Prion Allele Review

NCBI ... by Orest Hurko et al... 5/8/1996

Gajdusek (1991) provided a chart of the PRNP mutations found to date: 5 different mutations causing single amino acid changes and 5 insertions of 5, 6, 7, 8, or 9 octapeptide repeats. He also provided a table of 18 different amino acid substitutions that have been identified in the transthyretin gene (TTR; 176300) resulting in amyloidosis and drew a parallel between the behavior of the 2 classes of disorders.

Schellenberg et al. (1991) sought the missense mutations at codons 102, 117, and 200 of the PRNP gene, as well as the PRNP insertion mutations, which are associated with CJD and GSSD, in 76 families with Alzheimer disease, 127 presumably sporadic cases of Alzheimer disease, 16 cases of Down syndrome, and 256 normal controls; none was positive for any of these mutations. Jendroska et al. (1994) used histoblot immunostaining in an attempt to detect pathologic prion protein in 90 cases of various movement disorders including idiopathic Parkinson disease, multiple system atrophy, diffuse Lewy body disease, Steele-Richardson-Olszewski syndrome, corticobasal degeneration, and Pick disease. No pathologic prion protein was identified in any of these brain specimens, although it was readily detected in 4 controls with Creutzfeldt-Jakob disease.

Perry et al. (1995) used SSCP to screen for mutations at the prion locus in 82 Alzheimer disease patients from 54 families (including 30 familial cases), as well as in 39 age-matched controls. They found a 24-bp deletion around codon 68 which removed 1 of the 5 gly-pro rich octarepeats in 2 affected sibs and 1 offspring in a late-onset Alzheimer disease family. However, the other affected individuals within the same pedigree did not share this deletion, which was also detected in 3 age-matched controls in 6 unaffected members from a late-onset Alzheimer disease family. Another octarepeat deletion was detected in 3 other individuals from the same Alzheimer disease family, of whom 2 were affected. No other mutations were found. Perry et al. (1995) concluded that there was no evidence for association between prion protein mutations and Alzheimer disease in their survey.

Hsiao et al. (1990) found no mutation in the open reading frame of the PRP gene in 3 members of the family analyzed, but Hsiao et al. (1992) later demonstrated a phe198-to-ser mutation.

Palmer and Collinge (1993) reviewed mutations and polymorphisms in the prion protein gene.


The human gene for prion-related protein has been mapped to 20p12-pter by a combination of somatic cell hybridization and in situ hybridization (Sparkes et al., 1986) and by spot blotting of DNA from sorted chromosomes (Liao et al., 1986). Robakis et al. (1986) also assigned the PRNP locus to 20p by in situ hybridization.

By analysis of interstitial 20p deletions, Schnittger et al. (1992) demonstrated the following order of loci: pter--PRNP--SCG1 (118920)--BMP2A (112261)--PAX1 (167411)--cen. Puckett et al. (1991) identified 5-prime of the PRNP gene a RFLP that has a high degree of heterozygosity, which might serve as a useful marker for the pter-p12 region of chromosome 20.

The structural gene for prion (Prn-p) has been mapped to mouse chromosome 2. A second murine locus, Prn-i, which is closely linked to Prn-p, determines the length of the incubation period for scrapie in mice (Carlson et al., 1986). Yet another gene controlling scrapie incubation times, symbolized Pid-1, is located on mouse chromosome 17. Scott et al. (1989) demonstrated that transgenic mice harboring the prion protein gene from the Syrian hamster, when inoculated with hamster scrapie prions, exhibited scrapie infectivity, incubation times, and prion protein amyloid plaques characteristic of the hamster. Hsiao et al. (1994) found that 2 lines of transgenic mice expressing high levels of the mutant P101L prion protein developed a neurologic illness and central nervous system pathology indistinguishable from experimental murine scrapie. Amino acid 102 in human prion protein corresponds to amino acid 101 in mouse prion protein; hence, the P101L murine mutation was the equivalent of the pro102-to-leu mutation which causes Gerstmann-Straussler disease in the human. Hsiao et al. (1994) reported serial transmission of neurodegeneration to mice who expressed the P101L transgene at low levels and Syrian hamsters injected with brain extracts from the transgenic mice expressing high levels of mutant P101L prion protein. Although the high-expressing transgenic mice accumulated only low levels of infectious prions in their brains, the serial transmission of disease to inoculated recipients argued that prion formation occurred de novo in the brains of these uninoculated animals and provided additional evidence that prions lack a foreign nucleic acid.

Studies on PrP knockout mice have been reported by Bueler et al. (1994), Manson et al. (1994), and Sakaguchi et al. (1996). Sakaguchi et al. (1996) reported that the PrP knockout mice produced by them were apparently normal until the age of 70 weeks, at which point they consistently began to show signs of cerebellar ataxia. Histologic studies revealed extensive loss of Purkinje cells in the majority of cerebellar folia. Atrophy of the cerebellum and dilatation of the fourth ventricle were noted. Similar pathologic changes were not noted in the PrP knockout mice produced by Bueler et al. (1994) and by Manson et al. (1994). Sakaguchi et al. (1996) noted that the difference in outcome may be due to strain differences or to differences in the extent of the knockout within the PrP gene. Notably, in all 3 lines of PrP knockout mice described, susceptibility to prion infection was lost.

Based on their studies in PrP null mice, Collinge et al. (1994) concluded that prion protein is necessary for normal synaptic function. They postulated that inherited prion disease may result from a dominant negative effect with generation of PrP-Sc, the posttranslationally modified form of cellular PrP ultimately leading to progressive loss of functional PrP (PrP-C). Tobler et al. (1996) reported changes in circadian rhythm and sleep in PrP null mice and stressed that these alterations show intriguing similarities with the sleep alterations in fatal familial insomnia.

Chapman et al. (1996) demonstrated fatal insomnia and significant thalamic pathology in a patient heterozygous for the pathogenic lysine mutation at codon 200 and homozygous for methionine at codon 129 of the prion protein gene. They stressed the similarity of this phenotype to that associated with mutations in codon 178


Owen et al. (1989) demonstrated an insertion in the open reading frame of the prion gene that tracked with Creutzfeldt-Jakob disease in a family. This was identified by an MspI polymorphism. With this restriction enzyme, controls and unaffected family members showed a single band; similar analysis of DNA from lymphocytes or postmortem brain tissue of affected individuals showed 2 bands. Restriction mapping suggested that the atypical band resulted from an insertion of about 150 bp in the open reading frame of the PRNP gene. Using the polymerase chain reaction (PCR), Owen et al. (1989) confirmed the presence of the insertion. Collinge et al. (1989) used the polymerase chain reaction to screen DNA samples from 12 unrelated persons with various familial dementias and ataxias for mutation in part of the prion protein gene. In a family in which GSD was not previously suspected, 2 members were found to have a 0.15-kb insertion similar in size to that found in another kindred with pathologically proven spongiform encephalopathy. Collinge et al. (1990) reported further on the family with presenile dementia in which GSD had been diagnosed on the basis of prion protein gene analysis which showed the 144-bp inframe insertion in the open reading frame previously identified by Owen et al. (1989, 1990). Extensive histologic examination of the brain of an affected individual showed no characteristic features of either GSD or Creutzfeldt-Jakob disease. This indicates that spongiform encephalopathy cannot always be excluded on neuropathologic grounds in a person dying of a dementing condition, and, therefore, that the true prevalence of these diseases is likely to be underestimated. From genealogic and molecular studies in 4 families in which early-onset dementia was inherited as an autosomal dominant, Poulter et al. (1992) demonstrated that the 4 families derived from 4 sibs whose parents were born in the late 18th century in southeast England. The disease was closely linked to a 144-bp insertion in the open reading frame of the PRNP gene; maximum lod = 11.02 at theta = 0. In the general population, the PRNP gene is polymorphic at codon 129 where approximately 30% of the population have valine and 70% methionine. The insertion in this extended family was always within a methionine-129 allele. Poulter et al. (1992) found that the age of death of affected individuals whose normal allele also encoded methionine at codon 129 (176640.0005) was significantly lower than those whose normal allele encoded valine. The clinical features were highly variable; the neuropathologic findings, as described by Collinge et al. (1992), sometimes included spongiform encephalopathy. At various times family members had carried diagnoses of Alzheimer disease, Huntington disease, Parkinson disease, myoclonic epilepsy, atypical dementia, Pick disease, Creutzfeldt-Jakob disease, and Gerstmann-Straussler syndrome.

In a family with affected members in 3 generations and a second family with affected members in 4 generations, Hsiao et al. (1989) showed that a change in codon 102 of the prion protein gene is linked to the putative gene for GSD. Furthermore, substitution of leucine for proline at codon 102 may play a pathogenic role in the etiology of the disease. The pro-to-leu change resulted from substitution of thymine for cytosine in the second position of codon 102, creating a DdeI restriction site. On the basis of clinical and pathologic criteria, Hsiao et al. (1989) classified the Gerstmann-Straussler syndrome into 3 forms: an ataxic form, for which the pro-to-leu substitution seems to be characteristic; a dementing form; and a dementing form that is accompanied by pathologic quantities of neurofibrillary tangles (NFTs). If the leucine substitution at codon 102 arose independently in the 2 pedigrees studied, a likely possibility, it may represent more than a linked genetic marker and may itself provoke the development of GSD. Although the composition of the GSD prion remained to be determined, it is likely that it is composed largely, if not entirely, of an abnormal isoform of the human prion protein. The pro102-to-leu substitution was found in none of a random sample of 100 Caucasian persons. Goldgaber et al. (1989) found the same mutation in a family with 3 persons affected with GSD. The base substitution responsible for the change in codon 102 may have involved deamination of a methylated cytosine situated 5-prime to guanine, a CpG mutation. The proline at codon 102 seems to be highly conserved, as all rodent proline genes sequenced to date also encode a proline at the equivalent codon. Doh-ura et al. (1989) reported that the leu102 mutation was found in all 11 Japanese GSD patients studied. Speer et al. (1991) added to the evidence that the pro102-to-leu mutation is responsible for GSD; in a large German family they found a peak lod score of 1.15 at a recombination fraction of 0.00 for linkage between the mutation and the disease. Combined with previous data, the peak lod score of 4.52 at theta = 0.0 was obtained with no evidence of linkage heterogeneity in the combined data. Three asymptomatic members of the German family carried the substitution; their ages, 41, 42, and 42, were below the mean for age of onset (47 years) for GSD in this family. Goldhammer et al. (1993) described an Ashkenazi Jewish family living in Israel in which Gerstmann-Straussler syndrome was due to the pro102-to-leu mutation in the PRNP gene.

In a study of mutations in PRNP in patients with GSD, Hsiao et al. (1989) identified a PvuII polymorphism at codon 117 resulting from a 'silent' adenine-to-guanine substitution at the third position of alanine codon 117. This polymorphism was present in 1 of 2 families with a pro102-to-leu substitution.

A French patient was found by Doh-ura et al. (1989) to have a change from alanine to valine in codon 117. The patient with the val117 mutation was a member of an Alsatian GSD family that had at least 8 affected individuals spread over 4 generations. Although the Gerstmann-Straussler syndrome in Doh-ura's family presented with a dementia, so-called 'telencephalic Gerstmann-Straussler syndrome.' Mastrianni et al. (1995) presented a family in which heterozygotes for the identical mutation at codon 117 but presented with ataxia rather than dementia. No additional mutations were found at the polymorphic codon 129. Valine was encoded by both alleles in the proband. There was an additional silent GCA-to-GCG mutation at codon 117 on the normal allele. The authors suggested that other factors must be responsible for the ataxic presentation in this family rather than the telencephalic presentation in the previous families described for the same mutation.

The proband in the French family with GSD and the ala117-to-val substitution Doh-ura et al., 1989) was heterozygous for the PvuII polymorphism listed. Clones from the PvuII(-) allele were found to have 2 new nucleotide changes: a C-to-T transition at the second letter of codon 117 leading to the alanine-to-valine change, and an A-to-G transition at the first letter of codon 129 resulting in a methionine-to-valine substitution. Since the val129 change was found in subjects unrelated to GSD, Doh-ura et al. (1989) concluded that it represented a polymorphic change that is found in higher frequency in Caucasians. Owen et al. (1990) confirmed the conclusion and suggested that the met129-to-val polymorphism might be useful for genetic linkage studies of transmissible dementias in which mutation in the PRNP gene had not yet been identified. On the basis of studies in 36 Caucasians, they estimated that the met129 allele had a frequency of 0.68 and the val129 allele 0.32. They referred to these alleles as A1 and A2, respectively.

In a study of all patients in the United Kingdom who developed CJD following treatment with human cadaveric pituitary hormone, Collinge et al. (1991) found a significant excess of val129 homozygotes. In a further study, Palmer et al. (1991) found that 21 of 22 sporadic CJD cases and a further 19 of 23 suspected sporadic CJD cases were homozygous at the polymorphic amino acid residue 129; 51% of the normal population was heterozygous at this site. They interpreted these findings as suggesting that dimerization of the prion protein is an important element in the pathogenesis of CJD and that this is more likely to occur in homozygotes than in heterozygotes. De Silva et al. (1994) examined 29 cases of sporadic CJD and found amyloid plaques in only 7. In those patients with amyloid plaques, val/val at position 129 was present in 0.43, met/val in 0.29, and met/met in 0.29. These figures contrasted with the frequencies found in all sporadic CJD cases that they reviewed: val/val in 0.9, met/val in 0.9, and met/met in 0.83. Doh-ura et al. (1991) suggested that either homozygosity or heterozygosity for the val129 mutation could result in CJD in Japanese patients and that it usually took the form of Gerstmann-Straussler disease.

Goldfarb et al. (1992) reported the interesting observation that when the val129 allele was present on the same chromosome as the asp178-to-asn mutation, the phenotype was that of CJD, whereas the met129/asn178 allele segregated with fatal familial insomnia. The primary event in the pathogenesis of sporadic prion diseases is thought to be an acquired conformational change of the normal prion isoform that acts as a template, engendering the formation of insoluble aggregates (Brown et al., 1991; Prusiner, 1991). In inherited prion diseases, mutant isoforms would spontaneously assume conformations depending on the mutation. An interaction between methionine or valine at position 129 and asparagine at position 178 might result in 2 abnormal isoforms that differ in conformation and pathogenic consequences.

Monari et al. (1994) provided an explanation for the difference in phenotype of the asp178-to-asn mutation depending on whether methionine or valine was present as residue 129. They found that the abnormal isoforms of the prion protein in the 2 diseases differed both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the 2 diseases. These differences were thought to be responsible for the type and location of the lesions that characterized the 2 disorders. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing 2 altered conformations of the prion protein. See review of Gambetti et al. (1993).

In 2 patients with Creutzfeldt-Jakob disease from the same family, Goldgaber et al. (1989) found a substitution of lysine for glutamic acid at residue 200, resulting from a G-to-A transition changing GAG to AAG. Studying an unusual cluster of cases of CJD in rural Slovakia, Goldfarb et al. (1990) found the codon 200 mutation in all 11 tested cases of 'focal CJD,' in 12 of 40 healthy first-degree relatives, and in 6 of 23 other relatives. By contrast, no extrafocal cases or their relatives had the mutation; nor did any unrelated individuals within or outside the cluster regions. One of the healthy individuals with the codon 200 mutation was the 75-year-old mother of one of the patients. The unusually high incidence of CJD in the Orava and Lucenec regions of Slovakia appears to be of recent origin. Goldfarb et al. (1990) interpreted this as indicating that the mutation is a necessary but not sufficient factor in the disease. Another factor such as scrapie-infected sheep was proposed. Mitrova et al. (1990) described the familial occurrence of 3 definite and 2 possible cases of CJD with temporal and spatial separation in the area of focal CJD accumulation in Slovakia. The incubation period appeared to be about 51 years, judging by the interval between the death of the affected mother and the clinical onset in the first affected child. Affected offspring tended to die at the same time, not at the same age. Due to separation of the affected children, a possible common exposure to CJD infection was limited to approximately 7 years during their childhood.

Goldfarb et al. (1991) found the glu200-to-lys mutation in 45 of 55 CJD-affected families studied at the NIH laboratory. The families contained a total of 87 patients and originated from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Neuropathologic verification was available in 47 patients, and brain tissue from 14 patients transmitted disease to experimental primates. All the patients originating from the cluster areas carried the mutation but it was seen in only 1 of 103 unrelated control individuals from the same areas and in none of 102 controls from other areas. Branches of some families migrating from cluster areas to other countries continued to have CJD over several generations. Gajdusek (1991) suggested that the glu200-to-lys mutation may be frequent in Sephardic Jews and the descendants of converted Sephardic Jews. They found the mutation in Greek CJD patients who were Sephardic Jews and in Sephardic Jews who had come for diagnosis to France from Tunisia as well as in Sephardic Jews with CJD in Israel, both Libyan-born and Israel-born. Ashkenazic Jewish CJD patients did not have the codon 200 mutation. Gajdusek (1991) suggested that cases of CJD in the Iberian Peninsula and perhaps those in Chile may represent the codon 200 mutation inherited from Jewish ancestors converted to Catholicism. In reporting further on familial CJD in Chile, Brown et al. (1992) again suggested that Jewish migration from Spain may have brought the mutation to South America. Chapman et al. (1992) reported the first transmission of spongiform encephalopathy to a primate inoculated with material from a Libyan Jew with the codon 200 mutation. The incubation period was 6 years, but the authors commented that even longer incubation periods have occasionally been observed. Gabizon et al. (1993) reported that the lys200 mutation in Libyan Jewish patients is genetically linked to CJD with a lod score of greater than 4.8. No linkage was found between the development of familial CJD and the polymorphism encoding either met or val at residue 129.

Goldfarb et al. (1994) estimated the penetrance of the glu200-to-lys mutation to be 0.56. Chapman et al. (1994) estimated age-specific penetrance of CJD among Libyan-Tunisian Jews carrying the glu200-to-lys mutation, by performing lifetable analysis of 52 individuals with definite or probable CJD and 34 clinically unaffected carriers of the mutation. The cumulative penetrance reached 50% at age 60 years and 80% at age 80. If they included 7 elderly individuals with possible CJD, the penetrance approached 100% by age 80.

In a study of the largest kindred yet studied, of German ancestry with 368 members, 9 of whom were known to have died from CJD, Bertoni et al. (1992) identified a GAG-to-AAG transition in codon 200 resulting in substitution of lysine for glutamic acid. Clinically, the CJD in this kindred was atypical with early supranuclear gaze palsy but without myoclonus or characteristic electroencephalographic periodicity patterns.

In a Finnish family with Creutzfeldt-Jakob disease, Goldfarb et al. (1990) described a GAC-to-AAC mutation at codon 178 of the scrapie amyloid precursor gene. Nieto et al. (1991) found the same mutation, which resulted in substitution of asparagine for aspartic acid, as the cause of transmissible CJD in an American family of Dutch descent, an American family of Hungarian descent, and a French family from Brittany. The Finnish family was the only familial CJD identified in that country (Haltia et al., 1991). The pedigree included 15 affected members in 4 generations in a pattern consistent with autosomal dominant inheritance. The mean age at onset was 47, periodic EEG activity was not observed, and the mean duration of illness of 27.5 months was longer than usual in either familial or sporadic CJD. Neuropathologic examination of brain biopsy and autopsy specimens showed spongiform change without amyloid plaques, and brain tissue from 1 patient transmitted disease to a capuchin monkey. Goldfarb et al. (1992) identified the codon 178 mutation in 7 unrelated families of western European origin, among which a total of 65 members were known to have died from CJD. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control persons. Linkage analysis in informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggests that the codon 178 mutation is the cause of the disease.

Brown et al. (1992) compared a group of 43 patients from 7 families affected by CJD caused by the asp178-to-asn mutation to a group of 211 patients with the sporadic form of the disease. In general the patients with the codon 178 mutation had an earlier age of onset of illness (almost always presenting as an insidious loss of memory), a longer duration of illness, and an absence of periodic EEG activity. Transmission of the disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings were interpreted as indicating an accelerated induction of polymerized amyloid protein by its mutationally altered template precursor. Brown et al. (1992) suggested that the earlier age of onset in patients with the codon 178 mutation than in the sporadic patient group may reflect differing rates at which normal host precursor protein is converted into amyloid polymer. If one accepts that an altered protein molecule may serve as a nucleating template to initiate and sustain the conversion process, a 1-per-million probability of its random occurrence would equal the worldwide incidence of sporadic CJD. Precursor protein that has a primary structure already altered by the codon 178 mutation can be presumed to have a correspondingly altered 3-dimensional structure, and this structure may facilitate (by a millionfold) its conversion to the beta-pleated sheet configuration of amyloid fibrils.

An exception to the phenotypic rule of early onset found by Brown et al. (1992) was described by Laplanche et al. (1992) in a man who was well and professionally active until the age of 57 years when he had onset of loss of memory, vertigo, and disorientation, leading to professional disability 9 months later. The presence of periodic EEG activity also distinguished him from others carrying this mutation. Multiple genetic or environmental factors may modulate the clinical presentation of CJD associated with the codon 178 mutation.

The same asp178-to-asn mutation has been found as the cause also of fatal familial insomnia; the reason for the difference in phenotype was at first not clear. Goldfarb et al. (1992) demonstrated that the particular allele in the met129-to-val polymorphism was responsible for the difference. CJD was associated with val129 in all 15 affected members of 6 kindreds, whereas met129 was associated with FFI in all 15 affected members of 5 kindreds.

Familial CJD was first described in the Backer family living in northern Germany (Meggendorfer, 1930). Further clinical and neuropathologic details were reported by others. Autopsies were performed on 3 members of this family in the 1920s and 1940s. Kretzschmar et al. (1995) presented DNA sequencing data from brain tissue that had been embedded in celloidin 72 years previously. PCR amplification of DNA showed a GAC-to-AAC substitution at codon 178 of the prion protein gene.

The PRNP gene has an unstable region of 5 variant tandem octapeptide coding repeats between codons 51 and 91. Searching for the presence of extra repeats in this region, Goldfarb et al. (1991) screened 535 persons, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurologic and nonneurologic patients, and normal controls. They identified 3 CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had 'wobble' nucleotide substitutions. They also found 1 person with 9 repeats and no nucleotide substitutions who had no evidence of neurologic disease. These observations, together with data on British patients with 11 and 14 repeats (Owen et al., 1989, 1990; strongly suggested that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD. In an American family of English origin with an unusually early-onset and long-duration form of CJD, Brown et al. (1992) found a heterozygous insert mutation in the region of repeating octapeptide coding sequences between codons 51 and 91 of the PRNP gene. Affected members were 23 to 35 years old at the onset of the illness which lasted from 4 to 13 years; yet experimental transmission of disease from the proband, whose illness had gone on for 11 years, produced a typically brief incubation period and duration of illness in each of 3 inoculated primates. Also, the PrP amyloid protein that accumulated in the brain of one case with massive spongiform change was only barely detectable in extracted brain tissue and was undetectable in another case with no spongiform change. The insert in this case consisted of 7 extra copies of the octapeptide coding sequence. Other families with extra octapeptide coding repeats showed similar atypical features.

Krasemann et al. (1995) found heterozygosity for an insertion mutation predicting 9 octapeptide repeats between codons 51 and 91 in a 34-year-old woman with a 6 year history of progressive dementia and ataxia. The alignment of the insertion in this patient differed from that reported previously.

Campbell et al. (1996) demonstrated a novel 4-octarepeat insertional mutation in a sporadic case of Creutzfeldt-Jakob disease. The authors stated that since only 2 octarepeats are seen in the wildtype allele and the mutant consists of four R2 repeat elements, the mutation presumably evolved over several meioses.

Medori et al. (1992) used antibodies to prion protein to perform dot and Western blot analyses, with and without proteinase K, on brain tissue obtained at autopsy from 2 patients with FFI, as well as 3 patients with sporadic Creutzfeldt-Jakob disease and 6 control subjects. Protease-resistant PrP was found in both patients with FFI, but the size and number of protease-resistant fragments differed from those in Creutzfeldt-Jakob disease. Medori et al. (1992) found that in the family with FFI, all 4 affected persons and 11 of the 29 unaffected persons had a point mutation (GAC to AAC) in codon 178 resulting in the substitution of asparagine for aspartic acid. The mutation abolished a normal Tth111-I restriction site, permitting the identification of the mutation in heterozygous state in other members of the family. Linkage analysis showed a close relation between the point mutation and the disease (maximum lod score = 3.4 at theta = 0.0). Precisely the same mutation had been described in families with the Creutzfeldt-Jakob disease phenotype . The 3 families previously reported with the asp178-to-asn mutation and the CJD phenotype were Hungarian-Romanian, Finnish, and French, respectively. The family with FFI was of Italian ancestry. Goldfarb et al. (1992) suggested that the difference in phenotype resulting from the same mutation, asp178-to-asn, was the consequence of the particular allele at the met129-to-val polymorphism; all FFI cases were met129. In a French family with the asp178-to-asn mutation in the PRNP gene, Medori and Tritschler (1993) concluded that the FFI phenotype was not influenced by polymorphic site 129 and that the variation in phenotype may reflect the action of modifier loci or environmental influences. They found that individuals with early or late onset had the met129-to-val polymorphism. Moreover, of 5 asn178 asymptomatic FFI persons, 2, aged 62 and 68 years, showed homozygous met129, while the other 3 had met129val.

Medori et al. (1992) identified the asp178-to-asn mutation in another family with FFI. The family was Italian.

Tateishi et al. (1995) reported the successful transmission of fatal familial insomnia to experimental animals via intercerebral injection of affected patient brain tissue, thus placing FFI within the group of infectious cerebral amyloidoses. The patient from whom brain tissue was obtained was thought to be an isolated case but was later discovered to have ancestral ties to a previously reported American FFI family (Bosque et al., 1992). Illness began with episodic sensory, motor, and visual complaints and thereafter followed a fairly typical course that included intractable insomnia, with characteristic thalamic pathology, and the FFI genetic 'signature' PRNP genotype: asp178-to-asn and met129. Like other affected members of the distantly related branch of his family, he also had a 24-bp deletion between codons 51 and 91 (Reder et al., 1995). Of the inoculated mice, 14 of 18 developed typical signs of spongiform encephalopathy and died between days 397 and 506.

A variant form of Gerstmann-Straussler disease (GSD) was recognized in a large Indiana kindred which was traced to the year 1792 (Farlow et al., 1989; Ghetti et al., 1989). In each of the generations since 1792, affected members have been identified by either history or clinical examination. The neuropathologic findings were unique in that unlike other GSD patients with presenile onset of neurologic disability, all affected subjects had widespread Alzheimer-type NFTs, composed of paired helical filaments, in the cerebral cortex and subcortical nuclei. The amyloid core of plaques was immunolabeled with antibodies raised to PrP but not with antibodies raised to beta-amyloid. There was an autosomal dominant pattern of inheritance. A T-to-C transition in codon 198 leading to substitution of serine for phenylalanine was demonstrated by Hsiao et al. (1992). Dlouhy et al. (1992) showed absolute linkage of the phe198-to-ser mutation to the clinical phenotype in this kindred. Their studies suggested that methionine/valine heterozygotes at PRNP codon 129 have a later age of onset of the disease than individuals who are 129 valine/valine homozygotes. Giaccone et al. (1992) presented immunohistochemical evidence that the major amyloid component in the GSD Indiana kindred is an internal fragment of the prion protein and that full-length abnormal isoforms of the prion protein and/or large prion protein fragments accumulate in brain regions most affected by amyloid deposition. The findings were considered supportive of the view that in this kindred a stepwise degradation of PrP occurs in situ in the process of amyloid fibril formation.

Tagliavini et al. (1994) demonstrated that in the Indiana family, the amyloid fibrils contained only mutant peptides. The patients were heterozygous for the met-val polymorphism at PRNP codon 129 (176640.0005). In the amyloid of both patients, only val was present at position 129. Since val129 was in coupling phase with ser198, the finding indicated that only the mutant peptide was involved in amyloid formation.

In a Swedish family in which Gerstmann-Straussler-Scheinker disease was associated with the development of both PrP amyloid plaques and neocortical NFTs, similar to the findings in the Indiana kindred described in Hsiao et al. (1992) found a missense mutation resulting in the substitution of arginine for glutamine at codon 217. In this Swedish family, affected persons were heterozygous for the met-val polymorphism at codon 129; as in the Indiana family, deposited amyloid contained only val at position 129. Since val129 was in coupling phase with arg217, the finding indicated that only the mutant peptide was involved in amyloid formation.

In a 68-year-old woman with familial Creutzfeldt-Jakob disease, Pocchiari et al. (1993) described a G-to-A transition in codon 210 resulting in the substitution of isoleucine for valine. In 4 of 22 patients with CJD whose recorded family history was negative for demented illness, but in none of 103 healthy control subjects, the same val210-to-ile mutation was found. This and the finding that only the mutated protein accumulated in the brain tissue of the proband supported the pathogenetic significance of the mutation. However, 2 members of the proband's family were found to carry the mutation without symptoms of CJD at ages 81 and 82 years. Thus, environmental factors or reasons for incomplete penetrance may be involved.

In a Japanese man, aged 53 years at the time of death, Yamada et al. (1993) related Gerstmann-Straussler disease to the presence of heterozygosity for a CCA-to-CTA (pro-to-leu) change at codon 105. It was accompanied by val at the codon 129 polymorphism . The mother had died at age 78 after showing dementia for the last 3 years of her life but no other neurologic symptoms. The propositus first noticed clumsiness of the right hand at age 42, and then developed gait disturbance. At age 49, he showed spastic paraparesis, ataxia, memory impairment, and dysarthria. He became bedridden at age 50 and underwent progressive decline and intellectual function with death from ileus at age 53.

In a Japanese patient with CJD, Kitamoto et al. (1993) found a codon 180 mutation that resulted in a valine to isoleucine change in the prion protein. Clinical course was similar to that of the codon 178 mutation, in which the average age of onset is about 9 years younger than that of CJD due to the codon 200 mutation.

Kitamoto et al. (1993) found a met232-to-arg variant of the prion protein in combination with the val180-to-ile mutation in 2 patients who had typical clinical and pathologic findings of CJD.


1. Bertoni, J. M.; Brown, P.; Goldfarb, L. G.; Rubenstein, R.; Gajdusek, D. C. :
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95. Tagliavini, F.; Prelli, F.; Porro, M.; Rossi, G.; Giaccone, G.; Farlow, M. R.; Dlouhy, S. R.; Ghetti, B.; Bugiani, O.; Frangione, B. :
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97. Telling, G. C.; Scott, M.; Mastrianni, J.; Gabizon, R.; Torchia, M.; Cohen, F. E.; DeArmond, S. J.; Prusiner, S. B. :
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98. Tobler, I.; Gaus, S. E.; Deboer, T.; Ackermann, P.; Fischer, M.; Rullcke, T.; Moser, M.; Oesch, B.; McBride, P. A.; Manson, J. C. :
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99. Westaway, D.; DeArmond, S. J.; Cayetano-Canlas, J.; Groth, D.; Foster, D.; Yang, S.-L.; Torchia, M.; Carlson, G. A.; Prusiner, S. B. :
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