BACKGROUNDGenetic 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.OBJECTIVETo report a finding of heterozygosity at codon 219 in 2 patients with vCJD.DESIGNCase reports.SETTINGMRC (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.MAIN OUTCOME MEASURESClinical and genetic findings.RESULTSA 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.CONCLUSIONSThe 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.