MECP2 disorders in females include classic and atypical Rett syndrome, and learning disabilities. In males, MECP2 disorders include congenital encephalopathy, atypical Rett syndrome, mental retardation, and MECP2 duplication syndrome.

Epidemiology

• Prevalence - 1/10,000
• Age - presentation in early childhood
• Sex - F>M

Inheritance

• X-linked dominant with almost 100% penetrance
• Most MECP2 sequence changes or deletions are de novo; however, MECP2 duplications are maternally inherited
• The majority (~80%) of MECP2 mutations are sequence variants, up to 15% are deletions, gene duplications are rare and detectable by routine cytogenetic analysis in approximately 5% of cases
• MECP2 deletions or nonsense mutations are generally associated with a more severe phenotype than missense mutations
• MECP2 mutations are variably expressed based on sex
  • Females - usually classic Rett, but atypical Rett or mild learning disabilities may result due to skewed X chromosome inactivation
  • Males - clinical presentations can include severe congenital encephalopathy, atypical Rett, mild to severe mental retardation or MECP2 duplication syndrome
    • Males with XXY karyotype, or somatic MECP2 mutations may present with classic Rett
    • MECP2 duplication syndrome
      • Affected males; female carriers are unaffected due to skewed X inactivation
      • Severity is usually consistent within families but interfamilial variability may occur

Pathophysiology

• Probable abnormal development of the cortex in infancy
• Dysregulation of the autonomic system and associated brainstem dysregulation

Clinical Presentation

• Classic Rett
  • Apparently normal prenatal and perinatal history
  • Normal growth and development until 6-18 months of age followed by rapid neurodevelopmental regression
  • Normal head circumference at birth with postnatal head growth deceleration
  • Purposeful hand movements replaced with repetitive stereotyped hand movements
  • Loss of acquired speech
  • Non-ambulatory or gait ataxia
  • Social withdrawal or autistic features
  • Associated findings include; seizures (occur in up to 90%), abnormal EEG, breathing irregularities, sleep disturbances, bruxism and scoliosis
• Atypical Rett
  • Rett-like features that do not completely meet clinical criteria
• MECP2 duplication syndrome
  • Infantile hypotonia
  • Severe mental retardation
  • Absence of speech
  • Progressive spasticity
  • Recurrent respiratory infections (75%)
  • Seizures (50%)
  • Congenital encephalopathy
  • Mild to severe mental retardation
  • Carrier females may have mild cognitive symptoms due to skewed X chromosome inactivation
  • Clinical severity may be related to the specific mutation, its location within MECP2 and pattern of X inactivation

Treatment

• Mainly supportive
• Seizure control may require drug therapy
• Pharmacological therapies to reduce agitation, hyperventilation or sleep dysfunction may be used
• Restraints may be considered to prevent self injurious behavior and reduce agitation
• Assessment of feeding and digestive issues (constipation and reflux are common)
• Bracing or surgical intervention for scoliosis
• Avoid use of drugs associated with prolongation of QT interval (prokinetic agents, antipsychotics, antiarrhythmics, anesthetic agents, etc.)

Diagnosis

• Based on clinical criteria
• Confirmed by the identification of an MECP2 mutation
  • MECP2 gene sequencing - 80% clinical sensitivity
  • MECP2 duplication/deletion analysis - clinical sensitivity up to 15%
  • CGH array - detection of deletions or duplications only
• Targeted testing should be offered to parents who have a child with an MECP2 mutation to help define recurrence risk
• Prenatal diagnosis of subsequent pregnancies of a couple who has a child with an identified MECP2 mutation should be offered (germline mosaicism cannot be excluded)

Differential Diagnosis

• Angelman syndrome
• Autism
• Cerebral palsy
• Inborn errors of metabolism (in males with congenital encephalopathy)
• Mental retardation