Transmissible spongiform encephalopathy
Encyclopedia
Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of progressive conditions that affect the brain
and nervous system
of many animal
s, including human
s. According to the most widespread hypothesis they are transmitted by prion
s, though some other data suggest an involvement of a Spiroplasma
infection. Mental and physical abilities deteriorate and myriad tiny holes appear in the cortex
causing it to appear like a sponge (hence 'spongiform') when brain tissue obtained at autopsy
is examined under a microscope
. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen over time. Prion diseases of humans include classic Creutzfeldt–Jakob disease, new variant Creutzfeldt–Jakob disease (nvCJD, a human disorder related to mad cow disease), Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia
and kuru
. These conditions form a spectrum of diseases with overlapping signs and symptoms.
Unlike other kinds of infectious disease which are spread by microbes, the infectious agent in TSEs is a specific protein
called prion
protein. Misshaped prion proteins carry the disease between individuals and cause deterioration of the brain
. TSEs are unique diseases in that their aetiology may be genetic, sporadic or infectious via ingestion of infected foodstuffs and via iatrogenic
means (e.g. blood transfusion). Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant
prion allele
, which expresses prion proteins that contort by themselves into the disease-causing conformation
. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In recent times a type of TSE called bovine spongiform encephalopathy
(BSE) spread in cattle
in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries. The epidemic could have begun with just one cow with sporadic disease.
Prions cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization
procedures such as boiling or irradiating materials fail to render prions non-infective.
|+ Known spongiform encephalopathies
|-
! ICTVdb Code
! Disease name
! Natural host
! Prion name
! PrP isoform
|-
! colspan="5" {| Non-human mammal
s
|-
| 90.001.0.01.001.
| Scrapie
| Sheep and goat
s
| Scrapie prion
| OvPrPSc
|-
| 90.001.0.01.002.
| Transmissible mink encephalopathy
(TME)
| Mink
| TME prion
| MkPrPSc
|-
| 90.001.0.01.003.
| Chronic wasting disease
(CWD)
| Elk
, White-tailed deer
, Mule Deer
and Red Deer
| CWD prion
| MDePrPSc
|-
| 90.001.0.01.004.
| Bovine spongiform encephalopathy
(BSE)
commonly known as "Mad Cow Disease"
| Cattle
| BSE prion
| BovPrPSc
|-
| 90.001.0.01.005.
| Feline spongiform encephalopathy
(FSE)
| Cats
| FSE prion
| FePrPSc
|-
| 90.001.0.01.006.
| Exotic ungulate encephalopathy
(EUE)
| Nyala
and greater kudu
| EUE prion
| NyaPrPSc
|-
! colspan="5" {| Human diseases
|-
| 90.001.0.01.007.
| Kuru
| rowspan="5" {| Human
s
| Kuru prion
| rowspan="5" {| HuPrPSc
|-
| 90.001.0.01.008.
| Creutzfeldt-Jakob disease
(CJD)
| CJD prion
|-
|
| (New) Variant Creutzfeldt-Jakob disease (vCJD, nvCJD)
| vCJD prion
|-
| 90.001.0.01.009.
| Gerstmann-Sträussler-Scheinker syndrome
(GSS)
| GSS prion
|-
| 90.001.0.01.010.
| Fatal familial insomnia
(FFI)
| FFI prion
|}
al loss, astrocytosis and amyloid
plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate
in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological
diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system
in individual cases.
The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression
, lack of coordination, and/or an unsteady gait (ataxia
). Patients also may experience involuntary jerking movements called myoclonus
, unusual sensations, insomnia
, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia
) and lose the ability to move or speak.
Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.
Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt-Jakob disease has been transmitted to patients taking injections of growth hormone
harvested from human pituitary gland
s, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave
" sterilization process used for most surgical instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism
or similar practices allow the proteins to accumulate over more than one generation. An example is kuru
, which reached epidemic proportions in the mid 20th century in the Fore people of Papua New Guinea
, who used to consume their dead as a funerary ritual. Laws in developed countries now proscribe the use of rendered
ruminant
proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.
Note that not all encephalopathies
are caused by prions, as in the cases of PML
(caused by the JC virus
), CADASIL
(caused by abnormal NOTCH3 protein activity), and Krabbe disease
(caused by a deficiency of the enzyme
galactosylceramidase). Progressive Spongiform Leukoencephalopathy
(PSL) -- which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant which causes it among heroin smokers has not yet been identified. This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.
gene
cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. Rarely, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.
The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Normally, this protein may be involved in transporting copper into cells. It may also be involved in protecting brain cells and helping them communicate. 24 Point-Mutation
s in this gene cause cells to produce an abnormal form of the prion protein, known as PrPSc. This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.
Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.
In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.
This hypothesis is largely discredited, as no infectious, non-human nucleic acid has ever been isolated from the disease. It is largely based on the fact that infectious agents have previously been viral in origin, preferring this as more plausible than the infectious protein hypothesis.
Sc form has started. At present, there is virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrPSc, but there are still no fully accepted methods for use in materials such as blood.
In 2010, A team from New York described detection of PrPSc even when initially present at only one part in a hundred thousand million (10−11) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA)
and some specific antibodies against PrPSc. After amplifying and then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared.
Recent research from the University of Toronto
and Caprion Pharmaceuticals has discovered one possible avenue which might lead to quicker diagnosis, a vaccine or possibly even treatment for prion diseases. The abnormally folded proteins which cause the disease have been found to expose a side chain
of amino acids which the properly folded protein does not expose. Antibodies specifically coded to this side chain amino acid sequence have been found to stimulate an immune response to the abnormal prions and leave the normal proteins intact.
Another idea involves using custom peptide
sequences. Since some research suggests prions aggregate by forming beta barrel structures, work done in vitro has shown that peptides made up of beta barrel-incompatible amino acid
s can help break up accumulations of prion.
Yet a third idea concerns genetic therapy
, whereby the gene
for encoding protease-resistant protein is considered to be an error in several species, and therefore something to be inhibited.
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
of many animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s, including human
Human
Humans are the only living species in the Homo genus...
s. According to the most widespread hypothesis they are transmitted by prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
s, though some other data suggest an involvement of a Spiroplasma
Spiroplasma
Spiroplasma is a genus of Mollicutes, a group of small bacteria without cell walls. Spiroplasma shares the simple metabolism, parasitic lifestyle, fried-egg colony morphology and small genome of other Mollicutes, but has a distinctive helical morphology, unlike Mycoplasma. It has a spiral shape...
infection. Mental and physical abilities deteriorate and myriad tiny holes appear in the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
causing it to appear like a sponge (hence 'spongiform') when brain tissue obtained at autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
is examined under a microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...
. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen over time. Prion diseases of humans include classic Creutzfeldt–Jakob disease, new variant Creutzfeldt–Jakob disease (nvCJD, a human disorder related to mad cow disease), Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia
Fatal familial insomnia
Fatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
and kuru
Kuru (disease)
Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans...
. These conditions form a spectrum of diseases with overlapping signs and symptoms.
Unlike other kinds of infectious disease which are spread by microbes, the infectious agent in TSEs is a specific protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
called prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
protein. Misshaped prion proteins carry the disease between individuals and cause deterioration of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. TSEs are unique diseases in that their aetiology may be genetic, sporadic or infectious via ingestion of infected foodstuffs and via iatrogenic
Iatrogenesis
Iatrogenesis, or an iatrogenic artifact is an inadvertent adverse effect or complication resulting from medical treatment or advice, including that of psychologists, therapists, pharmacists, nurses, physicians and dentists...
means (e.g. blood transfusion). Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
prion allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
, which expresses prion proteins that contort by themselves into the disease-causing conformation
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In recent times a type of TSE called bovine spongiform encephalopathy
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
(BSE) spread in cattle
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries. The epidemic could have begun with just one cow with sporadic disease.
Prions cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization
Sterilization (microbiology)
Sterilization is a term referring to any process that eliminates or kills all forms of microbial life, including transmissible agents present on a surface, contained in a fluid, in medication, or in a compound such as biological culture media...
procedures such as boiling or irradiating materials fail to render prions non-infective.
Classification
{| class="wikitable"|+ Known spongiform encephalopathies
|-
! ICTVdb Code
! Disease name
! Natural host
! Prion name
! PrP isoform
|-
! colspan="5" {| Non-human mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s
|-
| 90.001.0.01.001.
| Scrapie
Scrapie
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
| Sheep and goat
Goat
The domestic goat is a subspecies of goat domesticated from the wild goat of southwest Asia and Eastern Europe. The goat is a member of the Bovidae family and is closely related to the sheep as both are in the goat-antelope subfamily Caprinae. There are over three hundred distinct breeds of...
s
| Scrapie prion
| OvPrPSc
|-
| 90.001.0.01.002.
| Transmissible mink encephalopathy
Transmissible mink encephalopathy
Transmissible mink encephalopathy is rare sporadic disease that affects the central nervous system of ranch-raised mink. It is classified as a transmissible spongiform encephalopathy, believed to be caused by proteins called prions...
(TME)
| Mink
Mink
There are two living species referred to as "mink": the European Mink and the American Mink. The extinct Sea Mink is related to the American Mink, but was much larger. All three species are dark-colored, semi-aquatic, carnivorous mammals of the family Mustelidae, which also includes the weasels and...
| TME prion
| MkPrPSc
|-
| 90.001.0.01.003.
| Chronic wasting disease
Chronic wasting disease
Chronic wasting disease is a transmissible spongiform encephalopathy of mule deer, whitetailed deer, elk , and moose. TSEs are caused by unusual infectious agents known as prions. To date, CWD has been found mainly in cervids...
(CWD)
| Elk
Elk
The Elk is the large deer, also called Cervus canadensis or wapiti, of North America and eastern Asia.Elk may also refer to:Other antlered mammals:...
, White-tailed deer
White-tailed Deer
The white-tailed deer , also known as the Virginia deer or simply as the whitetail, is a medium-sized deer native to the United States , Canada, Mexico, Central America, and South America as far south as Peru...
, Mule Deer
Mule Deer
The mule deer is a deer indigenous to western North America. The Mule Deer gets its name from its large mule-like ears. There are believed to be several subspecies, including the black-tailed deer...
and Red Deer
Red Deer
The red deer is one of the largest deer species. Depending on taxonomy, the red deer inhabits most of Europe, the Caucasus Mountains region, Asia Minor, parts of western Asia, and central Asia. It also inhabits the Atlas Mountains region between Morocco and Tunisia in northwestern Africa, being...
| CWD prion
| MDePrPSc
|-
| 90.001.0.01.004.
| Bovine spongiform encephalopathy
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
(BSE)
commonly known as "Mad Cow Disease"
| Cattle
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
| BSE prion
| BovPrPSc
|-
| 90.001.0.01.005.
| Feline spongiform encephalopathy
Feline spongiform encephalopathy
Feline spongiform encephalopathy is a disease that affects the brains and livers of felines. It is caused by proteins called prions.-Disease:Feline spongiform encephalopathy is a prion disease thought to be related to Bovine spongiform encephalopathy . This disease is known to affect domestic and...
(FSE)
| Cats
| FSE prion
| FePrPSc
|-
| 90.001.0.01.006.
| Exotic ungulate encephalopathy
Exotic ungulate encephalopathy
Exotic ungulate encephalopathy is a transmissible spongiform encephalopathy , or prion disease, identified in infected organs of zoo animals. This subgroup of the TSEs in captive animals was identified in zoo animals in Great Britain including species of greater kudu, nyala, gemsbok, the common...
(EUE)
| Nyala
Nyala
The Nyala is a Southern African antelope. It is a spiral-horned dense-forest antelope that is uncomfortable in open spaces and is most often seen at water holes. Nyalas live alone or in small family groups of up to 10 individuals.The male stands up to 110 cm , the female is up to 90 cm ...
and greater kudu
Greater Kudu
The Greater Kudu is a woodland antelope found throughout eastern and southern Africa. Despite occupying such widespread territory, they are sparsely populated in most areas, due to a declining habitat, deforestation and hunting....
| EUE prion
| NyaPrPSc
|-
! colspan="5" {| Human diseases
|-
| 90.001.0.01.007.
| Kuru
Kuru (disease)
Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans...
| rowspan="5" {| Human
Human
Humans are the only living species in the Homo genus...
s
| Kuru prion
| rowspan="5" {| HuPrPSc
|-
| 90.001.0.01.008.
| Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease
Creutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
(CJD)
| CJD prion
|-
|
| (New) Variant Creutzfeldt-Jakob disease (vCJD, nvCJD)
| vCJD prion
|-
| 90.001.0.01.009.
| Gerstmann-Sträussler-Scheinker syndrome
Gerstmann-Sträussler-Scheinker syndrome
Gerstmann–Sträussler–Scheinker syndrome is a very rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age...
(GSS)
| GSS prion
|-
| 90.001.0.01.010.
| Fatal familial insomnia
Fatal familial insomnia
Fatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
(FFI)
| FFI prion
|}
Features of TSE
The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change, neuronNeuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al loss, astrocytosis and amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
in individual cases.
The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, lack of coordination, and/or an unsteady gait (ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
). Patients also may experience involuntary jerking movements called myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
, unusual sensations, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
) and lose the ability to move or speak.
Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.
Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt-Jakob disease has been transmitted to patients taking injections of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
harvested from human pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
s, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave
Autoclave
An autoclave is an instrument used to sterilize equipment and supplies by subjecting them to high pressure saturated steam at 121 °C for around 15–20 minutes depending on the size of the load and the contents. It was invented by Charles Chamberland in 1879, although a precursor known as the...
" sterilization process used for most surgical instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism
Cannibalism
Cannibalism is the act or practice of humans eating the flesh of other human beings. It is also called anthropophagy...
or similar practices allow the proteins to accumulate over more than one generation. An example is kuru
Kuru (disease)
Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans...
, which reached epidemic proportions in the mid 20th century in the Fore people of Papua New Guinea
Papua New Guinea
Papua New Guinea , officially the Independent State of Papua New Guinea, is a country in Oceania, occupying the eastern half of the island of New Guinea and numerous offshore islands...
, who used to consume their dead as a funerary ritual. Laws in developed countries now proscribe the use of rendered
Rendering (industrial)
Rendering is a process that converts waste animal tissue into stable, value-added materials. Rendering can refer to any processing of animal byproducts into more useful materials, or more narrowly to the rendering of whole animal fatty tissue into purified fats like lard or tallow...
ruminant
Ruminant
A ruminant is a mammal of the order Artiodactyla that digests plant-based food by initially softening it within the animal's first compartment of the stomach, principally through bacterial actions, then regurgitating the semi-digested mass, now known as cud, and chewing it again...
proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.
Note that not all encephalopathies
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
are caused by prions, as in the cases of PML
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
(caused by the JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
), CADASIL
CADASIL
CADASIL is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19. The disease belongs to a family of disorders called the Leukodystrophies...
(caused by abnormal NOTCH3 protein activity), and Krabbe disease
Krabbe disease
Krabbe disease is a rare, often fatal degenerative disorder that affects the myelin sheath of the nervous system. This condition is inherited in an autosomal recessive pattern...
(caused by a deficiency of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
galactosylceramidase). Progressive Spongiform Leukoencephalopathy
Toxic leukoencephalopathy
Toxic leukoencephalopathy or toxic spongiform leukoencephalopathy is a condition that is characterized by progressive damage , of the white matter of the brain due to ingested toxins ....
(PSL) -- which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant which causes it among heroin smokers has not yet been identified. This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.
Genetics
Mutations in the PRNPPRNP
Major prion protein also known as CD230 is a protein that in humans is encoded by the PRNP gene...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. Rarely, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.
The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Normally, this protein may be involved in transporting copper into cells. It may also be involved in protecting brain cells and helping them communicate. 24 Point-Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in this gene cause cells to produce an abnormal form of the prion protein, known as PrPSc. This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.
Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.
In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.
Protein-Only hypothesis
Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrPC into PrPSc. Evidence for this theory:- infectivity titre correlates with PrPSc levels. However, this is disputed.
- PrPSc is an isomer of PrPC
- Denaturing PrP removes infectivity
- PrP-null mice cannot be infected
Multi-component hypothesis
While not containing a nucleic acid genome, prions may be composed of more than just a protein. Purified PrPC appears unable to convert to the infectious PrPSc form, unless other components are added, such as RNA and lipids. These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.Viral hypothesis
This hypothesis postulates that an infectious viral agent is the cause of the disease. Evidence for this hypothesis is as follows:- Incubation time is comparable to a lentivirusLentivirusLentivirus is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period...
- Strain variation of different isolates of PrPSc
- An increasing titre of PrPSc as the disease progresses suggests a replicating agent.
This hypothesis is largely discredited, as no infectious, non-human nucleic acid has ever been isolated from the disease. It is largely based on the fact that infectious agents have previously been viral in origin, preferring this as more plausible than the infectious protein hypothesis.
Epidemiology
These spontaneous disorders in humans are very rare, affecting only about one person per million worldwide each year. However, transmissible TSEs can reach epidemic proportions, as was seen in the UK BSE outbreak of the 80s and 90s. It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that if animals start to show the disease after an outbreak on a nearby farm, you cannot show that it is the same strain affecting both, suggesting transmission, or that the second outbreak came from a completely different source.Possible cure or vaccine and Diagnosis
There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrPSc form has started. At present, there is virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrPSc, but there are still no fully accepted methods for use in materials such as blood.
In 2010, A team from New York described detection of PrPSc even when initially present at only one part in a hundred thousand million (10−11) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA)
Surround Optical Fiber Immunoassay (SOFIA)
Surround Optical Fiber Immunoassay is an ultra-sensitive, in vitro diagnostic platform incorporating a surround optical fiber assembly that captures fluorescence emissions from an entire sample. The technology's defining characteristics are its extremely high limit of detection, sensitivity and...
and some specific antibodies against PrPSc. After amplifying and then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared.
Recent research from the University of Toronto
University of Toronto
The University of Toronto is a public research university in Toronto, Ontario, Canada, situated on the grounds that surround Queen's Park. It was founded by royal charter in 1827 as King's College, the first institution of higher learning in Upper Canada...
and Caprion Pharmaceuticals has discovered one possible avenue which might lead to quicker diagnosis, a vaccine or possibly even treatment for prion diseases. The abnormally folded proteins which cause the disease have been found to expose a side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
of amino acids which the properly folded protein does not expose. Antibodies specifically coded to this side chain amino acid sequence have been found to stimulate an immune response to the abnormal prions and leave the normal proteins intact.
Another idea involves using custom peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
sequences. Since some research suggests prions aggregate by forming beta barrel structures, work done in vitro has shown that peptides made up of beta barrel-incompatible amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s can help break up accumulations of prion.
Yet a third idea concerns genetic therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
, whereby the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for encoding protease-resistant protein is considered to be an error in several species, and therefore something to be inhibited.