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Laura C. Greaves, Patrick Yu-Wai-Man, Emma L. Blakely, Kim J. Krishnan, Nina E. Beadle, Jamie Kerin, Martin J. Barron, Philip G. Griffiths, Alison J. Dickinson, Douglass M. Turnbull, Robert W. Taylor; Mitochondrial DNA Defects and Selective Extraocular Muscle Involvement in CPEO. Invest. Ophthalmol. Vis. Sci. 2010;51(7):3340-3346. doi: 10.1167/iovs.09-4659.
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© 2017 Association for Research in Vision and Ophthalmology.
Chronic progressive external ophthalmoplegia (CPEO) is a prominent, and often the only, presentation among patients with mitochondrial diseases. The mechanisms underlying the preferential involvement of extraocular muscles (EOMs) in CPEO were explored in a comprehensive histologic and molecular genetic study, to define the extent of mitochondrial dysfunction in EOMs compared with that in skeletal muscle from the same patient.
A well-characterized cohort of 13 CPEO patients harboring a variety of primary and secondary mitochondrial (mt)DNA defects was studied. Mitochondrial enzyme function was determined in EOM and quadriceps muscle sections with cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) histochemistry, and the mutation load in single muscle fibers was quantified by real-time PCR and PCR-RFLP assays.
CPEO patients with mtDNA deletions had more COX-deficient fibers in EOM (41.6%) than in skeletal muscle (13.7%, P > 0.0001), and single-fiber analysis revealed a lower mutational threshold for COX deficiency in EOM. Patients with mtDNA point mutations had a less severe ocular phenotype, and there was no significant difference in the absolute level of COX deficiency or mutational threshold between these two muscle groups.
The more pronounced mitochondrial biochemical defect and lower mutational threshold in EOM compared with skeletal muscle fibers provide an explanation of the selective muscle involvement in CPEO. The data also suggest that tissue-specific mechanisms are involved in the clonal expansion and expression of secondary mtDNA deletions in CPEO patients with nuclear genetic defects.
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