Синдром Ретта

Usually Rett syndrome is caused by a mutation in the methyl CpG binding protein 2 (MECP2) gene that results in its abnormal function. The MECP2 gene is involved in the production of methyl-cytosine binding protein 2 (MeCP2), which is needed for brain development and can increase or inhibit expression of certain genes.

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).

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:

• Stage 1 (early onset) usually begins between 6 months and 18 months of age 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 because spoken language is absent, and repetitive hand movements may decrease.

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

• 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 gene mutation on the X chromosome (Xq28) and for other potentially confounding genetic mutations is used to complement the clinical diagnosis.

Explicit guidelines are used to confirm the clinical diagnosis of Rett syndrome. These guidelines divide the clinical diagnostic criteria into required, main, supportive, and exclusion (1).

The required diagnostic criteria are all of the following:

• A period of regression followed by recovery or stabilization (critical criterion)

• All main criteria

• All exclusion criteria

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

The supportive diagnostic criteria include awake breathing disturbances; scoliosis or kyphosis; awake bruxism; abnormal sleep patterns; cold, small hands and feet in relation to height; peripheral vasomotor disturbances; growth retardation; abnormal muscle tone; intense eye communication ("eye pointing"); inappropriate laughing or screaming; and decreased response to pain. Although supportive criteria are not required for a diagnosis of typical Rett syndrome, they may occur in some children with a diagnosis of typical Rett syndrome and can also help lead to a diagnosis of atypical Rett syndrome. A child who has had a period of regression followed by recovery or stabilization, who has all exclusion criteria, and who has at least 2 main criteria plus at least 5 supportive criteria has atypical Rett syndrome.

• Management of symptoms

• Multidisciplinary team support

• Treatment of seizures and behavior disturbances with antiseizure and behavioral medications

• Possible use of trofinetide

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.

Medications may be needed to control seizures and behavior disturbances, for breathing dysfunction, or for motor difficulties.

Trofinetide, a synthetic analog of the N-terminal tripeptide of insulin-like growth factor I, is available for the treatment of Rett syndrome in adults and children 2 years of age and older. Trofinetide produced modest improvement in these areas in clinical trials (1).

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.

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.

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

1. National Institute of Neurological Disorders and Stroke (NINDS): About Rett Syndrome

2. International Rett Syndrome Foundation