CYSTINURIA IN MASTIFFS
By Lisa Edwards-Filu, Mary DeLisa, and Emily Drew
What is Cystinuria?
WHAT IS CYSTINURIA? It is a urinary stone condition that can block your dog’s urinary tract. In Mastiffs, it affects MALE dogs.
Cystinuria is a genetic metabolic defect of the kidneys whereby they do not re-absorb the amino acid cystine correctly and then go on to form crystals and stones in the kidneys and bladder thereby causing urinary tract infections and dangerous, sometimes deadly, blockages. It has been found in over 60 breeds of dogs including Mastiffs, as well as cats, humans and other animals.
Canine Cystinuria can be of three types:
- Type I (autosomal recessive) Newfoundland/Labs
- Type II (autosomal dominant)
- Type III (formerly known as non-Type I). Type III cystinuria shows a complex inheritance pattern and is usually found in male dogs.
Mastiffs have Type III Cystinuria which is a more complex disease and the mode of inheritance is not fully understood
Many Mastiffs who test positive for Cystinuria do not go on to form stones. However, your Mastiff still has Cystinuria and still has the potential to form cystine stones. It is not fully understood why some Mastiffs form cystine stones and others do not. It is also unclear why male Mastiffs show clinical and biochemical signs of the disease and females do not. This is an area of on-going research and the researchers need our help. We are very fortunate that researchers have taken an interest in our beloved breed. As members of the Mastiff community, it is important to support those researchers in the form of data, specimen, and funding.
How is it Diagnosed?
If your Mastiff (or any dog in your household) is showing signs of:
- Bloody urine
- Frequent urination
- Frequent urinary tract infections
- Painful urination
- Straining when voiding
It is essential to get them to a veterinarian as quickly as possible. Many veterinarians do not think of Cystinuria or are quick to rule it out prematurely. Be an advocate for your dog and encourage your veterinarian to pursue a potential Cystinuria diagnosis.
Cystine stones are often NOT seen on x-ray and sometimes also missed on sonogram. A “clear” x-ray/sonogram does not mean that your dog does not have cystine stones or Cystinuria. There are three urine tests that can detect cystine:
- Basic urinalysis: This test is only reliable if cystine is present. A negative test does not mean that your dog does not have Cystinuria, but a positive result means that your dog does. While this is the least reliable test, it is the most readily available.
- Nitroprusside test: The sodium cyanide-nitroprusside test is a rapid, simple, and qualitative determination of cystine concentrations. Cyanide converts cystine to cysteine. Nitroprusside then binds causing a purple hue. The test is used to detect the level of cystine. This test is performed at the University of Pennsylvania. Owners can submit urine for testing without a vet and the cost is minimal. However, the urine does require overnight shipping and special packaging. A negative test does not mean that your Mastiff does not have Cystinuria and regular testing of male Mastiffs is encouraged.
- Urine amino acid quantitation test (qualitative amino acid analysis): This is a test that is performed in a human medical laboratory that includes quantitation of the following amino acids: phosphoserine, phosphoethanolamine, taurine, threonine, serine, asparagine, hydroxyproline, glutamic acid, glutamine, aspartic acid, ethanolamine, sarcosine, proline, glycine, alanine, citrulline, alpha-aminoadipic acid, alpha-amino-n-butyric acid, valine, cystine, cystathionine, methionine, isoleucine, leucine, tyrosine, phenylalanine, beta-alanine, beta-aminoisobutyric acid, ornithine, lysine, 1-methylhistidine, histidine, 3-methylhistidine, carnosine, anserine, argininosuccinic acid, allo-isoleucine, homocitrulline, gamma-amino-n-butyric acid, hydroxylysine, tryptophan, and arginine. It is extremely expensive but is the most accurate. However, again, a negative test result is not absolutely definitive. If owners are interested in this test, you should contact the University of Pennsylvania and try to arrange testing. A special rate may or may not be available if you go through them.
While many veterinarians don’t think of Cystinuria, they may also not be aware of the most recent research data. Before you do a scrotal urethrostomy (short version of an SU: this is where they make a hole lower down on penis so that a male can pee more like a female – this makes the male’s urethra shorter so less chance of stones to “block” the longer urethra they are born with), try for a neuter first (that is if your dog is not completely blocked of course!).
If your dog is blocked, it’s imperative you (i) neuter, (ii) remove all stones from bladder, and (iii) if there is a stone and they cannot remove from urethra, then you may need to have the SU done. Based on the research done at the University of Pennsylvania, there is a “timeframe” where your dog may still produce stones post-neuter until their testosterone hormone drops. Therefore, it is important to keep careful watch post-neuter.
Cystinuria and Breeding Programs
In Mastiffs (and a few other breeds), cystine stone formation has only affected MALE dogs. The University of Pennsylvania has been at the forefront of Cystinuria research and has developed a DNA marker test. With this test, Mastiff breeders and owners can now test their male and female Mastiffs. Breeders can use the DNA marker test as a tool in their breeding program. Based on the research that Dr. Henthorn and her team at the University of Pennsylvania have done, Cystinuria in Mastiffs appears to be linked to the y-chromosome and testosterone.
Based on what the Mastiff Club of America Health Committee has seen via posts/comments on social media and questions from the Mastiff community, there seems to be a lot of misinformation when it comes to the Cystinuria-Associated (Type 3) DNA test. It is important to note that unlike some of the other DNA tests that are available for the Mastiff breed, the Cystinuria-Associated Marker (Type 3) DNA test that is currently offered is an “at risk” test. It does not test for Cystinuria or stone formation. It tests for a susceptibility allele that provides high risk for stone formation in intact males (based on Dr. Henthorn’s initial research). Cystinuria is a very complex disease and on-going research is being conducted. For this reason, it is recommended to test the urine of intact adult male dogs on a yearly basis. Dr. Henthorn has also requested blood, urine, pedigree, and stone analysis report for any female or neutered adult males that have formed cystine stones or crystals. This data helps with existing and future research. The data and samples you provide can assist in trying to solve the big question … what causes Cystinuria in Mastiffs.
While it has been shown that if you neuter affected males, they will stop producing cystine stones, it is not 100% effective. There has been a male Mastiff who went on to form cystine stones post-neuter. This suggests additional genetic markers, another form of Cystinuria, other factors, etc. Dr. Henthorn’s lab is dedicated to on-going research in hopes of identifying the gene(s)/mutation(s) to improve the Type III DNA Cystinuria test. This will help with the betterment of the Mastiff breed. Dr. Henthorn’s lab has been able to sequence the genomes of a 1:1 (two copies of marker allele 1), 1:2 (one copy of marker allele 1 and marker allele 2), and 2:2 (two copies of marker allele 2) of multiple breeds with the money that has been donated by breed clubs (and fanciers) that are affected with Type III Cystinuria. This includes the money that the Mastiff Club of America raised in collaboration with the Deerhound Club of America at our 2018 National Specialty. In addition, Dr. Henthorn personally donated the funds needed in memory of Anna May to sequence the genome of a 1:1 Mastiff that formed stones. This dog’s DNA has provided valuable data and a possible gene mutation. There are current plans to sequence the genome of a second 1:1 stone former to help further research as to whether a possible gene mutation has been identified. As mentioned, this research is on-going. While Dr. Henthorn has plans to publish her findings in a multiple edition manuscript, she is unable to release any research-related data prior to publication due to policies put in place by the University of Pennsylvania.
Since the Cystinuria-Associated Marker (Type 3) DNA test is an “at risk” test, it is recommended that the nitroprusside urine testing through the University of Pennsylvania (PennGen) for ALL intact males regardless of their DNA test results be done annually. Any time there is cystine in the urine, there is the risk of forming cystine stones. If you have a Mastiff that has tested 1:1 on the Cystinuria-Associated Marker (Type 3) DNA test and went on to form cystine stones, please contact the Mastiff Club of America Health Committee and/or Dr. Henthorn (cystinuriaDNAtest@gmail.com).
While research is on-going, if your male is diagnosed with Cystinuria and he is not neutered, neutering should be the first decision that you explore in an effort to treat (in addition to removing all the stones that are currently in the bladder). It is important to recheck urine cystine to see if you dog is dumping cystine post neuter. The following stone chart from the University of Minnesota provides additional detail: https://www.vetmed.umn.edu/sites/vetmed.umn.edu/files/canine_cystine_uroliths.pdf.
There have been intact male Mastiffs under 24 months of age that have blocked from urinary cystine stones, but some Mastiffs do not test positive for elevated levels of cystine in their urine until after 24 months of age. Thus, an annual urine test is recommended. Some Mastiffs have tested positive for elevated cystine in their urine when they were fed a high protein diet or certain supplements. When switched to a lower protein diet and/or when they were taken off the supplements, they tested normal. If there is a significant diet change, is also recommended to test intact males a month after a significant change in diet. This is also of interest to researchers … are there additional factors other than genetics in play?
Here are some additional links to testing tools and information:
- Cystinuria in the Mastiff: https://www.mastiff.org/if-your-mastiff-has-cystinuria/
- Canine Cystinuria: http://www.caninecystinuria.com/indextest2.html
- Breeds Affected: http://www.caberfeidh.com/CystinuriaBreeds.htm
- University of Pennsylvania (PennGen) website: http://research.vet.upenn.edu/penngen/
- DNA Testing Instructions: https://www.vet.upenn.edu/research/academic-departments/clinical-sciences-advanced-medicine/research-labs-centers/penngen/instructions-resources/dna-testing-instructions
- Urine Testing and DNA Testing: https://www.vet.upenn.edu/research/academic-departments/clinical-sciences-advanced-medicine/research-labs-centers/penngen/penngen-tests
- UK DNA Testing: http://bit.ly/2uNcxwe