Prion Disease

Question 1

What are abnormal prions?

Answer 1

Infectious misfolded proteins that can trigger abnormal folding

Question 2

What level of protein folding is not affected by heat and why?

Answer 2

Primary structure as amino acids are joined by peptide bonds that are covalent bonds which are strong

Question 3

What are the 2 most common types of secondary structure?

Answer 3

alpha-helices and ß-pleated sheets

Question 4

Types of Prion Disease

Answer 4

CJD - Creutzfeldt-Jacob Disease
vCJD - Variant CJD
Kuru
Scrapie
Bovine spongiform encephalopathy (BSE) or madcow disease

Question 5

What is classic CJD?

Answer 5

Classic CJD is a transmissible subacute spongiform encephalopathy (causes brain dysfunction)
It is a fatal degenerative brain disorder

Question 6

CJD Aetiology

Answer 6

1. Sporadic(mostly) - sporadic mutation of PRNP by substitution at position 129 on gene due to aging of cellular machinery
2. Genetic - (less than 10%) inherited mutation of PRNP at position 129 - Autosomal Dominant disorder
3. Aquired - Transmission via exposure to brain or spinal tissue from infected person
   -Canabalism

Question 7

What is PRNP?

Answer 7

Prion Protein gene

Question 8

What is the incubation period usually for CJD?

Answer 8

Usually 10+ years

Question 9

Why is the incidence of CJD increasing?

Answer 9

Increased surveillance
Aging population
Increasing population
Clinical awareness
Diagnostic methods

Question 10

CJD average incidence age?

Answer 10

67 years

Question 11

How is vCJD transmitted?

Answer 11

Variant CJD is transmitted via eating BSE-infected beef, genetic susceptibility, blood product transmission possible

Question 12

BSE surveillance in Ireland?

Answer 12

Active surveillance - all animals that die on the farm over age of 48 months must be tested for BSE
Passive surveillance - Animals showing symptoms of BSE must be isolated & tested

Question 13

CJD Pathogenesis

Answer 13

Prion disease occurs when normal prion proteins become abnormally folded and trigger abnormal folding of other prion proteins causing clumps and consequent brain damage.

In CJD, the infectious prion (PrP^p) shows conversion of alpha helices to amyloid-like ß-pleated sheets

Question 14

Early Signs and Symptoms of CJD

Answer 14

Memory problems, behavioual changes, poor coordination, visual disturbances

Question 15

Late Signs and Symptoms of CJD

Answer 15

Dementia, involuntary movements, blindness, coma, psychosis, anxiety, depression, paranoia, obsessive compulsive symptoms

Question 16

Can you treat CJD?

Answer 16

No specific treatment just symptom management
-Opioids for pain relief
-Anticonvulsants or sedatives for involuntary movements
-Antidepressants and sedatives to manage anxiety and depression

Question 17

CJD Prognosis

Answer 17

Universally fatal - approx 70% of people die within a year of diagnosis

Question 18

CJD Diagnosis

Answer 18

Signs and symptoms
Brain MRI - sponge like pattern

Elevated tumour marker neuron-specific enolase
Elevelated 14-3-3 protein on CSF analysis
Genetic testing

Confirmation - brain biopsy at post mortem

Question 19

BSE cases

Answer 19

1989 - first cases (15)
1996 - epidemic ban on mamillan meat and bone meal for livestock (infected)
2002 - cases peaked- 333 cases
Low levels - Beef export banned to China

Question 20

How much of PrP^c is beta-pleated sheets?

Answer 20

<5% -

Question 21

What is PrP^c?

Answer 21

cellular prion protein - found in healthy brain tissue

Question 22

What is PrP^p?

Answer 22

Infectios prion - different structure and resistant to proteases

Question 23

How much of PrP^p is beta-pleated sheets?

Answer 23

> 50%