Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

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

Unique clinicopathological features and PrP profiles in the first autopsied case of dura mater graft-associated Creutzfeldt–Jakob disease

Articles in Press

ABSTRACT

Unique clinicopathological features and PrP profiles in the first autopsied case of dura mater graft-associated Creutzfeldt–Jakob disease with codon 219 lysine allele observed in Japanese population

Masamichi Ikawaa, Makoto Yonedaa, Akiko Matsunagaa, Hiroto Nakagawaa, Asuka Kazama-Suzukib, Nobuo Miyashitab, Hironobu Naikic, Tetsuyuki Kitamotod, Masaru Kuriyamaa

Received 2 April 2009; received in revised form 22 June 2009; accepted 23 July 2009. published online 10 August 2009. Corrected Proof

Abstract Polymorphism at codon 219 lysine in prion protein (PrP) is considered to affect the clinicopathological features of prion diseases including Creutzfeldt–Jakob disease (CJD) and to have an inhibiting effect on the pathogenesis of these diseases. We describe the first autopsied case of dura mater graft-associated CJD (dCJD) with heterozygosity of lysine at codon 219 in PrP observed in a Japanese subject. Although this case demonstrated the non-plaque type of dCJD and MM1 subgroup of CJD pathologically and biochemically, the patient demonstrated a long incubation period (19.3years), atypical periodic sharp-wave complexes with a dominant rhythm on EEG, partially scattered small deposits of plaque-like PrP along with synaptic type deposits of PrP on immunohistochemistry and an atypical MM1 glycosylation pattern with a relatively increased diglycosylated isoform of proteinase-resistant PrP on western blot analysis (i.e. “MM1 variant” pattern). These findings in this case were atypical of the non-plaque type of dCJD and MM1 subgroup of CJD. Thus, these findings can be unique to dCJD with codon 219 lysine allele, and this allele may influence the clinicopathological features and PrP profiles in dCJD.

Keywords: Dura mater graft-associated Creutzfeldt–Jakob disease, Codon 219 polymorphism, Glycosylation pattern in prion protein a Second Department of Internal Medicine (Neurology), Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaiduki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan

b Department of Neurology, Koshigaya Municipal Hospital, 10-47-1 Higashi-Koshigaya, Koshigaya, Saitama 343-8577, Japan

c Department of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaiduki, Matsuoka, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan

d Division of CJD Science and Technology, Department of Prion Research, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan

Corresponding author. Tel.: +81 776 61 8351; fax: +81 776 61 8110.

PII: S0022-510X(09)00741-2

doi:10.1016/j.jns.2009.07.019

© 2009 Elsevier B.V. All rights reserved

http://www.jns-journal.com/article/S0022-510X(09)00741-2/abstract



PLEASE NOTE ;

the patient demonstrated a long incubation period (19.3years)

[7] CJD in dura mater grafts - Japan, 1978-2008 Date Fri 24 Oct 2008 Source: MMWR Weekly 57(42);1152-1154 [edited]

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5742a3.htm



http://www.promedmail.org/pls/otn/f?p=2400:1001:2012455953418954::::F2400_P1001_BACK_PAGE,F2400_P1001_ARCHIVE_NUMBER,F2400_P1001_USE_ARCHIVE:1202,20081103.3458,Y



Thursday, October 23, 2008 Creutzfeldt-Jakob Disease Associated with Cadaveric Dura Mater Grafts - Japan, 1979-2008 : UPDATE

http://creutzfeldt-jakob-disease.blogspot.com/2008/10/creutzfeldt-jakob-disease-associated.html



http://www.wellsphere.com/cjd-article/medical-procedures-and-risk-for-sporadic-creutzfeldt-jakob-disease-japan-1999-2008-warning-to-neurosurgeons-and-ophthalmologi/641229



Thursday, January 29, 2009

Medical Procedures and Risk for Sporadic Creutzfeldt-Jakob Disease, Japan, 1999-2008 (WARNING TO Neurosurgeons and Ophthalmologists) Volume 15, Number 2-February 2009 Research

http://creutzfeldt-jakob-disease.blogspot.com/2009/01/medical-procedures-and-risk-for.html



Tuesday, August 11, 2009

Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants

http://creutzfeldt-jakob-disease.blogspot.com/2009/08/characteristics-of-established-and.html



TSS