Creutzfeldt-Jakob disease (CJD) is a degenerative disease of the central nervous system (CNS) that is caused by infectious proteins called prions. CJD typically presents with dementia and myoclonus, is relentlessly progressive, and usually results in death within a year of onset. Most patients with CJD are between 50 and 75 years of age; however, patients as young as 17 years and as old as 83 years have been recorded.
In 1920, Hans Gerhard Creutzfeldt described the first case of a progressive mental and neurological disturbance in a 23 year old woman. Alfons Maria Jakob described another three cases of defects in the motor systems one year later. In 1922 the eponym ‘Creutzfeldt-Jakob disease’ (CJD) was first used to describe a number of degenerative central nervous system diseases (1-4).
In 1950s, a peculiar disease known as ‘kuru’, in the Eastern Highlands of Papua New Guinea has been discovered and turned out to be due ingesting brain tissue of dead relatives for religious reasons. The neuroplathological similarity between kuru, CJD, and scrapie (which is a disease affecting sheep discovered 1973 with higher incidence in the UK) was discovered (3-6).
In 1960s, the term transmissible spongiform encephalopathy was applied after the discovery of the transmissible ability of both kuru and CJD diseases to chimpanzees (5, 7). Prions are the only known infectious pathogens that are devoid of nucleic acid. All other infectious agents possess genomes composed of either RNA or DNA that direct the synthesis of their progeny. Prion diseases may be manifest as infectious, genetic, and sporadic disorders.
Bovine spongiform encephalopathy (BSE or ‘mad cow disease’). Which occurred in outbreak in mid 1980 followed by outbreak of special type of CJD (varient CJD) in the UK and to lesser extent other European countries.
For years it was thought that the disease is caused by ‘slow’ or ‘unconventional’ viruses causing amyloidoses of the nervous system. In 1976 Daniel Carleton Gajdusek was awarded the first Nobel prize for his work on ‘slow virus’ infections theory (8).
1980s the term ‘prion’ was used to designate a small proteinaceous infectious particle that was resistant to inactivation by most of the procedures that modify nucleic acids, and to distinguish the agent from virus and viroids. These protein particles are the causative infectious agents for the prion diseases. This theory, also known as the ‘protein-only’ hypothesis and has been under criticism for years (5).
Routes of infection
- Acquired infection (diet and following medical procedures such as surgery, growth hormone injections, corneal transplants) i.e. an infectious agent is implicated. Prions are ‘sticky’ proteins that tend to aggregate. Being resistant to heat and to digestive enzymes they can reach the circulation after oral ingestion of infected animal meat products (9-11).
- Apparent hereditary (an autosomal and dominant trait) 10-15%. The human PrP-gene (PRNP), which encodes the 253-amino acid prion protein, is localized on the short arm of chromosome 20. Studies have shown a strong, but not absolute, correlation between specific PRNP mutations and different clinical forms of familial prion diseases (1-3, 8, 12).
Post-mortem examination reveals non-inflammatory lesions, vacuoles, amyloid protein deposits and astrogliosis.
Animal diseases (13-15): are mainly
- Scrapie affecting mainly sheep rarely goats.
- Transmissible mink encephalopathy (TME) affecting minks.
- Chronic wasting disease (CWD) of mule-deer, elk
- Bovine spongiform encephalopathy (BSE or ‘mad cow disease’). Which occurred in outbreak in mid 1980 followed by outbreak of special type of CJD (varient CJD) in the UK and to lesser extent other European countries.
In humans are mainly (16-20):
- Creutzfeldt-Jakob disease (sCJD).
- New variant form of CJD (vCJD)
- Gerstmann-Sträussler-Scheinker disease (GSS)
Symptoms and Clinical picture (13, 20, 21)
The diseases are characterised by loss of motor control, progressive dementia, paralysis and wasting. In the terminal stage, the patient is usually mute, rigid and unresponsive (akinetic mutism) with decorticated or decerebrate posture as well as fecal and urinary incontinence.
CJD typically occurs a decade later, has cerebral involvement so dementia is more common and the patient seldom survives a year .
GSS is distinct from CJD, it occurs typically in the 4th-5th decade, characterised by cerebellar ataxia and concomitant motor problems, dementia is less common and disease course lasts several years before ultimate death.
Fatal insomnias present with an untreatable insomnia and dysautonomia. Pathological changes are characterized by severe selective atrophy of the thalamus.
Alpers syndrome is the name given to prion diseases in infants.
Prognosis: death within one year after the onset of symptoms in 90%, and a further 5% of patients die within the next year.
Anti-prion drugs are being developed. Researchers focus on agents which reduce PrP expression. Similarly agents destabilising the PrPsc conformation may be effective. In this regard several vaccines to Alzheimers amyloid plaques are in clinical trials (both diseases show similarity in the pathological changes). Agents which interfere with PrPc-PrPsc interaction may be effective. A number of reagents showing affinity for amyloid proteins are known e.g congo red and are being studied.
Chemicals affecting the endocytosis, exocytosis, intracellular trafficking and degradation of proteins and in particular PrP aiming to decrease expression level of the prions in the cells. Amphotericin for instance is reported to delay prion disease in hamsters (although it apparently has little effect in humans). Also, a trial of quinacrine, an anti-malarial, and chlorpromazine, an anti-psychotic was completed.
Very recently a successful trial of injecting antibodies that latch onto prions into mice that that were 30 days into the disease - before symptoms occur, but at a time when prions are multiplying ferociously. The animals stayed healthy for at least two years, rather than dying by the time they reached seven months (22).
Scientists are now concerned about processing this antibody and hope for wining the battle against this disease in humans. An achievement that might give scientists the 3rd Nobel prize in the same disease.
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