Epilepsia 2007 Sep 11;48(9):1678-1685. Epub 2007 Jun 11.
Epilepsy, Neurophysiology and Neurogenetic Unit, Institute of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Calambrone, Pisa, ItalyNeurogenetic Laboratory, Pediatric Hospital A. Meyer, Florence, ItalyUnidade de Neuropediatria, Seviço de Pediatria, Hospital Geral de Santo António, Porto, PortugalChild Neurology Unit, Pediatric Hospital A. Meyer, Florence, ItalyPediatric Neurology Unit, Hospital Dona Estefania, Lisbon, PortugalClinical Neurophysiology and Developmental Neuropsychiatry, School of Life and Health Sciences, Aston University, The Birmingham Children's Hospital NHS Trust, Birmingham, United KingdomNeurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, United KingdomPediatric Neurology Unit, Clínica Universitaria de Navarra, Pamplona, SpainCambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge, United KingdomDepartment of Neurosciences, Division of Neurology, Bellaria Hospital, Bologna, ItalyChild Neurology and Psychiatry Unit, Ospedale S. Chiara, Trento, ItalyUniversity of Florence, Florence, Italy.
Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations.
Methods: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients.
Results: We classified patients as: SMEI/SMEB = 55; GEFS+= 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations.
Conclusion: We obtained a frequency of 71%SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes.