Your browser doesn't support javascript.
loading
The landscape of epilepsy-related GATOR1 variants.
Baldassari, Sara; Picard, Fabienne; Verbeek, Nienke E; van Kempen, Marjan; Brilstra, Eva H; Lesca, Gaetan; Conti, Valerio; Guerrini, Renzo; Bisulli, Francesca; Licchetta, Laura; Pippucci, Tommaso; Tinuper, Paolo; Hirsch, Edouard; de Saint Martin, Anne; Chelly, Jamel; Rudolf, Gabrielle; Chipaux, Mathilde; Ferrand-Sorbets, Sarah; Dorfmüller, Georg; Sisodiya, Sanjay; Balestrini, Simona; Schoeler, Natasha; Hernandez-Hernandez, Laura; Krithika, S; Oegema, Renske; Hagebeuk, Eveline; Gunning, Boudewijn; Deckers, Charles; Berghuis, Bianca; Wegner, Ilse; Niks, Erik; Jansen, Floor E; Braun, Kees; de Jong, Daniëlle; Rubboli, Guido; Talvik, Inga; Sander, Valentin; Uldall, Peter; Jacquemont, Marie-Line; Nava, Caroline; Leguern, Eric; Julia, Sophie; Gambardella, Antonio; d'Orsi, Giuseppe; Crichiutti, Giovanni; Faivre, Laurence; Darmency, Veronique; Benova, Barbora; Krsek, Pavel; Biraben, Arnaud.
Afiliación
  • Baldassari S; Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.
  • Picard F; INSERM, U1127, F-75013, Paris, France.
  • Verbeek NE; CNRS, UMR 7225, F-75013, Paris, France.
  • van Kempen M; Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
  • Brilstra EH; Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
  • Lesca G; Department of Clinical Neurosciences, University Hospitals and Medical School of Geneva, Geneva, Switzerland.
  • Conti V; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Guerrini R; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Bisulli F; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Licchetta L; Service de Génétique, Hospices Civils de Lyon - GHE; CNRS UMR 5292, INSERM U1028, CNRL, et Université Claude Bernard Lyon 1, GHE, Lyon, France.
  • Pippucci T; Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, A. Meyer Children's Hospital, Florence, Italy.
  • Tinuper P; Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, A. Meyer Children's Hospital, Florence, Italy.
  • Hirsch E; IRCCS, Istituto delle Scienze Neurologiche of Bologna; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
  • de Saint Martin A; IRCCS, Istituto delle Scienze Neurologiche of Bologna; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
  • Chelly J; Medical Genetics Unit, Polyclinic Sant' Orsola-Malpighi University Hospital, Bologna, Italy.
  • Rudolf G; IRCCS, Istituto delle Scienze Neurologiche of Bologna; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
  • Chipaux M; Department of Neurology-centre de référence des épilepsies rares, University Hospital of Strasbourg, Strasbourg, France.
  • Ferrand-Sorbets S; Department of Pediatrics - centre de référence des épilepsies rares, University Hospital of Strasbourg, Strasbourg, France.
  • Dorfmüller G; IGBMC, INSERM, CNRS, Strasbourg University, Strasbourg, France.
  • Sisodiya S; IGBMC, INSERM, CNRS, Strasbourg University, Strasbourg, France.
  • Balestrini S; Department of Pediatric Neurosurgery, Fondation Rothschild, F-75019, Paris, France.
  • Schoeler N; Department of Pediatric Neurosurgery, Fondation Rothschild, F-75019, Paris, France.
  • Hernandez-Hernandez L; Department of Pediatric Neurosurgery, Fondation Rothschild, F-75019, Paris, France.
  • Krithika S; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.
  • Oegema R; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.
  • Hagebeuk E; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.
  • Gunning B; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.
  • Deckers C; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.
  • Berghuis B; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Wegner I; Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.
  • Niks E; Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.
  • Jansen FE; Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.
  • Braun K; Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.
  • de Jong D; Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.
  • Rubboli G; Leiden University Medical Center, Leiden, The Netherlands.
  • Talvik I; Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.
  • Sander V; Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.
  • Uldall P; Department of Neurology, Academic Center for Epileptology Kempenhaeghe, Heeze, The Netherlands.
  • Jacquemont ML; Danish Epilepsy Centre, Dianalund, University of Copenhagen, Copenhagen, Denmark.
  • Nava C; Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia.
  • Leguern E; Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia.
  • Julia S; Danish Epilepsy Centre, Dianalund, Denmark.
  • Gambardella A; Unit of Medical Genetics, CHU La Réunion, Saint Pierre, F-97448, France.
  • d'Orsi G; Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.
  • Crichiutti G; INSERM, U1127, F-75013, Paris, France.
  • Faivre L; CNRS, UMR 7225, F-75013, Paris, France.
  • Darmency V; Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
  • Benova B; Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
  • Krsek P; Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.
  • Biraben A; INSERM, U1127, F-75013, Paris, France.
Genet Med ; 21(2): 398-408, 2019 02.
Article en En | MEDLINE | ID: mdl-30093711
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Proteínas Activadoras de GTPasa / Proteínas Supresoras de Tumor / Epilepsia Tipo de estudio: Guideline Límite: Adolescent / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2019 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Proteínas Activadoras de GTPasa / Proteínas Supresoras de Tumor / Epilepsia Tipo de estudio: Guideline Límite: Adolescent / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2019 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos