Genes May Play Greater Role in Focal Epilepsy than Previously Thought

The team discovered 5 mutations each in NPRL2 (4 familial and 1 sporadic) and NPRL3 (all familial) and 18 new mutations in DEPDC5 (17 familial and 1 sporadic). Exome sequencing analysis implicated NPRL2 and NPRL3 as the primary candidates underlying familial focal epilepsy among the 2 families studied.

Focal epilepsy–associated brain malformations, identified in 4 persons among the 404 study participants, were likely attributed to increased mTOR-activity resulting from the GATOR1 mutations, according to the researchers. Among the 4 cases were 2 that were sporadic but found to have a GATOR1 gene mutation: one was a case of frontal lobe epilepsy with a tumor-like brain lesion and the other a case of focal epilepsy with a bilateral brain malformation. The researchers surmised that dysregulation of mTOR-mediated control of cell growth causes patches of irregular growth that, in turn, disrupt neural circuitry, resulting in epilepsy. As for persons with focal epilepsy in whom brain lesions are not detected, further study into cryptogenic GATOR1 gene-related anatomical alterations in cell growth may be in order, the researchers said.

In all, the findings suggest that defective mTOR signaling and dysregulation of cell growth during brain development may play a greater role in focal epilepsy than has been recognized. In their forward-looking conclusion, the study authors said that further research may provide new avenues for therapeutic research, such as the prospect of mTOR inhibitors.


  1. Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45(5):546-551.
  2. Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mTOR pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2015; doi:10.1002/ana.24547.