Leber Hereditary Optic Neuropathy Electron Microscopy and Molecular Genetic Analysis of a Case John B. Kerrison, MD,l Neil Howell, PhD, 2 Neil R. Miller, MD,l Lawrence Hirst, MD, MPH/ W. Richard Green, MD 1 Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic dis- order characterized by bilateral central visual loss typically in early adulthood. Few histopath- ologic studies, including ultrastructural and molecular genetic analysis, have been reported. Methods: Ocular tissue was obtained postmortem from an 81-year-old woman with LHON from the Queensland 1 pedigree characterized by mutations at nucleotide positions 4160 and 14484. Routine histopathologic studies, electron microscopy, elec- tron-probe analysis, and molecular genetic analysis were performed. Results: Marked atrophy of the nerve fiber and retinal ganglion cell layers and optic nerves was present. Results of electron microscopic examination demonstrated 1 .2 JLm electron-dense, double-membrane-bound inclusions, consisting of calcium by electron- probe analysis, in retinal ganglion cells. The optic nerve was homoplasmic for mutations 4160 and 14484. Conclusion: Optic nerve and inner retinal atrophy in LHON may be a result of metabolic mitochondrial dysfunction leading to intramitochondrial calcification. Homo- plasmy for mitochondrial mutations 4160 and 14484 in the leukocyte/platelet fraction of whole blood may correlate with homoplasmy in the optic nerve. Ophthalmology 1 995; 102: 1509-1516 Leber hereditary optic neuropathy (LHON) is a mito- chondrial genetic disease in which there is bilateral loss of central vision, usually during early adulthood. Mito- chondrial mutations primarily responsible are located at nucleotide positions (np) 3460, 1 - 3 11778, 4 · 5 and 14484 6 involving subunits ND1, ND2, and ND6, respectively, of respiratory chain complex I (NADH-ubiquinone oxido- reductase). 7 Originally received: March 28, 1995. Revision accepted: June I, 1995. 1 The Wilmer Eye Institute, and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. 2 Department of Radiation Therapy, Research Division, University of Texas Medical Branch, Galveston, Texas. 3 Department ofSurgery, University of Queensland, Brisbane, Australia. Reprint requests to W. Richard Green, MD, Johns Hopkins Hospital, Eye Pathology Laboratory, Maumenee 427, 600 N. Wolfe St, Baltimore, MD 21287-9248. Several histopathologic studies have demonstrated the 13 optic atrophy that occurs in LHON. 8 - Sadun and co- workers13 recently reported genetic analysis of the optic nerve and retina as well as the ultrastructural features of the opfic nerve and extraocular muscles in a patient with LHON and the 11778 mitochondrial mutations. The ultrastructural features of the retina in LHON have not been reported. We present these findings, including molecular genetic analysis with assessment ofheteroplasmy (the coexistence of mutant and normal mitochondrial DNA within the same individ- ual),5 in a case of LHON from a large Australian pedigree with the np 4160 and 14484 mitochondrial mutations. 14 Case Report An 81-year-old white woman with LHON died of congestive heart failure. She belonged to the Queensland I (QLDI) pedigree described by Wallace 15 • 16 and expanded by Mackey and Buttery 17 1509
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