Can a female present with Becker muscular dystrophy (BMD)?

Can Females Present with Becker Muscular Dystrophy?

Yes, females can present with Becker muscular dystrophy (BMD), though it is rare, occurring through several distinct mechanisms including manifesting carrier status (approximately 8% of female carriers), skewed X-inactivation, or extremely rare homozygous mutations. 1, 2

Mechanisms of Female Presentation

Manifesting Carriers (Most Common)

• Approximately 8% of female DMD/BMD carriers develop clinical symptoms ranging from mild to significant muscle weakness 2
• Manifesting carriers typically present with asymmetrical muscle weakness affecting proximal limb girdle muscles, which distinguishes them from the more symmetrical pattern seen in affected males 2
• Onset age is highly variable, ranging from childhood (as early as 8 years) to adulthood (late 20s or beyond) 2, 3
• The mechanism involves non-random X-chromosome inactivation (skewed lyonization), where the normal X chromosome is preferentially inactivated in muscle tissue, leaving the mutated dystrophin gene predominantly expressed 3

Clinical Presentation Patterns in Females

Female carriers can present with three distinct patterns:

• Asymmetrical bilateral proximal upper and lower extremity weakness 2
• Scapulohumeral pattern mimicking scapulohumoral muscular dystrophy 2
• Isolated bilateral asymmetric proximal lower extremity weakness 2

Homozygous BMD (Extremely Rare)

• Homozygous dystrophin mutations can occur in females born to consanguineous parents where both parents carry the same dystrophin deletion 4
• These patients present with typical BMD features including exercise intolerance, recurrent myoglobinuria, and elevated CK levels 4
• Unlike Turner syndrome-associated female DMD, homozygous BMD patients have normal karyotypes 4

Diagnostic Approach

Laboratory Findings

• Serum creatine kinase (CK) is elevated in all female BMD patients, though levels do not correlate with severity of muscle weakness 2
• CK elevation in female carriers should prompt further investigation even in the absence of symptoms 1

Muscle Biopsy and Dystrophin Analysis

• Immunohistochemical staining shows a mosaic pattern with both dystrophin-positive and dystrophin-negative fibers in manifesting carriers 3
• Immunoblotting may reveal dystrophin of normal size but reduced abundance 3
• Western blot can confirm the presence of truncated but functional dystrophin protein 4

Genetic Testing

• Multiplex ligation-dependent probe amplification (MLPA) is essential for diagnosis in female carriers, as it detects both deletions and duplications with higher accuracy than conventional multiplex PCR 2
• Extended multiplex PCR and mRNA analysis may be needed when standard testing is negative 3
• Genetic testing should be performed even without family history, as approximately one-third of manifesting female carriers represent new mutations 2

Critical Management Considerations

Cardiac Surveillance (Highest Priority)

• Cardiomyopathy is the most frequent and life-threatening complication in female BMD carriers and requires systematic monitoring 1, 5
• The American Heart Association guidelines note that manifesting female carriers of DMD/BMD mutations can develop dilated cardiomyopathy late in life 6
• Annual cardiac evaluation with echocardiography and ECG is recommended for all female carriers, even those without skeletal muscle symptoms 5
• Cardiac complications can occur independently of skeletal muscle involvement severity 1

Multidisciplinary Follow-up

• Female carriers require the same multidisciplinary approach as affected males, including neurological, respiratory, cardiac, and orthopedic assessments 5
• Respiratory function should be monitored, though respiratory complications are less common than cardiac involvement in female carriers 5

Clinical Pitfalls to Avoid

• Do not dismiss elevated CK in females as laboratory error—it warrants full dystrophinopathy workup 2
• Asymmetrical weakness patterns can mimic other conditions such as limb-girdle muscular dystrophy or inflammatory myopathies; dystrophin analysis is essential 2
• Absence of family history does not exclude BMD in females—one-third of cases represent new mutations 2
• Normal conventional multiplex PCR does not rule out carrier status—MLPA is required for comprehensive detection 2
• Cardiac screening must continue lifelong even in asymptomatic female carriers, as cardiomyopathy can develop at any age 1, 5

Genetic Counseling

• Genetic counseling should be systematically offered to all female carriers and their families 1
• Female carriers have a 50% risk of transmitting the mutation to offspring regardless of their own symptom status 1