Rett syndrome (RS) is a neurological disease of children that is also referred to as Rett's disorder or by the compound name of autism , dementia , ataxia , and loss of purposeful hand use. Named for the Austrian pediatrician who first described it, RS is sometimes grouped together with other childhood neurological disorders under the category of pervasive developmental disorders (PDDs) or autistic spectrum disorders. RS is classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), as a developmental disorder of childhood. More recently, Rett syndrome has been categorized along with Rubinstein-Taybi syndrome (RSTS), Coffin-Lowry syndrome (CLS), and several other rare disorders as a chromatin disease. Chromatin is the easily stained part of a cell nucleus that contains the cell's DNA, RNA, and several proteins that maintain its structure.
RS was first described by an Austrian pediatrician, Andreas Rett, in 1966. His article attracted little attention, however, because it appeared in a German-language medical journal that was not widely read outside Europe. In 1983, a Swedish researcher named Bengt Hagberg published a follow-up study in the English-language Annals of Neurology, which led to worldwide recognition of RS as an identifiable neurological disorder.
RS has a distinctive onset and course. The affected child—almost always a girl—develops normally during the first five months of life. After the fifth month, head growth slows down and the child loses whatever purposeful hand movements she had developed during her first five months. After 30 months, the child frequently develops repetitive hand-washing or hand-wringing gestures; 50–80% of children with the disorder will eventually have seizures . RS is also associated with varying degrees of mental retardation .
The doctors who first studied RS attributed it to the breakdown or destruction of brain tissue. Later research indicated, however, that it is caused by the failure of the infant's brain to develop normally. This developmental failure is in turn associated with a genetic mutation affecting production of a key protein that organizes the structure of chromatin. Changes in chromatin structure lead to inappropriate activation of the genes that regulate brain development. About 80% of patients who meet the updated 2002 criteria for "classic" RS have this mutation on one of their two X chromosomes.
According to the National Institute of Neurological Disorders and Stroke (NINDS), RS affects between one in 10,000 and one in 15,000 female infants. It is thought to occur in all races and ethnic groups with equal frequency. Although Rett syndrome is associated with a genetic mutation, less than 0.5% of reported cases are recurrences within families. Almost all cases represent sporadic (new) mutations of the gene responsible for the syndrome. The risk that the parents of a daughter with RS will have a second child with the disorder is less than 1%.
The reason that almost all patients with RS are female is that the mutation that causes the disorder is located on the X chromosome. While boys have an X and a Y chromosome, girls have two X chromosomes, only one of which is active in any given body cell. The other X chromosome is turned off in a process known as X inactivation, which helps to explain why the symptoms of RS vary from patient to patient. According to mathematical probability, the X chromosome with the mutation will be active in about half the girl's cells, with the healthy X chromosome active in the other half. If by chance a majority of the girl's cells have an active healthy X chromosome, she will have only mild symptoms of RS. On the other hand, if the X chromosome with the mutation is active in a majority of the girl's cells, she will have more severe symptoms. Since boys have only one X chromosome, they have no "backup" healthy X chromosome to compensate for one that contains the mutation. As a result, boys affected by the mutation usually die shortly before or after birth. The few cases of boys surviving with RS involve another genetic disorder known as Klinefelter's syndrome, in which the boy is born with three or more sex chromosomes, two or more Xs and a Y. If one of the X chromosomes contains the RS mutation, the boy may develop RS.
Causes and symptoms
RS is the first neurological disorder in humans to be traced to defects in a protein that controls the expression of other genes. The molecular cause of Rett's disorder is a genetic mutation on the long arm of the X chromosome (Xq28) at a locus known as MECP2. Dr. Huda Zoghbi at Baylor College of Medicine and her collaborator, Dr. Uta Francke at Stanford University, discovered the gene in 1999. The gene contains instructions for the formation of a protein known as methyl cytosine-binding protein 2 or MeCP2, which is crucial to the normal development of the human brain. The mutation associated with RS results in insufficient production of MeCP2. When this key protein is lacking, other genes are "turned on" or remain active at inappropriate points in the brain's development. These activated genes interfere with the normal pattern of brain maturation. The discovery of the MECP2 gene showed that RS should be understood as a genetic interference with normal brain development rather than the result of tissue loss or destruction.
The areas of the brain that are most severely affected by the lack of MeCP2 are the frontal, motor, and temporal portions of the brain cortex; the brain stem; the base of the forebrain; and the basal ganglia. These parts of the brain control such basic functions as movement, breathing, and speech. In addition, the disruption of the normal pattern of brain development in RS affects the child's emotions and ability to learn. RS is now known to be one of the most common causes of mental retardation in girls.
The symptoms of RS are usually described in terms of four stages in the child's development.
STAGE 1, EARLY ONSET (SIX TO 18 MONTHS OF AGE) The early symptoms of RS are not always noticeable in stage 1. The infant may not make eye contact with family members and may not show much interest in toys. She may be considered a "good baby" because she is so calm and quiet. She may also be able to use single words or word combinations before she loses the ability to speak in stage 2. On the other hand, there may also be noticeable hand-wringing and slowing of head growth in this early stage.
STAGE 2, RAPID DETERIORATION (ONE TO FOUR YEARS) The second stage may be either rapid or gradual in onset. The child loses her ability to speak and to make purposeful hand movements—a condition known as apraxia . Hand-to-mouth movements may appear, as well as hand-wringing or hand-clapping gestures. These movements may be nearly constant while the child is awake, but disappear during sleep. There may be noticeable episodes of breath holding, air swallowing, and hyperventilating (rapid shallow breathing). The child may have trouble sleeping, and may become irritable or agitated. If she is able to walk, she will start to look unsteady on her feet (ataxia) and may have periods of trembling or shaking. Some girls completely lose the ability to walk in stage 2 and move by crawling or "bottom scooting." Slowed growth of the child's head is usually most noticeable during this stage.
STAGE 3, PLATEAU (TWO TO 10 YEARS) Motor problems and seizures often appear during this stage. The child's behavior, however, often shows some improvement, with less irritability and crying. She may show greater interest in her surroundings, and her attention span and communication skills often improve.
STAGE 4, LATE DETERIORATION OF MOTOR SKILLS (USUALLY AFTER 10 YEARS OF AGE) In stage 4, patients with RS gradually lose their mobility; some stop walking, while others have never learned to walk. There is, however, no loss of cognitive or communication skills, and the repetitive hand movements may decrease. Seizures and breathing problems typically lessen in severity by late adolescence. The spine, however, begins to develop an abnormal sideways curvature (scoliosis), which is usually more severe in girls that have never learned to walk. The patient may also develop muscle rigidity, or spasticity . Puberty begins at the same age as in most girls.
Other symptoms associated with RS include a greater risk of bone fractures due to low bone density in spite of adequate calcium in the diet; constipation, which results from poor muscle tone in the digestive tract, scoliosis, and the side effects of anticonvulsant medications; excessive salivation and drooling; gastroesophageal reflux disease (GERD), which results from poor muscle tone in the esophagus; and crying or emotional agitation, which is thought to result from frustration with the inability to communicate.
The diagnosis of RS is clinical, which means that it is based on external observation of the patient's symptoms rather than on the results of laboratory tests or imaging
studies. In some cases, however, the child's doctor may order blood or urine tests or an electroencephalogram (EEG) to rule out epilepsy or other disorders. The doctor will observe the affected child—usually over a period of several hours or days at various intervals—and interview the parents. In most cases, the diagnosis cannot be made with certainty until the child is three to five years old. A diagnosis of RS can be made by a pediatrician or primary care physician, but should be confirmed by a pediatric neurologist (specialist in disorders of the nervous system in children) or developmental pediatrician. In addition to ordering genetic testing, a specialist who is evaluating a child for RS will use several different types of criteria.
The diagnostic criteria for RS, which were first established in 1985, were revised by an international committee in 2001–2002 in order to improve the consistency of diagnosis as well as take recent genetic discoveries into account. The criteria are divided into three groups: necessary criteria, which must be present for the doctor to make the diagnosis; supportive criteria, which are present in many patients with RS; and exclusion criteria, which rule out a diagnosis of RS.
Necessary criteria include the following:
- child is apparently normal before and around the time of birth
- psychomotor development (development of skills that involve the brain's regulation of motor activity) is either normal for the first six months or is slightly delayed from birth
- circumference of child's head at birth is normal
- head growth slows down after birth
- child loses purposeful hand motions between six and 30 months
- child makes repeated gestures, most commonly hand wringing or squeezing, clapping or tapping, and washing or rubbing motions
- child withdraws socially, loses ability to communicate in words, and loses cognitive skills
- ability to walk is impaired or lost
Supportive criteria include the following:
- disturbed breathing (hyperventilation, air swallowing, breath holding) when awake
- bruxism (grinding the teeth during sleep)
- disturbed sleeping pattern from early infancy
- muscle wasting and loss of muscle tone
- scoliosis or kyphosis
- retarded growth
- hands and feet that are very small compared to the rest of the child's body
- vasomotor disturbances
Exclusion criteria include the following:
- enlargement of the internal organs or other signs of storage diseases
- cataract formation or damage to the retina of the eye
- evidence of brain damage before or shortly after birth
- identification of a metabolic or other progressive neurological disorder
- damage to the nervous system resulting from an infectious disease or head trauma
About 15% of children who are evaluated for RS have RS-like symptoms, or have the MECP2 mutation without fulfilling all the diagnostic criteria. These children are said to have "variant" or "atypical" RS. Children below the age of three years who show some of the signs of RS but do not yet meet the full criteria are said to have "provisional" RS.
It is important to understand that even though RS is associated with mutations in the MECP2 gene, the syndrome sometimes occurs without the mutation. Conversely, the mutation can occur without producing the symptoms of RS. Genetic testing can identify about 80% of RS cases but is not sufficient to use alone to make the diagnosis. Researchers think that the remaining 20% of cases may be caused either by mutations in other parts of the gene or by genes that have not yet been identified.
Treatment for patients with RS is highly individualized because the severity of specific symptoms varies from patient to patient; for example, some may never have seizures. In almost all cases, however, the treatment team for a child with RS will include a neurologist, an orthopedic surgeon, a physical therapist, an occupational therapist, a dietitian, and a speech-language therapist in addition to a pediatrician and a dentist. In some cases, the treatment team may include a psychiatrist who specializes in childhood and adolescent psychiatry. Most patients will also have a case manager to coordinate treatments.
When the patient reaches puberty, she should be seen by a developmental pediatrician and an orthodontist. Respite and in-home caregivers may also be added to the treatment team for adults with RS.
There is no cure for RS; treatment is intended to ease the symptoms and to keep the patient mobile as long as possible. It will include most or all of the following:
- Medications. A patient with RS may be given drugs for breathing problems and difficulties with muscle control. One medication that is useful is baclofen (Lioresal), a muscle relaxant. Patients with seizures are given anticonvulsant (anti-seizure) medications.
- Special diets. Many patients with RS have a poor appetite and problems swallowing. The patient may need an assessment by a dietitian to plan meals that are appealing as well as nutritionally sound. Patients with seizures that cannot be controlled by medications may benefit from a special high-fat, low-carbohydrate diet known as a ketogenic diet.
- Physical therapy. Physical therapy of patients with RS is focused on maintaining or improving the patient's balance and ability to walk; maintaining full range of motion whenever possible; and preventing the muscle contractures that lead to deformities in adult life.
- Splints and braces. Hand or elbow splints may be used to reduce repetitive hand movements and increase the child's purposeful use of her dominant hand. Patients who develop kyphosis (humpback) or scoliosis may be fitted for spinal braces.
- Occupational therapy.
- Speech therapy. Some patients with RS are taught to communicate with body language; others use eye blinking, communication boards, or electronic devices.
- Complementary and alternative therapies. Music therapy has been successfully used in patients with RS, as well as hydrotherapy, equine therapy (horseback riding), and acupuncture.
As of late summer 2003, there are no open clinical trials for RS at the National Institutes of Health (NIH). There are, however, two medical centers funded by the NIH that evaluate patients for RS and conduct research on the disorder; contact information for the Blue Bird Circle Rett Center and the Kennedy Krieger Institute is listed under Resources.
It is difficult to predict the severity or the course of RS in any specific individual. Although the symptoms of RS are disabling, most patients survive into the 40s and 50s. Little is known about patients' long-term prognosis after age 40 because the disorder has been studied intensively only since the mid-1980s.
What is known about the short-term prognosis of middle-aged adults with RS is encouraging, however. Their mental state stabilizes and they are often able to continue to learn as well as improve the use of their hands. They make better eye contact with others. In addition, patients are usually less irritable, sleep better, and have fewer seizures and breathing problems. The chief additional problem for adults with RS is decreased mobility. After the early adult years, the patient's muscles may become rigid or spastic, causing joint deformities and increased difficulty in walking.
Educational and social needs
Most patients with RS can benefit from special educational programs. Education in the public schools is available in most areas until the patient is 21. After that age, the patient may be able to attend sheltered workshops or day centers, depending on where she lives. In the last few years, some young women with milder forms of RS have been able to attend classes at local community colleges or find employment with the help of a job coach.
It is important for patients with RS to participate in community activities and social events precisely because they have a fairly long life expectancy. Personal accounts of adults with RS indicate that they enjoy travel, church or synagogue activities, volunteer work, swimming, camping, music, sports events, and similar outings.
The most pressing long-term concern for patients with RS is working out a life plan for ongoing care, since many are likely to outlive their parents. The parents of a girl diagnosed with RS should consult an estate planner, an attorney, and a certified public accountant (CPA) in order to draft a life plan and letter of intent. A letter of intent is not a legally binding document, but it gives the patient's siblings and other relatives or caregivers necessary information on providing for her in the future. The attorney can help the parents decide about such matters as guardianship as well as guide them through the legal process of appointing a guardian, which varies from state to state.
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Blue Bird Circle Rett Center, Baylor College of Medicine, Department of Pediatrics, One Baylor Plaza, Room 319C, Houston, TX 77030. (888) 430-7388 or (713) 798-RETT. (February 25, 2004).<http://bluebirdrett.bcm.tmc.edu>.
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Rebecca J. Frey, PhD