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Fred N. Ross-Cisneros, Chiara La Morgia, Vallerio Carelli, Alfredo A Sadun; Optic Neuropathy in a DNMT-1-Related Disease with a Mitochondrial Pattern of Axonal Loss. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5079.
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© ARVO (1962-2015); The Authors (2016-present)
To describe the histopathological features of postmortem ocular tissue from a patient with optic neuropathy carrying a DNMT-1 mutation . Mutations in the DNMT-1 gene impair DNA methylation and have been associated with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN), and hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE)..
Eyes and optic nerves were obtained at autopsy from a 60 year old male affected with DNMT-1 (with ADCA-DN) and compared with two healthy age and gender-matched controls. Eyes were immersion-fixed in formalin within 17 hours after death. Eyes were dissected at the horizontal meridian at the level of the temporal and nasal regions of the retina and the optic nerve head. Retrobular optic nerves were dissected in cross-sections just posterior to the globe. All tissues were processed for and embedded into paraffin. Tissue sections were cut at 5 μm and placed on glass slides. Retinas were stained with H & E for general morphology and the optic nerves were immunostained for neurofilament protein and myelin basic protein to examine the integrity of the axonal fibers.
The control retinas and optic nerves showed a normal cellular architecture. The DNMT-1 retina demonstrated widespread loss of retinal ganglion cells (RGCs) which appeared to be greatest in the temporal region of the retina, especially those contributing to the papillo-macular bundle. In the DNMT-1 optic nerve, there appeared to be a "diffuse" loss of axons throughout the nerve, but this loss appeared more remarkable in the temporal and inferior regions.
There was a depletion of RGCs in the DNMT-1 retina, most notably those contributing to the papillo-macular bundle. This corresponded to axonal loss predominantly in the temporal and inferior sectors of the nerve in a pattern characteristic of a mitochondrial optic neuropathy. We hypothesize that DNMT-1 mutations may also affect mitochondrial DNA methylation possibly leading to mitochondrial dysfunction producing this classic pattern of mitochondrial optic neuropathy.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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