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A. Prion Proteins navigator

  1. Prions are infectious proteins devoid of nucleic acids
  2. Prions reproduce by converting normal cellular prion protein, PrP(C), to scrapie isoform, PrP(Sc)
  3. Normal PrP(C) Protein
    1. PrP derives from a gene on chromosome 20 called PRNP (prion protein gene)
    2. PrP gene codes for a 33-35K protein, normal housekeeping gene
    3. High levels in neurons; likely involved in neuronal copper metabolism, synaptic transmission
    4. Normal PrP protein, called PrP(C) is found in uninfected brain
    5. PrP(C) consists primarily of alpha-helical structures with little ß-sheet
    6. Normal PrP is cell membrane linked through GPI and can be severed at GPI linkage
    7. PrP(C) has properties typical of most proteins: sensitive to proteases and detergents
    8. PrP knockout mice grow and reproduce, but develop age related progressive ataxia
    9. PrP deficient mice have abnormal circadian rhythms and do not develop scrapie
    10. Dominant negative alleles (mainly Japanese) of PRNP have lysine at codon 219
    11. These K219 PrP interfere with conversion of PrP(C) to PrP(Sc)
    12. PrP is polymorphic at codon 129, where methionine (M) or valine (V) can be encoded
    13. The M polymorphism appears to confer increased risk for disease [5]
  4. Pathogenic PrP Protein
    1. Normal and pathogenic PrP have same amino acid sequence; both are glycosylated
    2. Pathogenic forms of PrP, called PrP(Sc), named after original isolate from Scrapie
    3. PrP(Sc) protein accumulates in brain of infected persons and causes disease
    4. PrP(Sc) is proteinase K resistant and insoluble in nondenaturing detergent
    5. PrP(Sc) is also resistant to GPI linkage severing
    6. PrP(Sc) is primarily ß-sheet, with little alpha-helix
    7. PrP(Sc) is also designated PrP(res) for resistance to proteases
  5. Unique Properties of Prions [1]
    1. Prions are the only known infectious pathogens devoid of nucleic acid
    2. Prion diseases may be manifested as infectious, genetic or sporadic disorders
    3. Prion diseases result from accumulation of PrP(Sc)
    4. PrP(Sc) can hae a variety of conformations, each associated with a specific disease
    5. Prions are highly resistant to disinfection, require very harsh conditions [19]
  6. Prion diseases are also called transmissible spongiform encephalopathies (TSE)

B. Spongiform Encephalopathies navigator

  1. Spongiform refers to lack of inflammation and presence of vacuolation of nervous tissue
  2. Characteristics
    1. All are prion diseases, or at least involve unusual protein-containing particles
    2. Progressive disorders with mainly neurological dysfunction
    3. Spongiform (vacuolar) degeneration and variable amyloid plaque formation
    4. These diseases also considered transmissible amyloidoses
  3. Types of TSE
    1. Sporadic
    2. Iatrogenic
    3. Familial
  4. TSE Diseases
    1. Classic and Variant Creutzfeldt-Jacob Disease (CJD)
    2. Gerstmann-Straussler-Scheinker syndrome
    3. Fatal familial insomnia
    4. Kuru
  5. Symptoms
    1. All infect the cerebellar hemispheres ± other parts of the CNS
    2. Progressive dementia occurs in most of the cases
    3. Stroke-like symptoms can occur, particularly in PML
    4. Headaches and low grade fevers may also occur
  6. Kuru [16]
    1. Occurred in isolated populations in highlands of New Guinea (South Fore region)
    2. Cerebellar ataxia, progressive motor incapacity, dysarthria, and death
    3. Linked to preparing brain of dead persons for cannibalistic consumption
    4. Kuru means "trembling with fear"
    5. Incidence has fallen dramatically since cannabilism has stopped
    6. May be identical to CJD
    7. Minimal incubation periods are 31-44 years, longer in men (39-56 years)
    8. Most patients with kuru heterozygous PRNP codon 129
    9. From 1996-2004, 11 patients identified all from New Guinea
  7. Scrapie
    1. Best studied of these rare diseases, occurs in sheep
    2. Can be passaged to other species, with increasingly short incubation times
  8. Decontamination Methods [1]
    1. Resistant to usual methods of decontamination
    2. The following reduce infectivity:
    3. Autoclaving at 134°C for at 18 minutes in porous load device
    4. Autoclaving at standard temperature for at 1 hour
    5. Soaking instruments in 1M (1mol/L) sodium hydroxide or >5000 parts per million available chlorine sodium hypochlorite for 1 hour
    6. Resins which absorb prion proteins and reduce infectivity have been developed for treatment of blood products [21]

C. Creutzfeldt-Jacob Diseases (CJD) [1,3,4]navigator

  1. Rapidly evolving confusion, dementia with myoclonus, unsteady gate
    1. Infectious form - usually iatrogenic
    2. Familial form (~14%) - insertions into region between codons 51 and 91 in PRNP gene
    3. Sporadic form (~86%) - mutations at codon 129 (also found in familial form)
    4. Sporadic CJD accounts for ~85% of all prion disease in humans
  2. Incidence is worldwide about ~1 per million persons per year
    1. Rapid progression of disease with death in 3-12 months
    2. About 5% of patients will live >2 years
    3. Mean age of patients with typical CJD is ~60 (50-75) years old
    4. Mean age of patients with variant CJD is younger (<50 years)
    5. Worldwide, CJD accounts for >85% of prion disease
  3. Variant CJD (vCJD) [5,6,7,8]
    1. BSE from cattle can cause a CJD-like illness in humans
    2. Early psychiatric symptoms, most often depression, are prominant
    3. Eight of 14 patients developed early sensory symptoms, often persistent and painful
    4. Agent is transmissible with blood transfusion
    5. In UK, 3 of 66 exposed persons have developed vCJD within 6 years of transfusion [5]
    6. Persons with MM genotype in PRP appear to be at higher risk for developing vCJD
    7. Neurological signs (ataxia, involuntary movements), developed in all cases
    8. MRI shows bilateral high intensity T2 or proton density in posterior thalamus (pulvinar) [9]
    9. EEG abnormal in most patients, but typical periodic complexes of CJD are not seen
    10. Mice infected with human brains from NV-CJD show BSE signatures [10]
  4. Iatrogenic CJD [1]
    1. Very uncommon case-to-case horizontal transmission
    2. Neurosurgery
    3. Corneal graft
    4. Human dura matter implantation
    5. Contaminated brain-derived hormones
    6. Stereotactic electroencephalography electrodes
    7. Blood transfusion (vCJD, see above)
    8. Exposure to symptoms as little as 16 months up to 30 years
  5. Prion Proteins in CJD [10]
    1. Four major abnormal types of PrP, called PrP(sc), are found in CJD
    2. Types 1-3 PrP(sc) are found in all cases of sporadic and iatrogenic CJD
    3. All cases of variant CJD are associated with a distinctive type 4 PrP(sc)
    4. Methionine homozygosity at codon 129 of PrP occurs in ~70% of sporadic CJD [11,20]
    5. Valine 129 substitution with D178N mutation leads to familial CJD
    6. All forms of CJD associated with transition of PrP(c) alpha helical structure to the PrP(sc) beta-pleated sheats which form amyloid-like bodies
    7. Detectable in olfactory biopsy material in living persons [17]
    8. Pathologic prion proteins detectable in spleen and muscle samples from ~33% sporadic CJD [18]
  6. Diagnosis
    1. Symptoms are usually classical dementia - myoclonus complex
    2. MRI is very helpful only late in course, showing bilateral cortical atrophy
    3. Hyperintense grey matter signal in cortex, basal ganglia, thalamus or combination (T2)
    4. Regions are not enhanced with gadolinium, and T1 weighting not helpful
    5. Standard CSF analyses are usually within normal limits
    6. PrP reactive proteins (especially 14-3-3 and tau) have been found at autopsy
    7. PrP proteins are detectable in olfactory biopsies in living persons with CJD [17]
    8. Olfactory biopsy may provide a rapid method for detection in living persons
    9. Variant CJD can be detected by antibody staining of PrP(sc) Type 4 in tonsils [12]
    10. EEG (electroencephalogram) characteristic complexes
  7. Histopathology
    1. Spongiform degeneration and marked astrocytic gliosis
    2. Vacuolization of neuropil in gray matter
    3. ~10% of cases have amyloid deposits which include PrP(Sc)
    4. Variant CJD has florid plaques composed of PrP(Sc) amyloid core surrounded by vacuoles
    5. PrP(sc) detectable in spleen and muscle samples from ~33% sporadic CJD [18]
  8. Cerebrospinal Fluid (CSF) Analysis
    1. The 14-3-3 brain protein is found elevated in CSF in ~50% of CJD [12,13]
    2. Protein 14-3-3 should only be assayed for in patients with dementia
    3. Protein 14-3-3 levels in CSF are lower in patients with variant CJD (BSE relative)
    4. Tau protein in CSF may be more useful marker, positive in >50% of patients
  9. High T2 MRI signal in posterior thalamus present in ~75% of variant CJD patients
  10. Prognosis
    1. Begins focally and then spreads to entire brain
    2. Involvement of multiple and rapidly fatal course is the rule
    3. Interval between onset and death: mean 8 months, median 4.5 months
    4. No current therapies

D. Bovine Spongioform Encephalopathy (BSE) [1,2,5]navigator

  1. Also called "Mad Cow Disease"
  2. Epidemic occurred in Britain and agent may have been transmitted to humans
  3. Up to 100 cases with a CJD-like illness have been analyzed
  4. Brain homogenates from patients with "New Variant" CJD have been passaged to mice
  5. Initial data suggest that BSE is in fact transmitted to mice from New Variant CJD
  6. Very likely that BSE is responsible for New Variant CJD
  7. Current Theory on BSE Origin [5]
    1. BSA may have been acquired from human transmissible spongiform encephalopathy
    2. Route of infection may have been oral, through animal feed containing mamilian materials
    3. Origin may have been on the Indian subcontinent (human remains incorporated into meals)

E. Gerstmann-Straussler-Scheinker Diseasenavigator

  1. Inherited autosomal dominant illness
  2. At least 8 distinct mutations in PRNP gene have been identified
  3. Mutation P102L was initial description and is most common, ~40% of cases
  4. Spinocerebellar ataxia with dementia
  5. Dense core of amyloid deposits surrounded by smaller globules of amyloid
  6. Usual onset of disease at 5th decade

F. Fatal Familial Isomnianavigator

  1. Very rare, fatal, progressive neurological disease
  2. Intractable insomnia with other autonomic anomalies
  3. Cerebellar and pyramidal signs
  4. Myoclonus and dementia
  5. Monogenic Disease of Known Cause
    1. Majority of patients have PrP mutation in single allele at codon 178 of PRNP gene
    2. This mutation substitutes asparagine for the normal PrP aspartic acid (D178N)
    3. FFI requires that a methionine occur at codon 129, which is polymorphic (M129)
    4. Sporadic version of FFI can occur with methionine at 129 without D178N [15]
  6. Pathology
    1. Severe neuronal loss with gliosis (reaction) in ventral and mediodorsal thalamic nuclei
    2. Low levels of proteinase resistant amyloid protein (PrP) in the brain
  7. Disease has been transmitted to animals
  8. Member of infectious cerebral amyloidoses

G. "Slow" Virus CNS Infections navigator

  1. Considered in differential diagnosis of spongiform encephalopathy
  2. Subacute sclerosing panencephalitis (SSPE)
  3. Progressive multifocal leukoencephalopathy (PML)
  4. Progressive rubella enceaphlitis
  5. Tropical spastic paraparesis (HTLV-1 Myelopathy)
  6. HIV Encephalopathy
  7. Persistent infection in immunodeficient patients

References navigator

  1. Collins SJ, Lawon VA, Masters CL. 2004. Lancet. 363(9402):51 abstract
  2. Prusiner SB. 2001. NEJM. 344(20):1516 abstract
  3. Johnson RT, Gonzalez RG, Frosch MP. 2005. NEJM. 353(10):1042 (Case Record) abstract
  4. Shinobu LA and Frosch MP. 1999. NEJM. 341(12):901 (Case Record)
  5. Wine SJ, Pal S, Siddique D, et al. 2006. Lancet. 368(9552):2061 abstract
  6. Zeidler M, Stewart GE, Barraclough CR, et al. 1997. Lancet. 350(9082):903 abstract
  7. Zeidler M, Johnstone EC, Bamber RW, et al. 1997. Lancet. 350(9082):908 abstract
  8. Collinge J. 1999. Lancet. 354(9175):317 abstract
  9. Zeidler M, Sellar RJ, Collie DA, et al. 2000. Lancet. 355(9213):1412 abstract
  10. Hill AF, Butterworth RJ, Joiner S, et al. 1999. Lancet. 353(9148):183 abstract
  11. Alperovitch A, Zerr I, Pocchiari M, et al. 1999. Lancet. 353(9165):1673 abstract
  12. Hsich G, Kenney K, Gibbs CJ Jr, et al. 1996. NEJM. 335(13):924 abstract
  13. Zerr I, Bodemer M, Otto M, et al. 1996. Lancet. 348:846 abstract
  14. Colchester ACF and Colchester NTH. 2005. Lancet. 366(9488):781 abstract
  15. Mastrianni JA, Nixon R, Layzer R, et al. 1999. NEJM. 340(21):1630 abstract
  16. Collinge J, Whitfield J, McKintosh E, et al. 2006. Lancet. 367(9528):2068 abstract
  17. Zanusso G, Ferrari S, Cardone F, et al. 2003. NEJM. 348(8):711 abstract
  18. Glatzel M, Abela E, Maissen M, Aguzzi A. 2003. NEJM. 349(19):1812 abstract
  19. Fichet G, Comoy E, Duval C, et al. 2004. Lancet. 364(9433):521 abstract
  20. Johnson RT, Gonzalez G, Frosch MP. 2005. NEJM. 353(10):1042 (Case Record) abstract
  21. Gregori L, Gurgel PV, Lthrop JT, et al. 2006. Lancet. 368(9554):2226 abstract