Prion diseases (transmissible spongiform encephalopathies) Dr. Mohammad Shakeeb, MD Specialist in clinical pathology/Microbiology and immunology

Are a unique group of fatal neuro-degenerative disorders occurring in human beings and animals that possess major characteristics: All are transmissible to a variety of mammals, either experimentally or by natural exposure. The infectious agent is composed entirely of protein, without any nucleic acid. prion (proteinaceous infectious particle) No evidence of a conventional host immune reaction has been found in prion diseases.

The diseases caused by these agents are characterized in all species by neurodegeneration in the central nervous system (CNS) usually with spongiform change. This consists of numerous small vacuoles (10–200 μm) that are formed within neuronal cell bodies and their processes. probably through dilatation of neuronal lysosomal, Golgi and endoplasmic reticulum structures. Spongiform change may be reversible in its early stages. Ultimately, neuronal death occurs accompanied by reactive proliferation of astrocytes and microglia.

The normal cellular form of the prion protein (PrPC) is converted by misfolding into an abnormal disease-associated form (PrPSc) and accumulates within the CNS, usually as diffuse deposits, but occasionally in the form of amyloid plaques

The transmissible agent: a prion? They are sub-viral in size and resistant to inactivation by many physical and chemical agents, including: Heat exposure to ionizing or ultraviolet radiation. deoxyribonuclease (DNAase) and ribonuclease (RNAase) formaldehyde and glutaraldehyde. PrPC is expressed in a variety of cells, including neurones in the CNS. Where it may act as a copper-binding protein, and is thought to play a role in synaptic function.

During prion infection, PrPC appears to undergo a conformational change to convert to PrPSc beta-pleated sheet conformation This abnormal isoform has a relatively high beta-pleated sheet conformation, which renders it partially resistant to digestion with proteinase K and allows it to aggregate as amyloid fibrils in the brain. direct interaction In the prion hypothesis, conversion of the PrPC to PrPSc occurs by a direct interaction

Human prion diseases Creutzfeldt–Jakob disease (CJD). The most common form of human prion disease was first described in the 1920s and is known as Creutzfeldt–Jakob disease (CJD). ever-widening spectrum of human prion diseases has been identified with three main subgroups, comprising: idiopathic disorders, where the cause is unknown familial disorders, occurring as autosomal dominant disorders acquired disorders, following accidental infection by inoculation or ingestion.

The identification of the prion protein and sequencing of the human prion protein gene on chromosome 20 have greatly increased our understanding of human transmissible spongiform encephalopathies.

Diagnosis Careful assessment of the clinical features: presumptive diagnosis of CJD. Analysis of the prion protein gene is essential to identify cases of familial CJD associated with a pathogenic mutation. disease susceptibility: polymorphism at codon 129 in the prion protein gene. At present, there is no form of screening test for human prion diseases and no specific treatment is available. A definitive diagnosis depends on examination of the brain at autopsy.

Neuropathology The principal neuropathological features of human prion diseases are: spongiform change spongiform change neuronal loss neuronal loss Astrocytosis. Astrocytosis. accumulation of PrPSc. accumulation of PrPSc. amyloid plaque formation. amyloid plaque formation.

Sporadic CJD CJD occurs most commonly as a sporadic disorder. Sporadic CJD usually presents as a rapidly progressive dementia of less than 1 year’s duration. Often accompanied by other neurological abnormalities. The peak incidence is in the seventh decade of life, but the disease has been described in teenagers and even in the ninth decade. The disease is untreatable and invariably fatal. patients survive for only 4 months after the onset of major symptoms.

Familial prion diseases Around 10% of cases of CJD occur as autosomal dominant inherited disorders. These are associated with mutations or insertions in the open reading frame of the human prion protein gene on chromosome 20. Gerstmann–Sträussler–Scheinker syndrome (GSS) Gerstmann–Sträussler–Scheinker syndrome (GSS) very rare disorder, which affects middle-aged adults cerebellar ataxia, nystagmus and gait abnormalities are prominent clinical features, with dementia occurring only towards the end of the illness

Numerous multicentric PrP amyloid plaques are present throughout the CNS Fatal familial insomnia Fatal familial insomnia is an extremely rare inherited disorder, characterized clinically by disturbances of sleep and autonomic function with relative intellectual preservation in middle age. neuropathological changes mainly in the thalamus.

Acquired prion diseases Iatrogenic CJD Iatrogenic CJD accidental transmission from one person to another iatrogenic CJD have involved accidental inoculation of contaminated CNS tissue from a CJD patient to another patient. following the implantation of inadequately decontaminated intracerebral electrodes, or via human dura mater grafts. most common form of iatrogenic CJD occurs in recipients of human growth hormone derived from cadaveric pituitary glands

Kuru Kuru An example of human-to-human transmission of a TSE. a disease in which the infectious agent is acquiredby an individual’s exposure to diseased brain tissue in the courseof ritualistic cannibalism ( اكل لحوم البشر )among members of a tribe in NewGuinea. infection occurs by consuming contaminated brain tissue or via inoculation through breaks in the skin following the handling of diseased tissue. With cannibalism cessation in the late 1950s,the disease is disappearing.

Variant CJD Variant CJD BSE, commonly called mad cow disease, arose in British cattle presumably caused by their feed processed with animal parts prepared from diseased sheep and cattle. The obvious question raised by this occurrence is whether the BSE from infected cattle can be transmitted to humans? A study of infectious material from a cluster of histologically distinctive British CJD cases in unusually young patients (now referred to as “variant,” or vCJD) indicated that animal-to- human transmission very likely did take place.

The age of onset is unusually young (mean 28 years), with a range from 12–74 years. The clinical illness is prolonged, with an average duration of 14 months (range 6–39 months). The clinical features are also unusual, with psychiatric and sensory symptoms at onset, followed by ataxia and myoclonus, with dementia only in the final stages of the illness. Variant CJD differs from other forms of human prion disease in that PrPSc can be detected in lymphoid tissues (in follicular dendritic cells) both during the clinical illness and in the late preclinical illness.

Animal diseases Many animal species may be afflicted by spongiform encephalopathies. Examples include: Scrapie: which affects sheep and goats. It was the first disease to be associated with prions. Bovine Spongiform Encephalopathy (BSE) (also called mad cow disease): This cattle disease is believed to be transmitted to humans through diet and causing vCJD.