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Rett Syndrome

Rett Syndrome

New Insight Into Rett Syndrome Severity

A research collaboration between Australia and Israel has identified a genetic variation that influences the severity of symptoms in Rett syndrome.

Dr Helen Leonard, who heads the Australian Rett Syndrome Study at the Telethon Institute for Child Health Research, said the finding was exciting in that it identifies a potential new target for treatment of the debilitating neurological disorder.

"We know that there is a wide range in the onset and severity of symptoms in patients with Rett syndrome but it has been difficult to give families a firm idea of how the disorder would progress," Dr Leonard said.

"This information is potentially helpful in predicting the clinical progression, but importantly, gives us another area to explore for potential therapies."

In the study, clinical information and DNA samples were gathered from 125 patients from the Australian Rett Syndrome Database and an Israeli cohort coordinated by Dr Bruria Ben Zeev at the Safra Pediatric Hospital, Sheba Medical Centre, Sackler School of Medicine, Tel Aviv. The genetic testing was undertaken by Professor John Christodoulou, from the NSW Centre for Rett Syndrome Research at the Children's Hospital at Westmead in Sydney and Dr Eva Gak from the Sagol Neuroscience Center at the Sheba Medical Centre.

Professor Christodoulou said while it has been established that Rett syndrome is caused by mutations in the MECP2 gene, these new findings have established a correlation between the severity of clinical symptoms and a common brain-derived neurotrophic factor (BDNF) polymorphism.

"Those patients with the normal BDNF genetic variant had less severe symptoms, with later onset and frequency of seizures," Dr Christodoulou said.

"We know that BDNF plays a major role in the development, survival and function of brain cells. What we now have to establish is the nature of the interaction between MECP2 and BDNF."

"It may be that if we can stimulate BDNF within patients with Rett syndrome, there is a chance that we can delay the onset of seizures and reduce some of the more debilitating aspects of the disorder."

The finding is published in the latest edition of the international journal Neurology.

The research was supported by funding from the National Institutes of Health (USA), the National Health and Medical Research Council (Australia), the International Rett Syndrome Foundation and the Rett Syndrome Australian Research Fund.


Rett syndrome (also called Retts disorder) is a neurodevelopmental disorder that is classified as a pervasive developmental disorder by the DSM-IV. It was first described by Austrian neurologist Andreas Rett in 1966. 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 disorder 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 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. Many argue that it is misclassified as a pervasive developmental disorder, 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, cerebral palsy and autism.


Rett syndrome (symbolized RTT) is caused by mutations in the gene MECP2 located on the X chromosome and can arise sporadically or from germline mutations.
Sporadic mutations
Rett syndrome is usually caused (95% or more) by a de novo mutation in the child (so it is NOT inherited from either parent. Parents are generally genotypically normal, i.e. one without a MECP2 mutation).
In sporadic cases of Rett syndrome, it is thought that the mutated MECP2 is usually derived from the male copy of the X chromosome. 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. 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

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.
Most individuals with Rett syndrome are female. Because the disease-causing gene is located on the X chromosome, a female born with a 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 check 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 at least to birth. Research shows that males with Rett syndrome almost all have Klinefelter's syndrome as well (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 due to low survival of male fetuses with the Rett syndrome associated MECP2 mutations, and partly to differences between symptoms caused by MECP2 mutations and those caused by Rett's.

The severity of Rett syndrome in females can vary depending on the type and position of the mutation of MECP2 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

The infant with Rett syndrome often avoids detection until 6-18 months due to a relatively normal appearance and some developmental progress. However closer scrutiny reveals disturbance of the normal spontaneous limb and body movements that are thought to be regulated in the brainstem. The brief period of developmental progress is followed by stagnation and regression of previously acquired skills. During regression some 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
Balance and coordination problems, including losing the ability to walk in many cases

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, but studies have shown that restoring MECP2 function may lead to a cure. One area of research is in the use of Insulin-like Growth Factor 1 (IGF-1), which has been shown to partially reverse symptoms in MeCP2 mutant mice. Such a treatment works because the neuronal cells have not atrophied, but rather are in an immature state.

Treatment of Rett syndrome includes:

management of gastrointestinal (reflux, constipation) and nutritional (poor weight gain) issues
surveillance of scoliosis and long QT syndrome
increasing the patient's communication skills, especially with augmentative communication strategies
parental counseling
modifying social medications
sleep aids
anti-psychotics (for self-harming behaviors)
beta-blockers rarely for long QT syndrome
Occupational therapy, Speech therapy and Physical therapy are use to treat children with Rett syndrome.

The challenge of developing therapies for MECP2 disorders

The recent studies demonstrating that neurological deficits resulting from loss of MeCP2 can be reversed upon restoration of gene function are quite exciting because they show that neurons that have suffered the consequences of loss of MeCP2 function are poised to regain functionality once MeCP2 is provided gradually and in the correct spatial distribution. This provides hope for restoring neuronal function in patients with RTT. However, the strategy in humans will require providing the critical factors that function downstream of MeCP2 because of the challenges in delivering the correct MeCP2 dosage only to neurons that lack it, given that the slightest perturbation in MeCP2 level is deleterious. Thus, therapeutic strategies necessitate the identification of the molecular mechanisms underlying individual RTT phenotypes and picking out the candidates that can be therapeutically targeted. The next phase of research needs to assess how complete the recovery is. Clearly, lethality, level of activity, and hippocampal plasticity are rescued, but are the animals free of any other RTT symptoms such as social behavior deficits, anxiety, and cognitive impairments? Since postnatal rescue results in viability, it will be important to evaluate if even the subtler phenotypes of RTT and MECP2 disorders are rescued when protein function is restored postnatally. This is particularly important given emerging data about early neonatal experiences and their long-term effects on behavior in adults.

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 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-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
cardiac conduction abnormalities - abnormally prolonged QT interval on ECG
gastric perforation

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