Do patients with Duchenne Muscular Dystrophy (DMD) have dystrophin?

Dystrophin Status in Duchenne Muscular Dystrophy Patients

Patients with Duchenne muscular dystrophy (DMD) have nearly complete absence of dystrophin protein, which is the defining pathological feature that distinguishes DMD from the milder Becker muscular dystrophy (BMD). 1

Molecular Basis of Dystrophin Deficiency

DMD results from mutations in the dystrophin gene that disrupt the reading frame and preclude translation of full-length dystrophin protein. The truncated protein produced is unstable and degrades, resulting in nearly complete absence of functional dystrophin. 1

• The most common mutations are multiple exon deletions that disrupt the reading frame, preventing production of stable dystrophin protein 1
• Smaller gene deletions, duplications, and point mutations account for a smaller fraction of cases 1
• The absence of dystrophin leads to instability of the sarcolemmal membrane, resulting in excessive calcium entry, muscle fiber necrosis, chronic inflammation, and progressive fibrotic replacement of muscle tissue 2

Diagnostic Confirmation of Dystrophin Absence

Diagnosis is confirmed by finding absent or abnormal dystrophin using immunohistology or protein analysis of muscle tissue when DNA analysis is normal (which occurs in approximately 1/3 of patients). 1

• Standard genetic tests detect approximately 95% of DMD mutations, but 5% may be missed 3, 4
• The absence of dystrophin protein on muscle biopsy is sufficient to confirm dystrophinopathy and guide management as DMD, regardless of genetic test results 3, 4
• Muscle biopsy becomes necessary when genetic testing is negative to evaluate dystrophin protein expression 3, 4

Secondary Protein Deficiencies

The absence of dystrophin leads to dramatic reduction in all dystrophin-associated proteins in the sarcolemma of DMD muscle. 5

• Dystrophin exists in a large oligomeric complex tightly associated with several sarcolemmal glycoproteins that provide linkage to the extracellular matrix protein laminin 5
• This abnormality is common in all DMD patients, irrespective of age 5
• The loss of dystrophin-associated proteins renders DMD muscle fibers susceptible to necrosis 5

Rare Exceptions

Extremely rare patients with nonsense mutations may have a milder phenotype despite total absence of muscle dystrophin, though the mechanisms protecting these exceptional cases remain unknown. 6

• These observations indicate it is theoretically possible to have functional muscle even without dystrophin, though this represents exceptional cases rather than typical DMD 6
• Three reported polymorphisms in genes LTBP4, SPP1, and ACTN3 were excluded as possible genetic modifiers in these rare cases 6

Contrast with Becker Muscular Dystrophy

In contrast to DMD, Becker muscular dystrophy results from mutations that do not disrupt the reading frame, producing internally deleted but partially functional dystrophin protein. 1

• BMD mutations result in dystrophin protein with internal deletion but retention of amino and carboxy termini that localize the protein to the sarcolemma 1
• This provides a partially functional protein, explaining the milder phenotype of BMD compared to DMD 1