Duchenne muscular dystrophy (DMD) affects the muscles, leading to muscle wasting that gets worse over time. DMD occurs primarily in males, though in rare cases may affect females. The symptoms of DMD include progressive weakness and loss (atrophy) of both skeletal and heart muscle. Early signs may include delayed ability to sit, stand, or walk and difficulties learning to speak. Muscle weakness is usually noticeable in early childhood. Most children with DMD use a wheelchair by their early teens. Heart and breathing problems also begin in the teen years and lead to serious, life threatening complications. DMD is caused by genetic changes (DNA variants) in the DMD gene. DMD is inherited in an X-linked recessive pattern and may occur in people who do not have a family history of DMD. Diagnosis of DMD is based on the symptoms, clinical exam, and the result of a biopsy to remove a small piece of muscle for examination under a microscope. The result of genetic testing may also help confirm the diagnosis. While there is no known cure for DMD, there are treatments that can help control symptoms.

Becker muscular dystrophy (BMD), a milder form of muscular dystrophy, is also caused by DNA variants in the DMD gene.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) can have the same symptoms and are caused by mutations in the same gene. BMD symptoms can begin later in life and be less severe than DMD. However, because these two kinds are very similar, they are often studied and referred to together (DBMD).

How many people are affected?
About 14 in 100,000 males 5 – 24 years of age

Who is more likely to be affected: males or females?
Males

When does muscle weakness typically begin?
DMD symptoms usually begin before 5 years of age. In BMD, symptoms usually appear later, even into adulthood.

Which parts of the body show weakness first?
Upper legs and upper arms

What other parts of the body can be affected?
Heart, lungs, throat, stomach, intestines, and spine

Duchenne muscular dystrophy (DMD) is a rapidly progressive form of muscular dystrophy caused by a mutation in the DMD gene.

What is Duchenne muscular dystrophy?

DMD is a rapidly progressive form of muscular dystrophy that occurs primarily in boys. It is caused by an alteration (mutation) in a gene, called the DMD gene that can be inherited in families in an X-linked recessive fashion, but it often occurs in people from families without a known family history of the condition. Individuals who have DMD have progressive loss of muscle function and weakness, which begins in the lower limbs. The DMD gene is the second largest gene to date, which encodes the muscle protein, dystrophin. Boys with Duchenne muscular dystrophy do not make the dystrophin protein in their muscles.

Duchenne muscular dystrophy affects approximately 1 in 3500 male births worldwide. Because this is an inherited disorder, risks include a family history of Duchenne muscular dystrophy.

What are the symptoms of Duchenne muscular dystrophy?

The symptoms usually appear before age 6 and may appear as early as infancy. Typically, the first noticeable symptom is delay of motor milestones, including sitting and standing independently. The mean age for walking in boys with Duchenne muscular dystrophy is 18 months. There is progressive muscle weakness of the legs and pelvic muscles, which is associated with a loss of muscle mass (wasting). This muscle weakness causes a waddling gait and difficulty climbing stairs. Muscle weakness also occurs in the arms, neck, and other areas, but not as severely or as early as in the lower half of the body.

Calf muscles initially enlarge and the enlarged muscle tissue is eventually replaced with fat and connective tissue (pseudohypertrophy). Muscle contractures occur in the legs, making the muscles unusable because the muscle fibers shorten and fibrosis occurs in connective tissue. Occasionally, there can be pain in the calves.

Symptoms usually appear in boys aged 1 to 6. There is a steady decline in muscle strength between the ages of 6 and 11 years. By age 10, braces may be required for walking, and by age 12, most boys are confined to a wheelchair. Bones develop abnormally, causing skeletal deformities of the spine and other areas.

Muscular weakness and skeletal deformities frequently contribute to breathing disorders. Cardiomyopathy (enlarged heart) occurs in almost all cases, beginning in the early teens in some, and in all after the age of 18 years. Intellectual impairment may occur, but it is not inevitable and does not worsen as the disorder progresses.

Few individuals with DMD live beyond their 30s. Breathing complications and cardiomyopathy are common causes of death.

How is Duchenne muscular dystrophy diagnosed?

Duchenne muscular dystrophy is diagnosed in several ways. A clinical diagnosis may be made when a boy has progressive symmetrical muscle weakness. The symptoms present before age 5 years, and they often have extremely elevated creatine kinase blood levels (which are described below) . If untreated, the affected boys become wheelchair dependent before age 13 years.

A muscle biopsy (taking a sample of muscle) for dystrophin studies can be done to look for abnormal levels of dystrophin in the muscle. The dystrophin protein can be visualized by staining the muscle sample with a special dye that allows you to see the dystrophin protein. A muscle which has average amounts of dystrophin will appear with the staining technique as though there is caulking around the individual muscles cells and it is holding them together like window panes. A boy with Duchenne, on the other hand, will have an absence of dystrophin and appear to have an absence of the caulking around the muscle cells. Some individuals can be found to have an intermediate amount of the dystrophin protein. Often these boys are classified as having Becker muscular dystrophy.

Genetic testing (looking at the body's genetic instructions) on a blood sample for changes in the DMD gene can help establish the diagnosis of Duchenne muscular dystrophy without performing a muscle biopsy. Genetic testing is constantly changing, but the methods currently being used look for large changes in the gene (deletion/duplication) and another method, which looks at the letters that spell out the instructions found within the DMD gene (sequencing). Together these two methods can detect the disease causing changes in about 95% of patients. Those individuals who are not found to have a detected change in the DMD gene using this method, and who are diagnosed with DMD by biopsy, still have a change in their gene but it is in areas of the gene that are not examined using these methods. However, the results of genetic testing may not be conclusive of a diagnosis of DMD, and only the muscle biopsy can tell the level of dystrophin protein for sure.

For the remaining individuals, a combination of clinical findings, family history, blood creatine kinase concentration and muscle biopsy with dystrophin studies confirms the diagnosis. Creatine kinase is an enzyme that is present normally in high concentrations in the muscle cells of our body. During the process of muscle degeneration or breakdown, the muscle cells are broken open and their contents find their way to the bloodstream. Therefore elevated levels of creatine kinase can be detected from a blood test and it is a measure of muscle damage. Elevated levels can be the result of multiple reasons including acute muscle injury, or chronic condition such as Duchenne muscular dystrophy.

What is the treatment for Duchenne muscular dystrophy?

Treatment for Duchenne muscular dystrophy is aimed at the symptoms. Aggressive management of dilated cardiomyopathy with anti-congestive medications is used, including cardiac transplantation in severe cases. Assistive devices for respiratory complications may be needed, especially at night. The medication prednisone - a steroid - is given to improve the strength and function of individuals with DMD. Prednisone has been shown to prolong 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. A synthetic form of prednisilone, called Deflazacort, is used in Europe and believed to have fewer side effects than prednisone. A medication called cyclosporine has been used and has improved clinical function in children, but its use is controversial due to cyclosporine-induced myopathy. Oxandrolone, a medication used in a research study, has similar effects to prednisone with fewer side effects. Several other therapies are also under investigation, including coenzyme Q10, glutamine, pentoxifylline, and PTC124.

Physical therapy is used to promote mobility and prevent contractures. Surgery may be needed for severe contractures and scoliosis.

Is Duchenne muscular dystrophy inherited?

Duchenne muscular dystrophy is inherited in an X-linked recessive pattern. Males have only one copy of the X chromosome from their mother and one copy of the Y chromosome from their father. If their X chromosome has a DMD gene mutation, they will have Duchenne muscular dystrophy. Females, on the other hand, have two copies of the X chromosomes.. Since females have two copies of this gene, if one copy does not work, they have a second back up copy to produce the dystrophin protein. A woman who has a genetic change in one of her two copies is said to be "a carrier" of Duchenne muscular dystrophy. Carriers do not have Duchenne muscular dystrophy and most are unaware that they even carry this change in their genetic material unless they have a family history. However, recent studies have shown that some carrier females (approximately 20 percent) will show symptoms of DMD, including muscle weakness and cardiac abnormalities.

With an X-linked recessive condition, the chance of passing on the changed (non-working) copy of the gene to a child is different for males and females.

Females who carry the changed copy of the gene have a 50 percent chance of passing it on with each pregnancy. Thus, there is a 25 percent chance of having a affected child with DMD (eg., 50 percent of boys have the chance of having DMD and 50 percent of girls will be carriers). The chance of a woman who has one affected son (and no family history) of being a carrier of the changed DMD gene is approximately 2/3. However, in the remaining third of individuals with DMD, the change in the dystrophin gene is a new genetic change, or de novo change and about 10 percent of new mutations are due to gonadal mosaicism. Gonadal mosaicism refers to a condition where an individual has two or more cell populations that differ in genetic makeup in their eggs or sperm.

Males who inherit or are born with a changed copy of the DMD gene will have DMD since they have a Y chromosome, and do not have back-up X chromosome. If a male with DMD were to have children, all of his daughters would be carriers and none of his sons would be affected.

Currently various reproductive options are available to families. The preconception options include MicroSort which is a technology that can separate sperm containing X chromosomes allowing for an increase in chances of having a female. The second reproductive option is preimplantation genetic diagnosis (PGD), which is a technique that can allow the cells of a fertilized egg to be tested to determine if it contains a change in the DMD gene and then implant those eggs which do not. The post conception options include Chorionic Villus Sampling (CVS) and amniocentesis which analyze sampled cells derived from the developing fetus.

Several of the prenatal testing options for pregnancies at increased risk are available when the DMD disease-causing mutation has been identified in a family member, or if informative, genetically-linked markers have been identified.

Normal Function

DMD, the largest known human gene, provides instructions for making a protein called dystrophin. This protein is located primarily in muscles used for movement (skeletal muscles) and in heart (cardiac) muscle. Small amounts of dystrophin are present in nerve cells in the brain.

In skeletal and cardiac muscles, dystrophin is part of a group of proteins (a protein complex) that work together to strengthen muscle fibers and protect them from injury as muscles contract and relax. The dystrophin complex acts as an anchor, connecting each muscle cell's structural framework (cytoskeleton) with the lattice of proteins and other molecules outside the cell (extracellular matrix). The dystrophin complex may also play a role in cell signaling by interacting with proteins that send and receive chemical signals.

Little is known about the function of dystrophin in nerve cells. Research suggests that the protein is important for the normal structure and function of synapses, which are specialized connections between nerve cells where cell-to-cell communication occurs.

Health Conditions Related to Genetic Changes

Duchenne and Becker muscular dystrophy

More than 2,000 mutations in the DMD gene have been identified in people with the Duchenne and Becker forms of muscular dystrophy. These conditions occur almost exclusively in males and are characterized by progressive muscle weakness and wasting (atrophy) and a heart condition called dilated cardiomyopathy. Most of the mutations that cause these conditions delete part of the DMD gene. Other mutations abnormally duplicate part of the gene or change a small number of DNA building blocks (nucleotides) in the gene.

Mutations that cause Becker muscular dystrophy, which typically has milder features and appears at a later age than Duchenne muscular dystrophy, usually lead to an abnormal version of dystrophin that retains some function. Mutations that cause the more severe Duchenne muscular dystrophy typically prevent any functional dystrophin from being produced.

Skeletal and cardiac muscle cells without enough functional dystrophin become damaged as the muscles repeatedly contract and relax with use. The damaged cells weaken and die over time, causing the characteristic muscle weakness and heart problems seen in Duchenne and Becker muscular dystrophy.

X-linked dilated cardiomyopathy

More than 30 mutations in the DMD gene can cause an X-linked form of familial dilated cardiomyopathy. This heart condition enlarges and weakens the cardiac muscle, preventing the heart from pumping blood efficiently. Although dilated cardiomyopathy is a sign of Duchenne and Becker muscular dystrophy (described above), X-linked dilated cardiomyopathy is typically not associated with weakness and wasting of skeletal muscles.

The mutations that cause X-linked dilated cardiomyopathy preferentially affect the activity of dystrophin in cardiac muscle cells. As a result of these mutations, affected individuals typically have little or no functional dystrophin in the heart. Without enough of this protein, cardiac muscle cells become damaged as the heart muscle repeatedly contracts and relaxes. The damaged muscle cells weaken and die over time, leading to the heart problems characteristic of X-linked dilated cardiomyopathy.

The mutations that cause X-linked dilated cardiomyopathy often lead to reduced amounts of dystrophin in skeletal muscle cells. However, enough of this protein is present to prevent weakness and wasting of the skeletal muscles.

Familial dilated cardiomyopathy

MedlinePlus Genetics provides information about Familial dilated cardiomyopathy

Other Names for This Gene

• BMD
• DMD_HUMAN
• dystrophin (muscular dystrophy, Duchenne and Becker types)

Genomic Location

• Delayed motor development (taking longer to learn to sit, stand, or walk)
• Enlarged calf muscles (pseudohypertrophy)
• Muscle weakness that gets worse over time
• Toe walking or waddling gait
• Using hands to get up off the floor (Gower's maneuver)
• Progressive enlargement of the heart (cardiomyopathy)

Duchenne muscular dystrophy (DMD) is a type of dystrophinopathy, which is a group of muscle diseases caused by mutations in the DMD gene, which encodes the protein dystrophin; the other dystrophinopathies are Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy (DCM). Although these disorders are caused by mutations in the same gene, they do differ with regard to age of onset, course and pace of progression, symptoms, and life expectancy. DMD and BMD primarily affect the skeletal muscles, while DCM primarily affects the heart.

Conditions that may be part of the differential diagnosis of the dystrophinopathies include:

• Limb-girdle muscular dystrophy (LGMD): a group of disorders that are similar to DMD but occur in both sexes as a result of autosomal recessive and autosomal dominant inheritance. LGMD type 2I has symptoms that resemble DMD and/or BMD and is caused by mutations in the FKRP gene.
• Emery-Dreifuss muscular dystrophy (EDMD): characterized by joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting that follows a specific distribution pattern over time, and cardiac (heart) involvement that may include palpitations, presyncope (feeling of faintness) and syncope (fainting), poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of the muscle and cardiac involvement are variable. The two genes known to be associated with EDMD are EMD (X-linked EDMD) and LMNA (autosomal dominant EDMD and autosomal recessive EDMD).
• Spinal muscular atrophy (SMA): suspected in individuals with poor muscle tone, symmetric muscle weakness that does not affect the face and ocular (eye) muscles, and evidence of anterior horn cell involvement (a motor neuron in the spinal cord), including muscle twitches of the tongue and absence of deep tendon reflexes. SMA is caused by mutations in the SMN1 gene. Inheritance is autosomal recessive.
• Dilated cardiomyopathy (DCM): can be familial or non-familial. Familial DCM can have autosomal dominant, autosomal recessive, or X-linked inheritance.

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.

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.