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Rett syndrome is a neurodevelopmental disorder that is classified as a pervasive developmental disorder by the DSM-IV. Many argue that this is a mis-classification just as it would be to include such disorders as fragile X syndrome, tuberous sclerosis, or Down syndrome where one can see autistic features. The symptoms of this disorder are most easily confused with those of Angelman syndrome and autism. The clinical features include a deceleration of the rate of head growth (including microcephaly in some) and small hands and feet. Stereotypic, repetitive hand movements such as mouthing or wringing are also noted. Symptoms of the disease include cognitive impairment and problems with socialization, the latter during the regression period. Socialization typically improves by the time they enter school. Girls with Rett syndrome are very prone to gastrointestinal disorders and up to 80% have seizures. They typically have no verbal skills, and about 50% of females are not ambulatory. Scoliosis, growth failure, and constipation are very common and can be problematic.
Rett syndrome (symbolized RTT) is caused by sporadic mutations in the gene MECP2 located on the X chromosome. It almost exclusively affects girls -- male fetuses with the disorder rarely survive to term. Development is typically normal until 6-18 months, when language and motor milestones regress, purposeful hand use is lost and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypies are typical and breathing irregularities such as hyperventilation, breathholding, or sighing are seen in many. Early on, autistic-like behavior may be seen. Rett syndrome is usually caused (95% or more) by a de novo mutation in the child (so it is inherited from a genotypically normal mother, i.e. without a MECP2 mutation). It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MECP2. MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of Rett syndrome, 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). Rett syndrome affects one in every 12,500 female live births by age 12 years.
Gender and Rett syndrome
Most individuals with Rett syndrome are female. One explanation given for this was that the genetic defect that caused Rett syndrome in females caused embryonic lethality in males (that is, males with disease-causing MECP2 mutations died before they were born). While a plausible hypothesis, more recent research has contradicted this explanation. The incidence of Rett in males is unknown.
The severity of Rett syndrome in females can vary depending on the type and position of the MECP2 mutation and the pattern of X-chromosome inactivation. It is generally assumed that 50% of a female's cells use the maternal X chromosome while the other 50% uses the paternal X chromosome (see X-inactivation). However, if most cells in the brain activate the X chromosome with the functional MECP2 allele, the individual will have very mild Rett syndrome; likewise, if most neurons activate the X chromosome with the mutated MECP2 allele, the individual will have very severe Rett syndrome just as males with MECP2 mutations do (as they only have one X chromosome).
Development and symptoms
Infants with Rett syndrome typically develop normally until they are 6-18 months old. Neurological development tends to plateau after this brief period of normal development, and is followed by regression of previously acquired skills. Early features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism.
Symptoms of Rett syndrome that are similar to autism:
- screaming fits
- panic attack
- inconsolable crying
- avoidance of eye contact
- lack of social/emotional reciprocity
- general lack of interest
- markedly impaired use of nonverbal behaviors to regulate social interaction
- loss of speech
Symptoms 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 should rarely be made):
- possible short stature, and/or might be unusually proportioned because of difficulty walking or malnutrition due to difficulty swallowing.
- delayed or absent ability to walk
- gait/movement difficulties
- microcephaly in some - abnormally small head, poor head growth
- some forms of spasticity
- chorea - spasmodic movements of hand or facial muscles
- bruxism - grinding of teeth
Symptoms may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Anti-social behavior may change to highly social behavior. Motor functions may slow as rigidity and dystonia appear. Seizures may be problematic, with a wide range of severity. Scoliosis occurs in most and requires corrective surgery in about 10%. Those who remain ambulatory tend to have less progression of scoliosis.
Treatment and prognosis
Currently there is no cure for Rett syndrome, although there has been some promising results with gene therapy in mice.
Treatment of Rett syndrome includes:
- management of gastrointestinal (reflux, constipation) and nutritional (poor weight gain) issues
- prevention of seizures
- surveillance of scoliosis and prolonged QT syndrome
- increasing the patient's communication skills, especially with augmentative communication strategies
- parental counseling
- modifying social difficulties
- behavioral interventions
Common drug therapies include:
- anti-epileptic medications
- anti-reflux medications
- anti-constipation medications
- sleep aids
- anti-psychotics (for self-harming behaviors)
- beta-blockers rarely for prolonged QT syndrome
Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic mosaicism.
Females can live up to 60 years or more. Lab studies on Rett syndrome may show abnormalities such as:
- EEG abnormalities from 2 years of age
- atypical brain glycolipids
- elevated CSF levels of beta-endorphins 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
- heart conduction problem - abnormally prolonged QT interval on ECG
- ↑ "Is Rett Syndrome a Subtype of Pervasive Developmental Disorders" Tsai, L.Y., Journal of Autism and Developmental Disorders
- ↑ "Predictors of Seizure Onset in Rett Syndrome" Le Jian et al. 
- ↑ "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2" Amir, R. et al. 
- ↑ "New Study Reveals Rett Syndrome Can Strike Males" ScienceDaily  August 12, 2006
- ↑ "Autism-like disorder 'reversible'"  8 February 2007.
- "Getting a Read on Rett Syndrome", Science 8 December 2006: Vol. 314. no. 5805, pp. 1536 - 1537
- Progress Is Reported on a Type of Autism
- Ben Zeev Ghidoni B (2007). Rett syndrome. Child Adolesc Psychiatr Clin N Am 16 (3): 723–43.
- The International Rett Syndrome Association
- The UK Rett Syndrome Association
- RSRF Rett Syndrome Research Foundation
- The Blue Bird Circle Rett Center
- Rett Syndrome Society of Alberta
-  Study found a reversal of neurological defects in a mouse model of Rett Syndrome.
- Katie's Clinic for Rett Syndrome
Pervasive developmental disorders / Autism spectrum
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