Prion diseases: causes, symptoms, diagnosis, treatment

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

ICD-10 code

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

What causes prion diseases?

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

To denote the conformational form of the cellular prion protein, which has infectious properties, the designation PrP ^{Sc is used}. Infectiousness of prion protein is the first letter of the most common prion disease - scrapie - "Sc" (from the English scrapie). Infectious forms of prions are low molecular weight (molecular weight 27-30 kDa) protein particles, sometimes referred to as PrP27-30. The length of their polypeptide chain is 253-254 amino acid residues.

The accumulation of the infectious prion protein is caused by contact of two molecules - starting PrP protein ^with and infectious prion protein PrP ^Sc. In the process of interaction with the normal cellular protein PrP ^{c, the} infectious protein induces structural (conformational) changes in it and turns it into itself a similar, irreversibly infectious protein. Thus, the accumulation of the infectious prion protein is not a result of synthesis in the infected organism molecules PrP ^Sc, and due to conformational changes are already present in the body normal PrP molecules ^with. The process of accumulation of infectious prion protein is avalanche-like.

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

Prions of different animal species have serious differences in the primary structure. Since infectious prion only initiates the process of conversion of a normal cellular homolog in PrPS, as a result of the infectious process, prions appear with a primary structure peculiar only to this species. Molecular and biological evidence of prion crossing of interspecific barriers and ability to adapt to a new host has been obtained, that is, the possibility of transmitting an agent of prion infections from animals to humans has been proved.

Morphology of prions

Prions in infected cells are found predominantly in the microsomal fraction. Morphologically, the prions in the body tissues are represented by a polymeric form (aggregated molecules of the 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 possess infectious properties.

Physicochemical Properties of Prions

Prions are characterized by an unusually high level of resistance to chemical and physical factors, atypical even for thermostable proteins. Prions are stable at a temperature of 90 ° C for 30 minutes and are inactivated only when autoclaved for 30 minutes 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 actions and reagents: aldehydes, nuclease, organic solvents, nonionic and ionic detergents, ultraviolet irradiation and ionizing radiation.

Pathogenesis of prion diseases

Primary reproduction of prions occurs in dendritic cells, lymphatic 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, the brain and upper spinal cord are affected. Strain differences are manifested in the duration of the incubation period, the topography of the affected brain structures, the specificity with respect to the host.

Characteristic of the complete absence of an immune response and inflammatory response of the host organism to infection, which predetermines chronic, progressing without remission, the course of the disease.

Prions induce apoptosis of infected cells. The ability of PrP ^Sc molecules to create a blockade of mitochondrial genome replication and to cause their degeneration is proved . The accumulation of PrP ^Sc in synaptic structures and the associated disorganization of synapses may be the cause of the development of deep neurological defects and dementia. In the morphological plan, the common features of all prion diseases are noted. Due to the damaging effect of prions, vacuolization and death of neurons occurs, resulting in the brain visually looking like a sponge (spongioform degeneration). Macroscopically determine the atrophy of the brain. Histologically, spongioform degeneration, atrophy and loss of nerve cells, proliferation of glia (astrocytic gliosis), death of white matter fibers (leuco-respiration), amyloid plaques containing prion protein, and the absence of inflammatory reactions are histologically detected. Diseases of this group are pathologically differed by the ratio of intensity of spongiosa, 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?

The Gerstmann-Streussler-Sheinker Syndrome

Gerstmann-Streussler-Scheinker syndrome is a rare family disease attributed to genetically determined forms of spongiform encephalopathy with an autosomal dominant type of inheritance (mutations of the PRNP gene). The disease is recorded with a frequency of 1 case per 10 million population. Clinical manifestations of the disease are recorded in the 3rd or 4th decade of life. In contrast to Creutzfeldt-Jakob disease, dementia may not appear. The initial manifestations of the disease are cerebellar disorders. Depending on the location of the mutation in PRNP, cerebellar or extrapyramidal disorders, paralysis of the eyes or deafness and blindness may dominate the expanded stage of the disease. Duration of the disease is 4-5 years.

Family death insomnia

Synonym: fatal family insomnia.

It was first described in 1986. Family death insomnia is a rare disease inherited by an autosomal dominant type. In this disease, a mutation is recorded in the 178th codon, which is also recorded in patients with Creutzfeldt-Jakob disease. What disease will develop depends on which amino acid is in position 129: if methionine, then the family's lethal insomnia develops, if valine, then Creutzfeldt-Jakob disease develops. A family is described in which a mutation is recorded in the 183rd codon. By 2003, 26 families from Italian and Italian-American families have been described. The disease can make its debut at the age of 25 years to 71 years and has a variable in duration (from 6-13 months to 24-48 months). The main symptoms of the disease: non-vessel insomnia, loss of circadian rhythms, motor disorders and dementia. The early symptoms include vegetative disorders: changes in sweating and salivation, constipation, hypertension, tachycardia, tachypnea, sometimes fever. Spongious lesions in the cerebral cortex are rarely seen, mainly they are localized in the nuclei of the thalamus.

[1], [2], [3], [4], [5]

Kuru

ICD-10 code

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

Symptoms of Kuru

Kuru was the first disease of the prion group, the infectiousness of which was proved by the experimental infection of monkeys with biological material obtained from humans. Kuru is an endemic, slow infection that occurs in the eastern part of the island. New Guinea. For the first time the disease was discovered in 1953, and then described by the American researcher D, Gajdusek in 1957. The disease was identified among the tribes of the people of the Fores who practiced the customs of ritual cannibalism. Representatives of these tribes, including children, used to eat the brain of their ancestors without heat treatment. When the traditions of cannibalism were abolished by the legislative order, the incidence on the island fell sharply, and at the end of the 20th century cases were registered only in persons born before 1956, when there was an official cannibalism abolition. The disease can begin at the age of 5 to 60 years and older. The incubation period is long, from 5 to 30 years (an average of 8.5 years). The central clinical symptom of this disease is progressive cerebellar ataxia. Then they join dysarthria, tremor of the head, uncontrolled laughter ("kuru" is translated as "laughing" or "trembling with fear"). The disease lasts from 4 months to 3 years. Patients die from respiratory failure or bronchopneumonia on the background of pronounced muscular hypotension and muscle weakness. Dementia occurs only in the late stages of the disease. EEG is usually not changed. At autopsy, the cerebellar atrophy, primarily a worm, is identified. Microscopically, the largest changes are also localized in the cerebellum. They are expressed in the loss of neurons, gliosis and amyloid plaques. In the cerebral cortex, the changes are represented by the faintly expressed spongiosis of the neuroglia.

Classification of prion diseases

A person has 4 nosological variants of prion diseases:

• Creutzfeldt-Jakob disease (sporadic, familial and infectious forms) - iatrogenic and new variant:
• the Gerstmann-Streussler-Sheinker syndrome;
• family death insomnia;
• kuru.

[6], [7], [8], [9], [10], [11], [12], [13],

How are prion diseases diagnosed?

Diagnosis of prion diseases has not been developed.

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

MRI has a low diagnostic significance, since 80% of the subjects register nonspecific signals. Nevertheless, MRI reveals the atrophy of the brain, the severity of which is aggravated as the disease progresses.

Investigation of cerebrospinal fluid. A test for the presence of a neurospecific protein 14-3-3 is possible. This study by ELISA or Western blotting demonstrates good sensitivity and specificity in sporadic cases of Creutzfeldt-Jakob disease in both early and late stages of the disease. With family forms and iatrogenic Creutzfeldt-Jakob disease this method is less informative (specificity about 50%).

Blood test. It is possible to identify prions by the method of immuno-blotting in peripheral lymphocytes.

Molecular-genetic studies. At present, methods of immunoblotting with the use of monoclonal antibodies (MCA-15B3) have been developed, which make it possible to recognize PrP ^Sc and PrP ^s.

PCR methods are used that allow the sequencing of the human genome and the localization of mutations in the PRNP gene.

Investigation of autopsy material. Identify Status spongiosis (forms of vacuolization of the nervous tissue), signs of cerebral amyloidosis, the formation of characteristic amyloid plaques.

Biological methods of diagnosis. Transgenic mice bearing the gene. Encoding normal human PrP, are recommended by WHO for testing the infectious activity of materials that are prone to contamination by prions.

Differential diagnosis of prion diseases

Differential diagnosis of prion diseases, including Creutzfeldt-Jakob disease, is performed with all diseases, one of the manifestations of which is dementia: Alzheimer's disease, vasculitis, neurosyphilis. Streptococcal meningitis, herpetic encephalitis, myoclonus-epilepsy, Parkinson's disease, etc.

[14], [15], [16], [17], [18], [19]

Treatment of prion diseases

Treatment of prion diseases has not been developed.

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

How to prevent prion diseases?

Methods of disinfection, recommended in the practice of hospitals and aimed at inactivating prions

With respect to prions, the effectiveness of the inactivation method can be considered proven only after treatment of the infectious material with inactivating agents, followed by infection of intracerebral laboratory animals with this treated sample. Since there is still no consensus on the maximum duration of the incubation period, it is not yet possible to judge the absence of residual infectious activity of the sample treated with inactivators. Currently, there is no legally accepted method for titrating prion infectious activity.

WHO, at the current stage, recommends three types of treatment of non-disposable medical instruments:

• physical processing: 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.

A certain risk is the processing of pathoanatomical samples, so laboratory personnel are strictly required to burn any one-time instruments along with samples of the material under study.

Used materials associated with the treatment of a patient with Creutzfeldt-Jakob disease (CJD) or a patient at risk of contracting Creutzfeldt-Jakob disease, are immediately burned.

In case of suspicion of Creutzfeldt-Jakob disease, the patient must be quarantined for endoscopic equipment. For any cut or puncture of the skin of a health worker during medical manipulations, a patient with Creutzfeldt-Jakob disease is advised to treat the health worker's wound with bleach (12.5% concentration) for 5-10 minutes after thorough washing. In case of any contact with the infected material, a thorough and long-term eye wash with water or an isotonic solution of sodium chloride is necessary.

Prion diseases can not be prevented urgently, that is, emergency prevention of personnel contamination is not developed.