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Progressive Retinal Atrophy: An Overview
World Small Animal Veterinary Association World Congress Proceedings, 2003
Simon M. Petersen-Jones, DVetMed, PhD, DVOphthal, DECVO, MRCVS
Department of Small Animal Clinical Sciences, Michigan State University
East Lansing, MI, USA

Progressive retinal atrophy (PRA, formerly called generalized PRA) is a group of hereditary conditions that result in a progressive degeneration of the retina and loss of vision. They are the veterinary equivalent of the retinitis pigmentosas in man. PRA has been recorded in over 100 breeds of dog and is less widespread in cats. Some breeds have a high incidence of the problem.

Mode of inheritance of PRA

Most forms of PRA are inherited in an autosomal recessive manner, although both X-linked and dominant forms are recognized.

Clinical signs of PRA

The initial changes in typical PRA are a loss of rod photoreceptor responses leading to night blindness. This is followed by a slower loss of cone responses and progressive deterioration in daytime vision. The age at onset and rate of progression varies both between the types of PRA, and also within the individual forms of PRA. The latter is particularly true for the progressive rod cone degeneration (prcd) form of PRA. As the condition progresses the owners may notice a more dilated pupil and increased reflection from the eye (due to a combination of a more dilated pupil and tapetal hyper-reflectivity). Secondary cataracts accompany the loss of vision in the later-onset and more slowly progressive forms of PRA such as prcd, and are sometimes mistakenly assumed to be the primary cause of the vision loss. Vision should be accurately assessed for example by obstacle course negotiation in both light and dark conditions. Ophthalmoscopic examination will reveal a sluggish PLR and possibly secondary cataract. On fundus examination in the early stages of PRA a granular appearance affecting the peripheral tapetal fundus may be appreciated and as the condition progresses typical signs of a generalized retinal thinning become apparent. There is tapetal hyper-reflectivity, superficial retinal blood vessel attenuation and then in the later stages pigmentary changes in the non-tapetal fundus and atrophy of the optic nerve head. The changes are bilateral and similar between the two eyes. Some exceptions to the classic appearance may be seen, for example, in some forms of prcd a more hyper-reflective zone may be seen in the tapetal fundus as a horizontal stripe at the ventral tapetal/nontapetal junction. In dominant PRA in Mastiffs, some areas of the retina may degenerate prior to others (see below).

Electroretinography in PRA

The electroretinogram can be useful in the early diagnosis of many forms of PRA.

Specific forms of PRA

Rod cone dysplasias (rcd)

Rcd is recognized in 4 dog breeds and is an autosomal recessive trait. In the Irish setter and Sloughi (rcd1) it is due to mutations (a different mutation in each breed) in the gene encoding beta subunit of cylic GMP phosphodiesterase (PDE6B). In the Cardigan Welsh Corgi (rcd3) it is due to a mutation in the alpha subunit of cylic GMP phosphodiesterase (PDE6A). The Rough Collie (rcd2) has a similar disease although the causal gene mutation has remained elusive. Secondary cataract formation is not a prominent feature of this form of PRA. DNA-based mutation detection tests are available for the rcds in Irish Setter, Sloughi and Cardigan Welsh Corgi.

Progressive rod cone degeneration (prcd)

This is numerically the most important form of PRA with several different breeds being affected including Miniature and Toy Poodles, Labrador Retrievers, English and American Cocker Spaniels, Portuguese Water Dogs, Chesapeake Bay Retrievers, Australian Cattle Dogs and Nova Scotia Duck Tolling Retrievers etc. As more breeds with later-onset PRA are investigated more are likely to be shown to suffer from prcd. Prcd is an automsomal recessive trait and the gene mutation has been mapped to canine chromosome 9. Very closely linked DNA markers have been identified that are used in commercial DNA-based tests but the actual gene mutation has yet to be identified. The tests divide dogs into three groups. The first group contains dogs that are unaffected by prcd, the second group contains carriers of prcd but also some normal dogs; the third group contains the affected dogs but also some normal dogs and some carriers. Linked marker tests do not definitively identify the presence/absence of the causal gene mutation so are not so useful as mutation detection tests, but nevertheless are extremely valuable.

Prcd is a later-onset form of PRA but the age of onset and rate of progression varies considerably between the breeds affected and also within the breeds (notably the English Cocker Spaniel). There is also some suggestion that genetically affected dogs in certain breeds may never develop clinical signs of PRA (incomplete penetrance e.g., Nova Scotia Duck Tolling Retrievers). Such variation is likely to depend on a combination of background genetics (modifying genes) and environmental factors. Using DNA markers known to be closely linked to the prcd locus, it has been possible to prove that some breeds with late-onset PRA have a form of PRA that is not linked to the prcd locus.

X-linked PRA

X-linked PRA is described in two breeds of dog, the Siberian Husky and the Samoyed. The two breeds suffer from different mutations of the same gene, retinitis pigmentosa GTPase regulator (RPGR). Both mutations are in the same region of the gene (open reading frame 15) which is a "hot spot" for mutations in human X-linked RP. The severity of disease differs between the two breeds; with that in the Samoyed (Xlinked PRA type 2-XLPRA2) being a more severe disease than XLPRA1 in the Siberian Husky. The female carriers of XLPRA also develop some retinal degeneration. In carriers of XLPRA1 this is limited to patches of retinal degeneration. The degenerate regions of retina represent parts of the retina where the X chromosome that is expressed is the one with the mutant RPGR gene (only one X chromosome is active in each cell and patches of cells expressing the same X chromosome occur). Females carriers of the XLPRA2 gene develop a progressive retinal degeneration. The areas of retina that express the defective X chromosome degenerate and this leads to a degeneration of the genetically normal surrounding retina (innocent bystander effect).

Dominant PRA

Dominantly inherited PRA occurs in the Mastiff breeds. It is due to a mutation in the rod opsin gene which results in an alteration of one amino acid (a missense mutation). The disease phenotype is dissimilar to the previously described PRAs. There is a marked variation in the severity of retinal thinning across the retina with the most severely affected area being the central retina. This perhaps suggests an affect of light exposure on the speed of retinal degeneration. The same effect is seen in humans with retinitis pigmentosa due to some rod opsin mutations.

Other forms of PRA

Several other forms of PRA are described in other breeds of dog. As the dog genome project progresses the mutations underlying many of these forms will become apparent.

Feline PRA

The Abyssinian suffers from two forms of PRA. The first is a dominantly inherited early-onset form that exists as a colony at the Animal Health Trust, in the UK. The second form is autosomal recessive middle-age onset and is relatively prevalent in Scandinavia the UK and USA. This latter form is similar to prcd in dogs.

References

1.  Acland GM, Ray K, Mellersh CS. et al (1998) Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans. Proc Natl Acad Sci U S A 95:3048-53

2.  Acland GM, Ray K, Mellersh CS, et al (1999) A novel retinal degeneration locus identified by linkage and comparative mapping of canine early retinal degeneration. Genomics 59:134-42

3.  Aguirre GD (1978) Retinal degeneration in the dog. I. Rod dysplasia, Experimental Eye Research 26: 233-253

4.  Aguirre GD, Acland GM. (1988) Variation in retinal degeneration phenotype inherited at the prcd locus. Exp Eye Res 46:663-87

5.  Curtis R, Barnett KC, Leon A. (1987) An early-onset retinal dystrophy with dominant inheritance in the Abyssinian cat. Clinical and pathological findings. Invest Ophthalmol Vis Sci 28:131-9

6.  Kijas JW, Cideciyan AV, Aleman TS, et al (2002) Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Natl Acad Sci USA 99:6328-33

7.  Lin CT, Gould DJ, Petersen-Jones SM, Sargan DR. (2002) Canine inherited retinal degenerations: update on molecular genetic research and its clinical application. J Small Anim Pract 43:426-32

8.  Narfstrom K, Wilen M, Andersson BE. (1988) Hereditary retinal degeneration in the Abyssinian cat: developmental studies using clinical electroretinography. Doc Ophthalmol 69:111-8

9.  Petersen-Jones S (2001) Current DNA-based tests for hereditary eye disease. Vet Ophthalmol 4:233-6

10. Petersen-Jones SM, Clements PJ, Barnett KC, Sargan DR. (1995) Incidence of the gene mutation causal for rod-cone dysplasia type 1 in Irish setters in the UK. J Small Anim Pract 36:310-4

11. Petersen-Jones SM, Entz DD. (2002) An improved DNA-based test for detection of the codon 616 mutation in the alpha cyclic GMP phosphodiesterase gene that causes progressive retinal atrophy in the Cardigan Welsh Corgi. Vet Ophthalmol 5:103-6

12. Petersen-Jones SM, Entz DD, Sargan DR. (1999) cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest Ophthalmol Vis Sci 40:1637-44

13. Suber ML, Pittler SJ, Quin N, et al (1993), Irish setter dogs affected with rod-cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene, Proc Natl Acad Sci U S A 90: 3968-3972

14. Zeiss CJ, Acland GM, Aguirre GD. (1999) Retinal pathology of canine X-linked progressive retinal atrophy, the locus homologue of RP3. Invest Ophthalmol Vis Sci 40:3292-304

15. Zhang Q, Acland GM, Wu WX, et al (2002) Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Genet 11:993-1003

Speaker Information
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Simon M. Petersen-Jones, DVetMed, PhD, DVOphthal, DECVO, MRCVS
Department of Small Animal Clinical Sciences, Michigan State University
East Lansing, MI, USA


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