Duchenne and Becker muscular dystrophy: Viva

Branch 1: Confirming the diagnosis

The candidate should recognise the classic picture of Duchenne muscular dystrophy, with the delayed walking, the frequent falls, the calf pseudohypertrophy, the Gowers sign, the reduced reflexes, and a creatine kinase of 24,000 units per litre that is off the scale. A strong candidate states that the creatine kinase is typically above 10,000 and between 10,000 and 100,000 in Duchenne, that it is raised from birth before any weakness, and that a value of this magnitude in a weak boy points to a dystrophic process until the genetics prove otherwise. The candidate should add that the mildly raised transaminases are muscle-derived, because the same enzymes leak from the damaged fibre, and that a high transaminase in a weak boy is muscle, not liver. [3]

If the examiner presses on the confirmation, the candidate should state that the genetic test has now replaced the muscle biopsy as the first investigation, with multiplex ligation-dependent probe amplification as the first-line method for the exon deletions and duplications, and whole-gene sequencing for the point and splice mutations when the multiplex is normal. A muscle biopsy with dystrophin immunostaining is reserved for the inconclusive case. The candidate should offer the carrier testing of the mother and the female relatives, because the disease is X-linked recessive, with about two thirds inherited and one third new mutations. [4]

Branch 2: The molecular basis of the severity

If the examiner moves to the molecular basis, the candidate should explain the dystrophin protein and the reading-frame hypothesis. Dystrophin, identified by Hoffman, Brown, and Kunkel in 1987, sits beneath the sarcolemma and links the actin cytoskeleton to the dystrophin-associated glycoprotein complex that anchors the fibre to the extracellular matrix, and its loss tears the membrane with each contraction, admits calcium, and drives the necrosis and the fat and fibrosis that replace the muscle. [1]

The reading-frame hypothesis of Koenig explains the Duchenne-versus-Becker gradient, and the candidate should give it precisely. The gene is read in triplets, and a deletion that removes a whole number of triplets keeps the reading frame intact, so translation continues and a shorter, partly functional protein is made, the in-frame lesion of Becker. A deletion that throws the frame out of step introduces a premature stop, the ribosome falls off, and almost no protein is made, the out-of-frame lesion of Duchenne. A strong candidate notes that this same logic, run in reverse, is the basis of the exon-skipping therapy, which skips a neighbouring exon to restore the reading frame and produce a shorter functional dystrophin. [2]

Branch 3: The glucocorticoid and the surveillance

If asked for the treatment, the candidate should name the glucocorticoid as the disease-modifying backbone and give the timing and the dose. The care considerations say to start the steroid at the motor plateau, the point at which the boy stops gaining new skills, typically between four and seven years, and to continue it through the loss of ambulation. The FOR-DMD trial established prednisolone 0.75 mg per kg per day and deflazacort 0.9 mg per kg per day as equivalent and superior to placebo, with deflazacort producing less weight gain, so either is started now. The candidate should mention the harms, the weight, the growth, the behaviour, the osteoporosis, and the adrenal suppression, and the bone protection with calcium and vitamin D. [7][4]

The candidate should then build the systems surveillance. The cardiac care turns on a baseline echocardiogram and electrocardiogram at diagnosis, repeated at least annually, and an angiotensin-converting-enzyme inhibitor started by the age of ten even before symptoms, because the cardiomyopathy is progressive and silent. The respiratory care turns on the spirometry from age five or six, the forced vital capacity as the bellwether, and the non-invasive ventilation for the nocturnal hypoventilation. A strong candidate adds the two acute traps, that suxamethonium and volatile anaesthetics are contraindicated because of the anaesthesia-induced rhabdomyolysis and hyperkalaemia, and that a glucocorticoid-treated boy needs stress-dose hydrocortisone for severe illness or surgery. [4]

Branch 4: Appraising the trial evidence and the precision therapy

If the examiner moves to the evidence, the candidate should appraise the two landmark trials. The FOR-DMD trial of Griggs and colleagues in 2016 randomised 196 ambulatory boys aged four to seven years to deflazacort 0.9 mg per kg per day, prednisone 0.75 mg per kg per day, or placebo over 52 weeks, and it found that both steroids improved the muscle strength score over placebo, with deflazacort producing significantly less weight gain. The implication is the equivalence of the two doses and the preference for deflazacort where weight gain is the concern. [7]

The candidate should then describe the precision therapies chosen by the mutation. The exon-skipping antisense oligonucleotides, eteplirsen for exon 51 and golodirsen and viltolarsen for exon 53, restore a small amount of dystrophin by the reading-frame logic, and ataluren promotes read-through of the nonsense mutation. The adeno-associated-virus gene therapy of delandistrogene moxeparvovec delivers a micro-dystrophin, and the EMBARK phase 3 trial of Mendell and colleagues in 2025 tested its effect on the motor function. A strong candidate closes by stating that the precision therapy is offered alongside the glucocorticoid backbone, that the prognosis has been rewritten by the modern multidisciplinary care with survival into the fourth decade, and that the heart is now the leading cause of death in the well-treated boy. [10][4]