First report of vCJD without susceptibility genotype

5 January 2010

Variant Creutzfeldt-Jakob disease or vCJD is a fatal progressive neurodegenerative condition, the human version of Bovine Spongiform Encephalopathy (BSE), also known as ‘mad-cow disease’. Both these conditions are forms of Transmissible Spongiform Encephalopathy (TSE) or prion diseases; prions are abnormal versions of normal brain proteins that can be transmitted and induce normal proteins to convert to the same abnormally folded form. There is currently no treatment for prion diseases, and recent research has also suggested that prions may be able to effectively mutate and develop resistance to prospective therapeutics (see BBC news).

vCDJ, as opposed to classical CJD (another rare disease, mostly sporadic but with some familial cases), is associated with consumption of beef from cows infected with BSE. The original UK outbreak of vCJD caused major concern about the possible extent of cases, given the large numbers potentially exposed, but over time fears have been somewhat allayed by relatively low numbers of cases, though the incubation period can be very long.

To date there have been fewer than 200 cases of vCJD in the UK, and notably all have been in individuals with a particular variant of the human prion protein PRNP gene, being homozygous for methionine at position 129 in the gene. This genotype, common to about one third of the UK population, is associated with susceptibility to vCJD.

Now a new paper in the Lancet reports the first apparent instance of vCJD in an individual heterozygous (methionine / valine) at this position [Kaski D et al. (2009) Lancet 374: 2128]. The affected man was diagnosed in 2008 and died early in 2009. The authors note the possibility that individuals with the heterozygous genotypes (almost 50% of the UK population) may in fact be as susceptible to infection, but display longer incubation periods before the disease becomes clinically apparent. If this is so, then further cases among this group are likely. However, the authors also note that both susceptibility to infection and disease incubation period may be subject to other genetic influences as yet undiscovered.

A Department of Health spokesperson commented: "The Spongiform Encephalopathy Advisory Committee (SEAC) have noted this finding, which confirms the need for ongoing vigilance and robust surveillance of CJD… We are continuing to provide resources for CJD surveillance and research, and the development of a test for vCJD remains a priority" (see BBC news). Of note, at present definitive diagnosis of vCJD is only possible on the basis of post-mortem examination of the brain, which was not done in the case of this patient; rather, diagnosis was made on the basis of clinical features and brain scans.

Comment: The total number of cases of vCJD expected to emerge in coming years is predicted to be relatively small, in the hundreds; although cases among heterozygotes could boost numbers somewhat, they would be unlikely to make a major difference, particularly if the incubation periods are long. However, there is undoubtedly a gap in current understanding of genetic influences on this and other forms of prion disease that should be addressed by ongoing research.

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