Prion-Related Diseases 

  • Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP; Chief Editor: Karen L Roos, MD   more...
 
Updated: Feb 6, 2012
 

Background

The prion diseases are a large group of related neurodegenerative conditions, which affect both animals and humans.[1] Included are Creutzfeldt-Jakob disease (CJD) and Gerstmann-Strãussler-Scheinker (GSS) in humans, bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle, chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep. These diseases all have long incubation periods but are typically rapidly progressive once clinical symptoms begin. All prion diseases are fatal, with no effective form of treatment currently; however, increased understanding of their pathogenesis has recently led to the promise of effective therapeutic interventions in the near future.

Prion diseases are unique in that they can be inherited, they can occur sporadically, or they can be infectious. The infectious agent in the prion disease is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the prion protein. The replication of prions involves the recruitment of the normally expressed prion protein, which has mainly an alpha-helical structure, into a disease-specific conformation that is rich in beta-sheet.

The first of these diseases to be described was scrapie, a disease of sheep recognized for over 250 years. This illness, manifested by hyperexcitability, itching, and ataxia, leads to paralysis and death. It is called scrapie because of the tendency of affected animals to rub against the fences of their pens in order to stay upright, reflecting their cerebellar dysfunction. The transmission of this disease was demonstrated first in 1943 when a population of Scottish sheep was accidentally inoculated against a common virus using a formalin extract of lymphoid tissue from an animal with scrapie.[2] Accidental transmission of prions is a recurrent event in the history of these agents and is related to their unusual biophysical properties.

For related information, see eMedicine article Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy.

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Pathophysiology

A unifying feature of all the prionoses is their neuropathology. These illnesses tend to affect the gray matter of the central nervous system (CNS), producing neuronal loss, gliosis, and characteristic spongiform change. The latter is a vacuolation of the neuropil, and to a variable degree, of the neurons, shown below.

Prion-related diseases. Spongiform change in prionPrion-related diseases. Spongiform change in prion disease. This section shows mild parenchymal vacuolation and prominent reactive astrocytosis.

In addition, plaques with the typical staining properties of amyloid (eg, apple-green birefringence after Congo Red staining when viewed under polarized light) are observed in many of these conditions. In approximately 10% of patients with CJD, amyloid is present in the cerebellum or in the cerebral hemispheres. All cases of GSS are associated with multicentric cerebellar plaques. These amyloid plaques are immunoreactive with antibodies to the prion protein and do not immunoreact with antibodies to other amyloidogenic proteins, such as the amyloid-beta (which is deposited in Alzheimer disease).

Etiology of PrP-related diseases

Highly divergent hypotheses have been put forward regarding the makeup of the prions, including that they consist of nucleic acid only or protein only, are lacking both protein and nucleic acid, or are a polysaccharide. The most widely accepted hypothesis, first described by Griffith[3] and more explicitly detailed by Stanley Prusiner, MD, is the protein only hypothesis.[4] Prusiner introduced the term prion to indicate that scrapie is related to a proteinaceous infectious particle (PrP).[5]

This hypothesis was initially greeted with great skepticism in the scientific community; now it represents the current dogma, and Prusiner won the 1998 Noble Prize for Science. This hypothesis suggests that prions contain no nucleic acid and are referred to as PrPSc. The latter represents a conformationally modified form of a normal cellular PrPC, which is a normal host protein found on the surface of many cells, in particular neurons. PrPSc, when introduced into normal healthy cells, causes the conversion of PrPC into PrPSc, initiating a self-perpetuating vicious cycle.[4]

Other hypotheses for prion have included the virino hypothesis.[6] This hypothesis suggests that the infectious agent consists of a nucleic acid with host-derived PrPSc serving as a coat. The latter would explain the lack of an immunological and inflammatory response, while the presence of a nucleic acid provides an explanation for the numerous strains of scrapie, each with distinctive features. Other investigators have also suggested that the scrapie agent is a conventional virus with highly atypical properties. However, despite extensive searches, no nucleic acid associated with prion infection has been detected so far.

The protein-only hypothesis of prion propagation proposes the existence of an infectious agent composed solely of protein.[5] Recent reports claim that apart from the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.[7, 8, 9]

Cell biology of prions - Normal cellular function of PrP

The human PrP gene (PRNP) is found on chromosome 20 and encodes a protein of 253 amino acids. PrPC is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein; some have speculated that it may have a role in cell adhesion or signaling processes, but its exact cellular function remains unknown. The N-terminal region of PrP contains a segment of 5 repeats of an 8–amino acid sequence (ie, octapeptide repeat region) that contains a high-affinity binding site for copper ions; hence, PrP may have a role in copper transport or metabolism. Recent evidence suggests that copper imbalance is an early change during prion infections.[10] The function(s) of PrPC is likely to be of some importance because PrP is highly conserved among mammals and is found in all vertebrates.[11, 12] Also, prionlike proteins called PSI and URE3 are expressed in yeast.[13]

PrP is found in most tissues of the body but is expressed at highest levels in the CNS, in particular in neurons. PrP is also expressed widely on cells of the immune system. PrP knockout mice, which are engineered not to express the PrP gene, show no obvious pathological phenotype.[14] However, these mice have been shown to have abnormalities in synaptic physiology[15] and in circadian rhythms and sleep.[16]

The secondary structure of PrPC was first elucidated by nuclear magnetic resonance (NMR) imaging using recombinant mouse PrP protein.[17] More recently, this has been achieved using recombinant hamster and human PrP.[18, 19, 20] These studies have shown that PrPC is about 40% alpha-helix and about 3% beta-sheet. No high-resolution structural studies, such as NMR imaging, have been performed on PrPSc because it is highly insoluble and aggregated, which are properties that prevent use of these techniques. However, less exact structural methods such as circular dichroism and Fourier transform infrared spectroscopy have shown PrPSc to contain about 45% beta-sheet and 30% alpha-helix.[21, 22] This high beta-sheet content correlates with PrPSc resistance to enzymatic digestion and infectivity.

Prion strains and the species barrier

Many lines of evidence support the protein only hypothesis of prion propagation; however, a difficulty is the existence of several distinct isolates or strains of prions that can be stably passaged among inbred mice of the same genotype.[23] The existence of strains suggests that PrPSc could adopt multiple distinct pathological conformations. Strains are defined by the production of distinct patterns of incubation time, distributions of CNS involvement, and the pattern of proteolytic cleavage of PrPSc following proteinase K (PK) digestion.[4, 24] For example, at least 14 significantly different scrapie strains have been isolated from natural sheep scrapie by passage into mice.[23, 25]

The best studied are the two strains of transmissible mink encephalopathy (TME) called hyper (HY) and drowsy (DY).[26, 27] The truncated DY PrPSc fragments (PrP27-30) migrate 1-2 kd faster than similar preparations of HY because sites of PK cleavage differ and the two strains differ in terms of beta-sheet content.[27, 26]

Parchi et al defined 2 distinct types of sporadic CJD based on the analysis of PrP codon 129, which encodes either a valine or a methionine, and by the pattern of sodium dodecyl sulfate-polyacrylamide (SDS-PAGE) migration of the PrP27-30. Type 1 sporadic CJD has a molecular weight of the deglycosylated PrP27-30 of about 21 kd, while type 2 has a mobility of about 19 kd.[28] Collinge et al reported 2 further types related to infectious CJD.[29] These distinct types of sporadic CJD appear to have slightly different beta-sheet content that correlates with the degree of resistance to proteinase K digestion of each strain.[21]

Each strain of prion has characteristic range of infectivity. For example the 263K strain is pathogenic for hamsters but does not infect mice.[30] This effect is called a species barrier and is related to PrPSc being an effective template for homologous PrPC and a poor template for heterologous PrPC; hence, mouse PrPSc can effectively convert mouse PrPC, but it is a very poor template for human or hamster PrPC. This species barrier is not absolute, as is illustrated by the emergence of new variant CJD (vCJD).

The structure and folding properties of the cellular prion protein are well characterized, and, although its precise function remains enigmatic, constitutive knockout of protein expression in mice produces apparently healthy animals that are fully resistant to prion infection. In addition, data show that neuronal knockout of the gene encoding for prion protein during established brain infection leads to reversal of pathology and behavioral deficits.[31]

How prions reach the CNS

Prion diseases are transmitted naturally by peripheral routes, either orally or transcutaneously; hence, how prions are able to reach the CNS is an important issue. Although the prion diseases are neurological conditions, critical events in their pathogenesis take place in restricted sites out of the nervous system, especially in peripheral lymphoid organs.[32]

Lymphoid organs have long been known to be involved in the early stages of prion diseases.[33, 34, 35] In particular, the spleen and lymph nodes have been demonstrated to be the first sites of PrPSc replication after infection by peripheral routes, and they are also affected significantly following intracerebral challenge. Their importance for neuroinvasion after peripheral inoculation was suggested by studies showing that splenectomy and other methods that reduce peripheral lymphoid structures delay clinical manifestations.[34]

The hematogenic spread of prions to the CNS is suggested by experiments that show BSE to be transmissible from sheep to sheep by blood transfusion.[36] Three cases of vCJD infection associated with blood transfusion have also been observed (Health Protection Agency, Variant CJD and blood products). All received nonleucodepleted red blood cells.

The first case developed vCJD in 2003, 6.5 years following transfusion from a donor who developed vCJD 3.5 years following donation. The second patient died of causes unrelated to vCJD in 2004, 5 years following the transfusion. At autopsy, this individual had abnormal prion protein in the spleen and cervical lymph node but not in the brain, and other pathological features of vCJD were not observed. The donor developed symptoms of vCJD 18 months after his donation. The third patient developed vCJD in 2006, about 8 years following transfusion from a donor who was diagnosed with vCJD about 20 months after donation.

Hematogenic neuroinvasion has been shown to be dependent on the presence of B lymphocytes.[37] However, because expression of the cellular prion protein by B cells is not required for neuroinvasion, some have suggested that their main function is to allow maintenance of follicular dendritic cells.[38] However, more recent studies suggest that neuroinvasion is possible in the absence of both B cells and follicular dendritic cells.[39] Other studies have implicated the distinct CD11c+ dendritic cell population in prion neuroinvasion.[21]

In addition to hematogenous spread, prions can reach the brain via the parasympathetic vagus nerve.[40] Hence, following intraperitoneal delivery of prions, disease can be delayed by sympathectomy or can be accelerated by sympathetic hyperinnervation of lymphoreticular organs.[41]

Which of these two routes for neuroinvasion is most important remains unclear; it may be scrapie strain–dependent. However, a more complete understanding of these stages and the cells involved in prion spread from the periphery may allow for development of a pharmacological gatekeeper that can be used to stop the movement of infectivity.

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Epidemiology

Frequency

United States

The most common prion disease is CJD, with a uniform incidence of approximately 1 case per million population both in the United States and internationally. Familial forms of prion diseases, such as GSS and fatal familial insomnia (FFI), are much more rare. About 10% of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PRNP gene.

International

As of February 2006, 159 cases of definite or probable vCJD have been reported in the United Kingdom of which 153 persons have died (see The National Creutzfeldt-Jakob Disease Surveillance Unit). Whether these patients represent the beginning of a growing epidemic (such as that which occurred with BSE) or whether the number of cases will remain relatively low remains unclear. The first confirmed 3 cases were reported in 1995, with numbers of subsequent cases remaining relatively stable between 1996 and 2004 (9-28 cases per year). Only 5 cases were confirmed in 2005.

Two populations are disproportionally affected by CJD: Libyan-born Israelis and some populations in restricted areas of Slovakia where the incidence of CJD is 60-100 times greater than expected. These clusters were postulated to be related to dietary exposure of the scrapie agent; however, this was not supported by case-controlled studies. These local high rates of CJD are linked to a high prevalence of codon 200 mutations in the PRNP gene.

Mortality/Morbidity

Prion-related diseases are relentlessly progressive and invariably lead to death.

  • The mean duration of sporadic CJD is 8 months.
  • vCJD has a slightly longer course, with a mean duration of 14 months.
  • Familial CJD has a mean duration of 26 months, while GSS has the longest course, about 60 months.

Race

Sporadic CJD occurs throughout the world in people of all races and typically has similar features.

  • Some familial forms of prion disease, such as familial CJD, can have distinct features in an ethnic group. For example, familial CJD in the Libyan Jewish population associated with a codon 200 mutation has features of a peripheral neuropathy in addition to the more typical manifestations of CJD.[42, 43]
  • vCJD has been limited to Europe, with almost all cases occurring in the United Kingdom.

Sex

No sex preponderance is known in prion diseases, with some rare exceptions. For example, women had a greater tendency than men to develop kuru because it was part of the ritual cannibalism for women to eat the brains (and neural tissue has the highest dose of PrPSc).

Age

  • The mean age of onset of sporadic CJD is 62 years. The incidence of sporadic CJD is about 1 case per million population; however, among individuals aged 60-74 years, the incidence is 5 cases per million population.[44] The age range can be broad; cases have been reported in people as young as 17 years and as old as 83 years.[45, 46]
  • vCJD occurs in younger patients, with a mean age of onset of 28 years.
  • Familial CJD, GSS, and FFI have mean ages of onset ranging from 45-49 years.
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Contributor Information and Disclosures
Author

Tarakad S Ramachandran, MBBS, FRCP(C), FACP  Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine

Disclosure: Abbott Labs None None; Teva Marion None None; Boeringer-Ingelheim Honoraria Speaking and teaching

Coauthor(s)

Arun Ramachandran  State University of New York Upstate Medical University

Arun Ramachandran is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Roberta J Seidman, MD  Associate Professor of Clinical Pathology, Stony Brook University; Director of Neuropathology, Department of Pathology, Stony Brook University Medical Center

Roberta J Seidman, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuropathologists, New York Association of Neuropathologists (The Neuroplex), and Suffolk County Society of Pathologists

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed  Director, Regional MS Center of Excellence, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Karen L Roos, MD  John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Thomas Wisniewski, MD and Einar M Sigurdsson, PhD to the development and writing of this article.

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Prion-related diseases. Spongiform change in prion disease. This section shows mild parenchymal vacuolation and prominent reactive astrocytosis.
Prion-related diseases. A representation of the human proteinaceous infectious particle, or PrP, gene. Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations. The locations of the 4 putative helical regions, H1-H4, correspond to residues 109-122, 129-141, 178-191, and 202-218, respectively. This diagram does not illustrate all of the alpha-helical regions. A diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial Creutzfeldt-Jakob disease (CJD).
Shows characteristic signal changes of an MRI taken from a patient with sporadic CJD, using diffusion-weighted imaging (DWI). An abnormal signal is shown in both the basal ganglia (red arrows) and the cortical ribbon (yellow arrow).
Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission
DiseaseHostMechanism
KuruHumanCannibalism
Sporadic CJDHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
Iatrogenic CJDHumanInfection from prion-containing material, eg, dura mater, electrode
Familial CJDHumanMutations in the PrP gene
vCJDHumanInfection from BSE
GSSHumanMutations in the PrP gene
FFIHumanD178N mutation in the PrP gene, with M129 polymorphism
Sporadic fatal insomniaHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
ScrapieSheepInfection in susceptible sheep
BSECattleInfection from contaminated food
TMEMinkInfection from sheep or cattle in food
CWDMule, deer, elkUnclear
Feline spongiform encephalopathyCatsInfection from contaminated food
Exotic ungulate encephalopathyNyala, oryx, kuduInfection from contaminated food
Table 2. Paraneoplastic Syndromes, Associated Tumors, and Autoantibodies
Clinical SyndromeNeoplasmAutoantibodies
Limbic encephalitisSmall cell lung carcinoma



Testicular/breast, thymoma



Anti-Hu, antiCV2,PCA-2, ANNA-3



Anti-Ma2 Anti-VGKC, anti-CV2



Cerebellar degenerationBreast, ovary, lung, othersAnti-Yo, anti-Ma, anti-Ri



Anti-Hu, anti-CV2



Opsoclonus myoclonusBreast, ovarian, small cell carcinoma of lung



Neuroblastoma



Anti-Ri, anti-Yo, Anti-Hu,



Anti-amphiphysin Anti-Hu



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