Rett Syndrome Causes, Symptoms, Diagnosis, Treatment, Prevention

Rett Syndrome Causes, Symptoms, Diagnosis, Treatment, Prevention


What is Rett syndrome?


Rett syndrome is a childhood neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. It affects females almost exclusively.

The disorder was identified by Dr. Andreas Rett, an Austrian physician who first described it in a journal article in 1966. It was not until after a second article about the disorder was published in 1983 that the disorder was generally recognized.

The course of Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Before the symptoms begin, however, the child appears to grow and develop normally. Then, gradually, mental and physical symptoms appear. Hypotonia (loss of muscle tone) is usually the first symptom. As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing. The onset of this period of regression is sometimes sudden.

Another symptom, apraxia — the inability to perform motor functions — is perhaps the most severely disabling feature of Rett syndrome, interfering with every body movement, including eye gaze and speech.

Individuals with Rett syndrome often exhibit autistic-like behaviors in the early stages. Other symptoms may include toe walking; sleep problems; wide-based gait; teeth grinding and difficulty chewing; slowed growth; seizures; cognitive disabilities; and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing.

What are the stages of the disorder?


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 1 and 4 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.

The last stage, stage IV — 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.

What causes Rett syndrome?


Rett syndrome is caused by mutations (structural alterations or defects) in the MECP2 (pronounced meck-pea-two) gene, which is found on the X chromosome (see section on "Who gets Rett syndrome" for a discussion of the importance of the involvement of the X chromosome). Scientists identified the gene — which is believed to control the functions of several other genes — in 1999. When functioning normally, the MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which acts as one of the many biochemical switches that tell other genes when to turn off and stop producing their own unique proteins. Because the MECP2 gene does not function properly in those with Rett syndrome, insufficient amounts of the protein are formed. The absence of the protein causes other genes to be switched on and stay on at inappropriate stages, forming excessive amounts of proteins. This, in turn, may cause the neurodevelopmental problems that are characteristic of the disorder.

Seventy to 80 percent of girls given a diagnosis of Rett syndrome have the MECP2 genetic mutation. Scientists believe the remaining 20 to 30 percent of cases may be caused by mutations in other parts of the gene or by genes that have not yet been identified; thus, they continue to search for other mutations.

Who gets Rett syndrome?


Rett syndrome affects one in every 10,000 to 15,000 live female births. It occurs in all racial and ethnic groups worldwide. Prenatal testing is available for families with an affected daughter who has an identified MECP2 mutation. Since the disorder occurs spontaneously in most affected individuals, however, the risk of a family having a second child with the disorder is less than 1 percent.

Genetic testing is also available for sisters of girls with Rett syndrome to determine if they are asymptomatic carriers of the disorder, which is a rare possibility.

Girls have two X chromosomes, but only one is active in any given cell. This means that in a child with Rett syndrome only about half the cells in the nervous system will use the defective gene. Some of the child's brain cells use the healthy gene and express normal amounts of the proteins.

The story is different for boys who have the MECP2 mutation. Because boys have only one X chromosome they lack a back-up copy that could compensate for the defective one, and they have no protection from the harmful effects of the disorder. Boys with the defect die shortly before or after birth.

Is Rett syndrome inherited?


Although Rett syndrome is a genetic disorder — resulting from a faulty gene or genes — less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are sporadic, which means the mutation occurs randomly and is not inherited.

What Are the Symptoms of Rett Syndrome?


Babies with Rett syndrome are generally born after a normal pregnancy and delivery. Most seem to grow and behave normally for the first six months. After that, signs and symptoms start to appear. The most pronounced changes generally occur at 12 to 18 months of age, over a period of weeks or months.

Rett syndrome signs and symptoms include:


Slowed growth. Brain growth slows after birth. Smaller than normal head size is usually the first sign that a child has Rett syndrome. It generally starts to become apparent after 6 months of age. As children get older, delayed growth in other parts of the body becomes evident.

Loss of normal movement and coordination. The most significant loss of movement skills (motor skills) usually starts between 12 and 18 months of age. The first signs often include a decrease of hand control and a decreasing ability to crawl or walk normally. At first, this loss of abilities occurs rapidly and then continues more gradually.

Loss of communication and thinking abilities. Children with Rett syndrome typically begin to lose the ability to speak and to communicate in other ways. They may become uninterested in other people, toys and their surroundings. Some children have rapid changes, such as a sudden loss of speech. Over time, most children gradually regain eye contact and develop nonverbal communication skills.

Abnormal hand movements. As the disease progresses, children with Rett syndrome typically develop their own particular hand patterns, which may include hand wringing, squeezing, clapping, tapping or rubbing.
Unusual eye movements. Children with Rett syndrome tend to have unusual eye movements, such as intense staring, blinking or closing one eye at a time.

Breathing problems. These include breath-holding (apnea), abnormally rapid breathing (hyperventilation), and forceful exhalation of air or saliva. These problems tend to occur during waking hours, but not during sleep.

Irritability. Children with Rett syndrome become increasingly agitated and irritable as they get older. Periods of crying or screaming may begin suddenly and last for hours.

Abnormal behaviors. These may include sudden, odd facial expressions and long bouts of laughter, screaming that occurs for no apparent reason, hand licking, and grasping of hair or clothing.

Seizures. Most people who have Rett syndrome experience seizures at some time during their lives. Symptoms vary from person to person, and they can range from periodic muscle spasms to full-blown epilepsy.

Abnormal curvature of the spine (scoliosis). Scoliosis is common with Rett syndrome. It typically begins between 8 and 11 years of age.

Irregular heartbeat (dysrhythmia). This is a life-threatening problem for many children and adults with Rett syndrome.

Constipation. This is a common problem in people with Rett syndrome.

When to see a doctor


Signs of Rett syndrome can be subtle in the early stages. See your child's doctor right away if you begin to notice physical problems or changes in behavior such as:

  • Slowed growth of your child's head or other parts of the body
  • Decreased coordination or mobility; repetitive hand movements
  • Decreasing eye contact or loss of interest in normal play
  • Delayed speech development or loss of previously acquired speech abilities
  • Problem behavior or marked mood swings (emotional dysregulation)
  • Any clear loss of previously gained milestones in gross motor or fine motor skills

How is Rett syndrome diagnosed?


Doctors diagnose Rett syndrome by observing signs and symptoms during the child's early growth and development, and conducting ongoing evaluations of the child's physical and neurological status. Recently, scientists developed a genetic test to confirm the clinical diagnosis of this disorder; the test involves searching for the MECP2 mutation on the child's X chromosome. Given what we know about the genes involved in Rett syndrome, such tests are able to identify up to 80 percent of all cases.

Some children who have Rett syndrome-like characteristics or MECP2 genetic mutations do not fulfill the diagnostic criteria for the syndrome as defined below. These persons are described as having "atypical" Rett syndrome. Atypical cases account for about 15 percent of the total number of diagnosed cases.

A pediatric neurologist or developmental pediatrician should be consulted to confirm the clinical diagnosis of Rett syndrome. The physician will use a highly specific set of guidelines that are divided into three types of clinical criteria: essential, supportive, and exclusion. The presence of any of the exclusion criteria negates a diagnosis of "classic" or "typical" Rett syndrome.

Examples of essential diagnostic criteria or symptoms include having apparently normal development until between the ages of 6 and 18 months and having normal head circumference at birth followed by a slowing of the rate of head growth with age (between 3 months and 4 years). Other essential diagnostic criteria include severely impaired expressive language, repetitive hand movements, shaking of the torso, and toe-walking or an unsteady, wide-based, stiff-legged gait.

Supportive criteria are not required for a diagnosis of Rett syndrome but may occur in some patients. In addition, these symptoms — which vary in severity from child to child — may not be observed in very young girls but may develop with age. A child with supportive criteria but none of the essential criteria does not have Rett syndrome. Supportive criteria include breathing difficulties; electroencephalogram (EEG) abnormalities; seizures; muscle rigidity, spasticity, and/or joint contracture which worsen with age; scoliosis; teeth-grinding; small feet in relation to height; growth retardation; decreased body fat and muscle mass (although there may be a tendency toward obesity in some affected adults); abnormal sleep patterns, irritability, or agitation; chewing and/or swallowing difficulties; poor circulation of the lower extremities with cold and bluish-red feet and legs; decreased mobility with age; and constipation.

In addition to the essential diagnostic criteria, a number of specific conditions enable physicians to rule out a diagnosis of Rett syndrome. These are referred to as exclusion criteria. Children with any one of the following criteria do not have Rett syndrome: enlargement of body organs or other signs of storage disease, vision loss due to retinal disorder or optic atrophy, microcephaly at birth, an identifiable metabolic disorder or other inherited degenerative disorder, an acquired neurological disorder resulting from severe infection or head trauma, evidence of growth retardation in utero, or evidence of brain damage acquired after birth.

Why are some cases more severe than others?


The course and severity of Rett syndrome vary from individual to individual. Some girls have congenital (at or before birth) onset, while others may have late regression or milder symptoms.

Because females have two copies of the X chromosome and need only one working copy for genetic information, they turn off the extra X chromosome in a process called X inactivation. This process occurs randomly so that each cell is left with one active X chromosome. The severity of Rett syndrome in girls is a function of the percentage of cells with a normal copy of the MECP2 gene after X inactivation takes place: if X inactivation turns off the X chromosome that is carrying the defective gene in a large number of cells, the symptoms will be mild, but if a larger percentage of cells have the healthy X chromosome turned off, onset of the disorder may occur earlier and the symptoms may be more severe.

Treatments and drugs for Rett Syndrome


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.

Treatments for Rett Syndrome that can help children and adults with Rett syndrome include:


Medications

Though medications can't cure Rett syndrome, they may help control some of the signs and symptoms associated with the disorder, such as seizures and muscle stiffness.

Physical and speech therapy

Physical therapy and the use of braces or casts can help children who have scoliosis. In some cases, physical therapy can also help maintain walking skills, balance and flexibility, while occupational therapy may improve purposeful use of the hands. If repetitive arm and hand movement is a problem, splints that restrict elbow or wrist motion may be helpful. Speech therapy can help improve a child's life by teaching nonverbal ways of communicating.

Nutritional support

Proper nutrition is extremely important for both normal growth and for improved mental and social abilities. Some children with Rett syndrome may need a high-calorie, well-balanced diet. Others may need to be fed through a tube placed in the nose (nasogastric tube) or directly in the stomach (gastrostomy).

Prevention for Rett Syndrome


There's no known way to prevent Rett syndrome. In most cases, the genetic mutation that causes the disorder occurs spontaneously. Even so, if you have a child or other family member with Rett syndrome, you may want to ask the doctor about genetic testing.

What is the outlook for those with Rett syndrome?


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.

What research is being done?


Within the Federal Government, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), two of the National Institutes of Health (NIH), support clinical and basic research on Rett syndrome. Understanding the cause of this disorder is necessary for developing new therapies to manage specific symptoms, as well as for providing better methods of diagnosis. The discovery of the Rett syndrome gene in 1999 provides a basis for further genetic studies and enables the use of recently developed animal models such as transgenic mice.

One NINDS-supported study is looking for mutations in the MECP2 gene of individuals with Rett syndrome to find out how the MeCP2 protein functions. Information from this study will increase understanding of the disorder and may lead to new therapies.

Scientists know that lack of a properly functioning MeCP2 protein disturbs the precisely regulated pattern of development but they do not know the exact mechanisms by which this happens. Investigators are also trying to find other genetic mutations that can cause Rett syndrome and other genetic switches that operate in a similar way to the MeCP2 protein. Once they discover how the protein works and locate similar switches, they may be able to devise therapies that can substitute for the malfunctioning switch. Another outcome might involve manipulating other biochemical pathways to compensate for the malfunctioning MECP2 gene, thus preventing progression of the disorder.