The muscular dystrophies cause progressive weakness and disability often with cardiorespiratory complications. Duchenne Muscular Dystrophy (DMD), the most common childhood form, typically causing death in early adult life. The high de novo mutation rate means genetic counselling alone will not reduce incidence.
DMD is a devastating X-linked disorder characterized by progressive muscle wasting, leading to loss of ambulation by age 12 and premature death from cardiorespiratory failure between ages 20-30. The dystrophin (DMD) gene encodes the cytoskeletal protein dystrophin which interacts with proteins at the sarcolemma to form the dystrophin-associated protein complex (DAPC). DMD is typically caused by DMD gene mutations that disrupt the translation reading frame. In the absence of dystrophin, the DAPC fails to form and the sarcolemma becomes susceptible to contraction-induced injury, leading to muscle necrosis and fibrosis, resulting in progressive muscle degeneration. This process extends to heart muscle leading to cardiomyopathy. Dystrophin isoforms are also expressed in brain, leading to neurodevelopmental defects in a significant fraction of DMD patients.