Prion Diseases

Question 1

What are abnormal prions

Answer 1

Abnormal prions are infectious misfolded proteins that can trigger abnormal folding of other prions

Question 2

Which level of protein structure do prions affect

Answer 2

Secondary structure

Question 3

What is the largest class of protein secondary structures

Answer 3

alpha helices

Question 4

Function of alpha helices

Answer 4

They have a major role in mediating protein-protein interactions (allows hydrogen bonding)

Question 5

What does CJD stand for

Answer 5

Creutzfeldt-Jakob disease

Question 6

what does vCJD stand for

Answer 6

Variable Creutzfeldt-Jakob Disease

Question 7

What does BSE stand for

Answer 7

Bovine Spongiform Encephalopathy

Question 8

Description of CJD

Answer 8

A transmissible subacute spongiform encephalopathy

Question 9

Subacute meaning

Answer 9

There is a very long incubation time (long time between getting the disease and showing symptoms)

Question 10

What does encephalopathy mean

Answer 10

Brain disease

Question 11

What does spongiform mean

Answer 11

Brain tissue turns into a sponge like pattern

Question 12

CJD aetiology (3)

Answer 12

1.Sporadic -> (majority of cases), hypothesised to occur as a result of aging cellular machinery, sporadic mutation of prion protein gene PRNP
2.Familial -> less than 10% of CJD is inherited in an autosomal dominant manner, mutation of prion protein gene also
3.Acquired -> all types are transmissible

Question 13

What occurs to result in the mutation of the prion protein gene (PRNP)

Answer 13

Substitution of one amino acid to another at position 129 of PRNP (prion protein gene)

Question 14

3 ways CJD can be acquired

Answer 14

1. Transmission via exposure to brain / spinal tissue from infected person
2. Canabalism -> Kuru, a prion disease, among Fore people in Papua New Guinea due to funerary canabalism
3. Routine sterilisation procedures may fail to inactivate infectious prions

Question 15

5 types of prion disease

Answer 15

1. CJD
2. vCJD
3. Kuru
4. Scrapie -> sheep
5. BSE/mad cow disease -> cows

Question 16

worldwide incidence of CJD

Answer 16

1 to 2 cases per one million people per year

Question 17

Why is the incidence of CJD increasing (5)

Answer 17

1. Increased surveillance
2. Aging population
3. Increasing population
4. Clinical awareness
5. Diagnostic methods

Question 18

What is vCJD

Answer 18

The human equivalent of mad cow disease

Question 19

Aetiology of vCJD (3)

Answer 19

1. Transmission via eating BSE infected beef
2. Genetic susceptibility
3. Blood product transmission possible

Question 20

When was the BSE epidemic in Ireland

Answer 20

1996

Question 21

When did the no. of BSE cases in Ireland peak and how many cases were there

Answer 21

The cases peaked in 2002 with 333 cases

Question 22

PATHOGENESISSSS

When does prion disease occur

Answer 22

• When normal prion proteins (found on the surface of many cells) become abnormally folded.
• These trigger abnormal folding of other prion proteins causing clumps and consequent brain damage.

Question 23

PATHOGENESISSSS

What is abnormal folding in terms of protein structure

Answer 23

Alpha helices to beta sheets

Question 24

PATHOGENESISSSS

What does PrPc mean and where is it found

Answer 24

PrPc = normal prion protein, a normal consitute of brain tissue in all mammals

Question 25

# PATHOGENESISSSS Describe PrPp (infectious prion)

Answer 25

PrPp (infectious prion) is **found in infectious material**, has a **different structure** and is **resistant to proteases**

Question 26

# PATHOGENESISSSS What conversion does PrPp (infectious prion) and PrPsc (infectious prion, named after scrapie in sheep) show

Answer 26

The conversion of alpha helices to beta sheets (abnormal folding)

Question 27

# PATHOGENESISSSS What way are the amino acids folded in PrPc (normal prion protein)

Answer 27

PrPc has amino acids in **alpha helix** with **less than 5% of beta sheets**

Question 28

# PATHOGENESISSSS What way are the amino acids folded in PrPp (infectious prion protein)

Answer 28

**Majority of alpha helices are converted into beta sheets** resulting in **more than 50% of beta sheets**

Question 29

Signs and Symptoms: Early Stage (4)

Answer 29

1. Memory problems 2. Behaviourial changes 3. Poor coordination 4. Visual disturbances

Question 30

Signs and Symptoms: Late Stage (9)

Answer 30

1. Dementia 2. Involuntary movements 3. Blindness 4. Coma 5. Psychosis 6. Anxiety 7. Depression 8. Paranoia 9. Obsessive compulsive symptoms

Question 31

CJD tx

Answer 31

Symptom Management only: 1. **Opioids** for pain relief 2. **Anticonvulsants/sedatives/skeletal muscle relaxants** for involuntary movements 3. **Antidepressants and sedatives** for anxiety and depression 4. **Palliative care**

Question 32

CJD prognosis

Answer 32

* Fatal * 70% die within a year of diagnosis

Question 33

CJD diagnosis (6)

Answer 33

1. Signs & symptoms 2. Brain MRI 3. Elevated tumour marker neuron-specific enolase 4. Elevated 14-3-3 protein on CSF analysis 5. Genetic testing 6. Brain biopsy to confirm -> post mortem