Inherited prion diseases.

Almost 70 years ago, the first report of patients dying of a dementing illness in families (1, 2) resembling those described a few years earlier by Jakob was published (3). For decades, this disease, often referred to as Jakob-Creutzfeldt disease, was considered a central nervous system (CNS) degenerative disease of unknown etiology, where most cases were sporadic and a few were of familial origin (4). The transmission of JakobCreutzfeldt disease to apes and later monkeys in 1968 transformed thinking about the etiology of this disorder (5) and was accompanied by an inversion of the eponyms to Creutzfeldt-Jakob disease (CJD) (6). The prolonged incubation periods in experimental primates and its presumed relationship to kuru of New Guinea cannibals and scrapie ofsheep led to its classification as a slow virus disease (7). With the recognition that 10%o of the CJD cases are familial (8, 9), the study of prion diseases grew more perplexing. Over the past 15 years, studies on the transmissible pathogen causing CJD of humans and the animal disease scrapie have established that CJD and scrapie are not caused by viruses but are due to prions (10). The discovery of the prion protein (PrP) in fractions enriched for scrapie infectivity provided the first molecular probe for investigating CJD (11). Like scrapie of animals, patients dying ofCJD accumulate a modified form of PrP often designated PrPSc or PrPCJD in their brains. Molecular cloning ofthe PrP gene and genetic linkage between scrapie incubation times and codon variations in mice (12, 13) raised the possibility that mutation might feature in the hereditary human prion diseases. Since the first mutations of the PrP gene were reported 5 years ago in humans dying of familial CJD and GerstmannStriussler-Scheinker disease (GSS) (14, 15), 18 different mutations have been identified. Five ofthe 18 have been linked genetically to the inherited prion diseases which include familial CJD and GSS (1519); the cumulative lod (logarithm of odds) score exceeds 30. The most recent addition to the human prion disease group is fatal familial insomnia (FFI). This disease presents with insomnia, dysautonomia, ataxia, dysarthria, dysphagia, myoclonus, and signs of pyramidal tract dysfunction. In the later stages ofthe illness, patients exhibit total insomnia, dementia with frontal lobe release signs, rigidity and dystonia, and mutism. Prior to death patients become stuporous and ultimately comatose (20-23). The progressive insomnia of FFI is characterized by a reduction ofthe total sleep time (TST) affecting both the non-rapideye-movement and rapid-eye-movement (REM) phases of sleep. In general, the diminished TST is unresponsive to medications including benzodiazepines and barbituates. Selective involvement of the thalamus was documented in living patients by positron emission tomography (PET), which showed profound hypometabolism using [18F]2-fluoro-2-deoxyglucose (24). The neuropathological lesions in FFI consist of neuronal dropout and astrocytic gliosis, which preferentially affect the ventral anterior and medial dorsal nuclei of the thalamus (21, 25, 26). Although the cerebral cortex is generally spared, occasionally it exhibits focal spongiform degeneration. Once immunostaining for protease-resistant PrP was found on Western immunoblots, the open reading frame of the PrP gene was sequenced, demonstrating a mutation at codon 178 (17, 21, 27). The codon 178 mutation was puzzling because it had been previously described in patients with familial CJD who presented with dementia rather than insomnia (28-30). Some investigators thought that another nearby gene segregating with the PrP gene in the Italian families with FF1 might be governing the clinical presentation and neuropathology of this inherited prion disease, particularly since these families might have a common ancestor giving rise to a founder effect. To explore the cause of the two distinct clinical presentations in patients carrying the codon 178 mutation, the codon 129 polymorphism was examined because earlier studies showed that homozygosity at this position lowers the age ofonset of familial CJD (31) and predisposes to the sporadic form ofthe illness (32). At position 129, either methionine or valine is commonly found, with methionine being the most common amino acid. In FF1, a methionine residue was always found at 129 on the mutant allele encoding asparagine in place of aspartic acid at 178; in striking contrast, a valine residue at 129 was observed on the mutant allele ofpatients with familial CJD with the 178 mutation (33). Furthermore, patients homozygous for the 129 polymorphism tended to have an early age of onset. Familial CJD with the Asp-178 -Asn (D178N) mutation and valine at codon 129 is designated CJD(D178N,V129). Prior to the discovery of the D178N mutation in patients with FFI and the classification of this illness as an inherited prion disease, FFI was classified as a thalamic dementia. That the codon 178 mutation is the cause of FFI is supported by a lod score that exceeds 5 (17). Whether all patients with the D178N mutation and methionine at 129 will manifest their disease as FFI both clinically and neuropathologically remains to be established. Of note is a Tennessee family with the D178N mutation, a methionine residue at 129, and deletion of a single eightamino acid residue repeat ("octarepeat") (34). While the proband did complain of insomnia initially, it was a minor symptom compared to his dysarthria and ataxia, but no sleep study was performed. By history, dementia was the most prominent feature of the illness in other members of this family, while insomnia or dysautonomia were not mentioned. The histopathological changes seem in this family to be similar to those described in subjects with FFI of a duration of 2 years or more (25). Specifically, among the major thalamic nuclei, the medial dorsal was preferentially affected with neuronal loss and gliosis but not spongiosis. Severe spongiform degeneration was present only in the parahippocampal gyrus, while it was moderate or minimal in the neocortex (C. VnencakJones, M. Johnson, and P. Gambetti, personal communication). It is ofinterest that the first family with CJD to be described (1, 2, 35) carries the D178N mutation and valine at codon 129 (H. A. Kretzschmar, M. Neumann, and D. Stavrou, personal communication). To explore why the neuropathology of FFI is restricted to thalamic nuclei, studies of the scrapie isoform of the prion protein designated PrPsc were performed (36). PrPsc is distinguished from the cellular isoform (PrPC) by its (-sheet conformation, insolubility, posttranslational formation, and protease resistance (10, 37). Earlier studies with experimental scrapie in