eMedicine Specialties > Neurology > Neurological Infections
Prion-Related Diseases
Updated: May 1, 2006
Introduction
Background
The prion diseases are a large group of related neurodegenerative conditions, which affect both animals and humans (Sadowski, 2004). Included are Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) in humans, bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle, chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep. These diseases all have long incubation periods but are typically rapidly progressive once clinical symptoms begin. All prion diseases are fatal, with no effective form of treatment currently; however, increased understanding of their pathogenesis has recently led to the promise of effective therapeutic interventions in the near future.
Prion diseases are unique in that they can be inherited, they can occur sporadically, or they can be infectious. The infectious agent in the prion disease is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the prion protein. The replication of prions involves the recruitment of the normally expressed prion protein, which has mainly an alpha-helical structure, into a disease-specific conformation that is rich in beta-sheet.
The first of these diseases to be described was scrapie, a disease of sheep recognized for over 250 years. This illness, manifested by hyperexcitability, itching, and ataxia, leads to paralysis and death. It is called scrapie because of the tendency of affected animals to rub against the fences of their pens in order to stay upright, reflecting their cerebellar dysfunction. The transmission of this disease was demonstrated first in 1943 when a population of Scottish sheep was accidentally inoculated against a common virus using a formalin extract of lymphoid tissue from an animal with scrapie (Gordon, 1946). Accidental transmission of prions is a recurrent event in the history of these agents and is related to their unusual biophysical properties.
Pathophysiology
A unifying feature of all the prionoses is their neuropathology. These illnesses tend to affect the gray matter of the central nervous system (CNS), producing neuronal loss, gliosis, and characteristic spongiform change. The latter is a vacuolation of the neuropil, and to a variable degree, of the neurons (see Image 1). In addition, plaques with the typical staining properties of amyloid (eg, apple-green birefringence after Congo Red staining when viewed under polarized light) are observed in many of these conditions. In approximately 10% of patients with CJD, amyloid is present in the cerebellum or in the cerebral hemispheres. All cases of GSS are associated with multicentric cerebellar plaques. These amyloid plaques are immunoreactive with antibodies to the prion protein and do not immunoreact with antibodies to other amyloidogenic proteins, such as the amyloid-beta (which is deposited in Alzheimer disease).Etiology of PrP-related diseases
Highly divergent hypotheses have been put forward regarding the makeup of the prions, including that they consist of nucleic acid only or protein only, are lacking both protein and nucleic acid, or are a polysaccharide. The most widely accepted hypothesis, first described by Griffith (Griffith, 1967) and more explicitly detailed by Stanley Prusiner, MD, is the protein only hypothesis (Prusiner, 1998). Prusiner introduced the term prion to indicate that scrapie is related to a proteinaceous infectious particle (PrP) (Prusiner, 1982).
This hypothesis was initially greeted with great skepticism in the scientific community; now it represents the current dogma, and Prusiner won the 1998 Noble Prize for Science. This hypothesis suggests that prions contain no nucleic acid and are referred to as PrPSc. The latter represents a conformationally modified form of a normal cellular PrPC, which is a normal host protein found on the surface of many cells, in particular neurons. PrPSc, when introduced into normal healthy cells, causes the conversion of PrPC into PrPSc, initiating a self-perpetuating vicious cycle (Prusiner, 1998).
Other hypotheses for prion have included the virino hypothesis (Weissmann, 1996). This hypothesis suggests that the infectious agent consists of a nucleic acid with host-derived PrPSc serving as a coat. The latter would explain the lack of an immunological and inflammatory response, while the presence of a nucleic acid provides an explanation for the numerous strains of scrapie, each with distinctive features. Other investigators have also suggested that the scrapie agent is a conventional virus with highly atypical properties. However, despite extensive searches, no nucleic acid associated with prion infection has been detected so far.
Cell biology of prions - Normal cellular function of PrP
The human PrP gene (PRNP) is found on chromosome 20 and encodes a protein of 253 amino acids. PrPC is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein; some have speculated that it may have a role in cell adhesion or signaling processes, but its exact cellular function remains unknown. The N-terminal region of PrP contains a segment of 5 repeats of an 8–amino acid sequence (ie, octapeptide repeat region) that contains a high-affinity binding site for copper ions; hence, PrP may have a role in copper transport or metabolism. Recent evidence suggests that copper imbalance is an early change during prion infections (Thackray, 2002). The function(s) of PrPC is likely to be of some importance because PrP is highly conserved among mammals and is found in all vertebrates (Harris, 1993; Windl, 1995). Also, prionlike proteins called PSI and URE3 are expressed in yeast (Masison, 2000).
PrP is found in most tissues of the body but is expressed at highest levels in the CNS, in particular in neurons. PrP is also expressed widely on cells of the immune system. PrP knockout mice, which are engineered not to express the PrP gene, show no obvious pathological phenotype (Bueler, 1993). However, these mice have been shown to have abnormalities in synaptic physiology (Collinge, 1994) and in circadian rhythms and sleep (Tobler, 1996).
The secondary structure of PrPC was first elucidated by nuclear magnetic resonance (NMR) imaging using recombinant mouse PrP protein (Riek, 1996; Riek, 1997). More recently, this has been achieved using recombinant hamster and human PrP (Hosszu, 1999; James, 1997; Knaus, 2002). These studies have shown that PrPC is about 40% alpha-helix and about 3% beta-sheet. No high-resolution structural studies, such as NMR imaging, have been performed on PrPSc because it is highly insoluble and aggregated, which are properties that prevent use of these techniques. However, less exact structural methods such as circular dichroism and Fourier transform infrared spectroscopy have shown PrPSc to contain about 45% beta-sheet and 30% alpha-helix (Aucouturier, 1999; Pan, 1993). This high beta-sheet content correlates with PrPSc resistance to enzymatic digestion and infectivity.
Prion strains and the species barrier
Many lines of evidence support the protein only hypothesis of prion propagation; however, a difficulty is the existence of several distinct isolates or strains of prions that can be stably passaged among inbred mice of the same genotype (Baron, 2002). The existence of strains suggests that PrPSc could adopt multiple distinct pathological conformations. Strains are defined by the production of distinct patterns of incubation time, distributions of CNS involvement, and the pattern of proteolytic cleavage of PrPSc following proteinase K (PK) digestion (Prusiner, 1998; Kascsak, 1986). For example, at least 14 significantly different scrapie strains have been isolated from natural sheep scrapie by passage into mice (Baron, 2002; Carp and Rubenstein, 1991).
The best studied are the two strains of transmissible mink encephalopathy (TME) called hyper (HY) and drowsy (DY) (Bessen and Marsh, 1994; Caughey, 1998). The truncated DY PrPSc fragments (PrP27-30) migrate 1-2 kd faster than similar preparations of HY because sites of PK cleavage differ and the two strains differ in terms of beta-sheet content (Bessen and Marsh, 1994; Caughey, 1998).
Parchi et al (1996) defined two distinct types of sporadic CJD based on the analysis of PrP codon 129, which encodes either a valine or a methionine, and by the pattern of sodium dodecyl sulfate-polyacrylamide (SDS-PAGE) migration of the PrP27-30. Type 1 sporadic CJD has a molecular weight of the deglycosylated PrP27-30 of about 21 kd, while type 2 has a mobility of about 19 kd. Collinge et al (1996) reported two further types related to infectious CJD. These distinct types of sporadic CJD appear to have slightly different beta-sheet content that correlates with the degree of resistance to proteinase K digestion ofeach strain (Aucouturier, 1999).
Each strain of prion has characteristic range of infectivity. For example the 263K strain is pathogenic for hamsters but does not infect mice (Kimberlin and Walker, 1978). This effect is called a species barrier and is related to PrPSc being an effective template for homologous PrPC and a poor template for heterologous PrPC; hence, mouse PrPSc can effectively convert mouse PrPC, but it is a very poor template for human or hamster PrPC. This species barrier is not absolute, as is illustrated by the emergence of new variant CJD (vCJD).
How prions reach the CNS
Prion diseases are transmitted naturally by peripheral routes, either orally or transcutaneously; hence, how prions are able to reach the CNS is an important issue. Although the prion diseases are neurological conditions, critical events in their pathogenesis take place in restricted sites out of the nervous system, especially in peripheral lymphoid organs (Aucouturier, 2000).
Lymphoid organs have long been known to be involved in the early stages of prion diseases (Eklund, 1967; Fraser and DiDario, 1978; Kimberlin and Walker, 1979). In particular, the spleen and lymph nodes have been demonstrated to be the first sites of PrPSc replication after infection by peripheral routes, and they are also affected significantly following intracerebral challenge. Their importance for neuroinvasion after peripheral inoculation was suggested by studies showing that splenectomy and other methods that reduce peripheral lymphoid structures delay clinical manifestations (Fraser and DiDario, 1978).
The hematogenic spread of prions to the CNS is suggested by experiments that show BSE to be transmissible from sheep to sheep by blood transfusion (Houston, 2000). Three cases of vCJD infection associated with blood transfusion have also been observed (Health Protection Agency, Variant CJD and blood products). All received nonleucodepleted red blood cells. The first case developed vCJD in 2003, 6.5 years following transfusion from a donor who developed vCJD 3.5 years following donation. The second patient died of causes unrelated to vCJD in 2004, 5 years following the transfusion. At autopsy, this individual had abnormal prion protein in the spleen and cervical lymph node but not in the brain, and other pathological features of vCJD were not observed. The donor developed symptoms of vCJD 18 months after his donation. The third patient developed vCJD in 2006, about 8 years following transfusion from a donor
whowasdiagnosed with
vCJD about 20 months after donation. Hematogenic neuroinvasion has been shown to be dependent on the presence of B lymphocytes (Klein, 1997). However, because expression of the cellular prion protein by B cells is not required for neuroinvasion, some have suggested that their main function is to allow maintenance of follicular dendritic cells (Montrasio, 2000). However, more recent studies suggest that neuroinvasion is possible in the absence of both B cells and follicular dendritic cells (Shlomchik, 2001). Other studies have implicated the distinct CD11c+ dendritic cell population in prion neuroinvasion (Aucouturier, 2001).
In addition to hematogenous spread, prions can reach the brain via the parasympathetic vagus nerve (Beekes, 1998). Hence, following intraperitoneal delivery of prions, disease can be delayed by sympathectomy or can be accelerated by sympathetic hyperinnervation of lymphoreticular organs (Glatzel and Aguzzi, 2001).
Which of these two routes for neuroinvasion is most important remains unclear; it may be scrapie strain–dependent. However, a more complete understanding of these stages and the cells involved in prion spread from the periphery may allow for development of a pharmacological gatekeeper that can be used to stop the movement of infectivity.
Frequency
United States
The most common prion disease is CJD, with a uniform incidence of approximately 1 case per million population both in the United States and internationally. Familial forms of prion diseases, such as GSS and fatal familial insomnia (FFI), are much more rare. About 10% of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PRNP gene.
International
As of February 2006, 159 cases of definite or probable vCJD have been reported in the United Kingdom of which 153 persons have died (see The National Creutzfeldt-Jakob Disease Surveillance Unit). Whether these patients represent the beginning of a growing epidemic (such as that which occurred with BSE) or whether the number of cases will remain relatively low remains unclear. The first confirmed 3 cases were reported in 1995, with numbers of subsequent cases remaining relatively stable between 1996 and 2004 (9-28 cases per year). Only 5 cases were confirmed in 2005.
Two populations are disproportionally affected by CJD: Libyan-born Israelis and some populations in restricted areas of Slovakia where the incidence of CJD is 60-100 times greater than expected. These clusters were postulated to be related to dietary exposure of the scrapie agent; however, this was not supported by case-controlled studies. These local high rates of CJD are linked to a high prevalence of codon 200 mutations in the PRNP gene.
Mortality/Morbidity
Prion-related diseases are relentlessly progressive and invariably lead to death.
- The mean duration of sporadic CJD is 8 months.
- vCJD has a slightly longer course, with a mean duration of 14 months.
- Familial CJD has a mean duration of 26 months, while GSS has the longest course, about 60 months.
Race
Sporadic CJD occurs throughout the world in people of all races and typically has similar features.
- Some familial forms of prion disease, such as familial CJD, can have distinct features in an ethnic group. For example, familial CJD in the Libyan Jewish population associated with a codon 200 mutation has features of a peripheral neuropathy in addition to the more typical manifestations of CJD (Meiner, 1992; Neufeld, 1992).
- vCJD has been limited to Europe, with almost all cases occurring in the United Kingdom.
Sex
No sex preponderance is known in prion diseases, with some rare exceptions. For example, women had a greater tendency than men to develop kuru because it was part of the ritual cannibalism for women to eat the brains (and neural tissue has the highest dose of PrPSc).
Age
- The mean age of onset of sporadic CJD is 62 years. The incidence of sporadic CJD is about 1 case per million population; however, among individuals aged 60-74 years, the incidence is 5 cases per million population (Holman, 1996). The age range can be broad; cases have been reported in people as young as 17 years and as old as 83 years (Masters, 1979; Cathala and Baron, 1987).
- vCJD occurs in younger patients, with a mean age of onset of 28 years.
- Familial CJD, GSS, and FFI have mean ages of onset ranging from 45-49 years.
Clinical
History
Several different forms of prion disease exist (see Table 1 below). The first human prionosis to be described is called kuru (Gajdusek and Zigas, 1957; Gajdusek and Zigas, 1959). This is an illness of the Fore people living in the highlands of New Guinea that is thought to be linked to ritualistic cannibalism. Presumably, this illness originated with the consumption of an initial patient with sporadic CJD. Kuru was once the major cause of death among Fore women; however, the disease has virtually disappeared with the end of cannibalistic rituals. Similar to scrapie, patients clinically present with difficulty walking and they develop progressive signs of cerebellar dysfunction. Death occurs approximately 1 year following onset of symptoms.
The neuropathology of kuru, in common with all prionoses to a variable extent, includes widespread spongiform change and astrocytosis, as well as neuronal loss affecting the cerebral hemispheres and cerebellum. More intraneuronal vacuolation is observed in kuru compared to CJD (see below). In about 70% of cases, amyloid plaques are found, with amyloid deposition being a common, but not invariable, accompaniment of the prionoses. Gajdusek's detailed description of this illness led Hadlow to suggest that kuru might be the human representation of scrapie (Hadlow, 1959). This in turn inspired Gajdusek and his team to test whether kuru was also transmissible. In 1966, they first showed kuru was transmissible to chimpanzees, after a long incubation (Gajdusek, 1966). Gajdusek was awarded the Noble Prize in 1976 for this work.
Table 1. Prion-Related Diseases, Hosts, and Mechanism of TransmissionOpen table in new window
Table
| Disease | Host | Mechanism |
|---|---|---|
| Kuru | Human | Cannibalism |
| Sporadic CJD | Human | Spontaneous PrPC to PrPSc conversion or somatic mutation |
| Iatrogenic CJD | Human | Infection from prion-containing material, eg, dura mater, electrode |
| Familial CJD | Human | Mutations in the PrP gene |
| vCJD | Human | Infection from BSE |
| GSS | Human | Mutations in the PrP gene |
| FFI | Human | D178N mutation in the PrP gene, with M129 polymorphism |
| Sporadic fatal insomnia | Human | Spontaneous PrPC to PrPSc conversion or somatic mutation |
| Scrapie | Sheep | Infection in susceptible sheep |
| BSE | Cattle | Infection from contaminated food |
| TME | Mink | Infection from sheep or cattle in food |
| CWD | Mule, deer, elk | Unclear |
| Feline spongiform encephalopathy | Cats | Infection from contaminated food |
| Exotic ungulate encephalopathy | Nyala, oryx, kudu | Infection from contaminated food |
| Disease | Host | Mechanism |
|---|---|---|
| Kuru | Human | Cannibalism |
| Sporadic CJD | Human | Spontaneous PrPC to PrPSc conversion or somatic mutation |
| Iatrogenic CJD | Human | Infection from prion-containing material, eg, dura mater, electrode |
| Familial CJD | Human | Mutations in the PrP gene |
| vCJD | Human | Infection from BSE |
| GSS | Human | Mutations in the PrP gene |
| FFI | Human | D178N mutation in the PrP gene, with M129 polymorphism |
| Sporadic fatal insomnia | Human | Spontaneous PrPC to PrPSc conversion or somatic mutation |
| Scrapie | Sheep | Infection in susceptible sheep |
| BSE | Cattle | Infection from contaminated food |
| TME | Mink | Infection from sheep or cattle in food |
| CWD | Mule, deer, elk | Unclear |
| Feline spongiform encephalopathy | Cats | Infection from contaminated food |
| Exotic ungulate encephalopathy | Nyala, oryx, kudu | Infection from contaminated food |
By far the most common human prion disease is CJD, accounting for about 85% of all human prion disease. CJD was initially described by Jacob in 1921 (Jacob, 1921); ironically, the case reported by Creutzfeldt a year earlier is probably unrelated to the disease that carries his name. Clinically, CJD is characterized by a rapidly progressive dementia associated with myoclonic jerks, as well as a variable constellation of pyramidal, extrapyramidal, and cerebellar signs. The EEG findings typically show distinctive changes of high-voltage slow (1-2 Hz) and sharp wave complexes on an increasingly slow and low-voltage background. CJD is found throughout the world, with an incidence of about 1 case per million population. In addition to extensive cortical spongiosis, gliosis, and neuronal loss, 10% of CJD cases have amyloid plaques (Prusiner, 1998). Ten percent of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PrP gene.
- Creutzfeldt-Jakob disease
- Sporadic CJD is characterized by a rapidly progressive multifocal neurological dysfunction, myoclonic jerks, a terminal state of global severe cognitive impairment, and death in about 8 months.
- About 40% of patients with sporadic CJD present with rapidly progressive cognitive impairment, 40% with cerebellar dysfunction, and the remaining 20% with a combination of both.
- The clinical picture rapidly expands to include behavioral abnormalities, higher cortical dysfunction, cortical visual abnormalities, cerebellar dysfunction, and both pyramidal and extrapyramidal signs.
- Almost all patients with sporadic CJD develop myoclonic jerks that involve either the entire body or a limb. These myoclonic jerks can occur spontaneously or can be precipitated by auditory or tactile stimulation.
- During the course of sporadic CJD, most patients develop a characteristic picture on EEG with periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background. These periodic complexes have a sensitivity and specificity of 67% and 87% respectively on a single EEG. However, if repeated recordings are obtained, more then 90% of patients show periodic EEG abnormalities (Chiofalo, 1980).
- When evaluating a patient for possible sporadic CJD, the clinician should be guided by published case definitions; they are as follows:
- Definite CJD
- Characteristic neuropathology
- Protease-resistant PrP by Western blot
- Probable CJD
- Progressive dementia
- Typical findings on EEG
- At least 2 of the following - Myoclonus, visual impairment, cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism
- Possible CJD
- Progressive dementia
- Atypical findings on EEG or EEG not available
- At least 2 of the following - Myoclonus, visual impairment, cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism
- Duration less than 2 years
- Gerstmann-Strãussler-Scheinker disease, as described in a large kindred in 1936 (Gerstmann, 1936).
- Patients with this illness present with a slowly progressive limb and truncal ataxia, as well as dementia.
- Death occurs 3-8 years following presentation.
- The prominent involvement of the brainstem often leads to symptoms suggestive of olivopontocerebellar degeneration. The pattern of inheritance is autosomal dominant and is caused by mutations of the PrP gene. The neuropathology of GSS is remarkable in that extensive and invariable amyloid deposition occurs, in addition to the typical spongiform change, gliosis, and neuronal loss. Interestingly, in several kindreds of GSS, extensive neurofibrillary tangle (NFT) formation is found (Ghetti, 1994). NFTs are an essential feature of Alzheimer disease, but are also observed in other neurodegenerative conditions.
- Another variation of autosomal dominantly inherited human prionosis has been termed prion protein congophilic angiopathy (ie, prion protein cerebral amyloid angiopathy [PrP-CAA]), which is characterized by cerebral vessel amyloid deposition and the presence of NFT (Ghetti, 1996). Cerebral amyloid angiopathy (CAA) is also an essential feature of Alzheimer disease. Both these variants of prionoses further link the pathogenesis of Alzheimer disease and the prion-related diseases.
- Fatal familial insomnia
- Patients with FFI present with intractable insomnia, dysautonomia (ie, hyperthermia, hypertension, tachycardia, tachypnea, hyperhydrosis), dementia, and motor paralysis; however, the phenotypic expression is very variable even within the same family (Medori, 1992). The age of onset is also variable, ranging from 18-60 years. Once symptoms begin, the course ranges from 6 months to 3 years. Because of the diversity of clinical presentations of this disorder, genotyping is very important for definitive diagnosis. Neuropathologically, marked atrophy of the anterior ventral and mediodorsal thalamic nuclei occurs because of neuronal loss and gliosis. Unlike other prionoses, spongiform change can be a minor feature or can be absent altogether.
- All patients with FFI have a missense mutation at codon 178 of the PrP gene where Asn is replaced by Asp, coupled with a Met at the polymorphic codon 129 (Goldfarb, 1992). The somewhat divergent clinical and neuropathological features of FFI, in comparison to other human prionoses, highlight the wide spectrum of disease associated with PrP dysfunction and suggest that other human illnesses have yet to be recognized as prionoses.
- Variant Creutzfeldt-Jakob disease
- A recent epidemic of a new prionosis has occurred; BSE has led to more then 160,000 cattle deaths in the United Kingdom (Collinge, 1997). This new disease is thought to be caused by meat and bone meal dietary supplements to cattle that were contaminated with scrapie-infected sheep and other cattle with BSE. Extensive evidence suggests that BSE has also lead to a new type of CJD, called variant CJD (vCJD) (Collinge and Rossor, 1996). The first cases of vCJD were reported in 1995, when CJD was found in 2 British teenagers (Bateman, 1995; Britton, 1995).
- Only 4 cases of sporadic CJD have been reported previously among teenagers; the peak incidence of onset of sporadic CJD is in people aged 60-65 years. In addition to the early age, these cases had distinctive neuropathology that included so-called florid amyloid plaques, which are reminiscent of kuru-associated PrP amyloid plaques (Collee and Bradley, 1997; Will, 1997). Significantly, such florid amyloid plaques are also a feature of CWD (Liberski, 2001).
To date as of February 2006, 159 cases of vCJD have been diagnosed in Great Britain (see The National Creutzfeldt-Jakob Disease Surveillance Unit). The latest numbers from other countries as of November 2005 are 15 in France, 3 from Ireland, 2 in the United States, and one each from Canada, Italy, Japan, Netherlands, Portugal, Saudi Arabia, and Spain (see Centers for Disease Control and Prevention, Variant Creutzfeldt-Jakob Disease. Both of the US cases, 1 of the 3 in Ireland as well as the single cases from Canada and Japan were likely exposed while living in the UK. The emergence of vCJD has raised the specter of an epidemic of prion-related disease among the British population (and possibly a wider population) similar to that of BSE in cattle.
Physical
- Physical signs and symptoms vary with the type of prion disease. vCJD differs from sporadic CJD in that psychiatric abnormalities and sensory symptoms are much more common at presentation of vCJD.
- Mental status and/or neuropsychological examination
- This shows a rapidly worsening global cognitive status. The most common initial symptoms are cognitive impairment and ataxia.
- Many less common variations exist, such as presentations with initial cortical blindness (ie, Heidenhain variant).
- In sporadic CJD, an important and almost universal physical feature is the presence of myoclonus.
- Cerebellar findings are present in all patients with vCJD, while about 40% of those with sporadic CJD have cerebellar dysfunction.
Causes
Prion-related diseases are unique in that they can be related to infectious, sporadic, or familial causes (see Pathophysiology).
- Infectious causes
- Kuru, a form of prion disease, occurred among the Fore people of the Eastern Highlands of New Guinea and was related to ritualistic cannibalism. The disease is believed to have started with the ingestion of body parts of a patient with sporadic CJD, followed by a serial passage of the disease.
- Many cases of iatrogenic CJD have been reported. In clinical practice, CJD has been transmitted by surgical instruments, EEG electrodes, corneal transplants, dura mater grafts, human pituitary-derived gonadotrophins, and human-derived growth hormone. Concerns that vCJD could be transmitted by blood transfusion have been borne out with 3 documented case.
- vCJD in humans is presumed to have been caused by ingestion of beef products contaminated with BSE. BSE is presumed to have started because of the practice of supplementing the diets of calves and dairy cows with meat and bone products. These meat and bone products are thought to have been contaminated with scrapie material (from sheep) and/or with material from cattle with a sporadic form of bovine prion disease.
- Recently, a number of cases of apparent sporadic CJD have occurred in the United States among young individuals ( <30 y). The incidence of sporadic CJD among such young individuals has historically been about 1 case per billion population. In the years 1979-1996, 4 cases of sporadic CJD were reported in the United States among individuals younger than 30 years. In the years 1997-2000, 5 cases have occurred in the United States among young patients. Two of these individuals came from adjacent counties in Michigan (ages at onset were 26 and 28 y), and 3 cases occurred among individuals who were known hunters of deer and/or elk (Belay, 2001).
- Over the same period, a major outbreak of CWD occurred among the deer and elk populations in many western states, which has now spread to at least 10 states (see Chronic Wasting Disease Alliance). CWD is a form of prion disease that occurs naturally in the deer and elk population; however, the pathology has many similarities to BSE, including the presence of florid plaques (Liberski, 2001). Significantly, transmission studies of CWD PrPSc in the laboratory have shown that it can cross the species barrier from deer to human PrP at about the same efficiency as the BSE prion agent (Raymond, 2000). These observations have led to the speculation that limited transmission of CWD to humans has occurred recently in the United States.
Recent findings indicate that transgenic mice that express the deer/elk prion protein can be infected with intracerebral injection of muscle tissue from symptomatic cervids (Angers, 2006),which raises concerns about infectivity of meat products from these animals. Also, a nonhuman primate developed prion disease after intracerebral injection with brain material from symptomatic deer (Marsh, 2005).
- Familial causes
- The cause of familial forms of prion disease is related to mutations in the PrP gene. A number of mutations in the PrP gene are linked to autosomal dominant forms of prion disease. Image 2 is a representation of the human PrP gene, PRNP.
- A signal peptide of 22 amino acids (dotted area) is cleaved at the amino terminus (N-terminus) synthesis, and a further sequence at the carboxyl terminus (dotted area) is removed during the addition of a glycosyl-phosphatidylinositol anchor (GPI).
- Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations.
- The locations of the 4 putative helical regions are indicated by the boxes labeled H1 through H4, corresponding to residues 144-154, 179-193, and 200-218, respectively.
- The diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial CJD.
- Mutations at codons 102, 105, and 117 have been associated with GSS, while mutations at codons 198 and 217 are found in pedigrees with GSS and NFTs.
- PrP-CAA has been linked to a point mutation at codon 145 that results in a stop codon. Familial CJD has been associated with mutations at codons 178, 180, 200, 210, and 232.
- Interestingly, kindreds with FFI have the same D178N mutation as 178 familial CJD kindreds; however, the FFI phenotype is associated with a Met at codon 129, whereas the mutated allele in 178 CJD patients has a Val at the polymorphic codon 129.
- Sporadic causes
- Sporadic CJD is the most common form of prion disease.
- It probably arises as a spontaneous conformational change in PrPC to a PrPSc form. The PrPSc form is then self-propagating, inducing more PrPC to convert to the PrPSc form.
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Further Reading
Keywords
transmissible spongiform encephalopathies, TSE, bovine spongiform encephalopathies, BSE, mad cow disease, mad-cow disease, Creutzfeldt-Jakob disease, CJD, new variant CJD, nvCJD, variant CJD, vCJD, prionosis, prionoses, prion diseases, PrP diseases, chronic wasting disease, CWD, scrapie, Gerstmann-Straussler-Scheinker, GSS, fatal familial insomnia, FFI, kuru
