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Posted Apr 09 2009 7:13pm

BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc

C-terminal Truncated Fragments Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux,MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4; Monaco, S31University of Verona, of Neurological and Visual Sciences, Italy; 2CEA, IMETI/SEPIA,France; 3University of Verona, Neurological and Visual Sciences, Italy; 4IMETI/SEPIA,France; 5IZSPLVA, Italy; 6The Scripps Research Insitute, USA

The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent humanprion disease, remains still unknown. The marked disease phenotype heterogeneityobserved in sCJD is thought to be influenced by the type of proteinase K-resistantprion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility ofthe unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V)codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE)and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type,distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJDsubtypes. Based on the combination of CTFs and PrPSc type, we distinguished threePrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,;(ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V-2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJDsubtype M/V-2 shared molecular and pathological features with an atypical form ofBSE, named BASE, thus suggesting a potential link between the two conditions. Thisconnection was further confirmed after 2D-PAGE analysis, which showed an identicalPrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, weobtained brain homogenates from Cynomolgus macaques intracerebrally inoculatedwith brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting. We here showthat the PrPSc pattern obtained in infected primates is identical to BASE and sCJDMV-2 subtype. These data strongly support the link, or at least a common ancestry,between a sCJD subtype and BASE.

This work was supported by Neuroprion (FOOD-CT-2004-506579)


Transmission of Italian BSE and BASE Isolates in Cattle Results into a TypicalBSE Phenotype and a Muscle Wasting Disease

Zanusso, G1; Lombardi, G2; Casalone, C3; D’Angelo, A4; Gelmetti, D2; Torcoli, G2;Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3;Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L21University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA,Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy

The clinical phenotype of bovine spongiform encephalopathy has been extensivelyreported in early accounts of the disorder. Following the introduction of statutory activesurveillance, almost all BSE cases have been diagnosed on a pathological/molecularbasis, in a pre-symptomatic clinical stage. In recent years, the active surveillancesystem has uncovered atypical BSE cases, which are characterized by distinctconformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whoseclinicopathological phenotypes remain unknown. We recently reported two Italianatypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrPamyloid plaques. Experimental transmission to TgBov mice has recently disclosed thatBASE is caused by a distinct prion strain which is extremely virulent. A major limitationof transmission studies to mice is the lack of reliable information on clinical phenotypeof BASE in its natural host. In the present study, we experimentally infectedFresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c.route. BASE infected cattle showed survival times significantly shorter than BSE, afinding more readily evident in Fresian/Holstein, and in keeping with previousobservations in TgBov mice. Clinically, BSE-infected cattle developed a diseasephenotype highly comparable with that described in field BSE cases and inexperimentally challenged cattle. On the contrary, BASE-inoculated cattle developedan amyotrophic disorder accompanied by mental dullness.The molecular and neuropathological profiles, including PrP deposition pattern, closelymatched those observed in the original cases. This study further confirms that BASEis caused by a distinct prion isolate and discloses a novel disease phenotype in cattle,closely resembling the phenotype previous reported in scrapie-inoculated cattle and insome subtypes of inherited and sporadic Creutzfeldt-Jakob disease.

The MM2-cortical form of sporadic Creutzfeldt–Jakob disease presenting withvisual disturbance

Abstract—A subclass of sporadic Creutzfeldt–Jakob disease (sCJD) characterizedby onset with visual symptoms (Heidenhain variant) has been reported tobelong to the MM1 or MV1 type according to Parchi’s classification. The authorsreport a 65-year-old woman with MM2-cortical sCJD with slowly progressivevisual disturbance as the initial symptom. Diffusion-weighted MRIsrevealed hyperintensity in both occipital cortices at an early stage.

NEUROLOGY 2006;67:531–533

I. Nozaki, MD; T. Hamaguchi, MD, PhD; M. Noguchi-Shinohara, MD; K. Ono, MD, PhD; H. Shirasaki, MD;K. Komai, MD, PhD; T. Kitamoto, MD, PhD; and M. Yamada, MD, PhD


Discussion. This case was classified as MM2-cortical sCJD for the following reasons: no history ofdural grafting; spongiform changes and PrP depositswith a perivacuolar pattern in the cerebral cortices,but no thalamic or inferior olivary degeneration asfound in the thalamic form; no mutation and MM atpolymorphic codon 129 in the PrP gene; and a Type2A pattern (Parchi) of PrPres. Although it has beenreported that Type 1 and Type 2 PrPres coexist in a

third of patients with sCJD,7 Type 1 PrPres was notfound in our case as far as we examined.sCJD was not diagnosed on the basis of clinicaldiagnostic criteria8 before death because of few neurologicmanifestations and the absence of PSDs onEEG and of CSF 14-3-3 protein; however, we suspectedsCJD because of areas of hyperintensity onDW images of the brain. We have previously reportedthat cortical hyperintensity on DW images isuseful for the diagnosis of MM2-cortical sCJD.9

In a recent report, 22 (3.7%) of 594 patients in theUnited Kingdom with pathologically proven sCJDhad isolated visual symptoms at onset (Heidenhainvariant).4 The Heidenhain variant of sCJD is commonlyassociated with rapid progression of variousneuropsychiatric manifestations and presents withthe MM1 or MV1 PrP in all examined cases.1,3,4 Althougha case of the Heidenhain variant with a longclinical course (23 months) has been reported, molecularanalysis of PrP was not performed.10On the other hand, in the MM2-cortical sCJD,dementia is the most common manifestation at onset,and the clinical course is relatively slow, whileataxia and PSDs on EEG are typically absent.1 Visualdisturbance has never been reported throughoutthe clinical course of MM2 sCJD.1 In our patient, it isconsistent with the visual disturbance at onset thatthe early and most severe involvement of the occipitalcortex was proven with MR and pathologic examination.We emphasize that visual disturbance atonset (Heidenhain variant) in sCJD can be found notonly in the MM1 and MV1 types, but also in MM2-cortical type associated with relatively slow progressionof visual symptoms. In such cases, occipitalcortical hyperintensity on DW images helps to establishthe clinical diagnosis of sCJD, even if neurologicmanifestations, EEG, and CSF 14-3-3 protein do notsatisfy the diagnostic criteria for sCJD.8


The authors thank Dr. Minoru Tobiume (Department of Pathology,National Institute of Infectious Disease) for the measurementsof 14-3-3 protein, and Drs. Eisuke Furui, Ayumi Shibata,Akiyoshi Morinaga, Tomohiko Machiya, Takahiro Maruta, andKazuo Iwasa for technical support at autopsy.




A ProMED-mail post< >ProMED-mail is a program of theInternational Society for Infectious Diseases< >

[Note: With continuing decline of the number of cases of variant Creutzfeldt-Jacob disease (abbreviated previously as vCJD or CJD (new var.) in ProMED-mail) in the human population, it has been decided to broaden the scope of the occasional ProMED-mail reports to include other prion-related diseases. These updates supersede the previous update thread.

snip ...


[2] USA: National Prion Disease Pathology Surveillance CenterDate: June 2007Source: National Prion Disease Pathology Surveillance Center (USA) [edited]< >

CJD Cases examined----------------------Year / Referrals / Prion disease / Sporadic / Familial / Iatrogenic / vCJD

1996 / 42 / 32 / 26 / 4 / 0 / 01997 / 115 / 68 / 57 / 9 / 0 / 01998 / 93 / 53 / 45 / 7 / 1 / 01999 / 114 / 69 / 61 / 8 / 0 / 02000 / 151 / 103 / 89 / 14 / 0 / 02001 / 208 / 116 / 106 / 9 / 0 / 02002 / 255 / 143 / 118 / 23 / 2 / 02003 / 272 / 174 / 132 / 41 / 0 / 02004 / 334 / 183 / 157 / 21 / 0 / 1*2005 / 352 / 195 / 152 / 37 / 1 / 02006 / 372 / 186 / 143 / 30 / 0 / 1**2007 / 120 / 68 / 35 / 7 / 0 / 0TOTAL / 2428*** / 1390**** / 1121 / 210 / 4 / 2

*Acquired in UK** Acquired in Saudi Arabia*** Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007.**** Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, 26 from 2007).

-- Cases are listed based on the year of death when available. If the year of death is not available, the year of sample receipt is used.

-- Referrals: Cases with possible or probable prion disease from which brain tissue or blood in the case of familial disease were submitted.

-- Inconclusive: Cases in which the samples were not sufficient to make a diagnosis.

-- Non-vCJD type unknown are cases in which the tissue submitted was adequate to establish the presence but not the type; in all cases, vCJD could be excluded.

--Communicated by:Terry S. Singeltary Sr. < >

[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]

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USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling ittoday), please note that both the ALABAMA COW, AND THE TEXAS COW, both were''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 200711:52 PM. ...TSS

MADCOW USDA the untold story


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States

i am reminded of a few things deep throat (high ranking official at usda)told me years ago;

The most frightening thing I have read all day is thereport of Gambetti's finding of a new strain ofsporadic cjd in young people.........Dear God,

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