What is Rett Syndrome?
Rett syndrome (RTT) is a rare X-linked dominant neurodevelopmental disorder caused by mutations in the MeCP2 gene (methyl-CpG-binding protein 2) that predominantly affects females, characterized by early normal development followed by progressive loss of purposeful hand movements, speech, and motor skills, with the development of characteristic stereotyped hand-wringing or hand-washing movements. 1
Genetic Basis and Epidemiology
- Prevalence: 1-9 per 100,000 births 2
- Genetic cause: Over 90% of cases are linked to mutations in the MeCP2 gene located on the X chromosome (Xq28 locus) 3, 4
- Sex distribution: Occurs almost exclusively in females; males with the same mutations typically present with more severe manifestations ranging from fatal encephalopathy to nonspecific X-linked intellectual disability 1
- The MeCP2 protein plays pivotal roles in epigenome regulation, neuronal physiology, synaptic maintenance, and behavior 5
Clinical Presentation and Developmental Pattern
Early Development
- Normal at birth: Head circumference and development are normal during infancy 1
- Onset: Regression typically occurs before 4 years of age 1
Cardinal Features
The syndrome manifests through a distinctive pattern of developmental regression:
Motor deterioration:
- Deceleration of head growth before age 4 years 1
- Loss of purposeful hand movements 1
- Development of characteristic stereotyped hand movements (wringing or washing) 1
- Ataxia and apraxia 4
- Progressive loss of mobility 6
Communication impairment:
Behavioral and cognitive changes:
Associated Comorbidities
RTT presents with multiple systemic complications that significantly impact quality of life 3:
- Neurological: Frequent seizures, epilepsy 3, 4
- Respiratory: Irregular breathing with hyperventilation while awake, breath-holding spells 3, 4
- Musculoskeletal: Scoliosis (requiring surgery in 1.2%-50% of cases) 6
- Growth: Poor growth, feeding difficulties 3
- Sleep: Disrupted sleep patterns 3
Neuropathology
The underlying brain changes include 4:
- Decreased brain growth and brain atrophy
- Reduced size of individual neurons with thinned dendrites in cortical layers
- Abnormalities in substantia nigra (decreased neuromelanin content)
- Deficient synaptogenic development, likely starting before birth
- Reduced levels of multiple neurotransmitters (dopamine, serotonin, noradrenaline, glutamate) and nerve growth factors
Diagnostic Approach
Clinical diagnosis is based on the characteristic pattern of normal early development followed by regression with specific features 1.
Genetic testing for MeCP2 mutations confirms the diagnosis in most cases, though clinical and genetic heterogeneity exists with other genes involved in epigenetic regulation, neurotransmitter action, or RNA transcription/translation also implicated in Rett-like phenotypes 7.
Management Approach
Current management requires a multidisciplinary approach focusing on supportive care 3:
Ancillary services (utilization varies widely):
- Physical therapy: 24.4%-100% of patients 6
- Occupational therapy: 11.5%-91.7% of patients 6
- Note: Pediatric patients demonstrate 2-4 fold higher utilization compared to adults 6
Assistive devices:
- Wheelchair use reported in up to 90% of patients 6
Surgical interventions:
- Scoliosis correction when indicated 6
Assisted interventions:
- Enteral feeding: 2.0%-52.0% of patients 6
Symptomatic treatment:
- Anticonvulsive therapy for seizures 4
- Management of respiratory irregularities
- Sleep disorder management
Emerging Therapies
Research is actively pursuing genetic therapeutic approaches 5:
- Gene replacement therapies with controlled MeCP2 expression
- DNA/RNA editing strategies
- Reactivation of the silenced X chromosome
These approaches face current limitations in transduction efficiency and brain delivery but represent promising future directions 5.