SEMINARS IN NEUROLOGY-VOLUME
12, NO. 3
SEPTEMBER 1992
Human Transmissible Neurodegenerative Diseases (Prion Diseases)
HISTORY T h e transmissible neurode~enerativediseases (TNDs) (Table 1) are somewhat heterogeneous human and animal diseases grouped together because they share certain common features.l Among the hallmarks of these diseases are that: (1) the associated signs and symptoms involve the central nervous system (CNS), which receives the brunt of the iniurv: , . most of the diseases share the pathologic features of neuronal loss, reactive gliosis, and the development of neuronal vacuolation ("spongiform change"); (2) they progress to an inevitable fatalterminus after a clinical course lasting months to years, and following a long incubatiorl period that in some cases may last decades; and (3) they are transmissible, and the etiologic agents (see later) have a nurnber of unique physicochemical and biologic properties that distinguish them from other known classes of infectious agents (Table 21. T h e nonlenclature of these diseases and of their etiologic agents has not been officially established. O u r discussion will be limited to the human TNDs, including kuru, Creutzfeldt-Jakob disease (CJD), and the Gerstmann-Strausslcr-Scheinker (GSS) syndronie. 'lwo putative 'I'NDs, Alpers disease and fatal familial insomnia (FFI), are also briefly discussed. This group of diseases has also been referred to as "unconventional viral disea~es,"~ "spongiform encephalopathies,"" "transmissiand "prion diseases.""In this ble cerebral an~yloidoses,"~ article. we havc used the terrrl "transmissible neurodegenerative diseasesn"o refer to these diseases as a group. Following the demonstration that kuru and CJD were caused by a transmissible agent,",' and that this agent had unique biologic properties that separated it from other known infectious pathogens (Table S), several names were proposed fbr the agents responsible for the TNDs. In 1982, Yrusiner" proposed the term "prion," reflecting the hypothesis that the T N D agent was a "novel proleinaceous infectiol~s particle" that lacked a detectable associated nucleic acid.' Although this term has subsequently gained wide currency, J
and will be used here. it is not r~niversallv accepted. Gajdusek',' has preferred the designation "unconventional viruses." Implicit in both terms, prion and unconventional virus, are assumptions concerning the nature of the T N D agents, which are still unproven. However, the bulk of recent evidence suggests that prions are, in fact, the etiologic agent of the 'I'NDs, and no conclusive evidence exists that prions contain nucleic acid. T h e term prion thus appears to reflect the state of knowledge concerning the 'l'ND agents more closely than the alternative term, unconventional virus. A full discussion of the development of ideas concerning the I N D s is beyond the scope of this article. Selected scientific landmarks can be found in Table 4. CJD!"' was the first T N D to be described; descriptions of GSS'" and kuru followed.'"~'TTheveterinarian Hadlow initiallv drew attention to similaritv between kuru and the transrriissible disease of sheep known as "scrapie.""' Gajdusek, Gihhs, Alpers, Asher, and Masters subsequently established that brain material from kuru," CJL)," and GSS1' trarlsrrlitted these diseases to primates. Experimental work was greatly facilitated by the development of a small-animal T h e unique characteristics of the etiologic agent led to the hypothesis that the disease might be caused by a proteinaceous infectious particle (prion).' Although no corivincing direct evidence tbr thc presence of a-prion-associated-ni~cleic acid currently exists, not all theories of the pathogenesis of' T N D exclude this possibility."'." More recent studies, reviewed in the section "Molecular Bioloev and Pathogenesis," havc led to more detailed characterization of prions and the genes encoding then], the development of transgenic mouse models of FI'NDs, and an explosion of' studks, which continue, defining the genetic substrate thr familial fi)rms of human TNDs. L 8 ,
KURU EPIDEMIOLOGY Kuru was the first of the human TNDs to be studied in detail.2,:
12, NO. 3
SEPTEMBER 1992
Human Transmissible Neurodegenerative Diseases (Prion Diseases)
HISTORY T h e transmissible neurode~enerativediseases (TNDs) (Table 1) are somewhat heterogeneous human and animal diseases grouped together because they share certain common features.l Among the hallmarks of these diseases are that: (1) the associated signs and symptoms involve the central nervous system (CNS), which receives the brunt of the iniurv: , . most of the diseases share the pathologic features of neuronal loss, reactive gliosis, and the development of neuronal vacuolation ("spongiform change"); (2) they progress to an inevitable fatalterminus after a clinical course lasting months to years, and following a long incubatiorl period that in some cases may last decades; and (3) they are transmissible, and the etiologic agents (see later) have a nurnber of unique physicochemical and biologic properties that distinguish them from other known classes of infectious agents (Table 21. T h e nonlenclature of these diseases and of their etiologic agents has not been officially established. O u r discussion will be limited to the human TNDs, including kuru, Creutzfeldt-Jakob disease (CJD), and the Gerstmann-Strausslcr-Scheinker (GSS) syndronie. 'lwo putative 'I'NDs, Alpers disease and fatal familial insomnia (FFI), are also briefly discussed. This group of diseases has also been referred to as "unconventional viral disea~es,"~ "spongiform encephalopathies,"" "transmissiand "prion diseases.""In this ble cerebral an~yloidoses,"~ article. we havc used the terrrl "transmissible neurodegenerative diseasesn"o refer to these diseases as a group. Following the demonstration that kuru and CJD were caused by a transmissible agent,",' and that this agent had unique biologic properties that separated it from other known infectious pathogens (Table S), several names were proposed fbr the agents responsible for the TNDs. In 1982, Yrusiner" proposed the term "prion," reflecting the hypothesis that the T N D agent was a "novel proleinaceous infectiol~s particle" that lacked a detectable associated nucleic acid.' Although this term has subsequently gained wide currency, J
and will be used here. it is not r~niversallv accepted. Gajdusek',' has preferred the designation "unconventional viruses." Implicit in both terms, prion and unconventional virus, are assumptions concerning the nature of the T N D agents, which are still unproven. However, the bulk of recent evidence suggests that prions are, in fact, the etiologic agent of the 'I'NDs, and no conclusive evidence exists that prions contain nucleic acid. T h e term prion thus appears to reflect the state of knowledge concerning the 'l'ND agents more closely than the alternative term, unconventional virus. A full discussion of the development of ideas concerning the I N D s is beyond the scope of this article. Selected scientific landmarks can be found in Table 4. CJD!"' was the first T N D to be described; descriptions of GSS'" and kuru followed.'"~'TTheveterinarian Hadlow initiallv drew attention to similaritv between kuru and the transrriissible disease of sheep known as "scrapie.""' Gajdusek, Gihhs, Alpers, Asher, and Masters subsequently established that brain material from kuru," CJL)," and GSS1' trarlsrrlitted these diseases to primates. Experimental work was greatly facilitated by the development of a small-animal T h e unique characteristics of the etiologic agent led to the hypothesis that the disease might be caused by a proteinaceous infectious particle (prion).' Although no corivincing direct evidence tbr thc presence of a-prion-associated-ni~cleic acid currently exists, not all theories of the pathogenesis of' T N D exclude this possibility."'." More recent studies, reviewed in the section "Molecular Bioloev and Pathogenesis," havc led to more detailed characterization of prions and the genes encoding then], the development of transgenic mouse models of FI'NDs, and an explosion of' studks, which continue, defining the genetic substrate thr familial fi)rms of human TNDs. L 8 ,
KURU EPIDEMIOLOGY Kuru was the first of the human TNDs to be studied in detail.2,:
