REVIEW Recent advances in understanding zy v the spectrum of canine generalised progressive retinal atrophy P. J. M. Clements, D. zyxwvuts R. Sargan, D. J. Gould and S. M. Petersen-Jones zyxwvutsr Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 OES Journal of Small Animal Practice (1996) 37, 155-162 ABSTRACT Canine generalised progressive retinal atrophy (gPRA) is a large and ever-increasing collection of naturally occurring, heterogeneous, progres- sive disorders. Most are inherited in an autoso- ma1 recessive manner and new, breed-specific forms continue to be described. The gPRAs cause photoreceptor cell death and subsequent retinal degeneration, culminating in blindness. In humans, similar inherited retinal dystrophies are recognised as retinitis pigmentosa and macular dystrophy. Molecular biological studies have revealed disease-causing mutations in several genes in humans and also in mice with retinal dystrophies. Recently, molecular genetic tech- niques have identified the cause of one form of gPRA in Irish setters while important candidate genes have been investigated in other breeds. Identification of mutations responsible for dif- ferent forms of gPRA allows carrier and pre- degenerate animals to be detected using DNA-based tests. Such genetic tests will greatly facilitate the eradication of these diseases in different breeds. Correspondence and reprint requests to S. M. Petersen-Jones. P. J. M. Clements’ new address is Animal Health Product Development, Pfizer Central Research, Sandwich, Kent CT13 9NJ INTRODUCTION Generalised progressive retinal atrophy (gPRA) encompasses the autosomal recessive and the recently described X-linked recessive primary photoreceptor diseases. These are distinct from retinal pigment epithelial dystrophy (or central PRA), lipid retinopathies and retinopathies which have remained unclassified due to a lack of detailed investigation (Millichamp 1990). In dogs, as in mice, photoreceptor morpho- genesis is incomplete at birth and proceeds radi- ally from the central retina (Aguirre and others 1972). Clearing of the ocular media and full photoreceptor structural development are not achieved until 42 to 60 days post natal (Aguirre and others 1972, Noden and de Lahunta 1985). This is significant in terms of disease classifica- tion: conditions affecting photoreceptors before they are fully mature are termed dysplasias, as distinct from degenerations, where the onset of disease occurs after anatomic and functional mat- uration. This subdivision into photoreceptor dys- plasias and degenerations is summarised in Table 1, along with some of the clinical features demonstrating the phenotypic heterogeneity of the disease group. Certain clinical signs are common to all the gPRAs, but they do differ in their onset and rate of progression. Affected dogs typically show an initial night blindness which is followed by a progressive loss of day vision, culminating in complete blindness. Cell death progressively thins the retina and the blood supply subsequently diminishes, causing a progressive and generalised tapetal hyper- reflectivity with attenuation of the superficial retinal vasculature. With time, the non-tapetal fundus shows pigmentary changes and the optic nerve head atrophies. Electroretinographic (ERG) abnormalities are often detectable in advance of ophthalmoscopic signs. These changes reflect the selective cellular dysfunction and death occur- ring in the retina. Secondary cataracts are a com- mon sequel in gPFL4. A more detailed summary of those phenotypes not covered by the scope of this review is given by Curtis and others (1991). The recessive nature of these disorders means that founder and popular sire effects can result in a high incidence of asymptomatic carriers of a mutation within a breed. Carriers are then more likely to breed and potentially produce affected offspring. In some breeds, diagnosis may not be possible, except by ERG, until after sexual matu- rity (Table 1) when offspring may already have been produced. Molecular biological and genetic studies iden- tifying the locus of, or mutations in, genes caus- ing gPRA will enable specific genetic tests to be developed to genotype individuals. This is a 155