title: Familial severe myoclonic epilepsy of infancy: truncation of Nav1.1 and genetic heterogeneity.
abstract: BACKGROUND
  Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome has been long suspected of having a genetic origin. Recently, mutations in SCN1A and GABRG2 have been described in SMEI patients. The sporadic nature of the SMEI syndrome and the occurrence of SCN1A and GABRG2 mutations in a mild familial phenotype, termed generalized epilepsy with febrile seizure plus complicates genotype-phenotype correlations. In order to further investigate the role of SCN1A and GABRG2 in the pathogenesis of SMEI we have screened for mutations three families with at least two members affected by Dravet syndrome.
  
  
  METHODS
  Clinical criteria followed the international classification of epileptic syndromes. Mutational screening of SCN1A and GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram.
  
  
  RESULTS
  Thirty-eight fragments spanning 26 exons of SCN1A and nine exons of GABRG2 were analysed in three probands. Five variant chromatograms were identified; four corresponded to known polymorphisms, one to a novel dinucleotide insertion on exon 26 of SCN1A. The mutation leads to a frameshift and a premature stop codon at amino acid 1 779 of the protein. The mutation was present in the affected sibling and was inherited from the mother who had experienced a single febrile seizure in childhood.
  
  
  CONCLUSIONS
  Among three families analysed, a single family was mutant for SCN1A. Our study suggests that the syndrome is genetically heterogeneous. The variable expressivity we observed for the c5240insAA mutation suggests that other factors are needed for the development of the full SMEI phenotype.
authors.affiliation: Laboratory of Human Genetics, E.O. Galliera Hospital, Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gennaro
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Veggiotti
authors.forename: Michele
authors.initials: M
authors.lastname: Malacarne
authors.forename: Francesca
authors.initials: F
authors.lastname: Madia
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cecconi
authors.forename: Simonetta
authors.initials: S
authors.lastname: Cardinali
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cassetti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cecconi
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Amedeo
authors.initials: A
authors.lastname: Bianchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gobbi
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D002658:Developmental Disabilities / Q000150:complications; D004569:Electroencephalography; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics* / Q000503:physiopathology; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
chemical_list: C106350:GABRR2 protein, human; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C568242:SCN1A protein, human; D015222:Sodium Channels; D004247:DNA