and affects 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 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. interactive pathway map an interactive pathway map of rett syndrome has been published. diagnosis 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. after research proved the molecular mechanism, in 2013 the dsm-5 removed the syndrome altogether from classification as a mental disorder. rett syndrome diagnosis involves close observation of the child's growth and development to observe any abnormalities in regards to developmental milestones. a diagnosis is considered when decreased head growth is observed. conditions with similar symptoms must first be ruled out. there is a 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. 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. 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. ruling in 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 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 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: 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 (regression of the type seen in rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made): possible short stature, sometimes with unusual body proportions because of difficulty walking or malnutrition caused by 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 - spasmodic movements of hand or facial muscles dystonia bruxism – grinding of teeth treatment main article: treatment of rett syndrome currently there is no cure for rett syndrome. treatment is directed towards improving function and addressing symptoms. 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. 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. while medicinal interventions to mitigate breathing challenges in children with rett syndrome (rtt) are still being developed, children with rtt may be prescribed rebreathing techniques (e.g., rebreathing masks), oxygen delivery, or non-invasive ventilation as preventative or rescue breathing treatments. high oxidative stress levels in individuals with rtt have exacerbated effects on their cardiorespiratory health and functionality, dramatically increasing the risk for sudden cardiac death—an anomaly that has an associated 300x increased occurrence risk in children with rett syndrome. 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. 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. for forceful breathers, for example, rebreathing masks may be used while the child is awake. in dec 2021, australian company neuren pharmaceuticals reported positive results in a phase 3 trial of trofinetide for the treatment of rett syndrome. in sep 2022, the fda accepted a new drug application for trofinetide and granted it priority review. in march 2023 the drug received fda approval for treatment of rett syndrome. prognosis girl with rett syndrome with stereotyped hand movements. 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 somatic mosaicism. 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. 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. 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. 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. females can live up to 40 years or more. laboratory studies on rett syndrome may show abnormalities such as: eeg abnormalities from 2 years of age atypical brain glycolipids elevated csf levels of 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 seizures gastric perforation history andreas rett, a pediatrician in vienna austria, first described the condition in 1966. as his writings were in german, they did not become widely known in the english-speaking world. bengt hagberg, a swedish pediatrician, published an english article in 1983 and named the condition after rett. in 1999, lebanese-american physician huda zoghbi discovered the mutation that causes the condition. there are organizations that support this syndrome's awareness campaigns and fundraise to support treatment and research. for instance, the noemie association hosts football competitions for young girls with rett syndrome. thierry breton, an osteopath at the parisis clinic, is the organizer of this event, which takes place in cormeilles-en-paris. twelve teams will compete in this event. this particular moment has already occurred countless times. it is a soccer competition in support of the group la vie selon noémi. shirts from professional footballers zlatan ibrahimovic, adrien rabiot, gianelli imbula, axel ngando, and karl toko-ekambi will be among the prizes given away. two to three children with the syndrome will receive some of the treatment they need in a specialized facility in barcelona thanks to the money contributed (spain). this is the story of noémie, who was born at the hospital in cormeilles, paris. the girl's parents founded this organization to aid her and other kids with multiple disabilities and to spread awareness of this condition. research gene therapy is under study in animal models to achieve regulated expression of a normal mecp2 gene. 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 investigational gene therapy for adult females with rett syndrome. in fiction in august 2021, a novel by british author victoria scott, patience, was published by head of zeus. the novel featured a character with rett syndrome and explored recent developments in gene therapy.