Rett syndrome

Rett syndrome

Rett syndrome (also called Rett disorder) is a neurodevelopmental disorder that is classified as a pervasive developmental disorder by the DSM-IV. It was first decribed 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 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. 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.

Cause

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 (so it is inherited from a genotypically normal mother, 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.

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.

Sex 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 staunch 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's 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 brain stem. 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):

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 have been some promising results with gene therapy in mice.

Treatment of Rett syndrome includes:

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.

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. Lab studies on Rett syndrome may show abnormalities such as:

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

Notes

References

Further reading

  • Ben Zeev Ghidoni B (2007). "Rett syndrome". Child Adolesc Psychiatr Clin N Am 16 (3): 723–43.
  • Bittner JG, et al (2008). "Rett Syndrome and gastric perforation". Am Surg 74 (4): 315–317.

Rett Disorder and the Developing Brain. edited by Alison Kerr & Ingegerd Witt Engerstrom Oxford University Press ISBN 0-19-856815-0, 2005

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