ATYPICAL BSE, CJD, spontaneous, sporadic, or sourced

ATYPICAL CREUTZFELDT JAKOB DISEASE's AND ATYPICAL BSE's - sporadic, spontaneous, or sourced ?

Date: July 22, 2007


By Terry S. Singeltary Sr.



If, on the other hand, atypical BSE continues to occur as typical BSE
disappears, this would be a strong indication that it is indeed sporadic,
and if in addition at least 1 form of what is presently considered as
sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot
signature like BASE) were to increase, this would suggest (although not
prove) a causal relationship (Figure 5).


http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm


Creutzfeldt-Jakob Disease Mortality in Japan, 1979-2004: Analysis of
National Death Certificate Data


Yuriko Doi1), Tetsuji Yokoyama2), Miyoshi Sakai2) and Yosikazu Nakamura3)

1) Department of Epidemiology, National Institute of Public Health.
2) Department of Technology Assessment and Biostatistics, National Institute
of Public Health.
3) Department of Public Health, Jichi Medical University.

(Received: September 13, 2006)
(Accepted: March 18, 2007)


Abstract
BACKGROUND: Trend of the mortality rate of Creutzfeldt-Jakob disease (CJD)
in Japan is still unclear. This study aimed to estimate annual crude
mortality rates due to CJD and examine the CJD mortality trend in Japan
during the period of 1979-2004.
METHODS: National death certificate data on CJD were used (CJD coded as
046.1 for ICD-9 and A81.0 for ICD-10). Trends in age-standardized mortality
rates for CJD were examined by using time series analyses including the
joinpoint regression analysis.
RESULTS: A total of 1,966 deaths (862 males and 1,104 females) were
identified with CJD coded as the underlying-cause-of-death. The annual
number of deaths and crude mortality rates peaked in 2004 at 163 (66 for
males and 97 for females) deaths and 1.28 (1.06 for males and 1.48 for
females) deaths per million population per year, respectively. The
age-specific mortality rates rapidly increased with age between 50 and 74
years, especially among females, and sharply declined at 80+ years.
Throughout the observed period, there were no significant change points, and
the annual percentage changes (95% confidence intervals) were +3.09 (2.18 -
4.02) % for males and +3.90 (2.98-4.83) % and females. The total number of
CJD deaths under 50 years of age was 131, and there was found no increase in
the annual number of deaths for the past few years in this age group.
CONCLUSION: CJD mortality in trend data based on death certificates has
significantly increased in Japan during the period of 1979-2004.
J Epidemiol 2007; 17: 133-139.

Key words: Creutzfeldt-Jakob Syndrome; Regression Analysis; Mortality;
Death Certificate; Japan


snip...


AS demonstrated in this study, we found a significant linear increase in
trends for age standardized mortality rates from the disease, with +3-4% of
annual percentage change, between 1979 and 2004. In interpreting the
results, we should consider some factors that might contribute to a false
increase in mortality, such as the change of ICD codes and the enhancement
of case findings (e.g., physicians9 recognition of the disease, diagnostic
tests, and quality of health care). No revolutionary new diagnostic test for
CJD became available throughout the observational period. On the other hand,
there were a few critical points of time to consider: in 1991, patients with
CJD transmitted by cadaveric dura transplants were identified in Japan9, in
1995, the ICD code for CJD was changed from 9th to 10th version in Japan;
and in 1996, a new case of vCJD causally linked to BSE was reported from the
United Kingdom.6 Without an abrupt rise of age-standardized mortality rates
from CJD after these years for both sexes, however, it is unlikely that
these events artificially affected the increase in CJD mortality.

Rather, it may be the true fact that in Japan our results reflect to a large
extent a genuine increase in CJD. The number of iCJD cases may still
increase even after the total ban on the practice of causal grafts.5,8
Regarding sporadic CJD (sCJD), a recent report from the European Unions
collective study on CJD suggests that the mortality rates from sCJD
increased with time between 1993 and 2002.20 It is quite probable that this
temporal increase of sCJD may also exist in Japan. The increase may have
been accompanied to some extent by the improvement of physicians diagnostic
skills for CJD since 1997 when a manual for clinical practice on CJD was
introduced in our country.20,21


click here

http://www.jstage.jst.go.jp/article/jea/17/4/133/_pdf


doi:10.1016/S0140-6736(02)09384-4
Copyright © 2002 Elsevier Ltd All rights reserved.
Fast track — Research Letters

Incidence of Creutzfeldt-Jakob disease in Switzerland

Markus Glatzel MDa, Colette Rogivue DVMb, Azra Ghani PhDc, Johannes R
Streffer MDd, Lorenz Amsler MDb and ProfAdriano Aguzzi MDa, ,
aInstitute of Neuropathology and National Reference Center for Prion
Diseases, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
bFederal Office of Public Health, Division of Epidemiology and Infectious
Diseases, Bern, Switzerland
cDepartment of Infectious Disease Epidemiology, Faculty of Medicine,
Imperial College of Science, Technology and Medicine, London, UK
dDivision of Psychiatry Research, University of Zurich, Zurich, Switzerland

Available online 11 July 2002.


Summary

The incidence of Creutzfeldt-Jakob disease (CJD) in Switzerland increased
two-fold in 2001, and figures from the first quarter of 2002 indicate that
it continues to rise. Neither age at onset nor duration of disease were
different from previous years. Genetic analysis of the 27 reported cases
revealed only one disease-associated mutation in the prion gene. None of the
recognised risk factors for acquired CJD were reported on the offical
notification forms. Glycotype profiling, histopathology, and
immunohistochemistry indicate that none of the cases fulfilled the
definition of variant CJD, which is thought to be caused by bovine prions.
Several scenarios could account for the increase in CJD, including improved
reporting, iatrogenic transmission, and transmission of a prion zoonosis.


Correspondence to: Prof Adriano Aguzzi


click here


please notice the dramatic increase in sporadic cjd in France, from 82 in
2005, to 116 in 2006, the highest number of sporadic CJD cases ever
documented in a year in France. ...TSS


Nombre de cas de maladie de Creutzfeldt-Jakob

click here


COMPARE SPORADIC CJD TO BASE SLIDES AND SEE FRENCH, ITALIAN, GERMAN,
BELGIUM, BASE


Atypical Atypical cases of TSE in cases of TSE in
cattle and sheep cattle and sheep
H. De H. De Bosschere Bosschere
CODA/CERVA CODA/CERVA
Nat. Ref. Lab. Vet. Nat. Ref. Lab. Vet. TSEs TSEs
Belgium

Identification of a second bovine amyloidotic
spongiform encephalopathy: Molecular similarities
with sporadic Creutzfeldt-Jakob disease

C. Casalone, G. Zanusso, P. Acutis, S. Ferrari, L. Capucci,
F. Tagliavini, S. Monaco, and M. Caramelli

vol.101: 3065-3070 (2004)


http://www.var.fgov.be/pdf/1100_TSEDAY.pdf


Creutzfeldt–Jakob disease in Germany: a prospective 12-year surveillance

U. Heinemann1, A. Krasnianski1, B. Meissner1, D. Varges1, K. Kallenberg2, W.
J. Schulz-Schaeffer3, B. J. Steinhoff4, E. M. Grasbon-Frodl5, H. A.
Kretzschmar5 and I. Zerr1
1National TSE Reference Center at Department of Neurology, Georg-August
University Göttingen, Germany, 2Department of Neuroradiology, Georg-August
University Göttingen, Germany, 3Department of Neuropathology, Georg-August
University Göttingen, Germany, 4Epilepsy Center Kork, Diakonie Kork, Germany
and 5Department of Neuropathology, Ludwig-Maximilian University Munich,
Germany

Correspondence to: Inga Zerr, MD, National Reference Center for TSE,
Department of Neurology, Georg-August University Göttingen,
Robert-Koch-Strasse 40, 37075 Göttingen, Germany E-mail:
IngaZerr@med.uni-goettingen.de

Creutzfeldt–Jakob disease (CJD) is a rare and fatal neurodegenerative
disorder with a worldwide incidence of 1–1.5 per million. As in other
countries, a CJD surveillance unit with a clinical and neuropathological
approach was established in Goettingen (Germany) in 1993. Here we report the
epidemiological data from a prospective 12-year surveillance. Since 1993,
there has been an increasing incidence of CJD, from 0.7 in 1993 to 1.6 in
2005 with a quite stable level since 1998. During this period, the
proportion of patients with MV and VV codon 129 genotype rose, possibly
because of better identification of atypical subtypes. Six percent of all
patients had a PRNP mutation, mainly D178N-129M (FFI), E200K and V210I.
Iatrogenic CJD was a rare phenomenon. No patient infected by cadaveric
growth hormone extracts was reported. Furthermore, no variant CJD patient
has yet been identified in Germany. Differential diagnoses revealed a
variety of neurodegenerative diseases, with Alzheimer's disease in the lead.
One-third of the non-CJD patients included in this study suffered from a
potentially treatable disorder such as metabolic or inflammatory diseases.
The incidence and mortality rates in Germany are similar to those in other
European countries. In contrast, however, acquired forms, such as iatrogenic
and variant CJD are still rare in Germany or have not yet been identified.


Key Words: CJD; dementia; epidemiology; diagnosis; CSF; MRI; codon 129
genotype; genetic CJD; reversible/treatable dementia


Abbreviations: BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt–Jakob
disease; FFI, fatal familial insomnia; GSS, Gerstmann–Straeussler–Scheinker
syndrome

Received August 10, 2006. Revised December 25, 2006. Accepted March 8, 2007.


snip...


Results
Patients
Between June 1993 and December 2005, 2094 patients with suspected CJD were
referred to the CJD Surveillance Unit Goettingen. Additionally, 76 patients
were notified at the time of autopsy (these were included in incidence and
mortality calculations) or because a mutation in PRNP was detected without
clinical evaluation ( Table 1 ). Of this total of 2170 patients, the
diagnosis of sporadic CJD was confirmed neuropathologically in 753 (35%)
patients and further 575 (26%) patients were classified as probable sCJD.
This reveals an incidence of 0.7 in 1994 to 1.6 in 2005 but an almost stable
level since 1998. One hundred and six (5%) patients were classified as
possible sCJD with typical clinical symptoms but negative 14-3-3 test and no

PSWCs in EEG. Neuropathology failed to detect any hints for prion disease in
102 patients (5%), and in 447 patients (21%) clinical classification as
other disease was established. The autopsy rate of all patients was 66%
(836/1266), the autopsy rate within the patients classified as other disease
50%. Thus, single cases of unidentified prion disease might be included
within the clinically other patients. Additionally, genetic analysis
revealed 123 patients with inherited prion disease (6% of all spongiform
encephalopathies in this study). A further 10 patients were classified as
iatrogenic CJD. Up to now, no patients with vCJD has been confirmed in
Germany despite careful surveillance.

Classification
Six hundred and fifty-eight patients were clinically classified according to
the diagnostic criteria and neuropathologically confirmed. The majority of
88% (n = 581) of these patients were finally classified as probable sCJD,
and in 47 (7%) patients clinical symptoms allowed the classification as
possible sCJD ( Table 2 ). Only in 35 patients (5.3%) sCJD could not be
identified by the established clinical criteria and thus were initially
classified as other disease. Further analysis of these patients showed five
patients classified as other case because of inflammatory findings on
routine examination in CSF. Another problem was absence of dementia,
isolated dementia or only dementia with cerebellar ataxia at last
classification during follow-up, so that these had to be classified as other
case (n = 26). The remaining patients were classified as other case (and
neuropathology turned out sCJD) because of indications for other diagnoses,
such as genetically proven SCA12, paraneoplastic disease (predominant
polyneuropathy and massive elevated protein content in CSF), epileptic fits
(initially epileptic fits, later reduced vigilance and EEG suggestive of
status epilepticus similar to PSWCs) or fluctuations (interpreted as
repetitive epileptic events). MRI of these 35 sCJD patients classified as
other was available in 26 patients. Thirteen of them (50%) showed the sCJD
typical finding of hyperintense basal ganglia.

The highest final clinical classification and neuropathological results
stratified by age are shown in Table 2 . Autopsy rate was similar over the
age groups, ranging between 45 and 88% of the probable and possible sCJD
patients, and 39–80% of the patients with other diagnoses. In those
classified as probable sCJD, neuropathology confirmed the diagnosis in most
patients across all age groups (95–100%). Non-CJD patients within the
patients classified as probable (n = 16) suffered mainly from Alzheimer's
disease ( Table 2 ). MRI analysis of these patients found none with sCJD
typical hyperintense basal ganglia. Clinical classification as possible sCJD
shows a broad range of the proportion of confirmed sCJD patients (33–79%). A
high number of patients classified as other disease are still alive, which
makes a prion disease unlikely in the majority of patients.

Clinical and Epidemiological Characteristics in Sporadic CJD
Age- and sex-matched incidence showed a peak for both sexes between 70 and
79 years with 5.27 (females) and 5.97 (males), but a marked decrease in the
age over 80 years to 1.62 and 1.65, respectively (Fig. 1). Since 1994, there
has been an increase in incidence for all age groups.


Figure 1. (click image to zoom)
sCJD incidence (per year per 1 million inhabitants) stratified by sex in
10-year intervals. Dotted white spots = female; black spots = male; dashed
triangles = all.


Genetic analysis for polymorphism of codon 129 in all confirmed and probable
sCJD patients (available in n = 992) revealed 655 (66%) methionine
homozygous (MM), 159 (16%) valine homozygous (VV) and 178 (18%) heterozygous
(MV) sCJD patients. Although the numbers of all patients who underwent a
genetic analysis per year remained stable, there was a decrease in the
proportion of MM in contrast to an increase of MV and VV, but without
statistical significance (P = 0.438) (Fig. 2). Median disease duration
stratified by genotype was the shortest for MM with 5.3 months (range
1.1–81.4), followed by VV with 7 months (1.6–48.2) and a prolonged disease
duration in the MV type with 12 months (range 2–45) (ANOVA P < 0.001).
Interestingly, we found a disease duration of more than 24 months mostly in
the MV genotype (9.6% of all MV patients), followed by the VV type (7.1% of
all VV patients) and the MM type (4.3% of all MM patients) (Fig. 3). MM
patients (46%) were predominant within the other cases (39% MV and 15% VV).
Additionally, we investigated the influence of codon 129 within the sCJD
patients on clinical core data and test sensitivity resulting for the
patients with at least one methionine allele in shorter disease duration (P
< 0.001) and higher sensitivity of PSWCs (P < 0.001) ( Table 3 ).


Figure 2. (click image to zoom)
Genotype distribution of all confirmed and probable sCJD patients per year
of surveillance. Line with black spots = MM; line with white spots = MV and
VV; dotted line = MV; dashed line = VV.



Figure 3. (click image to zoom)
Kaplan–Meyer survival time of all confirmed sCJD patients stratified by
codon 129 genotype. Black line = MM; dashed line = MV; dotted line = VV.


In 243 patients, PrPsc type 1 or 2 was available. PrPsc type 1 was
associated with shorter disease duration (P < 0.001), higher 14-3-3
sensitivity (P = 0.0013) and higher PSWC frequency (P < 0.001) ( Table 3 ).
In combination with the polymorphism at codon 129, the subgroup allocation
[according to (Parchi et al., 1999)] is shown in Table 3 .

Altogether 56 sCJD patients with age at onset below 50 years were examined
(3%), the youngest patient at the age of 19 years. The age group over 80
years at onset consisted of 118 patients (8.8%). Median disease duration in
the young patients was longer (16.6 months, range 2.5–81) than in all sCJD
(median 6.2 months, P < 0.001). Instead, we found shorter disease duration
in the patients over 80 years (3.7 months, range 1.2–18.9, P < 0.001).
Results of technical analyses stratified by age at onset revealed a reliably
high value for 14-3-3 in over 95% of the age groups over 40 years. In
younger patients, 14-3-3 was less frequently positive (76%). In EEG, PSWCs
were very rarely found in younger age groups, and there was a continuous
increase up to 66% in the age over 80 years. In contrast, MRI showed a
decreasing value in the elder patients (Fig. 4). Genotype distribution of
codon 129 in the patients below 50 years showed 52% MM, 15% MV and 33% VV
with an increase of MM with increasing age and with a relative decrease of
the VV subtype (Fig. 5).


Figure 4. (click image to zoom)
Frequency of sCJD typical diagnostic test results in CSF, EEG and MRI in
different age groups. Typical for sCJD is considered when 14-3-3 was
positive in CSF, periodic sharp waves complexes are found in EEG and
hyperintense basal ganglia in MRI scan (independent of weightening). The
differences among the groups are statistically significant for 14-3-3 (ANOVA
P = 0.002), EEG (ANOVA P < 0.001) and MRI (ANOVA P = 0.001). Grey = 14-3-3;
black = PSWC; light grey = basal ganglia hyperintensities.



Figure 5. (click image to zoom)
Genotype distribution at different age groups. The differences between the
age groups are statistically significant (ANOVA P = 0.04). grey = MM; light
grey = MV; black = VV.


Inherited Prion Diseases
Genetic TSE had a frequency of 6% of all TSE patients in this study. Within
the group of patients with available mutation analysis, 7.3% were positive
for a PRNP mutation. Genetic analysis for PRNP revealed 32 patients with FFI
(26%) (D178N-129M), 12 GSS (10%) and 79 inherited CJD (64%) patients with
various mutations. Within the group of inherited CJD we identified 21
patients with E200K and 15 with V210I mutations. Inherited prion disease led
to a younger age at onset of 61 years (range 20–83, P < 0.001) and for some
mutations to lower sensitivity of clinical tests ( Table 4 ). Several
mutations were already reported as case reports (Krasemann et al., 1995;
Grasbon-Frodl et al., 2004a, b; Krebs et al., 2005; Roeber et al., 2005).

Iatrogenic CJD
During the 12 years of surveillance, we identified nine patients with
iatrogenic CJD (eight patients due to dura mater grafts and one patient
after cornea transplant). The dura patches or the corneal transplant were
performed between 1979 and 1987. Incubation time varied from 10 to 24 years
(median 18 years) for dura cases and 31 years in the cornea case. Median
disease duration is longer than in sCJD with 10 months (range 2.4–19.2)
(Lang et al., 1995, 1998, 2001; Kretzschmar et al., 2003). An additional
patient died in 2005, suffering from neuropathologically confirmed CJD.
Medical history found a cornea transplant 13 years before onset of symptoms,
but the donor is not yet identified. Thus, because of the incubation time
and medical history, iatrogenic CJD is very likely, but the final
confirmation is still pending. Up to now, no human growth hormone-related
disease transmission was identified.

Differential Diagnosis
Differential diagnosis included mainly neurodegenerative diseases
[Alzheimer's disease (35%), Lewy-body dementia (9%), multiple system atrophy
(MSA 3%)], vascular dementia (16%), malignancies/paraneoplastic diseases
(6%) and metabolic dysfunction (8%) ( Table 5 ). Fourteen of these other
cases were initially clinically classified as probable sCJD:
neuropathologically, these patients suffered from Alzheimer's disease (AD; n
= 7), vascular dementia (n = 3), encephalitis (n = 2) and each one from
dementia with Lewy bodies (DLB) and DLB associated with Alzheimer's disease.
Clinical criteria for possible sCJD were fulfilled in 34 patients, namely 15
patients with Alzheimer's disease and several other diagnoses (inflammatory
disease n = 5, mixed dementia n = 4, lymphoma n = 3, metabolic disorder n =
3, vascular dementia n = 2, DLB n = 1, one without clear pathological
diagnosis). Alzheimer's disease represents the major group of non-reversible
(mainly neurodegenerative) diseases (50%) within all differential diagnoses.
A substantial group of 28% (n = 49) suffered from a potentially treatable
disorder such as encephalitis, tumour-associated diseases or metabolic
disorders. As expected, patients with neurodegenerative disorders had a
higher median age at onset than those with potentially treatable disorders
( Table 5 ).


snip...


Discussion
This study analyses a large number of patients with spongiform
encephalopathy with different aetiological origin within the population of
83 million inhabitants of Germany since 1993. In keeping with a number of
other epidemiological studies in many European countries, we used a
prospective approach. We found an increase in incidence (1.1–1.6) and
mortality (0.9–1.3) of sCJD during the years 1994–2005 as also described for
other countries, but more or less stable levels since 1998. This might be
associated with improvement in the diagnostic techniques and better
recognition of atypical clinical presentations, which is underlined by a
trend towards higher proportion of MV and VV (Brandel et al., 2000; Zerr et
al., 2000b; Saiz et al., 2001; Krasnianski et al., 2006b). Furthermore,
after the recognition of vCJD and its connection to BSE became widespread,
an increased awareness on the part of physicians and relatives might have
influence differential diagnostic considerations. In 2001, Switzerland
described a rise of incidence from 1.4 in 2000 to 2.5 in 2001 and a stable
level of about 2.5 within the last few years (Glatzel et al., 2003). Initial
surmises for the presence of a cluster and possible connection to BSE could
not be confirmed. Instead, these figures seem to be the effect of better
surveillance with a potentially higher percentage of the atypical MV2
subtype. An equivalent sudden rise is not observed in Germany ( Table 1 ).

The median age of our sCJD patients (66 years) was comparable to the data
from the literature. Incidence and mortality clearly decrease after a peak
between 70 and 79 years similar to other studies on sCJD, but in contrast to
other neurodegenerative diseases which tend to increase with age (Ott et
al., 1998; Ladogana et al., 2005). This finding can be explained by an
under-ascertainment of patients in the group of old and very old people.
Another potential explanation could be that clinical presentation is less
typical in elder people. However, our data found similar diagnostic value of
14-3-3 (>80 years, 94%; 60–69 years, 96%), higher frequency of PSWCs (>80
years, 66%; 60–69 years, 54%), but lower sensitivity of MRI findings (>80
years, 35%; 60–69 years, 57%) in patients over 80 years as compared to the
median age groups. The correct clinical classification for sCJD by
comparison of clinical classification and autopsy result is similar to
middle age groups (Table 2). Hence, there might be other (clinical) factors,
which influence the decrease of incidence in the elderly.

The patients with 50 years age or younger at symptom onset are rare (3% of
all sCJD). While up to now no patient with vCJD in Germany was identified,
these patients are of special interest. The clinical syndrome in young sCJD
patients in Germany differs not only from vCJD, but also from sCJD patients
at the typical age at onset between 60 and 70 years (Boesenberg et al.,
2005). Thus, it seems unlikely that a patient with variant CJD was
misclassified as sCJD. The detection of the pulvinar sign in the MRI is an
important non-invasive tool to distinguish vCJD and sCJD and is reported in
78% of vCJD patients (Will et al., 2000), but also in MV2 sporadic CJD
subtype (Krasnianski et al., 2006b). In our subgroup of young sCJD patients,
we observed hyperintense basal ganglia in 56%, but no pulvinar sign
(Boesenberg et al., 2005). However, because the MRI might be normal in early
disease stages, we would like to stress the importance of neuropathological
examination of all suspected CJD patients, being extremely important in
young patients with dementia.

Many reports on patients with clinical syndromes mimicking CJD are found in
the literature with a broad range of diagnoses (Haik et al., 2000; Tschampa
et al., 2001; Slee et al., 2006; Valadi et al., 2006). Additionally, reports
on false positive 14-3-3 and EEG findings exist (Vander et al., 2004;
Bersano et al., 2006; Hoffman Snyder et al., 2006). This raises the question
of the value of the clinical criteria which include clinical signs and
symptoms and technical investigations. In our patient group, the value of
these criteria seem to be very high, especially for the classification as
probable sCJD. The clinical symptoms can be masqueraded by several
syndromes, and they might be hard to distinguish without positive 14-3-3,
PSWCs or MRI scans. This is underlined by a worse reliability of the
classification possible sCJD (in autopsy only 58% confirmed sCJD, 42% other
disease). The patients classified as other and later confirmed as sCJD were
not recognized because the clinical criteria were not fulfilled (missing
dementia, isolated dementia, dementia and ataxia only). The proportion of
these patients is relatively low and change of the criteria for
less-stringent clinical symptoms might result in decreased specificity. On
the other hand, 50% of these patients had typical MRI changes. Thus, MRI can
support diagnosis also in atypical patients.

Codon 129 polymorphism analyses revealed a genotype distribution as known
for sCJD, with an increase of methionine homozygous in favour of MV compared
to the normal population. In recent years, the proportion of patients with
the MM genotype is slightly decreasing in favour of the MV and the VV type
(Fig. 1). This might be due to better diagnosis in patients with atypical
subtypes and also explains in part the increase in overall incidence of sCJD
since 1993 in Germany. The homozygous patients presented with shorter
disease duration than MV patients as reported previously (Deslys et al.,
1998; Parchi et al., 1999; Pocchiari et al., 2004). Clinical characteristics
in our cohort were influenced by PrPsc type 2 (longer disease duration, less
sensitivity of 14-3-3 and EEG) and the presence of at least one valine
allele (longer disease duration, less sensitivity of EEG, trend to younger
age at onset) ( Table 3 ). These data are in line with studies on sCJD which
showed higher sensitivity for 14-3-3 and PSWCs and shorter disease duration
for patients with PrPsc type 1 protein (Zerr et al., 2000a; Castellani et
al., 2004; Pocchiari et al., 2004; Sanchez-Juan et al., 2006) and lower
sensitivity of EEG in presence of a valine allele (Collins et al., 2006).

Genetic analysis of the PRNP gene revealed a number of mutations resulting
in GSS, FFI or genetic CJD (Windl et al., 1999). The proportion of patients
with inherited prion disease in Germany (6%) is comparable to the data given
in the literature. The percentage of inherited prion diseases varies among
the countries and is higher in Slovakia (69.5%), Italy (17%) and Austria
(14%) and lower in Switzerland (1%) and the Netherlands (2%) (Kovacs et al.,
2005). The average rate of inherited prion diseases in Europe is 10.2%, and
after exclusion of Slovakia (nearly 70% inherited prion diseases), the rate
is 9.45%. Thus, the figures from Germany are only slightly lower. The cause
of the large variance in proportion of inherited prion diseases between the
countries is not clear. One reason of high incidence of inherited prion
diseases in other countries might be due to the founder effect (Lee et al.,
1999). Because of quite long disease duration, atypical clinical course and
low sensitivity of the technical analyses, patients with genetic TSE might
be misdiagnosed as another neurodegenerative disorder ( Table 4 ).

In Germany, the incidence of iatrogenic transmission has been much lower
than for other countries with CJD surveillance. Most iatrogenic cases
worldwide (n = 138) are associated with human pituarity growth hormone (n =
105), especially in France and UK (Brown et al., 2000, 2006; Swerdlow et
al., 2003). In Germany, there has been no patient with such a transmission
reported to date. Of the 10 iatrogenic patients in Germany, eight came from
transmission by lyophilized dura mater grafts and two by corneal transplant.
As described in the literature, incubation time in the patients in our study
varied from 1 to 30 years (Brown et al., 2000; Will, 2003).

Analysis of differential diagnosis revealed Alzheimer's disease as the most
frequent other diagnosis among our selected patients. This is not
surprising, as it represents the most frequent cause of dementia in the
elderly (Ruitenberg et al., 2001; McMurtray et al., 2006). Other diagnoses
such as inflammatory diseases and metabolic disorders presented with a
clinical syndrome similar to that of prion diseases in our study.
Surprisingly, a few cases later neuropathologically confirmed as sCJD
(supplemental data) were diagnosed clinically as other diseases because of
results of the CSF tests which were suggestive of inflammatory illnesses.
Thus, in particular, inflammatory diseases of the CNS might represent a
problem in differential diagnosis (Poser et al., 1999). Neurodegenerative
disorders are especially frequent in patients over 75 years at onset. In
contrast, as expected, in younger patients below the age of 50 years at
onset, potentially reversible disorders play a major role (Harvey et al.,
2003; Sampson et al., 2004).

Despite intensive analysis and careful epidemiology, no patient with vCJD
has been found in Germany so far. Since the first description in 1996 in the
UK, 201 patients have been registered with vCJD worldwide. Although by far
most of the cases are still identified in UK, a few patients with vCJD have
been reported in several other countries. Thus, further surveillance and
evaluation of all suspected CJD patients is necessary to recognize the
implications for the healthcare system and allow it to react promptly.


click here


doi:10.1016/j.vetmic.2006.06.016
Copyright © 2006 Elsevier B.V. All rights reserved.
Atypical BSE in Germany—Proof of transmissibility and biochemical
characterization

A. Buschmanna, A. Gretzschela, A.-G. Biacabeb, K. Schiebelc, C. Coronad, C.
Hoffmanna, M. Eidena, T. Baronb, C. Casaloned and Martin H. Groschupa, ,
aFriedrich-Loeffler-Institut (FLI), Institute for Novel and Emerging
Infectious Diseases, Boddenblick 5a, 17493 Greifswald, Insel Riems, Germany
bAFSSA-Lyon, Unite ATNC, Lyon, France
cInstitut für Biochemie, Universitity Erlangen-Nürnberg, Germany
dCEA, Instituto Zooprofilattico di Turino, Turin, Italy
Received 11 January 2006; revised 23 May 2006; accepted 2 June 2006.
Available online 17 August 2006.



Abstract

Intensive active surveillance has uncovered two atypical German BSE cases in
older cattle which resemble the two different atypical BSE phenotypes that
have recently been described in France (designated H-type) and Italy
(designated L-type or BASE). The H-type is characterized by a significantly
higher molecular size, but a conventional glycopattern of the proteinase K
treated abnormal prion protein (PrPSc), while the L-type PrPSc has only a
slightly lower molecular size and a distinctly different glycopattern. In
this paper we describe the successful transmission of both German atypical
BSE cases to transgenic mice overexpressing bovine PrPC. Upon challenge with
the L-type, these mice developed BSE after a substantially shorter
incubation period than any classical BSE transmission using these mice to
date. In contrast, the incubation period was distinctly prolonged when these
mice were challenged with the H-type. PrPSc accumulated in the brains of
these mice were of the same atypical BSE type that had been used for the
transmission. These atypical cases suggest the possible existence of
sporadic BSE cases in bovines. It is thus feasible that the BSE epidemic in
the UK could have also been initiated by an intraspecies transmission from a
sporadic BSE case.

Keywords: BSE; Cattle; PrPSc; Biochemical differentiation


Corresponding author. Tel.: +49 383517163.

Veterinary Microbiology
Volume 117, Issues 2-4, 31 October 2006, Pages 103-116


click here


Subject: TAFS1 Position Paper on Atypical scrapie and Atypical BSE
Date: July 9, 2007 at 1:38 pm PST

TAFS1 Position Paper on Atypical scrapie and Atypical BSE


TAFS

INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY

a non-profit Swiss Foundation

(May 16, 2007)

TAFS1 Position Paper on Atypical scrapie and Atypical BSE

In recent years there have been a small number of reports in the scientific
literature that
unusual isolates of BSE have been detected in cattle in various countries
around the world. In
addition, following the introduction of enhanced surveillance programmes for
scrapie in small
ruminants in Europe, unusual or unexpected results were also widely
reported. In both
instances, the shortage of scientific data at the time did not enable
scientists to precisely
identify what they were dealing with. Because of similarities with the
diseases that they were
searching for, namely BSE in cattle and scrapie in sheep, the immediate
response was to call
the isolates “atypical BSE” and “atypical scrapie” for reasons that will be
explained below.
Some additional local terminology was applied in some countries, but for the
moment the
term “atypical” is more commonly applied. This paper aims to provide the
background to
these findings, and explain their signficance.


snip...


Is it transmissible?

?? Experimentally, it has been shown that it can be transmitted to
genetically modified
mice(2, and by intracerebral inoculation to sheep (unpublished work in
progress).
?? These transmissions do not prove that it will transmit naturally from
sheep to sheep,
but studies involving oral infection of sheep are under way.
?? Although most atypical cases occur singly in flocks, there are some
instances where
two affected sheep have been identified in flocks. This may indicate that
natural
transmission may occur, or that the sheep were infected from a common
alternative
source(22, 29). Possible indications of an association with the feeding of
vitamins and
mineral feed supplements were detected in Norway, but remain to be
proven(22).

Does it represent a risk to human health?

Does it represent a risk to human health?

?? This is currently unknown, but if atypical scrapie is not a new
phenomenon, and has
simply been discovered recently, then the lack of epidemiological
association between
TAFS
6
prion diseases in humans and sheep, or consumption of sheep products,
suggest that
atypical scrapie does not represent a risk to humans. This is not however
demonstration of absolute safety.
?? This is currently unknown, but if atypical scrapie is not a new
phenomenon, and has
simply been discovered recently, then the lack of epidemiological
association between
TAFS
6
prion diseases in humans and sheep, or consumption of sheep products,
suggest that
atypical scrapie does not represent a risk to humans. This is not however
demonstration of absolute safety.


======================================================


PLEASE NOTE ;


EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE

This is provided by the statistically significant increase in the incidence
of sheep scrape from 1985, as determined from analyses of the submissions
made to VI Centres, and from individual case and flock incident studies.
........


click here


1: J Infect Dis 1980 Aug;142(2):205-8


Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to
nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep
and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were
exposed to the infectious agents only by their nonforced consumption of
known infectious tissues. The asymptomatic incubation period in the one
monkey exposed to the virus of kuru was 36 months; that in the two monkeys
exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months,
respectively; and that in the two monkeys exposed to the virus of scrapie
was 25 and 32 months, respectively. Careful physical examination of the
buccal cavities of all of the monkeys failed to reveal signs or oral
lesions. One additional monkey similarly exposed to kuru has remained
asymptomatic during the 39 months that it has been under observation.

snip...


The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie
by natural feeding to squirrel monkeys that we have reported provides
further grounds for concern that scrapie-infected meat may occasionally give
rise in humans to Creutzfeldt-Jakob disease. ...end

(from full text study pdf...TSS)

PMID: 6997404
click here


EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE

This is provided by the statistically significant increase in the incidence
of sheep scrape from 1985, as determined from analyses of the submissions
made to VI Centres, and from individual case and flock incident studies.
........


click here

12/10/76
AGRICULTURAL RESEARCH COUNCIL
REPORT OF THE ADVISORY COMMITTE ON SCRAPIE
Office Note
CHAIRMAN: PROFESSOR PETER WILDY

snip...

A The Present Position with respect to Scrapie
A] The Problem

Scrapie is a natural disease of sheep and goats. It is a slow
and inexorably progressive degenerative disorder of the nervous system
and it ia fatal. It is enzootic in the United Kingdom but not in all
countries.

The field problem has been reviewed by a MAFF working group
(ARC 35/77). It is difficult to assess the incidence in Britain for
a variety of reasons but the disease causes serious financial loss;
it is estimated that it cost Swaledale breeders alone $l.7 M during
the five years 1971-1975. A further inestimable loss arises from the
closure of certain export markets, in particular those of the United
States, to British sheep.

It is clear that scrapie in sheep is important commercially and
for that reason alone effective measures to control it should be
devised as quickly as possible.

Recently the question has again been brought up as to whether
scrapie is transmissible to man. This has followed reports that the
disease has been transmitted to primates. One particularly lurid
speculation (Gajdusek 1977) conjectures that the agents of scrapie,
kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of
mink are varieties of a single "virus". The U.S. Department of
Agriculture concluded that it could "no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed
for human or animal food at slaughter or rendering plants" (ARC 84/77)"
The problem is emphasised by the finding that some strains of scrapie
produce lesions identical to the once which characterise the human
dementias"

Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety
of laboratory personnel requires prompt attention. Second, action
such as the "scorched meat" policy of USDA makes the solution of the
acrapie problem urgent if the sheep industry is not to suffer
grievously.

snip...

76/10.12/4.6

click here


=====================================================


snip...


Where has atypical BSE been found?

?? Although the greatest number of cases is in France(12), increasing
numbers of cases
have now been identified in other countries – Canada (1), Germany (2), Italy
(2),
Japan (2), Netherlands (4), Poland (7), Sweden (1), Switzerland (1), UK (1),
and USA
(2). In Sweden and the USA the atypical cases represent the only indigenous
cases
detected. In other words – typical BSE has not been detected in native
cattle in these
two countries (34).
?? In France, Poland, Netherlands and Germany both H and L forms of atypical
BSE
have been reported(25).

Is there anything else unusual about the cases?

?? Yes. With the exception of the first Japanese case, others have generally
occurred in
old cows – 8 to 18 years reported in France, 11 and 15 in Italy. Most BSE
cases occur
in animals between the age of four and six, although very young and very old
animals
can be affected too.
?? In one case, still unpublished, a mutation of the PrP gene has been
detected, similar to
one found in one form of CJD in humans.It has to be stressed that this has
not been
identified in every case of atypical BSE, although not all have been
analysed in this
way.


snip...


Where has atypical BSE been found?

?? Although the greatest number of cases is in France(12), increasing
numbers of cases
have now been identified in other countries – Canada (1), Germany (2), Italy
(2),
Japan (2), Netherlands (4), Poland (7), Sweden (1), Switzerland (1), UK (1),
and USA
(2). In Sweden and the USA the atypical cases represent the only indigenous
cases
detected. In other words – typical BSE has not been detected in native
cattle in these
two countries (34).
?? In France, Poland, Netherlands and Germany both H and L forms of atypical
BSE
have been reported(25).

Is there anything else unusual about the cases?

?? Yes. With the exception of the first Japanese case, others have generally
occurred in
old cows – 8 to 18 years reported in France, 11 and 15 in Italy. Most BSE
cases occur
in animals between the age of four and six, although very young and very old
animals
can be affected too.
?? In one case, still unpublished, a mutation of the PrP gene has been
detected, similar to
one found in one form of CJD in humans.It has to be stressed that this has
not been
identified in every case of atypical BSE, although not all have been
analysed in this
way.

TAFS
9

Is there more than one strain of atypical BSE?

?? At this stage it is too early to say, but there are early indications
that this may be so.
Caution is needed because there is a need to be certain that the variations
in results are
not artifacts, either generated by differences in test methods between
countries, or due
to degradation of samples before they are tested. This has been shown to
generate
variations in blotting patterns, but is unlikely to have produced the
extensive
variations seen in the Italian cases or the H form detected in France and
elsewhere.
?? So the key to confirming whether or not H and L isolates actually
represent different
strains will be further characterization following transmission to
laboratory rodents
and/or cattle. These are the methods normally used to characterize prion
strains
comprehensively.
?? This will also help to confirm the extent to which the atypical BSE cases
differ from
BSE. In the meantime, especially if it proves possible to transmit isolates
to other
animals, additional biochemical methods can be used to investigate other
aspects of
prion protein biology of the different isolates.
?? Two publications have already highlighted the difficulties of
interpreting data on
biological transmissibility. One demonstrates that BSE and “H-type” BSE are
different, based upon their behaviour in genetically modified mice,
examination of
fixed and unfixed brain tissue, and comparison of incubation periods(6). The
other,
studying “L-type” BSE (Italian BASE), and using different mouse models,
acknowledges apparent differences between it and BSE when first inoculated
into
mice, but claims that further transmission from mouse to mouse by
inoculation
produces a strain indistinguishable from BSE (by the limited criteria used
in the study)
(11).
?? These findings suggest that it may prove possible to understand the
relationship
between BSE and atypical BSE isolates, and between the criteria used to
classify them
at present, and the actual strain of prion that infects the animal.

Is atypical BSE transmissible?

?? Investigations are under way in France, Italy, Germany and Japan.
Experimental
transmissibility to cattle and primates has now been demonstrated for L-type
BSE, and
to mice for both H and L types (3, 6, 11). Some of this work remains
incomplete and
unpublished at the time of writing.
?? This does not prove that atypical BSE transmits from animal to animal
naturally.
Does it represent a risk to human health?
?? It is too early to tell whether or not it represents a risk to humans.
For the moment it is
assumed to be a danger, and is treated like BSE. Results of experimental
transmission
to primates remain unpublished. Some scientists suggest that similarities
between the
molecular features of H-type BSE and some prion diseases of humans may
indicate
that they are related. Care must be exercised in interpreting such
preliminary data(
specifically with regard to suggestions of a cause and effect.
?? Transmissibility to cattle has been confirmed, but remains currently
unpublished as the
study is incomplete. It may therefore be possible to investigate further, by
oral
challenge, whether or not the infectious agent is distributed around the
body in a
different way from BSE, possibly infecting tissues that are not
considered-infectious
in BSE. This may have implications for risk management and public health.
?? It is however important to remember that so far only small numbers of
atypical BSE
cases have been detected compared to the many thousands of BSE cases
TAFS
10

?? Depending on how atypical BSE cases arise, they may represent a long term
problem
when BSE has been eradicated, or they may disappear along with BSE because
the
controls are equally effective in preventing spread of infection. As
transmissibility to
cattle has now been partially demonstrated, it can be presumed that atypical
BSE may
transmit to cattle orally through feed, in which case rendering and feed
controls should
prevent further transmission by that route.

What is the impact of this finding on measures to control BSE, and to
protect
consumers?

?? At the moment all measures in place to protect cattle and humans from
becoming
infected with BSE are considered adequate to protect against atypical BSE.
Tests used
to detect BSE in cattle have detected the atypical cases too, and on brain
tissue, which
is already defined as SRM in countries where controls are in place.
?? Care will be needed in relaxing such controls, especially if atypical BSE
proves to be
transmissible directly between cattle, or to humans via tissues that are not
currently
defined as SRM.
?? Similarly, if atypical BSE is demonstrated to arise spontaneously, rare
sporadic cases
may be expected to occur in all countries with significant cattle
populations. This in
itself will challenge expectations of total eradication as a result of
controls.
Nevertheless, the existence of sporadic cases would indicate potential to
give rise to
further large epidemics if some protective measures are not maintained
indefinitely.
These may involve prohibitions on the use of certain proteins in animal
feed, more
rigorous rendering processes, and possibly continued removal and destruction
of
certain SRM from human food and animal feed chains.


snip...


click here


Titel Basisproject BSE, scrapie en andere TSEs
Abstract [Project objective]:
This project takes care of the statutory tasks of TSE diagnosis as well as
the enlargement of the basic knowledge on TSEs to keep advices to
Government, EU and other expert groups up-to-date. Furtherrmore this project
provides basic support to several other (mainly EU) research projects by
means of co-finances, samples or animals (mainly sheep and mice). The key
objectives of this project are securing the TSE statutory tasks and keeping
them up-to-date by surveillance- and research projects, and cooperation in
EU projects and TSE expert groups.
[Results]:
The data obtained will allow us to;
Continue, improve and extend the BSE and scrapie surveillance in the
Netherlands and act as the national reference lab (NRL) for TSEs.
Maintain and expand (if necessary) the basic means like sheep flocks and
normal/transgenic mice to be used for pathogenesis research or TSE
straintyping.
Act as an (inter)national resource for TSE related matters as well as
providing presentations at seminars, classes and/or courses.
Keeping TSE safety measures and accompanying TSE inactivation methods
up-to-date.
Gain basic knowledge and networking possibilities by active participation in
EU TSE projects.
[Progress 2005-2006]:
BSE diagnostics (for most up-to-date figures please visit the CIDC website
at www.CIDC-Lelystad.nl);
o In 2005 and 2006, respectively 7 and 9 clinical suspects have been
examined of which one from 2006 was found to be TSE positive.
o Active surveillance ( rapid testing ) 2005 and 2006 (till September 1st);
?? Slaughtered animals; resp. 473,436 and 275,000 animal tests performed by
private labs under CIDC-Lelystad supervision of which resp. 3 and 1 were
confirmed TSE positive.
?? Fallen stock; total 48,856 and 33,371 animals tested by CIDC-Lelystad of
which none were found to be positive.
?? Stamping-out animals; 77 and 29 animals tested resp. of which none were
found to be TSE positive.
Scrapie diagnostics (for most up-to-date figures please visit the CIDC
website at www.CIDC-Lelystad.nl);
o In 2005 and 2006, respectively 3 and 8 clinical suspects have been
examined of which five from 2006 was found to be TSE positive.
o Active surveillance ( rapid testing ) 2005 and 2006 (till September 1st);
?? Slaughtered animals; resp. 27,965 and 22,648 animal tests performed by
CIDC-Lelystad of which resp. 14 and 5 were confirmed to be TSE positive.
?? Fallen stock; total 11,221 and 7,772 animals tested by CIDC-Lelystad of
which resp. 23 and 14 were found to be positive.
?? Stamping-out animals; 2,034 and 576 animals tested respectively. In
addition resp. 261 and 248 fallen animals were tested from known positive
farms. In total resp. 34 and 34 were found and confirmed to be TSE positive.
Scrapie isolate characterisation;
o All scrapie isolates from 2002 till August 2006 and several isolates from
before 2002 have been tested by the CIDC-developed BSE/Scrapie
discriminatory blot test for the presence of the BSE strain. No BSE or
BSE-like isolates were found.
o In 2005 on two different farms atypical scrapie of the Nor98 type has been
diagnosed. In 2006 no atypical scrapie cases have been recorded.
Basic means; since several years two independent flocks of sheep are
maintained. One flock is kept under scrapie-free conditions while the other
is scrapie endemic. Several lines of classical and transgenic mice are
maintained for TSE strain typing, sensitive bioassays and/or antibody
development.
Currently there are two EU projects running and one is starting up this
year. The first project aims at the improvement of (pre)clinical diagnosis,
the second investigates the routes of pathogenesis of BSE in sheep, while
the third will focus on BSE and scrapie in goats. All experimental
infections for the first project are still running and no conclusions can be
drawn from the preliminary results yet. The second project has determined
that the pathogenic route of BSE in sheep is identical to scrapie in sheep.
Fortunately, this project also revealed that discrimination between scrapie
and BSE in sheep is also possible by a microscopic technique in which
accumulated prion proteins are differently stained in specific types of
cells by a panel of antibodies. This discriminatory microscopic test, in
addition to the certified discriminatory blot test developed by CIDC as
well, has been certified by the CRL for use to discriminate BSE from scrapie
in sheep as well.
[Products]:
Articles


click here


Identification of putative atypical scrapie in sheep
in Portugal
Leonor Orge,1,2 Alexandre Galo,1 Carla Machado,1 Carla Lima,1
Cristina Ochoa,1 Joa˜o Silva,1 Manuel Ramos1 and J. Pedro Simas2,3
Correspondence
J. Pedro Simas
jpsimas@igc.gulbenkian.pt
1Laborato´ rio Nacional de Investigac¸a˜o Veterina´ ria, Lisboa, Portugal
2Instituto Gulbenkian de Cieˆ ncia, Rua da Quinta Grande 6, 2780-156 Oeiras,
Portugal
3Laborato´ rio de Microbiologia, Faculdade de Medicina, Universidade de
Lisboa, Lisboa, Portugal


Experimental transmission of bovine spongiform encephalopathy to sheep has
prompted the
implementation of a surveillance plan of scrapie in small ruminants by the
European Union in all
member states. Since its start over 30 000 animals have been tested, and the
first seven cases of
sheep with detectable PrPres deposition in the central nervous system have
been identified in
Portugal. Notably, the pattern of PrPres distribution in the brainstem was
different from that
previously described for scrapie and consistent in all seven animals.
Moreover, the profile of
the electrophoretic mobility of PrPres after proteinase K treatment was
equivalent in all cases
analysed but distinct from that observed for scrapie. Notably, four animals
had genotypes rarely
associated with scrapie, including one animal homozygous for A136R154R171.
There were no cases
found to exhibit vacuolation, a pattern of PrPres distribution or PrPres
electrophoretic mobility
corresponding to scrapie. These data reveal a putative atypical scrapie
strain in Portugal
not linked to specific Prnp genotypes.


snip...


This finding is consistent with the fact that to date
no clinical scrapie has been diagnosed in Portugal. Thus, it
is not clear if the cases described in this study represent an
endemic form of a prion disease in sheep not previously
identified and not linked to any specific Prnp genotypes or
represent a recently acquired new form of scrapie.
In order to gain further insight into the epidemiological
and public health relevance of this apparent atypical scrapie,
it is extremely important to show if it is transmissible
and assess if it constitutes a new scrapie strain like Nor98.
The occurrence of such a putative atypical scrapie strain,
independently of the Prnp genotype, may be of significance
for current EU sheep breeding programmes for selection of
non-susceptible haplotypes. Furthermore, given the recent
BSE epidemic in Portugal (Donnelly et al., 1999), and thus
the geographical risk of transmission of BSE into sheep, a
possible link to BSE cannot be excluded. Although, we
cannot rule out the possibility of adaptation of BSE in
sheep following natural transmission, the fact that the
PrPres electrophoretic profile described for this putative
atypical scrapie strain is distinct from that observed in
BSE experimentally infected sheep, makes this link less
probable.


click here


Subject: Classic Scrapie in Sheep with the ARR/ARR Prion Genotype in Germany
and France
Date: July 12, 2007 at 9:55 am PST

http://www.cdc.gov/eid/content/13/8/pdfs/07-0077.pdf


click here


Unexpected atypical scrapie case: audit of sample handling and biosecurity

S t a t ement from the Chief

S c i e n t i f i c A d v i s e r

In November 2006 the Veterinary Laboratories Agency (VLA) informed Defra
they had detected atypical scrapie in a research flock considered to be free
of
Transmissible Spongiform Encephalopathies (TSEs). Defra issued an
information bulletin1 on the 14th November.
The origin of the atypical scrapie case was not clear. I initiated an
independent audit of the research facilities concerned with the finding to
investigate two aspects:
• Sample handling and identification procedures
• Biosecurity procedures at the site where the flock is held.
The audit was conducted by the UK Accreditation Service (UKAS)2, which has
now provided its report. I am confident that the audit has thoroughly
investigated the issues concerned, insofar as it was able in the time
available,
and pleased that the findings will now be considered by the Spongiform
Encephalopathy Advisory Committee (SEAC), together with additional
evidence, in their scientific assessment of this case and its implications.
SIR HOWARD DALTON
9th May 2007

click here


Subject: SEAC Food standards agency atypical scrapie contingency plan
Date: July 18, 2007 at 12:39 pm PST

SEAC
Position Statement

----------------------------------------------------------------------------
----

Food standards agency atypical scrapie contingency plan
Issue
1. In June 2006 the Food Standards Agency (FSA) Board considered current
precautionary risk management measures for small ruminants. The Board agreed
that current precautionary measures were sufficient. However, they wished to
develop a contingency plan in case SEAC’s understanding of the risk of
atypical scrapie for human health changed. To inform this contingency plan
the FSA requested SEAC advice on potential outcomes of research on atypical
scrapie, or surveillance results, that may lead to a change in SEAC’s
estimate of the risk to human health.

Background
2. In February 2006 the SEAC sheep subgroup published a position statement
on atypical scrapie1 which concluded that atypical scrapie should be
considered a distinct transmissible spongiform encephalopathy (TSE) of small
ruminants and not simply a variant of classical scrapie. While there was no
evidence that atypical scrapie could infect humans, a theoretical risk could
not be excluded. SEAC concluded, however, that there were insufficient data
available to adequately assess the potential risks to human health. The
subgroup recommended that an adequate assessment of the potential risk to
human health of atypical scrapie might come from studies on the prevalence,
transmission in animal models, tissue distribution and human health
surveillance.

3. SEAC considered the potential significance of the outcomes of these areas
of research for the human health risk from atypical scrapie, based on
scenarios put forward by the FSA2.

Prevalence
4. The SEAC sheep subgroup statement concludes that there could be around
82,000 sheep in the UK infected with atypical scrapie. Future surveillance
and epidemiological studies along with the analysis of sheep brain tissue
samples dating back to 1964 may confirm the historical presence of the
disease, changes in prevalence over time, and whether or not atypical
scrapie may occur in countries previously thought to be free from classical
and atypical scrapie. SEAC considered that the identification of historical
cases, new cases in scrapie-free countries, and changes in prevalence of
atypical scrapie would be significant from a public health perspective. If
such data indicate that atypical scrapie has been present for many years,
and is not increasing in prevalence then, by analogy with classical scrapie
the human health risk would be considered low. However, if atypical scrapie
were found to be spreading rapidly, this would imply it is a new disease and
any human health risk would be more uncertain. It is therefore important to
continue to assess the historic prevalence of atypical scrapie, and for
archived sheep samples be analysed for the presence of the disease.

5. A human health risk would only be confirmed by concomitant changes in the
prevalence of new types of Creutzfeldt-Jakob Disease (CJD). Because of the
long incubation periods of prion diseases, such data may not become apparent
for many years, although atypical scrapie has been identified in a UK sheep
from 1989, implying that humans may have been exposed to atypical scrapie
via the dietary route for a number of years. In the absence of data
suggesting a link to a new type of CJD SEAC would be unlikely to change its
current assessment of the human health risk.

Transmission studies
6. Results from transmission studies using non-human primates, particularly
via the oral route, would strongly inform the understanding of human health
risk. The immune and lymphoreticular systems of non-human primates are
closely related to those of humans and the peripheral pathogenesis of TSEs
in non-human primates mimics that in humans. However, non-human primates
only provide data relating to one genotype, MM, which comprises about 37% of
the UK population3. Assessment of the level of risk would require comparison
with transmissions of other TSEs in the same models, in particular BSE, some
of which are already available.

7. Humanised mice can provide data on all three human prion protein
genotypes. It is important to be aware of the possibility that such mice may
not show any clinical sign of infection after primary transmission of
atypical scrapie, yet a secondary transmission from these animals to others
may result in clinical disease due to loss of the interspecies transmission
barrier. Although humanised mice are a good model for human disease, it will
be critical to compare the behaviour of atypical scrapie with other TSEs,
especially classical scrapie and BSE, in several mouse models after
secondary transmission in order to obtain the most reliable risk
assessments.

8. The barrier to transmission of atypical scrapie between animal and human
can be tested in vitro by cell free conversion assays. However, care is
needed in interpreting the significance of such experiments as ex vivo data
do not always correlate well with in vivo studies. Nevertheless, they could
provide data on whether conversion of the normal prion protein in humans to
the abnormal form by the atypical scrapie prion is or is not possible.

Tissue Distribution
9. Little is known about the tissue distribution of abnormal prion protein
(PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie
is found to be a health risk to humans, data from studies to assess the
tiss

by Terry S. Singeltary Sr. (1 articles, 0 quicklinks, 0 diaries, 5 comments) on Tuesday, July 24, 2007 at 4:11:17 PM
 

ATYPICAL BSE, CJD, spontaneous, sporadic, or sourced ?

greetings editor,

i posted a comment to this article ;


click here


however, only half of it got posted, then i could never get anything else posted, short or long. i agree it's long winded, but needs to be said. with that, here is PART 2 TO MY post. maybe you can post it for me ???


continued part 2

ATYPICAL CREUTZFELDT JAKOB DISEASE's AND ATYPICAL BSE's - sporadic,
spontaneous, or sourced ?

continued part 2


Tissue Distribution

9. Little is known about the tissue distribution of abnormal prion protein
(PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie
is found to be a health risk to humans, data from studies to assess the
tissue distribution of PrPsc and infectivity are essential to allow an
assessment of the risk under specific control measures.

Human Health
10. Establishing a definitive link between an animal and a human TSE is
extremely difficult. Animal model data will only be indicative, and not
definitive, although if carried out appropriately could be strongly
indicative of a human health risk. The emergence of a new type of CJD which
shows the same transmission characteristics as atypical scrapie in non-human
primates and humanised mice would provide a strong indication that
transmission had occurred through the consumption of infected material.
Thus, ongoing human surveillance is critical.

11. It is difficult to conclude that atypical scrapie is not a human health
risk from negative experimental or surveillance results. However, negative
results from current and retrospective surveillance and transmission
studies, over a significant period of time to allow for possibly long
incubation periods, would imply a negligible human health risk.

Conclusion
12. It is not possible to assess the human health risk from atypical
scrapie, or changes in risk, in the absence of hard scientific data. No
single data set is likely to be definitive and it would be essential to
consider all the information available, rather than data from single studies
in isolation. Studies comparing the properties of atypical scrapie and other
TSE agents using the same animal model, especially humanised mice or
non-human primates, would be most informative in the short term.
Surveillance data to assess any association between forms of CJD and
atypical scrapie prevalence would be most persuasive but are unlikely to
become available in the short term. SEAC would have to review experimental
methods and results, should they emerge, before any conclusion of a change
to the risk to human health from atypical scrapie could be made.

1 click here (97 KB)

2 http://www.seac.gov.uk/papers/97-3.pdf (110 KB)

3 Palmer and Collinge (1993) Mutations and polymorphisms in the prion
protein gene. Hum. Mutat. 2, 168-173.

Page updated: 16 July, 2007
http://www.seac.gov.uk/statements/fsa-scrapieplan.htm


Published online before print October 20, 2005

Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102
Medical Sciences

A newly identified type of scrapie agent can naturally infect sheep with
resistant PrP genotypes

( sheep prion | transgenic mice )

Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *,
Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ||,
Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude *
*Virologie Immunologie Moléculaires and ||Génétique Biochimique et
Cytogénétique, Institut National de la Recherche Agronomique, 78350
Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de la
Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions
Hôte Agent Pathogène, 31066 Toulouse, France; Agence Française de Sécurité
Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels,
69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut
National de la Recherche Agronomique, 37380 Nouzilly, France; and
¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway


Edited by Stanley B. Prusiner, University of California, San Francisco, CA,
and approved September 12, 2005 (received for review March 21, 2005)

Scrapie in small ruminants belongs to transmissible spongiform
encephalopathies (TSEs), or prion diseases, a family of fatal
neurodegenerative disorders that affect humans and animals and can transmit
within and between species by ingestion or inoculation. Conversion of the
host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a
misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission
and pathogenesis. The intensified surveillance of scrapie in the European
Union, together with the improvement of PrPSc detection techniques, has led
to the discovery of a growing number of so-called atypical scrapie cases.
These include clinical Nor98 cases first identified in Norwegian sheep on
the basis of unusual pathological and PrPSc molecular features and "cases"
that produced discordant responses in the rapid tests currently applied to
the large-scale random screening of slaughtered or fallen animals.
Worryingly, a substantial proportion of such cases involved sheep with PrP
genotypes known until now to confer natural resistance to conventional
scrapie. Here we report that both Nor98 and discordant cases, including
three sheep homozygous for the resistant PrPARR allele (A136R154R171),
efficiently transmitted the disease to transgenic mice expressing ovine PrP,
and that they shared unique biological and biochemical features upon
propagation in mice. These observations support the view that a truly
infectious TSE agent, unrecognized until recently, infects sheep and goat
flocks and may have important implications in terms of scrapie control and
public health.


snip...


In conclusion, decoding the biochemical PrPSc signature of individual human
and animal TSE strains may allow the identification of potential risk
factors for human disorders with unknown etiology, such as sCJD. However,
although BASE and sCJD share several characteristics, caution is dictated in
assessing a link between conditions affecting two different mammalian
species, based on convergent biochemical properties of disease associated
PrPSc types. Strains of TSE agents may be better characterized upon passage
to transgenic mice. In the interim until this is accomplished, our present
findings suggest a strict epidemiological surveillance of cattle TSE and
sCJD based on molecular criteria. ...


-----------------

Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R.,
T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B.
contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data;
and H.L. wrote the paper.

A.L.D. and V.B. contributed equally to this work.

To whom correspondence should be addressed.

Hubert Laude, E-mail: laude@jouy.inra.fr

www.pnas.org/cgi/doi/10.1073/pnas.0502296102


http://www.pnas.org/cgi/content/abstract/0502296102v1



Medical Sciences
Identification of a second bovine amyloidotic spongiform encephalopathy:
Molecular similarities with sporadic Creutzfeldt-Jakob disease

Cristina Casalone *, Gianluigi Zanusso , Pierluigi Acutis *, Sergio Ferrari
, Lorenzo Capucci , Fabrizio Tagliavini ¶, Salvatore Monaco ||, and Maria
Caramelli *
*Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto
Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via
Bologna, 148, 10195 Turin, Italy; Department of Neurological and Visual
Science, Section of Clinical Neurology, Policlinico G.B. Rossi, Piazzale
L.A. Scuro, 10, 37134 Verona, Italy; Istituto Zooprofilattico Sperimentale
della Lombardia ed Emilia Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and
¶Istituto Nazionale Neurologico "Carlo Besta," Via Celoria 11, 20133 Milan,
Italy


Edited by Stanley B. Prusiner, University of California, San Francisco, CA,
and approved December 23, 2003 (received for review September 9, 2003)

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are
mammalian neurodegenerative disorders characterized by a posttranslational
conversion and brain accumulation of an insoluble, protease-resistant
isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and
animal TSE agents exist as different phenotypes that can be biochemically
differentiated on the basis of the molecular mass of the protease-resistant
PrPSc fragments and the degree of glycosylation. Epidemiological, molecular,
and transmission studies strongly suggest that the single strain of agent
responsible for bovine spongiform encephalopathy (BSE) has infected humans,
causing variant Creutzfeldt-Jakob disease. The unprecedented biological
properties of the BSE agent, which circumvents the so-called "species
barrier" between cattle and humans and adapts to different mammalian
species, has raised considerable concern for human health. To date, it is
unknown whether more than one strain might be responsible for cattle TSE or
whether the BSE agent undergoes phenotypic variation after natural
transmission. Here we provide evidence of a second cattle TSE. The disorder
was pathologically characterized by the presence of PrP-immunopositive
amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE
cases, and by a different pattern of regional distribution and topology of
brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc
type with predominance of the low molecular mass glycoform and a
protease-resistant fragment of lower molecular mass than BSE-PrPSc.
Strikingly, the molecular signature of this previously undescribed bovine
PrPSc was similar to that encountered in a distinct subtype of sporadic
Creutzfeldt-Jakob disease.


C.C. and G.Z. contributed equally to this work.

||To whom correspondence should be addressed.

E-mail: salvatore.monaco@mail.univr.it.
www.pnas.org/cgi/doi/10.1073/pnas.0305777101


http://www.pnas.org/cgi/content/abstract/0305777101v1



ProMED-mail


******
[2] Germany: Characterization of atypical BSE
Date: Sun 20 Aug 2006
From: Terry Singeltary
Source: Vet Microbiol., 14 Aug 2006 (E-pub ahead of print) [edited]



Germany: Characterization of an atypical form of bovine spongiform
encephalopathy (BSE)
-----------------------------------------------
The following recently published paper is reproduced here because of
its relevance to theories of the origin of new variant CJD, the human
form of BSE.

Title of paper: Atypical BSE in Germany - Proof of transmissibility
and biochemical characterization. By Buschmann A, Gretzschel A,
Biacabe AG, Schiebel K, Corona C, Hoffmann C, Eiden M, Baron T,
Casalone C, Groschup MH. At the Friedrich-Loeffler-Institut (FLI),
Institute for Novel and Emerging Infectious Diseases, Boddenblick 5a,
17493 Greifswald, Insel Riems, Germany.

ABSTRACT. Intensive active surveillance has uncovered 2 atypical
German BSE (bovine spongiform encephalopathy) cases in older cattle
which resemble the 2 different atypical BSE phenotypes that have
recently been described in France (designated H-type) and Italy
(designated L-type or BASE). The H-type is characterized by a
significantly higher molecular size, but a conventional glycopattern
of the proteinase K treated abnormal prion protein (PrP(Sc)), whereas
the L-type PrP(Sc) has only a slightly lower molecular size and a
distinctly different glycopattern.

In this paper, we describe the successful transmission of both German
atypical BSE cases to transgenic mice over-expressing bovine PrP(C).
Upon challenge with the L-type, these mice developed BSE after a
substantially shorter incubation period than any classical BSE
transmission using these mice to date. In contrast, the incubation
period was distinctly prolonged when these mice were challenged with
the H-type. PrP(Sc) accumulating in the brains of these mice were of
the same atypical BSE type that had been used for the transmission.
These atypical cases suggest the possible existence of sporadic BSE
cases in bovines. It is thus feasible that the BSE epidemic in the UK
could have also been initiated by an intraspecies transmission from a
sporadic BSE case.

--
Terry S. Singeltary Sr.


[Terry Singeltary Sr. has added the comment that these atypical cases
suggest the possible existence of sporadic BSE cases in bovines. It
is thus feasible that the BSE epidemic in the UK could have also been
initiated by an intraspecies transmission from a sporadic BSE case. -
Mod.CP]

******
[3] China (Hong Kong SAR): Suspected vCJD case
Date: Thu 31 Aug 2006
From: ProMED-mail
Source: Xinhua News Agency online, Wed 30 Aug 2006 [trans. from
Chinese by Mod.RY, edited]



China (Hong Kong SAR): Suspected 2nd Case of CJD (new var.) now discounted
-----------------------------------------------
The Department of Health of the Hong Kong [SAR] government and Bureau
of the Hong Kong Hospital Administration issued a joint statement on
Wed 30 Aug 2006 reporting that a suspected case of variant
Creutzfeldt-Jakob disease (vCJD) was being assessed in Hong Kong. So
far, laboratory test results have proved negative, and it remains
uncertain whether the suspected case is truly a case of vCJD.

The patient is a 23-year old male born in Britain who returned to
Hong Kong at the beginning of April this year [2006]. He became ill
and was unconscious on 6 Apr 2006, when he was admitted to the
Overseas Chinese Hospital in Guangzhou, and was subsequently
transferred to the Prince of Wales Hospital in the Hong Kong SAR for
treatment.

The patient's condition is critical at the present time due to
necrotic changes in some of his organs. Though the patient shows
clinical symptoms similar to those observed in vCJD,
electroencephalograms (EEC) and magnetic resonance imaging (MRI) do
not correspond with those observed in vCJD. Tonsil tissue samples
were sent by the hospital to Britain for further examination, but
proved negative.

Therefore, so far, there is no definite indication that the patient
is suffering from vCJD. The Bureau of HK Hospital Administration has
stated that vCJD is a rare degenerative disease of brain and is not
contagious. Nevertheless, the hospital's disease control and
prevention authority will follow a set of strict procedures for
disinfection of medical instruments that have been used for
examination and treatment of the patient to avoid transmission to
other patients.

Hong Kong's 1st case of confirmed vCJD was discovered in 2001. The
patient was a 34-year-old woman who had lived in Britain for an
extended period of time and eventually succumbed to the disease in
2002.

[Byline: Tang Yun and Kuang Peng]

--
ProMED-mail


[There appears to be no positive reason to diagnose the patient's
illness as vCJD. The report, however, is a reminder that there has
been a previous vCJD case in Hong Kong, a fact that has been
overlooked in most accounts of vCJD in the literature. - Mod.CP]

snip...


http://www.promedmail.org


CJD (NEW VAR.) UPDATE 2006 (10)
*******************************
A ProMED-mail post

ProMED-mail is a program of the
International Society for Infectious Diseases



snip...


[These data are accessible via
. -
Mod.CP]

--
ProMED-mail


******
[2] Correction
Date: Tue 5 Sep 2006
From: "Terry S Singeltary Sr"


Characterization of atypical BSE in Germany: correction
-------------------------------------------------------
[In the Moderator's comment accompanying the abstract of the paper entitled
"Atypical BSE in Germany-Proof of transmissibility and biochemical
characterization'" by A Buschmannaet et al, (see part [2] of CJD (new var.)
update 2006 (09) 20060904.2519) it was wrongly implied that Terry S
Singeltary Sr endorsed the conclusions of the paper, whereas his comments
were intended merely to highlight the conclusions of the paper. Namely that
the atypical cases suggested the possible existence of sporadic BSE cases
in bovines and perhaps the BSE epidemic in the UK could have also been
initiated by an intraspecies transmission from a sporadic BSE case. I
apologize for inadvertently misrepresenting Terry's views. - Mod.CP]

Terry S Singeltary Sr has written the following. "In fact I disagree with
the spontaneous/sporadic BSE/TSE theory, IF this is what the authors of
this paper meant by 'sporadic BSE' to mean. For one thing, it has never
been proven. IF atypical BSE i.e. BASE is so similar to some sporadic CJDs,
then how did they all of a sudden become spontaneous? Could it not be so
simple as an atypical BSE i.e. BASE was transmitted the same way most of
all of the other BSE cattle were i.e. feed of just an atypical source, thus
causing atypical strain? Why would these animals not develop an atypical
BSE i.e. BASE from the same oral route? WHAT about an atypical strain
mutating to become infectious via a lateral or horizontal mode in the
bovine, as with CWD and scrapie? Also, please explain to me how a distinct
synthetic prion, of a strain that is supposedly unlike any other we have
ever seen, how can this explain 6 different documented phenotypes of
sporadic CJD to date?

It's like trying to explain away all the 6 phenotypes of sporadic CJD with
the spontaneous theory, it's just not scientific. OR, if you render an
atypical TSE of what ever phenotype, in what ever species, of the atypical
strain and feed it to another whatever species, nothing happens x 1 x 2 x 3
x 4 etc passage? This all has been proven?

Please show me these transmission studie