The retinal pathology of ovine ceroid-lipofuscinosis : a thesis presented in fulfilment of the requirement for the degree of Master of Veterinary Science at Massey University

Abstract

Ovine ceriod-lipofuscinosis is an animal model of a rare genetic disease of man and some domestic animals. The disease is characterized by blindness idiocy and premature death. In order to investigate the development of pathological changes in this model it was important to be able to accurately diagnose those sheep affected at an early age before clinical disease was apparent. In this thesis a number of methods such as skin biopsy, bone marrow examination and brain biopsy were investigated and it was concluded that brain biopsy was the most suitable and reliable method for establishing the preclinical diagnosis of ceroid-lipofuscinosis. On clinical grounds the ovine disease most closely resembled the juvenile form of human disease and blindness was the important clinical finding in both diseases. A time course study of the development of retinal pathology was carried out. Electroretinography was used as a clinical tool to ascertain the functional status of the retina. Pathological changes to the retina were investigated using light and electron microscopy. Electroretinography revealed a decline in rod and cone 'b' wave amplitudes over a relatively short time span. Changes to the rod responses preceeded, and were generally more dramatic than those of the cones. These changes paralleled a loss of rod and cone photoreceptor cells. Although there was some variation between animals and between readings it was suggested that electroretinography was a useful method of monitoring changes to the retina and may be useful in assessing therapeutic strategies. In affected retinas photoreceptor cell outer segments appeared to be shorter than those of controls. By 84 weeks of age the outer nuclear layer was reduced to a single row of nuclei with only remnants of outer segments present. Electron microscopy confirmed these findings and showed that the formation of abnormal dystrophic outer segments of photoreceptor cells was a significant early pathological change. Most cell types in the retina contained autofluorescent lipopigment bodies in their cytoplasm with the ganglion cells usually containing the largest amount. Ultrastructural studies showed that the storage bodies were made up of electron dense granular material and a variety of membranous and tubular structures giving them a similar appearance to those which were reported in the central nervous system. Very small electron dense 'smudges' were seen in the cytoplasm of some cells and these may have been early storage body precursors. This study showed that electroretinography could be used to monitor the development of blindness in ovine ceroid-lipofuscinosis. It also revealed early severe pathological changes to the photoreceptor outer segments which may be of pathogenic significance in ovine and juvenile human ceroid-lipofuscinosis and therefore worthy of further investigation.