Rett Syndrome: Introduction

Rett syndrome is a rare genetic neurodevelopmental disorder that primarily affects females. It is characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability.

Key points:

• Prevalence: Approximately 1 in 10,000 to 15,000 live female births
• Genetic cause: Mutations in the MECP2 gene (Xq28) in about 95% of cases
• Inheritance: X-linked dominant; typically sporadic (de novo mutations)
• Almost exclusively affects females; males with the mutation usually do not survive to birth
• Progressive disorder with distinct stages of development

Clinical Features of Rett Syndrome

Developmental Stages:

1. Early Onset Stage (6-18 months):
   • Developmental delays become apparent
   • Deceleration of head growth
   • Decreased interest in play
   • Hypotonia
2. Rapid Destructive Stage (1-4 years):
   • Regression of acquired skills
   • Loss of purposeful hand movements
   • Development of stereotypic hand movements (hand wringing, washing, clapping)
   • Autistic-like behavior
   • Breathing irregularities
3. Plateau Stage (preschool to adulthood):
   • Relative stabilization of symptoms
   • Improved eye contact and communication
   • Continued motor problems
   • Seizures often begin during this stage
4. Late Motor Deterioration Stage (can last for decades):
   • Reduced mobility
   • Muscle weakness and spasticity
   • Scoliosis

Key Clinical Features:

• Loss of acquired purposeful hand skills
• Loss of acquired spoken language
• Gait abnormalities: impaired (dyspraxic) or absent ability to walk
• Stereotypic hand movements (hand wringing/squeezing, clapping/tapping, mouthing)
• Acquired microcephaly (deceleration of head growth)
• Breathing dysrhythmias (hyperventilation, breath-holding, apnea) while awake
• Impaired sleep pattern
• Seizures (60-80% of patients)
• Scoliosis (up to 85% of patients by age 16)
• Growth retardation
• Gastrointestinal issues (constipation, gastroesophageal reflux)
• Small, cold hands and feet

Atypical Rett Syndrome:

Some individuals may have variant forms of Rett syndrome with milder or more severe features:

• Preserved Speech Variant (Zappella variant)
• Early Seizure Variant (Hanefeld variant)
• Congenital Variant (Rolando variant)

Diagnosis of Rett Syndrome

Clinical Diagnosis:

Based on characteristic clinical features and developmental history. Diagnostic criteria have been established by the Rett Syndrome Diagnostic Criteria Working Group (2010):

Main Criteria (all required):

1. Partial or complete loss of acquired purposeful hand skills
2. Partial or complete loss of acquired spoken language
3. Gait abnormalities
4. Stereotypic hand movements

Supportive Criteria (at least 2 required):

1. Breathing disturbances when awake
2. Bruxism when awake
3. Impaired sleep pattern
4. Abnormal muscle tone
5. Peripheral vasomotor disturbances
6. Scoliosis/kyphosis
7. Growth retardation
8. Small cold hands and feet
9. Inappropriate laughing/screaming spells
10. Diminished response to pain
11. Intense eye communication ("eye pointing")

Genetic Testing:

• Molecular genetic testing of MECP2 gene
  • Sequence analysis
  • Deletion/duplication analysis
• Consider testing for other genes (CDKL5, FOXG1) if MECP2 testing is negative and clinical suspicion is high

Differential Diagnosis:

• Angelman syndrome
• Autism spectrum disorders
• Cerebral palsy
• Landau-Kleffner syndrome
• Other genetic disorders (Pitt-Hopkins syndrome, CDKL5 disorder)

Additional Evaluations:

• Neurological examination
• Developmental assessment
• EEG (for seizure activity)
• Brain MRI (to rule out other conditions)
• Orthopedic evaluation (for scoliosis)
• Gastrointestinal assessment

Management of Rett Syndrome

Management of Rett syndrome is multidisciplinary and focuses on symptomatic treatment and supportive care:

Neurological Management:

• Anticonvulsant medications for seizure control
• Regular neurological follow-up
• Monitoring of EEG patterns

Physical and Occupational Therapy:

• Maintenance of motor skills and mobility
• Prevention of contractures
• Assistance with activities of daily living
• Use of assistive devices and adaptive equipment

Speech and Language Therapy:

• Alternative and augmentative communication strategies
• Eye gaze technology for communication

Nutritional Support:

• Dietary management to ensure adequate nutrition
• Gastrostomy tube feeding if necessary

Gastrointestinal Management:

• Treatment of constipation and gastroesophageal reflux
• Monitoring of feeding and swallowing difficulties

Orthopedic Care:

• Monitoring and management of scoliosis
• Bracing or surgical intervention if necessary

Respiratory Care:

• Monitoring of breathing abnormalities
• Management of hyperventilation and apnea episodes

Sleep Management:

• Sleep hygiene practices
• Consideration of melatonin or other sleep aids if necessary

Psychological Support:

• Behavioral interventions for anxiety and mood issues
• Family counseling and support

Educational Planning:

• Individualized Education Program (IEP)
• Adaptive learning strategies

Emerging Therapies:

• Gene therapy (in research phase)
• Targeted drug therapies (e.g., trofinetide, in clinical trials)

Long-term Care:

• Regular multidisciplinary follow-up
• Transition planning to adult care services
• Consideration of long-term care needs