Editing Rett syndrome (section)

==Cause==
Genetically, Rett syndrome (RTT) is often caused by mutations in the gene [[MECP2]]<ref name=":4">{{Cite journal |last1=Neul |first1=Jeffrey L. |last2=Kaufmann |first2=Walter E. |last3=Glaze |first3=Daniel G. |last4=Christodoulou |first4=John |last5=Clarke |first5=Angus J. |last6=Bahi-Buisson |first6=Nadia |last7=Leonard |first7=Helen |last8=Bailey |first8=Mark E. S. |last9=Schanen |first9=N. Carolyn |last10=Zappella |first10=Michele |last11=Renieri |first11=Alessandra |last12=Huppke |first12=Peter |last13=Percy |first13=Alan K. |date=2010 |title=Rett Syndrome: Revised Diagnostic Criteria and Nomenclature |journal=Annals of Neurology |volume=68 |issue=6 |pages=944–950 |doi=10.1002/ana.22124 |issn=0364-5134 |pmc=3058521 |pmid=21154482}}</ref> located on the X chromosome (which is involved in [[transcriptional silencing]] and [[epigenetic regulation]] of [[methylated DNA]]), and can arise sporadically or from [[germline mutations]]. In less than 10% of RTT cases, mutations in the genes [[CDKL5]] or [[FOXG1]] have also been found to resemble it.<ref>{{Cite journal |last1=Fahmi |first1=Muhamad |last2=Yasui |first2=Gen |last3=Seki |first3=Kaito |last4=Katayama |first4=Syouichi |last5=Kaneko-Kawano |first5=Takako |last6=Inazu |first6=Tetsuya |last7=Kubota |first7=Yukihiko |last8=Ito |first8=Masahiro |date=2019 |title=In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment |journal=International Journal of Molecular Sciences |language=en |volume=20 |issue=22 |pages=5593 |doi=10.3390/ijms20225593 |doi-access=free |issn=1422-0067 |pmc=6888432 |pmid=31717404}}</ref><ref>{{Cite journal |last1=Cutri-French |first1=Clare |last2=Armstrong |first2=Dallas |last3=Saby |first3=Joni |last4=Gorman |first4=Casey |last5=Lane |first5=Jane |last6=Fu |first6=Cary |last7=Peters |first7=Sarika U |last8=Percy |first8=Alan |last9=Neul |first9=Jeffrey L |last10=Marsh |first10=Eric D |date=2020 |title=Comparison of core features in four Developmental Encephalopathies in the Rett Natural History Study |journal=Annals of Neurology |volume=88 |issue=2 |pages=396–406 |doi=10.1002/ana.25797 |issn=0364-5134 |pmc=8882337 |pmid=32472944}}</ref> Rett syndrome is initially diagnosed by clinical observation, and is commonly associated with a genetic defect in the MECP2 gene.<ref name=":4" />

A 2021 study by scholars based at Scottish universities states that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults. This information has also helped lead to further studies aiming to treat the disorder.<ref>{{Cite journal |last1=Guy |first1=J. |last2=Gan |first2=J. |last3=Selfridge |first3=J. |last4=Cobb |first4=S. |last5=Bird |first5=A. |year=2007 |title=Reversal of Neurological Defects in a Mouse Model of Rett Syndrome |journal=[[Science (journal)|Science]] |volume=315 |issue=5815 |pages=1143–7 |doi=10.1126/science.1138389 |pmid=17289941|bibcode=2007Sci...315.1143G |s2cid=25172134 |pmc=7610836 }}</ref>

===Sporadic mutations===

In at least 95% of Rett syndrome cases, the cause is a [[De_novo_mutation|''de novo'' mutation]] in the child, almost exclusively from a de novo mutation on the male copy of the X chromosome.<ref>{{Cite journal |last1=Trappe |first1=R. |last2=Laccone |first2=F. |last3=Cobilanschi |first3=J. |last4=Meins |first4=M. |last5=Huppke |first5=P. |last6=Hanefeld |first6=F. |last7=Engel |first7=W. |year=2001 |title=MECP2 Mutations in Sporadic Cases of Rett Syndrome Are Almost Exclusively of Paternal Origin |journal=[[The American Journal of Human Genetics]] |volume=68 |issue=5 |pages=1093–101 |doi=10.1086/320109 |pmc=1226090 |pmid=11309679}}</ref><ref>{{Cite web |title=Rett Syndrome - Symptoms, Causes, Treatment {{!}} NORD |url=https://rarediseases.org/rare-diseases/rett-syndrome/ |access-date=5 February 2024 |website=rarediseases.org |language=en-US}}</ref> It is not yet known what causes the sperm to mutate, and such mutations are rare.

===Germline mutations===
It can also be inherited from phenotypically normal mothers who have a [[germline]] mutation in the gene encoding ''methyl-CpG-binding protein-2'', [[MeCP2]].<ref>{{Cite journal |last1=Zoghbi |first1=Huda Y. |last2=Van Den Veyver |first2=Ruthie E. |last3=Wan |first3=Ignatia B. |last4=Tran |first4=Mimi |last5=Francke |first5=Charles Q. |last6=Zoghbi |first6=Uta |s2cid=3350350 |year=1999 |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=185–8 |doi=10.1038/13810 |pmid=10508514}}</ref> In these cases, inheritance follows an [[X-linked dominant inheritance|X-linked dominant]] pattern and is seen almost exclusively in females, as most males die ''[[Uterus|in utero]]'' or shortly after birth.<ref>{{Cite web |url=https://ghr.nlm.nih.gov/condition/rett-syndrome#inheritance |title=Rett syndrome |website=Genetics Home Reference |archive-url=https://web.archive.org/web/20160727231653/https://ghr.nlm.nih.gov/condition/rett-syndrome#inheritance |archive-date=27 July 2016 |url-status=live |access-date=29 May 2016}}</ref> MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of RTT, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding ''cyclin-dependent kinase-like 5'' ([[CDKL5]]). As stated by [[Aine Merwick]], [[Margaret O'Brien]], and [[Norman Delanty]] in an article on gene disorders titled ''Complex single gene disorders and epilepsy'', "Rett syndrome affects one in every 12,500 female live births by age 12 years."<ref>{{Cite journal|last1=Merwick|first1=Aine|last2=O'Brien|first2=Margaret|last3=Delanty|first3=Norman|year=2012|title=Complex single gene disorders and epilepsy|journal=Epilepsia|language=en|volume=53|issue=s4|pages=81–91|doi=10.1111/j.1528-1167.2012.03617.x|pmid=22946725|s2cid=37226510|issn=1528-1167|doi-access=free}}</ref>