Genetics and pathophysiology of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the DMD gene located on the Xp21.2-Xp21.1 region of the X chromosome. This gene encodes dystrophin, a cytoskeletal protein that is critical for the stability of muscle fibers. With an incidence of approximately 1 in 5,000 males, DMD is the most common form of inherited muscular dystrophy in childhood. The DMD gene produces multiple tissue-specific dystrophin isoforms. Absence of the full-length Dp427 isoform leads to DMD, while residual expression results in milder phenotypes, such as Becker muscular dystrophy (BMD). Mostmutations are intragenic deletions, and the reading-frame rule predicts disease severity: Out-of-frame mutations abolish dystrophin synthesis, whereas in-frame deletions produce partially functional proteins. Dystrophin anchors the cytoskeleton to the dystrophin-associated protein complex (DAPC), linking contractile elements to the extracellular matrix. Loss of dystrophin disrupts sarcolemmal stability, leading to calcium influx, mitochondrial dysfunction, oxidative stress, and myofiber necrosis. This is followed by inflammation, fibrosis, and fatty infiltration. The mislocalization of neuronal nitric oxide synthase (nNOS) and reduced vascular endothelial growth factor (VEGF) impair vasoregulation and exacerbate ischemic injury. Brain involvement results from the loss of the Dp427, Dp140, and Dp71 dystrophin isoforms, which regulate synaptic and glial membrane architecture. The deficiency of these proteins contributes to cognitive impairment through disrupted GABAergic signaling, altered neurovascular function, and an imbalance in neuronal excitatory-inhibitory transmission.