title: Heterozygosity at polymorphic codon 219 in variant creutzfeldt-jakob disease.
abstract: BACKGROUND
  Genetic variants of the prion protein gene (PRNP) strongly determine susceptibility to prion diseases. All tested patients with definite variant Creutzfeldt-Jakob disease (vCJD) are homozygous for methionine at a common polymorphism at codon 129. A further genetic polymorphism at codon 219, a common variant in several Asian populations, is considered protective against sporadic CJD.
  
  
  OBJECTIVE
  To report a finding of heterozygosity at codon 219 in 2 patients with vCJD.
  
  
  METHODS
  Case reports.
  
  
  METHODS
  MRC (Medical Research Council) Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, and National Prion Clinic, National Hospital for Neurology and Neurosurgery. Patients Two patients with clinical and investigation findings consistent with the diagnoses of probable vCJD.
  
  
  METHODS
  Clinical and genetic findings.
  
  
  RESULTS
  A 34-year-old man had a 15-month history of behavioral change progressing to ataxia, dysarthria, involuntary choreiform movements, and severe cognitive impairment. Cerebrospinal fluid analysis was positive for 14-3-3 protein, electroencephalography showed generalized slowing, and magnetic resonance imaging revealed thalamic high signal bilaterally, typical of vCJD. A 31-year-old woman had a 16-month history of cognitive decline, ataxia, involuntary choreiform movements, and myoclonic jerks. Magnetic resonance imaging showed bilateral pulvinar high signal. The diagnosis was confirmed by a tonsillar biopsy demonstrating abnormal prion protein deposition in a typical pattern for vCJD. PRNP sequencing showed a methionine homozygous codon 129 genotype and an E219K polymorphism in both patients.
  
  
  CONCLUSIONS
  The E219K polymorphism is neutral or may even confer susceptibility to vCJD. The observations are interpretable in the context of the conformational selection model of prion replication. A barrier to prion disease transmission depends on the degree to which permitted pathologic conformations of the prion protein overlap between the inoculum and the host.
authors.affiliation: MRCP, National Prion Clinic and Prion Unit, Uneversity College London Institue of Neurology, Queen Square, London WCIN 3BG, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Lukic
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beck
authors.forename: Susan
authors.initials: S
authors.lastname: Joiner
authors.forename: Julian
authors.initials: J
authors.lastname: Fearnley
authors.forename: Steve
authors.initials: S
authors.lastname: Sturman
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000328:Adult; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011328:Prions / Q000235:genetics*
chemical_list: D048948:14-3-3 Proteins; D011328:Prions