Cystic fibrosis and genetics
Cystic fibrosis (CF) is a genetic disorder primarily caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which leads to the production of thick and sticky mucus in various organs, particularly the lungs and pancreas. This condition is inherited in an autosomal recessive manner, meaning that individuals must receive a mutated copy of the gene from both parents to develop the disease. While cystic fibrosis is most prevalent among the Caucasian population, it can occur in individuals from diverse backgrounds, albeit at lower frequencies.
The CFTR gene, located on chromosome 7, is large and contains numerous mutations, each affecting the protein's function differently. The consequences of these mutations can lead to a range of symptoms, including respiratory infections, digestive issues, and reproductive challenges. Genetic testing can confirm the presence of CFTR mutations and is a crucial component of screening, especially for newborns and couples considering pregnancy.
Current treatments for cystic fibrosis focus on managing symptoms, preventing infections, and enhancing quality of life, including therapies for lung function and nutritional support. Advances in research and newborn screening have contributed to improved life expectancy and quality of life for individuals with cystic fibrosis, which now averages into the mid-thirties, with ongoing efforts aimed at further enhancing outcomes and understanding the disease's complexities.
Cystic fibrosis and genetics
Also known as: CFTR-related disorders, mucoviscidosis
Definition: Cystic fibrosis is a life-limiting, multisystem, autosomal recessive disorder that results from a defective channel in the epithelial cell membrane that is responsible for chloride transport. Progressive, chronic lung problems, pancreatic insufficiency, endocrine abnormalities, and infertility are the major health problems associated with this disease.
Risk Factors
The primary risk factor for cystic fibrosis is having two abnormal copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, both genetic and nongenetic modifiers exist that can affect the course of the disease. Cystic fibrosis most commonly occurs in the Caucasian population, although it occurs less frequently in all other populations.
Etiology and Genetics
The CFTR gene is located on chromosome 7 at band q31.2. The gene is large, containing 180,000 base pairs and 1,480 amino acids. More than 1,500 disease-associated mutations have been detected, which are classified according to their effect on the function of the CFTR protein. Class I mutations cause no protein to be made, class II mutations prevent the protein from reaching its location in the cell membrane, class III mutations result in problems with the function of the protein, class IV mutations result in the reduced ability of the channel to transport chloride across the membrane, and class V mutations cause a reduced amount of functioning CFTR protein to be produced. Some genotype-phenotype correlation is possible, primarily in relation to determining whether an affected individual with be pancreatic sufficient or insufficient. Unfortunately, genotype-phenotype correlation remains poor for determining the severity of lung disease.
Cystic fibrosis follows an autosomal recessive inheritance pattern. Everyone has two copies of the CFTR gene; individuals with cystic fibrosis have a mutation in each of their copies of the gene that causes it to malfunction. Usually an affected individual has inherited one malfunctioning copy of the gene from each parent, who are both carriers of the disease. Carriers of cystic fibrosis have one functioning and one malfunctioning copy of the gene. Their functioning copy allows for enough normal transport of chloride across cell membranes that they do not develop cystic fibrosis. If two parents are carriers, they have, in each pregnancy, a 25 percent chance to have an affected child. In addition, they have a 50 percent chance to have a child who is a carrier and a 25 percent chance to have a child who is neither a carrier of nor affected with cystic fibrosis.
The effects of abnormal transport of chloride across the cell membrane are best understood in the sweat gland. Secretion of sweat across the gland is modified before it reaches the skin. Usually, sodium, followed by chloride, is reabsorbed through the gland through both sodium channels and the CFTR protein. When the CFTR protein is not functioning, limited amounts of chloride are reabsorbed, which in turn limits the amount of reabsorption of sodium. The sweat contains large amounts of sodium, which can lead to salt loss syndromes.
The problem with chloride transport in lung epithelial cells is less clear. The low-volume model contends that malfunctioning CFTR causes increased sodium, chloride (through other pathways), and fluid absorption. Airway surfaces become dehydrated; mucus becomes thick and viscous and cannot be eliminated from the lungs. The high-salt model contends that with chloride unable to be reabsorbed efficiently, more sodium chloride will be present in the airway surface liquid. The high salt content disables some of the body’s immune defense mechanisms, causing affected individuals to be more susceptible to bacterial infection. It is also possible that defective chloride transport plays a role in the inflammatory process in the lungs, a theory that is supported by the increased inflammatory response in affected individuals prior to, or in the absence of, infection. The last hypothesis suggests that a natural immune response of normally functioning CFTR protein helps eliminate bacteria from the lung, and when the CFTR protein malfunctions this immune response is disabled.
In general, all organ systems affected in cystic fibrosis have problems with chloride and fluid secretion. The thick, sticky mucus blocks pancreatic ducts (pancreatic insufficiency) and prevents the release of enzymes into the intestine, which help us digest and obtain nutrients from our food. Fibrosis and replacement of pancreatic tissue with fatty deposits also interfere with pancreatic functioning and can lead to additional problems. Obstruction of the liver bile duct can lead to cirrhosis. Thickening of cervical mucus in women and absent or abnormal formation of the vas deferens in men occurs as well.
Current research is focusing on eradication of bacterial infection in the lung and maximizing and prolonging lung functioning. In addition, researchers are exploring other routes for chloride reabsorption in epithelial cells and developing therapies that correspond to the effect on protein function of the cystic fibrosis mutation classes.
Symptoms
Symptoms and their age of onset vary greatly in cystic fibrosis, even between individuals with the same genotype. Prenatally, an echogenic bowel is a sign of cystic fibrosis. About 15 percent of babies with cystic fibrosis are born with meconium ileus, a fatal condition if not treated. Infants and children may have poor weight gain, frequent loose and greasy stools, and recurrent respiratory infections with colonization in the lung of specific bacterial pathogens. In addition, pancreatitis, diabetes developing in adolescence, nasal polyps, and cirrhosis of the liver can occur. About 95 percent of men are infertile because of abnormalities of the vas deferens, and women’s fertility may be reduced. Any individual, even an adult with only some of the above symptoms, should be referred for clinical evaluation.
Screening and Diagnosis
Cystic fibrosis is diagnosed by either a positive sweat chloride test, genetic testing identifying two known mutations in the CFTR gene, or an abnormal nasal transepithelial potential difference (NPD). Genetic testing should always be confirmed by a sweat chloride test or NPD because, with the variability in clinical symptoms that can be associated with CFTR gene mutations, it is becoming more difficult to determine exactly what health problems should constitute a diagnosis of cystic fibrosis. CFTR mutations have been found in healthy men who are infertile as a result of congenital bilateral absence of the vas deferens (CBVAD) and in adults who have only pancreatitis. Interpretation of genetic test results should be performed by a genetics professional that is familiar with cystic fibrosis.
Sequencing of the CFTR gene remains labor intensive, and clinical significance of novel mutations is often difficult to determine. Therefore, genetic screening of common, clearly understood mutations has been developed, and two types are available to the general population. The first is genetic carrier screening. Uncommon mutations are not detected, and a negative screen does not eliminate a person’s risk to be a carrier of cystic fibrosis, but reduces it. The amount of risk reduction depends on the number of mutations that are screened and the person’s ethnicity. Genetic screening is available to all couples considering pregnancy but has primarily been marketed to the Caucasian population. In addition, newborn screening is performed in many states. The level of immunoreactive trypsinogen (IRT) is measured and when abnormal, is followed by either a repeat measurement of IRT in one to three weeks or with genetic screening of commonly occurring CFTR mutations. Follow-up diagnostic testing, usually via a sweat test, is required, as false-positive results can occur on the newborn screen.
Treatment and Therapy
Respiratory problems and infections that are associated with cystic fibrosis are treated with antibiotics and medication to dilate air passages. Chest physiotherapy, in which drainage of mucus from the lungs is assisted by percussion of the chest, is performed one or more times per day. Lung transplantation may be an option for individuals whose disease has become severe. Weight gain is optimized by nutritional supplementation through medication, diet, and vitamins. Artificial reproductive technologies may be helpful in managing fertility problems.
Prevention and Outcomes
Newborn screening has provided one significant area of prevention of some of the major problems associated with cystic fibrosis. Prompt nutritional supplementation can prevent many of the secondary problems that occur because of malnutrition and has been associated with improved lung functioning later in life. Strict adherence to the type and amount of chest physiotherapy and compliance with taking medications necessary to open lung airways can minimize the occurrence of airway obstruction and recurrence of infection. The first isolation of typical cystic fibrosis-associated bacteria in airway secretions is treated aggressively with antibiotics in hopes of eradicating the bacteria from the lung. Early detection of diabetes and liver problems allows for prompt management of these complications, which play a significant role in the mortality and morbidity of cystic fibrosis.
Average life expectancy for an individual with the typical health problems of cystic fibrosis has extended into the mid-thirties; however, there is significant variation. With the onset of newborn screening, improvements in the understanding of the function of the CFTR gene, what factors modify its functioning, and the underlying pathophysiology of cystic fibrosis, life expectancy will continue to increase and quality of life will continue to improve.
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