title: From focal epilepsy to Dravet syndrome--Heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the Nav1.1 subunit.
abstract: OBJECTIVE
  The aim of this study was to analyze the intra-/interfamilial phenotypic heterogeneity due to variants at the highly evolutionary conservative p.Arg1596 residue in the Nav1.1 subunit.
  Among patients referred for analysis of the SCN1A gene one recurrent, heritable mutation was found in families enrolled into the study. Probands from those families even clinically diagnosed with atypical Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+), and focal epilepsy, had heterozygous p.Arg1596 His/Cys missense substitutions, c.4787G>T and c.4786C>T in the SCN1A gene.
  
  
  METHODS
  Full clinical evaluation, including cognitive development, neurological examination, EEGs, MRI was performed in probands and affected family members in developmental age. The whole SCN1A gene sequencing was performed for all probands. The exon 25, where the identified missense substitutions are localized, was directly analyzed for the other family members.
  
  
  RESULTS
  Mutation of the SCN1A p.1596Arg was identified in three families, in one case substitution p.Arg1596Cys and in two cases p.Arg1596His. Both mutations were previously described as pathogenic and causative for DS, GEFS+ and focal epilepsy. Spectrum of phenotypes among presented families with p.Arg1596 mutations shows heterogeneity ranged from asymptomatic cases, through FS and FS+ to GEFS+/Panayiotopoulos syndrome and epilepsies with and without febrile seizures, and epileptic encephalopathy such as DS. Phenotypes differ among patients displaying both focal and generalized epilepsies. Some patients demonstrated additionally Asperger syndrome and ataxia.
  
  
  CONCLUSIONS
  Clinical picture heterogeneity of the patients carrying mutation of the same residue indicates the involvement of the other factors influencing the SCN1A gene mutations' penetrance.
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Poland; Institute of Genetics and Biotechnology, Warsaw University, Poland. Electronic address: dhoffman@wp.pl.
authors.forename: Dorota
authors.initials: D
authors.lastname: Hoffman-Zacharska
authors.affiliation: Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Szczepanik
authors.affiliation: Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Terczynska
authors.affiliation: Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Goszczanska-Ciuchta
authors.affiliation: Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Zalewska-Miszkurka
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Tataj
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bal
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D004828:Epilepsies, Partial / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Dravet syndrome; Focal epilepsy; GEFS+; Panayiotopoulos syndrome; SCN1A