Familial focal epilepsy with variable foci

The Causal Disease Familial focal epilepsy with variable foci (FFEVF) is an autosomal dominant disorder typically characterized by different electroclinical focal seizure patterns in different family members. The disease was first mapped to chromosome 22q11-q12 in 1999 [1]. The causative gene, DEPDC5, was identified 14 years later through exome sequencing [2,3]. Mutations inDEPDC5 are also identified in up to 16% of families with focal epilepsies [2–5]. Mutations inDEPDC5 have also been identified in a variety of other defined familial focal epilepsy syndromes, including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [6], familial mesial temporal lobe epilepsy [3] and autosomal dominant epilepsy with auditory features (ADEAF, also called familial lateral temporal lobe epilepsy) [7,8], as well as in rare cases of rolandic epilepsy [5] and severe infantile-onset epilepsies [5,9,10]. DEPDC5 contains 43 exons and codes for the protein DEP domain-containing protein 5 [11]. DEPDC5 is a subunit of the GATOR1 complex, a negative regulator of the mechanistic target of rapamycin complex mTORC1 in response to decreased amino acid availability (Figure 21.1) [12]. mTORC1 is a kinase complex involved in pivotal neuronal functions, including cell proliferation, survival, growth and plasticity [13]. Recently, heterozygous mutations have also been identified in NPRL2 and NPRL3 in patients with various types of focal epilepsies [10,14–16]. NPRL2 and NPRL3 encode the proteins nitrogen permease regulator-like 2 and 3, respectively, the two remaining components of the GATOR1 complex. Subsequently, malformations of cortical development were identified in some of the individuals carrying mutations in DEPDC5, NPRL2 and NPRL3 [16–19]. Expression studies in human and mouse tissues have demonstrated that DEPDC5, NPRL2 and NPRL3 are ubiquitously expressed, with higher levels in brain regions in comparison to other organs [2,10]. The genes are expressed in all brain regions and throughout brain development. In-vitro studies have demonstrated disruption of the DEPDC5-dependent inhibition of mTORC1 for some of the mutations, lending support to the hypothesis that excessive mTORC1 signalling is responsible for the epilepsy in these [20]. Hyperactivation of mTORC1 was also demonstrated in brains of Depdc5 homozygous knockout rats [21]. Similarly, resected dysplastic brain tissue from patients with truncating mutations inDEPDC5, NPRL2 andNPRL3 showed a significant decrease in expression, consistent with haploinsufficiency, as well as evidence of activation of the mTOR pathway [14,16,19]. These observations are reminiscent of tuberous sclerosis, in which mutations in TSC1 and TSC2 are also associated with excessive activation of the mTORC1 pathway, suggesting common pathogenic mechanisms underlying these disorders. Similar to a ‘second hit’ in tuberous sclerosis complex giving rise to cortical tubers in the presence of a germline TSC1 or TSC2 mutation [22], it is hypothesized that a second hit somatic mutation in a GATOR1 gene or another gene gives rise to the focal epilepsy and/or the associated brain malformation in these patients. A recent report described one patient from a family with a germline DEPDC5 mutation carrying an additional somatic mosaic DEPDC5 variant in resected dysplastic brain tissue [18]. Collectively, these findings establish mutations in GATOR1 complex genes as the most common cause of familial focal epilepsy identified to date.