Molecular characteristics

  • Most AKT3 mutations identified to date are de novo.
  • Mutations can be either germline (constitutional) or post-zygotic (mosaic).
  • AKT3 mutations are known to be associated with Gain of Function (GOF) of PI3K-AKT-MTOR pathway activity.
  • The mutational spectrum of AKT3 mutations is somewhat narrow with most identified mutations involving amino acid residue 17 (p.E17K).
  • Preliminary genotype-phenotype correlations suggest that phenotypes depend on tissue distribution, levels of mosaicism and type of the AKT3 mutation with three general correlations appreciated:
    • The most severe GOF mutations (i.e. E17K) are associated with severe overgrowth and cellular dysplasia causing HMEG or FCD.
    • Intermediate GOF mutations are, with rare exceptions, associated with MEG and PMG (i.e. features similar to MCAP syndrome).
    • The least severe GOF mutations are associated with diffuse MEG with apparently normal gyral pattern.