Alzheimer Disease
Duchenne/Becker Muscular Dystrophy
Down Syndrome
Fragile X Syndrome All the symptoms of Fragile X can be traced back to a mutation in one gene called FMR1 on the X chromosome. People who have Fragile X carry an FMR1 gene that is much bigger than usual. The gene is bigger in a region where three bases CGG are repeated. The number of repeats varies from person to person, usually ranging from 7 to 60 repeats in people without Fragile X. The most common version of the gene has 30 repeats. People with Fragile X have 200 or more repeats. In this case, the gene is called a "full mutation." When there are so many repeats in the gene, other molecules called methyl groups attach to the cytosine (C) bases in the repeats. The added methyl groups inactivate, or "turn off," the gene, and the gene fails to produce its protein FMRP (Fragile X Mental Retardation Protein). Without this protein, a person develops the mental impairment and other characteristics of Fragile X. Exactly how this happens is unclear, but scientists believe FMRP helps produce other proteins. Without FMRP, these other proteins are never made. In the following audio sections, Fragile X researcher Dr. Esther Nimchinsky explains how the absence of these proteins affects cells in the brain. Ironically, when were young, we have more connections between our brain cells than when we're older. As we grow and mature, unnecessary connections are cut in a process called pruning. In people with Fragile X, the connections are not pruned. Geneticists frequently use two DNA tests to diagnose Fragile X. Both of these tests measure the size of the FMR1 gene but they cover different ranges. One test PCR detects normal-sized genes and pre-mutations, while the other Southern blot detects larger, full mutations. The patient need only supply a blood sample to take both tests. Technicians isolate and purify the DNA from the white blood cells after the sample is sent to a lab. First we'll explain the PCR test. In this test, a small segment of DNA containing the FMR1 gene is isolated from the sample and copied millions of times. The next procedure in the test measures the size of the gene. The geneticist loads the DNA into the top of a slab of gel. (The gel looks remarkably like Jello but doesn't taste as good). Several different samples can be loaded into the same gel. After the samples are loaded, electric current "pushes" the DNA fragments down the length of the gel. (Not sideways, not up, just down). 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, small pieces have migrated to the bottom of the gel, while big pieces have remained near the top. The DNA is invisible but shows up as dark "bands" after it is dyed. This is a real gel showing DNA from two males. (Males have one X chromosome, so they only have one band). The male on the left, with the lower band, has the smaller number of repeats. The male on the right has a larger gene (a pre-mutation) with more repeats. The female patterns are more complicated. Each female has two bands representing her two X chromosomes. The first female has two normal-sized genes with slightly different numbers of repeats. The second female has one normal-sized gene and one pre-mutation with about 58 repeats. Though the PCR test can pick up normal-sized genes and pre-mutations, it can't detect full mutations (200 or more repeats). Geneticists use another test Southern blot analysis to detect these larger mutations and diagnose Fragile X. Though the details differ from the PCR test, the gist of the test remains the same: measuring the size of the FMR1 gene. First, enzymes cut the DNA on both sides of the gene. In the diagram below, the enzymes free a small fragment containing a FMR1 gene with 7 repeats. First, enzymes cut the DNA on both sides of the gene. In the diagram below, the enzymes free a small fragment containing a FMR1 gene with seven repeats. When the FMR1 gene has 200 repeats or more, the enzymes free a much larger fragment. In essence, identifying a person with Fragile X is easy. The geneticist simply looks for the presence of this very large fragment on a gel. The large DNA fragment with a full mutation shows up as a fuzzy smear above the dark blue line. The line is a size marker. The blue arrow points to a male with a full mutation (notice he has no other bands), and the red arrow points to a female with a full mutation. She has additional bands representing her other X chromosome. If you're wondering why the full mutation band is so much fuzzier than the others (and if you're not you can quit now), the answer lies in the source of the DNA. Each band is filled with DNA from many different cells. When every cell in the sample contains the same-sized gene, all the DNA fragments migrate to the same spot in the gel, and make a distinct band. When every cell in the sample contains the same-sized gene, all the DNA fragments migrate to the same spot in the gel, and make a distinct band. When cells have different-sized FMR1 genes as the cells of most people with Fragile X do the sample contains DNA fragments of various sizes. These migrate to different locations, and the end result is a diffuse smear. Fragile X is just like any other sex-linked disorder, because the "Fragile X" gene (FMR1) is on the X chromosome. The X is one of two types of sex chromosomes: X and Y. 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 X's, and therefore, she has two copies of the FMR1 gene. If one is mutated, she can fall back on the unmutated copy. A boy has only one X. If he has a mutated copy, he has no other copy to fall back on. A boy gets Fragile X when he inherits an X with a FMR1 mutation from his mother. (She is called a "carrier," because she carries the mutation but doesn't have the disorder). For most sex-linked disorders, this would be the end of the story, but Fragile X has an additional mode of inheritance that's just plain weird. In this mode, a boy gets Fragile X when the X from his mother carries a pre-mutation in the gene. (A pre-mutation has between ~55 and 200 repeats and does not cause Fragile X). If a boy inherits the pre-mutation, it can expand into a full-sized mutation during his early embryonic development. In this mode, a boy gets Fragile X when the X from his mother carries a pre-mutation in the gene. (A pre-mutation has between ~55 and 200 repeats and does not cause Fragile X). If a boy inherits the pre-mutation, it can expand into a full-sized mutation during his early embryonic development. Even weirder, the mother's pre-mutation does not always expand into a full mutation in her son. The chance of a pre-mutation (between ~55 and 200 repeats) expanding into a full mutation (greater than 200 repeats) depends on the number of repeats in the pre-mutation. (We'll discuss this more later). Though people with Fragile X are predominantly male, girls can also develop the disorder. Just like a boy, a girl can get Fragile X when she inherits her mother's full-sized mutation. Also like a boy, a girl can get a full mutation from her mother's pre-mutation if the pre-mutation expands. (The chance of a pre-mutation expansion in a girl is the same as the chance in a boy). Notice that we haven't labeled these girls with "Fragile X" signs. That's because, even though they have the full mutation, they may not develop the disorder. We have to consider another weird bit of biology called "X-inactivation." In X-inactivation a normal process in all females every cell in the early embryo inactivates one X chromosome. Once inactivated, the chromosome shrivels up and sits on the edge of the cell nucleus. No proteins 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. Though people with Fragile X are predominantly male, girls can also develop the disorder. Just like a boy, a girl can get Fragile X when she inherits her mother's full-sized mutation. Also like a boy, a girl can get a full mutation from her mother's pre-mutation if the pre-mutation expands. (The chance of a pre-mutation expansion in a girl is the same as the chance in a boy). Notice that we haven't labeled these girls with "Fragile X" signs. That's because, even though they have the full mutation, they may not develop the disorder. We have to consider another weird bit of biology called "X-inactivation." In X-inactivation a normal process in all females every cell in the early embryo inactivates one X chromosome. Once inactivated, the chromosome shrivels up and sits on the edge of the cell nucleus. No proteins 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. On average, half of the cells inactivate the mother's X, and the other half inactivate the father's X. 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 brain mostly contains cells with an inactive X from Dad, the cells must use the fully mutated FMR1 gene from Mom's X. This gene does not produce any protein, and this girl develops Fragile X. If the girl's brain mostly contains cells with her Dad's inactive X, the cells must use the fully mutated FMR1 gene from Mom's X. This gene does not produce any protein, so the girl develops Fragile X. If the girl's brain mostly contains cells with her Mom's inactive X, the cells must use the functional FMR1 gene from her Dad's X. This gene produces protein, so the girl will remain unaffected by the disease. These two girls the completely unaffected and the fully affected are simply extreme examples in a range of possibilities. Other girls may be only mildly impaired, some may have some learning disabilities, and some may just be socially anxious. About 70% of girls with a full mutation develop some symptoms of Fragile X, while the other 30% are unaffected. Here's one final bit of weirdness about Fragile X inheritance in girls. You may be wondering why we haven't shown a father's pre-mutation expanding into a full mutation in his daughter. Though this is theoretically possible, scientists don't understand why it never happens in reality. Even though the father's pre-mutation may contain many repeats, it doesn't expand in his daughter. However, this father will give his daughter a pre-mutation, which she can pass on to her own children as a pre- or full mutation. Therefore, her father is called a "transmitting male." The chance of a child getting Fragile X depends on the usual laws of inheritance. Let's start with the simplest example: a woman with a full mutation and her partner with no mutation. A Punnett Square easily illustrates their possible children. First, we arrange each parent's genes on the outer edges of the square. A Punnett Square easily illustrates their possible children. First, we arrange each parent's genes on the outer edges of the square. The inner boxes of the square will show what possible combinations (also called genotypes) are possible in the child. Since each parent contributes one of his/her chromosomes to the child, we simply copy and paste the parent's chromosomes into the inner boxes to see the possible genotypes. The inner boxes of the square will show what possible combinations (also called genotypes) are possible in the child. Since each parent contributes one of his/her chromosomes to the child, we simply copy and paste the parent's chromosomes into the inner boxes to see the possible genotypes. Each genotype is equally likely, so there is a 1 in 4 (25%) chance of having an unaffected girl (XX), a 25% chance of having an unaffected boy (XY), a 25% chance of having a girl with the full mutation (XXFRAX), and a 25% chance of having a boy with Fragile X (XFRAXY). Of the four possible genotypes, two contain an X chromosome with a full-sized mutation. So, this couple has a 2 in 4 (50%) chance of having a child with a full mutation. (Remember, though, a girl with the full mutation does not necessarily develop Fragile X.) When the mother carries a pre-mutation on one of her X chromosomes, she also has a 50% chance of passing the pre-mutation to her child. Remember, though, that the pre-mutation can expand into a full mutation in the early embryo. The chance of this happening depends on the number of repeats in the pre-mutation. Remember, though, that the pre-mutation can expand into a full mutation in the early embryo. The chance of this happening depends on the number of repeats in the pre-mutation. Let's say the mother has a pre-mutation with 65 repeats. To calculate her chance of having a child with a full mutation, we multiply the chance of having a child with a pre-mutation (50%) by the expansion risk, in this case 17%.If the mother has a different number of repeats in her pre-mutation, we repeat the math to find out her odds of having a child with a full-sized mutation. (Remember, though, a girl with a full mutation does not necessarily develop Fragile X.) The most important thing to remember about these numbers is that they apply to every child this couple has. This concept is easiest to understand when we consider the following couple that has a 50% chance of passing a full mutation to their child. Each child is a separate "spin of the wheel," so each child has a 50% chance of receiving the full mutation. In this example, one in four children has Fragile X. It's also possible that this couple could have four unaffected children or four children with Fragile X. Notice what the 50% chance does not mean. It does not mean that precisely 50% of this couple's children will have the full mutation. And it does not mean that a second child will have a full mutation if the first one lacks it. (Or vice versa; it does not mean that a second child will lack the full mutation if the first child has it.) Fragile X gets its name from the broken appearance of the X chromosome in people with the disorder. The break is where the Fragile X gene, FMR1, is found. Fragile X individuals are mentally impaired, with problems ranging from slight learning disabilities to severe mental impairment. They may be hyperactive and hyper-sensitive to external stimuli and have short attention spans. Physically, a Fragile X individual may have a long, narrow face, prominent ears, nose and forehead, enlarged testicles and loose joints. Fragile X is the most common inherited cause of mental impairment. An estimated 1 in 2,000 boys are mentally impaired because of Fragile X. Girls are also affected, but the incidence rate is lower and the effects are usually milder. DNA tests identify persons with the disorder and women who are carriers. Approximately 1 in 260 women carry a pre-mutated FMR1 gene. Fragile X is caused by a mutation in the FMR1 gene on the X chromosome. The mutation turns off the production of the FMR1 protein, which is implicated in the development of neuronal connections in the brain. There is no known cure for Fragile X. Current drug therapies are available to improve attention span and decrease hyperactivity. Early intervention and special education programs, including speech and physical therapy, are often beneficial. Treatment Facts and Theories Symptoms Incidence Cause Testing and Screening What is it? What causes it? How is it inherited? How is it diagnosed? What is it like to have it? For more information
Acknowledgments Overview of Treatments Dr. Ted Brown, Director of the New York State Institute Developmental Disabilities, talks about the treatments available to ameliorate Fragile X symptoms. Occupational Therapy Dr. Vicki Sudhalter, a clinical psycholinguist, talks about the need for occupational therapy, whick improves the physical coordination of children with Fragile X. Speech Therapy Classical methods of teaching language do not work with Fragile X children. Dr. Vicki Sudhalter talks about how speech therapy can help. Behavior Therapy Dr. Vicki Sudhalter talks about therapy of the most prevalent behavior: anxiety. Medicines Drugs that regulate hyperactivity and anxiety help 90% of children with Fragile X, according to Dr. Vicki Sudhalter. Gene Therapy Prospects Inserting a new gene into people with Fragile X may provide a complete treatment in as soon as ten years. Early Symptoms Dr. Ted Brown, director of the NYS Institute of Developmental Disabilities, talks about early symptoms in Fragile X individuals. Katie Clapp and Debbie Stevenson talk about symptoms in their sons, Andy and Taylor. Behavioral Severity Debbie Stevenson and Dr. Ted Brown talk about the severity of behaviors in Fragile X individuals. Kinds of Behavior Katie Clapp and Michael Tranfaglia talk about different kinds of behavior in Fragile X individuals and in their son, Andy. Dealing with Meltdowns Debbie Stevenson and Michael Tranfaglia talk about meltdowns (tantrums) in their sons, and how to deal with them.Dealing with others Datie Clapp talks about how strangers react to her son Andy, and what she does about it. Laura Tranfaglia talks about her friends reactions to her brother, Andy. Laura Tranfaglia talks about her brother, Andy, who has Fragile X. Debbie Stevenson talks about how her son, Taylor, who has Fragile X, interacts with her son, James.Blame and Guilt Katie Clapp and Michael Tranfaglia talk about their feelings of blame and guilt for their son, Andy, who has Fragile X. Family History Dr. Ted Brown talks about the family history of individuals with Fragile X. Mary Lou Supple and Debbie Stevenson talk about Fragile X in their extended families. Telling Family Katie Clapp and Debbie Stevenson talk about telling other family members and helping them understand their risk of having a child with Fragile X. Older Kids Mary Lou Supple talks about her 13-year old son, James, who has Fragile X. Michael Tranfaglia talks about older children and adults with Fragile X. Expectations Katie Clapp, Debbie Stevenson, and Mary Lou Supple talk about their expectations for their sons: Andy, Taylor, and James, who have Fragile X. Future Debbie Stevenson, Michael Tranfaglia, and Katie Clapp talk about planning for the future of their children with Fragile X. Alzheimer Disease
Duchenne/Becker Muscular Dystrophy
Down Syndrome
Fragile X Syndrome ...
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