Autosomal dominant progressive external ophthalmoplegia - Distribution of multiple mitochondrial DNA deletions

Objective: To relate signs and symptoms to morphologic changes and presence of multiple mitochondrial DNA (mtDNA) deletions in a patient with autosoma l dominant progressive external ophthalmoplegia (adPEO) and mitochondrial m yopathy. Background: An etiologic association between the somatic multiple mtDNA deletions in adPEO and clinical manifestations other than the myopath y has so far not been demonstrated. Methods: The authors investigated a pat ient with adPEO and multiorgan system manifestations including levodopa-res ponsive parkinsonism. She died at age 61 years of pancreatic carcinoma. Aut opsy tissue specimens were investigated for morphologic alterations and occ urrence of mtDNA deletions by Southern blot and long-extension PCR analyses . Results: The patient had carcinoma of the pancreas with metastases to liv er, lymph nodes, and bone marrow. The brain revealed slight gliosis of the gray and white matter and degeneration of the substantia nigra. The myocard ium showed focal areas with loss and atrophy of myocytes and fibrosis. Anal ysis of mtDNA revealed multiple deletions in different regions of the brain , skeletal muscle, and myocardium. Twenty-five different mtDNA deletions we re identified. Most of these were flanked by large direct-sequence repeats. Six identical deletions were found in muscle and brain. Conclusions: These findings indicate that somatic multiple mtDNA deletions are associated wit h degenerative tissue changes and clinical manifestations in adPEO.