Surgical analysis of patients with GATOR1 complex gene mutations presenting mainly with epilepsy_Journal of Epilepsy

Authors：

HE Jing ,  ZHOU Wenjing , LIN Jiuluan , WANG Haixiang , ZHANG Bingqing , BAI Jianjun

Department of Epilepsy Center, Yuquan Hospital Tsinghua University, Beijing 100049, China;

Corresponding author：

ZHOU Wenjing, Email: closejeo@hotmail.com

Keywords：

Refractory epilepy; GATOR1 complex; DEPDC5 gene; NPRL2 gene; NPRL3 gene

DOI：

10.7507/2096-0247.202411016

Video：

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Background To summarize the genetic characteristics of GATOR1 complex gene mutations and the surgical prognosis of patients with refractory epilepsy. Methods A retrospective analysis was conducted on 16 patients with GATOR1 complex gene mutations who presented with mainly refractory epilepsy and underwent surgical treatment at the Epilepsy Center of Tsinghua University Yuquan Hospital from May 2019 to August 2024. The follow-up period ranged from 0.5 to 4.0 years. The genetic characteristics, clinical data, treatment, and prognosis of the patients were analyzed. Results Among the 16 patients, 9 were male and 7 were female, with an onset age ranging from 0.6 to 9.4 years, and seizure frequency ranging from once a day to dozens of times a day. Twelve patients (75.0%) had no seizures after surgery, and three of them had completely stopped taking medication. EEG were focal or multifocal, and all clinical seizures were monitored. Two patients had negative MRI. Among the 16 patients, there were 8 with DEPDC5 gene mutations, 5 with NPRL3 gene mutations, and 3 with NPRL2 gene mutations. Conclusions Patients with refractory epilepsy related to GATOR1 complex gene mutations are good surgical candidates, with a high rate of no seizures after surgery. For confirmed patients, surgical treatment should be considered.

Citation： HE Jing, ZHOU Wenjing, LIN Jiuluan, WANG Haixiang, ZHANG Bingqing, BAI Jianjun. Surgical analysis of patients with GATOR1 complex gene mutations presenting mainly with epilepsy. Journal of Epilepsy, 2025, 11(2): 100-105. doi: 10.7507/2096-0247.202411016 Copy

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2.	Baulac S. mTOR signaling pathway genes in focal epilepsies. Prog Brain Res, 2016, 226: 61-79.
3.	Kovacevic M, Jankovic M, Brankovic M, et al. Novel GATOR1 variants in focal epilepsy. Epilepsy Behav, 2023, 141: 109139.
4.	Baud MO, Perneger T, Racz A, et al. European trends in epilepsy surgery. Neurology, 2018, 91(2): 96-106.
5.	Blumcke I, Spreafico R, Haaker G, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med, 2017, 377(17): 1648-1656.
6.	Yulin S, Lin W, Huimin Y, et al. Phenotypic and genotypic characterization of NPRL2-related epilepsy: two case reports and literature Review. Front Neurol, 2021, 12: 780799.
7.	Baldassari S, Picard F, Verbeek NE, et al. The landscape of epilepsy-related GATOR1 variants. Genet Med, 2019, 21(2): 398-408.
8.	Stevelink R, Sanders MW, Tuinman MP, et al. Epilepsy surgery for patients with genetic refractory epilepsy: a systematic review. Epileptic Disord, 2018, 20(2): 99-115.
9.	Carvill GL, Crompton DE, Regan BM, et al. Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol Genet, 2015, 1(2): e17.
10.	Barbora B, Thomas S. Jacques. Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery. Brain Pathol, 2019, 29(4): 473-484.
11.	Ahmed N Sahly, Robyn W, Gregory C, 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.
12.	Lamberink HJ, Otte WM, Blümcke I, et al. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study. Lancet Neurol, 2020, 19(9): 748-757.
13.	Rowland NC, Englot DJ, Cage TA, Sughrue ME, Barbaro NM, Chang EF. A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia. J Neurosurg, 2012, 116(5): 1035-1041.
14.	Barbora B, Maurits WCB Sanders, Anna UM, et al. GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: a possible gradient in severity? Eur J Paediatr Neurol, 2021, 30: 88-96.

1. Bar-Peled L, Chantranupong L, Cherniack AD, et al. A tumor suppressor complex with GAP Activity for the rag GTPases that signal amino acid sufficiency to mTORC1. Science, 2013, 340(6136): 1100-1106.
2. Baulac S. mTOR signaling pathway genes in focal epilepsies. Prog Brain Res, 2016, 226: 61-79.
3. Kovacevic M, Jankovic M, Brankovic M, et al. Novel GATOR1 variants in focal epilepsy. Epilepsy Behav, 2023, 141: 109139.
4. Baud MO, Perneger T, Racz A, et al. European trends in epilepsy surgery. Neurology, 2018, 91(2): 96-106.
5. Blumcke I, Spreafico R, Haaker G, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med, 2017, 377(17): 1648-1656.
6. Yulin S, Lin W, Huimin Y, et al. Phenotypic and genotypic characterization of NPRL2-related epilepsy: two case reports and literature Review. Front Neurol, 2021, 12: 780799.
7. Baldassari S, Picard F, Verbeek NE, et al. The landscape of epilepsy-related GATOR1 variants. Genet Med, 2019, 21(2): 398-408.
8. Stevelink R, Sanders MW, Tuinman MP, et al. Epilepsy surgery for patients with genetic refractory epilepsy: a systematic review. Epileptic Disord, 2018, 20(2): 99-115.
9. Carvill GL, Crompton DE, Regan BM, et al. Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol Genet, 2015, 1(2): e17.
10. Barbora B, Thomas S. Jacques. Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery. Brain Pathol, 2019, 29(4): 473-484.
11. Ahmed N Sahly, Robyn W, Gregory C, 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.
12. Lamberink HJ, Otte WM, Blümcke I, et al. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study. Lancet Neurol, 2020, 19(9): 748-757.
13. Rowland NC, Englot DJ, Cage TA, Sughrue ME, Barbaro NM, Chang EF. A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia. J Neurosurg, 2012, 116(5): 1035-1041.
14. Barbora B, Maurits WCB Sanders, Anna UM, et al. GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: a possible gradient in severity? Eur J Paediatr Neurol, 2021, 30: 88-96.

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