Prion diseases ---kuru

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Prion diseases ---kuru

  1. 1. PRION DISEASES DR SRIRAMA ANJANEYULU RESIDENT,NEUROLOGY KING GEORGE HOSPITAL,VIZAG
  2. 2. INTRODUCTION • Prions-infectious proteins causing degenerative CNS disease. • Rapidly progressing dementia. • Myoclonus. • Death. • 50-75 yrs(17-93).
  3. 3. PRION STRUCTURE
  4. 4. PRION CONCEPTS • Infectious pathogens devoid of nucleic acid. • Manifest s as infectious ,genetic and sporadic. • Prion diseases results from accumalution of PrP sc which differs from its precursor Pr P c. • PrP sc exists in different conformations- disease phenotype.
  5. 5. SPECTRUM
  6. 6. EPIDEMIOLOGY • Sporadic-85% • Inherited-15% • Infectious-<1% • World wide-1 in mn population.
  7. 7. PRION TERMINOLOGY
  8. 8. PRION PROTEIN ISOFORMS
  9. 9. PATHOGENESIS • Limited proteolysis of Pr P sc----PrP 27-30 (smaller protease resitant ). • Polymerizes into amyloid. • Deposition of Prion rods and amyloid filaments.
  10. 10. SPORADIC AND INHERITED PRION Initiation of prion disease • Somatic mutation. • Crossing of activation barrier. • PrP sc may present at lower levels in normal cells with unknown function. • Imbalance between production and clearing Pr P sc.
  11. 11. SPECIES BARRIER • Transmission between species is less efficient . • Differences in amino acid sequences of PrP c. • 28 between human-mouse. • 2 between human chimpanzee. • Complex interactions with prion associated proteins- protein X .
  12. 12. INFECTIOUS PRION Iatrogenic CJD. • Corneal transplants. • Contaminated EEG electrodes. • Surgical procedures. • hGH ,gonadotropins. Variant CJD. • Consumption of contaminated beef.
  13. 13. NEUROPATHOLOGY • Vacuolar changes in grey matter. • Spongiform degeneration and astrocytic gliosis and lack of an inflammatory response. • Vacuoles are 5-25 micro m ( cross sections of swollen dendritic and axonal process). • Spongiform changes –cerebral cortex,putamen,thalamus and molecular layer of cerebellum.(sporadic,familial,iotrogenic) • Heidenhein- visual cortex • Brownell-Oppenheimer- cerebellar • Stern –Garcin- basal ganglia and thalmus • V CJD –florid plaques. highest spongiosis. • GSS-severe amyloidosis. • FFI-neuronal loss and atrophy of AV&MD thalamus ,spongiosis of cerebral cortex. • Kuru-highest neuronal dropout in cerebellum followed by medial temporal lobe,basal ganglia and thalmus.
  14. 14. CLINICAL FEATURES SPORADIC CJD • 45-75 yrs,mean-67 yrs. • Core features-rapidly progressive multidomain dementia with myoclonus. • Addl.features-cerebellar ataxia,extra pyramidal signs,pyramidal signs and cortical blindness. • Clinical course-days-yrs,avg-7 months. • Type 1 banding----20-21 KDa . • Type 2---------------18-19 KDa . • Six subclasses depending on M/V genotype at 129 codon.{MM1,MV1(most common types), VV1,MM2,MV2,VV2}.
  15. 15. CJD IATROGENIC CJD- • IP- 6-7 yrs. FAMILIAL CJD- • AD,variable penetrance,early onset ,slow progression,F/H +. VARIANT CJD- • Transmission of BSE to humans. • Mean age of death-29 yrs.psychiatric symptoms (anxiety ,depression and withdrawal), rarely psychosis. • Dementia,ataxia,chorea,dystonia and myoclonus follows.
  16. 16. DIAGNOSTIC CRITERIA
  17. 17. GERSTMANN-STRUSSLER-SCHEINKER SYNDROME • Slowest inherited prion disease,ataxia,dysarthria followed by dementia. • Parkinsonism features . • Gaze palsy,deafness,cortical blindness,extensor plantar. • Myoclonus rare. • Early age, slow progression. • Difficult differentiate from SCA,MSA,early PD. • Analysis for mutations in PRNP gene definite diagnosis.
  18. 18. FFI &sFI • Age of onset-20-72.avg-49 yrs. • Course—6 months to 3 yrs. • Progressive intractable insomnia and symptoms of sympathetic overactivity . • HTN,tachycardia,hyperthermia,hyperhydrosis. • Tremor ,ataxia,hyperreflexia and myoclonus. • Dementia –mild . • Disorientation,confusion ,complex hallucinations. • Endocrine abnormalities.PRL,ACTH,GH.
  19. 19. KURU • Kuru-fore language-trembling associated with fear or cold. • Women and children of fore people of New Guinea. • Ritualistic cannibalism. • Progressive cerebellar ataxia. • 3 phases. • 1-initial phase-ambulant with minimal truncal ataxia,dysarthria and tremor. • 2-sedentary phase-loss of ambulation due to ataxia choreoathetosis,worsening of tremor and mood instability. • 3-terminal phase-generalized hyperreflexia,progression of dysarthria and dysphagia. • Muscle strength and sensorium normal. • Down hill course within 12 months from onset.
  20. 20. DIAGNOSIS • Brain biopsy histology with western blot analysis of proteinase K treated brain homogenate. • iqPCR as one of the choice methods for PrPres detection in brain surgical biopsy and autopsy specimens. • CSF ---14-3-3 protein and tau protein. • Sensitivity 94% and specificity ---93% in s CJD. • Less sensitive in v CJD&f CJD, rarely elevated in GSS,not in FFI. • False positive in acute stroke,MS,encephalitis,AD.FTD,HAD.
  21. 21. DIFFERENTIALS • AD. • FTD. • CBD. • DLB. • Thyroid. • Syphilis. • B12 def. • Lymphoma,meningitis and encephalitis (HSV)
  22. 22. CARE OF CJD PTS • Although CJD should not be considered either a contagious or communicable disease, it is transmissible. • The risk of accidental inoculation by aerosols is very small. • Procedures producing aerosols should be performed in certified biosafety cabinets. • Inadvertent infection of health care workers by needle and stab wounds.
  23. 23. DECONTAMINATION • Autoclaving at 132C for 5 h or treatment with 2 N NaOH for several hours is recommended for sterilization of prions. • Treating CJD-contaminated materials once with 1 N NaOH at room temperature, this procedure may be inadequate.
  24. 24. TREATMENT • Antipsychotics,BZD,L-dopa,amantadine. • Congo red ,amphoterecin B - tired,found ineffective. • Quinacrine under clinical trials. • Short peptide homologs to Pr P c to interact with PrP sc and act as beta sheet breakers. • Drugs inhibiting conversion . • Splenectomy –prolong incubation period. • Immunization with recombinant Pr P.
  25. 25. Thank you

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