EXAMINING FANCONI SYNDROME
by Mary Lou Kenworthy
Do "we" have the answer?
Let's look at what we know about Fanconi syndrome. It has plagued Basenjis for a long time and very little progress has been made in understanding the malady and its inheritance. Although the symptoms can be treated there is no cure. The ideal solution would be to identify the genes and/or environmental components responsible for causing this syndrome. If the inherited components could be identified the syndrome could be controlled in breeding programs. The average age of onset is 5 to 7 years but can range from 3 to 11 years.
So what exactly is Fanconi syndrome?
Fanconi syndrome is a renal tubular dysfunction. The present knowledge believes the defect occurs in the proximal renal tubules of the kidney. One of the functions of the renal tubules is reabsorption of electrolytes, amino acids, bicarbonate, glucose and phosphate. When this function is impaired, as it is in FS, it upsets the homeostasis and results in a series of physical signs of disease in the affected individual. Symptoms include polyuria (excessive urinating), polydipsia (excessive drinking), weight loss, muscle wasting and myalgia (muscle pain). Vitamins, minerals, electrolytes, bicarbonate and glucose are lost in the urine leading to acidosis and eventually death.
How long has FS been present in the breed?
FS has probably been in the breed since the beginning. In the '60 breeders were becoming aware of what they called the 'Basenji Kidney Disease' and finding that it was something different from diabetes. There have been articles written on FS in basenji periodicals and veterinary journals ever since.
FS was first reported (to researchers) in 1976 and drew the interest of Drs. Bovee and Breitschwerdt. (The latter also did some extensive study of IPSID in Basenjis.)
In February 1986, the Meriden Research Group, Schulhof Animal Hospital and The Basenji magazine collaborated in a joint effort to study FS. One thousand surveys were sent out with 63% being returned. From these, Jeffery Kay, DVM & C.H.B. Noonan, DVM published a report in the November 1986 Basenji titled "Fanconi Syndrome In The Basenji". The prevalence rate among all basenjis reported as Fanconi positive was 10% - (92 Basenjis). Another 68 were Fanconi 'suspect'. Since all age Basenjis were included in the survey many were not old enough to show FS symptoms so 10% is probably a low estimate. The survey also included 'Other diseases'. The most reported of these was Hypothyroidism at 28% and Diabetes mellitus at 19%.
The Drs. Noonan & Kay original studies report, "Prevalence and geographic distribution of Fanconi syndrome in Basenjis in the United States" was published in JAMA, Vol.197, No. 3, August 1, 1990.
Some of you may remember the Bulletin's "Supplement: Health Research" (printed on blue paper). It was a collection of articles, previously published in The Basenji, from breeders and research veterinarians on the various health problems. In his 1979 article "Hereditary Disorders of the Basenji" Dr. Russell Brown had this to say, "Fanconi syndrome has not been found in other breeds to my knowledge. It seems to run in certain families. Problems of this sort are generally inherited and Fanconi syndrome seems to be. However, the exact mode of transmission is not known. It may be a recessive trait or several genes may be involved."
Several decades of watching FS in basenjis has shown us that it is not a simple recessive and that multiple genes are involved.
Does FS appear in other breeds?
It can and does. However, it appears that the FS in other breeds is acquired. Only in Basenjis is Fanconi syndrome thought to be inherited. This information came out of a veterinary nephrolofy conference held in MI. Dr. Bovee, who came directly from this conference and spoke at the 1991 BCOA National Specialty Health Seminar, reported that this was the conclusion of veterinarians from all over the country. Also the incidence of FS in the Basenji breed was estimated to be around 15%.
An article in the Dec. 1989 Basenji, "Confusion About Fanconi Syndrome In Basenji Dogs" by Kenneth C. Bovee, DVM, MmedSC has this to say: "Kidney defects similar to the Fanconi Syndrome have been seen in a few other breeds, but none of these are similar to the Basenji and a genetic basis has not been shown in other breeds".
Can FS be acquired? If so, how?
Yes, it can and is. A multitude of toxic and immunologic factors can impair the proximal tubule function resulting in a Fanconi syndrome. FS in humans is described as "An acquired or inherited disorder..." according to the Fifteenth Edition of the Merck manual of Diagnostic and Therapy.
An article in "Kidney International" (Official Journal of the International Society of Nephrology), Volume 42 (1992) pp. 586-594 reports of mongrel dogs with Fanconi syndrome caused by toxin.
From the Merck Manual "Acquired Fanconi's syndrome may be caused by 6-mercaptopurine or outdated tetracycline, renal transplantation, multiple myeloma, amyloidosis, intoxication with heavy metals or other chemical agents, and vitamin D deficiency."
If infusion of a toxin can cause complete FS in dogs, as it can in humans, researchers should be aware that causation of FS may be more than just 'simple genetics'. [Note: 4-pentenoate (or 4-pentenoic acid) is a toxin and inhibitor of fatty acid oxidation (anti-oxidant), and also a hypoglycemic agent.] Pet foods are preserved with anti-oxidants some thought to be harmful - remember ethoxyquin?
Cystinosis leads to renal failure and is one of the most common causes of FS in children. Renal stones, occasionally reported in Basenjis, are caused when cystine and other amino acids appear in the urine. Cystinuria has been recognized in over 70 breeds of dogs. Newfoundlands have a severe form resembling type I (human) that is caused by a mutated gene with a truncated protein located on canine chromosome 10.
Think of all the chemicals that our dogs are exposed to. We put chemicals on them, in them and around them. If the individual chemicals do not cause problems by themselves, what happens when they combine in the dogs system? Also, canines are being over vaccinated. The timing and combinations can add further problems by affecting the immune systems of our dogs.
Fanconi syndrome can also be caused by researchers' experiments such as artificially disabling genes to see what happens like the knockout mouse genes, HNF1 & HNF2 for example.
If FS can be acquired, why is it thought to be inherited in Basenjis?
FS is thought to be inherited in Basenjis because of the high incidence of affected in the breed (15%) as compared to other breeds (1 to 2 % or less) and also because of the familial aspects of the syndrome in Basenjis.
This is a very complex syndrome as can be seen in human literature. Some things are the same as in Basenjis and some are not. The 'inherited' Fanconi syndrome in humans was considered, in the past, to be recessive. More recently human medicine reports of an extensive pedigree that shows a dominant inheritance. Many of the individual abnormalities that lead to FS are though to be inherited recessively.
Are there different kinds of Fanconi syndrome?
The key word here is SYNDROME: a group of symptoms and/or signs which, occurring together, produce a pattern or symptom complex, typical of a particular disease.
Basenjis affected with FS can have some or all of the associated symptoms and to various degrees. This is why the Basenji protocol for management of the disease requires testing and the treatment varies from patient to patient.
Also, as previously stated, some FS is inherited and some is acquired. We may yet discover that both inheritance and environment are involved in causing the syndrome. All cases of FS are, at least slightly, different. FS can result from many different causes.
It is speculated that FS is polygenic. Why do many believe this?
First of all, any simple dominant or recessive inheritance in Basenjis has long been ruled out. Such inheritance would be obvious in pedigrees. Although in a few cases whole litters have been known to develop FS, this is not usually the case. Many litters have consisted of FS affected, IPSID affected and perfectly healthy, long lived siblings. Also the fact that the syndrome varies from dog to dog is an indicator that multiple genes (or causes) may be at work.
One symptom of Fanconi that is often seen separate from the rest is glucose loss. Some Basenjis can have a high glucose loss in their urine for their entire lives without experiencing any of the other symptoms of FS. These dogs are long lived without treatment of any kind. Other Basenjis can have FS and loose all the other nutrients except glucose (electrolytes, amino acids, bicarbonate, phosphate, etc). These dogs do not loose glucose in their urine until the final stages of disease when the kidney goes into full failure.
So while two separate parts of FS can be shown, this is probably an oversimplification. There could be a separate gene (or separate cause) affecting the reabsorption of each nutrient. But let's go with just two to demonstrate. We'll call the gene responsible for preventing the reabsorption of glucose, gene 'A' and for all the other nutrients, gene 'B'
In order to have the complete syndrome most commonly known to basenjis we must have both 'A' and 'B' in the dogs makeup. 'A' and 'B' may be dominant where only one of the pair needs to be present or they may be recessive with both genes of the pair needing to be present (aa and bb). Or it could be a combination. 'A' & 'B' genes could be at the same locus, at different ones or even on different chromosomes. Regardless, all necessary genes must be present for the dog to be affected. These genes are mixed and matched throughout the gene pool.
Let's look at the big picture.
The Basenji is an ancient, natural breed that has been around for thousands of years. If, as seems likely at this time, Fanconi syndrome is an inherited breed specific dysfunction it may have been in the breed since its beginning or the result of a mutation thousands of years ago a good reason to not rule out a mitochondrial DNA mutation as a contributing factor. Findings of a case of FS (human) in France support the view that tubulopathies of unknown origin (like FS) may be related to a deletion in the mitochondrial respiratory chain deficiency.
So if the make-up of all pure bred basenjis is predisposed to FS, why are some affected and some not?
Start with 'the luck of the draw'. Even if the two parents of a given litter may have all the ingredients to produce FS the odds are good that an average litter (5) will 'dodge the bullet.' Even two litters may hit it lucky. Three litters or more of the same breeding will provide a good chance that FS will present. Remember we are talking 15% affected in the breed. All the top producing dogs have sired FS at one time or another. Any basenji that produces 100 or more offspring is going to produce FS. Of course it is harder to tell about females because most don't produce enough offspring to show the correct percentages.
The fact that some breedings produce FS and some don't is further evidence of FS being polygenic.
One of the few patterns of inheritance is that FS occurs less often in line bred basenjis and more often in out crosses. Line breeding perpetuates like genes; therefore continued line breeding will cause the genes to become homogeneous in a line. Both 'A' & 'B' are not likely to be propagated by line breeding as breeders will change course when FS appears. However, some lines may 'fix' the 'A' genes while other lines may 'fix' the 'B' genes both harmless by themselves. Out crossing perpetuates more 'different' genes and the individuals, being heterogeneous, are more likely to have both the 'A' & 'B' genes. Again, this is an oversimplification as many more genes are most likely involved but it should convey the general idea supporting multiple genes (and/or other factors).
We would all like to know the exact inheritance of Fanconi syndrome. Oddly enough, I think "we" (collectively) do know. The problem is that no one person has enough of the information to put it all together. If all the basenjis that have FS were known (and admitted to) there could be an extensive pedigree study. Of most interest would be what lines can be safely crossed and which ones can't. This can only be determined by looking at 'the big picture'. If it was possible to pool all the odds and ends of data that 'we' as USA Basenji owners and breeders know the answer would probably be clear.
