Duchenne Muscular Dystrophy (DMD)

1. DuchenneMuscular Dystrophy(DMD) By: Jon Jensen

2. What We Will Be Discussing Today Topic 1 Topic 2 Phenotype Description and Inheritance Normal Gene Function The 6 Main topics in relation to DMD: An Introduction to this Disorder. Diagnosis and Treatment Implications Topic 3 Abnormal Gene Functions Topic 4 Topic 5 Topic 6

3. Introduction History: • Duchenne Muscular Dystrophy (DMD) • It is the most common form of muscular dystrophy in children. • In 1986 researchers found a gene that when mutated caused DMD. • One of the first to be discovered in this way. • In 1987 the protein was identified and named dystrophin. http://www.nejm.org/doi/full/10.1056/NEJM199707173370320 http://mda.org/disease/duchenne-muscular-dystrophy/causes-inheritance

4. Introduction Has a gene been located as the cause? • The gene has been found that is the cause of this disorder. • The gene codes for the protein dystrophin. • It is found on the X Chromosome. • Because it is found on the X-chromosome, it occurs mainly in men. (http://www.ncbi.nlm.nih.gov/books/NBK22263/)

5. Introduction What are the odds? Statistics Who can get it? • Duchenne Muscular Dystrophy affects approximately 1 in every 3,500-5,000 male babies. • Between 400 and 600 boys are born with this in the US every year. • While it can be passed on through the parent, about 35% of cases are due to spontaneous mutations! • Therefore, anyone can be affected by it. • Not exclusively a childhood disorder. • All ethnic groups can attain this disorder. (http://yourgenesyourhealth.org/dmd/whatisit.htm) (http://www.ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy) (http://www.parentprojectmd.org/site/PageServer?pagename=Understand_about)

6. Phenotype Description and Inheritance Description: • DMD is caused by a mutation in the gene which codes for dystrophin. • Without this protein, the cells are weaker and are easily damaged. • It causes a loss of strength that is very progressive. • DMD can lead to serious complications relating to the heart and lungs. • People with this condition generally do not live past their twenties. http://www.parentprojectmd.org/site/PageServer?pagename=Understand_about

7. Phenotype Description and Inheritance Symptoms: • A person with DMD may begin to stumble and have a hard time walking up stairs. • May develop “toe walking”: • This is when a person walks on their toes without letting their heels hit the ground. • May begin to develop enlarged calf muscles because the muscle tissue is replaced by fat. • May lose the ability to walk, speak, and sometimes even lose the ability to breath altogether. • Other symptoms include: obesity, frontal baldness, mental impairment, and joint conjunctures, just to name a few. (http://kidshealth.org/parent/medical/bones/muscular_dystrophy.html) (http://www.muscle.ca/index.php?id=893)

8. Phenotype Description and Inheritance Affects on the quality of life: • Many people with DMD will need crutches or wheelchairs. • They will need help with transportation. • They need assistance lifting objects • People with DMD and their families often participate in support groups with others that are going through the same or similar situations, which helps encourage them by relating to others with similar problems. • They often feel left out from activities, as they are no longer physically able to perform many tasks that others their age can. • It helps to plan activities that they can participate in and enjoy, such as board games. (http://www.muscle.ca/index.php?id=893)

9. Phenotype Description and Inheritance What is the prognosis and mortality rate? • Life Expectancy • Mortality Rate • As the disease grows, more serious health concerns arise. • Heart and Respiratory conditions are common among DMD sufferers. • It is important to have regular evaluations done, especially concerning the heart. • Men who have DMD often do not live past their late twenties. • There has been a lot of research done on this disease, especially since the isolation of the dystrophin which causes this disease. • There is no cure for this disease, and therefore the mortality rate is at 100%. • You can treat the symptoms, but you cannot cure the disease. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517561/) (http://www.parentprojectmd.org/site/PageServer?pagename=Understand_stages_adult)

10. Phenotype Description and Inheritance What are the genetics of the disorder? • How is it inherited? • It is inherited through one of the two sex chromosomes. • In males, one copy of the gene will result in DMD. • In females, both copies need to be present to result in DMD. • Is it Autosomal or X-linked? • It is an x-linked disorder. • This is why it is more dominant in men. • Is it a dominant or recessive trait? • It is a recessive trait, which explains why, along with it being an x-linked disorder, it is more common in young males. • Women are often carriers of the mutated gene, then pass it on to their children. • Is it a deletion/substitution? • Many of the mutations are caused by deletions in the gene. http://www.ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy)

11. Phenotype Description and Inheritance Genetic Counseling: • What would a genetic counselor suggest? • They would suggest using a Punnett square. • For a female carrier and unaffected male: XY-XX^D there is a 25% chance the child will have it and a 25% chance the child will carry it. • For an affected male and unaffected female: X^DY-XX there is a 50% chance the boy will be unaffected, and a 50% chance the girl will carry it. • Careful consideration of this information is critical in the decision to have offspring. • The Pedigree: • The pedigree above shows what could happen given it begins with a mother carrier and unaffected father. • The mother passes the gene to one son, making him affected, and to two daughters, making them carriers. • The affected son passes the gene to his female carrier daughters. • The carrier daughter passes it on to an affected son and carrier daughter. http://www.uvm.edu/~cgep/Pic/XRec2.gif)

12. Normal Gene Function How does this gene function normally? • The gene is found on the x-chromosome. • It encodes a large protein, Dystrophin. • Dystrophin is necessary for structural support. • It is believed that this protein strengthens the muscle cells by anchoring elements. • It is thought to do this through the internal cytoskeleton to the surface membrane. http://www.ncbi.nlm.nih.gov/books/NBK22263/)

13. Abnormal Gene Effects What type of mutation is involved, and where does it take place? • Where does it take place? • A mutation of the glutamic acid 3367 is a highly conserved residue adjacent to the dystrophin domain. • This results in a reduction of protein production as well as removes large regions of the protein dystrophin. • What type of mutation? • There can be many deletions involved in this mutation. • Dystrophin is one of the largest in the genome for humans. About 70% of people with DMD have deletions in a condensed region around exons 45-53. • The more severe the deletions reflect the type of muscular dystrophy that occurs. (http://www.ncbi.nlm.nih.gov/pubmed/14961551) (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008647)

14. Abnormal Gene Effects How does the abnormal protein function? • When the dystrophin protein has been mutated, it no longer functions as it normally would. • Without this protein, the muscle tissue will progressively be damaged. • This prolonged and progressive damage to the muscle tissues will eventually lead to those muscles dying. • This causes severe problems to the individual with DMD (http://www.parentprojectmd.org/site/PageServer?pagename=Understand_about_dystrophin)

15. Diagnosis and Treatment How do you diagnose DMD? • Diagnosis: • Clinical Features • Your doctor may witness the first physical signs of this disorder. • CPK Test • This measures the level of CPK enzyme in the blood. • A boy who has DMD has high levels of CPK in the blood stream due to a leak from the muscle cells. • DNA Testing • This can show the missing exon from the dystrophin gene. • Muscle Biopsy • A biopsy is performed from different muscle tissues and compared to each other. • The affected muscles should be dramatically different in size and character from the normal muscles. • Prenatal Testing • This is usually done in women who have a family history of DMD. It can be used to find the probability of passing on the mutation for DMD. (http://yourgenesyourhealth.org/dmd/diagnosis06.htm)

16. Diagnosis and Treatment How is it treated? • There are treatments for this disorder, but no cure. • Medications • There are medications that can help strengthen muscle tissue. • These are often corticosteroids like Prednisone • Prolonged use of these drugs may lead to weakened bones. • Therapy • There are several types of therapy that may be effective in people with DMD. • Range-of-motion-exercises • DMD can cause the muscles to become less flexible, so this type of therapy helps loosen the muscles to keep them as flexible as possible. • Mobility aids • Leg braces can provide support where the leg muscles have deteriorated. The use of walkers, canes, and often wheelchairs can help to offer more mobility to people with DMD than would otherwise be possible. • Breathing assistance • Sleep apnea can be common in people with DMD, so the use of a C-PAP machine may help them get better rest during the night. • Surgery • There are some surgeries that can be done to combat some of the affects of DMD. • Tendon Surgery • This can be done to loosen joints that have been drawn inward due to contractures. • Spinal Surgery • This can be done to help correct problems with the spine, such as scoliosis, which is common among DMD patients. • Heart Surgery • A pacemaker can be used to help the heart beat properly. (http://www.mayoclinic.com/health/muscular-dystrophy/DS00200/DSECTION=treatments-and-drugs)

17. Diagnosis and Treatment What research is being done, and how can I help? Current research How you can help • Currently research has been focused on improving the muscle and joint function in order to extend the DMD patient’s life. • There is also research being done that is experimenting with the technology of “exon skipping”. • Most research mainly focuses on prolonging the patient’s life and improving the quality of life. • There are several ways that you can help in the fight against DMD. • You can volunteer at a local hospital that treats patients with DMD • You can make a donation to a number of charities that fund research for Duchenne Muscular Dystrophy • You can donate to the Muscular Dystrophy Association (MDA) using the following contact information: Muscular Dystrophy Association National Headquarters 3300 East Sunrise Drive Tucson, AZ 85718 888-HELP-MDA 888 (435-7632) https://secure.mdausa.org/donate/ (http://www.muscular-dystrophy.org/research) (http://kidshealth.org/parent/medical/bones/muscular_dystrophy.html

18. Implications What legal, ethical and social implications are there? • Legal • There are end-of-life issues that come up when considering a disorder such as this that has such a short life expectancy. • Families often refuse to talk about end-of-life issues while the patient is relatively healthy, which causes problems later because of the progressive nature of the disorder. • Once the disorder takes a turn for the worse, it can be hard to get the legal matters in order when considering the death of that individual. • Ethical • There are some serious ethical issues when talking about DMD as well. • There are different types of treatments available, and not all are suited for everyone. • Once a patient’s life begins to deteriorate, families often have to decide how long to continue to fight a disease where the mortality rate is 100%. • Is keeping someone alive who no longer wants to live due to the pain an ethical decision? • Social • There are also some serious social implications because of this disorder. • Patients can exhibit an increase in behavioral problems due to having DMD. • These social problems may be due to the lack of dystrophin isoforms, and are not solely due to the patients own response to having DMD. • DMD patients have a hard time fitting in, leading to increased social issues. (http://www.columbia.edu/cu/md/behaviorJDBP.pdf) http://www.ncbi.nlm.nih.gov/pubmed/20687186)

19. Implications Just a few questions to consider: Question One: • Who should have access to your personal genetic information? • I believe it is a person’s own right to their genetic information, but at the same time, it is the right of the employer, court, school, adoption agency, and military to ask for this information. If you want to participate in these areas of life, it is only fair to present your information.

20. Implications Question Two: • How does this disorder affect reproductive decision making? • It would affect it if a woman knew she was a carrier because she should absolutely get checked out and find out all of the risk factors involved in having a child. • A person has a right to their reproductive organs, and this disorder does not change that.

21. Implications Question Three • Should genetic testing be performed when no treatment or cure is available, and should parent be given the right to have their minor children tested for adult-onset disorders? • Yes, there should absolutely be test done to help and try to find a better treatment or cure for this disorder. Without this, there would never be any results, leading to there never being any advancement in the research of this disorder. • Yes, parents should have the right to have their children tested. If they do not have the right, who would? The parents would be able to make the best informed decision for their child.

22. Implications Question Four: • Is their Psychological impact and stigmatization due to an individual’s genetic differences? • Yes, because without this disorder they would not have to go through something that most people could never even imagine as far as the physical and mental stress that would put on any individual. It is unfortunate, but it is true. There will always be a psychological impact and stigmatization of people with DMD.

23. Works Cited • About duchenne. (n.d.). Retrieved from http://www.parentprojectmd.org/site/PageServer?pagename=Understand_about) • About dystrophin and utrophin. (n.d.). Retrieved from http://www.parentprojectmd.org/site/PageServer?pagename=Understand_about_dystrophin • Adult stage. (n.d.). Retrieved from http://www.parentprojectmd.org/site/PageServer?pagename=Understand_stages_adult • Becker, K., Robb, S., Hatton, Z., Yau, S., Abbs, S., & Roberts, R. (2003, June 21). Loss of a single amino acid from dystrophin resulting in duchenne muscular dystrophy with retention of dystrophin protein. . Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14961551 • Clark, A. (2010, July). About md. Retrieved from http://kidshealth.org/parent/medical/bones/muscular_dystrophy.html • Collins. , & Morgan (2003, Aug). Duchenne. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517561/ • Duchenne/becker muscular dystrophy. (n.d.). Retrieved from http://yourgenesyourhealth.org/dmd/whatisit.htm • Duchenneand becker muscular dystrophy . (2012, Nov 12). Retrieved from http://www.ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy • Duchenne muscular dystrophy . (1998). Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK22263/ • Frequently asked questions about muscular dystrophy . (n.d.). Retrieved from http://www.muscle.ca/index.php?id=893 • General donation. (n.d.). Retrieved from https://secure.mdausa.org/donate/ • Hinton, V., Nereo, N., Fee, R., & Cyrulnik, S. (2006, Oct).Social behavior problems in boys with duchenne muscular dystrophy. Retrieved from http://www.columbia.edu/cu/md/behaviorJDBP.pdf • Leading research . (n.d.). Retrieved from http://www.muscular-dystrophy.org/research • Muscular dystrophy. (2012, June 18). Retrieved from http://www.mayoclinic.com/health/muscular-dystrophy/DS00200/DSECTION=treatments-and-drugs • Penner, L., Cantor, R., & Siegel, L. (2012, July). Joseph. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20687186 • Walmsley, G., Gomeza, V., Fernandez-Fuente, M., Burke, M., Nagel, N., Holder, A., Stanley, R., & Shelton, D. (n.d.). A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping . Retrieved from http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008647