Familial Prion Disease

Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

The prion diseases are a closely related group of neuro-degenerative conditions which affect both humans and animals. They have previously been described as the subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and the human prion diseases, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and kuru. Prion diseases are... 

Collinge, J. et al. Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases. Am. J. Hum. Genet. 49 1351-1354,1991. 

Fig. 3. Classification of human prion diseases. Sporadic the transformation from PrPc (circle) to PrPSc (square) occurs without apparent cause. Familial a point mutation ( ) is thought to facilitate the transformation. Infectious the transformation arises via PrPSc which acts as a template. The kinetic equations are defined by Eigen (1996). The infectious form includes kuru, iatrogenic CJD (iCJD), variant CJD (vCJD first reported in 1996), bovine spongiform encephalopathy (BSE first reported in 1985), and scrapie. In the nucleation-dependent model, monomeric PrPc and PrPSc are in chemical equilibrium.

The mysterious prions (proteinaceous infective agents), which are described briefly on p. 248, are under intensive investigation. Prion diseases affect fewer than one in 100,000 persons, but there is fear of a possible epidemic. Furthermore, there is a close relationship of prions to a large family of amyloid diseases. The most frequent of these is Alzheimer disease, which is estimated to affect one-third of people over 85 years of age in the United States.3/b... 

About 85% of all cases of prion disease are sporadic CJD. These are thought to arise by spontaneous conversion of PrPc to PrPSc. Inherited (familial) forms of CJD, GSS, and FFI are also known. 

The role of copper in other disease states is being investigated. For Alzheimer s disease studies, it has been found that the amyloid precursor protein interacts with copper to produce increased oxidant damage, and trace amounts of copper promote the precipitation of the amyloid p protein. In familial myotrophic lateral sclerosis about a quarter of the cases are caused by inherited dominant mutations in the Cu/Zn superoxide dismutase that probably result in abnormal Cu binding and the generation of reactive oxygen species. Copper has also been proposed to be involved in prion metabolism and fimction however, whether or not this imphcates copper in the prion diseases is unclear at this time. ... 

The familial prion diseases are inherited in an autosomal dominant manner and account for 10-15% of all human prion disease. They include familial CID (fCJD), GSS, and fatal familial insomnia (FH) (reviewed by Gambetti et al., 2003 and by Kong et al., 2003). The familial prion diseases are caused by pathogenic mutations in the PRNP coding sequence. To date, these include 24 mis-sense mutations that result in amino... 

The sites of prion agent replication and spread are largely cUctated by v hether the etiology of prion disease is sporadic, familial, or acquired. For example, in sCJD and fCJD, disease initiates in, and is largely confined to, the nervous system. In... 

CNS Pathogenesis of Sporadic, Familial, and Iatrogenic Prion Diseases... 

In familial prion diseases germ line mutations in the prion protein gene leads to PrP " deposition in the brain and nervous system. Prion agent has not been found in peripheral tissues in the limited number of familial prion disease cases that have been examined. 

The immune system plays a central role in the pathogenesis of prion infection. In the acquired human prion diseases, it is the initial site of agent replication prior to entry into the nervous system but the immune system does not appear to be essential in the pathogenesis of the familial and sporadic human prion diseases. Followdng peripheral exposure to the prion agent, the immune system can amplify prion infection but, interestingly, the adaptive immune response does not play a role in the clearance of the prion agent. 

Creutzfeldt-Jakob disease (CJD) the most common prion disease of humans and can have a sporadic, familial or acquired etiology. 

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