Medg550/Student Activities/Cystic Fibrosis

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Cystic Fibrosis (CF) is a life-long condition that affects many organs in the body including the lungs, the pancreas, the intestines, the sweat glands and the male reproductive organs. It is the most common lethal genetic disorder affecting individuals of Caucasian descent.[1]

Genetics

Genetic Cause

Cystic Fibrosis is caused by gene changes, called mutations, in the "Cystic Fibrosis Transmembrane Conductance Regulator" (CTFR) gene located on human chromosome 7.[2] The CTFR gene produces a protein that is found on the cells lining many tissues throughout the body including those of the airways, intestines, pancreas, vas deferens and sweat ducts.[3] These proteins play an important role in regulating the consistency of secretions in these tissues by controlling the movement of chloride and sodium into and out of those cells.[1]

Over 1000 different CTFR gene mutations have been found to cause CF. The most common gene change found in CF patients is called the ΔF508 deletion mutation. It accounts for approximately 70% of all CF mutations in the Caucasian population.[1][4]

CF is inherited in an autosomal recessive manner

Inheritance

CF is inherited in an "autosomal recessive" manner, which means that an individual must have gene changes on both of their copies of the CFTR gene in order to develop CF. Those who have one mutation do not develop CF, but are referred to as "carriers". Carriers have a 50% chance of passing the gene mutation on to each of their children (and a 50% chance of passing on their working copy of the gene). If two gene carriers have a child together, there is a 25% chance that the child will inherit both mutated copies of the CFTR gene (one from each parent) and develop cystic fibrosis; there is a 50% chance that the child will inherit only one mutated copy (from one parent and the other copy from the other parent is a working copy) and be a carrier themselves; and there is a 25% the child will inherit two working copies of the CTFR gene.

Prevalence

Although CF is observed in all ethnicities, it is much more common in those of northern European ancestry and is thought to be the most common life-shortening, autosomal recessive disorder in the Caucasian population.[1] It is estimated that approximately 1 in every 25 people of North American or northern European heritage carry a CF-causing mutation in the CTFR gene.[5] A high prevalence of CTFR mutations have also been observed in the Ashkenazi Jewish population (approximately 1 in 29 people carry a CF-causing genetic change).[6] It is estimated that CF affects over 30,000 individuals in the United States and approximately 70,000 people world-wide.[7]

Clinical Features

Many of the clinical features of CF result from thickened mucus secretions that cause blockages in multiple body systems.

Respiratory

Thickened mucus in the lungs of those with CF cause blockage of airways, resulting in breathing difficulties such as shortness of breath and coughing spells. These blockages also makes it easier for infection to occur. Recurring infections cause inflammation and sometimes life-threatening airway damage. This can also increase the secretion in the lungs, exacerbating the infections in a kind of "vicious cycle". Difficulties in lung function are thought to be the most concerning and life threatening complications of CF.[8]

Digestive

Pancreatic

Approximately 85% of patients with CF have problems with digestion because they lack digestive enzymes made by the pancreas, which help break down nutrients. This is called exocrine pancreatic insufficiency and results from thickened secretions in the pancreatic ducts that can block the ducts and lead to pancreatic damage. This hinders nutrient absorption and can result in poor nutrition, cystic fibrosis related diabetes (CFRD) and poor growth.[9]

Intestinal

Up to 20% of newborns with CF have a blockage in part of the small intestine caused by thickened bowel secretions. This blockage, called meconium ileus, is strongly suggestive of CF. Obstruction of the intestine can also occur in older patients and is called distal intestinal obstructive syndrome.[10]

Male Reproductive Tract

Approximately 97% of males with CF do not develop the duct that carries sperm from the testicles to the urethra, called the vas deferens. This is commonly referred to as congenital absence of the vas deferens (CAVD).[11] These men may also have a lower sperm count as well. As a result, these males are infertile. However, sperm extraction methods are available and may be helpful for some men who are interested in having children.[12] In some males with CF, CAVD is their only symptom.[11]

Diagnosis

The diagnostic criterion for CF has been laid out as follows:[13]

Positive newborn screen or Family history or Clinical concern for CF

Plus one of the following:

Positive sweat test or Two CF-associated mutations identified or Intermediate sweat test result with zero to one identified gene mutations and additional evidence of CF including:

Respiratory infection or Pancreatic insufficiency or Chronic respiratory problems or Positive NPD test

Sweat Test

The sweat test is a reliable diagnostic tool for approximately 98% of patients with CF. The amount of salt in the sweat of those with CF is high as a result of irregular ion (sodium and chloride) regulation in the sweat ducts. A high concentration of sweat chloride (greater than 60mmol/L) detected on two separate occasions is considered to be enough evidence to diagnose CF.[14]

Genetic Diagnosis

A diagnosis of CF can be made using genetic testing to look at the CFTR gene and an individual is found to have two CF-causing mutations, one in each copy of the CTFR gene. Genetic testing can also determine carrier status. These genetic tests are generally done by looking directly at the DNA sequence from a blood sample. Ethnic background and/or family history may direct exactly which genetic test is used.[10]

Newborn screening

In much of Canada and the United States, newborns can be screened for CF in the first few days of life. This involves a small blood sample collected by heel prick and measurement of a pancreatic protein (immunoreactive trypsinogen, "IRT") that is present at increased levels in patients with CF.[15] Newborn screening of CF has proven to be widely effective in improving quality of life for those with the disorder as it allows for much earlier interventions.[16]

Management and Prognosis

Due to the management techniques used today, most individuals born with cystic fibrosis in the current century are expected to live into their 50s or 60s[7]. This is a vast improvement from the 1950s where most individuals with cystic fibrosis did not live past 5.[17] With improved therapies and management, the life expectancy is expected to continue to increase in the coming years.[7] Management of CF focuses on reducing lung infection and improving nutrition. Existing therapies treat the symptoms of CF, but not the underlying cause.

Respiratory Management

To treat and prevent respiratory complications, antibiotics, anti-inflammatory medications and agents that break down mucus and/or dilate airways may be given. Chest physiotherapy may be done to help remove mucus from the breathing passages. In severe cases, a heart/lung transplant may be considered.[18]

High-Frequency Chest Wall Oscillation

Otherwise known as airway clearance systems, these machines vibrate at a high frequency while wrapped around the individual's chest, as a means of mechanically preforming chest physical therapy. Individuals with CF can use these vests at home multiple times a day to loosen and thin the mucus that collects in the lungs and improve airway clearance.[19]

Contact with other Individuals with CF

There is a particular strain of bacteria that causes pneumonia, an infection of the lungs, at an increased rate in those with cystic fibrosis. The strain is called Pseudomonas aeruginosa, and it is mostly resistant to antibiotic treatment. The thick mucus lining the airway of those with CF provides an optimal growth environment for this bacteria. Once it creates infection, it can lead to lung deterioration and possibly death[20]. As a result, it is very dangerous for individuals with CF to be exposed to this bacteria.

Since this bacteria is spread easily among those with CF, it is highly recommended that individuals with CF do not interact closely, and maintain a distance of 6 foot distance from each other[21].

Digestive Management

Individuals with CF may need nutritional supplements and vitamins to ensure they are getting the proper nutrition. Pancreatic enzymes can be taken by mouth to treat pancreatic insufficiency and help break down food.[18]

Cystic Fibrosis Related Diabetes

As a result of damage to the pancreas overtime, individuals with CF may develop insulin deficiency (not enough insulin being produced) and insulin resistance (the body doesn't respond to the insulin). This leads to the development of CFRD.[22]

Most individuals with CF will develop CFRD in adulthood, with a smaller chance of developing it in adolescence and childhood. It is recommended that individuals 10 years and older with CF are tested annually with an oral glucose tolerance test to detect CFRD. If detected, blood sugar monitoring and insulin injections may be used to manage CFDR.[17]

Genetic Counselling & Reproductive Options

Chorionic Villus Sampling (CVS) takes a small sample of the placenta to look at the DNA in those cells.
Amniocentesis takes a small sample of amniotic fluid from around the fetus to look at the DNA in skin cells and other cells from the fetus that are found in that fluid.

Genetic counselling may be a good option for people with a family history of CF. A genetic counsellor can review your family history, explain your chances of having a child affected by CF, and discuss options including genetic testing. For more information on genetic counselling services near you, visit the Canadian Association of Genetic Counsellors (Canada) or the National Society of Genetic Counselors (USA).

Prenatal Diagnosis

Families at risk of having children with CF may opt to undergo prenatal diagnosis during pregnancy through a diagnostic genetic test such as amniocentesis or chorionic villus sampling. These tests, which can only be done at certain times during the pregnancy, can diagnose CF while the baby is still in utero by looking directly at the baby’s DNA.[10]

Preimplantation Genetic Diagnosis

Couples also have the option of using in vitro fertilization (IVF) coupled with preimplantation genetic diagnosis (PGD). IVF involves putting sperm and egg together in the lab, while PGD involves testing the fertilized egg(s) to determine if they will develop the disorder. A fertilized egg that will not develop the disorder is then transferred into the uterus of the mother.[23]

Sperm Extraction

Men who have CF and are infertile due to CAVD can attempt sperm extraction followed by IVF if they are interested in having children.[12]

Resources and Support for Families

Here are some websites with more information on Cystic Fibrosis. These are not intended to be used as medical advice. If you are worried or have questions about CF, talk to your doctor.

References

  1. ↑ 1.0 1.1 1.2 1.3 Nussbaum, R., McInnes, R. R. & Willard, H. F. Thompson and Thompson Genetics in Medicine: 8th Edition (Saunders, 2007). Cite error: Invalid <ref> tag; name "[1]" defined multiple times with different content Cite error: Invalid <ref> tag; name "[1]" defined multiple times with different content Cite error: Invalid <ref> tag; name "[1]" defined multiple times with different content
  2. ↑ Kerem, B. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).http://www.ncbi.nlm.nih.gov/pubmed/2570460
  3. ↑ Tsui, L. C. The cystic fibrosis transmembrane conductance regulator gene. Am. J. Respir. Crit. Care Med. 151, S47–53 (1995).http://www.ncbi.nlm.nih.gov/pubmed/7533605
  4. ↑ Alfonso-Sánchez, M. A., Pérez-Miranda, A. M., García-Obregón, S. & Peña, J. A. An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations. Med. Hypotheses 74, 989–992 (2010).http://www.ncbi.nlm.nih.gov/pubmed/20110149
  5. ↑ Hamosh, A. et al. Comparison of the clinical manifestations of cystic fibrosis in black and white patients. J. Pediatr. 132, 255–259 (1998).http://www.ncbi.nlm.nih.gov/pubmed/9506637
  6. ↑ Kerem, B., Chiba-Falek, O. & Kerem, E. Cystic fibrosis in Jews: frequency and mutation distribution. Genet. Test. 1, 35–39 (1997).http://www.ncbi.nlm.nih.gov/pubmed/9506637
  7. ↑ 7.0 7.1 7.2 Hurley, M. N., McKeever, T. M., Prayle, A. P., Fogarty, A. W. & Smyth, A. R. Rate of improvement of CF life expectancy exceeds that of general population—Observational death registration study. J. Cyst. Fibros. 13, 410–415 (2014).http://www.ncbi.nlm.nih.gov/pubmed/24418187
  8. ↑ Chmiel, J. F. & Davis, P. B. State of the art: why do the lungs of patients with cystic fibrosis become infected and why can’t they clear the infection? Respir. Res. 4, 8 (2003).http://.www.ncbi.nlm.nih.gov/pubmed/14511398
  9. ↑ Kristidis, P. et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am. J. Hum. Genet. 50, 1178–1184 (1992).http://www.ncbi.nlm.nih.gov/pubmed/1376016
  10. ↑ 10.0 10.1 10.2 Brennan, M.-L. & Schrijver, I. Cystic Fibrosis: A Review of Associated Phenotypes, Use of Molecular Diagnostic Approaches, Genetic Characteristics, Progress, and Dilemmas. J. Mol. Diagn. 18, 3–14 (2016).http://www.ncbi.nlm.nih.gov/pubmed/26631874
  11. ↑ 11.0 11.1 Mennicke, K., Klingenberg, R. D., Bals-Pratsch, M., Diedrich, K. & Schwinger, E. Rational approach to genetic testing of cystic fibrosis (CF) in infertile men. Andrologia 37, 1–9 (2005).https://www.ncbi.nlm.nih.gov/pubmed/15644056 Cite error: Invalid <ref> tag; name "[11]" defined multiple times with different content
  12. ↑ 12.0 12.1 Gordon, U. D. Assisted conception in the azoospermic male. Hum. Fertil. Camb. Engl. 5, S9–S14 (2002).http://www.ncbi.nlm.nih.gov/pubmed/11897909
  13. ↑ Farrell, P. M. et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J. Pediatr. 153, S4–S14 (2008).http://www.ncbi.nlm.nih.gov/pubmed/18639722
  14. ↑ Mishra, A., Greaves, R. & Massie, J. The Relevance of Sweat Testing for the Diagnosis of Cystic Fibrosis in the Genomic Era. Clin. Biochem. Rev. Aust. Assoc. Clin. Biochem. 26, 135–153 (2005).http://www.ncbi.nlm.nih.gov/pubmed/16648884
  15. ↑ Heeley, A. F., Heeley, M. E., King, D. N., Kuzemko, J. A. & Walsh, M. P. Screening for cystic fibrosis by dried blood spot trypsin assay. Arch. Dis. Child. 57, 18–21 (1982).http://www.ncbi.nlm.nih.gov/pubmed/7039516
  16. ↑ Wagener, J. S., Sontag, M. K., Sagel, S. D. & Accurso, F. J. Update on newborn screening for cystic fibrosis. Curr. Opin. Pulm. Med. 10, 500–504 (2004).http://www.ncbi.nlm.nih.gov/pubmed/15510057
  17. ↑ 17.0 17.1 Nazareth, Dilip; Walshaw, Martin (2013). "A review of renal disease in cystic fibrosis". Journal of Cystic Fibrosis. 12 (4): 309–317.
  18. ↑ 18.0 18.1 Moskowitz, S. M., Chmiel, J. F., Sternen, D. L., Cheng, E. & Cutting, G. R. in GeneReviews(®) (eds. Pagon, R. A. et al.) (University of Washington, Seattle, 1993).http://www.ncbi.nlm.nih.gov/pubmed/20301428
  19. ↑ Scherer, Thomas A.; Barandun, Jurg; Martinez, Elena; Wanner, Adam; Rubin, Eben M. (1998). "Effect of High-Frequency Oral Airway and Chest Wall Oscillation and Conventional Chest Physical Therapy on Expectoration in Patients With Stable Cystic Fibrosis". Chest. 113 (4): 1019–1027.
  20. ↑ Scoffield, Jessica A.; Duan, Dingyu; Zhu, Fan; Wu, Hui (2017). "A commensal streptococcus hijacks a Pseudomonas aeruginosa exopolysaccharide to promote biofilm formation". PLoS Pathogens. 13 (4): e1006300.
  21. ↑ Saiman, L.; et al. (2014). "Infection Prevention and Control Clinical Care Guidelines". Infection Control and Hospital Epidemiology. 35 (S1): S1–S67. Explicit use of et al. in: |first= (help)
  22. ↑ Ong, Thida; Marshall, Susan G.; Karczeski, Barbara A.; Sternen, Darci L.; Cheng, Edith; Cutting, Garry R. (2001). "Cystic Fibrosis and Congenital Absence of the Vas Deferens". GeneReviews [Internet].
  23. ↑ Girardet, A. et al. Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center’s 10-year experience. Clin. Genet. 87, 124–132 (2015).http://www.ncbi.nlm.nih.gov/pubmed/24762087
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