DMD Fund - Duchenne Muscular Dystrophy Info

Introduction

"Muscular Dystrophy" is a broad term used to label gene-related disorders that affect muscles throughout the body. There are more than 20 specific genetic disorders considered to be Muscular Dystrophy. Most have the same result (a reduction in muscle strength due to weakening and deterioration) but these various types of Muscular Dystrophies are specific to different muscles in the body and different rates of degeneration.

All forms of Muscular Dystrophy are considered rare, but Duchenne Muscular Dystrophy, (DMD) first identified in the 1860s, is the most common and the most lethal of the Muscular Dystrophies in existence. Duchenne MD, which is 100% fatal, affects approximately 1 in every 2,400 boys. Another type of Muscular Dystrophy, first diagnosed in the 1950s, is Becker Muscular Dystrophy (BMD). BMD occurs in about 1 in 18,000 male births and is considered to be a less severe form of Duchenne MD.

In Depth - What does “dystrophy” mean?
The word “dystrophy” was coined in the 1860s by a French physician named Guillaume Duchenne when he noticed that the muscles in some young boys were weakening and wasting away. He called it a “dystrophy,” after the Greek word roots, "dys-" meaning abnormal, diseased or faulty and "-trophy" which refers to nutrition or growth. Duchenne believed that dystrophy progressed as muscles continued to develop without the nutrients they needed.

Muscular dystrophy is always a genetic disorder, which means that it always results from a gene defect. This mutation may be inherited from a parent who also has it, even if it is not “expressed” (manifested). Such an inherited genetic flaw is called a “familial mutation.” All mutations begin somewhere, and it is possible that the mutation occurred long ago, in a previous generation. It is also possible that the mutation occurs only in the afflicted individual (or in the egg or sperm that created that person), in which case the new mutation is considered “spontaneous.” Duchenne MD is notable for the large proportion of cases (roughly 40%) that occur spontaneously.

The high incidence of spontaneous mutation in Duchenne MD is due to the large size of the dystrophin gene. The larger the gene, the greater the odds are that some error will occur.

The term "muscular dystrophy" is considered by many to be misleading when it comes to DMD and BMD because technically, the muscles in boys with DMD do not lack any required nutrients. The problem actually stems from the absence of a critical muscle protein, called dystrophin. So DMD and BMD are best referred to as “myopathies” (from the Greek root "myo-" for muscle and "-pathos" for abnormal or diseased).

Myopathies occur when the fault lies in the muscle itself rather than in some other tissue that controls, serves or attaches to the muscle.

But due to the common use and familiarity of the term “muscular dystrophy”, Duchenne Muscular Dystrophy is referred to as a muscular dystrophy. Back to top

Who gets DMD?

Duchenne MD is not specific to any one group. All ethnic groups are equally susceptible to both Duchenne and Becker MD. But what often sets these two Muscular Dystrophies apart is that they occur mainly in boys (with very few exceptions), making it a sex-linked disorder.

Because boys have one X-chromosome and one Y-chromosome, and girls have two X-chromosomes, boys are always at a greater risk of inheriting disorders caused by damaged genes on the X-chromosome. To put it simply, if something is wrong with a gene on a boy’s X-chromosome, his body has no other way to recreate a fully functional version of that damaged gene. Girls are fortunate to have an "extra" X-chromosome to fall back on if one of their genes is damaged.

In Depth -- How do chromosomes work?
The nucleus of each human cell holds 46 chromosomes. They are responsible for all genetic traits (such as eye color). Twenty-three chromosomes are inherited from the mother (via her egg) and 23 from the father (via his sperm). These two separate sets of 23 chromosomes carry the same genes and pair up with each other upon conception. As a result, the 46 chromosomes are thus organized into 23 pairs of chromosomes, called gene pairs. The 23rd pair contains the sex chromosomes. This is where the dystrophin gene lives. (The dystrophin gene and the protein it makes both carry the same name.) Back to top

What causes DMD?

Within our gene makeup, the dystrophin gene, one of the largest genes found to date, “codes” for an important muscle protein also called dystrophin. Dystrophin acts as the glue that holds muscles together by maintaining the structure of muscle cells. Dystrophin is also believed to carry signals between the inside and outside of muscle fibers. Without dystrophin, muscles are not able to operate properly and eventually suffer progressive damage.

The dystrophin gene is carried on the X-chromosome. Boys are therefore more susceptible to dystrophin damage because they have only one X-chromosome. When a boy is diagnosed with Duchenne MD, his body is not able to produce any dystrophin. In Becker MD, a distorted, over-sized version of dystrophin is generated. In either disorder, without fully functional dystrophin, muscle cells within the body gradually weaken and eventually die.

In Depth -- What is dystrophin and what does it do?
Each gene, such as the dystrophin gene, “codes” for (carries the message to make) a specific and unique protein. These proteins help build the body, and help it to run smoothly. There are thought to be roughly 100,000 genes, and as many proteins, in each human.

When a gene mutates, it produces a different protein than what it’s supposed to. Depending on which gene is altered and the severity of the mutation, it may not be a serious problem. But in the case of DMD, it is lethal. If the gene that codes for dystrophin is never turned on, or if a faulty type of dystrophin is produced, the fatal DMD results.

Dystrophin’s main function is to serve as a "connector" in the cell’s structural support system (or cytoskeleton). Dystrophin anchors contractile muscle filaments to the membrane (surrounding surface) of a muscle cell. Each protein has a unique three-dimensional structure. Different portions of this structure enable the protein to fold over onto itself or to connect with other molecules. This allows the entire cell to shorten during muscle contraction, generating the forces needed to move the skeleton. When any of these connecting membrane proteins is faulty, two things happen. First, muscle cannot contract normally, which leads to weakness since less force can be generated. Second, as a muscle cell contracts, its delicate membrane tears, spilling the contents of the cell into the surrounding fluid.

Not only do vital substances leak out of muscle fibers, but harmful substances (like calcium ions) pour in. As with any injury to the body, normal immune cells (or lymphocytes) arrive to mend or remove the damaged cells and debris. The injured muscle cells are "cleared away" and are replaced with hard, fibrous or rubbery scar tissue. This leads to “pseudohypertrophy,” in which muscles (particularly of the calf) appear much larger than normal. Ironically, what appears to be a sign of strength is really a sign of weakness, as the increased mass consists not of strong muscle, but rather of useless scar tissue.

This pseudohypertrophy is one of the early indicators that physicians use to diagnose Duchenne MD in young boys.

In Depth -- Is dystrophin found in all muscles?
Yes. There are three types of muscle tissue. By far, the most common and familiar is the “skeletal” muscle that attaches to the bones. Skeletal muscle is what people typically think of when they hear the word "muscle." It is the prime target of Duchenne MD. Dystrophin is also found in the other two kinds of muscle: “cardiac” (of the heart) and “smooth” (of the digestive tract). Unlike skeletal, these muscles are involuntary, meaning that they cannot be moved at will. But like skeletal, dystrophin is integral in them as well. Back to top

How is DMD detected?

Duchenne MD is typically diagnosed in boys between the ages of 3 and 7. Usually parents will notice that their son is behind other boys their age in developmental milestones. Often, parents will notice that their son’s calves appear to be enlarged (pseudohypertrophy), which is another indicator that may result in a DMD diagnosis.

Boys between the ages of 3 and 5 (pre-school) may appear to be clumsy and will often lose their balance, causing them to fall down a lot during regular activity. Climbing stairs, running and rising up from the floor becomes very difficult. By school age, Duchenne MD causes contractures (loss of elasticity) in their Achilles tendons, which forces them to walk either on their toes or on the balls of their feet, resulting in a "walk" that appears to be a waddle. In order to keep their balance and maintain their center of gravity, boys with Duchenne MD will stick out their bellies and push their shoulders back. This condition is called Lordosis.

Between the ages of 7 and 12, most boys with Duchenne MD will lose their ability to walk and depend on a wheelchair for mobility. Throughout the years that follow, all activities that call for the use of arms, legs or trunk muscles will require assistance.

Fatigue is a problem for boys with Duchenne MD. They struggle with normal levels of activity, but especially when much walking or stair climbing is required. If parents notice that their son grows excessively tired from these everyday tasks, they should consult a doctor. The doctor (or often physical therapist) will have the boy perform certain functional tests to assess the contractile ability of various muscles and the flexibility of joints, indicating a possible Duchenne MD diagnosis. These tests include walking, running, climbing, pulling, and rising from a sitting position. Back to top

Tests/Screens
There are two reliable tests available that will help doctors confirm a preliminary diagnosis of Duchenne MD.

1. Creatine Kinase
The body creates an enzyme called “creatine kinase” (also known as CK) that normally lives inside muscles. When muscles are functioning normally, CK levels in the bloodstream are relatively low. But when muscles are damaged, the muscle cells split open, causing their contents to spill out into the bloodstream. This creates a rise in the levels of CK in the blood. Measuring CK levels may verify that there has been muscle damage and may indicate more muscle damage to come.

2. Muscle Biopsy/DNA
Once a CK test comes back showing high levels of the enzyme in the blood, conclusions can be made that muscles are likely damaged. But a CK test alone cannot diagnose Duchenne MD. In order to determine the cause of the muscle damage, doctors will usually perform a muscle biopsy. This requires a doctor to surgically remove a small sample of muscle and examine it closely to determine what is happening inside the cells. This test is the most reliable way to diagnose Duchenne MD, and distinguish it from the other inflammatory disorders, and from other Muscular Dystrophies.

DNA testing (using blood cells or muscle cells) remains the best way to obtain exact genetic information leading to a conclusive Duchenne MD diagnosis. In the future, as this type of testing becomes more commonplace, it will lead to faster diagnosis of all Muscular Dystrophies.

In Depth -- DNA
DNA is supremely important. It determines how our bodies are made and how they work. It is a simple molecule in terms of its construction, and a complicated one because of the huge quantity of information it stores. DNA lies at the heart of Duchenne MD. As we learn more about DNA, we will likely find new ways to treat and cure Duchenne MD.

DNA testing is generally performed using a tool called a “PCR”, an acronym for "polymerase chain reaction". Essentially this is a way to make large quantities of DNA from a small sample so that multiple tests can be performed. PCR uses the original DNA double helix to make copies of DNA, called cDNA. Back to top

Prevention of DMD

There is no way to stop Duchenne MD from progressing once a boy is born with the disorder. However once a child with Duchenne MD is born into a family, it is possible to offer prenatal diagnosis in future pregnancies, either for the mother or for other women in her family who may be at risk of being carriers of the damaged X-chromosome.

Genetic Tests and Genetic Counseling
After a boy is diagnosed with Duchenne MD, it is important to seek genetic advice and appropriate tests for those members of the family who are at risk of being carriers. “Genetic testing” refers to the analysis of the gene itself and is used to predict if a person is likely to develop a certain disease. A woman’s genes can be tested to see if she is a carrier of Duchenne MD. If she is, doctors may make recommendations about childbearing options. Duchenne MD can be detected with about 95% accuracy by genetic studies performed during pregnancy. Back to top

Symptoms of DMD

The progression of Duchenne MD leads to many physical symptoms that typically affect different portions of the body, including the back (spine), legs, feet, joints and tendons.

The progression of symptoms (in order of occurrence) are:

1. General Weakness
General weakness and fatigue can be symptoms of Duchenne MD. Due to the additional effort that boys with Duchenne MD put forth when climbing stairs, running or even standing, they will often grow weak from these routine tasks and complain that their legs are tired. As Duchenne MD continues to weaken muscles, boys will often have to use their arms to get up from a sitting position. Usually they will experience a range in their levels of strength and fluctuate between good days and bad days.

2. Overdeveloped Calves
One of the early indicators of Duchenne MD is an enlargement or overdevelopment of the calves, also known as “pseudohypertrophy”. During exercise, most people experience muscle hypertrophy, or enlargement of the muscles. Boys with Duchenne MD also experience this enlargement, initially. But instead of getting stronger, Duchenne MD causes the muscles to soon become permanently damaged and die due to damaged or missing dystrophin (the glue that holds muscles together). As this is happening, there are other cells that may respond by producing fibrous connective tissue with fatty deposits. Because of this bulking of the muscle by fat, not by muscle cells, the volume of the muscle increases and becomes enlarged.

3. Lordosis
The spine is a column of small bones, or vertebrae that supports the entire upper body. This column is made up of three sections of vertebrae: the five bones that support the neck, the twelve bones that support the rib cage and the five lowest and largest bones that support the lumbar. Most of the body’s weight and stress falls on the lumbar vertebrae.

Lordosis is the curvature of the lumbar and cervical spine. The term is also used to refer to any condition characterized by an excessive curvature of the spine, with the bend towards the front (hollow back, saddle back and sway back). It affects the lumbar region, between the ribs and the pelvis) and is the opposite of hunchback. Lordosis is commonly found in pregnant women and obese people with weak back muscles and heavy abdomens. It also affects boys with Duchenne MD. As their back muscles become weaker, Lordosis cause their bodies to lean forward, and a curvature of the spine results.

4. Foot Problems
Often boys with Duchenne MD will have problems with their feet. This occurs as muscle weakness spreads and the Achilles tendons (heel cords that anchor the muscles at the back of the lower leg to the heel bone) are often contracted, pulling feet into an abnormal position and interfering with the ability to walk. Frequently, boys with Duchenne MD will wear ankle-straightening splints at night to help keep their feet straight.

Other foot problems relating to Duchenne MD include a purple discoloration of the feet and/or cold feet. This occurs as the muscle function of the legs and feet decrease. Active muscles require a high blood flow to provide nourishment, and the reverse holds true: inactive muscles do not need as much blood flow. The cardiovascular system automatically adjusts in order to send blood where it is needed most throughout the body; blood is diverted from the feet to the active organs that need it most, such as the kidneys and the brain.

5. Joint and Tendon Cord Elasticity
Joint and tendon restriction (called “contracture”) is another symptom that boys with Duchenne may suffer from. It typically affects the ankles first, followed by the hips and knees, and finally, the joints of the upper limbs. Physiotherapy and occupational therapy are often used to help offset this. A variety of exercises that stretch the joints and advice on good and bad sitting positions and activities may be employed to cultivate elasticity.

6. Scoliosis
Scoliosis is a three-dimensional curvature of the spine. It most commonly develops in the area between the mid and lumbar portion of the spine. If severe, scoliosis can be disfiguring and eventually limit the function of the lungs and upper limbs. Increasingly, parents of boys who have Duchenne MD are turning to surgery to help straighten their sons’ spines. In this major operation, doctors insert a metal rod to keep the spine straight. The optimal time for boys with scoliosis to have this surgery is generally believed to be between ages 11 and 13.

7. Speech/Intellectual Handicaps
Due to dystrophin abnormalities in the brain that cause subtle cognitive and behavioral deficits, intellectual handicaps are more frequent in boys with Duchenne MD than in the general population, but still only affect a small percentage. About one third of boys with Duchenne MD have some degree of a learning disability, although only a few have severe cases of retardation. And unlike progressive muscle weakness, when a learning disability does occur in a boy with Duchenne MD, it seldom worsens as time goes on. Whatever intelligence he has at birth, he maintains throughout his life unless he is affected by another ailment.

For boys who suffer from both Duchenne MD and learning disabilities, language and communication skills are typically the main concern. But manual skills, visual skills and creativity are often excellent in boys with Duchenne MD, which is perhaps why many become very good artists.

8. Respiratory Problems
Duchenne MD causes many changes throughout the body, and the lungs are affected by these changes. Respiratory function usually remains normal until around age 10. Afterwards, respiratory muscle function may begin to decline enough to change the way lungs pull air in and push it out. The diaphragm muscle is situated below the lungs and is the responsible for this crucial movement of air. As Duchenne MD progresses, the diaphragm becomes weakened (due to scar tissue buildup) and breathing becomes more difficult. At the same time, muscles responsible for coughing are also growing weaker and are not able to support the diaphragm.

As a result, the amount of oxygen in the blood decreases and is replaced by carbon dioxide as the exchange of air becomes more and more difficult for the lungs. This can lead to symptoms like headaches, mental lapses, and difficulty concentrating or staying awake during the day. In addition to the lung difficulties, the weakened muscles responsible for coughing may permit bacteria and viruses to grow, since coughing is the normal defense to rid the lungs of extra secretions. This often allows a simple cold to quickly progress into deadly pneumonia in boys with Duchenne MD. Back to top

Progression of DMD

Typically Duchenne MD is diagnosed between the ages of three and seven, however, the rates of progression and severity of each case is different. There are four stages that are usually associated with Duchenne MD:

Early Phase | Transitional Phase | Loss of ambulation | Adult Stage

1. Early Phase (diagnosis through age 7)
Once a boy is diagnosed with Duchenne MD, it is often quite difficult to accept or believe that there is anything wrong with him. The onset of physical symptoms may be tough to recognize. Often times he will appear to be improving on the outside while his muscles are deteriorating on the inside. It is during this early phase that the calves may seem overdeveloped. He may appear clumsy and fall a lot. Jumping from a standing position may become near impossible.

2. Transitional Phase (6-12 years)
Between the ages of 6 and 12, Duchenne MD has usually been diagnosed. The child will likely have trouble walking, mostly because his quadriceps (muscles in the front of the thighs) have grown weaker. This tends to keep him off balance as he attempts to shift his weight and walk. He may walk on the balls of his feet or on his toes with a slight, rolling gait. In order to compensate for a feeling of falling forward, boys with Duchenne MD will stick their bellies out and throw their shoulders Back to keep their balance as they walk.

When asked to get up off of the floor, he will often put his rear end up in the air first and then "walk" his arms up his legs with his hands until he is standing; using his arms for supports. The medical term for this is “Gowers Maneuver.”

3. Loss of ambulation (8-14 years)
By about 12 years old, he will likely need a wheelchair for at least part of the time as mobility becomes more difficult. His weakened muscles will cause him to tire easily. In most cases teen years are when the most significant loss of skeletal muscle strength takes place. It is at this point that activities involving the arms, legs, or trunk of the body will require assistance or mechanical support. Most boys will retain the use of their fingers through this phase so they can generally still write and use a computer.

4. Adult Stage (15+ years)
During the teen years, in addition to skeletal muscle problems, boys with Duchenne MD will often develop heart muscle problems. Heart complications become the main threat to both health and life due to damage and loss of respiratory muscle. The muscle layer of the heart (called “myocardium”) begins to deteriorate, much like the skeletal muscles do. This puts the boys at risk of a heart attack. Major symptoms of myocardium include shortness of breath, fluid in the lungs, or swelling in the feet and lower legs (caused by fluid retention).

Even with the best management currently available, boys with Duchenne MD typically die from respiratory failure and/or cardiac failure in their teens or early twenties at the latest. There is no treatment, and no cure for Duchenne Muscular Dystrophy – it is 100% fatal.
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DMD Care Guidelines for New Families (click on each topic to download)

Resources

TREAT-NMD
TREAT-NMD is a major initiative in the neuromuscular field that is creating the infrastructure to ensure that the most promising new therapies reach patients as quickly as possible. Since the network was launched in January 2007, our focus has been on the development of tools that industry, clinicians and scientists need to bring novel therapeutic approaches through preclinical development and into the clinic, and on establishing best-practice care for neuromuscular patients worldwide. http://www.treat-nmd.eu/patients/DMD/intro/

DuchenneConnect
DuchenneConnect serves as a central hub linking the resources and needs of the Duchenne/Becker muscular dystrophy community: young men with Duchenne; their families and caregivers; and the provider community: clinical care providers, policymakers, industry professionals and the medical research fields. DuchenneConnect offers registered members resources to assist with early, appropriate and least invasive diagnosis; explore the benefits and limitations of genetic testing; offer access to resources and services, including care and treatment; and assist in understanding and development of new treatment trials. http://www.duchenneconnect.org/

Center for Duchenne Muscular Dystrophy at UCLA
The UCLA Duchenne Muscular Dystrophy Center Fund is intended to support Duchenne related muscular dystrophy translational research and clinical care at UCLA. Key missions include building and supporting a state of the art multidisciplinary care program for children and adults with muscular dystrophy, building and supporting a clinical trials infrastructure to accelerate clinical investigation into new treatments, and the support of translational biomedical research relevant to muscular dystrophy.
http://www.cdmd.ucla.edu/

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