Rett Syndrome

Genetics

• Rett syndrome is a rare genetic disorder that is inherited in an X-linked dominant fashion.
• Second most common cause of severe intellectual disability after Down syndrome (trisomy 21) 
• Genetic mutations that cause the disease occur sporadically (99% are de novo)
  • 90%–95% of cases are caused by mutations of the MECP2 gene (methyl-CpG binding protein 2).
  • Mutation affects protein production critical for brain development 
  • The mutated copy is often associated with the paternal allele since it occurs during spermatogenesis (only females inherit the paternal X chromosome, as the paternal Y chromosome determines the male sex of the fetus).
• Females are almost exclusively affected.
  • Most males with this mutation are believed to die in utero or during early infancy.
  • Incidence is 1 in 10,000 girls by age 12 in the United States.
• Some boys may have a different mutation, resulting in a less destructive form of Rett syndrome. 
  • Life expectancy is higher.
  • Lower risk for intellectual and developmental problems

Clinical Presentation and Diagnosis

Clinical presentation

• Individuals with Rett syndrome often have normal development until 7–24 months of age.
• Developmental stagnation occurs between 6 and 18 months of age.
• Around the ages of 1–4 years, individuals lose previously acquired skills (regression).

Diagnosis

• Diagnosis is based on clinical presentation, a detailed patient history, and thorough clinical evaluation.
• Genetic testing for MECP2 gene mutations may be used to confirm and/or rule out similar syndromes.

Stages

Stage I: Developmental arrest (6–18 months of age)

• Signs and symptoms are subtle.  
• Lasts for a few months up to a year
• May present with less eye contact and placidity
• The achievement of developmental milestones becomes slowly and increasingly delayed.

Stage II: Rapid deterioration or regression (1–4 years of age)

• Children lose the ability to perform previously acquired skills.
• Loss can be rapid or more gradual.
• Reduced head growth
• Abnormal hand movements (“wringing”)
• Hyperventilating
• Screaming or crying for no apparent reason
• Problems with movement and coordination
• Loss of social interaction and communication

Stage III: Plateau or pseudo-stationary (2–10 years)

• Minimal regression may be seen in the symptoms with some improvement of skills.
• Seizures may begin in this stage.

Stage IV: Late motor deterioration (> 10 years)

• Marked by reduced mobility 
• Muscle weakness
• Joint contractures
• Scoliosis

Complications

• Sleep problems cause significant fatigue and restlessness.
• Difficulty eating leads to malnutrition.
• Bowel and bladder problems
  • Constipation
  • Gastroesophageal reflux disease (GERD)
  • Bowel or urinary incontinence 
  • Gallbladder disease
• Pain may accompany other problems, such as gastrointestinal issues or bone fractures.
• Muscle, bone, and joint problems
• Anxiety and problematic behavior that may hinder social functioning
• Needing lifelong care and assistance with activities of daily life
• Shortened life span (median survival is approximately 45 years of age)

Differential Diagnosis

The following conditions are differential diagnoses for Rett syndrome:

• Angelman syndrome: an autosomal neuro-developmental disease resulting from epigenetic sex-specific genomic imprinting and uniparental disomy of paternal chromosome 15 with a simultaneous functional loss of the maternal part. Characterized by inappropriate laughter, seemingly happy demeanor, short attention span, lack of proper speech, use of non-verbal communication skills, ataxia, fine tremors, jerky movements, and severe developmental delay.
• Prader-Willi syndrome: a rare autosomal neuro-developmental disease resulting from genomic imprinting and uniparental disomy of maternal chromosome 15 with a simultaneous functional loss of the parental part. Characterized by hypotonia, lethargy, feeding difficulties, breathing difficulties, and hypogonadism at birth; with scoliosis, strabismus, speech delay, intellectual delays, and behavioral issues during childhood.
• Landau-Kleffner syndrome: a rare neurodevelopmental disorder characterized by the loss of language comprehension, aphasia, and seizures, with severely abnormal electroencephalogram (EEG) findings during sleep and seizures.
• Autism spectrum disorder: a neurodevelopmental disorder with early-childhood onset, marked by poor social skills, restricted social interaction and communication, and repetitive and stereotyped behaviors. Because it is a spectrum, some patients exhibit impairment in language and intellectual levels, while others may have normal or even advanced levels.
• Cerebral palsy: a syndrome of motor impairment caused by a nonprogressive central nervous system injury. Classified according to muscle tone, distribution, and the presumed time of injury. May also present with sensory, cognitive, communication, and behavioral disturbances; epilepsy; and musculoskeletal impairment.
• CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder: a rare genetic disorder that is inherited in an X-linked pattern and characterized by early-onset seizures and severe neurodevelopmental impairment. May also present with scoliosis, visual impairment, sensory issues, and various gastrointestinal difficulties. 
• FOXG1-related disorders or FOXG1 syndrome: a group of disorders caused by a mutation of the FOXG1 gene. Affected individuals develop normally in the perinatal period. This is followed by progressive microcephaly, seizures, developmental delays, and severe intellectual disability. May also present with constipation, gastroesophageal reflux, scoliosis, foot deformities, and stereotypic hand movements.