Definition And Genetics
Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) are dystrophinopathies resulting from mutations in the dystrophin gene.
- They are inherited as X-linked recessive (XLR) disorders.
- The gene is located at the Xp21 locus and encodes a 427 kD cytoskeletal protein called dystrophin.
- Dystrophin anchors the muscle fibre membrane through the dystroglycan complex.
- In DMD, mutations lead to the absence of dystrophin, whereas in BMD, dystrophin is reduced or patchy.
- Approximately 65-70% of cases have a gene deletion, while almost 35% are new mutations where the mother is not a carrier.
Epidemiology
- DMD is the most common neuromuscular disease, with an incidence of 1 in 3500 live male births.
- BMD is less common and presents with a milder phenotype.
- Carrier females are typically asymptomatic but may demonstrate elevated Creatine Phosphokinase (CPK) levels.
Pathogenesis
- Reading Frame Hypothesis: Phenotypic variation between DMD and BMD is explained by the reading frame hypothesis.
- In >90% of DMD cases, mutations disrupt the reading frame (frameshift mutations), leading to severe dystrophin deficiency.
- In BMD, mutations maintain the reading frame (in-frame mutations), resulting in the production of an abnormal but partly functional dystrophin protein.
Clinical Manifestations
Duchenne Muscular Dystrophy (DMD)
- Onset: Usually early, before 5 years of age. Recognition may be delayed up to 4 years.
- Motor Milestones: Delayed gross motor milestones, including head control, sitting, and walking.
- Gait And Posture: Waddling gait on a wide base associated with lumbar lordosis becomes apparent at 3-4 years. Tendency to walk on toes.
- Specific Signs:
- Gower sign: Difficulty getting up from the floor, requiring the child to climb up on themselves.
- Valley sign: Wasting of posterior axillary fold muscles with hypertrophy of deltoid and infraspinatus muscles.
- Muscle Enlargement: Symmetrical pseudohypertrophy is classical, resulting from fat and connective tissue deposition. Most commonly affects calves, deltoid, biceps, and tongue. Muscles feel firm despite weakness.
- Reflexes: Knee jerks and upper limb tendon reflexes are retained early and lost after wasting; the ankle jerk may be retained until late.
- Progression: Weakness of neck flexors is an early sign. Ambulation is typically lost between 7-13 years (untreated patients lose independent ambulation between 8.8 and 10.5 years).
- Complications: After loss of ambulation, patients develop worsening kyphoscoliosis, joint contractures (ankle, knee, elbow), and respiratory deficits due to weak intercostal and diaphragmatic muscles.
- Systemic Involvement:
- Subclinical cardiomyopathy is common; symptomatic in 20%. Deletion of exons 48, 48-49, and 45-53 strongly predisposes to cardiac complications and arrhythmias.
- Intellectual impairment (IQ < 70) occurs in about 20% of cases. Impaired gastric motility is also noted.
- Mortality: Death typically occurs before 20 years of age due to respiratory insufficiency and cardiomyopathy.
Becker Muscular Dystrophy (BMD)
- Onset: Later onset, typically >6 years of age.
- Progression: Slower progression with ambulation preserved until early or mid-adult life.
- Specific Features: Higher incidence of myalgias, occasional rhabdomyolysis following exercise, and early cardiomyopathy.
Comparison Of DMD And BMD
| Feature | Duchenne Muscular Dystrophy | Becker Muscular Dystrophy |
|---|---|---|
| Onset | < 5 years | > 6 years |
| Mutation Type | Frameshift (Absent dystrophin) | In-frame (Patchy/reduced dystrophin) |
| Loss of Ambulation | 7-13 years | Early/mid adult life |
| Associated Features | Severe scoliosis, respiratory failure | Prominent myalgia, exertional rhabdomyolysis |
Differential Diagnosis
- Spinal Muscular Atrophy (SMA): Presents with fasciculations, early areflexia, and normal to mildly elevated CPK.
- Congenital Myopathies: Static or slowly progressive, associated with facial/bulbar weakness, normal/mildly elevated CPK, and confirmed by specific biopsy findings (cores, rods).
- Limb Girdle Muscular Dystrophy (LGMD): Autosomal recessive or dominant; may present with calf hypertrophy but lacks facial involvement, and parent may be variably affected.
- Congenital Myotonic Dystrophy: Characterized by myotonia in the mother, neonatal onset, and generalized weakness.
Investigations And Diagnosis
- Serum CPK: Grossly elevated (>10 times upper limit of normal) in both DMD and BMD. Levels may reduce in advanced disease. Elevated CPK is also useful for carrier detection in females.
- Electrophysiology: Electromyogram (EMG) and Nerve Conduction Velocity (NCV) demonstrate a myopathic pattern, helping to rule out neurogenic syndromes.
- Genetic Studies: Multiplex PCR and Multiplex Ligation-Dependent Probe Amplification (MLPA) detect gene deletions (65-70%) or duplications. Restriction Fragment Length Polymorphism (RFLP) and haplotypic analysis are used for non-deleted patients.
- Muscle Biopsy: Indicated for mutation-negative cases or to differentiate DMD from BMD. Routine H&E shows necrosis, regeneration, variable fiber diameter, central nuclei, and replacement by fibrofatty tissue. Immunohistochemical staining uses dystrophin antibodies (α, β, γ); dystrophin is absent in DMD and reduced/patchy in BMD.
Diagnostic Algorithm
Index Patient → DNA (gene deletion screening via PCR/MLPA) → If No Gene Deletion → Southern Blot or Duplication analysis → Haplotypic analysis → Muscle Immunohistochemistry / Western blot → Confirms diagnosis and enables detection of point mutation.
Management
Pharmacotherapy
- Corticosteroids: The current standard of care. Reduces apoptosis and decelerates myofibre necrosis, prolonging ambulation.
- Prednisolone: 0.75 mg/kg/day.
- Deflazacort: 0.9 mg/kg/day (preferred due to fewer long-term side effects and less excessive weight gain).
- Immunization against pneumococcus, influenza, and varicella must be ensured before initiating steroids.
Supportive And Multidisciplinary Care
- Physical Therapy: Avoid prolonged immobility to encourage ambulation. Effective stretching, passive exercises, appropriate positioning, and night splints prevent contractures.
- Rehabilitation: Prolong active walking with leg braces (orthoses) when independent ambulation declines.
- Surgery: Surgical release of contractures (tenotomy) and interventions for progressive spinal deformities (scoliosis).
- Monitoring:
- Pulmonary function tests (biannually if non-ambulatory).
- Echocardiography (every 2 years for <10 years old; annually if >10 years).
- DEXA scan annually, along with serum calcium and vitamin D monitoring.
- Nutrition: Low-fat diet to prevent obesity, which hampers ambulation and complicates care.
Newer Therapies
- Exon Skipping: Antisense oligonucleotides targeting Exon 45, 51, and 53.
- Stop Codon Read-Through: Ataluren.
- Gene Therapy: Currently under research and development.
- Others: Utrophin regulators, myostatin inhibitors.
Genetic Counseling And Prenatal Diagnosis
- Accurate pedigree charting tracing back at least two generations is essential.
- Identify carrier status of females by CPK screening (normal in 20% of carriers) and targeted DNA studies.
- Prenatal Diagnosis: Fetal sex identification is the first step. If male, Chorionic Villus Sampling (CVS) is conducted at the 11th to 12th week of gestation for multiplex PCR or Southern blot analysis.