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Rett Syndrome

By

Stephen Brian Sulkes

, MD, Golisano Children’s Hospital at Strong, University of Rochester School of Medicine and Dentistry

Last full review/revision Apr 2020| Content last modified Apr 2020
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Rett syndrome is a neurodevelopmental disorder occurring almost exclusively in females that affects development after an initial 6-month period of normal development. Diagnosis is based on clinical observation of symptoms and signs during the child's early growth and development, regular ongoing evaluations of the child's physical and neurologic status, and genetic testing to search for the MECP2 gene mutation on the child's X chromosome (Xq28). Treatment involves a multidisciplinary approach that is focused on the management of symptoms.

Rett syndrome is estimated to affect 1 in every 10,000 to 15,000 live female births in all racial and ethnic groups worldwide. Most cases are random, spontaneous mutations; < 1% of recorded cases are inherited or passed from one generation to the next. Because the gene abnormality is most often present on the paternally derived X chromosome but almost never manifested in the father, it is hypothesized that the gene abnormality arises during spermatogenesis. Girls with the typical clinical picture of Rett syndrome are usually born at term after an uneventful pregnancy and delivery. Boys are rarely affected.

Etiology

Usually Rett syndrome is caused by a mutation in the methyl CpG binding protein 2 (MECP2) gene. The MECP2 gene is involved in the production of a protein called methyl-cytosine binding protein 2 (MeCP2), which is needed for brain development and acts as a biochemical switch that can either increase gene expression or tell other genes when to turn off and stop producing their own unique proteins. The MECP2 gene does not function normally in Rett syndrome; structurally abnormal forms or inadequate amounts of the protein are produced and can cause other genes to have abnormal gene expression.

Rett syndrome is not always caused by an MECP2 mutation but may be caused by partial gene deletions, mutations in other genes (eg, CDKL5 and FOXG1 genes) that affect brain development in atypical Rett syndrome, mutations in other parts of the MECP2 gene, and possibly other genes that have not yet been identified.

Now that a genetic cause of Rett syndrome has been identified, it has been separated from the autism spectrum disorders (inconsistently associated with genetic causes) based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

Symptoms and Signs

The course, age of onset, and severity of symptoms of Rett syndrome vary from child to child.

Rett syndrome is characterized by normal early growth and development followed by slowing of developmental milestones, and then regression of skills with loss of purposeful hand use with compulsive hand-wringing and hand-washing behavior, slowed head and brain growth, seizures, walking difficulty, and intellectual disability.

There are 4 stages used to describe the symptoms of Rett syndrome:

  • Stage 1 (early onset) usually begins when the child is between ages 6 months and 18 months with subtle slowing of development. Symptoms may include less eye contact, decreased interest in toys, delays in sitting or crawling, decreased head growth, and hand wringing.

  • Stage 2 (developmental regression or rapid destructive stage) usually begins between ages 1 year and 4 years. The onset may be rapid or gradual with loss of purposeful hand skills and spoken language. During this stage, characteristic hand movements begin such as wringing, clapping, washing, and tapping and repeatedly bringing the hands to the mouth. The movements disappear during sleep. Breathing irregularities may occur, such as episodes of apnea and hyperventilation. Walking may be unsteady, and initiating motor movements may be difficult. Some girls may also have symptoms similar to those of autism spectrum disorders, such as impaired social interaction and impaired communication.

  • Stage 3 (pseudostationary stage) usually begins between ages 2 years and 10 years and can last for years. Seizures, motor deficits, and apraxia are common during this stage. Sometimes, symptoms such as crying, irritability, and autism-like symptoms decline during this stage. Alertness, communication skills, attention span, and interest in the surroundings may increase during this stage.

  • Stage 4 (late motor deterioration stage) can last for years or decades. Common characteristics include scoliosis, decreased mobility, muscle weakness, spasticity, or rigidity. Sometimes walking may stop. Eye gaze for communication purposes becomes prominent as spoken language is absent, and repetitive hand movements may decrease.

Children may develop scoliosis. Cardiac abnormalities (such as prolonged QT interval) are often present. Affected children may have slowed growth and tend to have difficulty maintaining weight.

Diagnosis

  • Clinical evaluation

  • Genetic testing

Diagnosis of Rett syndrome is made clinically by observing symptoms and signs during the child’s early growth and development. Ongoing evaluation of the child’s physical and neurologic status is needed.

Genetic testing for the MECP2 mutation on the X chromosome (Xq28) is used to complement the clinical diagnosis.

The National Institute of Neurological Disorders and Stroke (NINDS) provides guidelines used to confirm the clinical diagnosis of Rett syndrome. These guidelines divide the clinical diagnostic criteria into main, supportive, and exclusion.

The main diagnostic criteria include loss of all or part of purposeful hand skills, repetitive hand movements (such as wringing or squeezing, clapping or rubbing), loss of all or part of spoken language, and gait abnormalities including toe-walking or an unsteady, wide-based, stiff-legged walk.

The supportive diagnostic criteria are not required for a diagnosis of Rett syndrome but may occur in some children. A child with supportive criteria but none of the main criteria does not have Rett syndrome. Supportive criteria include scoliosis, teeth-grinding, abnormal sleep patterns, small hands and feet in relation to height, cold hands and feet, abnormal muscle tone, intense eye communication, inappropriate laughing or screaming, and decreased response to pain.

The exclusion diagnostic criteria include the presence of other disorders that cause similar symptoms, including traumatic brain injury, grossly abnormal psychomotor development during the first 6 months of life, and severe infection causing neurologic problems.

Prognosis

Rett syndrome is rare, so there is little information about long-term prognosis and life expectancy beyond about age 40. Sometimes cardiac or autonomic abnormalities may predispose children with Rett syndrome to sudden death, but usually children survive well into adulthood with comprehensive, multidisciplinary team support.

Treatment

  • Management of symptoms

  • Multidisciplinary team support

There is no cure for Rett syndrome.

Optimal treatment of Rett syndrome includes a multidisciplinary approach that addresses symptoms and signs.

A program of occupational therapy, physical therapy, and communication therapy (with a speech and language therapist) should be provided to address self-help skills such as feeding and dressing, limited mobility, walking difficulty, and communication deficits.

Drugs may be needed to control seizures, for breathing dysfunction, or for motor difficulties.

Regular re-evaluation is needed for scoliosis progression and to monitor cardiac abnormalities.

Nutrition support may be needed to help affected children maintain weight. Special education programs and social and support services are needed.

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