The Diagnosis of Rett Syndrome (RTT)

I. Introduction

• Definition: Rett Syndrome (RTT) is a rare neurodevelopmental disorder, primarily affecting females, characterized by developmental regression, loss of acquired skills, and stereotypic hand movements.
• Historical Milestones:
  • 1966: First described by Dr. Andreas Rett.
  • 1999: Association with mutations in the MECP2 gene (Amir et al.).
• Current Understanding:
  • RTT is neurodevelopmental rather than degenerative.
  • Despite advances, diagnosis remains clinical due to imperfect genotype-phenotype correlations.

II. Overview of Clinical Features

1. Developmental Regression (Defining Feature):
   • Loss of acquired purposeful hand use and spoken language.
   • Onset typically after 6–18 months of normal development.
2. Dynamic Course:
   • Periods of regression followed by stabilization or partial recovery.
3. Neurological Features:
   • Hand stereotypies (e.g., wringing, mouthing).
   • Gait abnormalities (e.g., ataxia, dyspraxia).
   • Seizures: High prevalence but variable severity.
4. Behavioral Features:
   • Initial autism-like behaviors, followed by anxiety and mood instability.
   • Inappropriate laughing/screaming (supportive diagnostic criterion).
5. Systemic Features:
   • Orthopedic: Scoliosis, kyphosis, contractures.
   • Growth abnormalities: Deceleration in head growth, small hands and feet.
   • Cardiac: Prolonged QT interval.
   • Other: Osteopenia, gastrointestinal issues.

III. Evolution of Diagnostic Criteria

1. 1985 Criteria:
   • Introduced inclusion and exclusion criteria.
   • Emphasis on female predominance and regression of language and hand use.
2. 1988 Criteria:
   • Included supportive criteria to assist diagnosis.
3. 2002 Revision:
   • Acknowledged MECP2 mutations and recognized atypical RTT.
4. 2010 Criteria (Current):
   • Simplified framework validated on a large cohort.
   • Introduced two clinical forms:
     • Typical RTT: Requires all core features.
     • Atypical RTT: Requires at least two core features and five supportive criteria.

IV. Current Diagnostic Criteria (2010)

Typical RTT

• Required Criteria:
  1. Period of regression followed by stabilization.
  2. Loss of purposeful hand use.
  3. Loss of spoken language.
  4. Gait abnormalities.
  5. Hand stereotypies.
• Exclusion Criteria:
  • Severe brain injury.
  • Abnormal psychomotor development in the first 6 months.

Atypical RTT

• Requires:
  • Developmental regression plus:
    • At least 2 of the 4 core criteria.
    • At least 5 of 11 supportive criteria.

V. Supportive Criteria (Atypical RTT)

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

VI. Genetic Considerations

• MECP2 Mutations:
  • Found in 95–97% of typical RTT cases.
  • Phenotypic spectrum includes asymptomatic carriers and severe encephalopathy in males.
• Atypical RTT Genes:
  • CDKL5: Early seizure variant.
  • FOXG1: Congenital variant.
  • Other associated genes: SCN8A, TCF4, IQSEC2.

VII. Diagnostic Challenges

• Overlap with other disorders:
  • Autism spectrum disorder.
  • Angelman syndrome.
  • Intellectual disability.
• Differentiating regression:
  • Post-epileptic changes vs. primary regression.
• Early diagnosis:
  • Possible RTT diagnosis in children under 3 years with suggestive features.

VIII. Prognostic and Management Implications

• Diagnosis impacts:
  • Therapeutic strategies (e.g., gene therapy).
  • Supportive care: Occupational therapy, physical therapy.
  • Prognosis: Guides expectations and interventions.

IX. Future Directions

• Continuous updates to diagnostic criteria.
• Increasing reliance on genetic testing and whole exome sequencing.
• Potential for newborn screening for MECP2 mutations.

X. Conclusion

• RTT diagnosis remains predominantly clinical despite genetic advances.
• Accurate diagnosis is essential for effective management and prognosis.
• Collaboration through initiatives like RettSearch is critical for refining diagnostic frameworks and improving patient outcomes.

References

Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23(2): 185‒188