Clinical Aspects of Cystic Fibrosis Flashcards
Incidence
1 in 2500 live births in white British UK pop
carrier frequency 1 in 25
Cause
mutations in the cystic fibrosis transmembrane regulator gene.
Function of CFTR protein
Forms an ion channel in the apical membrane of secretory epithelial cells
Regulates chloride ion transport in a cAMP dependent manner
Requires ATP binding to nucleotide binding domains and phosphorylation of regulatory domain
positively charged domains within the channel act as an electrostatic attractant of anions leading to their expulsion from the cell
thought to inhibit ENaC reducing amount of sodium taken up by cell
creates osmotic gradient that allows water to leave the cell, contributing to cell secretions
Absent or defective CFTR channels result in accumulation of ions within the cell leading to viscous mucus lining the epithelia
What is cystic fibrosis?
Complex multi-system disorder:
- epithelia of respiratory tract
- intestine
- pancreatic secretion (exocrine)
- hepatobiliary system
- male genital tract
Lung function effect
Viscous mucus affects cillia function leading to build up of biofilms, as bacteria cannot be cleared from the lungs
Common infections:
Pseudomonas aeruginosa
Staphylococcus aureus
Haemophilus influenzae
Pancreas
Pancreatic insufficiency (85-90% of patients) with malabsorption due to thick mucus blocking digestive enzymes from entering duodenum
Pancreatitis causes atrophy of exocrine glands and fibrosis
Difficulty in absorption of fat soluble vitamins (A,D,E,K)
Leads to poor growth and development
Meconium ileus occurs in 10-20% newborns
Infertility in males
Congenital bilaternal absence of vas deferens
Affects majority of males with classical CF
May be present as a CFTR related disorder without other symptoms
Hyperviscous mucus blocks the vas deferens during development causing them to deteriorate prior to birth
Manifests as obstructive azoospermia
Spermatogenesis unaffected, so patients may benefit from ARTs
Cystic fibrosis diagnosis
One or more phenotypic features:
- chronic sinopulmonary disease
- gastrointestinal/nutritional abnormalities
- obstructive azoospermia
- salt loss syndrome
Plus:
- 2 disease causing CFTR mutations
- 2x sweat tests with Cl >60 mEq/l
- transepithelial nasal potential difference characteristic of CF
Complication of CF diagnosis
Classical and non-classical forms of the disease
Classical CF: obstructive lung disease, bronchiectasis, exocrine pancreatic insufficiency, elevated sweat cholride
Non-classical (CFTR related disease): chronic pulmonary disease, with/without pancreatic disease, elevated chloride, or CBAVD
CBAVD alone
Management of CF symptoms
Respiratory: Physio Antibiotics (oral or inhaled) Bronchodilators Mucolytic agents Anti-inflammatories Exercise Lung transplant
GI:
High calorie
Vitamin supplements
Pancreatic enzyme replacement
CBAVD:
ART
Long-term outlook
Median survival 31.6y
If pancreatic sufficient (
CFTR gene genomic location, organisation, and types of mutation
7q31.2
190Kb
27 exons
De novo mutations v rare
Majority coding SNVs
~30 mutations account for 90% of disease
> 1900 rare mutations described
Name the 5 classes of CFTR mutation
- Defective translation (includes nonsense, frameshift, splice mutations) resulting in absence of protein e.g. G542X
- Incorrect protein folding resulting in defective protein e.g. Phe508del (susceptible to proteolysis)
- Channel gating causing improper activation e.g. G551D
- Defective ion conduction e.g. R1347P
- Reduced synthesis e.g. PolyT affecting splicing
Gene therapy compacted DNA
Single molecules of plasmid DNA containing CFTR gene compacted into nanoparticles
No immune response or significant side effects
Evidence of transfer transient (6-28d)
Efficiency of gene transfer increased if delivered using liposomes
Work ongoing phase 2
PTC124
Drug against nonsense mutations
Analog of Gentamycin (antibiotic), which promotes read-through of premature stop codons e.g. W1282X (60% mutations in Ashkenazi Jewish pop)
Compares favorably to Gentamycin
Phase 3
