A number sign (#) is used with this entry because of evidence that familial focal epilepsy with variable foci-2 (FFEVF2) is caused by heterozygous mutation in the NPRL2 gene (607072) on chromosome 3p21.

Familial focal epilepsy with variable foci (FFEVF) is an autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and nocturnal frontal lobe epilepsy (NFLE). A subset of patients have structural brain abnormalities, particularly focal cortical dysplasia (FCD). There is significant incomplete penetrance, with many unaffected mutation carriers within a family (summary by Ricos et al., 2016).

For a discussion of genetic heterogeneity of FFEVF, see FFEVF1 (604364).

Ricos et al. (2016) reported 10 patients from 5 unrelated families with FFEVF2. Seizure types included NFLE, TLE, and FLE. One patient had intellectual disability and perisylvian polymicrogyria, and another had a frontal tumor-like brain lesion on imaging. Additional clinical details were limited.

Weckhuysen et al. (2016) reported 2 sisters from a nonconsanguineous family (family E) of French descent with FFEVF2. The 27-year-old proband had onset of refractory NFLE at age 3 years. EEG showed abnormal activity in the frontal regions. Although brain MRI was normal, PET scanning showed hypometabolism in the right frontal region which was associated with an area with increased cortical thickness and blurring of the gray-white matter. She underwent a right frontoorbital brain resection at age 18 years, which resulted in a 50% decrease in seizure frequency. Histopathology showed focal cortical dysplasia. Her 20-year-old sister had onset of TLE at age 13 years. EEG showed left temporal epileptic activity; MRI was normal. Family history was limited, but there were 3 additional family members on the paternal side of the family who had nonspecific seizures, including 1 individual who died suddenly of seizures at age 22 years, with a diagnosis of possible SUDEP (sudden death in epilepsy).

The transmission pattern of FFEVF2 in the families reported by Ricos et al. (2016) and Weckhuysen et al. (2016) was consistent with autosomal dominant inheritance with incomplete penetrance.

In 10 patients from 5 unrelated families with FFEVF2, Ricos et al. (2016) identified 5 different heterozygous mutations in the NPRL2 gene (see, e.g., 607072.0001-607072.0003), including 2 truncating mutations and 3 missense mutations. There was evidence of incomplete penetrance. The mutation in 1 large family was found by exome sequencing; the remaining 4 probands were ascertained from a cohort of 404 individuals with focal epilepsy who underwent targeted sequencing for genes in the GATOR1 complex. Functional studies of the variants and studies of patient cells were not performed. The NPRL2 gene is part of the GATOR1 complex, which negatively regulates mTOR (601231), a regulator of cell growth and metabolism. The findings suggested that loss of function of the GATOR1 complex due to NPRL2 mutations can cause deregulated cellular growth and may play an important role in cortical dysplasia and focal epilepsy.

In 2 French sisters with FFEVF2, Weckhuysen et al. (2016) identified a heterozygous frameshift mutation in the NPRL2 gene (607072.0004). The mutation, which was found by sequencing a targeted epilepsy gene panel, was confirmed by Sanger sequencing. The unaffected father and an unaffected sib also carried the mutation, consistent with incomplete penetrance. A distant relative on the paternal side of the family with an unspecified epilepsy also carried the mutation. Analysis of patient cells showed that the mutant transcript was not subject to nonsense-mediated mRNA decay, but was predicted to result in a very shortened protein. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in neurons of normal appearance. These findings suggested the NPRL2 mutation resulted in a loss of function of the GATOR1 complex. The family was from a larger cohort of 93 probands with focal epilepsy with or without FCD who underwent screening; NPRL3 mutations thus occurred in 1.1% of probands studied.