Atypical Prion Protein Conformation in Familial Prion Disease with PRNP P105T Mutation

RESEARCH A R T I C L E bpa_439 1..6

Atypical Prion Protein Conformation in Familial Prion Disease with PRNP P105T Mutation

Magdalini Polymenidou1,2,*; Stefan Prokop1,3,*; Hans H. Jung4; Ekkehard Hewer1; David Peretz5,6;

Rita Moos1; Markus Tolnay1,7; Adriano Aguzzi1

4 Department of Neurology, 1 Institute of Neuropathology, University Hospital Zurich and 7 Basel, Switzerland.

5 Novartis Vaccines and Diagnostics, Emeryville, Calif.

2 Current address: Department of Cellular and Molecular Medicine, University of California at San Diego, Calif.

3 Current address: Department of Neuropathology, Charité—Universitätsmedizin Berlin, Germany.

6 Current address: Tethys Bioscience, Emeryville, Calif.


Abstract

Protease-resistant prion protein (PrPSc) is diagnostic of prion disease, yet its detection is

frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical

familial prion disease. Brain PrPSc was undetectable by conventional Western blotting and

barely detectable after phosphotungstate precipitation, where it displayed an atypical pattern

suggestive of noncanonical conformation. Therefore, we used a novel misfolded protein

assay (MPA) that detects PrP aggregates independently of their protease resistance. The

MPA revealed the presence of aggregated PrP in similar amounts as in typical sporadic

Creutzfeldt-Jakob disease. These findings suggest that measurements of PrP aggregation

with the MPA may be potentially more sensitive than protease-based methodologies.


Keywords

familial prion disease, misfolded protein assay, prion.

Corresponding authors:

Adriano Aguzzi, MD PHD, Institute of

Neuropathology, University Hospital of Zurich,

Schmelzbergstrasse 12, Zurich CH-8091,

Switzerland (E-mail: adriano.aguzzi@usz.ch);

Magdalini Polymenidou, PHD, Department of

Cellular and Molecular Medicine, University of

California, San Diego, 9500 Gilman Drive, La

Jolla, CA 92093-0670, USA (E-mail:

mpolymen@ucsd.edu)

Received 2 June 2010; accepted 2 August

2010.

* These authors contributed equally to this

work.

doi:10.1111/j.1750-3639.2010.00439.x

http://www.pathol.uzh.ch/publications/2010/Polymenidou_BrainPath_2010.pdf



Sunday, November 28, 2010

Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, a synuclein and AB pathology


http://prionopathy.blogspot.com/2010/11/variably-protease-sensitive-prionopathy.html



http://sporadicffi.blogspot.com/



TSS

Inherited Creutzfeldt–Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology

J Neurol Neurosurg Psychiatry 2009;80:1386-1389 doi:10.1136/jnnp.2008.169359

Short report

Inherited Creutzfeldt–Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology

C Jansen1, J C van Swieten2, S Capellari3, R Strammiello3, P Parchi3, A J M Rozemuller1 + Author Affiliations

1Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands 2Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands 3Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy Correspondence to Dr C Jansen, Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, The Netherlands; c.jansen@umcutrecht.nl Received 2 December 2008 Revised 22 February 2009 Accepted 5 March 2009 Abstract An atypical case of inherited Creutzfeldt–Jakob disease (CJD) is described in a 35-year-old Dutch woman, homozygous for methionine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by slowly progressive cognitive decline and parkinsonism. Neuropathological findings consisted of scanty spongiosis and only faint to absent immunohistochemical staining for the abnormal prion protein, PrPSc, with patchy deposits in the cerebellar cortex. Purkinje cells were abnormally located in the molecular layer of the cerebellum. Western blot analysis showed the co-occurrence of PrPSc types 1 and 2 with an unusual distribution. Sequence analysis disclosed a novel 120 bp insertion in the octapeptide repeat region of the PRNP, encoding five additional R2 octapeptide repeats. These features define an unusual neuropathological phenotype and novel genotype, further expanding the spectrum of genotype–phenotype correlations in inherited prion diseases and emphasising the need to carry out pre-mortem PRNP sequencing in all young patients with atypical dementias.

snip...

METHODS Case history The patient presented with forgetfulness and difficulties in writing at the age of 35 years, after the birth of her second child. Her family noted that she had become increasingly absentminded and apathetic. Her clinical history was otherwise unremarkable. Her father had suffered from dementia and parkinsonism from the age of 45 years and died at the age of 55 years. At neurological examination, 2.5 years after the first symptoms, the patient was disoriented in time and place, and exhibited echolalia, perseveration and disturbed visual perception. She had a masked face with vertical gaze palsy, and increased tone of the extremities. Neuropsychological evaluation revealed an intact memory with acalculia, agraphia and apraxia. Brain MRI showed generalised cortical atrophy without evidence of hyperintensity or atrophy of either the caudate nucleus or the basal ganglia (fig 1A). The 14-3-3 test in CSF was negative. An electroencephalogram was not recorded. Genetic analysis revealed no abnormalities in the tau protein gene (MAPT), the Presenilin 1 gene (PSEN1) or the Huntingtin gene. Over the next 3 years, rigidity increased with the appearance of a slight tremor in her right hand, without any beneficial effect on levodopa and amantadin treatment. She increasingly developed dysarthria and swallowing problems, and suffered from anxiety and panic attacks. She was admitted to a nursing home where she died from bronchopneumonia at the age of 42 years, 92 months after the clinical onset of the disease.


snip...


DISCUSSION

Seventeen patients with six different 5-OPRI have been described so far in the literature.6 As in other inherited prion diseases, these disorders show a considerable degree of phenotypic variability, partly accounted for by the codon 129 Met/Val polymorphism. Age at onset in codon 129 heterozygous patients is usually later (58.0 years) than in codon 129 homozygous patients (42.3 years).6 Approximately half of these patients show a disease duration of more than 60 months. Although the clinical and pathological features of 5-OPRI mutations are relatively well known, genotype–phenotype correlation has not been clearly established, warranting the description of further genetic cases.

In this report, we describe a novel insertion mutation in PRNP, consisting of five extra R2 octapeptide repeats (R1-(R2)7- R3-R4). The clinical phenotype in our patient was characterised by slowly progressive cognitive decline, parkinsonism, anxiety and a long disease duration of 92 months. Neuropathological findings included scanty spongiosis and faint synaptic or even absent immunohistochemical staining, except for small patchy deposits in the cerebellar cortex, without the characteristic perpendicular orientation to the meningeal outline, as described in other patients with insertion mutations.8 12 An intriguing finding, although described before in three other patients with a 5-OPRI mutation,13 was the abnormal localisation of Purkinje cells in the molecular layer of the cerebellum. The type of abnormalities, combined with the absence of ataxia and significant cerebellar pathology, strongly suggest this defect as being longstanding and likely related to a developmental defect. Thus although largely speculative, the observation may suggest a role for PrPC in cerebellar neuronal migration or in the elimination of misplaced Purkinje cells during development which likely involve the programmed cell death machinery, as recently suggested.14 Furthermore, in the absence of a specific histopathological picture, the observation of misplacement of Purkinje cells in the molecular layer might be a helpful diagnostic clue prompting the suspicion of inherited prion disease with OPRI mutation.

Another interesting finding was the co-occurrence of PrPSc types 1 and 2 in brain homogenates, as demonstrated by immunoblotting. To our knowledge, this has only been described once before in a patient with one extra octapeptide repeat in PRNP, who showed widespread spongiosis and diffuse synaptic immunoreactivity in all cortical lobes.15 In light of the scanty spongiosis and faint immunohistochemical staining in the brain of our patient, the presence of type 2 protein is a peculiar finding, since in methionine homozygotes (MM) at codon 129, type 2 is usually associated with prominent spongiosis with confluent vacuoles and more consistent coarse and perivacuolar deposits of PrPSc in the cerebral cortex.11 Furthermore, type 2 in MM cases preferentially accumulates in the cerebral cortex11 whereas it was mainly detected in the striatum and cerebellum in the present case. The 5-OPRI mutation in this patient was probably inherited in an autosomal dominant pattern but a positive family history in patients with inherited prion disease is not obligate. In all patients with a clinical history of frontotemporal dementia or atypical dementia and abnormal localisation of Purkinje cells in the molecular layer of the cerebellum, inherited prion disease should always be considered and pre-mortem PRNP sequencing should be carried out.

snip...see full text ;





http://jnnp.bmj.com/content/80/12/1386.abstract




http://sporadicffi.blogspot.com/



TSS

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

Brain Advance Access published September 1, 2008

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

T. E. F.Webb,1,2 M. Poulter,1 J. Beck,1 J.Uphill,1 G. Adamson,1 T. Campbell,1 J. Linehan,1 C. Powell,1 S. Brandner,1,2 S. Pal,1,2 D. Siddique,1,2 J. D.Wadsworth,1 S. Joiner,1 K. Alner,2 C. Petersen,2 S. Hampson,2 C. Rhymes,2 C. Treacy,2 E. Storey,3 M. D.Geschwind,4 A. H. Nemeth,5 S.Wroe,1,2 J. Collinge1,2 and S. Mead1,2 1MRC Prion Unit and Department of Neurodegenerative Disease,UCL Institute of Neurology, 2National Prion Clinic and National Hospital for Neurology & Neurosurgery, Queen Square, London,WC1N 3BG, 3Department of Medicine (Neuroscience), Monash University, Melbourne, Australia, 4Department of Neurology,University of California, San Francisco (UCSF), San Francisco, CA,USA and 5Department of Clinical Genetics, Churchill Hospital and Weatherall Institute of Molecular Medicine, John Radcliffe Hospital,Oxford,OX3 9DU, UK Correspondence to: Prof. John Collinge, Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, LondonWC1N 3BG, UK E-mail: j.collinge@prion.ucl.ac.uk

The largest kindred with inherited prion disease P102L, historically Gerstmann-Stra«ussler-Scheinker syndrome, originates from central England, with e¤migre¤ s now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors.This collection represents by far the largest series of P102L patients so far reported.Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M andwere not connected by genealogy ormicrosatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Stra«ussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P=0.02).Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by10 years (P=0.02).We found a preponderance of female patients comparedwithmales (54 females versus 30 males,P=0.01), which probably relates to ascertainment bias.However, thesemodifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients.These data allow an appreciation of the range of clinical phenotype, modern imaging andmolecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

snip...

Discussion

The patients presented here constitute by far the largest study of the classical GSS-associated PRNP mutation, P102L. Modern investigation, molecular genetic techniques and advances in pathological examination have allowed us to revisit a historical British pedigree and other smaller kindreds. We find evidence of a mutation hot spot at codon 102, a subgroup presenting with rapid cognitive decline and the significant modification of phenotype by two single nucleotide polymorphisms. The microsatellite haplotyping presented here demonstrates the existence of multiple separate and worldwide P102L kindreds of UK origin, confirmed in most patients by established genealogical links that had not been identified previously. However, the identification of a further six UK P102L kindreds along with two others of European origin suggests that multiple mutational events have occurred in the recent past. This might be supported by the identification of at least one of these patients (6.VIII.1) in an individual without suggestive family history or of known P102L patients living nearby, suggesting that this might represent a novel mutation. Given the identification of IPD patients in otherwise typical sCJD presentations, as well as in patients without a family history of neurodegeneration, novel mutational events may occur more commonly than previously thought. The commonest point mutations associated with IPD occur at cytosine-phosphate diesterguanidine dinucleotide sites hypothesized to be mutation ‘hot spots’ in human DNA (Vollmert et al., 2006). These hot spots are related to the spontaneous demethylation of cytosine to thymidine. Cytosine-phosphate diester-guanidine dinucleotide sites are associated with E200K, D178N and P102L point mutations, which between them account for the bulk of IPD patients worldwide (Dagvadorj et al., 2002; Mead, 2006). An alternative possibility to multiple separate mutational events being responsible for these apparently unconnected P102L IPD kindreds is that these small pedigrees do share a common ancestor with the large pedigree but that this was long enough in the past for linkage to the disease haplotype to have broken down. We estimate a probability of recombination of the 3MB microsatellite haplotype as about 10% per generation (assuming a genetic:physical ratio of 3.7). The unexpected finding that significantly greater numbers of females were identified with P102L IPD and the consequently higher number of individuals having an affected mother rather than father as the parent from whom the mutation was inherited is puzzling. This discrepancy has been reported once previously in this family, albeit with smaller numbers of individuals and without available genetic techniques, allowing the linkage of kindreds not known to share ancestry (Baker et al., 1985). It has also been observed in the large 6-OPRI IPD kindred from the South-East of England (Mead et al., 2006). In the earlier study in P102L, the finding was explained by postulating that affected females had significantly more children than their unaffected siblings and that greater than half these were daughters. Such an explanation is intriguing, though hard to explain. Alternatively, because of possible illegitimacy, we suspected that genealogical research might more readily identify affected mothers than affected fathers. In order to consider the possibility of ascertainment bias, the gender of members of the kindred identified from parish records or census entries, but who have not been identified as having suffered from IPD P102L, were collected. An excess of males in these untraced individuals was indeed identified. When these were added to the presumed affected male and female individuals, an excess of females to males remained (82–68), although this was not significantly different from an expected proportion of 0.5. It seems likely that ascertainment bias is responsible for this gender difference, although the intriguing possibility of a biological explanation remains. While the majority of P102L IPD patients here present with progressive ataxia accompanied by mild or absent cognitive symptoms and signs, a subset present with a predominantly cognitive and or psychiatric onset, with mild or absent cerebellar signs initially. Psychiatric involvement has been severe enough to necessitate antipsychotic medication in four patients (VII.1, VII.8, VIII.4 and 3.VIII.1) and inpatient treatment in two (VII.1 and VII.8). The existence of these distinct phenotypes (cognitive and psychiatric versus cerebellar onset) is supported by the finding of early prominent frontal executive impairment on neuropsychology in these patients not seen in other patients so tested. Neuropsychological assessment is now routine at the National Prion Clinic but in the past this was more usually performed only when clinical evidence of cognitive impairment existed. In addition to these neuropsychological differences, there is a suggestion that the cognitive and Fig. 9 Photograph of original 1871 asylum entry relating to admission and care of III.3 from Fig. 2. His condition is described as hereditary and reference ismade to his relatives’ care in the same institution.He is reported as being ‘scarcely able to move one leg in ront of another’ and his countenance is described as ‘imbecile’. He appears to have had dementia as well as weakness: ‘Can only answer in monosyllables & then incoherently; is much paralysed’. He was treated with daily doses of brandy until he died. ‘Paralysis’ was listed as the cause on the death certificate. Page 12 of 15 Brain (2008) T. E. F.Webb et al. psychiatric presentations have an earlier age at onset and death. Neuropsychology also highlights, however, that most if not all patients have cognitive deficits when psychology is performed, even if the findings are subtle, although selection bias may limit this conclusion. No pathological correlates of these two syndrome types have been identified, although numbers compared are small. Kuru and growth hormone-associated prion disease are notable for their onset with cerebellar symptoms (Collinge, 2001), which prompts speculation that cerebellar onset in P102L might result from the onset of prion replication outside the central nervous system. The range of tissue available did not permit the thorough testing of this hypothesis. The high degree of clinical heterogeneity and the lack of characteristic findings on commonly available clinical neurological investigations make correct diagnosis of P102L IPD challenging. The finding of positive CSF 14-3-3 combined with the albeit unusual occurrence of periodic sharp wave complexes on EEG and an sCJD-like phenotype in some individuals raises the possibility of missed diagnosis. It also supports our clinical practice of advising PRNP analysis routinely in all those presenting with otherwise undiagnosed pre-senile dementing or ataxic illnesses. Peripheral sensory symptoms and muscle weakness appear almost universal during the course of P102L IPD. The demonstration of muscle denervation and axonal sensorimotor neuropathy suggest peripheral neurological pathology is responsible. Experimental mice over-expressing wild-type PrP have shown demyelinating peripheral nerve pathology (Westaway et al., 1994). However, evidence of peripheral neuropathy in P102L IPD was inconsistent and where present was axonal, a form that is not uncommon in the population from unrelated causes. No prion protein (scrapie isoform) positivity could be demonstrated on two muscle biopsies examined here and although an indirect pathological process could still be responsible, peripheral findings in P102L IPD may be incidental, while sensory symptoms could be centrally rather than peripherally driven. Presented for the first time here is the finding that P102L IPD patients with methionine homozygosity at codon 129 present significantly earlier than codon 129 heterozygotes. Earlier age at onset is well recognized in codon 129 homozygotes in other IPD mutations (Collinge et al., 1992; Poulter et al., 1992; Mead et al., 2006), although the association with IPD associated with point mutations rather than OPRIs is less clear (Dlouhy et al., 1992). The less strong effect in P102L with respect to 6-OPRI may explain why this observation has not been made before where smaller numbers of patients have been examined (Hainfellner et al., 1995; Barbanti et al., 1996). There are several possible mechanisms of action of codon 129 genotype on clinical phenotype. It has long been known that the interaction between prion protein, scrapie isoform (PrPSc) and prion protein, normal cellular isoform (PrPc) occurs most efficiently when the proteins have an identical primary structure (Palmer et al., 1991); therefore, prion replication may occur more rapidly and clinical onset earlier in 129MM individuals. As a further complexity, the primary structure of PrP determines the permissible conformations of PrPSc. The extent to which a pathogenic 102L-129M PrP conformer is permitted by wild-type PrPc with 129V or 129M may also be important [see Collinge, 2007 for a recent review (Collinge and Clarke, 2007)]. 102L-129M PrP may be able to adopt several different pathogenic conformations, which may be permissible to a greater or lesser extent by the wild-type protein (Parchi et al., 1998; Hill et al., 2006). The involvement of wild-type protein is known to be a variable phenomenon in P102L and a possible determinant of phenotype (Wadsworth et al., 2006). The identification of the P102L mutation on a methionine allele in all of the patients presented here with adequate haplotype data probably relates simply to the frequency of this allele in the background population. P102L patients existing on a codon 129 valine allele have been reported, apparently occurring in the context of a distinct phenotype with prominent psychiatric features and seizures, different from classical P102L codon 129 methionine patients (Young et al., 1997; Bianca et al., 2003). Such a phenotypic difference could relate to different prion strain propagation originating from the valine allele. Genotype–phenotype correlations presented here, corrected for codon 129, demonstrate an effect of APOE genotype on age at onset, with individuals carrying the E4 allele having a significantly later age at onset than those without. While this evidence appears in contrast to the strong association of E4 with risk of Alzheimer’s disease (Corder et al., 1993) and to published work on the possible impact of APOE polymorphisms in sCJD showing an overrepresentation of the E4 allele in sCJD patients (Amouyel et al., 1994; Van Everbroeck et al., 2001), such findings have not been replicated in all published studies (Nakagawa et al., 1995; Zerr et al., 1996) nor in our own observations (387 sCJD patients versus unaffected controls, unpublished data). Recent reports present a similar result in frontotemporalobar degeneration, with later disease onset in those with the APOE E4 genotype in the context of progranulin mutations (Gass et al., 2006; Beck et al., 2008). APOE may thus have contrasting effects in the context of different neurodegenerative disease types. Most of the P102L IPD patients shared common features on pathological analysis. Spongiform change, astrocytosis and PrP deposition, both as multicentric plaques and synaptic deposits, were seen in the majority. However, the degree of severity of spongiform change and plaque deposition were very variable. This did not seem to correlate with age at onset or duration of illness. Neither did predominantly cerebellar or cognitive clinical presentations seem to correlate with pathological findings. PRNP codon 129MM homozygotes and MV heterozygotes were equally represented in the pathology series but no significant differences were seen between these two groups. However, the small Inherited prion disease P102L Brain (2008) Page 13 of 15 numbers in each subgroup and the age of some of the samples examined (with tissue up to 30 years old) may prevent correlations from being made. A single highly atypical clinical patient showed no significant histological differences from the rest of the series, while an atypical pathological patient has limited clinical data, although what is known about this individual is not obviously different from the other patients examined. These results suggest no clear clinicopathological correlations, but sample size was necessarily small. Immunoblots of proteinase K-digested brain homogenate from P102L patients demonstrate a spectrum of involvement of protease-resistant wild-type PrP in P102L IPD (Wadsworth et al., 2006). Four of the seven P102L IPD patients examined in this study were negative for prion protein (scrapie isoform), which most probably relates to sampling issues and the differing density of PrP deposition in tissue samples both within and between patients. Our large study therefore does not expand the existing data and we were unable to test whether protease-resistant PrP diversity might contribute to clinical heterogeneity. This remains a plausible concept in IPD that requires a large series of fresh frozen brain tissue and molecular analysis of PrP type following partial protease digestion. The need for public health control measures, together with the evident diagnostic challenges that IPD heterogeneity causes, make a strong argument for including PRNP gene analysis in he list of investigations for suspected prion disease of any type and indeed of all undiagnosed familial dementia or cerebellar syndromes. Successful diagnosis allows clinicians to provide more accurate prognostic information to patients, to allow participation in the clinical trials and reduce the risk of iatrogenic transmission of disease. As a consequence of these geographically highly mobile ancestors, and the large number of untraced individuals in the nineteenth century who were clearly at risk of inheriting the P102L mutation, it remains likely that further patients and at-risk individuals exist who have yet to be identified. It is hoped that the data presented here will help to raise awareness of P102L IPD and its associated presentations.

snip...end...TSS

http://brain.oxfordjournals.org/cgi/reprint/awn202v2


please see also ;

http://sporadicffi.blogspot.com/


TSS

Sporadic Fatal Insomnia with Unusual Biochemical and Neuropathological Findings

P03.121

Sporadic Fatal Insomnia with Unusual Biochemical and Neuropathological Findings

Giaccone, G1; Mangieri, M1; Priano, L2; Limido, L1; Brioschi, A2; Albani, G2; Pradotto, L2; Fociani, P3; Orsi, L4; Mortara, P4; Tagliavini, F1; Mauro, A2 1Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy; 2IRCCS Istituto Auxologico Italiano, Italy; 3Università di Milano, Ospedale Luigi Sacco, Italy; 4Università di Torino, Dipartimento di Neuroscienze, Italy

Sporadic fatal insomnia (SFI) is a rare subtype of human prion disease, whose clinical and neuropathological phenotype is very similar to familial fatal insomnia (FFI). SFI patients reported until now were all homozygous for methionine at codon 129 of PRNP with deposition of type 2 PrPres (Parchi classification) in the brain. Here we describe a 56-year-old woman who died after a 10-month illness characterized by progressive drowsiness, cognitive deterioration, autonomic impairment and myoclonus. Polysomnography demonstrated a pattern similar to that described in FFI cases with loss of circadian pattern of sleep-wake cycle. A remarkable finding was that 20 years before the onset of symptoms, the patient had undergone surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus. The PRNP gene showed no mutation and methionine homozygosity at codon 129. The neuropathologic examination revealed neuronal loss, gliosis, and spongiosis that were mild in the cerebral cortex, while relevant in the caudate nucleus, putamen, thalamus, hypothalamus and inferior olives. In the thalamus, the mediodorsal nuclei were more severely affected than the ventral ones. PrPres immunoreactivity was consistent in the striatum, thalamus and hypothalamus, patchy and of low intensity in the cerebral cortex and absent in the cerebellum. Western blot analysis confirmed this topographic distribution of PrPres. The bands corresponding to di- glycosylated, monoglycosylated and non-glycosylated PrPres were equally represented. The nonglycosylated PrPres band had an electrophoretic mobility identical to that of type 1 by Parchi classification, in the multiple cortical and subcortical regions examined. These findings demonstrate the existence of further rare molecular subtypes of human prion diseases, whose characterization may provide clues for the elucidation of the relation between biochemical characteristics of PrPres and clinico-pathological features of these disorders.




http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf





Greetings,

IT could also be that this sFFI is just another case of iCJD (via friendly fire from the surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus), some 20 years before the onset of symptoms of this so called sFFI case, from some sub-type of sporadic CJD, now called sporadic FFI ???


I believe it was Gambetti et al that coined this term sporadic FFI, from some conspicuous sub-type of sporadic CJD possibly? seems they could not tie it to a true FFI by diagnostic standards to date, so it was then termed a sFFI, confusing matters even worse ;

A subtype of sporadic prion disease mimicking fatal familial insomnia



http://www.neurology.org/cgi/content/abstract/52/9/1757?ck=nck





THIS seems to raise more questions than answers, confusing the TSEs even worse.

WHAT is sporadic CJD, and how many sub-types and atypical strains, phenotypes etc. will there be, arising from nothing. a spontaneous happening of sorts??? i think not. ...tss



Manuscript Draft Manuscript Number: Title:
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory
Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.

first submitted ;

Comments sent via JAMA Feedback Page

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

NAME: Terry S. Singeltary Sr.
E-MAIL: flounder9@verizon.net

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COMMENTS:

I wish to submit the following ;

HUMAN and ANIMAL TSE Classifications i.e. mad cowdisease and the UKBSEnvCJD only theory




http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf




http://cjdmadcowbaseoct2007.blogspot.com/2008/06/human-and-animal-tse-classifications-ie.html




Tuesday, August 19, 2008
Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate



http://bse-atypical.blogspot.com/2008/08/atypical-bse-base-transmitted-from.html



http://bse-atypical.blogspot.com/2008/08/bovine-spongiform-encephalopathy-mad.html




Sunday, August 10, 2008

A New Prionopathy OR more of the same old BSe and sporadic CJD



http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html




Friday, August 22, 2008
Creutzfeldt Jakob Disease and Veterans and how they are treated at death



http://creutzfeldt-jakob-disease.blogspot.com/2008/08/creutzfeldt-jakob-disease-and-veterans.html



http://organicconsumers.org/forum/index.php?showtopic=1965





August 19, 2008, Publish Ahead of Print:

First Report of Creutzfeldt-Jakob Disease Occurring in 2 Siblings Unexplained by PRNP Mutation.

Original Article

Journal of Neuropathology & Experimental Neurology. POST EDITOR CORRECTIONS, 19 August 2008 Webb, Thomas E.F. MRCP; Pal, Suvankar MRCP; Siddique, Durrenajaf MRCP; Heaney, Dominic C. MRCP; Linehan, Jacqueline M. BSc; Wadsworth, Jonathan D.F. PhD; Joiner, Susan BSc; Beck, Jon BSc; Wroe, Stephen J. FRCP; Stevenson, Valerie MRCP; Brandner, Sebastian MRCPath; Mead, Simon PhD; Collinge, John FRS Abstract: Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.

(C) 2008 American Association of Neurop




http://www.jneuropath.com/pt/re/jnen/abstract.00005072-900000000-99931.htm





GEN-07

SPORADIC FATAL INSOMNIA IN A FATAL FAMILIAL INSOMNIA PEDIGREE

S. Capellari1a, P. Cortelli1, P. Avoni1, G.P. Casadei2, A. Baruzzi1, E. Lugaresi1, M. Pocchiari3, P. Gambetti4, P. Montagna1, P. Parchi1. 1Department of Neurological Sciences, University of Bologna, Bologna, Italy; 2Department of Cell Biology and Neurosciences, ISS, Roma, Italy; 3Servizio di Anatomia Patologica, Ospedale Maggiore, Bologna, Italy, 4Division of Neuropathology, CWRU, Cleveland, OH, USA. a mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000208/!x-usc:mailto:capellari@neuro.unibo.it

We describe a case of sporadic fatal insomnia (sFI) occurring in a family in which several members carried the D178N mutation in the PRNP gene and died of fatal familial insomnia (FFI). A 43-year-old woman presented with an 11-month history of diplopia, withdrawal, confusion, memory loss, unsteady gait and inability to sleep with episodes of agitation and dream enactment. After a progressive course characterized by cognitive impairment, marked gait ataxia, signs of autonomic hyperactivity, and myoclonus the patient died 24 months after the onset of symptoms. The patient did not have any personal contact with FFI affected relatives and her closest one was a paternal uncle, the son of her grand-grand mother. Analyses of DNA from various tissues of endo- ecto- and meso-dermal origin, including 5 different regions of the CNS revealed no pathogenic mutations and methionine homozygosity at codon 129 of PRNP. Brain histopathology and PrPSc typing showed typical features of FI such as thalamic and olivary atrophy, focal spongiform degeneration limited to the cerebral cortex, relative sparing of basal ganglia and cerebellum, and relatively low amount of PrPSc type 2A accumulation. sFI represents the rarest among the sporadic human TSE subtypes described to date with less than twenty cases described worldwide and only three cases diagnosed in Italy since the establishment of TSE surveillance. Similarly, only six unrelated FFI families have been observed in Italy to date, making the probability of a chance association between sFI and FFI in the same family extremely low. Thus, we believe that our observation emphasizes the importance of undiscovered factors modulating the susceptibility to human prion diseases. Supported by the EU Network of Excellence “NeuroPrion” (FOOD-CT-2004-506579).




http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf







UK- Wife And Sister Of Man Die Of Sporadic CJD By Helen Morgan The Scotsman 10-3-4

A man today described the deaths of his wife and sister from Creutzfeldt-Jakob Disease (CJD) as a "horrific coincidence". The man's wife, from Walham Green, Sandhurst, Gloucestershire, died last month after battling the sporadic form of the brain disease for 9 months.

The man's sister died 2 years ago after contracting the same form of the disease. Both women were 67 when they died. They were both treated in the same ward in the Gloucestershire Royal Hospital. His wife's walking was first affected before her memory started to go. He said latterly she got very angry and violent due to her frustration at the disease.

Her husband, a retired fitter who is 70, said: "I feel terrible. I can't believe it. I feel completely in the dark and have no idea whatsoever why they died." CJD Support Network co-ordinator Gill Turner said there was one in a million cases of this form of the disease. She said every case of the disease is looked at by the CJD incident panel and believed the findings of these deaths would be "very interesting". "The likelihood of such close non-blood relatives getting CJD would be very unusual," she added.

According to the CJD Surveillance Unit in Edinburgh, 993 people have died of all forms of CJD in Britain between 1990 and 2004. Some 740 of those deaths were attributed to sporadic CJD, the most common form of the disease.



http://news.scotsman.com/latest.cfm?id=3572329




In October 1998 the simultaneous occurrence of spongiform encephalopathy in a man and his pet cat was reported. The report from Italy noted that the cat did not display the same clinical features as FSE cases previously seen. Indeed, the presence of a new type of FSE was suggested. The man was diagnosed as having sporadic CJD, and neither case (man nor cat) appeared to be affected by a BSE-related condition.



http://www.defra.gov.uk/animalh/bse/bse-science/level-4-othertses.html



Image] Research letters Volume 352, Number 9134 [Image] 3 October1998[Previous] [Next] [Image][Image]

Simultaneous occurrence of spongiform encephalopathy in a manand his cat in Italy

[Image] Gianluigi Zanusso, Ettore Nardelli, Anna Rosati, GianMaria Fabrizi, SergioFerrari, Antonella Carteri, Franco De Simone, Nicola Rizzuto, SalvatoreMonaco

Transmissible spongiform encephalopathies (TSE) encompass inherited,acquired, and sporadic mammalian neurological disorders, and arecharacterised by the conversion of the cellular prion protein (PrP) in aninsoluble and protease-resistant isoform (PrPres). In human TSE, four typesof PrPres have been identified according to size and glycoform ratios, whichmay represent different prion strains. Type-1 and type-2 PrPres areassociated with sporadic Creutzfeldt-Jakob disease (CJD), type 3 withiatrogenic CJD, and type 4 with variant CJD.1,2 There is evidence thatvariant CJD is caused by the bovine spongiform encephalopathy (BSE)-prionstrain.2-4 The BSE strain has been identified in three cats with felinespongiform encephalopathy (FSE), a prion disease which appeared in 1990 inthe UK.5 We report the simultaneous occurrence of sporadic CJD in a man anda new variety of FSE in his cat. A 60-year-old man, with no unusual dietary habits, was admitted in November,1993, because of dysarthria, cerebellar ataxic gait, visual agnosia, andmyoclonus. An electroencephalogram (EEG) showed diffuse theta-deltaactivity. A brain magnetic resonance imaging scan was unremarkable. 10 dayslater, he was speechless and able to follow only simple commands. RepeatEEGs showed periodic triphasic complexes. 2 weeks after admission, he wasmute, akinetic, and unable to swallow. He died in early January, 1994. His 7-year-old, neutered, female shorthaired cat presented in November,1993, with episodes of frenzy, twitching of its body, and hyperaesthesia.The cat was usually fed on canned food and slept on its owner's bed. Nobites from the cat were recalled. In the next few days, the cat becameataxic, with hindquarter locomotor dysfunction; the ataxia got worse andthere was diffuse myoclonus. The cat was killed in mid-January, 1994. No pathogenic mutations in the patient's PrP gene were found. The patientand the cat were methionine homozygous at codon 129. Histology of thepatient's brain showed neocortical and cerebellar neuronal loss,astrocytosis, and spongiosis (figure A). PrP immunoreactivity showed apunctate pattern and paralleled spongiform changes (figure B). The cat'sbrain showed mild and focal spongiosis in deeper cortical layers of all fourlobes (figure C), vacuolated cortical neurons (figure D), and mildastrogliosis. The cerebellar cortex and the dentate nucleus were gliosed.Immunoreactive PrP showed a punctate pattern in neocortex, allocortex, andcaudate nucleus (figure E). Western blot analysis of control and affectedhuman and cat brain homogenates showed 3 PrP bands of 27-35 kDa. Afterdigestion with proteinase K and deglycosylation, only samples from theaffected patient and cat showed type-1 PrPres, with PrP glycoform ratioscomparable to those observed in sporadic CJD1 (details available fromauthor). [Image] Microscopic sections of patient and cat brains A: Occipital cortex of the patient showing moderate spongiformdegeneration and neuronal loss (haematoxylin and eosin) and B: punctateperineuronal pattern of PrP immunoreactivity; peroxidaseimmunohistochemistry with monoclonal antibody 3F4. C: cat parietal cortexshowing mild spongiform degeneration (haematoxylin and eosin).D:vacuolated neurons (arrow, haematoxylin and eosin), E: peroxidaseimmunohistochemistry with antibody 3F4 shows punctate perineuronaldeposition of PrP in temporal cortex. This study shows a spatio-temporal association between human and felineprion diseases. The clinical features of the cat were different frompreviously reported cases of FSE which were characterised by gradual onsetof behavioural changes preceding locomotor dysfunction and ataxia.5Neuropathological changes were also at variance with the diffuse spongiosisand vacuolation of brainstem neurons, seen in FSE.5 The synaptic pattern ofPrP deposition, similar in the cat and in the patient, was atypical for aBSE-related condition. Evidence of a new type of FSE was further provided bythe detection of a type-1 PrPres, other than the BSE-associated type 4.2Taken together, our data suggest that the same agent strain of sporadic CJ was involved in the patient and in his cat. It is unknown whether these TSE occurred as the result of horizontaltransmission in either direction, infection from an unknown common source,or the chance occurrence of two sporadic forms. 1 Parchi P, Castellani R, Capellari S, et al. Molecular basis of phenotypicvariablity in sporadic Creutzfeldt-Jakob disease. ...end...TSS


24-nucleotide deletions in the prion gene: analysis of associated phenotypes Cervenakova, L, Brown, P,Piccardo, P, ... Gajdushek, DC, Goldfarb, LG in Transmisablle Subacute Spongiform Encephalopathies: Prion Diseases pp 433-444 L Court, B Dodet, editors. Elsevier, Paris 1996 Article notes by webmaster 20 Sept 1997 This is an interesting case where clinical, pathological, and immunocytochemical data strongly support the diagnosis of CJD in both husband and wife. The wife was the only caregiver during the husband's illness. The husband had died at age 54, after a 9 month illness of progressive mental and physical decline five years before the onset of clinical symptoms in his wife, who died at age 54, after subacute onset of agitation, confusion and mental slowness progressing to ataxic gait and myoclonic jerks, with severe gliosis and punctate prion imunoreactivity.

Genetically, the husband's prion gene was normal: no changes and homozygous methionine at codon 129. The wife had an R3/R4 deletion in one repeat region (a common polymorphism) and was also met/met. This allele may provide genetically determined susceptibility to environmentally CJD but is not normally causative.

The couple evidently lived in the US. The case record is consistent with horizontal transfer from husband to wife. There is no information provided as to occupation, dietary preferences, or travel history. Strain-typing was not reported -- however, this would not be expected to distinguish between horizontal transfer and common dietary exposure. Two unrelated cases of sporadic CJD at such early ages seems unlikely if the incidence is 250 cases per year in the entire US.



http://www.mad-cow.org/~tom/husband.html#in




NEUROLOGY 1998;50:684-688 © 1998 American Academy of Neurology

Creutzfeldt-Jakob disease in a husband and wife P. Brown, MD, L. Cervenáková, MD, L. McShane, PhD, L. G. Goldfarb, MD, K. Bishop, BS, F. Bastian, MD, J. Kirkpatrick, MD, P. Piccardo, MD, B. Ghetti, MD and D. C. Gajdusek, MD From the Laboratory of CNS Studies (Drs. Brown, Cervenáková, Goldfarb, and Gajdusek), NINDS, and Biometric Research Branch (Dr. McShane), NCI, National Institutes of Health, Bethesda, MD; the Department of Obstetrics (K. Bishop), Gynecology and Reproductive Sciences, University of Texas Houston Health Science Center, Houston, TX; the Department of Pathology (Dr. Bastian), University of South Alabama Medical Center, Mobile, AL; the Department of Pathology (Dr. Kirkpatrick), The Methodist Hospital, Houston, TX; and the Department of Pathology (Drs. Piccardo and Ghetti), Indiana University School of Medicine, Indianapolis, IN.

Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.

A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.

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

Received May 5, 1997. Accepted in final form September 10, 1997.



http://www.neurology.org/cgi/content/abstract/50/3/684




Q J Med 2000; 93: 617-631 © 2000 Association of Physicians

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Commentary papers

Is there evidence for exogenous risk factors in the aetiology and spread of Creutzfeldt-Jakob disease? C. E. M. Hillier and R. L. Salmon From the Welsh Combined Centres for Public Health, University of Wales College of Medicine, Cardiff, UK


snip...

Case-to-case transmission in humans: case reports and series in which spread through everyday human contact is suggested There are six reports in which this possible mode of transmission is considered. The most recent is that of a couple from the USA who had been married for 30 years.47 The husband died at age 53. He had no relevant family history, but had had a rotator cuff repair one year before disease onset. His wife developed symptoms four and half years after her husband's death. She was morbidly obese and had had a previous hysterectomy, hernia repair and cholecystectomy. Both occasionally ate brains in the form of ‘kizka’, a type of sausage.

Immunocytochemistry confirmed pathogenic prion protein deposition in brain tissue from both husband and wife. Full sequencing of the open reading frame of the PRNP failed to demonstrate any pathogenic mutations. Another suspected conjugal case has recently been shown not to be CJD. The histopathological specimens did not stain for prion protein despite the microscopic appearance of spongiform change.48

Sporadic CJD has been described in two co-workers who shared a school wing for 9 months.49 The first was a 48-year-old Californian-born man of Hispanic American descent who had had a traumatic leg amputation at age 23, but was otherwise well. The second was a 48-year-old Chilean-born male who had a blood transfusion 6 months before onset of symptoms, and was known to eat lambs' brains. The first patient developed symptoms 5 months after the last contact with his colleague and was confirmed to have spCJD 2 months after this. The second patient developed symptoms months later and died 9 months after the last contact with his colleague.

An English woman, who died of CJD, histologically confirmed at post mortem, was known to have contact with several affected members of a family with familial CJD and was related to them by marriage.39 She had known one of the family, who later died of CJD and had afternoon tea with her at family gatherings, twice a year, for 20 years, as well as visiting in her final illness. The woman herself died 12 years later. There is another similar case of probable CJD, reported in a Chilean woman who died 13 years after contact with a family with familial CJD. No details of contact are given. A third case of death from CJD in someone related in marriage to a family with familial CJD has been reported in France, in a Tunisian family. No details are given with regards to family history or contact.21 What is notable about these last three incidents of supposed infection by social contact is that all have occurred in association with familial CJD. Although these patients were not known to have been genetically related to their spouses, the possibility that they came from the same gene pool cannot be dismissed.




http://qjmed.oxfordjournals.org/cgi/content/full/93/9/617




Vol. 56 No. 12, December 1999

Mother With Amyotrophic Lateral Sclerosis and Daughter With Creutzfeldt-Jakob Disease

Bradford B. Worrall, MD; Lewis P. Rowland, MD; Maura Del Bene, RN; Dora Leung, MD; Steven S.-M. Chin, MD, PhD

Arch Neurol. 1999;56:1502-1504.

Objective To describe a mother who had autopsy-proved amyotrophic lateral sclerosis and her daughter who had clinically diagnosed Creutzfeldt-Jakob disease.

Design Case reports with molecular genetic analyses.

Setting A tertiary care center.

Patients The mother had progressive upper and lower motor neuron symptoms and signs starting at the age of 54 years. Electrophysiological testing supported the diagnosis of amyotrophic lateral sclerosis. Autopsy results confirmed the diagnosis. Her daughter had received injections of human growth hormone prepared from pooled human pituitary glands as a child. At the age of 31 years, she experienced the onset of gait ataxia and dysarthria. Cerebrospinal fluid showed the 14-3-3 protein. Cognitive difficulties ensued. She progressed to a nearly akinetic and mute state. She had overt visible fasciculations and muscle atrophy in the legs.

Main Outcome Measures and Results Neither patient carried a mutation in the prion protein gene. Both were homozygous for methionine at the polymorphic codon 129. Neither patient carried a deletion of the 5 exons of the superoxide dismutase 1 gene.

Conclusions It is uncertain whether the 2 cases occurred in the same family by chance or whether the patients shared genetic risk factors for the 2 diseases. The possibility that homozygosity at codon 129 is a risk factor for amyotrophic lateral sclerosis is being tested in a case-control study.

From the Departments of Neurology (Drs Worrall, Rowland, and Leung and Ms Del Bene) and Pathology (Dr Chin), Columbia University College of Physicians & Surgeons, New York, NY. Dr Worrall is now with the Department of Neurology, University of Virginia Health System, Charlottesville.



http://archneur.ama-assn.org/cgi/content/abstract/56/12/1502




FAMILIAL CREUTZFELDT-JAKOB DISEASE WITH TEMPORAL AND SPATIAL SEPARATION OF AFFECTED MEMBERS




http://www.jstor.org/pss/3520537




Original Article Gerstmann-Sträussler-Scheinker disease: Immunohistological and experimental studies Dr. June Tateishi, MD 1 *, Tetsuyuki Kitamoto, MD 1, Hideyuki Hashiguchi, MD 2, Hirofumi Shii, MD 2 1Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University 60, Fukuoka 812, Japan 2Department of Neurology, Kokura Kinen Hospital, Kitakyushu 802, Japan

*Correspondence to June Tateishi, Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University 60, Fukuoka 812, Japan

Abstract The older brother of the patient from whom the Fukuoka-l strain was isolated was found to have numerous kuru plaques, the main finding common to both siblings. Other clinicopathological features including spongiform change were absent in the older brother. Immunostaining using anti-kuru plaque core protein and anti--protein peptide revealed many kuru plaques and a few senile plaques in the older brother. Experimental transmission of the disease to laboratory animals was successful, using tissues from both siblings, through inoculation of fresh brain homogenates, purified prion protein, and formalin-fixed brain homogenates. Prion protein fractions from the patient's brain shortened the incubation periods and formalin-fixed mouse brains did not lengthen the periods. The disease in the two brothers can be classified as Gerstmann-Sträussler-Scheinker disease, a familial variant of Creutzfeldt-Jakob disease. Gerstmann-Sträussler-Scheinker disease manifests a variety of clinicopathological features. Immunohistological verification of kuru plaques has major diagnostic value in assessing dementia.

-------------------------------------------------------------------------------- Received: 30 November 1987; Revised: 20 January 1988; Accepted: 23 January 1988 Digital Object Identifier (DOI)




http://www3.interscience.wiley.com/journal/109678254/abstract




TSS


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518