Eic In Labradors

[Wuppywoman]

Hi all. I know this may have been covered before but just interested in some info re EIC testing, inheritance and anything related anyone may have to say re Labradors. I live in NSW and have 8 Labs of various ages. I have hear there are already restrictions in some states re breeding carriers? Any info would be appreciated.

[zenchel]

Hi all. I know this may have been covered before but just interested in some info re EIC testing, inheritance and anything related anyone may have to say re Labradors. I live in NSW and have 8 Labs of various ages. I have hear there are already restrictions in some states re breeding carriers? Any info would be appreciated.

There are NO breeding restrictions anywhere on EIC results, except possibly in individual breeding programs, but that's up to the individual breeders, as it is with so many other aspects of breeding.

This flyer is really quite informative:

EIC FAQ

However there are points made in the flyer that are not relevant to the situation here in Australia, mainly that it is not only field trial bred dogs that are carrying the mutation. The mutation is widely distributed amongst UK and US show bred dogs and hence many Australian show bred dogs.

Although the DNA test results seem to be totally valid, the correlation between them and the clinical features of the dogs give cause for concern. There are many dogs world wide that have tested DNA affected but have never collapsed. Possible reasons for this are:

(1) The dog has not been stimulated to a high enough level to collapse.

(2) There is an environmental "trigger" for each individual dog that causes it to collapse and this dog has not experienced its trigger. (e.g. live game, competition with other dogs, a bitch in season etc)

(3) There is a modifying gene that either "protects" the dog from collapsing, or the dog needs this modifier to collapse and this non collapsing DNA affected dog does not have it.

Many responsible, ethical breeders all over the world are very sceptical about this test and even the existence of this thing called EIC, as they have never seen a dog collapse, even during high level activity. They see no point in DNA testing as there is no evidence in their breeding program of a problem. Some breeders are convinced, usually by witnessing a dog collapse, that it is a very important issue that Lab breeders the world over need to address and are DNA testing everything and making breeding decisions based on those test results. I'm guessing the majority of breeders are somewhere between these two ends of the spectrum.

This is a link to video of a collapsing dog

EIC Video

Sylvia

[Joan of Arc]

Most of this is US based but if you are interested I have pasted for you

Exercise Induced Collapse In Labrador Retrievers: 2008

Update: August 2008

INTRODUCTION

Exercise induced collapse (EIC) is a common cause of episodic exercise intolerance and collapse in otherwise healthy, adult, Labrador Retrievers. Dog owners and professional trainers have recognized affected individuals for at least 20 years, but they have not had a name for the disorder. Veterinarians have speculated that the episodes might be due to heat intolerance, low blood sugar, electrolyte (sodium, potassium or chloride) disturbances, heart rhythm abnormalities, or an inherited muscle disorder. Dogs with EIC are normal at rest and able to tolerate mild to moderate exercise but occasionally become incoordinated and collapse after 5 to 15 minutes of strenuous exercise. It is common for related dogs (littermates) to be affected.

A comprehensive investigation into EIC has been ongoing for nearly a decade, involving investigators from the University of Saskatchewan (Sue Taylor, Cindy Shmon), the University of Minnesota (Ned Patterson, Jim Mickelson, Katie Minor) and the Comparative Neuromuscular Unit at the University of California (Diane Shelton). This article will describe the research and the results, and provide the reader with some insight into this syndrome.

RESEARCH METHODS

(1) Surveys were completed by owners of 225 Labrador Retrievers with EIC, and the results were analyzed.

(2)

(2) Fourteen dogs with EIC were exercised according to a standardized strenuous exercise protocol during which they repeatedly retrieved a hand-thrown bumper for 10 minutes. Clinical parameters were measured and laboratory tests were performed before and after exercise and results were compared with 14 normal, exercise tolerant, Labrador Retrievers completing the same exercise protocol.

(3) Pedigrees and whole blood were collected from dogs with EIC and their clinically unaffected (normal) relatives. Pedigree analysis was performed using software established for that purpose. DNA isolated from the blood of the affected and normal dogs was analyzed for similarities and differences and a whole genome scan was performed to determine the chromosome and then the particular site on t he chromosome where linkage to EIC occurred. Once this was established, candidate genes in the region were sequenced in order to identify the actual genetic mutation causing EIC.

RESULTS

Who gets EIC?

EIC is the most common reason for exercise intolerance and collapse in apparently healthy Labrador Retrievers. Signs typically first become apparent in young dogs between 5 months and 5 years of age (average 12 months). Labradors of all colors (black, yellow, chocolate) are affected, and males and females are equally affected. Dogs with EIC are often described by their owners as being extremely fit and muscular with a very excitable temperament and lots of retrieving drive.

Description of Collapse

Affected dogs can tolerate mild to moderate exercise, but occasionally, after 5 to 15 minutes of strenuous exercise, they develop weakness, apparent incoordination, and may collapse. Most owners report that during episodes of collapse their dog’s rear legs are floppy and unable to support weight. It is common for the dogs to continue trying to run while dragging their rear legs. Although rear limb signs are most prominent, during some episodes of collapse dogs will be unable to rise and may actually lose the ability to voluntarily move any of their limbs. Staggering and falling to the side or difficulty maintaining balance is common during recovery from episodes. Most dogs with EIC are mentally normal, but some dogs (25%) have had one or more episodes during which the owners report that they seemed dazed or confused.

Trigger Activities

Activities most often associated with inducing collapse episodes in EIC susceptible dogs include repetitive “fun” retrieves, land retrieves during training or at a field trial, excited play with other dogs and upland hunting for pheasant or other game. Collapse during swimming or during waterfowl hunting is less common.

Contributing Factors

Owners were asked to speculate on factors that they felt contributed to causing collapse in their dogs. The most common factor implicated was excitement or stress associated with a trigger activity. Many owners reported that they “could tell” when their dog was at risk of having an episode because they were excessively excited even before they started the trigger activity. The use of live birds in training or trials, chasing crippled birds, and stress during training (difficulty finding a mark, electronic collar correction, repeating an unsuccessful retrieve) were all cited as factors that would sometimes lead to increased excitement or stress and promote collapse. A few severely affected dogs were reported to routinely collapse with very minimal exercise if they were in a highly excited state. In contrast, owners reported that their EIC affected dogs could engage indefinitely in moderately strenuous activity not associated with excitement such as jogging, hiking or running alongside a bicycle with no signs of collapse.

Approximately one-third of owners had the impression that hot environmental temperatures and high humidity increased the likelihood that their dog would collapse. Although collapse does appear to be more likely when the weather is hot, collapse episodes have been reported in all environmental conditions. A few affected dogs have exhibited collapse while breaking ice retrieving waterfowl, and many have collapsed while quartering for pheasants in frigid temperatures.

Veterinary Evaluation of EIC Dogs

Dogs with EIC are normal at rest. They are typically extremely fit and well muscled. Examinations of their heart and lungs are normal at rest and during collapse. After exercise, during collapse, EIC dogs have very high body temperatures (often > 108F, >42C), but this is not different from dogs without EIC exercised in the same manner, and the time that it takes them to cool down after exercise is not different. Dogs with EIC are not lame and they do not have sore joints, muscles, bones or spine before or after exercise. Nervous system examination is normal at rest, but patellar reflexes are diminished or absent in dogs with EIC during collapse and these do not reappear until after the dog has completely recovered, which usually takes 10 to 30 minutes. Routine blood analysis is normal at rest and there are only minor changes following exercise when compared with normal exercising Labradors. Dogs with EIC have normal thyroid gland function, and normal adrenal gland cortisol production. Muscle biopsies are normal. EIC is a distinct disorder that is different from heat stroke, malignant hyperthermia (MH), myasthenia gravis, mitochondrial myopathies and centronuclear myopathy (CNM).

Long Term Outlook

Dogs symptomatic for EIC must often be retired from the activities that cause them to collapse and if participation in these trigger activities is limited, these dogs can live normal lives. Dogs with EIC do not develop progressive systemic or nervous system dysfunction over time, and except for their EIC, they are normal. Many affected field trial dogs have been adopted out as pets, and if intense exercise, excitement and training stress are avoided, they typically never experience another episode of collapse.

Some dogs with EIC are able to continue to participate in trigger activities if the owner watches them carefully and halts exercise as soon as they notice subtle gait abnormalities. Their participation in prolonged strenuous exercise, especially if associated with a high state of excitement or stress or high environmental temperatures should be limited. Many dogs with EIC seem to be less prone to collapse as they age or after castration, perhaps because their activity and excitement levels decrease.

Dogs with EIC, even if they are older or neutered, must always be considered to be at risk for an episode of collapse, so they should be watched carefully. Owners and handlers of these dogs should make every effort to stop the dog’s activity at the first hint of abnormality. Symptoms typically worsen for 3 to 5 minutes after exercise has been terminated, so dogs with EIC should be closely monitored after exercise, not just put away in the truck or kennel. A few affected dogs have died during exercise or (more commonly) while resting immediately after exercise - these dogs have not always been recognized as severely affected dogs, so all dogs with EIC should be considered at risk for a fatal episode.

Treatment

The best treatment in most dogs with EIC consists of avoiding intensive exercise in conjunction with extreme excitement and ending exercise at the first sign of weakness/wobbliness. There are, however, numerous anecdotal reports of dogs being able to resume trigger activities such as retriever training and competition when they are treated with the anti-seizure medication, Phenobarbital. Phenobarbital and other sedative drugs may simply decrease the dog’s level of excitement or anxiety, thereby decreasing the likelihood of collapse. There are a few very successful field trial dogs on the circuit that have EIC and are only able to compete when they are receiving daily Phenobarbital. In some dogs, however, Phenobarbital administration will cause noticeably impaired judgment, interfering with training or trialing. Phenobarbital is a controlled drug with potential side effects, so it should only be administered under the direction and monitoring of a veterinarian.

Heredity of EIC

Pedigree analysis has established that the mode of inheritance for EIC is autosomal recessive, meaning that all dogs with EIC have received two mutant genes - one from each parent. This means that both parents of a dog with EIC are either carriers of EIC (1 mutant EIC gene) or affected by EIC (2 mutant EIC genes).

The Mutation

During the summer of 2007, the mutation causing EIC was identified and a reliable genetic (DNA based) test to look for this mutation was developed. Details regarding the mutation and the changes in nervous system function caused by the mutation cannot be released to the public until after scientific publication.

The test will determine whether a dog is:

*Affected by EIC (has 2 copies of the causative mutation: homozygous for EIC)

*A carrier of EIC (has 1 copy of the causative mutation: heterozygous for EIC)

*Clear of EIC (no copies of the causative mutation: normal)

UNDERSTANDING TEST RESULTS: THE INHERITANCE OF EIC

Every dog gets 2 copies of every gene - one from its dam and one from its sire. The mutation in the gene that causes EIC is inherited as an autosomal recessive trait, which means that all affected dogs (those showing signs of collapse) have 2 copies of the mutated gene - one that they got from their dam and one from their sire.

Clear dogs are dogs that do not have any copies of the mutation. These dogs do not have EIC and will not show signs of collapse. If bred, they will not pass a copy of the EIC mutation on to any of their puppies.

Carriers, by definition, are dogs that have one copy of the mutated gene that they got from either their dam or their sire and they have one normal copy of the gene that they got from the other parent. These dogs do not have EIC and will not show signs of collapse. They will, however, pass their copy of the mutated gene on to approximately half of their puppies.

Affected dogs have 2 copies of the mutation, one of which came from each parent. Dogs with 2 copies of the mutated gene (affected dogs) have EIC and most will show occasional signs of exercise intolerance or collapse when participating in trigger activities with a very high level of excitement or stress. Some affected dogs will never exhibit signs of EIC - this could be because they do not participate in high excitement strenuous activities or because they have a laid-back temperament.

WHAT TO DO IF YOUR DOG HAS EPISODES OF COLLAPSE

EIC is the most common cause of exercise intolerance and collapse in Labrador Retrievers that seem otherwise healthy, but it is important to realize that there are many other medical conditions that can cause similar signs. Complete veterinary evaluation should therefore be performed in any dog with exercise intolerance to eliminate treatable disorders such as low blood sugar, anemia, heart rhythm disturbances, laryngeal paralysis, joint or muscle disease, cauda equina syndrome, low blood cortisol, myasthenia gravis and epilepsy. If veterinary evaluation suggests that the dog may have EIC, your veterinarian should submit a blood sample to confirm the diagnosis.

If a collapsing Labrador Retriever is confirmed to have EIC (i.e. blood test confirms two copies of the EIC mutation), it should be recommended that participation in trigger activities be limited and that the dog be monitored closely so that exercise can be ended at the first sign of weakness/wobbliness. If the dog does collapse, (1) make sure that it has unobstructed breathing so it can hyperventilate to blow off heat, (2) offer water and ice orally, and (3) cool the dog by immersing it in cool water or wetting it down. Enforce rest until the dog is fully recovered.

If a collapsing Labrador Retriever does not have two copies of the EIC mutation, then the collapse must be due to something other than EIC. In my experience, the disorder most often confused with EIC is epilepsy, a condition that can be very difficult to diagnose in dogs. Labradors sometimes have a unique excitement-triggered form of epilepsy characterized by unusual episodic events (seizures) during which the dog maintains consciousness but experiences abnormalities of gait and/or balance that look a lot like EIC episodes. Clinically, the best differentiating feature between these epileptic seizures and EIC episodes seems to be that the epileptic seizures occur suddenly and resolve suddenly while dogs with EIC get gradually worse during a collapse episode and then gradually recover over 5 to 30 minutes. Later in life, many Labrador Retrievers with epilepsy also develop more typical gene ralized seizures, where they fall over, lose consciousness and paddle their legs.

BREEDING/TESTING RECOMMENDATIONS

From the limited testing that has been done so far, it appears that more than 25% of the Labrador Retrievers participating in field trials have at least one copy of the EIC mutation (i.e. they are either carriers or affected). The apparently very high frequency of the mutation causing EIC in the Labrador breed and the presence of the mutation in some of the most successful field trial lines make it unreasonable to suggest breeding only dogs that are clear of this mutation. There are many other factors to consider when breeding, including other health conditions and positive and negative inherited talents and traits. Breeders simply need to be selective in their breeding, avoiding the production of dogs that actually have EIC. All breeding dogs should be tested, and if carrier dogs are bred they should only be bred to dogs that are genetically clear of EIC so that affected puppies will no t be produced (see Table). Puppy buyers can insist on documentation that the puppy they are buying does not have EIC. Ideally, whenever a dam or sire of a litter is a known carrier of EIC, each puppy should be tested before 7 weeks of age and if everything else is equal the pups that are clear of EIC are the ones that should go to homes interested in future breeding (see table).■

TABLE

EIC: IMPLICATIONS FOR BREEDING

Clear dogs: no copies of the mutation

bred to a clear dog: 100% of pups clear

bred to a carrier: 50% of pups clear, 50% of pups carriers*

bred to an affected: 100% of pups will be carriers

Carrier dogs: one copy of the mutation

bred to a clear dog: 50% of pups clear, 50% of pups carriers*

bred to a carrier: 25% of pups clear, 50% of pups carriers, 25% of pups affected

bred to an affected: 50% of pups carriers, 50% of pups affected

Affected dogs: two copies of the mutation (breeding is not recommended)

bred to a clear dog: 100% of pups will be carriers

bred to a carrier: 50% of pups carriers, 50% of pups affected

bred to an affected: 100% of pups affected

*puppies from carrier matings can be tested to determine which ones are clear and which ones are carriers

[Lablover]

If you do not wish to send samples to the US, GTpets (Australia) is able to test for EIC.

[sandgrubber]

Does anyone have any idea how many dogs have been found to be carriers? In the US, or in Australia?

I'm happy to do tests for genetic diseases that are a real possibility, but don't want to end up in a regime where breeders are required to test for everything they've been able to develop a test for, even if there's been no evidence of the diseases being present. (Eg, I've been told there's never been a reported case of narcolepsy in Australian Labs and many vets are recommending against testing. Would be interested to know if that's true).

[zenchel]

Does anyone have any idea how many dogs have been found to be carriers? In the US, or in Australia?

(Eg, I've been told there's never been a reported case of narcolepsy in Australian Labs and many vets are recommending against testing. Would be interested to know if that's true).

The last figures I had from Univ Minn were:

700 affected

2595 carrier

3664 clear

6959 Total

I just can't put my hands on the exact figures from GTG at the moment, but from memory there had been ~100 dogs tested, with approx 60% carrier rate. The US figures are slowly approaching their expected 3-5% affected, which have initially been higher - skewed because people with collapsing dogs and implicated bloodlines have been the major uptake of the test. The Australian figures are still skewed on the high side for the same reason.

I have NEVER heard of a case of narcolepsy in Labs - plenty in Lab breeders and plenty of Lab breeders wish that their dogs suffered from it sometimes :D

I haven't got the time nor the inclination to investigate the issue with the DNA mutation obviously existing (if there is a DNA test for it) and the complete lack of clinical manifestation of it. The same applies to the DNA test for cystinuria in Labs. The important thing is for all breeders, breed clubs, NBCs and the ANKC to take control of this DNA testing lark before it runs away with us.

Sylvia

[sandgrubber]

Great to have some statistics, Sylvia. I'm amazed that prevalence is so high; and on that basis, it looks like testing is a good idea.

I'm uncertain, re seriousness. It's a strange condition. My stock are calm-tempered and rarely get worked up into an intensely excited state. Thus, even if they were affected, I doubt I would have seen manifestations of the condition. I haven't sold a single pup into a family that does hunting: there are few places where you can hunt waterfowl or game birds in WA. Nor have I ever had a report of one of my pups collapsing. I think there was suspicion that one of my girl's sire was affected, but this was never confirmed and I've heard nothing suggesting that any of my pups has ever collapsed.

As more and more genetic conditions are identified and more tests become available, we're going to have to make more decisions about what to require, and what to do voluntarily. For the time being, I think I'll give EIC a miss . . .

On the other hand, given the relatively high frequency of epilepsy identified in Danish Labradors (3.1%, 70% of which were partial seizures: see http://cat.inist.fr/?aModele=afficheN&cpsidt=13669562 or do Google on epilepsy Danish Labrador) I would say epilepsy is a greater concern . . . and hope genetic tests become available for it in the near future.

Edited November 18, 2009 by sandgrubber

[Lablover]

I think there was suspicion that one of my girl's sire was affected, but this was never confirmed and I've heard nothing suggesting that any of my pups has ever collapsed.

If you do not wish to test, ask owners if their studs have been tested.

I concentrate on working lines. During my overseas travels some affected dogs have particular triggers, which when removed or conditioned, the dogs have lead successful trial careers. Do I think any less of these dogs.........no......most have outstanding hip, elbow and eye clearances and have produced such.

[Wuppywoman]

Thank you for the info. As it is easy to test for and relatively easy to get out of your breeding program I will test all 8 of my dogs and takes steps over the next couple to generations to ensure I breed EIC clear pups. I still have doubts about the whole thing but better to get onto it now before it becomes a requirement in the future. Fingers crossed the news isn`t too bad! Thanks again for your comments and info. Kel.

[blackdog]

Thank you for the info. As it is easy to test for and relatively easy to get out of your breeding program I will test all 8 of my dogs and takes steps over the next couple to generations to ensure I breed EIC clear pups. I still have doubts about the whole thing but better to get onto it now before it becomes a requirement in the future. Fingers crossed the news isn`t too bad! Thanks again for your comments and info. Kel.

Hi there Wuppywoman - I still have very real concerns with the efficacy of the EIC test.

If certain labs are tested as being "affected" and yet do not show signs of collapse then what is it exactly that we are testing for?

By all means go ahead and have your 8 tested - but what will your strategy be if all come back as affected or carriers?

And in reference to your concern about EIC becoming a compulsory test in future - is that really foreseeable?

We still don't have recommended upper level hip & elbow limits, nor is DNA eye testing for PRA a prerequisite for breeding.

I would suggest that EIC needs to take a number and wait at the end of a very long line.

And in reply to Lablover and her recommendation that breeders ask whether stud dogs have been EIC tested?

Nice sentiment but what if they're not tested - which dogs are you going to use?

Would a top class stud dog that has not been EIC tested be automatically excluded from a breeding programme?

Personally I would have thought that there are still far bigger issues prevalent in our breed that need fixing.

Maybe everybody's energy would be better expended on fixing those things rather than running about looking for "new" things to worry about.

regards to all.

[Lablover]

And in reply to Lablover and her recommendation that breeders ask whether stud dogs have been EIC tested?

Nice sentiment but what if they're not tested - which dogs are you going to use?

Would a top class stud dog that has not been EIC tested be automatically excluded from a breeding programme?

Excluded no - but pedigree highly researched (as we do whatever the concern).

If I were to use an untested high quality prepotent stud, I would test puppies before placement. If any carriers and the dam is clear/normal, obviously the stud is at least a carrier. If all pups carriers I would assume the high probability stud is affected.

May I throw a question back, do you feel bench quality has deteriorated since the PRA test?

Edited November 19, 2009 by Lablover

[Lablover]

On the other hand, given the relatively high frequency of epilepsy identified in Danish Labradors (3.1%, 70% of which were partial seizures: see http://cat.inist.fr/?aModele=afficheN&cpsidt=13669562 or do Google on epilepsy Danish Labrador) I would say epilepsy is a greater concern . . . and hope genetic tests become available for it in the near future.

Some say, a test is not too far away.

http://www.bsdaofgb.co.uk/idiopathic_epilepsy.htm

Idiopathic Epilepsy in the Belgian Tervueren

By Dr Jeff Sampson, KC Genetics Co-ordinator

Genetics of epilepsy in the Tervueren

Idiopathic, or primary, epilepsy is the form of epilepsy that is believed to be inherited in over 30 different breeds of dog. Although inheritance is suspected in all of these breeds, definitive data showing a precise mode of inheritance is only available for a small number of these breeds. In the Keeshond, data suggest a very simple single autosomal recessive gene disorder. In most other breeds where genetic studies have been undertaken, including the Tervueren, the picture looks more complicated than that seen in the Keeshond.

As many of you will know, epilepsy in the Belgian Tervueren has been the focus of research work at Davis, University of California for some time now. Both Tom Famula and Anita Oberbauer have been supported by the Canine Health Foundation (an American Trust Fund closely associated with the AKC) to study epilepsy in the Tervueren. Their initial work on analysing pedigrees in which one or more of the offspring had been diagnosed with idiopathic epilepsy indicated that although this is a heritable disorder governed by a number of different genes, there exists a single gene which has a very large effect on the incidence of epilepsy in the Tervueren. The epileptic condition influenced by this particular gene is inherited as an autosomal recessive.

Autosomal recessive mutations

So, what does ‘autosomal recessive’ mean? The adjective ‘autosomal’ means that the gene is present on one of the chromosomes known as an autosome. The dog has 39 pairs of chromosomes, 38 different autosomes and a pair of sex chromosomes (the X and Y chromosomes that determine the sex of a dog). The fact that it is recessive means that a dog has to have two copies of the recessive mutation before it is clinically affected. A dog that has one recessive mutant version of this gene and one normal version of the gene (remember dogs have two copies of each and every gene) will not be clinically affected with epilepsy, but will, genetically, be a carrier. Both parents of an affected dog (affected because it has two mutant versions of this major gene) will be carriers of the major gene involved.

Let’s look at this in a little bit more detail. Present estimates suggest that around 30,000 to 40,000 different genes are required to specify the dog. Each of these different genes will be distributed along one of the 39 chromosomes that make up the dog genome. Each autosome contains anywhere between 1000 and 2000 different genes arranged side by side along the length of the chromosome. Running along the length of each chromosome is a single molecule of DNA , the chemical that genes are made from. Chromosomes are often likened to beads on a string. It is not the best analogy, but it will do. The string running along the length of a necklace represents the DNA molecule, each bead represents a stretch of DNA that comprises a given gene. There are 38 pairs of autosomes and two sex chromosomes that contain each one of the 30,000 or 40,000 different genes. Each gene is present in two copies, one on each of the chromosome pairs.

A picture of the chromosomes present in a female dog. It is a female because it has two X chromosomes. A male set of chromosomes would have identical autosome pairs (1-38) and one X and one Y chromosome.

What are genes?

Genes are simply genetic plans, the information being stored in the chemical structure of the DNA that makes up the gene. The plan embedded in each gene is used to make a protein and it is the activity of proteins, either working individually or in groups, that determines the characteristics of dogs. So there are in excess of 40,000 different proteins required for a perfectly functioning dog. (Some genes actually contain a plan for more than one protein). Occasionally, the chemical structure in the DNA making up a gene is changed, a process known as mutation. Generally speaking, the majority of mutations in DNA are neutral and have little, if any, consequence. Some mutations are actually beneficial giving rise to an improved genetic plan. The whole of evolutionary theory is based on the generation of new mutations that offer a new competitive edge to individuals that carry such mutations. Other mutations are deleterious because they impair the genetic plan so much that the protein produced doesn’t function correctly. If the protein that is mutated plays a crucial role in a biological process, then an inherited disease might ensue.

That is clearly what is happening with epilepsy in the Tervueren. This major gene that has been discovered clearly contains a plan for a protein that plays a crucial role in the brain, probably involved in regulating the electrical activity that balances excitatory and inhibitory responses. Some time in the dim and distant past this particular gene has undergone a mutation that has either inactivated the protein or severely altered its activity so that it can no longer balance electrical activity under certain circumstances, causing affected individuals to fit. The original dog in which the mutation occurred will have passed on the mutant gene to half of its offspring who, in turn will have passed on the mutation to approximately half of their offspring, and so on. Because the original mutation was a recessive mutation, the early recipients of the mutant gene would have been carriers and therefore clinically unaffected. So, unbeknown to Tervueren breeders, the frequency of the mutant gene would slowly build up in the population, as will have the number of unidentified carriers. Eventually, the carrier frequencies will have got so high that there is a reasonable chance that two carriers will, through bad luck, be mated and then there will be a chance of producing one or more epileptic puppies.

Clearly, dogs that contain two normal, unmutated copies of this gene will be able to make active protein and will therefore be clinically unaffected. A carrier will have one normal copy of the gene and one mutated copy of the gene. The normal copy of the gene in the carrier will allow it to make sufficient protein, hence carriers will be clinically normal. Only the dog that receives two copies of the mutant gene will be affected because both of its plans are mutated so it has no chance of making normal protein.

The inheritance of an autosomal recessive mutation

Let’s now take a look at how this mutation is inherited. The diagram below represents a mating between two carriers of this major gene involved in epilepsy. In the diagram the normal gene is represented as a white circle and the recessive mutant version as a black circle. So, both parents have one normal gene and one mutant gene; they are carriers but they are clinically normal. From such a mating we would expect to get 25% normal offspring (two white circles), 50% carrier offspring (one white and one black circle) and 25% clinically affected offspring (two black circles). Where do these estimates come from?

When the bitch produces eggs, each egg receives just one copy of each and every maternal gene. This is achieved by putting one complete set of maternal chromosomes into each egg. This means that the carrier bitch produces two types of egg with respect to this major gene involved in epilepsy: one egg carrying the normal version of the gene (white circle) and one carrying the mutant version (black circle). Similarly, each sperm produced in the male has a complete set of paternal genes, achieved by placing a complete set of paternal chromosomes into the sperm head. So, again, there will be two types of sperm

produced by the carrier dog: one type carrying the normal gene version and the other carrying the mutant gene version.

Fertilisation of eggs by sperm is a purely random process. So, consider egg A in the diagram below, it could be fertilised either by a sperm carrying a normal gene or a sperm carrying the recessive mutant gene. If egg A is fertilised by a carrying a normal gene, the fertilised egg will have two normal copies of the gene. This single fertilised cell is the source of all of the cells in the puppy that develops and the genes in this puppy are identical to those present in the fertilised egg. Therefore the puppy that develops from this fertilisation will be clinically and genetically clear of epilepsy because it has two normal versions of the gene in question. If egg A was fertilised by a sperm carrying the mutant gene, the puppy that develops from this will be a carrier. Now look at egg B, which carries a mutant version of the gene. If egg B is fertilised by a sperm carrying a normal version of the gene, the ensuing puppy will be a carrier. The problem arises when egg B is fertilised by a sperm carrying a mutant version of the gene. The subsequent fertilised egg will now have two copies of the mutant gene and the puppy that develops from this fertilised egg will be clinically affected because it has two mutant genes.

Thus in a carrier mated to a carrier you would expect one clear to two carriers to one affected, and this is where the 25%:50%:25% comes from. It is worth pointing out that these are what you would expect to happen. Reality can often be quite different. Because of the total randomness of the process of fertilisation in any individual litter you might experience significant deviation from these expected ratios.

Towards a DNA test for carriers of epilepsy in the Tervueren

Progress from now on should be quite rapid. Anita Oberbauer at Davis, University of California has now been awarded a new grant from the Canine Health Foundation to develop genetic markers for idiopathic epilepsy in the Tervueren. What does this actually mean? Although we know this major gene now exists, we don’t know what it is, neither do we know where it is on one of those 38 different autosomes. Using the newly developed genetic map of the dog, Anita Oberbauer hopes to be able to localise the gene to one small region of one of those chromosomes. The genetic map of the dog is made up of a series of special DNA markers, each marker uniquely identifying just one region of one of the chromosomes. The map contains 100s of different markers ensuring that each chromosome is evenly decorated with DNA markers. What Oberbauer is trying to find out is which of these markers is always co-inherited with the mutant version of the gene. DNA regions that are always co-inherited are physically close to one another on a chromosome. Markers that are co-inherited with the mutant version of the gene are said to be linked to the gene.

The identification of markers linked to the mutant gene will immediately locate the mutant gene to one small region of one of those 38 chromosomes. The next stage of Oberbauer’s research will be to search this small region until she finds the major gene involved in epilepsy in the Tervueren. The ultimate goal of course is to find and identify the major gene responsible. However, the identification of DNA markers linked to the disease gene will be a major landmark for the Tervueren in respect of epilepsy. The identification of linked markers will permit the development of a simple DNA test that will be able to identify carriers. This will be what we call a ‘linked marker DNA test’. Once the gene is identified then scientists will be able to develop the ‘Rolls Royce’ of DNA tests, a test actually based on the mutation identified in the gene (a mutation based, or gene based, DNA test). Whereas linked marker tests have an inherent inaccuracy in them, usually less than 1 or 2%, gene based tests offer 100% accuracy. So, the immediate future will see the development of a linked marker test for epilepsy in the Tervueren. In the fullness of time this linked marker test will evolve into a gene based DNA test, once the gene in question has been identified.

How will a DNA test help breeders control epilepsy through selective breeding?

There is now a real possibility that in the not too distant future Tervueren breeders will have a DNA test that will be able to identify carriers of this major gene involved in epilepsy. This, of course, will be a very significant step forward. Breeders will be able to use the test to pre-screen all potential breeding stock. If a carrier is identified in this process, the breeder will know it and will be able to choose a genetically compatible mate. The breeder will know that if a carrier is mated to a dog that has DNA tested clear, then about half of the offspring will be carriers and half will be clears. Furthermore, the existence of the DNA test means that all of the progeny can be DNA tested to identify those that are carriers and those that are clear. The availability of the DNA test means that breeders will be able to mate carriers with confidence and also identify genetically clear progeny from carriers that can form the basis of future breeding programmes. The availability of a DNA test ensures that owners can mate their carrier dog with confidence. They can choose a mate using traditional values of breed type and temperament, but then back up, or fine tune, their selection using DNA testing.

The arrival of a DNA test for epilepsy in the Tervueren will not be quite the ‘god send’ that other DNA tests have been in other breeds, for example the DNA test for CLAD in the Irish Setter, because, remember what you are testing for is a major gene involved in epilepsy, not the only gene. However, the arrival of a DNA test for this major gene will permit breeders to make very significant in-roads into controlling epilepsy through selective breeding. There may still be the odd surprise in litters, even when DNA testing has been undertaken. However, this should not dampen breeder enthusiasm, being able to identify carriers of this major genetic mutation, if not all of them, will ultimately lead to a very significant reduction in the frequency of this condition in the breed.

Is there anything that breeders can do now?

Is there anything that Tervueren breeders can be doing whilst waiting for the American research to come up with the ‘goods’? I think there is. The value of any DNA testing is to use it on the breeding stock, these, after all, are the source of future generations. It is their genetic status that needs to be known. For a long time now I have felt that breed clubs would benefit by generating blood banks of all of their breeding stock. These blood samples would represent DNA archives of those dogs that have contributed to the development of a breed. If the Tervueren had such a bank of DNAs, these would be the first to be tested with any new DNA test. Since these are the parents of future generations, knowing what each dog’s individual genetic status is will identify those offspring who need to be tested. For example, if a litter has been produced from two genetically clear parents, their progeny will not need to be tested because they will also be genetically clear. Generating such a bank of blood is not amazingly difficult. All you would need is approximately 5ml of blood collected into a special tube that contains chemicals that prevent blood clotting and then stored in a simple domestic freezer. Tervueren breeders could easily begin collecting and storing bloods from dogs that have produced litters. Obviously, the availability of these DNAs will be very helpful for the epilepsy problem when a DNA test does become available, but the store will represent a true DNA archive that will be invaluable for identifying genes that cause other inherited diseases in the Tervueren.

WHAT CAN YOU DO TO HELP?

The Northern Belgian Shepherd Dog Club and the Belgian Shepherd Dog Association of Great Britain feel that now is the time to start archiving blood samples. The priority is to archive blood from families of dogs who have epileptic and non-epileptic members, preferably including at least parents and offspring. However other blood samples would be useful once markers are produced for other hereditary conditions. If you are interested in participating in this please send a copy of each dog's pedigree and whether or not it has been diagnosed as epileptic. If breeders can co-ordinate this information for whole litters or a more extensive family that would be preferable. An information pack will then be sent out with details of exactly how the blood should be collected and how to deliver it to a central storage point. It is possible that the owners own vet will take such a sample free of charge, if the storage tubes etc are provided and if it is explained that this is for genetic analysis under the auspices of the KC and Animal Health Trust. If sufficient dogs are identified it may be possible to arrange for a vet to collect samples at a show or other club event. Send information to Dr M.K. Pratten, Concord, 145, Belper Road, Stanley Common, Ilkeston, Derbyshire DE7 6FT e mail [email protected].

[blackdog]

And in reply to Lablover and her recommendation that breeders ask whether stud dogs have been EIC tested?

Nice sentiment but what if they're not tested - which dogs are you going to use?

Would a top class stud dog that has not been EIC tested be automatically excluded from a breeding programme?

Excluded no - but pedigree highly researched (as we do whatever the concern).

If I were to use an untested high quality prepotent stud, I would test puppies before placement. If any carriers and the dam is clear/normal, obviously the stud is at least a carrier. If all pups carriers I would assume the high probability stud is affected.

May I throw a question back, do you feel bench quality has deteriorated since the PRA test?

Interesting question - I don't look at something called "bench quality" BTW.

I look at something called breed type and in this regard the short answer to your question is no - IMHO.

But there would be lots of other reasons for Variation (not deterioration) in type which does seem to be a more prevalent thing.

What does appear to be happening is the increased incidence of frozen AI litters and these outcross sires are having an effect on type.

But that would be as expected - nobody should expect any outcross to immediately click with every bitch.

But in response to the question I think you were asking which I read as:

"Is breed type suffering because breeders are insisting on always using PRA clear sires and dams".

Again my short answer is no - there are significant numbers of clear sires available for this not to be an issue.

[sandgrubber]

Thank you for the info. As it is easy to test for and relatively easy to get out of your breeding program I will test all 8 of my dogs and takes steps over the next couple to generations to ensure I breed EIC clear pups. I still have doubts about the whole thing but better to get onto it now before it becomes a requirement in the future. Fingers crossed the news isn`t too bad! Thanks again for your comments and info. Kel.

Just curious, have you ever seen a dog with EIC? I haven't.

With -- based on the statistics Sylvia posted -- 50% of dogs being carriers or affected, you may have to do some serious culling to end out with entirely clear stock. Personally, I think most of us have other faults to work on that are higher on list of priorities than a condition most of us have never seen manifested -- even if our dogs are affected.

I hope the day comes when we can submit one swab and get the whole battery of genetic tests . . . hopefully to include HD/OCD factors, epilepsy factors, overshot jaw, colours, and mismark genes along with PRA. Until there's a good, reasonably priced, integrated genetic testing program, I don't want to get sucked into doing every new test that comes along.

Edited November 19, 2009 by sandgrubber

[Lablover]

And in reply to Lablover and her recommendation that breeders ask whether stud dogs have been EIC tested?

Nice sentiment but what if they're not tested - which dogs are you going to use?

Would a top class stud dog that has not been EIC tested be automatically excluded from a breeding programme?

Excluded no - but pedigree highly researched (as we do whatever the concern).

If I were to use an untested high quality prepotent stud, I would test puppies before placement. If any carriers and the dam is clear/normal, obviously the stud is at least a carrier. If all pups carriers I would assume the high probability stud is affected.

May I throw a question back, do you feel bench quality has deteriorated since the PRA test?

Interesting question - I don't look at something called "bench quality" BTW.

I look at something called breed type and in this regard the short answer to your question is no - IMHO.

But there would be lots of other reasons for Variation (not deterioration) in type which does seem to be a more prevalent thing.

What does appear to be happening is the increased incidence of frozen AI litters and these outcross sires are having an effect on type.

But that would be as expected - nobody should expect any outcross to immediately click with every bitch.

But in response to the question I think you were asking which I read as:

"Is breed type suffering because breeders are insisting on always using PRA clear sires and dams".

Again my short answer is no - there are significant numbers of clear sires available for this not to be an issue.

Sorry for the incorrect wording. No matter, I hope.

When looking into EIC (some referred to it as heat stroke or a form of epilepsy), years ago, I thought Australia was relatively safe (but had heard otherwise). While discussing with a canine geneticist, a very nice man, he replied "you have an island mentality".

At the time I was looking at working pedigrees, and was floored when EIC was discovered in show lines, in America, Canada and UK, where the breed split DECADES ago.

When we look at large labrador populations in other countries, where they have been breeding around diseases since the development of DNA tests, PRA, CNM, RD and EIC, I cannot help noticing other lesser problematic diseases, CCL tears being one example becoming more common.

BTW, a test for CCL disease is expected sooner than later. October 2010.

I like DNA tests. We live in exciting times.

Edited November 20, 2009 by Lablover

[Lablover]

With -- based on the statistics Sylvia posted -- 50% of dogs being carriers or affected,

Not speaking for Sylvia, but she typed 60% carrier, which should mathematically translate to 8% affected, but the latest figures showa higher total in Australia.

Some say, PRA was/is a "hiccup" in comparison.

Closed gene pools are a bitch.

[gundoglover]

Sandgrubber,

I agree - eliminating all carriers would have profound consequences for the breed. If it were my breed, I would test to eliminate not carriers, but carrier x carrier matings.

[sandgrubber]

With -- based on the statistics Sylvia posted -- 50% of dogs being carriers or affected,

Not speaking for Sylvia, but she typed 60% carrier, which should mathematically translate to 8% affected, but the latest figures showa higher total in Australia.

Sylvia's numbers:

(700 affected +2595 carriers) /6959 total =47% affected or carriers

. . . but 40% or 60%, the point is the gene is widespread and the decision to breed it out will mean dropping a lot of dogs from the gene pool.

[blackdog]

And in reply to Lablover and her recommendation that breeders ask whether stud dogs have been EIC tested?

Nice sentiment but what if they're not tested - which dogs are you going to use?

Would a top class stud dog that has not been EIC tested be automatically excluded from a breeding programme?

Excluded no - but pedigree highly researched (as we do whatever the concern).

If I were to use an untested high quality prepotent stud, I would test puppies before placement. If any carriers and the dam is clear/normal, obviously the stud is at least a carrier. If all pups carriers I would assume the high probability stud is affected.

May I throw a question back, do you feel bench quality has deteriorated since the PRA test?

Interesting question - I don't look at something called "bench quality" BTW.

I look at something called breed type and in this regard the short answer to your question is no - IMHO.

But there would be lots of other reasons for Variation (not deterioration) in type which does seem to be a more prevalent thing.

What does appear to be happening is the increased incidence of frozen AI litters and these outcross sires are having an effect on type.

But that would be as expected - nobody should expect any outcross to immediately click with every bitch.

But in response to the question I think you were asking which I read as:

"Is breed type suffering because breeders are insisting on always using PRA clear sires and dams".

Again my short answer is no - there are significant numbers of clear sires available for this not to be an issue.

Sorry for the incorrect wording. No matter, I hope.

When looking into EIC (some referred to it as heat stroke or a form of epilepsy), years ago, I thought Australia was relatively safe (but had heard otherwise). While discussing with a canine geneticist, a very nice man, he replied "you have an island mentality".

At the time I was looking at working pedigrees, and was floored when EIC was discovered in show lines, in America, Canada and UK, where the breed split DECADES ago.

When we look at large labrador populations in other countries, where they have been breeding around diseases since the development of DNA tests, PRA, CNM, RD and EIC, I cannot help noticing other lesser problematic diseases, CCL tears being one example becoming more common.

BTW, a test for CCL disease is expected sooner than later. October 2010.

I like DNA tests. We live in exciting times.

No drama re your wording at all Lablover.

I too "like" DNA testing but only for defects that are widely recognised in our breed.

Beware the trap that many of our American comrades seem to have fallen into.

In their resolve to be seen as "responsible" breeders they now seem to test for everything.

But IMO it is fair to suggest that type has, in many instances, been lost.

A similar issue seems to be manifesting itself in Sweden - on paper at least the soundest labs in the world but......

In the immortal words of "Black Mary" (Mary Roslin-Williams : Mansergh Labradors UK):

A Labrador Should Look Like A Labrador And Nothing Else.

[zenchel]

With -- based on the statistics Sylvia posted -- 50% of dogs being carriers or affected,

Not speaking for Sylvia, but she typed 60% carrier, which should mathematically translate to 8% affected, but the latest figures showa higher total in Australia.

Sylvia's numbers:

(700 affected +2595 carriers) /6959 total =47% affected or carriers

. . . but 40% or 60%, the point is the gene is widespread and the decision to breed it out will mean dropping a lot of dogs from the gene pool.

Hells bells - serves me right for quoting from memory. I have found the email (dated Sep 1) with the Aus numbers in it:

98 tested

51 carriers 52%

23 affected 24%

24 clear 24%

BUT - remember these are really skewed as there has been an influx of presumed DNA affecteds (ie dogs that have collapsed) and their relatives and also it is a really small sample. The figures from U Minn are much closer to the mark.

Yes, SG I have seen dogs collapse with EIC. I had a bitch collapse several times in the mid nineties; try as I might I couldn't get to the bottom of what was going on. I sent blood to Susan Taylor for the original research, however was told my bitch can't have had EIC as they were working with US field trial lines and my bitch's pedigree was so far removed from those as to be of no use. Rather unscientific I thought, but there you go.

Having been cleared from all known genetic issues at the time, that bitch had three litters; there has been no report of collapsing dogs amongst her offspring, however her daughter came back DNA affected (as of course did she). They are boarding with me at the moment - the collapsing bitch turns 15 next January.

We now know what her issue was, however I concur with SG and BlackDog's concerns re making rash decisions based on the EIC DNA test. For me, PRA is almost a non issue now - yes, there are still a few carriers around and I would certainly use them if I thought they were the best choice, assuming the partner was clear. In fact I have a carrier bitch (daughter of my Master Mariner son Pete, who was a carrier) who I'm waiting to mate next season. She's also an EIC carrier, which is making life interesting

Sylvia