Crisis-like Seizure Exacerbations in NPRL3-related Epilepsy: Phenotypic Features and Treatment Outcomes

Abstract

Background

NPRL3 (nitrogen permease regulator-like 3) variants are associated with focal epilepsy syndromes, including sleep-related hypermotor epilepsy (SHE) and familial focal epilepsy with variable foci (FFEVF), with or without focal cortical dysplasia (FCD). The NPRL3 gene encodes a protein that forms the GATOR1 complex, which regulates the mTOR signaling pathway.

Objective

To characterize the epilepsy phenotype associated with NPRL3, assess treatment strategies, and evaluate patient prognosis.

Methods

We conducted a multicenter, retrospective study using an online questionnaire to collect clinical data on seizure onset, crisis-like seizure exacerbations, MRI findings, neuropsychological assessment, treatment, and genetic variants. Variants were classified per ACMG guidelines. The study was part of the Network for Therapy in Rare Epilepsies (NETRE).

Results

Data from 37 patients with NPRL3-associated epilepsy were analyzed. Mean age at seizure onset was 3.7 years (median with interquartile range [IQR] 1.3–4.9). Over 1 to 45 years of follow-up (mean 13.6, IQR 5.4–18), 21/37 (57%) experienced crisis-like seizure exacerbations. MRI abnormalities were present in 10/36 (28%) cases: 8 FCD, 1 hippocampal sclerosis, and 1 hippocampal asymmetry. Persistent focal epileptiform discharges were present on serial EEGs in 20/37 patients (54%). Highest drug response rates were seen with lacosamide, followed by clobazam, carbamazepine/oxcarbazepine, and lamotrigine. Epilepsy surgery (n = 8) led to seizure freedom in four and significant reduction in one case.

Conclusion

Crisis-like seizure exacerbations were common in NPRL3-associated epilepsy. Sodium channel blockers showed notable efficacy. Epilepsy surgery was beneficial even in MRI-negative cases. No distinct genotype–phenotype correlation was identified.

Keywords

NPRL3 - GATOR1 - epilepsy - FFEVF - SHE

• References

• 1 Dainelli A, Iacomino M, Rossato S. et al. Refining the electroclinical spectrum of NPRL3-related epilepsy: a novel multiplex family and literature review. Epilepsia Open 2023; 8 (04) 1314-1330
• 2 Riney K, Bogacz A, Somerville E. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63 (06) 1443-1474
• 3 Zhang H, Deng J, Wang X. et al. Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy. Front Neurol 2023; 14: 1113747
• 4 Baldassari S, Picard F, Verbeek NE. et al. The landscape of epilepsy-related GATOR1 variants. Genet Med 2019; 21 (02) 398-408
• 5 Iffland PH, Everett ME, Cobb-Pitstick KM. et al. NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold. Brain 2022; 145 (11) 3872-3885
• 6 Ricos MG, Hodgson BL, Pippucci T. et al; Epilepsy Electroclinical Study Group. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol 2016; 79 (01) 120-131
• 7 ClinVar. Bethesda (MD): National Center for Biotechnology Information, U.S. National Library of Medicine [Internet]. Accessed May 26, 2025 at: https://www.ncbi.nlm.nih.gov/clinvar/
• 8 Weckhuysen S, Marsan E, Lambrecq V. et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 2016; 57 (06) 994-1003
• 9 Yang D, Wang J, Qin Z. et al. Phenotypic and genotypic characterization of NPRL3-related epilepsy: two case reports and literature review. Epilepsia Open 2024; 9 (01) 33-40
• 10 Rehm HL, Berg JS, Brooks LD. et al; ClinGen. ClinGen—the clinical genome resource. N Engl J Med 2015; 372 (23) 2235-2242
• 11 Iffland II PH, Carson V, Bordey A, Crino PB. GATORopathies: the role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia 2019; 60 (11) 2163-2173
• 12 Baldassari S, Licchetta L, Tinuper P, Bisulli F, Pippucci T. GATOR1 complex: the common genetic actor in focal epilepsies. J Med Genet 2016; 53 (08) 503-510
• 13 Osborne LR. Caveat mTOR: aberrant signaling disrupts corticogenesis. J Clin Invest 2010; 120 (05) 1392-1395
• 14 Zimmer TS, Broekaart DWM, Gruber VE, van Vliet EA, Mühlebner A, Aronica E. Tuberous sclerosis complex as disease model for investigating mTOR-related gliopathy during epileptogenesis. Front Neurol 2020; 11: 1028
• 15 Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA. Tuberous sclerosis complex. Nat Rev Dis Primers 2016; 2: 16035
• 16 Pun RYK, Rolle IJ, Lasarge CL. et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron 2012; 75 (06) 1022-1034
• 17 Zou J, Zhang B, Gutmann DH, Wong M. Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner. Epilepsia 2017; 58 (12) 2053-2063
• 18 Blümcke I, Thom M, Aronica E. et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011; 52 (01) 158-174
• 19 NETRE Network for Therapy in Rare Epilepsies [Internet]. Accessed November 4, 2024 at: https://netre.typeform.com/to/aTe5tVpx
• 20 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 21 Cristofoli F, Sorrentino E, Guerri G. et al. Variant selection and interpretation: an example of modified VarSome classifier of ACMG guidelines in the diagnostic setting. Genes (Basel) 2021; 12 (12) 1885
• 22 Riggs ER, Andersen EF, Cherry AM. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 2020; 22 (02) 245-257
• 23 Boßelmann CM, Antonio-Arce VS, Schulze-Bonhage A. et al. Genetic testing before epilepsy surgery—an exploratory survey and case collection from German epilepsy centers. Seizure 2022; 95: 4-10
• 24 Klau J, Abou Jamra R, Radtke M. et al. Exome first approach to reduce diagnostic costs and time—retrospective analysis of 111 individuals with rare neurodevelopmental disorders. Eur J Hum Genet 2022; 30 (01) 117-125
• 25 Korenke GC, Eggert M, Thiele H, Nürnberg P, Sander T, Steinlein OK. Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia 2016; 57 (03) e60-e63
• 26 Sim JC, Scerri T, Fanjul-Fernández M. et al. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol 2016; 79 (01) 132-137
• 27 Baulac S, Ishida S, Marsan E. et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol 2015; 77 (04) 675-683
• 28 Bennett MF, Hildebrand MS, Kayumi S. et al. Evidence for a dual-pathway, 2-hit genetic model for focal cortical dysplasia and epilepsy. Neurol Genet 2022; 8 (01) e652
• 29 Moloney PB, Kearney H, Benson KA. et al. Everolimus precision therapy for the GATOR1-related epilepsies: a case series. Eur J Neurol 2023; 30 (10) 3341-3346
• 30 Sahly AN, Whitney R, Costain G. et al. Epilepsy surgery outcomes in patients with GATOR1 gene complex variants: report of new cases and review of literature. Seizure 2023; 107: 13-20
• 31 Krenn M, Wagner M, Hotzy C. et al. Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes. J Med Genet 2020; 57 (09) 624-633
• 32 Shaw RJ. mTOR signaling: RAG GTPases transmit the amino acid signal. Trends Biochem Sci 2008; 33 (12) 565-568