Duchenne Muscular Dystrophy (DMD)

Overview

• Tietz Textbook of Laboratory Medicine, 7th Ed
• Goldman-Cecil Medicine International Edition

Genetics and Molecular Pathophysiology

The DMD Gene

• Located at chromosome Xp21.2, the DMD gene is one of the largest in the human genome (spanning ~2.4 Mb with 79 exons)
• Encodes dystrophin, a 427 kDa (3685 amino acid) rod-like cytoskeletal protein
• Dystrophin has four domains: actin-binding domain, central rod domain (with spectrin-like repeats), cysteine-rich domain, and a C-terminal domain

Mutation Types

Dystrophin-Associated Protein Complex (DAPC)

• Connects the actin cytoskeleton to the extracellular matrix (ECM), stabilizing the sarcolemma during cycles of contraction/relaxation
• Maintains Ca²+ homeostasis
• Transmits force from sarcomeres to the ECM

• Sarcolemmal integrity is lost
• Pathological calcium influx occurs
• Activation of proteases, immune cell infiltration, and cytokine release follow
• Downstream: autophagy, necrosis, fibrosis, and progressive replacement of muscle by adipose and connective tissue
• Dysregulated NF-κB, MAPK, and PI3K/AKT signaling contributes further
• Tietz Textbook, 7th Ed

Clinical Manifestations

Early Childhood (2-5 years)

• Delayed motor milestones (walking, running)
• Frequent falls, difficulty climbing stairs
• Toe walking (early sign)
• Gowers' sign - uses hands to push up from floor (proximal lower limb weakness)
• Calf pseudohypertrophy - muscle replaced by fat/connective tissue but appears enlarged

Progression

• Weakness predominantly affects proximal muscles first, then distal
• Lower extremities affected before upper extremities
• Wheelchair dependency by 10-15 years of age
• Joint contractures (hip flexors, heel cords, iliotibial bands)
• Kyphoscoliosis - worsens after loss of ambulation; impairs respiratory function

Cardiac Involvement

• Dilated cardiomyopathy (DCM) is the hallmark cardiac manifestation
• Caused by cardiac fibrosis and sarcolemmal instability in cardiomyocytes
• Also: rhythm and conduction abnormalities
• Left ventricular dilation and ultimately congestive heart failure
• Cardiorespiratory failure is the primary cause of death

Respiratory Involvement

• Chronic respiratory insufficiency develops in all patients
• Scoliosis accelerates the decline
• Nocturnal hypoventilation, then daytime respiratory failure

Cognitive and Neurodevelopmental

• Lower mean IQ and nonprogressive cognitive impairment in a subset
• Associated learning disorders, autism, and ADHD
• Correlates with the location of the mutation within the DMD gene (mutations near the 3' end affect brain isoforms like Dp71)
• Goldman-Cecil Medicine

Diagnosis

Laboratory

• Serum Creatine Kinase (CK): markedly elevated - typically 20-100x normal (can be >10x normal even in neonates)
• CK elevation can be detected from newborn screening dried blood spots
• Myoglobinuria may occur

Genetic Testing

• First-line: DNA analysis of the DMD gene (multiplex ligation-dependent probe amplification - MLPA, or NGS)
• Detects >90-95% of mutations
• If genetic testing negative: proceed to muscle biopsy

Muscle Biopsy

• Histology: variation in fiber size, necrosis, inflammation, fibrosis, fiber regeneration (chronic myopathy pattern)
• Immunohistochemistry (IHC) for dystrophin: shows complete or near-complete absence of carboxy-terminal dystrophin
• Rare "revertant fibers" may show dystrophin expression (exon skipping in vivo)

Carrier Detection

• Female carriers are usually asymptomatic (X-inactivation)
• Up to 20% of carrier females can manifest some symptoms (muscle weakness, elevated CK, DCM)
• Severe disease in females: due to skewed lyonization or X-autosome translocation involving the DMD gene

Treatment

1. Glucocorticoids (Standard of Care)

• Prednisone 0.75 mg/kg/day - prolongs ambulation, slows muscle strength decline, may help respiratory function and slow scoliosis progression
• Deflazacort 0.9 mg/kg/day - equivalent efficacy with less weight gain compared to prednisone
• Significant side effects include weight gain, growth suppression, behavioral changes, osteoporosis, and cataracts

2. Exon-Skipping Antisense Oligonucleotides (FDA-Approved)

3. Gene Therapy (Newest Development - 2023)

• Delandistrogene moxeparvovec (Elevidys) - FDA-approved in 2023, an AAV-rh74 vector delivering a microdystrophin gene
• Phase 3 EMBARK trial (published Nature Medicine 2025, PMID: 39385046) confirmed functional benefits
• The first approval review by Hoy SM (Drugs, 2023) summarizes the approval data
• Represents a major advance: targets the underlying genetic defect rather than restoring a reading frame

4. Cardiac Management

• ACE inhibitors - started early; slow progression of myocardial fibrosis (associated with poorer prognosis)
• Beta-blockers - for DCM management
• Diuretics - for heart failure
• Cardiology follow-up is mandatory even in asymptomatic patients

5. Respiratory Management

• Pulmonology assessment and monitoring
• Noninvasive ventilation (NIV/BiPAP) - initiation and titration
• Cough assist devices
• Annual pulmonary function tests

6. Orthopaedic Management

• Physical therapy to prevent contractures
• Ankle-foot orthoses (AFOs)
• Spinal fusion for scoliosis if indicated (performed while respiratory function allows)
• Appropriate wheelchair prescription
• Bone health monitoring (glucocorticoid-induced osteoporosis risk)

7. Multidisciplinary Team

Becker Muscular Dystrophy (BMD) - Allelic Variant

• Caused by in-frame mutations in DMD gene (usually exon deletions 45-60)
• Incidence ~1 in 18,500
• Partially functional/reduced dystrophin produced
• Much milder phenotype; mean age of death in mid-40s
• Half of BMD patients are still symptomatic by age 10 years
• Deletions of the distal rod domain (exons 45-60) = mildest phenotype

Prognosis

Key Numbers to Remember

• The EMBARK Phase 3 RCT (Mendell et al., Nat Med 2025) on AAV gene therapy is the most important recent advance in DMD treatment
• A comprehensive therapeutic review by Roberts, Wood & Davies (Nat Rev Drug Discov 2023) covers all emerging strategies