Lecture 23 Part I: Duchenne Muscular Dystrophy (DMD)

What is DMD?

• Recessive, X-linked single gene disorder; most common neuromuscular genetic disorder.

• Incidence: 1 in 3,600 males; <1 per million females.

• 1/3 of cases arise from de novo mutations.

• No racial or ethnic predilection.

What are the early clinical manifestations of DMD?

• Common: delayed motor milestones, muscle weakness, hypertrophic calves, Gowers sign.

• Less common (30–50%): cognitive impairment, speech delay, autism/ADHD/OCD.

What are the late clinical manifestations of DMD?

• Dilated cardiomyopathy, loss of ambulation, decreased respiratory function.

• Scoliosis/kyphosis, compression fractures, contractures.

What does the DMD disease progression timeline look like?

• Chart shows function declining over age.

• Early ambulatory → mid ambulatory → late ambulatory plateau → loss of ambulation.

• Respiratory and cardiac decline follow after ambulation is lost.

What does progressive muscle tissue look like across DMD stages?

• Early stage: relatively normal muscle fiber arrangement.

• Mid stage: increased fiber size variability, some inflammatory infiltrate.

• Late stage: nearly complete replacement of muscle with fat and fibrotic tissue.

How is DMD diagnosed?

• Serum: elevated creatine kinase (CK), alanine aimonotransferase (ALT), and aspartate aminotransferase (AST).

• Genetic testing: MLPA, chromosomal array, Southern blot, or sequence analysis.

• Muscle biopsy: morphology, dystrophin staining, Western blot.

What is the dystrophin gene and where is it located?

• Encoded by DMD at Xp21.2-21.1; largest gene in the human genome (2,400 kb, 79 exons).

• Mutation hot spots: exons 45–55 or 3–9 (54% of cases); over 7,000 mutations identified.

What types of mutations cause DMD, and why are they pathogenic?

• Out-of-frame mutations: 60–70% deletions, 5–15% duplications, ~20% point mutations/small indels.

• Frameshift/nonsense → prematurely truncated protein → non-functional, unstable dystrophin.

What is the function of dystrophin?

• Critical component of the dystrophin-glycoprotein complex (DGC).

• Bridges intracellular cytoskeleton (actin) to extracellular matrix; anchors proteins to the sarcolemma.

• Also expressed in retina, kidney, brain, and peripheral nerves, not only muscle.

What are the two main structural mechanisms behind DMD?

• Sarcolemma weakening: repeated contraction/relaxation without dystrophin → loss of membrane integrity (normally maintained by the DGC).

• Failure to regenerate: dystrophin normally establishes polarity in asymmetric satellite cell division; without it, muscle repair fails.

What supportive treatments are used in DMD?

• Physical therapy, braces or surgical orthopedic correction, gastrostomy tube, respiratory assistive devices.

• Cardiac: ACE inhibitors, ARBs, β-blockers.

• Skeletal muscle: corticosteroids/glucocorticoids.

What molecular therapies exist for DMD?

• Exon-skipping ASOs: restore reading frame by skipping a mutated exon → shorter but partially functional dystrophin.

• Gene therapy.

• Utrophin upregulation (ezutromid): utrophin is a functional analog of dystrophin.

• Nonsense read-through (ataluren): allows ribosome to read through a premature stop codon.

How does exon-skipping work?

• In DMD, frameshift mutation → ribosome stops early → truncated, nonfunctional protein.

• Antisense oglionucleotide (ASO) binds pre-mRNA → spliceosome skips the mutated exon → shorter but in-frame mRNA.

• Translation continues → partially functional dystrophin (analogous to Becker MD).

How do DMD and Becker Muscular Dystrophy (BMD) compare?

• Both: X-linked recessive, caused by DMD/dystrophin mutation, similar symptoms.

• DMD: early onset (childhood), almost no dystrophin, faster progression.

• BMD: late onset (adolescence), 10–40% dystrophin expression, slower progression.