Friday, March 16, 2012

Boxer JKD from My Side ~ Dr Bruce M Cattanach, Steynmere Boxers, UK

Since the recent PDE TV programme (27th February), comments on the content have been presented from all sides in the UK dog press and online – all except mine that is – and as one of the participants in the Boxer Juvenile Kidney Disease section of the film, and as I have since been the subject of some outrageous charges, I think it appropriate that I give “my side” of Boxer JKD.

Unfortunately, because the shocking developments at Crufts have dominated the news reported by the UK dog press, I can't give my response in the same media this week and maybe not for several weeks, so here I offer my story as it actually happened: 

I have for years monitored cases of kidney failure in UK Boxers and have seen no indication of it being inherited.  Therefore, when the subject was raised at a Breed Council Health Committee meeting a few years ago, I expressed little interest, although another member of the committee was eager to investigate.  

However, in late September 2010, I received a call from a vet seeking help for a client, Ms Sharon McCurdy, who had a number of cases of JKD and had failed to get any help from her previous vet. I was initially rather skeptical and took the news rather lightly, but a subsequent letter threatening me with legal action, received after I responded to Ms McCurdy’s vet but before I had any idea what was going on, did get my attention.

Examination of Sharon McCurdy's and further cases that quickly came to light revealed an extraordinary picture of litters with one or more kidney deaths occurring with very close inbreeding (father x daughter, half-brother x half-sister, g’father x g'daughter, etc, focusing on one dog).  But as more cases were found, some revealed close inbreeding on dogs that were further back in the first pedigrees.  There was therefore clear evidence of an inheritance that nobody could miss.  The close inbreeding suggested a recessive gene inheritance.  But there were also a few cases that derived from total outcrosses.  This meant either that they had a different causal basis (poisons, etc) or that the gene responsible was more widely spread than yet recognized.

Professor Bell, a specialist in Internal Medicine at Glasgow University Veterinary School, agreed to help devise a questionnaire on which the vets could enter their diagnostic evidence.  Retrospectively this was achieved for almost all cases. The cause of these deaths can therefore be ascribed to a juvenile kidney disease (JKD).  One of these familial cases died in Sweden and went to a full post mortem to get the more specific diagnosis of familial renal dysplasia. 

I reported the findings in Boxer Breed Notes as the cases emerged and, on request, subsequently (February 2011) exhibited the pedigrees to the Breed Council Executive and a new Health Committee.  I presented only my general conclusions and left interpretation to those present to decide for themselves. There were no questions on the pedigrees as I recall, only questions on the diagnoses.  Because of the perceived magnitude of the problem, I offered only one recommendation for breeders – “to try and avoid inbreeding.”  Judging from a subsequent report in the dog press by the new Health Committee, everything appeared to be accepted, including my aim to initiate a study to find the responsible gene.

I was lucky enough to find an interested molecular geneticist, Michel Georges from Belgium, who was using a new gene scanning method that seemed appropriate for our situation.  Week after week thereafter, I therefore put requests in the dog press for blood samples.  I needed samples from both affected cases and parents, but the response for each was very poor.  People seemed frightened.  Two owners actually told me that the breeder had told them not to cooperate.  However, I managed with great difficulty to get 5 samples from affected cases and 6 from parents.  All offers of samples were accepted and in fact I am still looking for more.  I also needed unrelated controls and managed to get enough contributions from concerned breeders to be able to select ones I hoped would be suitable for the gene screen. The screen started but it was not successful. Other investigations elsewhere in the world with other Boxers have likewise failed.

 Coming now to the film, when Jemima Harrison informed me that she had been besieged by Boxer breeders to take up the JKD problem and asked me if I would contribute and explain the genetics, I of course agreed.  I could not possibly stand back and let other brave souls fight alone.  I therefore told her the story much as above, but eventually had to produce the evidence – the pedigrees – and I know these were then carefully analyzed by two other geneticists.  The film makers also sought out other factual information on events which made my own efforts on the genetics seem puny. Believe me, there is so much more information, but only a small part was given in the 10 minute slot in the 1 hour programme, and I know that every word was scrutinized by a team of lawyers.

I do want to make it clear that what I actually said can be literally “seen” on the film. The remainder came from the narrator, not me.  It was selective, excluding much, but still accurate in content.  I was saddened that my comment on the exceptional past record of UK Boxer breeders on health matters was not given.  And I was annoyed that the narrator made it seem that the evidence that JKD was inherited was not definitive just because the gene had not been found (a lawyer issue, I'm told).  But let's be clear.  One needs breeding evidence before one searches for a gene, not the other way around. The evidence that JKD is inherited is absolutely firm, and two other geneticists agree.

Where do we go from here?  Further research upon JKD is needed but I hope it can be seen that this would be impossible at present.  Instead we are left with the one option of separately trying again to find the gene.  Here, I thought we might still get stuck because what research group would be willing to invest much time and a huge funding to look for a gene when there is not total positive breeder support.  

However, I was delighted to receive a message after the film from Swedish canine geneticist, Ake Hedhammar, who works with American/Swedish molecular genetics guru, Kerstin Lindblad-Toh, on JKD in Continental and American Boxers.  He suggested we collaborate with him in his effort to find the gene for JKD in Boxers internationally. This could be the way to go, but would we get full support from owners of cases and parents a second time around?  I actually had 5 possible JKD cases reported in the three days following PDE2 with blood samples promised, which is quite a change. Maybe the film has actually rescued the breed.

Postscript:  I have just had another offer of help to find the gene, this time from Professor Harvey of University College London.  His interests are medical, but he has taken an interest in disease genes in dogs that may have relevance for human disease. This route seems a very promising one, as collaboration with human researchers has worked very well for me with Boxer Cardiomyopathy as I hope will soon be seen.  So, if the Boxer breed in the UK wants to get itself together, face the problem, and do something, there could be a way forward.  And please note, it to be expected that any further research will require blood samples from additional affected cases and also from their parents, so all of you out there, please help.

NEWS FLASH!!!   Dr Kerstin Lindblad-Toh of the Broad Institute at MIT, who has been collecting DNA samples for JKD in both the US and Europe for some time, has now also  expressed an interest in the UK investigations and collaborating in an extended search for the gene responsible for this fatal Boxer kidney disease!

Tuesday, March 6, 2012

How Many VPCs Are Too Many VPCs?

In the last BU Blog, I related a conversation I’d had with my cardiologist in which we discussed how frustrating it was for Boxer breeders to have one board certified veterinary cardiologist clear a dog of SAS with a flow rate of 2.21 m/s…and another equally qualified cardiologist grade the same dog with exactly the same flow rate as “equivocal.”

Alas – the upshot of that conversation was that although cardiologists all agree about grading very low flow rates (e.g. 1.2 m/s) and very high flow rates (e.g. 3.0 m/s), none of them can say for sure what the ranges in the middle mean in terms of SAS, if the dog doesn’t have any other sign of the disease, such as a fibrous ridge in the aorta or a turbulent blood flow.  

So we concluded the blog by saying that diagnosing SAS seems to be another area in which there’s a lack of black and white guidelines on Boxer heart disease; and another reason for breeders to try to get comfortable with using our own best judgment along with the opinions of the professionals when making decisions about our own breeding programs.

More recently, Boxer breeders have been expressing their frustration at the lack of guidelines to help us navigate through an even murkier gray area of Boxer heart disease – ARVC and the VPCs (Ventricular Premature Contractions) that often indicate the presence of cardiomyopathy in an individual boxer. Those breeders are saying, some of them in so many words, that since the ABC website provides us with guidelines on a range of flow rates that clear our dogs of SAS, why doesn’t the ABC publish guidelines that tell us how many VPCs it’s acceptable for our dogs to have at different ages?

Well for one thing, the ABC is not a medical research institution and the SAS flow-rate guidelines that appear on the ABC website represent the opinion of only one cardiologist with whom the leaders of the ABC Health & Research Committee happen to agree. What’s more, there’s a difference of opinion among cardiologists on those “ABC guidelines,” because they do not conform to the standards set by the ACVIM (American College of Veterinary Internal Medicine) for American board-certified veterinary cardiologists.

But back to ARVC and VPCs:

At the present time, the only absolutely surefire way a cardiologist can tell whether a non-symptomatic dog has BCM/ARVC is by doing a necropsy. And unfortunately, at that point the dog is dead and the question is academic, except perhaps for the owners of the dog’s offspring.

Of course, a reliable DNA test would also tell us whether a dog had the mutant gene(s) that causes ARVC and was therefore likely to develop the disease and reproduce it. But the ARVC-1 test has not lived up to its initial promise, and so we’re back to where we were before Dr Meurs made her announcement in April 2009 – holtering our breeding stock regularly and trying to figure out how many VPCs are too many VPCs. And the sad fact is that we don’t have any better an understanding of exactly what that number is now than when the late Wendy Wallner, DVM, proposed a set of very broad guidelines for Boxer Cardiomyopathy in an article on Boxer heart disease she wrote for the April 1999 issue of The Boxer Underground.

As chair of the ABC Boxer Health & Research Committee and a member of the board of the American Boxer Charitable Foundation (ABCF), Wendy devoted her tragically brief life to the cause of Boxer health and led the fight against what we then knew as Boxer Cardiomyopathy (BCM).  A read of the entire article at will give newcomers to the breed a good idea of what we were up against in 1995 when the ABCF was founded and the ABC membership voted in a survey to make BCM research a priority for our new foundation. In the meantime, based on experience and observation, I firmly believe the fact that breeders have been following the guidelines in the excerpt printed below has led to our seeing fewer Boxers suddenly “just drop dead” at 3, 4, and 5 years of age. RIP Wendy – your work continues.
“A few years ago, upon my appointment to the ABC's Health and Research Committee, I came up with a protocol for heart testing for boxers. These guidelines were published in the ABC News Bulletin in December of 1996. The recommendations were as follows:
“Minimum Heart Screening for boxers involved in breeding programs and/or performance events:
Age 1 year: auscultation by a board certified veterinary cardiologist (If arrhythmia detected - Holter exam; if murmur detected - Echocardiogram) 
Rationale: One year is the accepted time for clearance of sub-aortic stenosis. This auscultation screening could be performed at the national specialty and at individual breed club's specialty shows for a nominal fee. Any dogs with murmurs would be referred to a cardiologist in their area for further workup.
“Age 2 years: Holter monitor, auscultation (Echo if murmur detected)
Rationale: The 2-year check would occur before the animal was used for breeding (at least extensively) and would be useful in detecting dogs with early arrhythmias before they are bred. In some dogs, arrhythmias have been detected as early as 12 weeks of age.
“Age 5 years: Holter monitor, auscultation (Echo if murmur detected)
Rationale: By 5 years, many animals would show signs of arrhythmia if they were going to develop CM, since the arrhythmia often precedes clinical disease by several years.
“The main purpose of these screens was to develop a database which could be analyzed and related to causes of death in dogs so that some sort of standardized system of interpreting the holter results could be determined. Not only would it help to identify and eliminate dogs with SAS from breeding programs, it would also help identify and eliminate those asymptomatic boxers with very large numbers of VPCs. It was never intended to eliminate any and all dogs with VPCs from breeding programs. There simply is not enough information available to use the results in this manner. If large numbers of boxers are not holtered and followed over time, there never will be a database large enough to provide meaningful holter results. If this is the case, we are at the mercy of the only other test that will identify boxer CM - a genetic marker for the disease. Unfortunately, this type of test can take decades to establish. Since we know that the hallmark of boxer CM is arrhythmia and that the Holter is the best tool to detect arrhythmia, it is the only method we currently have to try to evaluate our breeding stock before they have produced offspring. While there currently are no concrete numbers to identify normal vs. abnormal dogs, the Holter is still extremely important in identifying those grossly abnormal dogs with hundreds or thousands of VPCs who are asymptomatic and would otherwise be unknowingly reproduced. Until many Holtered dogs have been followed into old age and their medical histories analyzed and causes of death determined, we will not know the true significance of lower numbers of VPCs. We can, however, use all information obtained through Holter testing responsibly by slanting a breeding program toward those boxers that seem less affected.”
NEWS FLASH!!!  The Drawbridge Inn in Ft Mitchell, KY – the site of the 2012 ABC National Specialty – was sold this morning (March 6) to the mortgage holder, who intends to keep the property open as a hotel and start making major improvements. Kudos to ABC President Salli Moore-Kottas, who stayed on top of this situation as it developed and was prepared to proceed with a "Plan B" if the sale had not ended favorably.  Now...on with the show!!!