Duchenne and Becker's Muscular dystrophy

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

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.

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 #recents

• 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.