Causes of autism: Difference between revisions

There are many known environmental, genetic, and biological causes of autism. Research indicates that genetic factors arepredominantly predominantcontribute into theits appearance. of autism; however, theThe [[heritability of autism]] is complex, and many of the genetic interactions involved are unknown.<ref name="Waye_2018" /> In rare cases, autism has been associated with [[Teratology|agents that cause birth defects]].<ref name="Arndt_2005">{{cite journal |vauthors=Arndt TL, Stodgell CJ, Rodier PM |year=2005 |title=The teratology of autism |journal=International Journal of Developmental Neuroscience |type=Review |volume=23 |issue=2–3 |pages=189–199 |doi=10.1016/j.ijdevneu.2004.11.001 |pmid=15749245 |s2cid=17797266}}</ref> Many other causes have been proposed.

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> However, there is overwhelmingOverwhelming [[scientific evidence]] showing that there isshows no causal association between the [[MMR vaccine controversy|measles-mumps-rubella (MMR) vaccine and autism]]. Although there is no definitive evidence that the vaccine preservative [[Thiomersal controversy|thimerosal]] causes autism, studies have indicated a possible link between thimerosal and autism in individuals with a hereditary predisposition for autoimmune disorders.<ref name="Di_Pietrantonj_2021">{{cite journal | vauthors = Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V | title = Vaccines for measles, mumps, rubella, and varicella in children | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 11 | pages = CD004407 | date = November 2021 | pmid = 34806766 | pmc = 8607336 | doi = 10.1002/14651858.CD004407.pub5 | collaboration = Cochrane Acute Respiratory Infections Group }}</ref><ref name="Mercury as a hapten: A review of th">{{cite journal | vauthors = Kern JK, Geier DA, Mehta JA, Homme KG, Geier MR | title = Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations | journal = Journal of Trace Elements in Medicine and Biology | volume = 62 | pages = 126504 | date = December 2020 | pmid = 32534375 | doi = 10.1016/j.jtemb.2020.126504 | bibcode = 2020JTEMB..6226504K | s2cid = 219468115 }}</ref> In 2007, the [[Centers for Disease Control and Prevention|Center for Disease Control]] stated there was no support for a link between thimerosal and autism, citing evidence from several studies, as well as a continued increase in autism cases following the removal of thimerosal from childhood vaccines.<ref>{{cite web |title=Timeline: Thimerosal in Vaccines (1999-2010) |url=https://www.cdc.gov/vaccinesafety/concerns/thimerosal/timeline.html |access-date=2024-04-24 |website=CDC|date=19 August 2020 }}</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 |url=https://pubmed.ncbi.nlm.nih.gov/31378642/ |journal=Journal of the Formosan Medical Association = Taiwan Yi Zhi |volume=119 |issue=1 Pt 3 |pages=516–523 |doi=10.1016/j.jfma.2019.07.015 |issn=0929-6646 |pmid=31378642|doi-access=free }}</ref> Since autism manifests in the early developmental period, sleep apnea in Down's Syndrome and other genetic syndromes such as Fragile X start early (at infancy or shortly after), and sleep disturbances alter brain development,<ref>{{Cite journal |last1=Lord |first1=Julia S. |last2=Gay |first2=Sean M. |last3=Harper |first3=Kathryn M. |last4=Nikolova |first4=Viktoriya D. |last5=Smith |first5=Kirsten M. |last6=Moy |first6=Sheryl S. |last7=Diering |first7=Graham H. |date=2022-08-29 |title=Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice |journal=Molecular Autism |volume=13 |issue=1 |pages=35 |doi=10.1186/s13229-022-00514-5 |doi-access=free |issn=2040-2392 |pmc=9425965 |pmid=36038911}}</ref> it's plausible that some of the neurodevelopmental differences seen in these genetic syndromes are at least partially caused by the effects of untreated sleep apnea.

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 |lastlast1=Tioleco |firstfirst1=Nina |last2=Silberman |first2=Anna E. |last3=Stratigos |first3=Katharine |last4=Banerjee‐BasuBanerjee-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 |url=https://onlinelibrary.wiley.com/doi/full/10.1002/aur.2499meta-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>

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.

Multiple studies have made attemptsattempted to study the relationship between toxic exposure and autism. However, these studies often met withdespite limitations related to the measurement of toxic exposure the methods for which were often indirect and cross-sectional. Systematic reviews have been conducted for numerous toxins including air pollution, thimerosal, inorganic mercury, and levels of heavy metals in hair, nails, and bodily fluids.<ref name="Modabbernia_2017" />

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> However, theThe author notes that such individuals likely foraged by themselves while occasionally interacting with intimate people or groups. A study conducted by Spikins et al. (2016) examined the role of Asperger syndrome as "an alternative [[pro-social]] adaptive strategy", which may have developed as a result of the emergence of "collaborative morality" in the context of small-scale [[hunter-gathering]]. The authors further suggest that "mutual interdependence of different social strategies" may have "contributed to the rise of innovation and large scale social networks".<ref>{{cite journal | vauthors = Spikins P, Wright B, Hodgson D |date=1 October 2016 |title=Are there alternative adaptive strategies to human pro-sociality? The role of collaborative morality in the emergence of personality variation and autistic traits |journal=Time and Mind |volume=9 |issue=4 |pages=289–313 |doi=10.1080/1751696X.2016.1244949 |issn=1751-696X |s2cid=151820168|doi-access=free }}</ref>

However, dueDue to their small population and resulting reduced effectivity of natural selection, Neanderthals accumulated several weakly harmful mutations, which were introduced to and slowly selected out of the much larger modern human population; the initial hybridised population may have experienced up to a 94% reduction in fitness compared to contemporary humans. By this measure, Neanderthals may have substantially increased in fitness.<ref name=juric>{{cite journal |first1=I. |last1=Juric |first2=S. |last2=Aeschbacher |first3=G. |last3=Coop |year=2016 |title=The strength of selection against Neanderthal introgression |journal=PLOS Genetics |volume=12 |issue=11 |pages=e1006340 |doi=10.1371/journal.pgen.1006340 |pmid=27824859 |pmc=5100956 |doi-access=free }}</ref> A 2017 study focusing on archaic genes in Turkey found associations with [[coeliac disease]], [[malaria]] severity and [[Costello syndrome]].<ref>{{cite journal |first1=R. O. |last1=Taskent |first2=N. D. |last2=Alioglu |first3=E. |last3=Fer |display-authors=et al. |year=2017 |title=Variation and functional impact of Neanderthal ancestry in Western Asia |journal=Genome Biology and Evolution |volume=9 |issue=12 |pages=3516–3624 |doi=10.1093/gbe/evx216 |pmc=5751057 |pmid=29040546}}</ref>