Duchenne muscular dystrophy (DMD)

What it is

Dystrophin links the muscle-fibre cytoskeleton to the extracellular matrix through the dystroglycan complex. Without it, the sarcolemma is mechanically fragile and tears with every contraction; calcium leaks in, proteases activate, and muscle fibres are repeatedly damaged and replaced — first with regeneration, but ultimately with fibrosis and fat. Cardiac muscle is similarly affected and develops a dilated cardiomyopathy. The smaller, milder Becker muscular dystrophy is caused by in-frame deletions of the same gene that allow some truncated but functional dystrophin to be produced.

How it presents

Delayed walking (after 18 months) is the most common first sign, followed in the next two years by:

• Frequent falls, difficulty climbing stairs and running
• Calf pseudo-hypertrophy — calves look enlarged but are fibrofatty replacement, not muscle
• Gowers' sign — child 'walks' up their own legs to stand from the floor
• Toe-walking and a lordotic gait
• Mildly delayed early speech and learning in many
• Markedly elevated creatine kinase (CK) on a routine blood test — often >10,000 IU/L, the single most useful screening test
• By age 8–10 — loss of ability to climb stairs, then loss of walking around age 10–12 (untreated)
• Adolescence — scoliosis, respiratory weakness, cardiac involvement

Diagnosis

A child with delayed walking, calf pseudo-hypertrophy and Gowers' sign needs a CK on the same day. A CK above 5,000 is highly suggestive of DMD and is the trigger for genetic testing. Comprehensive testing requires MLPA / array (for large deletions/duplications, ~75%) and DMD gene sequencing (for the remaining point mutations and small indels). Identifying the exact mutation matters because eligibility for exon-skipping therapies and gene therapy depends on it. Muscle biopsy is now reserved for atypical cases or when genetic testing is inconclusive.

Female carriers can have manifestations from very mild (mildly elevated CK only) to a clinically symptomatic 'manifesting carrier' phenotype with proximal weakness and cardiomyopathy. All female relatives need carrier testing and cardiac surveillance.

Current standard care

Modern DMD care has transformed life expectancy. The cornerstones — established by the international DMD care considerations group and updated several times — are:

• Glucocorticoids — daily deflazacort (preferred where available) or prednisolone from age 4–6, lifelong. Studies show preserved ambulation by 2–4 years and significant improvements in cardiac and respiratory outcomes. Vamorolone (Agamree) is a dissociative steroid approved in 2023 with similar efficacy and fewer bone, growth and behavioural side effects
• Cardiac surveillance — annual cardiology with echocardiogram from diagnosis; ACE inhibitor or ARB (perindopril, lisinopril, losartan) from age 10 prophylactically, regardless of left ventricular function. Beta-blocker added when LV function declines
• Bone health — calcium and vitamin D; DEXA every 1–2 years; bisphosphonates for vertebral or low-trauma fractures
• Respiratory — annual spirometry, sleep studies; non-invasive ventilation when daytime hypoventilation; cough assist for secretion management
• Spine — surveillance for scoliosis; surgery (posterior spinal fusion) when curve >25–30 degrees once non-ambulant
• Nutrition and gastroenterology — manage steroid-related weight changes; reflux; constipation
• Endocrinology — growth, puberty, adrenal axis (steroid-related)
• Psychology and education — assess learning and emotional support; cognitive issues common in DMD

Mutation-specific molecular treatments

Four exon-skipping antisense oligonucleotides are FDA-approved in the US (some now in EU/UK regulatory review). They work by modifying pre-mRNA splicing to restore the reading frame across a deletion, producing a partly functional Becker-like dystrophin:

• Eteplirsen (Exondys 51) — exon 51 amenable mutations (~13% of DMD); IV weekly
• Golodirsen (Vyondys 53) and viltolarsen (Viltepso) — exon 53 amenable mutations (~8%); IV weekly
• Casimersen (Amondys 45) — exon 45 amenable mutations (~8%); IV weekly
• All show modest but measurable dystrophin restoration in muscle biopsy and small clinical benefit; debate continues about the clinical magnitude versus cost

Gene therapy

Delandistrogene moxeparvovec-rokl (Elevidys, Sarepta) is the first FDA-approved gene therapy for DMD: a one-time IV AAVrh74 vector carrying a micro-dystrophin transgene under a muscle-specific promoter. Initially approved June 2023 for ambulatory boys aged 4–5; expanded in June 2024 to all ambulatory and most non-ambulatory patients (≥4 years) regardless of DMD mutation. The Phase 3 EMBARK trial in 2023 did not meet its primary efficacy endpoint on North Star Ambulatory Assessment but met secondary endpoints, and accumulating real-world data through 2025–2026 will refine where it sits in the care pathway.

Safety: serious adverse events include myocarditis, immune-mediated necrotising myopathy, hepatotoxicity (especially in non-ambulatory patients with severe scoliosis and metabolic risk), and rare thrombotic microangiopathy. Steroid co-treatment is required for at least 2 months. The treatment is not available for patients with anti-AAVrh74 antibodies above a threshold.

Several other gene-therapy programmes (Pfizer fordadistrogene, Solid Biosciences SGT-001 paused after safety signals, Regenxbio RGX-202) are in trials.

Prognosis

With modern multidisciplinary care including glucocorticoids, cardiac protection from age 10, non-invasive ventilation and structured orthopaedic care, median survival has moved from the historical 19 years to about 30 years (and continues to improve year-on-year). The molecular treatments add to this but the magnitude of benefit beyond foundational care will become clearer over the next 5 years of real-world data.

How an educational review can help

DMD families face an increasingly complex landscape: which steroid? When? Which exon-skipping treatment is right? Is Elevidys appropriate for this child? An educational review can map a child's specific mutation against the current evidence, summarise the modern care pathway, and help you prepare focused questions for your treating team — particularly around steroid choice, the cardiology / respiratory schedule, and the molecular treatments.

It is an educational second opinion — not a diagnosis, treatment or prescription — and it does not replace the care of your child's own clinicians.