In 1987, the protein associated with the DMD gene was identified and named dystrophin. The dystrophin gene is located in the short arm of the X chromosome, in the Xp21.2 locus

The majority of mutations of the dystrophin gene are deletions of one or more parts of it.1

 

Pathogenesis

DMD occurs because the mutated DMD gene fails to produce virtually any functional dystrophin.

Individuals with BMD genetic mutations make dystrophin that is partially functional, which protects their muscles from degenerating as badly or as quickly as in DMD.

The dystrophin protein transfers the force of muscle contraction from the inside of the muscle cell outward to the cell membrane. Because it connects the center of the muscle cell to the edge of the cell, the dystrophin protein is extremely long. One end is specialized for linking to the muscle cell interior and the other end is specialized for linking to a variety of proteins at the cell membrane. The long middle section, called the rod domain, is taken up by a series of repeating units called spectrin repeats.

The repeated spectrin units in the middle of the protein play an important role in linking the two ends, but studies have shown that the exact number of these units is not critical for the function of the protein as a whole. Many cases of DMD are caused by mutations in the part of the gene that encodes this middle section. Production of the entire protein stops when the mutation is encountered.

The absence of dystrophin sets in motion a cascade of harmful effects. Fibrous tissue begins to form in the muscle, and the body’s immune system increases inflammation. In addition to its force-transfer role, dystrophin provides the scaffold for holding numerous molecules in place near the cell membrane. Loss of dystrophin displaces these molecules, with consequent disruptions in their functions. Lack of dystrophin causes muscle damage and progressive weakness, beginning in early childhood.

Inheritance in DMD

DMD is inherited in an X-linked pattern because the gene that can carry a DMD-causing mutation is on the X chromosome. Every boy inherits an X chromosome from his mother and a Y chromosome from his father, which is what makes him male. Girls get two X chromosomes, one from each parent.

Each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50 percent chance of inheriting the flawed gene and having DMD. Each of her daughters has a 50 percent chance of inheriting the mutation and being a carrier. Carriers may not have any disease symptoms but can have a child with the mutation or the disease. DMD carriers are at risk for cardiomyopathy.

Although DMD often runs in a family, it is possible for a family with no history of DMD to suddenly have a son with the disease. There are two possible explanations. The first is that the genetic mutation leading to DMD may have existed in the females of a family for some generations without anyone knowing. Perhaps no male children were born with the disease, or, even if a boy in an earlier generation was affected, relatives may not have known what disease he had.

The second possibility is that a child with DMD has a new genetic mutation that arose in one of his mother’s egg cells. Because this mutation is not in the mother’s blood cells, it is impossible to detect by standard carrier testing.

A man with DMD cannot pass the flawed gene to his sons because he gives a son a Y chromosome, not an X. But he will certainly pass it to his daughters, because each daughter inherits her father’s only X chromosome. They will then be carriers, and each of their sons will have a 50 percent chance of developing the disease and so on.

A good way to find out more about the inheritance pattern in your family is to talk to your MDA Care Center physician or a genetic counselor. More information also is included in MDA’s booklet Facts About Genetics and Neuromuscular Diseases.

Females and DMD

Diseases inherited in an X-linked recessive pattern mostly affect males because a second X chromosome usually protects females from showing symptoms.
Diseases inherited in an X-linked recessive pattern mostly affect males because a second X chromosome usually protects females from showing symptoms.

Why don’t girls usually get DMD?

When a girl inherits a flawed dystrophin gene from one parent, she usually also gets a healthy dystrophin gene from her other parent, giving her enough of the protein to protect her from the disease. Males who inherit the mutation get the disease because they have no second dystrophin gene to make up for the faulty one.

Early in the embryonic development of a female, either the X chromosome from the mother (maternal X) or the one from the father (paternal X) is inactivated in each cell. Chromosomes become inactivated at random. In each cell, there is a 50 percent chance that either the maternal or paternal X chromosome will be inactivated, with the other left active.

Usually, girls do not experience the full effects of DMD the way boys do, although they still have symptoms of muscle weakness. A minority of females with the mutation, called manifesting carriers, have some signs and symptoms of DMD.

For these women, the dystrophin deficiency may result in weaker muscles in the back, legs, and arms that fatigue easily. Manifesting carriers may have heart problems, which can show up as shortness of breath or an inability to do moderate exercise. The heart problems, if untreated, can be quite serious, even life-threatening.

In very rare instances, a girl may lack a second X chromosome entirely, or her second X may have sustained serious damage. In these cases, she makes little or no dystrophin (depending on the type of dystrophin mutation), and she develops a dystrophinopathy just as a boy would.

A female relative of a boy with DMD can get a full range of diagnostic tests to determine her carrier status. If she is found to be a DMD carrier, regular strength evaluations and close cardiac monitoring can help her manage any symptoms that may arise. For more on DMD in females, see Debatable Destinies: Duchenne muscular dystrophy carriers carry on, despite uncertainty.

References

  1. Hoffman, E. P., Brown, R. H. & Kunkel, L. M. Dystrophin: The protein product of the duchenne muscular dystrophy locus. Cell (1987). doi:10.1016/0092-8674(87)90579-4
https://www.mda.org/disease/duchenne-muscular-dystrophy/causes-inheritance

 

 

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A 4-year-old boy develops weakness of proximal lower back and extremity muscles, manifested by lordosis, a waddling gait, and the need to push on his knees in order to stand (Gower sign). Examination reveals proximal muscle weakness and bilateral enlargement of the calves. His younger brother has begun to display similar findings, as has his older half-brother, who has the same mother. Serum CK is markedly elevated. Which of the following is characteristic of this disorder?

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    A. Aberrant protein coded by a very small gene sequence on the Y chromosome

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    B. Autosomal dominant mode of inheritance

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    C. Mitochondrial inheritance

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    D. Regression of findings in late adolescence and adult life

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    E. Total absence or marked decrease of an important gene product

 

The answer is E. The clinical picture is that of Duchenne muscular dystrophy, the most common and most severe of the muscular dystrophies. This X-linked disorder is characterized by failure of synthesis of dystrophin, most often because of deletion of one or many exons in the DMD gene. Patients manifest with proximal muscle weakness, progressing to muscle necrosis. Serum CK is markedly increased. Compensatory hypertrophy is followed by pseudohypertrophy, in which necrotic muscle is replaced by fat and connective tissue. Most patients become wheelchair bound and die of respiratory or cardiac failure in their late teenage years or in their early twenties. 


 

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Update March 28, 2021