Different types of PRA found in ESS

Note: There have been a number of updates in the literature on PRA in the last two years. This post is an attempt to bring people up-to-date with what is currently published. This is a very long explanation and you may have to read it several times to understand everything. Also, some of the following material has been really simplified to clarify concepts for members with a non-science backgrounds and non-native English speakers. If you need further explanation, please ask. 

As most of you know, Progressive Retinal Atrophy (PRA) is commonplace in its distribution throughout the dog world. The term PRA is used to cover a multitude of disease processes, all of which are characterized by a progressive loss of vision. Initially PRA was divided into two types based on the clinical appearance of the diseased retina. The two original descriptions were central progressive retinal atrophy (CPRA), and general progressive retinal atrophy (GPRA). Now that the fully mapped canine genome is complete scientists have identified upwards of sixteen different disease processes that fall under the canine PRA umbrella and research continues. At this point in history, it appears that at least three types of PRA diseases can be found in English Springer Spaniels.

The three types of PRA that have been documented so far in the published literature for ESS are a type of CPRA (central progressive retinal atrophy), a type of GPRA (general progressive retinal atrophy, and the cord1 PRA a condition for which we now have a genetic test.

Let me start with the cord1 PRA since that is the condition we have heard the most about for the last couple of years. As we all have been told, it is a recessive condition that occurs because of a mutation. This mutation inserts a premature stop into a gene responsible for manufacturing an important structural protein that helps the vision cells of the eye (the rods and cones) hold their distinctive shapes.

It helps to think of the gene like a computer program. It is a series of instructions on how to create stuff the body needs. When you press the start button, a little chemical called a messenger RNA runs along the gene reading and making copies of the code. When the messenger RNA gets to a stop code, it quits copying the instructions from the DNA and runs off to the cellular production line to translate its copied code into a protein. The problem with the cord1 mutation is that somehow an extra and premature stop code got inserted 80 spaces downstream from where it is suppose to be. So, when the messenger RNA gets to this premature stop, it thinks is done copying the instructions for that given protein and ends up giving the cellular production line instructions to make a protein that is too short to do its job properly. When the short proteins get incorporated into the rods and cones the vision cells don’t function efficiently and start breaking down. The more massive cone cells start to die first followed by the rod cells. So this process is labeled cone-rod dystrophy 1 or cord1 for short.

The cone cells are responsible for day time color vision and the rod cells are responsible for high contrast nighttime vision so in the cord1 disease we expect to see dog’s lose their day time vision first followed by their low light or night vision. In dogs and also for the human version of this genetic mutation (called Leber congenital amaurosis) we expect individuals affected by this genetic condition to lose sight at a very young age, typically within the first couple years of life. However this is not always the case. We know in Springers that only a small percentage of dogs are affected at a young age, and a great many don’t show symptoms until they are quite old. Many never show symptoms of this disease at all. There are ongoing ERG studies being conducted by Dr. Kristina Narfström in the USA and another separate study by David Sargan at Cambridge University to help determine what is occurring within the eyes of these affected animals. Although these studies are not yet completed there is some information in the literature that may shed light on the mystery of why so many dogs test DNA affected with this condition, yet so few exhibit symptoms. 

For this mutation to occur in multiple canine species that are as different as Long Haired Mini Dachshunds and English Springer Spaniels means cord1 is a very ancient mutation. The fact that the mutated gene is so widespread in both these populations tells us the canine body has found a way to compensate for the mutation. After all, animals that go blind early in life seldom have an opportunity to survive, let alone breed and continue the species. Obviously the mechanism that corrects this mutation is not fool proof because we do see some animals with symptoms. It is, however, effective most of the time. What follows are a couple of working theories on what is keeping the DNA affected animals from loosing their sight:

Dr. Catherine Mellersh, one of the primary researchers on this condition published some interesting data in the fall of 2007. Her research team studied a highly inbred population of Long Haired Mini Dachshunds (LHMD) genetically affected with the cord1 mutation. In this inbred population the affected dogs lost their vision very early. Using electroretinogram (ERG) testing, the researchers could detect changes in the retina as early as 6 weeks and by 40 weeks of age the disease had progressed such that no electrophysiological indication of photoreceptor function remained (the dogs were completely blind). The ERG data indicated that cone cells where affected first, followed by progressive rod cell involvement.

The experiment was repeated using a population of LHMD with out-crossed pedigrees. All the dogs in the second study also had two copies of the cord1 mutation, but these dogs didn’t lose their vision until much later. On average, these dogs retained vision until 4.82 years and some of the out-crossed dogs in the study never lost vision. The research paper concluded that the variability in age-of-onset of clinical signs for this condition “could suggest the presence of a modifier gene that controls the penetrance or expressivity of the cord1 mutation, (although additional analyses would be necessary to confirm this hypothesis)”.

The results from these two studies imply that whatever is modifying the expression of the cord1 genetic mutation you are more likely to see early onset symptoms if you breed closely related individuals.

On Sunday, Virginia Huxley explained in her post to the ESSBREEDERgroup how little molecules called microRNAs have been discovered and can actually regulate gene expression by riding piggyback on non-coding sections of messenger RNA and prevent the messenger RNA from giving instructions for faulty proteins to the cellular production line. These types of newly discovered messenger proteins are really interesting and hopefully future research can tell us if they are involved with gene expression in the cord1 disease 

There is yet another working theory on the lack of clinical symptoms for the dogs genetically affected with the cord1 mutation. This theory involves the recently reported enzymes called DNA methytransferases. Enzymes are the body’s way of making chemical reactions work faster or better. Making a protein is a chemical reaction and researchers have found that these DNA methytransferases play a major role in control of gene expression. They are especially active around nerve tissues and that includes the eyes. Study of these enzymes is one of the most active fields of research in the molecular biosciences. Although we are still discovering exactly how they work, these enzymes repair defective proteins or prevent them from being made in the first place. In situations similar to the cord1 mutation it is thought they mask the premature stop code on the DNA strand and allow for complete manufacturing of the protein. If the animal stays healthy, then these enzymes may protect the animal from symptoms for their entire life; however, if the dog loses its ability to absorb critical trace minerals (called co-enzymes) or in animals whose immune systems start to break down, some of the body’s enzymes cease working and in this case we might see animals start to show symptoms later in life.  

IF DNA methyltransferases are the protective mechanism in cord1 PRA, then another recent discovery by researchers at the University of Toronto in Canada may help to explain why a small percentage of dogs lose vision at a young age, some at middle age and most never loose their vision. The Canadian researchers solved the crystal structure for one type of methyltransferase designated TPMT. They discovered it exhibits genetic polymorphism (it has a non-functional form that is inherited as a genetic recessive trait). Approximately 90% of individuals inherit high activity, 10% inherit intermediate activity because of heterozygosity (one good gene and one bad gene), and 0.3% has low or no detectable activity because they inherit two nonfunctional TPMT alleles. If methyltransferase enzymes are part of what is controlling gene expression in the cord1 PRA disease, then dogs inheriting two copies of the recessive non-functional enzyme would have no protection from the cord1 mutation and would go blind at a very young age. Dogs inheriting two copies of the high functioning genes may never loose vision because the active methyltransferase enzymes would keep the cord1 mutation from producing defective proteins.

We currently do not know what is causes some dogs that are genetically affected with cord1 PRA to go blind and others to keep their sight; however it is important that people understand that it is not because the genetic test is faulty. Although there were some troubles with the test early on, the labs have staked their reputations on the test in its current form.  It is important to understand there are a number of mechanisms that the body has developed to protect itself from genetic mutations. It is just that we are too early in the research process to understand the rest of the story. There are theories, as I explained above, but we will have to wait for the rest of the story. Please do understand that we have ERG proof that the cord1 PRA mutation does causes blindness. The patterns on the ERG recordings are distinct and show the cone cells breaking down before the rod cells.

Now to the second known cause of PRA in Springers.

According to Dr. Kristina Narfström (Small Animal Ophthalmology By Robert L. Peiffer, Simon M. Petersen-Jones, p 120) the most common form of PRA in dogs is a form of progressive rod-cone degeneration (prcd). Some forms of prcd have been found to occur in at least a dozen pure-breeds and for a long time some sort of rod-cone degeneration was presumed to be the predominant form of late onset PRA (age 5 and over) in Springers. ERG results consistent with rod degeneration prior to cone degeneration are not uncommon in Springers and the clinical symptoms of a dog losing nighttime vision before daytime vision are well known. There have always been a number of ERG findings recorded in the literature as atypical. We now understand that the "atypical" readings are consistent with the cord1 disease, but the root cause of the blindness caused by progressive rod-cone degeneration in Springers has not been precisely determined. For now, most veterinary ophthalmologists classify it as gPRA or prcd based on clinical symptoms. According to a statement on their website, Dr. Johnson at the University of Missouri research center, feels that Springers with non-cord1 PRA symptoms represents a very small percentage of the clinically afflicted animals.

As many breeders are aware, Optigen, the commercial offshoot of Cornell University, has patented a genetic test for a "single novel gene" that they feel covers one type of prcd that affects a number of breeds of dogs including English Cocker Spaniels a close relative to ESS. The genetic location they patented occurs on canine chromosome 9 and is similar to retinitis pigmentosa in humans. Optigen included English Springer Spaniels in their patent application for their prcd genetic test although they do not have enough Springer tissue samples to definitively determine that the gene they have located is the root cause for the prcd-like clinical symptoms found in Springers. Since they hold the patent on that gene they have essentially extinguished research by other labs on prcd. As a result there is currently no genetic test for this condition in Springers.

There are a number of reasons that the US Springer parent club and foundation are no longer working with Optigen on this disease process. This post is probably not the best place to discuss that issue, except to say there have been problems in the past with the way Optigen operated and I don’t see evidence they have significantly changed their business practices. But I digress. Let me get back to prcd

While maintaining the open cord1 PRA test results database for the Spanielgenes discussion group, we have received close to a thousand voluntary emails from breeders and owners that report the dog’s cord1 genetic status and the current vision status of the dog. We have received two emails that seem to confirm a small number of a prcd related conditions.

Dog 1: cord1 PRA status - Normal-clear. Vision status: Advanced clinical PRA, ERG results consistent with rod followed by cone degeneration (prcd). European pedigree. Age of onset 5-6 years.

Dog 2: cord1 PRA status – Carrier. Vision status: moderate clinical PRA, ERG results consistent with rod followed by cone degeneration (prcd). American pedigree. Age of onset 4.5-7 years. 

So at this point in time, prcd doesn’t appear to be a major contributor to the PRA problem in Springers, but the fact that it does exist, should remind us to check both the cord1 status of a dog and the current vision or CERF status before breeding. While we are trying to reduce the incidence of cord1 worldwide, we don’t want to inadvertently increase the incidence of another type of retinal disease.

The third type of PRA that has been reported in Springers is a type of Central Progressive Retinal Atrophy  (CPRA) called Retinal Pigment Epithelial Dystrophy (RPED). 

RPED is documentments in ESS in a number of the veterinary Ophthalmology atlases including Color Atlas of Veterinary Ophthalmology By Kirk N. Gelatt, the third edition of Veterinary Ophthamology, pp 903-980 and Essentials of Veterinary Ophthamology, pp 276-278.

RPED is less common that GPRA. It is characterized by accumulation of pigment spots in the retina surrounded by retinal atrophy and a mottled appearance of the non-reflective portion of the retina. The pigmented spots eventually merge into a single mass and fade as the atrophy of the retina increases. It is an inherited condition. RPED tends to occur in older dogs. The dog's peripheral vision is retained for a long time and vision is better in low light and for moving or distant objects. Not all affected dogs go blind. Secondary cataracts are common. 

RPED isn’t a primary disease of the rods and cone cells. It is a disease of the retinal pigment epithelium. This is the outermost layer of the retina and is important in maintaining the health of the rods and cones. Because the rod and cone cells are dependent on the retinal pigment epithelium layer if it becomes diseased and breaks down then the rods and cones also break down and the dog's lose vision.

According to a 1999 article written by Professor Peter G C Bedford, B VetMed, PhD, FRCVS, DvOphthal, DipECVO Guide Dogs Chair of Canine Medicine and Surgery, Royal Veterinary College, University of London, dogs that develop this disease, have a defect in the vitamin E metabolic pathway. The research data indicated the serum levels of vitamin E where usually lower than normal and resulted in less vitamin E being available to the retina. One of the chemical forms of vitamin E is an important antioxidant substance that helps protect retinal tissue from damage caused by light. When there is insufficient vitamin E the retina can be easily damaged. The greater the deficiency the quicker the disease appears and the quicker it progresses. Dr. Bedford and his colleagues believe the source of the defect may be a deficiency of the transport factor produced by the liver that is required to move vitamin E around in the blood stream. The most exciting outcome of his work showed that the supplementation of vitamin E to the dog's diet could maintain the blood levels at sufficiently high values to stop the disease in its tracks. Obviously the rods and cones that had been damaged could not be repaired, but they felt that RPED need not be the considered the progressive retinal disease it was once thought to be. They concluded that this disease was primarily a metabolic defect that was genetic in origin. There is currently no genetic test for this disease. 

I had several editors helping me to streamline this post to help me make sure the important messages were conveyed. Two of the editors said I needed some conclusions.

So... in conclusion, what can we take from this ongoing research and apply to our breeding practices in ESS?

1. If we have dogs that are genetically affected or carriers of the cord1 mutation, we are less likely to breed dogs that actually have clinical symptoms if we use avoid line breeding or inbred pedigrees.  

2. In the USA where the cord1 mutation is prevalent, we need to continue slowly breeding away from this condition without losing genetic diversity. With so many genetically affected dogs retaining life long vision, there is no need to rush to eliminate this mutation in a single generation.

3. There are other types of PRA diseases in the Springer population and although they appear to be rare compared to the cord1 mutation, we need to be aware they exist and ask about both the cord1 status and complete vision status of both dogs in a breeding pair. Eventually there may be other genetic tests to helps us, but for now, asking questions is your best option. We do not want to increase the incidence of another type of retinal disease while breeding away from cord1. 

4. As many have said, we need to remember to consider the whole dog in our breeding choices and not just focus on one disease.

5. We need to encourage our researchers to keep us up to date on developments in PRA and other research areas and let the fancy know when they can help facilitate the research process. An open dialog among the fancy and good communication with our partners in the research labs can make important discoveries happen faster. All of which will help ensure that as a breed, English Springer Spaniels stay healthy long into the future. 


Joan Beck, MS: Biomedical Communications,  BA: General Biology, Biochemistry and Animal Nutrition