Archive for September 12th, 2010

Just when you thought it was safe….

12 September, 2010

…to have a hamburger. ProMED, those wonderful people who brought you Ebola case by case, describe a new way to rot your brain. Read on.

New sporadic prion disease
Date: Fri 13 Aug 2010
Source: Science Daily [edited]

BSE Transmission

New sporadic prion protein disease:
variably protease-sensitive prionopathy shares genotype characteristics with Creutzfeldt-Jakob

A new sporadic prion protein disease has been discovered. Variably protease-sensitive prionopathy (VPSPr), as it has been named, is the 2nd type of complete sporadic disease to be identified since Creutzfeldt-Jakob disease (CJD) was reported in the 1920s. The landmark finding from the National Prion Disease Pathology Surveillance Center at Case Western Reserve University is published in the August [2010] issue of Annals of Neurology [see abstract below].

Normally, the human prion protein gene comes in 3 types due to its
capability to encode prion proteins that contain only the amino acid
methionine, commonly identified as M, both methionine and valine, commonly identified as V, or only for the amino acid valine at position 129. Therefore, when it comes to the prion protein gene unaffected people can be identified as 129MM, 129MV or 129VV. Sporadic CJD (sCJD), which is the most common human prion disease, can affect patients who have any one of the 3 types of the prion protein gene.

In 2008, Pierluigi Gambetti and Wen-Quan Zou, with collaborators, reported the discovery of this novel disease, which affected patients who exhibit only one of the 3 types of the prion protein gene. In this follow-up study, they discovered that all 3 genetic groups can be affected also by this novel disease which now joins sCJD in displaying this feature. However, VPSPr is associated with an abnormal prion protein that exhibits characteristics very different from those of sCJD, as well as other prion diseases, suggesting that it may be caused by a different mechanism, perhaps more akin to other neurodegenerative diseases, such as Alzheimer’s disease. This finding may exemplify, for the 1st time, the possibility that the prion protein affects the brain with different mechanisms.

While examining cases received at the National Prion Disease Pathology Surveillance Center where he is the director, Dr Gambetti observed that a subset of cases had clinical and pathological features quite different from those of all known types of human prion diseases. Further, after being tested for prion proteins via the Western blot [technique] — the gold standard of prion disease diagnosis — the cases were negative. Dr Gambetti then collaborated with Dr Zou, associate director at the center, to solve the riddle of a disease that exhibited some features of a prion disease in histopathological examination but was negative using the standard Western blot test.

Dr Zou’s lab performed a full characterization of the disease and discovered that the VPSPr-associated abnormal prion protein formed a ladder-like electrophoretic profile on Western blotting. “When I obtained the 1st Western blot result of these cases with a different antibody against prions, I was surprised that these cases consistently exhibited this particular profile; one that I had never seen in my more than 10 years of work on human prion diseases,” Dr Zou, assistant professor of pathology at Case Western Reserve School of Medicine, recalls. This ladder-like profile is quite distinctive and very different from the profile of common prion diseases. “Discovery of this unique type of prion provides solid evidence that this novel disease may possess a pathogenesis that is different from that of the major prion diseases currently known,” Dr Zou adds.

Despite extensive research, a relatively large group of neurodegenerative diseases associated with dementia remain undefined. Before being discovered and characterized, VPSPr was one of the undefined dementing diseases. The discovery of VPSPr is chipping away at that group. In the 2 years since its discovery, more than 30 cases have been reported.

“If, as the current evidence indicates, the VPSPr mechanism of affecting the brain is different from that of other sporadic prion diseases, such as sCJD, the discovery of VPSPr would also provide the 1st example that the prion protein may spontaneously damage the brain with different mechanisms,” concludes Dr Gambetti, professor of pathology at Case Western Reserve School of Medicine. “This might apply to other dementing illnesses as well, and has implications for the strategies that need to be followed to attain a cure.”

Drs Gambetti and Zou, along with their extensive research team, plan to further characterize the abnormal prion protein associated with VPSPr as well as other important features of the protein, such as the disease’s propensity for transmission upon inoculation and its replication in test tubes. These features in VPSPr will be compared with those of sCJD to obtain a complete picture of how the abnormal prion protein attacks the brain in these 2 diseases.

– — communicated by: ProMED-mail rapporteur Mary Marshall

[The following is the reference for the paper discussed above followed by the authors’ abstract: Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, et al. Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein. Ann Neurol. 2010 Aug;68(2):162-72. ().

Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio.


Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: A total of 15 affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with “variably protease- sensitive prionopathy” (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the 2nd sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Straussler-Scheinker disease.

VPSPr is not linked to eating infected meat. However, like CJD, the new condition happens sporadically. It was 1st identified because of the fast-advancing form of dementia seen in those affected. They were also unable to speak or move. But tests for CJD proved negative. Further molecular examination as described above has shown VPSPr was a prion disease, but one which looked very different to those already known. – Mod.CP]

Enough said.  Just more to worry about…B-)