Iatrogenic transmission of Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease is a rare progressive neurological disorder which is eventually fatal. Attention has recently been focused upon the iatrogenic transmission of this disease by four published reports of patients developing Creutzfeldt-Jakob disease associated with the administration of human growth hormone preparations originally prepared from human cadaver pituitaries. Characterized clinically by ataxia, usually by dementia, and often by myoclonic movements, Creutzfeldt-Jakob disease progresses to a stuporose state and death within a few months of onset (Masters & Richardson, 1978). The disease has an incidence of approximately 1 per million of the population per year (Brown et al. 1985), and mainly affects those over 50 years of age; cases under 30 years old are very rare (Brown et al. 1985). Pathologically, Creutzfeldt-Jakob disease exhibits a characteristic histologic appearance of spongiform change in the neutropil of the cerebral cortex. Electron microscopy has shown that the spongiform change is due to the swelling and vacuolation of dendrites (Lampert et al. 1971, Gray, 1986). In patients surviving for more than 6 months with the disease, there is usually widespread gliosis of the cortex, basal ganglia and cerebellum with varying degrees of cerebral and cerebellar atrophy (Masters & Richardson, 1978). The transmissible nature of Creutzfeldt-Jakob disease became clear in 1968 when cerebral biopsy tissue from a patient with the disease was injected into the brain of a chimpanzee (Gibbs et al. 1968). After a period of 13 months, the animal developed the clinical and pathological signs of CreutzfeldtJakob disease. Although the identity of the transmissible agent was unknown at that time, it was soon recognized that Creutzfeldt-Jakob disease in man had many similarities to scrapie in sheep and that both diseases were due to unconventional agents or 'slow viruses'. The unconventional agent associated with scrapie has been much more extensively characterized than has the agent causing Creutzfeldt-Jakob disease (Kimberlin, 1986). However, neither the exact nature of the infective agents nor the mechanisms by which they cause scrapie or Creutzfeldt-Jakob disease has been fully elucidated. A proteinaceous infectious particle (prion) has been isolated from scrapie and from Creutzfeldt-Jakob infected brains (Prusiner, 1982; Prusiner et al. 1987). The protein is a glycoprotein with an apparent molecular weight of 27000-30000 daltons and is designated PrP 27-30 (Prusiner et al. 1987). This protein is a major constituent of the minute scrapie-associated fibrils (SAF), 4-6 nm in diameter, which can be isolated from scrapie and Creutzfeldt-Jakob infected brains, but not from normal brain (Merz et al. 1981, 1983; Carp et al. 1985). Coded by a single gene, PrP 27-30 is present in several species and is expressed in uninfected brains (Kimberlin, 1986). This normal protein seems to be modified in scrapie infected brains, so that it accumulates as scrapie-associated fibrils and as amyloid deposits. Although injection of preparations of scrapie-associated fibrils will transmit the disease, it is still not certain that the fibrils themselves are the infectious agent in scrapie or whether the agent itself is merely adherent to the fibrils (Kimberlin, 1986). It does appear from chemical studies that the scrapie and Creutzfeldt-Jakob agents do not contain significant amounts of DNA or RNAs as both agents are resistant to nucleases, ultraviolet light irradiation and other procedures which inactivate DNA and RNA. The protein nature of the scrapie agent is emphasized by its susceptibility to processes which inactivate proteins, such as the hydrolytic activity of trypsin (Griffin, 1985). However, it has been shown in scrapie that the infectious agent can undergo mutation and that it interacts with host genes; such observations suggest that there may be a small amount of nucleic