Duchenne muscular dystrophy (DMD), followed by Becker muscular dystrophy (BMD) and the relatively new phenotype DMD associated dilated cardiomyopathy (DCM) are among the most recognized of a group of X-linked muscle disorders called dystropinopathies. They also include other conditions caused by dystrophin mutations, such as X-linked cardiomyopathy and isolated quadriceps myopathy.

Duchenne Muscular Dystrophy (DMD)

• Epidemiology: Most common muscular dystrophy of childhood, affecting 1 in 5000 boys.
• Cause: Mutations in the dystrophin gene.
• Age of Onset: Symptoms typically present between 3-5 years.
• Clinical Features:
  • Common: Motor delay, gait abnormalities, frequent falls, difficulty rising from the ground.
  • Less Common: Language/global developmental delay, raised serum creatine kinase, or hepatic transaminases.
  • Typical Signs: Proximal lower limb and trunk weakness, waddling gait, prominent calves, positive Gowers’ sign, and neck flexor weakness.
• Progression:
  • Initial increase in motor skills until age 6, followed by progressive weakness.
  • Loss of independent ambulation by age 13.
• Complications:
  • Respiratory: Chronic restrictive lung disease, sleep-disordered breathing, nocturnal and diurnal hypercapnia.
  • Cardiac: Dilated cardiomyopathy, arrhythmias, with early signs such as resting tachycardia.
  • Cognitive: Lower average IQ (verbal IQ more affected), ADHD, autism spectrum disorders.

Becker Muscular Dystrophy (BMD)

• Epidemiology: Less common and milder than DMD.
• Cause: Mutations in the dystrophin gene, similar to DMD.
• Clinical Features:
  • Independent ambulation typically persists beyond age 16.
  • Variable onset of weakness; some individuals remain ambulant throughout life.
• Cardiac Manifestations:
  • Higher incidence of symptomatic cardiomyopathy compared to DMD.

Key Complications in DMD

1. Respiratory:
   • Chronic restrictive lung disease from around 12 years of age.
   • Sleep-disordered breathing progressing to nocturnal and diurnal hypercapnia.
   • Exacerbated by scoliosis.
2. Cardiac:
   • Dilated cardiomyopathy (affects all patients over 18).
   • Asymptomatic in DMD due to low physical activity.
   • More symptomatic and severe in BMD.
3. Cognitive:
   • Lower verbal IQ compared to performance IQ.
   • Associated neurodevelopmental conditions such as ADHD and autism spectrum disorders.
4. Orthopedic Complications in DMD

• Contractures:
  • Commonly affect ankles, knees, iliotibial bands, and hips.
  • Lead to characteristic lumbar lordosis and toe-walking while ambulant.
• Scoliosis:
  • Develops in adolescence, especially after wheelchair confinement.
  • Less common now due to the introduction of steroid therapy.
• Fractures:
  • Frequently seen in boys treated with steroids.
  • Can lead to permanent loss of ambulation.

Female Carriers of Dystrophin Mutations

• Muscle Weakness:
  • Up to 20% experience mild to moderate muscle weakness.
  • Raised creatine kinase levels in 50–60%.
• Cardiac Involvement:
  • Up to 8% develop dilated cardiomyopathy in adulthood.

Genetic Basis of DMD

• Gene: Mutations in the DMD gene on chromosome Xp21.
• Structure:
  • DMD is one of the largest known genes, containing 79 exons, making it susceptible to mutations.
• Inheritance:
  • Two-thirds of cases are maternally inherited.
  • One-third arise from de novo mutations.
• Function of Dystrophin:
  • Localizes to the skeletal muscle sarcolemmal membrane.
  • Forms a complex with the dystrophin-associated glycoprotein complex.
  • Acts as a structural link between the cytoskeleton and extracellular matrix.
• Pathophysiology:
  • Loss of dystrophin results in:
    • Muscle fiber degeneration due to cytoskeletal instability.
    • Abnormal calcium homeostasis.

• Protein Defect:
  • Mutations in the DMD gene lead to a truncated, unstable dystrophin protein.
  • The reading frame rule explains the phenotypic differences:
    • DMD: Mutations disrupt the open reading frame, resulting in a complete absence of functional dystrophin.
    • BMD: Mutations maintain the reading frame, allowing partial production of dystrophin.
• Mutation Types:
  • 65–70%: Deletions.
  • 10–15%: Point mutations.
  • 5–7%: Partial duplications.
• Diagnostic Methods:
  • MLPA and chromosomal microarray to detect deletions/duplications.
  • Direct sequencing for point mutations if MLPA is negative.
  • Muscle biopsy:
    • Histology: Necrosis, regeneration, size variability, fat/connective tissue replacement.
    • Immunostaining/Western blot: Complete absence of dystrophin in DMD, milder defects in BMD.

Biochemical Findings

• Serum Creatine Kinase (CK):
  • Levels are 10–20 times the upper limit of normal from birth.
• Liver Enzymes:
  • Elevated alanine and aspartate transaminases (muscle-derived, not liver pathology).

Clinical Management

1. Multidisciplinary Approach:
   • Focuses on respiratory, cardiac, orthopedic, and nutritional issues, and effects of corticosteroid therapy.
   • Genetic counseling is critical.
2. Physiotherapy and Orthotics:
   • Regular therapy helps maintain ambulation and prevent contractures and scoliosis.
3. Bone Health:
   • Monitoring of calcium, phosphate, and vitamin D.
   • Bone densitometry in steroid-treated/non-ambulant patients.
   • Calcium and vitamin D supplementation are recommended.
4. Scoliosis Management:
   • Spinal fusion for curvatures >20° in growing boys.
5. Anesthesia Precautions:
   • Increased risk of malignant hyperthermia-like reactions with inhalational anesthetics and depolarizing muscle relaxants.

Respiratory Care

• Monitoring:
  • Begins at 5–6 years with regular assessments, including annual overnight pulse oximetry or sleep studies in non-ambulant boys.
• Interventions:
  • Early treatment of respiratory infections with antibiotics and chest physiotherapy.
  • Non-Invasive Ventilation (NIV):
    • Introduced for sleep-disordered breathing with hypoventilation/hypercapnia.
    • Benefits include reduced infections, fewer hospital admissions, and improved life expectancy.

Advancements in Care

• Improved Outcomes:
  • Advances over the last 2–3 decades have significantly enhanced life expectancy and quality of life.
• International Standards:
  • Published in 2010 to provide a benchmark for best practices and preparatory care for clinical trials.
• Steroid Therapy:
  • Prevents rapid progression of scoliosis and contractures, maintaining mobility.

Cardiac Surveillance in DMD

• Monitoring:
  • Regular electrocardiograms (ECGs) and echocardiograms to detect arrhythmias and dilated cardiomyopathy.
• Management:
  • Angiotensin-converting enzyme (ACE) inhibitors and/or beta blockers for left ventricular dysfunction.
  • Treatment for steroid-induced hypertension may be necessary in boys on corticosteroids.

Supportive Therapy

1. Nutrition:
   • Address constipation, gastro-oesophageal reflux, and dysphagia, which are common late-stage complications.
2. Physical Fitness:
   • Essential for cognitive health and maintaining cardiorespiratory function.
3. Psychological and Palliative Care:
   • Psychological input for cognitive and mood issues.
   • Palliative care to manage social isolation, depression, and pain in advanced stages.

Corticosteroid Therapy

1. Effectiveness:
   • Proven to improve muscle strength, prolong independent ambulation, preserve cardiorespiratory function, reduce scoliosis risk, and improve life expectancy.
   • Maximal muscle strength improvement is seen by 3 months after initiation.
   • Extends independent ambulation by up to 3 years.
2. Common Steroids:
   • Prednisone or prednisolone: 0.75 mg/kg/day.
   • Deflazacort: 0.9 mg/kg/day; choice depends on availability, cost, and side-effect profile.
3. Initiation of Therapy:
   • Recommended start age: 4–6 years, before the onset of motor decline.
   • Daily dosing is more effective than alternate-day dosing.
4. Post-ambulation Use:
   • Continued after loss of ambulation to preserve upper limb and cardiorespiratory function and limit scoliosis progression.
5. Side Effects:
   • Weight gain and behavioral problems: Can sometimes improve by switching the type of corticosteroid.
   • Growth suppression and delayed puberty: Virtually universal in long-term therapy.
   • Increased risk of vertebral and long bone fractures.

Advances in Care

• Consensus care guidelines recommend corticosteroid therapy as a standard treatment.
• Multidisciplinary care has significantly improved life expectancy and quality of life in boys with DMD.

Genetic Counseling and Prenatal Diagnosis

1. Referral:
   • All affected families and potential carriers should be referred for genetic counseling.
2. Prenatal Diagnosis:
   • Available for carrier mothers to detect dystrophin mutations.
3. Adult Monitoring:
   • Carrier mothers should undergo cardiac monitoring in adulthood due to the risk of dilated cardiomyopathy.

Advanced Therapeutic Strategies in DMD

Gene Replacement Therapy

• Objective: Deliver functional copies of the dystrophin gene.
• Method:
  • Utilizes Adeno-associated virus (AAV) vectors.
  • Delivery of micro-dystrophin, a shortened but functional dystrophin gene, suitable for the limited carrying capacity of AAV.
• Recent Advances:
  • SRP-9001 (delandistrogene moxeparvovec):
    • Clinical trials demonstrate improved motor function (North Star Ambulatory Assessment).
    • FDA accelerated approval in the USA (2023).
  • Challenges:
    • Immune response to AAV vectors.
    • Limited re-dosing due to pre-existing immunity.

Exon Skipping Therapy

• Objective: Skip specific exons to restore the reading frame of dystrophin mRNA, producing a truncated but functional dystrophin protein.
• Mechanism:
  • Utilizes antisense oligonucleotides (ASOs) targeting specific exons.
• FDA-approved Therapies:
  • Eteplirsen (Exondys 51): Targets exon 51 (effective in ~13% of patients).
  • Viltolarsen: Targets exon 53.
  • Golodirsen: Targets exon 53.
  • Casimersen: Targets exon 45.
• Recent Developments:
  • Development of multi-exon skipping approaches to target larger patient populations.
  • Improved chemical modifications of ASOs for enhanced delivery and reduced toxicity.

Stop Codon Read-Through Therapy

• Objective: Address nonsense mutations by bypassing premature stop codons to produce functional dystrophin.
• Key Drug:
  • Ataluren (Translarna):
    • Targets nonsense mutations (~10–15% of patients).
    • Approved in Europe; under evaluation in other regions.
  • Limitations:
    • Effectiveness is mutation-specific.
    • Requires high drug concentrations for efficacy.

CRISPR/Cas9 Gene Editing

• Objective: Correct mutations at the DNA level for permanent dystrophin restoration.
• Mechanism:
  • Uses CRISPR/Cas9 to excise mutations, restore the reading frame, or insert functional gene segments.
• Recent Advances:
  • In vivo studies: Demonstrated restoration of dystrophin expression in animal models.
  • Base editing and prime editing: More precise and safer alternatives to traditional CRISPR.
  • Challenges:
    • Off-target effects.
    • Delivery efficiency to muscle tissue.
    • Ethical considerations.

Gene Silencing and Upregulation of Compensatory Proteins

• Targeting Myostatin Inhibition:
  • Rationale: Myostatin limits muscle growth; its inhibition promotes muscle regeneration.
  • Key Therapy:
    • Domagrozumab: Monoclonal antibody targeting myostatin.
    • Ongoing trials for efficacy.
• Upregulation of Utrophin:
  • Utrophin is a dystrophin homolog.
  • Therapies aim to increase utrophin expression to compensate for dystrophin deficiency.
  • Ezutromid: Oral utrophin modulator (discontinued due to lack of efficacy).

Stem Cell and Regenerative Therapies

• Objective: Replace damaged muscle fibers or introduce dystrophin-expressing cells.
• Approaches:
  • Mesenchymal stem cells (MSCs): Anti-inflammatory properties.
  • Induced pluripotent stem cells (iPSCs): Potential for patient-specific therapies.
  • Challenges:
    • Immune rejection.
    • Delivery to affected muscles.
    • Limited engraftment success.

Supportive Molecular Approaches

• Gene Regulation:
  • Targeting pathways to reduce inflammation and fibrosis (e.g., NF-κB inhibitors).
• Small Molecules:
  • Cathepsin inhibitors to slow muscle degeneration.
  • Tamoxifen to modulate estrogen receptor signaling and reduce fibrosis.

Challenges and Future Directions

• Challenges:
  • Immune response to therapies.
  • Variable efficacy across mutation subtypes.
  • High costs and accessibility issues.
• Future Directions:
  • Combination therapies to address multiple aspects of disease pathology.
  • Development of universal delivery vectors for gene therapy.
  • Improved biomarkers for therapy monitoring and patient stratification.
  • Greater focus on early-stage interventions to prevent disease progression.

References

 Arzimanoglou, A., O'Hare, A., Johnston, M., & Ouvrier, R. (Eds.). (2018). Aicardi's Diseases of the Nervous System in Childhood (4th ed.). Mac Keith Press.