Volume 2: Science
2.
The Spongiform Encephalopathies - knowledge existing in 1986
Animal and human transmissible spongiform encephalopathies (TSEs)
Scrapie
Transmissible Mink Encephalopathy (TME)
Chronic Wasting Disease (CWD)
Creutzfeldt-Jakob Disease (CJD)
Gerstmann-Sträussler-Scheinker syndrome (GSS)
Kuru
Fatal Familial Insomnia (FFI)
Prion mutations
2.4 TSEs are progressive, degenerative diseases of the nervous system, causing the appearance of microscopic holes (vacuoles) in the brain. They are invariably fatal, affect both humans and animals, and are biologically unique in character, occurring without any sign of an immune response. They tend to have a long incubation period, a characteristic which led to use of the term 'slow-virus' diseases to describe them. However, this term is misleading, and is no longer used.
2.5 By 1986 the following TSEs had been identified:
2.6 Various aspects of these diseases, including the clinical symptoms, aetiology, 1 pathology, 2 transmission, epidemiology, 3 genetic factors and pathogenesis 4 had been investigated and documented. Key features of the various diseases are discussed in this chapter. Although many of these characteristics are common to all TSEs, the diseases can be distinguished from each other through careful examination of specific features. One of the most commonly used diagnostic features is the lesion profile, ie, the pattern of brain tissue damage.
2.7 At the time of identification of BSE, the occurrence of scrapie in sheep and goats had been known for over 250 years. The disease is endemic in the UK and in most countries worldwide, with the exception of Australia and New Zealand. Scrapie was not a notifiable disease in the UK in 1986. MAFF's Veterinary Investigation Diagnosis Analysis (VIDA) recorded that 153 incidents reported by Veterinary Investigation Centres (VICs) had been diagnosed as scrapie in 1986. However, the VIDA report noted that specimens received by VICs represented a biased sample of the field problems of animal disease, and cautioned against extrapolating from these data. In 1988, on the basis of a voluntary survey, Morgan estimated that a third of British flocks were affected, with infected flocks distributed throughout the UK. 5 The clinical signs of scrapie, which include nervousness, pruritis (itching) and incoordination, were well recognised by farmers. Morgan's study used an anonymous self-administered questionnaire in two independent surveys, though it was recognised that, even given anonymity, a degree of under-reporting and unwillingness to take part would introduce a negative bias to the calculations. The incidence of clinical cases of scrapie in affected flocks of 100 or more sheep was calculated to be either 0.5 or 1.1 cases per 100 sheep per year, depending on which survey was analysed.
2.8 Questions on the validity of some of Morgan's data have, however, been posed. 6 It was noted that of the farmers making a positive diagnosis of scrapie, approximately 15 to 20 per cent could not select three of the four signs of scrapie from a list of six possibilities. It was also thought that such a questionnaire, listing four indefinite but possibly positive signs of scrapie with only two negative signs, would bias respondents towards the selection of scrapie signs. 7 A further possibility of bias lay in the fact that, in a voluntary survey, farmers who believed they had a problem on their farms might be most likely to respond.
2.9 Research carried out in Scotland also cast doubt on Morgan's findings, since it revealed that 15 per cent of sheep which exhibited signs of scrapie were not confirmed histopathologically. 8 This suggests that respondents to Morgan's survey who made a positive diagnosis may well have misdiagnosed the condition. Thus it is possible that the true prevalence of scrapie in UK flocks is lower than that estimated by Morgan.
2.10 Although the first record of the disease was made in 1732, the first published article only appeared in 1913 in the Journal of Comparative Pathology. 9 This described symptoms such as 'trotting', itchiness and excitability, and noted a disease course of three to four months. Proof that scrapie was a transmissible disease came in 1936, when spinal cord homogenate from 80 affected animals was inoculated into healthy sheep leading to the development of disease. 10
2.11 Extensive investigation of scrapie has taken place in Great Britain since the 1940s. Indeed, Great Britain did, and still does, possess several leading institutions for research into diseases of sheep and spongiform encephalopathies. These institutions include the Moredun Research Institute in Edinburgh, which was established in 1920. Much research was also undertaken by the Agricultural Research Council (ARC), either at its institute in Compton, Berkshire, or at the ARC Animal Breeding Research Organisation (ABRO) in Edinburgh, established in 1948. In recent times, these institutions have undergone a great deal of reorganisation. Most significantly, in 1981, the ARC and the Medical Research Council (MRC) established a joint institution, the Neuropathogenesis Unit (NPU), which combined and coordinated the research programmes and facilities of relevance to scrapie of all three of the institutions described above. The NPU is one of the major institutions in the UK providing expertise in scrapie and spongiform encephalopathies.
2.12 During the 1960s and 1970s, investigations into the neuropathology of both natural and experimentally induced scrapie in goats, mice and hamsters at these institutions resulted in the identification of the main features of scrapie:
- vacuolation of the grey matter, ie, holes which give the brain a characteristic 'sponge-like' appearance;
- loss of neurones (nerve cells) in the brain;
- astrocytosis (the proliferation of particular brain cells in response to the destruction of nervous tissue); and
- occurrence of amyloid plaques (areas of build-up of the complex protein amyloid) - found in some cases only.
2.13 Investigations also showed that many strains of scrapie exist, as revealed by the differences in the disease produced in inbred lines of experimental mice by isolates of scrapie derived from different sheep sources. Two strains examined in one study (ME7 and 22A) produced long and short incubation periods in one line of mice, but these incubation periods were reversed in a different line. 11 It was also shown that the lesion profiles produced in the brains of affected animals differed according to strain. 12 This method of inoculating different lines of inbred mice is still used to identify strains of agent, since they can be classified according to the characteristics of disease produced. To date, some 22 different strains of scrapie agent have been identified in this manner. 13 However, while the length of the incubation period was known to be influenced by strain, it was also shown to be under genetic control of the host (see paragraphs 2.96-2.99).
2.14 Transmission of scrapie has been successfully shown in goats, 14 mice 15 and hamsters 16 by various routes, including injection into the brain (intracerebral inoculation), and oral ingestion. Transmission to other species has been less successful. Attempts to transmit two different strains of the disease to cats were unsuccessful, while mink were only susceptible to some strains. 17
2.15 The Chief Veterinary Officer's annual report for 1986 noted that a scrapie-like disease had been diagnosed in a captive nyala. 18 This is discussed at paragraph 3.19 below.
Transmissible Mink Encephalopathy (TME)
2.16 The first paper on TME was published in 1965 and documented several outbreaks of the disease on mink farms in Wisconsin in the US, the first of which was observed in 1947. 19 It is a rare, sporadic disease found only in commercially farmed mink, and has a particularly short clinical course. Affected animals present with behavioural changes such as hyper-excitability and aggressiveness, followed by incoordination and rapid death.
2.17 It was generally accepted by those studying the disease that infection originated in a feed-borne source. 20 Cannibalism was considered to play an additional role, as disease developed in mink from litters where maternal flesh and entrails had been ingested. 21 Other evidence suggested that infection through bite wounds inflicted by littermates whilst fighting had a greater role than the oral route in spreading disease. 22 However, the origin of the disease was not fully understood. The clinical and pathological similarities between TME and scrapie suggested that TME might be a form of scrapie, introduced by feeding mink with scrapie-infected tissues. 23 Support was lent to the theory of a scrapie-related origin for TME when, in 1986, two strains of TME were identified, one of which closely resembled a particular strain of scrapie, in terms of incubation period and disease pattern. 24 However, only some scrapie isolates were found to transmit to mink viaintracerebral inoculation, 25 and oral administration was not successful in transmitting disease. 26 Consequently, a scrapie origin for TME was questioned. Studies of worldwide occurrences of TME revealed probable exposure to scrapie in only 1 of 14 instances. 27 Furthermore, a 1986 report noted that there was no evidence of exposure to sheep or sheep by-products in the animals affected by an outbreak in Canada. 28
2.18 Other scientists suggested a bovine origin for the disease, since they had observed a TME outbreak where only cattle and horsemeat had been fed to the mink. They concluded that this outbreak might be due to a 'scrapie-like disease in cattle'. 29 The cattle meat was from fallen (downer) cattle, but confirmation that they were TSE-infected had not been sought.
2.19 CWD is a naturally occurring TSE of deer, found almost exclusively in the wildlife parks of Colorado and Wyoming in the US, and was first reported in 1980 by Williams and Young. 30 Symptoms included behavioural changes, excessive salivation and weight loss, with death occurring after two weeks to eight months.
2.20 Williams and Young were unclear how the disease was transmitted, although they considered the possibility of maternal and/or lateral routes. There was indeed some evidence of lateral transmission of the disease between mule deer and Rocky Mountain elk housed in the same facility. 31 However, the primary source of the disease was not known. Transmission of CWD by the oral route has recently been demonstrated in mule deer fawns. Examination at 10-80 days after oral inoculation revealed abnormal PrP in LRS tissues as early as 42 days afterwards. Detection of abnormal PrP within a few weeks of oral exposure is consistent with the efficient lateral transmission of CWD in nature. 32
Creutzfeldt-Jakob Disease (CJD)
2.21 CJD was first described in 1920 when two scientists, Jakob and Creutzfeldt, independently described patients with a demential, degenerative, neurological disorder. CJD is a rare human TSE with an incidence of about one in a million per year globally. It typically affects adults in middle to old age, although cases have been seen in younger people, albeit in very small numbers: two cases worldwide before 1986. 33 Symptoms include memory loss and confusion, leading to progressive dementia, ataxia (loss of coordination), involuntary movements, blindness and loss of speech. Most patients die within 6 to 12 months of the onset of symptoms, some much earlier.
2.22 In 1986 three distinct forms of the disease had been recognised: sporadic, familial and iatrogenic (ie, acquired by medical intervention). Although most cases showed a characteristic clinical pattern, atypical cases had also been identified, with patients showing rarer clinical symptoms such as seizures, sensory loss and vegetative dysfunction (dysfunction of the involuntary nervous system), 34 or a longer clinical course. 35 Since 1986 it has been suggested that some of this variation could be the result of slight differences in prion protein conformation due to genetic or other factors in the host (see Chapter 3 of this volume for a more detailed discussion).
2.23 Sporadic CJD, which is the commonest form of the disease, accounted for around 85 per cent of cases in the mid-1980s. 36 Familial CJD accounted for between 6 per cent 37 and 15 per cent 38 of cases, although since 1986 this figure has been reported as being higher in certain countries, eg, Chile. 39 Vertical transmission (via the placenta or through breastmilk) was considered not to be involved in the spread of familial CJD, although in 1978 Masters and co-workers had suggested that lateral transmission (through close contact) could be responsible for case clustering. 40 Although the mechanism for familial clustering was not known in 1986, the pattern was suggestive of dominant inheritance of a gene mutation. 41 This was subsequently confirmed in 1989 by two groups working on familial CJD and on another human disease, Gerstmann-Sträussler Syndrome (see paragraph 2.176). 42
2.24 By 1986 only a small number of cases of iatrogenic CJD had been seen - fewer than 40 worldwide. Transmission had been reported via corneal transplants, 43 stereotactic intracerebral electrodes, 44 and human growth and gonadotrophin hormones derived from pooled pituitary glands from cadavers. 45
2.25 CJD had been reported in almost all parts of the world. 46 There was no evidence of gender differences in the occurrence of the disease, although a UK survey published in 1986 found a significant excess of disease in women, compared with men, in the over-65 age-group. 47 (However, it was later found that the age-adjusted death rate in men was slightly higher in a survey of CJD reported from the US. 48) Higher frequencies of cases of CJD had been reported by 1986 in certain ethnic groups, such as Libyan Jewish immigrants to Israel, 49 and Tunisian and Algerian immigrants to France. 50 These and other observations suggested several risk factors for the disease, such as the consumption of scrapie-infected sheep-meat and eyeballs 51 (which was known to be high among Libyans and other North Africans), surgical procedures, 52 and occupational or recreational exposure to animals. 53 In order to set these observations in perspective, we note that in 1990 Goldfarb and co-workers determined that these clusters in ethnic groups were due to familial CJD arising from mutations of the prion protein (PrP) gene (see paragraphs 2.66-2.78 for an explanation of the prion theory). 54 The mutation has been identified in other large clusters of patients with familial CJD in Slovakia and Chile, 55 raising the possibility of a common founder of the three clusters (Slovakian, Chilean and Libyan) spread by population dispersal. 56 It is, however, considered more likely that the mutation appeared spontaneously in diverse populations at a site in the prion gene prone to biochemical conversion. 57 Such a theory is supported by the identification of the mutation in the presence, as well as in the absence, of a family history of CJD in the US, 58 England, 59 France 60 and Japan, 61 suggesting the occurrence of multiple independent mutations.
2.26 Returning to the position in 1986, by the early 1980s various workers had undertaken experimental transmission studies with CJD, with successful transmission to primates, 62 goats, cats 63 and various rodent species. 64 These studies were important in developing knowledge of transmission by different routes and involving different tissues. In particular, they demonstrated that infectivity was not confined to the tissues of the central nervous system (CNS), and that it could be transmitted via oral, intracerebral and peripheral routes.
2.27 Techniques to diagnose CJD in living patients (ante-mortem) had also been investigated. Brain biopsy was one of the possibilities considered, but problems existed with false negatives arising from brain material taken from sites not affected by the disease. Overall, no reliable technique other than post-mortem histological examination was available in 1986. 65
Gerstmann-Sträussler-Scheinker syndrome (GSS)
2.28 GSS is one of the rarest TSEs with an incidence of two to five per 100 million per year, compared with about one case per million for CJD. It was first described in 1928 as a disease affecting movement and speech, progressing to severe dementia. 66 The majority of patients presented first symptoms in their 30s or 40s, and the mean clinical duration of the disease was around five years. 67 Although predominantly an inherited disorder, what were thought to be sporadic cases had also been identified. 68 Since 1986 further features of GSS have been discovered. In 1989 genetic mutations were first found to be responsible for GSS. Since then it has been recognised that the variable clinical and pathological features of GSS are associated with different mutations of the PrP gene. 69
2.29 GSS diagnosis by clinical observations is difficult and is therefore only normally identified by post-mortem examination. Because of the similar clinical symptoms GSS may often have been misdiagnosed as Alzheimer's disease. 70
2.30 Kuru (trembling) is a form of CJD which reached endemic proportions in Papua New Guinea. It was first reported in 1957, when Zigas and Gajdusek described the disease found in about 1 per cent of the Fore people, though in certain clans and tribes the incidence of the disease was as much as 5 to 10 per cent of the population. 71 The disease was almost extinct by 1986, but it did provide an important example, at that time, of an acquired TSE in humans.
2.31 The epidemiological pattern of the disease provided important clues as to its cause. The disease was twice as common in women and children as in men, and occasional clusters of cases were seen. It was concluded that kuru was transmitted through a certain mortuary ritual, during which various tissues from dead relatives were consumed as a mark of respect. The brain and internal organs were eaten predominantly by the women and children, who also prepared the cadavers and frequently smeared their bodies with brain. Practice of the ritual ceased during the late 1950s, and by 1970 the incidence in all age-groups had declined. 72
2.32 Although cannibalism was generally presumed to be the main route of transmission, Gajdusek suggested in 1979 that kuru could have been transmitted predominantly through cuts and abrasions rather than through the actual ingestion of brains. 73 Preparation of the cadavers involved exposure to various tissues, including brain, via the skin and mucous membranes. Both oral and intracerebral transmission had been shown experimentally in primates. 74 In 1980 experiments on squirrel monkeys showed transmission of kuru from natural feeding but not by feeding infected material directly into the stomach via the gastric tube. 75 Consequently, the authors concluded that mucosal lesions in the mouth and pharynx might be the main route of infection.
2.33 Although the origin of the disease was not clear, it had been suggested that it could have been initiated by a case of sporadic CJD arising in a member of the tribe early in the 20th century. 76
2.34 FFI was first described in 1986 as an inherited sleep disorder in humans. 77 Symptoms included progressive insomnia and problems with the autonomic nervous system. Death occurred nine months after the onset of symptoms. Several relatives of this first patient had died of a similar disease, and examination of their brains showed degeneration of nerve cells and astrocytosis, but no vacuolation or inflammatory changes. In 1986 there was no evidence that the disease was transmissible, and it had therefore not been classified as a TSE. It was not until 1992 that PrP gene mutations were identified, showing that FFI was a prion disease. 78
2.35 Before 1986 it was known that familial cases of CJD and GSS were autosomal dominant disorders, ie, due to gene mutations on one member of a chromosome pair (but not a sex chromosome). However, it was not until 1989 that the gene responsible for these mutations was identified. This discovery had important ramifications. They warrant interrupting our account of knowledge in 1986 in order to explain the discovery and its importance.
2.36 The experimental transmission of familial CJD and GSS to animals demonstrated that the diseases were at the same time infectious and inherited, though this was largely interpreted within the framework of a viral illness. Work carried out by Prusiner and co-workers on scrapie identified a protein unique to the scrapie-infected hamster brain in fractions enriched for scrapie infectivity. 79 The protein was designated the prion protein (PrP) and its isolation ultimately resulted in the identification and sequencing of the prion protein gene. It was in the prion gene that the causative mutations of GSS and familial CJD were found. This discovery provided an explanation for the infectious and inheritable nature of the transmissible spongiform encephalopathies, whereby disease can be acquired either through the inheritance of a mutated prion protein gene or through the acquisition of abnormal prion protein by infection. The prion hypothesis is considered in more detail in paragraphs 2.66-2.78.
2.37 While mutations of the prion gene are the only established originating cause of CJD, it remains possible, but unproven, that environmental agents such as toxic chemicals can lead to the conversion of the prion protein from its normal soluble form to its insoluble disease-producing form. This conversion is believed to result in a conformational change in the shape of the prion protein molecule that makes it resistant to enzyme degradation. Aggregates of the insoluble form appear to be the cause of the neurodegeneration.
2.38 There are now more than 20 mutations of the prion gene known to cause CJD and related TSEs. Most are familial, but in some instances the mutation is believed to have arisen de novo in a parental germ cell. It is also likely that sporadic CJD can be caused by non-familial mutations of the prion gene occurring in body cells (somatic mutations). Since these mutations do not involve the eggs and sperm, they cannot be passed to offspring.
1 The cause of a disease
2 The changes occurring as a result of the disease
3 The occurrence and distribution of disease
4 The development of the disease within the body
5 Morgan, K., Nicholas, K., Glover, J. and Hall, P. (1990) A Questionnaire Survey of the Prevalence of Scrapie in Sheep in Britain, Veterinary Record, 127, 373-76
6 Martin, W.B. (1990) Prevalence of scrapie in British flocks, Veterinary Record, 127, 409; Clark, A.M. (1991) Diagnosis of scrapie, Veterinary Record, 128, 214
7 Martin, W.B. (1990) Prevalence of scrapie in British flocks, Veterinary Record, 127, 409
8 Clark, A.M. (1991) Diagnosis of scrapie, Veterinary Record, 128, 214
9 Stockman, S. (1913) Scrapie: An Obscure Disease of Sheep, Journal of Comparative Pathology, 26, 317-27
10 Cuille, J. and Chelle, P. (1936) La Maladie dite tremblante du mouton, est-elle inoculable? Comptes Rendus De L'Académie Des Sciences, 203, 1552-4
11 Dickinson, A.G. and Meikle, V.M. (1969) A comparison of some biological characteristics of the mouse-passaged scrapie agents, 22A and ME7, Genetical Research, 13, 213-25
12 Fraser, H. and Dickinson, A. (1973) Scrapie in Mice Agent-Strain Differences in the Distribution and Intensity of Grey Matter Vacuolation, Journal of Comparative Pathology, 83, 29-40
13 Bradley, R. (1997) Animal Prion Diseases, Prion Diseases, edited by Collinge, J. and Palmer, M.S., United Kingdom, Oxford University Press, 93; Dickinson, A., Meikle, V. and Fraser, H. (1968) Identification of a Gene which Controls the Incubation Period of some Strains of Scrapie Agent in Mice, Journal of Comparative Pathology, 78, 293-9
14 Pattison , I., Gordon, W., and Millson, G., (1959) Experimental Production of Scrapie in Goats, Journal of Comparative Pathology, 69, 300-12
15 Chandler, R. (1961) Encephalopathy in Mice Produced by Inoculation with Scrapie Brain Material, The Lancet, 196II, 1378- 9; Zlotnik, I. and Rennie, J. (1962) The Pathology of the Brain of Mice Inoculated with Tissues from Scrapie Sheep, Journal of Comparative Pathology, 72, 360-5
16 Marsh, R. and Kimberlin, R. (1975) Comparison of Scrapie and Transmissible Mink Encephalopathy in Hamsters. II Clinical Signs, Pathology, and Pathogenesis, Journal of Infectious Diseases, 131, 104-10
17 Amyx, H., Gibbs, C. and Gajdusek, D. (1983) Experimental Creutzfeldt-Jakob Disease in Cats, Unconventional Viruses and the Central Nervous System, edited by Court, L.A. and Cathala, F., Paris, Masson, 358; Hanson, R., Eckroade, R., Marsh, R., Zu Rhein, G., Kanitz, C. and Gustafson, D. (1971) Susceptibility of Mink to Sheep Scrapie, Science, 72, 859-61
18 M24 tab 2 p. 69
19 Hartsough, G. and Burger, D. (1965) Encephalopathy of Mink: I. Epizootiologic and Clinical Observations, Journal of Infectious Diseases, 115, 387-92
20 Ibid.
21 Burger, D. and Hartsough, G. (1965) Encephalopathy of Mink: II Experimental and Natural Transmission, Journal of Infectious Diseases, 115, 393-9
22 Marsh, R. F. (1979) On the Origin of Transmissible Mink Encephalopathy, Slow Transmissible Diseases of the Nervous System, vol. 1, edited by Prusiner, S.B. and Hadlow, W.J., New York, Academic Press, 451-60
23 Ibid.
24 Kimberlin, R., Cole, S. and Walker, C. (1986) Transmissible Mink Encephalopathy (TME) in Chinese Hamsters: Identification of Two Strains of TME and Comparisons with Scrapie, Neuropathology and Applied Neurobiology, 12, 197-206
25 Hanson, R., Eckroade, R., Marsh, R., Zu Rhein, G., Kanitz, C. and Gustafson, D. (1971) Susceptibility of Mink to Sheep Scrapie, Science, 172, 859-61; Marsh, R. F. (1979) On the Origin of Transmissible Mink Encephalopathy, Slow Transmissible Diseases of the Nervous System, vol. 1, edited by Prusiner, S.B. and Hadlow, W.J., New York, Academic Press, 451-60
26 Marsh, R. F. (1979) On the Origin of Transmissible Mink Encephalopathy, Slow Transmissible Diseases of the Nervous System, vol. 1, edited by Prusiner, S.B. and Hadlow, W.J., New York, Academic Press, 451-60
27 Ibid.
28 Hadlow, W. and Karstad, L. (1968) Case Report: Transmissible Encephalopathy of Mink in Ontario, Canadian Veterinary Journal, 9, 193-6
29 Marsh, R. and Hartsough, G. (1985) Is there a Scrapie-Like Disease in Cattle? Proceedings of the US Animal Health Association, 89, 8-9
30 Williams, E. and Young, S. (1980) Chronic Wasting Disease of Captive Mule Deer: A Spongiform Encephalopathy, Journal of Wildlife Diseases, 16, 89-98
31 Williams, E. and Young, S. (1982) Spongiform Encephalopathy of Rocky Mountain Elk, Journal of Wildlife Diseases, 18, 465-71
32 Sigurdson, C.J., Williams, E.S., Miller, M.W., Spraker, T.R., O'Rourke, K.J. and Hoover, E.A. (1999) Oral transmission and early lymphoid tropisim of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus), Journal of General Virology, 80(10), 2757-64
33 Britton, T., Al-Sarraj, S., Shaw, C., Campbell, T. and Collinge, J. (1995) Sporadic Creutzfeldt-Jakob Disease in a 16-year-old in the UK, The Lancet, 346, 1155
34 Davanipour, Z., Alter, M. and Sobel, E. (1986) Creutzfeldt-Jakob Disease, Neurologic Clinics, 4, 415-26
35 Brown, P., Rogers-Johnson, P., Cathala, F., Gibbs, C., and Gajdusek, D. (1994) Creutzfeldt-Jakob Disease of Long Duration: Clinicopathological Characteristics, Transmissibility, and Differential Diagnosis, Annals of Neurology, 16, 295-304
36 Brown, P., Cathala, F., Raubertas, R., Gajdusek, D. and Castaigne, P. (1987) The Epidemiology of Creutzfeldt-Jakob Disease: Conclusion of a 15-Year-Investigation in France and Review of the World Literature, Neurology, 37, 895-904
37 Will, R., Matthews, W.B., Smith, P. and Hudson, C. (1996) A Retrospective Study of Creutzfeldt-Jakob Disease in England and Wales (1970-79) II: Epidemiology, Journal of Neurology, Neurosurgery and Psychiatry, 49, 749-55
38 Masters, C., Harris, J., Gajdusek, D., Gibbs, C., Bernoulli, C. and Asher, D. (1979) Creutzfeldt-Jakob Disease: Patterns of Worldwide Occurrence and the Significance of Familial and Sporadic Clustering, Annals of Neurology, 5, 177-88
39 Galvez, S., Cartier, L., Monari, M. and Araya, G. (1993) Familial Creutzfeldt-Jakob Disease in Chile, Journal of the Neurological Sciences, 59, 139-47
40 Masters, C., Harris, J., Gajdusek, D., Gibbs, C., Bernoulli, C. and Asher, D. (1979) Creutzfeldt-Jakob Disease: Patterns of Worldwide Occurrence and the Significance of Familial and Sporadic Clustering, Annals of Neurology, 5, 177-88
41 Gajdusek, D. (1985) Unconventional Virus Causing Subacute Spongiform Encephalopathies, Virology, edited by Fields, B., 1547 (M8 tab 1, 1547)
42 Owen, F., Poulter, M., Lofthouse, R., Collinge, J., Crow, T., Risby, D., Baker, H., Ridley, R., Hslao, K. and Prusiner, S. (1989) Insertion in Prion Protein Gene in Familial Creutzfeldt-Jakob Disease, The Lancet, 1989I, 51-2; Hsiao, K., Baker, H., Crow, T., Poulter, M., Owen, F., Terwilliger, J., Westaway, D., Ott, J. and Prusiner, D. (1989) Linkage of a Prion Protein Missense Variant to Gerstmann-Sträussler Syndrome, Nature, 338, 342-5
43 Duffy, P., Wolf, J., Collins, G., DeVoe, A., Streeten, B. and Cowen, D. (1974) Possible Person-to-Person Transmission of Creutzfeldt-Jakob Disease, New England Journal of Medicine, 290, 692-3
44 Bernoulli, C., Siegfried, J., Baumgartner, G., Regli, F., Rabinowicz, T., Gajdusek, D., Gibbs, C. (1977) Danger of Accidental Person-to-Person Transmission of Creutzfeldt-Jakob Disease by Surgery, The Lancet, 1977I, 478-9
45 Koch, T., Berg, B., DeArmond, S. and Gravina, R. (1985) Creutzfeldt-Jakob Disease in a Young Adult with Idiopathic Hypopituitarism Possible Relation to the Administration of Cadaveric Human Growth Hormone, New England Journal of Medicine, 313, 731-3
46 Masters, C., Harris, J., Gajdusek, D., Gibbs, C., Bernoulli, C. and Asher, D. Creutzfeldt-Jakob Disease: Patterns of Worldwide Occurrence and the Significance of Familial and Sporadic Clustering, Annals of Neurology, 5, 177-88
47 Will, R., Mathews, W., Smith, P. and Hudson, C. (1986) A Retrospective Study of Creutzfeldt-Jakob Disease in England and Wales (1970-79) II: Epidemiology, Journal of Neurology, Neurosurgery and Psychiatry, 49, 749-55
48 Holman, R.C., Khan, A.C., Kent, J., Strine, T.W. and Schonberger, L.B. (1995) Epidemiology of Creutzfeldt-Jakob Disease in the United States, 1979-1990: Analysis of National Mortality Data, Neuroepidemiology, 14, 174-81
49 Kahana, E., Alter, M., Braham, J. and Sofer, D. (1974) Creutzfeldt-Jakob Disease: Focus Among Libyan Jews in Israel, Science, 183, 90-1
50 Cathala, F., Brown, P., LeCanuet, P. and Gajdusek, D.C. (1985) High Incidence of Creutzfeldt-Jakob Disease in North African Immigrants to France, Neurology, 35, 894-5
51 Herzberg, L., Herzberg, B.N., Gibbs, C.J. Jr, Sullivan, W., Amyx, H. and Gajdusek, D.C. (1974) Letter: Creutzfeldt-Jakob disease: hypothesis for high incidence in Libyan Jews in Israel, Science, 186, 848; Davanipour, Z., Alter, M., Sobel, E. and Callahan, M. (1985) Sheep Consumption: A Possible Source of Spongiform Encephalopathy in Humans, Neuroepidemiology, 4, 240-9
52 Masters, C., Harris, J., Gajdusek, D., Gibbs, C., Bernoulli, C. and Asher, D. (1979) Creutzfeldt-Jakob Disease: Patterns of Worldwide Occurrence and the Significance of Familial and Sporadic Clustering, Annals of Neurology, 5, 177-88
53 Matthews, W., Campbell, M., Hughes, J. and Tomlinson, A. (1979) Creutzfeldt-Jakob Disease and Ferrets, The Lancet, 1979I, 828
54 Goldfarb, L.G., Korczyn, A.D., Brown, P., Chapman, J. and Gajdusek, D.C. (1990) Mutation in Codon 200 of Scrapie Amyloid Precursor Gene Linked to Creutzfeldt-Jakob Disease in Sephardic Jews of Libyan and Non-Libyan Origin, The Lancet, 336, 637-8
55 Goldfarb, L.G., Korczyn, A.D., Brown, P., Chapman, J. and Gajdusek, D.C. (1990) Mutation in Codon 200 of Scrapie Amyloid Precursor Gene Linked to Creutzfeldt-Jakob Disease in Sephardic Jews of Libyan and Non-Libyan Origin, The Lancet, 336, 637-8; Brown, P., Gálvez, S., Goldfarb, L.G., Nieto, A., Cartier, L., Gibbs, C.J. Jr and Gajdusek, D.C. (1992) Familial Creutzfeldt-Jakob Disease in Chile is Associated with the Codon 200 Mutation of the PRNP Amyloid Precursor Gene on Chromosome 20, Journal of Neurological Science, 112, 65-7
56 Goldfarb, L.G., Brown, P., Mitrova, E., Cervenakova, L., Goldin, L., Korczyn, A.D., Chapman, J., Gálvez, S., Cartier, L., Rubenstein, R. and Gajdusek, D.C. (1991) Creutzfeldt-Jacob Disease Associated with the PRNP Codon 200Lys Mutation: an Analysis of 45 Families, European Journal of Epidemiology, 7, 477-86
57 Barker, D., Schafer, M. and White, R. (1984) Restriction Sites Containing CpG Show a Higher Frequency of Polymorphism in Human DNA, Cell, 36, 131-8; Korczyn, A.D. (1994) Neurological Genetic Diseases of Jewish People, Biomedicine and Pharmacotherapy, 48, 391-7
58 Bertoni, J.M., Brown, P., Goldfarb, L.G., Rubenstein, R. and Gajdusek, D.C. (1992) Familial Creutzfeldt-Jakob Disease (Codon 200 Mutation) With Supranuclear Palsy, Journal of the American Medical Association, 268, 2413-15
59 Collinge, J., Palmer, M.S., Campbell, T., Sidle, K.C., Carroll, D. and Harding, A. (1993) Inherited Prion Disease (PrP lysine 200) in Britain: Two Case Reports, British Medical Journal, 306, 301-2
60 Laplanche, J.L., Delasnerie-Laupretre, N., Brandel, J.P., Chatelain, J., Beaudry, P., Alperovitch, A. and Launay, J.M. (1994) Molecular Genetics of Prion Diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies, Neurology, 44, 2347-51
61 Inoue, I., Kitamoto, T., Doh-ura, K., Shii, H., Goto, I. and Tateishi, J. (1994) Japanese family with Creutzfeldt-Jakob Disease with Codon 200 Point Mutation of the Prion Protein Gene, Neurology, 44, 299-301
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63 Mitrova, E. and Mayer, V. (1977) Neurohistology of Early Preclinical Lesions in Experimental Subacute Spongiform Encephalopathy, Biologia (Bratislava), 32, 663-71
64 Manuelidis, E., Angelo, J., Gorgacz, E. and Manuelidis, L. (1977) Transmission of Creutzfeldt-Jakob Disease to Syrian Hamster, The Lancet, 1977I, 479
65 Davanipour, Z., Alter, M. and Sobel, E. (1986) Creutzfeldt-Jakob Disease, Neurologic Clinics, 4, 415-26
66 Gerstmann, J. (1928) Über ein noch nicht beschriebenes Reflexphänomen bei einer Erkrankung des Zerebellaren Systems, Wiener Medizinische Wochenschrift, 78, 906-8. Also known as Gerstmann-Sträussler-Scheinker syndrome
67 Masters, C., Gajdusek, D. and Gibbs, C. (1981) Creutzfeldt-Jakob Disease Virus Isolations from the Gerstmann-Sträussler Syndrome with an Analysis of the Various Forms of Amyloid Plaque Deposition in the Virus-Induced Spongiform Encephalopathy, Brain, 104, 559-88
68 Ibid.
69 Hsiao, K., Baker, H., Crow, T., Poulter, M., Owen, F., Terwilliger, J., Westaway, D., Ott, J. and Prusiner, S. (1989) Linkage of a Prion Protein Missense Variant to Gerstmann-Sträussler Syndrome, Nature, 338, 342-5
70 Ironside, J.W. and Bell, J.E. (1997) Pathology of Prion Disease, Prion Diseases, edited by Collinge, J. and Palmer, M.S., New York, Oxford University Press, 57-88
71 Zigas, V. and Gajdusek, D. (1957) Kuru: Clinical Study of a New Syndrome Resembling Paralysis Agitans in Natives of the Eastern Highlands of Australian New Guinea, Medical Journal of Australia, 2, 745-54
72 Alpers, M. (1970) III. Kuru in New Guinea: Its Changing Pattern and Etiologic Elucidation, American Journal of Tropical Medicine and Hygiene, 19, 133-7
73 Gajdusek, D. (1979) Observations on the Early History of Kuru Investigation, Slow Transmissible Diseases of the Nervous System, vol. 1, edited by Prusiner, S.B. and Hadlow, W.J., New York, Academic Press, 7-35
74 Gajdusek, D. and Gibbs, C. (1972) Transmission of Kuru from Man to Rhesus Monkey (Macaca Mulatta) eight-and-a-half Years after Inoculation, Nature, 240, 351; Gajdusek, D.C., Gibbs, C. and Alpers, M. (1966) Experimental Transmission of a Kuru-like Syndrome to Chimpanzees, Nature, 209, 794-6
75 Gibbs, C., Amyx, H., Bacote, A. and Masters, C. (1980) Oral Transmission of Kuru, Creutzfeldt-Jakob Disease, and Scrapie to Non-Human Primates, Journal of Infectious Diseases, 142, 205-8
76 Alpers, M. (1979) Epidemiology and Ecology of Kuru, Slow Transmissible Diseases of the Nervous System, vol. 1, edited by Prusiner, S.B. and Hadlow, W.J., New York, Academic Press, 7-35
77 Lugaresi, E., Medori, R., Mentagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., Tinuper, P., Zucconi, M. and Gambetti, P. (1986) Medical Intelligence: Fatal Familial Insomnia and Dysautonomia with Selective Degeneration of Thalamic Nuclei, New England Journal of Medicine, 315, 997-1003
78 Medori, R., Tritschler, H., Le Blanc, A., Vilare, F., Monetto, V., Chen, H., Xue, R., Leal, S., Montague, P., Cortelli, P., Tinuper, P., Avant, P., Mochi, M., Baruzzi, A., Hauw, J., Ott, J., Lugaresi, E., Autilio-Gambetti, L. and Gambetti, P. (1992) Fatal Familial Insomnia, a Prion Disease with a Mutation at Codon 178 of the Prion Protein Gene, New England Journal of Medicine, 326, 444-9
79 Bolton, D.C., McKinley, M.P. and Prusiner, S.B. (1982) Identification of a protein that purifies with the scrapie prion, Science, 218, 1309-11; Prusiner, S.B. (1982) Novel proteinaceous infectious particles cause scrapie, Science, 216, 136-44
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