Constant Transmission Properties of Variant Creutzfeldt-Jakob Disease in 5 Countries - - Emerging Infectious Disease journal - CDC
Constant Transmission Properties of Variant Creutzfeldt-Jakob Disease in 5 Countries
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Variant Creutzfeldt-Jakob disease (vCJD) is an acquired transmissible spongiform encephalopathy (TSE), or prion disease, that results in a fatal neurodegenerative condition in humans. vCJD was first reported in the United Kingdom in 1996 (1) and was most likely caused by dietary exposure to contaminated products from cattle that had bovine spongiform encephalopathy (BSE). The similarity between BSE and vCJD was shown by experimental transmission of the 2 diseases into standard panels of inbred wild-type mouse lines (RIII, C57BL, and VM [1,2]) and into FVB mice (3).
AbstractVariant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases.
The strain properties of vCJD and BSE have been extensively characterized in these sets of mice by using a combination of the order in which each strain of mouse dies of disease (incubation period rankings), distribution of brain vacuolation at the terminal stage of disease (lesion profiles), distribution pattern of abnormal prion protein (PrPSc) in the brain, and glycosylation pattern of PrPSc as assessed by Western blot analysis. BSE and vCJD produce highly reproducible and similar incubation period rankings and neuropathology, which indicates that they are the same strain in the RIII, C57BL, and VM mice, whereas in the FVB mice, both diseases exhibit the same pattern of PrPSc deposition (3–5).
During 1996–2011, a total of 176 cases of definite or probable vCJD were reported in the United Kingdom; the number of deaths peaked at 28 in 2000. Since 2006, deaths from vCJD have leveled off to 2–5 per year (6). Although vCJD was originally restricted to the United Kingdom, 49 cases have been reported in 11 other countries, including some outside Europe, bringing the worldwide total number of cases to 225. Most cases outside the United Kingdom have occurred in France, which is believed to be related to the large volume of beef imports; ≈60% of UK beef exports to Europe were destined for France (7). This possible relationship is borne out by a peak in vCJD cases in France 5 years after a similar peak in cases in the United Kingdom, which fits in well with the timing of an increase in beef imports from the United Kingdom during 1985–1995 (7).
More recently, comparative studies of vCJD cases from France and the United Kingdom have shown evidence from clinical, epidemiologic, pathologic, and biochemical analyses that a common strain of agent may be responsible for vCJD infection in both countries (8). In Europe, active surveillance to monitor BSE cases was implemented in 2001 (6,9). Although it appears that exports of meat, cattle, or both from the United Kingdom may have played a major role in the incidence of vCJD cases in other countries (10), indigenous BSE from before 2001 or another unidentified source may have caused some vCJD infections.
To determine whether vCJD cases in different countries have been caused by the same infectious agent, samples from 4 vCJD case-patients from the Netherlands, Italy, France, and the United States were made available for strain typing analysis using a standard panel of wild-type mouse lines. Each sample was methionine homozygous at codon 129 of the prion gene (Table). None of the patients had received blood or organ donations. Two patients (from Italy and the United States) were treated with quinacrine. All case-patients showed classic clinical characteristics of vCJD; postmortem examination confirmed the diagnosis. We conducted transmission studies in mice using brain samples from these 4 vCJD case-patients and compared transmission characteristics of all 4 cases to those of 2 historical cases of vCJD in the United Kingdom.