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From: TSS ()
Subject: A novel subtype of Creutzfeldt–Jakob disease characterized by a small 6 kDa PrP fragment
Date: June 26, 2007 at 8:41 am PST

A novel subtype of Creutzfeldt–Jakob disease characterized by a small 6 kDa
PrP fragment


Bjarne Krebs1, Benedikt Bader1, Juliane Klehmet3, Eva Grasbon-Frodl1,
Wolfgang H. Oertel4, Inga Zerr2, Sarah Stricker3, Rolf Zschenderlein3 and
Hans A. Kretzschmar1

(1) Center for Neuropathology and Prion Research,
Ludwig-Maximilians-Universität München, National Reference Center for
Transmissible Spongiform Encephalopathies, Feodor-Lynen-Str. 23, 81377
Munich, Germany
(2) Department of Neurology, Georg-August Universität Göttingen, National
Reference Center for Transmissible Spongiform Encephalopathies, Göttingen,
Germany
(3) Department of Neurology, Charité, Humboldt Universität Berlin, Berlin,
Germany
(4) Department of Neurology, Justus-Liebig Universität Marburg, Marburg,
Germany

Received: 16 February 2007 Revised: 21 May 2007 Accepted: 21 May 2007
Published online: 19 June 2007

Abstract We report on a novel subtype of Creutzfeldt–Jakob disease with a
single proteinase K-resistant prion protein fragment of about 6 kDa in
Western blots of brain homogenates. Clinically this patient showed a
progressive spastic disorder and dementia over 3 years. No mutation of the
prion protein gene was found. Since this patient had received a blood
transfusion, an iatrogenic cause, albeit unlikely, cannot be ruled out.
Future studies will have to be attentive to small prion protein fragments,
which may cause or be associated with unusual clinical disease that might
possibly only be diagnosed by immunoblotting of brain homogenates.

Keywords Prion protein - PrP - Creutzfeldt–Jakob disease - CJD - Fragment -
6 kDa

Bjarne Krebs and Benedikt Bader have contributed equally to this work.

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Hans A. Kretzschmar
Email: hans.kretzschmar@med.uni-muenchen.de

http://www.springerlink.com/content/g15736932t26168h/

further into this study, some interesting findings ;


Discussion

As shown by the presence of spongiform changes in routine
histology and the deposition of PrP aggregates in immunohistochemistry
and the PET blot this is a deWnite case of
CJD. In the CSF the tau protein was elevated and proteins
14-3-3 were positive, a constellation which is often found
in CJD. Interestingly, the electroencephalogram did not
show periodic sharp wave complexes (PSWC) that are
often seen in CJD patients. MRI revealed a T2-weighted
signal loss in the basal ganglia, a Wnding quite atypical of
CJD, where most patients show hyperintensity.
The constellation of Wndings is exceptional in two
respects. First, the clinical course spanning over 3 years
with predominant dementia, spasticity and rigor is quite
atypical of CJD. The clinical duration of CJD is under
1 year in most cases, spasticity is rarely a leading clinical
feature. Typically, codon 129 VV-homozygous patients
either present with progressive ataxia (VV2) or predominant
dementia at an early age at onset (VV1) [8]. Second,
even more striking than the unusual clinical features, the
Western blot of a brain homogenate showed a single PKresistant
PrP band of 6 kDa, which has never been noted in
a CJD case to date.
The 6-kDa fragment of the presented case is detectable
in Western blot by the antibodies 3F4 (aa 109–111) and
6H4 (aa 144–152), but not 3B5 (octapeptide) and proteinase
K resistant PrP was recognized by antibodies L42
(around aa 144) in immunohistochemistry and 12F10 (aa
142–160) in the PET blot. Therefore the fragment must
comprise residues 111–144 (Fig. 3). This would correspond
to a MW of 3.9 kDa. With an apparent MW of 6.2 kDa on
the Western blot it seems that this PrP fragment contains
about 25 additional amino acid residues but cannot reach
beyond residue 90, because the antibody 3B5 does not
bind. Thus, in the amino acid backbone of PrPC this fragment
would comprise the C-terminal amino residues of the
Xexible tail, the -pleated strand S1 and probably part of
Helix 1.
Supattapone and co-workers [18] reported on a PrP deletion
mutant, MHM2 (23–88, 141–176), designated
PrP106, that successfully forms “miniprions”. This protein
is largely diVerent from the PrP fragment observed in our
patient (Fig. 3). Detailed Western blot analysis of PKtreated
PrPSc from human brains aVected by various prion
diseases has recently shown additional bands of 7–8, 11–13
and 14 kDa in various forms of human prion disease [16].
About 7–8 kDa fragments have only been found in GSS
[14, 19, 20]. In a study on 7 GSS patients with the P102L
mutation Parchi et al. [10] identiWed a 21-kDa peptide and
an additional band of 8 kDa in 5 cases. Two out of the 7
patients showed only an 8 kDa fragment. This fragment had
N-terminal cleavage sites at residues 78, 80, and 82, the Cterminus
spanned positions 147–153. It correlated with the
appearance of plaques. In contrast to Parchi et al. we did
not see PrP plaques, which may be due to the small biopsy
sample size of the case reported here, where plaques may
be present in other areas of the brain.
The case presented herein is not a case of familial
(genetic) CJD since there is neither a family history of
dementia nor was a mutation of the PrP gene found on
sequencing DNA from peripheral blood lymphocytes and a
brain homogenate. The patient had a blood transfusion
22 years in the past. Thus, although iatrogenic transmission
of CJD by blood transfusion from a sporadic CJD case has
never been reported, an iatrogenic cause cannot be ruled
out, even if this possibility appears to be extremely
unlikely. As to the question of whether this could be a case
of vCJD, one has to bear in mind that BSE-caused prion
disease has never been diagnosed in codon 129 VV homozygous
humans; therefore, the possible phenotype of the
disease on this genetic background is unknown. There is
only indirect evidence on this hypothetical phenotype stemming
from experiments with transgenic mice that express
human codon 129 VV PrP (129VV Tg152 mice). When
these mice were infected with vCJD they showed PrP
plaques and a doubly glycosylated PrPSc band. More important,
when 129VV Tg159 mice were infected with BSE,
no detectable PrPSc was observed in their brains [22]. Due
to the small sample size, the co-existence of other neurodegenerative
diseases cannot be ruled out completely,
although we found no evidence in immunohistochemistry
and silver impregnations.
Amongst the 400 Western blots that have been evaluated
at the German National Reference Center between 1993
and 2006, 6-kDa PrP fragments have not previously been
noted nor has such a fragment been reported from any other
CJD surveillance center. This may be related to the fact that
short gels for Western blots do not show 6-kDa bands.
Therefore, the importance of the case presented here may
lie in calling attention to unusual phenotypes of CJD possibly
mimicking other neurodegenerative diseases. The novelty
is that this can happen in the absence of the known
larger PK-resistant PrPSc fragments of 19 or 21 kDa MW.
If prion diseases can arise spontaneously in humans, this
may also be the case in animals. Thus there is always a
chance of newly emerging prion strains in animals, which
may or may not be transmissible to humans. Although the
etiology of the case presented here is unknown, it certainly
highlights the importance of ongoing CJD surveillance programs
using a sophisticated arsenal to closely monitor
human prion diseases and possibly detect new human prion
strains. Further investigations will aim at clarifying their
origin, be it acquired or spontaneous.

Acknowledgments This work was supported by the EC, NeuroPrion
NoE FOOD-CT-2004-506579. The National Reference Center for
Human Spongiform Encephalopathies is supported by the Federal
Ministry of Health of Germany.

Acta Neuropathol
DOI 10.1007/s00401-007-0242-5
TSS




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