Alzheimer Disease
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Fragile X Syndrome Tay-Sachs is an inherited disorder in which nerve cells deteriorate and eventually die. All the problems associated with Tay-Sachs are caused by the malfunction of a protein called hexosaminidase A (HEX A). The protein has two parts: the alpha and beta subunits. There is also an activator subunit that can bind to alpha and beta. Normally HEX A is found in the lysosomes of cells, specifically nerve cells. Lysosomes are the recyling plants of the cells. Large complicated molecules are broken down into component parts to be reused for other reactions. Lysosomes are also waste storage organelles for molecules that can't be broken down and reused. Hexosaminidase A has a specific purpose. It breaks down a large molecule called GM2 ganglioside needed for making nerve cell membranes. The activator subunit brings the GM2 molecule to the lysosome where it binds to the alpha and beta subunits. The binding turns on hexosaminidase A and the GM2 molecule is processed into smaller component pieces to be used again. In people with Tay-Sachs, the alpha subunit of hexosaminidase A is either missing or not working properly. In a similar disorder called Sandhoff disease, the beta subunit of HEX A and HEX B is problematic. In both cases, hexosaminidase A can no longer hold the GM2 ganglioside brought by the activator. GM2 ganglioside molecules can't be broken down and they accumulate in the lysosomes. The nerve cells swell up as GM2 ganglioside accumulates. Since GM2 ganglioside can't be recycled, its availability for repair or the making of new cell membrane is limited. The build-up is also toxic to the nerve cell. The alpha subunit of hexosaminidase A is encoded by a gene called HEX A on chromosome 15. There are more than 90 known mutations of this gene that can cause Tay-Sachs. The mutations that cause infantile Tay-Sachs, the most severe form, changes the DNA sequence such that no protein is produced. Other mutations change the protein product, which affects beta-hexosaminidase A's ability to process GM2. Teenagers and adults with Tay-Sachs (juvenile and late onset Tay-Sachs) have hexosaminidase A proteins that work, but not very well. Their symptoms and the progression of their Tay-Sachs can vary depending on the "activity" of their hexosaminidase A proteins. Low or non-existent levels of the enzymes hexosaminidase A and B result in Tay-Sachs or Sandhoff disease. An enzymatic test is used to measure the levels of these enzymes. Let's first review the structure and function of HEX A and HEX B. Each enzyme is made up of two parts. HEX A is made of one alpha and one beta subunit. HEX B is made up of two beta subunits. If the beta subunit gene is mutated, neither HEX A nor HEX B enzymes can form. A mutation in the beta subunit does not cause Tay-Sachs disease. This mutation causes the related Sandhoff disease. Both HEX A and HEX B are enzymes that break down gangliosides in the neurons. Scientists have created a tester molecule in the laboratory that mimics the natural ganglioside. When either HEX A or HEX B break down this "artificial" molecule, one of the products of the reaction is fluorescent. A doctor can take blood serum from a patient, add the artificial substrate, and see how strongly the blood serum glows. Since both HEX A and HEX B can react with the artificial substrate to create the glowing product, this enzymatic test measures the total concentration of HEX A + HEX B. In order to measure the concentration of HEX A and HEX B separately, the blood serum is heated. This inactivates the HEX A in the sample, so that only the HEX B can act on the artificial substrate. This gives the doctor the total concentration of HEX A + HEX B, and the concentration of HEX B. The difference between these two gives the concentration of HEX A. In order to differentiate between Tay-Sachs and Sandhoff, a doctor examines the levels of both HEX A and HEX B enzymes. If both are low or nonexistent, the patient has Sandhoff disease; if only HEX A levels are low, the patient has Tay-Sachs disease. In this way, the enzymatic test can be used to diagnose Tay-Sachs and Sandhoff. However, the results are sometimes influenced by pregnancy and certain medications. Because of this potential problem, a diagnosis made using an enzyme test is often confirmed with a DNA test. It is also possible to look directly at a persons DNA to determine whether they have a mutation in the alpha subunit of HEX A. A blood sample is taken, and DNA is isolated from the white blood cells. In order to test the DNA, the geneticist needs a lot of it. The Polymerase Chain Reaction (PCR) is used like a molecular copy machine to make many many copies of the DNA from the gene for the alpha subunit of HEX A. These copies of the gene can now be tested for mutations using a restriction enzyme. Restriction enzymes are enzymes that recognize a specific sequence. Because of this, they are very useful tools in genetic testing. If the sequence the enzyme recognizes is present in a piece of DNA, the DNA will be cut. If that sequence is disrupted (by a mutation, for example), then the DNA will not be cut. A mutated HEX A gene will not be cut by the enzyme. A functional HEX A gene will be cut into small pieces of DNA. In order to see these tiny pieces of DNA, the geneticist loads the DNA into the top of a slab of gel. Multiple samples of DNA can be loaded into the same gel. In order to see these tiny pieces of DNA, the geneticist loads the DNA into the top of a slab of gel. Multiple samples of DNA can be loaded into the same gel. Next, an electric current is applied to the gel. The current pushes the DNA through the gel. The gel is made up of a matrix of fibers. Small pieces of DNA are able to get through the matrix quickly; large pieces take longer. After a set period of time, the current is stopped. Large pieces of DNA will be stuck toward the top of the gel, while small pieces will be near the bottom. When a dye is added, the DNA is visible as blue bands. A person with only mutated copies of the gene has Tay-Sachs disease. A person with only functional copies does not have the disease. Because everybody has two copies of every gene - one from their father and one from their mother - it is also possible to have both a functional copy and a mutated copy. This person is a carrier, and while they have no symptoms of Tay-Sachs, their children may inherit the disease. How is Tay-Sachs diagnosed? Carrier Diagnosis Dr. Edwin Kolodny explains how Tay-Sachs carriers are diagnosed. Screening Dr. Kolodny talks about who should be tested for Tay-Sachs. Diagnosis of Newborns Dr. Kolodny talks about the clinical symptoms of Tay-Sachs in newborns. Tay-Sachs Tests Dr. Kolodny explains and compares the two tests normally done for Tay-Sachs diagnosis: the blood serum test and the white blood cell test. Sandhoff Disease Dr. Edwin Kolodny discusses the differences between Tay-Sachs and Sandhoff disease. Late Onset Tay-Sachs Dr. Kolodny talks about late onset Tay-Sachs disease: symptoms of how to test for it. Life Expectancy Dr. Kolodny talks about the life expectancy of individuals with late onset Tay-Sachs disease. Tay-Sachs is an inherited disorder and is not contagious. A person gets Tay-Sachs when he/she inherits TWO severe mutations in the HEX A genes, one from each parent. The HEX A gene is on chromosome 15. The child receives one of his chromosome 15s from his father, and one from his mother. If both of these chromosomes have a severe mutation in the HEX A gene (represented below by the black spots and the hs label), he will develop Tay-Sachs as a baby. His parents do not have Tay-Sachs because they both have a normal copy of the HEX A gene on their other chromosome. The parents are carriers. Tay-Sachs only develops when a person has two copies of the mutated gene, and is, therefore, a recessive disorder. Tay-Sachs is an inherited disorder and is not contagious. A person develops Tay-Sachs when he/she inherits TWO mutated HEX A genes, one from each parent. The severity of the disorder depends on the severity of the mutation. The HEX A gene is on chromosome 15. A child inherits one of her chromosome 15s from her father, and one from her mother. If she inherits one chromosome with a severe HEX A mutation (black spot and labelled hs) and another with a mild HEX A mutation (blue spot and labelled hm), she will grow up and develop late onset Tay-Sachs. If a couple carries a mutated HEX A gene, their chance of producing a child with Tay-Sachs can be calculated with a Punnett square. In this case, the father is a carrier for early onset Tay-Sachs; he has a normal HEX A gene (H) and a severe HEX A mutation (hS). The mother doesn't have any HEX A mutations. In a Punnett square, we first move the parents' genes to the outer edges of the box. 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. In this case, none of the children will have early onset Tay-Sachs, though half of the potential children will be carriers for the early onset Tay-Sachs mutation the HhS combination. If a couple carries a mutated HEX A gene, their chance of producing a child with Tay-Sachs can be calculated with a Punnett square. In this case, the father is a carrier for early onset Tay-Sachs; he has a normal HEX A gene (H) and a severe HEX A mutation (hS). The mother doesn't have any HEX A mutations. In a Punnett square, we first move the parents' genes to the outer edges of the box. 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. In this case, none of the children will have early onset Tay-Sachs, though half of the potential children will be carriers for the early onset Tay-Sachs mutation the HhS combination. If a couple carries a mutated HEX A gene, their chance of producing a child with Tay-Sachs can be calculated with a Punnett square. In this case, the father is a carrier for early onset Tay-Sachs; he has a normal HEX A gene (H) and a severe HEX A mutation (hS). The mother doesn't have any HEX A mutations. In a Punnett square, we first move the parents' genes to the outer edges of the box. 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. In this case, none of the children will have early onset Tay-Sachs, though half of the potential children will be carriers for the early onset Tay-Sachs mutation the HhS combination. However, if both parents carry a mutated HEX A gene, the chance of having a child with Tay-Sachs changes. In this case, both father and mother carry the early onset Tay-Sachs mutation (hS). This couple has a 1 in 4 chance of having a child with early onset Tay-Sachs (hShS). Half of the potential children of this couple are carriers for the early onset Tay-Sachs mutation (HhS). Finally, this couple has a 1 in 4 chance of having a normal child (HH). 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 early onset Tay-Sachs. In this family, one in four children has early onset Tay-Sachs. Other couples with the severe HEX A mutation may have two, three, four, or even no children with the disorder. If a couple carries a mutated HEX A gene, their chance of producing a child with Tay-Sachs can be calculated with a Punnett square. In this case, the father is a carrier for late onset Tay-Sachs; he has a normal HEX A gene (H) and a mild HEX A mutation (hM). The mother doesn't have any HEX A mutations. In a Punnett square, we first move the parents' genes to the outer edges of the box. 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. In this case, none of the children will have early onset Tay-Sachs, though half of their potential children will be carriers for the early onset Tay-Sachs mutation the HhM combination. None of this couple's children will have Tay-Sachs. However, half of their potential children will be carriers of the late onset Tay-Sachs mutation the HhM combination. However, if both parents carry a mutated HEX A gene, the chance of having a child with late onset Tay-Sachs changes. In this case, both father and mother carry the late onset Tay-Sachs mutation (hM). This couple has a 1 in 4 chance of having a child with late onset Tay-Sachs (hMhM). Half of the potential children of this couple are carriers for the late onset Tay-Sachs mutation (HhM). Finally, this couple has a 1 in 4 chance of having a normal child (HH). This couple will have a 1 in 4 chance of having a child with late onset Tay-Sachs (hShM). Rollover the boxes to see the other percentages. This couple will have a 50% chance of having a child with late onset Tay-Sachs (hMhM). They also have a 50% chance of having a child who is a carrier for the late onset HEX A mutation. There are three types of Tay-Sachs: infantile or early onset, juvenile, and adult or late onset. Early onset Tay-Sachs was first described independently by Drs. Tay and Sachs in the mid-1880s. Dr. Tay was an opthalmologist who noticed characteristic "cherry-red" spots in the retina of babies with the problem. Dr. Sachs was a neurologist who noticed the familial inheritance among Eastern European Jews. Babies with early onset Tay-Sachs show symptoms at about six months; they lose or do not gain motor and mental skills. This is followed by paralysis and death by about age five. Juvenile Tay-Sachs can start at about age five with symptoms similar to early onset; the progression of juvenile Tay-Sachs is slower. Adult onset Tay-Sachs starts later in life. Symptoms include muscle weakness and cramps, slurred speech, and behavioral changes. Tay-Sachs presents frequently in Jews of Eastern European descent (Ashkenazi Jews). One in every 27 Jews in the United States is thought to be a carrier of a Tay-Sachs mutation. Similar carrier frequencies (1 in 27) also occur in French-Canadians and Cajuns in Lousiana. In the general population, the incidence of Tay-Sachs carriers is about 1 in 250. A blood test can screen for carriers or non-carriers of the Tay-Sachs disorder. At-risk parents are encouraged to be tested before pregnancy to prepare for the possibilities. This kind of carrier screening has significantly reduced the incidence rate of babies born with Tay-Sachs among the Ashkenazi Jewish population. Tay-Sachs is caused by a mutation in the HEX A gene on chromosome 15, HEX A normally codes for the alpha subunit of the hexosaminidase A protein, which is necessary for breaking down GM2 gangliosides in nerve cells. The accumulation of GM2 is toxic and eventually causes cell death. There is currently no cure or effective treatment for Tay-Sachs. Prospective parents who are at high risk to be Tay-Sachs carriers are encouraged to get tested for the Tay-Sachs gene mutation. There are three types of Tay-Sachs: infantile or early onset, juvenile, and adult or late onset. Early onset Tay-Sachs was first described independently by Drs. Tay and Sachs in the mid-1880s. Dr. Tay was an opthalmologist who noticed characteristic "cherry-red" spots in the retina of babies with the problem. Dr. Sachs was a neurologist who noticed the familial inheritance among Eastern European Jews. Facts and theories Symptoms Incidence Testing and screening Cause Treatment. Types of Tay-Sachs Dr. Robert Desnick, the Chair of the Department of Human Genetics at Mount Sinai School of Medicine, talks about infantile, juvenile and late onset Tay-Sachs and their relationship to HEX A levels. Wheelchairs Dr. Desnick talks about providing locomotive support for people with late onset Tay-Sachs. Mental Defect Dr. Desnick discusses the need for psychiatric care in rare cases of late onset Tay-Sachs. Enzyme Therapy People with Tay-Sachs are missing the HEX A exzyme, which normally degrades large molecules called gangliosides in the neurons. Dr. Desnick talks about enzyme replacement trials a possible therapy. Limitations of Enzyme Therapy Limitations of Enzyme Therapy Dr. Desnick talks about the limitations of enzyme therapy for neurological disorders like Tay-Sachs. Gangliosides Dr. Desnick talks about the possible functions of gangliosides. Getting Rid of Gangiosides Dr. Desnick answers the question: If gangliosides are the problem in Tay-Sachs, why not get rid of the genes that produce gangliosides? Gene Therapy Dr. Desnick comments on the possibility of using gene therapy to cure Tay-Sachs. Symptoms Susan Fishbein has late onset Tay-Sachs, which wasnt diagnosed until she was in her late thirties. She talks about some of the symptoms she has had all her life. Being Misdiagnosed Susan talks about how her late onset Tay-Sachs was mistaken for other disorders. Confirming Tay-Sachs Susan and her husband, Marc, talk about how Susans late onset Tay-Sachs was finally confirmed. Complications Susan has had bad fractures because Tay-Sachs has made her clumsy. Getting Around Susan uses a wheelchair. Wheelchair access isgetting better but there are still places she cannot go to easily. Medication Susan talks about doctors she deals with and her caution with medication. DNA Testing Susans children have been tested for Tay-Sachs. The DNA test lets them know what mutations they have and how it might affect their futures. Alzheimer Disease
Duchenne/Becker Muscular Dystrophy
Down Syndrome
Fragile X Syndrome ...
Phenylketonuria | |
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