Rett Syndrome

Rett syndrome is a disorder of brain development that occurs almost exclusively in girls. After 6 to 18 months of apparently normal development, girls with the classic form of Rett syndrome develop severe problems with language and communication, learning, coordination, and other brain functions. Early in childhood, affected girls lose purposeful use of their hands and begin making repeated hand wringing, washing, or clapping motions. They tend to grow more slowly than other children and have a small head size (microcephaly).

Other Names

 * Autism-Dementia-Ataxia-Loss of Purposeful Hand Use Syndrome
 * Cerebroatrophic Hyperammonemia
 * Rett's Syndrome
 * RTS
 * RTT

Types
There are several different types of Rett syndrome:


 * Classical (meets the diagnostic criteria)
 * Provisional (some evidence between ages of one and three)
 * Atypical

Rett syndrome is classified as atypical if:


 * It begins early (soon after birth) or late (beyond 18 months of age, sometimes as late as 3 or 4 years old).
 * Speech and hand skill problems are mild.
 * It is diagnosed in a boy (very rare).

Symptoms
An infant with Rett syndrome usually has normal development for the first 6 - 18 months. Symptoms range from mild to severe.

Symptoms may include:


 * Hypotonia(floppy arms and legs) -- frequently the first sign
 * Slowed head growth beginning at approximately five to six months of age
 * Change in development
 * Severe language development problems
 * Loss of purposeful hand movements; for example, the grasp used to pick up small objects is replaced by repetitive hand motions like hand wringing or constant placement of hands in the mouth
 * Apraxia (loss of the ability to carry out purposeful movement)
 * Shaky, unsteady, or stiff gait; or toe walking
 * Loss of social engagement
 * Seizures
 * Breathing problems -- which tend to get worse 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
 * 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 problems including ongoing, severe constipation and gastroesophageal reflux (GERD)
 * Excessive saliva and drooling

There are four stages of Rett syndrome

 * Stage I, called early onset, generally begins between 6 and 18 months of age. Quite frequently, this stage is overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can persist for more than a year.


 * Stage II, or the rapid destructive stage, usually begins between ages one and four and may last for weeks or months. This stage may have either a rapid or a gradual onset as purposeful hand skills and spoken language are lost. The characteristic hand movements begin to emerge during this stage and often include wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth. Hands are sometimes clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements persist while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing is usually normal during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. General irritability and sleep irregularities may be seen. Gait patterns are unsteady and initiating motor movements can be difficult. Slowing of head growth is usually noticed during this stage.


 * Stage III, also called the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features. An individual in stage III may show more interest in her surroundings, and her alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives.


 * Stage IV is the last stage and is called the late motor deterioration stage — can last for years or decades and is characterized by reduced mobility. Muscle weakness, rigidity (stiffness), spasticity, dystonia (increased muscle tone with abnormal posturing of extremity or trunk), and scoliosis (curvature of the spine) are other prominent features. Girls who were previously able to walk may stop walking. Generally, there is no decline in cognition, communication, or hand skills in stage IV. Repetitive hand movements may decrease, and eye gaze usually improves.

Causes
Most cases of classic Rett syndrome are caused by mutations in the MECP2 gene. This gene provides instructions for making a protein (MeCP2) that is critical for normal brain development. The MeCP2 protein likely plays a role in forming connections (synapses) between nerve cells. Researchers believe that this protein has several functions, including regulating other genes in the brain by switching them off when they are not needed. The MeCP2 protein may also control the production of different versions of certain proteins in nerve cells. Although mutations in the MECP2 gene disrupt the normal function of nerve cells, it is unclear how these mutations lead to the signs and symptoms of Rett syndrome.

Males with mutations in the MECP2 gene often die before birth or in infancy. A small number of males with a MECP2 mutation, however, have developed signs and symptoms similar to those of classic Rett syndrome. Some of these boys have an extra X chromosome in many or all of the body's cells. The extra X chromosome contains a normal copy of the MECP2 gene, which produces enough of the MeCP2 protein for the boys to survive. Other males with features of Rett syndrome have mutations in the MECP2 gene that occur after conception and are present in only a fraction of the body's cells. In rare cases, researchers have discovered that the MECP2 gene is abnormally duplicated in boys with mental retardation and some developmental problems characteristic of Rett syndrome.

Mutations in the CDKL5 gene cause an atypical form of Rett syndrome in females called the early-onset seizure variant. The CDKL5 gene provides instructions for making a protein that appears to be essential for normal brain development. Although the function of this protein is unknown, it may play a role in regulating the activity of other genes. Researchers are working to determine how mutations in the CDKL5 gene lead to seizures and the features of Rett syndrome in affected girls.

Diagnosis
Rett syndrome is most often misdiagnosed as autism, cerebral palsy, or non-specific developmental delay. In the past, making the correct diagnosis called not only for a long list of diagnostic tests and procedures to rule out other disorders, but it also took from months to years waiting to confirm the diagnosis as new symptoms appeared over time. Today, a simple blood test can confirm the diagnosis. However, since the MECP2 mutation is also seen in other disorders, the presence of the MECP2 mutation in itself is not enough for the diagnosis of Rett syndrome. Diagnosis requires either the presence of the mutation (a molecular diagnosis) or fulfillment of the diagnostic criteria (a clinical diagnosis, based on signs and symptoms that can be observed) or both.

The diagnostic criteria for Rett sundrome according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition---Text Revision) (DSM-IV-TR):

All of the following:
 * Apparently normal prenatal and perinatal development
 * Apparently normal psychomotor development through the first five months after birth
 * Normal head circumference at birth

Onset of all of the following after the period of normal development:
 * Deceleration of head growth between ages 5 and 48 months
 * Loss of previously acquired purposeful hand skills between 5 and 30 months with the subsequent development of stereotyped hand movements (e.g., hand-wringing or hand washing)
 * Early loss of social engagement (although often social interaction develops later)
 * Appearance of poorly coordinated gait or trunk movements
 * Severely impaired expressive and receptive language development with severe psychomotor retardation

Treatment
There is no cure for Rett syndrome. Treatment for the disorder is symptomatic — focusing on the management of symptoms — and supportive, requiring a multidisciplinary approach. Medication may be needed for breathing irregularities and motor difficulties, and antiepileptic drugs may be used to control seizures. There should be regular monitoring for scoliosis and possible heart abnormalities. Occupational therapy (in which therapists help children develop skills needed for performing self-directed activities — occupations — such as dressing, feeding, and practicing arts and crafts), physiotherapy, and hydrotherapy may prolong mobility. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight. Special academic, social, vocational, and support services may also be required in some cases.

Living with
The International Rhett Syndrome Foundation has several information sheets relating to living with Rett Syndrome. Topics include:
 * Adaptive clothing
 * Bathing
 * Caring and Coping
 * Entering Adulthood
 * Adaptive Equipment and Devices
 * School and Day Programs
 * Government Assistance Programs

They also have links to an online community and regional representatives.

Chances of Developing
More than 99% of classic Rett syndrome cases occur in people with no history of the disorder in their family. Many of these cases result from new mutations in the MECP2 gene.

A few families have been described with more than one affected family member. These cases helped researchers determine that Rett syndrome has an X-linked dominant pattern of inheritance. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition.

Related Problems
Some common problems common in people with Rett syndrome include:
 * Sleep problems
 * Seizures (occur in as many as 80% of patients)
 * Increase risk of fractures
 * Scoliosis
 * Feeding difficulties

Clinical Trials
A list of ongoing studies is available at ClinicalTrials.gov: rett syndrome trials

Recent discoveries
Recently completed studies related to Rett syndrome include:
 * Evaluating the functional abilities in Rett syndrome conforming to the established Pediatric Evaluation of Disability Inventory (PEDI).
 * A study of cardiac abnormality and frequency of seizures in Rhett syndrome.
 * Studying the natural history, search for DNA markers, and identifying future therapeutic options for Rett syndrome.
 * An evaluation of nutritional issues related to Rett syndrome

Expected Outcome
Despite the difficulties with symptoms, most individuals with Rett syndrome continue to live well into middle age and beyond. Because the disorder is rare, very little is known about long-term prognosis and life expectancy. While it is estimated that there are many middle-aged women (in their 40s and 50s) with the disorder, not enough women have been studied to make reliable estimates about life expectancy beyond age 40.

History
Dr. Andreas Rett (1924-1997), an Austrian pediatrician, first noticed two girls as they sat in his waiting room with their mothers. He observed these children making the same repetitive hand-washing motions. Curious, he compared their clinical and developmental histories and discovered they were very similar. Dr. Rett checked with his nurse and learned that he had six other girls with similar behavior in his practice. Surely, he thought, all these girls must have the same disorder. Not content with studying his own patients, Dr. Rett made a film of these girls and traveled throughout Europe seeking other children with these symptoms.

Meanwhile, in 1960, young female patients in Sweden with quite similar symptoms caught the eye of their own physician, Dr. Bengt Hagberg. Dr. Hagberg collected the records of these girls and put them aside, intending to return to them when he had more time to study this curious phenomenon.

Then, in 1966, Dr. Rett published his findings in several German medical journals, which, however well-known in that part of the world, were hardly mainstream reading for much of the rest of the world’s medical community. Even after Dr. Rett published a description of the disease in English in 1977, Rett syndrome remained in the backwaters of medical concern: the pre-internet world lacked the electronic information highways taken for granted in the 21st Century.

But in 1983 an article on Rett syndrome appeared in the mainstream, English-language journal, Annals of Neurology. Written by none other than Dr. Hagberg and his colleagues, the report finally raised the profile of Rett syndrome and put it on the radar screen of many more investigators. This article was a breakthrough in communicating details of the disease to a wide audience, and the authors honored its pioneering researcher by naming it Rett syndrome.

As investigators continued to chip away at the shell of mystery surrounding Rett syndrome, increased research funding ensured that the work would continue. A team of scientists from Baylor University (Houston, TX) and Stanford University (Palo Alto, CA), toiled in the labs and clinics trying to pinpoint the cause of Rett syndrome.

A major breakthrough occurred in 1999, when a research fellow at Baylor named Ruthie Amir discovered MECP2, the gene that, when mutated, causes Rett syndrome. The discovery of the gene, located at the Xq28 site on the X chromosome was a triumph for the Baylor team, led by Huda Y. Zoghbi, MD, a professor in the departments of pediatrics, neurology, neuroscience, and molecular human genetics at the Howard Hughes Medical Institute.

The discovery that MECP2 is on the X chromosome proved that Rett syndrome is an X-linked disorder. And because only one of the two X chromosomes need have the mutation in order for it to cause the disorder, this is a dominant disorder as well. The fact that Rett syndrome is an X-linked dominant disorder also helps explain why it is usually found only in girls.

Notable Experts
A list of labs and scientists that can do the MECP2 sequencing + deletion analysis:


 * DNA Diagnostic Testing Laboratory, Baylor College of Medicine, Houston, TX
 * Dr. Mike Friez, Greenwood Genetic Center, Houston, TX
 * Iris L. Gonzalez, Ph.D., Molecular Diagnostics Laboratory, Wilmington, DE
 * Center for Human Genetics, Boston University School of Medicine, Boston, MA
 * University of Chicago, Genetic Services Laboratories, Chicago, IL
 * Children’s Hospital Boston, DNA Diagnostic Laboratory, Boston, MA