Tintookie Kennels - Perth, Western Australia

 

Canine Leukocyte Adhesion Deficiency
in Irish Red and White Setters

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CLAD is an inherited abnormality of the immune system where the white blood cells are unable to fight infection. It is manifested in affected puppies by the following symptoms.
Affected puppies are often, but not always, comparatively small and slow to develop. They show infections from a very early age - umbilical infection at birth, tonsillitis, sores on the body and accidental wounds or scratches that will not heal. Between 8 and 14 weeks there can be inflammation of the gums that become red and swollen. Most puppies get swollen joints, the bone beside the joint thickening and affecting movement; this in turn becomes unsteady until finally the animal is unable to stand up. The puppies seem to be sore all over the body. The lower jaw becomes wider, due to bone deposits and they have difficulty in opening their mouths. The temperature is raised and they seem to sleep more than usual. Puppies will not necessarily have all of these symptoms at one time. 
Treatment with antibiotics or cortisone does work initially and sick puppies appear to recover from their setbacks - although they still have a high white blood cell count and the red gums still persist. However, when treatment ceases all the symptoms return; the puppy is as ill as before.

CLAD is inherited as a single recessive gene. Genes are the "plans" to make the new puppy. For every bit of the dog there is a gene from its sire and a gene from its dam, it needs two genes to make the plan work. The CLAD gene has been changed slightly by the mutation and is "sick". The other gene for this particular bit of the dog is strong enough to carry the "plan" by itself - so the dog is healthy, its immune system works, but in its make-up it still carries the sick gene (which is hidden and therefore called recessive). This dog is called a "carrier" and no one would suspect its secret until it happened to be mated to another carrier. Then the two sick CLAD genes would meet and have only their faulty plan for the immune system - the puppy would be affected with the symptoms of the disease. It would either die quite young or if treated, live a precarious sickly life.

This condition was observed in Irish Setters in the 1970s and by the 1980s was causing such concern that serious research was conducted in the USA and in Sweden - where the incidence was relatively high and the gene pool relatively concentrated. The Irish Setter Association (England) and the Irish Setter Breeders Club were pro-active, too, particularly as the reports of sick puppies increased in show-bred litters to alarming proportions.
The consensus of opinion is that CLAD arose from a spontaneous mutation of the DC18 gene (a gene involved in the structure of the immune system) in an Irish Setter whelped in 1964. This bitch, mated to 4 popular and influential studs of the time, produced 6 litters and a proportion of these litters - probably 50% - were carriers of the mutated gene. Important dogs, in Irish Setter breeding programmes came from these litters and are behind many Irish Setter pedigrees today.
Such is the nature of progress, that very recently CLAD carriers have been identified in Irish Setters of wholly field trial breeding. This triggers the line of research that it is far older than was first thought.
In the 30 odd years since what was thought to be the mutation occurred, the CLAD gene has multiplied unchecked until science has made it possible to identify the gene and DNA testing made it possible to identify the carriers.
Those intervening years, however, saw litters of puppies decimated by an unknown affliction, suffering while their desperate breeders sought some way of prevention or cure. Puppies that appeared healthy and settled in their new homes would succumb later, adding more heartache and worry before giving up their struggle for life.
Now Irish Setter breeders are able to DNA test their breeding stock and screen out carriers of CLAD. The saga of this miserable disease has reached a satisfactory conclusion.

SO WHAT ABOUT IRISH RED AND WHITE SETTERS?

More than two hundred years ago setters were used to hunt and point game birds for the table and, in Ireland, were more often than not white coloured dogs with patches of red on the body. With the increasing interest in dog shows, the highly desirable red colour was encouraged and a self-coloured red dog was preferred to the old red and white dog. Puppies with white were put down and this discrimination persisted until quite recently. Only the "shooting" fraternity kept Red and White Setters as they occasionally occurred in "working" red litters and could be good working dogs. Attempts were made to revive the old breed but it was not until the end of the 1970s, when the number of "pure" Red and White Setters was less than 10 in Ireland, that any headway was made. In 1979, 4 red and white litter sisters and later the important stud, Meudon Amber Glow, were imported into the UK and were the foundation of the breed in this country.
It is important to state here, that in the UK, Red and Whites were considered to be a completely separate breed from Irish Setters and the concern of breeders was to preserve the integrity of the breed. The founder breeders were very aware that the gene pool was very small with the implication that genetic problems could arise in the future. With this in mind the newly formed breed club, the Irish Red & White Setter Club of Great Britain, set up a sub-committee to monitor the development of the breed and maintain a database, recording all KC registrations, imports and any untoward condition reported by breeders or owners. This was an opportunity to collect data before numbers grew to unmanageable proportions.

In 1986 the report of two puppies put down because of repeated bouts of infection that failed to respond to treatment and thought to be "some sort of autoimmune deficiency" was recorded, followed in 1989 by three puppies from the same dam succumbing to the same condition. Then in 1990, a troubled litter produced a puppy that had the classic symptoms and survived long enough for investigations to be carried out - but vets were unable to say more than it seemed to be some sort of autoimmune deficiency.
The condition became the "mystery disease" and two more puppies from another litter in 1990 were added. Repeated requests to owners of IRWS to report anything similar produced no further cases and the condition was discussed at a seminar, again without making any progress.
The publication of "CLAD/CGS Case Study" issued by Irish Setter Breeders Club in November 1997 became the breakthrough that gave a lead for further investigation into IRWS pedigrees and pointed the way to solve the problem in IRWS. An extra help was given by the autopsy, conducted in Berlin, on a puppy bred in Belgium giving the cause of death as being CLAD.
So there was CLAD in IRWS. Could this be the same as the Irish Setter? It is unlikely that two separate breeds should mutate the same gene fault simultaneously, but a study of the published Irish Setter CLAD pedigrees produced no link to IRWS - until the Swedish case 6. This litter, with a positive tested puppy, was out of a carrier dam but by a dog unrelated to any of the Irish Setters implicated in CLAD. To have a tested CLAD case needs to have both parents as carriers. The dog, Moanruad Sapphire, (a "working" red it is presumed, since the Moanruad kennel was a "working" Irish Setter kennel) is a grandson of the Irish Setter, Moanruad Brendan, who features in IRWS pedigrees. In the ISBC study, there is a note to say there is a query on the authenticity of this pedigree - it does not go back beyond M. Brendan. 
The preservation of the few IRWS in Ireland was only accomplished by their close connection with "working" Irish Setters. What happened with Moanruad in those days we do not know, but an alliance with a CLAD carrier is not unthinkable.
Suffice it to say that looking at the "mystery" disease pedigrees in the UK Red and White Setters and plotting the path of inheritance, leads to Moanruad Brendan as the link to the CLAD in Irish Setters. (see attached graphic pedigree) No other cases have come to light, to date.

Six litters have been reported as having CLAD symptoms. Cases A, B, C and D were simply recorded as "autoimmune…?", but Case E was diagnosed as CLAD. With the availability of the DNA test and the co-operation of the Animal Health Trust, 8 blood samples (from a batch of 75 already held for the breed at the AHT) were DNA tested. These blood samples were from the few remaining dogs of the direct line of UK IRWS in this study connected to Moanruad Brendan. Of these, 4 were clear and 4 were proved carriers - so it is official, Irish Red and White Setters have Irish Setter CLAD.
Then, news of Case F came in - would this one upset our theory? No, it fits in and in so doing, illustrates that the recessive gene can remain inactive for generations until it meets up with another. It also illustrates that several dogs in each intervening generation must also be carriers.
Here we must also add that Winnowing Grouse had four other IRWS littermates - Guillemot, Gannet, Goshawk and Goldfinch, all of whom have been used in breeding - some of those could well be carriers, as could some of the siblings of Brosna Grouse and Brosna Judy. The cases we know of have arisen because carriers occurred on both sides of the pedigree, early on in the establishment of the breed in the UK. We will always be indebted to the Ashfield, Elaphill, Autumnwood, Copatain and Exclusive's kennels for their openness, co-operation and inspired reporting of those elusive facts that have now been used to benefit all IRWS.

This threat to the breed can be eliminated quite easily and quickly.
There is no point in looking backwards and pinpointing other dogs; we have arrived at a situation where action for the future can be taken.

The complete information on CLAD must be widely distributed through all the connections with breed and measures taken to ensure that people understand the disease and the procedures to get rid of it. Then it will need the immediate and wholehearted support of all breeders

CLAD - THE WAY FORWARD - IRWSCGB POLICY

1 The occurrence of Irish Red & White Setters affected with CLAD will be rare. However, an affected animal might be identified. The disease is such that there can be absolutely no circumstance to justify breeding from an affected animal, even if it survives long enough to reach sexual maturity, which is doubtful.

2 All breeding stock must be DNA tested before being bred from and their CLAD status be in the public domain.

3 Carrier to carrier matings should be avoided and discouraged as 25% of the litter will be affected and 75% of the "normal" offspring will be carriers. 

4 Because IRWS are a numerically small and developing breed, the mating of carriers to clear stock can be permitted at the moment - but this situation will be under constant review. 

5 The progeny of carrier/clear matings should be permanently identified by microchip or tattoo, registered with the KC, DNA tested and registrations endorsed accordingly.

6 There should be a fast track system for both registration and DNA testing for puppies produced from a carrier/clear mating.

7 A dog's CLAD status should not affect its eligibility for entry to KC licensed events.

8 Puppies born on or after 1st January 2001 can only be put on the Puppy Register if the CLAD status of their parents is known.

PUBLICATION OF RESULTS

After blood samples have been tested, the testing centre will send a certificate to the owner and a copy to Dr Jeff Sampson at the KC.
A 4 week buffer before results are published will allow for appeals and results that are subject to appeal will not be published until the appeal has been resolved.
The results of DNA CLAD tests will be: recorded on the KC Database; published in the Breed Records Supplement; available from Information Officers at the KC on request and printed on progeny registration certificates. Updated lists will be sent to Club Secretaries and published on the KC Health pages on the KC Web site.
Results will be published on the IRWSCGB Web site.
Results will also be recorded on the Non-Confidential table of the IRWSCGB Database and available on request.


IN SHORT

Who would knowingly breed puppies that are doomed to suffer from sores that will not heal, infection that races through the body, bones that grow distorted - making it difficult to stand, jaws that swell - making it difficult to open the mouth and skin that hurts when you stroke them?

These are the puppies that have two CLAD genes - one from their sire and one from their dam. They can be helped for a while by antibiotic treatment but relapse when the treatment is withdrawn. They rarely live to breeding age. Their short lives have been a misery.
Their healthy littermates have no problems; although both parents must be carriers to produce affected puppies, 25% of the litter will be clear and the other 50% will be carriers.
DNA testing will tell us who are carriers and who are clear BUT there is no need for all IRWS to be tested - ONLY THOSE THAT WILL BE BRED FROM, from now on.
This is a ONCE ONLY test - your dog is either a CARRIER or a CLEAR.
Ideally only CLEAR to CLEAR should be bred, BUT in our breed, with so few dogs breeding of CARRIER to CLEAR can be permitted. A dog could have many attributes of great value to the breed and it would be unwise to eliminate it from a breeding programme solely on one point - breeds with huge populations can afford this, we can not.
However, using a carrier puts the responsibility on the owner of the bitch of having all the puppies tested, permanently identified (microchip/tattoo), KC registered and the carriers registrations endorsed "not to be bred from". There would be a fast track for this, but it is still something to be considered when planning a mating.

The main thrust of the control programme is that the CLAD status of future breeding stock is known - by the owner AND by the breed.
So if you have a dog at stud his CLAD status should be part of his attributes. If you intend to breed from your bitch, you should have her CLAD DNA tested and then look for a suitable stud.
From 1st January 2001 puppies will not be accepted onto the Puppy Register unless the CLAD status of their parents is known.

The results of CLAD testing will be published by the KC, in the Breed Records Supplement and on the KC web site and by the IRWSCGB on the Club's web site and also recorded in the Club's Database - in the Non-Confidential table.

All future IRWS should be clear of CLAD by parentage and the disease never seen again in our breed, IF we all work together.

If you are thinking of breeding a litter - THINK "CLAD STATUS" first and know that you will not pass Canine Leucocyte Adhesion Deficiency to the next generation.

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