The prion diseases, also referred to as the spongiform encephalopathies, comprise diseases that are now grouped together because they share a common disease mechanism involving aberrant protein folding (Prusiner et al. 1998).
- Creutzfeldt–Jakob disease (CJD),
- variant CJD,
- Gerstmann–Straussler–Schenker syndrome,
- familial fatal insomnia;
The novel disease mechanism which results in a disorder that can be both hereditary and transmissible, together with a threat of an epidemic of variant CJD consequent upon the bovine spongiform encephalopathy (BSE) crisis in Europe, has focused considerable attention on these diseases, despite their rarity.
The transmission of kuru, the spongiform encephalopathy found amongst the Fore highlanders of Papua New Guinea, to non-human primates by Gajdusek led to the concept of a ‘slow virus’, although the transmissible agent remained elusive. Ultimately this was shown to be a protein devoid of nucleic acid—the prion protein (PrP) (Prusiner 1991).
The transmissible prion protein (PrPsc) is derived from a normal cellular protein (PrPC) by post-translational modification, resulting in a high β-sheet content; the mechanism of the subsequent cellular degeneration is not established. The abnormal isoform of the protein (PrPsc) has the ability to induce aberrant folding of the host protein, hence the transmission, which can occur either through cannibalism, as in kuru, or iatrogenically, as with growth hormone derived from cadaveric pituitary glands and surgical interventions. Species differences in the PrP sequence make transmission of the disease across species inefficient (species barrier) but this can occur experimentally and is now believed to have occurred with variant CJD following the BSE epidemic. Mutations in the PrP gene are believed to facilitate the aberrant protein folding and underlie familial CJD, familial fatal insomnia, and Gerstmann–Straussler–Schenker syndrome. A common methionine/valine polymorphism at PrP 129 is a genetic risk factor for the disease (Palmer et al. 1991).
Prion diseases are multisystem central nervous system disorders with variable degrees of dementia, cerebellar, pyramidal, and extrapyramidal features. CJD occurs worldwide, with an annual incidence of about 1 per million. It is invariably fatal. The classical triad of dementia, myoclonus, and abnormal EEG with periodic or pseudoperiodic complexes is seen typically in patients between the ages of 50 and 70 years. It has a subacute onset; rarely, the disease can be extremely rapid with death within 2 months, whereas in others there is a slower progression of the disease over 1–2 years (Brown et al. 1986).
The different clinical phenotypes in terms of progression have been related to different isoforms of the aberrant prion protein (PrPsc) (Parchi et al. 1996). About 10 per cent of cases of prion disease are familial, with autosomal dominant transmission due to mutations in the PrP gene. The phenotype can be varied, some mimicking Alzheimer's disease and others Huntington's disease; cases with the 144 bp insert tend to have a slow progression with a variable phenotype (Collinge et al. 1992).
Patients with a prominent cerebellar component were originally described as Gerstmann–Straussler-Schenker syndrome, and the recently described familial fatal insomnia (Lugaresi et al. 1986) is characterized by insomnia with loss or dramatic reduction of slow wave and REM sleep, together with autonomic disturbance.
Iatrogenic cases have been associated with corneal grafting, dura mater grafts, and in-depth electrode recording. The majority of iatrogenic cases have been associated with cadaveric pituitary derived growth hormone treatment, a practice which was discontinued in the mid 1980s. These cases have more cerebellar features and less dementia (Fradkin et al. 1991).
A variant of CJD has emerged in the UK and France in the past 5 years and is believed to have resulted from ingestion of contaminated food from BSE-infected cattle. It is associated with a characteristic PrPsc isoform (Collinge et al. 1996). The cases of variant CJD are younger than classical CJD, some even in their teens, with early depression and anxiety. Cerebellar and basal ganglia features are more prominent than cognitive impairment early in the disorder (Will et al. 1996).
The characteristic histopathology is the spongiform change, although this is variable; it is associated with neuronal intracytoplasmic vacuolation together with astrocytosis and gliosis. The abnormal prion protein (PrPsc) can be demonstrated on immunohistochemistry and can form plaques, especially in the cerebellum in Gerstmann–Straussler–Schenker syndrome. Variant CJD is also associated with PrP plaques reminiscent of kuru (Will et al. 1996).
Blood tests are usually normal in prion disease, although there can be mildly abnormal liver function tests. PrP genotyping will identify mutations in the familial cases and cases of variant CJD reported to date have all been methionine homozygous at PrP 129. Magnetic resonance imaging may show signal changes on T2-weighted images in the basal ganglia and characteristic posterior thalamic signal change in variant CJD. Cerebrospinal fluid is unremarkable, although P14–3–3, which probably reflects rapid neuronal disintegration, is found in classical CJD cases (Hsich et al. 1996). The EEG may be normal or non-specific early in the disease, but in classical CJD pseudoperiodic or periodic complexes are seen. Tonsillar biopsy in variant CJD can reveal the specific PrPsc isoform (Hill et al. 1999).
At present there is no specific treatment for the prion diseases. The PrPsc is highly resistant to degradation and thus instruments cannot be routinely sterilized. Neurosurgical instruments must be quarantined and if the diagnosis confirmed, destroyed. There is no need to barrier-nurse patients but disposable instruments should be used for invasive procedures, and all samples should indicate the suspected diagnosis clearly (Health Service Circular 1999).