Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia

Ann Neurol. 2015 Apr;77(4):720-5. doi: 10.1002/ana.24357. Epub 2015 Feb 26.

Abstract

Focal malformations of cortical development, including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycin pathway may hold promise for malformation-associated epilepsy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Hemimegalencephaly / diagnosis
  • Hemimegalencephaly / genetics*
  • Humans
  • Malformations of Cortical Development / diagnosis
  • Malformations of Cortical Development / genetics*
  • Mutation / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Repressor Proteins / genetics*
  • Signal Transduction / genetics*
  • TOR Serine-Threonine Kinases / genetics*

Substances

  • DEPDC5 protein, human
  • Repressor Proteins
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt