Aetiology

The 3 types of prion diseases (sporadic, genetic, and acquired) are grouped based on known aetiology.

Sporadic Creutzfeldt-Jakob disease (sCJD)

  • This is believed to occur spontaneously. This disease process begins when endogenous prion proteins, consisting of mostly alpha-helical and a small portion of beta-pleated sheet structure, spontaneously change shape into predominantly beta-pleated structures, called proteinaceous infectious particles or prions. It is not yet known how the prion forms from the prion protein. The working model is that once a prion forms, it becomes a template so that when prion proteins (primarily alpha-helical structured) come in contact with it, they are also transformed into the beta-pleated structure, the prion.

  • Patients and families have been known to report an association between stressful life events and the onset of sCJD symptoms. Although it is not believed that stress causes the misfolding of the prion protein, it has been suggested that stress may precipitate the underlying symptoms in a patient with subclinical prion disease.[20]

Genetic prion diseases

  • These are caused by a mutation in the gene encoding the endogenous prion protein (PRNP) located on chromosome 20.[6] To date more than 40 different PRNP mutations have been identified, many presenting with their own disease phenotype (i.e., familial CJD, Gerstmann-Straussler-Scheinker, and fatal familial insomnia). Generally, PRNP mutations are transmitted in an autosomal dominant manner and most are 100% penetrant, but rare cases of CJD have occurred in association with PRNP polymorphisms that may be incidental, not causal.[7] Although most are point mutations, some are due to insertions or deletions.[6] Importantly, about 60% of patients with prion disease that is found to be genetic were not known to have a family history of prion disease; however, further inspection will often find a family history of Alzheimer's or Parkinson's disease that was likely misdiagnosed.[21][22]

  • Onset and clinical manifestations of all forms of prion disease are often strongly influenced by the polymorphic codon 129 of PRNP. Codon 129 can be either methionine (M) or valine (V). Homozygotic combinations (e.g., MM or VV) result in higher risk for developing prion disease. Depending on the size of the unglycosylated prion fragment after treatment with proteinase, as determined by migration on a western blot, the prion is referred to as type 1 (21 kd) or type 2 (19 kd). Some patients have a mixture of type 1 and type 2 prions. The prion type also seems to play a role in how the disease will manifest (e.g., time course, major symptoms).[23]

Acquired prion diseases

  • These include iatrogenic CJD (iCJD), variant CJD (vCJD), and the nearly extinct kuru. iCJD is categorised by the transmission of prions from one person to another through medical procedures. Prions are in highest concentrations in the brain (the eyes are directly connected to the brain through the optic nerve). Although not contagious in the traditional sense, prions can be directly transferred through invasive medical procedures such as cadaver-derived corneal transplants, dura mater grafts, and pituitary hormone replacement, as well as any other neurosurgery involving prion-contaminated surgical instruments.[24] Although iCJD is relatively uncommon, minimising transmission can be difficult, as the molecular conformation of prions as prion pathogen (PrPSc) is particularly resistant to common sterilising practices.[25] vCJD prions can be found outside the central nervous system, including in the gut (appendices), liver, salivary glands, kidney, lung, and bone marrow.[26] The UK Department of Health has published guidelines to reduce the risk of transmission of CJD and vCJD in hospital, research, and community settings.[27]

  • vCJD occurs primarily from the transmission of prion disease in bovines to people through ingestion of prion-contaminated beef, with evidence that PrPSc is absorbed through the GI tract, travels through the enteric nervous system to the spinal cord and brain, and may also enter the reticuloendothelial system and bloodstream with secondary centrifugal spread to other tissues.[28] Although prion diseases affect other animals - scrapie in sheep and goats, and chronic wasting disease in cervids - bovine spongiform encephalopathy is the only known form to be transmitted to humans. vCJD is also the only human form of disease known to have been transmitted through transfusion of blood or blood products.[10][13][29][30][31][32][33]

Pathophysiology

The pathogenicity of prion disease is highly unlike other infectious agents in that it does not contain any nucleic acids; rather, it is believed to be purely an infectious protein. Prion diseases are caused by the conversion of healthy, endogenous prion proteins, PrPC (where C stands for the normal cellular form of prion protein), into a pathogenic form called a prion or PrPSc (where Sc stands for scrapie, the prion disease of sheep and goats). This transformation of PrPC, a predominantly alpha-helix structure, transforms the entity into a largely beta-sheeted form called PrPSc. When PrPC is converted into PrPSc, the new PrPSc act as templates that help convert adjacent PrPC into PrPSc. This process is very rapid, occurring within one minute of exposure of PrPC to PrPSc.[34] Once converted, these misshapen proteins then become PrPSc templates, initiating a transformational cascade of nearby PrPC. This conversion eventually becomes an exponential process,​​​ and although cells probably initially clear PrPSc, the rate of PrPSc conversion eventually surpasses the rate at which they can be cleared.[3][4][35]​​​

The transformation of prion proteins into prions and/or the resulting accumulation of prions in the CNS causes nerve cell injury and eventually death. During the process of nerve cell injury, fluid-filled vesicles appear in the dendritic tree of neurons. These vesicles are called vacuoles and enlarge to 10 to 20 micrometres or larger and cause the brain tissue to have a spongiform appearance when examined under the microscope, hence the alternate name for prion diseases, transmissible spongiform encephalopathies. This vacuolation (or spongiform) change is a hallmark characteristic of this disease, although other conditions can also have these microscopic changes. Other microscopic features of Creutzfeldt-Jakob disease (CJD) brain tissue include neuron loss, astrogliosis, and, most importantly, the presence of PrPSc by immunohistochemistry or western blot.[3][36] In approximately 10% of CJD, amyloid plaques of PrPSc are found; and in cases of Gerstmann-Straussler-Scheinker, an amyloid PrPSc core is surrounded by another group of smaller amyloid globules. vCJD also has a relatively unique pathological feature of core PrPSc amyloid plaques surrounded by vacuoles; these are called florid plaques, as they are thought to resemble a flower. PrPSc plaques and pericellular deposits are found throughout the cerebrum and cerebellum in vCJD.[12] In vCJD, PrPSc can also be identified in non-neuronal tissues, including the lymphoreticular system, during the disease course;[26] hence, tonsil biopsies often show PrPSc in vCJD, but not in other forms of human prion disease.[3][37] At the cellular level, although much work has been done, we still do not understand the processes that lead to neuronal injury and death in prion disease, although oxidative stress may play an important role.[38][39][40][41] There appears to also be damage to the GABAergic system in prion disease.[42][43] One issue that is clear is that the prion protein, PrPC, is required, and may be sufficient, for development of prion disease.[44][45][46][47][48]

Classification

Standard classification[1][2][3][4]

Prion diseases can be classified into three categories: sporadic (85% to 90%), genetic (10% to 15%), and acquired (<1%).[5]

Sporadic Creutzfeldt-Jakob disease (sCJD)

  • Idiopathic (aetiology is unknown but it is believed to be a spontaneous disease).

  • Typically presents with cognitive complaints, lack of co-ordination or other motor problems, behavioural/personality changes, and/or abnormalities in vision.

Genetic prion diseases

  • Familial CJD

    • More than 40 mutations found on the prion protein gene (PRNP) on chromosome 20 and are autosomal dominant, most with complete penetrance.[1][6][7]

    • Presentation varies between type of PRNP mutation and sometimes even within a family.

    • Course often longer than sCJD, but some mutations may present clinically and pathologically identically to sCJD.[6]

  • Fatal familial insomnia

    • Begins with increasing insomnia and psychiatric symptoms, such as anxiety.

    • Progresses with hallucinations, weight loss, dementia, and eventually death.

  • Gerstmann-Straussler-Scheinker

    • Presentation may vary depending on the type of PRNP mutation disease phenotype and sometimes even within a family.

    • Early presentations of the disease often include behavioural changes, parkinsonian features, or ataxia.

    • Many cases have been misdiagnosed as familial Alzheimer's or Parkinson's disease.

Acquired prion disease

  • Iatrogenic CJD

    • Due to medical procedures such as administration of human growth hormone, or to contaminated surgical instruments during corneal transplant, dura mater graft, and insertion of EEG deep brain electrodes.[8][9]

    • Incubation period can be as short as one year but is typically several years and even decades long.

  • Variant CJD (vCJD)

    • Acquired from consumption of beef contaminated with bovine spongiform encephalopathy (mad cow disease), or transfusion of blood or blood products from a patient with pre-symptomatic or latent vCJD.[10]

    • Median age of onset is around 29 years, with most cases occurring in patients in their 20s or 30s, much younger than most with sCJD.

    • Initially presents with psychiatric and behavioural changes, with later symptoms of dysaesthesia, dementia, ataxia and/or chorea, myoclonus, or dystonia.[11][12][13]

  • Kuru

    • Endemic to the Fore tribe of Papua New Guinea, where practices of endocannibalism contributed to its transmission, and was essentially eliminated with end of endocannibalism, although rare cases may still occur, as incubation period may be as long as 50 years in some cases.[14]

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