Cause of Duchenne/Becker Muscular Dystropy (DBMD) Cause of Duchenne/Becker Muscular Dystropy (DBMD)
Centers for Disease Control and Prevention

Until the 1980s, little was known about the specific cause of any kind of muscular dystrophy. However, during that decade, the gene for DMD was identified. Genes contain codes, or recipes, if you will, for proteins. Proteins are very important biological components (parts) in all forms of life. In 1986, MDA-supported researchers identified the gene that, when flawed (a problem known as a mutation), causes DMD. They found that the gene’s failure to make a working version of the muscle protein dystrophin is the cause of the disease. Flawed dystrophin was also found in Becker muscular dystrophy (BMD), so that we now view DMD and BMD as variants of the same disease (DBMD). Patients with DBMD have decreased or abnormal dystrophin in their muscles. Further research has shown that dystrophin is found inside the muscle cell, where it helps support the cell membrane and minimizes injury related to the stress of muscle movement. Dystrophin could have other functions that have not yet been defined.

The particular gene that causes DBMD is found on the X chromosome. A functional copy of the gene is needed for normal muscle function. Males carry one X chromosome and one Y chromosome. Females carry two X chromosomes. Because the gene involved in DMD is on the X chromosome, it is called X-linked. Because males have only one X chromosome, a male carrying a copy with a DBMD mutation will have the condition. Because females have two copies of the X chromosome, a female can have one copy with a DBMD mutation and one functional copy. The functional copy is usually enough to compensate, and a female with a DBMD mutation usually has few or no symptoms. However, because she can pass the mutation on to her children, she is called a “carrier”. Each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50% chance of inheriting the flawed gene and having DBMD. Each of her daughters has a 50% chance of inheriting the mutation and being a carrier. For more information on genes and mutations, see “About Genes and Mutations”.

Most boys with DBMD inherited the mutation from their mother. However, in about one-third of the patients with DBMD, the mother is not a carrier. Rather, there was a new mutation that formed in the egg that produced that child. In these cases, it is unlikely that future children will also have DBMD. However, in some cases, more than one egg was affected, in which case the chance of having another child with DBMD is increased.

Genetic counselors are professionals that help families understand how genes run in families and what the chances are that future children will also have DBMD. They can help arrange for genetic testing and can help families understand the test results. For more information on genetic counseling, or to find a genetic counselor in your area, see the National Society of Genetic Counselors at www.nsgc.org.

DBMD Mutation in Females

Females rarely get DBMD. Because females have two copies of the X chromosome, the second functional copy is usually enough to compensate for the flawed one. In females, one of the X chromosomes in each cell is turned “off” in a process called X inactivation. The X chromosome that gets turned “off” is random, so on average a female with a DBMD mutation will have the functional (or, nonmutated) X “on” in about half of her cells and the flawed X “on” in the other half. If, by random chance, most of her muscle cells end up with the flawed X “on” (and the functional one “off”), then she will have the signs and symptoms of DBMD. However, this is rare. These females are sometimes referred to as manifesting carriers, and their form of the disease can be mild or it can be as severe as is seen in males.

Carrier females in later adult life (whether or not they are manifesting) sometimes develop heart problems that are characterized by shortness of breath or an inability to do moderate exercise. The chance that a carrier female will develop heart problems is not known. These heart problems, if untreated, can be serious and life threatening.

DIAGNOSIS

Boys with DMD are usually diagnosed when they are around 3 to 6 years of age. In diagnosing DBMD (or any form of muscular dystrophy), a doctor begins by taking a patient and family history and performing a physical examination. Much can be learned from these, including the pattern of muscle weakness. The history and physical can suggest the diagnosis, even before any diagnostic tests are done. It is, however, important to do the diagnostic tests because other diseases have some of the same symptoms as DBMD. Following are brief descriptions of some of the more commonly performed tests or procedures recommended when DMD is suspected.

Creatine Kinase (CK) Test
Creatine kinase (CK) is a blood test. CK is normally found at high levels in the muscle and low levels in the blood. When there is injury to muscle or when there is a breakdown of the muscle membrane as in DBMD, the CK leaks out of the muscle and into the blood. In DBMD, the CK level is usually 20 to 200 times higher than normal. Very few other diseases cause such a high level of CK in the blood. The blood level of CK is increased from the time of birth in people with DBMD.

Many of the signs and symptoms of DMD are exceedingly difficult to detect in the early stages because many other conditions can produce similar signs and symptoms. Moreover, parents often are told by their doctor (or even several doctors) that their child will outgrow the clumsiness or other performance problems. Because of this difficulty in diagnosing, doctors are now being taught to do a CK test on young boys with these signs and symptoms, even if they do not find anything when they examine the child.

Genetic Testing
When a child is found to have an extremely high CK level, the next step usually is genetic testing on the blood to look for a mutation in the dystrophin gene. There are two types of genetic testing for DBMD. The first looks for large pieces of the dystrophin gene that are either missing (deleted) or duplicated. If a deletion or duplication is found in the dystrophin gene, then the diagnosis is confirmed and additional testing is generally not needed. Approximately 65% to 70% of patients with DBMD have a deletion or duplication that can be identified with this type of test.

The remaining 30% to 35% of DBMD patients have a tiny mutation that is much more difficult to find. In recent years, several approaches have been developed to identify these very small changes (point mutations). Currently, this type of testing is not routinely used to make a diagnosis, but is useful for genetic counseling.

The gene that carries the mutation for DBMD is the largest human gene that has been identified, which can make the task of identifying the flaw in the gene difficult. Hundreds of different mutations in the dystrophin gene have been found to result in DBMD. For more details on genes and mutations, see “About Genes and Mutations”.

Muscle Biopsy
Not all mutations in DBMD patients can be identified, so a negative genetic test does not necessarily mean that the patient does not have DBMD. Therefore, if the genetic testing is negative, then a muscle biopsy is usually recommended to make a diagnosis.

When seen under a microscope, muscle from patients with DBMD looks different from muscle of individuals who do not have DBMD. By examining a small sample of the patient’s muscle, doctors can tell a great deal about what is actually happening inside the muscle. Modern techniques can use the biopsy to distinguish MD from inflammation and other disorders. Other tests on the biopsy sample can provide information about which muscle proteins are present in the muscle cells, and whether they are present in the expected amounts and in the right places. During a muscle biopsy, a small piece of muscle (about the size of a pencil eraser) is removed and cut into very thin slices. These slices are stained with a series of special dyes to show the different types of muscle and are studied by a pathologist (a doctor who evaluates diagnostic tests). The slices can also be stained to see whether or not functional dystrophin is present in sufficient levels for normal muscle function.