Alzheimer Disease
Duchenne/Becker Muscular Dystrophy
Down Syndrome
Fragile X Syndrome Hemophilia is caused by a dysfunctional or absent blood-clotting protein. Without this protein, stable clots do not form quickly over wounds. Weak clots form, but they are easily dislodged, so that people with hemophilia can bleed for days as clot after clot is dislodged from place. To understand why these changes cause hemophilia, and to understand the difference between hemophilia A and hemophilia B, we need to look at the details of clotting. The clotting process starts after the wall of a blood vessel is breached. The vessel constricts to reduce blood flow, and the platelets (bits of larger bone marrow cells) congregate at the damaged site. Though the platelets stop the bleeding, at this stage they are easily dislodged, and bleeding can resume. As the platelets arrive, molecules released from the damaged vessel activate clotting Factor 12. Factor 12 then activates another clotting protein by snugly fitting into the molecule, as a key fits inside a lock. Activated thrombin then snips small pieces off another protein called fibrinogen. When lots of fibrinogen is cut, the pruned molecules cover the platelets and stabilize the clot. To form a stable clot, all the molecules in the cascade must be present and properly shaped. In people with mild or moderate hemophilia A, Factor 8 is present but has a slightly dysfunctional shape that sometimes doesn't fit into the next molecule. Because the mutated Factor 8 succeeds in activating Factor 10 some of the time (doctors say its activity is between 5 and 35 percent of normal), people with mild or moderate hemophilia A don't bleed as long when injured and only rarely, or never, bleed spontaneously. People with mild hemophilia A have mutated Factor 8 proteins. This is due to a small mutation in their Factor 8 gene, located on the X chromosome. The gene's code carries the instructions for building the protein, so a minor change in the instructions causes a minor change in the shape of the protein. For people with severe hemophilia A, Factor 8 is usually absent, and the clotting cascade comes to a complete halt. Factor activity is less than one percent of normal. People with severe hemophilia A bleed spontaneously and can bleed for days after minor injuries. In people with severe hemophilia A, Factor 8 is not present, because their gene contains a much bigger mutation, like an inversion, that completely garbles the instructions for the protein. No Factor 8 can be produced from the garbled gene. When Factor 8 is normal, but the person still has hemophilia, a change in Factor 9 is usually the culprit. The disorder is called hemophilia B. In mild or moderate hemophilia B, a small mutation in the gene leads to a slightly dysfunctional Factor 9. The protein works occasionally to activate thrombin, and stable clots are eventually formed. When hemophilia B is severe, a more critical mutation in the gene completely misshapes the Factor 9 protein. The protein either can not be activated or can not activate the next molecule in the cascade. Before effective treatments were developed in the late 1960s, people with severe hemophilia died young (median age 11) from bleeding. With effective treatment, life expectancy is nearly normal, but repeated bleeding episodes can cause disabling arthritis in the joints. Damage to the joints (mainly knees, elbows, and ankles) starts when the synovium a thin lining inside the joint capsule thickens to absorb blood lost from the vessels. As the synovium thickens, it also acquires more blood vessels that make the joint prone to further injury. Another injury means more blood to absorb, and the synovium thickens again. With frequent re-injuries, the synovium never shrinks and remains swollen. Enzymes from the swollen synovium eat away at the cartilage that cushions the ends of the bones in the joint. The longer the synovium stays swollen, the more damage occurs. Eventually, the cartilage is eaten away, and bone begins to grind against bone, causing pain and reducing the joint's range of motion. Before making a diagnosis of hemophilia, a doctor will have to perform several blood tests to rule out other disorders that share symptoms with the disorder. The final blood test a Factor activity test confirms the person has hemophilia and also determines the type (A or B) and severity. This test determines how well each Factor performs relative to that of an unaffected person. A fully functional Factor has 100% of normal activity, while a completely non-functional Factor has 0% of normal activity. The amount of activity determines the severity of the disorder. The technical details of the test involve separating the patient's blood sample into red blood cells and plasma, and then adding a sample of the patient's plasma to another tube of normal plasma. But first, Factor 8 (represented by the blue dots) is removed from the normal plasma. A sample of the patient's plasma is then added to the tube. When the patient has hemophilia A, and therefore little or no Factor 8, the test tube still lacks sufficient amounts of the clotting protein. After a reagent is added to start the clotting cascade, white blood cells begin to clump together and form clots, which sink to the bottom. When the patient has hemophilia A, the absence of Factor 8 slows this process. If the patient has hemophilia B instead, his blood contains a normal amount of Factor 8, and the plasma clots quickly after the clotting reagent is added. To confirm the diagnosis of hemophilia B, another test measures the activity of Factor 9. This test is exactly the same as the hemophilia A test, except Factor 9 (represented by the red dots) is removed from the normal plasma instead of Factor 8. When the patient has hemophilia B, his plasma does not add any (or much) Factor 9 to the tube after a sample is transferred. Because there is little Factor 9 in the tube, clots form slowly, and the patient is diagnosed with hemophilia B. Once one person in a family has been diagnosed with hemophilia, it may be desirable to pinpoint the mutation so other family members can learn if they carry the mutation. (The blood test used for diagnosis does not detect asymptotic carriers). This is easy to do if the boy has a certain type of mutation called an inversion. About 50% of people with severe hemophilia A have this type of mutation. The test for an inversion generates a DNA fingerprint of the boy's Factor 8 gene. The inversion is absent when the fingerprint shows two dark bands of DNA at the 21.5 and 16.0 positions. The inversion is present when the fingerprint shows two bands of DNA closer together at the 20.0 and 17.5 positions. The basis for the inversion test lies in a structural difference between a gene with an inversion and a gene without an inversion. Enzymes that recognize this difference are added to the person's DNA sample. To measure the DNA, the geneticist sends them through a gel that separates and orders the pieces by size. She loads the sample at the top of the gel, and an electric current pushes them down through the gel matrix. (Several samples can be loaded next to each other in the same gel). As the pieces move down the gel, they wind their way through the tangled gel matrix. Small pieces do this easily so they zip through the gel quickly. Big pieces have a harder time so they move more slowly. After a set period of time, the pieces have lined up by size with the smallest pieces at the bottom and the biggest near the top. The DNA fingerprint is complete after the pieces are dyed, and they show up as dark bands. When a boy has the inversion, the same test is used on his female relatives to identify the carriers in his family. In this case, a person is a carrier if her results match the boy's inversion pattern. Searching for mutations is easier when the boy has hemophilia B, because the Factor 9 gene is four times smaller than the Factor 8 gene. Many labs simply determine the sequence of bases in the boy's gene and look for differences between it and a "normal" gene. In the example below, the boy's hemophilia is caused by a single base change (from a C to a G). Hemophilia is like any other sex-linked disorder, because the "hemophilia" gene is on the X chromosome. The X is one of two types of chromosomes X and Y that determine sex. Girls have two X chromosomes (making a girl a girl), and boys have one X and one Y (making a boy a boy). This "mismatch" in the sex chromosomes of boys makes them more susceptible to disorders caused by genes on the X. A girl has two Xs, and therefore, two Factor genes. If one is mutated, she can fall back on the other gene. A boy has only one X and one Factor gene. If he has a mutated Factor gene, he has no other copy to fall back on. A boy gets hemophilia when he inherits an X chromosome with a mutated Factor gene (XH) from his mother. He also inherits a Y chromosome from his father, but the Y does not contain the Factor gene. Therefore, the boy's clotting factors are produced from the mutated gene he got from his Mom. A boy can also get hemophilia even if his mother does not carry a mutated Factor gene. This happens if the gene mutates during egg production or early in the development of the embryo. About 20% of boys with hemophilia get the disorder in this manner. The severity of the boy's hemophilia depends on the specific mutation in his Factor gene. If the mutation is small like a one letter change in the gene the symptoms are usually mild or moderate. If the mutation is larger like a backward chunk the symptoms are usually severe. Another way a girl can get hemophilia though this is exceedingly rare is by inheriting TWO mutated Factor genes, one from her father and one from her mother. Hemophilia is a recessive disorder caused by mutated genes on the X chromosome. Girls have two X chromosomes, so two mutated Factor genes, one on each X, have to be inherited in order for a girl to develop hemophilia. Though girls also inherit the mutated Factor gene, they rarely develop hemophilia, because their second X chromosome has a normal gene. Because she has inherited the mutated gene (from either her father or mother), she is a carrier of hemophilia and can pass it to her own sons. In 90% of the case, the girl DOES NOT show any signs of hemophilia, because she has a second X chromosome that carries an unmutated Factor gene. The unmutated gene produce fully functional Factors that compensate for the "irregular" Factors produced by the mutated gene. In X-inactivation a normal process in all females every cell in the early embryo inactivates one of the two X chromosomes. Once inactivated, the chromosome shrivels up and sits on the edge of the cell nucleus. No Factor can be produced from the inactivated X. In each cell, the inactivation is random, like a coin flip. The chance that the mother's X will be inactivated is the same as the chance that the father's X will be inactivated. Usually, about half of the cells inactivate the mother's X, and the other half inactivate the father's X, but sometimes, the ratio heavily favors one type just by chance. After each cell inactivates one X, development continues, and each cell produces more "daughter" cells. Daughter cells inherit their chromosomes from the parent cell, so all daughter cells have the same active X as their parent. As development continues further, cells organize into different organs, including the brain. If the girl's liver mostly contains cells with an inactive X from Dad, the cells must use the fully mutated Factor gene from Mom's X. This gene does not produce any protein, and this girl develops hemophilia. If a couple carries a mutated Factor gene, their chance of producing a child with hemophilia, or a child who is a carrier, can be calculated with a Punnett Square. Let's start with a common situtation: a female carrier (XH represents her X chromosome with the mutated gene) and her unaffected male partner. To use the square, we first move the parents' chromosomes to the outer edges of the box. Each parent donates only one of their two sex chromosomes to the child, so we place one of the father's and one of the mother's into each box. Each completed box shows a potential combination (or genotype) in the child, and the entire square contains all possible combinations. Each box, or genotype, is equally likely, so there is a 1-in-4 (25%) chance that this couple will have a boy with hemophilia (rollover the XHY combo). There's also a 25% chance this couple will have an unaffected boy (XY), an unaffected girl (XX), or a girl who is a carrier (XXH). 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 being a boy with hemophilia (or an unaffected boy, or an unaffected girl, or a carrier). In this family, two out of four children have hemophilia. Other couples with the mutation may have one, three, four, or even no children with the disorder. A Punnett Square also shows us the potential children a man with hemophilia can have. Usually, his partner will be a woman who does not carry the mutation. As before, we move the parents' chromosomes to the outer edges of the square, and then copy and paste them into the inner boxes. As before, we move the parents' chromosomes to the outer edges of the square, and then copy and paste them into the inner boxes. Two out of four boxes are unaffected boys, so there is a 50% chance this couple will have an unaffected boy (rollover the XY boxes). The other two boxes contain girls who carry the hemophilia mutation (XHX), so there is also a 50% chance this couple will have a girl who is a carrier. In the early 1980s, most people with hemophilia were infected with HIV, because the factors used for treatment were isolated from infected human plasma. Since then, virus-sterilizing techniques and the use of artificial factors have greatly reduced this risk. People with hemophilia bleed longer because their blood does not clot well. Without treatment, a person with severe hemophilia can bleed to death. With treatment, internal bleeding in the joints is the most problematic complication, because it leads to painful arthritis. Hemophilia is a sex-linked disorder that affects males of all races and ethnic groups. About 1 in 4,000 males are born with the disorder. Females can have the disorder but it is significantly rarer. A physician will use several blood tests to rule out other blood disorders before diagnosing hemophilia. The final test determines which factor is responsible and the factor's activity level. Genetic testing can uncover carriers and people with mild hemophilia. Hemophilia occurs when a person has a mutation in one of the clotting factor genes. Approximately 90% have a mutation in the Factor VIII gene (hemophilia A), 9% have a mutation in the Factor IX gene (hemophilia B), and 1% have a mutation in another clotting gene. People with hemophilia inject themselves with purified clotting factors to prevent or stop bleeding episodes. Additional treatment is necessary if the person's immune system attacks the injected clotting factors. What is it? What causes it? How is it inherited? How is it diagnosed? How is it treated? What is it like to have it? For more information
Acknowledgments Characteristics Dr. Catherine Manno, Associate Director of the Hemophilia Program at the Childrens Hospital of Philadelphia, talks about bleeding episodes and two kinds of hemophilia. Symptoms Dr. Catherine Manno talks about symptoms in infants. Bleeds Dr. Catherine Manno talks about delaying bleeding and other kinds of bleeding. Mutations Dr. Catherine Manno talks about the severity of levels of hemophilia and the relation of severity levels to mutations. Factor Therapy Dr. Catherine Manno recommends recombinant concentrates. She discusses what it does and the age at which it would be used. History Dr. Catherine Manno discusses how treatments have evolved due to the risk of virus transmission. Easier Injections Dr. Catherine Manno talks about surgically implanted solutions and their risks. Spontaneous Bleeds Dr. Catherine Manno discusses spontaneous bleeds and locations in the body. Inhibitors Dr. Catherine Manno talks about the risks of developed antibodies and the treatments for them. Joint Disease Dr. Catherine Manno talks about chronic joint disease and its treatments. Mild Cases Dr. Catherine Manno talks about how desmopressin acetate (DDAVP) can be used to release stored Factor 8 in cases of mild hemophilia. Gene Therapy Dr. Katherine High, Medical Director of the Coagulation Laboratory at The Childrens Hospital of Phladelphia, talks about gene therapy and why hemophilia is a good model disease. Type B vs. A Dr. Katherine High explains the differences between hemophilia A and hemophilia B. AAV Dr. Katherine High talks about the advantages of using adeno-associated virus (AAV). Immune Response Dr. Katherine High discusses issues concerting the development of inhibitors. Muscle vs. Liver Dr. Katherine High explains the difference between injecting the vector intramuscularly and injecting the vector directly into the liver. Dog Trials Dr. Katherine High discusses results from working with hemophilic dogs to test the adeno-associated virus (AAV). Germline Transfer Dr. Katherine High talks about conflicts concerning delivering the vector to reproductive cells. Timeline Dr. Katherine High discusses the timeline in which their method of gene therapy must be validated so that it can be available to everyone. Bleeds and Treatments Paul talks about the experience of bleeds and how he prefers episodic treatment. Greg Price and his mother Linda talk about Prophylaxis treatment and how bleeds may occur. Advice for Parents (1) Paul supports the idea of a hemophilic child exploring his or her own boundaries of physical activity. Greg Price and his mother discuss physical freedom. Advice for Parents (2) Linda Price talks about issues concerning the manufacturers of treatments. Benefits of Summer Camp Greg Price explains how camp gave him exposure to illnesses other than hemophilia. Paul recalls how he found companionship with people who dealt with similar difficulties. Friends and School Greg Price talks about his experiences in school. Paul sometimes felt left out of the crowd because of hemophilia. Injections Paul explains how his mother would inject him when he was an infant. Linda Price talks about her sons self-injections. Paul talks about learning to inject himself at a camp in Colorado. Expenses and Insurance Linda Price talks about issues concerning insurance and how only specific job positions will offer the insurance coverage they need. Carrier Testing Linda Price discusses the importance of carrier testing and her concerns for relatives. Treatment Centers Dr. Catherine Manno talks about the advantages of a hemophilia treatment center. Greg Price and his mother discus the treatment center that they attend. Diagnosis Feelings Linda Price speaks about the unexpectedness and the life-changing effects of her sons diagnosis. Alzheimer Disease
Duchenne/Becker Muscular Dystrophy
Down Syndrome
Fragile X Syndrome ...
Phenylketonuria | |
|
