Disorders usually first diagnosed in
infancy, childhood, or adolescence.
Rett's Disorder--

Rett syndrome is a neurodevelopmental disorder that is classified as a pervasive developmental
disorder by the DSM-IV. Many [1] 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 [2]. They typically have few or 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 X-linked dominant, affecting almost exclusively girls.
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 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
pathogenic 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.[3]

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. Psychomotor abilities rapidly decline between 1-2 years of
age. 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.
* 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

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.[4]

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 first 2 years from severe encephalopathy,
unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic

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
* seizures
* heart conduction problem - abnormally prolonged QT interval on ECG

*References provided by request.