Tibetan terrier model of canine ceroid lipofuscinosis

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Abstract
Over a 10‐year period, we have studied the Tibetan terrier's visual electrophysiology, light and electron microscopic (EM) retinal characteristics of a slowly evolving inherited ceroid lipofuscinosis (CL). The retinal degeneration with CL inclusions (rdi) in the inner nuclear layer (bipolar cells) and nerve fiber layer (ganglion cells) has been called “rdi” to differentiate the visual abnormality from typical early retinal degeneration (erd) reported also in the Tibetan terrier. The unique “rdi” electroretinogram (ERG) gives a predominant P III wave at age 7 weeks but becomes more characteristically depressed in all phases over several years. Nyctalopia is the only functional abnormality for the first 5 to 6 year of life. Signs are remarkably few considering the pathology. Microscopic studies of the retina show accumulations, increasing with age, of autofluorescent dense inclusion particles which stain intensely by Luxol fast blue, PAS, and acid‐fast procedures. Ultrastructural studies of the retina show the dense particles to be lamellar membranes repeating every 2 to 4 nm, consistent with ceroid lipofuscin. The inner retinal layers were always the target layer to be affected first and most severely. The ganglion cells were most frequently involved. The photoreceptors eventually degenerated but relatively few particles were found in this layer. The cytosomes in the cerebral cortex and brainstem neurons resemble lipofuscin, containing granular, lamellar, and globular components. Different pigment bodies were present in the cerebellar Purkinje cells. Neuronal loss which was moderate in the cerebellum and mild in the cerebrum was accompanied by astrogliosis and a striking presence of macrophages. The fine struture of the accumulated lipopigment varied regionally so that cytosomes in the cerebral cortical neurons differed from those in both the Purkinje cells and Bergmann glia of the cerebellum. While it was not possible to identify conclusively successive stages in a neurodegenerative progression, many remarkable cytologic changes were observed. These changes included 1) astrocyte swelling, 2) an abundance of lipopigment‐laden and vacuolated macrophages diffusely arrayed in the cerebrum but more focally concentrated in the cerebellum, and 3) distended macrophages encroaching upon abutting and distorting cerebral cortical neurons. Personality and learning changes along with mild functional abnormalities begin to show up from 4 to 6 years. The slow progression of neuronal degeneration and the greatly delayed appearance of mild clinical signs suggest that this canine disease may be a practical model for studies on the pathogenesis of neuronal senescence and the adult human form of CL.

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