Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review

Abstract

Objective: NPRL3-related epilepsy (NRE) is an emerging condition set within the wide GATOR-1 spectrum with a particularly heterogeneous and elusive phenotypic expression. Here, we delineated the genotype-phenotype spectrum of NRE, reporting an illustrative familial case and reviewing pertinent literature.

Methods: Through exome sequencing (ES), we investigated a 12-year-old girl with recurrent focal motor seizures during sleep, suggestive of sleep-related hypermotor epilepsy (SHE), and a family history of epilepsy in siblings. Variant segregation analysis was performed by Sanger sequencing. All previously published NRE patients were thoroughly reviewed and their electroclinical features were analyzed and compared with the reported subjects.

Results: In the proband, ES detected the novel NPRL3 frameshift variant (NM_001077350.3): c.151_152del (p.Thr51Glyfs*5). This variant is predicted to cause a loss of function and segregated in one affected brother. The review of 76 patients from 18 publications revealed the predominance of focal-onset seizures (67/74-90%), with mainly frontal and frontotemporal (32/67-47.7%), unspecified (19/67-28%), or temporal (9/67-13%) onset. Epileptic syndromes included familial focal epilepsy with variable foci (FFEVF) (29/74-39%) and SHE (11/74-14.9%). Fifteen patients out of 60 (25%) underwent epilepsy surgery, 11 of whom achieved complete seizure remission (11/15-73%). Focal cortical dysplasia (FCD) type 2A was the most frequent histopathological finding.

Significance: We reported an illustrative NPRL3-related epilepsy (NRE) family with incomplete penetrance. This condition consists of a heterogeneous spectrum of clinical and neuroradiological features. Focal-onset motor seizures are predominant, and almost half of the cases fulfill the criteria for SHE or FFEVF. MRI-negative cases are prevalent, but the association with malformations of cortical developments (MCDs) is significant, especially FCD type 2a. The beneficial impact of epilepsy surgery in patients with MCD-related epilepsy further supports the inclusion of brain MRI in the workup of NRE patients.

Keywords: NPRL3; FCD; epilepsy; focal cortical dysplasia; focal seizures; frontal lobe.

FIGURE 1

Pedigree of the reported family. The proband is indicated by an arrow. Affected individuals and asymptomatic subjects are indicated by shaded or empty symbols, respectively. Where available, the segregation of the wild‐type (wt/wt) and mutant (wt/mut) NPRL3 allele is indicated.

FIGURE 2

EEG recordings of the proband (II‐5). Amplitude 10 μV/mm; TC:0.10 s‐HF 30.0 Hz. A, EEG during nREM sleep (phase 1) shows increased paroxysmal activity with high‐voltage spikes/slow‐wave complexes over the anterior regions of both hemispheres with a relatively well‐organized sleep structure. B, EEG during nREM sleep (phase 2) shows paroxysmal activity with high‐voltage spikes/slow‐wave complexes over the anterior and central areas in both hemispheres and low‐voltage fast rhythms on the right frontal and central areas.

FIGURE 3

EEG recordings of the proband (II‐5). Amplitude 10 μV/mm; TC:0.10 s‐HF 30.0 Hz. Rest EEG at the age of 4 showing mid‐amplitude polymorphic delta activity intermixed with wave/slow‐wave complexes over the right hemisphere (arrows).

FIGURE 4

EEG recordings of the proband (II‐5). Amplitude 10 μV/mm; TC:0.10 s‐HF 30.0 Hz. During drowsiness, the EEG shows increased slowed rhythms and high‐voltage wave/slow‐wave complexes over the central and anterior right regions with diffusion on the left anterior brain regions (arrows).

FIGURE 5

Schematic spectrum of seizure focus in patients with NPRL3‐related epilepsy (NRE). Frontal‐onset seizures are predominant, followed by temporal, central, and frontotemporal. In a large proportion of patients seizure focus remains unclear.