Scientific article
Open access

Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations

Published inAnnals of neurology, vol. 77, no. 4, p. 675-683
Publication date2015-04

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 four 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, five of them underwent surgery, and one a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although MRI was typical in only four cases. Histopathology confirmed FCD IIa in two patients (including one MRI-negative case) and showed FCD I in two other patients, and remained inconclusive in the last two. Three patients were seizure-free post-surgically and one had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all four families; one mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in one 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 "two-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. This article is protected by copyright. All rights reserved.

Citation (ISO format)
BAULAC, Stéphanie et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. In: Annals of neurology, 2015, vol. 77, n° 4, p. 675–683. doi: 10.1002/ana.24368
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Article (Accepted version)
ISSN of the journal0364-5134

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