Prion diseases: causes, symptoms, diagnosis, treatment

Prion diseases are a group of neurodegenerative diseases characterized by progressive brain damage and death.

ICD-10 code

A81.9. Slow viral infections of the central nervous system, unspecified.

What causes prion diseases?

The cause of prion diseases in humans and animals is a protein called prion - a conformer (conformational form) of a normal cellular protein found in the body of all mammals and humans. In the human body, the gene encoding the synthesis of cellular prion protein is designated as PRNP. Non-infectious, "cellular" prion protein is usually designated as PrP ^c (the index "C" is the initial letter of the English word cell ). "Cellular" prion protein is involved in the transmission of physiological signals, interacting with the components of synapses, that is, it takes part in the functioning of cell signaling systems, in particular neurons. The half-life of PrP ^c is 4-6 hours.

To designate the conformational form of the cellular prion protein that has infectious properties, the designation PrP ^Sc is used. The infectivity of the prion protein is designated by the first letters of the most common prion disease - scrapie - "Sc" (from the English scrapie). Infectious forms of prions are low-molecular (molecular weight 27-30 kDa) protein particles, sometimes designated as PrP27-30. The length of their polypeptide chain is 253-254 amino acid residues.

The process of accumulation of infectious prion protein is caused by contact of two molecules - the initial protein PrP ^c and infectious prion protein PrP ^Sc. In the process of interaction with normal cellular protein PrP ^c the infectious protein induces structural (conformational) changes in it and converts it into a similar, irreversibly infectious protein. Thus, the process of accumulation of infectious prion protein occurs not as a result of synthesis of PrP ^{Sc molecules in the infected organism, but as a result of conformational changes of normal PrPc} molecules already present in the organism. The process of accumulation of infectious prion protein is of an avalanche-like nature.

If cells are infected with single infectious molecules, the number of PrP ^Sc molecules formed during the day reaches 500-1000, during the year - up to half a million. This is immeasurably less compared to the rate of reproduction of bacteria and viruses (many millions of particles in hours), which explains the long incubation period of prion diseases.

Prions of different animal species have significant differences in their primary structure. Since the infectious prion only initiates the process of conversion of the normal cellular homologue into PrPS, the infectious process results in prions with a primary structure characteristic only of this species. Molecular biological evidence has been obtained of prions overcoming interspecies barriers and the ability to adapt to a new host, i.e. the possibility of transmission of the causative agent of prion infections from animals to humans has been proven.

Morphology of prions

Prions in infected cells are found mainly in the microsomal fraction. Morphologically, prions in body tissues are represented by a polymeric form (aggregated molecules of the infectious prion protein PrP27-30) and look like rod-shaped elements (fibrils). In terms of ultrastructural and histochemical properties, they are identical to amyloid, but this amyloid-like material is non-infectious, since only individual prion molecules have infectious properties.

Physicochemical properties of prions

Prions are characterized by an unusually high level of resistance to chemical and physical factors, which is not typical even for heat-stable proteins. Prions are stable at a temperature of 90 °C for 30 min and are inactivated only by autoclaving for 30 min at 135 °C. Infectious prion molecules are hydrophobic and have a pronounced tendency to aggregate with each other and with cellular proteins and structures. Prions (PrP ^Sc ) are resistant to the following physical influences and reagents: aldehydes, nucleases, organic solvents, non-ionic and ionic detergents, ultraviolet irradiation and ionizing radiation.

Pathogenesis of prion diseases

Primary reproduction of prions occurs in dendritic cells, lymph glands, spleen and thymus. PrP ^Sc accumulates in cells, accumulating in cytoplasmic vesicles. Prions can spread by axonal transport, from the spleen through the thoracic lymphatic duct and further along the nerve trunks, causing damage to the brain and upper spinal cord. Strain differences are manifested in the duration of the incubation period, the topography of the affected brain structures, and the specificity in relation to the host.

Characterized by a complete absence of immune response and inflammatory reaction of the host organism to infection, which predetermines a chronic, progressive course of the disease without remissions.

Prions induce apoptosis of infected cells. The ability of PrP ^Sc molecules to block mitochondrial genome replication and cause their degeneration has been proven. Accumulation of PrP ^Sc in synaptic structures and the associated disorganization of synapses may be the cause of the development of profound neurological defects and dementia. In morphological terms, common features are noted in all prion diseases. Due to the damaging effect of prions, vacuolization and death of neurons occur, as a result of which the brain visually looks like a sponge (spongioform degeneration). Macroscopically, cerebral atrophy is determined. Histologically, spongiform degeneration, atrophy and loss of nerve cells, proliferation of glia (astrocytic gliosis), death of white matter fibers (leukospongiosis), amyloid plaques containing prion protein, and the absence of inflammatory reactions are detected. Diseases of this group differ pathohistologically in the ratio of the intensity of spongiosis, amyloidosis and gliosis in the brain tissue, in addition, each of these diseases has significant clinical and epidemiological features. Unlike viral slow infections, there is no demyelination process.

What are the symptoms of prion diseases?

Gerstmann-Sträussler-Scheinker syndrome

Gerstmann-Sträussler-Scheinker syndrome is a rare familial disease that is classified as a genetically determined form of spongiform encephalopathy with an autosomal dominant type of inheritance (PRNP gene mutations). The disease is registered with a frequency of 1 case per 10 million population. Clinical manifestations of the disease are registered in the 3rd or 4th decade of life. Unlike Creutzfeldt-Jakob disease, dementia may not manifest itself. The initial manifestations of the disease are cerebellar disorders. Depending on the localization of the mutation in PRNP, cerebellar or extrapyramidal disorders, gaze palsy or deafness and blindness may dominate in the advanced stage of the disease. The duration of the disease is 4-5 years.

Familial fatal insomnia

Synonym: fatal familial insomnia.

First described in 1986. Familial fatal insomnia is a rare disease inherited in an autosomal dominant pattern. This disease is characterized by a mutation in codon 178, which is also registered in patients with Creutzfeldt-Jakob disease. Which disease will develop depends on which amino acid is in position 129: if it is methionine, then familial fatal insomnia develops, if it is valine, then Creutzfeldt-Jakob disease develops. A family has been described in which a mutation in codon 183 was registered. By 2003, 26 families from Italian and Italian-American families had been described. The disease can debut at the age of 25 to 71 years and has a variable course (from 6-13 months to 24-48 months). The main symptoms of the disease are: incurable insomnia, loss of circadian rhythms, movement disorders and dementia. Early symptoms include autonomic disorders: changes in sweating and salivation, constipation, hypertension, tachycardia, tachypnea, and sometimes fever. Spongy lesions in the cerebral cortex are rare, and are mainly localized in the thalamic nuclei.

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Kuru

ICD-10 code

A81.8. Other slow viral infections of the central nervous system.

Symptoms of kuru

Kuru was the first prion disease whose infectiousness was proven by experimentally infecting monkeys with biological material obtained from humans. Kuru is an endemic slow infection found in the eastern part of New Guinea. The disease was first discovered in 1953 and then described by the American researcher D. Gajdusek in 1957. The disease was identified in the Fore tribes, who practiced ritual cannibalism. Representatives of these tribes, including children, ate the brains of their ancestors without cooking. When the traditions of cannibalism were abolished by law, the incidence of the disease on the island dropped sharply, and at the end of the 20th century, cases of the disease were registered only in people born before 1956, when cannibalism was officially abolished. The disease can begin at the age of 5 to 60 years and older. The incubation period is long, from 5 to 30 years (on average 8.5 years). The central clinical symptom of this disease is progressive cerebellar ataxia. Then dysarthria, head tremor, uncontrollable laughter ("kuru" is translated as "laughing" or "trembling with fear") join in. The disease lasts from 4 months to 3 years. Patients die from respiratory failure or bronchopneumonia against the background of severe muscle hypotonia and muscle weakness. Dementia occurs only in the late stages of the disease. EEG is usually unchanged. Autopsy reveals atrophy of the cerebellum, primarily the vermis. Microscopically, the greatest changes are also localized in the cerebellum. They are expressed in the loss of neurons, gliosis and amyloid plaques. In the cerebral cortex, changes are represented by a mild spongiosis of neuroglia.

Classification of prion diseases

There are 4 known nosological variants of prion diseases in humans:

• Creutzfeldt-Jakob disease (sporadic, familial and infectious forms) - iatrogenic and new variant:
• Gerstmann-Sträussler-Scheinker syndrome;
• familial fatal insomnia;
• kuru.

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How are prion diseases diagnosed?

Diagnostics for prion diseases has not been developed.

EEG. It has been established that 60-80% of patients with Creutzfeldt-Jakob disease have 0.5-2.0 Hz generalized two- or three-phase complexes, repeating at a frequency of 1 time per second (similar EEG characteristics occur in other pathologies of the brain). However, a negative EEG result cannot serve as a basis for canceling the diagnosis of Creutzfeldt-Jakob disease.

MRI has low diagnostic value, since non-specific signals are recorded in 80% of those examined. However, MRI allows us to detect brain atrophy, the severity of which worsens as the disease progresses.

Cerebrospinal fluid examination. It is possible to test for the presence of the neurospecific protein 14-3-3. This study by ELISA or Western blot demonstrates good sensitivity and specificity in sporadic cases of Creutzfeldt-Jakob disease both at early and late stages of the disease. In familial forms and iatrogenic Creutzfeldt-Jakob disease, this method is less informative (specificity is about 50%).

Blood tests. Identification of prions by immunoblotting in peripheral lymphocytes is possible.

Molecular genetic studies. Currently, immunoblotting methods have been developed using monoclonal antibodies (MKA-15BZ), which allow the recognition of PrP ^Sc and PrP ^c.

PCR methods are used to perform sequencing of the human genome and analysis of the localization of PRNP gene mutations.

Examination of autopsy material. Status spongiosis (forms of vacuolization of nervous tissue), signs of cerebral amyloidosis, formation of characteristic amyloid plaques are revealed.

Biological diagnostic methods. Transgenic mice carrying the gene encoding normal human PrP are recommended by WHO for testing the infectious activity of materials suspected of being contaminated with prions.

Differential diagnosis of prion diseases

Differential diagnostics of prion diseases, including Creutzfeldt-Jakob disease, is carried out with all diseases, one of the manifestations of which is dementia: Alzheimer's disease, vasculitis, neurosyphilis, streptococcal meningitis, herpes encephalitis, myoclonus epilepsy, Parkinson's disease, etc.

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Treatment of prion diseases

There is no treatment for prion diseases.

Patients with clinical manifestations are disabled. Prion diseases have an unfavorable prognosis, the disease ends in death.

How to prevent prion diseases?

Methods of disinfection recommended for practical use in hospitals and aimed at inactivating prions

In relation to prions, the effectiveness of the inactivation method can be considered proven only after treating the infectious material with inactivating agents followed by intracerebral infection of laboratory animals with this treated sample. Since no consensus has yet been reached on the maximum duration of the incubation period, it is also impossible to judge the absence of residual infectious activity of the sample treated with inactivators. There is currently no legislatively accepted method for titrating the infectious activity of prions.

WHO currently recommends three types of processing of non-disposable medical instruments:

• physical treatment: autoclaving at 134-138 °C for 18 min;
• chemical treatment: soaking in 1 N NaOH solution for 1 hour at 20 °C;
• chemical treatment: soaking in a 2.5-12.5% solution of bleach for 1 hour at 20 °C.

Processing pathological samples poses a certain risk, so laboratory personnel are strictly required to incinerate any disposable instruments along with the samples of the material being examined.

Used materials related to the treatment of a patient with Creutzfeldt-Jakob disease (CJD) or a patient at risk for contracting Creutzfeldt-Jakob disease are immediately incinerated.

If Creutzfeldt-Jakob disease is suspected in a patient, endoscopic equipment must be quarantined. In case of any cut or puncture of the health care worker's skin during medical procedures, a patient with Creutzfeldt-Jakob disease is recommended to treat the health care worker's wound with bleach (12.5% concentration) for 5-10 minutes after thorough rinsing. In case of any contact of contaminated material with the eyes, it is necessary to thoroughly and continuously rinse the eyes with water or isotonic sodium chloride solution.

Prion diseases cannot be prevented in an emergency, that is, emergency prevention of infection of personnel has not been developed.