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Fragile X Syndrome Sickle cell is one of the most common genetic disorders in the United States, affecting about 1 in every 375 African-American children. The painful crises, anemia, and organ damage of sickle cell can be traced back to the structure of an important blood protein called beta globin. Beta globin proteins are found inside red blood cells. The protein's job is to carry another molecule called heme. Inside the cells, beta and alpha globins combine to form hemoglobin, the molecule that delivers oxygen to all our cells. Two beta globins plus two alpha globins (and each globin's heme group) make one molecule of hemoglobin. The heme of each globin binds the oxygen molecule. The instructions for making beta globin are encoded inside a gene located on chromosome 11. Everybody has two chromosome 11s, so everyone has two beta globin genes. Inside the gene, code letters tell the cells protein-making machinery how to construct the protein. The machinery translates the code and puts the appropriate amino acids the building blocks of proteins into the proper positions. In people with sickle cell, the code inside both beta globin genes is different from usual. Instead of containing the letters G-A-G near the beginning of the gene, the code reads G-T-G. The usual G-A-G code tells the protein machine to put a glutamate amino acid into the protein, but the new G-T-G code tells the machine to put a valine in. The valine has a critical effect on the behavior of the entire hemoglobin molecule. When oxygen is released by the molecule, the valine becomes very sticky to the nearby V-shaped notch shown below. When two separate hemoglobins come near each other, the valine and notch interlock. More and more hemoglobins link up to the pair, and the structure explosively grows into a long rod of hemoglobins. (Because the rod is made up of interconnected hemoglobins, it is also known as a hemoglobin polymer.) The long polymers of hemoglobin are stiff and they stretch the red blood cell into the shape of a sickle, or a banana. The cell only springs back to its normal shape after it returns to the lung and captures more oxygen. Oxygen-binding instantly breaks up the polymers. As the red blood cells cycle through the body delivering oxygen, they repeatedly spring in and out of the sickle shape until the cells get stuck in the sickle shape. The stress of the shape changes also damages the cells, and the cells die after 10 to 20 days instead of living out their normal lifespan of 120 days. The premature death of the red bloods cells causes a shortage of red blood cells, a condition doctors call anemia. The shortage lowers the amount of oxygen delivered to the bodys tissues and causes the fatigue, shortness of breath, and the slow rate of growth seen in people with sickle cell disease. For reasons not completely understood, sickled cells and even normally-shaped cells are more likely to adhere to the walls of the blood vessels. The stiff sickled cells cant squeeze past the blockage and they start piling up, creating a larger barrier that prevents even normally-shaped cells from passing by. With no red blood cells passing the obstruction, no oxygen can get to the tissues downstream, and cells in these tissues begin to die. This can cause very localized and severe pain in these tissues that can last hours, days, or even weeks. The blockages can occur anywhere in the body, but there are particular areas that are especially vulnerable. In the spleen, tissue damage impairs the ability of the spleen to filter bacteria out of the bloodstream and make antibodies to fight bacterial infections. Lungs can also be damaged by blocked vessels, a bacterial or viral infection, or fatty pieces of bone marrow that dislodge from the bone and get stuck in the lung. Red blood cells cant pick up enough oxygen, and less oxygen causes more cells to sickle. The whole process can spiral into lung failure. Blockages in the brains blood vessels can cause a stroke if brain cells are killed. Usually, a person who has a stroke loses some ability to think; perceive sights, sounds, or smells; and walk or move easily. Most states in the U.S. screen for sickle cell disease at birth with a test called hemoglobin electrophoresis. This test uses a sample of blood from the infant and determines what types of hemoglobins are present. The final result looks something like this, where each different type of hemoglobin clusters into different dark spots in the electrophoresis gel. In this case, two different types of hemoglobin are present. The A-type is the normal type of hemoglobin, and the S-type is the sickle cell hemoglobin. Because this person makes both types, he carries one normal beta globin gene and one sickle beta globin gene. This makes him a carrier of sickle cell, but he does not have sickle cell disease. A person with sickle cell will have results like this, where only the S-type of hemoglobin is present. This person also has two genes for beta globin, but both make the same sickle cell version. Finally, a person who does not have sickle cell and does not carry the sickle cell gene will only make the A-type of hemoglobin. Both of his beta globin genes produce the non-sickling version of the protein. The different results in this test occur because the A-type form of hemoglobin has a different mobility than the S-type form. The A-type moves quickly through a slab of gel, while the S-type moves more slowly. If the two forms are propelled through a gel for the same amount of time, they will separate into distinct bands in different parts of the gel. If two bands are present, then the person being tested has both forms of hemoglobin. He or she is a carrier for the sickle cell disease. If the person being tested has the disease, he or she will have two copies of the S-type of hemoglobin, and only one band will appear on the gel. If the person being tested has the disease, he or she will have two copies of the S-type of hemoglobin, and only one band will appear on the gel. If the person being tested does not have the disease (and is not a carrier), only one band will appear on the gel, that of the A-type hemoglobin. One blood test can distinguish the difference between people with and without sickle cell, and people who are carriers of sickle cell. Sickle cell disease can also be detected in the unborn fetus or in an embryo conceived in a test tube. In these cases, the test looks directly into the genes of the fetus or embryo, and a DNA fingerprint of the beta globin genes is constructed. When the test is complete, the pattern on the DNA fingerprint reveals whether the embryo does or does not have sickle cell disease, or is a carrier. The first step in making the fingerprints is isolating the embryo's two beta globin genes, and copying them millions of times with a chemical reaction called polymerase chain reaction (PCR). When enough copies of the genes are made, a special enzyme is added to the mixture. The enzyme cuts A-type DNA pieces in two, but leaves the S-type untouched. Therefore, an embryo with both A- and S-type genes will produce three different groups of DNA fragments: the two small pieces from the A-type gene and the larger, untouched, S-type gene. The final step in the test is to visualize the DNA pieces generated through a process called gel electrophoresis. The process sorts each group of pieces into a unique position inside a hard slab of gel. A pattern with three spots indicates the embryo does not have sickle cell disease but is a carrier. A pattern with one spot indicates the embryo has sickle cell. A pattern with two spots indicates that the embryo does not have the sickle cell disease. A pattern with three spots means the embryo is a carrier; one spot means the embryo has sickle cell disease, and two spots means the embryo does not have the disease. Sickle cell anemia is an inherited disorder and is not contagious. A person gets sickle cell when he inherits an S-type beta globin gene from each parent. Each parent has two beta globin genes: one is the "normal" A-type, and the other is the sickling S-type (represented by the red chromosome). When the father and mother produce sperm and eggs, only one of their two beta globin genes enter each cell. About half the cells get the S-type gene, while the others get the A-type gene. When a sperm (from the father) carrying the S gene fertilizes an egg (from the mother) carrying the S gene, the resulting child inherits both genes and develops sickle cell anemia. Inheritance begins with the parents, and like all people, each parent has two beta globin genes, as represented by the chromosome pairs below. Both have one "normal" A-type (grey chromosomes), but the father also has a C (blue chromosome), while the mother has an S (red chromosome). When the father and mother produce sperm and eggs, only one of their two beta globin genes enter each cell. About half of the father's sperm get the A-type gene, while the other half get the C-type gene. Similarly, half the mother's eggs get the A-type gene, the other half get the S-type gene. When a sperm carrying the C-type gene fertilizes an egg carrying the S-type gene, the resulting child will inherit both genes and develop SC disease. The symptoms of SC disease are generally milder than sickle cell anemia (SS). A person gets Sß when she inherits an S-type beta globin gene from one parent and a ß-type beta globin gene from the other. (ß genes produce little or no beta globin). Inheritance begins with the parents, and like all people, each parent has two beta globin genes, as represented by the chromosome pairs below. Both have one "normal" A-type (grey chromosomes), but the father also has a ß (purple chromosome), while the mother has an S (red chromosome). When the father and mother produce sperm and eggs, only one of their two beta globin genes enter each cell. About half the cells get the A-type gene, while half the sperm get the b-type gene, and half the eggs get the S-type gene. When a sperm carrying the b-type gene fertilizes an egg carrying the S-type gene, the resulting child will inherit both genes and develop the sickling Sb disease. The severity of Sb depends on the specific variant of b inherited. When both parents carry an S gene, every child they have has a 1-in-4 chance of inheriting sickle cell anemia. To see why, we'll construct a Punnett square. First, we place the parents' genes on the outside of the square, as shown in the animation. Each box inside the Punnett square represents a possible child of this couple. To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes sickle cell anemia (SS). Out of four boxes, only one contains the SS pair, so each child of this couple has a 1-in-4 (25%) chance of getting sickle cell anemia. The most important thing to remember about these odds is that they apply to every child this couple has. It may be useful to think of the Punnett square as a roulette wheel. Each child is a separate "spin of the wheel," so each child has a 25% chance of developing sickle cell. In this family, one in four children has sickle cell disease. Other couples with the mutation may have two, three, four, or even no children with the disease. When one parent carries a C-type gene and the other carries an S-type, every child they have has a 1-in-4 chance of inheriting SC disease. To see why, we'll construct a Punnett square. First, we place the parents' genes on the outside of the square, as shown in the animation. Each box inside the Punnett square represents a possible child of this couple. To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes SC disease (SC). Out of four boxes, only one contains the SC pair, so each child of this couple has a 1-in-4 (25%) chance of getting SC. The most important thing to remember about these odds is that they apply to every child this couple has. It may be useful to think of the Punnett square as a roulette wheel. Each child is a separate "spin of the wheel," so each child has a 25% chance of developing SC disease. In this family, one in four children has sickle cell disorder. Other couples with the mutation may have two, three, four, or even no children with the disorder. When one parent carries a b-type gene and the other carries an S-type, every child they have has a 1-in-4 chance of inheriting Sb disease. To see why, we'll construct a Punnett square. First, we place the parents' genes on the outside of the square, as shown in the animation. Each box inside the Punnett square represents a possible child of this couple. To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes Sb disease (Sb). Out of four boxes, only one contains the Sb pair, so each child of this couple has a 1-in-4 (25%) chance of getting the sickling Sb disease. The most important thing to remember about these odds is that they apply to every child this couple has. It may be useful to think of the Punnett square as a roulette wheel. Each child is a separate "spin of the wheel," so each child has a 25% chance of developing Sb disease. In this family, one in four children has sickle cell disorder. Other couples with the mutation may have two, three, four, or even no children with the disorder. Sickle cell disease is common in many regions of the world where mosquito-borne malaria is present. It is believed that people who carry only one sickle cell mutation (they do not have the disease) can tolerate malaria better than people who carry no mutations. This may be why the mutation persists in the population despite the high mortality associated with untreated sickle cell disease. Pain associated with blocked blood vessels is the most obvious symptom, and can be severe enough to warrant hospitalization. The blocked blood vessels frequently lead to spleen, lung, and heart damage and stroke. Sickle cell also causes anemia, which leads to fatigue. Sickle cell disease is the most common single gene disorder in African-Americans, affecting one in every 375. Globally, a quarter of a million children are born with the disease each year, mainly in Africa, the Mediterranean, Arabia, and South Asia. In most states, newborns are screened for hemoglobin disorders, including sickle cell. The screening test determines which hemoglobin types each child makes. A child with sickle cell makes hemoglobin S instead of the usual hemoglobin A. Sickle cell diseases include three distinct types: sickle cell anemia, SC disease, and Sb disease. They are caused by a mutation in a blood protein called beta globin. The mutation leads to changes in the shape and behavior of red blood cells. The sickled, stiff, and sticky red blood cells of sickle cell disease cause severe organ damage and intense pain. A bone marrow transplant is the only available cure, but it is a high risk operation. Although it has been successful in severely affected children, adults have a tendency to reject the transplant. The drug hydroxyurea helps to prevent or lessen sickle cell's complications; blood transfusions and narcotics for pain also help to alleviate the symptoms. Facts and Theories Symptoms Incidence Testing and Screening Cause Treatment. How is sickle cell treated? Acute Chest Syndrome Dr. Kusm Viswanathan talks about the danger of ACS as one major complication resulting from sickle cell. She discusses ACS treatment options for children and adults. Pain Dr. Viswanathan talks about the cause of pain associated with sickle cell and how it can be treated. Strokes Dr. Viswanathan talks about the dangers of strokes in children with sickle cell. She describes the transcranial Doppler imaging that can help detect potential stroke victims. Heart Problems Dr. Viswanathan talks about the need to monitor heart function in people with sickle cell. Kidneys and Gallbladders Dr. Viswanathan talks about kidney and gallbladder problems that people with sickle cell may have to deal with. Retinopathy Dr. Viswanathan talks about retinopathy, a condition associated with sickle cell that can cause blindness. However, with early detection and treatment, blindness can be prevented. What is it like to have sickle cell? School Maya Priest talks about how sickle cell affected her ability to attend school, and how she had to work with tutors in order to keep up with her schoolwork. Dealing with the Pain Maya discusses the different levels of tolerance and how she deals with the pain. Skepticism Maya talks about the skeptical attitudes of some doctors and nurses; they cant see the pain, so it must not be real. She also talks about her friend who died, partially because of these dangerous attitudes. Complications Maya talks about some of the physical complications that she may have to deal with as she gets older. Job complications Maya discusses the difficulty of securing a normal job because of her unpredictable illness. Having Fun Maya talks about the importance of having fun despite the risk of getting sick. Setting Limits Maya talks about the importance of setting limits and how the limits can vary for different people. Having Children Maya discusses her desire to have children and the health risks she faces if she becomes pregnant. Relationships Maya talks about her relationships with other people and the possibility of finding a partner who can understand and deal with the complications of her condition. Advice to Parents Maya gives parents some advice: education and support. Alzheimer Disease
Duchenne/Becker Muscular Dystrophy
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