Editing Rett syndrome

{{Short description|Genetic brain disorder}}
{{Distinguish|Tourette syndrome}}
{{Use dmy dates|date=July 2024}}
{{Use American English|date=December 2017}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox medical condition (new)
| name = Rett syndrome
| synonyms = Cerebroatrophic hyperammonemia (''obsolete''),<ref>{{cite book|title=Handbook of Pediatric Neuropsychology|first=Andrew S.|last=Davis|date=25 October 2010|publisher=[[Springer Publishing Company]]|isbn=978-0826157362|quote=Rett initially called this syndrome cerebroaatrophic hyperammonemia, but the elevated ammonia levels in the bloodstream were later found to be only rarely associated with this condition (can Acker, Loncola, & Can Acker, 2005).|url-status=live|archive-url=https://web.archive.org/web/20171105195823/https://books.google.com/books?id=SU9-LSh4HgcC&pg=PT703|url=https://books.google.com/books?id=SU9-LSh4HgcC&pg=PT703|archive-date=5 November 2017|page=703}}</ref><ref>{{cite journal | doi=10.1155/2014/345270 | title=Rett Syndrome: Coming to Terms with Treatment | date=2014 | last1=Percy | first1=Alan | journal=Advances in Neuroscience | volume=2014 | pages=1–20 | doi-access=free }}</ref> dementia, ataxia, and loss of purposeful hand use syndrome<ref>{{cite web |title=MeSH Browser |url=https://meshb.nlm.nih.gov/record/ui?ui=D015518 |website=meshb.nlm.nih.gov |access-date=22 October 2019 |archive-date=4 December 2020 |archive-url=https://web.archive.org/web/20201204072904/https://meshb.nlm.nih.gov/record/ui?ui=D015518 |url-status=live}}</ref>
| image = Rett Girl Smiling.jpg
| caption = A girl with Rett syndrome
| image_size = 225px
| alt = A girl with short brown hair sits in a neon orange pushchair.
| field = [[Psychiatry]], [[clinical psychology]], [[pediatrics]], [[neurology]]
| symptoms = Impairments in language and coordination, and repetitive movements, slower growth, [[microcephaly|smaller head]]<ref name=GHR2013/>
| complications = [[Seizures]], [[scoliosis]], [[sleeping problems]]<ref name=GHR2013/>
| onset = After 6–18 months of age<ref name=GHR2013/>
| duration = Lifelong<ref name=NIH2017/>
| types = 
| causes = Mutation in the [[MECP2]] gene<ref name=GHR2013/>
| risks = 
| diagnosis = Based on symptoms, [[genetic testing]]<ref name=NIH2017/>
| differential = [[Angelman syndrome]], [[autism]], [[cerebral palsy]], [[childhood disintegrative disorder]], various [[Neurodegeneration|neurodegenerative disorder]]s<ref name=NORD2015>{{cite web|title=Rett Syndrome|url=https://rarediseases.org/rare-diseases/rett-syndrome/|website=NORD (National Organization for Rare Disorders)|access-date=14 October 2017|year=2015|url-status=live|archive-url=https://web.archive.org/web/20170219085529/https://rarediseases.org/rare-diseases/rett-syndrome/|archive-date=19 February 2017}}</ref>
| prevention = 
| treatment = [[Special education]], physiotherapy, braces<ref name=NIH2017/>
| medication = [[Anticonvulsant]]s<ref name=NIH2017/>
| prognosis = Life expectancy for many is middle age.<ref name=NIH2017/>
| frequency = 1 in 8,500 females<ref name=GHR2013/><br/>Lethal in males, with rare exceptions.
| deaths = 
}}
<!-- Definition and symptoms -->
'''Rett syndrome''' ('''RTT''') is a [[genetic disorder]] that typically becomes apparent after 6–18 months of age and almost exclusively in girls.<ref name=GHR2013>{{cite web|title=Rett syndrome|url=https://ghr.nlm.nih.gov/condition/rett-syndrome|website=Genetics Home Reference|access-date=14 October 2017|language=en|date=December 2013|url-status=live|archive-url=https://web.archive.org/web/20171014183826/https://ghr.nlm.nih.gov/condition/rett-syndrome|archive-date=14 October 2017}}</ref> Symptoms include impairments in language and coordination, and repetitive movements.<ref name=GHR2013/> Those affected often have slower growth, difficulty walking, and a [[microcephaly|smaller head size]].<ref name=GHR2013/><ref name=NIH2017>{{cite web|title=Rett Syndrome Fact Sheet|url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Rett-Syndrome-Fact-Sheet|website=National Institute of Neurological Disorders and Stroke|access-date=14 October 2017|url-status=live|archive-url=https://web.archive.org/web/20171014183306/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Rett-Syndrome-Fact-Sheet|archive-date=14 October 2017}}</ref> Complications of Rett syndrome can include [[seizures]], [[scoliosis]], and [[sleeping problems]].<ref name=GHR2013/> The severity of the condition is variable.<ref name=NIH2017/>

<!-- Cause and diagnosis -->
Rett syndrome is due to a genetic mutation in the ''[[MECP2]]'' gene,<ref name=GHR2013/> on the [[X chromosome]].<ref name=NIH2017/> It almost always occurs as a new mutation, with less than one percent of cases being inherited.<ref name=GHR2013/><ref name=NIH2017/> It occurs almost exclusively in girls;<ref name=GHR2013/> boys who have a similar mutation typically die shortly after birth.<ref name=NIH2017/> Diagnosis is based on the symptoms and can be confirmed with [[genetic testing]].<ref name=NIH2017/>

<!-- Treatment and prognosis -->
There is no known cure for Rett syndrome.<ref name=NIH2017/> Treatment is directed at improving symptoms.<ref name=NIH2017/> [[Anticonvulsant]]s may be used to help with seizures.<ref name=NIH2017/> [[Special education]], [[Physical therapy|physiotherapy]], and leg braces may also be useful depending on the needs of the child.<ref name=NIH2017/> Many of those with the condition live into middle age.<ref name=NIH2017/>

<!-- Epidemiology -->
The condition affects about 1 in 8,500 females.<ref name=GHR2013/>  In 1999, Lebanese-American physician [[Huda Zoghbi]] discovered the mutation that causes the condition.<ref name="Per2013">{{Cite journal |last=Percy |first=Alan |date=January 2014 |title=The American History of Rett Syndrome |journal=Pediatric Neurology |volume=50 |issue=1 |pages=1–3 |doi=10.1016/j.pediatrneurol.2013.08.018|pmid=24200039 |pmc=3874243}}</ref><ref name=Huda1999>{{cite journal | doi=10.1038/13810 | title=Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 | year=1999 | last1=Amir | first1=Ruthie | last2=Van den Veyver | first2=Ignatia | last3=Wan | first3=Mimi | last4=Tran | first4=Charles | last5=Francke | first5=Uta | last6=Zoghbi | first6=Huda | s2cid=3350350 | journal=Nature Genetics | volume=23 | issue=2 | pages=185–8 | pmid=10508514}}</ref>

==Signs and symptoms==
===Stage I===
Stage I, called early-onset, typically begins between 6 and 18 months of age.<ref name=NIH2017/> This stage is often overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first.<ref name=NIH2017/> The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling.<ref name=NIH2017/> Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year.<ref name=NIH2017/>

===Stage II===
Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months.<ref name=NIH2017/> Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language.<ref name=NIH2017/> Characteristic hand movements such as wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth often begin during this stage which is called mouthing.<ref name=NIH2017/> The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing.<ref name=NIH2017/> The movements continue while the child is awake but disappear during sleep.<ref name=NIH2017/> Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep.<ref name=NIH2017/> Some girls also display autistic-like symptoms such as loss of social interaction and communication.<ref name=NIH2017/> Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage.<ref name=NIH2017/>

===Stage III===
Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years.<ref name=NIH2017/> [[Apraxia]], motor problems, and [[seizure]]s are prominent during this stage.<ref name=NIH2017/> However, there may be improvement in behavior, with less irritability, crying, and [[autistic]]-like features.<ref name=NIH2017/> In stage III there may be more interest in the surroundings and alertness, attention span, and communication skills may improve.<ref name=NIH2017/> Many girls remain in this stage for most of their lives.<ref name=NIH2017/>

===Stage IV===
Stage IV, or the late motor deterioration stage, can last for years or decades.<ref name=NIH2017/> Prominent features include reduced mobility, [[scoliosis|curvature of the spine]], and muscle weakness, rigidity, spasticity, and increased muscle tone with abnormal posturing of an arm or leg.<ref name=NIH2017/> Girls who were previously able to walk may stop walking.<ref name=NIH2017/> Cognition, communication, or hand skills generally do not decline in stage IV.<ref name=NIH2017/> Repetitive hand movements may decrease and eye gaze usually improves.<ref name=NIH2017/>

===Variants===
The signs and symptoms of the typical form of the Rett syndrome are well described.
In addition to the classical form of Rett syndrome, several atypical forms have been described over the years;<ref>{{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 |year=2010 |title=Rett syndrome: Revised diagnostic criteria and nomenclature |journal=Annals of Neurology |volume=68 |issue=6 |pages=944–50 |doi=10.1002/ana.22124 |pmc=3058521 |pmid=21154482 |last10=Zappella |first10=Michele |last11=Renieri |first11=Alessandra |last12=Huppke |first12=Peter |last13=Percy |first13=Alan K. |collaboration=Rettsearch Consortium}}</ref> the main groups are:
* Congenital variant (Rolando variant): in this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth.<ref>{{Cite journal |last1=Ariani |first1=Francesca |last2=Hayek |first2=Giuseppe |last3=Rondinella |first3=Dalila |last4=Artuso |first4=Rosangela |last5=Mencarelli |first5=Maria Antonietta |last6=Spanhol-Rosseto |first6=Ariele |last7=Pollazzon |first7=Marzia |last8=Buoni |first8=Sabrina |last9=Spiga |first9=Ottavia |date=11 July 2008 |title=FOXG1 is Responsible for the Congenital Variant of Rett Syndrome |journal=The American Journal of Human Genetics |volume=83 |issue=1 |pages=89–93 |doi=10.1016/j.ajhg.2008.05.015 |pmc=2443837 |pmid=18571142 |last10=Ricciardi |first10=Sara |last11=Meloni |first11=Ilaria |last12=Longo |first12=Ilaria |last13=Mari |first13=Francesca |last14=Broccoli |first14=Vania |last15=Zappella |first15=Michele |last16=Renieri |first16=Alessandra}}</ref> The typical gaze of Rett syndrome patients is usually absent;
* [[Michele Zappella|Zappella]] variant of Rett Syndrome or preserved speech variant: in this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed.<ref>{{Cite journal |last=Zappella |first=Michele |s2cid=4782923 |year=1992 |title=The rett girls with preserved speech |journal=Brain and Development |volume=14 |issue=2 |pages=98–101 |doi=10.1016/S0387-7604(12)80094-5 |pmid=1621933}}</ref><ref>{{Cite journal |last1=Skjeldal |first1=O. H. |last2=Von Tetzchner |first2=S. |last3=Jacobsen |first3=K. |last4=Smith |first4=L. |last5=Heiberg |first5=A. |year=2007 |title=Rett Syndrome - Distribution of Phenotypes with Special Attention to the Preserved Speech Variant |journal=Neuropediatrics |volume=26 |issue=2 |pages=87 |doi=10.1055/s-2007-979732 |pmid=7566462|s2cid=260243402 }}</ref><ref>{{Cite journal |last1=Sørensen |first1=E. |last2=Viken |first2=B. |date=20 February 1995 |title=[Rett syndrome a developmental disorder. Presentation of a variant with preserved speech] |journal=Tidsskrift for den Norske Laegeforening |language=no |volume=115 |issue=5 |pages=588–590 |issn=0029-2001 |pmid=7900110}}</ref><ref>{{Cite journal |last=Zappella |first=M |year=1997 |title=The preserved speech variant of the Rett complex: A report of 8 cases |journal=[[European Child & Adolescent Psychiatry]] |volume=6 |issue=Suppl 1 |pages=23–5 |pmid=9452915}}</ref><ref>{{Cite journal |last1=Renieri |first1=A. |last2=Mari |first2=F. |last3=Mencarelli |first3=M.A. |last4=Scala |first4=E. |last5=Ariani |first5=F. |last6=Longo |first6=I. |last7=Meloni |first7=I. |last8=Cevenini |first8=G. |last9=Pini |first9=G. |date=March 2009 |title=Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant) |journal=Brain and Development |volume=31 |issue=3 |pages=208–16 |doi=10.1016/j.braindev.2008.04.007 |pmid=18562141 |last10=Hayek |first10=G. |last11=Zappella |first11=M.|s2cid=6223422 }}</ref><ref>{{Cite journal |last1=Buoni |first1=Sabrina |last2=Zannolli |first2=Raffaella |last3=De Felice |first3=Claudio |last4=De Nicola |first4=Anna |last5=Guerri |first5=Vanessa |last6=Guerra |first6=Beatrice |last7=Casali |first7=Stefania |last8=Pucci |first8=Barbara |last9=Corbini |first9=Letizia |date=May 2010 |title=EEG features and epilepsy in MECP2-mutated patients with the Zappella variant of Rett syndrome |journal=[[Clinical Neurophysiology (journal)|Clinical Neurophysiology]] |volume=121 |issue=5 |pages=652–7 |doi=10.1016/j.clinph.2010.01.003 |pmid=20153689 |last10=Mari |first10=Francesca |last11=Renieri |first11=Alessandra |last12=Zappella |first12=Michele |last13=Hayek |first13=Joseph|s2cid=12976926 }}</ref> The Zappella variant is a milder form of Rett syndrome;
* Hanefeld variant or early epilepsy variant. In this form of Rett syndrome, the patients have epilepsy before 5 months of age.<ref>{{cite journal |doi=10.1016/S0387-7604(03)00018-4 |title=The spectrum of phenotypes in females with Rett Syndrome |year=2003 |last1=Huppke |first1=Peter |last2=Held |first2=Melanie |last3=Laccone |first3=Franco |last4=Hanefeld |first4=Folker |s2cid=9566219 |journal=Brain and Development |volume=25 |issue=5 |pages=346–51 |pmid=12850514}}</ref>
The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form (Hagberg & Gillberg, 1993), the "Rett Complex" terminology has been introduced.<ref>{{Cite journal |last=Gillberg |first=d. |year=1997 |title=Communication in Rett syndrome complex |journal=[[European Child & Adolescent Psychiatry]] |volume=6 |issue=Suppl 1 |pages=21–2 |pmid=9452914}}</ref><ref>{{Cite journal |last1=Zappella |first1=Michele |last2=Gillberg |first2=Christopher |last3=Ehlers |first3=Stephan |s2cid=22152062 |year=1998 |title=The preserved speech variant: A subgroup of the Rett complex: A clinical report of 30 cases |journal=Journal of Autism and Developmental Disorders |volume=28 |issue=6 |pages=519–26 |doi=10.1023/A:1026052128305 |pmid=9932238}}</ref>

==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>

==Mechanism==
[[File:X Rett.PNG|thumb|The location of the gene responsible for Rett syndrome]]

===Pontine noradrenergic deficits===
Brain levels of [[norepinephrine]] are lower in people with Rett syndrome<ref>{{cite journal |doi=10.1002/ana.410250109 |title=Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome |year=1989 |last1=Zoghbi |first1=Huda Y. |last2=Milstien |first2=Sheldon |last3=Butler |first3=Ian J. |last4=Smith |first4=E. O'Brian |last5=Kaufman |first5=Seymour |last6=Glaze |first6=Daniel G. |last7=Percy |first7=Alan K. |journal=Annals of Neurology |volume=25 |pages=56–60 |pmid=2913929 |issue=1|s2cid=351243 }}</ref> (reviewed in<ref name="Roux JC">{{cite journal |doi=10.1007/s10519-009-9303-y |title=Biogenic Amines in Rett Syndrome: The Usual Suspects |year=2009 |last1=Roux |first1=Jean-Christophe |last2=Villard |first2=Laurent |s2cid=20352177 |journal=Behavior Genetics |volume=40 |pages=59–75 |pmid=19851857 |issue=1}}</ref>). The genetic loss of ''MECP2'' changes the properties of cells in the [[locus coeruleus]], the exclusive source of noradrenergic innervation to the [[cerebral cortex]] and [[hippocampus]].<ref name="Hokfelt">{{Cite book |title=Handbook of Chemical Neuroanatomy |last1=Hokfelt |first1=T. |last2=Martensson |first2=R. |last3=Bjorklund |first3=A. |last4=Kleinau |first4=S. |last5=Goldstein |first5=M |publisher=Elsevier |year=1984 |editor-last=Bjorklund |editor-first=A. |series=Classical Transmitters in the CNS, Part I |volume=2 |location=New York |pages=277–379 |chapter=Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain |editor-last2=Hokfelt |editor-first2=T.}}</ref><ref name="Berridge">{{cite journal |doi=10.1016/S0165-0173(03)00143-7 |title=The locus coeruleus–noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes |year=2003 |last1=Berridge |first1=Craig W |last2=Waterhouse |first2=Barry D |s2cid=477754 |journal=Brain Research Reviews |volume=42 |pages=33–84 |pmid=12668290 |issue=1}}</ref> These changes include hyperexcitability and decreased functioning of its noradrenergic innervation.<ref name="Taneja">{{cite journal |doi=10.1523/JNEUROSCI.3156-09.2009 |title=Pathophysiology of Locus Ceruleus Neurons in a Mouse Model of Rett Syndrome |year=2009 |last1=Taneja |first1=P. |last2=Ogier |first2=M. |last3=Brooks-Harris |first3=G. |last4=Schmid |first4=D. A. |last5=Katz |first5=D. M. |last6=Nelson |first6=S. B. |journal=Journal of Neuroscience |volume=29 |issue=39 |pages=12187–95 |pmid=19793977 |pmc=2846656}}</ref> Moreover, a reduction of the [[tyrosine hydroxylase]] (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole [[pons]] of ''MECP2''-null male as well as in adult heterozygous (''MECP2''+/-) female mice.<ref name="Roux">{{cite journal |doi=10.1002/jnr.22312 |title=Progressive noradrenergic deficits in the locus coeruleus of Mecp2 deficient mice |year=2009 |last1=Roux |first1=Jean-Christophe |last2=Panayotis |first2=Nicolas |last3=Dura |first3=Emmanuelle |last4=Villard |first4=Laurent |journal=Journal of Neuroscience Research |pmid=19998492 |pages=1500–9 |volume=88 |issue=7|s2cid=3404695 }}</ref> Using immunoquantitative techniques, a decrease of Th protein staining level, number of locus coeruleus Th-expressing neurons and density of [[dendritic arborization]] surrounding the structure was shown in symptomatic ''MeCP2''-deficient mice.<ref name="Roux" /> However, locus coeruleus cells are not dying, but are more likely losing their fully mature phenotype, since no apoptotic neurons in the pons were detected.<ref name="Roux" />

Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of ''MECP2'' results in CNS dysfunction." The restoration of normal locus coeruleus function may therefore be of potential therapeutic value in the treatment of Rett syndrome.<ref name="Taneja" /><ref name="Roux" />

===Midbrain dopaminergic disturbances===
The majority of [[dopamine]] in the mammalian brain is synthesized by nuclei located in the [[mesencephalon]]. The [[substantia nigra]] pars compacta (SNpc), the [[ventral tegmental area]] (VTA) and the [[retrorubral field]] (RRF) contain dopaminergic neurons expressing tyrosine hydroxylase (Th, i.e. the rate-limiting enzyme in catecholamine synthesis).<ref>{{Cite book |title=Handbook of Chemical Neuroanatomy |last1=Björklund |first1=A. |last2=Lindvall |first2=O |publisher=Elsevier |year=1984 |editor-last=Björklund |editor-first=A. |series=Classical Transmitters in the CNS, Part l |volume=2 |location=New York |pages=55–122 |chapter=Dopamine-containing systems in the CNS |editor-last2=Hökfelt |editor-first2=T.}}</ref><ref>{{Cite book |title=Handbook of Chemical Neuroanatomy |last1=Hokfelt |first1=T. |last2=Martensson |first2=R. |last3=Björklund |first3=A. |last4=Kleinau |first4=S. |last5=Goldstein |first5=M. |publisher=Elsevier |year=1984 |editor-last=Björklund |editor-first=A. |series=Classical Transmitters in the CNS, Part I |volume=2 |location=New York |pages=277–379 |chapter=Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain |editor-last2=Hökfelt |editor-first2=T.}}</ref><ref>{{Cite journal |last1=Björklund |first1=Anders |last2=Dunnett |first2=Stephen B. |s2cid=14239716 |year=2007 |title=Dopamine neuron systems in the brain: An update |journal=Trends in Neurosciences |volume=30 |issue=5 |pages=194–202 |doi=10.1016/j.tins.2007.03.006 |pmid=17408759}}</ref>

The nigro-striatal pathway originates from the SNpc; its principal rostral target is the caudate-putamen (CPu), which it irradiates through the median forebrain bundle (MFB). This connection is involved in the tight modulation of motor strategies computed by a cortico-basal ganglia-thalamo-cortical loop.<ref>{{cite journal |doi=10.1016/0165-0173(94)00007-C |title=Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop |year=1995 |last1=Parent |first1=André |last2=Hazrati |first2=Lili-Naz |s2cid=28252990 |journal=Brain Research Reviews |volume=20 |pages=91–127 |pmid=7711769 |issue=1}}</ref>

Indeed, based on the canonical anatomofunctional model of basal ganglia, nigrostriatal dopamine is able to modulate the motor loop by acting on dopaminergic receptors located on striatal GABAergic medium spiny neurons.<ref>{{Cite journal |last=Gerfen |first=Charles R. |s2cid=3965480 |year=2000 |title=Molecular effects of dopamine on striatal-projection pathways |journal=Trends in Neurosciences |volume=23 |issue=10 Suppl |pages=S64–70 |doi=10.1016/S1471-1931(00)00019-7 |pmid=11052222}}</ref>

Dysregulation of the nigrostriatal pathway is causative from Parkinson disease (PD) in humans.<ref>{{cite journal |doi=10.1016/S0140-6736(09)60492-X |title=Parkinson's disease |year=2009 |last1=Lees |first1=Andrew J |last2=Hardy |first2=John |last3=Revesz |first3=Tamas |s2cid=42608600 |journal=The Lancet |volume=373 |issue=9680 |pages=2055–66 |pmid=19524782}}</ref> Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates.<ref>{{cite journal |doi=10.1016/S0896-6273(03)00568-3 |title=Parkinson's Disease |year=2003 |last1=Dauer |first1=William |last2=Przedborski |first2=Serge |s2cid=10400095 |journal=Neuron |volume=39 |issue=6 |pages=889–909 |pmid=12971891|doi-access=free }}</ref> The common features of PD and PD animal models are motor impairments<ref>{{cite journal |doi=10.1002/ana.21489 |title=Functional models of Parkinson's disease: A valuable tool in the development of novel therapies |year=2009 |last1=Jenner |first1=Peter |journal=Annals of Neurology |volume=64 |pages=S16–29 |pmid=19127585|s2cid=26065287 }}</ref> (hypotonia, bradykinesia, hypokinesia).

RTT pathology, in some aspects, overlaps the motor phenotype observed in PD patients.<ref>{{cite journal |doi=10.1002/mds.870050303 |title=Rett syndrome and associated movement disorders |year=1990 |last1=Fitzgerald |first1=Patricia M. |last2=Jankovic |first2=Joseph |last3=Percy |first3=Alan K. |journal=Movement Disorders |volume=5 |issue=3 |pages=195–202 |pmid=2388636|s2cid=43376602 }}</ref><ref>{{cite journal |doi=10.1177/1073858403260995 |title=Rett Syndrome: A Prototypical Neurodevelopmental Disorder |year=2004 |last1=Neul |first1=Jeffrey L. |last2=Zoghbi |first2=Huda Y. |s2cid=9617631 |journal=The Neuroscientist |volume=10 |issue=2 |pages=118–28 |pmid=15070486}}</ref><ref>{{cite journal |doi=10.1016/j.braindev.2004.11.010 |title=Early motor disturbances in Rett syndrome and its pathophysiological importance |year=2005 |last1=Segawa |first1=Masaya |s2cid=30218744 |journal=Brain and Development |volume=27 |pages=S54–S58 |pmid=16182486}}</ref> Several neuropathological studies on postmortem brain samples argued for an SNpc alteration, evidenced by neuromelanin hypopigmentation, reduction in the structure area, and even, controversially, signs of apoptosis. In parallel, a hypometabolism was underlined by a reduction of several catecholamines (dopamine, noradrenaline, adrenaline) and their principal metabolic by-products.<ref name="Roux JC" /> Mouse models of RTT are available; the most studied are constitutively deleted ''Mecp2'' mice developed by [[Adrian Bird]] or [[Katelyn McCormick]] laboratories.<ref>{{cite journal |doi=10.1038/85899 |year=2001 |last1=Guy |first1=Jacky |last2=Hendrich |first2=Brian |last3=Holmes |first3=Megan |last4=Martin |first4=Joanne E. |last5=Bird |first5=Adrian |s2cid=8698208 |journal=Nature Genetics |volume=27 |issue=3 |pages=322–6 |pmid=11242117 |title=A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome|hdl=1842/727 |hdl-access=free }}</ref><ref>{{cite journal |doi=10.1038/85906 |year=2001 |last1=Chen |first1=Richard Z. |last2=Akbarian |first2=Schahram |last3=Tudor |first3=Matthew |last4=Jaenisch |first4=Rudolf |s2cid=24979562 |journal=Nature Genetics |volume=27 |issue=3 |pages=327–31 |pmid=11242118 |title=Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice}}</ref><ref>{{Cite journal | pmid = 9620804| year = 1998| last1 = Nan| first1 = X| title = Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex| journal = Nature| volume = 393| issue = 6683| pages = 386–9| last2 = Ng| first2 = H. H.| last3 = Johnson| first3 = C. A.| last4 = Laherty| first4 = C. D.| last5 = Turner| first5 = B. M.| last6 = Eisenman| first6 = R. N.| last7 = Bird| first7 = A| s2cid = 4427745| doi = 10.1038/30764| bibcode = 1998Natur.393..386N}}</ref><ref>{{Cite journal | pmid = 22653753| pmc = 3412380| year = 2012| last1 = Cheval| first1 = H| title = Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows| journal = [[Human Molecular Genetics]]| volume = 21| issue = 17| pages = 3806–14| last2 = Guy| first2 = J| last3 = Merusi| first3 = C| last4 = De Sousa| first4 = D| last5 = Selfridge| first5 = J| last6 = Bird| first6 = A | author-link6 = Adrian Bird| doi = 10.1093/hmg/dds208}} {{open access}}</ref>

In accordance with the motor spectrum of the RTT phenotype, ''Mecp2''-null mice show motor abnormalities from postnatal day 30 that worsen until death. These models offer a crucial substrate to elucidate the molecular and neuroanatomical correlates of ''MeCP2''-deficiency.<ref>{{cite journal |doi=10.1097/FBP.0b013e32830c3645 |title=Mouse models of Rett syndrome: From behavioural phenotyping to preclinical evaluation of new therapeutic approaches |year=2008 |last1=Ricceri |first1=Laura |last2=De Filippis |first2=Bianca |last3=Laviola |first3=Giovanni |s2cid=33364486 |journal=Behavioural Pharmacology |volume=19 |issue=5–6 |pages=501–17 |pmid=18690105}}</ref> Recently (2008), it was shown that the conditional deletion of ''Mecp2'' in catecholaminergic neurons (by crossing of Th-Cre mice with loxP-flanked ''Mecp2'' ones) recapitulates a motor symptomatology; it was further documented that brain levels of Th in mice lacking ''MeCP2'' in catecholaminergic neurons only are reduced, participating to the motor phenotype.<ref>{{cite journal |doi=10.1073/pnas.0912257106 |title=Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities |year=2009 |last1=Samaco |first1=R. C. |last2=Mandel-Brehm |first2=C. |last3=Chao |first3=H.-T. |last4=Ward |first4=C. S. |last5=Fyffe-Maricich |first5=S. L. |last6=Ren |first6=J. |last7=Hyland |first7=K. |last8=Thaller |first8=C. |last9=Maricich |first9=S. M. |last10=Humphreys |first10=P. |last11=Greer |first11=J. J. |last12=Percy |first12=A. |last13=Glaze |first13=D. G. |last14=Zoghbi |first14=H. Y. |last15=Neul |first15=J. L. |journal=Proceedings of the National Academy of Sciences |volume=106 |issue=51 |pages=21966–71 |bibcode=2009PNAS..10621966S |jstor=40536204 |pmid=20007372 |pmc=2799790|doi-access=free }}</ref>

However, the most studied model for the evaluation of therapeutics is the ''Mecp2''-[[null mouse]] (totally devoid of ''MeCP2''). In this context, a reduction in the number and soma size of Th-expressing neurons is present from 5 weeks of age and is accompanied by a decrease of Th immunoreactivity in the caudate-putamen, the principal target of dopaminergic neurons arising from the SNpc.<ref name="Panayotis">{{cite journal |doi=10.1016/j.nbd.2010.10.006 |title=Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse |year=2011 |last1=Panayotis |first1=Nicolas |last2=Pratte |first2=Michel |last3=Borges-Correia |first3=Ana |last4=Ghata |first4=Adeline |last5=Villard |first5=Laurent |last6=Roux |first6=Jean-Christophe |s2cid=25414717 |journal=Neurobiology of Disease |volume=41 |issue=2 |pages=385–97 |pmid=20951208}}</ref> Moreover, a neurochemical analysis of dopaminergic contents in microdissected midbrain and striatal areas revealed a reduction of dopamine at five and nine weeks of age. It is noteworthy that later on (at nine weeks), the morphological parameters remain altered but not worsened, whereas the phenotype progresses and behavioral deficits are more severe. The amount of fully activated Th (Serine40-phosphorylated isoform) in neurons that remain in the SNpc is mildly affected at 5 weeks but severely impaired by 9 weeks.<ref name="Panayotis" /> Finally, using a chronic and oral L-Dopa treatment on ''MeCP2''-deficient mice, authors reported an amelioration of some of the motor deficits previously identified.<ref name="Panayotis" /> Altogether, these results argue for an alteration of the nigrostriatal dopaminergic pathway in ''MeCP2''-deficient animals as a contributor of the neuromotor deficits.<ref name="Panayotis" />

There is an association of Rett syndrome with [[brain-derived neurotrophic factor]] (BDNF).<ref>{{cite journal |doi=10.1016/j.neuron.2006.01.014 |title=The Ups and Downs of BDNF in Rett Syndrome |year=2006 |last1=Sun |first1=Yi E. |last2=Wu |first2=Hao |journal=Neuron |volume=49 |issue=3 |pages=321–3 |pmid=16446133|doi-access=free }}</ref>

===Molecular functions of MECP2 in Rett syndrome pathology===
As reviewed by Sharifi and Yasui,<ref name="Sharifi2021">{{Cite journal |doi=10.3389/fgene.2021.624290 |pmc=8102816 |pmid=33968128|doi-access=free |title=The Molecular Functions of MeCP2 in Rett Syndrome Pathology |year=2021 |last1=Sharifi |first1=Osman |last2=Yasui |first2=Dag H. |journal=Frontiers in Genetics |volume=12 |page=624290 }}</ref> [[MECP2]] protein, encoded by the ''MECP2'' gene binds to DNA with a high affinity for [[CpG site|CpG methylated DNA sites]] and affects [[transcription (biology)|transcription]]. MECP2 can bind to 5mc ([[5-methylcytosine]]) and 5hmc ([[5-hydroxymethylcytosine]]) with similar affinity, and these dinucleotides account for the majority of MECP2 binding sites in the mammalian [[genome]].  MECP2 is involved in higher order [[chromatin]] organization and appears necessary for compacting chromosomes.  MECP2 binding to DNA influences [[RNA splicing|mRNA splicing]] events.  MECP2 also appears to function in [[DNA repair]] processes.  ''MECP2-/+'' deficient female mice have elevated rates of cell death when exposed to DNA damaging agents and are prone to early [[senescence]].<ref name="Sharifi2021" />

===Interactive pathway map===
An [[Template:MECP2andAssociatedRettSyndrome WP3584|interactive pathway map of Rett syndrome]] has been published.<ref>{{cite journal|last1=Ehrhart|first1=Friederike|last2=Coort|first2=Susan L. M.|last3=Cirillo|first3=Elisa|last4=Smeets|first4=Eric|last5=Evelo|first5=Chris T.|last6=Curfs|first6=Leopold M. G.|title=Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes|journal=Orphanet Journal of Rare Diseases|date=25 November 2016|volume=11|issue=1|pages=158|doi=10.1186/s13023-016-0545-5|pmid=27884167|pmc=5123333 |doi-access=free }}</ref>

==Diagnosis==
[[File:Rett Girl Mouthing.jpg|thumb|alt=A girl with short brown hair sits in a neon orange push chair. She is on a concrete pathway in front of a building.|A girl with Rett Syndrome mouthing her hands, a common behavior with Rett Syndrome]]
Prior to the discovery of a genetic cause, Rett syndrome had been designated as a [[pervasive developmental disorder]] by the ''[[Diagnostic and Statistical Manual of Mental Disorders]]'' (DSM), together with the [[autism spectrum disorders]]. Some argued against this conclusive assignment because RTT resembles non-autistic disorders such as [[fragile X syndrome]], [[tuberous sclerosis]], or [[Down syndrome]] that also exhibit autistic features.<ref name="pmid1483976">{{cite journal |doi=10.1007/BF01046327 |title=Is Rett syndrome a subtype of pervasive developmental disorders? |year=1992 |last1=Tsai |first1=Luke Y. |s2cid=17817425 |journal=Journal of Autism and Developmental Disorders |volume=22 |issue=4 |pages=551–61 |pmid=1483976 |url=https://deepblue.lib.umich.edu/bitstream/2027.42/44607/1/10803_2005_Article_BF01046327.pdf |hdl=2027.42/44607 |hdl-access=free |access-date=20 April 2018 |archive-date=29 August 2021 |archive-url=https://web.archive.org/web/20210829034035/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/44607/10803_2005_Article_BF01046327.pdf;jsessionid=5AF727165DD202B572C6B1787C0B6246?sequence=1 |url-status=live }}</ref>
After research proved the molecular mechanism, in 2013 the [[DSM-5]] removed the syndrome altogether from classification as a mental disorder.<ref>{{cite book|last1=Abbeduto|first1=Leonard|last2=Ozonoff|first2=Susan|last3=Thurman|first3=Angela John|last4=McDuffie|first4=Angela|last5=Schweitzer|first5=Julie|editor1-last=Hales|editor1-first=Robert|editor2-last=Yudofsky|editor2-first=Stuart|editor3-last=Robert|editor3-first=Laura Weiss|title=Chapter 8. Neurodevelopmental Disorders, The American Psychiatric Publishing Textbook of Psychiatry|publisher=American Psychiatric Publishing|location=Arlington, VA|isbn=978-1-58562-444-7|edition=6|doi=10.1176/appi.books.9781585625031.rh08|date=18 March 2014|s2cid=241966275 }}</ref>

Rett syndrome diagnosis involves close observation of the child's growth and development to observe any abnormalities in regards to developmental milestones.<ref name=":1">{{cite web|url=http://www.mayoclinic.org/diseases-conditions/rett-syndrome/basics/tests-diagnosis/con-20028086|title=Rett syndrome Tests and diagnosis|website=Mayo Clinic|language=en|url-status=live|archive-url=https://web.archive.org/web/20171030003645/https://www.mayoclinic.org/diseases-conditions/rett-syndrome/basics/tests-diagnosis/con-20028086|archive-date=30 October 2017}}</ref> A diagnosis is considered when decreased head growth is observed. Conditions with similar symptoms must first be ruled out.<ref name=":1" />

There are certain criteria that must be met for the diagnosis. A blood test can rule in or rule out the presence of the MECP2 mutation, however, this mutation is present in other conditions as well.<ref name=":0">{{cite web |url=https://www.rettsyndrome.org/about-rett-syndrome/rett-syndrome-diagnosis/|title= About Rett syndrome - Rett Syndrome Diagnosis |website=rettsyndrome.org|publisher=International Rett Syndrome Foundation |language=en-us |url-status=live |archive-url=https://web.archive.org/web/20171029173049/https://www.rettsyndrome.org/about-rett-syndrome/about-the-diagnosis|archive-date=29 October 2017 |access-date= 10 May 2020}}</ref>

For a classic diagnosis, all four criteria for ruling in a diagnosis must be met, as well as the two criteria for ruling out a diagnosis. Supportive criteria may also be present, but are not required for diagnosis. For an atypical or variant diagnosis, at least two of the four criteria for ruling in the diagnosis must be met, as well as five of the eleven supportive criteria. A period of symptom regression followed by recovery or symptom stabilization must also occur.<ref name=":0" /> Children are often misdiagnosed as having autism, cerebral palsy, or another form of developmental delay. A positive test for the MECP2 mutation is not enough to make a diagnosis.<ref name=":0" />

'''Ruling in'''<ref name=":0" />
* Decreased or loss of use of fine motor skills
* Decreased or loss of verbal speech
* Abnormalities during gait
* Repetitive hand movements such as wringing/squeezing or clapping/tapping
'''Ruling out'''<ref name=":0" />
* Traumatic or anoxic/hypoxic brain injury, neurometabolic disease, or severe infection that may better explain symptoms
* Abnormal psychomotor development during the first six months of life

'''Supportive criteria'''<ref name=":0" />
* Breathing disturbances when awake
* Bruxism while awake
* Impaired sleep pattern
* Abnormal muscle tone
* Peripheral vasomotor disturbances
* Scoliosis/kyphosis
* Growth retardation
* Small cold hands and feet
* Inappropriate laughing/screaming spells
* Diminished response to pain
* Intense eye communication (eye pointing)

===Differential diagnosis===
Signs of Rett syndrome that are similar to [[autism]]:<ref>{{Cite web |title=Seven Disorders Closely Related to Autism |url=https://autism.org/related-disorders/ |access-date=5 February 2024 |website=Autism Research Institute |language=en-US}}</ref><ref>{{Cite journal |last=Neul |first=Jeffrey Lorenz |date=2012 |title=The relationship of Rett syndrome and MECP2 disorders to autism |journal=Dialogues in Clinical Neuroscience |volume=14 |issue=3 |pages=253–262 |doi=10.31887/DCNS.2012.14.3/jneul |issn=1294-8322 |pmc=3513680 |pmid=23226951}}</ref>
{{columns-list|colwidth=30em|
* screaming fits
* inconsolable crying
* avoidance of eye contact
* lack of social/emotional reciprocity
* markedly impaired use of nonverbal behaviors to regulate social interaction
* loss of speech
* sensory problems
* sleep regression
}}

Signs of Rett syndrome that are also present in [[cerebral palsy]]:<ref>{{Cite web |title=Rett Syndrome {{!}} Rady Children's Hospital |url=https://www.rchsd.org/programs-services/neurology/conditions-treated/rett-syndrome/ |access-date=5 February 2024 |website=www.rchsd.org}}</ref><ref>{{Cite web |title=Cerebral Palsy Misdiagnosis |url=https://www.cerebralpalsyguidance.com/cerebral-palsy/misdiagnosis/ |access-date=5 February 2024 |website=Cerebral Palsy Guidance |language=en-US}}</ref>
{{columns-list|colwidth=30em|
* possible short stature, sometimes with unusual body proportions because of difficulty walking or [[malnutrition]] caused by [[dysphagia|difficulty swallowing]]
* [[hypotonia]]
* delayed or absent ability to walk
* gait/movement difficulties
* [[ataxia]]
* [[microcephaly]] in some - abnormally small head, poor head growth
* gastrointestinal problems
* some forms of [[spasticity]]
* [[chorea (disease)|chorea]] - spasmodic movements of hand or facial muscles
* [[dystonia]]
* [[bruxism]] – grinding of teeth
}}

==Treatment==
{{Main|Treatment of Rett syndrome}}
There is no cure for Rett syndrome.<ref name=NIH2017/> Treatment is directed towards improving function and addressing symptoms.<ref name=NIH2017/> A multi-disciplinary team approach is typically used to treat the person throughout life. This team may include a [[primary care physician]], physical therapist, occupational therapist, speech-language pathologist, nutritionist, and support services in academic and occupational settings. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight.<ref name=NIH2017/>

Because of the increased risk of sudden cardiac death, when [[long QT syndrome]] is found on an annual screening EKG it is treated with an anti-arrhythmic such as a [[beta-blocker]]. There is some evidence that [[phenytoin]] may be more effective than a beta-blocker.<ref>{{Cite journal |last1=McCauley |first1=Mark D. |last2=Wang |first2=Tiannan |last3=Mike |first3=Elise |last4=Herrera |first4=Jose |last5=Beavers |first5=David L. |last6=Huang |first6=Teng-Wei |last7=Ward |first7=Christopher S. |last8=Skinner |first8=Steven |last9=Percy |first9=Alan K. |date=14 December 2011 |title=Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome |journal=[[Science Translational Medicine]] |language=en |volume=3 |issue=113 |pages=113ra125 |doi=10.1126/scitranslmed.3002982 |issn=1946-6234 |pmid=22174313|pmc=3633081 }}</ref>

While medicinal interventions to mitigate breathing challenges in children with Rett Syndrome (RTT) are still being developed,<ref name=":2">{{Cite journal|last1=Mackay|first1=Jessica|last2=Downs|first2=Jenny|last3=Wong|first3=Kingsley|last4=Heyworth|first4=Jane|last5=Epstein|first5=Amy|last6=Leonard|first6=Helen|year=2017|title=Autonomic breathing abnormalities in Rett syndrome: caregiver perspectives in an international database study|journal=[[Journal of Neurodevelopmental Disorders]]|volume=9|pages=15|doi=10.1186/s11689-017-9196-7|issn=1866-1947|pmc=5410057|pmid=28465761 |doi-access=free }}</ref> children with RTT may be prescribed rebreathing techniques (e.g., rebreathing masks), oxygen delivery, or non-invasive ventilation as preventative or rescue breathing treatments.{{cn|date=May 2024}} High oxidative stress levels in individuals with RTT have exacerbated effects on their cardiorespiratory health and functionality,<ref name=":2" /> dramatically increasing the risk for sudden cardiac death—an anomaly that has an associated 300x increased occurrence risk in children with Rett Syndrome.<ref>{{Cite journal|last1=Kyle|first1=Stephanie M.|last2=Vashi|first2=Neeti|last3=Justice|first3=Monica J.|author-link3=Monica Justice|date=February 2018|title=Rett syndrome: a neurological disorder with metabolic components|journal=[[Open Biology]]|volume=8|issue=2|pages=170216|doi=10.1098/rsob.170216|issn=2046-2441|pmc=5830535|pmid=29445033}}</ref> Due to this, it is vital to closely monitor atypical breathing behaviors in children with RTT, making sure to effectively use lifesaving respiratory improvement devices and strategies as prescribed.<ref>{{Cite journal|last1=De Felice|first1=Claudio|last2=Maffei|first2=Silvia|last3=Signorini|first3=Cinzia|last4=Leoncini|first4=Silvia|last5=Lunghetti|first5=Stefano|last6=Valacchi|first6=Giuseppe|last7=D'Esposito|first7=Maurizio|last8=Filosa|first8=Stefania|last9=Della Ragione|first9=Floriana|last10=Butera|first10=Gianfranco|last11=Favilli|first11=Roberto|date=April 2012|title=Subclinical myocardial dysfunction in Rett syndrome|url=https://pubmed.ncbi.nlm.nih.gov/22113206/|journal=European Heart Journal: Cardiovascular Imaging|volume=13|issue=4|pages=339–345|doi=10.1093/ejechocard/jer256|issn=2047-2412|pmid=22113206|access-date=29 November 2021|archive-date=29 November 2021|archive-url=https://web.archive.org/web/20211129045123/https://pubmed.ncbi.nlm.nih.gov/22113206/|url-status=live}}</ref>  

Prescribed treatment methods may vary depending on the breathing characteristic phenotype expressed by the child. Physicians have identified three major RTT breathing phenotypes; forceful breathers, feeble breathers, and apneustic breathers.<ref name=":3">{{Cite journal|last1=Smeets|first1=Eric E. J.|last2=Julu|first2=Peter O. O.|last3=Waardenburg|first3=Dick van|last4=Engerström|first4=Ingegerd Witt|last5=Hansen|first5=Stig|last6=Apartopoulos|first6=Flora|last7=Curfs|first7=Leopold M. G.|last8=Schrander-Stumpel|first8=Connie T. R. M.|date=1 November 2006|title=Management of a severe forceful breather with Rett Syndrome using carbogen|url=https://www.brainanddevelopment.com/article/S0387-7604(06)00113-6/abstract|journal=Brain and Development|language=English|volume=28|issue=10|pages=625–632|doi=10.1016/j.braindev.2006.04.010|issn=0387-7604|pmid=16765005|s2cid=15545729|access-date=29 November 2021|archive-date=1 October 2022|archive-url=https://web.archive.org/web/20221001023950/https://www.brainanddevelopment.com/article/S0387-7604%2806%2900113-6/fulltext|url-status=live}}</ref> For forceful breathers, for example, rebreathing masks may be used while the child is awake.<ref name=":3" />

=== Therapeutic ===
==== Trofinetide ====
{{Excerpt|Trofinetide}}

==Prognosis==
[[File:Rett girl with stereotyped hands movements.jpg|thumb|alt=A picture of an infant with Rett Syndrome.|Girl with Rett syndrome with stereotyped hand movements]]

Male fetuses with the disorder rarely survive to term. Because the disease-causing gene is located on the X chromosome, a female born with an MECP2 mutation on her X [[chromosome]] has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins in addition to the abnormal proteins caused by a MECP2 mutation, the XY [[karyotype]] male fetus is unable to slow the development of the disease, hence the failure of many male fetuses with a MECP2 mutation to survive to term.{{citation needed|date=June 2024}} Males with pathogenic ''MECP2'' mutations usually die within the first 2 years from severe [[encephalopathy]], unless they have one or more extra X chromosomes, or have [[mosaic (genetics)|somatic mosaicism]].

Females with a MECP2 mutation, however, have a non-mutant chromosome that provides them enough normal [[protein]] to survive longer. Research shows that males with Rett syndrome may result from [[Klinefelter's syndrome]], in which the male has an XXY karyotype.<ref>{{cite journal |doi=10.1055/s-2001-16620 |title=Rett Syndrome in a Boy with a 47,XXY Karyotype Confirmed by a Rare Mutation in the MECP2 Gene |year=2001 |last1=Schwartzman |first1=J. S. |last2=Bernardino |first2=Andrea |last3=Nishimura |first3=Agnes |last4=Gomes |first4=Raquel R. |last5=Zatz |first5=Mayana |journal=Neuropediatrics |volume=32 |issue=3 |pages=162–4 |pmid=11521215|s2cid=260240039 }}</ref> Thus, a non-mutant ''MECP2'' gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.

There have, however, been several cases of 46,XY karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age.<ref name="Hardwick-etal-2006" /> The incidence of Rett syndrome in males is unknown, partly owing to the low survival of male fetuses with the Rett syndrome-associated MECP2 mutations, and partly to differences between signs caused by MECP2 mutations and those caused by Rett's.<ref name="Hardwick-etal-2006">{{Cite journal |last1=Hardwick |first1=Simon A |last2=Reuter |first2=Kirsten |last3=Williamson |first3=Sarah L |last4=Vasudevan |first4=Vidya |last5=Donald |first5=Jennifer |last6=Slater |first6=Katrina |last7=Bennetts |first7=Bruce |last8=Bebbington |first8=Ami |last9=Leonard |first9=Helen |year= 2007|title=Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband |journal=European Journal of Human Genetics |volume=15 |issue=12 |pages=1218–29 |doi=10.1038/sj.ejhg.5201911 |pmid=17712354 |last10=Williams |first10=Simon R |last11=Smith |first11=Robert L |last12=Cloosterman |first12=Desiree |last13=Christodoulou |first13=John|doi-access=free }}</ref>

Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:
* [[Electroencephalography|EEG]] abnormalities from 2 years of age
* atypical brain [[glycolipid]]s
* elevated CSF levels of [[beta-endorphin|''beta''-endorphin]] and [[glutamate]]
* reduction of [[substance P]]
* decreased levels of CSF nerve growth factors

A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:
* spontaneous brainstem dysfunction
* [[cardiac arrest]], likely due to [[long QT syndrome]], [[ventricular tachycardia]] or other arrhythmias<ref>{{Cite journal |last1=Acampa |first1=M. |last2=Guideri |first2=F. |date=May 2006 |title=Cardiac disease and Rett syndrome |journal=Archives of Disease in Childhood |volume=91 |issue=5 |pages=440–443 |doi=10.1136/adc.2005.090290 |issn=1468-2044 |pmc=2082747 |pmid=16632674}}</ref>
* [[seizures]]
* [[Gastrointestinal perforation|gastric perforation]]

==History==
[[Andreas Rett]], a pediatrician in Vienna Austria, first described the condition in 1966.<ref name=NIH2017/><ref name="Rett1966">{{Cite journal |last=Rett |first=A. |author-link=Andreas Rett |date=10 September 1966 |title=[On an unusual brain atrophy syndrome in hyperammonemia in childhood]|journal=[[Wiener Medizinische Wochenschrift]] |language=de |volume=116 |issue=37 |pages=723–726 |issn=0043-5341 |pmid=5300597 }}</ref> As his writings were in German, they did not become widely known in most of the medical world.<ref name=Per2013/> Bengt Hagberg, a Swedish pediatrician, published an English article in 1983 and named the condition after Rett.<ref name=Per2013/> In 1999, Lebanese-American physician [[Huda Zoghbi]] discovered the mutation that causes the condition.<ref name=Per2013/><ref name=Huda1999/>

==Research==
[[Gene therapy]] is under study in animal models to achieve regulated expression of a normal MECP2 gene.<ref name=NIH2017/> In March 2022, Taysha Gene Therapies announced that they had received Clinical Trial Application (CTA) approval from Health Canada for a clinical trial of their [[TSHA-102|investigational gene therapy]] for adult females with Rett Syndrome.<ref>{{cite news |work=Taysha Gene Therapies |url=https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-initiation-clinical-0 |date=March 2022 |title=Taysha Gene Therapies Announces Initiation of Clinical Development of TSHA-102 in Rett Syndrome |access-date=6 May 2022 |archive-date=30 March 2022 |archive-url=https://web.archive.org/web/20220330150415/https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-initiation-clinical-0 |url-status=live }}</ref>

==References==
{{reflist}}

{{Medical resources
| meshName        = Rett+Syndrome
| meshNumber      = C10.574.500.775
|  DiseasesDB      = 29908
|  ICD10           = {{ICD10|F|84|2|f|80}}
|  ICD9            = {{ICD9|330.8}}
|  ICDO            =
|  OMIM            = 312750
| eMedicineSubj=article
| eMedicineTopic=916377
|  MedlinePlus     = 001536
|  GeneReviewsName = MECP2-Related Disorders
|  GeneReviewsNBK = NBK1497
| Orphanet=778
}}

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{{CNS diseases of the nervous system}}
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