To address the research gap in familial focal epilepsy with variable foci (FFEVF), investigators assessed the clinical features of a family with FFEVF that included 4 patients in 3 generations and 1 healthy member.
The study, carried out among patients in China, revealed that clinical features of FFEVF varied, while the variant NPRL3: c.1137dupT could change the relative quantity of mRNA and cause abnormal splicing. This could produce difference phenotypes of the disease in different family members, the authors said.
FFEVF can have different epilepsy locations among family members, which can be ascertained via clinical features, neuroimaging, and electroencephalogram (EEG).
Although previous research shows FFEVF is associated with the NPRL3 variant, relevant reports are rare in China, the authors noted. To address this research gap, investigators assessed the clinical features of a family with FFEVF that included 4 patients in 3 generations and 1 healthy member.
The researchers assessed each individual’s medical history and conducted cranial MRI, EEG, and whole exon sequencing. They then compared features with other patients in published reports.
To understand mRNA splicing changes, the investigators used real-time quantitative–polymerase chain reaction (q-PCR) and reverse transcription (RT)-PCR. They also compared findings between the patients and 3 healthy individuals with no history of epileptic seizures and no neurological diseases.
Analyses revealed that patients with NPRL3: c.1137dupT variant exhibited:
In addition, “significantly different relative quantities of mRNA were found between patients and healthy individuals in real-time qPCR,” while “abnormal splicing was observed in patients compared with healthy individual in RT-PCR,” the researchers wrote.
Although they had the same gene variant, different family members exhibited different mRNA splicing, which may explain different phenotypes. Treatment efficacy also varied among patients included in the current study and those in published reports.
“Some patients’ seizures were well controlled, while others did not respond well to antiseizure medications,” the authors wrote.
“Epileptiform discharges in the interictal phase were found in some patients’ EEGs. However, our patients’ EEGs findings were significantly abnormal,” they added.
Two patients had EEG findings that suggested a certain degree of brain function decline, potentially related to recurrent seizures, the researchers explained. In the patient with subclinical epilepsy, EEG findings were also abnormal, indicating regular EEG follow-up could be helpful in early detection for asymptomatic family members with FFEVF.
Severity of FFEVF varied greatly, and patients were likely to receive a misdiagnosis of either sporadic epilepsy or other familial focal epilepsy forms until new members with FFEVF were identified.
“Our study has expanded the phenotype spectrum of FFEVF and found a new NPRL3 variant that had not been reported. Compared with unrelated healthy controls, we found that the NPRL3 variant was associated with the relative expression level of mRNA and abnormal splicing in vitro,” the authors wrote.
The study’s case-control design was underpowered, limiting the investigators’ ability to evaluate the variant’s pathogenicity. In addition, some family members did not provide blood samples out of privacy concerns and only one unaffected family member was included in the genetic analysis, marking a limitation to the investigation.
The researchers plan to continue to follow-up with each patient in the future.
“More unaffected family members will be recruited, which could enable assessment of the relationship of the variants with focal epilepsy,” they wrote. “Relevant functional studies, such as minigene report detection, will be conducted to provide clues for the in-depth study of FFEVF, which is important for the accurate diagnosis and treatment of FFEVF.”
Wang Y, Yu P, Zhu G, Wu X, Ding D, Hong Z. The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant. PLoS One. Published online April 26, 2023. doi:10.1371/journal.pone.0284924