CLONAL EXPANSION OF MITOCHONDRIAL-DNA WITH MULTIPLE DELETIONS IN AUTOSOMAL-DOMINANT PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA

Sporadic progressive external ophthalmoplegia and Kearns-Sayre syndrom e are usually associated with single large-scale mitochondrial DNA del etions in muscle. In progressive external ophthalmoplegia with autosom al dominant inheritance, multiple mitochondrial DNA deletions have bee n reported. We studied several members of a Swedish family with autoso mal dominant progressive external ophthalmoplegia and multiple mitocho ndrial DNA deletions by polymerase chain reaction analysis of single m uscle fibers and by in situ hybridization, combined with enzyme histoc hemical analysis. Muscle fiber segments with deficiency of cytochrome c oxidase, which is partially encoded by mitochondrial DNA, had accumu lated mitochondrial DNA with deletions and showed reduced levels of wi ld-type mitochondrial DNA. The deletions varied between individual mus cle fibers. There was one predominant deletion in each cytochrome c ox idase-deficient muscle fiber segment. Sequencing of the deletion break points showed that most but not all of the deletions were flanked by d irect repeats. Young, clinically affected individuals of this family w ithout limb muscle symptoms did not show mitochondrial DNA deletions o r cytochrome c oxidase-deficient muscle fibers. Our results indicate t hat a nuclear factor predisposes to the development of somatic multipl e mitochondrial DNA deletions. Mitochondrial DNA with multiple differe nt deletions shows clonal expansion, which leads to mitochondrial myop athy with ragged-red fibers and muscle weakness.