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
list
- 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
list
- 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.
