Transmissible Spongiform Encephalopathies (Prion Diseases)

Question 1

What are Prions?

Answer 1

These are abnormal forms of a cellular protein that cause transmissible neurodegenerative
disorders. [23,] [24]

Question 2

Prion which includes ________________and bovine spongiform encephalopathy—share this etiologic basis that
distinguishes them from other neurodegenerative and infectious diseases.

Answer 2

• Creutzfeldt-Jakob disease (CJD),
• Gerstmann-Sträussler-Scheinker syndrome (GSS),
• fatal familial insomnia,
• and kuru in humans;
• scrapie in sheep and goats;
• mink-transmissible encephalopathy;
• chronic wasting disease of deer and elk;

Question 3

While Prion has differences
exist among these disorders, they are all associated with _______________ that is both infectious and transmissible.

Answer 3

abnormal forms of a specific protein,
termed prion protein (PrP),

Question 4

As the name implies, Prion
are predominantly characterized by

Answer 4

** “spongiform change**”

Question 5

what is the reason for the spongiform change in prion?

Answer 5

they are caused by intracellular vacuoles in
neurons and glia.

Question 6

Clinically, most of the affected patients of Prion develop ___________.

Answer 6

progressive dementia

Question 7

What is the most common disorder of Prion?

Answer 7

The
most common disorder is CJD.

The sporadic form of CJD has an annual incidence of
approximately 1 case per 1,000,000 population and accounts for about 90% of cases;

familial
and transmitted forms make up the rest.

Question 8

Normal PrP is a 30-kD cellular protein present in neurons. When does the Disease occurs?

Answer 8

It is when the PrP
undergoes a conformational change from its normal α-helix-containing isoform (PrP c ) to an
abnormal β-pleated sheet isoform, usually termed PrP sc (for scrapie) ( Fig. 28-31 ).

Question 9

Associated
with the conformational change, PrP acquires____________.

Answer 9

resistance to digestion with proteases, such as
proteinase K

Question 10

___________in neural tissue seems to be the cause of the pathology in
these diseases, but how this material induces the development of cytoplasmic vacuoles and
eventual neuronal death is still unknown.

Answer 10

Accumulation of PrP sc

Question 11

__________________ allows detection of PrP sc , which is diagnostic.

Answer 11

Western blotting of tissue extracts after partial
digestion with proteinase K

Question 12

The conformational change resulting in PrP sc may occur spontaneously at an extremely low
rate(resulting insporadic cases)or at ahigher rate if various mutations are present in PrP c ,
such as occurs in familial forms of CJD and in GSS and fatal familial insomnia.

Question 13

PrP sc ,
independent of the means by which it originates, then facilitates, in a cooperative fashion, the
conversion of other PrP c molecules to PrPsc molecules.

It is this activity of___________ that
accounts for the infectious nature of prion diseases.

Answer 13

PrP sc

Question 14

The gene encoding PrP, termed __________, shows a high degree of conservation across species. variety of mutations in PRNP have been found to underlie familial forms of prion diseases.

Answer 14

PRNP

Question 15

​ In
addition, a polymorphism at codon 129 that encodes either _________________has
been found to influence the disease: individuals who are homozygous for either Met or Val are
over-represented among cases of CJD compared with the general population, implying that
heterozygosity at codon 129 is protective against development of the disease. Interestingly, this
protection also applies against iatrogenic CJD.

It has been suggested that the amino-acid at
this polymorphic site influences disease by altering the kinetics of aggregation and the
conformations of PrP molecules

Answer 15

methionine (Met) or valine (Val)

Question 16

___________ the most common prion disease, is a rare disorder that manifests clinically as a rapidly
progressive dementia.

It is primarily sporadic (about 85% of cases) in its occurrence, and has a
worldwide annual incidence of about 1 per million; familial forms also exist that are caused by
mutations in PRNP.

Answer 16

CJD,

Question 17

What is the peak incidence of CJD?

Answer 17

The disease has a peak incidence in the seventh decade.

Question 18

There are wellestablished
cases of iatrogenic transmission of CJD, notably by ________________

Answer 18

• corneal transplantation,
• deep implantation electrodes,
• and contaminated preparations of human growth hormone.

Question 19

What is the clinical
onset of CJD?

Answer 19

It is marked by subtle changes in memory and behavior followed by a rapidly progressive
dementia, often withpronounced involuntary jerking muscle contractionsonsudden stimulation
(startle myoclonus).

Signs of cerebellar dysfunction, usually manifested as ataxia, are present
in a minority of affected individuals.

The disease is uniformly fatal, with an average survival of
only 7 monthsfrom the onset of symptoms, although a few patients have lived for several years.
These long-surviving cases show extensive atrophy of involved gray matter.

Question 20

Starting in 1995, a series of cases of a CJD-like illness came to medical attention in the United
Kingdom.

These new cases were different from typical CJD in several important respects: the
disease affected young adults, behavioral disorders figured prominently in the early stages of
the disease,and the neurologic syndrome progressed more slowly than in individuals with other
forms of CJD.

The neuropathologic findings and molecular features of these new cases were
similar to those of CJD, suggesting a close relationship between the two illnesses.

Answer 20

vCJD

Question 21

Pathologically, variant CJD (vCJD) is characterized by the ______________

Answer 21

• presence of extensive cortical plaques with a surrounding halo of spongiform change.
• No alterations in the PRNP gene are present;
• nearly all affected patients are Met/Met homozygotes at codon 129.
• With the recent report of a case of vCJD arising in a Val/Val homozygote, the possibility of an influence of codon 129 on incubation period rather than susceptibility has emerged.

Question 22

Several lines of evidence have linked vCJD with ______________raising complex public health issues.
There has also been documented transmission of vCJD by blood products.

Answer 22

bovine spongiform encephalopathy,

Question 23

The progression of the dementia in CJD is usually so rapid that there is little if
any grossly evident brain atrophy.

Question 24

On microscopic examination what is the pathognomonic finding in CJD is
_________________

Answer 24

• a spongiform transformation of the cerebral cortex and, often, deep gray-matter structures (caudate, putamen);
• this multifocal process results in the uneven formation of small, apparently empty, microscopic vacuoles of varying sizes within the neuropil and sometimes in perikaryon of neurons ( Fig. 28-32A ).

Question 25

What happens In the advanced cases of CJD?

Answer 25

• there is **severe neuronal loss, **reactive gliosis, **
• and sometimes** expansion of the vacuolated areas into cystlike spaces (“status spongiosus”)**.
• No inflammatory infiltrate is present.

Question 26

What is seen in the electron microscopy of CJD?

Answer 26

shows the
vacuoles to be membrane-bound and located within the cytoplasm of neuronal processes.

Question 27

What are Kuru plaques?

Answer 27

These are extracellular deposits of aggregated abnormal protein;

they are Congo
red- and PASpositive and usually occur in the cerebellum ( Fig. 28-32B ) although they are
present in abundance in the cerebral cortex in cases of vCJD, surrounded by the spongiform
changes ( Fig. 28-32C ).

In all forms of prion disease immunohistochemical staining
demonstrates the presence of proteinase K–resistant PrP sc in tissue.

Question 28

What is Fatal familial insomnia (FFI), named in part for the____________

Answer 28

sleep disturbances that characterize its initial
stages, is also caused by a specific mutation in the PRNP gene.

The mutation, which leads to
an aspartate substitution for asparagine at residue 178 of PrP c , results in FFI when it occurs in
a PRNP allele encoding methionine at codon 129, but causes CJD when present in tandem with
a valine at this position.

How these amino acids influence disease phenotype is not understood.
In the course of the illness, which typically lasts fewer than 3 years, affected individuals develop
other neurologic signs, such as ataxia, autonomic disturbances, stupor, and finally coma. A
noninherited form of the disorder (fatal sporadic insomnia) has also been described.

Question 29

Unlike other prion diseases, FFI does not show spongiform pathology. Instead,
the most striking alteration is ____________

Proteinase K–resistant PrP sc can be detected by immunostaining or western
blotting.

Answer 29

neuronal loss and reactive gliosis in the anterior ventral and
dorsomedial nuclei of the thalamus; neuronal loss is also prominent in the inferior olivary
nuclei.