Fault In The Cystic Fibrosis Gene

Cystic Fibrosis is caused by a fault in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7 at q31.2. For CF to be expressed, a faulty copy of the gene must be present at both alleles; autosomal recessive. Therefore both parents must be carriers of, or affected by the cystic fibrosis gene (fig. 1) for the gene to be passed on. If a person has one copy of the faulty allele (are heterozygous) they are carriers of the gene and can pass this allele on; if they possess two copies of the faulty allele (are homozygous), they will have CF. People who have CF must consider that their children will definitely be carriers at the very least, and depending on the genotype of their partner, may also suffer from CF.
SYMPTOMS
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Cystic fibrosis is usually diagnosed in childhood and the most obvious symptoms include (6-9):

 Persistent coughing
 Salty-tasting skin
 Breathing difficulties
 Bowel Obstruction (meconium ileus)
 Wheezing
 Failure to thrive (malnutrition and malabsorption)
 Recurring infections
 Large, foul-smelling stools
 Sinus pain
 Osteoporosis
 Arthritis
 Infertility (more serious in men)
 Urinary incontinence
 Clubbed fingers
 Cyanosis
Children with CF vary in the intensity of the symptoms displayed; most children with CF are diagnosed before they reach 2, but a small minority will not be diagnosed until adulthood due to the relative mildness of their symptoms.

INCIDENCE –
There are 10,583 people registered on the UK CF registry and 1 in 2,500 babies born in the UK are born with CF (around 2,800 in 2013 (10)) (11). 1 in 25 people in the UK carry a damaged version of the gene for the CFTR protein(6) predominantly in the Caucasian population. There is a disproportionate prevalence of CF in Caucasians of North European descent (fig. 2), thought to be due to a mutation which probably conferred some selective advantage in a heterozygous capacity to a disease which was more prominent in that area, such as typhoid or cholera(12).

PATHOPHYSIOLOGY –
Mutation on chromosome 7q(13), most commonly at ∆508(14) which codes for a channel protein; cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is found at the surface of epithelial cells. This protein regulates the levels of Na⁺ & Cl⁻ in cells(15) and without it, there is an increased level of Cl⁻ in the cell which causes water to flow into the cell down a water potential gradient, from the surroundings. In this case, the surroundings include mucus, and as a result of water leaving, it becomes thicker and sticky(16).
Ciliated epithelial cells are unable to shift this thick sticky mucus, resulting in its accumulation around the respiratory tract and ducts such as the pancreatic duct. This mucus prevents pancreatic enzymes from leaving to go to the small intestine. The resulting build-up of enzymes damages the surrounding pancreatic cells, and over time, can damage the organ’s production of insulin and lead to diabetes mellitus(17). A similar process occurs with thickened bile blocking bile ducts and causing liver damage and possibly cirrhosis(18).
As a result of the inability to shift mucus, infectious bacteria, most commonly Pseudomonas aeruginosa and Staphylococcus aureus, is able to stick to the respiratory tract without being cleared, causing frequent infections and thus inflammation, as was the case for Sarah.
In men, the vas deferens, which carries sperm from the testes to the ejaculatory ducts, fails to form, resulting in male infertility. The testes are still producing sperm; the men are not sterile, and with a testicular sperm extraction, they can still have children (19).
TREATMENT –
Living with cystic fibrosis is a challenge, but there is a variety of treatments to help patients improve the quality of their life.
One of the most common treatments is physiotherapy, where a trained person (usually a family member) manipulates the tissue around the trachea to shift mucus but this can be painful and is time consuming. Medication that is taken orally or through a nebulizer include mucolytics (which break down mucus), corticosteroids (improves respiratory function), bronchodilators (which relax the smooth muscle in lungs) and antibiotics (to treat continuous infections). Pancreatic enzyme supplements are also taken during meal times. (20). It has also been suggested that the cholera toxin may be able to thin mucus and help to alleviate the symptoms. However this has only been hypothesised as of yet (21).
CURE –
There is currently no tested cure for cystic fibrosis. There are 2 types of potential treatments which corrects the inherent problem behind the disease; correctors and potentiators (fig. 3). Both of these treatments show promise in improving patient standard of living. Both of these could deliver huge improvements in patients’ life, there is a long time to go before these therapies are approved for widespread usage.
PROGNOSIS
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People with cystic fibrosis are living a lot longer than previously and with a better standard of living. Many patients now go on to higher education and into employment. However they do still have a lower than usual life expectancy of 37 (22) although new estimates place the life expectancy for a baby born with CF today at over 50 (23). Towards the end of their life, their standard of life falls to such an extent that they cannot work or live independently.