Progressive Retinal Atrophy (PRA) is a common term used for a group of inherited retinal diseases. During the progression of the disease, retina of the eye degenerates over time, eventually worsening the condition and ultimately leading to blindness.This condition affects both the eyes, and is not painful for the dog. Age-at-onset and rate of progression of the disease differ between breeds. While, some breeds experience an earlier onset, the other breeds do not develop PRA until later in life. It may take months or even years to develop complete blindness in the affected dogs. The affected dogs either experience an arrested development (retinal dysplasia) or an early degeneration (retinal atrophy) of the photoreceptors in retina. In typical PRA, rod photoreceptor responses are lost first, followed by cone photoreceptor responses. It is seen in several breeds of the dogs and very rarely in cats. It is similar to retinitis pigmentosa (RP) in human. RP is transmitted in different modes—autosomal dominant, autosomal recessive, X-linked, and digenic—as well as maternal inheritance). Likewise, PRA shows several modes of transmission (autosomal recessive being most common followed by autosomal dominant and X-Linked) involving a large number of genes and mutations. Each PRA disease generally occurs in only one or a few breeds, depending upon the associated mutations. PRA- Progressive rod-cone degeneration is a notable exception, affecting more than 20 breeds. The first described case of PRA in dogs was in the early twentieth century and today more than 100 breeds have had cases of retinal degeneration. At least 22 mutations in 19 genes have been identified to be associated with different forms of PRA in more than 50 breeds. The mutations causing PRA in some breeds of dogs remain uncharacterized.
Symptoms of progressive retinal atrophy
Usually, night blindness is the first sign of Progressive Retinal Atrophy (PRA). In this condition, the dog begins to lose its night vision, and has problems seeing obstacles or finding their way around in low light and darkness. As the condition progresses, the dog’s pupils become dilated. Cataracts may also develop simultaneously with the condition, leading to a milky or clouded appearance of the lens of the eyes in some cases too. During the progression of the disease, several signs like reluctance to jump on or off furniture during darkness, Sluggish pupillary light responses, decreased menace response, cloudy or opaque eye surface; grayish discoloration of the surface of the eye, bumping into furniture or walls, tripping or stumbling over objects, pawing at the air when going down stairs, reluctance to navigate stairs etc. may indicate the presence or progression of the condition in dog.
An Australian shepherd affected with progressive retinal atrophy (PRA).
Diagnosing PRA in Dogs
When PRA is suspected in a dog, dog must have formal diagnosis by a full genetic history of dog and examining the eyes with an ophthalmoscope. An electroretinogram (ERG) scan is required, if the eyes are clouded with cataracts as well as affected by progressive retinal atrophy (PRA) because this can make physical examination of the eyes difficult. For diagnosis of PRA in dogs generally two tests are performed as described below:
The electroretinography is a test of electrical function within the retina, and is a sensitive indicator of progressive retinal atrophy, often revealing abnormal findings long before clinical sign are apparent. An electroretinogram (ERG) measures the electrical impulses produced by the retina. This test is performed under General anesthetic and involves the placing of a special contact lens onto the cornea plus two tiny needles (electrodes) placed under the skin around the eye. Flashing lights are then used to stimulate the retina and the electrical response of the retina is recorded.
It is a DNA-based blood test that helps to confirm the presence of the defective gene. This test identifies dogs with PRA as well as those who are carriers i.e. who may pass the defective gene to their offspring. The PRA-PRCD test is a DNA-based test that helps you avoid one form of Progressive Retinal Atrophy (PRA).
Types of PRA
Progressive retinal atrophy can be classified based upon symptoms, genetic mutations, types of breeds as well as based upon the age of onset as follows:
PRA Types Based Upon Symptoms
Progressive retinal atrophy is divided into two categories based on the symptoms of the disease: Generalized PRA and Central PRA. In both the instances, less amount of nutrients reach the eye because the receptor (nerve) cells lining the retina start degenerating and the blood vessels feeding the retina become smaller.
Generalized PRA is characterized by night blindness or nycteralopia involves dysplasia (enlargement) followed by atrophy (wasting away) of the rods and/or cones and sometimes it may be marked solely by atrophy of the rods and cones. It commonly affects but not restricted to the following breeds of dogs:
Tibetan Terrier, Samoyed, Irish Setter, Sloughi, Collie, Cardigan Welsh Corgi, Norwegian Elkhound, Miniature Schnauzer, Akita, Belgian Shepherd Dog, Miniature longhaired Dachshund, Alaskan Malamute, Glen of Imaal Terrier, Papillon, Poodle, English Cocker Spaniel, American Cocker Spaniel, Labrador Retriever, Portuguese Water Dog, Tibetan Spaniel, Chesapeake Bay Retriever, Australian Cattle Dog, Nova Scotia Duck Tolling Retriever, American Eskimo Dog
Central PRA is a rare form of PRA, also known as retinal pigment epithelial dystrophy (RPED) which affects the Retinal Pigmented Epithelium (the superficial layer of the retina) resulting in loss of its ability to process light, and this consequentially impairs vision. It is characterized by day blindness or hemeralopia that involves atrophy of the cones and subsequent atrophy of the rods, eventually terminating in blindness. It occurs later in life and generally progresses slowly. As this condition affects older dogs, the symptoms will often be dismissed, in the early stages, as age-related weakening of the eyesight. Vision of moving or distant objects will be less impaired than vision of static or near objects. Peripheral vision is usually retained for a long time. It commonly affects but not restricted to the following breeds of dogs:
Border Collie, Chesapeake Bay Retriever, Cavalier King Charles, Collie, English Cocker Spaniel, English Springer Spaniel, Golden Retriever, Labrador Retriever, Poodle, Shetland Sheepdog, Spaniel, Briard (particularly susceptible).
PRA Types Based Upon Genetic Mutation
Rod-cone dysplasia type 1 (PRA-RCD1)
Rod-cone dystrophy is an early onset, autosomal recessive disease caused by a nonsense mutation in the canine rod cyclic GMP phosphodiesterase beta-subunit (PDE6B) gene causing a premature stopcodon that involves G to A transition in codon 807 at nucleotide position 2420. The non-mutated gene helps in producing phosphodiesterase holoenzyme that are involved in the amplification of the visual signal. The disease mainly affects Irish setter breeds in which Rod cell response is nearly absent and during six to eight weeks of age night blindness begins to occur and the animal becomes completely blind by one year age. This disease also occur in Sloughi breed, and associated mutation can be detected by DNA test.
Rod-cone dysplasia type 2 (PRA-RCD2)
Rod-cone dystrophy type 2 (PRA-RCD2) is an early onset autosomal recessive disease and only found in collie breed of dog. The RCD 2 locus has been mapped previously to a ~4 Mb region on CFA7.gene. In RCD 2 cone cells as well as rod cells degenerate slowly but the degeneration of cone cells is slower than that of rod cells. These signs can be seen by ophthalmoscope examination when the puppies are about 3.5-4 month of age. By 6 to 8 months of age, RCD 2 dogs become functionally blind.
Rod-cone dysplasia type 3 (PRA-RCD3)
Rod-cone dysplasia type 3 (PRA-RCD 3) is an autosomal recessive disease caused due to a 1-bp deletion in codon 616 of PDE6A gene (a-subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase). The deletion incurs a frame shift mutation. This disease has been found in Cardigan Welsh corgi and Chinese Crested dog breeds in which Rod photoreceptor cells degenerate followed by cone photoreceptors resulting in complete blindness by 1 year of age, but some breeds may retain limited sight until 3 to 4 years of age.
Rod-cone dysplasia type 4 (PRA-RCD4)
The PRA-RCD4 is also known as LOPRA (Late Onset PRA) because the age of onset varies from few years of age (2-3 years) up to old age (10-11 years). This disease is inherited as an autosomal recessive trait. This disease is caused due to single-base insertion mutation in C2orf71 gene. This causes a frameshift, leading to subsequent premature termination codon. Australian Cattle Dog, Tibetan Terrier, Gordon Setter, English (& Llewellyn) Setter, Irish Setter, Polish Lowland Sheepdog, Small Munster lander and Standard Poodles are the breeds which are affected due to this disease.
Rod-cone dysplasia affected Labrador Retriever puppy and close up of the eye of the puppy.
Early retinal degeneration
Early retinal degeneration also called as the Erd-disease found in the Norwegian elkhound breed. This disease is caused due to mutation in SHARP1 gene that is located on the 27th chromosome. The disease shows early onset and dogs become totally blind within 12 to 18 month of age. In this type of disease the inner and outer segments of both rods and cone cells show abnormalities already during the postnatal retinal development and degenerates with the same speed.
Photoreceptor dysplasia is an autosomal recessive disease with early onset and it is caused due to a ‘C’ to ‘G’ transversion in the PDC (phosductin) gene that is located on the 7th canine chromosome. This gene is responsible for metabolic activity of photoreceptor segments. Miniature schnauzer and Belgian Shepherd dog breeds are mainly affected due to this disease. Affected breeds are initially night blind and then progress to day blindness due to abnormal development of photoreceptor cells.
Cone degeneration (CD)
Cone degeneration (CD) is inherited as an autosomal recessive trait. The disease is caused due to 2 known mutations of the CNGB3 gene. One form of mutation was found in Alaskan Malamute-derived dogs due to deletion in all exons of canine CNGB3 gene and second mutation that is missense mutation in exon 6 (D2a62N, nucleotide 784) in the same gene was observed in German Shorthaired Pointers affected with an allelic disorder. In these breeds temporary loss of vision in daylight occur at eight to ten weeks of age. For the diagnosis of Cone Degeneration Disease in these affected breeds a DNA based test called “CD”test is done.
Cone-Rod Dystrophy; type 1 (PRA-CORD1)
Cone-Rod dystrophy is inherited as an autosomal recessive disease. RPGRP1 (“Retinitis pigmentosa GTPase regulator-interacting protein 1 gene) gene located on chromosome 15 in dogs, is responsible to cause frameshift mutation in this disease. Miniature longhaired dachshund is the most commonly affected breed followed by other breeds, such as English Springer Spaniel, Lhasa Apso, Newfoundland, Miniature Schnauser and Beagel.
Cone-Rod Dystrophy, type 2 (PRA-CORD2)
Cone-Rod Dystrophy, type 2 (PRA-CORD2) is caused due to mutation in the Nephroretinin-4 (NPHP4) gene. This gene is mapped to the 5th canine chromosome and the mutation found is a 180-bp-deletion. This gene codes for a protein involved in renal tubular development and function. Standard wire-haired dachshund, miniature long-haired dachshund and Pit Bull Terrier are the breeds which are affected due to this disease. In the affected dachshund the connection between kidney failure and vision loss has not been seen.
Multifocal Retinopathy (CMR1, CMR2, CMR3)
Multifocal retinopathy is an inherited autosomal recessive disorder. This disease is caused due to mutation in Bestrophin gene affecting several breeds of dogs with late onset and loss of vision due to rod cells degeneration. Most commonly affected breeds are Great Pyrenees, Coton de Tulear Labradoodle, English Mastiff, Cane Corso, Borzoi and Lapponian Herder breeds showing symptoms as blister-like lesions on both eyes. Progression of retinal changes is slow and new lesions are not noted until 6 to 12 months of age.
Progressive rod-cone degeneration (PRA-PRCD)
Progressive retinal degeneration is inherited as an autosomal recessive trait and it is caused due to substitution of nucleotide G to A in PRCD gene. Labrador Retrievers and Golden Retrievers are the most commonly affected breeds with the late age of onser. However, age of onset of the disease and disease progression varies within breeds showing late onset degeneration of the rod cells followed by the cone cells. Poodle, English Cocker Spaniel, American Cocker Spaniel Labrador Retriever, Portuguese Water Dog, Chesapeake Bay Retriever, Australian Cattle Dog, American Eskimo Dog are also affected breeds due to mutation in PRCD gene.
X-linked PRA (XLPRA1, XLPRA2)
This disease has X-linked inheritance pattern. Three types of XLPRA have been found in different breeds of dogs with different mutation in the RPGR gene that is located on X- chromosome. XLPRA1 is caused by a five nucleotide deletion in RPGR gene leading to a premature stop codon, resulting in a truncated protein. Siberian Huskies and Samoyeds show night blindness by two to four years of age. XLPRA2 is caused by a GA deletion in the same gene in mongrel dogs, and XLPRA3 in Border Collies
Dominant PRA (D-PRA)
It is inherited as an autosomal dominant trait. RHO gene for rhodopsin is responsible for this type of disease that is caused by a missense mutation resulting in C to G change. Rhodopsin works as a G-protein receptor to induce the pathway for light sensitivity. English Mastiff and Bullmastiff are the most affected breeds in which progression of the disease is quick and complete blindness is usually experienced within 1-2 years from the onset of symptoms.
PRA in Specific Dog Breeds
PRA in Schapendoes breed
The Schapendoes, also named Dutch Sheep Dog, is a shaggy breed. Holland was the origin point of Schapendoes. Progressive retinal atrophy in Schapendoes has age of onset between 12-16 years. Progressive Retinal Atrophy and Hip Dysplasia are the main health issues found in this breed. In the Schapendoes breed gPRA found on gene coiled-coil domain containing 66 (CCDC66) that is located on canine chromosome 20, was identified through linkage analysis. The disease is caused due to 1-bp insertion in exon 6 leading to a stop codon in CCDC66 gene. All affected dogs show insertion either in homozygous or heterozygous state. CCDC66 protein is absent in the retina of the affected Schapendoes. There is 4-bp deletion in exon 9 (c.1752_1755delAACT), identified through sequencing that causes a frameshift mutation and a premature stop codon.
PRA in Shetland Sheepdog
PRA in Shetland Sheepdog is different from progressive retinal atrophy in other breeds by showing different age of onset but same mode of inheritance that is autosomal recessive. CNGA1-PRA and Collie eye anomaly (CEA) are the associated mutations found in the Shetland Sheepdog (Sheltie), and identified by veterinary ophthalmologists in between 5–10 weeks of age. It results in a frameshift mutation leading to PRA in Shelties and can be diagnosed within an average age of 5 years.
Treatment and Management
Unfortunately, at present there is no effective treatment available that can reverse or cure progressive retinal atrophy (PRA) associated blindness. It has been recommended that antioxidant therapy can be useful in an attempt to prolong the dog’s vision for as long as possible and slow down the progression of the disease, in the absence of any definitive treatment or cure. At present, research is being undertaken into gene therapy for animals with progressive retinal atrophy (PRA).
Downs, LM, Mellersh, CS. (2014.): An Intronic SINE Insertion in FAM161A that Causes Exon-Skipping Is Associated with Progressive Retinal Atrophy in Tibetan Spaniels and Tibetan Terriers. PLoS One.9.
Zeiss, C., J., (2000.): Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3). Hum. Mol. Genetic. 9(4): 531-537.