The spectrum of SCN1A-related infantile epileptic encephalopathies
1Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia2Department of Paediatrics, The University of Adelaide, Adelaide, South Australia3Department of Medicine and Epilepsy Research Centre, The University of Melbourne, Austin Health, Melbourne, Victoria, Australia4Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK5Departments of Paediatrics, Capital Coast Health and University of Otago, Wellington, New Zealand6Neurogenetics Unit, Montreal Neurological Institute and Hospital, and Departments of Neurology, Neurosurgery and Human Genetics, McGill University, Montreal, Canada7TY Nelson Department of Neurology, The Children's Hospital at Westmead, Westmead, Australia8Department of Neurology, British Columbia Children's Hospital, University of British Columbia, Vancouver, Canada9Department of Paediatrics and Child Health, Flinders Medical Centre, Adelaide, South Australia, Australia10Athena Diagnostics Inc., Worcester, MD, USA11School of Molecular and Biomedical Sciences, The University of Adelaide, South Australia12Department of Paediatrics, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria13Department of Neurosciences, Monash Medical Centre, Melbourne, Victoria, Australia
Correspondence to: Prof. Ingrid Scheffer, Epilepsy Research Centre, Neuroscience Building, Heidelberg Repatriation Hospital, Banksia Street, West Heidelberg, Victoria 3081, Australia. E-mail: scheffer{at}unimelb.edu.au
The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.
Key Words: SCN1A; SMEI; SMEB; epileptic encephalopathy; channelopathies
Abbreviations: dHPLC, denaturing high performance liquid chromatography; GEFS+, generalized epilepsy with febrile seizures plus; ICEGTC, intractable childhood epilepsy with generalized tonic clonic seizures; LGS, Lennox–Gastaut syndrome; MAE, Myoclonic–astatic epilepsy; PCR, polymerase chain reaction; SCN1A, sodium channel alpha 1 subunit gene; SMEB, SMEI-borderland; SMEB-M, SMEI-borderland-myoclonic seizures; SMEB-O, SMEI-borderland more than one feature; SMEB-SW, SMEI-borderland-spike wave; SMEI, severe myoclonic epilepsy of infancy
Received November 13, 2006. Revised December 13, 2006. Accepted January 4, 2007.
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