Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene. The DMD gene provides instructions for making a protein called dystrophin. Dystophin is primarily made in the muscle cells of the heart and skeletal muscle. The main job of dystrophin in muscle cells is to help stabilize and protect muscle fibers.

Small amounts of dystrophin are also made in nerve cells (neurons) in specific parts of the brain, including the hippocampus. The hippocampus is the part of the brain involved in learning and memory, as well as emotions. Scientists do not yet understand the job of dystrophin in neurons.

DMD is caused by genetic changes in the DMD gene that stop any functional dystrophin from being made. When dystrophin is missing, the muscle cells become damaged more easily. In response to the damage, inflammation occurs, which only worsens the process. Over time, the muscle cells without dystrophin weaken and die, leading to the muscle weakness and heart problems seen in DMD. The non-progressive memory and learning problems, as well as social behavioral problems, in some boys with DMD are most likely linked to loss of dystrophin in the neurons of the hippocampus and other parts of the brain where dystrophin is normally produced in small amounts, but at this point it is not known why this occurs and why only some people with DMD have these problems.

Different genetic changes in the DMD gene can cause a spectrum of disorders known as dystrophinopathies. The dystrophinopathies can range from very mild symptoms to the more severe symptoms seen in people with DMD. Other dystrophinopathies include Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy (DCM).

A child's doctor may suspect Duchenne muscular dystrophy (DMD) in young boys who have the signs and symptoms of DMD, including progressive muscle weakness. Family history is also important. Blood tests can be used to check for increased levels of certain special proteins called muscle enzymes in the blood which can leak from damaged muscles. Most commonly, the blood level of the enzyme creatine phosphokinase (CPK or CK) is checked, but a doctor may also check the blood levels of transaminases such as aspartate transaminase and alanine transaminase. Finding a change in the DMD gene that can cause DMD through genetic testing confirms the diagnosis of DMD.

Testing for DMD may include:

• Blood test which measures the levels of serum creatine phosphokinase (CK or CPK). Very high CK levels indicate muscle damage is causing the muscle weakness, rather than nerve damage.
• Molecular genetic testing (usually blood cells are used) to see whether there is a change or mutation in the DMD gene that can cause DMD or one of the related dystrophinopathies.
• Electromyography can be used to distinguish conditions that only impact the muscles (myotonic) from those that involve that brain and muscles (neurogenic).
• Muscle biopsy is rarely used to diagnose DMD due to the decreased cost and higher accuracy of genetic testing.

Genetic changes causing Duchenne muscular dystrophy (DMD) can be passed down in families. The DMD gene is located on the X chromosome, one of the two types of sex chromosomes. Males have an X and a Y chromosome; whereas females have two X chromosomes. Since males only have one X chromosome, they also only have one copy of the DMD gene. If this copy has a genetic change that causes DMD, the male will have DMD. Males get their X chromosome from their mother and the Y chromosome from their father.

Since females have two X chromosomes, they have two copies of the DMD gene. Having two changed copies of the DMD gene that can cause DMD is unlikely, but would cause DMD in females. A female with only one changed copy of the DMD gene is called a "carrier". She can pass on the changed gene, but usually does not have symptoms of DMD. Carriers of changes in the DMD gene that can cause DMD are at an increased risk of developing heart problems, including cardiomyopathy. In addition, due to a process called X-inactivation, in rare cases, female carriers may have mild, moderate, or severe DMD.

If a man with DMD has children, all of his daughters will be carriers. Since boys inherit the Y chromosome from their father, sons will not inherit DMD from their fathers, even if the father has DMD.

Women who are carriers of a change in the DMD gene that can cause DMD have a 50% chance of passing it on to each child, whether the child is a boy or a girl. In other words, each daughter will have a 50% risk of being a carrier. Each son will have a 50% risk of having DMD.

In some cases, a child is the first person in his family to be diagnosed with DMD. This can happen if the change in the DMD gene happened by mistake during the making of the egg or sperm. When this happens it is called a new or de novo mutation. In this case, the risk that the mother would have another child with DMD is low. However, sometimes, the boy's mother is a carrier of DMD, but is the first person in her family with the change in the DMD gene. This means the change in the DMD gene happened by mistake during the making of the egg or the sperm that came together to form the fertilized egg that developed into her. In this case, the mother is a carrier and would have a 50% risk that each son will have DMD and also a 50% risk that each daughter will be a carrier. To complicate the inheritance even more, a woman may not have the change in the DMD gene in all of her cells. She may only have the change in the gene in some of the cells of her body, including her eggs, or even just in some of her eggs. This can happen if the mistake happens after the egg is fertilized, but sometime early in development of the fetus. In these cases the risk of passing the changed gene to her children depends on how many of her eggs are affected.

Since the inheritance of DMD can be complicated, a family with a newly diagnosed child with DMD should speak with a genetic counselor or other genetic specialist to understand if there is a risk of having more children with DMD and to understand the available genetic testing options.

Currently, there are multiple clinical trials that are testing the safety and effectiveness of various treatments for Duchenne muscular dystrophy. These treatments are currently being studied and are not yet available for use outside of a research setting.

Exon skipping drugs are currently being researched as a treatment option for DMD. This treatment is designed to get the muscle cells of individuals with Duchenne muscular dystrophy to produce the missing protein, called dystrophin. Many different pharmaceutical companies (GlaxoSmithKline, PTC Therapeutics, and AVIBioPharma) are working on developing different versions of this treatment. The different names that have been used for these drugs are PRO051 (GSK2402968), PTC124 (ataluren), and eteplirsen. The type of mutation an individual has will determine if an individual is eligible for this exon skipping treatment. This type of treatment is expected to be approved in 2014.

Another type of treatment is Coenzyme Q10, which is an antioxidant that can be used in addition to prednisone (a steroid) to help improve the symptoms of DMD. Multiple studies have shown an increase in muscle strength when using this treatment.

Also, a small study was done to look at the effectiveness of the use of idebenone therapy in children. This treatment was safe and well tolerated and seemed to help improve the symptoms of DMD.

There is also another treatment that will soon be studied in clinical trials. This treatment combines three medicines, sildenafil, spironolactone, and ibuprofen. This combination of medicines was found to reduce the severity of DMD in mice.

Two other treatment options for DMD have been studied but neither of these has improved symptoms. One treatment is called pentoxifylline, which helps improve circulation of blood in the body. The other treatment is with glutamine, which is an amino acid essential for muscle strength. Further research may be done to find out ways to make these treatments effective.

ClinicalTrials.gov lists trials that are studying or have studied Duchenne muscular dystrophy. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

The DuchenneConnect Profile provides a patient registry for individuals with Duchenne muscular dystrophy. This resource gives people access to information about new treatments and trials, services like genetic testing and counseling, and regional and local resources for patients and their families.

In addition, the Muscular Dystrophy Association (MDA) MDA offers quality medical care from doctors, nurses and therapists experienced in dealing with neuromuscular diseases at 225 hospital-affiliated clinics. These clinics also serve as sites for clinical trials of the latest experimental therapies and drugs. You can contact the MDA directly for more information. ****

Muscular Dystrophy Association (MDA) - USA
National Headquarters
3300 E. Sunrise Drive
Tucson, AZ 85718
Toll-free: 800-344-4863
Web site: http://www.mdausa.org

Carriers of Duchenne muscular dystrophy (DMD) usually do not experience signs and symptoms of the disorder. Occasionally, however, females who carry a DMD gene mutation may have muscle weakness and cramping. These symptoms are typically milder than the severe muscle weakness and atrophy seen in affected males. Females who carry a DMD gene mutation also have an increased risk of developing heart abnormalities including dilated cardiomyopathy.

The Muscular Dystrophy Association (MDA) provides additional information about manifesting carriers at the following link. http://quest.mda.org/article/girls-dont-get-duchenne-or-do-they

The Human Gene Mutation Database (HGMD) is a resource where you may be able to find out if your son's mutation has been previously reported. Free registration is available to users from academic institutions and non-profit organizations. HGMD lists mutations in the DMD gene by type, and your son's mutation may be included in the small deletion category. There is also a professional version of HGMD that includes newly described mutations, but it requires a subscription.

If you cannot access the public version of this database, you may want to try to contacting an advocacy organization for Duchenne muscular dystrophy. These organizations should be able to gain access to the database if they have not already registered. Most organizations also have medical or scientific advisory boards consisting of experts in the field. These experts may have access to HGMD professional or additional information on DMD mutations. You can find advocacy organizations for DMD listed on our resource page.

You can also find journal articles that report DMD mutations through a service called PubMed, a searchable database of medical literature. Some articles are available for free, while most other articles have a summary (abstract) available. To obtain the full article, contact a medical/university library or your local library for interlibrary loan. You can also purchase most articles online using the link publisher's Web site. Using "Duchenne muscular dystrophy mutations" as your search term should locate articles. To narrow your search, enter more specific information on your son's mutation or click on the “Limits” tab under the search boxand select your criteria.

The National Library of Medicine (NLM) Web site has a page for locating libraries in your area that can provide direct access to these journals (print or online). The Web page also describes how you can get these articles through interlibrary loan and Loansome Doc (an NLM document-ordering service). You can access this page at the following link http://nnlm.gov/members/. You can also contact the NLM toll-free at 888-346-3656 to locate libraries in your area.

There is no known cure for Duchenne muscular dystrophy (DMD) but research is ongoing. The goal of treatment is to control the symptoms of DMD and related complications caused by severe progressive muscle weakness and loss in order to maximize the quality of life. An enlarged, weakened heart (dilated cardiomyopathy) may be treated with medications, but in severe cases a heart transplant may be necessary. Assistive devices for breathing difficulties may be needed, especially at night and as the disease progresses.

Gentle exercise is encouraged for people with DMD. Physical inactivity (such as bed rest) can worsen the muscle disease, but so can overexertion. Physical therapy may be helpful to maintain muscle strength and function. Orthopedic devices (such as braces and wheelchairs) may improve the ability to move and take care of oneself.

Steroids (corticosteroids) may improve the strength and function of muscles in people with DMD, including lung function. Steroid options include:

• Prednisone is a steroid that has been shown to extend the ability to walk by 2 to 5 years. However, the possible side effects of prednisone include weight gain, high blood pressure, behavior changes, and delayed growth.
• Deflazacort (another form of prednisone), is used in Europe and believed to have fewer side effects and was recently approved in the United States by the FDA.
• Oxandrolone, a medication used in a research study, also has similar benefits to prednisone, but with fewer side effects.

The U.S. Food and Drug Administration of United States approved Exondys 51 (eteplirsen) injection to treat people with DMD who have a change in the DMD gene that will allow a shortened form of dystrophin to be made if exon 51 is skipped. An exon is the part of the gene that actually codes for the protein. The DMD gene has 79 exons. About 13% of those with DMD may be helped by Exondys 51.

Because chronic use of corticosteroids can lead to side effects, and rapid withdrawal of corticosteroids can result in life-threatening complications, there are recommended guidelines on how to proceed with withdrawal. The PJ Nicholoff Protocol guides withdrawal from corticosteroids following long term treatment.

The Muscular Dystrophy Association (MDA) has current information about the medical management of DMD.

Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for individuals affected by Duchenne or Becker Muscular Dystrophy. Pediatrics 2006; 116: 1569-1573.

BrainPOP presents the topic of Duchenne muscular dystrophy in a short, animated movie. BrainPOP produced this video in partnership with Parent Project Muscular Dystrophy, this four minute video strives to provide kids of all ages with a clear understanding of Duchenne.