Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan Terriers with ceroid-lipofuscinosis

Abstract

Behavioral assessments of the affected dogs revealed moderate visual impairment in low-light conditions but good vision in bright light. On funduscopic evaluation of these dogs, abnormalities detected ranged from none to signs of moderately advanced retinal degeneration. Compared with findings in the control dog, electroretinography revealed depressed rod cell function with some impairment of cone cell function in the affected dogs. Morphologically, disease-specific storage bodies were detected in retinal Müller cells and neurons, particularly in ganglion cells, and in cells of the cerebral cortex and cerebellum in affected dogs. Substantial photoreceptor cell loss and disruption of photoreceptor outer segment morphology appeared to develop late in the disease. IMPLICATIONS FOR HUMAN MEDICINE: The similarities between ceroid-lipofuscinosis in Tibetan Terriers and some forms of ceroid-lipofuscinosis in humans suggest that the canine disease may have a genetic and biochemical basis similar to that of one of the ceroid-lipofuscinosis disorders in humans.

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

“…In Alexander disease, GFAP accumulation occurs in cytoplasmic aggregates called Rosenthal fibres that differ morphologically from NCL storage bodies (Hsiao et al 2005;Li et al 2005). The accumulation is restricted to astrocytes in Alexander disease (Hsiao et al 2005), unlike in NCL where storage body accumulation occurs in both neurons and glia (Katz et al 2005b). In the Tibetan terrier disease, little if any of the storage body accumulation occurs in cells that have morphologies typical of astrocytes (Fig.…”

“…NCL in Tibetan terriers has been extensively characterized in our laboratories by analysis of behavioural signs and examination of brain and retinal tissues for accumulation of disease-specific storage bodies (Katz et al 2002(Katz et al , 2005b. Behavioural changes typically first become apparent at 5-7 years of age and progress until the dogs are euthanized, usually by age 10 years.…”

“…Small slices of cerebral cortex and cerebellum were placed in the same fixative, and the remainder of the brain was frozen. The other eye and portions of the same brain tissues were fixed for electron-microscopic examination (Katz et al 2005b). The preserved samples were shipped for next-day delivery to the laboratory.…”

“…The preserved samples were shipped for next-day delivery to the laboratory. The fixed tissues were processed and examined using fluorescence microscopy and electron microscopy to determine whether there was storage body accumulation typical of this disease (Katz et al 2005b). Dogs that showed the typical pattern of behavioural signs with an age of onset greater than 5 years and that exhibited the characteristic pattern of storage body accumulation in retina, cerebral cortex and cerebellum were designated as being affected with NCL.…”

“…A small fraction of each storage body preparation (less than 5 ml) was applied to a glass microscope slide, covered with a coverslip, and examined with fluorescence microscopy under conditions optimized for visualization of storage body autofluorescence (Katz et al 2005b). Another portion of the isolated storage material was processed for electron-microscopic examination (Katz et al 1995).…”