Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS),
fatal familial insomnia (FFI) and
kuru constitute major human
prion disease phenotypes. Each has been successfully transmitted in animal models and all are invariably fatal
neurodegenerative disorders, with the brains of affected individuals harbouring variable amounts of an abnormal,
protease-resistant form of the
prion protein (PrPres), which is inextricably linked to pathogenesis and transmissibility. Classical
sporadic CJD is the most common human
transmissible spongiform encephalopathy (TSE), but recently the variant form (vCJD), first described in the UK in 1996, has drawn considerable attention. In contrast to
sporadic CJD, FFI and GSS are almost invariably genetically determined TSEs, caused by a range of mutations within the open reading frame of the
prion protein gene (PRNP) on chromosome 20. By definition, the nosologic term FFI is reserved for patients manifesting prominent
insomnia, generally in combination with
dysautonomia,
myoclonus, and eventual
dementia, with the predominant pathologic changes lying within the thalami and a specific underlying mutation in PRNP. GSS, however, encompasses a more diverse clinical spectrum ranging from progressive
cerebellar ataxia or
spastic paraparesis (both usually in combination with
dementia), to isolated
cognitive impairment resembling
Alzheimer's disease. Additional extra-pyramidal features, which may respond to dopaminergic
therapy can also be seen. Neuropathological findings are also relatively diverse, partly overlapping with those found in
Alzheimer's disease, especially the presence of neurofibrillary tangles (NFTs). Although GSS and FFI in their classical forms are differentiable clinical profiles, such divisions may have no intrinsic
biological validity given the considerable intra-familial clinico-pathological diversity so commonly seen.
Kuru constitutes a horizontally transmitted
prion disease, which after a lengthy incubation period, presents clinically as a progressive
cerebellar ataxia associated with
tremors. It has now almost disappeared since the cessation of ritualistic endocannibalism in the late 1950s but was previously exclusively endemic amongst the Fore linguistic group and neighbouring tribes in the Eastern Highlands of New Guinea. Uniform topographical central nervous system histopathology includes spongiform change and neuronal loss, with
amyloid (
kuru) plaques in approximately 75% of cases.