Cystine stones?
The Bulldog Breed Council Health Committee is aware that a question of Cystinuria has been raised recently. For some weeks we have been gathering information to be able to make a meaningful statement.
It is the most complex of conditions so we will try to make it more understandable, we have known about this condition and at least a decade ago we investigated the testing available here in the UK and were told, it was not a reliable test. So, following professional advice at the time we did not proceed.
The test reliability is not the problem it is the interpretation of the results. We debated about putting the test with the HUU forward but there was no evidence or data to help us. Looking at other countries at the time nowhere had a plan. The Kennel Club had no plans to store data.
It is known that cystine stones can occur in the breed, according to the published information, but the inheritance is not straightforward in Bulldogs. Confusingly it is not the same in some other breeds, there is a variation of the factors not in common across the breeds.
HUU is very straightforward because it is an autosomal recessive condition – you run the test, and a dog will be clear, carrier, or affected – those are the only options, and it is clearcut. Once you’ve done the test, for each dog, you can use the results to select away from the condition. We have been pleased with the efforts made by breeders by this method we have more clear, fewer carriers, and a small amount of affected.
This is not the case for Cystinuria, where several mutations can cause the same disease making control much more problematic.
The cellular machine that causes cystinurea is composed of two proteins, each coded for by a different gene. These genes are known as SCL3A1 and SCL7A9. In the Bulldog breeds mutations in both these genes exist and can cause cystinuria, but they are not on the same chromosome in the genome, and therefore are inherited independently.
Labrador Retrievers and Newfoundlands have a mutation in the gene called SCL3A1. This mutation gives a disease known as Cystinuria Type 1, which removes a DNA base pair from the gene and hence the test offered for them is the Cystinuria Type 1 test. The inheritance of the SCL3A1 mutation in these breeds is fully autosomal recessive. In autosomal recessive diseases the disease occurs only in dogs that inherit the mutated allele from both parents (homozygote). The mutation SCL3A1 means that they do not produce any SCL3A1 protein from copies of the mutated gene, but if one SCL3A1gene is mutated but the other gene is unaffected by the mutation then the SCL3A1 part of the mature SCL3A1/SCL7A9 protein complex can be produced from the unaffected gene. In Type 1 cystinuria one unaffected gene is in general sufficient to allow enough protein to be produced to prevent cystinuria. Individuals with one mutated and one normal gene are said to be heterozygous for the mutation and are likely to be normal, although diet also contributes, and very protein rich diets can cause stones later in life
In Bulldogs and French Bulldogs a mutation has been found, that will identify one genetic mutation causing susceptibility to Cystinuria Type 3 (the type found in Bulldogs and French Bulldogs) by a DNA test. This will give you the genetic status of your dog, and breeders should use that information to breed selectively reducing that incidence, giving then knowledge to act on.
The specific mutations responsible for these problems in English and French Bulldogs are exchanges of one nucleotide in the gene SCL3A1 for another at two different positions SLC3A1 c.574A>G (I192V) in exon 2, together with SLC3A1 c.2092A>G(S698G) in exon 10 of the gene and SLC7A9 c.649G>A.
However the commercially available Type 3 cystinurea genetic test is linked to and detects only the SC3LA1 mutations in the Bulldog and French Bulldog Proteins can still be assembled from the affected genes, or mixes of affected and normal proteins but these are not effective in recycling cystine. .
The SCL7A9 mutant form is not detected by the Type 3 test. Dogs with this mutation can go on to develop Cystine stones and confusingly this means Type 3 clears can develop and suffer from the stones. What this means is that although the Type 3 test is reliable in detecting one cause of cystinuria in Bulldogs, it does not detect all animals who might develop the disease. A further confusion is caused by the nature of the disease. Development of stones takes a variable amount of time and signs of disease can be cryptic.
We know this complexity is hard to take in, but this explains why there has not been a test and a result procedure that is fully reliable. It has been investigated in many countries, and continues to be investigated in Bulldogs and a large number of other breeds without a firm universal plan of action.
The Breed Council would like to confirm that this is not a compulsory test but would like to make breeders aware that there is a test available for Type 3, and that its use will gradually result in the burden of cystinurea on our breed. It is hoped that all responsible breeders will test and if the results are affected or a carrier, whether dog or bitch, breed to a clear partner. This is responsible breeding.
What are the symptoms to look for? How will I know if my dog has cystinuria?
1. Cystine is an amino acid that is freely filtered in urine and almost completely reabsorbed by the kidney tubules (i.e. Removed from the urine).
2. As urine cystine concentration increases, a positive urine nitroprusside test, cystine crystals and cystine stones are indicators of disease.
3. Although cystinuria and cystine crystalluria do not cause clinical signs, cystine stones can irritate the lining of the urinary tract resulting in urinary accidents, urgency, straining, or bloody urine. There is an indication that males sleeping raising their rears could be a clue they are uncomfortable with irritation. In some cases, the stones could result in life-threatening urinary obstruction. Females normally pass these crystals and stones which is why usually we only see affected males; they too should be tested.
Cystine stones are not always visible on X-rays and may require special contrast studies
What diets minimize risk factors for cystine stones?
1. A 25% reduction in 24-hour urine cystine was associated with consumption of Hill’s Prescription diet u/d. [figures supplied by Hills]
2. Avoid diets that promote formation of acidic and concentrated urine, which are risk factors for stone formation. Make sure your dog always has plenty of access to water.
3. Diets rich in methionine (a precursor of cysteine and a common amino acid in animal protein sources) may contribute to cystine recurrence.
Consider lower protein foods with reduced quantities of animal protein.
4. Studies in cystinuria humans suggest that dietary sodium enhances cystinuria, and therefore high sodium diets (>100-150mg/Kcal) should be avoided. ultrasound for diagnosis.
The Health Committee is working on a more general advice document. TO BE ADDED SOON on feeding and management which will be on a web page, in the Health section, so that people will be able to get answers to their concerns. There is an enormous amount of information for us to sift through to find the best advice.
We saw someone ask if there are increased incidents of the condition across bulldogs? There are not, nor are there any recent data indicating it is increasing.
This condition is not new, there is evidence it has been known for over a century. It is a condition that is well known in humans and can be affected by the area water, for this reason we have been told bottled water WILL NOT help as its rich in elements, which form all 5 types of recognised stones.
The best advice would be to use a water butt to collect rainwater, this has an added gain in reducing tear stains in some dogs.
For clarity for breeders, if you test for Cysturina stones you can only know that the inherited DNA sequence C3 is not present. You must specify in your advert that it is type 3 not ADVERTISE TESTED CLEAR FOR CYSTINE. We are told a few laboratories are testing for the other types, but the science is an ongoing process of discovery.
Advice from a vet is a general recommendation is that if you are using genetic testing for HUU or Cystine that is an easy start to preventing or reducing risk. But avoiding using dogs known to have kidney stones, irrespective of genetic test results, is ideal. Vets know this can be challenging if there are important breeding lines where stones are common.
In these cases, it would be especially important to ensure that at least the dam or the sire does not have stones, and ideally that their parents/siblings (and grandparents if you know) also do not have stones. This is far less precise than using genetic tests, but it can be helpful for practical use.
More information will follow as we have made many contacts who will submit new progress on this.
