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Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

Posted Aug 11 2010 7:34pm
Vol. 67 No. 8, August 2010

Observation

Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

Ana Lukic, MD, MRCP; Jonathan Beck, BSc; Susan Joiner, BSc; Julian Fearnley, FRCP; Steve Sturman, FRCP; Sebastian Brandner, FRCP; Jonathan D. F. Wadsworth, PhD; John Collinge, FRS; Simon Mead, PhD, MRCP

Arch Neurol. 2010;67(8):1021-1023. doi:10.1001/archneurol.2010.184

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.

Design Case reports.

Setting 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.

Main Outcome Measures 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.

Author Affiliations: MRC (Medical Research Council) Prion Unit (Drs Lukic, Wadsworth, Collinge, and Mead; Mr Beck; and Ms Joiner) and Department of Neurodegenerative Disease (Drs Brandner, Collinge, and Mead), University College London Institute of Neurology, London; National Prion Clinic, National Hospital for Neurology and Neurosurgery, London (Drs Lukic, Collinge, and Mead); The Barts and Royal London Hospital National Health Service Trust, London (Dr Fearnley); and Queen Elizabeth Neuroscience Unit, University Hospital Birmingham National Health Service Trust, Birmingham (Dr Sturman), United Kingdom.

http://archneur.ama-assn.org/cgi/content/abstract/67/8/1021


Tuesday, August 03, 2010

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein

http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html


Monday, August 9, 2010

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more Prionbaloney ?

http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html


In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000156


http://www.plospathogens.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000156&representation=PDF


Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

(PLEASE WATCH THE VIDEO...TSS)

http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html


TSS
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