Rett Syndrome

Rett syndrome is a neurodevelopmental disorder. It is characterized by typical early growth and development that is then followed by a slowing of development.

Rett syndrome was first reported by Dr. Andreas Rett in 1966. Over time, the effects of Rett syndrome can lead to cognitive, sensory, emotional, motor, cardiac and such autonomic nervous system problems as difficulties with digestion or breathing.

There are two main types of Rett syndrome: classic and atypical. The two types may differ by their symptoms or by the specific gene mutation.

The majority of Rett syndrome patients have the classic form, which typically develops in four phases.

• Early Onset Phase. In this phase, development stalls or stops completely. Sometimes, the syndrome takes hold at such a subtle pace that parents and healthcare providers do not notice it at first. Researchers once thought that this phase began around 6 months of age. However, after analyzing videotapes of Rett individuals taken from birth, they now know that some infants with Rett syndrome only seem to develop normally. In fact, these infants show problems with very early development. In one study,5 all of the infants with Rett syndrome showed problems with body movements from birth through age 6 months. Another 42 percent showed stereotyped hand movements during this period.
• Rapid Destructive Phase. The child loses skills (regresses) quickly. Purposeful hand movements and speech are usually the first skills lost. Breathing problems and stereotypic hand movements such as wringing (clasping or squeezing), washing (a movement that resembles washing the hands) and clapping or tapping also tend to start during this stage.
• Plateau Phase. The child's regression slows and other problems may seem to lessen, or there may even be improvement in some areas. Seizures and movement problems are common at this stage. Many people with Rett syndrome spend most of their lives in this stage.
• Late Motor Deterioration Phase. Individuals in this stage may become stiff or lose muscle tone; some become immobile. Scoliosis (an abnormal curvature of the spine) may be present and even become severe enough to require bracing or surgery. Stereotypic hand movements and breathing problems seem to become less common.

There are currently five known variants of atypical Rett syndrome, defined by characteristic symptoms, the age at which the symptoms present or genetic makeup.

Forms of atypical Rett syndrome that have been identified to date include:

• Congenital Rett syndrome (Rolando variant)
• Early-onset Rett syndrome (Hanefeld variant)
• Late-childhood Rett syndrome
• Forme fruste Rett syndrome
• Preserved-speech variant of Rett syndrome (Zappella variant)

Nearly all cases of Rett syndrome are caused by a mutation in the methyl CpG binding protein 2, or MECP2 (pronounced meck-pea-two) gene. The MECP2 gene contains instructions for the synthesis of a protein called methylcytosine binding protein 2 (MeCP2) which is needed for brain development and acts as one of the many biochemical switches that activate and deactivate gene functions. Because the MECP2 gene does not function properly in individuals with Rett syndrome, they may have too little MeCP2, or the MeCP2 they do have doesn’t work properly.

Not everyone who has an MECP2 mutation has Rett syndrome. Scientists believe some cases may be caused by partial gene deletions, mutations in other parts of the MECP2 gene or additional genes that have not yet been identified. Genetic and environmental factors can contribute to differences in the severity and types of symptoms found in individuals with Rett syndrome. Those may include: where the MECP2 mutation is located in the gene, how the individuals’ sex chromosomes interact and other genes that can make the symptoms worse or protect from the effects of the mutation.

Although Rett syndrome is a genetic disorder, less than 1 percent of recorded cases are passed from one generation to the next. Most cases are spontaneous, which means the mutation occurs randomly. However, in some families of individuals affected by Rett syndrome, other family members have a mutation in the MECP2 gene. Families that already have an identified MECP2 mutation can get genetic testing to identify if they are carriers of the disorder.

Any racial or ethnic group can experience Rett syndrome. Rett syndrome most commonly affects girls, although boys are also (rarely) affected. Boys are usually more severely affected than girls.

Scientists are studying mutations in the MECP2 gene of individuals with Rett syndrome to learn about MeCP2 protein function and dysfunction. Information from this study will increase our understanding of the disorder and may lead to new therapies. Other research aims at identifying molecular pathways that are affected, developing animal models of the disorder and early-stage therapy development.

Some researchers suggest that the specific type of mutation in the MECP2 gene affects the severity of symptoms of Rett syndrome. Studies are underway to understand the mutations and genes that contribute to the varied symptoms and severity of this disorder. One National Institutes of Health-funded natural history study also should provide new information about these topics.

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. Scientists have developed a genetic test to find MECP2 mutations to complement observations and diagnosis by doctors. To confirm a diagnosis of Rett syndrome, families should consult a pediatric neurologist, clinical geneticist or developmental pediatrician.

Rett syndrome is a neurodevelopmental disorder that is characterized by typical early growth and development that is then followed by a combination of the following symptoms:

• A slowing of development
• Loss of mobility or function in the hands
• Distinctive hand movements
• Slowed brain and head growth
• Problems with walking, walking on the toes or a wide-based gait
• Seizures
• Cognitive problems
• Digestive problems
• Trouble performing motor functions, including speaking and controlling eye movements (apraxia)
• Breathing difficulties while awake, including breath holding, hyperventilation and swallowing air
• Other symptoms may include sleep problems, teeth grinding and difficulty chewing.

Age of onset, severity of symptoms and how Rett syndrome progresses varies from child to child. While children who go on to develop Rett syndrome grow and develop as expected initially, there are often subtle differences even in early infancy and toddlerhood, such as:

• Difficulty feeding
• Jerkiness in limb movements 
• Loss of muscle tone (hypotonia)
• Less eye contact
• Problems crawling or walking

The loss of functional use of the hands is followed by compulsive hand movements such as hand wringing. The onset of these symptoms is sometimes sudden.

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. Scientists have developed a genetic test to find MECP2 mutations to complement observations and diagnosis by doctors. To confirm a diagnosis of Rett syndrome, families should consult a pediatric neurologist, clinical geneticist or developmental pediatrician.  

Genetic evaluation of a blood sample can identify whether a child has one of the known mutations that cause Rett syndrome. Even if a child has a mutation of the Methylcytosine-binding protein 2 (MECP2) gene (which also occurs in other conditions), the symptoms of Rett syndrome may not always be present, so healthcare providers also need to evaluate the child's symptoms to confirm a diagnosis.
 

• A pattern of development, regression, then recovery or stabilization
• Partial or complete loss of purposeful hand skills such as grasping with fingers, reaching for things or touching things on purpose
• Partial or complete loss of spoken language
• Repetitive hand movements, such as wringing the hands, washing, squeezing, clapping or rubbing
• Gait abnormalities, including walking on toes or with an unsteady, wide-based, stiff-legged gait

A slowing of head growth between 3 months and 4 years of age, leading to acquired microcephaly, is also characteristic of Rett syndrome and calls for a diagnosis to be considered.

Genetic mutations causing some atypical variants of Rett syndrome have been identified. After a blood test to confirm a child's genetic makeup, a healthcare provider may diagnose the child with atypical Rett syndrome if the child demonstrates development, followed by regression and then recovery or stabilization. In addition, the healthcare provider will confirm at least two of the other four main criteria, and five of the 11 supportive criteria before making a diagnosis.

Sometimes Rett syndrome is misdiagnosed as regressive autism, cerebral palsy or nonspecific developmental delays.

For some males, the features of Rett syndrome occur with another genetic condition called Klinefelter syndrome, in which a boy has two X chromosomes and one Y chromosome. This means that the boy may have one mutated MECP2 gene and one normal MECP2 gene, reducing the effects of the mutated gene.

While there is no cure for Rett syndrome, in 2023 the U.S. Food and Drug Administration (FDA) approved a new drug trofinetide to treat Rett syndrome in children aged 2 and older. Trofinetide works by reducing swelling in the brain, increasing the amount of a protective protein in the brain and stopping some cells from becoming too active.

Other treatments focus on treating specific symptoms or behaviors seen in Rett syndrome. Medication can help with breathing and movement problems and seizures.

Individuals affected by Rett syndrome should be regularly monitored for scoliosis (curving in the spine) and heart problems. Occupational therapy may help children develop skills needed for everyday activities like dressing, eating and drawing, while physical therapy and water therapy (hydrotherapy) can help with mobility.

Some children may require special equipment and aids like spinal braces, splints for their hands and wrists and nutritional support to help them maintain adequate weight. Children with Rett syndrome may need extra help with school and social support.  

Many individuals with Rett syndrome live into middle age and beyond despite symptoms. Because the disorder is rare, very little is known about long-term prognosis and life expectancy. 

Most people with Rett syndrome benefit from well-designed interventions no matter what their age, but the earlier that treatment begins, the better. With therapy and assistance, people with Rett syndrome can participate in school and community activities.

These treatments, forms of assistance and options for medication generally aim to slow the loss of abilities, improve or preserve movement and encourage communication and social contact. A list of treatment options is presented below; the need for these treatments depends on the severity of different symptoms. 

• Improves or maintains mobility and balance
• Reduces misshapen back and limbs
• Provides weight-bearing training for patients with scoliosis (an abnormal curvature of the spine)

• Improves or maintains use of hands
• Reduces stereotypic hand movements such as wringing, washing (a movement that resembles washing the hands), clapping, rubbing or tapping
• Teaches self-directed activities like dressing and feeding

• Teaches nonverbal communication
• Improves social interaction

• Supplements calcium and minerals to strengthen bones and slow scoliosis
• High-calorie, high-fat diet to increase height and weight
• Insertion of a feeding tube if patients accidentally swallow their food into their lungs (aspiration)

• Braces or surgery to correct scoliosis
• Splints to adjust hand movements

• To reduce breathing problems
• To eliminate problems with abnormal heart rhythm
• To relieve indigestion and constipation
• To control seizures

Individuals affected by Rett syndrome should be regularly monitored for scoliosis (curving in the spine) and heart problems. Occupational therapy may help children develop skills needed for everyday activities like dressing, eating and drawing, while physical therapy and water therapy (hydrotherapy) can help with mobility.

Some children may require special equipment and aids like spinal braces, splints for their hands and wrists and nutritional support to help them maintain adequate weight. Children with Rett syndrome may need extra help with school and social support.

Many individuals with Rett syndrome live into middle age and beyond despite symptoms. Because the disorder is rare, very little is known about long-term prognosis and life expectancy.

Consider participating in a clinical trial so clinicians and scientists can learn more about Rett syndrome and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat or prevent disease.

All types of volunteers — those who are healthy or may have an illness or disease — of all different ages, sexes, races, and ethnicities are needed to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with Rett syndrome at Clinicaltrials.gov.