Dataset Information

The landscape of epilepsy-related GATOR1 variants.

ABSTRACT:

Purpose

To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.

Results

The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.

Conclusion

Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

SUBMITTER: Baldassari S

PROVIDER: S-EPMC6292495 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

The landscape of epilepsy-related GATOR1 variants.

Baldassari Sara S Picard Fabienne F Verbeek Nienke E NE van Kempen Marjan M Brilstra Eva H EH Lesca Gaetan G Conti Valerio V Guerrini Renzo R Bisulli Francesca F Licchetta Laura L Pippucci Tommaso T Tinuper Paolo P Hirsch Edouard E de Saint Martin Anne A Chelly Jamel J Rudolf Gabrielle G Chipaux Mathilde M Ferrand-Sorbets Sarah S Dorfmüller Georg G Sisodiya Sanjay S Balestrini Simona S Schoeler Natasha N Hernandez-Hernandez Laura L Krithika S S Oegema Renske R Hagebeuk Eveline E Gunning Boudewijn B Deckers Charles C Berghuis Bianca B Wegner Ilse I Niks Erik E Jansen Floor E FE Braun Kees K de Jong Daniëlle D Rubboli Guido G Talvik Inga I Sander Valentin V Uldall Peter P Jacquemont Marie-Line ML Nava Caroline C Leguern Eric E Julia Sophie S Gambardella Antonio A d'Orsi Giuseppe G Crichiutti Giovanni G Faivre Laurence L Darmency Veronique V Benova Barbora B Krsek Pavel P Biraben Arnaud A Lebre Anne-Sophie AS Jennesson Mélanie M Sattar Shifteh S Marchal Cécile C Nordli Douglas R DR Lindstrom Kristin K Striano Pasquale P Lomax Lysa Boissé LB Kiss Courtney C Bartolomei Fabrice F Lepine Anne Fabienne AF Schoonjans An-Sofie AS Stouffs Katrien K Jansen Anna A Panagiotakaki Eleni E Ricard-Mousnier Brigitte B Thevenon Julien J de Bellescize Julitta J Catenoix Hélène H Dorn Thomas T Zenker Martin M Müller-Schlüter Karen K Brandt Christian C Krey Ilona I Polster Tilman T Wolff Markus M Balci Meral M Rostasy Kevin K Achaz Guillaume G Zacher Pia P Becher Thomas T Cloppenborg Thomas T Yuskaitis Christopher J CJ Weckhuysen Sarah S Poduri Annapurna A Lemke Johannes R JR Møller Rikke S RS Baulac Stéphanie S

Genetics in medicine : official journal of the American College of Medical Genetics 20180810 2

<h4>Purpose</h4>To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.<h4>Results</h4>The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g. ...[more]

PMID: 30093711

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Project description:ObjectivesTo summarize the clinical features of epilepsy related to DEPDC5, NPRL2, and NPRL3 genes encoding the GATOR1 complex in children and to evaluate the factors affecting the prognosis of these epilepsies.MethodsIn this retrospective study, we reviewed the clinical and genetic characteristics of children with epilepsy related to GATOR1 variants who were admitted to the Peking University First Hospital between January 2016 and December 2021. Potential prognostic factors were assessed by comparing children with and without ongoing seizures.ResultsFifty probands, including 31 boys and 19 girls were recruited. The median age at onset of epilepsy was 4 months, and 64% of patients had early-onset epilepsy (≤1 year). The most frequent epileptic seizure type was focal seizure (86%). Among the 50 patients, only six were with de novo variants. According to the novel classification framework for GATOR1 variants, 36 patients were with pathogenic variants and 14 with likely pathogenic variants. DEPDC5 variants were found in 37 patients, NPRL3 in 9, and NPRL2 in 4. The phenotype was similar among the probands, with variants in DEPDC5, NRPL2, or NPRL3. 76% (38/50) of epilepsy related to GATOR1 variants was neuroimaging positive, including brain MRI positive in 31 patients, and MRI combined F-18-fluorodeoxyglucose positron emission tomography positive in the other seven patients. Twenty-seven patients underwent epilepsy surgery. In total, after initial antiseizure medications alone, 92% (46/50) of patients were drug-resistant epilepsies, only 8% (4/50) of the probands became seizure-free but seizure-free (≥6 m) occurred in 92.6% (25/27) of patients with drug-resistant epilepsy after epilepsy surgery at the last follow-up. Patients undergoing epilepsy surgery had better epilepsy prognosis.SignificanceEpilepsy related to GATOR1 variants had high possibility to be drug-resistant epilepsy and to have positive neuroimaging finding. Epilepsy surgery is the only favorable factor for better seizure prognosis in this kind epilepsy.

Project description:Epilepsy is a multifactorial neurological disorder with recurrent epileptic seizures. Current research stresses both inflammatory and autoimmune conditions as enablers in the pathophysiological process of epilepsy. In view of the growing concern about the role of adipocytokines in antiepileptic and modulating immune responses, we aimed to investigate the relevance of the adipocytokine signaling pathway in the pathological process of epilepsy and its impacts on peripheral immune characteristics. In this study, expression profiles of 142 peripheral blood samples were downloaded from the Gene Expression Omnibus (GEO) database. Adipocytokine pathway-related genes were screened out by feature selection using machine-learning algorithms. A nomogram was then constructed and estimated for the efficacy of diagnosis. Cluster analysis was employed for the recognization of two distinct epilepsy subtypes, followed by an estimation of the immune cell infiltration levels using single-sample gene-set enrichment analysis (ssGSEA). The biological characteristics were analyzed by functional enrichment analysis. The aberrant regulation of adipocytokine signaling pathway was found in the peripheral blood of patients with epilepsy. Twenty-one differently expressed adipocytokine pathway-related genes were identified and five (RELA, PRKAB1, TNFRSF1A, CAMKK2, and CPT1B) were selected to construct a nomogram. Subsequent validations of its forecasting ability revealed that this model has satisfactory predictive value. The immune cell infiltration degrees, such as those of innate immune cells and lymphocytes, were found to significantly correlate to the levels of adipocytokine pathway-related genes. Additionally, 239 differentially expressed genes (DEGs) were identified and their biological functions were mainly enriched in the regulation of the immune response. In conclusion, our results confirmed the predictive value of adipocytokine pathway-related genes for epilepsy and explored their effects on immune infiltration, thereby improving our understanding of the pathogenesis of epilepsy and providing assistance in the diagnosis and treatment of epilepsy.

Project description:This article emphasizes the role of the technological progress in changing the landscape of epilepsy surgery and provides a critical appraisal of robotic applications, laser interstitial thermal therapy, intraoperative imaging, wireless recording, new neuromodulation techniques, and high-intensity focused ultrasound. Specifically, (a) it relativizes the current hype in using robots for stereo-electroencephalography (SEEG) to increase the accuracy of depth electrode placement and save operating time; (b) discusses the drawback of laser interstitial thermal therapy (LITT) when it comes to the need for adequate histopathologic specimen and the fact that the concept of stereotactic disconnection is not new; (c) addresses the ratio between the benefits and expenditure of using intraoperative magnetic resonance imaging (MRI), that is, the high technical and personnel expertise needed that might restrict its use to centers with a high case load, including those unrelated to epilepsy; (d) soberly reviews the advantages, disadvantages, and future potentials of neuromodulation techniques with special emphasis on the differences between closed and open-loop systems; and (e) provides a critical outlook on the clinical implications of focused ultrasound, wireless recording, and multipurpose electrodes that are already on the horizon. This outlook shows that although current ultrasonic systems do have some limitations in delivering the acoustic energy, further advance of this technique may lead to novel treatment paradigms. Furthermore, it highlights that new data streams from multipurpose electrodes and wireless transmission of intracranial recordings will become available soon once some critical developments will be achieved such as electrode fidelity, data processing and storage, heat conduction as well as rechargeable technology. A better understanding of modern epilepsy surgery will help to demystify epilepsy surgery for the patients and the treating physicians and thereby reduce the surgical treatment gap.

Dataset Information

The landscape of epilepsy-related GATOR1 variants.

Purpose

Results

Conclusion

Publications

The landscape of epilepsy-related GATOR1 variants.

Similar Datasets

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