Duchenne Muscular Dystrophy

Duchenne muscular dystrophy is a severe X-linked recessive disorder caused by mutation of the dystrophin gene at Xp21, which leaves the muscle with no dystrophin and the child with progressive muscle degeneration. Everything the orthopaedic surgeon meets - the contractures, the collapsing spine, the fragile bones - sits downstream of that one missing protein.

Who. Boys, about 1 in 3,500-5,000 male births. Inheritance is X-linked recessive, so males are affected and females are carriers, and roughly a third of cases are sporadic, arising from a new mutation with no family history to give warning.

The natural history runs to a timetable, and knowing where a boy sits on it tells you which orthopaedic problem is next.

• Age 3-5 - symptom onset: delayed walking, difficulty climbing stairs
• Age 5-10 - progressive weakness, Gowers' sign, toe-walking
• Age 10-12 - loss of ambulation, wheelchair
• Age 15 onwards - scoliosis progresses, respiratory function declines, cardiomyopathy declares itself
• Age 20-30 - death, usually respiratory or cardiac failure

With modern multidisciplinary care life expectancy now runs to 20-30 years, where it once ended in the teens.

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The mutations. Deletions account for about 60%, point mutations 30% and duplications 5-10%; in Duchenne the consequence is the same however it is achieved, which is complete absence of the protein.

What dystrophin does. It links the fibre cytoskeleton to the extracellular matrix and stabilises the sarcolemma each time the fibre contracts. Without it the membrane is fragile, calcium influx rises, and fibres undergo necrosis.

Why the muscle disappears. Cycles of necrosis and regeneration repeat until what replaces the lost fibres is fibrous tissue and fat. Creatine kinase in the blood is leakage from those damaged fibres.

Becker muscular dystrophy is the same gene with a kinder mutation: in-frame changes that allow partial dystrophin function, giving a milder phenotype, later onset and longer survival.

What the failing muscle looks like. Histology and MRI show the same process at different scales.

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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 - the severe Duchenne phenotype
• In-frame mutations delete whole codons but preserve the downstream frame, giving a shortened but partly functional dystrophin - the milder Becker phenotype

The rule holds in roughly 90 percent of cases. Exceptions exist - large in-frame deletions that disrupt critical actin-binding or dystroglycan-binding domains can still behave like Duchenne - so genotype is strongly correlated with, but not absolutely predictive of, phenotype.

Exon skipping is the rule turned into treatment. 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.

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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. The antigravity muscles - gastrocnemius-soleus, hip flexors, iliotibial band - retain relative strength longer than their antagonists, the tibialis anterior and the hip extensors. That imbalance, together with the prolonged sitting that follows loss of ambulation, drives fixed equinus, hip flexion contracture and ITB tightness.

The equinus is doing useful work. While still ambulant, boys adopt toe-walking and a lordotic, wide-based stance that keeps 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 the 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.

Fragile bone. Disuse osteoporosis from immobility and glucocorticoid-induced bone loss together produce a fracture-prone skeleton. Vertebral compression fractures and low-energy long-bone fractures, especially of the distal femur, are common, and 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.

History. Parents describe a boy who walked late, after 18 months, and who cannot run, climb or jump as his peers do. Ask about the family: an X-linked pattern, a carrier mother, affected brothers or uncles.

The signs all say the same thing. Weakness is bilateral and proximal, greater proximally than distally: Gowers' sign is the boy putting his hands on his thighs to climb up himself from the floor, lumbar hyperlordosis follows weak hip extensors, and scapular winging follows weak scapular fixators. The calves look powerful, but that is pseudohypertrophy - fibrofatty replacement rather than muscle.

Contractures and the spine. Equinus is the commonest contracture, with hip flexion and iliotibial band tightness behind it, and toe-walking is that equinus made visible. Scoliosis follows the loss of ambulation.

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Serum CK is the screening test, and in DMD it is massively elevated at 10-100 times normal.

Genetic testing confirms the mutation and is the gold standard, by multiplex PCR, MLPA or sequencing. Muscle biopsy shows absent dystrophin on immunohistochemistry and is used less now that genetics answers the question directly.

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The orthopaedic work-up is aimed at the spine, the lungs, the heart and the bones:

• Spine radiographs, AP and lateral, with the Cobb angle measured
• Whole-spine MRI when fusion is planned
• Pulmonary function, before scoliosis surgery is contemplated
• Echocardiography and ECG for the cardiomyopathy
• DEXA for bone density

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"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 with ECG and echocardiography, whatever her muscles are doing.

Germline mosaicism. 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 or 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.

It is not malignant hyperthermia. Avoid succinylcholine and volatile agents and use TIVA, propofol with remifentanil - the instruction everyone knows. The reason usually given is wrong, and the wrong reason kills: DMD is not an RYR1 channelopathy and these boys are not MH-susceptible.

What they suffer is anaesthesia-induced rhabdomyolysis: acute muscle breakdown without preceding hypermetabolism, presenting as hyperkalaemic cardiac arrest, sometimes in recovery rather than on the table.

The heart and the lungs. All patients with DMD develop cardiomyopathy, so cardiac clearance comes before any surgery, and the progressive respiratory muscle weakness compounds the risk.

A fracture can cost a boy his walking. A lower-limb fracture in a marginal ambulator often ends walking permanently, so splint for comfort and keep him upright rather than resting him.

Vertebral compression fractures are frequently painless. Steroids cause them, and because they can be silent, surveillance spine imaging is part of care. Symptomatic or progressive fractures are an indication for bisphosphonates, as is established osteoporosis, and fracture prevention also means calcium and vitamin D.

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The classic natural history. Scoliosis develops in nearly 100% of boys with DMD after ambulation is lost, and progresses rapidly, on the order of 15-20 degrees a year. Those figures come from the pre-steroid era; daily glucocorticoids have changed them, as the controversies below set out.

Indications for fusion. Two numbers and a judgement:

• Cobb angle over 20-30 degrees and progressing
• FVC over 35%, and some accept over 30%; below that the perioperative risk is very high

The operation. Posterior spinal fusion from T2/T3 to the pelvis, segmental pedicle screws with iliac or S2 alar-iliac screws distally. An anterior release is usually not needed.

Expect significant blood loss and plan for it with cell salvage and tranexamic acid. Post-operative intensive care is usual, and prolonged non-invasive ventilation may be needed.

What fusion achieves. It halts progression of the curve and maintains sitting balance and posture, and it may improve respiratory function or slow its decline, and improve quality of life.

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The complications that matter follow from the cardiomyopathy, the weak respiratory muscles, the soft bone and the anaesthetic.

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:

Which 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, and vamorolone, a dissociative steroid, is an emerging alternative with a potentially better bone and 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, and the 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, for the hyperkalaemic arrest it causes. The risk from modern volatile agents, rhabdomyolysis and hyperkalaemia, is real but lower; many centres still use total intravenous anaesthesia as the safest default, while acknowledging that 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.