Overview of Rett Syndrome (RTT)

  • Definition: Rett syndrome (RTT; OMIM #312750) is a severe neurodevelopmental disorder predominantly affecting girls, one of the most common genetic causes of intellectual disability in females.
  • Clinical Characteristics:
    • Initial variable developmental delay
    • Regression of spoken language and hand function typically begins in the second year of life and concludes before age 3
    • Subsequent development and progression of neurological symptoms, prominently distinctive hand stereotypies

    Genetic Basis

    • Main Genetic Cause:
      • More than 96% of RTT cases involve loss-of-function (LOF) de novo mutations in the MECP2 gene
      • MECP2 is located on X chromosome (Xq28; chrX:154,021,573–154,097,717 GRCh38/hg38)
      • Encodes methyl-CpG-binding protein 2 (MeCP2)

      Clinical Diagnosis

      • Over 300 known MECP2 variants identified
      • Eight hotspot pathogenic variants represent more than 60% of documented RTT cases
      • Commonly involve C-to-T transitions at methylated CpG sites, susceptible to spontaneous deamination and thymine conversion

      Pathophysiology

      • A minority carry variants in other genes or have no known genetic mutations
      • MECP2 variants also associated with other clinical presentations, complicating genotype–phenotype correlation

      Clinical Manifestations and Evolution

      • Clinical Criteria:
        • RTT diagnosis remains clinical due to variability in MECP2 genotype–phenotype correlation
        • Boys with MECP2 pathogenic variants typically have severe disease, shortened life expectancy
        • Females generally survive into adulthood, with ~70% reaching their 50s

        Management and Treatment

        • Function of MeCP2:
          • Highly expressed in the brain, essential for normal neural development and function
          • Primarily acts as a transcriptional repressor by linking methylated DNA to deacetylated histones
          • Other gene-regulatory roles are proposed but less well-characterized

          Quality of Life Considerations

          • Alterations in neuronal function, particularly affecting synaptic connections
          • Critical roles in astrocyte functioning

          Current Research and Future Directions

          • Neurological Symptoms:
            • Characteristic hand stereotypies (wringing, clasping, tapping)
            • Seizures
            • Progressive motor impairments, spasticity, dystonia

            Epidemiology of Rett Syndrome (RTT)

            • Osteoporosis and other skeletal abnormalities
            • Respiratory dysfunction, gastrointestinal issues
            • Sleep disturbances, autonomic dysfunction

            Genetics of Rett Syndrome (RTT)