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From: TSS ()
Subject: Evidence of a new human genotype susceptible to variant CJD
Date: June 1, 2006 at 11:06 am PST

Evidence of a new human genotype susceptible to variant CJD
Thu Jun 1, 2006 13:31

Evidence of a new human genotype susceptible to variant CJD

HJT Ward (

National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh, Edinburgh, United Kingdom

There is now evidence that a new human genotype is susceptible to variant Creutzfeldt-Jakob disease (vCJD) infection [1]. A previous prevalence study showed accumulation of prion protein (a marker of vCJD infection) in three out of 12 674 appendix and tonsil specimens, which is more than expected based on the current number of reported clinical cases [3]. In this recent study, the prion protein gene (PRNP) was sequenced for two of the three positive samples (the third sample was not available for analysis). These two positive samples were found to be valine homozygous (VV) at codon 129 of the PRNP. This genotype is present in approximately 10% of the UK population [1]. This is the first time that evidence of vCJD infection has been found in codon 129 valine homozygotes.
To date, there have been 191 definite or probable clinical cases of vCJD reported worldwide; 161 in the United Kingdom (UK), a further 25 from other European countries and five cases outside Europe. All of those tested have been methionine homozygous (MM) at codon 129 in the PRNP, which is found in approximately 40% of the UK population. There has also been one previous case of iatrogenic infection (via a blood transfusion) reported in a patient who was methionine/valine heterozygous at PRNP codon 129 (MV). It is estimated that 50% of the UK population are heterozygous at codon 129 of this gene [2].

Important implications
This new information on the PRNP codon 129 genotype shows that the entire UK population (that is, all PRNP codon 129 genotypes) is susceptible to vCJD infection, which was not known before. The immunohistochemical technique used in the prevalence study appears to be specific, but is unlikely to be 100% sensitive, suggesting that the true prevalence in the UK population may be even greater than estimated from the study. Therefore, these results indicate that there may be a large subgroup of the population who are carriers for the disease (60% of people with non-MM genotypes) and that such carriers may have a long incubation period or may die before developing CJD. These findings are supported by studies of kuru and recent studies in transgenic mice, which show that PRNP codon 129 MV and VV genotypes are associated with longer incubation periods, and possibly with different phenotypes, than MM genotypes [4,5,6].

These findings have important public health implications, as these carriers may be able to spread the disease through blood transfusion, through surgical procedures or through organ or tissue donation. A self-sustaining secondary epidemic is possible, unless measures are taken to prevent it. Accordingly, countries throughout the world have implemented various public health measures in an attempt to prevent such an outcome. However, until a reliable test becomes available, we must rely on measures such as excluding certain blood donors with identifiable risk, leucoreduction of blood components, enhanced decontamination of medical and surgical equipment and the development of technologies such as prion filters for blood.

In addition to implementing these essential public health measures, we must continue surveillance of vCJD in order to detect the possibility of MV and VV codon 129 genotypes presenting with different clinical phenotypes and to continue to monitor for secondary transmission of vCJD infection. Another priority is to try and determine the prevalence of subclinical vCJD infection in the UK population. This is being undertaken in the UK by the Health Protection Agency in the form of a National Anonymous Tonsil Archive [7].

The author would like to thank James Ironside for his assistance in the preparation of this article.

Ironside JW, Bishop MT, Connolly K, Hegazy D, Lowrie S, Le Grice M, et al. Variant Creutzfeldt-Jakob Disease: a prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study. BMJ 2006; 332: 1186-1188. (
Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP individual codon 129 heterozygous patient. Lancet 2004; 364: 527-529.
Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Ritchie D, et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 2004; 203: 733-739.
Goldfarb LG, Cervenakova L, Gadjusek DC. Genetic studies in relation to kuru: an overview. Curr Mol Med 2004; 4: 375-384.
Bishop MT, Hart P, Aitchison L, Baybutt HN, Plinston C, Thomson V, et al. Predicting susceptibility and incubating time of human-to-human transmission of vCJD. Lancet Neurol 2006; 5: 393-398.
Wadsworth JD, Asante EA, Desbruslais M, Linehan JM, Joiner S, Gowland I, et al. Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype. Science 2004; 306(5702): 1793-6
Health Protection Agency. National Anonymous Tonsil Archive ( [accessed 30 May 2006].


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