PRA in Mastiffs: Questions and Answers

The MCOA (1997) Specialty was very worthwhile for me and has allowed a much better understanding on my part of the natural history of PRA in the Mastiff. I was able to see several affected dogs -- some of which we knew about before and a couple of new cases. I met people face to face that were only names previously, and that is always a major improvement. The hospitality and cooperation was wonderful.

The first issue resolved for me was that PRA in the Mastifff is really classical PRA. The fundus appearrance is very consistent from dog to dog, and very compatible with prcd-like PRA in other breeds. From my still fairly limited data set, I expect that a careful examination of dogs at risk should pick up early but recognizable ophthalmoscopic evidence signs of PRA by 2 years of age, but probably not much younger. The dogs that I saw at this general age had quite early signs, and the older dogs had much more advanced disease, consistent with a fairly uniform age of onset and progression.

It is now highly likely that PRA in Mastiffs is a prcd (Progressive Rod Cone Degeneration) disease. That is, it is likely to be caused by the same gene as PRA in poodles etc. We still don't know that for a fact, but we are starting to see PRA like this in an unbelievable number of breeds. Many breeds that formerly were not known to have PRA, turn out to not have been examined. Disease in these breeds looks very consistent with PRA in the known prcd affected breeds. This suggests to me that all these breed specific diseases will probably turn out to be prcd. If that is true, only two possible explanations are likely. Either the gene is very highly mutable, perhaps having some sort of unstable element in it, or else the mutation is extremely old, predating the separation of dogs into breeds. This is not impossible, or even particularly surprising if true, as there probably is very little natural selection against a late onset blinding disease in the wild canids. There certainly hasn't been any in purebred dogs until now.

Is it true that you are getting close to finding the PRA gene?

We have now mapped the location of the prcd gene very precisely, and have a set of markers that are very close to and on both sides of the gene, but the actual gene itself has not yet been identified. We are working very hard on this, but there is a big element of luck involved as well as hard work. None of the formerly "obvious" candidate genes are even close to prcd, so we have to look for anonymous genes for evidence that they may be involved. This is really like looking for a needle in a haystack, except now we at least know in which part of which haystack to search. The other thing that drives us of course is the fear of being scooped. We are about to publish our prcd mapping paper, and once we do everyone "and their dog" will be out to beat us to the finish line.

The markers that we have found are very reliable in our research colony dogs in detecting which dogs carry which prcd alleles, and therefore can be used as a PRA test. We are currently establishing just how to make such a test reliable and available in real world purebred dogs, and like so many things, the details involve more work than we really expected.
We expect and intend to have this test ironed out for at least one breed by the end of the year -- hopefully for Labradors, and almost certainly for Portuguese Water Dogs. If we can do this, then we will gradually extend its application to other breeds. Mastiffs are high on the list to be addressed. We also have to figure out how to really make it available to dog owners and breeders. We can't deal with all the research work we have on our plates now, and don't have the resources or desire to become a service lab. Plus, the companies that own the technologies for molecular biology have a totally different pricing and licensing structure for anything they consider a commercial rather than a research application, so we can't mix large scale testing services with research.

Is PRA in mastiffs still believed to be recessive?

All the PRA-affected Mastiffs that I have seen, and all the others for which I have obtained exam forms, blood, pedigrees etc., fit into a pedigree that absolutely fits an autosomal recessive mode of inheritance, as a single gene defect.

How many mastiffs have donated blood?

I don't actually have a very recent update. The last time I counted, in early summer, it was 80 dogs, and at that stage we had several kits outstanding and several ready to ship. I wouldn't discourage further donations of blood, but we probably have sufficient to resolve the main question -- that is, is PRA in Mastiffs prcd?

What is the difference between PRA and PRA suspicious?

That means different things to different people and different things in different breeds. I don't use the term "PRA suspicious" myself, as I don't think it conveys any useful information. The CERF form is set up to encourage ACVO diplomates to use the term, but I am not at all in favor of it.

In some breeds there are peculiar retinal abnormalities that are either non-PRA diseases, or just strange non-disease appearrances of the fundus, that can resemble very early PRA, or even later stages of ther disease. Sometimes these will get labelled "PRA suspicious". So far I have not seen much evidence of these problems in Mastiffs.
In some dogs with very early PRA the changes are subtle enough that an ophthalmologist will not be certain of the diagnosis, so will call them "PRA suspicious". A dog with such disease usually becomes obviously PRA affected within 6-12 months maximum.
The typical CERF exam is a pretty rushed affair, and is only a screening for obvious disease. I would hope that any dog seen with "PRA suspicious" (whatever that is) would have a subsequent more complete workup as a private consultation with the ophthalmologist, and then a follow up exam in 6 to 12 months. This probably doesn't always happen, and anyway CERF has no way to amend its data base to include the results of such a follow up.

Will an ERG confirm that a PRA suspicious mastiff actually has PRA?

How many caveats? It is reasonable to expect that it should, if the dog is really affected, and if the ERG is done properly, with an adequate ERG protocol. There is no data however to establish that this is true. Any such expectation assumes that what is true and reliable for one disease in one breed applies to another disease in another breed. This premise is far from certain in general, and is definitely wrong in many cases that I know of.

More importantly, an ERG as being used widely in veterinary practice, can not prove that a "PRA suspicious" Mastiff does not have PRA, and can very easily suggest that a nonaffected dog does have PRA.

A number of mastiffs have been diagnosed as having PRA before a year of age?

The more we discover about PRA, the more complex the story becomes. We have now found evidence that in at least two breeds there are 2 separate genes causing PRA, and we also have evidence that in at least one breed an early onset form of prcd exists.

It is likely that the age of diagnosis in some affected dogs could be significantly less than 2 years, though I doubt that anyone could categorically make such a diagnosis at 6 months.
One should also remember that being able to recognize disease in some affected dogs by (say) 15, or 18, or 24 months does not mean that a dog with no apparent signs of disease at that age is going to remain clear.
The age of onset and rate of progression of diseases like PRA is probabilistically distributed, in the familiar bell-shaped curve. Most dogs will fit in the middle of the curve, but as larger numbers of dogs are examined more and more will be found in the tails of the distribution, with either earlier or later disease than the "average". A good friend once told me "you have to remember that 50% of the population is below average in intelligence"; and this is true for height, weight, and age of onset of PRA. Half he dogs will have faster PRA than "average" and 50% have slower disease. We do know that there is such a distribution, and would dearly love to know what influences it. This would have great significance for human disease.

Has some of the donated blood been checked for the PRA gene in Irish Setters?

Yes, PRA in the Mastiffs that we have blood from is definitely not caused by rcd1 (the Irish Setter PRA mutation).

Is there something that needs to be done, that we could help with, that could get mastiff PRA classified as prcd?

The "old-fashioned way", which we used for poodles, Labradors, cocker spaniels, and Portuguese water dogs, was to do cross breedings. This is very slow and expensive, and I have no desire to cross a Mastiff with a poodle.

What we now seek to do is to test each purebred pedigree with our prcd marker test to tell whether PRA is segregating as a prcd allele. So what you have already been doing, in obtaining PRA informative Mastiff pedigrees, is what we need.

The second issue is, please make sure that people don't panic! This disease is not fatal, not painful, and the affected dogs can lead a happy life under appropriate circumstances. This disease is not caused by any single particular dog or breeder. Blame should not be assumed by or imparted to any person or dog. The problem is caused by a mutant gene that has become widespread in the population, because a very valuable ancestor unfortunately carried this gene. Despite this misfortune, the likelihood is that desirable genes are also being transmitted with this disease allele. It is also not a recent mutation. I can prove that the gene was present in Mastiffs long ago, before the responsible ancestors were imported into the US, and I suspect that it is the same prcd mutation present in many other breeds. In the latter case, it may have been present in dogs since before there were breeds.

We really are within sight of a gene test, and once it is available this will be a solvable problem. It is really important to not throw the baby out with the bathwater in the meantime. 

Gregory M. Acland, B.V.Sc.; Dip.ACVO          (607) 256-5684 [phone]
Center for Canine Genetics & Reproduction     (607) 256-5689 [fax]
James A. Baker Institute for Animal Health    gma2@cornell.edu
Cornell University, College of Veterinary Medicine
Hungerford Hill Rd, Ithaca, New York 14853