Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by the progressive deterioration and weakening of muscle tissue throughout the body. It is the most severe and common form of muscular dystrophy, affecting skeletal, heart, and lung muscles. DMD is caused by a change in the genetic code for dystrophin, a protein that provides structural support and protection to muscle fibers. The absence of functional dystrophin leads to chronic muscle cell damage, resulting in the loss of strength and function.
X-Linked Inheritance and Biological Sex
The single greatest determinant of risk for developing DMD is biological sex, stemming from the disorder’s pattern of X-linked recessive inheritance. The dystrophin gene resides on the X chromosome.
Biological males (XY) possess only one X chromosome. Males who inherit a mutated copy of the gene will develop the condition because they lack a second X chromosome to compensate for the mutation. This mechanism means DMD predominantly affects males, with an incidence of approximately 1 in every 3,500 to 5,000 male newborns worldwide.
Biological females (XX) have two X chromosomes. If one X chromosome carries the mutation, the healthy copy on the other X chromosome is usually sufficient to prevent the disease’s full manifestation. Consequently, females are most often carriers of the genetic variant rather than affected individuals, though their health risks are still significant.
Origin of the Mutation: Inherited Versus Spontaneous Cases
The risk for DMD is not confined solely to families with a known history of the disorder, as the mutation can arise in two distinct ways.
Approximately two-thirds of all DMD cases are inherited, meaning the mother is a carrier who passes the mutated X chromosome to her son. For carrier mothers, there is a 50% chance with each male pregnancy that the son will inherit the affected gene and develop DMD.
The remaining third of cases (roughly 30% to 33%) are caused by a spontaneous or de novo genetic change. In these instances, the mutation occurs randomly during the formation of reproductive cells or very early in embryonic development, and is not inherited from either parent. This means the dystrophin gene change can appear without any prior evidence of the disorder in the family line.
Genetic testing is necessary to distinguish between a de novo mutation and an inherited case, especially when there is no family history. The high rate of spontaneous mutation ensures that the risk is present across all populations and families.
Risk Profile for Female Carriers
While biological males face the highest risk for developing the full disease, biological females who carry the mutated dystrophin gene face a specific health risk profile. These females are heterozygous, possessing one normal and one mutated copy of the gene. They are protected from the severe form of the disorder by X-inactivation (lyonization), where one of the two X chromosomes is randomly silenced in each cell.
In most female carriers, the inactivation process is random, ensuring that enough cells express the normal dystrophin gene to maintain muscle function. However, a subset of female carriers can become “manifesting carriers,” meaning they experience symptoms of the disorder. This manifestation is linked to a non-random, or skewed, X-inactivation pattern, where the X chromosome carrying the normal gene is preferentially silenced.
Manifesting carriers can experience milder muscle-related symptoms, such as muscle weakness, fatigue, or cramping. Skeletal muscle involvement is estimated to occur in 2.5% to 19% of carriers. Female carriers have an increased risk for cardiac issues, particularly dilated cardiomyopathy, which can be clinically significant even in the absence of obvious muscle weakness. Studies estimate the risk for cardiac dysfunction in carriers to be between 7.3% and 16.7%, necessitating regular cardiac monitoring for all female carriers.