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Autosomal dominant progressive external ophthalmoplegia

Distribution of multiple mitochondrial DNA deletions

From the Departments of Pathology (Drs. Moslemi and Oldfors) and Clinical Chemistry (Dr. Holme), Sahlgrenska University Hospital, Göteborg; and the Department of Neuroscience, Neurology (Dr. Melberg), Uppsala University Hospital, Uppsala, Sweden.

Address correspondence and reprint requests to Dr. Anders Oldfors, Department of Pathology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.

OBJECTIVE: To relate signs and symptoms to morphologic changes and presence of multiple mitochondrial DNA (mtDNA) deletions in a patient with autosomal dominant progressive external ophthalmoplegia (adPEO) and mitochondrial myopathy.

BACKGROUND: An etiologic association between the somatic multiple mtDNA deletions in adPEO and clinical manifestations other than the myopathy has so far not been demonstrated.

METHODS: The authors investigated a patient with adPEO and multiorgan system manifestations including levodopa-responsive parkinsonism. She died at age 61 years of pancreatic carcinoma. Autopsy tissue specimens were investigated for morphologic alterations and occurrence of mtDNA deletions by Southern blot and long-extension PCR analyses.

RESULTS: The patient had carcinoma of the pancreas with metastases to liver, lymph nodes, and bone marrow. The brain revealed slight gliosis of the gray and white matter and degeneration of the substantia nigra. The myocardium showed focal areas with loss and atrophy of myocytes and fibrosis. Analysis of mtDNA revealed multiple deletions in different regions of the brain, skeletal muscle, and myocardium. Twenty-five different mtDNA deletions were 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 with degenerative tissue changes and clinical manifestations in adPEO.

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