Molecular characteristics

  • Most AKT3 mutations identified to date are de novo (i.e. not inherited)
  • Mutations can be either germline (constitutional; present in all tissues of an affected child) or post-zygotic (mosaic; present in only a small fraction of cells of an affected child).
  • AKT3 mutations are known to be associated with gain of function (or activation) of PI3K-AKT-MTOR pathway activity.
  • The mutational spectrum of AKT3 mutations is somewhat narrow with most identified variants 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 severely activating mutations (i.e. E17K) are associated with severe overgrowth and cellular dysplasia causing epilepsy phenotypes (such as 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 and usually intellectual disability and or autism but with mild or no epilepsy.