Transcript bovine identification

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
• 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.
• In the prion hypothesis, conversion of the PrPC to PrPSc
occurs by a direct interaction
Human prion diseases
• 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:
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spongiform change
neuronal loss
Astrocytosis.
accumulation of PrPSc.
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)
• 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 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
• 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
• 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 البشر‬among 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
• 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-tohuman 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.