Duchenne Muscular Dystrophy

The single principle that unifies DMD genetics, the Duchenne-versus-Becker distinction and modern antisense therapy is the reading-frame (Monaco) rule.

• Out-of-frame (frameshift) mutations shift the triplet reading frame, generate a premature stop codon and abolish dystrophin - producing the severe Duchenne phenotype.
• In-frame mutations delete whole codons but preserve the downstream frame, producing a shortened but partly functional dystrophin - producing the milder Becker phenotype.
• The rule holds in roughly 90 percent of cases; exceptions exist (for example, large in-frame deletions disrupting critical actin-binding or dystroglycan-binding domains can still behave like Duchenne), so genotype is strongly correlated with, but not absolutely predictive of, phenotype.

Therapeutic corollary - exon skipping: antisense oligonucleotides (such as eteplirsen for exon-51-amenable deletions) mask a neighbouring exon during splicing so the mutated transcript is read back in frame, converting a Duchenne-type out-of-frame defect into a Becker-like in-frame product with partial dystrophin restoration.

Why weakness becomes deformity: The orthopaedic burden of DMD is a direct downstream consequence of progressive, asymmetric muscle weakness acting across growing joints and a growing spine.

• Contractures: Antigravity muscles (gastrocnemius-soleus, hip flexors, iliotibial band) retain relative strength longer than their antagonists (tibialis anterior, hip extensors). The resulting muscle imbalance, combined with prolonged sitting once ambulation is lost, drives fixed equinus, hip flexion contracture and ITB tightness.
• Equinus gait compensation: While still ambulant, boys adopt toe-walking and a lordotic, wide-based stance to keep the ground-reaction force anterior to the knee and posterior to the hip, stabilising both joints despite quadriceps and gluteal weakness. Aggressive Achilles lengthening that destroys this equinus "lock" can precipitate loss of ambulation.
• Neuromuscular scoliosis: Once truncal and paraspinal muscles can no longer balance the seated spine, a long C-shaped collapsing curve with pelvic obliquity develops. Unlike idiopathic scoliosis, it progresses even after skeletal maturity and through the wheelchair years.
• Fragility bone: Disuse osteoporosis (immobility) plus glucocorticoid-induced bone loss produces a fracture-prone skeleton. Vertebral compression fractures and low-energy long-bone fractures (especially distal femur) are common; a femoral fracture in a marginal ambulator frequently ends walking permanently.

DMD is staged by functional ambulatory status, which drives the timing of every orthopaedic decision. The Brooke (upper limb) and Vignos (lower limb) scales remain the classic clinical grading tools.

"Females are carriers" is an over-simplification examiners probe.

• Manifesting carriers: because of skewed X-inactivation (lyonisation) a minority of female carriers have skeletal-muscle symptoms - calf hypertrophy, cramps, mild-to-moderate proximal weakness and a raised CK. The most severe female presentations occur with Turner syndrome (45,X) or an X-autosome translocation that disrupts the dystrophin gene.
• Carrier cardiomyopathy: carriers are at risk of dilated cardiomyopathy even when they have no skeletal-muscle weakness, so every confirmed or obligate carrier needs baseline and periodic cardiac surveillance (ECG and echocardiography) regardless of muscle symptoms.
• Germline mosaicism in counselling: about one-third of cases are apparently "new" mutations, but a mother whose blood test is negative is not guaranteed a zero recurrence risk, because the mutation may be present in a subset of her oocytes (gonadal/germline mosaicism, giving a recurrence risk of the order of 10 percent). Prenatal or preimplantation genetic diagnosis should therefore still be offered.

The classic triad of a young boy with proximal weakness, a positive Gowers' sign and a markedly raised CK has a focused differential. Distinguishing features are exam favourites.

• With Modern Care: Life expectancy now 20-30 years (previously teens).
• Steroids: Prolong ambulation ~2 years. Delay scoliosis.
• Spinal Fusion: Halts scoliosis progression. Maintains sitting posture. May improve QOL.

Global epidemiology:

• Birth incidence approximately 1 in 3,500-5,000 live male births; one of the most common lethal childhood genetic disorders worldwide.
• Roughly one-third of cases arise from de novo mutations with no family history.
• With contemporary multidisciplinary care (daily steroids, cardiac and respiratory support, spinal surgery), median survival has risen from the teens into the late 20s-30s.

Side-by-side guidance:

• Glucocorticoid regimen: The FOR-DMD randomised trial showed daily prednisone and daily deflazacort both outperform the 10-days-on/10-days-off intermittent regimen, with no significant difference between the two daily drugs. Deflazacort causes less weight gain and fewer behavioural effects but worse growth and more cataracts. Vamorolone (a dissociative steroid) is an emerging alternative with a potentially better bone/growth profile. The "best" regimen remains individualised.
• Should the pelvis always be fused? Long constructs to the pelvis control pelvic obliquity but increase operative time, blood loss and implant prominence. Some series of early, limited instrumentation in low curves (correcting before pelvic obliquity is fixed) report good seating with shorter, lower-morbidity surgery. Threshold of pelvic obliquity at which pelvic fixation becomes mandatory is debated.
• Has steroid use changed the scoliosis equation? Daily glucocorticoids dramatically reduce the incidence and severity of scoliosis, so far fewer steroid-treated boys now require spinal fusion than in the pre-steroid era. The classic teaching of near-universal, rapidly progressive scoliosis largely predates routine daily steroids.
• Are volatile anaesthetics absolutely contraindicated? Succinylcholine is unequivocally contraindicated (hyperkalaemic arrest). The risk from modern volatile agents (rhabdomyolysis/hyperkalaemia) is real but lower; many centres still use total intravenous anaesthesia as the safest default, while acknowledging the volatile-agent recommendation is less absolute.
• Disease-modifying genetic therapy: Exon-skipping antisense oligonucleotides (eteplirsen for exon 51-amenable mutations and related agents) and micro-dystrophin gene therapy (delandistrogene moxeparvovec) are approved in some regions but produce only partial dystrophin restoration; durable functional benefit, cost and access remain uncertain. They supplement, not replace, multidisciplinary musculoskeletal care.