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Many '''causes of autism''', including [[environmental disease|environmental]] and [[genetic disorder|genetic]] factors, have been recognized or proposed, but understanding of the [[Etiology|theory of causation]] of [[autism]] is incomplete.<ref name="Waye_2018">{{cite journal | vauthors = Waye MM, Cheng HY | title = Genetics and epigenetics of autism: A Review | journal = Psychiatry and Clinical Neurosciences | volume = 72 | issue = 4 | pages = 228–244 | date = April 2018 | pmid = 28941239 | doi = 10.1111/pcn.12606 | type = Review | s2cid = 206257210 | eissn = 1440-1819 | doi-access = free }}</ref> Attempts have been made to incorporate the known genetic and environmental causes into a comprehensive causative framework.<ref name="Sarovic_2021">{{cite journal | vauthors = Sarovic D | title = A Unifying Theory for Autism: The Pathogenetic Triad as a Theoretical Framework | journal = Frontiers in Psychiatry | volume = 12 | pages = 767075 | date = November 2021 | pmid = 34867553 | pmc = 8637925 | doi = 10.3389/fpsyt.2021.767075 | s2cid = 244119594 | doi-access = free | type = Review }}</ref> 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.<ref>{{Cite book |url=https://doi.org/10.1176/appi.books.9780890425787 |title=Diagnostic and statistical manual of mental disorders: DSM-5-TR |publisher=American Psychiatric Association Publishing |year=2022 |doi=10.1176/appi.books.9780890425787 |edition=5th |isbn=978-0-89042-575-6 |s2cid=249488050 |last1=American Psychiatric Association }}</ref>
There are many known environmental, genetic, and biological causes of autism. Research indicates that genetic factors
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]].<ref name="Waye_2018" /><ref name="Hodges_2020">{{cite journal | vauthors = Hodges H, Fealko C, Soares N | title = Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation | journal = Translational Pediatrics | volume = 9 | issue = Suppl 1 | pages = S55–S65 | date = February 2020 | pmid = 32206584 | pmc = 7082249 | doi = 10.21037/tp.2019.09.09 | doi-access = free }}</ref> 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.<ref name="Salari_2022">{{cite journal | vauthors = Salari N, Rasoulpoor S, Rasoulpoor S, Shohaimi S, Jafarpour S, Abdoli N, Khaledi-Paveh B, Mohammadi M | display-authors = 6 | title = The global prevalence of autism spectrum disorder: a comprehensive systematic review and meta-analysis | journal = Italian Journal of Pediatrics | volume = 48 | issue = 1 | pages = 112 | date = July 2022 | pmid = 35804408 | pmc = 9270782 | doi = 10.1186/s13052-022-01310-w | doi-access = free }}</ref>
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="Quan_2019">{{Cite journal | vauthors = Quan J, Panaccione N, King JA, Underwood F, Windsor JW, Coward S, Gidrewicz D, Kaplan GG | display-authors = 6 |title=A257 Association Between Celiac Disease and Autism Spectrum Disorder: A Systematic Review |date=March 2019 |journal=Journal of the Canadian Association of Gastroenterology |volume=2 |issue=Supplement_2 |pages=502–503 |doi=10.1093/jcag/gwz006.256 |issn=2515-2084 |pmc=6512700}}</ref> [[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]], and [[illicit drug]]s.<ref name="Salari_2022" /> 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]].<ref name="Resurgence of Measles in Europe: A">{{cite journal | vauthors = Wilder-Smith AB, Qureshi K | title = Resurgence of Measles in Europe: A Systematic Review on Parental Attitudes and Beliefs of Measles Vaccine | journal = Journal of Epidemiology and Global Health | volume = 10 | issue = 1 | pages = 46–58 | date = March 2020 | pmid = 32175710 | pmc = 7310814 | doi = 10.2991/jegh.k.191117.001 }}</ref><ref name="Beliefs around childhood vaccines i">{{cite journal | vauthors = Gidengil C, Chen C, Parker AM, Nowak S, Matthews L | title = Beliefs around childhood vaccines in the United States: A systematic review | journal = Vaccine | volume = 37 | issue = 45 | pages = 6793–6802 | date = October 2019 | pmid = 31562000 | pmc = 6949013 | doi = 10.1016/j.vaccine.2019.08.068 }}</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. 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 | vauthors = Man L, Lekovich J, Rosenwaks Z, Gerhardt J | title = Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations | journal = Frontiers in Molecular Neuroscience | volume = 10 | pages = 290 | date = 2017-09-12 | pmid = 28955201 | pmc = 5600956 | doi = 10.3389/fnmol.2017.00290 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hatton DD, Sideris J, Skinner M, Mankowski J, Bailey DB, Roberts J, Mirrett P | title = Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP | journal = American Journal of Medical Genetics. Part A | volume = 140A | issue = 17 | pages = 1804–1813 | date = September 2006 | pmid = 16700053 | doi = 10.1002/ajmg.a.31286 | s2cid = 11017841 }}</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 | vauthors = Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY | title = Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 | journal = Nature Genetics | volume = 23 | issue = 2 | pages = 185–188 | date = October 1999 | pmid = 10508514 | doi = 10.1038/13810 | s2cid = 3350350 }}</ref>
Besides these early examples, the role of ''de novo'' mutations in autism 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 |display-authors=6 |vauthors=Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Månér S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M |date=July 2004 |title=Large-scale copy number polymorphism in the human genome |journal=Science |volume=305 |issue=5683 |pages=525–528 |bibcode=2004Sci...305..525S |doi=10.1126/science.1098918 |pmid=15273396 |s2cid=20357402}}</ref><ref>{{cite journal |author-link5=Patricia K. Donahoe |display-authors=6 |vauthors=Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C |date=September 2004 |title=Detection of large-scale variation in the human genome |journal=Nature Genetics |volume=36 |issue=9 |pages=949–951 |doi=10.1038/ng1416 |pmid=15286789 |s2cid=1433674 |doi-access=free}}</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 autism than in controls and contribute to approximately 5–10% of cases.<ref name="Sebat_2007" /><ref>{{cite journal |display-authors=6 |vauthors=Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW |date=May 2014 |title=Convergence of genes and cellular pathways dysregulated in autism spectrum disorders |journal=American Journal of Human Genetics |volume=94 |issue=5 |pages=677–694 |doi=10.1016/j.ajhg.2014.03.018 |pmc=4067558 |pmid=24768552}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M |date=June 2011 |title=Rare de novo and transmitted copy-number variation in autistic spectrum disorders |journal=Neuron |volume=70 |issue=5 |pages=886–897 |doi=10.1016/j.neuron.2011.05.015 |pmid=21658582 |s2cid=11132936|doi-access=free }}</ref><ref name="Sanders_2011">{{cite journal |display-authors=6 |vauthors=Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Geschwind D, Roeder K, Devlin B, State MW |date=June 2011 |title=Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism |journal=Neuron |volume=70 |issue=5 |pages=863–885 |doi=10.1016/j.neuron.2011.05.002 |pmc=3939065 |pmid=21658581 |author65-link=Kathryn Roeder}}</ref> Based on these studies, there are predicted to be 130–234 autism-related CNV loci.<ref name="Sanders_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="Brandler_2016">{{cite journal |display-authors=6 |vauthors=Brandler WM, Antaki D, Gujral M, Noor A, Rosanio G, Chapman TR, Barrera DJ, Lin GN, Malhotra D, Watts AC, Wong LC, Estabillo JA, Gadomski TE, Hong O, Fajardo KV, Bhandari A, Owen R, Baughn M, Yuan J, Solomon T, Moyzis AG, Maile MS, Sanders SJ, Reiner GE, Vaux KK, Strom CM, Zhang K, Muotri AR, Akshoomoff N, Leal SM, Pierce K, Courchesne E, Iakoucheva LM, Corsello C, Sebat J |date=April 2016 |title=Frequency and Complexity of De Novo Structural Mutation in Autism |journal=American Journal of Human Genetics |volume=98 |issue=4 |pages=667–679 |doi=10.1016/j.ajhg.2016.02.018 |pmc=4833290 |pmid=27018473}}</ref>
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.<ref>{{cite journal |display-authors=6 |vauthors=Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M |date=April 2012 |title=De novo gene disruptions in children on the autistic spectrum |journal=Neuron |volume=74 |issue=2 |pages=285–299 |doi=10.1016/j.neuron.2012.04.009 |pmc=3619976 |pmid=22542183}}</ref><ref name="DeRubeis_2016">{{cite journal |display-authors=6 |vauthors=De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD |date=November 2014 |title=Synaptic, transcriptional and chromatin genes disrupted in autism |journal=Nature |volume=515 |issue=7526 |pages=209–215 |bibcode=2014Natur.515..209. |doi=10.1038/nature13772 |pmc=4402723 |pmid=25363760}}</ref><ref name="Iossifov_2014">{{cite journal |display-authors=6 |vauthors=Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M |date=November 2014 |title=The contribution of de novo coding mutations to autism spectrum disorder |journal=Nature |volume=515 |issue=7526 |pages=216–221 |bibcode=2014Natur.515..216I |doi=10.1038/nature13908 |pmc=4313871 |pmid=25363768}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ |date=April 2012 |title=Patterns and rates of exonic de novo mutations in autism spectrum disorders |journal=Nature |volume=485 |issue=7397 |pages=242–245 |bibcode=2012Natur.485..242N |doi=10.1038/nature11011 |pmc=3613847 |pmid=22495311}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW |date=April 2012 |title=De novo mutations revealed by whole-exome sequencing are strongly associated with autism |journal=Nature |volume=485 |issue=7397 |pages=237–241 |bibcode=2012Natur.485..237S |doi=10.1038/nature10945 |pmc=3667984 |pmid=22495306}}</ref><ref>{{cite journal |display-authors=6 |vauthors=O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE |date=April 2012 |title=Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |journal=Nature |volume=485 |issue=7397 |pages=246–250 |bibcode=2012Natur.485..246O |doi=10.1038/nature10989 |pmc=3350576 |pmid=22495309}}</ref> There are predicted to be 350-450 genes that significantly increase susceptibility to autism when impacted by inactivating ''de novo'' mutations.<ref>{{cite journal |vauthors=Ronemus M, Iossifov I, Levy D, Wigler M |date=February 2014 |title=The role of de novo mutations in the genetics of autism spectrum disorders |journal=Nature Reviews. Genetics |volume=15 |issue=2 |pages=133–141 |doi=10.1038/nrg3585 |pmid=24430941 |s2cid=9073763}}</ref> A further 12% of cases are predicted to be caused by protein altering [[missense mutation]]s that change an amino acid but do not inactivate a gene.<ref name="Iossifov_2014" /> 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 [[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="Brandler_2016" />
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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.<ref>{{cite journal |author=[[Columbia University Irving Medical Center]] |date=September 4, 2022 |title=60 New Genes Linked to Autism Uncovered |url=https://scitechdaily.com/60-new-genes-linked-to-autism-uncovered/amp/ |journal=Nature Genetics |publisher=[[SciTech (magazine)|SciTech Daily]] |volume=54 |issue=9 |pages=1305–1319 |doi=10.1038/s41588-022-01148-2 |pmc=9470534 |pmid=35982159 |access-date=September 7, 2022}}</ref>
==Disorders==
===
* [[Phenylketonuria]] (untreated)
* [[Homocystinuria]]
* [[Branched-chain keto acid dehydrogenase kinase deficiency|Branched-chain ketoacid dehydrogenase kinase deficiency]]
===
* [[Succinic semialdehyde dehydrogenase deficiency]]
===
* [[Smith-Lemli-Opitz syndrome]]
===
* [[Folate receptor 1]] gene mutations
* [[Dihydrofolate reductase deficiency]]
===
* [[Arginine:glycine amidinotransferase deficiency]]
* [[Guanidinoacetate methyltransferase deficiency]]
* X-linked [[creatine transporter defect]]
===
* 6-N-trimethyllysine dioxygenase deficiency
===
* [[Adenylosuccinate lyase deficiency]]
* [[Adenosine deaminase deficiency]]
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* [[Phosphoribosyl pyrophosphate synthetase]] superactivity
===Lysosomal storage
* [[Sanfilippo syndrome]] (mucopolysaccharidosis type III)
===
* [[Mitochondrial
* [[Nuclear DNA]] mutations
===
* [[Biotinidase deficiency]]
* [[Urea cycle]] defects
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{{Main|Epigenetics of autism}}[[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>{{cite book |vauthors=Miyake K, Hirasawa T, Koide T, Kubota T |title=Neurodegenerative Diseases |chapter=Epigenetics in Autism and Other Neurodevelopmental Diseases |series=Advances in Experimental Medicine and Biology |year=2012 |type=Review |volume=724 |pages=91–98 |doi=10.1007/978-1-4614-0653-2_7 |isbn=978-1-4614-0652-5 |pmid=22411236}}</ref> Interest has been expressed in imprinted regions on chromosomes 15q and 7q.<ref name="Schanen_2006">{{cite journal |vauthors=Schanen NC |date=October 2006 |title=Epigenetics of autism spectrum disorders |journal=Human Molecular Genetics |type=Review |volume=15 Spec No 2 |issue= |pages=R138–R150 |doi=10.1093/hmg/ddl213 |pmid=16987877}}</ref>
Most data supports a [[Polygenic disease|polygenic]], [[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.<ref name="Pickles_1995">{{cite journal |vauthors=Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M |date=September 1995 |title=Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism |journal=American Journal of Human Genetics |volume=57 |issue=3 |pages=717–726 |pmc=1801262 |pmid=7668301}}</ref><ref name="Risch_1999">{{cite journal |display-authors=6 |vauthors=Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Petersen PB, Pingree C, McMahon W, Wong DL, Cavalli-Sforza LL, Kraemer HC, Myers RM |date=August 1999 |title=A genomic screen of autism: evidence for a multilocus etiology |journal=American Journal of Human Genetics |volume=65 |issue=2 |pages=493–507 |doi=10.1086/302497 |pmc=1377948 |pmid=10417292}}</ref>
[[Epigenetic]] mechanisms can contribute to disease [[phenotype]]s. Epigenetic modifications include [[DNA cytosine methylation]] and post-translational modifications to [[histone]]s. 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.<ref name="Schanen_2006" /> [[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.<ref name="Samaco_2005" /><ref name="Lopez-Rangel_2006">{{cite journal |vauthors=Lopez-Rangel E, Lewis ME |date=2006 |title=Further evidence for pigenetic influence of MECP2 in Rett, autism and Angelman's syndromes |journal=Clinical Genetics |volume=69 |issue=1 |pages=23–25 |doi=10.1111/j.1399-0004.2006.00543c.x |s2cid=85160435}}</ref><ref name="Hagerman_2005">{{cite journal |vauthors=Hagerman RJ, Ono MY, Hagerman PJ |date=September 2005 |title=Recent advances in fragile X: a model for autism and neurodegeneration |journal=Current Opinion in Psychiatry |volume=18 |issue=5 |pages=490–496 |doi=10.1097/01.yco.0000179485.39520.b0 |pmid=16639106 |s2cid=33650811}}</ref>
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[[Sleep apnea]] can result in intermittent [[Hypoxia (medical)|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.<ref name="Maternal diabetes and the risk of a">{{cite journal |vauthors=Xu G, Jing J, Bowers K, Liu B, Bao W |date=April 2014 |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 |volume=44 |issue=4 |pages=766–775 |doi=10.1007/s10803-013-1928-2 |pmc=4181720 |pmid=24057131}}</ref><ref>{{cite journal |vauthors=Maher GM, O'Keeffe GW, Kearney PM, Kenny LC, Dinan TG, Mattsson M, Khashan AS |date=August 2018 |title=Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis |journal=JAMA Psychiatry |volume=75 |issue=8 |pages=809–819 |doi=10.1001/jamapsychiatry.2018.0854 |pmc=6143097 |pmid=29874359}}</ref><ref>{{cite journal |vauthors=Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A |date=May 2012 |title=Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=51 |issue=5 |pages=477–486.e1 |doi=10.1016/j.jaac.2012.02.018 |pmid=22525954}}</ref><ref>{{cite journal |vauthors=Wang Y, Tang S, Xu S, Weng S, Liu Z |date=September 2016 |title=Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis |journal=Scientific Reports |volume=6 |pages=34248 |bibcode=2016NatSR...634248W |doi=10.1038/srep34248 |pmc=5043237 |pmid=27687989}}</ref> Likewise, these are all known risk factors for sleep apnea.<ref>{{cite journal |display-authors=6 |vauthors=Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TG |date=April 2000 |title=Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study |journal=JAMA |volume=283 |issue=14 |pages=1829–1836 |doi=10.1001/jama.283.14.1829 |pmid=10770144}}</ref><ref>{{cite journal |vauthors=Muraki I, Wada H, Tanigawa T |date=September 2018 |title=Sleep apnea and type 2 diabetes |journal=Journal of Diabetes Investigation |volume=9 |issue=5 |pages=991–997 |doi=10.1111/jdi.12823 |pmc=6123041 |pmid=29453905 |s2cid=4871197}}</ref><ref>{{cite journal |vauthors=Punjabi NM |date=February 2008 |title=The epidemiology of adult obstructive sleep apnea |journal=Proceedings of the American Thoracic Society |volume=5 |issue=2 |pages=136–143 |doi=10.1513/pats.200709-155MG |pmc=2645248 |pmid=18250205}}</ref>
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.<ref>{{cite journal | vauthors = Bin YS, Cistulli PA, Roberts CL, Ford JB | title = Childhood Health and Educational Outcomes Associated With Maternal Sleep Apnea: A Population Record-Linkage Study | journal = Sleep | volume = 40 | issue = 11 | date = November 2017 | pmid = 29029347 | doi = 10.1093/sleep/zsx158 | doi-access = free }}</ref> 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.<ref name="Tauman_2015">{{cite journal | vauthors = Tauman R, Zuk L, Uliel-Sibony S, Ascher-Landsberg J, Katsav S, Farber M, Sivan Y, Bassan H | display-authors = 6 | title = The effect of maternal sleep-disordered breathing on the infant's neurodevelopment | journal = American Journal of Obstetrics and Gynecology | volume = 212 | issue = 5 | pages = 656.e1–656.e7 | date = May 2015 | pmid = 25576821 | doi = 10.1016/j.ajog.2015.01.001 }}</ref> There was also an increase in the amount of snoring the mothers with sleep apnea reported in their infants when compared to controls.<ref name="Tauman_2015" /> Children with sleep apnea have "hyperactivity, attention problems, aggressivity, lower social competency, poorer communication, and/or diminished adaptive skills".<ref name="pmid235439012">{{cite journal | vauthors = Perfect MM, Archbold K, Goodwin JL, Levine-Donnerstein D, Quan SF | title = Risk of behavioral and adaptive functioning difficulties in youth with previous and current sleep disordered breathing | journal = Sleep | volume = 36 | issue = 4 | pages = 517–525B | date = April 2013 | pmid = 23543901 | pmc = 3595180 | doi = 10.5665/sleep.2536 }}</ref> One study found significant improvements in ADHD-like symptoms, aggression, social problems and thought problems in autistic children who underwent [[Tonsillectomy|adenotonsillectomy]] for sleep apnea.<ref>{{cite journal | vauthors = Murata E, Mohri I, Kato-Nishimura K, Iimura J, Ogawa M, Tachibana M, Ohno Y, Taniike M | display-authors = 6 | title = Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder | journal = Research in Developmental Disabilities | volume = 65 | pages = 127–139 | date = June 2017 | pmid = 28514706 | doi = 10.1016/j.ridd.2017.04.012 | doi-access = free }}</ref> Sleep problems in autism have been linked in a study to brain changes, particularly in the hippocampus, though this study does not prove causation.<ref>{{cite journal | vauthors = MacDuffie KE, Shen MD, Dager SR, Styner MA, Kim SH, Paterson S, Pandey J, St John T, Elison JT, Wolff JJ, Swanson MR, Botteron KN, Zwaigenbaum L, Piven J, Estes AM | display-authors = 6 | title = Sleep Onset Problems and Subcortical Development in Infants Later Diagnosed With Autism Spectrum Disorder | journal = The American Journal of Psychiatry | volume = 177 | issue = 6 | pages = 518–525 | date = June 2020 | pmid = 32375538 | pmc = 7519575 | doi = 10.1176/appi.ajp.2019.19060666 }}</ref> A common presentation of sleep apnea in children with autism is insomnia.<ref>{{Cite journal |last1=Santapuram |first1=Pooja |last2=Chen |first2=Heidi |last3=Weitlauf |first3=Amy S. |last4=Ghani |first4=Muhammad Owais A. |last5=Whigham |first5=Amy S. |date=July 2022 |title=Investigating differences in symptomatology and age at diagnosis of obstructive sleep apnea in children with and without autism |url=https://pubmed.ncbi.nlm.nih.gov/35636082/#:~:text=Children%20with%20OSA%20can%20present,in%20children%20with%20both%20conditions. |journal=International Journal of Pediatric Otorhinolaryngology |volume=158 |pages=111191 |doi=10.1016/j.ijporl.2022.111191 |issn=1872-8464 |pmid=35636082}}</ref> All known genetic syndromes which are linked to autism have a high prevalence of sleep apnea. The prevalence of sleep apnea in Down's Syndrome is 50% - 100%.<ref>{{Cite journal |last1=Maris |first1=Mieke |last2=Verhulst |first2=Stijn |last3=Wojciechowski |first3=Marek |last4=Van de Heyning |first4=Paul |last5=Boudewyns |first5=An |date=2016-03-01 |title=Prevalence of Obstructive Sleep Apnea in Children with Down Syndrome |journal=Sleep |volume=39 |issue=3 |pages=699–704 |doi=10.5665/sleep.5554 |issn=0161-8105 |pmc=4763351 |pmid=26612391}}</ref> Sleep problems and OSA in this population have been linked to language development.<ref>{{Cite journal |last1=Lee |first1=Ni-Chung |last2=Hsu |first2=Wei-Chung |last3=Chang |first3=Lih-Maan |last4=Chen |first4=Yi-Chen |last5=Huang |first5=Po-Tsang |last6=Chien |first6=Chun-Chin |last7=Chien |first7=Yin-Hsiu |last8=Chen |first8=Chi-Ling |last9=Hwu |first9=Wuh-Liang |last10=Lee |first10=Pei-Lin |date=January 2020 |title=REM sleep and sleep apnea are associated with language function in Down syndrome children: An analysis of a community sample
=== Infectious
A 2021 meta-analysis of 36 studies suggested a relationship between mothers recalling an infection during pregnancy and having children with autism.<ref>{{Cite journal |last1=Tioleco |first1=Nina |last2=Silberman |first2=Anna E. |last3=Stratigos |first3=Katharine |last4=Banerjee-Basu |first4=Sharmila |last5=Spann |first5=Marisa N. |last6=Whitaker |first6=Agnes H. |last7=Turner |first7=J. Blake |date=2021 |title=Prenatal maternal infection and risk for autism in offspring: A meta-analysis |journal=Autism Research |language=en |volume=14 |issue=6 |pages=1296–1316 |doi=10.1002/aur.2499 |issn=1939-3792 |doi-access=free|pmid=33720503 }}</ref>
=== Environmental agents ===
[[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 name="Waye_2018" /> [[paracetamol]],<ref>{{cite journal | vauthors = Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, García-Esteban R, Galán IR, Tardón A, Rodríguez-Bernal CL, Iñiguez C, Andiarena A, Santa-Marina L, Sunyer J | display-authors = 6 | title = Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms | journal = International Journal of Epidemiology | volume = 45 | issue = 6 | pages = 1987–1996 | date = December 2016 | pmid = 27353198 | doi = 10.1093/ije/dyw115 | doi-access = free }}</ref> [[thalidomide]] or [[misoprostol]].<ref name="Dufour_2011">{{cite journal | vauthors = 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 = Neuroscience and Biobehavioral Reviews | volume = 35 | issue = 5 | pages = 1254–1265 | date = April 2011 | pmid = 21195109 | doi = 10.1016/j.neubiorev.2010.12.013 | type = Review | s2cid = 5180756 }}</ref> These cases are rare.<ref>{{cite journal | vauthors = 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 = International Journal of Developmental Neuroscience | volume = 23 | issue = 2–3 | pages = 201–219 | year = 2005 | pmid = 15749246 | doi = 10.1016/j.ijdevneu.2004.06.007 |s2cid=14248227}}</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="Dufour_2011" /> 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_2005" />
A small
=== Autoimmune and inflammatory diseases ===
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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>{{cite journal | vauthors = Lyall K, Schmidt RJ, Hertz-Picciotto I | title = Maternal lifestyle and environmental risk factors for autism spectrum disorders | journal = International Journal of Epidemiology | volume = 43 | issue = 2 | pages = 443–464 | date = April 2014 | pmid = 24518932 | pmc = 3997376 | doi = 10.1093/ije/dyt282 }}</ref>
[[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>{{cite journal | vauthors = Kinney DK, Munir KM, Crowley DJ, Miller AM | title = Prenatal stress and risk for autism | journal = Neuroscience and Biobehavioral Reviews | volume = 32 | issue = 8 | pages = 1519–1532 | date = October 2008 | pmid = 18598714 | pmc = 2632594 | doi = 10.1016/j.neubiorev.2008.06.004 | type = Review }}</ref>
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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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>{{cite journal | vauthors = 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 | volume = 49 | pages = 82–89 | date = February 2015 | pmid = 25498856 | doi = 10.1016/j.neubiorev.2014.11.020 | s2cid = 8862487 | hdl = 10722/207262 | hdl-access = free }}</ref> There is evidence, for example, that this association may be an artifact of confounding by maternal mental illness.<ref>{{cite journal | vauthors = Brown HK, Hussain-Shamsy N, Lunsky Y, Dennis CE, Vigod SN | title = The Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Systematic Review and Meta-Analysis | journal = The Journal of Clinical Psychiatry | volume = 78 | issue = 1 | pages = e48–e58 | date = January 2017 | pmid = 28129495 | doi = 10.4088/JCP.15r10194 }}</ref>
=== Paracetamol ===▼
[[Paracetamol]] (acetaminophen) use during pregnancy has been suggested as a possible risk factor for autism. A large prospective review of 2,480,797 children published in [[JAMA Pediatrics]] in April 2024 found "acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis".<ref>{{cite journal |last1=Ahlqvist |first1=Viktor H. |last2=Sjöqvist |first2=Hugo |last3=Dalman |first3=Christina |last4=Karlsson |first4=Håkan |last5=Stephansson |first5=Olof |last6=Johansson |first6=Stefan |last7=Magnusson |first7=Cecilia |last8=Gardner |first8=Renee M. |last9=Lee |first9=Brian K. |date=2024 |title=Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability |url=https://jamanetwork.com/journals/jama/article-abstract/2817406#:~:text=Conclusions-,Acetaminophen%20use%20during%20pregnancy%20was%20not%20associated%20with%20children%27s%20risk,Publication%3A%20February%2022%2C%202024 |journal=JAMA |volume=331 |issue=14 |pages=1205–1214 |doi=10.1001/jama.2024.3172 |pmc=11004836 |pmid=38592388}}</ref>
== Perinatal environment ==
Autism is associated with some [[perinatal]] and [[obstetric]] conditions. Infants that are born pre-term often have various neurodevelopmental impairments related to motor skills, cognition, receptive and expressive language, and socio-emotional capabilities.<ref name="Rogers_2018">{{cite journal | vauthors = Rogers CE, Lean RE, Wheelock MD, Smyser CD | title = Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children | journal = Journal of Neurodevelopmental Disorders | volume = 10 | issue = 1 | pages = 38 | date = December 2018 | pmid = 30541449 | pmc = 6291944 | doi = 10.1186/s11689-018-9253-x | eissn = 1866-1955 | doi-access = free }}</ref> Pre-term infants are also at a higher risk of having various neurodevelopmental disorders such as cerebral palsy and autism, as well as psychiatric disorders related to attention, anxiety, and impaired social communication.<ref name="Rogers_2018" /> It has also been proposed that the functions of the hypothalamic-pituitary-adrenal axis and brain connectivity in pre-term infants may be affected by NICU-related stress resulting in deficits in emotional regulation and socio-emotional capabilities.<ref name="Rogers_2018" /> A 2019 analysis of perinatal and neonatal [[risk factors]] found that autism was associated with abnormal fetal positioning, umbilical cord complications, low [[Apgar score|5-minute Apgar]] score, low birth weight and gestation duration, fetal distress, [[meconium aspiration syndrome]], trauma or injury during birth, maternal hemorrhaging, multiple birth, feeding disorders, neonatal anemia, birth defects/malformation, incompatibility with maternal blood type, and [[Hyperbilirubinemia|jaundice/hyperbilirubinemia.]] These associations do not denote a causal relationship for any individual factor.<ref>{{cite journal | vauthors = Gardener H, Spiegelman D, Buka SL | title = Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis | journal = Pediatrics | volume = 128 | issue = 2 | pages = 344–355 | date = August 2011 | pmid = 21746727 | pmc = 3387855 | doi = 10.1542/peds.2010-1036 }}</ref> 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.<ref>{{cite journal | vauthors = Weisskopf MG, Kioumourtzoglou MA, Roberts AL | title = Air Pollution and Autism Spectrum Disorders: Causal or Confounded? | journal = Current Environmental Health Reports | volume = 2 | issue = 4 | pages = 430–439 | date = December 2015 | pmid = 26399256 | pmc = 4737505 | doi = 10.1007/s40572-015-0073-9 | bibcode = 2015CEHR....2..430W }}</ref><ref>{{cite journal | vauthors = Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ | title = Childhood autism spectrum disorders and exposure to nitrogen dioxide, and particulate matter air pollution: A review and meta-analysis | journal = Environmental Research | volume = 151 | issue = | pages = 763–776 | date = November 2016 | pmid = 27609410 | pmc = | doi = 10.1016/j.envres.2016.07.030 | bibcode = 2016ER....151..763F }}</ref> A few studies have found an association between autism and frequent use of acetaminophen (e.g. Tylenol, Paracetamol) by the mother during pregnancy.<ref>{{cite journal | vauthors = Parker W, Hornik CD, Bilbo S, Holzknecht ZE, Gentry L, Rao R, Lin SS, Herbert MR, Nevison CD | display-authors = 6 | title = The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism | journal = The Journal of International Medical Research | volume = 45 | issue = 2 | pages = 407–438 | date = April 2017 | pmid = 28415925 | pmc = 5536672 | doi = 10.1177/0300060517693423 }}</ref><ref>{{cite journal | vauthors = Borchers A, Pieler T | title = Programming pluripotent precursor cells derived from Xenopus embryos to generate specific tissues and organs | journal = Genes | volume = 1 | issue = 3 | pages = 413–426 | date = November 2010 | pmid = 24710095 | doi = 10.3390/e14112227 | pmc = 3966229 | bibcode = 2012Entrp..14.2227S | doi-access = free }}</ref> 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
▲=== Paracetamol ===
=== Amygdala neurons ===
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=== Autoimmune disease ===
This theory hypothesizes that autoantibodies that target the brain or elements of brain metabolism may cause or exacerbate autism. It is related to the [[#Maternal infection|maternal infection]]
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 autism.<ref>{{cite journal | vauthors = Ashwood P, Wills S, Van de Water J | title = The immune response in autism: a new frontier for autism research | journal = Journal of Leukocyte Biology | volume = 80 | issue = 1 | pages = 1–15 | date = July 2006 | pmid = 16698940 | doi = 10.1189/jlb.1205707 | type = Review | s2cid = 17531542 | doi-access = free }}</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>{{cite journal |journal=Res Autism Spectr Disord |volume=3 |issue=4 |year=2009 |pages=840–860 |doi=10.1016/j.rasd.2009.01.007 | vauthors = 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 autism, and are not always present in autism,<ref>{{cite journal | vauthors = Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J | title = Autoantibodies in autism spectrum disorders (ASD) | journal = Annals of the New York Academy of Sciences | volume = 1107 | issue = 1 | pages = 79–91 | date = June 2007 | pmid = 17804535 | doi = 10.1196/annals.1381.009 | type = Review | s2cid = 24708891 | bibcode = 2007NYASA1107...79W }}</ref> the relationship between immune disturbances and autism remains unclear and controversial.<ref>{{cite journal | vauthors = Schmitz C, Rezaie P | title = The neuropathology of autism: where do we stand? | journal = Neuropathology and Applied Neurobiology | volume = 34 | issue = 1 | pages = 4–11 | date = February 2008 | pmid = 17971078 | doi = 10.1111/j.1365-2990.2007.00872.x | type = Review | s2cid = 23551620 }}</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>{{cite journal | vauthors = Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, Mao P | title = Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis | journal = Neuroscience and Biobehavioral Reviews | volume = 55 | pages = 322–332 | date = August 2015 | pmid = 25981892 | doi = 10.1016/j.neubiorev.2015.05.004 | s2cid = 42029820 }}</ref>
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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>{{cite journal | vauthors = Christison GW, Ivany K | title = Elimination diets in autism spectrum disorders: any wheat amidst the chaff? | journal = Journal of Developmental and Behavioral Pediatrics | volume = 27 | issue = 2 Suppl | pages = S162–S171 | date = April 2006 | pmid = 16685183 | doi = 10.1097/00004703-200604002-00015 }}</ref> As of 2021, reliable studies have not demonstrated the benefit of gluten-free diets in the treatment of autism.<ref name="Aranburu_2021">{{cite journal | vauthors = Aranburu E, Matias S, Simón E, Larretxi I, Martínez O, Bustamante MÁ, Fernández-Gil MD, Miranda J | display-authors = 6 | title = Gluten and FODMAPs Relationship with Mental Disorders: Systematic Review | journal = Nutrients | volume = 13 | issue = 6 | pages = 1894 | date = May 2021 | pmid = 34072914 | pmc = 8228761 | doi = 10.3390/nu13061894 | doi-access = free }}</ref><ref name="Quan_2019" /> In the subset of people who have [[Non-celiac gluten sensitivity|gluten sensitivity]] there is limited evidence that suggests that a gluten-free diet may improve some autistic behaviors.<ref name="Aranburu_2021" /><ref name="Quan_2019" />
=== Nutrition-related
There have been multiple attempts to uncover a link between various nutritional deficiencies such as vitamin D and folate and autism risk.<ref name="Modabbernia_2017">{{cite journal | vauthors = Modabbernia A, Velthorst E, Reichenberg A | title = Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses | journal = Molecular Autism | volume = 8 | issue = 1 | pages = 13 | date = 2017-03-17 | pmid = 28331572 | pmc = 5356236 | doi = 10.1186/s13229-017-0121-4 | doi-access = free }}</ref> 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.<ref name="Modabbernia_2017" /> 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.<ref name="Modabbernia_2017" /> 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.<ref name="Modabbernia_2017" /> 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.<ref name="Modabbernia_2017" /><ref>{{cite journal | vauthors = Rossignol DA, Frye RE | title = Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis | journal = Journal of Personalized Medicine | volume = 11 | issue = 11 | pages = 1141 | date = November 2021 | pmid = 34834493 | pmc = 8622150 | doi = 10.3390/jpm11111141 | doi-access = free }}</ref>
=== Toxic
Multiple studies have
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.<ref name="Mercury as a hapten: A review of th"/><ref name="Modabbernia_2017" />
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==Evolutionary explanations==
{{See also|Evolutionary psychology}}
Research exploring the [[evolution]]ary benefits of autism and associated genes suggests that people with autistic traits may have made facilitated crucial advancements in technology and knowledge of natural systems in the course of human development.<ref>{{cite web | vauthors = Spikins P |date=March 27, 2017 |title=How our autistic ancestors played an important role in human evolution |url=https://theconversation.com/how-our-autistic-ancestors-played-an-important-role-in-human-evolution-73477 |website=[[The Conversation (website)|The Conversation]] }}</ref><ref>{{cite book | vauthors = Spikins P |title=Recent Advances in Autism Spectrum Disorders - Volume II |date=March 6, 2013 | veditors = Fitzgerald M |chapter=The Stone Age Origins of Autism}}</ref> It has been suggested that these trait advantages may have resulted from the exchange of socially beneficial traits with ones that promote technological skills and systematic thought processes. In future studies, autism may the shown to be similar to diseases, such as [[Sickle cell disease|sickle cell anemia]], that demonstrate [[balanced polymorphism]].<ref>{{cite journal | vauthors = Lomelin DE |date=2010 |title=An Examination of Autism Spectrum Disorders in Relation to Human Evolution and Life History Theory |url=https://digitalcommons.unl.edu/nebanthro/57/ |journal=Nebraska Anthropologist |volume=57}}</ref>
A 2011 study proposed the "Solitary Forager Hypothesis" in which autistic traits, including increased abilities for spatial intelligence, concentration and memory, could have been [[Natural selection|naturally selected]] to enable self-sufficient [[foraging]] in a more solitary environment.<ref>{{cite journal | vauthors = Reser JE | title = Conceptualizing the autism spectrum in terms of natural selection and behavioral ecology: the solitary forager hypothesis | journal = Evolutionary Psychology | volume = 9 | issue = 2 | pages = 207–238 | date = May 2011 | pmid = 22947969 | doi = 10.1177/147470491100900209 | s2cid = 25378900 | doi-access = free | pmc = 10480880 }}</ref><ref>{{cite web |date=June 3, 2011 |title=Autism may have had advantages in humans' hunter-gatherer past, researcher believes |url=https://www.sciencedaily.com/releases/2011/06/110603122849.htm |website=ScienceDaily }}</ref><ref>{{cite web | vauthors = Rudacille D |date=8 July 2011 |title=Lonely hunters |url=https://www.spectrumnews.org/opinion/lonely-hunters/ |website=Spectrum}}</ref>
Conversely, noting the [[Missing heritability problem|failure to find specific alleles]] that reliably cause autism or [[Mutation rate|rare mutations]] that account for more than 5% of the [[Heritability|heritable variation]] in autism established by [[Twin study|twin]] and [[Adoption study|adoption studies]], research in [[evolutionary psychiatry]] has concluded that it is unlikely that there is or has been [[Evolutionary pressure|selection pressure]] for autism when considering that, [[Evolution of schizophrenia#Balancing Selection and Positive Selection Hypothesis|like schizophrenics]], autistic people and their siblings [[Fitness (biology)|tend to have fewer offspring on average]] than non-autistic people, and instead that autism is probably better explained as a [[Spandrel (biology)|by-product]] of [[Psychological adaptation|adaptive traits]] caused by [[Pleiotropy#Autism and schizophrenia|antagonistic pleiotropy]] and by genes that are retained due to a [[fitness landscape]] with an [[Skewness|asymmetric distribution]].<ref>{{cite book|last=Nesse|first=Randolph M.|author-link=Randolph M. Nesse|year=2019|chapter=14. Minds Unbalanced on Fitness Cliffs|title=Good Reasons for Bad Feelings: Insights from the Frontier of Evolutionary Psychiatry|place=New York|publisher=Dutton|pages=245–261|isbn=978-1101985663}}</ref><ref>{{cite book|last=Nesse|first=Randolph M.|editor-last=Buss|editor-first=David M.|editor-link=David Buss|year=2016|orig-year=2005|chapter=43. Evolutionary Psychology and Mental Health|title=The Handbook of Evolutionary Psychology, Volume 2: Integrations|place=Hoboken, NJ|publisher=Wiley|edition=2nd|pages=1018–1019|isbn=978-1118755808}}</ref><ref>{{cite magazine|last=Nesse|first=Randolph M.|date=March 4, 2019|title=The Puzzle of the Unbalanced Mind|magazine=Psychology Today|url=https://www.psychologytoday.com/us/articles/201903/the-puzzle-the-unbalanced-mind|access-date=October 13, 2024}}</ref>
===Neanderthal theory===
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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 [[Recent African origin of modern humans|Out-of-Africa migration]], and also showed more equal Neanderthal DNA percentages for European and Asian populations.<ref name="Chen Wolf Fu Li Akey">{{cite journal |first1=L. |last1=Chen |first2=A. B. |last2=Wolf |first3=W. |last3=Fu |first4=J. M. |last4=Akey |year=2020 |title=Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals |journal=Cell |volume=180 |issue=4 |pages=677–687.e16 |doi=10.1016/j.cell.2020.01.012 |pmid=32004458 |s2cid=210955842|doi-access=free }}</ref> Such low percentages of Neanderthal DNA in all present day populations indicate infrequent past interbreeding,<ref>{{cite journal |first=S. |last=Pääbo |author-link=Svante Pääbo |title=The diverse origins of the human gene pool |journal=Nature Reviews Genetics |volume=16 |number=6 |pages=313–314 |year=2015 | doi=10.1038/nrg3954 |pmid=25982166 |s2cid=5628263}}</ref> unless interbreeding was more common with a different population of modern humans which did not contribute to the present day gene pool.{{sfn|Reich|2018}} Of the inherited Neanderthal genome, 25% in modern Europeans and 32% in modern East Asians may be related to viral immunity.<ref>{{cite journal |first1=D. |last1=Enard |first2=D. A. |last2=Petrov |year=2018 |title=Evidence that RNA viruses drove of adaptive introgression between Neanderthals and modern humans |journal=Cell |volume=175 |issue=2 |pages=360–371 |doi=10.1016/j.cell.2018.08.034 |pmc=6176737 |pmid=30290142}}</ref> In all, approximately 20% of the Neanderthal genome appears to have survived in the modern human gene pool.<ref name=vernot2014>{{cite journal |title=Resurrecting surviving Neandertal lineages from modern human genomes |journal=Science |volume=343 |issue=6174 |pages=1017–1021 |year=2014 |bibcode=2014Sci...343.1017V |last1=Vernot |first1=B. |last2=Akey |first2=J. M. |doi=10.1126/science.1245938 |pmid=24476670 |s2cid=23003860|doi-access=free }}</ref>
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,<ref name=Zorina-Lichtenwalter2019>{{cite journal |last1=Zorina-Lichtenwalter |first1=K. |last2=Lichtenwalter |first2=R. N. |last3=Zaykin |first3=D. V. |display-authors=et al. |title=A study in scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect |journal=Human Molecular Genetics |year= 2019 |volume=28 |issue=12 |pages=2093–2106 |doi=10.1093/hmg/ddz018 |pmid=30657907 |pmc=6548228 |doi-access=free}}</ref> is primarily found in [[East Asia]]n, rather than European, individuals.<ref name=Ding2014>{{cite journal |last1=Ding |first1=Q. |last2=Hu |first2=Y. |last3=Xu |first3=S. |last4=Wang |first4=C.-C. |last5=Li |first5=H. |last6=Zhang |first6=R. |last7=Yan |first7=S. |last8=Wang |first8=J. |last9=Jin |first9=L.|title=Neanderthal origin of the haplotypes carrying the functional variant Val92Met in the MC1R in modern humans |journal=Molecular Biology and Evolution |year= 2014 |volume=31 |issue=8 |pages=1994–2003 |doi=10.1093/molbev/msu180 |pmid=24916031 |doi-access=free}} "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%)."</ref> Some genes related to the [[immune system]] appear to have been affected by introgression, which may have aided migration,<ref name=Segurel2014>{{cite journal |first1=L. |last1=Ségurel |first2=L. |last2=Quintana-Murci |year=2014 |title=Preserving immune diversity through ancient inheritance and admixture |journal=Current Opinion in Immunology |volume=30 |pages=79–84 |doi=10.1016/j.coi.2014.08.002 |pmid=25190608}}</ref> such as [[OAS1]],<ref name=Mendez2013>{{cite journal |first1=F. L. |last1=Mendez |first2=J. C. |last2=Watkins |first3=M. F. |last3=Hammer |year=2013 |title=Neandertal origin of genetic variation at the cluster of OAS immunity genes |journal=Molecular Biology and Evolution |volume=30 |issue=4 |pages=798–801 |doi=10.1093/molbev/mst004 |pmid=23315957 |s2cid=2839679 |url=http://pdfs.semanticscholar.org/4960/a4cb348c36a636721213898bce2c4fd99e4e.pdf |archive-url=https://web.archive.org/web/20190223155415/http://pdfs.semanticscholar.org/4960/a4cb348c36a636721213898bce2c4fd99e4e.pdf |url-status=dead |archive-date=2019-02-23}}</ref> [[STAT2]],<ref name=Mendez2012>{{cite journal |first1=F. L. |last1=Mendez |first2=J. C. |last2=Watkins |first3=M. F. |last3=Hammer |title=A haplotype at STAT2 introgressed from Neanderthals and serves as a candidate of positive selection in Papua New Guinea |journal=American Journal of Human Genetics |volume=91 |issue=2 |year=2012 |pages=265–274 |doi=10.1016/j.ajhg.2012.06.015 |pmc=3415544 |pmid=22883142}}</ref> [[TLR6]], [[TLR1]], [[TLR10]],<ref name=Dannemann2016>{{cite journal |first1=M. |last1=Dannemann |first2=A. A. |last2=Andrés |first3=J. |last3=Kelso |year=2016 |title=Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human toll-like receptors |journal=American Journal of Human Genetics |volume=98 |issue=1 |pages=22–33 |doi=10.1016/j.ajhg.2015.11.015 |pmc=4716682 |pmid=26748514}}</ref> and several related to [[immune response]].<ref name=Nedelec2016>{{cite journal |first1=Y. |last1=Nédélec |first2=J. |last2=Sanz |first3=G. |last3=Baharian |display-authors=et al. |year=2016 |title=Genetic ancestry and natural selection drive population differences in immune responses to pathogens |journal=Cell |volume=167 |issue=3 |pages=657–669 |doi=10.1016/j.cell.2016.09.025 |pmid=27768889 |doi-access=free}}</ref>{{efn|OAS1<ref name=Mendez2013/> and STAT2<ref name=Mendez2012/> both are associated with fighting viral inflections ([[interferon]]s), and the listed [[toll-like receptor]]s (TLRs)<ref name=Dannemann2016/> allow cells to identify bacterial, fungal, or parasitic pathogens. African origin is also correlated with a stronger inflammatory response.<ref name=Nedelec2016/>}} In addition, Neanderthal genes have also been implicated in the structure and function of the brain,{{efn|Higher levels of Neanderthal-derived genes are associated with an [[occipital bone|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).<ref>{{cite journal |first1=M. D. |last1=Gregory |first2=J. S. |last2=Kippenhan |first3=D. P. |last3=Eisenberg |display-authors=et al. |year=2017 |title=Neanderthal-derived genetic variation shapes modern human cranium and brain |journal=Scientific Reports |volume=7 |issue=1 |page=6308 |doi=10.1038/s41598-017-06587-0 |pmid=28740249 |pmc=5524936 |bibcode=2017NatSR...7.6308G}}</ref>}} [[intermediate filament|keratin filaments]], [[sugar metabolism]], muscle contraction, body fat distribution, enamel thickness and [[oocyte]] [[meiosis]].<ref name=Dolgova2018>{{cite journal |first1=O. |last1=Dolgova |first2=O. |last2=Lao |year=2018 |title=Evolutionary and medical consequences of archaic introgression into modern human genomes |journal=Genes |volume=9 |issue=7 |page=358 |doi=10.3390/genes9070358 |pmc=6070777 |pmid=30022013 |doi-access=free}}</ref> Nonetheless, a large portion of surviving introgression appears to be [[non-coding DNA|non-coding]] ("junk") DNA with few biological functions.{{sfn|Reich|2018}}
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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.<ref>{{cite news |title=Human-Neanderthal Gene Variance is Involved in Autism |url=https://neurosciencenews.com/neuroscience-evolution-genetics-autism-4778/ |access-date=24 March 2024 |publisher=Neuroscience News |date=4 August 2016}}</ref><ref>{{cite news |last1=McCarthy |first1=Michael |title=Human-Neanderthal gene variance is involved in autism |url=https://medicalxpress.com/news/2016-08-human-neanderthal-gene-variance-involved-inautism.html |access-date=24 March 2024 |publisher=Medical Express |date=4 August 2016}}</ref>
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
Another 2017 study that analyzed 68 genes associated with [[neurodevelopmental disorder]]s, including autism, found that these disorders were also affected by [[natural selection]] and interbreeding between ''Homo sapiens'' and other [[archaic human]] species. The study also recommended further research into the link between Neanderthal [[single nucleotide polymorphism]]s (SNPs) and neurodevelopmental disorders, including autism, in modern-day humans.<ref>{{cite journal |last1=Mozzi |first1=Alessandra |last2=Forni |first2=Diego |last3=Cagliani |first3=Rachele |last4=Pozzoli |first4=Uberto |last5=Clerici |first5=Mario |last6=Sironi |first6=Manuela |title=Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders |journal=Scientific Reports |date=21 July 2017 |volume=7 |issue=6116 |page=6116 |doi=10.1038/s41598-017-06440-4 |pmid=28733602 |pmc=5522412 |bibcode=2017NatSR...7.6116M |hdl=2434/554557 |hdl-access=free }}</ref>
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