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.
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
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.
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I wish to submit the following ;
HUMAN and ANIMAL TSE Classifications i.e. mad cowdisease and the UKBSEnvCJD only theory
Tuesday, August 19, 2008
Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate
Sunday, August 10, 2008
A New Prionopathy OR more of the same old BSe and sporadic CJD
Friday, August 22, 2008
Creutzfeldt Jakob Disease and Veterans and how they are treated at death
August 19, 2008, Publish Ahead of Print:
First Report of Creutzfeldt-Jakob Disease Occurring in 2 Siblings Unexplained by PRNP Mutation.
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
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:firstname.lastname@example.org
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).
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.
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.
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.
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.
Q J Med 2000; 93: 617-631 © 2000 Association of Physicians
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
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.
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.
FAMILIAL CREUTZFELDT-JAKOB DISEASE WITH TEMPORAL AND SPATIAL SEPARATION OF AFFECTED MEMBERS
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)
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518