Causes and Symptoms Genetic diseases are inherited rather than caused by any specific injury or infectious agent. Thus, unlike many other types of diseases, genetic diseases range throughout a person’s lifetime and often begin to exert their debilitating effects prior to birth. Since in many cases the primary defect or underlying cause of the disease is unknown, treatment is difficult or impossible and is usually restricted to treating the symptoms of the disease.
In a genetic disease, a specific normal function is impaired because of a mutation in the individual’s genes. Genes are sequences of deoxyribonucleic acid (DNA) contained on the chromosomes of an individual that are passed to the next generation via ova and sperm. Usually the primary result of a genetic disease is the inability to normally produce a certain enzyme, which is a type of protein that is used to speed up, or catalyze, the chemical reactions that are necessary for cells to function. If a genetic mutation does not allow the production of a necessary enzyme, then some element of metabolism will be missing from the affected individual. This lack of function leads to the symptoms associated with genetic diseases, such as the lack of insulin production in juvenile diabetes or the inability of the blood to clot in hemophilia. In the 1940s and 1950s, when the understanding of basic cellular metabolism made clear the relationship between mutant genes and lack of enzyme function, the modern definition of genetic disease came into routine medical use.
Cystic fibrosis (CF), one such genetic disease, has several major effects on an individual. These effects begin before birth, extend into early childhood, and become progressively more serious as the affected individual ages. Major symptoms include the blockage of several important internal ducts, which occurs because the cystic fibrosis mutation has a critical effect on the ability of certain internal tissues, called secretory epithelia, to transport normal amounts of salt and water across their surfaces. These epithelia are often found in the ducts that contribute to the digestive and reproductive systems.
The blockage of ducts resulting from the production and export of overly viscous secretions reduces the delivery of digestive enzymes from the pancreas to the intestine; thus, proteins in the intestine are only partly digested. Fat-emulsifying compounds, called bile salts, are often blocked on their way from the pancreas to the intestine as well, so the digestion of fats is often also incomplete. These two conditions may occur prior to birth. According to the Johns Hopkins Cystic Fibrosis Center, approximately 18 percent of newborns with cystic fibrosis have a puttylike plug of undigested material in their intestines called the meconium ileus (MI), which prevents the normal movement of food through the digestive system and can be very serious. All babies born with MI should be tested for cystic fibrosis, as approximately 98 percent of full-term infants with such a plug have the disease.
Because of their overall inefficiency of digestion, young children with cystic fibrosis can seem to be eating quite normally yet remain severely undernourished. They often produce bulky, foul-smelling stools as a result of the high proportion of undigested material. This symptom serves as an indicator of the progress of the disease, as such digestive problems often increase as the affected child ages.
As individuals with cystic fibrosis grow older, their respiratory problems increase because of the secretion of a thick mucus on the inner lining of the lungs. This viscous material traps white blood cells that release their contents when they rupture, which makes the mucus all the more thick and viscous. The affected individuals constantly cough in an attempt to remove this material. Of greater importance is that the mucus forms an ideal breeding ground for many types of pathogenic bacteria, and the affected individual suffers from continual respiratory infections. Male patients are almost always infertile as a result of the blockage of the ducts of the reproductive system, while female fertility is sometimes reduced as well.
Advances in treatments for cystic fibrosis have drastically improved an affected individual’s chances of survival and quality of life. In the 1950s, a child with cystic fibrosis usually lived only a year or two. Thus, cystic fibrosis was originally described as a children’s disease and was intensively studied only by pediatricians. Today, aggressive medical intervention has increased survival rates dramatically. Affected individuals are treated with a package of therapies designed to alleviate the most severe symptoms of the disease, and taken together, these therapies have allowed many patients with cystic fibrosis to live well into adulthood. It is difficult to calculate an average life expectancy for individuals with cystic fibrosis, as data from some regions is largely unavailable. In addition, life expectancy varies greatly depending on the age at which a patient was diagnosed, the extent of medical care available, and various environmental factors. Individuals with access to the necessary treatments may live into middle age.
The available treatments, however, do not constitute a cure for the disease. The major roadblock to developing a cure was that the primary genetic defect remained unknown. All that was clear until the mid-1980s was that many of the secretory epithelia had a problem transporting salt and water. By the late 1980s, the defect had been further narrowed down to a problem in the transport of chloride ions, one of the two constituents of ordinary salt and a critical chemical in many important cellular processes. Because individuals who had severe forms of cystic fibrosis could still live, however, this function was deemed important but not absolutely essential for survival. Furthermore, only certain tissues and organs in the body seemed to show abnormal functions in a cystic fibrosis patient, while other organs—the heart, brain, and nerves—seemed to function normally. Thus, the defect was not uniform.
The pattern of inheritance of cystic fibrosis was relatively easy to determine. The genetic defect that causes the disease is recessive. Humans, like most animals, have two copies of each gene: one that is inherited on a chromosome from the egg, and one inherited on a similar chromosome from the sperm. There is a gene in all humans that controls some normal cellular function related to the transport of chloride from the inside of a cell to the outside. If this function is missing or impaired, the individual shows the symptoms of cystic fibrosis.
A recessive trait is one that must be inherited from both the mother and the father in order to take effect. Inheriting only a single copy of the mutation from one parent does not have a deleterious effect, and such an individual would not demonstrate any of the disease symptoms. However, that person would be a carrier of the disease and could still pass the mutation on to his or her own children. Thus, genetic diseases caused by recessive mutations, such as cystic fibrosis, can remain hidden in a family for many generations. When two carriers of the disease procreate, their children may be born with the disease. The rules of genetics, as first described by Gregor Mendel in the nineteenth century, predict that in such a union, each child has a 25 percent chance of inheriting cystic fibrosis and a 50 percent chance of being an asymptomatic carrier of the disease like his or her parents.
The classic approach to studying any genetic phenomenon involves mapping the gene. First, it must be determined which of a human’s twenty-three chromosome pairs contains the DNA that makes up the gene. By studying the inheritance of the disease, along with other human traits, researchers located the gene responsible for cystic fibrosis on chromosome number 7. To localize the gene more precisely, however, modern molecular techniques had to be applied. Success came in 1989, when two independent groups, led by Lap-Chee Tsui of the Hospital for Sick Children in Toronto and Francis Collins of the University of Michigan in Ann Arbor, announced that they had identified the location of the gene. The groups not only located the exact chromosomal location of the gene but also purified the gene from the vast amount of DNA in a human cell so that it could be studied in isolation. Then the structure of the normal form of the gene was compared to the DNA structure found in individuals with the disease.
DNA from more than thirty thousand individuals with cystic fibrosis was analyzed, and to the surprise of most, more than 230 differences between the normal and the mutated genes were found. While the same gene and gene product were affected in each case, the type and extent of the mutations varied widely in about 30 percent of the affected individuals, which accounts for the range in severity of symptoms. Since then, more than one thousand unique mutations in this single gene have been discovered to cause cystic fibrosis.
Tsui’s and Collins’s groups, as well as several others, tried to determine the normal function of the affected gene product. This protein, called cystic fibrosis transmembrane conductance regulator (CFTR) and encoded by the CFTR gene, was found to create an ion channel that allows cells to move chloride ions across their membranes. In an individual with cystic fibrosis, this channel does not work properly, disturbing both the salt and the water balance of the affected cell, and ultimately of the whole tissue. The thick mucus buildup in the lungs is a direct consequence of this disturbance, as is the high salt concentration in the patient’s perspiration.
CFTR is an enormous protein, consisting of 1,480 amino acids linked end to end, and is embedded in the membranes of cells found in the lungs, pancreas, and reproductive tracts. The CFTR found in 70 percent of individuals with cystic fibrosis is identical to that produced by a non-mutated CFTR gene, with one exception: the amino acid at position 508 is missing. Thus, the extensive debilitating symptoms of this disease result from the mere omission of one amino acid from a long chain containing 1,479 identical ones. The other mutations that cause cystic fibrosis affect different parts of this protein; in all cases, they reduce the ability of the CFTR protein to carry out its normal function.
Treatment and Therapy The treatment of cystic fibrosis typically focuses on preventing or delaying lung damage and optimizing growth and nutrition. Traditional treatments usually include daily dietary supplements that contain the digestive enzymes and bile salts that cannot pass through the blocked ducts. Individuals with cystic fibrosis are also placed on balanced diets to ensure proper nutrition despite their difficulties in digesting fats and proteins. One characteristic of cystic fibrosis treatment is the long daily ritual of backslapping, which is designed to help break up the thick mucus in the lungs; individuals may also use high-frequency chest-wall oscillation vests for the same purpose. Aggressive antibiotic therapy can keep infections of the lungs from forming or spreading. In the 1990s, a new therapy was introduced that uses a genetically engineered enzyme, deoxyribonuclease I (DNase I), to break down DNA in the lung mucus. Many white blood cells rupture while trapped in the thick mucus lining of the lungs, and the release of their DNA adds to the high viscosity of the mucus. DNase I, also called dornase alfa and sold under the trade name Pulmozyme, has been found to help degrade this extra DNA, thus making it easier for affected patients to cough out the mucus.
Therapies for cystic fibrosis, as for many genetic diseases, are largely limited to treating the symptoms. Since every cell in the affected individual lacks a particular metabolic function as a result of the disease, there is no easy way to replace these functions. For cystic fibrosis, this problem was exacerbated by the lack of understanding of the primary defect. The work of Tsui’s and Collins’s teams allowed a more direct assault on the actual defect. Gene therapy involves either replacing a defective gene with a normal one or inserting an additional copy or copies of the normal gene in the affected cells, in an attempt to restore the same functional enzymes and thus reestablish a normal metabolic process. In the case of cystic fibrosis, animal studies have shown that it is possible to produce normal lung function when either genes or genetically engineered viruses containing normal genes are sprayed into the lungs of affected animals. However, there is no similar direct route to the cells in the pancreas or the reproductive system, and an effective and efficient delivery vector for the non-mutated genes has yet to be discovered.
Perspective and Prospects Patients with the symptoms of cystic fibrosis were first described in medical records dating back to the eighteenth century. The disease was initially called mucoviscidosis and later cystic fibrosis of the pancreas. It was not clear that these symptoms were related to a single specific disease, however, until the work of Dorothy Anderson of Columbia University in the late 1930s. Anderson studied a large number of cases of people who had died with similar lung and pancreas problems. She noticed that siblings were sometimes affected and thus suspected that the disease had a genetic cause. Anderson was responsible for naming the disease on the basis of the fibrous cysts on the pancreas that she often saw in autopsies performed on affected individuals.
Because treatment of cystic fibrosis is largely confined to managing the disease's symptoms, a premium has been placed on the development of inexpensive and accurate diagnostic procedures, which along with genetic counseling could greatly reduce the incidence of cystic fibrosis in the population. Yet because carriers experience no symptoms and often do not realize that they are indeed carrying the gene, conventional genetic counseling cannot easily reduce the incidence of the mutation in human populations at risk. Only the widespread use of a DNA-based diagnostic procedure could serve to identify large populations of carriers, and due to the relatively low chance of even a child of two carriers developing the disease, counseling would be fraught with severe ethical problems.
Bibliography
Allen, Julian L., Howard B. Panitch, and Ronald C. Rubenstein, eds. Cystic Fibrosis. New York: Informa, 2010. Print. Lung Biology in Health and Disease 242.
Carson-DeWitt, Rosalyn. "Cystic Fibrosis (CF)." Rev. Rimas Lukas. Health Library. EBSCO, 7 May 2014. Web. 17 Sept. 2014.
"Cystic Fibrosis." Updated by Neil K. Kaneshiro. Rev. David Zieve and Isla Ogilvie. MedlinePlus. Natl. Lib. of Medicine, 14 May 2014. Web. 17 Sept. 2014.
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation, n.d. Web. 17 Sept. 2014.
Johns Hopkins Cystic Fibrosis Center. Johns Hopkins Cystic Fibrosis Center, 2014. Web. 17 Sept. 2014.
Kepron, Wayne. Cystic Fibrosis: Everything You Need to Know. Buffalo: Firefly, 2004. Print.
"Neonatal Cystic Fibrosis Screening Test." Updated by Neil K. Kaneshiro. Rev. David Zieve and Isla Ogilvie. MedlinePlus. Natl. Lib. of Medicine, 14 May 2014. Web. 17 Sept. 2014.
Orenstein, David M., Jonathan E. Spahr, and Daniel J. Weiner. Cystic Fibrosis: A Guide for Patient and Family. 4th ed. Philadelphia: Lippincott, 2012. Print.
Parker, James N., and Philip M. Parker, eds. The Official Parent’s Sourcebook on Cystic Fibrosis: A Revised and Updated Directory for the Internet Age. San Diego: ICON Health, 2005. Print.
Pierce, Benjamin A. The Family Genetic Sourcebook. New York: Wiley, 1990. Print.
Riordan, John R., Richard C. Boucher, and Paul M. Quinton, eds. Cystic Fibrosis: A Trilogy of Biochemistry, Physiology, and Therapy. Cold Spring Harbor: Cold Spring Harbor Lab., 2013. Print.
Thomson, Anne H., and Ann Harris. Cystic Fibrosis: The Facts. 4th ed. New York: Oxford UP, 2008. Print.
Tsui, Lap-Chee. “Cystic Fibrosis, Molecular Genetics.” Encyclopedia of Human Biology. Ed. Renato Dulbecco. 2nd ed. Vol. 2. New York: Academic, 1997. Print.
United States. Cong. Office of Technology Assessment. Cystic Fibrosis and DNA Tests: Implications of Carrier Screening. Washington: GPO, 1992. Print.
United States. Cong. Office of Technology Assessment. Genetic Counseling and Cystic Fibrosis Carrier Screening: Results of a Survey. Washington: GPO, 1992. Print.
Watson, Ronald Ross, ed. Diet and Exercise in Cystic Fibrosis. Waltham: Academic, 2015. Print.
Yankaskas, James R., and Michael R. Knowles, eds. Cystic Fibrosis in Adults. Philadelphia: Lippincott, 1999. Print.
