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

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

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1
Division of Genetics and Genomics, Department of Medicine, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA.

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.

PMID:
25599672
PMCID:
PMC4471336
DOI:
10.1002/ana.24357
[Indexed for MEDLINE]
Free PMC Article

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