Copper

 Fact – not Fiction ! 

 

 

Copper and Bedlingtons 
Bedlington terriers are by and large a healthy, long living breed. Those of us who are devoted to this breed know, though, to our cost that we have a problem called Copper Toxicosis (CT). Bedlington breeders have worked very hard to get rid of this problem, been very open about it, and so it is often thought of as “only” a Bedlington disease. However, more than twenty other breeds and some cross breeds have been reported to have CT so it is not just a Bedlington problem.

So..what is copper toxicosis?

Early Research.

(the figures in brackets refer to references you can read to learn more)
In the 1970s a lady called Marianna Padula in America reported that she had a number of Bedlingtons, particularly bitches, become ill with a mysterious liver disease, some of them died (1). She wrote that those which became ill had had something happen to them which caused them upset (stress), for example having puppies, moving house or being shown a great deal. She asked for help from some Veterinary scientists who investigated some of the dogs which died. They found that they all had a lot of copper in their livers (2) which had poisoned the liver, caused a problem called cirrhosis and/or a sudden onset liver crisis which killed the dogs.
Other scientists started looking at the Bedlington problem and found some dogs which became very, very, ill at about 2 to 4 years old and died. They also had a lot of copper in their livers and very characteristic changes in their liver cells.(2 and 3) 
Next they took liver samples (a biopsy) from dogs which seemed to be healthy and found that many of these also had a lot of copper in their livers and from very little to a lot of liver cell damage. 
In other biopsies of Bedlingtons they did not find any copper or liver damage.
All the dogs which had a lot of copper were called “affecteds” and those which did not were called “biopsied normal” or “normal”.
In 1980 some scientists (4) mated a Bedlington they knew was “affected” (because it had been biopsied and found to have a high copper value and liver cell changes) to a Wire Fox Terrier (WFT), which they believed would not have the problem. They wanted to know if the Bedlington liver problem was inherited. They mated two of the cross Bedlington X WFT puppies together and then biopsied the puppies born from these cross breeds. They found that some had high copper when biopsied and others did not. They came to the conclusion that what had become known as Copper Toxicosis in Bedlingtons was inherited as a “recessive” gene (see below, genetics). They believed that a single “gene” (the unit of inheritance) had changed from the working “good” form to a non-working “bad” form. Only in dogs which had two “bad genes” would there be a lot of copper in the livers. They believed all dogs with a lot of copper, even though they were not ill when biopsied, would later become ill and die, either suddenly at between 2 and 4 years of age in complete liver failure, or more slowly of a “chronic” form of CT from 7 or 8 years old onwards.

What do we know now?
1. A high percentage of UK Bedlingtons biopsied in the 1980s and early 1990s (14) had greater than normal amounts of copper in their livers.
2. Of these we know a small but significant number died, between the ages of 2 and 4, from liver failure associated with copper poisoning, true cases of copper toxicosis.

3. As the surviving biopsied dogs which had had high liver copper levels and other signs which led to them being called “affecteds” reached old age, it became obvious that excess liver copper had neither killed them nor made them ill (as far as the owner could observe). They retained copper but it did not damage them enough to make them visibly ill or kill them, these could be called “copper retainers”.
Significantly, many had not had the recommended medication which removes copper from the liver (5,6). 
4. Of the Bedlingtons which have died of CT some have had less copper in their livers than those who have “lived with” much greater levels of excess liver copper.

So we can conclude that excess liver copper is not necessarily a death sentence even without medication and perhaps a great deal of misunderstanding and worry could have been avoided if dogs with high liver copper but NO SYMPTOMS OF ILLNESS had been called “copper retainers” and ONLY dogs which were ill &/or died of liver failure, due to poisoning by their liver copper, had been called “Copper Toxicosis cases”.

What symptoms would suggest further investigation for possible CT?
1. Excessive thirst.
2. Swollen abdomen.
3. Loss of appetite.
4. Yellow eye balls.
5. Yellow or very pale gums/mouth.
6. Lethargy.
7. Depression.
8. Weight loss, with or without swollen abdomen
9. Behavioral changes, such as aggression, convulsions and standing staring as if in a trance.
10. Sickness and/or diarrhoea (not just an occasional “off day” but severe and not clearing up) 
These are some of the symptoms regularly reported by owners of Bedlingtons who are sick as a result of copper poisoning their livers (true copper toxicosis). It is vitally important that if your dog shows some of these symptoms and appears quite ill, but you have been told your dog/bitch is “clear” or a carrier that you do not tell your Vet. “It can’t be copper toxicosis because mine is 1:2 (or 1:1)” because 1:1s or 1:2s CAN have CT and the same can apply to one or no deletion dogs. (see below for more details) and any delay in diagnosis and treatment can be fatal.

What can I do if my dog is unlucky and is a Cu retainer or develops CT?
First, do not panic! Many copper retaining dogs do not ever become visibly ill and live to a ripe old age even though they have very large amounts of copper in their livers.
Secondly, if your dog shows signs of liver failure and CT is diagnosed, modern veterinary care and knowing what is wrong with the dog early in the disease means intensive care will sometimes pull the dog through a liver crisis.

Thirdly, there are drugs available to remove the copper. Removing the copper stops the liver being damaged further and there is some reported evidence that once the liver is de-coppered some dogs do not build it up again (7.)
Penicillamine is one drug used to remove copper from affecteds. This can have side effects which is why many dogs have been taken off it after a short trial. Owners opted for “a short life but a happy one”… but thankfully in many cases the dogs went on to live normal lives and to a ripe old age.
To minimize any side effects the drug dose can be split up into smaller doses, trial and error is needed. Once the copper is well down a Zinc compound may be substituted for the penicillamine.
It can take about 2 years for very copper loaded livers to reach a “safe” copper level.

How can I tell if my dog actually has excess copper and, if so, if damage has been done to the liver?
Many Bedlingtons with a lot of copper in their livers seem to cope with it and lead normal lives and live to a ripe old age.
If your dog is ill a blood test would show up any signs of liver failure.
If the blood tests show the liver is struggling then you would need to follow up with a liver biopsy as this is the only completely sure way to tell if a dog has excess copper in its liver and how significant the damage to the liver is (13)
By definition an “affected” Bedlington Terrier is one that has excess copper in its liver (>400?g/g dry weight); furthermore the copper must occur in particular regions of the liver, together with characteristic changes in the liver cells and liver structure- such changes are absolutely diagnostic and can not be confused with any other liver disease .(8) A liver biopsy would also tell you if the liver was being damaged by another disease such as Cushing’s syndrome, when there would not be the same kind of liver damage as found in CT cases.

NB An affected MAY be a 2:2, but a 2:2 is not necessarily an affected, some are clear, some are carriers and to treat a 2:2 for CT without an actual diagnosis by biopsy could harm the dog unnecessarily.

Genetics.

Genes are areas of DNA which control every part of how the dog is put together and how the dog “works”. Each characteristic of a dog has one pair, or many pairs of genes controlling it. An example of a simple single gene action would be the coat colour of dogs.

There are two coat colour genes, a gene pair, which controls whether a dog will be black or brown.
A black dog can have two black genes, or one gene for black and one for brown.

A brown dog will have two brown producing genes.

In Bedlingtons the basic black/brown coat colour has other gene pairs which produce silvering, control the dilution of the basic colour and so on, so the “blue” coat colour is controlled by several genes working together. Most inherited characteristics involve many genes working together, but always each gene has a partner, which form a gene pair.

If, as has been assumed, only one gene is involved in copper being retained in Bedlingtons’ livers then in each Bedlington there will be a pair of genes controlling whether or not it will retain copper in its liver. The two genes will be on two chromosomes which are made up of paired genes and “between gene” DNA.

The genes are made of DNA and between the genes there is DNA, the purpose of which is not yet fully understood.

We could use the letter capital “C” to represent a copper-controlling gene. This is sometimes faulty “bad” and therefore does not give the proper instructions, but if the partner is a “good”, working, gene the animal will be able to deal with its copper normally.

A “clear” (homozygous normal) dog would have two good genes “CC” (think “capital C capital C”) an affected dog has two “bad” genes, (think “small c small c”) “cc” and a carrier one good “C”(capital C) and one bad “c” (small c).

The C04107 DNA test uses a marker within a gene thought to be involved in causing copper retention.

There are two types of marker, a “1” type and “2” type.

Each dog has a gene pair. Each dog has a marker pair.

It was decided that there was one pair of genes which would lead to a dog developing CT if the dog had two non-working forms of the gene (4). The “non-working form of the gene” has been shortened to “bad gene” for convenience and similarly the working form of the gene has been called a “good gene”. Hence an affected dog would have two bad genes making up the pair, a carrier a good and a bad form and a non-carrier (or “clear” as it is often referred to) would have two good forms of the gene.
Usually the non-working changed form of a gene such as this is called a “recessive gene” and the working, usually the so called “wild type”, original or normal form is a “dominant gene”. (If a dominant gene becomes “bad” it is easily got rid of because it always shows its effect)
Dominant genes are bossy, if there is one in the gene pair it insists on the cell doing things its way and only if two of the recessive genes occur together do they get their own way and stop the animal working properly in some way.
When reproductive cells (eggs and sperm) are produced, only one of the gene pair gets into each egg in a bitch or each sperm in a dog. For example a dog which has one good and one bad gene will produce sperm which have either a good OR a bad form of the gene in them. When a mating occurs any egg will also only have one form of the gene until the sperm joins with it and we are back to having a gene pair.
If two bad genes are present in the Dam and Sire (i.e. they are “affecteds”) then all their eggs or sperm and thus all their offspring will have “bad” genes and all the offspring will retain copper.
If both Sire and Dam have only “good” genes (are “clear”) then all reproductive cells (eggs and sperm) will contain a “good” gene copy and thus the puppies they produce will all have two “good” genes and the offspring will not retain copper.
If a dog or bitch has one “good” and one “bad” gene then it is called a carrier and about 50% of eggs or sperm will have a “good” gene and 50% a “bad” gene and on average over a large number of puppies about 25% will inherit 2 “good genes”, about 2%% will inherit 2 “bad genes” and about 50% will be carriers..ie have a “good” and a “bad” gene, thus about 75% of any puppies will not retain copper.
To work out the possible results of any mating a “Punnet square” is used, this is explained in most good dog breeding books. Obviously the most desirable mating is between two “clears”, followed by a carrier and a “clear”. A carrier mated to a carrier is not desirable and a carrier mated to an affected is not at all desirable as about 50% of the puppies will be affected. Obviously mating two affecteds is highly undesirable.

How can I know my dog’s genotype, ie if it is a non-carrier, a carrier or an affected?

1.Biopsy

……..this will identify an affected dog and thus the genotype of that dog, as it MUST have two “bad” genes (cc if using a Punnet square) otherwise it would not be affected!
Biopsy can identify non-affected dogs but cannot distinguish between carriers (Cc) and non-carriers (CC) except when used alongside pedigree analysis and/or carefully controlled test –breeding. So biopsy is not a “perfect” test, but it is still the only way of knowing for sure if a dog has a lot of copper in its liver.

2. The linked marker DNA test. .

Scientists were aware that having to have dogs operated on to obtain the specimen for analysis was not an ideal situation.
In the 1990s a group of scientists in the USA investigated what are called “DNA markers” as a possible way of eventually removing the need to biopsy. 
They obtained samples from a lot of Bedlingtons which had been biopsied and some which they could also know something about the genotype of because of their breeding. An example of this would be that all puppies of an affected dog must be at least carriers. They then looked for a DNA marker. They needed a marker with two types, usually different length pieces of DNA. Each such marker which seemed promising was investigated using the biopsied dogs and their pedigrees. If the marker seemed to track through the pedigree alongside known good and bad genes then it would probably be a useful one (complicated mathematics were used to help decide if the marker was useful or not.). It could have taken years and years to find a useful marker, but they were lucky and found one quite quickly (9). They set up a testing service under the name “VETGEN”. The marker used was “C04107”
The marker found was not perfect as the two forms were not always inherited with either a good or a bad gene so it is not a DNA marker, it is a DNA LINKED marker. 
The two forms of the marker were called “1” and “2”, though it could have been anything, e.g. “a” and “b”. What they found on the pedigrees they looked at were the following combinations of “good” and “bad” genes with the two marker types, as worked out by using the biopsy results for many animals in each pedigree used.

1:1 and two bad genes (affected)
1:1 and a good and a bad gene (a carrier)
1:1 and two good genes ( a “clear”, or non-carrier)

1:2 and two bad genes (affected)
1:2 and a good and a bad gene (a carrier)
1:2 and two good genes (a “clear”, or non-carrier)

2:2 and two bad genes (affected)
2:2 and a good and a bed gene (a carrier)
2:2 and two good genes. (a “clear”, or non-carrier)

They then applied some complicated mathematics to what they found and it was shown that the 1 marker was most often found linked to a “good” gene and the “2” marker was most often found linked to a bad gene but NOT ALWAYS.(9)

If one has a biopsied affected dog, it must have two bad genes. Therefore, if its DNA markers are 1:1 then both are linked to bad genes, both “1”s are bad gene linked. 
If it is 1:2 then this dog has a 1 and a 2 marker linked to bad genes.
If it is a 2:2 then this dog has both 2 markers linked to bad genes. 
Exactly the same applies to carriers and clears, they can be 1:1, 1:2 or 2:2.

Vetgen recognized the limitations of their test and urged breeders and owners to continue to biopsy, especially to uncover the “1” markers which were “bad” gene linked, (ie. “1” markers where if two were found in one dog the dog would retain copper to excess in its liver and the dog would thus be an “affected”).

As more information built up on dogs with UNQUESTIONABLY KNOWN genotypes, the biopsied affected dogs and almost certainly known “clears” i.e. biopsied normal dogs which had also been carefully test bred to try to work out if they were carriers or non-carriers (clear), it looked possible to GUESS what the numbers meant with a reasonable degree of accuracy. 
The AHT in the UK began to use Vetgens test and looked at a sample of about 40 British Bedlingtons where some had biopsy results and some they believed they knew the genotype of because they had been test-bred. It looked as if when the good/bad :1/2 linkage was GUESSED then based on this small sample the guess was about 95% likely to be right.(10)
However, later surveys of dogs which have enough biopsy information to unequivocally show what their DNA marker linkage is suggest a much greater chance of “guessing wrongly”. The revised statistics indicate that the likelihood of WRONGLY GUESSING the linkage in the absence of biopsy information is in the region of 20%, this means about 1 in 5 of dogs with “guessed” linkages will have been WRONGLY identified as carrier, clear or affected. (5,6,8, Vetgen statistics sheets)

(Some people have tried to cast doubt on biopsy results when what they believe are “strange” DNA results have turned up e.g. an affected dog with a 1:2 marker type. However, if biopsy is claimed to be inaccurate then the DNA test, since it was “discovered” by looking at biopsy results would cease to exist as a viable test, test matings would have to be discounted and so on .
There is a more detailed explanation and advice on using marker information on the VETGEN web site, the organization which discovered and developed the linked marker test, at www.vetgen.com)

If there is biopsy and test breeding information a breeder will have a very useful DNA tool to work out the C04107 marker genotypes of their breeding dogs and bitches and their subsequent offspring. If there is no biopsy or biopsy based breeding information then the breeder can make educated guesses, but they could be wrong for at least 1 in every 5 dogs.
SO..the linked marker test, though very, very, useful, is also NOT PERFECT.

3. The “deletion test” (COMMD1)

A group of scientists in Utrecht discovered that a gene (COMMD1 formerly known as MURR1) (11), which they believed to be involved with copper processing in dogs, had a large piece missing in some Bedlingtons, this is called a “deletion mutation”, shortened to “a deletion”. In the UK a commercial organization attempted to produce a test based on this “deletion”. At first it seemed to “work” and a seminar was held at which the “test” was launched but later the test was withdrawn and none of us were given our money back! Sadly any certificates issued must be ignored, they are not valid. More recently, however, a number of organisations can carry out “deletion testing” with reliable results as to the presence or absence of the deletion. When claims are made by scientists that the deletion test is reliable/accurate it must be born in mind that what they are claiming is that the test will show the presence or absence of the deletion reliably/accurately..this is quite different from claiming that the deletion test can always accurately show the presence or absence of CT in the dog being tested. There are problems with the deletion test as further described below.

Several groups of scientists (12, 15, Vetgen personal communication) have reported that the COMMD1 deletion test does not identify the liver copper status (phenotype) of ALL dogs correctly. When the deletion test was about to be released in the UK at my suggestion the Health Group requested that a “blind study” be done. This involved a number of dogs whose genotype and phenotype were UNEQUIVOCALLY known being sent for deletion testing without the testers knowing anything at all about the dogs. Because I and two friends supplied some of the dogs and compiled a list of a number of others which were useful, (eg 1:2s known to be affected by biopsy, offspring of 1:1 affecteds which MUST therefore be carriers of something which causes CT), I am aware that of the 18 dogs tested at least 8 were wrongly assigned a phenotype or genotype by the deletion test in the blind study.

Nowhere in the world where deletion tests have been carried out, eg Australia, UK, Scandinavia, Canada and the USA has there ever been a 1:1 with any deletions. Therefore it is a waste of money to test 1:1s. A significant number of 1:2s have been uncovered which have NO deletions and some 2:2s tested have only one or no deletions. A group researching CT in Australia produced a paper “Evaluation of haplotypes associated with copper toxicosis in Bedlington Terriers in Australia” (AJRV, vol 65, No 11, November 2004) in which they state “the deletion of exon 2 was not the sole cause of copper toxicosis”. To be a bit technical for a moment exon 2 is one of three exons found within the normal form of the gene COMMD1 and the deletion test looks for exon 2 to be missing from the gene. Genes are made up of exons…bits of DNA which have a known function, and introns, bits of DNA between the exons whose function is not yet understood. The “numbers” C04107 marker is found in the intron between exon 1 and exon 2 in the normal gene, The deletion test will identify some “good” 2s which is helpful, but if you have 1s in dogs which are IN FACT affecteds these dogs will be wrongly “diagnosed” as not affected even though we know with certainty that the 1:1 or 1:2 no deletion dog or 1:2 one deletion dog IS affected!!!.

SO the deletion test, though again very, very, helpful is far from PERFECT.

 

Towards a 100% accurate test.

So, what is the current state of affairs?

We know that none of the three tests discussed is perfect. We know only a biopsy specimen taken from the liver can tell us with certainty whether a dog has excess copper and characteristic structural changes in its liver or not. We know guessing what “numbers” or deletions” appear to tell us aboout a dogs liver is not always correct. We know some dogs which are eg 1:1 and have no deletions have EXCESS COPPER AND LIVER DAMAGE and can become seriously ill with CT. Therefore it must be concluded that a second gene (at least) is involved in CT/copper retention. When I wrote my Masters thesis in the early 1990s I stated that I believed more than one gene must be involved, for a variety of reasons. Since the DNA tests have emerged others are now saying the same thing and at least two groups of researchers are actively trying to find the “other genetic factor” which leads to a Bedlington having actual CT or excessive copper in its liver (which it somehow manages to cope with and so it does not become observably ill.)

MY PERSONAL EXPERIENCE.

Before the C04107 numbers test came out I had bred from a bitch I bought in. When the “numbers” test was first announced by the Vetgen people I sent samples from large numbers of my dogs to them in America for testing. Because I had many biopsy results I was given a chart showing what the “numbers” linkage was for many of my dogs and how the linkage was worked out. The bitch, I was told, because Vetgen did not have a sample of an affected close to her in her pedigree, could not have her “numbers” linkage worked out, but she was a 1:2. Like everyone else I “guessed” that she was “only a carrier”. This bitch had produced a 1:2 which in turn had a litter which included a 1:2 daughter. When I heard that this young bitch was ill of suspected CT I contacted the owner. The symptoms sounded like CT. I paid for a biopsy and we discovered that she was indeed affected and she subsequently died of CT. I sought advice from Dr Jeff Sampson and Nigel Holmes who were both at that time at AHT. While I was doing my Masters degree I spent time in Jeff Sampsons lab when he was still at Leicester University and also with Nigel in his lab at the AHT. Jeff was also the external examiner for my Masters, so I felt I could go to them for help. I flew down to AHT and had lengthy discussions which concluded that, given all the available biopsy and DNA numbers information I had, the Dam of the dead youngster, although also a 1:2 must be affected. I had this Dam, pet name Solo, biopsied and she was affected with a copper level almost 2000 ppm dry matter…no doubt at all that she was indeed affected. This was a terrible blow to my breeding plans. I now had what appeared to be a “bad gene linked 1 marker” in my stock.

I then had to breed and biopsy to try to find out where in any of my dogs descended from “Grandma” the “bad 1” might be lurking. By using only 1:1s it could have taken a very long time to get two of the “bad 1s” in a puppy show up through a biopsy. Looking at the grandmother (Grandma) of the youngster which died it seemed she must have a “good 2”, as she herself was the ONLY possible source of the “bad 1”..but she was biopsied normal. To go into all the details would take far too long, but during all my efforts I nagged anyone I could find to seek help to find an answer to the question “how can I find any bad 1s”? Dr Jeff Sampson, Dr Susan Haywood and Bart van de Sluis were all very helpful. Dr Haywood was able to assure me she was getting similar cases from other blood lines..1:1s and 1:2s which became very ill and even died with CT. Before Bart van de Sluis published his thesis he carried out the deletion test on some of my dogs. Solo had only one deletion. A bitch bred the same way as Solo, also 1:2, had only one deletion and was BIOPSIED NORMAL. Disaster, yet another hopeful test was not of direct help to me! As my evidence grew it became very obvious that to talk of COMMD1 deletions as the cause of the CT in a few of my dogs could not be correct. I had examples of 1:2s, which were definitely AFFECTED but they only had one deletion, obviously they had one functioning form of COMMD1. They had one INTACT COMMD1 GENE THEREFORE THEY SHOULD BEHAVE AS NORMAL DOGS..AS CARRIERS DO, yet they ARE affected, therefore there MUST be a different gene causing CT in such dogs.

I have also for several years been helping Prof. Diane Cox who has tested many of my dogs for “numbers” and “deletions”. More recently I sent many (hair) samples to a Scandinavian lab and have now got results for another second C04107 marker..this did not help either. I have been able to construct haplotypes for some of my dogs, this still does not solve the problems.

Then I had a breakthrough, nagging Dr Jeff Sampson about the Australian paper among other things led to him suggesting I find a lab who would do a similar kind of study to that which had been done in Australia and get them to apply for a grant from the Kennel Club in the UK. I am now involved with the KC funded project led by Dr Susan Haywood which is investigating the existance of an “as yet unrecognised second mutant copper gene”.

I believe my results over the years offer proof to support the firm belief of a number of researchers that there is another gene..and furthermore it may be as proposed by one research group, that the as yet undiscovered gene is the MAIN cause of CT. Since 1 markers have never been shown to have the deletion in COMMD1 this deletion in this gene cannot be the cause of CT in 1:1 or 1:2 affecteds. Could it be that COMMD1 only modifies the undiscovered genes effect?

We must hope the present researches bring an answer which allows us to finally remove this problem from our breed, but we can also help as outlined below.

The role of breeders and owners.
Apart from the technological problems, progress towards a “perfect” test has also been hindered by breeders and owners. Information available to develop new tests is scanty for four main reasons.

Firstly, many dogs with high liver copper values often show no visible symptoms of CT during their lives, even if they are bred from, eventually die at a “normal” sort of age from other causes and thus may never be identified as copper retainers.

Secondly, many owners and breeders in the UK steadfastly refuse to even consider liver biopsy, thus unequivocally diagnosed affecteds and non-affecteds (carriers plus clears) are virtually impossible to find in the UK. Conscientious scientists cannot/will not work with dogs whose liver status has been “guesstimated” from C04107 numbers and/or deletion results alone, they require the liver biopsy information.

Thirdly, despite all advice and evidence to the contrary, many breeders and owners still have difficulty accepting the established fact that “1 :1″s and “1:2”s, no deletion and one deletion dogs have been unequivocally found with active Copper Toxicosis or are “affecteds” with high liver copper levels which are not actually making the dog ill but are causing characteristic changes to the stucture of the liver/liver cells.

Finally, those who have ONLY “guesstimated” interpretations of their dogs numbers have used only the 1:1s and occasionally 1:2s in the belief that all offspring are “safe”. Unfortunately with no biopsy results to back their belief they may well have had a 1:1 or 1:2 affected which has gone unrecognized because NOT ALL AFFECTEDS SHOW SIGNS OF ILLNESS at any time during their lives. When the deletion test started we knew NO 1:1s would have any deletions..but some 1:1s and 1:2s are never-the-less AFFECTEDS hence the additional information that the dog has no or only one deletion is still not PROOF POSITIVE that the dog in question is free from copper problems!!!!!, But still people refuse to biopsy even a sample of their stock and when an affected does surface as ill or dead the breeders appear to be in denial..”the biopsy must have been wrong”, “it must be something else” and “it must have been a virus” are examples of self delusional comments heard. As long as this situation persists obtaining the samples scientists need to make progress towards a conclusive DNA based test for CT will remain very difficult indeed. Luckily many in the USA and Canada and a very small number in the UK have heeded Vetgens’ advice and still continued to biopsy and are actively helping the various research projects under way.

As a consequence of the lack of biopsy information we simply do not know how many dogs there are in the breed today with high liver copper values.

How you can help..and what is being done to find the “final answer”?

To help build up the data required and biopsy material to develop and then validate potential CT tests Bedlington owners can do two things:-
1. If you are uncomfortable with having a biopsy on an apparently well dog/bitch please consider lodging a letter of intent with your Vet asking him or her to send an autopsy specimen, without further reference to you, for biopsy analysis if your beloved Bedlington has to be put to sleep for whatever reason. Then you do not have to think about this at a very difficult time. (Dr Susan Haywood , Liverpool, UK will analyse UK specimens free of charge.)

2. If you have ANY biopsied affected or biopsied normal dogs (whether 1:1, 1:2,or 2:2) and would donate cheek cell or blood samples please let me know so I can pass on your contact details to the research groups I am currently involved with. NO-ONE involved in the research, which includes myself, can or would divulge any information given by you without your permission in writing, it can be totally confidential. If, as has happened, the breeder does not want you to tell a Health Group/committee, that you have, eg a 1:1 no deletion dog which is affected, you do not have to agree to make the information public.

However, by now we should have a system for making all health related information public for the good of the breed, to identify possible new inherited problems before they become too widespread and to help to find the “final answer” for CT.

Thank you to all the people from the USA and Canada who have alredy let me put the research groups in contact with them and a very big thank you to Sheila Baldwin and Pam Morton in the UK, for samples, brain storming sessions, help and moral support!!!!.

 

References
1. Padula, M., (1974). A Breeders Experience with Liver Malfunctions. Spring Bulletin, Bedlington Terr. Club of America. 11-16.
Padula, M., (1973) Pure Bred Dogs. American Kennel Gazette (Nov) 89 76-77 
Padula, M., (1973) Pure Bred Dogs. American Kennel Gazette (Dec) 90 104-105
2. Hardy, R.M., Stevens, J.B. & Stowe, C.M. (1975). Chronic progressive hepatitis in Bedlington Terriers associated with elevated copper concentrations. Minnesota Veterinarian. 15 13-24
3. Hardy, R.M., Stevens, J.B. (1977). Chronic progressive hepatitis in Bedlington Terriers (Bedlington Liver Disease). Current Veterinary Therapy. VI. Small Animal Practice (ed. Kirk, R.W.), W.B.Sanders, Philadelphia. 995 – 998.
4. Johnson, G.F., Sternlieb, I., Twedt, D.C., Grushoff, P.S. & Schenberg, I.H. (1980). Inheritance of copper toxicosis in Bedlington Terriers. American Journal of Veterinary Research. 41 1865-1866.
5. Davies, S (1996) The Inheritance and Diagnosis of Copper Retention in the Bedlington Terrier. MPhil thesis, Univ.of Strathclyde.
6. Davies, S (2004) Copper toxicosis in Bedlington Terriers: a Breeders perspective. Vet.Times. 34. 20-21.
7. Nagy,J.A (1999) An Experience With Liver Disease, A Research Paper. Tassels and Tales
8. Haywood S, Fuentealba IC , Kemp SJ and Trafford J. (2001) Copper toxicosis in the Bedlington terrier: a diagnostic dilemma. Journal of Small Animal Practice; 42 181-185
9. Yuzbasiyan-Gurkan, V., Blanton, S.H., Cao, Y., Ferguson, P., Li, J., Venta,P.J., Brewer, G.J. (1997). Linkage of a micro satellite marker to the canine copper toxicosis locus in Bedlington Terriers. American Journal Veterinary Research. 58 23-27.
10. Holmes, N.G., Herrtage, M.E., Ryder, E.J., Binns, M.M. (1998) DNA marker C04107 for copper toxicosis in a population of Bedlington terriers in the United Kingdom. Vet. Record. April 4, 351-352.
11. Van de Sluis, B.J., Rothuizen, J., Pearson, P.l., van Oost, B.A., Wijmenga, C. Identification of a new copper metabolism gene by positional cloning in a pure bred dog population. (2002) Human Molecular Genetics.; 11 (2):165-173.
12. Coronado VA, Damaraju D, Kohijoki R and Cox D. (2003) New haplotypes in the Bedlington Terrier indicate complexity in copper toxicosis” Mammalian Genome (July); 14 (7) :483- 491.
13. Haywood S, Statement prepared for the BTHealth Group.
14. Herrtage, M.E., Seymour, C.A., White, R.A.S., Small, G.M., Wight, D.G.D. (1987) Inherited Copper Toxicosis in the Bedlington terrier: the prevalence in asymptomatic dogs. Journal of Small Animal Practice. 28 1141 – 1151.

15.A.J.A.van de Sluis. Identification of a copper toxicosis gene in Bedlington terriers. PhD thesis, University of Utrecht,

Useful Information.

1.VETGEN in the USA carry out DNA linked marker testing and deletion testing, You ideally need both results to keep tracking through pedigrees. You can get details from their web-site or, for test kits in the UK phone Susan Santoriello at 01234 851647. Credit card payment is possible, which means no charges for foreign currency cheques, or, you can get dollar travellers cheques free from many travel agents. Their website www.vetgen.com has some useful information pages. 
2. The Animal Health Trust here in the UK carry out deletion testing but it is more expensive and in my experience a slower service than Vetgen’s. Obtain kits by phoning 01638 751000.
3. University of Liverpool. Carry out testing of biopsy and autopsy specimens for copper and histology, “a biopsy”. They also give advice to Vets on obtaining biopsy specimens from the liver, treatment etc. Under the lead of Dr Susan Haywood Liverpool is currently involved in the search for the other genetic factor involved in CT. Dept. of Vet.Pathology, Faculty of Vet. Science, Univ.of Liverpool, L69 3BX or email Dr Haywood: shaywood@tiscali.co.uk 
4. There is an excellent pamphlet produced by the Kennel Club “From Dog to DNA. A Beginner’s Guide To Molecular Genetics of The Dog” written by Jeff Sampson and Diana Nicholson which gives an excellent, understandable explanation of all the various aspects of DNA testing and its application to dog breeding.

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Shirley Davies