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Familial focal epilepsy with focal cortical dysplasia due to DEPDC 5 mutations
Author(s) -
Baulac Stéphanie,
Ishida Saeko,
Marsan Elise,
Miquel Catherine,
Biraben Arnaud,
Nguyen Dang Khoa,
Nordli Doug,
Cossette Patrick,
Nguyen Sylvie,
Lambrecq Virginie,
Vlaicu Mihaela,
Daniau Maïlys,
Bielle Franck,
Andermann Eva,
Andermann Frederick,
Leguern Eric,
Chassoux Francine,
Picard Fabienne
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24368
Subject(s) - cortical dysplasia , epilepsy , germline mutation , mutation , epilepsy surgery , magnetic resonance imaging , gene mutation , pathology , medicine , cancer research , biology , neuroscience , genetics , gene , radiology
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. Ann Neurol 2015;77:675–683