Duchenne muscular dystrophy (DMD) is a severe genetic disorder causing progressive muscle degeneration and weakness throughout the body, including skeletal, heart, and lung muscles. While DMD is far more prevalent and typically more severe in males, females can also be affected, often in different ways and with varying degrees of severity.
The Genetic Basis of Duchenne Muscular Dystrophy
DMD is an X-linked recessive genetic disorder. The dystrophin gene, responsible for DMD, is located on the X chromosome. This gene provides instructions for making dystrophin, a protein essential for maintaining muscle cell structure and function. Without enough functional dystrophin, muscle cells become damaged, leading to progressive weakness.
Males inherit one X chromosome from their mother and one Y chromosome from their father. If this single X chromosome carries a dystrophin gene mutation, he will develop DMD, as there is no healthy second X chromosome to compensate. This explains why DMD primarily affects males, with an incidence of about 1 in 3,500 to 6,000 live male births.
Females have two X chromosomes, inheriting one from each parent. If one X chromosome carries a mutated dystrophin gene, a second, healthy X chromosome often provides enough functional dystrophin to prevent the full disease. This genetic redundancy generally protects females from the severe symptoms seen in affected males.
How Females Can Be Affected by Duchenne Muscular Dystrophy
Females can still be impacted by DMD, most commonly as carriers. A female carrier has one X chromosome with a mutated dystrophin gene and one normal X chromosome. While many carriers remain asymptomatic, “manifesting carriers” can experience symptoms. This occurs due to skewed X-inactivation, where the X chromosome carrying the healthy dystrophin gene is preferentially inactivated, leaving the mutated gene active.
Manifesting carriers may develop mild to moderate muscle weakness, fatigue, or muscle cramps. Muscle weakness often presents asymmetrically and is less severe than in males with DMD. A major concern for female carriers, even those without skeletal muscle symptoms, is the increased risk of cardiac involvement, particularly dilated cardiomyopathy. 10-50% of carriers may have heart changes, with dilated cardiomyopathy present in about 7.3–16.7% of female DMD carriers.
In rare instances, females can develop the full, severe form of DMD, similar to affected males. This can occur by inheriting a mutated dystrophin gene on both X chromosomes. Another cause is Turner syndrome, where a female has only one X chromosome; if this carries the DMD mutation, she develops the disease. Additionally, X-autosome translocations, especially coupled with skewed X-inactivation, can lead to DMD in females.
Importance of Diagnosis and Care for Females
Diagnosing DMD in females can be challenging due to its variable presentation and rarity. Symptoms, when present, might be subtle or manifest differently, leading to delayed or missed diagnoses. Healthcare providers should consider DMD in females with unexplained muscle weakness, fatigue, or cardiac issues, especially if there is a family history.
Early recognition is important, particularly for cardiac monitoring, as cardiomyopathy is a significant concern for both manifesting carriers and those with the full disease. Regular cardiac evaluations, such as echocardiograms or cardiac MRIs, are recommended for all female carriers, starting in adolescence or early adulthood, and repeated every three to five years. Comprehensive medical care for females with DMD or carrier status includes monitoring muscle function, cardiac health, and genetic counseling. Genetic counseling is important for family planning, providing information about inheritance patterns and reproductive options for carriers.