Rett Syndrome

Rett Syndrome - What is Rett Syndrome?

Rett syndrome is a neurodevelopmental disorder that is classified as an autism spectrum disorder by the DSM-IV. It was first described by Austrian pediatrician Andreas Rett in 1966. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some).

Repetitive hand movements such as mouthing or wringing are also noted. 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.

Some argue that it is misclassified as an autism spectrum 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 signs of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy and autism.

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Causes of Rett Syndrome

Genetically Rett syndrome (symbolized RTT) is caused by mutations in the gene MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations.

Sporadic mutations

Rett syndrome is usually caused (95% or more) by a ''de novo'' mutation in the child, and not inherited from either parent. Parents are generally genotypically normal, 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.

Locus coeruleus and MECP2

Brain levels of norepinephrine are lower in people with Rett syndrome (reviewed in). The genetic loss of MECP2 changes the properties of cells in the locus ceruleus, the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus. These changes include hyperexcitability and decreased functioning of its noradrenergic innervation. 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. 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. 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 signs 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).

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Rett Syndrome Mortality

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

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Rett Syndrome Symptoms

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. 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.

Signs 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
  • gastrointestinal problems
  • sensory problems

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, and/or might be unusually proportioned because of difficulty walking or malnutrition due to difficulty swallowing.
  • hypotonia
  • delayed or absent ability to walk
  • gait/movement difficulties
  • ataxia
  • microcephaly in some - abnormally small head, poor head growth
  • some forms of spasticity
  • chorea - spasmodic movements of hand or facial muscles
  • dystonia
  • bruxism - grinding of teeth

Signs 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 may require corrective surgery. Those who remain ambulatory tend to have less progression of scoliosis.

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Rett Syndrome Treatment

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 signs 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
  • SSRIs
  • anti-psychotics (for self-harming behaviors)
  • beta-blockers rarely for long QT syndrome
  • Occupational therapy, Speech therapy and physical therapy are used to treat children with Rett syndrome.

There is an association of the disease with brain-derived neurotrophic factor (BDNF).

The challenge of developing therapies for MECP2 disorders

The recent studies (funded by the International Rett Syndrome Foundation) 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 signs 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.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Rett syndrome" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.