Med |volume=31 |issue=8 |pages=1261–9 |year=2012 |month=August |pmid=22837291 |url=http://www.jultrasoundmed.org/content/31/8/1261.long |type=Review}}</ref> |
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Some research suggests that maternal exposure to [[selective serotonin reuptake inhibitor]]s during pregnancy is associated with an increased risk of autism, but it remains unclear whether there is a causal link between the two.<ref>{{vcite journal|author=Man KK, Tong HH, Wong LY, Chan EW, Simonoff E, Wong IC|title=Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies|journal=Neuroscience and biobehavioral reviews|date=9 December 2014|volume=49C|pages=82-89|doi=10.1016/j.neubiorev.2014.11.020|pmid=25498856}}</ref> |
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==Perinatal environment== |
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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 (medical)|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.<ref>{{vcite journal |author= Kolevzon A, Gross R, Reichenberg A |title= Prenatal and perinatal risk factors for autism |journal= Arch Pediatr Adolesc Med |volume=161 |issue=4 |year=2007 |pages=326–33 |pmid=17404128 |doi= 10.1001/archpedi.161.4.326|type=Review}}</ref> |
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==Postnatal environment== |
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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.<ref name="Rutter">{{vcite journal|author=Rutter M|title=Incidence of autism spectrum disorders: changes over time and their meaning|journal=Acta Paediatr|volume=94|issue=1|year=2005|pages=2–15|pmid=15858952|doi=10.1111/j.1651-2227.2005.tb01779.x|authorlink=Michael Rutter|type=Review}}</ref> |
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===Amygdala neurons=== |
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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.<ref>{{vcite journal|journal=Int J Dev Neurosci|year=2005|volume=23|issue=2–3|pages=125–41|title=Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area|author=Schultz RT|doi=10.1016/j.ijdevneu.2004.12.012|pmid=15749240|type=Review}}</ref> |
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===Autoimmune disease=== |
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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|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|viral infection]] has been hypothesized to cause autism via an autoimmune mechanism.<ref>{{vcite journal |journal= Autoimmun Rev |year=2004 |volume=3 |issue=7–8 |pages=557–62 |title= Is autism an autoimmune disease? |title.= |author= Ashwood P, Van de Water J |doi=10.1016/j.autrev.2004.07.036 |pmid=15546805 |type=Review}}</ref> |
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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.<ref>{{vcite journal |journal= J Leukoc Biol |year=2006 |volume=80 |issue=1 |pages=1–15 |title= The immune response in autism: a new frontier for autism research |author= [[Paul Ashwood|Ashwood P]], Wills S, Van de Water J |doi=10.1189/jlb.1205707 |pmid=16698940 |url=http://www.jleukbio.org/cgi/content/full/80/1/1|type=Review}}</ref> 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.<ref>{{vcite journal |journal=Res Autism Spectr Disord |volume=3 |issue=4 |year=2009 |pages=840–60 |doi=10.1016/j.rasd.2009.01.007 |author=Stigler KA, Sweeten TL, Posey DJ, McDougle CJ |title=Autism and immune factors: a comprehensive review |type=Review}}</ref> As [[autoantibodies]] are found in diseases other than ASD, and are not always present in ASD,<ref>{{vcite journal |journal= Ann N Y Acad Sci |year=2007 |volume=1107 |pages=79–91 |title= Autoantibodies in autism spectrum disorders (ASD) |author= Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J |doi=10.1196/annals.1381.009 |pmid=17804535|type=Review}}</ref> the relationship between immune disturbances and autism remains unclear and controversial.<ref>{{vcite journal |journal= Neuropathol Appl Neurobiol |year=2008 |volume=34 |issue=1 |pages=4–11 |title= The neuropathology of autism: where do we stand? |title.= |author= Schmitz C, Rezaie P |doi=10.1111/j.1365-2990.2007.00872.x |pmid=17971078|type=Review}}</ref> 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.<ref>{{vcite journal|title=Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis.|author=Wu S|journal=Neuroscience and biobehavioral reviews|date=15 May 2015|volume=55|pages=322-332|doi=10.1016/j.neubiorev.2015.05.004|pmid=25981892}}</ref> |
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When an underlying maternal autoimmune disease is present, antibodies circulating to the fetus could contribute to the development of autism spectrum disorders.<ref>{{vcite journal |author=Fox E, Amaral D, Van de Water J |title=Maternal and fetal antibrain antibodies in development and disease |journal=Dev Neurobiol |volume=72 |issue=10 |pages=1327–34 |year=2012 |month=October |pmid=22911883 |doi=10.1002/dneu.22052 |pmc=3478666|type=Review}}</ref> |
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===Endogenous opiate precursor theory=== |
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{{Main|Opioid excess theory}} |
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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.<ref>{{vcite journal | author = Panksepp J | year = 1979 | title = A neurochemical theory of autism | url = | journal = Trends in Neurosciences | volume = 2 | issue = | pages = 174–177 | doi=10.1016/0166-2236(79)90071-7}}</ref> Opiate theory hypothesizes that autism is caused by a digestive disorder present from birth which causes gluten (present in wheat-derived foods) and casein (present in dairy products) to be converted to the opioid peptides [[gliadorphin]] (aka gluteomorphin) and [[casomorphin]]. |
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According to the theory, exposure to these opiate compounds in young children interferes with normal neurological development by dulling sensory input. Lacking sufficient sensory input, the developing brain attempts to artificially generate the auditory, vestibular, visual, and tactile input on its own. This attempt at generating input manifests itself as behaviors common to autism, such as grunting or screaming (auditory), spinning or rocking back and forth (vestibular), preoccupation with spinning objects or waving of the fingers in front of the eyes (visual), and hand flapping or self-injury (tactile). |
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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.<ref>{{vcite journal |journal= J Dev Behav Pediatr |year=2006 |volume=27 |issue=2 Suppl 2 |pages=S162–71 |title= Elimination diets in autism spectrum disorders: any wheat amidst the chaff? |author= Christison GW, Ivany K |pmid=16685183 |doi= 10.1097/00004703-200604002-00015}}</ref> The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by [[Kalle Reichelt]] in 1991.<ref>{{vcite journal | author = Reichelt KL, Knivsberg A-M, Lind G, Nødland M | year = 1991 | title = Probable etiology and possible treatment of childhood autism | url = | journal = Brain Dysfunct | volume = 4 | issue = | pages = 308–19 }}</ref> The scientific evidence is not yet adequate to make treatment recommendations regarding diets, such as the [[Gluten-free, casein-free diet|GFCF diet]], which exclude these substances.<ref>Shattock P, Whiteley P. (2002) "Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention" "Autism Research Unit, University of Sunderland, UK.</ref> |
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===Gastrointestinal connection=== |
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Parents have reported [[gastrointestinal]] (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut,<ref name="Johnson">{{vcite journal |journal= Top Clin Nutr |volume=21 |issue=3 |pages=212–25 |year=2006 |author= Johnson TW |title= Dietary considerations in autism: identifying a reasonable approach |doi=10.1097/00008486-200607000-00008}}</ref> but the results so far are inconclusive. |
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There is some research evidence that autistic children are more likely to have GI symptoms than typical children.<ref>{{vcite journal |author=McElhanon BO, McCracken C, Karpen S, Sharp WG |title=Gastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis |journal=Pediatrics |volume=133 |issue=5 |pages=872–883 |year=2014 |month=May |pmid=24777214 |doi=10.1542/peds.2013-3995}}</ref> Even so, design flaws in studies of elimination diets mean that the data are inadequate to guide treatment recommendations.<ref name="Christison">{{vcite journal |journal= J Dev Behav Pediatr |year=2006 |volume=27 |issue= 2 Suppl 2 |pages=S162–71 |title= Elimination diets in autism spectrum disorders: any wheat amidst the chaff? |title.= |author= Christison GW, Ivany K |pmid= 16685183|doi= 10.1097/00004703-200604002-00015|type=Review}}</ref> |
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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.<ref name="Johnson" /> Later studies found secretin clearly ineffective in treating autism.<ref>{{vcite journal |author=Krishnaswami S, McPheeters ML, Veenstra-Vanderweele J |title=A systematic review of secretin for children with autism spectrum disorders |journal=Pediatrics |volume=127 |issue=5 |pages=e1322–5 |year=2011 |month=May |pmid=21464196 |pmc=3387870 |doi=10.1542/peds.2011-0428 |type=Review}}</ref> |
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===Lack of vitamin D=== |
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There is limited evidence for the hypothesis that vitamin D deficiency has a role in autism, and it may be biologically plausible,<ref>{{vcite journal |author=Eyles DW, Burne TH, McGrath JJ |title=Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease |journal=Front Neuroendocrinol |volume=34 |issue=1 |pages=47–64 |year=2013 |month=January |pmid=22796576 |doi=10.1016/j.yfrne.2012.07.001 |type=Review}}</ref> but more research is needed.<ref>{{vcite journal |author=Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C |title=Vitamin D and autism: clinical review |journal=Res Dev Disabil |volume=33 |issue=5 |pages=1541–50 |year=2012 |pmid=22522213 |doi=10.1016/j.ridd.2012.02.015 |type=Review}}</ref> |
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===Lead=== |
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[[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.<ref name="Zafeiriou2006">{{vcite journal |journal= Brain Dev |year=2007 |volume=29 |issue=5 |pages=257–72 |title= Childhood autism and associated comorbidities |author= Zafeiriou DI, Ververi A, Vargiami E |doi=10.1016/j.braindev.2006.09.003 |pmid=17084999|type=Review}}</ref> |
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The atypical eating behaviors of autistic children, along with habitual mouthing and [[pica (disorder)|pica]], make it hard to determine whether increased lead levels are a cause or a consequence of autism.<ref name="Zafeiriou2006" /> |
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===Locus coeruleus–noradrenergic system=== |
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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.<ref>{{vcite journal |author= Mehler MF, Purpura DP |title= Autism, fever, epigenetics and the locus coeruleus |journal= Brain Res Rev |volume=59 |issue=2 |pages=388–92 |year=2009 |pmid=19059284 |doi=10.1016/j.brainresrev.2008.11.001 |laysummary=http://www.time.com/time/health/article/0,8599,1889436,00.html |laysource=TIME |laydate=2009-04-07 |pmc= 2668953|type=Review}}</ref> |
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===Mercury=== |
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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.<ref>{{vcite journal |journal=Int J Risk Saf Med |year=2008 |volume=20 |issue=3 |pages=135–42 |title=An epidemiological analysis of the 'autism as mercury poisoning' hypothesis |author= Austin D |doi=10.3233/JRS-2008-0436 }}</ref> This view has gained little traction in the scientific community as the [[Mercury toxicity#Signs and symptoms|typical symptoms of mercury toxicity]] are significantly different from [[Autism#Characteristics|symptoms seen in autism]].<ref name="Nelson">{{vcite journal |author= Nelson KB, Bauman ML |title= Thimerosal and autism? |journal=Pediatrics |volume=111 |issue=3 |pages=674–9 |year=2003 |pmid=12612255 |doi=10.1542/peds.111.3.674 |url=http://pediatrics.aappublications.org/cgi/content/full/111/3/674|type=Review}}</ref> The principal source of human exposure to organic mercury is via fish consumption and for inorganic mercury is [[dental amalgam]]s. 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.<ref>{{vcite journal |journal=Pediatrics |year=2004 |volume=113 |issue=4 Suppl |pages=1023–9 |title=Mercury exposure and child development outcomes |author=Davidson PW, Myers GJ, Weiss B |pmid=15060195 |url=http://pediatrics.aappublications.org/content/113/Supplement_3/1023.long|doi=10.1542/peds.113.4.S1.1023|type=Review, historical article}}</ref> A meta-analysis published in 2007 concluded that there was no link between mercury and autism.<ref>{{vcite journal|journal=Pediatr Int|year=2007|volume=49|issue=1|pages=80–7|title=Low-level chronic mercury exposure in children and adolescents: meta-analysis|author=Ng DK, Chan CH, Soo MT, Lee RS|doi=10.1111/j.1442-200X.2007.02303.x|pmid=17250511 |type=Meta-analysis}}</ref> |
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===Oxidative stress=== |
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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]].<ref>{{vcite journal |journal= Int J Neuropsychopharmacol |year=2008 |title= Oxidative stress in psychiatric disorders: evidence base and therapeutic implications |author= Ng F, Berk M, Dean O, Bush AI |doi=10.1017/S1461145707008401 |pmid=18205981 |volume=11 |issue=6 |pages=851–76|type=Review}}</ref> One theory is that stress damages [[Purkinje cell]]s in the [[cerebellum]] after birth, and it is possible that [[glutathione]] is involved.<ref>{{vcite journal|journal=J Toxicol Environ Health B Crit Rev|year=2006 |volume=9|issue=6|pages=485–99|title=Evidence of toxicity, oxidative stress, and neuronal insult in autism|author=Kern JK, Jones AM|doi=10.1080/10937400600882079|pmid=17090484|type=Review}}</ref> Autistic children have lower levels of total glutathione, and higher levels of oxidized glutathione.<ref>{{vcite journal |author=Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A |title=Glutathione-related factors and oxidative stress in autism, a review |journal=Curr. Med. Chem. |volume=19 |issue=23 |pages=4000–5 |year=2012 |pmid=22708999 |type=Review |doi=10.2174/092986712802002572}}</ref> Based on this theory, [[antioxidant]]s may be a useful treatment for autism.<ref>{{vcite journal |author=Villagonzalo KA, Dodd S, Dean O, Gray K, Tonge B, Berk M |title=Oxidative pathways as a drug target for the treatment of autism |journal=Expert Opin. Ther. Targets |volume=14 |issue=12 |pages=1301–10 |year=2010 |month=December |pmid=20954799 |doi=10.1517/14728222.2010.528394 |type=Review}}</ref> |
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===Refrigerator mother=== |
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{{main|Refrigerator mother}} |
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Child 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. Parents, especially mothers, of individuals with autism were blamed for having caused their child's condition through the withholding of affection.<ref>{{vcite book |author= Bettelheim B |title= The Empty Fortress: Infantile Autism and the Birth of the Self |year=1967 |publisher= Free Press |isbn=0-02-903140-0 |authorlink= Bruno Bettelheim}}</ref> [[Leo Kanner]], who first described autism,<ref>{{vcite journal |author= Kanner L |title= Autistic disturbances of affective contact |journal= Nerv Child |volume=2 |pages=217–50 |year=1943 |authorlink= Leo Kanner}} Reprinted in {{vcite journal |year=1968 |journal=Acta Paedopsychiatr |volume=35 |issue=4 |pages=100–36 |pmid=4880460 |author=<!-- Pacify Citation bot --> }}</ref> suggested that parental coldness might contribute to autism.<ref>{{vcite journal |journal= [[Am J Orthopsychiatry]] |volume=19 |issue=3 |pages=416–26 |year=1949 |author=Kanner L |title= Problems of nosology and psychodynamics in early childhood autism |pmid=18146742 |doi=10.1111/j.1939-0025.1949.tb05441.x}}</ref> 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.<ref>{{vcite journal |journal= Skeptical Inquirer |volume=24 |issue=6 |pages=12–4 |year=2000 |title= The brutality of Dr. Bettelheim |author=Gardner M |authorlink= Martin Gardner}}</ref> |
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===Vaccines=== |
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Scientific studies have refuted a [[Vaccine controversies#Autism controversies|causal relationship between vaccinations and autism]].<ref name="Fombonne2006">{{vcite journal |author=Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D |title=Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations |journal=[[Pediatrics (journal)|Pediatrics]] |volume=118 |issue=1 |pages=e139–50 |year=2006 |month=July |pmid=16818529 |doi=10.1542/peds.2005-2993 |url=http://pediatrics.aappublications.org/content/118/1/e139.long }}{{closed access}}</ref><ref name="Gross2009">{{vcite journal |author=Gross L |title=A broken trust: lessons from the vaccine–autism wars |journal=[[PLoS Biol.|PLoS Biology]] |volume=7 |issue=5 |pages=e1000114 |year=2009 |pmid=19478850 |doi=10.1371/journal.pbio.1000114 |pmc=2682483 }}{{open access}}</ref><ref name="Taylor2014">{{vcite journal |author=Taylor LE, Swerdfeger AL, Eslick GD |title=Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies |journal=[[Vaccine (journal)|Vaccine]] |volume=32 |issue=29 |pages=3623–9 |year=2014 |month=June |pmid=24814559 |doi=10.1016/j.vaccine.2014.04.085 }}{{open access}}</ref> Despite this, some parents believe that vaccinations cause autism and therefore delay or avoid immunizing their children under the "[[Vaccine controversy#Vaccine overload|vaccine overload]]" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism,<ref name="Hilton2006">{{vcite journal |author=Hilton S, Petticrew M, Hunt K |title='Combined vaccines are like a sudden onslaught to the body's immune system': parental concerns about vaccine 'overload' and 'immune-vulnerability' |journal=[[Vaccine (journal)|Vaccine]] |volume=24 |issue=20 |pages=4321–7 |year=2006 |pmid=16581162 |doi=10.1016/j.vaccine.2006.03.003 }}{{open access}}</ref> even though this hypothesis has no scientific evidence and is biologically implausible.<ref name="Gerber2009">{{vcite journal |author=Gerber JS, Offit PA |title=Vaccines and autism: a tale of shifting hypotheses |journal=[[Clin. Infect. Dis.|Clinical Infectious Diseases]] |volume=48 |issue=4 |pages=456–61 |year=2009 |pmid=19128068 |doi=10.1086/596476 |laysummary=http://www.idsociety.org/Content.aspx?id=13336 |laysource=IDSA |laydate=2009-01-30 |pmc=2908388|type=Review}}{{open access}}</ref> 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.<ref name="Paul2009">{{vcite journal |author=Paul R |title=Parents ask: am I risking autism if I vaccinate my children? |journal=[[J. Autism Dev. Disord.|Journal of Autism and Developmental Disorders]] |volume=39 |issue=6 |pages=962–3 |year=2009 |pmid=19363650 |doi=10.1007/s10803-009-0739-y }}{{closed access}}</ref> |
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====MMR vaccine==== |
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{{main|MMR vaccine controversy}} |
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The [[MMR vaccine]] hypothesis of autism is one of the most extensively debated hypothesies 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.<ref name="Retraction" /> Although the paper, which was later retracted by the journal,<ref name="Retraction" /> concluded "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described,"<ref name="Wakefield1998">{{vcite journal |author= [[Andrew Wakefield|Wakefield A]], Murch S, Anthony A ''et al.'' |title= Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=351 |issue=9103 |pages=637–41 |year=1998 | note = doi was 10.1016/S0140-6736(97)11096-0 and URL was http://briandeer.com/mmr/lancet-paper.htm|pmid=9500320 |doi=10.1016/S0140-6736(97)11096-0}}{{Retracted paper|{{DOI|10.1016/S0140-6736(10)60175-7}}|intentional=yes}}</ref> Wakefield nevertheless suggested during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose. |
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In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors.<ref>{{vcite journal |author= Murch SH, Anthony A, Casson DH ''et al.'' |author.= |title= Retraction of an interpretation |year=2004 |journal=Lancet |volume=363 |issue=9411 |pages=750 |doi=10.1016/S0140-6736(04)15715-2 |pmid=15016483}}</ref> The retraction followed an investigation by ''[[The Sunday Times]]'', which stated that Wakefield "acted dishonestly and irresponsibly".<ref>{{vcite web |url=http://briandeer.com/mmr/lancet-summary.htm |title= The MMR-autism crisis - our story so far |accessdate=2008-12-06 |author= Deer B |date=2008-11-02}}</ref> The [[Centers for Disease Control and Prevention]],<ref name="CDC">{{vcite web |url=http://www.cdc.gov/vaccinesafety/concerns/mmr_vaccine.htm |title= Measles, mumps, and rubella (MMR) vaccine |date=2008-12-23 |accessdate=2009-02-14 |publisher= Centers for Disease Control and Prevention}}</ref> the [[Institute of Medicine]] of the [[United States National Academy of Sciences|National Academy of Sciences]],<ref name="IOM2004">{{vcite web |url=http://www.iom.edu/CMS/3793/4705/20155.aspx |title= Immunization safety review: vaccines and autism |publisher= Institute of Medicine, National Academy of Sciences |year=2004 |accessdate=2007-06-13}}</ref> and the U.K. [[National Health Service]]<ref>{{vcite web |url=http://www.mmrthefacts.nhs.uk/ |accessdate=2007-06-13 |title= MMR the facts |publisher= National Health Service}}</ref> have all concluded that there is no evidence of a link between the MMR vaccine and autism. |
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In February 2010, ''The Lancet'', which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed.<ref name="Retraction">{{vcite journal |title=Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=375 |issue=9713 |pages=445 |date=2010-02-06 |doi=10.1016/S0140-6736(10)60175-4 |laysource=BBC News |laydate=2010-02-02 |laysummary=http://news.bbc.co.uk/2/low/health/8493753.stm |pmid=20137807}}</ref> In January 2011, an investigation published in the journal ''BMJ'' described the Wakefield study as the result of deliberate fraud and manipulation of data.<ref name="WakefieldarticleBMJ">{{vcite journal |year=2011 |doi=10.1136/bmj.c7452 |pages=c7452 |volume=342 |title=Wakefield's article linking MMR vaccine and autism was fraudulent |author=Godlee F, Smith J, Marcovitch H |journal=[[BMJ]] |url=http://www.bmj.com/content/342/bmj.c7452.full |pmid=21209060}}</ref><ref name="BMJ2011">{{vcite journal |title=How the case against the MMR vaccine was fixed| author=Deer B| journal=BMJ| year=2011| volume=342| pages=c5347| url=http://www.bmj.com/content/342/bmj.c5347.full |doi= 10.1136/bmj.c5347| pmid=21209059}}</ref><ref name="NPRWakefield">{{vcite news |url= http://www.npr.org/2011/01/05/132692497/journal-study-linking-vaccine-to-autism-was-fraud |publisher=NPR | agency=Associated Press |title=Study linking vaccine to autism was fraud |date=2011-01-05 |accessdate= 2011-01-06}}</ref><ref name="CNN2011">{{vcite news |title=Retracted autism study an 'elaborate fraud,' British journal finds |url=http://edition.cnn.com/2011/HEALTH/01/05/autism.vaccines/index.html |date=2011-01-06 |accessdate=2011-01-06 | location=Atlanta}}</ref> |
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====Thiomersal (thimerosal)==== |
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{{main|Thiomersal controversy}} |
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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 [[vaccination]]s in developed countries including US and the EU.<ref>{{cite web|url= http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm096228.htm#thi| title= Vaccines, blood and biologics: thimerosal in vaccines |publisher=US Food and Drug Administration |year=2012 |accessdate= October 24, 2013}}</ref> 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]]<ref name="Doja" /> and increasing likelihood of disease outbreaks.<ref>{{vcite journal |author=Eaton L |title=Measles cases in England and Wales rise sharply in 2008 |journal=BMJ |volume=338 |pages=b533 |year=2009 |pmid=19208716 |doi= 10.1136/bmj.b533|url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19208716}}</ref><ref>{{vcite journal |author=Choi YH, Gay N, Fraser G, Ramsay M |title=The potential for measles transmission in England |journal=BMC Public Health |volume=8 |issue= |pages=338 |year=2008 |pmid=18822142 |pmc=2563003 |doi=10.1186/1471-2458-8-338 |url=}}</ref> Because of public concerns,{{Citation needed|reason=this may have been more motivated by a precautionary principle|date=July 2015}} 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. |
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A causal link between thimerosal and autism has been rejected by international scientific and medical professional bodies including the [[American Medical Association]],<ref>{{vcite web | author = [[American Medical Association]] | year = 2004-05-18 | url = |
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http://www.ama-assn.org/ama1/pub/upload/mm/36/press_iom_mmr.doc | title =AMA Welcomes New IOM Report Rejecting Link Between Vaccines and Autism | accessdate =2007-07-23}}</ref> the [[American Academy of Pediatrics]],<ref>{{vcite web | author = [[American Academy of Pediatrics]] | year = 2004-05-18 | url = http://www.cispimmunize.org/fam/autism/thimerosal.htm | title =What Parents Should Know About Thimerosal | accessdate =2007-07-23}}</ref> the [[American College of Medical Toxicology]],<ref>{{vcite journal |journal=J Med Toxicol |date=2006 |volume=2 |issue=4 |pages=170–1 |title= ACMT position statement: the Iom report on thimerosal and autism |author= Kurt TL |pmid=18072140 |url=http://jmt.pennpress.org/strands/jmt/pdfHandler.pdf?issue=20060204&file=20060204_170_171.pdf |format=PDF |doi=10.1007/BF03161188}}</ref> the [[Canadian Paediatric Society]],<ref>{{vcite journal |journal= Paediatr Child Health |year=2007 |volume=12 |issue=5 |pages=393–5 |title= Autistic spectrum disorder: No causal relationship with vaccines |author= Infectious Diseases and Immunization Committee, Canadian Paediatric Society |url=http://cps.ca/english/statements/ID/pidnote_jun07.htm |accessdate=2008-10-17}} Also published (2007) in ''Can J Infect Dis Med Microbiol'' '''18''' (3): 177–9. PMID 18923720.</ref> the [[United States National Academy of Sciences|U.S. National Academy of Sciences]],<ref name="IOM2004" /> the [[Food and Drug Administration]],<ref name="T-in-vaccines">{{cite web |date=2007-09-06 |url=http://www.fda.gov/cber/vaccine/thimerosal.htm |accessdate=2007-10-01 |title= Thimerosal in vaccines |publisher= Center for Biologics Evaluation and Research, U.S. Food and Drug Administration}}</ref> [[Centers for Disease Control and Prevention]],<ref name="CDC" /> the [[World Health Organization]],<ref name="WHO">{{cite web |author= World Health Organization |year=2006 |url=http://www.who.int/features/qa/85/en/ |title= Questions and answers about autism spectrum disorders (ASD) |accessdate=2014-11-02}}</ref> the [[Public Health Agency of Canada]],<ref>{{vcite journal|journal=Can Commun Dis Rep|date=2007|volume=33|issue=ACS-6|pages=1–13|title=Thimerosal: updated statement. An Advisory Committee Statement|author=National Advisory Committee on Immunization|pmid=17663033|url=http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vol33/acs-06/index_e.html}}</ref> and the [[European Medicines Agency]].<ref name="EMEA">{{vcite web | author = [[European Medicines Agency]] | year = 2004-03-24 | url = http://www.emea.europa.eu/pdfs/human/press/pus/119404en.pdf| title =EMEA Public Statement on Thiomersal in Vaccines for Human Use| accessdate =2007-07-22}}</ref> |
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===Viral infection=== |
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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 [[Herpesviridae|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.<ref name="Libbey">{{vcite journal|journal=J Neurovirol|year=2005|volume=11|issue=1|pages=1–10|title=Autistic disorder and viral infections|author=Libbey JE, Sweeten TL, McMahon WM, Fujinami RS|doi=10.1080/13550280590900553|pmid=15804954|type=Review}}</ref> |
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==Social construct== |
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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.<ref>{{vcite book|isbn=0-674-00412-4|author=Hacking I|title=The Social Construction of What?|title.= |publisher=Harvard University Press|year=1999|pages=114–23}}</ref> |
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[[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.<ref>{{vcite book |chapter= The dialectics of autism: theorizing autism, performing autism, remediating autism, and resisting autism |title= Constructing Autism: Unravelling the 'Truth' and Understanding the Social |author= Nadesan MH |publisher=Routledge |isbn=0-415-32181-6 |year=2005 |pages=179–213}}</ref> |
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==See also== |
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* [[List of topics characterized as pseudoscience]] |
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==References== |
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{{Research help|Med}} |
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{{Reflist|30em}} |
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{{Pervasive developmental disorders}} |
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{{Autism resources}} |
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{{Portal bar|Pervasive developmental disorders|Psychiatry}} |
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[[Category:Autism]] |
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[[Category:Etiology|Autism]] |
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[[Category:Social constructionism]] |
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