Prion Diseases Flashcards
Prion Disorders
definition
Prion diseases are neurodegenerative disorders caused by mutations and conformational changes of a normal cellular protein PrPC (prion protein). These are also known as “transmissible spongiform encephalopathies”. The function of the normal protein is incompletely understood but it may function as a signal transducer and help to regulate cleavage of amyloid precursor protein. Originally identified in scapie, the abnormal protein PrPSc is resistant to protease cleavage (PrPRes ), accumulates and proves toxic to neurons, resulting in progressive neuronal loss and brain dysfunction. Other characteristics include the ability to form fibrils and aggregates (amyloid) and the ability to cause the normal protein to change conformation in a self-perpetuating process. At a biologic level, prions are proteins that can exist in at least two different conformations, one of which can induce conversion of another to the same conformation.
Human forms of prion disease
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- Sporadic Creutzfeldt-Jakob disease (CJD)
- Familial Creutzfeldt-Jakob disease
- Iatrogenic CJD
- Gerstmann-Sträussler-Scheinker disease
- Familial insomnia syndromes, including fatal familial insomnia
- Human bovine spongiform encephalopathy (or variant Creutzfeldt- Jakob disease).
- Kuru (Fore tribesman in New Guinea)
Animal forms of prion disease
list
- Scrapie / sheep
- Mink encephalopathy / mink
- Murine encephalopathy / mice
- Bovine spongiform encephalopathy (BSE) / cattle 5. Chronic wasting disease / deer, elk
Sporadic CJD
Sporadic CJD accounts for 85- 90% of all cases of CJD (annually 1 per 1 million). Familial and transmitted forms, including iatrogenic forms, comprise the remainder.
Iatrogenic forms of CJD
Iatrogenic forms have been described in patients receiving human pituitary-derived hormone supplements, dural and corneal grafts, and contaminated neurosurgical instruments.
Variant CJD
chars
Variant CJD occurred in a series of cases originating in the United Kingdom in the mid 1990’s and was associated with ingestion of beef products contaminated with an animal form of prion disease called bovine spongiform encephalopathy. The recognition of clinical and pathological similarities between a rare degenerative disease affecting indigenous tribes in New Guinea called kuru and a common neurodegenerative disease affecting sheep called scrapie led to our current understanding of prion diseases.
Clinical features of CJD
Peak age
Peak age of onset 60-65 years.
No sex difference.
CJD
Clinical findings
Usually begins with subtle changes in memory and behavior evolving into rapidly progressive dementia. Patient eventually becomes rigid, cortically blind, incontinent, dysphagic, mute, and unresponsive, with overall course lasting 4-12 months until death.
Movement abnormalities include involuntary jerking movements, often in response to sudden stimulation (“startle myoclonus”), other extrapyramidal signs, and ataxia.
CJD
EEG
EEG often shows characteristic abnormalities known as periodic sharp waves.
CJD
Imaging studies
Imaging studies by MRI may show characteristic changes. CT is usually normal, apart from mild atrophy. On MRI, changes in signal intensity bilaterally localized to the corpus striatum are common and often characteristic.
CJD
Lab dx
a. There are no characteristic general tests.
b. Examination of CSF is often normal, but may show mildly increased protein. Detection of protein 14-3-3, a neuronal phosphoserine-binding protein, has a high degree of sensitivity and specificity for CJD.
c. Brain biopsy or autopsy can demonstrate characteristic pathologic findings and permit detailed molecular studies.
Rare variants of sporadic CJD
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- Visual disturbances preceding dementia (Heidenhain variant);
- Cerebellar form (Brownell-Oppenheimer), in which ataxia precedes dementia. This type shows microscopic amyloid plaques (“kuru plaques”) in the granular cell layer of the cerebellum;
- Thalamic type affects thalamus, basal ganglia and hippocampus.
CJD
Correlation with type and duration of disease
There is no correlation between type and duration of disease, which may vary from 3 months to 3 years or longer, though dementia of longer course may not be CJD.
Pathology of CJD
Char by…
The pathological picture is characterized by spongiform degeneration in gray matter, neuronal loss, excessive gliosis, and sometimes deposition of ß-pleated amyloid plaques which are made up of insoluble protease-resistant accumulation of the altered PrPSc
Spongiform degeneration
Gliosis
Neuronal loss
Amyloid plaques
Pathology of CJD
Spongiform degeneration
Formation of vacuoles in neuronal cytoplasm and nuclei. Many of the vacuoles are in the distal parts of neuronal processes; this produces a microscopic picture of numerous small vacuoles in the neuropil of involved areas of gray matter. The size of the vacuoles varies in the different sporadic forms. The vacuoles harbor the abnormal PrPSc-protein.
Pathology of CJD
gliosis
The gliosis is usually excessive for what would be expected for the degree of neuronal loss. The gliosis includes both proliferation of astrocytes and proliferation and activation of microglial cells.
Pathology of CJD
Neuronal loss
is probably due to apoptosis and may be related to activation of microglial cells and axonal damage. Brain atrophy is relatively mild, probably reflecting the rapid course of the disease.
Pathology of CJD
Amyloid plaques
Occurrence varies in different types of prion disorders. Plaques are usually not present in cerebral cortex in sporadic CJD.
- “Kuru plaques” in the cerebellar cortex: originally described in kuru, are characteristic of kuru and of the cerebellar form of sporadic CJD.
- Widespread amyloid plaques in the neocortex are characteristic of Gerstmann-Sträussler-Scheinker disease, an inherited form.
- Cortical amyloid plaques are characteristic of the human form of bovine spongiform encephalopathy (variant CJD).
Sporadic CJD
Genetics/epidemiology
Sporadic CJD cases are all defined by the genotype at codon 129 of the prion gene, PRNP, located on chromosome 20p. Differences in the methionine/valine polymorphism of this site and the degree of protease resistance (type 1 or type 2) of the conformationally changed protein determine the type, i.e., clinical symptoms and distribution of pathology. Glycoslation of the protein also affects phenotype. Typical sporadic CJD cases show either M/M1 or M/V1 genotype, whereas other clinical phenotypes show other genotypic patterns. Kuru, associated predominantly with the M/M2 genotype, occurred as an epidemic in isolated tribes in New Guinea and is thought to have been acquired through exposure to contaminated brain tissues through practices associated with ritual cannibalism. The epidemic may have originated from exposure to a single case of sporadic CJD and has disappeared with government banning of the practice.
Familial CJD
Genetics/epidemiology
Familial CJD (approx. 15%) of all cases occur with an autosomal dominant mode of inheritance. At least twenty different mutations of the PrP have been identified, representing different combinations of M or V and 1 / 2 genotypes. Each type shows a relatively uniform clinical and pathological picture. Familial case clusters have been identified in many countries, including Lybia and Tunisia Jewish populations, Slovakia, Chile, Japan, and the USA.
Types of CJD
autosomal inheritance
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Other types of autosomal inheritable prion disorders include Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia (FFI). These diseases have an autosomal dominant inheritance and represent a variety of different point mutations in the PrP gene.
Variant CJD
Char by…
Variant CJD is characterized by a prion protein isoform resembling that found in bovine spongiform encephalopathy and cases show M/M but lack mutations in PRNP. Glycosylation of the protein is common.
Prion disorders
Pathogenesis
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Prion disorders
tx
Currently, no treatment is available for sporadic or inherited forms of prion disease.
CJD
transmission
Although the disease is transmissible, the transmission has usually required direct contact between contaminated and normal tissues, through means such as neurosurgical implantation. No increased risk to family members has been recognized in cases of sporadic CJD, and occurrence of prion diseases in families reflects the occurrence of familial forms of the disease. Health care workers can potentially be exposed to prion- contaminated tissues such as CSF or CNS tissues. Most other tissues do not harbor the protein, with exceptions such as lymphoid tissues in variant CJD. The recognition of transmissibility through the kuru epidemic and the more recent occurrence of variant CJD via BSE-contaminated food products have raised public health concerns about exposure.
CJD
Decontamination procedures
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