The Prion Diseases

James A. Mastrianni, M.D., Ph.D. and Raymond P. Roos, M.D., Department of Neurology, The University of Chicago Medical Center, Chicago, Illinois.

Semin Neurol. 2000;20(3) 

In This Article

Phenotypes of Prion Disease

A remarkable feature of prions is the variety of dis-ease phenotypes with which they are associated. It is interesting to contrast this situation with Alzheimer dis-ease. Alzheimer disease is defined by one pathologic phenotype of A -plaques and neurofibrillary tangles59 yet is associated with at least four separate gene products. In contrast, prion disease, which appears to be due to a single gene product (although the role of Dpl is yet to be determined), presents with several, in some cases, strikingly different clinical and pathologic phenotypes. A potential explanation for the varied disease phenotypes first came from the recognition of different prion strains in animals.[60] In particular, the HYPER and DROWSY strains of hamster-passaged TME were found to be associated with different behavioral phenotypes, pathological profiles, and incubation periods.[61,62] The protease-resistant PrPSc associated with each strain has a different electrophoretic mobility, suggesting a difference in the conformation of PrPSc . Transmission of phenotypically distinct human prion diseases to transgenic mice has shown that PrPSc conformation and disease phenotype are interrelated.[63,64] Furthermore, studies using methods to estimate conformational differences of PrP molecules have shown that multiple subconformations of PrPSc are associated with different animal prion strains.[65] Surprisingly, a study suggested that more than one PrPSc conformer may coexist in the brains of some patients; further study of these issues is warranted.[66]

Several clinical varieties of prion disease have been described; however, the variability in presentation makes subdivision by clinical phenotypes alone difficult. A more consistent feature with which to discriminate different phenotypes is the pathologic profile. Based on this, five major subtypes have emerged: kuru, CJD, GSS, FI, and vCJD. Kuru is a prion disease confined to the Fore people in the highlands of New Guinea who practiced ritualistic cannibalism. It is the first recognized human TSE. Pathologic features include diffuse spongiform change, neuronal dropout, and dense core amyloid deposits ("kuru plaques"), found primarily within the cerebellum.[67] As the practice of cannibalism has ceased, kuru has disappeared. CJD is defined by the presence of diffuse spongiosis of the gray matter with few or no PrP-amyloid plaques, whereas extensive PrP-amyloid deposition with minimal spongiform change denotes the GSS subtype of prion disease. Neurofibrillary tangles, a common feature of Alzheimer disease, are also a feature in three variants of GSS.[68,69,70,71] The distinctive subtype of FI has a pathologic profile of thalamic gliosis with minimal or no spongiform change. The presence of dense core PrP-plaques surrounded by a halo of vacuolar change, the so-called "florid" plaques, are the pathognomic feature of vCJD. The following sections detail the clinical and pathologic phenotypes of the major categories of the current human prion diseases.

In its sporadic or nonfamilial form, CJD is the most common of the human prion diseases. Although Creutzfeldt is credited with the first description of this disease, it is questioned whether the patient he described actually had prion disease because spongiform change was not evident in the pathological specimens. In 1921 Jakob described four additional patients, only one of whom had spongiform change.[73,74,75,76]

Confusion and forgetfulness that progress rapidly to severe cortical dementia in combination with ataxia, myoclonus, and an abnormal electroencephalogram (EEG) represents the "classic tetrad" of CJD. However, a host of other neurologic signs and symptoms, including diffuse or focal weakness, painful neuropathy, chore-iform movements, hallucinations, cortical blindness, primary language disturbance, supranuclear ophthalmoplegia, and alien hand syndrome, among others, have been observed.[77,78] Vague complaints of fatigue, headache, sleep disturbance, vertigo, and behavioral changes may precede the development of frank progressive dementia by weeks or months in over 25% of cases. As the disease progresses from the early stage, ataxia commonly limits the patient's mobility and the family may report "walking like a drunk" or excessive falling. Myoclonic jerks may appear at any time but are more common in the middle to later stage of the disease. Frontal release signs may be evident and exaggerated along the course. Stimulus-related myoclonus is often present; clapping hands or turning on the lights in a darkened room may induce this response. Hallucinations and seizures may be observed in a smaller percentage of cases.

During the course of disease, the EEG generally exhibits periodic or pseudoperiodic paroxysms of triphasic or sharp waves of 0.5 to 2.0 Hz against a slow background. A negative EEG does not exclude the diagnosis, because at least 30% of cases may not demonstrate the typical features. There may be a window of opportunity to detect the abnormal EEG, as it may be negative early or late in the course. Therefore, serial EEGs weekly or every other week may be necessary to capture the periodic discharges.

The lumbar puncture is generally negative with the exception of mildly elevated protein. Detection of the 14-3-3 protein in the spinal fluid has been reported by some as helpful in the diagnosis,[79,80,81] although false positives and negatives are somewhat common. A small proportion (approx 10%) of sCJD cases also demonstrate hyperintensity on T2-weighted images within the basal ganglia.[82]

Once the disease declares itself, the pace of progression is generally rapid. In the terminal stage of dis-ease, the patient is bedridden and mute but may continue to have sleep-wake cycles and spontaneous motor movements. The average duration of the disease is 4 to 5 months, with death usually resulting from respiratory complications or sepsis related to incontinence.

A minority of CJD cases (<20%) may have atypical presentations, such as a relatively abrupt onset or prolonged duration, or an EEG that lacks the usual abnormalities. Some cases may have rather distinctive phenotypes and have been labeled as syndromes. For example, in 1929, the Heidenhain variant was described as a rapidly progressive dementia with prominent visual complaints and a pathologic profile of spongiform changes predominantly in the occipital lobes.[83] Brownell and Oppenheimer described an ataxic form of CJD based upon four CJD cases that had predominantly cerebellar ataxia with dementia being a late feature.[84] Pathologic changes in the ataxic variant are most prominent in the brainstem and cerebellum. An association of the ataxic variant of CJD with a PRNP genotype that is homozygous for Val at codon 129 has been recognized.[47] An "amyotrophic variant of CJD" in which lower motor neuron signs are observed, sometimes in conjunction with rapidly progressive dementia, has also been described85; this variant has been questioned as a true prion disease because attempts at experimental transmission were unsuccessful86 with a couple of exceptions.[87] Although there is other evidence for involvement of the spinal cord in prion disease, it has not been well studied.[88] A panencephalopathic form of CJD has been reported almost exclusively in Japan and is characterized by extensive white matter degeneration.[89] The magnetic resonance imaging (MRI) scan of these patients looks similar to that seen in a leukodystrophy. These clinical variations seen in sCJD may lead to diagnostic difficulties.

The defining pathology in all cases of CJD is the presence of vacuolation of cortical gray matter, commonly termed spongiform change or "spongiosis" (Fig. 3). The vacuoles observed by light microscopy represent focal swellings of axonal and dendritic neuronal processes associated with the loss of synaptic organelles and the accumulation of abnormal membranes, as visualized by electron microscopy.[90,91,92] They are most prominent in the cortical gray matter but are often visualized in the subcortical and deep white matter neuropil. The distribution of vacuolation in sCJD is typically within the cerebral neocortex, subiculum of the hippocampus, caudate, putamen, thalamus, and the molecular layer of the cerebellar cortex.[93] An inflammatory response is conspicuously absent in CJD as it is in all forms of prion disease, although a reactive gliosis is quite prominent. Protease-resistant PrP is generally easily detected in the brain of all patients with CJD. Transmission of sCJD into nonhuman primates has a relatively high success rate (85% of all cases tested)86; inoculation of transgenic (Tg) mice that express human PrP is even more efficient, approaching 100% of all cases tested.[17,94] The enhanced transmissibility in Tg mice expressing human PrPC reflects the importance of sequence homology between PrPSc and PrPC and helps explain the poor transmissibility between species with disparate PrP sequences, a feature termed the "species barrier." However, the outbreak of vCJD and transmission of human prions to transgenic mice that express bovine PrPC raise concern that sequence is not the only important factor in successful transmission. The ability of PrPC to adopt the conformation of PrPSc , which is presumably influenced by the protein sequence as well as other factors (e.g., chaperone proteins), may be the ultimate determinant.

Pathologic phenotypes of prion disease. (A) CJD. Hematoxylin and eosin staining of cerebral cortex from a patient with sCJD shows spongiform vacuolation of the gray matter in the absence of plaques. The vacuoles may vary greatly in size from 5 to 100 µm and may have a "bubble"-like appearance because of their coalescence. (B) FI. Hypertrophy and proliferation of astrocytes (i.e., "gliosis") is a consistent feature of all prion diseases but in FI it is most prominent in the thalamus along with neuronal dropout. (Immunoperoxidase stain for detection of glial fibrillary astrocytic protein.) (C) GSS. PAS staining of the cerebellum demonstrates the multicentric plaques of GSS that are most commonly located in the molecular layer. (D) vCJD. The "florid" plaques of vCJD consist of dense core PrP amyloid deposits surrounded by vacuoles. (Courtesy of Stephen J. DeArmord, UCSF.)

Familial CJD (fCJD) includes those cases with a dominantly inherited mutation of the PRNP gene, in which the pathologic features of spongiform change occur in the absence of GSS-type plaques (see later).

Although, familial cases of CJD tend to have a clinical and pathologic phenotype similar to that of sCJD, there are some distinct differences. Familial CJD patients tend to have a mean age of onset about 12 years earlier and a disease progression 18 months longer than sCJD. In addition, some of the clinical syndromes associated with particular mutations of PRNP differ from the typical clinical picture of sCJD.

Only three mutations of PRNP have been clearly linked to CJD, although several mutations have been detected in families affected with CJD. The association of disease in only the members of the family that carry the mutation indicates a casual relationship between disease and mutation. Pathogenic mutant PRNP genes that are associated with fCJD include those with a single base pair alteration at varying sites in the PRNP gene (i.e., a missense mutation leading to an abnormal PrP amino acid sequence), as well as insertions within a repeat segment of the gene.

Table 2 lists the mutations observed in families with the CJD phenotype. Of these, a change in coding of glutamate (E) to lysine (K) at codon 200 is the most common worldwide. It was first detected in an unusual cluster of CJD cases in rural Slovakia, where the annual mortality rate was about 100 per million people.[37] Almost simultaneously, the same mutation was identified in a Libyan Jewish family.[95] The extremely high frequency of CJD in the relatively small population of Libyan Jews initially led to concern that transmission was related to a regional dietary custom of eating sheep eyes. Once the gene defect was identified, a clear correlation between the presence of the mutation and disease was made. Carriers of this mutation have now been identified from over 10 different countries.[36,37,38,96,97,98] In general, the phenotype of fCJD(E200K) resembles that of sCJD and, like sCJD, shows considerable variation in disease presentation.[99,100] Memory loss and confusion are the typical early features of disease, which are soon accompanied by progressive dementia, pyramidal and extrapyramidal tract signs, ataxia, and myoclonus. Supranuclear ophthalmoplegia has been reported in a patient carrying this mutation,97 and demyelinating peripheral neuropathy has been reported in at least three patients.[101] The EEG commonly shows the characteristic periodic discharges of CJD.[102] In contrast to that of most other familial prion diseases, the duration of fCJD (E200K) is usually less than a year, as it is in sCJD. The age at disease onset is quite variable, occurring in patients from the fourth to the ninth decade of life, but most often beginning prior to age 60. This variability in age at disease onset suggests reduced penetrance; however, life table analyses demonstrate that penetrance is nearly complete by the ninth decade of life.[51,52] The importance of obtaining a detailed family history is under-scored by these results. Because the disease may manifest late in life, there are situations in which the parent who carries the mutation has died from other causes prior to developing prion disease, providing a false impression that the family history is negative. There is evidence that anticipation may also be associated with this mutation.[103] The pathologic features of this genetic prion disease are generally indistinguishable from those of sCJD, with diffuse spongiosis and gliosis as the primary features. As with sCJD, fCJD(E200K) has been experimentally transmitted to nonhuman primates104 and transgenic mice.[17]

The D178N mutation is the second most common mutation of PRNP. More importantly, the discovery of this mutation has provided a key element in the under-standing of prions. This single base pair change, resulting in the miscoding of asparagine (N) for aspartate (D) at residue 178, was initially reported in a Finnish family,105 then in two American families of Dutch and Hungarian origin106 and in a French family.[107] Memory disturbance is the usual presenting feature, typically followed by cerebellar ataxia, myoclonus, and varying degrees of visual disturbance, reduced speech output, and extrapyramidal and pyramidal tract features. Brain pathology shows diffuse spongiform degeneration, gliosis, and neuronal loss within the frontotemporal cerebral cortex, caudate, and basal ganglia, with relative sparing of deep thalamic nuclei and the cerebellum.[106,108,109,110] Although this disease overlaps considerably with sCJD, it presents at a younger age and has a more prolonged duration than the nonfamilial variety. Most important, the D178N mutation was subsequently recognized as the cause of both this disease and the distinct phenotype of FFI, with the observed phenotype determined by the polymorphism at codon 129 (see Fatal Insomina later).

Several PRNP gene insertions have also been associated with the CJD phenotype (Table 2). Between amino acids 51 and 91 of PrP lies an octapeptide repeat segment in which the sequence Pro-(His/Gly)-Gly-Gly-(-/Gly)-Trp-Gly-Glu is repeated five times. From one to nine additional octapeptide inserts have been reported within this segment. In contrast to the trinucleotide repeat diseases such as Huntington and Machado-Joseph disease, there has been no report of anticipation with these prion repeats, and the length of the insert appears stable during meiosis.[111] In general, the insert length correlates inversely with the age at onset of disease; in patients with seven to nine extra repeats, onset occurs in the 30s, whereas disease may be delayed until the sixth to seventh decade in those with one to four extra repeats.[112,113] The duration of illness, on the other hand, appears to be directly proportional to the length of insert, ranging from a mean of 5 months with a single extra repeat to a duration of 120 months with an increase in insert number to seven.[112]

The majority of patients with prion disease related to a PRNP insertion mutation have a chronic course that often includes atypical features such as dysphasia, apraxia, and a personality disorder associated with memory loss. Dementia eventually occurs. Cerebellar ataxia and extrapyramidal features are also common. Myoclonus may occur in less than one half of affected individuals, and periodic discharges on EEG are even less frequent (<30% of cases). Neuropathologic features vary within and among families with evidence of no or abundant pathology, focal or diffuse spongiform change in the cortex, and Congophilic or non-Congophilic PrP-plaques.[114,115,116] The variability in clinical and pathologic phenotype suggests that large inserts, because of their flexible nature, may produce variable effects on more conformationally important downstream regions of the protein.[117]

The original description by Gerstmann[118,119] of a German family with the onset of ataxia and dysarthria followed by variable degrees of pyramidal and extrapyramidal symptoms and late developing dementia defines the classic presentation of GSS. The periodic discharges on the EEG commonly observed in CJD are typically absent in GSS. Onset is generally early in life (<50 years), and duration of disease ranges from 2 to 10 years. Death usually results from secondary infection, often from aspiration pneumonia because of impaired swallowing. The presence of plaque deposits regionally or diffusely throughout the cortex that are immunoreactive to anti-human PrP antibodies is the hallmark of this form of prion disease. The amyloid is periodic acid- Schiff (PAS) positive and in most cases shows birefringence under polarized light after Congo Red staining. Vacuolation, although prominent in CJD, may be minimal in GSS. The identification of PRNP gene mutations underlying GSS and the development of antibodies to PrP have expanded our ability to diagnose this subtype of prion disease, some cases of which, not surprisingly, were previously misdiagnosed as familial Alzheimer disease.[120]

Mutations in GSS

A change in the amino acid coding from proline (P) to leucine (L) at codon 102 was the first mutation of PRNP linked to prion disease.[53] It is the most common GSS-related mutation recognized and has been reported in multiple families from nine different countries,[121,122,123,124,125] including the original Austrian family described by Gerst-mann.[126] The typical phenotype is that seen in classic GSS as already described. The progressive cerebellar syndrome associated with this mutation may be easily confused with a spinocerebellar degeneration syndrome. As noted above, variation in this presentation among and within families has been reported.[121,125,127] Despite the variation in PRNP mutations, common features among the GSS variants include the absence of periodic discharges on EEG, an early age at onset (third to fifth decade), a moderately prolonged duration (average 3 years), and the presence of GSS plaque pathology. Interestingly, the lack of easily detectable protease-resistant PrP in the brain is also a common feature.

Other mutations associated with the GSS phenotype are well documented (Table 2). Some of the interesting variations include P105L, which has been associated with a spastic paraparesis presentation; Y145Stop, which results in the expression of PrP truncated at residue 145 and is associated with a slowly progressive 20-year course, plaque deposits composed of truncated PrP, and neurofibrillary tangles;[71,128] and A117V, which is associated with either a telencephalic focus129 or a typical ataxic presentation,130 perhaps determined by the amino acid coding at the polymorphic codon 129. The A117V mutation has been associated with a transmembrane form of PrP, in contrast to the usual surface membrane GPI-anchored orientation of wild-type PrP,131 suggesting that A117V may affect the translocation of PrP at the endoplasmic reticulum. Whether this can explain the pathogenic properties of the molecule, the lack of protease resistance, and the reduced transmissibility seen with this particular prion disease variant remains to be determined. New evidence suggests, in fact, that the transmembrane form of PrP may be critical to the pathogenic process.[132]

The clinical and pathologic features of classic GSS, including ataxia and prominent PrP plaque deposition, were duplicated in a mouse carrying a transgene that expresses human PrP with the P102L mutation.[133] Although transmission to nonhuman primates has met with some success, the rate of transmission is low (40%) compared with transmission rates of sporadic and other familial forms CJD (~85%).[134] In addition, several attempts to transmit GSS to rodents have been unsuccessful.[135] The inefficiency in transmission may be related to the relative lack of easily detectable protease-resistant PrP in the brain of patients.

Over 20 kindreds and seven nonfamilial (sporadic) cases have been identified throughout the world with this unusual variety of prion disease.[110,136,137,138,139,140,141,142] Age at disease onset ranges from 25 to 61 years (average 48 years), and time from onset to death is generally 1 to 2 years (range from 7 to 33 months).[136,143,144] In the most characteristic presentation, the patient with FI develops untreatable insomnia, sometimes for a prolonged period of weeks or months. The insomnia is followed by dysautonomia, ataxia, and variable pyramidal and extrapyramidal signs and symptoms with relative sparing of cognitive function until late in the course. The dysautonomias may include episodic alterations in blood pressure, heart rate, temperature, respiratory rate, and secretions. The EEG shows diffuse slowing rather than periodic discharges. A sleep study is valuable to document a shortening of total sleep time if insomnia is not clinically obvious.[110,145] Positron emission tomography (PET) shows a reduction in metabolic activity or blood flow to the thalamus relatively early in the disease.[146] Not all cases have a typical disease phenotype. Some members of a family from Australia who carried the PRNP halpotype that predicts FFI were found to have clinically apparent insomnia early or late in the presentation, whereas other affected members did not exhibit insomnia.[147]

The neuropathologic features of FI include neuronal loss and astrogliosis within the thalamus and inferior olives and, to a lesser degree, the cerebellum. Vacuolation is minimal or absent in typical cases. In fact, Lugaresi et al argued in the original description of patients with FFI in 1986148 that this disorder was not likely to be the "thalamic form of CJD" because of the lack of significant spongiform change that was normally described for that disease.[149] Subsequent studies demonstrated that protease-resistant PrP is detectable in the brains of affected patients but is usually present only in small amounts and is often restricted to specific regions such as the thalamus and temporal lobe.[150]

The dominant D178N mutation of PRNP was found to be associated with both the familial form of CJD and FFI, with the phenotype determined by the polymorphic codon 129 coupled to the dominant D178N mutation.[151] The FFI phenotype is linked to the D178N mutation with Met at 129 (i.e., D178N/M129), whereas the fCJD phenotype (i.e., typical dementia with periodic EEG and diffuse spongiosis of the brain) is linked to Val at 129 on the same allele as the dominant 178 mutation (D178N/129V haplotype). FFI is likely to be the disease that was previously called "pure thalamic dementia" (PTD) because patients who had a diagnosis of the familial form of PTD were found to have the D178N mutation.[138]

In addition to the clinical phenotypic differences of fCJD and FFI, the characteristics of the protease-resistant PrPSc found in the brain of patients with these diseases also differ. After limited protease digestion and electrophoresis, the protease-resistant PrP from FFI patients migrates at 19 kDa and that from fCJD at approximately 21 kDa.[49] These observations suggest that the development of disease is due to the dominant D178N mutation, but the two clinical phenotypes linked to it are due to different conformational subtypes of PrPSc determined by the polymorphic amino acid at codon 129. Transmission studies with mice susceptible to human prion disease demonstrate that the protease-resistant PrPSc generated in the brain of the mouse has the same electrophoretic mobility as that derived from the brain of the patient used as the infecting inoculum. In other words, these different conformational subtypes of PrPSc are maintained following transmission.[63]

A case of FI was reported in which the patient did not carry the associated mutation at codon 129 but did have the characteristic clinical and pathologic features of FFI and the same PrPSc conformation as FFI, as determined by the PrP digestion pattern and electrophoretic mobility.[64] In addition, the characteristics of transmission of disease from this case to susceptible transgenic mice were similar to those of FFI. This report and a sub-sequent one demonstrate the existence of sporadic FI (sFI) that is not associated with the D178N mutation.[152] The occurence of sFI along with FFI provides further support that the PrP protein conformation, rather than its sequence, is the ultimate determinant of the disease phenotype.

The constellation of unusual clinical and pathologic features seen in FI underscores the high degree of variability with which prion disease presents and should raise suspicion that other prion diseases may exist that have not yet been detected. Prion diseases may be difficult to recognize because, like FI, they may have little protease-resistant PrP and also be inefficiently transmitted experimentally.

The transmission of prion disease through contaminated pharmaceutical preparations and surgical procedures has prompted fears regarding the potential for transmission of prion disease through blood transfusions and biological derivatives. The most noteworthy instance of iatrogenic prion disease was the development of CJD in over 100 individuals who received hGH obtained from pooled human pituitary glands. The contaminated hGH originated from at least three separate sources in the United Kingdom, France, and the United States.[153,154,155,156,157,158] Epidemiologic surveys suggest that disease risk correlated with the duration of hGH therapy.[157] In contrast to those with typical CJD, patients with this dis-ease present more often with cerebellar ataxia rather than higher cortical dysfunction, and the EEG shows a slow wave pattern rather than the periodic triphasic discharges of sCJD.[159] Although recombinant GH use began in 1985, cases of hGH-associated iCJD are still being observed because of the prolonged incubation period of up to 20 years.

Iatrogenic CJD has also been observed in patients who have undergone neurosurgical procedures. A number of cases of iCJD occurred following implantation of dura mater grafts, especially those originating from a single manufacturer who pooled samples and who used preparative procedures that were inadequate to decontaminate specimens.[160,161,162,163,164,165] A report from Japan describes over 40 cases of iCJD related to contaminated dura exposure between 1979 and 1996.[166] Other iatrogenic forms of prion disease have been reported in a corneal transplant recipient,167 two patients exposed to improperly decontaminated depth electrodes used for seizure focus localization,168 and at least five cases in women who received human pituitary gonadotropin.[169,170,171]

Concern has been building with respect to the risk of iCJD from whole blood, plasma-derived products (e.g., intravenous immunoglobulins), and organ transplantation. Although some experimental transmission studies suggest that blood may be infectious at some point during the course of the disease[172,173,174] and that the lymphoreticular system may be involved in the propagation of prions, there is little evidence to suggest that there is a significant risk of prion disease transmission via blood and blood products. In addition, epidemiologic surveys do not support blood transfusion as a significant risk factor for CJD.[175,176] This aspect of prion research is under intense study by several laboratories at the time of this writing.

This form of CJD has been reported in over 40 patients throughout the United Kingdom and (rarely) in France since 1995.[177,178,179,180,181] The occurrence of vCJD is sobering because it appears to represent a situation in which the prion has "jumped" species, in this case from cow to human. In 1987 Wells et al182 described spongi-form change in the brain of a cow affected with BSE. By 1990 reports indicated that over 300 herds per month were becoming infected.[183] The origin of the BSE epidemic may be related to a change in the rendering process in 1981 such that BSE prions were not completely inactivated prior to feeding cows meat and bone meal derived from other infected cows.[184] This practice of "cow cannibalism" has since been banned. In addition, over 2 million cattle in the United Kingdom were slaughtered to eliminate BSE. In December 1999, the Ministry of Agriculture Fisheries and Food (MAFF) declared British beef "safe" and free of BSE.

The clinical phenotype of vCJD is notably different from that of typical sCJD: the onset is commonly associated with psychiatric manifestations, it occurs primarily in younger individuals (average age 27, range 16 to 48 years) with a somewhat protracted course of approximately 16 months (range 9 to 38 months), and it is not associated with typical periodic complexes on the EEG.[181] The brain shows diffuse vacuolation and the presence of distinctive dense core PrP-containing plaques surrounded by a halo of spongiform change, described as florid plaques (Fig. 3). Because the pathologic features and clinical presentation of vCJD differ significantly from those of sCJD, it is considered a new "strain" of human prion disease. This is further supported by the finding that PrPSc derived from the brains of vCJD patients has a different electrophoretic mobility than that of typical sCJD, and in contrast to that from sCJD, which is predominantly monoglycosylated, PrPSc from vCJD is predominantly diglycosylated.[185] The same "protein signature" was observed following experimental transmission of BSE to several animal hosts, supporting the idea that vCJD results from the infection of humans with BSE. Interestingly, the polymorphic codon 129 in all patients with vCJD has been homozygous for Met at codon [129,186,187] suggesting that Met homozygosity increases susceptibility to vCJD. It may also be that patients who have the homozygous Val genotype do not develop the typical pathology currently described for vCJD. One wonders whether cases with Val at 129 will appear over time. Whether or not vCJD will develop into a true epidemic is unclear at this time, but it is encouraging to note that the rate of appearance of new cases in the United Kingdom has so far remained low. No cases have yet been reported in the United States, presumably because of the absence of BSE in this country.


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