Julien Denis1, Nathalie Villeneuve1, Pierre Cacciagli2, Cecile Mignon-Ravix3, Caroline Lacoste2, Jeremie Lefranc4, Sylvia Napuri5, Lena Damaj5, Frederic Villega6, Jean-Michel Pedespan6, Sebastien Moutton7, Cyril Mignot8, Diane Doummar8, Laurence Lion-François9, Svetlana Gataullina10,11, Olivier Dulac11, Melanie Martin12, Sophie Gueden13, Gaetan Lesca14,15, Sophie Julia16, Claude Cances17, Hubert Journel18, Cecilia Altuzarra19, Bruria Ben Zeev20,21, Alexandra Afenjar22, Magalie Barth23, Laurent Villard2,3, Mathieu Milh1,3. 1. Pediatric Neurology Department, Timone Children Hospital, Reference Center for Rare Epilepsies, APHM, Marseille, France. 2. Medical Genetics Department, Timone Children Hospital, Marseille, France. 3. Aix Marseille University, INSERM, UMR-S 1251, MMG, Marseille, France. 4. Pediatrics and Medical Genetics Department, CHU Brest, Brest, France. 5. Department of Pediatrics, Rennes University Hospital, Rennes, France. 6. Department of Pediatric Neurology, University Children's Hospital of Bordeaux, Bordeaux, France. 7. Medical Genetics Department, University Hospital of Bordeaux, Bordeaux, France. 8. Pediatric Neurology Department, Trousseau Hospital, AP-HP, Paris, France. 9. Department of Pediatric Neurology, Woman Mother Child Hospital, Bron, France. 10. Paediatric Neurology Department, Paris-Sud University, Bicêtre Hospital, Kremlin-Bicêtre, France. 11. Inserm U1129, Necker Hospital, Paris, France. 12. Department of Histology, Cytology, Cytogenetics and Cell Biology, University Hospital of Limoges, Limoges, France. 13. Pediatric Neurology Department, Angers Hospital and University, Angers, France. 14. Department of Medical Genetics, Groupement Hospitalier Est, and ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France. 15. Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Lyon, France. 16. Genetics Unit, Toulouse University Hospital, Toulouse, France. 17. Department of Pediatric Neurology, Toulouse Children Hospital, Toulouse University Hospital, Toulouse, France. 18. Department of Genetics, Vannes Bretagne-Atlantique Hospital, Vannes, France. 19. Department of Pediatrics, St. Jacques Hospital, Besançon, France. 20. Chaim Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel. 21. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 22. Medical Genetics Department, AP-HP, University hospital Armand Trousseau, Paris, France. 23. Department of Genetics, Angers Hospital and University, Angers, France.
Abstract
OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy. Wiley Periodicals, Inc.
OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy. Wiley Periodicals, Inc.