L11 - genetic determinants of lung function/personalised medicine

Question 1

CF genetics

Answer 1

autosomal recessive

defect in long arm of chromosome 7 coding for CFTR protein

Question 2

CFTR mutations

Answer 2

over 1600 mutations

Question 3

F508del mutation

Answer 3

causes CFTR 44% homozygous

Question 4

CF carrier ratio

Answer 4

1:25

Question 5

CF birth ratio

Answer 5

1:25,000

Question 6

CFTR protein

Answer 6

transport protein on membrane of epithelial cells for chloride and thiocyanate ions

Question 7

Normal CFTR protein

Answer 7

moves chloride ions to the outside of the cell

Question 8

Mutant CFTR protein

Answer 8

does not move chloride ions, causing sticky mucus to build up on the outside of the cell

Question 9

Abnormal CFTR protein leads to…

Answer 9

Dysregulated epithelial fluid transport, leading to thickened secretions in a number of organs

Question 10

% in lung and GI involvement

Answer 10

80%

Question 11

% in lung alone

Answer 11

15

Question 12

Failure of mucocilliary clearance leads to…

Answer 12

with impaired immune function this contributes to continued insult to the bronchial wall, through the recruitment of inflammatory cells and uncontrolled neutrophilic inflammation

Question 13

Pathophysiology flow chart

Answer 13

1. Microbial insults
2. Defect in host defence
3. Respiratory tract infection
4. bronchial inflammation
5. Respiratory tract damage
6. progressive lung disease

Question 14

Bronchitis leads to

Answer 14

Bronchiectasis resulting in fibrosis

Question 15

Clinical symptoms

Answer 15

Frequent infections, malabsorption, failure to thrive

Question 16

Abnormal salt/chloride exchange

Answer 16

raised skin salt and impaired nasal potential difference

Question 17

% diagnosed by 6 months

Answer 17

50%

Question 18

% diagnosed by 8 years

Answer 18

90%

Question 19

Normal symptoms

Answer 19

fatigue, chronic cough, recurrent URIs, thick mucus, chronic hypoxia, decreased absorption of vitamins and enzymes, abdominal distention, decreased digestive enzymes, rectal prolapse, meconium ileum in newborns

Question 20

Treatments

Answer 20

increased calories and protein, chest physiotherapy, breathing exercises and aerosol therapy

Question 21

Medications

Answer 21

antibiotics, supplement vitamins, aerosol bronchodilators, mucolytics and pancreatic enzymes

Question 22

Bromchiectasis

Answer 22

90% surviving neonatal period

Question 23

Infertility in males

Answer 23

98%

Question 24

Infertility n females

Answer 24

20%

Question 25

Pancreatic insufficency

Answer 25

malabsorption 85%

Question 26

CF-related diabetes

Answer 26

50% by age 30

Question 27

CF chronic liver disease

Answer 27

25%

Question 28

Cirrhosis

Answer 28

10%

Question 29

Sinonasal polyps

Answer 29

10-25%

Question 30

Distal intestinal obstruction syndromex

Answer 30

20%

Question 31

Arthropathy

Answer 31

10% adults

Question 32

Meconium ileus

Answer 32

10-20% in infants

Question 33

Low bone mineral density

Answer 33

10-25%

Question 34

Pneumothorax

Answer 34

4-20%

Question 35

Allergic lung disease

Answer 35

7%

Question 36

Rescue antibiotics

Answer 36

2 week course access is central/peripheral home vs. hospital issued with frequent antibiotics = allergies, renal impairment, resistance and access problems

Question 37

CF prevention management

Answer 37

segregation, surveillance, eradication infections early, antibiotics, airway clearance physiotherapy, bronchodilator and exercise, psychosocial sport, vaccinations, potentially lung transplant

Question 38

Nutrition prevention

Answer 38

pancreatic enzymes, diet high calories and fat, supplements including vitamins, percutaneous feeding

Question 39

Personalised medicine

Answer 39

individual tailored medicine, stratified based on predicted response or risk of disease, genetic information major factor

Question 40

Personalised medicine advantages

Answer 40

increased adherence to treatment, improved quality of life, prolongs life, help avoid adverse drug reactions/intolerances, shift the emphasis in medicine from rescue to prevention, help control overall healthcare costs, direct selection of optimal therapy and reduce trial-and-error prescribing, reveal additional or alternative uses for medicines and drug candidates

Question 41

Personalised medicine in CF

Answer 41

useful as it is a monogenic disorder, less known influence of environmental factors Well characterised pathophysiology with clear therapeutic targets

Question 42

Genotype-directed therapies

Answer 42

CF monogenic recessive diroder, malformed chloride pump leads to multi system disorder, different classes of defect

Question 43

Class 1

Answer 43

not synthesised Nonsense frameshift or splicing mutations prevents biosynthesis

Question 44

G542X

Answer 44

no synthesis

Question 45

Class 2

Answer 45

Reduced trafficking, misfiling in the ER< leading to an absence of functional protein at the cell membrane

Question 46

F508del

Answer 46

Reduced trafficking with ER misfolding

Question 47

Class 3

Answer 47

reduced gating, CFTR protein reaches membrane but less opening

Question 48

G551D

Answer 48

reduced gating

Question 49

Class 4

Answer 49

decreased conductance, protein reaches cell membrane but abnormal conformation of the pore leading to disrupted ion flow

Question 50

R117M

Answer 50

decreased conductance

Question 51

Class 5

Answer 51

Reduced synthesis so less protein at the cell membrane

Question 52

A455E

Answer 52

reduced synthesis

Question 53

Ivacaftor

Answer 53

``` CFTR potentiator for class II mutations, i.e. G551D improves FEV1, MI and QoL ```

Question 54

Potentiator

Answer 54

potentiates chloride secretion via increasing the CFTR channel opening time

Question 55

Orkambi

Answer 55

``` Combined Ivacaftor and Lumacaftor Potentiator and corrector improves stabilisation and processing so more on cell surface Class II mutations only available on compassionate use ```

Question 56

orkambi side effects

Answer 56

bronchospasm, GI upset and rash

Question 57

CFTR correctors

Answer 57

corrects cellular misprocessing of CFTR to facilitate transport from the ER improves stabilisation and processing to increase presence on cell surface

Question 58

Symkevi/Symdeko

Answer 58

``` Combined Ivacaftor and Tezacaftor Corrector and potentiator Class II mutations compassionate use programme less side effects ```

Question 59

Tripe therapy

Answer 59

VX445 and Symkevi Corrector and potentiator new drug final results not known

Question 60

Other agents under review

Answer 60

gene therapy, inhaled therapies and intravenous antibiotic therapies

Question 61

Challenges treating CF

Answer 61

adherence to treatment, high treatment burden, high cost, allergies/intolerances, different infectious organisms and drug resistance, restrictions, prevention vs. rescue

Question 62

Rescue treatment

Answer 62

disadvantages in terms of cost, time, decline in quality of life and life expectancy side effects of recurrent intravenous antibiotic therapy

Question 63

Treatment burden

Answer 63

physiotherapy, nebulisers, exercise, oral medications, oral supplements, percutaneous nutrition, insulin, intravenous antibiotics

Question 64

Treatment burden time

Answer 64

all adds up to 2-4 hours treatment daily

Question 65

Adherence to medication

Answer 65

amongst people with long-term conditions estimated at 30-50%

Question 66

CF adherence to nebulisers

Answer 66

36%