Course:MEDG 550/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 Caucasian individuals.[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 resides on cells that line 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 via the transport of ions such as chloride and sodium.[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 deltaF508 mutation. It accounts for approximately 70% of CF mutations in the Caucasian population.[1][4]

Inheritance

Autosomal recessive inheritance

CF is inherited in an autosomal recessive manner which means that an individual must carry two copies of the mutated gene to develop CF. Those who have one copy of the mutation are referred to as gene carriers. To pass on the disorder, both parents must be gene carriers, meaning they will not have the disorder themselves but there is a 50% chance they will pass the gene mutation on to each of their children. There is a 25% chance that two gene carriers will have a child with cystic fibrosis, a 50% chance their child will be a gene carrier themselves and a 25% their child will inherit two normal copies of the CTFR gene.

Prevelance

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).[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 and makes it easier for infection to occur. Recurring infections cause inflammation and sometimes life-threatening airway damage. 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 lead to pancreatic damage. This hinders nutrient absorption and can result in poor nutrition and 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, called the vas deferens, which carries sperm to the testicles. This is commonly referred to as congenital absence of the vas deferens (CAVD).[11] As a result, these males are infertile, however sperm extraction methods may be available for those 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 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 when an individual is found to have two CF-causing mutations in both copies of their CTFR genes. Genetic testing can also determine gene carrier status. These tests are generally done by looking directly at the DNA sequence from a blood sample. Ethnic background and/or family history may dictate exactly which genetic test is used.[10]

Nasal Potential Difference

The impaired transport of ions in the respiratory tract can be detected by measuring what is called the nasal potential difference (NPD).[15] This test may be used as evidence of CF if sweat test and genetic mutation analysis are inconclusive.[16]

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 blood sample collected by heel prick and measurement of a pancreatic protein (immunoreactive trypsinogen) that is present at increased levels in patients with CF.[17] Newborn screening of CF has proven to be widely effective in improving quality of life for those with the disorder.[18]

Management and Prognosis

Management of CF focuses on reducing lung infection and improving nutrition. Existing therapies treat the symptoms but not the underlying cause of CF. The current life expectancy for individuals with CF in the United States is approximately 37 years of age, however with improved therapies and management that number is expected to significantly increase in the coming years.[7]

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.[19]

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.[19]

Reproductive Options

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]

ChorionicVillus
Amniocentesis

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.[20]

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

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 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. ↑ Middleton, P. G., Geddes, D. M. & Alton, E. W. Protocols for in vivo measurement of the ion transport defects in cystic fibrosis nasal epithelium. Eur. Respir. J. 7, 2050–2056 (1994).http://www.ncbi.nlm.nih.gov/pubmed/7875281
  16. ↑ Rosenstein, B. J. & Cutting, G. R. The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J. Pediatr. 132, 589–595 (1998).http://www.ncbi.nlm.nih.gov/pubmed/9580754
  17. ↑ 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
  18. ↑ 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
  19. ↑ 19.0 19.1 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
  20. ↑ 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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