January 18, 2017

expert reaction to first reported case of variant Creutzfeldt–Jakob disease in a patient with MV genotype

In a Correspondence article published in the NEJM researchers report the first case of variant Creutzfeldt-Jakob disease (vCJD) in a patient with a methionine valine (MV) heterozygous genotype for a prion protein. Prior to this all definite diagnoses were in humans with a homozygous genotype (MM).

Prof. Giovanna Mallucci, Professor in the Department of Clinical Neurosciences, Cambridge, said:

“This is not unexpected given experience with other transmitted human prion diseases, particularly kuru, where some individuals had extremely delayed onset of disease, decades after exposure, due to the genetic makeup of individuals: being less susceptible and hence having much longer incubation times.

“This case is likely to reflect exposure in the peak of the BSE era before the measures that were brought in to remove BSE-infected beef from the food-chain. It is not a cause for alarm other than of course for unfortunate individuals that may be affected and their families: it remains a very rare disease.

“The total number of worldwide deaths from variant CJD was 223 by the end of 2015 (178 of these in the UK) from when the disease was first described in the early 1990s, with dropping incidence in last decade (all except one of those cases were in patients with the MM genotype). As the almost same proportion of people in the UK have the less susceptible MV genotype as the susceptible MM genotype, it is possible we might expect similar numbers of cases with the MV genotype to what we have already seen with the MM genotype, but spread over a longer time period, as the authors comment.”

Prof. Richard Knight, Chair of Clinical Neurology and Director of the National CJD Research and Surveillance Unit, University of Edinburgh, said:

“The initial cases of variant CJD were all of a certain genetic type called 129MM. There are three of these particular genetic types in the population: MM, MV and VV. This genetic variation is normal. There is a lot of evidence, however, to show that this genetic variation affects an individual’s susceptibility to contracting variant CJD and also the length of the incubation period (i.e. how long it takes to become ill after being exposed to infection). It has always been expected that MV and VV genetic individuals would develop variant CJD but in lesser numbers and at later periods than for MM individuals. This individual case report therefore reflects what has always been expected and an event that has been discussed in various previous publications.

“There are still no UK cases of variant CJD in individuals born after 1989 when measures were put in place to protect the human diet from BSE infectivity. Variant CJD may take a long time to develop into clinical illness after dietary exposure and, therefore, cases may arise many years after the risk of infection has ceased.

“Although the authors comment on differences between the clinical features of this case and those of ‘typical vCJD’, there is some variation in the clinical phenotype of MM variant CJD and this case does not provide firm evidence that MV variant CJD differs generally in presentation from MM cases.”

Prof. David Brown, Professor of Biochemistry, University of Bath, said:

“It is unlikely that this is the start of a second round of cases of variant CJD.

“From a biochemical point of view, contracting variant CJD requires the conversion of a host prion protein to an abnormal form of the protein by the variant CJD infectious agent. All previous cases of variant CJD have been M/M genotype, meaning their prion protein only carried a methionine at position 129. This has to be the form of the protein to be converted by the infection, which means that this form of the prion protein (M) is the preferred substrate for this conversion reaction – so the M protein type seems to be the preferred type for variant CJD to be contracted.

“In the M/V patient described here, the form of the protein with the methionine is also present (about half as much – the other half being the V type, valine), which means it can react with the infectious agent and so it is likely that such a patient could get variant CJD, but with a much lower probability. It is possible the presence of the prion protein with valine, which is also present in this patient, greatly diminishes the likelihood of the conversion reaction occurring, meaning people with the M/V genotype are much less likely to develop variant CJD than those we’ve already seen historically, with the M/M genotype. As this patient is one out of 230 people who have died of variant CJD in the world (178 in the UK), then this fits quite well with the biochemical model – so seeing one case of variant CJD in a patient with the M/V genotype is not unexpected, but we can expect it to be much rarer than in the M/M genotype.

“I would say it is likely that the patient acquired the disease in the same way and at the same time as all other variant CJD cases – this patient being slightly older than the average case fits with the same time frame. It may be that we might see more such cases appear in people with the M/V genotype but these are likely to be in low numbers and part of the same ‘tail’ of the initial epidemic for the reasons outline above.”

Dr Graham Jackson, MRC Prion Unit, Institute of Neurology, UCL, said:

“Since its first identification in 1995 there have been 223 deaths worldwide from variant CJD resulting from infection with BSE contaminated food. Prior to the identification of this new case all definite cases of vCJD had occurred in individuals with a specific variation in the prion protein gene. Such MM homozygous individuals comprise 42% of the population in the UK, with other genotypes accounting for the majority 58% (MV 46%, VV 12%).

“Although only a single case so far, the identification of variant CJD in an MV heterozygous individual suggests that more individuals, perhaps similar numbers to those we’ve already seen, may now begin to develop BSE related disease. We know from studies of the human prion disease kuru that the time taken to develop clinical disease in MV heterozygotes can be considerably longer than in MM homozygous individuals.

“Worryingly this patient presented with symptoms and diagnostic investigations that satisfied the diagnostic criteria for sporadic CJD, a disease unrelated to BSE. It was only through the detailed analysis of tissues after autopsy that a definite diagnosis of variant CJD was confirmed.

“Analysis of peripheral tissues, including appendix and spleen revealed a discrepancy between historical variant CJD cases where significant amounts of abnormal prion protein accumulate. In this new case abnormal PrP, a diagnostic marker of infection, was not readily detectable in the appendix. This has important implications for the interpretation of prevalence studies conducted using appendix tissues which have suggested around 1:2000 people in the UK might be silently infected with variant CJD. If variant CJD in MV heterozygous individuals does not consistently result in the accumulation of abnormal PrP in the appendix then this figure may be too low as such cases will not have been detected. Whilst the incidence of clinical variant CJD has fallen from a peak in 2000 it interesting that the incidence of sporadic CJD appears to have been steadily rising over the same period. The case reported satisfied all the criteria for classification as sporadic CJD and would have been reported as such if the unusually young age of the patient had not prompted detailed investigations following autopsy. There is now a possibility that BSE related prion disease can present cryptically as sporadic CJD in addition to the typical variant CJD.”

Prof. David Westaway, Head of the Centre for Prions and Protein Folding Diseases, University of Alberta, Canada, said:

“This is careful study documenting a variant CJD case in a common type of genetic makeup called M/V.

“As the patient’s history is unremarkable, I would not discount this case as an exotic one-off – instead, the study suggests upcoming cases of variant CJD in the UK, these set into motion by a low level of exposure to BSE about thirty years ago.”

* ‘Variant Creutzfeldt–Jakob Disease in a patient with heterozygosity at PRNP codon 129’ by Tzehow Mok et al. will be published in NEJM at 22:00 UK time on Wednesday 18 January 2017, which is also when the embargo will lift.

Declared interests

Prof. Giovanna Mallucci: “No declarations of interest.”

Prof. Richard Knight: “I am funded by DH in my research.”

Prof. David Brown: “I have no conflicts of interest.”

Dr Graham Jackson: “I am a prion disease researcher employed by the Medical Research Council and a shareholder in D-Gen Ltd, an academic spin-out company working in the field of prion disease diagnosis, therapeutics and decontamination.”

Prof. David Westaway: “Salary support from the Canada Research Chairs initiative (CRC). I am a CRC in Prion Diseases. My lab receives grant funding from the Canadian Institutes of Health Research, the Alberta Prion Research Institute (Alberta Innovates) and Genome Canada. I have no biotech investments nor biotech/pharma support for my laboratory. I am an ad hoc consult for Blue-Zone Technologies in Markham, Ontario.”