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Transmissible
Spongiform Encephalopathies Transmissible
Neurodegenerative Diseases Prion
Diseases 05 November 2004 CATEGORIES
ANIMAL DISEASE Scrapie (sheep & goats) Transmissible mink encephalopathy Wasting disease of deer & elk Bovine spongiform encephalopathy Transmissible spongiform encephalopathy of captive wild ruminants Feline spongiform encephalopathy Spongiform disease of ungulates (nyala, gemsbok, Arabian orynx, greater kudu, Rocky Mountain elk, captive mule deer) HUMAN DISEASES Sporadic Creutzfeldt Jakob disease Familial Creutzfeldt Jakob disease New variant Creutzfeldt Jakob disease Gerstmann Straussler Scheinker disease Fatal Familial Insomnia Kuru
Evolution
in understanding prion diseases Prion: Transmissible pathogen Proteinaceous infectious particle Devoid of nucleic acid Resist enzymes that destroy RNA & DNA Inactivated by treatment that destroys proteins (autoclave, pH) Prion protein (PrP) encoded on Chr 20p PrPsen or PrPc: isoform of protease sensitive normal host cellular protein PrPres or PrPsc: protease resistant protein associated with disease PrP
gene
ฎ
PrPc
PrP
gene
ฎ
PrPc
(posttranslationalฎmodification)
PrPsc
(a
helix)
(b
pleated sheet) PrP gene influences the phenotype Natural role of prion protein not known Mice with knockout prion gene never develop spongiform encephalopathy despite repeated inoculations. Scrapie present in UK for 300 years. 1920: original description Creutzfeldt Jakob disease 1936: (Cuille & Chelle) transmission from sheep to sheep; intraocular administration of scrapie infected spinal cord to goat 1966: (Gajdusek): transmissible to chimpanzees 1968: (Gibbs) disease is transmissible to chimpanzees from human CJD brain tissue species barrier crossed in mink, deer , elk, cats & captive wild ruminants CJD brain reacts against antiserum to a similar fraction made from scrapie infected hamster brain
Sporadic
Creutzfeldt Jakob disease Incidence: 1/1,000,000/year Equal sex distribution PRODROME Fatigue, depression Weight loss Disorder of sleep & appetite EARLY Changes in behavior, emotional response, intellectual function Subacute dementia Visual hallucinations Dysarthria Hemiparesis Alien hand syndrome Cerebellar ataxia (Brownell Oppenheimer variant) Visual disturbances (Heidenhain variant) Thalamic (Stern) Striatal (Garcin) LATE Myoclonic jerking / polymyoclonus Excess startle response Akinetic mutism Mean survival time: 5 months Survival time from onset of characteristic EEG: 8 weeks
INVESTIGATIONS PATHOLOGY LM, EM & immunostaining are gold standards Predominantly cerebral & cerebellar cortices Degeneration of nerve cells with replacement by extensive astroglial proliferation Vacuoles in cytoplasmic processes of glial cells & dendrites of nerve cells causing spongiform appearance CSF: enolase > 35ng/ml (80% Sensitive, 92% specific) 2dD gel electrophoresis (not practical) brain protein 14-3-3 (Sensitivity 96%, specificity 99% also seen in encephalitis, stroke) S100 >213pg/ml (Sensitivity 78%, specificity 80%) TONSILLAR BIOPSY Not useful EEG Sensitivity 90% specificity 90% Early: diffuse nonspecific slowing Late: periodic stereotypical slow & sharp wave complexes with slow, low voltage background. (time to death average is 8 weeks) MRI: T2 hyperintensitiy in basal ganglia (sensitivity 80%) GENETIC TESTING: ?risk profiling Differential
Diagnosis Lithium intoxication Metabolic encephalopathy Angiocentric lymphoma Meningitis carcinomotosa SSPE Limbic brainstem cerebellar encephalitis (paraneoplastic, AIDS) Neurosyphilis Infection
control Autoclave at 1340C for 1 hr 5% sodium hypochlorite for 1 hr
Iatrogenic
Creutzfeldt Jakob disease Risk factors: Corneal transplant Operative EEG electrodes Dura grafts Human growth hormones Human gonadotropins Mean incubation period 15 years Begins with cerebellar ataxia & movement disorders Late dementia Pathology in cerebellum & basal ganglia with notable plaques EEG: no classical changes Familial Creutzfeldt Jakob disease
10 % CJD Incidence: 1/10,000,000/yr Autosomal dominant Various mutations especially codon 200 for Libyan Jews Earlier age of onset More protracted course EEG: no classical changes CSF: brain protein 14-3-3 only 50% sensitivity
Single base pair changes of prion protein
Polymorphisms at codon 129 that may influence susceptibility to or phenotype of disease.
Coding alterations in octarepeat segment.
Bovine spongiform encephalopathy 1980: change in rendering process continuous instead of batch heating i.e. shorter time & lower temperatures hydrocarbon solvents not used in processing (because of oil crisis, decline in tallow market) 1985: increasing incidence of mad cows apprehensive then aggressive behavior with ataxia leading to falls brain pathology similar to scrapie diet supplemented by meat & bone meal
1988: statutory ban on feeding ruminant derived protein to ruminants 1989: cattle offal banned from human food 1997: meat on bone banned to stop contamination by dorsal root ganglia New
variant Creutzfeldt Jakob disease From 1994 new cases of unusual CJD Younger patients Prominent early psychiatric & behavioral manifestations e.g. depression Persistent paresthesia & dysesthesia 100% cerebellar ataxia EEG: no classical changes Pathology: prominent & diffuse PrPsc plaques Homozygous for Met at codon 129 All patients had eaten meat Association between BSE & nvCJD Nv CJD started appearing 10 years after BSE first identified (typical incubation period) Glycosylation patterns of PrPsc similiar in brains of nvCJD & BSE; distinct from sporadic & iatrogenic BSE & nvCJD brain tissue inoculated into cynomolgous monkeys causes identical spongiform neuropathology BSE transmits to hamsters only after passage through mice. Bovine derived products: catgut sutures, vaccines, implants (e.g. bullectomy), gelatin Issues Scrapie infected sheep has never been shown to be a cause of CJD; but BSE and scrapie are essentially the same disease, why BSE products are infectious for humans but not scrapie infected products. BSE products consumed equally amongst all age groups, why predominance in the young.
Meat
& milk from animals with BSE or scrapie are consistently without
demonstrable infectivity by most sensitive bioassay.
Species to species transmission of transmissible spongiform encephalopathies.
Comparison of new variant CJD aginst sporadic CJD.
Comparison of nvCJD versus sporadic CJD.
Confirmed cases of BSE by month and year of clinical onset in Great Britain from 1986 -1996.
Relative degree of infectivity of tissue types.
Gerstmann
Straussler Scheinker disease Rare, autosomal dominant Incidence: 1/30,000,000/year Begins midlife Most common mutation at codon 102 Chronic course (average 8 years) Progressive cerebellar ataxia Spastic paraparesis Dysarthrias Nystagmus Mild dementia EEG: no classical changes Mutations of PrP gene characterized Transmissible to chimpanzees (masters) Pathology: prominent plaques Fatal Familial Insomnia Very rare, autosomal dominant 11 kindred in the world Most common mutation at codon 178 (phenotype determined by codon 129) Average age of onset 48 years Intractable insomnia Sympathetic overactivity (hyperhidrosis, hyperthermia, tachycardia, hypertension) Endocrine disturbance Motor abnormalities: ataxia, myoclonus, spasticity, hyperreflexia, dysarthria Late dementia Onset to death is 1 year EEG: no classical changes Medial thalamic nuclei predominantly affected Not transmissible to chimpanzees (Compton strain)
Kuru
(shaking) Fore linguistic of Papua New Guinea highlands Initially, headache & arthralgia Afebrile, progressive cerebellar ataxia; intention tremor Abnormal extraocular movements Weakness progressing to immobility Incontinence in late stages Death within 3-6 mths onset EEG: no classical changes CSF: normal (no studies with brain protein 14-3-3) Increased incidence of codon 129 mutation 1966: (Gajdusek): transmissible to chimpanzees Loss of neurons predominantly in cerebellar cortex Kuru plaques: PAS positive stellate plaques of amyloid like material Transmission in humans by cannibalism & rubbing of victims materials over the body with absorption through conjunctivae, mucous membranes, skin abrasions.
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