Cystic Fibrosis Screening Introduction Flashcards
Describe Cystic Fibrosis.
- Most common, severe autosomal recessive disease in european populations (incidence about 1 in 2500 in european pops).
- Classic CF affects the lungs, pancreas, intestines, biliary tract, sweat glands and reproductive tract.
- Typical presentation: infant with recurrent chest infections, failure to thrive, malabsorption.
- Major cause of morbidity and mortality: chronic lung infection leading to fibrosis and bronchiectasis resulting in respiratory insufficiency. Progressive. Heart pumps harder to get oxygen around the body. Cardiac failure.
- Untreated death will occur by approximately 5 years.
- With treatment individuals live to approximately 33 years.
What is the typical presentation of CF?
- Typical presentation: infant with recurrent chest infections, failure to thrive, malabsorption.
What are the major causes of morbidity and mortality in CF?
- Major cause of morbidity and mortality: chronic lung infection leading to fibrosis and bronchiectasis resulting in respiratory insufficiency. Progressive. Heart pumps harder to get oxygen around the body. Cardiac failure.
What is the life expectancy for individuals with CF?
- Untreated death will occur by approximately 5 years.
- With treatment individuals live to approximately 33 years.
What are the common symptoms of classic CF?
- Classic CF affects the lungs, pancreas, intestines, biliary tract, sweat glands and reproductive tract.
Describe CFTR-related disease.
Milder spectrum of symptoms compared to classical CF. Often monosymptomatic.
- CBAVD, azoospermia, oligospermia
- Idiopathic pancreatitis
- Disseminated bronchiectasis
- Allergic bronchopulmonary aspergillosis
- Chronic rhinosinusitis
Harder to diagnose (adults). Later onset and other causes can result in the same symptoms.
What is the defect that leads to CF?
The defect is in the CFTR chloride channel in the apical surface of epithelial cells that are in mucosal areas.
Mutations in the CFTR gene lead to defective chloride transport.
It normally pumps chloride ions into the lumen and creates an ionic gradient so that water moves by osmosis from within the cell and creates normal mucus.
With a CFTR mutation you lose that chloride transport and the gradient and so you don’t get the movement of the water out of the cell. As a result you get abnormally thick mucus in the epithelia of organs with mucus secretory glands leading to multi-organ effects.
Describe CF genetics.
- Autosomal recessive
- CFTR gene located at 7q31
- > 1600 mutations known throughout 24 exons. Many private.
- Most mutations are missense and small dels.
- Mutation types and frequencies vary between populations.
- deltaF508 is common in white british people.
- W1282X is common in Ashkenazi Jewish people.
- The differences in prevalence of the different mutations in different populations has implications for test sensitivity.
What is the most common CF mutation in Western Europe?
deltaF508
What is the most common CF mutation in Ashkenazi jewish people?
W1282X
Describe the classes of CF mutations.
I). No synthesis - e.g. G542X.
II). Block in processing - proteins produced but the post-translational modifications are affected and so you don’t get any protein getting to the surface e.g. deltaF508.
III). Block in regulation - gets to the surface but the channel doesn’t open, mutations in nucleotide binding or regulatory domains e.g. G551D.
IV). Altered conductance - gets to the surface but doesn’t act as well as it should in conducting chloride e.g. R117H.
V). Reduced synthesis - reduced amounts of functional protein e.g. 3849+10kb.
Classes I-III = classic CF (e.g. deltaF508) no functional protein.
Classes IV-V = mild CF (e.g. R117H) some functional protein.
The less functional protein there is the more sever the CF symptoms will be.
Pancreatic insufficiency strongly correlates with the type of CF mutation whereas the pulmonary symptoms are quite variable as there are other genes and environmental factors involved.
What classes of mutation lead to classic CF?
Classes I-III = classic CF (e.g. deltaF508) no functional protein.
What classes of mutation lead to mild CF?
Classes IV-V = mild CF (e.g. R117H) some functional protein.
Outline the screening criteria generally used when considering whether a condition is worth doing population screening for.
Screening criteria (Wilson and Junger 1968).
1) . The condition:
- Important health problem (severe)
- Well understood
2) . The test:
- Simple, safe, precise and validated
- Clear cut-off values for positive cases
3) . The treatment:
- Effective treatment available
- Evidence of benefit for early intervention
4) . The screening programme:
- Evidence of benefit - reduced mortality and/or morbidity
- Clinically, socially and ethically acceptable to professionals and public
- Benefits outweigh harm
- Value for money
Outline the case that led to the introduction of CF newborn screening in the UK.
- To begin with the evidence that CF fit the screening criteria and should be included as part of newborn screening was not very strong.
- When the UK National Screening Committee came to look at it in May 2005 they felt that on the evidence available, a national neonatal screening programme should not be introduced. However, as one fifth of babies are already being screened in the UK, considerations of equity could not be ignored. The Minister of State for Health decided that screening should be introduced and an implementation group has been set up.
- In 2004 CF newborn screening was being carried out in 6 European countries and 5 US states. By 2010 it was being carried out by 14 European countries and all US states.
