A number sign (#) is used with this entry because of evidence that familial focal epilepsy with variable foci-3 (FFEVF3) is caused by heterozygous mutation in the NPRL3 gene (600928) on chromosome 16p13.

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 FFEVF3. Seizure types included NFLE, TLE, and FLE. One patient had neonatal seizures and another had intellectual disability and autism spectrum disorder. Additional clinical details were limited.

Sim et al. (2016) reported a family in which 4 children had FFEVF3. The proband, who was the most severely affected, presented with clonic seizures on the first day of life. Electroencephalogram (EEG) showed a focal suppression burst pattern. The 3 other patients had onset of focal or nocturnal seizures between 2 and 6 years of age. EEG studies were consistent with focal origin. Two patients had abnormal brain imaging suggesting focal cortical dysplasia, and both underwent resection, which confirmed FCD. The proband had global developmental delay, left hemiplegia, and hemianopia, but the other 3 children had normal development. Two additional unrelated patients with focal seizures associated with focal cortical dysplasia were also described. One had onset of focal seizures at age 4 months, whereas the other had onset at age 15 months. Brain resection in both patients confirmed FCD. One had normal cognition and the other had language delay; both had residual hemiparesis.

Weckhuysen et al. (2016) reported 2 unrelated families with FFEVF3. One family, of French descent, included 10 individuals with epilepsy and/or febrile seizures, sometimes with secondary generalization. Patients had onset of focal and nocturnal seizures in the first decade (range, 2 months to 8 years), although a few patients had later onset. EEG tended to show focal spike-wave complexes. Brain imaging was not performed, unavailable, or normal in most patients, but abnormal in 1; this patient had brain resection with documented FCD and hippocampal sclerosis. Several patients became seizure-free during young adulthood. One affected family member was found dead at age 23 years, with a diagnosis of possible SUDEP (sudden death in epilepsy). The second family, of Swiss descent, had 5 affected individuals with focal epilepsy. Three had onset of seizures in the first 5 years of life, 1 had onset at age 14 years, and the fifth had onset at age 51 years. One patient had imaging evidence of FCD: abnormal gyration, increased cortical thickness, and abnormal signals in the right frontoparietal area.

Iffland et al. (2022) reported clinical features in 133 members of an Old Order Mennonite pedigree with FFEVF3 and a heterozygous mutation in the NPRL3 gene. Forty-eight members had a history of seizures and 85 had no history of seizures. The average age of seizure onset was 5 years, with a range of 1 day to 37 years. Seizures were focal or generalized, 6 patients had infantile spasms, and 1 patient had isolated febrile seizures. Of 17 patients for whom MRI data were available, 8 had normal brain structure, 8 had focal cortical dysplasia, and 1 had megalencephaly. EEGs, which were available for 21 patients, were abnormal in 19.

The transmission pattern of FFEVF3 in the families reported by Ricos et al. (2016) was consistent with autosomal dominant inheritance with incomplete penetrance.

In 10 patients from 5 unrelated families with focal epilepsy with FFEVF3, Ricos et al. (2016) identified 5 different heterozygous mutations in the NPRL3 gene (see, e.g., 600928.0001-600928.0002), including 3 truncating mutations and 2 missense mutations. There was evidence of incomplete penetrance. The mutation in 1 large family was found by exome sequencing; the remaining 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 findings suggested that loss of function of the GATOR1 complex due to NPRL3 mutations can cause deregulated cellular growth and may play an important role in cortical dysplasia and focal epilepsy.

In 4 members of a family with FFEVF3, Sim et al. (2016) identified a heterozygous frameshift mutation in the NPRL3 gene (600928.0002). The mutation, which was found by whole-exome sequencing, showed incomplete penetrance in the family. Sequence analysis of the NPRL3 gene in 52 individuals with FCD identified 2 unrelated patients with heterozygous mutations (see, e.g., 600928.0003). Resected dysplastic brain tissue from 3 patients with truncating mutations showed a 50% decrease in NPRL3, consistent with haploinsufficiency, as well as evidence of activation of the mTOR (601231) pathway. Sim et al. (2016) suggested that therapy for this disorder may eventually include the use of mTOR inhibitors or highly focal brain resections aimed at removing only dysplastic tissue.

In affected members of 2 unrelated families with FFEVF3 and FCD, Weckhuysen et al. (2016) identified 2 different heterozygous truncating mutations in the NPRL3 gene (600928.0004-600928.0005). The mutations, which were found by sequencing a targeted epilepsy gene panel in 93 probands with focal epilepsy with or without FCD, were confirmed by Sanger sequencing. NPRL3 mutations thus occurred in 2.1% of probands studied.

In 133 members of an Old Order Mennonite pedigree segregating FFEVF3, Iffland et al. (2022) identified a heterozygous mutation in the NPRL3 gene (c.349delG; 600928.0006). Pedigree analysis demonstrated that all of the mutation carriers traced back to a single founder. Of the 133 patients, 48 had a history of seizures and 85 had no history of seizures. Whole-exome sequencing comparing 37 patients with no seizures to 24 patients with seizures did not identify any potential modifier genes that explained the epilepsy penetrance. Iffland et al. (2022) analyzed Nrpl3 knockout N2a cells and showed that the cells had enhanced ribosomal S6 protein (PS6) phosphorylation compared to wildtype cells. This enhanced PS6 phosphorylation was corrected with treatment with rapamycin. However, PS6 phosphorylation was not corrected in the Nrpl3 knockout cells under conditions of amino acid starvation, indicating that Nrpl3 abrogates the effect of GATOR1 on mTOR activation. The Nrpl3 knockout N2a cells formed abnormal cellular aggregates, which was corrected with rapamycin treatment.

Iffland et al. (2022) used CRISPR/Cas9 to target Nrpl3 in neuroglial progenitor cells in developing mouse embryos. The resulting pups had cortical laminar defects on postnatal day 3. These laminar defects were rescued with in utero treatment with rapamycin. At 5 weeks of age, the mice had abnormal EEGs and reduced seizure thresholds. Treatment with rapamycin corrected the abnormal seizure thresholds.