What is Rett syndrome?

Rett Syndrome: Clinical Features, Diagnosis, and Management

Rett syndrome is a severe, progressive neurodevelopmental disorder primarily affecting females that is caused by mutations in the X-linked MECP2 gene, characterized by apparently normal early development followed by regression of acquired skills, distinctive hand stereotypies, and multiple neurological impairments. 1, 2

Definition and Epidemiology

• Rett syndrome is one of the most common genetic causes of severe intellectual disability in females, with an incidence of approximately 1:10,000 female births 3, 4
• It occurs almost exclusively in females, although rare cases in males have been reported 5
• The disorder is primarily caused by mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene, which encodes a transcriptional repressor protein crucial for brain development 1, 2

Clinical Presentation and Diagnostic Features

Core Clinical Features

• Initial apparently normal development for the first 6-18 months of life 3, 2
• Developmental regression with loss of acquired fine and gross motor skills and social interaction 3
• Loss of purposeful hand movements replaced by distinctive stereotypic hand movements (hand wringing/washing) 1, 3
• Loss of speech and language skills 1, 2
• Impaired ambulation 2

Neurological Manifestations

• Seizures occur in a significant proportion of patients (5-46% of children with Rett syndrome) 1
• Breathing irregularities including hyperventilation while awake 4, 2
• Ataxia and apraxia affecting movement and coordination 3, 4
• Progressive motor deterioration 1, 2

Associated Features

• Acquired microcephaly (deceleration of head growth) 1
• Sleep disturbances 1
• Anxiety 2
• Gastrointestinal issues, particularly constipation 2
• Scoliosis and osteoporosis 3
• Spasticity affecting mobility 3

Genetic Basis

• Classical Rett syndrome is primarily caused by mutations in the MECP2 gene located on the Xq28 locus 4, 6
• The MeCP2 protein functions as a transcriptional regulator that affects multiple neurodevelopmental processes 2
• Atypical variants of Rett syndrome may be associated with mutations in other genes:
  • Early-onset seizure variant: mutations in CDKL5 gene 3, 6
  • Congenital variant: mutations in FOXG1 gene 3, 6
• Genetic testing should be performed in all suspected cases to confirm diagnosis 1, 6

Clinical Variants

• Classical form: The most common presentation with the typical developmental regression pattern 3
• Congenital variant: Abnormal development from birth without the typical regression period 3
• Early-onset seizure variant: Characterized by seizures beginning before 5 months of age 3
• Preserved speech variant: Milder form with some preservation of language skills 3
• "Forme fruste": Incomplete or atypical presentations 3

Diagnostic Evaluation

• Genetic testing is essential for diagnosis, with testing for MECP2 mutations being the primary diagnostic test 1, 6
• Comprehensive developmental evaluation to assess cognitive, motor, and social-emotional development 7
• Electroencephalography (EEG) is typically abnormal in later stages of the syndrome 4
• Neuroimaging may show brain atrophy and is helpful for differential diagnosis 4
• Audiological assessment should be performed to rule out hearing loss as a cause of speech delay 7

Management Approach

Multidisciplinary Care

• A coordinated multidisciplinary assessment is recommended for all patients with Rett syndrome 1, 3
• The team should include neurologists, geneticists, developmental pediatricians, physical therapists, occupational therapists, and speech-language pathologists 1, 3

Symptomatic Treatment

• Seizure management with appropriate anticonvulsant medications 3, 4
• Physical therapy to address mobility issues, prevent contractures, and manage scoliosis 3
• Occupational therapy for hand function and activities of daily living 3
• Speech and language therapy with consideration of alternative communication systems for severely affected individuals 7, 3
• Management of gastrointestinal issues, particularly constipation 2
• Monitoring and treatment of osteoporosis 3
• Behavioral therapy for anxiety and other behavioral issues 7, 2

Emerging Treatments

• Trofinetide, an IGF1-related compound, has been approved for Rett syndrome treatment 2
• Gene therapies are currently under investigation 2
• Clinical trials are ongoing for various targeted therapies 2

Prognosis

• Rett syndrome is a lifelong condition with variable progression and severity 3
• Most individuals require lifelong support and care 3, 2
• Life expectancy may be reduced, though many patients survive into adulthood 4
• Quality of life can be significantly improved with appropriate supportive care and symptom management 2

Important Considerations and Pitfalls

• Early diagnosis is crucial but often delayed due to the initial period of apparently normal development 5
• Relying solely on clinical observation without genetic testing may lead to misdiagnosis 7
• Regular reassessment is essential as the clinical manifestations evolve over time 7
• Seizures may be difficult to distinguish from non-epileptic paroxysmal events, requiring careful evaluation 3
• Development of scoliosis and spasticity can significantly impact mobility and requires proactive management 3