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L-2 HGA Information

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L-2 HGA testing






In the past few years a small number of Staffords have been diagnosed with a metabolic disorder; its clinical

title is L2 hydroxyglutaric aciduria or L2-HGA.  This condition has manifested itself in varied ways with dogs exhibiting behaviour changes and dementia (staring at walls, getting stuck under tables and in corners, loss of obedience and house training), anxiety states, having full blown seizures, as well as exercise intolerance, ataxia (unsteady gait), tremors and muscular stiffness.  Dogs from differing bloodlines have been found to be sufferers and the number of affected dogs diagnosed has risen.  The disorder (and a similar linked disorder, D-2 HGA) is found in humans, again very rare, but nevertheless, devastating for the families affected by it.  The disorder has an autosomal recessive method of inheritance, meaning that both parents must be carriers of the defective gene to produce affected offspring.


There has recently been discovered a genetic screening test to determine which dogs are carriers of the gene that causes L2.

 It is advisable that  “ALL BREEDING STOCK” should be screened in order to eradicate this condition in the future.


Hot off the press these are the answers given by Cathryn Mellersh and Jeff Sampson to the number of questions asked by BBO-ers recently. Jeff Sampson has also released a statement copied at the end.

The seminar did cover much ground and despite a bit of a rough ride at times with views expressed forcefully from all sides I would hope that all those attending found it interesting and useful in enabling them to make up their own minds on these issues. There were plenty of facts given to illustrate the messages.

Q. Australia wants to know when the test will be available over there. I.e. when can their own people do it.
A. We have already received 53 samples from Australia and 8 from New Zealand. However, we appreciate that there are problems in sending blood samples from Australia and we are trying very hard to get the L2HGA test to work on swabs. To this end we have conducted a trial on swab samples received from Australia. That trial is now near to completion and we will have further information available at the seminar
At the seminar itself it was explained that the AHT is in the process of having the DNA test published in a veterinary journal – once this has been done any country around the world will be able to use the test itself. The AHT is NOT patenting the test, but it was suggested there may be a royalty.

Q. As a percentage how accurate are the results and can you clarify the percentages quoted for the likelihood of offspring being carriers, clear and affected. People have commented to us that they know of carrier-to-carrier matings and non-affected puppies being born resulting in more doubts being cast
A. For both the HC and the L2HGA tests the mutations we have identified, upon which the tests are based on, account for all the cases identified thus far. This means we haven’t yet come across a dog affected with either HC or L2HGA that our tests wouldn’t have identified as affected. So, in those terms, it is 100% accurate. It is, in theory, possible for new mutations to arise that cause other forms of HC or L2HGA. This is unlikely (a 1 in 50 million chance quoted here), but formally possible. However, even if new mutations did arise it wouldn’t mean the current tests were worthless – it would just mean we would have to develop additional tests.
But it is entirely possible for carrier-to-carrier matings to produce unaffected offspring. Each puppy has a 1 in 4 chance of being affected if both its parents are carriers – so it has a 3 in 4 chance of being either clear or carrier with no symptoms of the disease. Therefore a litter of 4 puppies from a carrier x carrier mating will have about a 1 in 3 chance of having no affected dogs in it.

Q. How accurate is the test for crossbred Staffords, or so called Staffords that have some alien blood in there breeding.
A. The tests are both just as accurate for crossbreeds as for purebred dogs in that they will detect the presence of absence of the disease-causing mutations in mutts as well as in purebred dogs. However, they will not detect the presence of other mutations that cause similar diseases that may have come from the other breeds involved. For example, if a dog is a cross between a SBT and a Golden retriever, both of which suffer from HC, the AHT’s HC test can only detect the presence of the SBT HC mutation because the GR HC mutation is currently unknown. So if the dog has been unlucky and has inherited both the SBT mutation and the GR mutation the AHT test will only detect the SBT mutation. But if the 2 mutations are different it is unlikely one copy of each will cause a dog to be affected with HC – usually a dog needs 2 copies of the same mutation to be affected.

Q. What is the actual incidence/percentage of Stafford's exhibiting full-blown symptoms of L2.
A. The exact figure is unknown. In a study we carried out at the AHT we found 25 out of 80 dogs were carriers of the L2HGA mutation. If this figure is extrapolated to all SBTs it would mean close to 2.5% of dogs would be affected. However, the 80 dogs we examined were not a completely random selection of SBTs (they had all been recruited for the HC study) so the real percentage of affected dogs is probably somewhat lower than 2.5% - but still considerably higher than initially thought.

Q. How many dogs have been tested and what percentage are carriers?
A. For L2HGA we have tested over 600 samples, and about 15% are carriers.

Q. What measures will you take in the future to make the test more secure as some feel it's open to abuse or misuse.
A. The security of DNA testing is something that should be fully discussed between breeders and the Kennel Club and the AHT is very interested in hearing all arguments. But until micro chipping is mandatory, and unless vets are going to take every sample to be tested and verify the dog’s ID at the time of sampling it will be difficult to prevent all misuse.

Q. Why are the AHT going to accept mouth swabs for HC test? Isn't this type of sample easier to tamper with than blood samples?
A. Our experience is that breeders prefer mouth swabs. The AHT offers testing from swabs because it there is a greater take-up if that is the case and therefore the disease gene will be eradicated from the population within a shorter period of time.. As for the previous question the AHT will heed all arguments regarding security, but the benefit to the breed in general should also be weighed into the argument. In other words, is it better for the breed to offer swabs, and have a greater percentage of the breed tested (and accept that a small percentage of the results might be false) than have a lower percentage of the breed tested?

Q. At what age does it show when pups are affected and what are the first signs of L2?
A. Clinical signs usually appear when the dog is between 6 months and 1 year old. Affected dogs present with one or more clinical signs of epileptic seizures, incoordination, tremors, muscular stiffness at exercise and altered behaviour.

Q. Will the cost of the tests ever come down?
A. The cost of the test reflects the amount of work necessary to carry out and administer the testing and is comparable with charges for other tests. There are no plans currently to increase the price.

Q. Can future tests of HC and L2 be done from the same sample for a reduced fee?
A. The current cost of having both tests done on a single sample is 100, which is compared to the cost of 60 for an individual test.

Q. When will it be possible to test frozen semen for L2 and HC?
We can extract DNA from semen in other species and should be able to from dogs. We will accept semen samples , as a trial. Each sample will have to be processed individually so there will eventually be an extra charge for semen; however we are prepared to test semen initially at the same price as blood.
It was put to the speakers today that if semen was to be tested as the test is confidential between the owner of the dog and the AHT if the owner of the semen is not the owner of the stud dog would the dog owner’s permission be sought before testing takes place. Jeff and Cathryn both said that this would need to be considered. As yet, the situation hasn’t arisen.

Q. Are there any plans to halt testing whilst some form of ID DNA profiling system is put in place?
A. No. This question seems to refer to the security issues already raised. These will need to be fully discussed between breeders and the Kennel Club.

Q. How do you work out your percentages for inheritance?
A. If the question is referring to the percentages of affected, carrier and clear pups we expect from particular matings – these are calculated by assuming each parent has two copies of piece of DNA that causes the disease (each copy can be normal or mutant) and each parent passes one of the 2 copies to each of their offspring. The copy they pass is random. The same applies for each parent. So, for example, lets assume 2 carriers are mated together. Each of their puppies has a 1 in 2 chance of inheriting the mutant DNA from their mother and a 1 in 2 chance of inheriting the mutant DNA from their father. The chances of the puppy inheriting the mutant DNA from both parents is therefore a half times a half (0.5 x 0.5) which is 1 in 4 (or 25%).

Q. If L2 came from an apparently normal dog and it mutated once to give us the L2 we know now what is to say in 5 or 10 years it will mutate again? Could we be breeding dogs that have been tested for this particular muted gene for the presentL2 and have no idea that there is another form rearing it's ugly head?
A. It is formally possible that a new mutation could occur, that is different from the one we have identified, that also causes L2HGA. And this is known to have occurred in some breeds. For example Boston Terriers suffer from two forms of cataract…one is the juvenile/early onset form that is caused by the same mutation that causes HC in the SBT and the other appears later in life and is caused by a different (as yet undiscovered) mutation. These two forms of cataract are caused by different, randomly occurring, mutations. But this kind of thing is very rare and the chances of it happening are very small. Because this L2HGA mutation has arisen once in SBTs doesn’t make it any more likely to occur again. All mutations are random events and are not controlled by mutations that have arisen in the past.

Q. Being that L2 has come from a mutated gene in the past what are the odds of the same gene being mutated in a DNA tested clear dog?
A. This sounds like the same question to the previous one.

Q As the AHT is now running both the L2 and HC DNA test will there be one combined form to cover both tests.

A This will come about in due course. The AHT is currently working very hard to pull everything together having been delighted that the two tests are available but equally aware that there it will take time to sort out these kinds of areas.

Notes for the Staffordshire Bull Terrier Breed Club Meeting on Hereditary Cataract (HC) and L-2 Hdroxyglutaric Aciduria (L-2 HGA)

Dr Jeff Sampson, The Kennel Club


Both HC and L-2 HGA are inherited as single autosomal recessive conditions in the Staffordshire Bull Terrier and DNA tests have been developed at the Animal Health Trust to identify both of the mutations involved. This means that a DNA sample from an individual Staffordshire Bull Terrier can be analysed to see whether the dog is clear of, a carrier of, or affected by both of these mutations/conditions. The availability of these two new tests will be of great benefit to Staffordshire Bull Terrier breeders because it will enable them to select against the specific mutations in their breeding programmes and reduce the frequency of both mutant genes in future generations. Obviously, everyone involved in breeding and registering litters of Staffordshire Bull Terriers need to work together to ensure that the breed gains maximal benefit from these new DNA tests.


Following an application from the Breed Council, the Kennel Club has approved an Official DNA Testing Scheme for both HC and L-2 HGA in the Staffordshire Bull Terrier. This means that copies of DNA test certificates that are issued by the Animal Health Trust will be sent directly to the Kennel Club. Test results will then be added to the tested dog’s information on the Kennel Club’s Registration Database. This will mean the test result for that dog will be published in the next available Breed Records Supplement (BRS); it will also appear on any new registration certificate issued for the dog and on the registration certificates on any of the dog’s future progeny. This Scheme is now in operation and the Kennel Club will be issuing a Press Release shortly. In this release, the Kennel Club will invite all those owners who have already had a test done, to send in a copy of the DNA test certificate to the Kennel Club and we will add the information to the dog’s registration database.


Obviously, the first thing that needs to be done is to create an acceptance amongst Staffordshire Bull Terrier breeders that all potential breeding stock should be DNA tested for both conditions before they are bred from. Knowing the result for each test will then be able to better inform the breeder about choosing potential mates.

If a dog comes back clear for both diseases, then there really isn’t a problem because such dogs will have two normal copies of both of the genes involved and can therefore only pass on normal copies to their offspring.

What about if a dog comes back as a carrier, for either or both conditions? Being a carrier means that the dog will not become clinically affected, but it will have one normal copy of the gene and one mutant copy of the gene, and it will pass on the mutant gene copy to approximately half of its offspring if it is bred from. How breeders deal with identified carriers is, of course, up to the individual breeder. Some will say that they will not breed from an identified carrier, and that, of course, is their decision. However, my own view is that too few dogs enter the breeding pool in all breeds and to reduce this even further could be to the long-term detriment of the breed. Indeed, for me, one of the major advantages of having a DNA test is that it allows breeders to breed from identified carriers. However, breeding from a carrier imposes extra constraints on the choice of a mate. A known carrier should not be mated to an untested dog, because that dog could be at least an unidentified carrier, nor should a DNA tested carrier dog be mated to another DNA tested carrier dog. This is because if two carriers are mated together, each puppy will have a 1 in 4 chance of being affected, and this is far too high a risk. However, if a carrier is mated to a DNA tested normal dog, then the first thing to remember is that none of the subsequent litter will become clinically affected, but the litter will be a mixture of normal and carrier puppies. Obviously, the availability of two different DNA tests makes this choice slightly more complex, but not insurmountable.

We now have quite a bit of experience with the use of DNA testing for disease genes in other breeds and the following pattern seems to work exceedingly well to reduce the frequency of the offending disease-causing mutation without removing dogs from the breed’s breeding pool. The following steps should be followed:

All potential breeding stock should be DNA tested before they are bred from.
Identified carriers should not be mated to an untested dog, or to another identified carrier.
Identified carriers can be mated, but only to a DNA tested normal dog. This allows carriers that have qualities that future generations would benefit from, to pass on those qualities, for example good breed type and temperament. Remember, breeders are trying to produce good all round Staffordshire Bull Terriers, so don’t just choose a mate because it is normal with respect to these diseases, that probably will do the breed no favours; try to find a mate that you might have chosen anyway, that is also normal for these conditions.
If breeders choose to mate a tested carrier dog to a normal dog, then they must undertake to DNA test the resultant puppies to identify those that are carriers and those that are normal. The identified carriers should then be endorsed by the breeder, with the KC endorsement, ‘Progeny not eligible for registration’. In other breeds, the cost of litter testing has become an issue, and in these cases what the breed clubs have adopted is that breeders need not DNA test all of the progeny from a carrier X normal mating, but any untested puppies should be endorsed as above.


To my mind, there is absolutely no reason why a similar approach should not be adopted for the control of both HC and L-2 HGA in the Staffordshire Bull Terrier breed. However, I can see at least one complication that needs to be addressed. Thus far, breeding programmes linked to DNA testing for a specific disease-causing mutation have been adopted by breeds that are relatively small, numerically, where most breeders that register their litters with the Kennel Club are members of an appropriate breed club and, commonly, read the dog papers and breed notes. Engaging with these people to inform them about the various proposals has been relatively easy and most, if not all, will have heard of them.

These two new tests are probably the first in a numerically large breed, where significant numbers of breeders registering litters with the Kennel Club will not be members of a breed club and will not, necessarily, be avid readers of the dog press. This, of course, adds a new level of complexity in terms of communicating ideas and schemes to those that need to take the information on board. The one thing that we do have of course is the fact that most breeders are registering their litters with the Kennel Club and new owners are transferring these registrations. The Kennel Club therefore has the appropriate contact details and are thus in a position to disseminate information to these people. We are presently having discussions internally as to how to best achieve this, but there is no reason why we cannot communicate ideas to all those that breed Staffordshire Bull Terriers and register them with us, and get the right messages across with regard to DNA testing.

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