Prion diseases are also referred to as transmissible spongiform encephalopathies (TSE). They occur in humans and animals, primarily affecting the central nervous system.Â They can be sporadic (spontaneous), familial (genetic/inherited) or acquired (transmitted by infection).Â The hallmark of these diseases is the presence of microscopic vacuolization of the brain tissue, called spongiform degeneration, and an abnormal protein, called scrapie prion protein (PrPSc), which can transmit the disease. The average worldwide occurrence of prion diseases is approximately one case per million people per year.
The normal prion protein is designated as PrPc (cellular prion). Encoded by a gene on chromosome 20, it is found attached to a glycoprotein molecule on the surface of neurons, although small amounts are also present in other cells of mammals. Several functions have been proposed, including supporting neuronal synaptic activity and binding copper (Beekes, 2007). The normal and abnormal proteins have the same amino acid sequence, but differ in their three-dimensional structure. The normal protein has a high content of alpha helix (42%) and essentially no beta sheet (3%); the abnormal protein has an alpha helix content of 30% and a beta sheet content of 43%. The PrPSc is a protease resistant polypeptide, found in the cytoplasm of affected cells, resistant to heat, radiation, proteolytic enzimes and disinfectants such as alcohol, formalin and phenol (Garske & Ghani, 2010).
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The prion diseases have received great scientific and public interest due to the fact that they can be transmissible among humans and in certain conditions from animals to humans. The appearance of variant Creutzfeld-Jakob disease (vCJD) in 1996, followed a prion disease epidemic named Bovine Spongiform Encephalopathy (BSE) in cattle, and it was clear that vCJD was caused by the consumption of prion-contaminated meat from BSE-affected cattle. Therefore, the spread of BSE across Europe and the recently identified cases in North America have put a large human population at risk of prion infection (Belay& Schonberger 2005).
The German neurologists Creutzfeldt and Jakob first reported patients with rapidly progressive neurodegenerative illnesses in the early 1920s. Variant Creutzfeldt-Jakob disease (vCJD), differs etiologically and epidemiologically from sporadic CJD (classical form), and is a human variant of BSE derived from a cow-to-human species switch, rather than an actual variant of human sporadic CJD, instead the clinical presentations of the 2 diseases are similar (Belay, 1999). Garske and Ghani (2010) explained that genetics clearly play a role in susceptibility to vCJD: except for a patient with vCJD related to blood borne transmission, all patients tested to date have been homozygous for methionine at the polymorphic codon 129 of the human prion protein gene a condition present in the 40 % of the general population. Beekes and Mcbride (2007) suggested that methionine homozygosity might be associated with a shorter incubation period and younger age distribution. If this assumption is correct, vCJD could potentially occur in persons who are heterozygous or homozygous for valine at codon 129 after a possible longer incubation period, which may surface many years later. In the early preclinical stages of the disease, PrPSc is detected in lymphoid tissues, and it follows a retrograde spread from the alimentary tract to the CNS along efferent fibers of autonomic nerves, however the molecular basis of prion propagation is unknown (Beekes & Mcbride, 2007).
Beisel and Morens (2004) explains that variant CJD occurs mostly in young patients: the median age at presentation is 29 years, compared with 65 years for sporadic CJD. Median duration of illness is 4-5 months for the sporadic CJD and 13-14 months in the vCDJ. Presentation may be nonspecific and includes headache, anxiety, depression, dizziness, paresthesias and sensory abnormalities, balance and gait disturbance, memory loss, emotional and behavioral changes, cognitive disturbances, and visual disturbances. Most patients with vCJD present with behavioral changes and are often first referred to a psychiatrist. Such changes progress to profound dementia within a few months. As the condition advances, spontaneous and evoked myoclonic contractions of different muscle groups occur, accompanied by ataxia, dysarthria, delirium, and, finally, terminal coma.
The neuropathologic changes in general are shared for the prion diseases, and include spongiform changes and neuronal loss, proliferation of astrocytes and microglia, and accumulation of PrPSc. Typical of vCJD are fibrillary PrPSc amyloid plaques distributed mostly in the cerebral and cerebellar cortices, and when visualized with conventional staining, they have a "florid" appearance in which an amyloid core is surrounded by a zone of spongiform change according to Beekes (2007). Roma and Prayson (2005) explained that a confirmatory diagnosis of vCJD requires histopathologic or immunodiagnostic testing (Western blot and immunohistochemistry) of brain tissues obtained at autopsy. Also prion fragments can be detected by in the tonsils, lymph nodes, and spleen by immunohistochemistry in vCJD patients (but not in those of classic CJD patients) allowing ante mortem diagnosis without brain biopsy. Magnetic resonance imaging shows increased signal intensity in the bilateral pulvinar nuclei, and the protein 14-3-3 in the cerebrospinal fluid is elevated.
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Since the original report in 1996, a total of 225 confirmed cases of vCJD have been diagnosed, 176 in Great Britain (four of them alive), 25 in France, and 24 in other countries (three of them in USA). All these patients from these countries resided in the UK during a key exposure period of the UK population to the BSE agent (National Creutzfeldt-Jakob Disease Research & Surveillance Unit, 2011). Human prion diseases are invariably fatal and there is currently no proven treatment for the underlying process. Several laboratory studies found that immunization appear to be effective in prevention of prion infections in animal models, and metal chelation can be another promising therapeutic approach. Clinical trials are studying the effects of Quinacrine and Pentosan Polysulphate on variant and sporadic CDJ (Wisniewski & Sigurdsson, 2007).
In addition to variant CJD, another prion disease of potential public health concern in the United States is Chronic Wasting Disease (CWD) of deer and elk (Centers for Disease Control and Prevention, 2011), identified as a TSE since 1978, which has been endemic in a tri corner area of Colorado, Nebraska, and Wyoming, but new foci of this disease have been detected in another nine states and Canada in recent years (Figure 1) (Chronic Wasting Disease Alliance, 2011). There are an estimated 22 million elk and deer in the USA, and a large number of hunters who consume elk and deer meat. To date, no convincing evidence of CWD transmission to humans has been reported, however, "given uncertainties about the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated" as stated by Belay et al. (2005). Recent studies report that Chronic Wasting Disease prions are not transmissible to transgenic mice overexpressing human prion protein, although is possible that CWD may be caused by multiple prion strains (Kong et al., 2005; Sandberg et al., 2010). Analysis by immune histochemical studies of the tissue distribution of infectious prions in CWD infected cervids identified the agent in the brain, spinal cord, eyes, peripheral nerves, lymphoid tissues (Belay et al., 2004) and skeletal muscle (Angers et al., 2006). Surveillance for possible human CWD among high-risk populations (e.g., persons hunting in the CWD-endemic areas of Colorado and Wyoming) should continue to be monitored for the possibility that the CWD agent can cause disease in humans (Mawhinney et al.).
Suspected cases of iatrogenic CJD, vCJD, or human CWD cases should be reported to the Centers for Disease Control and Prevention (CDC) through local and state health departments. To facilitate surveillance for emerging forms of prion diseases, the CDC established a National Prion Disease Pathology Surveillance Center. This center provides diagnostic support and develops laboratory methods to detect emerging human prion diseases. Autopsies should be sought in all clinically suspected and diagnosed human prion disease cases. Brain tissues from these cases should be sent to this Center to confirm the diagnosis of CJD and determine the CJD subtype. Increased testing of brain tissues from suspected patients would facilitate detection of the emergence of any new prion diseases, such as vCJD or possible human CWD, in the United States.