Introduction to DMD
- Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder resulting from mutations in the dystrophin gene.
- The absence of the dystrophin protein leads to degeneration of skeletal and cardiac muscle, causing progressive muscle weakness and wasting.
- DMD is characterized by rapid disease progression, with patients typically requiring a wheelchair by the age of 10. Life expectancy has been extended with treatments like corticosteroid and medical care, but patients often succumb to cardiac and respiratory complications.
- Becker muscular dystrophy (BMD) is a milder form of dystrophinopathy, presenting later than DMD and varying in severity among patients.
- X-linked dilated cardiomyopathy (XLDCM) is another phenotype of dystrophinopathy, primarily affecting the heart.
Molecular Aspects of DMD
- The dystrophin gene is the largest in humans, producing multiple isoforms through various processes, including alternative splicing.
- Dystrophin protein is crucial for muscle stability. In healthy muscles, it's found on the intracellular surface of the sarcolemma and forms the dystrophin-associated glycoprotein complex (DGC) with other proteins.
- Mutations in the dystrophin gene, such as deletions, duplications, and other rearrangements, lead to the absence of dystrophin protein, causing muscle wasting, respiratory and cardiac failure, and early death.
- The loss of dystrophin disrupts the DGC complex, leading to muscle fiber necrosis and replacement of muscle with fibroadipose tissue.
Diagnosis
- Molecular diagnosis of DMD involves detecting deletions/duplications using techniques like microarray-based comparative genomic hybridization (array-CGH) and Multiple Ligation Probe Assay (MLPA).
- Next-generation sequencing (NGS) has emerged as a valuable tool for diagnosing DMD, especially given the large size of the dystrophin gene.
- The most common molecular defect in DMD is the deletion of one or more exons, accounting for 65% of cases. Duplications represent 6%-10% of cases, while the rest are due to small mutations and rearrangements.
Therapeutic Strategies
- Currently, there's no effective treatment for DMD. Steroids are the only approved drugs that can slow disease progression.
- Recent research has focused on strategies to restore dystrophin production and preserve muscle mass. RNA is a primary target, with Antisense Oligonucleotides (AONs) being the most used molecules for RNA modulation.
- Efforts are being made to identify delivery systems to enhance the efficacy of AONs, with nanomaterials showing promise as DNA/RNA vectors.