Optic Nerve Histopathology in a Case of Wolfram Syndrome Demonstrates a Mitochondrial Pattern of Axonal Loss

Abstract

Purpose: : To describe the histopathological features in postmortem optic nerves from a patient with Wolfram syndrome (WS), a rare usually autosomal recessive disease also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). The present patient had a compound heterozygous defect in the Wolfram gene (WFS1).

Methods: : Right and left retrobulbar optic nerves were obtained at autopsy from a twenty-five year old male WS patient who died of cardiorespiratory arrest and, as controls the nerves from a healthy twenty year old male who died in a motorcycle accident. Tissues were fixed in 10 % neutral buffered formalin (NBF), dissected into cross-sectional profiles and embedded into paraffin. Tissue blocks were sectioned at 5 microns and immunostained for neurofilament (NF) protein, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) using an indirect immunoperoxidase method with diaminobenzadine as the chromagen. Stained optic nerves were examined in five quadrants or "zones"; superior, inferior, nasal, temporal, and central on a Zeiss Axioskop bright field microscope. Images were captured with a Spot II digital camera at various magnifications.

Results: : The control optic nerves demonstrated a normal homogenous staining pattern reflecting intact bundles of axons (NF), with associated myelin (MBP), and normal astrocytes (GFAP) throughout its parenchyma. The WS optic nerves immunostained for NF and MBP revealed a moderately large zone of degeneration in both the temporal and inferior quadrants at various levels of magnification. The staining for NF and MBP in the remaining WS nerve parenchyma appeared homogenous. The WS optic nerves immunostained for GFAP appeared homogenous although there was a slight volume increase within the temporal and inferior zones of degeneration.

Conclusions: : There was a distinct zone of optic atrophy observed in the optic nerves of this case of WS located in the temporal and inferior quadrants that was bilaterally symmetric. This is the same pattern of axonal degeneration, reflecting involvement of the papillo-macular bundle, which is typical of Leber’s Hereditary Optic Neuropathy (LHON) and other mitochondrial optic neuropathies. The present results support the conclusion that WS appears to cause mitochondrial dysfunction with associated optic atrophy.

Keywords: neuro-ophthalmology: optic nerve • genetics • immunohistochemistry