title: De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study.
abstract: BACKGROUND
  Vaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel alpha1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified.
  
  
  METHODS
  We retrospectively studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 h of vaccination. We reviewed the relation to vaccination from source records and assessed the specific epilepsy phenotype. Mutations in SCN1A were identified by PCR amplification and denaturing high performance liquid chromatography analysis, with subsequent sequencing. Parental DNA was examined to ascertain the origin of the mutation.
  
  
  RESULTS
  SCN1A mutations were identified in 11 of 14 patients with alleged vaccine encephalopathy; a diagnosis of a specific epilepsy syndrome was made in all 14 cases. Five mutations predicted truncation of the protein and six were missense in conserved regions of the molecule. In all nine cases where parental DNA was available the mutations arose de novo. Clinical-molecular correlation showed mutations in eight of eight cases with phenotypes of SMEI, in three of four cases with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome.
  
  
  CONCLUSIONS
  Cases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. These findings have important clinical implications for diagnosis and management of encephalopathy and, if confirmed in other cohorts, major societal implications for the general acceptance of vaccination.
authors.affiliation: Epilepsy Research Centre and Department of Medicine, University of Melbourne, Austin Health, Heidelberg West, Victoria, Australia. s.berkovic@unimelb.edu.au
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Louise
authors.initials: L
authors.lastname: Harkin
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.forename: James T
authors.initials: JT
authors.lastname: Pelekanos
authors.forename: Sameer M
authors.initials: SM
authors.lastname: Zuberi
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Wirrell
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Gill
authors.forename: Xenia
authors.initials: X
authors.lastname: Iona
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
mesh_terms: D000293:Adolescent; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004673:Encephalomyelitis, Acute Disseminated / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012640:Seizures / Q000209:etiology / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D014611:Vaccination / Q000009:adverse effects
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C568242:SCN1A protein, human; D015222:Sodium Channels