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PH Win, V Carelli, FN Ross-Cisneros, AA Sadun; Morphometric Analysis of Optic Nerves In Leber's Hereditary Optic Neuropathy Reveals Preferential Loss Of Small Axons and Myelin Remodeling . Invest. Ophthalmol. Vis. Sci. 2002;43(13):233.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To investigate the qualitative and quantitative features of optic atrophy in optic nerve specimens from two Leber hereditary optic neuropathy (LHON) cases with 11778 and 3460 mutations, respectively. Method: Optic nerve specimens were obtained at autopsy from two LHON patients, and from four controls, age and post-mortem delay matched. Cross-sections were cut, embedded in EPON, and stained with PPD. Light microscopic examination showed areas of spared axons that were identified for electron microscopy (EM). Multiple (EMs) were used to reconstruct collages of extended areas to be analyzed. Axonal diameter (without the myelin ring) and myelin thickness were measured manually by the same investigator. Semi-automated fiber counting was also performed. Results: Light microscopic examination of PPD stained cross-sections revealed a complete loss of fibers in the central area of the optic nerve, but various degrees of peripheral sparing in the LHON cases compared to controls. The 11778/LHON case showed 48,000 axons left, while the 3460/LHON case had only 5,700 axons spared (5% and 0.5% of the 1.2 million axons of the controls, respectively). The mean axonal diameter of the four controls combined was 0.749 um ±0.423 (SD), while it was 1.368 um ±0.881 in the two LHON cases combined (P<0.005, two-tailed Student-t test). The mean myelin thickness normalized for the fiber diameter (Mi) was 0.422±0.114 in the controls and 0.330±0.117 in LHON (P<0.005, two-tailed Student-t test). Conclusion: A devastating loss of fibers, with only some peripheral sparing was evident in LHON. Our morphometric investigation indicated a preferential loss of smaller caliber fibers in LHON, about 80% loss in P-fibers (axons with diameter of 0.5-0.7 um) as compared to controls. Furthermore, there was a decrease of myelin thickness in the spared LHON axons. Smaller axons have a larger surface area to volume ratio compared to larger axons, and they possibly require more energy for ion pumps to maintain optimal intracellular conditions. Therefore, an energy defect, as postulated in LHON, would preferentially affect the smaller axons. This correlates with the clinical presentation of LHON, where the papillomacular bundle, mainly composed of small P-fibers, is preferentially affected, leading to the central vision defect. Demyelination seems an important related feature leading to axonal death in LHON.
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