PURINA Pro Club

Bulldog UpdVol. 1, Nao. 1 ■teJuly 2007

Research of Cystinuria in Bulldogs Looks for Genetic Cause

alph,” was a handsome, out complications from cystinuria. He dogs since 1998 and currently receives happy-go-lucky white died of natural causes at age 9 ½. AKC Canine Health Foundation fund- “RBulldog. He loved being Bulldogs are among about 70 ing to study cystinuria in Bulldogs with people. When he was about breeds that appear to be genetically and other breeds. In 2000, she led 22 months old, Ralph appeared to predisposed to cystinuria. Statistics research that resulted in a genetic test strain when he urinated. are not available on the prevalence for type 1 cystinuria in Newfoundlands, His owner, Jennifer Joseph, who of the condition in the breed; how- and has more recently developed a lives in northern California, breeds ever, males are more commonly genetic test for Labrador Retrievers. Adamant Bulldogs and is familiar affected than females. Males have a The tests identify carriers and affected with health conditions that affect narrower, less dilatable urethra,1 and and normal dogs. Bulldogs. She recognized Ralph’s when urine passes over the os penis, “We cannot say with absolute straining as a sign of cystinuria, a stones can get lodged and cause an certainty that all cases are inherited,” disorder that causes cystine crystals obstruction. Females rarely obstruct she says. “It is possible there is a non- and painful uroliths, or stones, that as they have no narrowing of the genetic basis, possibly environmental.” can lead to kidney, bladder or urinary urinary pathway. Henthorn and her research team tract obstruction. Obstruction, which can be fatal, are studying pedigrees of about 50 Joseph took Ralph right away to occurs when no urine or very little dogs, including English Bulldogs, the veterinarian. Ralph had surgery urine can pass. Whenever a Bulldog Mastiffs, Scottish Deerhounds and to remove multiple cystine uroliths exhibits any sign of difficulty urinat- Irish Terriers, to identify the defective from his bladder. “The stones had a ing, a veterinarian should be consulted gene in these dogs that appear to sandstone feel to them,” Joseph recalls. immediately. Sadly, the breed develops have a different form of cystinuria “They were sent to a stone analysis an adult-onset form of cystinuria, than seen in Newfoundlands. To laboratory and confirmed as being which means carriers have often advance the research, she needs DNA cystine uroliths.” already been bred and produced off- from affected dogs and their relatives Meanwhile, after surgery, Ralph spring before they are identified. — parents, grandparents, littermates, was put on a reduced protein diet Research funded by the Bulldog offspring, aunts and uncles. (See infor- and given potassium citrate to help Club of America and other parent mation in box below about contribut- raise the urine pH level and discour- clubs in conjunction with the AKC ing to the research.) age crystal formation. Eventually, Canine Health Foundation is helping The goal is to determine whether Joseph had Ralph neutered. She had to better understand the genetic cause the genes that cause cystinuria in him tested every six months for cys- of cystinuria in Bulldogs as well as humans are the same as the ones tine crystals and uroliths. When he other breeds. Though much progress that cause cystinuria in dogs. In was 4 years old, he had a minor recur- has been made, many unanswered humans cystinuria is an inherited rence of the clinical signs of cystin- questions remain about the mode of autosomal recessive disorder. “If not, uria that was resolved with a change inheritance, especially since cystinuria we have a long road ahead of us,” in diet and increase in water consump- varies among breeds. says Henthorn. “The gene that causes tion. Fortunately, he passed one small Paula Henthorn, Ph.D., professor canine cystinuria literally could be one stone and did not require surgery. of medical genetics at the University of thousands of genes.” With proper treatment and mainte- of Pennsylvania School of Veterinary The good news is that once the nance, Ralph lived a normal life with- Medicine, has studied cystinuria in gene is identified, Henthorn and her team potentially can develop a genetic test similar to the one for Newfound - How to Submit DNA Samples for Research lands and Labrador Retrievers. This would enable breeders to selectively aula Henthorn, Ph.D., professor of medical genetics at the University of breed animals to help reduce the PPennsylvania School of Veterinary Medicine, is researching the genetic incidence of cystinuria in the breed. cause of non-type 1 cystinuria in Bulldogs and other breeds. Her research is funded by the Bulldog Club of America and other parent clubs in conjunc- Two Types of Cystinuria tion with the AKC Canine Health Foundation. Cystine crystals and stones form in To help advance the research, she is seeking DNA samples from affected dogs when cystine, an insoluble amino Bulldogs and their relatives — parents, grandparents, littermates, offspring, acid, fails to filter properly through the aunts and uncles. For information about submitting samples, please con- kidney. Normally, cystine is absorbed tact the Section of Medical Genetics at the University of Pennsylvania through the intestines or synthesized School of Veterinary Medicine at [email protected]. Continued on page 2 Cystinuria in Bulldogs later in life after reaching adulthood. from urinary tract blockage, may continued from page 1 The mean age of dogs at the time of also indicate cystinuria. A definitive stone removal is 4.8 years plus or diagnosis comes from mineral analysis in the body, filtered through the kid- minus 2.5 years. The majority, 98 of stones retrieved during urination neys and then reabsorbed by special percent, are male dogs, and nearly or surgery. kidney transporters. In healthy dogs all stones — 97 percent — are removed Treatment is multifaceted, says Carl about 97 percent of cystine is reab- from the lower urinary tract. This Osborne, D.V.M., Ph.D., DACVIM, pro- sorbed, but in dogs that develop is the type of cystinuria common fessor of medicine at the University cystinuria, the kidney fails to reab- to Bulldogs. of Minnesota College of Veterinary sorb cystine. The availability of free stone analy- Medicine. “It generally consists of Only a small amount of cystine sis at the University of Minnesota and increasing urine volume and giving above the normal concentration pre- University of California-Davis has thiol-containing drugs that help to disposes a dog to the formation of helped to advance research by provid- increase the solubility of cystine in cystine crystals, uroliths and urinary ing large databases of dogs affected by the urine. You want to alkalinize the 1 obstruction in acidic urine.1 When stones. Researchers at the University urine to help minimize cystine crys- this occurs, it is not unusual to find of Minnesota studied the records of tals. Modifying the diet by reducing cystine calculi from the kidneys to 37,574 dogs, including 276 Bulldogs, dietary protein and increasing water the bladder and urethra. Treatment admitted to the Veterinary Teaching intake helps. We also generally rec- of cystinuria is more simple and suc- Hospital from June 1, 1981, to Dec. 31, ommend feeding wet food rather than cessful when stones are found in the 1991, and tracked the mineral com- dry food. If dry food is fed, it is impor- bladder compared to the kidneys and position of uroliths. They documented tant to add plenty of water.” upper urinary system. that Bulldogs were 32.3 percent more If urinary tract blockage occurs due Cystine stones account for only likely than other breeds to develop to cystine stones, a veterinarian may about 1 percent of all uroliths in cystine stones. Their findings were attempt to unblock a dog by surgically dogs in the United States; however, published in the June 1994 issue of the removing the stone. Another method in Europe, 20 percent of uroliths are Journal of the American Veterinary is to flush the stone out through a due to cystine formation.1 Though the Medical Association. catheter in a nonsurgical procedure percentage of canine stones due to Researchers also studied 11,188 called urohydropropulsion. Another cystine is low in this country, for some urolith samples submitted to the technique involves making an incision breeds, like Bulldogs, the occurrence Minnesota Urolith Center for analysis and removing stones from the body is higher. One study showed that the during the same period. Of these sam- or creating a new opening in the ure- odds of Bulldogs developing cystine ples, 94 were from Bulldogs. Similar thra to allow a dog to urinate more uroliths were 32 percent greater than to the findings at the Veterinary like a female. Lithotripsy is a proce- for other breeds.2 Teaching Hospital, they found Bulldogs dure used to break stones into small Cystine stones were first reported were 40.7 times greater than other pieces that can be passed through in dogs in 1823 during a postmortem breeds to develop cystine uroliths. the urine. discovery. Many years later, in 1935, This report included 387 Dalmatians, Since cystinuria is believed to be the first documented case of cystin- a breed that is predisposed to urinary genetic and no genetic test currently uria was recorded in a dog with evi- stones due its inability to convert uric is available to identify carriers, the dence of a metabolic defect related acid to allantoin, a urinary excretion best advice experts offer breeders to elevated cystine levels in the urine produce of purine metabolism. and owners of Bulldogs is to fre- and stone formation.1 Researchers quently test your dog’s urine for followed subsequent breedings of this Diagnosis and Treatment signs of cystine crystals or stones. A dog and his Irish Terrier family and To detect cystine crystals in a dog’s dog that is predisposed to cystinuria — proved a genetic basis for cystinuria urine, a veterinarian takes a urine one who has previously shown clini- in dogs.1 sample for urinalysis and examina- cal signs or has affected relatives — Two types of cystinuria have been tion of the sediment under a micro- should have a urinalysis several identified: Type 1, which occurs in scope, and he or she may submit times a year to check for evidence of Newfoundlands and Labradors, and a urine for an inexpensive cyanide- crystals or sediment in the urine. second type, with no official name, nitroprusside urine test. Ultrasound Fortunately, as research continues, that is clinically distinct from type 1. and radiography are used as well to it is likely that one day soon researchers Type 1 is considered a severe type of detect stones. Elevated cystine levels will know more about the genetic cystinuria. It has an autosomal reces- indicate a dog may be at increased cause of cystinuria in Bulldogs and sive form of inheritance, which means risk for forming stones; however, it other breeds. When breeders are able that an affected dog inherits a copy should be noted that cystine excre- to selectively breed against the con- of the gene mutation from both par- tion can vary. Low cystine levels do dition, then the chances of reducing ents. Carriers inherit one copy of the not prove a dog does not have cystinuria in the breed will become ■ causative allele and are not affected cystinuria, and the absence of stones more real. by the disease; thus, they have normal does not preclude a dog from devel- 1 Henthorn PS, Giger U. Cystinuria, p. 349-364. urinary amino acid concentrations. oping stones in the future. Due to the breed’s predisposition Ostrander EA, Giger U, Lindblad-Toh K. The The genetic test developed at the Dog and Its Genome. (Cold Spring Harbor, NY: University of Pennsylvania is a direct to develop cystine uroliths, Bulldog Cold Spring Harbor Laboratory Press, 2006.) DNA test that identifies carriers and owners should frequently check their 2 Osborne CA, et al. Journal of the American affected and normal dogs. dogs, especially males, to make sure Veterinary Medical Association. June 2004; Vol. 204. Type 1 cystinuria in dogs is similar they are urinating without any prob- to type 1 cystinuria in humans; both lems. A dog should not appear to be straining or in pain. A veterinarian have mutations in the SLC3A1 gene. Purina appreciates the support diagnoses cystinuria by evaluating This type has an early age of onset of the Bulldog Club of America clinical signs. He or she will want to in dogs, and it is not uncommon for and particularly Elizabeth Hugo, know whether a dog has had recur- stones to be removed when a male chairwoman of the BCA Health rent urinary tract infections, blood in dog is between 6 months and 1 year Committee, in helping to identi- the urine, or experienced straining or of age. Females develop stones as well fy topics for the Purina Pro Club difficulty urinating. Signs of kidney as males. Bulldog Update newsletter. In contrast, breeds that develop the failure, such as vomiting, depression non-type 1 cystinuria form stones and loss of appetite, which result

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