The most common human prion disease is Creutzfeldt-Jakob Disease (CJD). Death rates for CJD have been estimated from vital statistics in the United States. From 1979 to 1998, 4,751 deaths due to CJD were reported in the United States, resulting in an average annual death rate of 0.97 deaths per million persons (Gibbons, Holman, Belay, & Schonberger, 2000). Mortality data analysis is an efficient way of monitoring CJD incidence because CJD is invariably fatal within a short period (almost always within two years) and readily identifiable clinically. The incidence of CJD has not changed significantly during this period. In addition to CJD, other human prion diseases include kuru, fatal familial insomnia (FFI ), and Gerstmann-Straussler-Scheinker disease (GSS). Kuru was transmitted by ritualistic cannibalism among the Fore people of New Guinea, with no new cases reported since this practice was stopped. FFI and GSS, rare prion diseases caused by mutations in the prion protein gene, are discussed later in this chapter.
CJD has sporadic, familial (i.e., genetic), and transmissible (i.e., infectious) forms. This section focuses on sporadic and transmissible forms. Genetic forms of prion diseases are discussed in the next section. Sporadic CJD accounts for at least 85% of human prion disease cases. A review of 230 consecutive cases of sporadic CJD revealed that the disease affects men and women approximately equally with a majority of cases occurring between the ages of 55 and 75 years (range 19 to 83 years, average age of onset 61.5 years; Brown, Cathala, Castaigne, & Gajdusek, 1986). Cognitive decline was the earliest neurologic symptom in two-thirds of cases; however, one-third presented with noncognitive neurologic symptoms such as gait disturbances or, less commonly, changes in vision. Rapidly progressive dementia, myoclonus, extrapyramidal signs, and periodic EEG activity were seen in a majority of cases during their disease course. The mean duration of illness before death was 7.6 months.
Studies of the epidemiology of CJD have failed to identify consistent risk factors for sporadic CJD other than a family history of CJD or other non-CJD dementias (van Duijn et al., 1998; Wientjens et al., 1996). Wient-jens et al. reported an increase in risk of sporadic CJD in those with a family history of CJD, and van Duijn et al. reported an increased risk of sporadic CJD in those with a family history of non-CJD dementias. The odds ratio for having a family history of non-CJD dementia in those with sporadic CJD was 2.26 (95% Confidence Interval [CI] 1.31 to 3.90) in the 1993 to 1995 European Union Collaborative Study. Consumption of meat, contact with blood and blood products, occupational exposure including work in a health profession, and prior surgery involving the central nervous system were not significant risk factors for sporadic CJD. One explanation for the increased risk of sporadic CJD in those with a family history of CJD or other dementias is the possibility that some of these cases represented unrecognized familial CJD because these studies did not include genetic testing. However, a genetic risk factor for CJD, including sporadic and iatrogenic forms, has been identified in other research and may account for some of these findings. Whether this risk factor applies to other causes of dementia is not known.
A naturally occurring polymorphism in the prion protein gene has been identified that can modify the risk of developing a prion disease and alter the phenotype of that prion disease. The polymorphism consists of either carrying a methionine (Met) or valine (Val) at codon 129 of the prion protein gene. Neither amino acid is sufficient to cause disease; however, individuals that are homozygous at this codon (i.e., either Met/Met or Val/Val) are at increased risk of sporadic CJD. Case control studies suggest the 82% to 96% of patients with sporadic CJD are homozygous at codon 129 compared to 49% in the normal populations (Alperovitch et al., 1999; Palmer, Dryden, Hughes, & Collinge, 1991). The impact of this polymorphism on risk of other prion diseases and the influence of this polymorphism on the phenotype of prion diseases are discussed in other sections of this chapter.
Cases of prion diseases transmitted from one person to another and, more recently, from one species to another (i.e., transmissible or infectious form of CJD) have been documented. Person-to-person transmission has been termed iatrogenic CJD. Cases have been reported after receiving pituitary growth hormone therapy derived from human cadavers, dura mater grafts, corneal transplants, and after neurosurgery and epilepsy monitoring that used contaminated surgical instruments and depth electrodes (Brown et al., 2000). In the 267 cases of iatrogenic CJD that have been documented worldwide, the majority of cases have been caused by receiving cadaveric human growth hormone (139 cases, 52%) and dura mater grafting (114 cases, 43%). The median incubation periods for these types of iatrogenic CJD are between 6 and 12 years. The proportion of recipients acquiring CJD from growth hormone varies from 0.3% to 4.4%, and the proportion acquiring CJD from dura mater grafts range from 0.02% to 0.05%. Cerebellar symptoms at the onset of clinical presentation predominate in these iatrogenic causes of CJD. The incidence of these iatrogenic causes of CJD is expected to dramatically decrease in the future due to awareness of these high-risk sources of contamination, changes in treatment methods (e.g., use of human growth hormone produced by bacteria using recombinant DNA technology instead of use of human cadavers), and new methods to prevent contamination of materials with prions.
In 1996, the United Kingdom's national CJD surveillance unit described a new phenotype of CJD they termed new variant CJD (vCJD; Will et al., 1996). Ten cases were described that had a very early age at onset (mean age of 29 years), prominent psychiatric or sensory symptoms as the presenting symptoms, and more prolonged course than sporadic CJD (mean duration 14 months). In addition, these cases had numerous prion protein amyloid plaques surrounded by a halo of intense spongiform degeneration that is not seen in sporadic CJD. These cases occurred at a time when the country was experiencing an epidemic of bovine spongiform encephalopathy (BSE), also called mad cow disease. The occurrence of these cases at the height of the BSE epidemic, when more than 175,000 cattle were known to be affected, raised the possibility that these cases of vCJD may have resulted from human consumption of BSE-infected beef. Gel electrophoresis of the prion proteins from BSE and vCJD victims and transmission studies in mice and primates support strongly the possibility that BSE was transmitted to humans and resulted in vCJD. At the end of 2001, 111 cases of vCJD had been diagnosed, with 107 occurring in the United Kingdom, three in France, one in the Republic of Ireland, and one in Italy.
The evidence that vCJD may have resulted from contamination of the human food supply with BSE-infected beef has raised fears of BSE and vCJD worldwide. Intense efforts are underway around the world to identify BSE-infected animals and prevent BSE-infected products from being consumed by humans as food, medications, biological products, or cosmetics. Risk of contracting vCJD from cattle with BSE in the United States is thought to be very low because no known cases of BSE have occurred in the United States and a ban on entry of foreign sources of BSE is in place. In addition, there is a belief that adequate guidelines exist to prevent similar outbreaks of BSE in cattle in the United States and that appropriate guidelines are in place to monitor cattle for BSE and prevent the human consumption of BSE-infected materials if an outbreak were to occur (Tan, Williams, Khan, Champion, & Nielsen, 1999).
As in sporadic CJD, people are at increased risk of infectious CJD if they are homozygous at codon 129 of the prion protein gene. Between 71% and 89% of patients that developed CJD from cadaver-derived human growth factor were homozygous at codon 129, and nearly 100% of patients who developed CJD from dura mater grafts or consumption of BSE-infected materials were homozygous at codon 129 (Alperovitch et al., 1999; Brown et al., 1994;
Collinge, Palmer, & Dryden, 1991). The reproducible association of codon 129 genotype and risk of sporadic and transmissible CJD suggests that the codon 129 genotype must play an important role in the pathophysiology of prion disease in humans.
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