This article includes discussion of familial focal epilepsy with variable foci, familial focal epilepsy, and familial partial epilepsy with variable foci. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this update, Dr. Kobayashi highlights the finding of mutations in NPRL2 and NPRL3 genes, which together with DEPDC5, are part of the GATOR1 complex regulating mTOR pathway. Screening of mutations in GATOR1 complex genes expand on possible phenotypes, which include sporadic and familial focal epilepsies, with or without focal cortical dysplasia. In addition, sudden unexplained death associated with epilepsy and GATOR1 complex mutations have been reported.
• Diagnosis of familial focal epilepsy with variable foci depends on evaluation of all family members with a history of seizures, most having temporal or frontal epilepsy.
• Seizure focus is variable across affected individuals, but remains the same within individual patients.
• Mutations in the GATOR1 complex genes have been identified in various familial focal epilepsy with variable foci kindreds, but also in other focal familial epilepsy kindreds, including familial focal cortical dysplasia.
Historical note and terminology
Formerly known as familial partial epilepsy with variable foci, autosomal dominant familial focal epilepsy with variable foci (FFEVF) is a unique epilepsy syndrome first reported in an Australian kindred (Scheffer et al 1998), after other more homogeneous familial partial epilepsy syndromes, such as autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, and autosomal dominant partial epilepsy with auditory features had been described (Berkovic et al 1994; Scheffer et al 1994; Ottman et al 1995).
Familial focal epilepsy with variable foci is unique among the familial focal epilepsies because different clinical and EEG features can be observed in different family members, suggesting that different epileptic foci may be determined by the same genetic mutation. On the other hand, the epileptic focus in any 1 individual remains the same.
Two different loci have been previously associated with familial focal epilepsy with variable foci. The first suggestive linkage was on chromosome 2q (Scheffer et al 1998), but posterior reanalysis excluded such finding (Klein et al 2012). Indeed, no other tested families showed linkage to chromosome 2q (Morales-Corraliza et al 2010). Thus, the second described and proven linkage has been established on chromosome 22q (Xiong et al 1999; Morales-Corraliza et al 2010; Klein et al 2012).
In 2013 the first gene was finally identified, with different groups worldwide reporting mutations in the DEPDC5 gene on ch 22q, encoding the DEP domain containing 5 protein. This was found not only in familial focal epilepsy with variable foci, but also in other familial focal epilepsies (Dibbens et al 2013; Ishida et al 2013; Martin et al 2014; Striano et al 2015; Ricos et al 2016; Pippucci et al 2015) and epileptic spasms (Carvill et al 2015). In the families studied, the frequency of DEPDC5 mutations was observed as 5% to 37%.
Mutations in NPRL2 and NPRL3 genes, which belong to the GATOR1 complex (GAP activity toward RAGs complex 1) similar to DEPDC5 and mammalian target of rapamycin (mTOR) regulators, were found in 2% to 11% of probands of families with focal epilepsies with or without malformations of cortical development (Ricos et al 2016; Sim et al 2016; Weckhuysen et al 2016).
Familial focal epilepsy with variable foci can be defined on the basis of family rather than individual phenotypes. The occurrence of at least 2 different focal epilepsy syndromes in first and second-degree relatives with no identifiable structural brain abnormality, and segregating in a sufficient number of individuals in more than 1 generation, is suggestive of familial focal epilepsy with variable foci. Nevertheless, many small families in which the diagnosis and the inheritance pattern could not be confirmed share common mutations to definite familial focal epilepsy with variable foci large kindreds (Ishida et al 2013; Dibbens et al 2013; Martin et al 2014).
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