Rett syndrome

Overview

Rett syndrome is a rare, progressive neurodevelopmental disorder that primarily affects females. It is characterized by normal early growth followed by a loss of acquired skills, particularly purposeful hand movements and speech, along with the development of repetitive hand-wringing behaviors, slowed brain and head growth, and problems with movement and coordination.

First described by Austrian physician Dr. Andreas Rett in the 1960s, the condition is now known to be caused by mutations in the MECP2 gene. Although symptoms vary, Rett syndrome often leads to severe physical and cognitive impairments that require lifelong care. The disorder typically becomes apparent between 6 and 18 months of age, after an initial period of apparently normal development.

Causes

Rett syndrome is caused by mutations in the MECP2 gene located on the X chromosome (Xq28). This gene encodes the MeCP2 protein, which is essential for brain development and function. The MeCP2 protein plays a critical role in regulating the activity of other genes by modifying how DNA is expressed in the brain.

Genetic and Inheritance Pattern:

• Most cases are sporadic, meaning the mutation occurs randomly and is not inherited from the parents.

• A small number of cases result from X-linked dominant inheritance, but these are rare.

• Because the condition is linked to the X chromosome, it primarily affects females. Males with MECP2 mutations typically do not survive infancy or present with more severe forms of the disorder.

Symptoms

Rett syndrome symptoms usually appear in stages. Initially, a child develops normally for the first 6 to 18 months of life. This is followed by a period of regression where developmental milestones are lost. The progression can vary between individuals, but the hallmark signs are consistent.

Early Symptoms (6–18 months):

• Normal early development followed by slowing of head growth (microcephaly)

• Loss of purposeful hand skills (e.g., grasping toys)

• Loss of speech or language development

Later Symptoms:

• Repetitive hand movements: Hand-wringing, clapping, tapping, or mouthing

• Motor abnormalities: Gait disturbances, loss of mobility, tremors, or rigidity

• Breathing irregularities: Hyperventilation, breath-holding, or apnea while awake

• Intellectual disability: Severe cognitive impairment and learning difficulties

• Seizures: Common in later stages

• Autistic behaviors: Social withdrawal, limited eye contact

• Scoliosis: Curvature of the spine over time

• Sleep disturbances: Difficulty falling or staying asleep

• Feeding and digestion issues: Swallowing difficulties, constipation, or reflux

Diagnosis

Rett syndrome is diagnosed based on clinical criteria and confirmed through genetic testing. Because it can mimic other developmental disorders like autism or cerebral palsy, careful assessment is essential.

Diagnostic Criteria:

• Normal development in the first 6 months followed by loss of acquired skills

• Loss of purposeful hand use and speech

• Development of repetitive hand movements

• Gait abnormalities

Genetic Testing:

• Blood tests to identify mutations in the MECP2 gene confirm the diagnosis in more than 95% of classic Rett syndrome cases

• In atypical or variant cases, mutations in other genes (CDKL5, FOXG1) may be involved

Additional Evaluations:

• EEG to detect seizure activity

• Brain MRI to rule out other neurological conditions

• Developmental assessments to evaluate cognitive and motor function

Treatment

There is no cure for Rett syndrome, but a combination of therapies and medical interventions can help manage symptoms and improve quality of life. Treatment is highly individualized and typically requires a multidisciplinary team.

1. Medications:

• Anti-seizure drugs to control epilepsy

• Medications to manage breathing problems, sleep disturbances, or behavioral issues

• Muscle relaxants or botulinum toxin for spasticity and motor stiffness

2. Therapies:

• Physical therapy: Improves mobility, posture, and coordination

• Occupational therapy: Enhances daily living skills and adapts tools for self-care

• Speech and language therapy: Focuses on communication, often through alternative methods like picture boards or AAC devices

3. Nutritional Support:

• High-calorie diets or feeding tubes may be necessary for adequate nutrition

• Management of gastrointestinal symptoms like reflux and constipation

4. Assistive Devices:

• Orthopedic braces, walkers, or wheelchairs for mobility

• Adaptive communication tools

5. Family and Psychological Support:

• Genetic counseling for families

• Parent education and support groups

• Behavioral therapy for emotional regulation and social engagement

Prognosis

The prognosis for individuals with Rett syndrome varies, depending on the severity of symptoms and the presence of complications like seizures or scoliosis. While Rett syndrome significantly affects quality of life and independence, many individuals live into middle age or beyond with appropriate care and support.

Research into gene therapy, MECP2 reactivation, and disease-modifying treatments is ongoing and offers hope for future therapeutic breakthroughs. With advances in medical care and multidisciplinary management, many people with Rett syndrome can experience improved outcomes and a higher quality of life.