Neuropediatrics 2014; 45 - fp063
DOI: 10.1055/s-0034-1390568

De Novo SCN2A Mutations Cause Variable Phenotypes in Children with Epilepsy

M. Wolff 1, T. Bast 2, T. Loddenkemper 3, D. Jillella 3, M. Döcker 4, L. Wong-Kisiel 5, R. Möller 6, S. Weckhuysen 7, B. Ceulemans 8, J. Klepper 9, F. Baumeister 10, C. Finetti 11, G. Kurlemann 12, H. Muhle 13, G. Kluger 14
  • 1Universitäts-Klinik für Kinder- und Jugendmedizin, Neuropädiatrie, Tübingen, Germany
  • 2Epilepsiezentrum Kork, Kinderklinik, Kehl-Kork, Germany
  • 3Division of Epilepsy and Clinical Neurophysiology, Boston, Boston Children’s Hospital, Harvard Medical School, United States
  • 4CeGaT GmbH, Tübingen, Germany
  • 5Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, United States
  • 6Danish Epilepsy Centre, Dianalund, Dänemark
  • 7Department of molecular genetics, University of Antwerp, Neurogenetics group, Antwerpen, Belgien
  • 8Pediatric Neurology, Department of Neurology, University Hospital of Antwerp, Antwerpen, Belgien
  • 9Klinikum Aschaffenburg, Neuropädiatrie, Aschaffenburg, Germany
  • 10Children’s Hospital, RoMed Klinikum, Rosenheim, Germany
  • 11Klinik für Kinder- und Jugendmedizin, Elisabeth-Krankenhaus, Essen, Germany
  • 12Universitäts-Kinderklinik Münster, Schwerpunkt Neuropädiatrie, Münster, Germany
  • 13Klinik für Neuropädiatrie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
  • 14Epilepsy Center for Children and Adolescents, Schön Klinik, Vogtareuth, Germany

Purpose: Mutations in the sodium channel gene SCN2A have been associated with benign epileptic phenotypes such as benign familial neonatal-infantile seizures. Recently, several de novo SCN2A mutations have been found in children with more severe forms of epilepsy. Here, we describe the phenotypic spectrum of a cohort of children with drug resistant epilepsies due to de novo SCN2A mutations.

Patients and Methods: Children with drug resistant and otherwise unexplained epilepsies were screened for SCN2A mutations across multiple centers using next generation sequencing. Clinical, electroencephalography (EEG) and magnetic resonance imaging (MRI) data were analyzed in the SCN2A positive cases.

Results: A total of 16 children with de novo SCN2A mutations were identified. The age of seizure onset ranged from 1 day to 3 years. Children with neonatal onset (n = 7) either exhibited severe epileptic encephalopathy with multifocal seizures (n = 4) and suppression burst EEG pattern or transitory epilepsy with cessation of seizures during the first year of life (n = 3). Of interest, sodium channel blockers reduced seizure frequency in most cases. The other children (n = 9) presented various seizure types including tonic-clonic or hemiclonic, myoclonic, myoclonic-tonic, atonic, and focal seizures as well as atypical absences or spasms of later onset (mean age, 2 years). Most of the children showed decreased muscle tone and severe mental disability. Abnormal MRI patterns were found in six cases.

Conclusion: De novo SCN2A mutations seem to cause more severe epilepsies compared with the inherited SCN2A mutations reported so far. The clinical spectrum includes various phenotypes possibly due to different properties of the affected sodium channels. Electrophysiological analyses of the mutated channels are needed to check this hypothesis.