NR ASBT
AU Hardie,D.
TI Spongiform encephalopathies (Prion diseases)
QU NEUROLOGICAL DISEASES CAUSED BY VIRUSES
IA http://web.uct.ac.za/depts/mmi/jmoodie/neurol2.html
VT
A number of transmissable neurological syndromes, caused by unconventional virus-like agents, have been identified in man and other animals. These diseases are characterized by the following features:
1. Confined to the CNS
2. Long incubation period
3. Progressive, uniformly fatal course
4. Typical brain histology: reactive gliosis, vacuolation of neurones, deposition of amyloid protein in the brain and the absence of an inflammatory response.
5. Infection is believed to be transmitted by means of a novel infectious protein, termed prion or PrP.
Diseases falling into this category include:
Scrapie - sheep, goats
Bovine spongiform encephalopathy - cattle
Transmissable Mink encephalopathy - mink
Creutzfeldt-Jakob disease - man, sporadic and familial
Gerstmann-Streussler disease - man, familial
Fatal Familial Insomnia - man, familial
Kuru - man, Fore people, New Guinea
Properties of Prions:
1. Infectivity is associated with a novel infectious protein, termed prion (PrP)
2. Infectious particles are very small - about 20-30 nm in size.
3. No nucleic acid has yet been found to form part of the agent
4. Prions are extremely resistent to inactivation by: ultra-violet light, formaldehyde and heat.
5. Prions can be transmitted by intra-cerebral or sub-cutaneous inoculation of material from infected brain.
Pathogenesis of prion diseases
The pathogenesis of prion diseases is still a great mystery. The pathology appears to
be both infectious as well as genetic.
Recent evidence has demonstrated that the prion protein has the same primary amino acid sequence as a host protein which is normally present at low levels in healthy brain tissue. The cellular protein has been termed PrPc. Although the amino acid sequence is the same
as the cellular one, the prion protein, has an abnormal conformation, due to different post translational modification. Exposure to the abnormal form triggers a conversion of the cellular isoform to the infectious form. This is followed by progressive accumulation of the abnormal form (prion protein) in the brain, which is deposited as amyloid.
Scrapie
Scrapie is a neurological disease occurring in sheep and goats. It was first identified in Britain, but it is now known to occur world wide. It is the prototype disease of the spongiform encephalopathies; the scrapie prion is termed PrPsc. The disease is clearly infectious as it can be transmitted to sheep, mice and hamsters by intra-cerebral or sub cutaneous inoculation of material from the brains of infected sheep. Susceptibility to infection appears to be genetically determined.
Clinical features
The disease is transmitted by contact in flocks of sheep and also vertically, from ewes to lambs. In natural infection, the incubation period is 2 to 5 years. Following intra-cerebral inoculation, however, the incubation is much shorter, only 3 to 24 months. Affected sheep develop ataxia, tremor and muscular in co-ordination; the symptoms progress to paralysis and death.
Bovine Spongiform encephalopathy
Similar disease to scrapie which occurs in cattle. It is believed that scrapie was introduced into cattle herds fed on feeds containing scrapie-infected sheep offal. The condition is now epidemic in cattle herds in England and Wales ("Mad Cow Disease"). There is concern that the infection may be transmitted to humans, but no cases have been reported yet.
Transmissable Mink encephalopathy
Scrapie has been introduced into minks, bred in captivity through feeds containing sheep brains.
Creutzfelt-Jakob disease (CJD)
In 1920, Creutzfeldt described a progressive dementing illness in a 22 year old woman. The following year, Jakob described four older patients with a clinically similar presentation and course. Since then, numerous cases of CJD have been described. CJD occurs world wide. It is very rare, with an incidence of about 1 case per million population. While most cases are sporadic, 5-10% are familial. In the familial form, CJD is inherited as an autosomal dominant condition.
Clinical features
The onset of the disease typically occurs between the ages of 50 and 65 years. There are two main modes of presentation:
1. Chronic dementing illness
2. Progressive cerebellar dysfunction
The condition is relentlessly progressive and patients usually die within a year of presentation.
Transmission:
The natural route of infection is not known, but CJD has been accidently transmitted by:
1. Corneal grafts - where the corneas were harvested from cadavers that died of CJD.
2. Growth hormone preparations, derived from human pituitary glands.
3. In two patients who received grafts of dura mater, prepared from cadavers, and
4. through electrodes used for electro-encephalography which had previously been used in a patient with CJD.
The prion detected in the brains of patients with CJD is termed PrPcJD. The disease has also been experimentally transmitted to chimpanzees and other primates. Following intracerebral inoculation, the incubation period is 11-14 months. The disease can also be transmitted peripherally (IV, intra peritoneal or intramuscular routes). But transmission is much less efficient and the incubation period is much longer (many years).
Decontamination procedures:
Prions are extremely resistent to inactivation by ultra-violet light, forrmaldehyde and heat. Recommended methods of decontaminating infected material include:
1. Autoclaving for 4.5 hours (121°, 15 p.s.i)
2. 1N NaOH followed by autoclaving for 1.5 hours
Gerstmann-Sträussler Syndrome
Rare familial neurodegenerative disease which usually manifests in the third to the seventh decade of life. The condition is both infectious and genetic: the predisposition is inherited as an autosomal dominant condition; while, in addition, the disease can be transmitted to non human primates by intra cerebral inoculation with brain tissue from cases of GSS.
Recent genetic studies have revealed that affected individuals have a point mutation in their PrPc gene. The altered amino-acid sequence of the PrPc protein may make it more susceptible to transformation to the abnormal conformation.
Fatal familial insomnia
Kuru
This is a transmissable prion disease found only in the Fore people of New Guinea. It first appeared about 60 years ago and the incidence increased until the late 1950's. The disease is now known to have been transmitted through ritual cannibalism: until the late 1950's it was the practice of women and children to eat the brains and viscera of dead relatives, including those who had themselves died of Kuru. Cannibalism stopped in 1957 and the incidence of Kuru has declined sharply since then.
Clinical features:
The incubation period varied from 4-20 years. Patients presented with progressive cerebellar dysfunction. Death usually occurred within a year of initial presentation.
Transmission studies:
Intra-cerebral inoculation of brain tissue from Kuru victims into non human primates leads to the development of symptoms within two years.
SP englisch
PO Internet
OR Prion-Krankheiten H