A large family is described with an autosomal dominant distal myopathy, the nature of which prompts the reevaluation of current classifications of these disorders. The disease begins in early to middle adulthood with gait disturbance due to distal leg weakness, and progresses over 5-10 years to involve all extremities, as well as bulbar, respiratory, and facial muscles. There is frequent cardiac involvement, manifest by arrhythmias, conduction blocks, and congestive failure, resulting in premature demise. On electromyography there is prominent spontaneous activity, short duration motor unit potentials, and polyphasia. Muscle biopsies from multiple family members at different stages of the disease are characterized by desmin storage and autophagocytosis. This distal myopathy differs from other phenotypically similar disorders in its rapidity of progression, fatal course and pathologic features. The role and specificity of excessive desmin accumulation in this and other myopathic and cardiac disorders are unknown.