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CREUTZFELDT-JACOB DISEASE AND OTHER PRION DISEASES

CREUTZFELDT-JACOB DISEASE AND OTHER PRION DISEASES. Killian O’Rourke Dept. of Neurology CUH. PRION DISEASES-ANIMAL. Scrapie(sheep and goats) Transmissible mink encephalopathy Wasting disease of deer and elk

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CREUTZFELDT-JACOB DISEASE AND OTHER PRION DISEASES

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  1. CREUTZFELDT-JACOB DISEASE AND OTHER PRION DISEASES Killian O’Rourke Dept. of Neurology CUH

  2. PRION DISEASES-ANIMAL • Scrapie(sheep and goats) • Transmissible mink encephalopathy • Wasting disease of deer and elk • Bovine spongiform encephalopathy • Transmissible spongiform encephalopathy of captive wild ruminants • Feline spongiform encephalopathy

  3. PRION DISEASES-HUMAN • Kuru • Sporadic Creutzfeldt-Jacob disease • Familial Creutzfeldt-Jacob disease • Gerstmann-Straussler-Scheinker disease • Familial fatal insomnia • New variant Creutzfeldt-Jacob disease

  4. Nature of Prions • Prusiner:”a small proteinaceous infectious particle which is resistant to most proceedures that modify nucleic acids”1982 • A proteinase-resistant isoform of a normal host cellular protein accumulates in neural cells,leading to vacuolization and cell death

  5. Genetics • Prusiner 1993: “Knockout”mice lacking the gene for PrP cannot be infected with scrapie • Prusiner 1996: Studies in “transgenic”mice indicated that mutations in the gene coding for PrP or overexpression of the gene can lead to spongiform changes

  6. Pathogenesis- experimental observations Lambs in scrapie infected flocks:infectivity in intestines/lymphatics at one year and brain at two years Mice inoculated subcutaneously:infectivity in spleen/lymphatics then brain Infectivity found in blood in experimentally infected rodents Mice inoculated intraperitoneally:differentiated B-cells important for CNS invasion Mice inoculated in limbs:scrapie travels along nerves to CNS

  7. Sporadic CJD-NOT a communicable disease • Incidence 1/1000,000 • Worldwide • No clustering except for familial cases • No relation to scrapie prevalence(UK versus New Zealand) • No relation to diet(brain/offal versus lifelong vegetarianism) • No relation to occupation (surgeons,pathologists,cooks,abbatoir workers,butchers) • No evidence of transplacental spread

  8. Sporadic CJD-clinical features • Dementia100% • Myoclonus 80% • Pyramidal signs 50% • Cerebellar signs 50% • Extrapyramidal signs 50% • Less common:cortical visual defects,LMNL,abnormal extraocular movt.,sensory defects,seizures,vestibular disturbance,autonomic dysfunction • Mean survival five months

  9. Sporadic CJD-investigations • EEG:characteristic periodic sharp-wave complexes superimposed on slow background rhythm present in>90% • MRI: T2 hyperintense signal in basal ganglia in 80% • CSF:Elevated levels of protein 14-3-3 without pleocytosis in 96%

  10. Iatrogenic CJD-surgical 1974 report of disease eighteen months post corneal transplant from CJD donor • More than 80 cases recognised sixteen months to seventeen years post neurosurgical placement of grafts of human cadaveric dura mater(common source) • Contaminated neurosurgical instruments also implicated

  11. Iatrogenic CJD-pituitary hormones • 1985 report of CJD developing in recipients of growth hormone derived from pooled human cadaveric pituitary glands given four to fifteen years previously • More than 100 cases worldwide(0.2% in USA,1% in UK,2.5% in France with corresponding length of incubation 8-18 years) • Cerebellar and basal ganglia disease precedes dementia-?related to age of exposure or route of inoculation

  12. Iatrogenic CJD-blood products • No increased risk in IVDA • Tracking of blood donated by those in whom CJD subsequently develops has not shown an increased risk in recipients • Transfusion to primates from patients with CJD shows no increased risk • Several reports of disease in mice inoculated intracerebrally with blood from CJD patients • FDA mandates withdrawal of blood products donated by patients in whom CJD develops be withdrawn but not recipient notification

  13. Familial CJD • 10-15% autosomal dominant • Earlier onset,more protracted course • EEG findings and protein 14-3-3 often absent • More than 20 mutations in gene for PrP on chromosome 20 identified;codon 200 mutation explains disease clusters • Genetic testing possible but issues of pre-symptomatic testing of relatives are analagous to Huntington’s disease-counselling essential

  14. Gerstmann-Straussler-Scheinker disease • Autosomal dominant mutation in PrP gene,usually codon 102 • Cerebellar ataxia and spastic paraparesis +/ myoclonus with dementia appearing late • Mean age at death 48 • Neuropathology:many PrP+ amyloid plaques

  15. Fatal familial insomnia • Mutation in PrP gene at codon 178 • Progressive insomnia,dysautonomia and dementia leading to death in 7 to 15 months • Neuropathology:selective atrophy of the thalamic nuclei including spongiform changes in some patients and staining for PrP

  16. Bovine Spongiform Encephalopathy and CJD • 1985 “Mad-Cow disease” reported in UK • Neuropathological changes included spongiform lesions with gliosis and neuronal loss resembling scrapie • No. of cases increased to 36,000 in 1992 • Data indicative of an epidemic with a common source-assumed source the addition of material from scrapie infected sheep to cow diet • Spread further by addition of material from infected cows to cattle feed

  17. BSE and CJD-continued • BSE has been experimentally transmitted to a variety of species including laboratory rodents and nonhuman primates including orally to some species • BANS:1988 feeding of ruminant derived protein to ruminants in UK 1989 cattle offal banned from human food in UK;450,000 infected cattle already in food chain 1997 sale of meat on the bone banned in UK

  18. “New variant” CJD(1994) • National surveillanve unit for CJD 1990 in UK • All had eaten meat;prior to 1989 processed meat often included brain and spinal cord • Oral intake of meat products contaminated with BSE before the ban in 1989 or an artifact of intense surveillance?

  19. NVCJD CJD

  20. Evidence for BSE-NVCJD link • Glycosylation patterns of PrP in NVCJD and BSE are similar and distinct from sporadic and iatrogenic disease • Similarity in distribution of lesions in NVCJD and BSE also suspicious-distinct from sporadic CJD • Evidence of common origin of causative agents,not direct proof that humans were infected by eating bovine nervous tissue

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