Progressive Muscular Dystrophies

Progressive muscular dystrophies are inherited disorders of progressive skeletal muscle degeneration and weakness. They result from mutations affecting structural or functional proteins essential for muscle fibre integrity. Duchenne muscular dystrophy, from mutations in the dystrophin gene, is the commonest and most severe childhood-onset form.

• Becker muscular dystrophy is generally milder. A different pattern of mutation in the same dystrophin gene typically produces a partially functional, rather than entirely absent, dystrophin protein.
• Facioscapulohumeral and limb-girdle muscular dystrophies are further, distinct conditions with differing inheritance patterns, age of onset, and pattern of muscle involvement.

Gene-targeted and, more recently, gene therapy approaches for Duchenne muscular dystrophy are an important, evolving therapeutic advance in a previously incurable, relentlessly progressive condition.

Pathophysiology and classification

• Duchenne muscular dystrophy results from X-linked recessive mutations in the dystrophin gene (the largest known human gene, located on the X chromosome). It predominantly affects males.
• The mutation is most commonly a large deletion, though duplications and point mutations also occur. It generally disrupts the reading frame and abolishes functional dystrophin, an essential structural protein linking the intracellular cytoskeleton to the extracellular matrix in muscle fibres. Absence of dystrophin produces progressive muscle fibre membrane instability and damage. Over time, muscle is progressively replaced by fibrous and fatty tissue.
• Becker muscular dystrophy results from mutations in the same gene that typically preserve the reading frame. A partially functional dystrophin protein is produced, reduced in quantity or quality. The course is generally substantially milder, later-onset, and more slowly progressive than Duchenne muscular dystrophy.
• Female carriers of dystrophin gene mutations are generally, though not universally, asymptomatic or only mildly affected, reflecting a typically favourable pattern of X-chromosome inactivation. A proportion (manifesting carriers) develop clinically significant muscle weakness and cardiac involvement (cardiomyopathy). Confirmed female carriers need structured cardiac surveillance regardless of their own symptoms.
• Facioscapulohumeral muscular dystrophy and the limb-girdle muscular dystrophies are genetically and clinically distinct. Facioscapulohumeral muscular dystrophy generally follows autosomal dominant inheritance. The limb-girdle muscular dystrophies include both autosomal dominant and autosomal recessive subtypes, depending on the genetic cause.
• Both generally produce a milder, later-onset, and more slowly progressive course than Duchenne muscular dystrophy.
• The pattern of muscle involvement is reflected in the names: facial, shoulder girdle, and upper arm predominant for facioscapulohumeral muscular dystrophy; predominantly proximal, pelvic and shoulder girdle for the limb-girdle muscular dystrophies.

• Duchenne muscular dystrophy typically presents in early childhood, generally between two and five years of age. Features are delayed motor milestones (particularly delayed independent walking), a waddling gait, and difficulty rising from the floor.
• The classical Gower sign is a characteristic finding. The child uses the hands to progressively "walk up" the legs when rising from the floor, reflecting proximal muscle weakness.
• Calf pseudohypertrophy is a further characteristic finding. The calf muscles are enlarged but weak, reflecting fibrofatty replacement of normal muscle.
• The disease is relentlessly progressive. Affected boys typically lose independent ambulation by around ten to twelve years of age. Corticosteroid therapy generally extends this timeframe; without disease-modifying treatment it is not extended.
• Loss of ambulation is followed by progressive loss of upper limb function, respiratory muscle weakness and, of particular significance, cardiomyopathy.
• Respiratory failure and cardiac complications are the principal causes of death. Historically this occurred in the second or third decade without treatment. Survival is now substantially extended with full multidisciplinary management.
• Becker muscular dystrophy presents with a broadly similar but substantially milder, later-onset pattern of proximal muscle weakness. Affected individuals frequently retain independent ambulation well into adulthood.
• In Becker muscular dystrophy, cardiomyopathy can occur. In some cases it is disproportionately prominent, or even the predominant manifestation, relative to skeletal muscle weakness.
• Facioscapulohumeral muscular dystrophy typically presents in adolescence or early adulthood. Facial weakness causes difficulty with facial expression, including inability to fully close the eyes or purse the lips. It is accompanied by scapular winging and shoulder girdle weakness.
• The course is generally slowly progressive, with substantial variability in severity between affected individuals, including within the same family.
• Cognitive impairment and learning difficulty are more frequent in Duchenne muscular dystrophy, reflecting dystrophin expression within the central nervous system. Consider this in the assessment and support of affected boys.

• Elevated serum creatine kinase, often very substantially, is a valuable initial screening investigation in any child with a compatible pattern of motor delay or weakness. It reflects ongoing muscle fibre membrane damage and leakage of this intracellular enzyme.
• Genetic testing for dystrophin gene mutations is the standard, definitive diagnostic approach for suspected Duchenne or Becker muscular dystrophy. It avoids the need for muscle biopsy in the great majority of contemporary cases.
• Genetic testing also provides essential information on eligibility for specific, mutation-targeted therapies.
• Muscle biopsy, with dystrophin immunohistochemical staining, may be considered where genetic testing is inconclusive or the clinical picture remains genuinely uncertain. It is now less central, given the increasing sensitivity and accessibility of genetic testing.
• Baseline and ongoing surveillance is an essential component of evaluation and monitoring throughout the disease course. It includes:
  • Echocardiography (screening for cardiomyopathy).
  • Pulmonary function testing (screening for progressive respiratory muscle weakness).
  • Formal assessment of motor function using validated, structured tools.

• Corticosteroid therapy (prednisolone or deflazacort) is standard, established treatment for Duchenne muscular dystrophy. There is clear, substantial evidence that it prolongs independent ambulation and slows respiratory and cardiac decline. It is generally started once a functional plateau is reached in early childhood.
• Monitor in a structured way for recognised adverse effects of long-term corticosteroids, including growth impairment, weight gain, and reduced bone density. This is an integral part of treatment.
• Exon-skipping therapies (including eteplirsen, golodirsen, and viltolarsen, each targeting a specific dystrophin gene exon) are an important, mutation-specific advance. They apply to the subset of patients with a mutation amenable to skipping of the exon each agent targets. They restore the disrupted reading frame, allowing production of a partially functional, Becker-like dystrophin protein.
• Gene therapy delivers a functional but truncated "micro-dystrophin" gene via a viral vector. It is a significant and relatively recent advance, approved for appropriately selected, eligible patients, and remains an evolving area of development.
• Multidisciplinary supportive care is central and has substantially extended survival and quality of life over recent decades. It includes:
  • Physiotherapy (maintaining range of motion and function, and managing the progressive risk of contracture).
  • Occupational therapy, and mobility aids and equipment as the disease progresses.
  • Proactive cardiac surveillance and, where indicated, standard heart failure management for confirmed cardiomyopathy.
  • Respiratory surveillance, with proactive introduction of non-invasive ventilatory support as respiratory muscle weakness progresses.
• Educational and psychosocial support addresses the learning needs of affected boys (given the increased incidence of cognitive and learning difficulty) and the substantial, ongoing emotional and practical impact of this progressive, life-limiting condition on the individual and family.
• Genetic counselling covers the X-linked recessive inheritance pattern, implications for female carrier relatives, and future reproductive planning. It includes the recommendation for cardiac surveillance in confirmed carriers regardless of symptoms. Management is lifelong and multidisciplinary.