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jcole711

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Reply with quote  #1 
I started my puppy search almost 4 months ago.... and am now trying to make sense of all of the health testing. I have searched online and on the board but haven't found the exact answer to my questions...

Correct me if I'm wrong here... a male cannot be a carrier for cystinuria - he either has it or he doesn't (because it's carried on the X chromosome?). If he has it he may or may not produce stones. So could his testing come up negative if he has it or there is no possible way? So if he has it and he is bred - is it a 50/50 chance that his puppies have it or which would have it - boys or girls or both or does he only pass it on his X so only his girls are carriers and his boys are fine? I'm confused... I'm sure how I asked it was confusing too.. :-)

A female can have it or be a carrier? If she is a carrier... can her cystinuria test still be negative? For her to have it, both parents would have to positive? Finally, how could a boy have it if both parents tested negative - or is that not possible? I'm so confused....

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Castlecreek

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Reply with quote  #2 
This may help you to understand. If you are looking fora  puppy best thing to do at this point is buy one that both parents have been cleared.
___________________________________________________________________
These observations raise many issues. Perhaps one of the most pressing is what are the implications of X-linked inheritance of cystinuria for breeding choices? In simple X-linked recessive inheritance, the gene involved is located on the X-chromosome, the X-chromosome being present in two copies (XX) in females and only one copy (XY) in males. In order for the disease to be exhibited in a female, both copies of the gene must be mutated. If a female has one mutant version and one normal version, she will NOT be affected, but on average will pass the mutant version of the gene to 1/2 of her. Such a female is referred to as a carrier (she appears normal clinically and by urine testing, but carries a hidden mutant version of the gene). A female with two normal alleles is normal, and cannot pass mutant alleles to her offspring. The terms affected, carrier, and normal female therefore refer to females with 2, 1 and 0 copies of the mutant allele, respectively. More importantly for this discussion, carrier females are indistinguishable from normal females. For X-linked genes, males come in two varieties, affected (with one mutant allele on their single X chromosome), and normal (with a normal allele on their single X chromosome).

Now let us consider the possible outcomes of different types of matings, assuming simple X-linked inheritance of the disease.

  • Normal female to normal male This type of mating will produce only normal offspring.
  • Carrier female to normal male - When a carrier female is bred to a normal male, the sons who receive their mothers mutant version of the gene, also referred to as the mutant allele, will have the disease, since their only copy of the gene is a mutant version. The sons who get her normal allele will be normal. Therefore, on average, 1/2 of the sons will be normal, and 1/2 will be affected. The daughters of the carrier female by normal male breeding will all get a normal allele from their normal father. They will get either a normal allele or a mutant allele from their mother. Therefore, while all of the daughters will be clinically normal, approximately 1/2 of them will be carrier females. There are two important issues to consider here.
    • The proportion 1/2 stated above is an average. Each offspring has a 50:50 chance of getting the mutant allele from the mother. Consequently, it is possible, by chance, that a carrier mother will not give her mutant allele to ANY of her offspring, particularly, if she does not produce many pups. (Think of tossing a coin for example three times and getting three heads in a row. You wouldnt be too surprised.) Consider a litter of six, containing three females. If, by chance, none of the three male puppies received a mutant allele from their carrier dam, this carrier female would not be recognized as a carrier because she did not produce any affected offspring, and her daughters would not be recognized as being at risk of being carriers themselves.
    • Since a carrier female is indistinguishable from a normal female, without any additional information, there is no way to know if the normal-appearing female is normal or a carrier. In the case of cystinuria, the only way to identify a carrier female is from knowledge of her parents or offspring. If a female had an affected parent, she is an obligate carrier, having only the possibility of getting a mutant allele from that parent. Or, if the female produced an affected offspring, that offspring had to get a mutant allele from the mother, making her a carrier. This emphasizes why family information is so important.
  • Normal female to affected male The normal female can only contribute normal alleles to her offspring, while the affected male contributes his only X chromosome, which carries the mutant allele, to all of his daughters, and contributes his Y chromosome to his sons. Therefore, all males produced from this type of mating will be normal and ALL females produced will be CARRIERS. Important issues here are:
    • Carrier and normal females are indistinguishable, so without additional information, it would not be possible to know if the normal-appearing female used for mating was normal or a carrier.
    • The daughters of an affected male are obligate carriers, because all daughters get their fathers only X chromosome, which has a mutant allele in an affected male. This is a case where additional information allows us to differentiate between normal and carrier females.
  • Affected female to normal male The affected female has only mutant alleles to contribute to her offspring, and the normal male has only normal alleles. Consequently, ALL male puppies are AFFECTED (they get their X chromosome from their mother), and ALL female offspring are CARRIERS. Remember that:
    • Due to anatomical differences, unlike affected males, affected females are much less likely to form stones that will cause clinical problems, and in the absence of urine testing, are very likely to be undetected.
  • Carrier female to affected male Here, the mother contributes either a mutant allele, or a normal allele, while the father has only a mutant allele to contribute. On average, 1/2 of the daughters will be affected and 1/2 will be carriers. Of the sons, on average, 1/2 will be affected and 1/2 will be normal. Therefore, on average, 1/2 of any litter will be affected. The important issues are:
    • As explained above, the 1/2 ratios are the average that would be seen from this type of mating. Within a single litter, the actual ratios will vary. Litters from this type of mating could range from containing no affected dogs to containing all affected dogs.
    • Affected females can be produced, even when a disease shows X-linked inheritance.
  • Affected female to affected male All offspring will be affected. In the case of cystinuria, they may not all form stones or develop clinical signs of the disease.
    • This is a good place to reiterate the additional complications present for cystinuria in particular. In the case of cystinuria, we know that there can be cystinuric dogs without uroliths, and that uroliths often form for the first time after a dog has been bred. For both of these cases, mutant alleles that are not detected in the parents are passed from parent to offspring.


 

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jcole711

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Reply with quote  #3 
Thanks Valerie!  That explained a lot!  Just to be sure I understand - a female can be a carrier but test negative because testing is currently only done by looking for cystine in the urine?  So if you have a female who is negative you should also check the results of the parents?  And if a male is negative there is no way he is passing it on?  Thanks again!



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Castlecreek

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Reply with quote  #4 
If it is possible to check results of parents and grand parents that would be very helpful for you.

Good Luck in your puppy search.

Be sure to share pictures when you get him/her.

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margelutz

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Reply with quote  #5 
And if a male is negative there is no way he is passing it on?  Thanks again!

HI :>)
Most of the time i just read this board :>)
I think this is my first time posting ,on it :>)

But i just had to say ,even tho, a Male comes back with a negative test .
Does not mean 100%  that he is negative .

Most of us feel a Male should be tested every year ,maybe till 5 yrs old .

And all Studs ,should be tested before ,a breeding ,if it hasn't been in that year .


Plus ,nothing in the testing or the X linked gene is 100% positive .

So we don't really know for sure ,how it  comes down the pike :>)


All we can do is test often ,and hope for the best :>)

But just an FYI ,it is not caused by any food , and once a dog tests Positive .
Its positive PERIOD !!


From others that came forward ,with it ,in their lines .
We have learned one test in a life time is not enough . Hopefully  UPENN
will find the DNA and we can stop this illness :>)

OK I'm back to Lurking :>)
Take care
Marge

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jcole711

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Reply with quote  #6 
Thanks for the info, Marge!  I wasn't sure if a negative for a male was definitive or not.  I have been kind of confused about this... but I think I'm starting to get it. :-)



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Jen
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margelutz

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Reply with quote  #7 

Today at 07:24 PM Reply #6


Thanks for the info, Marge!  I wasn't sure if a negative for a male was definitive or not.  I have been kind of confused about this... but I think I'm starting to get it. :-)


Hi Jen :>)
Well I think we are all confused ,on Cystinuria :>)
Since there are no real answers , and no one Person to give them :>)

All we can do is test :>) and make sure we are not breeding  Postive Dogs

Marge

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Reply with quote  #8 

Hi Marge.  Long time no talk.  I am just playing devil's advocate here.  I personally am of the belief that it is x-linked(from my own observations) and that the likelihood of false positive is high, but...... 
     There has been at least one prominent veterinarian publish an article stating that cystinuria in mastiffs is not the typical form seen in other breeds.  He also says that a diet high in chicken can lead to positive results in non-infected dogs.  It has been a bit since I read the info, so please don't ask where.  LOL  I could probably find it in a google search, but I believe it was published in the UK if I am remembering correctly.  I am sure that someone else here will remember it or know where to find it.  It may have even been published by one of the mastiff clubs, but don't hold me to that.  Since nothing is really known for sure, it may be a bit misleading to say that a male cannot have a false positive or that it is x-linked either one(despite my personal beliefs).  I guess when it comes to cystinuria, if a real flag is raised, it is best to proceed very cautiously!  I don't know that the opinions of any workers at UPENN are always worth a lot at this point though.  They have already proven themselves wrong more times than I can remember and they are at the mercy of breeders honestly giving them information.  Believe it or not, some breeders would intentionally muddy the waters and cause unnecessary delays/obstacles in proving inheritance to save their own dogs reputation.  I find it easier to put my trust in my own observations and that of others I know/trust.  UPENN's research/recommendations are only now catching up with the views a lot of breeders have had for a while.  The same thing happened with the fluffy coat.  Once breeders spoke up and started showing them the way, they only had to prove the theory, instead of figuring one out.  Left to their own or with info from biased/careless breeders, we might still be waiting for that very simple test.  I guess the point I am trying to make is that you should trust the people and pedigrees that have a history worth trusting in.  Anything else is simply more of a gamble than it needs to be.  Especially with the testing being so unreliable and a mode of inheritance still not proven.  I hope I am wrong, but with the information I have, the proof of inheritence will be a long time in coming because of some misinformation being given to the researchers.  After all, if the urine is not collected at the correct time(or even the correct dog), even a positive dog will test negative and cause any familial based testing to show no real pattern.  If there is a pattern established in some families and not in others(due to poor testing practices/unethical sampling/unreliable tests), verifiable proof of inheritence cannot be published. 

     Now, with all that said, I will say that I do share your beliefs.  I am just playing devil's advocate for the sake of more discussions on the topic.  I think there is a lot of misunderstanding with the subject due to many of the vagueries(SP?) above.  I know of at least 4 seperate occurences in which a finger was pointed in the wrong direction due to the misunderstanding of how all this works.  I will talk briefly about two fo them.  One was an innocent party being pointed at by a concerned breeder with only the best of intentions.  They were merely wrong in their assumptions.  The other was a fairly small breeder that probably carries the problem in their dogs, but has other breeders with potential issues also helping to muddy the waters, so not many are looking their way for it.  A truly bad situation in either respect.  One is a bad situation because some really magnificant/beneficial dogs were, at one time, being pointed at without just cause.  The other is either deplorable or willfull ignorance.  Either way, it caused some to miss out on breeding to some really high quality dogs and others to bring in a bad condition into their formerly healthy dogs.  A truly lose/lose situation for the community.  At least the one unintentionally and falsely accused was able to prove otherwise.  That will happen again though and the unscrupulous with something to gain from it, will continue to cloud things up as will simple ignorance.  JMO  


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margelutz

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Reply with quote  #9 
 intentions.  They were merely wrong in their assumptions.  The other was a fairly small breeder that probably carries the problem in their dogs, but has other breeders with potential issues also helping to muddy the waters, so not many are looking their way for it.  A truly bad situation in either respect.  One is a bad situation because some really magnificent/beneficial dogs were, at one time, being pointed at without just cause.  The other is either deplorable or willfull ignorance.  Either way, it caused some to miss out on breeding to some really high quality dogs and others to bring in a bad condition into their formerly healthy dogs.  A truly lose/lose situation for the community.  At least the one unintentionally and falsely accused was able to prove otherwise.  That will happen again though and the unscrupulous with something to gain from it, will continue to cloud things up as will simple ignorance.  JMO  

HI Chris :>)
Its always good to hear from you :>) 

Here is what i think ,for what its worth :>)  Since we know nothing for sure ,i feel the only thing ,for now we have the pee test :>)

And if it comes up POSITIVE , its a POSITIVE ,as i understand it , you can get false negatives ,but not False Positives ???

I'm not so sure its a Xlinked ,but what do i know :>)  I feel if its found in your lines ,or is in your line ,breed else where ,and don't double up ,and make sure the male ,has been tested at least 6 months before the breeding .


As for Your info ,i have heard the same thing :>) But hell we don't know on that either , It would be WONDERFUL ,to know something for sure :>)

I also feel we should  ask MCOA to , have more than one Lab investigating this .

I also feel ,that a Breeder that tested for C+ ,and it still came up in their lines ,should not be Ashamed ,BUT!!! If you breed with it and the breeder knows it . Then shame on them , If  anyone has a  Mastiff that has  come back positive ,then freeze the sperm ,till they find the DNA .

I think this is the worst genetic fault we have seen come down the pike .

It can cost the owners tons of money and the Dog a lot of pain ,if he is a stone former .

 As i said if a breeder has tested ,and it still came down the lines ,its not their ,fault . They did all they could do . But to breed knowing its in your lines ,I wouldn't say ,your doing this breed any favors :>)

I don't care how awesome they are ,

Hope to see you at Bucks?????
Marge

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Reply with quote  #10 
Cystinuria has been documented in over 60 breeds of dogs as well as cats & people...  It is a known genetic molecular disorder and in Mastiffs it is very complex as the cystine levels fluctuate...  With Newfies an affected C+ dog will always have an elevated cystine level, but with Mastiffs the levels often fluctuate with diet, dehydration... 

It is not that the NP Urine screening test is inaccurate, it is that the cystine levels fluctuate in Mastiffs.  It is not that a dog fed a high protein diet or supplements is a false positive.  A dog with an elevated cystine level is considered Cystinuria positive and a Cystinuria positive dog is at risk of developing cystine crystals/stones.

Anna
 
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Reply with quote  #11 

UPenn has always been absolutely WONDERFUL to work with and they have maintained a close relationship with the MCOA.  The researchers working on our Cystinuria Grant are highly respected in the research field and they are very passionate about finding answers.  Since their Grants on Mastiffs are through the CHF there is a very thorough and strong peer review process that takes place.  They have a contracted agreement which must follow strict protocol.  They have used state of the art modern DNA techniques such as SNP Chip analysis... UPenn is also an Ivy League University with modern equipment and they have an excellent track record of finding answers in genetics and other areas.

 

The UPenn Cystinuria Researchers also collaborate with other top research facilities in the USA and they follow both human and animal scientific & genetic studies around the world.  They have friendships and relationships with researchers at Broad/MIT, Cornell, NIH, etc that they can call on when needed.  They are among the best of the best without any doubt in my mind. 

 

Financially our Cystinuria study has been funded by the MCOA and other breed clubs along with individual donations which have been matched by the CHF.  In addition to this, the Penn Genomic Frontiers Institute (of the University of Pennsylvania) has also matched the funding to help finance whole genome studies.  I cannot begin to communicate what that means as far as dedication, commitment and financial backing goes.

 

Cystinuria in Mastiffs is COMPLEX and the researchers around the world have been trying to figure out complex diseases for many years.  When UPenn cracks the code so to speak, I'm sure it will be an extremely important breakthrough that the entire medical community will appreciate.

 

In my opinion we do not have any reason to blame UPenn for not finding answers for us by now.  They require blood and urine samples from families of dogs and the breeder, stud dog owner, and dog owner participation is limited.  Think about it, how many Mastiff breeders are there that have generations of Cystinuria tested Mastiffs.  Take it a step further how many are there that have generations of ADULT tested Mastiffs & require it of their puppy buyers?  Have you looked for Cystinuria clear stud dogs lately (at least 2 negative tests as adults at the time of the breeding)? Also consider that Cystinuria in Mastiffs is very complex.  Now we should turn this around and think it through a little harder. It is our responsibility as Mastiff breeders, stud dog owners and Mastiff owners in general to give UPenn the resources (blood & urine) and information they need to break the code and find the gene(s) that cause Cystinuria in Mastiffs.

 

PLEASE Cystinuria test your Mastiffs, especially as adults and repeat the test annually on your dogs used at stud or before each breeding.  If you can do it, test the brothers & the father of your bitches before they are bred.  If your dogs come up positive, send blood and urine on them and their close relatives...  If they form cystine crystals or stones, it is even more important to participate in the study.

 

UPenn needs help from the breeders to prove the mode of inheritance.  There are plenty of affected families to document if they will step forward and participate in the research.

 

In addition to trying to find the gene(s) that cause Cystinuria in Mastiffs, UPenn needs our help in understanding and to prove the mode of inheritance in our breed.  They are also looking into better diagnostic tools to help identify C+ dogs and possible preventative measures that might help reduce the risk of stone formation.  They are working hard to find the answers we need and I cannot imagine having a more qualified, dedicated and passionate group working for us. 

 

Besides participating in the UPenn Cystinuria Study, the MCOA is also encouraging everyone to send blood to OFA to be added to the CHIC DNA Repository.  This is especially important for our veterans.  A healthy veteran's DNA can be used in all research projects that require unaffected dogs.  If the dog has had a medical condition that is being researched, its DNA will be available when affected dog samples are needed....  We need to be pro-active for future research.

 

Cystinuria is a metabolic, genetic defect in Mastiffs.  Test your Mastiffs for Cystinuria, encourage their relatives to be tested and make Cystinuria testing as an adult a requirement in your puppy contracts.  PLEASE test & retest and participate in the research studies. 

 

If you have a C+ dog, please offer them plenty of fresh, clean water through out the day and encourage them to drink it.  Let them go out to urinate often and don't ask them to hold their urine for very long.  In case your C+ Mastiff passes away, although it is hard to do, please consider prearrangement plans with UPenn to donate its kidneys to Cystinuria research.  This is important on C+ dogs that never formed stones as well as from C+ stone formers.

 

Thank you,

 

Anna May


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Reply with quote  #12 
Here's one on trying to understand the complexity of figuring out complex disease.....

COMPLEX DISEASES

 

If you are interested in trying to understand complex diseases and why it is so hard to crack their codes, there are numerous articles on the internet about the topic.  Even the basic explanations are somewhat complicated and that is why they are complex. 

 

The researchers have to understand the patterns and the triggers of the disease to try to help understand the metabolic processes that take place and to just understand the disease in the focused population.  With complex diseases there are variations that take place within individuals and within families. Those variations make it much more complicated than a simple form of the disease.

 

Along with that the researchers need pedigree information on affected families to understand the mode of inheritance.  

 

Even with research on humans, there have not been any major breakthroughs on complex disease to date that I'm aware of.  They might be able to identify specific genes that are associated with a specific complex disease, but then they still have to figure out the molecular processes that cause the genes to trigger...  For example with breast cancer researchers have identified a gene that's associated with the disease, but they do not fully understand why some people that have the gene develop breast cancers while others with the same gene do not…

 

Here are some articles on complex diseases:

 

Discovering genotypes underlying human phenotypes: past success for mendelian disease; future approaches for complex disease

 

http://www.nature.com/ng/journal/v33/n3s/full/ng1090.html

 

 

Mathematical Modeling of Complex Biological Systems

From Parts Lists to Understanding Systems Behavior

Hans Peter Fischer, Ph.D.

 

http://pubs.niaaa.nih.gov/publications/arh311/49-59.htm

 

So, as you can see complex diseases are complex!  Besides finding the genetic answers, we need to positively identify the mode of inheritance, the age of onset, the environmental factors such as diet….  UPenn is continuing to research Cystinuria in Mastiffs at the genetic level and now they are looking again at better diagnostic tools and possible preventative approaches for us to deal with this disease…

 

The answers will only be found if we participate in the research by submitting blood, urine, pedigrees, personal observations, environmental information...  Dr. Acland of Cornell University, Baker Institute, UPenn & OptiGen told me (not a direct quote) the best way to find answers on genetic diseases in dogs is to go to the experts "the breeders".  So, we need breeder participation for our research projects to be successful.  The breeders can only do it with participation from their puppy buyers and the owners of closely related dogs....  It's a team effort between the breeders, the owners, the researchers, and the parent clubs.....

 

Anna May

 


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Reply with quote  #13 
Hi Chris..I think there is alot of confusing information about cystinuria.
I have recently read an article published in the OEMC journal..Mastiff Legacy..Autumn/Winter 2008 issue, written by Marguerite Perrenoud.

Marguerite Perrenoud spoke at length with Dr William Newman, who heads the Health & Research Committee for the MCOA, and states in her article that he shared the following information;
..excerpts from article;

2)The condition is seriously aggravated by the BARF diet and/or large   amounts of chicken.
 
3) Dr Newman like myself (and my late mother who was first connected with mastiffs in 1932), says never feed Mastiffs chicken in any form(as chicken contains cystin). Any 'meal' fed to mastiffs should be checked to see that there is no trace of chicken present. ( Dr Newman mentioned he avoids soya for mastiffs too and I found this interesting because I always advise there should be no soya in their diet or supplementation)
 
6) Some Mastiffs may not have true cystinurea, they may be developing the crystal - a combination of eating too much chicken and of being given an acid diet.
 
 ..what do you make of that?

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Reply with quote  #14 
I have called Dr. Newman a while back to discuss the article being mentioned.  He may have already received it by now, but he had mentioned he would love to have a copy of the article if anyone can send him a copy.  Dr. Newman also told me he was very disappointed he was misquoted and is being misunderstood. He still strongly believes Cystinuria is a metabolic genetic disorder.

With Dr. Newman's own personal experience he was able to help his Mastiff "Danny" with his reoccurring urinary tract infections by not feeding him chicken and by monitoring his water intake.  Dr. Newman monitored Danny's cystine levels and urine pH regularly and was able to avoid stone formation and reoccurring urinary tract infections.

Dr. Newman is completely confident that Cystinuria is a metabolic genetic condition and has spent a lot of his own money to support Cystinuria Research studies in Mastiffs and other breeds through UPenn. 

He is very thankful that the Mastiff Community is finally paying attention and taking note of Cystinuria in our breed.  On the other hand, he is disappointed in those that would like to blame diet as the cause of Cystinuria instead of understanding that it is a metabolic genetic disease that can be influenced by diet and water intake...

UPenn understands (as mentioned in previous posts) that Cystinuria in Mastiffs is a very complex disease.  Cystine levels fluctuate in many Mastiffs.  UPenn needs the help of breeders & owners of C+ Mastiffs to participate in the research to try to understand what environmental influences such as diet cause some Mastiffs to form crystals and stones and why others under the same environmental influences do not...  What metabolic changes occur that cause stone formation to trigger in some dogs and not others?

This is similar to diabetes.  Why are some diabetic people able to control the disease and its symptoms through diet and others cannot.  Another example of a complex disease might be mental illness.  Why are some people able to control the disease with diet, sleep, counseling or medication and others are very unbalanced regardless of their environmental influences and may actually have psychotic episodes...

There are plenty of Mastiffs that have tested Cystinuria positive through the NP urine screening that have gone on to form cystine stones and there are plenty like Danny that have lived a long life without forming stones.  Many of those C+ non-stone formers have been fed a high protein BARF diet which may or may not include chicken that never went on to form stones & others that have.  There are also many Mastiffs that have tested C+ that have gone on to test negative after a diet change of reduced protein or switched to a standard, commercial kibble. 

In humans and within the medical community (both human and veterinarian), Cystinuria is treated through diet, increased water intake, and medication.  It is well known that once an animal or human starts forming cystine stones, it is hard to manage the disease and prevent stone formation from reoccurring without surgical intervention &/or expensive medication...

The good news is that the cystine levels often fluctuate in Mastiffs which is to their best interest.  The bad news is that this makes it a complex disease which is much harder to diagnose and much harder to knock the genetic code which is a huge disadvantage.

Please note:  If your Mastiff is fortunate enough to respond positively to a change in diet, please do not forget the genetic component of the disease.  Do your best to test as many relatives as possible & help UPenn figure out the puzzle.

Anna


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Reply with quote  #15 
Well said Anna May!!

UPENN should no be held responsible for lack of trying if we as a community are not supplying them with the samples they need.

While I did do some online research and find a site Online vet magazine .com that had some interesting articles.  The most understandable conversation I've had on the subject were with the people at UPenn.  I was very concerned while waiting for our boys results last year after specialty.


We need whole litters worth of samples and parents as well.  How can we expect them to crack something genetic if we do not send the genetic material.

Theresa

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Reply with quote  #16 
Thanks Anna.. for sharing all of that info with us. I had not realized how complex cystinuria was, and how many unknowns there are.. great info!

Theresa....excellent point.

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Reply with quote  #17 
this is the most educational thread that I have ever read....thank you!
Anna May, you are very good at explaining things. May I take some of this info and put it on our Club's website?

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"In humans and within the medical community (both human and veterinarian), Cystinuria is treated through diet, increased water intake, and medication.  It is well known that once an animal or human starts forming cystine stones, it is hard to manage the disease and prevent stone formation from reoccurring without surgical intervention &/or expensive medication..."

As an owner of a dog with C+ (with stones) I can speak from experience.  I have told many people my Drake's story but there are a few things I want to point out.   As some of you have stated each dog is different. Drake was 2 for his first surgery for stones (30) and a plugged up urethra (sp). 3 for the next and 4 for the last. He has been stone free for the last 8 years, he will be 12 in 2 weeks.  What did I do?  I neutered him and put him on a barf diet. I know, some of you are saying "to much protein" but it has worked for him and I truly feel that the neutering really helped with stones being able to pass.  Also the "wet" diet really adds to his flushing.  I do not suggest this for anyone Else's dog but I do think that if your dog is positive they should be neutered.  As to genetics, all of Drakes siblings are gone, his parents are gone so I have no-one to test. As far as I am aware Drake is the only one in his line that ever came up positive, of course 12 - 15 years ago not many were tested. I truly wish we can get rid of this soon, it is horrible to watch your baby trying to pee, crying and just a bit of blood comes out.


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Michelle
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Reply with quote  #19 
It is good to see such enthusiastic and sincere posts on the subject.  If everyone had as much passion for the subject as some do, we would probably have started the testing earlier and have proven results by now. 
     Please do not confuse my devil's advocate posting as somehow blaming or belittling the work or workers at UPENN.  They are the best ones for the job right now and are spear heading the movement so to speak.  I was trying to make the point that we cannot trust UPENN to find answers soon(with the current testing methods)because of the actions of some breeders.  NOT UPENN.    
      Breeders can intentionally/unintentionally be skewing results and the study right now.  That is why I feel there is so much confusion concerning the condition.  Some people will always have a desire to give their dog the best chance they can to test "good" and others will always do their best to make sure all protocols are followed because they want to know.  There are plenty enough ostriches out there that would rather not see problems than address them. 
     As I said before, we very quickly found the fluffy gene because we changed how we approached the issue and breeders showed them where to look.  I am sure that all the old timers to this board will remember me stating that I knew the mode of inheritence for the fluffy gene and another member here criticized and ridiculed me for making the statement.  Oddly enough, I was right.  LOL  I got my info from observing a couple of breeders who had the condition in their line, but were HONEST about it and simply followed the tree.  Many things are not as easy to spot or inherited in a manner as easilly tracked.  That is where UPENN definately can have an advantage over the simple minded breeder like myself.  They have the technology and ability to put things together from several different families and notice trends that may have exceptions, but predominant enough to show a pattern with several dogs.  
     Again, the problem is in the delivery there being done sporatically by breeders with something to potentially lose and possibly even their method, but certainly not their intent.  I personally feel pretty safe that all of my dogs are free of cystinuria.  I have currently dropped the whole cystinuria search personally due to the controversial nature of it.  Since it is not affecting me and I don't like to always be the bad guy(note I said always LOL), I dropped the issue.  I am moving on to less controversial things in reproduction.  At least less controversial to breeders.  PETA and the humane society would like to see all dogs infertile since the world has too many dogs and purebreds have no place.  LOL 
     Anyway, sorry to post such a long story again.  I am bad about that.  Since there are obviously knowledgable people in the realm of cystinuria here, I would like to pose a couple of questions to them concerning thoughts I have pondered on the subject, but have not been able to find answers to.

How much cystine can a normal dog filter out of their body in a given time?  I know they have set a proposed target level to judge them all by, but for that number to have any true merit, there must be a tolerance level in there of some measure or it is simply erroneous.  Just as there is with alchohol, protein, toxins, Kool-Aid die etc, there is a normal rate it is expelled from the body.  What is the amount per hour or day that a "normal" dog can filter out?

It is my understanding that a c+ dog is simply not efficient in filtering out cystine.  That is one reason that diet can control it in many cases.

If this is the case, there must be a limit to the amount of cystine that a normal dog can filter out and a lesser limit that an affected dog can filter out.

If that is true, then there HAS to be a breaking point in a diet in which the cystine is introduced.  Despite it being a larger amount in a dog free of the disease, even a normal dog must have it's limits.

As alcohol is filtered out by the liver in a normal human at a rapid rate, there is a limit with that too.  Some process it faster and others slower but there is a norm and a limit for everyone.  In any case, if it is consumed faster than it is filtered out, your levels grow(and we become more and more drunk) until we stop consuming it and our body catches up and eliminates the toxin. 

Why then are we under the assumption that there cannot be a false positive with any dog?  It appears to me that it could be possible for a diet high in cystine to produce a test showing higher levels, despite the dogs body filtering it at a normal rate.

     It may take me consuming over 24 ounces of beer in an hour to pass my alchohol tolerance, but I may only have to drink 2.5 ounces of stout liquor(or since I am from Kentucky 1 ounce of moonshine LOL) to surpass my tolerance and cause my levels to continually climb.  For example, I can safely and easilly consume 12 ounces of Budweiser every hour I am awake for the rest of my life(or until my liver failed LOL) and never be drunk and any urine or blood test would prove that.  If however I drank the same amount of moonshine I would not only test over the limit in the first hour, but I would be dead or approaching death before bedtime!

I know these are seperate conditions, but they do have a similar principle in that they have to be filtered out by the body and a certain amount is always going to be present after ingested until it is filtered out and eliminated.  So....  Again, if my understanding is correct what is the level that is normally filtered out by the body in a given time?  How would a diet surpassing that level be expected to do anything other than show a positive result on a normal dog?  Are we simply making an assumption that no diet can be high enough in cystine to surpass normal levels?  Are we assuming that no dog eats a diet exceptionally high in cystine?  If so, isn't that awefully presumptious at this stage in the game?  If not, and we do have a filtering rate for normal dogs, that limit should be known and passed on to other breeders so that we can make sure not to surpass that for our dogs health. 

Could another approach not be even better?  Why couldn't we load a dogs system with cystine and use that level as a starting point, control his diet to eliminate cystine completely for a time period and monitor how fast the levels drop?  We should be able to get a large number of dogs together and find an average or normal rate it is eliminated for the breed by simply monitoring those levels as they drop from the group.  It would then be very easy test for cystinuria by the same method, or since a norm would then exist, simply use a specific diet for a given time and then test the level found.  Without that information/test we are only measuring an arbitrary number without knowing all of the parameters in which the sample was collected in. 

Perhaps I am wrong and this has already been done.  I hope it has.  If it hasn't, then why not?  Is it simply an oversight or is the logic flawed?  

Again, these are just some questions and scenarios that I have been pondering about for a while now.

Bes, you can count on me at Bucks pretty much every year unless something unplanned for arises.    


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Reply with quote  #20 
Quote:
How much cystine can a normal dog filter out of their body in a given time?  I know they have set a proposed target level to judge them all by, but for that number to have any true merit, there must be a tolerance level in there of some measure or it is simply erroneous.  Just as there is with alchohol, protein, toxins, Kool-Aid die etc, there is a normal rate it is expelled from the body.  What is the amount per hour or day that a "normal" dog can filter out?

It is my understanding that a c+ dog is simply not efficient in filtering out cystine.  That is one reason that diet can control it in many cases.

If this is the case, there must be a limit to the amount of cystine that a normal dog can filter out and a lesser limit that an affected dog can filter out.

If that is true, then there HAS to be a breaking point in a diet in which the cystine is introduced.  Despite it being a larger amount in a dog free of the disease, even a normal dog must have it's limits.

As alcohol is filtered out by the liver in a normal human at a rapid rate, there is a limit with that too.  Some process it faster and others slower but there is a norm and a limit for everyone.  In any case, if it is consumed faster than it is filtered out, your levels grow(and we become more and more drunk) until we stop consuming it and our body catches up and eliminates the toxin. 

Why then are we under the assumption that there cannot be a false positive with any dog?  It appears to me that it could be possible for a diet high in cystine to produce a test showing higher levels, despite the dogs body filtering it at a normal rate.


Interesting thoughts Chris..I heard they can't measure the amount of cystin..the urine test certainly dosn't..
so a question...does any trace of cystine at all result in a pos reading?

Quote:

Even with research on humans, there have not been any major breakthroughs on complex disease to date that I'm aware of.  They might be able to identify specific genes that are associated with a specific complex disease, but then they still have to figure out the molecular processes that cause the genes to trigger...  For example with breast cancer researchers have identified a gene that's associated with the disease, but they do not fully understand why some people that have the gene develop breast cancers while others with the same gene do not…



As pointed out in the above excerpt for breast cancer...similarly the gene for cystinuria may be there in many dogs..but something triggers it in some.

We have heard there are fluctuating levels of cystine from Anna's post. On another board and thread on Cystinuria, UPENN communicated with a breeder who had a pos result..suggesting they feed the dog a low protein diet and then retest. 
... which brings me back again to the question.. does any trace of cystine result in a pos reading..and can a dog fluctuate between no trace of cystine at all..to some trace of cystine? Why else would a UPENN researcher suggest to test again? 

So I think there must be some evidence pointing to diet related factors since they are looking in that area..of course until they publish some findings its only summising.

The other thing that I found interesting is that I read there is incomplete penetrance of the gene...so it will not follow 'normal' genetic patterns of inheritance like the example of 'simple x-linked posted at the beginning of this thread.
... maybe this is why it is hard for the researches to find the mode of inheritance as well.

I have been looking for another line, a female puppy to import ..and based on information I have seen there are no definatively 'clear' bitches and very few tested dogs anywhere in the world...I doubt anyone could guarantee it won't show up..I guess everyones in the same boat when it comes to looking for a pup



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Karen Dyer
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Reply with quote  #21 
As many of you know, I've taken a huge interest in this topic and have tried to stay up with all the new thoughts, research and pedigree studies with the help of some VERY knowledgeable people. First, THANK YOU ANNA MAY. She has been tirelessly communicating what we currently know in such an eloquent manner. The thing is, I still don't think everyone is getting the point. The test only draw back is that it shows false negatives (C+ positive but not showing up yet). If your dog test positive, he is positive. A completely normal dog will not dump cysteine into the urine because they have the right genes (to produce the right enzyme (?) to insure that doesn't happen.  Think of it like a diabetic. If you dump glucose into the urine, it means there's not enough insulin to process the sugars within the body.

Quote:
Cystinuria in Mastiffs is COMPLEX and the researchers around the world have been trying to figure out complex diseases for many years.
 

This is huge point. It DOES NOT fit a simple x linked recessive model. The more pedigrees several of us have studied, the more we are finding that it is possible that it may NOT be a problem with just an x gene. There could be more alleles involved which THOROUGHLY muddy the waters. Therefore, all we can try to do is C+ test the stud dogs we are using and watch offspring from our girls. If they have C+ boys from a particular girl, then we add that piece of the puzzle into the studies by submitting blood/urine from every puppy in that litter and all others in previous/past litter. It's only a start, but we have to try to address this. Of course, it's just common sense to never breed a C+ boy, but you have to test him to know. In my opinion, it is a huge issue that we must face.

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Reply with quote  #22 
That's a good question... I'm not sure but even if you elevate the pH so there is no stone formation (meaning dissolution of the cystine) - the cystine should still be there, right? It still is not able to be reabsorbed in the kidney as it should be to prevent it from going in the urine. I wouldn't think a change in pH would actually make it go away -just be in a different form. I could be wrong.. that's just my logic. :-)

So when they do the cystinuria testing - what constitutes a positive? Above a certain percentage?

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Reply with quote  #23 

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The thing is, I still don't think everyone is getting the point. The test only draw back is that it shows false negatives (C+ positive but not showing up yet). If your dog test positive, he is positive.



So Teresa..what do you think the point of the UPENN researcher is then when he suggests to a breeder to change the diet of the C+ positive dog and test again?
I saw the email UPENN sent to this person posted on the other board..and thats exactly what they said to do.

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Reply with quote  #24 

I believe UPENN is looking at diet as a means to treat and control C+ dogs to prevent them from becoming a stone former.


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Reply with quote  #25 
so what additional information would re-testing in one weeks time give UPenn?
The test only provides information as to whether the dog is neg or pos.

There must be a possibility it could come back neg, otherwise they wouldn't have asked the person to do it.


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