Rett syndrome

Definition

Rett syndrome is a disorder of the nervous system that leads to regression in development, especially in the areas of expressive language and hand use. In most cases, it is caused by a genetic mutation.

Causes, incidence, and risk factors

Rett Syndrome occurs almost exclusively in girls and may be misdiagnosed as autism or cerebral palsy.

The gene associated with Rett syndrome is on the X-chromosome. This gene contains instructions for creating methl-CpG-binding protein 2 (MeCP2), a protein that regulates the manufacture of various other proteins.

Mutations in the MeCP2 gene causes these other proteins to be produced incorrectly, which damages the maturing brain. Studies link mutations in this gene to 75% of Rett syndrome cases.

Females have two X chromosomes, so even when one has this significant mutation, the other X chromosome provides enough normal protein for the child to survive.

Males conceived with this mutation do not have a second X chromosome to compensate for the problem. Therefore, the mutation is usually lethal, leading to miscarriage, stillbirth, or very early death.

Most cases of the mutation arise spontaneously. However, there also seem to be some clusters within families and certain geographic regions, for example Norway, Sweden, and Northern Italy.

Symptoms

An infant with Rett syndrome usually has normal development for the first 6-18 months. Once symptoms do begin, they vary greatly from mild to severe. In fact, there are at least six variants that have been identified to date. In addition, there seem to be four distinct stages of the disease. See the International Rett Syndrome Association website for additional information about these stages.

Symptoms may include:

• Hypotonia (floppy arms and legs) -- frequently the first sign
• Slowing head growth beginning at approximately 5-6 months of age
• Developmental regression
• Severely impaired language development
• Loss of purposeful hand movements; for example, the pincer grasp used to pick up small objects is replaced by repetitive hand motions like hand wringing or constant placement of hands in mouth
• Apraxia -- partial or complete inability to carry out purposeful movements
• Shaky, unsteady, or stiff gait; or toe walking
• Loss of social engagement
• Seizures (1/3 of patients)
• Intermittent hyperventilation with a disorganized breathing pattern, air swallowing, and breath holding
• Breathing abnormalities tend to worsen with stress; breathing is usually normal during sleep and abnormal while awake
• Scoliosis
• Loss of normal sleep patterns
• Poor circulation that can lead to cold and bluish arms and legs, and small feet
• Intellectual disabilities and learning difficulties (assessing cognitive skills in those with Rett syndrome, however, is difficult because of the speech and hand motion abnormalities)
• Gastrointestinal complaints including ongoing, severe constipation and gastroesophageal reflux (GERD)
• Sleep disturbances
• Excessive saliva and drooling

Signs and tests

Chromosomal analysis may now be used to search for the gene mutations that cause Rett syndrome. Studies have shown that mutations of the MeCP2 gene can be found in 75% of girls with Rett syndrome.

However, since this gene abnormality is not identified in everyone with the disease, the diagnosis of Rett syndrome is still based on the symptoms.

There are several different types of Rett syndrome:

• Classical (meets the diagnostic criteria)
• Provisional (some evidence between ages 1 and 3)
• Atypical

Rett syndrome is classified as atypical if:

• It begins earlier (soon after birth), or later (beyond 18 months of age, sometimes as late as 3 or 4 years old)
• Speech and hand skill abnormalities are milder
• It is found in a boy (very rare). One boy with Rett syndrome did not have the MECP2 gene mutation in every copy of the gene in his body. In another case, the boy was XXY -- that is, he had an extra X chromosome.

Treatment

Treatment may include:

• Supportive care (assistance with feeding, diapering, and treating symptoms like constipation and GERD).
• Supplemental feeding for those with slowed growth. Diets high in calores and fat, as well as nasogastric tube feeds, can help increase weight and height. Weight gain, in turn, may improve alertness and social interactions. If the person with Rett syndrome is prone to breathing in food, a feeding tube into the stomach may be recommended.
• Physical therapy for the hands to prevent them from contracting. Also, weight bearing exercises and frequent followup are recommended for those with scoliosis.
• Medication, like carbamazepine, to treat seizures.

Other medications or supplements that have been used or studied include:

• L-dopa for motor rigidity in later stages of the disease
• L-carnitine -- some families report improvement in language skills, increased muscle mass, decreased constipation, increased alertness, less daytime sleeping, increased energy, and improved quality of life while their daughters took carnitine
• Folate and betaine
• Dextromethorphan
• Bromocriptine

Given the discovery of a genetic mutation associated with Rett syndrome, research using gene therapy is underway. Stem cell therapy, alone or in combination with gene therapy, is another hopeful treatment that requires thorough study.

Abnormalities in breathing pattern may be the most upsetting and difficult symptom for parents to watch. Why they happen and what to do about them is not well understood. Studies are underway to evaluate various treatments, such as busperidone (Buspar), naltraxone, or magnesium citrate.

Most experts in Rett syndrome recommend that parents remain calm through an episode of irregular breathing like breath holding. It may help to remind yourself that normal breathing always returns and that your daughter will grow accustomed to the abnormal breathing pattern.

Support Groups

For additional information and resources, see the International Rett Syndrome Association.

Expectations (prognosis)

The progression of this disease usually levels off once the patient reaches teenage years. For example, if seizures or breathing abnormalities are present, they tend to lessen in late adolescence.

Each child's developmental regression or delays are different, so it is hard to generalize. Usually, a child with Rett syndrome sits up properly but may not crawl. For those who do crawl, many do so without using their hands (for example, "combat crawling" on the tummy).

Similarly, some children walk independently within the normal age range, while others are delayed, don't learn to walk independently at all, or don't learn to walk until late childhood or early adolescence. For those children who do learn to walk at the normal time, some keep that ability for their lifetime, while other children lose the skill.

Life expectancies are not well studied, although survival at least until the mid-20s is likely. The average life expectancy of a girl with Rett syndrome may be mid-40s. Death is often related to seizure, aspiration pneumonia, malnutrition, and accidents.

Calling your health care provider

Call your health care provider if you have any concerns about your child's development, if you notice a lack of normal development with motor or language skills in a child, or if there are associated disorders that need treatment.

Prevention

The likelihood of having another child with Rett syndrome is less than 1%.

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