Abstracts

Rationale: We recently reported that mutations in Dishevelled, Egl-10 and Pleckstrin Domain Containing protein 5 (DEPDC5) cause Familial Focal Epilepsy with Variable Foci (FFEVF). This epilepsy syndrome was first recognised in large multiplex families with heterogeneous focal epilepsies. Further to the identification of DEPDC5 as the causative gene for FFEVF, case ascertainment by the presence of a mutation is now possible, rather than relying on rare, large FFEVF kindreds. Here we analyse the DEPDC5 focal seizure phenotypes with the addition of new sporadic subjects and small families with DEPDC5 mutations.Methods: Epilepsy subjects were selected from a large cohort of individuals recruited for epilepsy genetics research. Informed consent was given by all participants. Detailed epilepsy phenotyping was performed by scrutinizing all available clinical data, and administering a validated seizure questionnaire. EEG, MRI, SPECT and PET data were also reviewed. DEPDC5 mutation detection was performed by High Resolution Melt Curve Analysis and validated by Sanger sequencing (Dibbens et al). DEPDC5 variants represented in databases of normal variation or predicted (using PolyPhen-2) to be benign or to have only possible pathogenicity were excluded. Results: We present clinical data on 46 subjects with epilepsies and mutations in DEPDC5. This includes 36 patients whose clinical phenotypes have not hitherto been detailed, together with updated clinical data from 10 subjects previously reported. The core epilepsy phenotypes were frontal lobe epilepsy (22 subjects), mesial temporal (10), lateral temporal (3), occipital (N=1), parietal (N=1) and non-localizable (N=9) focal epilepsies. 2 subjects with severe, refractory frontal lobe epilepsies showed cognitive decline. 2 subjects had a history of epileptic spasms, with favourable outcomes. Epilepsy onset ages were 6 weeks to 55 years, median 7.5 years. EEG data were available from 38 subjects and showed focal epileptiform abnormalities in 32. Conclusions: DEPDC5 mutations are a common cause of focal epilepsies, with frontal and temporal epilepsies most frequently seen. Case ascertainment through DEPDC5 mutation testing reveals an extended phenotypic spectrum, including subjects with epileptic spasms and others with severe focal epilepsies associated with cognitive decline. The recent discovery that DEPDC5 is a regulator of mTOR complex 1 suggests that DEPDC5 phenotypes may arise due to derepression of mTOR signalling. This raises the exciting possibility that mTOR inhibitors could offer effective therapy for individuals refractory to conventional anti-epileptic drugs.