Woe To That Child: A Case Of Cystic Fibrosis - Dayton J Ford PDF

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Woe to That Child: A Case of Cystic Fibrosis! By Dayton J. Ford

—Northern European folklore

Dr. Jeremy Aldritch examined the four-month-old infant that had been admitted to Barnes-Jewish Hospital earlier in the day. The baby's parents, Jayne and David Horowitz, had brought young Alvin to the emergency room because he had been suffering from a chronic cough and diarrhea for almost a week. In addition, they said that Alvin sometimes would "wheeze" a lot more than they thought was normal for a child with a cold. Their pediatrician had told them that Alvin had a cold and would be better in a few days. Upon arriving at the emergency room, the attending pediatrician detected a possible ear infection and noted that salt crystals were present on Alvin's skin. Chest auscultation revealed the presence of rhonchi in the right upper lobe (RUL) of the lung. The attending pediatrician had Alvin admitted immediately and called Dr. Aldritch, a pediatric pulmonologist. After Dr. Aldritch completed his examination, he asked Alvin's parents to sit with him in his office to discuss Alvin's situation. "Doctor, Alvin's going to be ... okay, isn't he?" asked Jayne anxiously. "It's just a cold after all, isn't it, doctor?" interjected David. "No, I'm afraid it is more serious than a cold, Mr. and Mrs. Horowitz. I believe that your son may be having trouble getting the mucus, or phlegm, out of his lungs. There is an inherited disease called cystic fibrosis that may be the culprit, but we won't know for sure if Alvin has this disease until further testing is completed." "Cystic fibrosis? Isn't that caused by smoking?" said Jayne, as she slumped over slightly in her seat, feeling suddenly very tired and lost. "No, Mrs. Horowitz. You may be thinking of bronchitis or emphysema, which may both be caused by smoking. Cystic fibrosis is a genetic disease that an individual is born with. The symptoms usually appear within the first year of life and, if diagnosed early enough,

is a treatable disease. Here, I have some pamphlets that may help you to understand cystic fibrosis a little better." Dr. Aldritch dug through his desk and removed several pamphlets, most with photographs of parents holding a young infant on the cover, and handed them to Mrs. Horowitz. "Is this fatal, doctor? I mean, our son isn't going to, to...." David couldn't finish the thought. "No, no, your son will be fine for now, there is no immediate danger. Cystic fibrosis, or CF for short, is a serious enough disease, but it is not fatal in the short term and there are treatments that can help your son to live a relatively normal and healthy life. You see, what has happened is that Alvin was born with this disease, caused by a faulty gene within his DNA, and it has just now begun to show itself. The coughing that you were initially concerned about occurs in those who have CF because their lungs are filled with mucus. You see, normally your lungs produce a slightly viscous, more fluid type of mucus that acts to trap debris and dust particles so that they may be swept out of the lungs. This system helps to keep the air passages clear. In children with CF, however, the mucus that is secreted into the lungs is more viscous and less fluid, or contains less water than normal; therefore, it tends to clog the air passages and triggers a coughing reflex in order to expel the mucus from the lungs." "You said that there are treatments, doctor, but is there a cure? How long will Alvin have to live like this?" Jayne asked. "I'm afraid that there is no cure yet, Mrs. Horowitz. There are some clinical trials being conducted on various treatments for the disease, but the only real cure for a genetically inherited disease is gene therapy. Right now many scientists around the world are trying to develop methods to replace faulty or abnormal genes with copies of normal genes. We haven't yet reached the level of sophistication required to do this, but I believe that within Alvin's lifetime we just may. I know that you have a lot more questions, but I want you to rest assured that your son will be OK. I am going to go check on Alvin and see how soon the lab results will be ready. While I am gone, I will have a group of staff pharmacists answer all of your questions about CF." In order to give Mr. and Mrs. Horowitz the correct answers to their questions, you will need to know the answers to the questions listed below. Remember that Mr. and Mrs. Horowitz consider you to be the experts on how their son got CF, what it does (e.g., what is its mechanism of action) and what treatment options are available for their son Alvin. Be sure to be thorough and professional in your preparation.

Questions: 1. What do scientists currently believe is the cause of CF? In other words, how is the faulty gene inherited and what direct effect does that have on the affected cells? Currently it is believed that a faulty gene located on chromosome 7 is the culprit in cystic fibrosis. The trait is recessive; therefore, both mother and father need to have copies of the gene. Thus, there is a 1 in 4 chance that two carriers will produce a child with the CF phenotype. The gene encodes for a cAMP-regulated chloride (anion) channel called cystic fibrosis transmembrane conductance regulator (or CFTR) found on the apical surface of the epithelial cells that line the lungs and other organs (liver, pancreas, etc.). It is believed that a single amino acid change in the protein sequence renders the channel inoperative or it is simply degraded prior to insertion in the membrane.

2. Draw a flow chart/concept map that illustrates the mechanism whereby the faulty CF gene causes the production of thick mucus with less water in it than normal.

3. What specific part of the cell/structure allows the mucus secretions to be thick and viscous rather than fluid (i.e., is it a membrane channel, organelle or something else)? Please be specific and describe the step-by-step mechanism whereby this altered structure/part of the cell causes the secretions to contain less water. The specific part of the cell structure that is ultimately responsible for the disease cystic fibrosis is a defective or misfolded CFTR protein, which tends to be degraded by the Golgi apparatus before it can be trafficked to the membrane. In the lungs, if CFTR is absent, hyper-absorption of solute occurs, and hyper-absorption of water occurs due to enhanced solute absorption. The result is a decrease in the airway surface liquid (ASL), which leaves a thick mucus layer that compromises ciliary function and mucociliary clearance and leads to increased occurrences of bacterial infection. (See figure below.)

4. Why does Alvin have salt crystals forming on his skin? Explain the mechanism for this. CFTR is expressed in the duct portion of sweat glands and is responsible for salt reabsorption (or recovery), which helps to minimize electrolyte loss during the sweating process. (CFTR is expressed on the apical side, which faces the lumen or inside of the sweat gland.) Also in the sweat glands, water permeability is low. Without CFTR, reabsorption of both Cl- and Na+ are compromised, and excess salts that remain in the ducts are subsequently delivered to the skin.

5. What is the accepted treatment for children with cystic fibrosis? Make sure to list at least three and explain why they work (i.e., what is the purpose of each individual treatment). - Chest physical therapy (CPT) is one of the common treatments for children with CFTR. It is a physical treatment that involves the pounding of the chest and/or back either by human force or the use of a device. This helps to loosen the thick mucus that accumulates in individuals with CF, which allows the individuals to cough up the mucus. The problem with this treatment is that many individuals find it uncomfortable or hard to do. Devices can help make the process easier; however, it is still uncomfortable to many patients and it must be done often in order to clear the chest. - Many physicians also prescribe bronchodilators, which are medications that help to open airways by relaxing the surrounding muscles. This process is often coupled with CPT or other medications that will help rid the mucus from the lungs. - Aerobic exercise can also be used as a treatment method for those with CF. Exercise can help to loosen the mucus in the lungs and also promotes coughing in order to free the mucus from the lungs. • Sources: http://www.nhlbi.nih.gov/health/health-topics/topics/cf/treatment.html

6. List and explain the mechanism of at least two experimental treatments that are currently being tried to help patients with cystic fibrosis. - New medications for the treatment of CF may be developed to help with the inflammation experienced with this disease. Researchers have identified a target gene (TLR5 gene) that may play a key role in anti-inflammation in individuals with CF. Developing a medication that would act on this gene would help to decrease lung inflammation that often accompanies the disease. Research has shown that lung cells containing the delta F508 gene attract an excessive amount of immune cells to the affected lung cells. This creates an increase in inflammation. Medications that act on the TLR5 gene would help to counteract this event and decrease inflammation. • Sources: http://www.sciencedaily.com/releases/2012/11/121107132920.htm http://www.ncbi.nlm.nih.gov/pubmed/21068401 - The FDA recently approved a new drug, Kalydeco. Previously, the medications prescribed to patients with cystic fibrosis focused on dealing with the symptoms that were already present. However, Kalydeco actually works to modify the CFTR. This drug would assist in the Cl- ion regulation of the CFTR. However, the drug only works in those individuals who have a G551D mutation that affects the gating of the CFTR.

Although this mutation only accounts for 4% of the individuals with cystic fibrosis, this medication is a major step in the overall treatment of the disease. • Sources: http://www.cfri.org/pdf/2012CFRInewsSpringIssue.pdf

7. Briefly describe how gene therapy may help cure a genetically inherited disease like cystic fibrosis. - The use of gene therapy with cystic fibrosis would help to cure the disease by corrected the defected delta F508 gene with a normal gene. This can be done either two ways through gene line therapy or through somatic gene therapy. In the process of germ therapy, the normal gene is placed into the germ cells of the parental carrier. This way, the defective delta F508 could not be passed down to the offspring of the parents. On the other hand, somatic gene therapy involves changing the genetic make-up of an individual already expressing the disease. In this approach, the defective gene is replaced with a normal gene in specific target cells in the individual. This alteration would then reverse cystic fibrosis because the target cells would have at least one copy of the normal gene and the CFTR would then once again function normally. • Source: http://www.genetherapynet.com/types!of!gene!therapy.html

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