genetic determinants of lung function

Question 1

CF genetics

Answer 1

• Most common lethal autosomal recessive genetic disorder in Caucasians
• Defect in long arm of chromosome 7 coding for the cystic fibrosis transmembrane regulator (CFTR) protein
• Static incidence with an increasing prevalence
• >1600 mutations of CFTR gene identified
 90% within a panel of 70 mutations
• F508del most common mutation causing CF

Question 2

CFTR protein

Answer 2

• Transport protein on membrane of epithelial cells
• Abnormal CFTR protein leads to dysregulated epithelial fluid transport
• 80% Lung & GI involvement
• 15% Lung alone

Question 3

CF diagnosis

Answer 3

• Genetic profile
• Clinical symptoms – frequent infections, malabsorption, failure to thrive
• Abnormal salt/chloride exchange – raised skin salt
• Late diagnoses via infertility services – azoospermia or via GI team with recurrent pancreatitis/malabsorption
• 50% diagnosed by 6months, 90% diagnosed by 8 yrs of age

Question 4

rescue antibiotics

Answer 4

•	2 week course IV antibiotics
•	Home vs hospital
•	Issues frequent antibiotics
	Allergies
	Renal impairment
	Resistance
	Access problems

Question 5

CF prevention management

Answer 5

• Segregation
• Surveillance – frequent review minimum every 3 months
• Airway clearance – physio & exercise
• Nutrition – pancreatic enzymes, diet high calorie & fat, supplements including vitamins, percutaneous feeding
• Psychosocial support

Question 6

CF prevention management - drugs

Answer 6

• Suppression of chronic infections – antibiotic nebs
• Bronchodilation – salbutamol nebs
• Anti inflammatory – azithromycin, steroids
• Diabetes – insulin
• Vaccinations – influenza, pneumococcal

Question 7

use of personalised medicine in CF

Answer 7

• Monogenic disorder (i.e. is the result of mutation(s) in a specific gene)
• Well-characterised pathophysiology with clear therapeutic targets
• Genotype directed therapies
• Targeted treatments based on infectious organisms and resistance patterns

Question 8

genotype directed therapies

Answer 8

• Small-molecule agents facilitate defective CFTR processing or function
 Ivacaftor in G551D (6%) & other specific mutations
 Improved lung function (FEV1), BMI, QoL
• Orkambi in F508del – only licensed for compassionate use in UK
 Mixed outcomes
• Gene therapy – further research needed as significant problems with delivery

Question 9

challenges treating CF

Answer 9

• Adherence to treatment
• High treatment burden
• High cost of certain treatments
• Allergies/intolerances to treatment
• Different infectious organisms and their resistance to drugs

Question 10

Alpha-1 antitrypsin deficiency (AATD)

Answer 10

• Autosomal recessive genetic disorder
• 80 different mutations of SERPINEA1 gene on chromosome 14
 Serum antiprotease
 M phenotype normal and healthy
• S and Z phenotypes major disease associations

Question 11

consequences of AATD

Answer 11

• Early onset emphysema and bronchiectasis

* Unopposed action of neutrophil elastase in the lung