Refining the electro-clinical spectrum of NPRL3-related epilepsy: a novel multiplex family and literature review

• Published in: Epilepsia open
• Main Authors: Dainelli, Alice, Iacomino, Michele, Rossato, Sara, Bugin, Samuela, Traverso, Monica, Severino, Mariasavina, Gustincich, Stefano, Capra, Valeria, Di Duca, Marco, Zara, Federico, Scala, Marcello, Striano, Pasquale
• Format: Journal Article
• Language: English
• Published: United States 25.07.2023
• Subjects: epilepsy; focal seizures; focal cortical dysplasia; FCD; NPRL3; frontal lobe
• ISSN: 2470-9239
• DOI: 10.1002/epi4.12798

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. Through exome sequencing (ES), we investigated a 12-year-old female 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 to the reported subjects. 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. We reported an illustrative 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 fulfil the criteria for SHE or FFEVF. MRI-negative cases are prevalent but the association with 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.