(A) Muscle areas (red) affected in the most common MDs. In Duchenne muscular dystrophy (DMD), progressive muscle weakness and atrophy are observed in major muscle groups, including heart and diaphragm. In myotonic dystrophy (DM), muscle degeneration leads to weakness and myotonia in distal muscles with progression to proximal muscles. DM also involves multiple organ systems, including cataracts, cardiac conduction defects, and other endocrine disorders. Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive weakness and wasting of muscles of the face, shoulder, and upper arm. Limb-girdle muscular dystrophy (LGMD) shows progressive proximal muscle weakness, plus different pathogenic variants depending on the type of genetic mutation. Numbers indicate prevalence of disease. (B) Muscle proteins involved in MDs. Dystrophic muscle is caused by mutations in genes encoding proteins in the sarcolemma (e.g., dystrophin, sarcoglycans, dysferlin) and sarcomere (e.g., myotilin), as well as expansion/contraction of different genomic locations. Dystrophin protein (mutated in DMD) has four functional domains: the first actin-binding domain (ABD-1) at the amino terminus (NH₂); the central rod domain, containing 24 spectrin-like repeats and ABD-2; the cysteine-rich domain (Cys); and the carboxyl-terminal domain (COOH).