Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy

Frontiers in Neurology · 7 authors, 3 centres

AI SUMMARY

FIDELITY 100%

POPULATION11 Chinese children with NPRL3-related epilepsy (9 boys, 2 girls; age at onset 4 months to 6 years 10 months) plus 77 previously reported patients from literature review

INTERVENTIONWhole-exome sequencing, clinical phenotyping, bioinformatics analysis, and review of treatment outcomes (sodium channel blockers, surgery, ketogenic diet, rapamycin)

COMPARISONNot applicable (descriptive case series with literature review)

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This study characterizes NPRL3-related epilepsy in 11 Chinese children, identifying infantile spasms as a new phenotype and expanding the known genetic spectrum. Loss-of-function mutations were most common (75%), and sleep-related hypermotor epilepsy and frontal lobe epilepsy were the predominant presentations. Sodium channel blockers were effective in 73% of patients, while surgery, ketogenic diet, and rapamycin showed promise for drug-resistant cases.

Full summary

3,795 CHARS

**Background:** NPRL3 is a component of the GATOR1 complex that negatively regulates the mTOR signaling pathway. Pathogenic variants in NPRL3 cause loss of GATOR1 function, leading to mTOR pathway hyperactivation and epilepsy. While NPRL3-related epilepsy has been associated with focal epilepsies such as frontal lobe epilepsy (FLE) and sleep-related hypermotor epilepsy (SHE), the full clinical and genetic spectrum remains incompletely characterized. This study aimed to describe the clinical and genetic features of 11 Chinese children with NPRL3-related epilepsy and to review all previously reported cases to clarify genotype-phenotype correlations and inform treatment strategies.

**Methods:** Eleven children with NPRL3-related epilepsy were recruited from two Chinese hospitals (March 2018 to May 2022). Whole-exome sequencing (WES) was performed on blood DNA, with Sanger sequencing used to validate variants and determine parental origin. Variants were classified according to ACMG guidelines and the new GATOR1 variant interpretation criteria. Bioinformatics analysis assessed conservation of missense sites and modeled protein tertiary structure changes. Clinical data including seizure type, epilepsy syndrome, EEG, brain MRI, cognitive function, treatment, and outcomes were collected. A systematic literature review of PubMed up to June 2022 identified 77 previously reported patients with NPRL3-related epilepsy.

**Key Results:** Among the 11 patients, 8 had novel variants not previously reported. Five frameshift, three nonsense, two missense, and one exon deletion were identified. Two patients (cases 4 and 8) presented with infantile spasms (IS), a new phenotype for NPRL3-related epilepsy. The most common epilepsy syndromes were SHE (5 cases) and FLE (2 cases). Brain MRI showed left frontal malformation of cortical development in case 3 and left frontal focal cortical dysplasia (FCD) in case 10; the remaining 9 patients had normal MRI. Cognitive function was normal in 4 patients, roughly normal in 2, mildly impaired in 2, severely impaired in 2, and extremely delayed in 1. Five patients had drug-resistant epilepsy. Six patients achieved seizure control: five with sodium channel blockers (oxcarbazepine, lamotrigine, lacosamide) and one with ketogenic diet (KD). One patient (case 3) with drug-resistant epilepsy and FCD underwent epilepsy surgery but remained seizure-free only after KD. Literature review of 88 total patients (including the 11) showed that 70% had normal neuroimaging; among those with abnormalities, FCD was most common (62.5%). Loss-of-function variants (nonsense, frameshift, exon deletion) accounted for 75% of mutations. Sodium channel blocker monotherapy was effective in 73% of patients. Surgery was effective in 75% of patients with neuroimaging abnormalities (9 of 12 seizure-free post-surgery). Two patients unresponsive to surgery or ASMs responded to KD. One patient treated with rapamycin early in the disease course showed efficacy. The most common recurrent mutations were c.275G>A, c.745G>A, and c.1270C>T.

**Clinical Implications:** This study expands the phenotypic spectrum of NPRL3-related epilepsy to include infantile spasms and confirms SHE and FLE as the most common presentations. The high rate of drug resistance (60.8%) underscores the need for early identification of surgical candidates, especially those with FCD. Sodium channel blockers should be considered first-line therapy. KD and mTOR inhibitors (e.g., rapamycin) represent promising options for refractory cases. The predominance of loss-of-function variants and autosomal dominant inheritance with incomplete penetrance highlights the importance of genetic counseling. These findings provide a framework for precision medicine in NPRL3-related epilepsy.

PICO

PPOPULATION

11 Chinese children with NPRL3-related epilepsy (9 boys, 2 girls; age at onset 4 months to 6 years 10 months) plus 77 previously reported patients from literature review

IINTERVENTION

Whole-exome sequencing, clinical phenotyping, bioinformatics analysis, and review of treatment outcomes (sodium channel blockers, surgery, ketogenic diet, rapamycin)

OOUTCOME

Seizure control, epilepsy syndrome classification, neuroimaging findings, cognitive function, drug resistance, and treatment response

STUDY TYPE

case_report

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10018541

Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy

Frontiers in Neurology

READ THE FULL PAPER

JUMP TO SECTION

ABSTRACT

Abstract Background As one of the assembly factors of the GATOR1 protein complex in the mechanism of rapamycin pathway, NPRL3 plays an important role in the pathogenesis of epilepsy. However, the correlation between genotype and clinical phenotype in patients with NPRL3 -related epilepsy has not been clarified. Methods A total of 11 Chinese children with NPRL3 -related epilepsy were identified through whole-exome sequencing (WES). The data from the clinical presentation, laboratory data, brain imaging findings, genetic results, and treatment methods were collected. All previously reported cases with NPRL3 -related epilepsy were collected and reviewed through PubMed search. Results Among the 11 children, eight have not been reported, and two of them presented infantile spasms (ISs) as a new phenotype of NPRL3 -related epilepsy. In addition, WES identified five frameshift mutations, three nonsense mutations, two missense mutations, and one exon deletion. Based on bioinformatics analysis, it was found that two missense mutation sites were highly conserved, and the c.400G>A mutation site of the NPRL3 gene caused the alteration of the protein structure. To date, 88 patients have been reported with NPRL3 -related defects, including our 11 cases. The most common presentations were sleep-related hypermotor epilepsy (SHE), frontal lobe epilepsy (FLE), and temporal lobe epilepsy. A majority of patients (70%) presented normal neuroimaging results, and focal cortical dysplasia was the most common neuroimaging abnormality (62.5%). Among the NPRL3 gene mutations, loss of function (nonsense mutations, frameshift mutations, and exons deletion) was the most common genetic variation (75%). For 73% of patients with NPRL3 -related epilepsy, monotherapy of sodium channel blockers was effective. Surgery was effective for 75% of children with neuroimaging abnormalities. Two cases unresponsive to surgery or anti-seizure medications were treated with ketogenic diets (KD), which were effective. One case was treated with rapamycin at an early stage of epilepsy, which was effective as well. Conclusion NPRL3 -related epilepsy has high clinical and genetic heterogeneity. SHE and FLE are the most common clinical presentations. Furthermore, ISs are the new phenotypes of NPRL3 -related epilepsy, while the variants c.275G>A, c.745G>A, and c.1270C>T may be the most common NPRL3 gene mutations. Sodium channel blockers, surgery, KD, and rapamycin may be the potential treatments for these patients. Our study expanded the clinical and genetic spectrum of NPRL3 -related epilepsy and provided important information for the precise treatment of patients. Keywords: NPRL3 , epilepsy, genotype, phenotype, treatment

CITATION EXPORT

Hongwei Zhang, Jie Deng, Xiaohui Wang et al.. Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy. Frontiers in Neurology. (2023). https://doi.org/10.3389/fneur.2023.1113747

AUTHORS

7 · 3 CENTRES

Hongwei Zhang, Jie Deng, Xiaohui Wang, Chunhong Chen, Shuhua Chen, Lifang Dai, Fang Fang

1Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
2Epilepsy Center, Children's Hospital Affiliated to Shandong University, Jinan, China
3Epilepsy Center, Jinan Children's Hospital, Jinan, China