Duchenne Muscular Dystrophy (DMD) is a severe, progressive disorder characterized by the wasting of muscle tissue, including skeletal, heart, and lung muscles. The condition is caused by a genetic mutation that prevents the body from producing functional dystrophin, a protein crucial for maintaining the structural integrity of muscle fibers. Without this protein, muscle cells become damaged and are eventually replaced by fat and scar tissue, leading to a loss of strength and function.
The X-Linked Nature of DMD
DMD is classified as an X-linked recessive disorder, meaning the gene responsible is located on the X chromosome. This specific gene, known as the DMD gene, contains the instructions for making the dystrophin protein. Because the mutation is tied to a sex chromosome, the inheritance pattern is different between males and females.
Males possess one X and one Y chromosome (XY), while females possess two X chromosomes (XX). This chromosomal difference is the primary factor dictating the expression of the disease. Since the mutation is recessive, having a second, functional copy of the gene is usually enough to prevent the full disease from developing. This is why the disorder predominantly affects males.
The mutation is located on the short arm of the X chromosome and is prone to large changes or deletions. Approximately two-thirds of DMD cases are inherited from a mother who is a carrier. However, about one-third of cases result from a new, spontaneous genetic change, known as a de novo mutation, which is not inherited from either parent.
Inheritance Patterns in Male Offspring
The inheritance of DMD in male offspring is a consequence of their single X chromosome. A male child inherits his X chromosome from his mother and his Y chromosome from his father. If the mother is a carrier, she can pass on either her healthy X or her affected X chromosome.
Each son born to a carrier mother has a 50% chance of inheriting the X chromosome with the mutation. If he inherits the affected X chromosome, he will develop DMD because he has no second copy to compensate for the faulty gene. The father’s genetic contribution does not influence the son’s risk, as he only contributes the Y chromosome.
Conversely, the son has a 50% chance of inheriting the mother’s healthy X chromosome, in which case he will be unaffected. Inheriting the mutated gene almost always results in the full expression of DMD in males. This mechanism explains why the disease occurs in approximately 1 in 3,500 to 6,000 male births globally.
Inheritance Patterns and Carrier Status in Female Offspring
The inheritance pattern for female offspring differs because they receive two X chromosomes, one from each parent. When a carrier mother passes on the gene, the daughter has a 50% chance of inheriting the affected X chromosome. Because she also inherits a healthy X chromosome from her father, the functional copy acts as a genetic “backup.”
This backup copy means that most daughters who inherit the mutation do not develop the full disorder; instead, they become carriers. The presence of the second, working DMD gene allows for enough dystrophin production to prevent the severe muscle degeneration seen in affected males. Females who are carriers have a 50% chance of passing the mutation on to their own children.
In a small minority of cases, a female carrier may experience symptoms and is called a “manifesting carrier.” This rare occurrence is typically due to “skewed X-inactivation,” where the healthy X chromosome is randomly turned off in a disproportionate number of cells. Manifesting carriers may exhibit symptoms ranging from mild muscle weakness and cramping to heart problems. A female can also be fully affected if she inherits an affected X chromosome from both parents, although this is extremely rare.
Recurrence Risk for Future Pregnancies
For a woman who is a known carrier of the DMD mutation, the risk of passing the gene applies to every pregnancy, regardless of the child’s sex. In each pregnancy, there is a 50% chance the child will inherit the affected X chromosome. This results in a 25% chance of having an affected male child and a 25% chance of having a carrier female child.
The overall risk for any child of a carrier mother to be affected with DMD is 1-in-4, or 25%. This is calculated by combining the 50% chance of having a male child with the 50% chance that male child inherits the mutation. The remaining 50% of children will be either unaffected males or non-carrier females.
If a male with DMD is able to have children, he will pass his only X chromosome, which carries the mutation, to all of his daughters. Therefore, all his daughters will be obligate carriers. His sons, however, receive a Y chromosome from him and are unaffected and not carriers.