Cystinuria, an Informal Discussion*
Teresa McMahan of Oasis Mastiffs
Definition of Cystinuria
Cystinuria is a metabolic disorder whereby the amino acid, Cysteine, is not properly metabolized by the canine kidney. In a non-affected dog, Cysteine is resorbed and not excreted into the bladder. It poses no health risk to the animal and is a normal amino acid used by the body for protein synthesis. In the affected dog, however, the excess Cysteine begins to form Cysteine stones in the bladder. Eventually, those stones will attempt to be excreted in the urine and can cause partial to complete urinary blockage in male dogs. Urinary blockage is a medical emergency and must be treated immediately. Initial symptoms are difficulty upon urinating or straining to urinate. Once blocked, the dog cannot urinate. It is a serious and painful condition.
Genetic versus Environment
There has been much discussion whether Cystinuria in Mastiffs is genetic or environmental. It has become increasingly clear that Cystinuria is a genetic disorder that can be exacerbated by environmental influences such as diet and supplementation though no definitive data has been published. Current research is being conducted by the University of Pennsylvania into this issue. It appears that substantial progress has been made into finding the genetic markers for the most serious form of Cystinuria. In this form, male Mastiff forms stone at a very young age. It is extremely important to note that there is more than one kind of Cystinuria in Mastiffs so simply clearing the males for the most serious form is not enough.
What Dogs are Affected
It is important to note that in the type(s) of Cystinuria that affects Mastiffs, only males are affected. There are several kinds of Cystinuria and Mastiffs are not affected by the same kind of Cystinuria that affects Newfoundlands. To repeat, it is very important to understand that there may very well be more than one kind of Cystinuria that affects Mastiffs. It is a complex disease and one that we are just beginning to elucidate through the research at the University of Pennsylvania under the auspices of Dr. Paula Henthorn. For the purposes of this report, we will primarily address the most serious form that affects young males.
Testing for Cystinuria
Prior to May 2011, the only test available for Cystinuria was the urine Nitroprusside Test administered by the University of Pennsylvania. This test was somewhat limited due to the fact is showed both false negatives, and possibly, false positives. However, it was a relatively good indicator in males of the presence of Cysteine in those males not treated with supplements**. Another limitation was the fact that bitches never tested positive on this test, so it was difficult to understand the role of the females in this disease. Through the outstanding efforts of the research at the University of Pennsylvania under Dr. Paula Henthorn and her team, a genetic marker test was designed. The test was based on data using SNIP chips (an advanced genetic mapping tool) that showed two areas of interest on the DNA sequence. The markers showed that those dogs affected with the most serious form of Cystinuria had dual copies of the mutation on the areas of interest in the DNA genome. These areas were also present in bitches though these females did not show symptoms of the disease. Furthermore, the study found that it appears that positive Cysteine males neutered prior to forming stone returned to normal Cysteine status after approximately 6 months. Consequently, it is suspected that Testosterone plays a role in the metabolism of Cysteine within the kidneys though the actual process remains elusive. The resulting DNA Marker test allowed breeders to test both their males and females for these markers. It is important to note that this DNA Marker test only test for ONE type of Cystinuria and some Mastiff may still form stones in later years due to other types of Cystinuria. Therefore, it is necessary to continue to test intact males throughout their life. It is again important to understand that Cystinuria is Mastiff is a very complex disease and we still have a great deal of research to do in order to completely elucidate this disease.
How to Test
In order to test for Cystinuria, all Mastiffs should undergo the Nitroprusside Test and DNA Marker test at approximately 18 months old using the following link:
http://www.oasismastiffs.com/uploads/1/0/0/7/10071983/mastiff_cystinuria_dna_marker_test_form_fillable_052412f1.pdf .
It is not necessary to submit urine for bitches, but can be used for research and is included in the total cost of the DNA Marker test. Please following the instructions contained on the form carefully for urine submission. DNA testing may be done using either blood or cheek swabs and may actually be done at any age. Cheek swabs may be obtained either by sending a self-addressed stamped envelope to UPENN or by requesting DNA swabs from AKC. After the initial screening, it is will still be necessary for males to be tested yearly with the Nitroprusside Urine test from UPENN. To repeat, other forms of Cystinuria may still be present and yearly screening is strongly advised. The DNA Marker test is not necessary once the initial test is done. The form for just urine submission is:
http://www.mastiff.org/images/Mastiff%20Cystinuria%20Urine%20Test%20Form%2012-4-09.pdf
Interpreting Results
The Nitroprusside test is reports as positive, negative or inconclusive. Please note that there has been much discussion regarding some previous results where it was reported as +1, +2, +3 or +4. This is an UPENN internal reporting system and is not important to the consumer and has only served to confuse the issue. Simply rely on the negative, positive or inconclusive designations. Of course, positive means that the dog tested positive for Cysteine in the urine (or was a false positive due to supplements**) and therefore, is at risk for forming stones. Negative means there was no Cysteine found in the urine at the time of testing, but does NOT rule out that the will remain negative in the future. Please remember, there are several forms of Cystinuria and some are later onset. Inconclusive simply means the test needs to be repeated because something in the testing procedure was out of the ordinary.
The DNA Marker test is a bit more complex. Basically, there are three designations a dog or bitch may have. In this test, the sex of the dog does not matter. Also, it bears repeating that a dog that does not have the markers may still be at risk for developing another type of Cystinuria so the Urine Nitroprusside test remains necessary for those dogs. For the sake of simplification, assume that the “2” means the mutant marker for Cystinuria and “1” is the designation for a normal marker. That means there are three possible results: 1:1, 1:2, and 2:2. The following is the interpretation of those results:
1:1 Means the dog or bitch does not have the mutation for the most serious form of Cystinuria, but does not rule out other forms.
1:2 Means the dog or bitch has one “good” copy of the gene and one “bad” copy of the gene. Males with this designation may still develop Cystinuria and must be monitored for progression of the disease, and therefore, are not TRUE carriers because they can suffer from the disease. They may also take several years to test positive on the urine nitroprusside test or they may begin testing at 2-3 years old. Bitches would be considered true "carriers" since they can never express the disease. The 1:2 males are at higher risk than 1:1 males and lower risk than 2:2 males. Females may either pass the good copy of the gene (1) or the mutant gene (2) to their offspring.
2:2 Means that males are at high risk of forming stones at a young age. It is recommended that these boys be neutered at 18-24 months***. Females with this designation will always pass on the mutated gene to all of their offspring and should be bred with extreme caution and those offspring should be carefully monitored and ONLY bred to 1:1 males.
In closing, there are a few things to note. First, it is important to remember that males that have already developed stones may still block despite being neutered. Never ignore a male who has difficulty urinating. Second, it is important to note that there is more than one form of Cystinuria and the DNA Marker test is not a guarantee of males never being affected. Thirdly, in order to not decimate the gene pool, breeders need to employ good breeding tools to eventually breed out the mutant gene while still preserving a healthy gene pool. As with any breeding, the breeder must evaluate whether their bitch or stud truly is an asset to the gene pool.
*Not an “official” publication and is only informative and is not endorsed by UPENN.
** There is some debate how supplements, antibiotics and diet affect a Cystinuric male.
***Some males may form stone and block at younger ages, but neutering too young also has its downfall so this issue is a matter for the owner to address as they feel comfortable.
Teresa McMahan of Oasis Mastiffs
Definition of Cystinuria
Cystinuria is a metabolic disorder whereby the amino acid, Cysteine, is not properly metabolized by the canine kidney. In a non-affected dog, Cysteine is resorbed and not excreted into the bladder. It poses no health risk to the animal and is a normal amino acid used by the body for protein synthesis. In the affected dog, however, the excess Cysteine begins to form Cysteine stones in the bladder. Eventually, those stones will attempt to be excreted in the urine and can cause partial to complete urinary blockage in male dogs. Urinary blockage is a medical emergency and must be treated immediately. Initial symptoms are difficulty upon urinating or straining to urinate. Once blocked, the dog cannot urinate. It is a serious and painful condition.
Genetic versus Environment
There has been much discussion whether Cystinuria in Mastiffs is genetic or environmental. It has become increasingly clear that Cystinuria is a genetic disorder that can be exacerbated by environmental influences such as diet and supplementation though no definitive data has been published. Current research is being conducted by the University of Pennsylvania into this issue. It appears that substantial progress has been made into finding the genetic markers for the most serious form of Cystinuria. In this form, male Mastiff forms stone at a very young age. It is extremely important to note that there is more than one kind of Cystinuria in Mastiffs so simply clearing the males for the most serious form is not enough.
What Dogs are Affected
It is important to note that in the type(s) of Cystinuria that affects Mastiffs, only males are affected. There are several kinds of Cystinuria and Mastiffs are not affected by the same kind of Cystinuria that affects Newfoundlands. To repeat, it is very important to understand that there may very well be more than one kind of Cystinuria that affects Mastiffs. It is a complex disease and one that we are just beginning to elucidate through the research at the University of Pennsylvania under the auspices of Dr. Paula Henthorn. For the purposes of this report, we will primarily address the most serious form that affects young males.
Testing for Cystinuria
Prior to May 2011, the only test available for Cystinuria was the urine Nitroprusside Test administered by the University of Pennsylvania. This test was somewhat limited due to the fact is showed both false negatives, and possibly, false positives. However, it was a relatively good indicator in males of the presence of Cysteine in those males not treated with supplements**. Another limitation was the fact that bitches never tested positive on this test, so it was difficult to understand the role of the females in this disease. Through the outstanding efforts of the research at the University of Pennsylvania under Dr. Paula Henthorn and her team, a genetic marker test was designed. The test was based on data using SNIP chips (an advanced genetic mapping tool) that showed two areas of interest on the DNA sequence. The markers showed that those dogs affected with the most serious form of Cystinuria had dual copies of the mutation on the areas of interest in the DNA genome. These areas were also present in bitches though these females did not show symptoms of the disease. Furthermore, the study found that it appears that positive Cysteine males neutered prior to forming stone returned to normal Cysteine status after approximately 6 months. Consequently, it is suspected that Testosterone plays a role in the metabolism of Cysteine within the kidneys though the actual process remains elusive. The resulting DNA Marker test allowed breeders to test both their males and females for these markers. It is important to note that this DNA Marker test only test for ONE type of Cystinuria and some Mastiff may still form stones in later years due to other types of Cystinuria. Therefore, it is necessary to continue to test intact males throughout their life. It is again important to understand that Cystinuria is Mastiff is a very complex disease and we still have a great deal of research to do in order to completely elucidate this disease.
How to Test
In order to test for Cystinuria, all Mastiffs should undergo the Nitroprusside Test and DNA Marker test at approximately 18 months old using the following link:
http://www.oasismastiffs.com/uploads/1/0/0/7/10071983/mastiff_cystinuria_dna_marker_test_form_fillable_052412f1.pdf .
It is not necessary to submit urine for bitches, but can be used for research and is included in the total cost of the DNA Marker test. Please following the instructions contained on the form carefully for urine submission. DNA testing may be done using either blood or cheek swabs and may actually be done at any age. Cheek swabs may be obtained either by sending a self-addressed stamped envelope to UPENN or by requesting DNA swabs from AKC. After the initial screening, it is will still be necessary for males to be tested yearly with the Nitroprusside Urine test from UPENN. To repeat, other forms of Cystinuria may still be present and yearly screening is strongly advised. The DNA Marker test is not necessary once the initial test is done. The form for just urine submission is:
http://www.mastiff.org/images/Mastiff%20Cystinuria%20Urine%20Test%20Form%2012-4-09.pdf
Interpreting Results
The Nitroprusside test is reports as positive, negative or inconclusive. Please note that there has been much discussion regarding some previous results where it was reported as +1, +2, +3 or +4. This is an UPENN internal reporting system and is not important to the consumer and has only served to confuse the issue. Simply rely on the negative, positive or inconclusive designations. Of course, positive means that the dog tested positive for Cysteine in the urine (or was a false positive due to supplements**) and therefore, is at risk for forming stones. Negative means there was no Cysteine found in the urine at the time of testing, but does NOT rule out that the will remain negative in the future. Please remember, there are several forms of Cystinuria and some are later onset. Inconclusive simply means the test needs to be repeated because something in the testing procedure was out of the ordinary.
The DNA Marker test is a bit more complex. Basically, there are three designations a dog or bitch may have. In this test, the sex of the dog does not matter. Also, it bears repeating that a dog that does not have the markers may still be at risk for developing another type of Cystinuria so the Urine Nitroprusside test remains necessary for those dogs. For the sake of simplification, assume that the “2” means the mutant marker for Cystinuria and “1” is the designation for a normal marker. That means there are three possible results: 1:1, 1:2, and 2:2. The following is the interpretation of those results:
1:1 Means the dog or bitch does not have the mutation for the most serious form of Cystinuria, but does not rule out other forms.
1:2 Means the dog or bitch has one “good” copy of the gene and one “bad” copy of the gene. Males with this designation may still develop Cystinuria and must be monitored for progression of the disease, and therefore, are not TRUE carriers because they can suffer from the disease. They may also take several years to test positive on the urine nitroprusside test or they may begin testing at 2-3 years old. Bitches would be considered true "carriers" since they can never express the disease. The 1:2 males are at higher risk than 1:1 males and lower risk than 2:2 males. Females may either pass the good copy of the gene (1) or the mutant gene (2) to their offspring.
2:2 Means that males are at high risk of forming stones at a young age. It is recommended that these boys be neutered at 18-24 months***. Females with this designation will always pass on the mutated gene to all of their offspring and should be bred with extreme caution and those offspring should be carefully monitored and ONLY bred to 1:1 males.
In closing, there are a few things to note. First, it is important to remember that males that have already developed stones may still block despite being neutered. Never ignore a male who has difficulty urinating. Second, it is important to note that there is more than one form of Cystinuria and the DNA Marker test is not a guarantee of males never being affected. Thirdly, in order to not decimate the gene pool, breeders need to employ good breeding tools to eventually breed out the mutant gene while still preserving a healthy gene pool. As with any breeding, the breeder must evaluate whether their bitch or stud truly is an asset to the gene pool.
*Not an “official” publication and is only informative and is not endorsed by UPENN.
** There is some debate how supplements, antibiotics and diet affect a Cystinuric male.
***Some males may form stone and block at younger ages, but neutering too young also has its downfall so this issue is a matter for the owner to address as they feel comfortable.
