Jan 9, 2008 (CIDRAP News) – A British woman who died of a brain disease suggestive of variant Creutzfeld-Jacob disease (vCJD) had a genetic marker not seen in any previous vCJD patients, raising the possibility that her illness represented a new form of the disease that could signal a new wave of infections, according to a recent research report.
The researchers, who reported their findings in the December 2007 issue of Archives of Neurology, found that the 39-year-old woman carried the VV (valine-homozygous) version of the prion protein gene (PRNP), a type previously thought to confer protection against vCJD.
Past research has linked vCJD to eating meat products contaminated with brain and spinal cord material from cattle infected with bovine spongiform encephalopathy (BSE), or mad cow disease. Normal prion proteins in the brain are corrupted after contact with the BSE agent, eventually causing death in both cattle and humans. BSE, vCJD, and sporadic CJD—a rare disease of unknown cause that closely resembles vCJD—are all prion diseases, also known as transmissible spongiform encephalopathies.
Cases of vCJD began surfacing in the United Kingdom in 1996, in the wake of a BSE epidemic in cattle. According to the most recent update from the National CJD Surveillance Unit (NCJDSU) based at the Western General Hospital in Edinburgh, Scotland, the number of patients in the UK who have died of confirmed or probable vCJD stands at 163. Until the case described, all vCJD patients who had been tested had the MM (methionine-homozygous) version of PRNP.
In early 1999 the patient described started having visual symptoms, followed by a host of other neurological problems, such as memory and gait impairments, according to the report. Polymerase chain reaction testing revealed that the patient had the VV variant of the PRNP gene. The patient died 14 months later.
Brain autopsy findings included severe gray- and white-matter degeneration and extensive prion protein deposits in the cortex and white matter, which the authors wrote is atypical for sporadic CJD. Molecular analysis of the pathologic prion protein (PrPSc) from the woman's cerebellar tissue showed a novel type of PrPSc that was similar in some, but not all, respects to type 4, which is seen in vCJD.
The authors wrote that it wasn't clear if the PrPSc typing points to a BSE cause of the patient's illness or if the finding represents another form of sporadic CJD.
Though a single case can't be the basis for connecting a novel PrPSc type to BSE, "it will be important to see whether other similar cases occur in the United Kingdom and other BSE-exposed countries," the researchers wrote.
Studies in transgenic mice are under way to explore transmission characteristics related to the woman's case, according to the report.
Simon Mead, the study's lead author, said the findings shouldn't cause alarm, according to a Jan 5 New Scientist report. "The final conclusion remains open. It is waving the flag for neurologists to watch for other cases," said Mead, who is at the Medical Research Council Prion Unit at University College London.
Mead told New Scientist that patterns of prion disease seem to vary among people depending on the prion gene variant they have, and incubation period could be one aspect in which the variants differ. Experts have said CJD is known to have a long incubation period, perhaps as long as 50 years.
In 2006, another group of British researchers analyzed DNA from three surgical samples that had previously tested positive in immunohistochemical studies of vCJD prevalence in the UK (though the patients had no clinical signs of the disease). Genotype analysis of the patients' PRNP at codon 129 found that two of the samples were of the VV type, providing the first evidence that patients from this subgroup could be infected. (DNA could not be extracted from the third sample.) Previously, people who carried at least one copy of the V variant of PRNP were thought to have no risk of contracting vCJD.
The authors of the 2006 study suggested their findings might mean that people who are infected with vCJD and have a VV type may have a prolonged incubation period, during which the disease could spread either via blood donations or from contaminated surgical instruments used on the individuals during the asymptomatic phase of the illness.
Will Hueston, DVM, PhD, director of the University of Minnesota Center for Animal Health and Food Safety in St. Paul, told CIDRAP News that it's too soon to say whether the DNA findings from the woman are associated with BSE. "I think that neurologists are probably attempting to be more cautious," he said. "This is most likely not BSE, but they [the researchers] want to be very clear that similar cases should be thoroughly evaluated."
The results of the study could also signify another variant of CJD, which is already known to occur in various forms, "but they don't know what box to put it in," said Hueston, adding that classifying prion disease types is often difficult.
Mead S, Joiner S, Desbruslais S, et al. Creutzfeldt-Jakob disease, prion protein gene codon 129VV, and a novel PrPSc type in a young British woman. Arch Neurol 2007 Dec;64(12):1780-74 [Abstract]
UK National CJD Surveillance Unit surveillance statistics
Jun 12, 2006, CIDRAP News story "Study implies broader risk for vCJD in UK"