title: Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sorbonne Universités, Pierre and Marie Curie University, UPMC Univ Paris 06, UM 75, ICM, Paris, France; National Institute of Health and Medical Research, INSERM U1127, ICM, Paris, France; National Center for Scientific Research, CNRS, UMR 7225, ICM, Paris, France; Brain and Spine Institute, Institut du Cerveau et de la Moelle (ICM), Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
authors.forename: Saeko
authors.initials: S
authors.lastname: Ishida
authors.forename: Elise
authors.initials: E
authors.lastname: Marsan
authors.forename: Catherine
authors.initials: C
authors.lastname: Miquel
authors.forename: Arnaud
authors.initials: A
authors.lastname: Biraben
authors.forename: Dang Khoa
authors.initials: DK
authors.lastname: Nguyen
authors.forename: Doug
authors.initials: D
authors.lastname: Nordli
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.forename: Sylvie
authors.initials: S
authors.lastname: Nguyen
authors.forename: Virginie
authors.initials: V
authors.lastname: Lambrecq
authors.forename: Mihaela
authors.initials: M
authors.lastname: Vlaicu
authors.forename: Maïlys
authors.initials: M
authors.lastname: Daniau
authors.forename: Franck
authors.initials: F
authors.lastname: Bielle
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.forename: Francine
authors.initials: F
authors.lastname: Chassoux
authors.forename: Fabienne
authors.initials: F
authors.lastname: Picard
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004828:Epilepsies, Partial / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000175:diagnosis* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; D012097:Repressor Proteins