Progressive Retinal Atrophy – Canine

Published by Rachel (Mathes) Davis, DVM, MS, DACVO October 2016
Publication: Veterinary Information Network (VIN)

Disease Description
Progressive retinal atrophy or PRA refers to a large group of genetic diseases that cause rapidly or slowly progressive retinal degeneration.  There are many different genetic defects that cause PRA, some of which are unidentified, but all the variations end in widespread photoreceptor (i.e. rods and cones) death, thus causing eventual blindness.

Etiology
PRA is an all encompassing term to designate a group of various genetic disorders leading to photoreceptor death and retinal degeneration.  All forms of PRA involve abnormal development or premature degeneration of the photoreceptors. PRA occurs much more commonly in the dog than the cat.

PRA can be divided into the uncommon inherited photoreceptor dysplasias and much more common generalized photoreceptor degenerative diseases.1  Inherited photoreceptor dysplasias affect young dogs and quickly lead to blindness as the photoreceptors never develop normally.  Several breeds have been shown to be affected by photoreceptor dysplasia including the Norwegian elkhound,2 Irish setter,3 collie,4 Welsh corgi,5 miniature schnauzer,6 pit bull terrier,7 short-haired and long-haired dachshund,8 Alaskan malamute,9,10 German short-haired pointer,10 Siberian husky,11 old English mastiff12 and bull mastiff.12

Generalized photoreceptor degenerative diseases affect rods prior to cones, thus loss of scotopic or “night” vision is noted before photopic or “day” vision.  These diseases have been shown to affect numerous breeds with 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 being the “poster children” for the disease.1 This condition; however, may be seen in a large number of purebred breeds and may affect mixed breeds.

Diagnosis
Funduscopy – Most clinical cases of PRA can be diagnosed based on funduscopic evidence of retinal degeneration diffusely, bilaterally and evenly as most canine cases of PRA are seen in middle aged to older dogs and usually have some degree of decreased scotopic vision (decreased night vision).

Electroretinography (ERG)  – Retinal function testing with an ERG may be diagnostic for early cases of PRA that do not yet have funduscopic evidence of degeneration.  Abnormal ERG waveforms do not specifically diagnose PRA, rather they are used in conjunction with clinical, ophthalmic and genetic information to assist with the diagnosis.  ERG analysis is able to detect this condition prior to funduscopic changes; however, which makes it useful.  More detailed ERG analysis is used in research settings and may be used for analyzing litters of puppies with early-life photoreceptor disease; however, this application requires patient general anesthesia and, generally, a laboratory setting.

Physical Examination Findings: PRA is a genetic disorder affecting photoreceptors only and does not cause any systemic changes.

Disease Description in this Species
Signalment
Photoreceptor dysplasias affect young dogs (typically <1yr), but the age of onset varies on the type of genetic disorder.  Except for the X-linked disorders, there is no sex predilection for photoreceptor dysplasias.  Progressive generalized retinal degeneration affects typically middle-aged to older dogs and there is no sex predilection.

Clinical Signs
Patients with photoreceptor dysplasias are usually very young and may be completely blind or have only hemeralopia (loss of day vision).  Referral to an ophthalmologist is recommended for any young dog affected with vision loss to further characterize the nature of the pathology.

Typically, patients with generalized PRA present for changes to scotopic or “night” vision as generalized PRA affects rods before cones.  Patients may be hesitant to go outside at night, may trip on steps in low-light conditions or may refuse to go from a lit room to a dark room in the house.  Because the disease tends to slowly progress, some dogs compensate very well and the decreased vision is not noted until late in the disease process when photopic or “day” vision is affected or when the patient goes to a new environment.

Etiology
Genetic

Breed Predilection
Many

Sex Predilection
None, except for X-linked diseases

Age Predilection
<1yr – photoreceptor dysplasia
Middle-aged to older – generalized PRA

Diagnostic Procedures
Maze testing: In addition to obtaining a clinical history on patient behavior, observing patients navigating a maze in bright and dim conditions may help the practitioner gather information on overall vision.

Clinical signs: Patients with PRA typically have resting mydriasis (dilated pupils at rest) and a delayed, sluggish or incomplete pupillary response, although pupil movement and position may be variable.  In late stages of PRA, secondary cataracts may form and obscure the fundus, making it difficult to determine the cause of blindness.  In these cases, ERG is necessary to diagnose the primary pathology.

Funduscopy: Generalized PRA is typically diagnosed based on supportive clinical signs of decreased scotopic vision and funduscopic evidence of generalized degeneration.  Early funduscopic signs of PRA are noted as subtle hyperreflectivity in the peripheral retina along with mild vascular attenuation.  The vascular attenuation is first noted with the arterioles, but progresses to venule attenuation.  Later, as the disease progresses, generalized hyperreflectivity, diffuse vascular attenuation, lack of vascular extension to the peripheral fundus and variable choroidal furrowing are noted.1  In the final stages of disease, optic disc atrophy and pallor are noted.  Funduscopic changes are bilateral and symmetric, helping to distinguish this disease from other causes of retinal degeneration.

ERG: Electroretinogram may be used to confirm the diagnosis or diagnose the condition prior to onset of funduscopically visible degeneration.  Detailed ERG analysis is also useful for photoreceptor dysplasia analysis in young dogs and in genetic PRA research studies.

DNA analysis: Specific gene mutations causing PRA have been identified in many breeds with new mutations being identified on an ongoing basis.  Optigen has several commercial gene tests available for breeders and dog owners.  Genetic testing is recommended for breeding animals for which the genetic PRA test is available.  The PRA genetic mutations are thought to be heterogenous within and between breeds, making it difficult to specifically determine each mutation for each breed.13

OFA eye examinations: Breeding animals should undergo OFA eye examinations with a veterinary ophthalmologist yearly to screen for PRA and other genetic disorders.  These examinations help make earlier diagnoses of PRA in breeding animals and help reduce the incidence of the disease.  Recently, selective breeding and breeding advice has been shown to significantly reduce the number of affected dachshunds over a 13-year period.14

Treatment/Management/Prognosis
Specific Therapy
There is no specific therapy available for most cases of PRA currently.  Recently, restoration of vision was accomplished in dogs affected with rod-cone dysplasia type 1, a specific type of photoreceptor dysplasia, utilizing subretinal gene therapy. Gene therapy may be a promising future treatment option for other photoreceptor dysplasias and generalized PRA.

Supportive Therapy
PRA causes cataract formation late in disease process, thought to occur secondary to oxidative stress on the lens (“toxic” cataracts), although there is limited data on the actual pathophysiology. Oral antioxidant therapy has been shown to improve retinal function in normal dogs and correct refractive error.16 Antioxidants have also been shown to decrease oxidative stress on canine lens cells and help delay cataract formation.17  While more research is needed to fully elucidate the effect of oral antioxidant therapy, its use in dogs with PRA may help delay secondary cataract formation as well as support ocular health.18

Monitoring and Prognosis
Clients should be educated on how to help their pet adjust to decreased vision.  In the early stages of disease, supplementing the dog’s environment with light will help them navigate (e.g. night lights, collar LED lights, flood lights outside, etc.).  Because this disease is progressive, complete blindness will ensure.  The vision loss occurs slowly for most dogs; however, so they are typically able to adjust to their handicap if their environment remains consistent.

Differential Diagnosis

• Post-inflammatory retinal degeneration
• Retinal pigment epithelial dystrophy
• Retinal dysplasias
• Sudden acquired retinal degeneration
• Glaucomatous retinal degeneration

References

1. Narfstrom K and Petersen-Jones S. Diseases and Surgery of the Canine Ocular Fundus. In Gelatt KN (ed): Veterinary Ophthalmology 4th ed. Pp 965-82
2. Aguirre GD, Rubin LF. Progressive retinal atrophy (rod dysplasia in the Norwegian Elkhound). J Am Vet Med Assoc 1971 Vol 158 (2) pp. 208-218.
3. Aquirre G, Farber D, Lolley R, et al. Rod-cone dysplasia in Irish setters: a defect in cyclic GMP metabolism in visual cells. Science 1978 Vol 201 pp. 1133-1134.
4. Wolf ED, Vainisi SJ, Santos-Anderson R. Rod-cone dysplasia in the collie. J Am Vet Med Assoc 1978 Vol 173 pp. 1331-1333.
5. Petersen-Jones SM, Entz DD, Sargan DR. cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest Ophthalmol Vis Sci 1999 Vol 40 pp. 1637-1644.
6. Parshall CJ, Wyman M, Nitroy S, et al. Photoreceptor dysplasia: An inherited progressive retinal atrophy of Miniature Schnauzer dogs. Prog Vet Comp Ophthal 1991 Vol 1 pp. 187-203.
7. Goldstein O, Mezey JG, Schweitzer PA, et al. IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds. Invest Ophthalmol Vis Sci. 2013;25:7005-19.
8. Curtis R, Barnett KC. Progressive retinal atrophy in miniature long-haired dachshund dogs. Br Vet J. 1993;149:71-85.
9. Seddon JM, Hampson EC, Smith RI, et al. Genetic heterogeneity of day blindness in Alaskan Malamutes. Anim Genet. 2006;37:407-10.
10. Sidjanin DJ, Lowe JK, McElwee JL, et al. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet. 2002;11:1823-33.
11. Zeiss CJ, Ray K, Acland GM, et al. Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3). Hum Mol Genet. 2000;9:531-7.
12. Kijas JW, Miller BJ, Pearce-Kelling SE, et al. Canine models of ocular disease: outcross breedings define a dominant disorder present in the English mastiff and bull mastiff dog breeds. 2003;94:27-30.
13. Downs LM, HItti R, Pregnolato S, et al. Genetic screening for PRA-associated mutations in multiple dog breeds shows that PRA is heterogeneous within and between breeds. Vet Ophthalmol. 2014;17:126-30.
14. Koll S, Reese S, Medugorac I, et al. The effect of repeated eye examinations and breeding advice on the prevalence and incidence of cataracts and progressive retinal atrophy in German dachshunds over a 13-year period. Vet Ophthalmol. 2016;13:epub.
15. Petit L, Lheriteau E, Weber M, et al. Restoration of vision in the pde6b-deficient dog, a large animal model of rod-cone dystrophy. Mol Ther. 2012;20:2019-30.
16. Wang W, Hernandez J, Moore C, et al. Antioxidant supplementation increases retinal responses and decreases refractive error changes in dogs. 2016;10:epub.
17. Barden CA, Chandler HL, Lu P, et al. Effect of grape polyphenols on oxidative stress in canine lens epithelial cells. Am J Vet Res. 2008;69:94-100.
18. Xue C, Rosen R, Jordan A, et al. Management of ocular diseases using lutein and zeaxanthin: what we have learned from experimental animal studies? J Ophthalmol. 2015;epub.