Prion diseases are a group of rare progressive neurodegenerative diseases caused by prions. Prions are made up entirely of protein material; so they are also called “proteinaceous infectious particles”.
The term prion refers to abnormal, pathogenic agents that are both infectious and transmissible. They are bits of misfolded protein (prion protein) (PrP) that have the ability to induce abnormal folding of specific normal cellular proteins called prion proteins that are found most abundantly in the brain. The functions of these normal prion proteins are still not completely understood. The resultant abnormal folding of the prion proteins leads to brain damage and the characteristic signs and symptoms of the disease. Prion diseases are usually rapidly progressive and always fatal.
Prion diseases or transmissible spongiform encephalopathies (TSEs) can affect both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response.
There is no effective medical treatment for these diseases. The illnesses are progressive and always fatal.
These are rare diseases affecting about 300 people in US every year.
Types of Prion Diseases
Human prion diseases
- Creutzfeldt-Jakob Disease (CJD)
- Variant Creutzfeldt-Jakob Disease (vCJD)
- Gerstmann-Straussler-Scheinker Syndrome (GSS)
- Fatal Familial Insomnia
Animal Prion diseases
- Bovine Spongiform Encephalopathy (BSE)
- Chronic Wasting Disease (CWD)
- Transmissible mink encephalopathy
- Feline spongiform encephalopathy
- Ungulate spongiform encephalopathy
Pathogenesis and Molecular Genetics
PrP is a 30-kDa normal cellular protein present in neurons. When this normal prion protein undergoes a conformational change from its normal α-helix-containing isoform (PrP c) to an abnormal β-pleated sheet isoform, usually termed either PrP sc (for scrapie) or PrP res (for protease resistant), it results in disease. Due to the conformational change, the prion protein becomes resistant to digestion with proteases such as proteinase K. The conformational change resulting in PrP sc may occur spontaneously at a very slow rate (resulting in sporadic cases) or at a higher rate if numerous mutations are present in PrP c as occurs in familial forms of CJD, GSS and fatal familial insomnia.
The resultant PrP sc then induces transformation of other normal PrP c molecules. Since the PrP sc molecule is able to disrupt the integrity of normal cellular components through conformational changes, it is said to have infectious nature.
PrP sc molecule when inoculated into experimental animals is able to transmit the disease into the host. PrP sc obtained from one species is more effective at transmitting disease to the same species than to others.
A gene on chromosome 20, called PRNP codes for PrP c protein. It has a single exon coding for the entire open reading frame and shows a high degree of conservation across species. In cases of familial CJD and GSS, a wide variety of disease-causing mutations have been identified. In certain families with CJD and fatal familial insomnia, the disease is caused due to a point mutation (D178N) in the PRNP gene. Also various polymorphisms have been identified in the PRNP gene. The Methionine/ Valine (Met/Val) polymorphism at codon 129 has been found to influence disease pattern. The combination of Met at codon 129 in the same allele as the D178N mutation results in fatal familial insomnia while a Val at codon 129 results in CJD. Individuals who are homozygous at codon 129 for either Met or Val are over-represented among cases of CJD compared to general population. This suggests that heterozygosity at codon 129 protects against development of disease.
Accumulation of PrP sc in neural tissue is the cause of the basic pathology in these diseases.
Morphological Changes in Brain
There is spongiform degeneration (vacuolation) of cerebral cortex and gray matter structures (caudate, putamen). This degeneration results in the formation of small, apparently empty microscopic vacuoles of varying sizes within the neuropil and sometimes in the perikaryon of neurons. In later stages, there is severe neuronal loss, reactive gliosis and at times, expansion of the vacuolated areas into cyst like spaces – status spongiosus. There is no associated inflammation.
Kuru plaques are extracellular deposits of aggregated abnormal protein. They occur in the cerebellum in cases of GSS. In variant CJD, they are present in cerebral cortex and consist of dense core PrP amyloid deposits surrounded by vacuoles.
In all prion diseases, immunohistochemical staining demonstrates the presence of proteinase-K-resistant PrP sc in tissue.
Unlike other prion diseases, fatal familial insomnia does not show spongiform pathology. Rather the characteristic feature is neuronal loss and reactive gliosis.
Transmission of Prion Diseasee
Prion diseases can occur in three different ways: acquired, familial, or sporadic.
Familial ones are associated with mutations at 34 different prion protein (PrP) amino acid residues.
The primary method of infection in animals is through ingestion. The prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil for long periods of time.
From animals, the disease can spread to humans by consumption of infected meat of the animals. It can also spread from humans to humans. The kuru epidemic that developed in the first half of the twentieth century in Papua New Guinea was caused by ritualistic cannibalism and is believed to have originated from a case of sporadic CJD.
Iatrogenic transmission of prion disease can occur by exposure to infected tissue during a medical procedure, such as a cornea transplant or intake of contaminated preprations of human growth hormone or through electrodes or surgical instruments previously used on a CJD patient.
Symptoms of Prion Diseases
- Rapidly developing dementia
- Difficulty in walking and changes in gait
- Hallucinations and confusion
- Muscle stiffness
- Anxiety or depression
- Muscle control loss, like sudden jerks or twitches
- Slurred speech
- Difficulty in swallowing
- Vision problems
Diagnosis of Prion Disease
These diseases are usually diagnosed clinically and confirmed by histopathological examination of brain tissue obtained during a biopsy or after death. The characteristic histopathological and immunohistochemical features produced by these diseases helps in definite identification and confirmation. Obtaining brain biopsy tissue in living humans or animals is risky and is usually not performed routinely for diagnosis of prion diseases.
It is also important to rule out other diseases with similar symptoms. Prion diseases should however always be considered in people with rapidly progressive dementia.
The following battery of tests can be helpful in supporting a clinical diagnosis
- Magnetic resonance imaging (MRI) scans of the brain
- Electroencephalogram (EEG) which analyses brain waves
- Neurological and visual examinations to check for nerve damage and vision loss
- Cerebrospinal fluid protein tests
- Genetic tests
- Tonsil biopsy
The only reliable molecular marker for prion diseases is PrPSc, the pathological prion protein that accumulates in the central nervous system and lymphoreticular tissues. For BSE, several commercial diagnostic kits based on the post-mortem immunochemical detection of PrPSc in brain tissue are available. These rapid screening tests have been used in active surveillance of BSE and have greatly improved the detection of infected cattle before their entry into the human food chain.
At present, no diagnostic test exists for the detection of prion diseases in live animals or humans. New diagnostic techniques aimed at increasing sensitivity and specificity of PrPSc detection in body fluids and at identifying novel surrogate markers are under development.
Treatment of Prion Diseases
Prion diseases are untreatable and fatal diseases. The mainstay of treatment is aimed at symptomatic treatment to keep the patients safe and comfortable.
The mainstay of treatment includes pain killers, antidepressants, sedatives, or antipsychotic drugs. Opioids may be used to relieve pain. Clonazepam or sodium valproate may be used to treat involuntary movements.
Various modalities of treatment including antibodies against PrP, gene therapy, stem cell therapy,etc have been proposed for prion diseases but as of now they are all in experimental stages and not used clinically.
Quinacrine and doxycycline- two drugs already in use for other diseases were found to be promising but have failed to prove effective. Several studies are being conducted on high-throughput screening to find new small molecule drugs against prion disease.
Strict regulations regarding the handling and feeding of cows should be implemented and followed to prevent the spread of prion diseases. Proper cleaning and sterilizing medical equipment helps to prevent the spread of iatrogenic disease. Patients suffering from CJD should not donate organs or tissue, including corneal tissue.
Brief About Different Prion Diseases
Creutzfeldt-Jakob Disease (CJD)
Most cases occur spontaneously (sporadic CJD), with a worldwide annual incidence of about 1 per million. Peak incidence is in the seventh decade. Familial and acquired CJD can also occur. Symptoms include subtle changes in memory and behavior followed by rapidly progressive dementia, ataxia, involuntary movements and muscle contractions. The disease is fatal with most of the people dying within a year of diagnosis.
Variant Creutzfeldt-Jakob Disease (vCJD)
The agent causing bovine spongiform encephalopathy (BSE) in cows is responsible for outbreak of vCJD in humans. Eating diseased meat has been implicated in disease causation in humans.
The neuropathological findings and molecular features are similar to those of CJD. However, it differs from CJD in several aspects. This disease usually affects younger people. Behavioral disorders occur in the early stages of the disease and the neurological symptoms progress more slowly as compared to CJD. There is presence of extensive cortical plaques with a surrounding halo of spongiform change.
Gerstmann-Straussler-Scheinker Syndrome (GSS)
It is an inherited disorder with mutations of the PRNP gene. The disease begins with a chronic cerebellar ataxia followed by a progressive dementia. The clinical course is usually slower than that of CJD with death occurring several years after the onset of symptoms. In addition to the pathological features of a spongiform encephalopathy, GSS is characterized by numerous plaques of PrP sc as well as neurofibrillary tangles.
Fatal Familial Insomnia
It is an autosomal dominant inherited disease which causes sleep disturbances in initial stages. Later other neurological signs such as ataxia, autonomic disturbances, stupor and ultimately coma occur. A non-inherited form of the disorder (fatal sporadic insomnia) has also been described. Unlike other prion diseases, this disease does not show spongiform changes in brain. Rather it is characterized by neuronal loss and reactive gliosis.
Kuru is a very rare, incurable neurodegenerative disorder caused by the transmission of abnormally folded prion proteins. It is a spongiform encephalopathy characterized by progressive cerebellar ataxia, or loss of coordination and control over muscle movements.
The term kuru derives from the Fore word kuria or guria that means to shake] due to the body tremors that are a classic symptom of the disease and kúru itself means “trembling”.