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

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.

Figure 1

MRI images of FCD and HME mutation-positive patients. A. This axial inverted T2 image from the MRI of Patient FCD-1, with the germline DEPDC5 p.N261Kfs*11 frameshift mutation, shows a right frontal FCD II (arrows), seen as blurring of the gray-white matter junction and abnormal gray matter signal extending toward the ventricle. B. This T2-weighted axial image from the MRI of Patient FCD-2, harboring the germline DEPDC5 c.624+1G>A splice-altering mutation, shows the FCD II characterized by blurring of the gray-white matter junction and abnormal deep gyral configuration in the left parietal region (arrows). C&D. These T2-weighted axial (C) and coronal (D) images from Patient HME-1, with the germline DEPDC5 p.N45Qfs*3 frameshift mutation, illustrate right hemimegalencephaly, with abnormally thick gray matter, abnormal signal in the white matter, and an enlarged right ventricle. Images are shown using MRI convention (R = right, L = left).

Figure 2

Schematic of the mTOR pathway annotated with pathogenic mutations and likely pathogenic variant identified in this study; mosaic mutations are bolded.