Sep. 27, 2023
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In this update, the author highlights recent studies investigating the role of DEPDC5 gene mutations in sudden unexpected death in epilepsy (SUDEP) and pharmacoresistance. Furthermore, the author describes recent work using novel mouse models for the investigation of NPRL2 and NPRL3 pathophysiology in human epilepsies and therapeutic responses to rapamycin as compared to DEPDC5 models.
• 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 (most frequently DEPDC5) 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.
• Pharmacoresistance in these families can occur and has been associated with NPLR3 and DEPDC5 gene mutations.
• Somatic mutations in DEPDC5 are a key pathophysiological genetic mechanism underlying the development of focal cortical dysplasia.
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 (64), 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 (12; 63; 52).
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 one individual remains the same. This syndrome with variable foci was included in the diagnostic scheme for epileptic syndromes proposed by the International League Against Epilepsy (24; 25).
Familial focal epilepsy with variable foci shows an autosomal dominant inheritance pattern with approximately 70% penetrance. Two different loci had been previously associated with this syndrome; the first suggestive linkage was found on chromosome 2q (64), but posterior reanalysis excluded such finding (37). Indeed, no other tested families showed linkage to chromosome 2q (49). Thus, the second described and proven linkage has been established on chromosome 22q (75; 74; 16; 14; 49; 37).
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 (23; 34; 46; 69; 61; 59) and epileptic spasms (17). In the families studied, the frequency of DEPDC5 mutations was observed as 5% to 37% (10).
Later, mutations in NPRL2 (nitrogen permease regulator 2-like protein) and NPRL3 (nitrogen permease regulator 3-like protein) genes, which similarly to DEPDC5 belong to the GATOR1 complex (GAP activity toward RAGs complex 1) and are 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 (61; 65; 72; 45; 70). Taken together, these findings gave rise to the conceptualization of GATORopathy or mTORopathy as an etiology for sporadic and familial focal epilepsies, with or without associated malformations of cortical development (48).
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 or without no identifiable structural brain abnormality, and segregating in a sufficient number of individuals in more than 1 generation, can be 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 (34; 23; 46).
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