Duchenne muscular dystrophy

Overview

•Most common and most severe inherited muscular dystrophy in childhood - X-linked recessive

•Caused by mutations in the DMD gene (chromosome Xp21) - most commonly large exon deletions (~65-70%)

•Disruption of reading frame → absent dystrophin → sarcolemmal fragility → myocyte necrosis → fibrofatty replacement

•Incidence ~1 in 3,500-5,000 live male births; ~one-third are de novo mutations (negative family history does not exclude)

•Becker MD - in-frame mutations → truncated but partially functional dystrophin → milder course

Presentation

•Typical age of presentation: 3-5 years (CK elevated from birth)

•Proximal muscle weakness - hip girdle and thigh first; waddling (Trendelenburg) gait

•Gower's sign - child walks hands up thighs to rise from floor; pathognomonic of proximal lower limb weakness

•Pseudohypertrophy of the calves - enlarged but rubbery due to fibrofatty infiltration, not true muscle growth

•Toe walking - from early ankle plantar flexion contractures

•Cognitive/behavioural features - ~one-third have intellectual impairment, dyslexia, or ADHD (dystrophin also expressed in brain)

•Upper limb weakness appears later

💡

Watch the child run and rise from the floor - observing Gower's sign and waddling gait is more diagnostically informative than formal neurological examination.

Investigations

🥇 First-line

•Serum CK - markedly elevated 10-100x upper limit of normal from birth; normal CK effectively excludes DMD in a newly presenting child

•Confirmatory: Genetic analysis (DMD gene sequencing and deletion/duplication testing) - identifies mutation in ~95%; avoids biopsy when positive

•EMG - myopathic pattern; distinguishes from neurogenic causes

•ECG + echocardiogram - at diagnosis and regularly thereafter to screen for cardiomyopathy

•Pulmonary function tests (spirometry, FVC) - serial monitoring of respiratory decline

🏆 Gold standard

•Muscle biopsy with immunohistochemistry for dystrophin - used when genetic testing is negative but CK raised and features consistent; shows absent/severely reduced dystrophin

🎯

If genetic testing is positive → biopsy not required. If genetic testing is negative but CK raised with consistent features → proceed to biopsy. Genetic testing after positive biopsy is still mandatory for mutation-specific therapy eligibility and genetic counselling.

⚠️

As muscle mass is lost over time, CK levels may fall - a normal CK in an established wheelchair user does not exclude the diagnosis retrospectively.

Management

🥇 First-line

•Prednisolone (or deflazacort) - corticosteroids slow muscle degeneration, prolong ambulation by ~2 years, reduce scoliosis risk; started age 4-6 once motor development plateaus

•Physiotherapy and stretching - prevent contractures (Achilles tendon, hip flexors), preserve range of movement

•Orthotic devices (ankle-foot orthoses, spinal bracing) - support ambulation, reduce scoliosis

•Cardiac: ACE inhibitors (e.g. lisinopril) or beta-blockers when cardiomyopathy detected; some centres start prophylactically in second decade

•Respiratory support: non-invasive ventilation (NIV/BiPAP) as FVC declines; nocturnal hypoventilation is often first sign

🥈 Second-line

•Ataluren - stop codon read-through agent for ~10-15% with nonsense mutations (NICE criteria apply)

•Exon-skipping therapies (e.g. casimersen, golodirsen) - antisense oligonucleotides restoring reading frame for specific exon deletions

•Surgical: Achilles tendon release; spinal fusion for scoliosis in non-ambulant patients

•Genetic counselling at diagnosis - carrier testing for mother and at-risk female relatives; discuss prenatal genetic diagnosis for future pregnancies

Complications and prognosis

•Dilated cardiomyopathy - develops in virtually all DMD patients; annual ECG and echocardiogram from diagnosis; cardiac failure can occur even in still-ambulant patients

•Without corticosteroids: wheelchair-dependent by ~12 years; death historically late teens to early twenties from respiratory failure

•With modern multidisciplinary care (NIV, cardiac management, physiotherapy): survival into late twenties and thirties now achievable

•Primary causes of death: dilated cardiomyopathy → heart failure; respiratory failure from ventilatory muscle weakness