Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations

Stéphanie Baulac*, Saeko Ishida, Elise Marsan, Catherine Miquel, Arnaud Biraben, Dang Khoa Nguyen, Doug Nordli, Patrick Cossette, Sylvie Nguyen, Virginie Lambrecq, Mihaela Vlaicu, Maïlys Daniau, Franck Bielle, Eva Andermann, Frederick Andermann, Eric Leguern, Francine Chassoux, Fabienne Picard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

196 Scopus citations


Objective The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). Methods Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. Results All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation. Interpretation Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "2-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.

Original languageEnglish (US)
Pages (from-to)675-683
Number of pages9
JournalAnnals of neurology
Issue number4
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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