Cystic fibrosis Flashcards
What is the incidence of cystic fibrosis? (2)
- 1 in 2500 live births
- Carrier frequency 1 in 25
What is the life expectancy of cystic fibrosis?
Approximately 42 years
What does the CFTR gene code for? (5)
- Cystic fibrosis transmembrane conductance regulator (chloride channel)
- In secretory epithelial cells which produce mucus, sweat, saliva, tears, digestive enzymes
- Lubrication of airways, digestive system, reproductive system
- Mutations cause defective chloride transport resulting in abnormally thick mucus
Which systems are affected by cystic fibrosis? (4)
- Pulmonary
- Pancreatic
- Gastrointestinal
- Reproductive (males)
What are the pulmonary features of CF? (3)
- Thick mucus blocks airways (COPD)
- Leads to bronchiectasis (persistent and progressive dilation of bronchi or bronchioles)
- Increased susceptibility to chronic respiratory infections
What are the reproductive features of CF? (5)
- 95% of males with CF are infertile
- Obstructive azoospermia
- Congenital absence of the vas deferens
- Can be seen as an isolated feature
- Females are fertile but some evidence of abnormal cervical mucus causing infertility
How is CF diagnosed? (2)
- Sweat chloride test (pilocarpine stimulated)
- Genetic testing
Why would a patient be referred for CF testing? (4)
- Diagnostic
- Family history
- Infertility
- Newborn screening
What features suggest diagnostic testing for CF? (5)
- Recurrent chest infection
- Failure to thrive
- Chronic pancreatitis
- Fetal echogenic bowel
- Meconium ileus (bowel obstruction)
What is newborn screening for CF? (2)
- Guthrie heel prick test
- Raised IRT indicates the need for further investigation
Where is the CFTR gene located?
7q31
How is CF inherited?
Autosomal recessive
What are the features of CFTR mutations? (3)
- Over 2000 mutations throughout 24 exons
- Most variants are missenses and small deletions
- Variant frequencies vary between populations
What is the most common CFTR mutation? (2)
- DeltaF508 (p.Phe508del)
- 3 nucleotide deletion causing loss of phenylalanine amino acid in exon 10
What are the classes of CFTR mutation? (5)
- Class I = protein production
- Class II = protein processing
- Class III = gating
- Class IV = conduction
- Class V = insufficient protein
Which classes of CFTR mutation results in no functional protein? (2)
- Classes I-III
- Classic CF
Which classes of CFTR mutation results in some functional protein? (2)
- Classes IV-V
- Mild CF
Why is there such a high frequency of CFTR heterozygotes? (2)
- Overstimulation of CFTR in intestinal epithelial cells by bacterial toxins (e.g. cholera) causes secretory diarrhoea
- CFTR mutations resulting in less CFTR protein provides a selective advantage
What is the genetic testing for CF? (4)
- Elucigene CF-EU2v1 assay
- PCR based assay
- Tests for the 50 most common variants
- Useful to know a persons’ ethnicity as variant frequency varies in populations
How does the CF-EU2V1 arms assay work? (5)
- Primer sequence is specific for the variant
- If not present, primer doesn’t bind = no PCR product
- If present, primer binds = PCR product
- Also contains a primer for WT so if heterozygous there will be a WT and a variant PCR product
- Blue peak indicates a pathogenic variant
What does compound heterozygous mean?
Patient has 2 different pathogenic variants causing recessive disease
Why is parental testing recommended following CFTR diagnosis?
- To confirm whether the 2 mutations are on the same or different alleles
- Expected to be on different alleles
What is the treatment for the respiratory symptoms of CF? (8)
- Physiotherapy
- Oral/inhaled/IV antibiotics
- Bronchodilators
- Mucolytic agents to reduce mucus viscosity
- Anti-inflammatory agents
- Home oxygen therapy
- Lung/heart-lung transplant
- Lifestyle (exercise)
What is the treatment for the GI symptoms of CF? (4)
- High calorie, high fat diet
- Supplemental feeding
- Oral pancreatic enzyme replacement therapy
- Tube feeding
What is the treatment for the reproductive symptoms of CF? (2)
- CBAVD = congenital bilateral absence of the vas deferens
- ART = assistive reproductive techniques such as microscopic epididymal sperm aspiration (MESA) and intracytoplasmic sperm injection (ICSI)
What molecular therapies are available for CF? (3)
- Symkevi = combination of ivacaftor and tezacaftor, effective for homozygous F508del and compound heterozygous for F508del and another
- Kalydeco = ivacaftor only, for gating mutations
- Orkambi = combination of ivacaftor and lumacaftor, effective for homozygous F508del, slows lung function decline by 42%
What proportion of CF patients in the UK are homozygous for F508del?
50%
How does ivacaftor work?
Increases open probability (gating mutations) to improve chloride transport
How does lumacaftor work?
Improves CFTR trafficking to the membrane
