Cystic fibrosis (CF) also known as mucoviscidosis is an inherited disease characterized by an abnormality in the glands that produce sweat and mucus. It is an autosomal recessive disorder which can be caused by various different mutations to the CFTR gene which codes for the CFTR protein located in the epithelial cells. The CFTR gene is found on chromosome 7 and is 230kb in length with 27 coding exons within this., and there are multiple mutations that can lead to CFTR dysfunction and therefore Cystic Fibrosis. It is a chronic, progressive and usually fatal disease, however, the life expectancy of CF patients is increasing due to advances in medical sciences and treatment and the median predicted survival age is currently 41 years old.
Cystic fibrosis affects various systems in children and young adults, including the following:
There are approximately 30,000 people in the US who are affected by the disease, and about 1,000 babies are diagnosed with it each year. It occurs mainly in Caucasians, who have a northern European heredity, although it also occurs in African-Americans, Asian Americans, and Native Americans. Cystic Fibrosis is a disease which has been around since the middle ages.
Approximately one in 31 people in the US are carriers of the cystic fibrosis gene. These people are not affected by the disease and usually, do not know that they are carriers. The most common type of cystic fibrosis mutation, affecting 75% of patients, is the mutation phe508del, previously named deltaF508.
How does CF affect the respiratory system?
The basis for the problem with CF lies in an abnormal gene. The result of this gene defect is an atypical electrolyte transport system within the cells of the body. The abnormal transport system causes the cells in the respiratory system, especially the lungs, to absorb too much sodium and water. This causes the normal, thin mucus secretions in our lungs to become very thick and hard to remove. These thick secretions put the child with CF at risk for constant infection.
The high risk of infection in the respiratory system leads to damage in the lungs, leading to lungs that do not work properly, and eventually death of the cells in the lungs. The most common causes for infection in the lungs of the CF patient are the following bacteria:
Over a period of time, PA becomes the most common bacteria that causes infection and becomes difficult to fight. A large percentage of respiratory infections in the CF patient are due to PA.
As a result of the high rate of infection in the lower respiratory tract, people with CF may develop a chronic cough, blood in the sputum, and sometimes can even have a collapsed lung. The cough is usually worse in the morning or after activity.
People with CF also have involvement of the upper respiratory tract. Some patients have nasal polyps that need surgical removal. Nasal polyps are small protrusions of tissue from the lining of the nose that goes into the nasal cavity. Children also have a high rate of sinus infections.
How does CF affect the gastrointestinal (GI) system?
The organ primarily affected is the pancreas, which secretes substances that aid digestion and help control blood-glucose levels.
As a result of the abnormal electrolyte transport system in the cells, the secretions from the pancreas become thick and lead to an obstruction of the ducts of the pancreas. This obstruction then causes a decrease in the secretion ofenzymes from the pancreas that normally helps to digest food. A person with CF has difficulty absorbing proteins, fats, and vitamins A, D, E, and K.
The problems with the pancreas can become so severe that some of the cells, such as ß cells in the Islets of Langerhans, in the pancreas can become destroyed. This may lead to glucose intolerance and cystic fibrosis-related diabetes. The ß cells are therefore unable to produce insulin as efficiently so develop diabetes. About 35% of CF patients develop this type of diabetes in their 20s and 43% develop the disease after 30 years of age. This can present difficulties in CF patients who are advised to consume a diet very high in calories (including sugars and fats) to combat the weight lost through poor uptake of nutrients as a result of excess mucus lining the digestive system. The patient with CF coupled with cystic fibrosis-related diabetes would have to ensure a diet high in calories but also must maintain their blood sugar within normal range.
Another organ which may be affected by CF is the small intestine; its function is to digest and absorb the nutrients from the food.
In a person with CF the enzymes which help the digestion process become thick and sticky and therefore block these ducts between the pancreas and small intestine.
Meconium (failure to pass faeces) is a condition that occurs in newborns with CF, where the intestines are completely blocked. This occurs in about 10% of newborns with the condition.
The symptoms that may be present due to the involvement of the GI tract
- Bulky, greasy stools
- Rectal prolapse--a condition in which the end part of the bowels comes out of the anus.
- Delayed puberty
- Fat in the stools
- Stomach pain
- Bloody diarrhoea
The liver may also be affected. A small number of patients may actually develop liver disease. Symptoms of liver disease may include:
- Enlarged liver
- Swollen abdomen
- Yellow colour to the skin
- Vomiting of blood
How does CF affect the reproductive system?
Most males with CF have obstruction of the sperm canal known as congenital bilateral absence of the vas deferens (CBAVD), in which the tubes that connect the testes to the penis are missing. This results from the abnormal electrolyte transport system in the cells (brought about by the absence of fine ducts), causing the secretions to become thick and lead to an obstruction and in male patients 95% become infertile. However, the sperm is not affected and can be used in IVF, if required. Women also have an increase in thick cervical mucus that may lead to a decrease in fertility, although many women with CF have children. This thick mucus acts as a plug, presenting a physical barrier to the sperm cells' passage to the uterus.
What are the symptoms of cystic fibrosis?
The following are the most common symptoms for cystic fibrosis. However, due to multiple mutations having the ability to cause disease, symptoms can vary amongst individuals and are, therefore, dependent upon the mutations the individual has inherited. This is described as variable expressivity.Symptoms may include:
- Abnormalities in the glands that produce sweat and mucus
This may cause a loss of salt. A loss of salt may cause an upset in the balance of minerals in the blood, abnormal heart rhythms, and, possibly, shock.
- Thick mucus that accumulates in the lungs and intestines as well as in the trachea. Figure below shows the difference.
This may cause malnutrition, poor growth, frequent respiratory infections, breathing difficulties, and/or lung disease.
Other medical problems, such as:
- Nasal polyps
- Clubbing of fingers and toes--a condition marked by the ends of the fingers and toes become enlarged; more prevalent in the fingers
- Pneumothorax--the presence of air or gas in the pleural cavity causing the lung to collapse
- Hemoptysis--coughing blood
- Cor pulmonale--enlargement of the right side of the heart
- Abdominal pain
- Gas in the intestines
- Rectal prolapse
- Liver disease
- Congenital bilateral absence of the vas deferens (CBAVD) in males
As stated above, the symptoms of CF differ for each person. Infants born with CF usually show symptoms by age two. Some children, though, may not show symptoms until later in life. The following signs are suspicious of CF, and infants having these signs may be tested for CF:
- Diarrhea that does not go away
- Foul-smelling stools
- Greasy stools
- Frequent episodes of wheezing
- Frequent episodes of pneumonia or other lung infections
- Persistent cough
- Skin tastes like salt
- Poor growth despite a good appetite
The symptoms of cystic fibrosis may resemble other conditions or medical problems. Consult a physician for a diagnosis.
How is cystic fibrosis diagnosed?
Most cases of cystic fibrosis are now identified with newborn screening. In addition to a complete medical history and physical examination, diagnostic procedures for cystic fibrosis include a sweat test to measure the amount of sodium chloride (salt) present. Higher than normal amounts of sodium and chloride suggest cystic fibrosis. A person with cystic fibrosis has about 5 times the normal salt concentration in their sweat. Other diagnostic procedures include:
- Chemical tests
- Chest X-rays
- Lung function tests
- Sputum cultures
- Stool evaluations
For babies, who do not produce enough sweat, blood tests may be used.
Treatment for cystic fibrosis
Specific treatment for cystic fibrosis will be determined by your doctor based on:
- Your age, overall health, and medical history
- Extent of the disease
- Expectations for the course of the disease
- Your tolerance for specific medications, procedures, or therapies
- Your opinion or preference
Currently, there is no cure for CF. A cure would call for gene therapy at an early age and this has not been developed yet, although research is being done in this direction. The gene that causes CF has been identified and there are hopes that this will lead to an increased understanding of the disease. Also being researched are different drug regimens to help stop CF. Goals of treatment are to ease the severity of symptoms and slow the progress of the disease. Treatment may include:
Management of problems that cause lung obstruction, which may involve:
- Physical therapy
- Exercise to loosen mucus, stimulate coughing, and improve overall physical condition
- Medications to reduce mucus and help breathing
- Antibiotics to treat infections
Management of digestive problems, which may involve:
- Appropriate diet
- Pancreatic enzymes to aid digestion
- Vitamin supplements
- Treatments for intestinal obstructions
- Newer therapies include lung transplantation for patients with end-stage lung disease. The type of transplant done is usually a heart-lung transplant or a double lung transplant. Not everyone is a candidate for a lung transplant. Discuss this with your physician.
The genetics of cystic fibrosis
Cystic fibrosis (CF) is a genetic disease. This means that CF is inherited. A person will be born with CF only if two CF genes are inherited - one from the mother and one from the father. A mutation in one of the copies of the cystic fibrosis gene has been shown to give protection against typhoid fever. However, this is not clearly understood. The cystic fibrosis gene is on the long q arm of autosomal chromosome 7 at position 31.2 A person who has only one CF gene is healthy and said to be a "carrier" of the disease. A carrier has an increased chance of having a child with CF. This type of inheritance is called "autosomal recessive." "Autosomal" means that the gene is on one of the first 22 pairs of chromosomes which do not determine gender so that the disease equally affects males and females. "Recessive" means that two copies of the gene, one inherited from each parent, are necessary to have the condition. Once parents have had a child with CF, there is a one in four, or 25% chance with each subsequent pregnancy, for another child to be born with CF. This means that there is a three out of four, or 75% chance, for another child to not have CF.
The birth of a child with CF is often a total surprise to a family since most of the time (in eight out of 10 families) there is no previous family history of CF. Many autosomal recessive conditions occur this way. Since both parents are healthy, they had no prior knowledge that they carried the gene, nor that they passed the gene to the pregnancy at the same time.
Genes are founds on structures in the cells of our body called chromosomes. There are normally 46 total or 23 pairs of chromosomes in each cell of our body. The seventh pair of chromosomes contains a gene called the CFTR (cystic fibrosis transmembrane regulator) gene. It is a chloride channel protein in the epithelial cell membrane. and contains 1,480 amino acids. It is a sub-member of the ABC family of transport proteins and as such, it has a motif in its amino acids sequence that is an ATP-binding cassette. It is thus phosphorylation regulated. It has a structure consisting of two nucleotide-binding sites and two domains made up of membrane that are separated by a cytoplasmic regulatory section (R) where phosphorylation sites are found. ATP controls the CFTR by protein phosphorylation and correlation with the nucleotide-binding sections The most common CF mutation is referred to as the delta F508 mutation and prevents the CFTR from reaching the membrane, it also affects the synthesis of the protein. Mutations or errors in this gene are what cause CF. This gene is quite large and complex. Over 1,000 different mutations in this gene have been found which cause CF.
The risk of having a mutation in the gene for CF depends on your ethnic background (for persons without a family history of CF):
Ethnic Background Risk of CF Mutation Risk of Child with CF
- Caucasian: 1 in 29 1 in 2,500-3,500
- Hispanic : 1 in 46 1 in 4,000-10,000
- African-American: 1 in 65 1 in 15,000-20,000
- Asian: 1 in 90 1 in 100,000
Testing for the CF gene can be done from a small blood sample or from a cheek swab, which is a brush rubbed against the inside of your cheek to obtain cells for testing. Laboratories generally test for the most common mutations.
There are many people with CF whose mutations have not been identified. In other words, all of the genetic errors that cause the disease have not been discovered. Because not all mutations are detectable, a person can still be a CF carrier even if no mutations were found by carrier testing.
Testing for the CF gene is recommended for anyone who has a family member with the disease, or whose partner is a known carrier of CF or affected with CF. The earlier screening is done, the earlier specific treatment can happen.
There is a proposed Heterozygous Advantage for the Cystic Fibrosis mutation which can be used to explain the prevalence of what could be considered a lethal allele. It has been proposed that being heterozygous for the mutation could provide a selective advantage against chloride secreting diarrhoeal diseases.
A study carried out by Garbriel et al. . demonstrated this using a mouse model organism. The CF mutation was introduced into the mice, some were homozygous and some were heterozygous. The mice were then injected with a dose Cholera Toxin and the chloride secretion measured. Mice heterozygous for the CF mutation showed half the secretion of wild-type mice, suggesting that by reducing the amount of CFTR in the epilthelium of the digestive tract, effects of cholera infection would be less severe.
Cystic Fibrosis is an autosomal recessive disease caused by a mutation on the long (q) arm of chromosome 7 on the q31-32 region. The mutation affects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel protein. The most common mutation is ΔF508, accounting for 70% of mutations in the Caucasian UK population, in which the triplet code (codon) for the amino acid phenylalanine is deleted, disrupting Cl- transport. This mutation belongs to the Class II group of mutations causing Cystic Fibrosis.
CFTR is composed of 3 types of domains. There are 12 Transmembrane spanning domains, 2 Nucleotide Binding Domains (NBD’s - part of the ATP Binding Cassette domains) and an R domain (regulatory domain). The NBD’s are involved in the binding and hydrolysis of ATP. It is believed that the mutation that causes Cystic Fibrosis occurs on the Nucleotide Binding Domain 1.
CFTR is part of the ABC (ATP Binding Cassette) superfamily of transporters.
Cystic Fibrosis Classes
Class I: Premature Stop Codons (e.g. W1282X)
W1282X mutation can be found in approximately 7% of the European population. This mutation occurs by an insertion of an extra amino acid tryptophan at the position 1282 of the target chromosome (one letter code W, hence the name of the mutation). This results in the protein translation being prematurely stopped (shown in the name of the mutation as X) so that the protein is not produced at all. The absence of CFTR protein leads to the symptoms of CF.
Class II: Abnormal Processing (e.g. ΔF508) This involves the deletion of the amino acid, Phenylalanine at NBD1 (Nucleotide Binding Domain 1) of the CFTR (Cystic Fibrosis transmembrane conductance receptor). This mutation takes effect on the processing of the protein after leaving the Endoplasmic Reticulum. It adversely comprimises the trafficking/passage of the protein across the cytosol ultimately resulting in the the protein being degraded by the proteasome. This mutation is the most common mutation of the CFTR, causing >90% of Cystic Fibrosis cases.
Deletion of phenylalanine causes the protein to be misfolded. It cannot adopt its tertiary structure and ends up in a wrong shape. There is an impact on CFTR not processing successfully to the apical plasma membrane. After the protein has folded, it is then degraded. This mutation causes common cystic fibrosis symptom “salty sweat”. In this occasion, due to the degraded CFTR protein in the duct cells of cuboidal epithelium Na+ and Cl- are not removed from the primary secretion of the sweat. So, it comes out to the surface of the skin very salty.
Class III: Altered Regulation (e.g. G551D)
At the position 551 of the target chromosome, an amino acid G (glycine) is replaced with aspartate (D).
Class IV: Conductance Defect (e.g. R117H)
Class I,II and III mutations usually lead to a full loss of function. CFTR dysfunction can occur in the failure of 5 key mechanisms: defective protein processing, defective channel conduction, reduced protein stability, defective protein production and reduced protein synthesis.
Approaches to Treatment
Oral and Inhaled Antibotics
How Does it affect everyday life?
Cystic fibrosis affects everyone differently, common daily routines involve physiotherapy in order to lift the mucus off the chest, a range of antibiotics which can be given orally, intravenously or through a nebuliser and enzymes which are given with food. Very ill patients find the most menial tasks difficult and can end up breathless and in some cases needing oxygen and wheelchairs.
- ↑ Bean, lora J.H., Pratt, V.M. molecular Pathology in Clinical Practice. 2nd Edition. Switzerland: Springer International Publishing. 2016.
- ↑ Genetic Home Reference(2012) Cystic Fibrosis(online) Available from:http://ghr.nlm.nih.gov/condition/cystic-fibrosis
- ↑ http://www.cftrust.org.uk/aboutcf/faqs#life [Accessed on 25th October 2012]
- ↑ http://reliawire.com/who-discovered-cystic-fibrosis/
- ↑ Vertex Pharmaceuticals Incorporated. A clinician's guide to CFTR. 2016. [Accessed 2ist November 2016}. Available from:http://www.cftrscience.com .
- ↑ Cystic Fibrosis Trust. Cystic Fibrosis. 2016 [accessed 21st November 2016]. Available from:https://www.cysticfibrosis.org.uk/.
- ↑ Hartl, D.L., Jones, E.W. Genetics: Analysis of genes and genomes. 7th Edition, Canada: Jones and Bartlett. 2009.
- ↑ Bourke, S.J., Respiratory Medicine, 7th Edition, 2007, Oxford: Blackwell Publishing Ltd
- ↑ Bradley, J., and Johnson, D., and Pober, B., Medical Genetics, 3rd Edition, 2006, Oxford: Blackwell Publishing
- ↑ Gabriel, S., Brigman, K.,Koller, B., Boucher, R. and Stutts, M. (1994). Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science, 266(5182), pp.107-109
- ↑ Zieleneski, J., Rozmahel, R., Bozon, D., Kerem, B., Grzelzak, Z., Riordan J., Rommens, J. And Tsui, L. (1991) ‘Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene’, Genomics, 10(1), pp. 214-228, Elsevier [online]. Available at: http://www.sciencedirect.com/science/article/pii/0888754391905037 (Accessed: 11 November 2014)
- ↑ J Biol Chem. 2010 Nov 12;285(46):35825-35. Epub 2010 Jul 28.
- ↑ David L. Rimoin, J. Michael Connor, Reed E. Pyeritz, Bruce R. Korf (2007). Emery and Rimoin's Principles and Practice of Medical Genetics edition. 5th ed. Amsterdam: Elsevier. p1354-1394.
- ↑ http://cysticfibrosis.org.uk/about-cf/frequently-asked-questions#na (date accessed 19th October 2015)
- ↑ http://reliawire.com/who-discovered-cystic-fibrosis/