In 12 patients with the clinical characteristics of Marinesco-Sjögren syndrome including an autosomal recessive inheritance, congenital cataracts, mental retardation, cerebellar ataxia and progressive muscle weakness, the most common pathological finding was rimmed vacuole formation comprising from 0.1% to 10% of fibers in their muscle biopsy samples. The nuclear changes varied from condensed chromatin granules to vacuolation with amorphous inclusions which were predominantly seen in younger patients with prominent rimmed vacuoles, suggesting a close relationship between nuclear change and rimmed vacuole formation. From the severe destructive changes in nuclei, we speculated that the nuclear changes in Marinesco-Sjögren syndrome play a primary role in muscle degeneration resulting in myofibrillar disorganization and rimmed vacuole formation. In 2 patients, the TUNEL method demonstrated scattered myonuclei with fragmented DNA, but "ladder formation" was not found, probably because of the small numbers of nuclei with fragmented DNA. Nuclear degeneration with focal myofibrillar degeneration seen in these muscle samples suggests that the apoptotic process may occur in muscle disorders, especially in diseases with rimmed vacuole formation.