Duchenne Muscular Dystrophy (DMD)

01Pathophysiology

Duchenne muscular dystrophy arises from a mutation in the dystrophin gene, the largest known human gene, located on the short arm of the X chromosome at position Xp21. The most common mutations are large intragenic deletions (accounting for about 60 to 70 percent of cases), followed by duplications and point mutations. These mutations disrupt the reading frame of the gene, resulting in a complete absence of dystrophin protein in skeletal and cardiac muscle cells.

Dystrophin is a cytoskeletal protein that functions as a mechanical link between the internal actin cytoskeleton of the muscle fiber and the extracellular matrix through the dystrophin-associated glycoprotein complex (DGC). Without dystrophin, the sarcolemma (muscle cell membrane) becomes fragile and susceptible to contraction-induced damage. Each cycle of muscle contraction causes microtrauma to the sarcolemma, allowing excessive calcium influx into the myofiber. This calcium overload activates proteases and triggers a cascade of necrosis, inflammation, and attempted regeneration.

Early in the disease, the muscle attempts to regenerate, but the regenerative capacity of satellite cells is eventually exhausted. Over time, necrotic muscle fibers are progressively replaced by fibrosis and adipose tissue. This fibrofatty replacement explains two hallmark findings: the calf pseudohypertrophy (enlarged calves that feel firm or rubbery because they are filled with fat and connective tissue, not functional muscle) and the relentless progression of weakness.

Because the disease follows an X-linked recessive pattern, it almost exclusively affects males. Females who carry one mutant copy are typically asymptomatic carriers, though some manifesting carriers can show mild weakness or isolated cardiomyopathy due to skewed X-inactivation. The reason proximal muscles are affected earlier than distal muscles is that proximal muscles bear greater mechanical load during activities like standing and climbing, making them more vulnerable to contraction-induced sarcolemmal injury.

The involvement of cardiac muscle leads to dilated cardiomyopathy, which becomes clinically significant in the second decade of life. Similarly, progressive weakness of the diaphragm and intercostal muscles leads to restrictive lung disease and respiratory failure, which remains the leading cause of death.

02Classification and Clinical Manifestation

A critical concept for exam purposes: the clinical course of Duchenne is predictably progressive. The timeline of wheelchair dependence by approximately age 12 is a commonly tested benchmark that distinguishes Duchenne from Becker muscular dystrophy.

03Diagnostic Workup

The diagnostic approach begins with clinical suspicion in a young boy presenting with proximal weakness, Gowers sign, and calf pseudohypertrophy. The best initial test is serum CK, which will be dramatically elevated. An important teaching point: CK in Duchenne is not mildly elevated. Values are typically in the range of tens of thousands. This degree of elevation should immediately raise concern for a muscular dystrophy rather than an inflammatory myopathy, where CK elevation is usually more modest.

Once CK confirms a myopathic process, the next step is genetic testing, not muscle biopsy. Modern practice has shifted toward genetic confirmation as the gold standard because it is noninvasive, identifies the exact mutation (which has implications for emerging gene-targeted therapies), and is diagnostic in approximately 95 percent of cases. Muscle biopsy is reserved for the small percentage of patients in whom genetic testing does not identify a mutation, or when the clinical picture is atypical and a broader differential needs to be evaluated.

On muscle biopsy, immunohistochemistry for dystrophin shows complete absence of the protein, distinguishing Duchenne from Becker muscular dystrophy, where dystrophin is present but reduced in quantity or abnormal in size.

EMG is not routinely needed for diagnosis but may appear as a distractor on exam questions. Recognize that EMG findings in Duchenne are myopathic (short duration, low amplitude motor unit potentials with early recruitment), which helps exclude neuropathic conditions like spinal muscular atrophy.

04Management and Treatment

Corticosteroids remain the cornerstone of treatment and the most commonly tested intervention. Prednisone at 0.75 mg/kg/day is the standard regimen. Deflazacort at 0.9 mg/kg/day is an alternative that may have a slightly better side effect profile regarding weight gain. Steroids slow the decline in muscle strength and function, prolong ambulation by approximately 2 to 3 years, reduce the need for scoliosis surgery, and delay the onset of cardiomyopathy and respiratory failure. Treatment is typically initiated when motor skills reach a plateau, usually around age 4 to 6, before the onset of decline.

The side effects of long-term steroid therapy are heavily tested. Expect questions about weight gain, growth suppression, osteoporosis, cushingoid features, behavioral changes, glucose intolerance, and adrenal suppression. Bone health management with calcium and vitamin D supplementation is essential, and patients should undergo periodic bone density assessment.

Cardiac management is critical because cardiomyopathy is a leading cause of death. ACE inhibitors or ARBs are started prophylactically by age 10 or at the first sign of myocardial dysfunction. Annual echocardiography and cardiac MRI are used to monitor ventricular function. Beta-blockers are added when ejection fraction declines.

Respiratory management follows a predictable trajectory. As respiratory muscles weaken, forced vital capacity declines. Patients progress from nocturnal hypoventilation (managed with BiPAP) to daytime respiratory insufficiency requiring continuous ventilatory support. Assisted cough devices and airway clearance techniques are added as cough effectiveness diminishes.

Exon-skipping therapies represent a newer pharmacologic approach. These antisense oligonucleotides promote skipping of a targeted exon during mRNA splicing, restoring the reading frame and allowing production of a truncated but partially functional dystrophin protein (essentially converting a Duchenne phenotype toward a Becker phenotype). These agents are mutation-dependent, meaning they benefit only the subset of patients whose deletion is amenable to the targeted exon skip.

05Differential Diagnosis and Distractors

The most commonly tested differential on exams is the distinction between Duchenne and Becker muscular dystrophy. Both are caused by mutations in the same dystrophin gene, but the critical difference lies in the reading frame. In Duchenne, the mutation disrupts the reading frame (out-of-frame deletion), producing no functional protein. In Becker, the reading frame is preserved (in-frame deletion), allowing production of a truncated but partially functional dystrophin. This is known as the reading frame rule and explains the milder phenotype in Becker.

The second most important distinction is from spinal muscular atrophy. Both present with a weak, floppy child. The key discriminators are: SMA presents with lower motor neuron signs (areflexia, fasciculations), CK is normal or near-normal, and EMG shows denervation. Duchenne presents with preserved reflexes early on, very high CK, and a myopathic EMG pattern.

06Traps and High-Yield Pearls

The most common trap in exam questions on Duchenne muscular dystrophy involves confusing the diagnostic sequence. Students frequently select muscle biopsy as the confirmatory test, which was historically accurate but is no longer the preferred approach. In current practice, once CK is found to be markedly elevated in a clinically suspicious patient, the confirmatory step is genetic testing, not biopsy. Biopsy is reserved for genetically inconclusive cases. Expect the exam to test whether you understand this updated algorithm.

A second common pitfall is failing to recognize the presymptomatic presentation. A vignette may describe a toddler with isolated language delay or an incidental finding of dramatically elevated CK (or elevated AST and ALT that are actually of muscle origin, not hepatic). Students who do not consider a muscular dystrophy in the differential for unexplained transaminase elevation will miss this diagnosis.

Another frequently tested concept is the inheritance pattern and genetic counseling implications. A question may present a mother asking about recurrence risk. Remember: if the mother is a confirmed carrier, each son has a 50 percent chance of being affected, and each daughter has a 50 percent chance of being a carrier. Approximately one-third of cases arise from de novo mutations, meaning the mother may not be a carrier.

Finally, know the complications and causes of death. Students sometimes focus exclusively on the skeletal muscle disease and forget that dilated cardiomyopathy and respiratory failure are the leading causes of mortality. Questions about long-term management will test your understanding of when to initiate cardiac medications (ACE inhibitors by age 10) and respiratory support (BiPAP when FVC falls below 30 percent predicted). The core competency being tested across all Duchenne questions is your ability to recognize the classic presentation, order the correct diagnostic sequence, and understand the natural history well enough to anticipate and manage complications proactively.