Task 1: Duchenne muscular dystrophy(DMD) is inherited disorder which affects muscles and causes progressive muscle weakness. DMD is caused by a faulty in the DMD gene which makes dystrophin. Mutations in the DMD gene cause Duchenne dystrophy. Mutations in the DMD gene affects the structure and function of the dystrophin. Muscle cells become damaged due to lack of dystrophin and this lead to muscle fibre damage . The damaged muscle fibers weaken and die over time, leading to a gradual weakening of the muscles. DMD is inherited X-linked recessive disorder and the fault gene is located in the X chr which is one of the sex chromosome. Males are more likely to have DMD, because males with the DMD gene have only X chr and one altered copy of the gene will enough to have the disease. Because they cannot compensate for the defective gene. Therefore males with DMD gene have symptoms of the disease. Women can carry DMD gene because of their two X chromosomes . The mutation must be preset in both gene to cause the disease .One of their X chromosome has the 'faulty' DMD gene, and the other X chromosome has a normal gene, which compensates for the defective gene. So women are carrier of the DMD gene. Women pass the defective gene but they typically do not show ssigns and symptoms of the disease. Carrier females can exhibit milder symptoms of DMD. There is 1in 2 chance of sons of women will have disease , while 1in 2 chance of daughters of women will be carrier.
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A characteristic of X-linked inheritance is that disease cannot pass from father to son. The disease is typically passed from an affected grandfather through his carrier daughter to half of his grandsons . All affected males inherit the mutation from their mothers who carry the DMD gene. The other cases result from new mutations in the gene.
Both the patient's medical history and a complete family history should be reviewed to determine DMD. Laboratory tests may be used to confirm the diagnosis of DMD. Blood and urine tests are done to detect defective gene and look specific neuromuscular disorders. Creatine kinase(CK) is test to look muscle damage. Elevated creatine kinase levels may indicate muscle damage.. Therefore further tests are needed to see whether this is due to DMD.The next step in the diagnosis includes muscle biopsy and genetic testing. A muscle biopys takes a small sample musle and examine it under the microscope to look at the muscle fibres and the dystrophin protein. . If DMD is present, alterations in the structure of muscle cells can be detected. Genetic testing is also available and identifies gene that cause the muscle disease. This looks DNA in the blood to identify defective gene. Genetic linkage studies detect specific marker on chromosome. DNA testing is usually performed using PCR to detect mutations in the dystrophin gene. This testing diagnoses the most cases of DMD. Neurophysiology studies such as Electromyography (EMG)used to identify physical changes in the nervous system ,especially muscle fibre.
Genetic counselling also help parents who have a family history of DMD and they might want to know , if they are carrying defective gene that cause the disease. Two prenatal tests can be used to check if their child is affected during pregnancy. Chorionic villus sampling and Amniocentesis are both prenatal tests and use DNA sample from unborn foetus to detect genetic changes .
As I am genetic counsellor of the couple, and before I began, allow me to go over family history of Brenda. Brenda has half brother Charles and he has DMD when he was 4yrs old. They are from same mother. Brenda's mother also has brother which diagnosed with DMD before and he died at age of 17 of pneumonia. Also Brenda's mother has healthy brother.No other family members are known to have muscle disease. Therefore I can tell Brenda that her mother is a carrier of DMD and that Brenda has %50 chance of being a carrier. Because she is inherited from her mother's X chromosomes. Her mother with an affected son and one other affected relative is obligate heterozygote in the maternal life. The risk to the sibs of a proband depends on the carrier status of the mother. The proband's mother has inherited a DMD mutation from her mother who was carrier. Therefore there will be risk that Brenda's unborn child will be affected with DMD. Brenda has %50 chance of passing defective gene in each pregnancy . Her daughter who inherits the mutation will be carrier or neither affected nor carrier . Her son who inherits the mutation will be affected. Father has 0 % chance to pass mutation to his son, but he has 100% chance of having carrier daughter. Sons have 0% chance of being carrier .If the couple has one male child with DMD before , the risk for second child of the couple is %50 from mother to son transmission. Because mother is usually carrier and father cannot pass the disease to his child. Second daughter will be carrier again .
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Female carriers have milder symptoms of disease, because they contain defective gene on one of their X chr and other normal gene on the other X chr. If the second copy of the gene is not enough to compensate partial levels of disease, she still becomes carrier . However, most female carriers have symptom-free in X linked recessive disorders.
Brenda is the only affected family member and this is due to several possibilities regarding her mother's carrier status and carrier risks of family members. Therefore couple are at the risk of having child with MDM in this condition. Brenda is 5 will be b possible carrier and she will pass the affected X to her son, but her daughters will not be affected due to their normal X from their father. Her daughters will be carrier. Therefore they consider to know , if the foetus will be affected or carry the gene during pregnancy. Therefore prenatal tests are necessary to carry out after about 10 weeks of pregnancy. If coupled want to get maximum benefit front these tests, it is important to investigate the career status before pregnacy is started. So carrier tests should be done in their late teens.
Pedigree of X Linked Recessive Disease (Brenda's Family)
Pedigree analysis symbols:
X Linked Recessive Inheritance
XY XX XY XX
Affected Carrier Normal son Normal daughter
There is no cure to stop Duchenne MD .However if any parents have already had one child with DMD in the family , it is possible to prefer prenatal tests for future pregnancies .Prenatal tests is possible for women who may be at risk being of carriers of DMD, if the mutation is identified in the family member. These tests are carried out during pregnancy to look if unborn child foetus is affected. Prenatal tests are carried out after 10 weeks of the pregnancy. Chorion villus sampling (CVS) and Amniocentesis are the most prenatal tests. Chorion villus sampling (CVS) is performed at 10-12 weeks and amniocentesis at about 14-16 weeks.Placental biopsy and fetal blood sampling are performed about 18 weeks.
Chorion is tissue that surrounds the foetus during early pregnancy and later becomes placenta. It contains same DNA as foetus and small sample of tissue is taken to test DNA. This looks genetic defect which has been identified previously in the family. The sex of foetus is important . There is a risk of miscarriage of 1-2% but if mother health is well , no any complications occur. She just needs to avoid any strenuous exercises. Test takes 20-30 mins and the results of DNA tests are available within 2 weeks.
Amniocentesis takes sample of about 200 ml of the amniotic fluid that surround foetus in the uterus. The amniotic fluid contain same DNA as foetus .It takes few minutes to do it and there is no any complication in women. Test is accurate as CVS and there is slight risk of miscarriage. The test results are available within 1-2 weeks
Preimplantation genetic diagnosis may be available for families, if the disease-causing mutation has been identified. This detects genetic defects in embryos through in vitro fertilization (IVF) before pregnancy. The woman takes drugs to stimulate ovaries to make more eggs and ensures that womb accepts developing eggs. Then these are harvested by tube near the ovary via vagina .Then eggs are fertilised with father sperm's until they become about 8 cells. One egg is taken and tested genetically. If it is not affected with DMD, it is selected to insert into woman's womb. Two eggs are usually given to increase the chance of the pregnancy. Those who are successful may have twin and multiple pregnancies.
Egg/sperm donation sometimes is available for parents who want to avoid having a child with DMD. Eggs or sperms are donated from a donor woman or man. Sperm donation is easier than egg .The donated sperm is inserted into womb at time of ovulation in the vagina. The resultant child will not be affected by the particular condition, if child is not the genetic offspring of the parent.
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DNA banking is the DNA storage and it will be possible for future use. It tests genes, mutations or diseases and give a clue about them. So it can be taken as consideration to give affected individuals.
Gene therapy may be available in the future. Studies showed that defective dystrophin gene can replace with a functional gene. Also mini dystrophin gene showed success in animal's model of DMD. So some researchers made important progress to deliver this mini dystrophin gene to muscle of model DMD.
'Cell therapy' may be possible and use cells to make normal dystrophin. The introduced muscle stem cells are used and they are capable of producing the missing dystrophin in the new muscle cell. So these new cells will protect progressive degeneration of DMD and assess the muscle function again in affected person
A new drug treatment such as utrophin may be possible to make similar dystrophin protein.
Early identification of children who are affected by DMD is important to avoid complications and prolong life. There is no treatment to stop the progression of the disease, because DMD is genetic and cannot be prevented. Treatment and management options keep the patient life long as a possible as and reduce complications of muscle weakness, cardiac and respiratory problems. The management and prevention of DMDM in children include physical and occupational therapy, dietary changes , surgery , cardiac and respiratory care and drug therapies.
The outlook for patients with DMD depends on the type and severity of the disease. In mild forms, the disease may progress slowly and patient may have a normal lifespan. In more severe cases, there is a marked increase of muscle weakness, functional disability, and loss of ability to walk. Most patients usually died in their late teens and twenties due to result of respiratory infections or cardiac failure.
Early identification is important step to detect patients with DMD and provide the best management and treatment options to prevent progression of the disease and improve quality of life