Gerstmann-Sträussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies

Abstract

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.